Child Health and Human Development Yearbook - 2008

CHILD HEALTH AND HUMAN DEVELOPMENT YEARBOOK-2008

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CHILD HEALTH AND HUMAN DEVELOPMENT YEARBOOK-2008

JOAV MERRICK EDITOR

Nova Science Publishers, Inc. New York

Copyright © 2009 by Nova Science Publishers, Inc.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Library of Congress Cataloging-in-Publication Data Available upon request

ISBN: 978-1-61728-180-8 (E-Book)

Published by Nova Science Publishers, Inc. Ô New York

Contents Preface

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Child Health and Human Development

1

Chapter I

Principles of Eating and the Individual with Rett Syndrome Judy Wine, Yael Yoshei and Meir Lotan

3

Chapter II

Ethics and Holistic Healthcare Practice Michael de Vibe, Erica Bell, Joav Merrick, Hatim A. Omar and Søren Ventegodt

25

Chapter III

Domestic Violence and Small Children: Key Directions for Holistic Healthcare Erica Bell

33

Therapeutic Horseback Riding (Hippotherapy) for Individuals with Rett Syndrome: A Review with a Case Study Maciques Rodríguez Elaime and Meir Lotan

47

A Community in Transition: Incidence and Characterization of Injuries among Israeli Bedouin Children Presenting to the Primary Care Clinic Elissa Lane Freedman, Zaid Afawi, Joav Merrick and Mohammed Morad

69

Information Technology and Medical Education: A Survey of Perceived Computing Skills among Medical Students in Northern Nigeria Zubairu Iliyasu, Isa S. Abubakar, Mohammed Kabir and Muktar H. Aliyu

85

Chapter IV

Chapter V

Chapter VI

Contents

vi Chapter VII

Chapter VIII

Attitudes of First-Year Israeli Tourism and Hotel Management Undergraduate Students toward Persons with Disability: A Pilot Study Tagrid Morad, Zaid Afawi, Joav Merrick, Jemila Caplan Kester and Mohammed Morad All Causes and Violent Deaths of Children (0-14) in England and Wales 1974-2002 Compared to the Major Western Nations: Indicators of Improved Child Protection? Colin Pritchard and Ann Sharples

Section II: Environment and Mood Chapter IX

Childhood Obesity and Depression: Connection between these Growing Problems in Growing Children Gloria M. Reeves, Teodor T. Postolach and Soren Snitker

97

105 121 123

Chapter X

Asthma and Mood Disorders Anupama Kewalramani, Mary E. Bollinger and Teodor T. Postolache

141

Chapter XI

Jet Lag: A Modern-Day Malaise Tatiana Menick, Joseph J. Soriano and Teodor T. Postolache

155

Chapter XII

Mindfulness Meditation in Patients with Mood Disorders. Feasibility, Safety and Efficacy: An Empirical Review Kalina Boteva

Chapter XIII

Chapter XIV

Chapter XV

Thinking Outside of the Light Box: Applications of Cognitive-Behavioral Theory and Therapy to Seasonal Affective Disorder Kelly J. Rohan and Yael I. Nillni Prepartum Depressive Symptoms Correlate Positively with CReactive Protein Levels and Negatively with Tryptophan Levels: A Preliminary Report Debra A. Scrandis, Patricia Langenberg, Leonardo H. Tonelli, Tehmina M. Sheikh, Anita C. Manogura, Laura A. Alberico, Tracey Hermanstyne, Dietmar Fuchs, Hugh Mighty, Jeffrey D. Hasday, Kalina Boteva and Teodor T. Postolache Mood Changes after Brief Exposure to Chemosensory Stimuli in Patients with Seasonal Affective Disorder Solomon S. Williams, Norman E. Rosenthal, Avery N. Gilbert, John W Stiller, Todd A. Hardin, and Teodor T. Postolache

167

193

207

219

Contents Chapter XVI

Chapter XVII

Mood Oscillations and Coupling between Mood and Weather in Patients with Rapid Cycling Bipolar Disorder Steven M. Boker, Ellen Liebenluft, Pascal R. Deboeck, Gagan Virk and Teodor T. Postolache The Body Speaking of Blues and Worries: Fibromyalgia in Children and Adolescents Lynn Hugger, Zinoviy Gutkovich and Harriet Knapp

Section III : Environment and Suicide Chapter XVIII

The Antisuicidal Efficacy of Lithium: A Review of the Clinical Literature and the Underlying Pharmacology Colleen E. Kovacsics, Harish K. Goyal, Koshy J. Thomas and Todd D. Gould

Chapter XIX

Suicidality in the Juvenile Justice Environment Srirangam S Shreeram and Aditi Malik

Chapter XX

Mood Disorders and Suicide in the Correctional Population: The Importance of Recognizing Comorbidity Alan A Abrams, Maheen Patel, Tyler Jones, Yu-Fei Huang, Nesibe Soysal, Lobna Ibrahim, Constance N Flanagan, Cessare Scott, KyleeAnn Stevens, Gavin Rose and Alan Newman

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255 275 277

301

323

Chapter XXI

Suicide in the Muslim World Farooq Mohyuddin

339

Chapter XXII

Ethnic Differences in Adolescent Suicide in the United States Theodora Balis and Teodor T. Postolache

347

Chapter XXIII

Allergen Specific IgE: No Relationship with Prior History of Suicide Attempts and Instability in Patients with Recurrent Mood Disorders Teodor T. Postolache, Darryl W. Roberts, Patricia Langenberg, Olesja Muravitskaja, John W. Stiller, Robert G. Hamilton and Leonardo H. Tonelli

Chapter XXIV

Chapter XXV

Acute Stress Promotes Aggressive-Like Behavior in Rats Made Allergic to Tree Pollen Leonardo H. Tonelli, Akina Hoshino, Morgan Katz, and Teodor T. Postolache Changes in Severity of Allergy and Anxiety Symptoms Are Positively Correlated in Patients with Recurrent Mood Disorders Who Are Exposed to Seasonal Peaks of Aeroallergens Teodor T. Postolache, Patricia Langenber, Sarah A. Zimmerman, Manana Lapidus, Hirsh Komarow,

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379

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Contents

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Jessica S. McDonald, Nancy Furst, Natalya Dzhanashvili, Debra Scrandis,, Jie Bai, Bernadine Postolache, Joseph J. Soriano, Bernard Vittone, Alvaro Guzman, Jong-Min Woo, John Stiller, Robert G. Hamilton and Leonardo H. Tonelli Section IV: Obesity and Adolescents

403

Chapter XXVI

Obesity and Sport Participation Dilip R. Patel and Donald E. Greydanus

405

Chapter XXVII

Obesity and Hypertension in Adolescents Alfonso D. Torres and Colette A. Gushurst

413

Chapter XXVIII

Hyperandrogenism and Obesity: Ominous Co-Morbidities Amit M. Deokar, Shawn J. Smith, Amanda J. Goodwin and Hatim A. Omar

423

Chapter XXIX

Bariatric Surgery and Adolescent Obesity Tara B. Mancl and Alan A. Saber

435

Chapter XXX

Endocrinologic Issues in Obesity Manmohan Kamboj

443

Chapter XXXI

Psychological Issues in Obesity Helen D. Pratt

453

Chapter XXXII

Overweight Children and Adolescents: Impact on Psychological and Social Development Kimberly K. McClanahan, Marlene B. Huff and Hatim A. Omar

463

Chapter XXXIII

Pharmacotherapy for Obese Adolescents Donald E. Greydanus, Cynthia Feucht, and Dilip R. Patel

475

Chapter XXXIV

Eating Disorders in Adolescents with Obesity Vinay N. Reddy

487

Chapter XXXV

Sexuality and Obesity in Adolescence Helen D. Pratt, Donald E. Greydanus and Kazue Ishitsuka

497

Chapter XXXVI

Concepts of Contraception for Adolescents with Obesity: Pathways of Judicial Moderation Donald E. Greydanus, Hatim A. Omar and Artemis K.Tsitsika

Chapter XXXVII

507

Nutrition and Adolescent Obesity Vinay N. Reddy

519

Chapter XXXVIII Dermatologic Aspects of Obesity Donald Hare

529

Chapter XXXIX

539

Down Syndrome and Obesity Joav Merrick and Isack Kandel

Contents Chapter XL

Chapter XLI

Chapter XLII

Environment and School Transportation: A Review of Evidence from Health and Equity Perspectives Important in Obesity Prevention Chanam Lee and Xuemei Zhu Insights into Bangkok Elementary Students’ Food Choice on School Days Chulanee Thianthai Israeli Adolescents and Obesity Mohammed Morad, Isack Kandel, Jason Ahn, Brian Seth Fuchs and Joav Merrick

ix

545

563 571

About the Editor

577

About the National Institute of Child Health and Human Development in Israel (NICHD-IL)

579

Index

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Preface The early years in the life of a child are critical for cognitive, social and emotional development. It is therefore important that we make sure that children grow up in an environment, where their social, emotional and educational needs are met. Children who grow up in an environment, where their developmental needs are not met are at risk for compromised health, well-being and sometimes also developmental delays. Failure in the first years of life or lack of invested time or resources (both family and society) during may have long term effects on not only development, but also the health, welfare and education systems. Society must therefore work to ensure that children develop in safe, loving, and secure environments. They are our future and our success or failure. The French historian Philippe Aries made us aware about the sentimentalization of childhood emerging in the nineteenth and twentieth century. Before this time children were just perceived as “small adults” documented with his analysis of art over time, where children indeed were depicted as small adults. So slowly in the last two centuries childhood and later adolescence were discovered as separate entities and periods with their own development, concerns and problems. We have therefore in the last century seen pediatrics, adolescent medicine and even geriatrics emerge as specialties concerned with different aspects of human development. This last century also saw advances in public health with decreased infant and maternal mortality in the Western World (or sometimes called the North), but in the new millennium the developing world (or South) are still struggling with disease and health concerns due to lack of resources. Since the global expansion of AIDS (Aquired Immunodeficiency Syndrome) mortality has increased (so far millions of people have died due to AIDS related causes) and resulted in a growing number of children becoming orphans. It is estimated that by year 2010, AIDS will leave 20 million children alone in Africa without one or both parents, which is double the current situation of 11 million orphaned children. At present 33.5 million people globally are HIV infected, which is estimated to increase to 45 million by year 2010 and most will be unable to effort the treatment. Poverty and human development were the themes of a recent research project undertaken by the World Bank and published in three books. This study describes the case studies from 14 countries. In all three books information were gathered from more than 60,000 poor men and women from sixty countries, the true experts on poverty with many stories to tell together

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with relevant and important observations. The study was different from other poverty studies in the fact that participatory and qualitative research methods were used. The voices of the poor from the whole world can be heard from each page you read. So with progress and positive development we still have to struggle with poverty and the results of poverty. Poverty is even today in developed countries like United States and Israel (about 30% of children living in poverty) a major public health problem of a magnitude that is markedly different than Scandinavian countries (3%). Chapter I - Rett syndrome (RS) is a genetic disorder affecting mainly females. The individual with RS experiences a wide range of functional limitations, in many cases leaving her in need of constant care. The individual with RS may have a variety of eating disorders, frequently leading to a very small and slim physique. Given that increased food consumption can yield positive results on both the functional abilities and the emotional state of individuals with RS, it is important that focused attention be given to the feeding ability of these individuals. The present article will address the principles of eating with individuals with RS. The article is an amalgamation of up-to date knowledge on feeding for individuals with disabilities from our clinical experience with individuals with RS. The article suggests different ways to evaluate and to positively influence the activity of eating with persons with RS by discussing the person herself, the setting, and the handling by caregivers. Chapter II - The paper aims to contribute to integrated discussion of ethics in holistic healthcare. Methods: Noting key aspects of the literature on ethics in holistic healthcare, the authors then focus on describing the working ethical statement for holistic healthcare practitioners produced for the International Society of Holistic Health (ISHH). Ethical principles, aims of holistic practice, and ethical guidelines are presented. The relationship of ethics to quality of care is outlined. Conclusions: The authors conclude that many of the ethical principles and guidelines, as well as expectations of quality and safety, that apply to mainstream healthcare, also apply to holistic practitioners. However, the multidisciplinary contexts of whole-of-patient healthcare present new challenges of application of these familiar ethical understandings. Chapter III - This analysis paper aims to identify key directions for developing holistic healthcare that is more responsive to the special needs of small children 0-5 exposed to domestic violence. It takes a ‘whole-of-patient’ as well as a ‘whole-of-systems’ approach to how health and allied health practitioners, service administrators, policy decision-makers, and researchers could work together to better meet the needs of these clients. Its focus is on mutually compatible health and allied health reforms, at the levels of research, practice, and policy. This analysis paper is based on select literature identified using the terms ‘children AND domestic violence’ in the databases SCOPUS and PUBMED. The emphasis was on papers for the period 1995-2006. Domestic violence is a prevalent social problem with known effects on small children that require early intervention if they are not to become more costly for the individual and society later. Much progress has been made, however, unless new approaches are energetically pursued, we may be facing another twenty years of program evaluations that do not give us the holistic evidence base needed for strong service development. Chapter IV – Individuals with Rett syndrome (RS) frequently present a constant ongoing need for therapeutic intervention. One of the therapeutic approaches suggested for this

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population is therapeutic horseback riding. Experience has shown that this type of intervention is extremely enjoyed by the individual with RS. The current article presents the possible benefits of applying Hippotherapy for individuals with developmental disabilities, the characteristics of RS compatible with this type of intervention and a case study describing the application of Hippotherapy for individuals with RS. It should be emphasized that the present article is not a research article, but rather a review of the literature on RS and therapeutic horseback riding, with a case study to illustrate the implementation of the theoretical background. The article presents clinical experience in these fields; therefore scientific generalization should be cautiously made. Chapter V - Objectives: To review the incidence and character of minor trauma that presented to family practice clinic and associated demographic variables. Design: A retrospective data analysis was conducted using data collected from the CLICKS computerized medical records of primary care consultations at The Clalit Health System’s Shatal Clinic in Beer Sheva, Israel. A systematic sample of every tenth child was taken from the alphabetical listing of all Bedouin children between the ages of zero and fourteen, registered at the clinic (n=156). Results: Of the 156 children sampled, 67 (42.9) had at least one injury and 31 (20.4) children had more than one childhood injury recorded in their medical record. Boys had a higher incidence of two or more childhood injuries compared to female children (23/80 (28.8) vs. 8/72 (11.1), p = .007). Girls had proportionally more injuries in early childhood with mean age at first injury 1.4 years younger for girls (4.0 ± 2.8 vs 5.4 ± 2.5, p=.035). Children of older parents in smaller families had more accidents. No significant association was found between family size or birth order and injury. Conclusions: Unintentional injuries have a huge morbidity and significant mortality world wide. The populations most vulnerable to the burden of injuries are found in the less developed societies. Current research has targeted at western society and the proven strategies for prevention inappropriate for the mechanisms of injury that are specific to the Bedouin culture. Further research is necessary to identify demographic characteristics and behaviors that are correlated with injury in Bedouin children. Chart review was not adequate for the study of demographic and SES factors affecting injury. Chapter VI - The application of information communication technology (ICT) to medical education and health care is increasing worldwide. But little is known about the computer skills of medical students in developing countries. We investigated the knowledge, attitude and ICT skills of medical students of Bayero University Kano, Nigeria. A pretested, structured questionnaire was administered to 300 medical students in their pre-clinical and clinical years of study. Of the 300 medical students, 22.0% owned a personal computer and 32.3% had previous formal computer training. One hundred and sixty three (54.3%), 77 (25.7%) and 60 (20.0%) had good, fair and poor knowledge of computing respectively. There was a significant gender gap with male dominance of computer knowledge (85.9% vs. 67.4%) (P=0.0001). Also, computer ownership (95.4% vs.75.5%) (P=0.0001) and formal training (89.7% vs. 57.1%) (P=0.0001) positively influenced knowledge. Only 112(37.3%) students had positive attitude towards application of computing to medicine. This was positively affected by being male (45.4% vs. 20.0%) (P=0.0001), computer ownership (54.6% vs. 32.6%) (P=0.001) and formal training (50.5% vs. 31.0%)(P=0.001). Only 89(29.7%) of the students had good computing skills. The remaining 107 (35.7%) and

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104(34.7%) students had fair and poor skills respectively. Computing skills were positively influenced by increasing years of study (74.4% vs. 56.8%) (P=0.04), computer ownership (95.5% vs. 57.0%) (P=0.0001) and formal training (85.6% vs. 55.7%) (P=0.0001). In conclusion, although most medical students had basic ICT knowledge, the level of selfassessed basic computing skills was low. Integration of ICT into the medical school curriculum could help enhance the ICT skills of future physicians in northern Nigeria. Chapter VII - To explore the attitudes of undergraduate students of tourism and hotel management toward people with disabilities. Design: A survey of all first year students of the tourism and hospitality mangement department was completed using a short validated questionnaire with 15 topics reflecting the full range of attitudes toward the disabled. Results: Of the 33/68 (48.5%) completed the questionnaire, while one was incomplete. 70% of the respondents demonstrated indepth understanding of the needs and rights of the disabled and the majority stressed their agreement with the need to make all places accessible without need for extra expenses by the disabled. Students believed that the presence of the disabled in the sphere of tourism had no negative effect on the industry image and use. While only half of the respondents feel comfortable in the presence of the disabled, 50% had reported that the disabled have the same abilities to enjoy and get excited as those without disabilities. Conclusions: Today students, future managers have to change their attitudes toward the disabled and most of the work has to be done during their academic studies and the educational system has to be responsible for such a change. Chapter VIII - In most Major Western Nations (MWN) there is considerable media criticism of failing to prevent the extremes of child abuse, namely a dead child. Testing whether services have prevented these extremes is trying to prove a `negative’, conversely measuring the `failure’ rate, children’s (0-14 years) deaths is a surrogate indicator of the level of societal child protection. Method: Utilising WHO mortality date, changes in all cause and violent-liked deaths in England and Wales were compared against the other nine MWN 3year average per annum rates for 1974-76 v 2000-02. Violent-linked deaths included homicide, undetermined and accident and adverse event (AAE) deaths, thus accounting for any notional `hidden’ abuse deaths. Results: The current two highest rate of all cause children’s (0-14 years) deaths were in USA at 2539pm (death rates per million), representing a fall of 55% and England and Wales 1921pm, a fall of 65% , with the lowest Japan at 1297pm, a 65% fall and France 1600pm a decline of 64%. In the 1970’s England and Wales baby (<1 years) homicide rates were 2nd highest at 57pm, but fell to 17pm, a 74% fall, whereas the USA were now highest at 84pm, a 56% increase. Baby AAE deaths fell in every country, England and Wales falling from 341pm to 71pm, a 76% reduction. Both these results were significantly better than eight other MWN, although England and Wales baby undetermined deaths at 26pm, were high compared to the other MWN. Initially England and Wales’ children’s combined `violent-linked’ deaths were 203pm p.a., now 61pm, a 70% decline, with only Italy having lower rates. The highest rates were the USA at 185pm. We concluded that the major reductions in both all cause and violent-linked deaths should be a boost to the morale of front-line children’s service staff, especially in England and Wales and correct the erroneous public image. However there must be continuing concerns about USA children’s homicides.

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Chapter IX - Depression and obesity have been recognized as major public health issues in youths. Although they have traditionally been compartmentalized as separate physical and emotional health conditions, evidence suggests interactions and common pathways between them, implying that successful treatment should ideally target shared underlying mechanisms. The purpose of the present article is to review the pediatric diagnostic criteria for depression and obesity, highlight similarities in their clinical presentation, identify common pathways and underlying mechanisms, describe their developmental trajectories, and suggest areas for future study to guide development of innovative prevention and treatment initiatives. Chapter X - The high rate of comorbidity of asthma and mood disorders would imply the possibility of potential shared pathophysiologic factors. Proposed links between asthma and mood disorders include a vulnerability (trait) and state connection. Vulnerability for both asthma and mood disorders may involve genetic and early developmental factors. Staterelated connections may include obstructive factors, inflammatory factors, sleep impairment, psychological reactions to chronic medical illness, as well as exacerbation of asthma in individuals with chronic stress. Treatment for asthma may also exacerbate mood disorders. New research suggests involvement of the central nervous system in asthma and allergy. Further characterization of clinical, psychological, cellular and molecular interconnections between asthma and mood disorders is needed to better evaluate and treat these patients. A close collaboration between mental health professionals and allergists could result in improved symptom control, quality of life, overall functioning and ultimately, decreased mortality. Chapter XI - Jet lag, a circadian rhythm sleep disorder associated with transmeridian travel, is the result of many factors, the most important being misalignments between the light-dark cycles of origin and destination, and between the social demands at the place of destination and internal, biological, representations of day and night which govern our abilities to fall asleep, stay alert and perform. Most of the time, sleep deprivation compounds the misalignment effects. The demands and duration of the trip, as well as the direction and number of time zones crossed and prior vulnerability to jet lag should determine if and how to treat jet lag. Treatment options include simple measures involving bright light exposure and avoidance, bright light treatment, timed meals, and exercise, and, sometimes, melatonin, short-acting hypnotics, and alertness promoting beverages and pharmacological agents. Given the long-term health implications of circadian rhythm sleep disorder, and their impact on individuals and society, further research and more effective treatments are needed. Chapter XII - Since 1979, when mindfulness-based stress reduction (MBSR) was first introduced at a mainstream medical center, there has been a rapidly growing interest in the science and clinical applications of mindfulness meditation. MBSR is efficacious in improving quality of life and decreasing symptoms of depression in a wide variety of medical patient populations. Mindfulness-based cognitive therapy (MBCT) incorporates elements of mindfulness meditation and cognitive therapy and was specifically designed for relapse prevention in depression. The objective of this study is to review the feasibility, safety, and efficacy of mindfulness based interventions in patients with mood disorders. Systematic searches for clinical studies were conducted on several databases and one relevant website. Fifteen articles met criteria for inclusion in this review. MBCT is feasible for patients with major depressive disorder (MDD), bipolar affective disorder (BAD), and history of suicidal

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thinking or behavior. The intervention has a low dropout rate and high degree of acceptability. MBCT is probably efficacious for decreasing the risk of relapse in patients with three or more depressive episodes. Preliminary evidence suggests that MBCT might be helpful in reducing symptoms of depression in moderately to severely depressed patients with MDD or BAD, in reducing anxiety and depressive symptoms in bipolar patients, and in possibly decreasing cognitive vulnerability to suicidality. MBSR is less well studied in mood disorder patients. MBCT and possibly MBSR have a potential as clinically valuable interventions in the treatment of mood disorders. Further research into their efficacy, feasibility, and safety is recommended. Chapter XIII - The purpose of this paper is to review: 1) current evidence that constructs proposed in cognitive and behavioral theories of depression have relevance to winter seasonal affective disorder (SAD) and 2) the results of preliminary randomized clinical trials testing the acute and long-term efficacy of cognitive-behavioral therapy (CBT) for SAD, alone and in combination with adjunct light therapy, as compared to solo light therapy. Research supports that factors related to a cognitive vulnerability to depression as well as low rates of response-contingent positive reinforcement in the winter and learned emotional and psychophysiological reactivity to light-relevant stimuli are operative in SAD and may represent a point of intervention via a SAD-tailored CBT. Preliminary randomized clinical trials suggest that CBT for SAD is acutely efficacious and may be prophylactic with regard to preventing winter depression recurrence. To advance the theoretical understanding of the psychopathology SAD, we advocate for an integrative biological-psychological conceptualization of SAD and for multi-disciplinary research to study interactive biological-psychological mechanisms in SAD onset and maintenance. To advance the treatment of SAD, we advocate for a greater focus on testing long-term outcomes in SAD treatment research. In contrast to establishing only acute treatment efficacy, a longer-term perspective reflects the recurrent nature of the disorder and should lead to the development of empirically-validated treatments that prevent winter depression recurrence. Chapter XIV - Prepartum and postpartum depression have negative, and sometimes devastating, effects on women and their families. As inflammatory processes are related to depression in general, we hypothesized that inflammatory perturbations, prepartum and postpartum, contribute to triggering and worsening of symptoms of peripartum depression. We conducted a longitudinal preliminary study on 27 women at high risk for developing postpartum depression measuring SIGH-SAD scores at three time points: 35-38 weeks gestation, 1-5 days postpartum, and 5-6 weeks postpartum. Serum C-reactive protein and interleukin-6, both markers of inflammation, as well as tryptophan, kynurenine, and the kynurenine/tryptophan ratio, as consequences of inflammation and pathophysiological steps towards depression, were measured at each time point. C-reactive protein levels were found to be positively related to atypical and total depression scores in the prepartum period and with atypical depression scores in the early postpartum period. Tryptophan was found to be negatively associated with total depression scores in the prepartum, as well. These findings warrant further investigation that could lead to novel interventions to decrease poor outcomes from peripartum depression. Chapter XV - As previous reports related olfaction to both mood and seasonality in humans, and as previous studies suggest that lemon odor may influence mood and behavior,

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we hypothesized that brief exposure to the scent of lemon would alter mood in patients with seasonal winter depression. Twenty-four patients with seasonal affective disorder (17 females and 7 males, aged 43±10 years) were briefly exposed to lemon and a control odor (fir tree) using a cross-over randomized nested design. Mood change following exposure to lemon scent was compared to mood change following exposure to fir tree using Wilcoxon nonparametric tests. There was a significant, although small, difference between change in mood after sniffing lemon odor (improvement) versus after sniffing fir odor (worsening) {Wilcoxon matched- pair signed rank test, Z = -2.58, N = 23, p = 0.01}. Studies evaluating potential antidepressant or antidepressant-augmenting effects of odorants will require longer repetitive exposures., , and randomized placebo controlled trials, Our limited conclusion is that even very brief exposure to chemosensory stimuli may influence mood reports in patients with seasonal depression. Chapter XVI –Rapid Cycling Bipolar Disorder (RCBD) outpatients completed twice-daily mood self--ratings for 3 consecutive months. These ratings were matched with local measurements of atmospheric pressure, cloud cover, and temperature. Several alternative second order differential equation models were fit to the data in which mood oscillations in RCBD were allowed to be linearly coupled with daily weather patterns. The modeling results were consistent with an account of mood regulation that included intrinsic homeostatic regulation as well as coupling between weather and mood. Models were tested first in a nomothetic method where models were fit over all individuals and fit statistics of each model compared to one another. Since substantial individual differences in intrinsic dynamics were observed, the models were next fit using an ideographic method where each individual's data were fit separately and best--fitting models identified. The best--fitting within--individual model for the largest number of individuals was also the best--fitting nomothetic model: temperature and the first derivative of temperature coupled to mood and no effect of barometric pressure or cloud cover. But this model was not the best--fitting model for all individuals, suggesting that there may be substantial individual differences in the dynamic association between weather and mood in RCBD patients. Heterogeneity in the parameters of the differential equation model of homeostatic equilibrium as well as the coupling of mood to an inherently unpredictable (i.e., nonstationary) process such as weather provide an alternative account for reported broadband frequency spectra of daily mood in RCBD. Chapter XVII - Fibromyalgia is a poorly understood pain disorder that can become disabling. Much less is known about fibromyalgia in children and adolescents and this paper will add to this body of literature. Recognition and treatment of children and adolescents provides an important opportunity to prevent illness from becoming a way of life. Fibromyalgia, is a pain disorder that can become a way for the body to speak what the mind does not know. The authors clinical experience indicates that fibromyalgia symptom severity can exist on a continuum from mild to severely disabling and those unconscious conflicts can move fibromyalgia from a mild pain disorder to a chronically disabling condition. It requires bridging the mind and body, both in understanding the mechanisms of the disorder and in guiding the treatment. The authors elucidate physiological and psychological mechanisms for this complex syndrome as well as a model for treatment intervention with children and adolescents. In doing so, they make bridges between literatures of medicine, neuropsychology, cognitive behavioral therapy and psychoanalytic theories; thereby

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paralleling the treatment process which moves from the physical through different layers of psychological depth. They provide a detailed clinical discussion of a young girl with a complex case of fibromyalgia that illustrates an application of this type of clinical theorizing applied to an individual and family treatment on an inpatient psychiatric unit. Chapter XVIII - The results of a large number of studies suggest the efficacy of lithium in the prevention of suicide. These studies include retrospective, prospective, and discontinuation studies, as well as comparison studies with other medications. Despite this extensive clinical data, it remains unclear what molecular mechanisms underlie the antisuicidal efficacy of lithium. Lithium has a number of undesirable side effects that often limit its clinical use. Determining the molecular mechanisms that underlie the therapeutic effects of lithium is a critically important task. It may be possible to develop a novel drug that mimics the efficacy of lithium in the prevention of suicide, but possesses a more limited side effect profile than lithium. We review molecular effects of lithium that may be related to its antisuicidal efficacy, focusing particularly on serotonin neurotransmission. Chapter XIX - This article provides an overview of the prevalence, risk factors, and screening instruments for suicidal thoughts and suicidal behaviors in the juvenile delinquent population. Factors specific to the juvenile justice environment and their interactions with suicidality in adolescents are examined. Methods: A search of the MEDLINE and SearchMedica Psychiatry databases was conducted for articles published since 1980 in the areas of suicide and suicidal behavior in the juvenile offender population as well as the general adolescent population. Results: Several studies reported an increased rate of suicide and suicidal behavior in juvenile delinquents as compared to the general adolescent population. Risk factors can be grouped in four major categories - Demographic factors – female gender, race (Native American >Hispanic>White>Black); Psychiatric illness- mood disorders, substance abuse, conduct disorder, history of suicidal behavior; Psychological factors- impulsivity, history of sexual abuse; Environmental factors- housing with adults, room confinement, locked sleeping rooms, short term facility. Conclusion: The environment (juvenile detention) is but one of several factors that might explain the increased rate of suicides in juvenile facilities. A continuum of universal screening at intake, adequate psychiatric treatment including medication management and therapy, appropriate facility level changes, adequate housing, staff training and restricted use of confinement are likely to be very helpful. Chapter XX - The identification or recognition of mental disorders in the Criminal Justice System (CJS) is fraught with difficulties. Some obstacles are merely definitional, e.g. delimiting where the boundaries of Impulse Control Disorder NOS or Paraphilia NOS might exist. More significant hurdles are the reliance on inaccurate self-report, persistent substance induced altered CNS functioning in many detainees, and the atypical presentation of individual psychiatric disorders in persons with multiple comorbidities, combined with troubled and deviant life histories. Identification and treatment of mood disorders in the CJS is presently an area requiring further development through studies on the multiply comorbid, both in and out of custody. Recent studies on pediatric mood disoders suggest that there may be a subgroup that end up in the CJS as they get older. Predicting suicide in the criminal justice system is similarly difficult because of the low specificity of predictive methods. Many inmates have multiple risk factors, and multiple psychiatric comorbidities. Nonetheless

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suicide and attempted suicide are rare events in the CJS. Programs of suicide prevention in the criminal justice system have been successful. Chapter XXI - Suicide is a cause of significant mortality and morbidity around the world. There has been research on the various risk factors and protective factors for suicide. One protective factor that has been of interest is the possible negative correlation between religion, religiosity/moral objections to suicide and suicide rates. There are several reports that the rate of suicide is lower in Muslim majority countries (Islamic countries). The various hypotheses about the lower suicidal rate include the impact of the Quran’s injunction against suicide, the prospect of an eternal life in hell, the social integrative and regulative benefits of religion, and underreporting of suicide due to stigma/criminal penalties. Despite the disagreement on the causal factors many of the studies have suggested that Muslims are at a lower risk for suicide compared to other populations. Some of this data comes from studies of Muslims in countries with mixed religious population. Scarcity of research about the incidence of suicide in Muslim majority countries precludes a definitive conclusion. This is a preliminary review of the subject with a key objective of pointing out directions for future research and the clinical implications. We will discuss the state of current knowledge about Islam as a possible protective factor against suicide. Chapter XXII - Suicide is the third-leading cause of death for adolescents between 15 and 24 years of age in the United States and its rate has been increasing. Factors that contribute to rate of, risks for, or protection against depression and suicide may be different for people from cultures with different values and health beliefs. Although typically seen as affecting Caucasians more than other groups in the U.S., the rates of suicide among African Americans, Latinos, and others have been increasing. 87 studies were reviewed looking at rates for suicide/suicidal ideation, risk factors for suicide, protective factors/coping mechanisms, service delivery/barriers to care, and specific treatment or management of suicidal thoughts for adolescents from different ethnic groups in the U.S. The following ethnic groups in the U.S. were compared: African American, Latino, Asian American, Native American/Alaskan Native, and Hawaiian American. Although studies report conflicting rates, most studies still show an overall higher risk for suicide among Caucasian youth than any other group. Rates for suicide are growing for African American teens (perhaps more in boys), Latino teens (especially Latina girls), Asian American youth, Native American youth, Alaskan Native youth, and Hawaiian American youth. Details about these differences are discussed along with recommendations for clinicians working with youth at risk for suicide from minority cultures in the U.S. Chapter XXIII - Suicide and decompensation of mental illness peaks in spring and to a lesser extent in fall. Several recent studies reported that suicide and decompensation peaks coincided with spring and fall aeroallergen peaks. Allergic symptoms occur as the result of a complex biochemical cascade initiated by IgE antibodies (sensitization) and allergens (triggers). Animal models have shown molecular/neurochemical changes in the brain as well as relevant behavioral changes associated with this IgE mediated biochemical cascade. These factors suggest that seasonal allergy could precipitate suicidality and mood instability. In the current study, we compared the prior suicide attempt and decompensation history in allergen sensitive and nonsensitive persons diagnosed with mood disorders. Patients with Major Depressive Disorder or Bipolar I or II Disorder (n=80) completed several instruments

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(Columbia Suicide History Form, Beck Scale of Suicidal Ideation and Beck Suicide Intent Scale). Serum was screened for allergen-specific IgE antibody. t-Test analysis was used to compare the history of suicide attempts and instability between the two groups, aeroallergen positive and negative. Further, we compared the ratio of attempts and decompensations during the allergy season to suicides in both groups occurring during the rest of the year. There were no statistical differences in any measurement performed between the psychologically ill and well groups. In contrast to previous studies that found an association between completed suicide and allergen exposure or prior history of allergy, the current study found no association between number or timing of prior suicide attempts and markers of allergic sensitization in patients with recurrent mood disorders. Chapter XXIV - It has been reported that allergies are associated with depression and possibly suicide in women. Aggression is an important behavioral component that predisposes depressed individuals to suicidal acts. In the present study we examined the relationship between allergies and aggression to determine a potential contribution of allergies in factors of risk for suicidal behavior. Because stress plays a critical role in the manifestation of clinical symptoms of allergies and also in suicidal behavior, we also studied the role of acute stress. Female inbred Brown Norway rats known for their susceptibility to respiratory allergies were sensitized and challenged with a mixture of tree pollen and evaluated in the resident-intruder test for detection of aggressive behaviors. They were also subjected to acute stress by sessions of inescapable forced swimming and re-evaluated in the resident intruder test. Animals made allergic to tree pollen and subjected to acute stress displayed increased aggressive-like behavior as compared with control-saline treated animals or to their own aggressive scores previous to the stress session. These results suggest that allergies and stress increases aggressive-like behavior, indicating that these conditions may be important factors promoting altered emotional reactivity with the potential to influence suicidal behavior. Chapter XXV - Considering clinical and animal evidence suggesting a relationship between allergy and anxiety, we hypothesized that, from low to high aeroallergen exposure, changes in anxiety symptom scores in patients with primary mood disorders will correlate with changes in allergy symptom scores. We also anticipated that sensitization to tree pollen, as determined by allergen specific IgE antibodies, will predict a greater worsening of anxiety during exposure to tree pollen. 51 patients with unipolar or bipolar disorder (age: 19-63 years, 65% female) were recruited. Tree- pollen IgE positive subjects (12) were included as the experimental group and patients negative to a multi-allergen serological test (39) were included in the control group. Self reports of anxiety and allergy symptoms were obtained once during the peak airborne pollen counts and once during the period of low airborne pollen counts, as reported by two local pollen counting stations. Using linear regression models, we confirmed a significant positive association between allergy scores and anxiety scores (p<0.04); however, the IgE specific tree pollen positivity was not significantly associated with changes in anxiety scores. Because changes in anxiety scores relate to changes in depression scores, the relationship between allergy and anxiety involves states rather than only traits, and as such, our results lead to future efforts to uncover potential anxiety triggering, exacerbating or perpetuating role of allergens in vulnerable individuals.

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Chapter XXVI - Obesity is increasingly prevalent in adolescents with significant lifelong medical complications. The exact prevalence of obesity among adolescent athletes is not known; however, there is research that suggests obesity prevalence varies by the type of sports. A few studies suggest that youth sport participation can be an effective tool in the management of obesity in children and youth. Regular physical activity and sport participation that is fun is strongly recommended. This discussion considers the role of sports in helping obese adolescents and also what physical activity is recommended. It is concluded that sports participation can be an important part of effective management of obese youth and setting the stage for a lifelong pursuit of physical activity to control and/or reduce obesity in the adolescent and adult population. Chapter XXVII - The link between obesity and hypertension is examined in this discussion. Underlying mechanisms include increase in sympathetic activity, sodium balance, renal tubular sodium reabsorption, glomerular filtration rate (GFR) and development of insulin resistance. The role of leptin is examined in the development of hypertension in obese adolescents. Also considered in this review are the definitions of hypertension and principles of management for obese youth with hypertension. Pharmacologic agents used for management of hypertension include diuretics, alpha blockers, beta blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin-2 receptor blockers (ARBs), and long acting calcium channel blockers. The importance of weight control, caloric restriction, and exercise in the management of obesity in youth is also stressed. Chapter XXVIII - This review has a two-fold objective. One, it addresses the association of hyperandrogenism and obesity and the complex metabolic derangements that are part of the problem. Clinical management of these co-morbidities is challenging and complex. Second, this article will aid health care providers with the key features to an early diagnosis and intervention to decrease the morbidities in the short as well as long term. Method: Systematic review of articles and information on the topic of interest that were published in the last 15 years. Conclusion: Obesity and hyperandrogenism are integral parts of Metabolic Syndrome/Polycystic Ovarian Syndrome (PCOS)/Hyperandrogenism, Insulin resistance, and Acanthosis Nigricans (HAIR-AN). With the childhood obesity epidemic, the metabolic syndrome and the associated abnormalities are routinely seen in clinical practice and these have a tremendous economic burden on the society and the quality of life. Chapter XXIX - Obesity is the most prevalent metabolic disorder in the United States with adolescents and children being the fastest growing segment of the population affected by this disorder. The initial management of obesity entails modification of diet and exercise as well as a trial of medications. Unfortunately, this usually has unsatisfactory results; as a result, bariatric surgery has been used in the adult population and seems to offer improved long term results. Because the results have been quite favorable in the adult population, specialists are also looking at bariatric surgery for the adolescent population. This appears to be a safe approach in conjunction with diet and exercise and it offers improved long term results. This article discusses the use of bariatric surgery in obese adolescents. Chapter XXX - There has been a profound increase in the prevalence of obesity over the last 20 to 30 years causing the coining of the term “obesity epidemic” in children, adolescents and adults. It is believed to be due to a complex interaction of social and environmental factors in the overall lifestyle pattern. The increased rate of obesity is seen to be associated

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with increasing incidence of type 2 diabetes mellitus in adolescents, along with perturbations of the other endocrine axes, as well as, higher risk of long term complications. It is therefore of the utmost importance that concerns about overweight and obesity be addressed from early childhood and adolescence to avoid resultant significant morbidity and/or mortality. Chapter XXXI - Obesity has been deemed a public health epidemic, which carries with it high financial and psychological stakes, social consequences, and ethics of public, mental, and medical health care research pushing for all adolescents, who are “obese” to lose weight. This article reviews the psychological aspects of overweight in adolescents. No single factor has been shown to cause obesity; most researchers agree that the causes of obesity are multifaceted and complicated. Adolescents who are overweight may experience the deleterious effects of obesity on psychological functioning. Concepts of beauty, perceptions of body image and satisfaction all contribute to the psychological attitudes and beliefs about personal value, worthiness, self image, body satisfaction, and dieting. Not all adolescents who are at-risk-for-overweight or are overweight are unhealthy. Clinicians should consider that just as they warn the obese about the risks of obesity, they must expend as much energy evaluating the risks of successful weight loss. They must also remember that there are other standards of beauty and body size among ethnic groups and other cultures. The weight for height by body type tables that are used to calculate BMI should be changed to reflect the body types and fat distributions of Latino- and African-Americans. Chapter XXXII - The global epidemic of childhood and adolescent overweight has become a major public health concern. Not only are these youth more likely to become obese as adults, and thus more prone to obesity-related diseases than their non overweight peers, they are also likely to suffer emotional and social effects associated with overweight. Overweight in youth has been linked to depression, low self-esteem, eating disorders, negative body image, and stigma. It appears to be bi-directional in nature, with overweight sometimes predicting certain psychological effects and psychosocial issues sometimes predicting overweight. Effective assessment and treatment of psychological and mental health issues in overweight youth will help overweight youth deal more effectively with their social and psychological milieus. Additionally, interventions for mental health concerns may have the added health benefit of increasing weight loss, thus decreasing obesity-related disease for which the overweight adolescent is prone. Chapter XXXIII - This discussion reviews various medications currently used and being studied for weight loss induction in adults and adolescents. The search for medication to induce weight loss was stimulated by the US FDA’s 1959 approval of phentermine, a sympathomimetic amine, for short-term weight loss despite limited research supporting its claims of causing weight loss. In addition to noradrenergic products like phentermine, other reviewed medications include herbal products (such as Korean herbal formula based on Taeumjowi-tang), sibutramine (mixed noradrenergic-serotonergic chemical), orlistat (lipase inhibitor), metformin (biguanide), rimonabant (CB1-selective cannabinoid receptor antagonist), and others. Only two non-amphetamine-related medications are FDA-approved for adolescents: sibutramine for those 16 years of age and older, and orlistat for those 12 years of age and older. Pharmacotherapy for morbidly obese adolescents should only be used as part of a comprehensive weight loss program that involves diet, exercise, and behavioral

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modification. The side effects of these products should always be considered as well as the potential for serious adverse events. Chapter XXXIV - Although obesity is not classified as an eating disorder, there are associations between obesity and anorexia nervosa, bulimia nervosa, and binge eating disorder. This article reviews some of these associations. For example, a proportion of patients with anorexia nervosa eventually become bulimic and some of these patients eventually become overweight, while anorexia is often seen in a previously obese patient who loses weight successfully and then cannot stop losing weight or continues to try to lose weight even after reaching an otherwise normal weight range. There are possible genetic components for obesity as there are for anorexia nervosa and bulimia nervosa, but there are also associations with the family environment, particularly with family dietary habits. Obese patients should be screened for the presence of an eating disorder, especially bulimia nervosa and binge eating disorder. Obese patients who successfully lose weight should also be carefully observed for the possible development of anorexia nervosa. Principles of management are also reviewed. Chapter XXXV - Adolescence is a critical period of growth and development in an individual’s maturation from puberty to adulthood. A key component of normal adolescence is the process of healthy sexual development that is influenced by an inevitable passage through the stages of maturation from infancy to adulthood. Primary care clinicians should understand and appreciate the importance of sexuality in the lives of their adolescent patients. Obesity is one of the factors that influences sexuality in adolescents. The purpose of this paper is to succinctly discuss the relationship between obesity and adolescent sexuality. In this regard, it is vital to examine whether obesity alone can derail healthy adolescent sexual development. Not all overweight adolescents experience severe negative outcomes because of their obesity. However, for those who do experience negative sexuality issues, the sensitive and caring clinician can help direct them to helpful resources to address these critical issues. Chapter XXXVI - All sexually active youth, whether obese or normal weight, should be offered counselling regarding contraception and appropriate contraceptive methods. However, obese youth who are sexually active may be less likely than their normal weight peers to use contraceptives correctly. Methods of contraception for obese adolescents are reviewed in this discussion. Combined oral contraceptives (COCs) and the contraceptive patch have higher failure rates in obese versus normal weight females, though failure rates are lower than noted with barrier contraceptives. The risk for venous thrombosis is higher in obese youth on COCs. Progestin-only pills and the levonorgestrel intrauterine system appear to be safe and effective methods in obese females. Depot-medroxyprogesterone acetate, intravaginal ring, and implants are also considered. Chapter XXXVII - The prevalence of obesity has increased to epidemic proportions in the United States in recent years. Obesity in the Western world is a disease of poverty that is seen much more often in minority populations. Obesity-related illnesses, such as type II diabetes, are now seen frequently in adolescents and even in younger children. Caloric intake has increased in adolescents over the last two decades along with changes in dietary composition fueled by advertisements of unhealthy foods by various food producers. Nutritional modification is an essential part of any weight-loss program. This article discuss

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various diet changes that are important to reverse this current trend of increasing obesity in all populations and ages. Highly-restrictive diets should be reserved only for the morbidly obese child or for those with obesity-related problems such as sleep apnea. Chapter XXXVIII - Obesity presents special challenges for skin care and is associated with several conditions that need careful attention. Among the conditions reviewed here include acanthosis nigricans, papillomatosis of Gougerot and Carteaud, polycystic ovary syndrome, striae distensae, Cushing disease, and Cushing syndrome in relation to their dermatologic aspects. Various treatment modalities reviewed include bathing, soaps, cleansers, shampooing, emollients, topical corticosteroids, topical antibacterials, antifungals, and topical retinoids. Chapter XXXIX - Obesity in childhood has particular concern, because if it continues into adulthood, the result will be increased morbidity and decreased life expectancy. An increase in obesity in the general population in the developed world has been documented in recent years. This trend is also seen in persons with intellectual disability and in particular in persons with Down syndrome (DS). Persons with DS are prone to obesity already at an early age and several studies have shown a high prevalence in this population compared to persons with intellectual disability without DS and the general population. Persons with DS have a low resting metabolic rate and low dietary intake of individual nutrients and therefore exercise and vitamin-mineral supplement diet must be instituted in this population to prevent or minimize obesity and its adverse consequences. Chapter XL - Obesity rates among children around the world have reached an epidemic level. Having an option to walk or bike to school is important for mobility, health and equity purposes. However, fewer students are walking or biking to school today than a generation ago, and fewer students live within a walkable distance to schools. This review highlights the existing evidence from multiple disciplines on health and equity issues related to school transportation. It then assesses the literature dealing with the built environmental correlates of walking or biking to school. Travel distance and safety were found to be the strongest predictors of walking or biking to school. Studies suggested that about one-half to one mile (0.8-1.6 km) between home and school was generally considered walkable. Other factors such as roadway conditions, sidewalk continuity, bike lane availability, signals, lighting, and neighborhood design appeared important but with some inconsistencies in the findings. Many commonly reported environmental barriers were related to transportation infrastructure, such as high-volume and high-speed roadways, unsafe street crossings, and railroads. Compared with distance, safety and transportation infrastructure, neighborhood characteristics such as density, land use, and overall street patterns appeared less significantly associated with school transportation. This review revealed evidence supporting the link between school transportation and the built environment. It also discovered many remaining questions for future research, such as interactions and causalities between personal and environmental factors, environmental influences from multiple spatial scales, and differences between objective and perceived measures. Chapter XLI - Research has focused on adolescent’s food choice with the hope of finding key factors preventing obesity. We aimed to specifically spot relevant key factors that influence Bangkok children, aged 9-11 years old, their food buying preferences and behaviors in schools. Nutritional anthropological research methodology namely, participant

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observation, in-depth interviews, and buying and eating behaviors-related observation questionnaires were carried out among 27 participating elementary schools in Central Bangkok. This research aimed to discover detailed factors associated with individuality, sociality, environmental, and external influence over children’s food choices. First, individuality factors associated to children’s food choices involved the amount of daily allowance, children’s food preferences, students’ perception towards food ability in correlation with the frequency of school breaks, and children’s rationale of food prices (reasonable/affordable range). Second, sociality factors concerned how individual(s) have shaped children’s knowledge of food, food-related beliefs, and individual(s) that accompany/are present at the moment when children are buying foods. Third, environmental factors discovered were the location, distance, and quality of where food is being sold, shelving/how food is being displayed, and the availability of food knowledge the school displayed/provided for their students. Last, external factors identified the variety of mass media channels, which triggered children to desire new food items, were tested and shown no influence over children’s food choice on school days. In conclusion, the insights gained can enlighten ways in which in-depth understanding of children’s food choice and behaviors can be obtained in order to create a more efficient and culturally suited future obesity prevention plan. Chapter XLII - Childhood and adolescent obesity are risk factors for poor health later in life as well as decreased life expectancy. This short communication reviews literature on obesity in Israel and examines several recent studies, which have clearly demonstrated rising rates of childhood and adolescent obesity similar in magnitude to those trends observed in other Westernized nations. It is incumbent upon relevant authorities within Israel to reverse these trends so as to prevent the long-term adverse health consequences associated with childhood and adolescent obesity. We recommend initiating a national educational campaign to promote exercise and healthy eating. This campaign would target children and adolescents and would rely upon evidence based guidelines for diet and exercise.

Child Health and Human Development

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter I

Principles of Eating and the Individual with Rett Syndrome Judy Wine1,2, Yael Yoshei1,3,4 and Meir Lotan∗1,5,6 1

Israel Rett Center, National Evaluation Team, Chaim Sheba Medical Center, Tel HaShomer, Ramat Gan 2 Mishaul Center for Augmentative Communication and Assistive Technology, Jerusalem 3 Beit Issie Shapiro Educational Facility, Raanana 4 Kalisher School for Special Education, Tel-Aviv 5 Zvi Quittman Residential Centers, Israel Elwyn, Jerusalem 6 Department of Physical Therapy, Academic College of Judea and Samaria, Ariel, Israel

Abstract Rett syndrome (RS) is a genetic disorder affecting mainly females. The individual with RS experiences a wide range of functional limitations, in many cases leaving her in need of constant care. The individual with RS may have a variety of eating disorders, frequently leading to a very small and slim physique. Given that increased food consumption can yield positive results on both the functional abilities and the emotional state of individuals with RS, it is important that focused attention be given to the feeding ability of these individuals. The present article will address the principles of eating with individuals with RS. The article is an amalgamation of up-to date knowledge on feeding for individuals with disabilities from our clinical experience with individuals with RS. The article suggests different ways to evaluate and to positively influence the activity of eating with persons with RS by discussing the person herself, the setting, and the handling by caregivers. ∗

Correspondence: Meir Lotan, BPT, MScPT, Department of Physical Therapy, Academic College of Judea and Samaria, Ariel. E-mail: [email protected]

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Keywords: Rett syndrome, eating, feeding, Israel.

Introduction Rett syndrome (RS) is a genetic disorder that primarily affects females (1, 2). The disorder causes a neurological and developmental arrest that manifests itself in a variety of disabilities such as loss of functional hand use, loss of acquired speech, apraxia, ataxia, autonomic system dysfunction, epilepsy, breathing abnormalities, failure to thrive, orthopedic problems and muscle tone irregularities (3, 4, 5). One of the issues that affect the functional ability of the individual with RS, in addition to affecting her appearance and stature, is that related to the individual eating ability. The present article addresses the difficulties with feeding typically exhibited by individuals with RS and suggests possible intervention techniques. The information is derived both from the limited existing literature on clinical issues relating to RS and from our clinical experience working with this population. There is a multitude of factors involved in the eating habits of individuals with RS that influence its correctness and speed. In order to decide on appropriate intervention, all of these factors must be taken into consideration (see figure 1).

Factors affecting the feeding ability of the individual with RS Oral/motor function

Level of development Safe and satisfying feeding

Cognitive level

Motor control

Epilepsy

Constipation

Posture & positioning Orthopedic state Functional abilities

Behavior Communication Respiratory problems

Figure 1. Factors affecting the feeding ability in persons with Rett syndrome.

In order to emphasize the severity of this issue among individuals with RS, it may be noted that 74% of the individuals with RS present gastroenterological problems (6).

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Assessment When considering the issue of feeding as it relates to people with developmental disabilities in general and to individuals with RS in particular, it is recommended that the subject be approached according to work done by Evans and Klein (7) adapted for RS: 1. The execution of a comprehensive assessment, 2. The use of a problem-solving approach, 3. The individual’s functioning within the overall framework of her disabilities and challenges 4. Mutual discussion and consent among therapists and caregivers (including parents) regarding the intervention regime. The assessment of the individual with RS can be divided according to the three main purposes of eating intervention: • Safe eating • Sufficient food intake • Social acceptability/esthetics. Safe eating relates to a state where the individual is not in danger of aspiration while eating or drinking. A decision regarding the danger during meal time is considered after gathering data from different sources, such as: • • • • •

•

Medical history (past lung infections and their frequency) Medical examination (examination of the respiratory system before and after eating). A questionnaire completed by the staff members familiar with the individual’s eating habits and functional abilities. Observations regarding the ability to intake different food and liquid items. Evaluation of the swallowing mechanism (in instances where the initial non-intrusive evaluation indicates that the individual is experiencing some difficulties in handling food intake, the execution of a video-fluoroscopy examination should be considered) Evaluation of the state of the respiratory system (when suspicion arises regarding the proper functioning of the swallowing mechanism due to recurrent lung problems, lung x-rays at random or on a regular basis should be taken).

Sufficient food intake is measured by the amount and type of food that the individual with RS consumes, together with its compatibility with her daily caloric expenditure and her growth curve. Deviation from the norm should provide the impetus for the initiation of a process intended to identify the difficulties exhibited by the person with RS and the application of appropriate measures aimed at improving the individual’s condition.

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Therapeutic Intervention during Mealtime Swallowing, or the ability to swallow food and fluids is a complex action which depends on an array of mechanisms. The tongue’s motion and the closing of the lips begin the swallowing process, as they move the food to the rear area of the mouth and pharynx. Sensory receptors in the pharyngeal area transfer information to different nerve centers, which start the reflexive swallowing process, while the food continues from there to the esophagus. A large number of persons with swallowing problems, including many individuals with RS, are not capable of halting the respiratory process during the swallowing process (as most people with a normally functioning system do). If there is food inside the individual’s mouth that she is not able to swallow between breaths, she must be able to block the entry of food to the esophageal area before attempting to swallow again. This action demands skilled and separate tongue movements, which generally cannot be executed by people with swallowing problems as part of their complex neurological profile. In such cases the joint air and food inhalation is expressed by coughing and could lead to suffocation. If the individual cannot achieve good lip closure, the formation of negative pressure which is necessary for the efficient flow of food to the esophagus while swallowing is affected. If the head and neck are not in the correct position (for example, hyperextension of the neck) then swallowing efficiency is affected and a high risk for aspiration exists. It may be stated that the most important physiological assistance for normal swallowing is a slight forward flexion of the neck. Many individuals with RS present postural problems, and therefore may have a hyper extended neck when sitting. This position causes the cervical vertebrae to protrude forward and press on the end of the esophagus, thus blocking the food pathway to a certain extent. However, exaggerated flexion (forward bending) of the neck also interferes with the closing of the epiglottis and causes food to be shoved into the bronchioles. Aspiration can be either active (coughing, interruption in breathing, cyanosis, noisy breathing) or without external indication (silent aspiration). Slow swallowing can derive from sensory abnormalities, oral-motor problems, reaction to medication, or a decreased state of awareness. Aspiration might occur when the eating process is slow and it becomes necessary to inhale before the food has completely left the mouth/pharynx area (in such cases spooning small amounts might be the solution). Additional eating problems which might interfere with swallowing are manifestations such as vomiting, spitting, gagging, and coughing. These problems, when reoccurring, may cause issues of malnutrition and/or dehydration. It is important to diagnose the cause and not to loosely hang the blame on personal or behavioral issues (“Joanne doesn’t like the rice”, “Tami is really stubborn today”). •

Vomiting (Gag reflex) – Abnormal gag reflex was found among 20% of individuals with RS (8). The gag reflex is usually located in the last third of the mouth, i.e. in the soft palate area, in people without neurological problems; the purpose of the gag reflex is to prevent unwanted and/or undesirable substances from being swallowed. The reflex can be produced by either internal stimulation (e.g. sickness) or external stimulation, for example, pressure or weight of different foods and substances in the mouth. Some individuals with RS have an inappropriately strong gag reflex and may

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•

•

7

feel ill as a result of stimulation in the area, in some cases, without the ability to cough. The therapist or caregiver should be sensitive to such a problem and if vomiting movements are noticed, a wash with water (if the food is the apparent cause) can be helpful. An opposite problem is the lack of the gag reflex, which implies that the bronchioles of the person with RS are defenseless. A postural change of the eater that will create a change in head position (forward or backward) will change movement of the food in the mouth, and may positively affect the pattern of movement of the head and shoulders, thus reducing the recurrence and severity of the gag reaction. Spitting – In general, this is defined as a strong emission of food in a voluntary manner from the mouth (9). In fact in some cases an individual may be defined as a "spitter" even if she did not voluntarily emit the food. It is a well known fact that individuals with RS show respiratory irregularities (4) expressed in some cases as explosive exhalation. A second reason for apparent deliberate spitting is a situation, where the person's mouth is full with food and there is a need to inhale. Such a situation might be resolved through the exhalation of air with food particles thereby forcefully spraying food out of the mouth. Additional reasons for the spitting of food can be either sensitivity in the mouth area or excessive drooling. Our clinical experience has shown that in some cases deliberate spitting is behavioral as the individual with RS enjoys the attention she gets as a result of this behavior. Intestinal problems have an effect on swallowing and on eating speed; for example, reflux and the slow emptying of the stomach will extend meal times. Chronic reflux may cause ulcers or bleeding, and pain during mealtime, thereby affecting esophagus/respiratory timing, which will in turn have a jeopardizing effect on the individual’s health. The slow emptying of stomach content if later accompanied by lying down will probably lead to reflux, and to the individual’s refusal to eat. The slow emptying of the stomach caused by the hypoactive para-sympathetic system (4) is commonly accompanied by constipation problems and/or fecal intestinal blockage (two well known manifestations in the digestive system of individuals with Rett syndrome).

Appropriate Environment during Mealtime When trying to create the most appropriate environment during mealtime, one should consider the following factors: •

Physical environment – The individual’s head, back, and legs should be well supported, and if necessary, the sides of her trunk as well. The head should be erect, in midline, and slightly tilted forward. The caregiver (feeder) should sit in front (if eye contact is desired) or to the side of the individual (if support to the jaw is required). If the individual is actively seeking eye contact with the caregiver yet is in need of support when eating, a mirror can be placed in front of her to enable both eye contact and proper support.

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8 •

•

•

Sensory environment – If the individual with RS is sensitive to noises (most RS individuals have a sensitive auditory system) a loud environment can cause sensory overflow, thereby leading to muscle tone increase. If the individual’s reaction is misunderstood by her caregivers the situation may be incorrectly interpreted as a behavioral problem. If the individual with RS is restless during mealtimes, all types of sensory stimulation which may be considered as possible disturbing elements (such as different scents, sounds, sights, and tactile stimulations) should be taken into consideration and modified until the individual is calm and is able to function in accordance with her maximal ability. Communicative environment – Food is usually an extremely positive motivator for the individual with RS. Thus mealtime is frequently the ideal time to develop and put into practice both manual and communicative skills. For example, the caregiver could wait for the individual to signal her wish to eat or drink, and then respond accordingly by giving the desired item, thereby enhancing her control over the situation and supporting communicative interaction. It is recommended to await the individual’s choice in regards to different food possibilities and then to serve her according to her choice. Mealtimes is a good opportunity to improve the eater’s eye contact, vocal abilities, and hand usage in a communicative manner. A possible recommendation is the preparation of tablemats that present the different utensils and food possibilities and might serve at the same time as mealtime communication boards. Facilitating caregiver support– It has been recommended that each person in need of an augmentative communication system have a Personal Communication Passport (10,11), in addition to all his/her other communication tools. The purpose of the Personal Communication Passport is to present important and relevant information about the person in a clearly written and interesting way so that it is accessible to all those who are in contact with the person. Within this Passport there can be a page on "eating" which describes the seating and eating methods, the required utensils, and the handling to be provided by the feeder. On this page the person’s personal preferences as well as dislikes in regards to food and drink should be specified. Personal reactions during emergency situations can also be described. The page should be prepared as a joint venture of the parents and habilitation\educational staff in consultation with the RS individual. It will serve to ensure that the same forms of assistance will be given to the individual with RS during mealtimes, even with changing caregivers and across settings.

Of the above mentioned aspects of feeding two are of immense importance as they are potentially the source of many eating problems and dealing with them may in many cases prevent or alleviate these problems themselves. These elements are the positioning and the caregiver's handling of the individual (special attention must be paid to them as they are potential sources of influence on oral-motor function). Most individuals with RS present a thin and short stature. Despite the fact that they are generally good eaters who enjoy their food, even though they spend an especially long time at their meals, they generally do not put on weight relative to peers. Some even suffer from

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Failure To Thrive (FTT), a condition which requires enhancing caloric intake and in extreme cases even using tube feeding through a gastro-intestinal tube (G-Tube) (12). The severity of eating problems of individuals with RS usually escalates until mid-childhood age and thereafter stabilizes (13). BMI (Body Mass Index) points to the relationship between the body height and weight of the individual (appropriate figures for the general population are 21-26 BMI). Individuals with RS have been found with average BMI values 17.5 (see table 1). This figure points to the fact in most cases (especially during childhood) the individual with RS is extremely thin relative to her height. Studies have shown that many individuals with Rett syndrome were in fact in a mild to moderate state of malnutrition (14) and that their calorie intake was 70% of normal caloric intake (15). Studies also showed that the stereotypical hand movements accounted for a high burning of calories enhancing the need for a high caloric intake (16). Since this imbalance is extended over a period of years, the individual with RS may reach malnutrition with its harmful effects. Often, the duration of mealtime (due to swallowing problems) may bring on the decision of inserting a G-Tube (gastrostomy). The Australian RS research group reported that 12.5% of the individuals used nutritional aids such as G-Tubes (6). Table 1. BMI values of individuals with RS (6) Age groups All ages 0-7 Year(s) 7-12 Years 12-17 Years 17+ Years

BMI 17.5 15.4 15.5 16.6 21

It was found that an eating program via a G-Tube helps to put on weight and sustain a proper growth rate in individuals with Rett syndrome. In addition, it has been found that an increase in caloric intake resulted in a calmer, more sociable disposition, as well as in the ability to become more physically active (12). On one hand, the goal is having the individual with RS take in as many calories as possible through a balanced diet in order for her to grow properly, be calm, be physically active, and build up her immunity to diseases. On the other hand, we are interested in sustaining the self feeding abilities of individuals with RS in order to enhance functional skill and prevent them from loosing those skills which they already possess. Therefore a balanced feeding program should be created for each individual with RS. Such a program must maintain daily exercises aimed at preserving functional eating abilities at the same time as it ensures sufficient caloric intake. It should be emphasized that a normative eating program can be implemented even with the insertion of a feeding tube, by using the G-tube to supplement caloric intake.

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Practical Aspects around Mealtime The caregiver involvement begins after proper planning and decisions are made based on the results of the initial evaluation. Factors to be considered include the physical condition of the individual (oral-motor abilities, oral structure, body movement patterns, level of assistance required at mealtime), behavioral and social abilities and environmental considerations (such as the availability of equipment, training and/or professional knowledge of the caregiving team, etc). According to these indicators we determine the correct therapeutic posture. One may photograph the individual in the correct position during mealtime and provide proper instructions to caregivers. A good tactic is to write these instructions out on a large poster, preferably with accompanying diagrams; this poster can then be hung on the wall both as a reminder to staff and family and as a teaching tool in the event that a new caregiver joins the team. Correct eating posture should: •

• • •

Enable correct arrangement of the eating area (of the seating system, position of the individual relative to the table, and the position of the caregiver in relation to the individual). Sustain and improve midline orientation. Provide support for the back/trunk and for the lower extremities. Allow the individual to function at her highest possible level of ability.

Individuals with RS generally love eating, and food can be used as a powerful motivational factor for them, with the intent of reaching additional therapeutic goals through the use of food. As mentioned above, despite their great appetite, individuals with RS consume about 50 calories less than the average per day, which results in some instances in malnutrition (12). It is important to remember that the limited communicative abilities of individuals with RS generally prevent them from expressing their hunger. Therefore if the individual with RS is thin, larger amounts of food and high caloric food supplements should be suggested, despite the prolonged mealtime. However mealtime should not exceed 30-40 minutes, and therefore it is sometimes necessary to add another meal per day. It is reiterated that individuals with RS who were given sufficient caloric intake were found to be calmer, more aware of their surroundings, more active and they also displayed proper growth curves (12). When an individual with RS has been noted to have reached an extremely low weight, despite constant feeding attempts, it is recommended that high-caloric food and liquid supplements be introduced, for example enriched liquid drinks such as Ensure or Pedishure® jello, ice cream, milkshake, whipped cream, olive oil, and more. At times, a high-caloric diet may prevent the use of a G-tube. It is common for the majority of individuals with RS (also those who have not been evaluated as having swallowing problems) to aspirate occasionally (the intake of food into the respiratory system). This constitutes a dangerous situation, especially if concealed aspiration is performed (when unaccompanied by coughing) as the caregiver is thus unaware

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of its existence and complications can occur, including pneumonia, a life-threatening illness. In cases of recurring lung pathology: •

• • •

•

•

•

It is important to undertake an evaluation by a specialist, in order to determine the occurrence and frequency of aspiration, (The foremost factor to be suspected and examined in individuals with RS presenting lung problems would be aspiration). A liquid thickener should be used (such as Thick and Easy, Thick-It® ThickenUp®, or No More Lumps) to reduce the risk of aspiration. An individual with RS who aspirates must be fed thickened pureed foods devoid of lumps. The positioning of the head should be re-evaluated and backward tilting of the head should be prevented during mealtime (since this is the posture wherein the bronchioles are at their most open/vulnerable position). It is necessary to keep the body erect, with the head stable. If the seating system does not support the required postural modifications, the hand of the caregiver not occupied with feeding can be wrapped around the shoulders in order to support the back of the neck from behind, as a tactic for achieving proper stability and positioning. If there is a lack of control of the jaw movements, the jaw may be stabilized to enhance proper chewing and swallowing with the help of the caregiver's free hand. It is important to keep steady pressure via the support and to keep the head and neck at the right position. Examples for the proper support can be found at http://www.dinf.ne. jp/doc/english/global/david/dwe002/dwe00238.htm. (17). It is important to try to place the food either on the tongue or between the upper and lower molars, as placing the food in these areas will enhance complex mouth action involving the teeth, tongue and jaws, for the purpose of encouraging chewing behavior.

It is recommended to keep a food diary tracking the amount of calories the individual with RS consumes. A food diary will also allow for the tracking of unusual events such as the making of strange sounds, epileptic attacks, manifestations of anxiety, or any other strange behavior which has occurred during or after the eating of a specific food, thus preventing needless future suffering. Previous studies have shown that individuals with RS do not have allergies on a level and frequency beyond those of the normative level (18). In spite of this knowledge, there are random reports from parents, which point to sensitivity of some individuals with RS to strawberries, wheat products, tomatoes, eggs, chocolate, corn, milk, nuts, and soy (19-21). When taking into accout the varsetile phenotypic expressions of individuals with RS, in combination with their communicative limitations than we (the caregiver/parents/therapists) must be attentive and resposible to take proper actions to improve their care, including on the gastronomical front. The individual with RS might be sensitive to a specific food item but not enough to elicit an allergic reaction. In other words, no allergic sensitivity would be found through allergy evaluation, and yet, she will react negatively to a certain food item. We must identify these

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food items (by conducting the food diary suggested earlier) and if in fact the manifestation escalates, remove them from her diet. It is possible and even common for individuals with RS to present oral sensory issues. Therefore one should pay attention during mealtime; it is possible that they do not eat/drink because the food texture is not pleasant (one should try and change the texture in order to verify this assumption) or the food/drink temperature is not adequate (one should try the same food at different temperatures until reaching the individual’s preferred temperature). Individuals with RS may present low oral muscle tone accompanied by sensory problems. It is therefore advisable to provide oral stimulation prior to mealtime when needed, in order to improve the oral functioning, thereby improving the quality of eating and shortening mealtime duration. Instruction for oral treatment is given by an occupational therapist/speech language pathologist/physical therapist who is familiar with this type of intervention and should be personalized for the needs of every individual with RS (22, 23). The intervention includes a gentle, yet firm massage of the cheeks, chin, lips, and if possible, the inside of the mouth, using a gentle brush of the kind used to massage a baby's teeth. It is important to remember that some individuals with RS may resist having the therapist's finger or a brush inserted into their mouth; it is paramount that we respect the person's wishes and avoid forcing this intervention if the person feels uncomfortable. Exercise before and during mealtime can include slow and rhythmic moving of the joints, together with the application of pressure in the direction of the center of support. Such procedures frequently reduce spasticity and give the individual the opportunity to achieve proper eating, as well as reduce her stereotypic hand movements. As opposed to the above mentioned intervention, a hypotonic individual (usually a younger individual) with RS, will actually gain from vigorous movement before mealtime. This procedure may include jumping on a physiotherapy ball, dancing (either standing on the floor or in the therapist's arms), jumping while sitting on the therapist's knees (if age-appropriate), or rolling – the person with RS is put in a prone position with the underarms supported with a small cylinder or folded up blanket; the therapist may use gentle backwards and forwards rolling movements which put pressure on the person's hands, arms and shoulder girdle. Immature tongue movement patterns prevent the individual with RS from performing coordinated movements which are required for the transfer of food from side to side inside the mouth, thus also preventing proper chewing (14). In order for the individual with RS to initiate proper tongue action, it is important to place the food at one side of the mouth between the molars, thereby enhancing execution of complex mouth, tongue, and lip movement. RS individuals fixate their trunks in order to prevent the unpleasant sensation which accompanies ataxic shuddering and to improve the slight control they have over their muscles. The negative side effect to this gain of control is prevention of proper stabilization of the back and head. If this is the case, trunk and neck muscle strengthening exercises are warranted together with manual techniques for the upper torso and neck, aimed at releasing tight tissue and enhancing joint range of movement during treatments in between meals. Since self-feeding and manual functioning are dependent on trunk control, the basic way to achieve improved trunk stability as well as manual functioning is by activating the trunk muscles. If better functioning can be attained while eating by the use of a specific exercise, it

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is advisable to plan a practice session of this kind before mealtime and start the meal immediately at the end of the exercise. This way, the individual will be physically prepared; moreover the practice session will serve as a framework for the meal, as she will come to recognize that food is served right after the exercise.

Seating System Individuals with RS have poor postural control. Therefore it is essential that the individual is properly seated during mealtime. Prior to the meal the therapist and caregivers should check to see that the individual with RS is seated in a proper chair, that her body is well supported, and that the distance and height of the table are individually adjusted to her needs. Without these initial conditions, the chances of enabling the individual with RS to manually function or eat properly are poor. In order to achieve maximal engagement during meal time, the individual's attention should be focused towards eating. If her body is not supported well enough and she is preoccupied with lack of stability, her oral functions will be inadequate for achieving the control and coordination necessary for the complex action of eating. Therefore the individual with RS should be provided with some form of seating which will enable her to support herself in the position desirable from the therapist’s standpoint. Generally this is also the position that is most comfortable for the individual. On the other hand it is important to remember that stabilization prevents movement; therefore we will always aim at achieving functional self-feeding with minimum external support from facilitators as well as equipment. One must remember that most individuals with RS present low muscle tone, and as such, they become more passive with growing external support. Therefore minimum required support should be provided. For example, using a chest support during mealtime will usually encourage forward leaning with hyperextension of the head and neck; as this is an undesired posture, the use of a chest support should therefore be avoided. It is recommended that a slight leaning backwards of the seat's back support, which will allow for a slight leaning forward of the head, is (as mentioned before) an ideal posture for eating. This suggestion is general in nature and does not prevent individual problem-solving proceedings when issues such as orthopedic neck problems, skewed sensations in regard to midline, and respiratory problems may in fact lead to the appropriateness of a completely opposing posture. Some individuals with RS show extremely high muscle tone. In order for such individuals to reduce their spasticity, thereby improving their functional abilities (and this is suggested only for extreme cases showing very high spasticity), it is advised to use slow, rhythmic and soothing movement before and during mealtimes. In such cases a suspended chair might be considered as a proper seating system and might help in reducing the individual's spasticity and thereby enabling function. Many individuals with RS show agitation in new unfamiliar situations. Therefore an acclimation period should be allowed when changing the seating arrangement of an individual with RS.

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Most individuals with RS will be unable to verbally communicate unease or distress in regard to discomfort caused by the seating system. Therefore when new postures are pursued the therapist should be attentive to the individual's non-verbal cues. Extensive hand mannerisms accompanied by high muscle tone might imply that the individual with RS needs some more time to get accustomed to the seating system or that some alterations are required for the individual to be comfortable and thus enjoy her meals. When constructing a seating system for individuals with RS, consideration should be given to the correct position of the pelvis, thighs, hips, trunk and shoulders in order to determine the preferred mealtime posture. Due to sensory dysfunction and faulty body scheme, individuals with RS frequently produce continuous movements of the lower and upper extremities. Such movements tend to distract the individual, thereby reducing her functional level. Due to the need for a careful balance between stabilization and mobilization, the individual with RS should receive a scrupulous evaluation when provided with a seating system. The functional outcome should serve as the guiding principle of the decision making process. It is important to decide what kind of support should be given and at what times; during feeding, for example, some individuals with RS might be in need of maximal support in order to prevent preoccupation with postural issues. At other times, less support enables the achievement of balance reactions and muscle strengthening. For the hypotonic person less support will enhance muscle tone thereby enhancing functional abilities If the individual presents different needs during mealtime and free time (i.e. a need for massive support during mealtimes but ability to achieve independent seating when individual intervention is not required) the use of two different seating systems might be considered.

The Human Environment Therapeutic intervention goals for the individual with RS should always emphasize her independence and maximal achievable function. Due to the fluctuating nature of RS the caregiver should always be informed and updated regarding intervention goals and the appropriate handling required for achieving such pre-set goals. Individuals with RS are apraxic meaning that they have difficulties in performing a motor act on demand or in learning a new function (24). Touch is a very meaningful modality for the apraxic individual, and therefore the caregiver's touch is of extreme importance. A sensitive attentive touch by the caregiver can reduce the individual's agitation and enhance function; however if unprofessionally applied this touch may do just the opposite and thus negatively influence the mealtime experience. A touch lacking attentiveness and sensitivity can cause the individual to disengage from the eating situation and thus diminish her cooperation. Due to the fact that individuals with RS are extremely sociable, the location of the feeder during mealtime is an important consideration. Having the feeder sit in front of the individual is a potent motivational factor since it encourages eye contact and communication. On the other hand sitting at the side of the individual enables the caregiver to achieve better control over her posture. Generally the location of the caregiver is determined by the amount of support required by the individual with RS as well as her interest in her close human

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environment. In the event that the individual with RS requires massive physical support (therefore suggesting that the caregiver should be situated at her side), but her need for personal interaction calls for direct eye contact, one might consider the option of placing a mirror in front of the individual with RS and her caregiver. Another option could be supporting the person with RS by sitting beside her during meal times, thereby enabling social interaction with other class/family members. Another factor influencing the seating arrangement of the person with RS and her feeder is the need to control stereotypical hand movements which may interfere with feeding. It is preferable for the feeder to sit on the side of the more active hand, thereby being in a position to assist in self feeding. This control is usually given by holding the non-dominant hand. The orthopedic condition of the person with RS can also determine the position of the feeder. If the individual with RS is diagnosed with scoliosis then the feeder is best to seat on the side of the scoliosis (i.e. at the right hand side of an individual diagnosed with a right scoliosis). In such a case a slight shifting of the plate away from the midline towards the right (of the individual with RS) is warranted. This will facilitate asymmetrical muscle action against the natural curve of the spine. The height of the feeder is an important issue as well, especially as the mealtime duration for individuals with RS is generally lengthy. The height of the feeder should allow him to assist for the entire duration of the meal without fatiguing his arms or back. Communication is another important and appropriate human factor that should be presented during mealtimes to the individual with RS. •

•

•

Communication should be directed at and with the individual with RS; Any discussion during mealtime between caregivers within a classroom setting or family members at home should include the person with RS. Conversation should be carried on with the person with RS; this conversation can include what food is available, information about the tastes, temperatures and textures of the food, the person's likes and dislikes, what is going to happen throughout the day, what happened yesterday, etc. Mealtime is an excellent opportunity for active communication through choicemaking. Choices can be made through the use of the food items themselves or through the use of pictures or written words representing those items; even when there is a set menu the person can be asked what she wants to eat first i.e. the vegetable or the chicken, or whether she wants to eat or drink first. The options of "I want more" and "I have had enough, thanks" can also be given. Even when giving a choice between two different foods (the vegetable or the chicken) it is often good to add a third choice, such as "neither of these" or "I have had enough". Frequently, messages such as "more" and "enough" can be uttered through the use of single message voice output communication device such as the BigMack. It must be remembered that persons with RS frequently indicate their choices through the use of eye gaze rather than through hand-pointing.

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The Food The fact that each individual should receive only food items and food textures that are appropriate for her chewing and manual abilities is probably very clear to all readers, nevertheless we chose to bring it up as basic as it is. For example, an individual with eating or chewing problems should receive a biscuit or varied pureed food choices rather than a carrot or apple, so she can safely enjoy her food. An individual with good gripping ability should be served long and graspable food items (chocolate bars, grissini sticks) which are easy to hold, instead of small items which might frustrate her (i.e. cheerios, trix). The same cautious approach should be taken towards liquids. Thickened liquids should be suggested if the individual with RS’s oral abilities put her in danger of aspiration when attempting to handle drinks of regular consistency. Thickened liquid can also be used both as a means for enhancing caloric intake and for increasing the sensation it creates when introduced to the mouth (allowing the individual with RS to easily handle the liquid). Thickened liquids also slow down the pace of swallowing, thereby enhancing the individual with RS’s efficiency for handling the liquid in her mouth. Most individuals with RS show clear preferences regarding food items. There are types of food which the individual with RS resists simply due to the fact that she does not like their taste. There are also types of food that are so delicious, that the individual who usually! does not eat independently (not even with her hands i.e. finger feeding) will agree to hold a spoon and eat independently!. (For example, an individual with RS known to the authors was willing to hold and independently eat a sandwich only if it contained chocolate spread, to independently hold and drink from a cup only if it contained Coca-Cola, and independently eat with a teaspoon only if she was served with a chocolate flavored dairy product). It is important to identify such food items in order to offer the individual with RS an enjoyable treat, as well as to facilitate improvement of her manual functioning based on the motivational element which such products hold. The improvement of manual functioning is a cornerstone in the therapeutic intervention for individuals with RS and should always be pursued. Furthermore a success in one situation may overflow to other situations and therefore the identification and usage of motivational factors is of immense importance. Due to such clear preferences regarding the taste of food items (and due to staff turnover in educational and residential facilities), it is recommended to list each individual’s preferred foods. Different tastes such as salty, spicy, sour, or sweet can be very arousing for the individual with RS and can be served when the individual is “under a cloud” (25). A detailed list of specific food likes and dislikes can be included in the individual's personal communication passport (as described earlier in this chapter); this will empower the individual with RS and will enhance her quality of life. Other items which should be included in such a list are known allergies, food items towards which the individual with RS demonstrates a slight sensitivity, or items that somehow create a negative reaction. A list of this kind will allow the planning of a diet which the individual will truly enjoy, thus turning mealtime into a positive experience. One should always aspire to enhance the oral abilities of each individual with RS by serving different types of food and introducing interesting textures, always taking into account individual preferences and abilities. On the other hand, many individuals with RS

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show difficulties in sensory processing in the oral area which may be manifested as either hyper- or hyposensitivity (14). Therefore foods of mixed textures (like soup), may deter such persons. If the individual with RS is orally hypersensitive, she may be more at ease with mashed foods (puree). On the other hand an individual with oral hyposensitivity may enjoy crunchy textured foods which stimulate the mouth. The food texture and size should be determined according to the oral sensitivity of the individual with RS as well as to her ability to chew and swallow and to her personal preferences. Appropriate food items for the individual with RS with oral hyposensitivity should include long cookies, biscuits, grissini (bread sticks), bananas etc. For the individual with RS who does not use her teeth for chewing, it is recommended to vary the diet as outlined in the "Non- chew Cookbook" (26). Some diets have been tried with individuals with RS, and the reports by their parents were positive. These diets include: • • • •

•

The Glutton-free diet: was reported to encourage weight gain and reduced constipation (27). A combination of the Glutton-free and Dairy-free diets: was reported to reduce screaming attacks and seizures (28). The Egg-free diet: was reported to reduce screaming episodes (29). The Macrobiotic diet which excludes red meat, dairy products, sugar, salt, tropical fruit, and white flour from one's diet: was reported to reduce constipation and to improve the function of the immune system (30). The Catogenic diet which is a diet based on the exclusive eating of fats (which is very difficult to hold). Its purpose is to improve epileptic conditions for individuals who do not respond well to anti-convulsive medication. For an individual with RS it was reported to improve epileptic conditions, vocalization, and intestinal conditions, while supporting an improved general health state (31).

Food Utensils Assistive equipment mediates between the food and the individual with RS. Specific assistive equipment is prescribed by taking into consideration the position of the individual with RS, as well as her manual, oral, and postural abilities. The goals in using assistive equipment are to improve the independent functional abilities of the individual with RS, to aid the caregiver\feeder in assisting the eater with RS, and to facilitate relaxation so that the individual with RS can increase her food intake and shorten meal duration. •

Cup/mug: In order to prevent the individual with RS from bending her neck back too far thus causing extension of the neck, a slanted cup (such as a flexi cup) should be used. Due the lack of precision typical of ataxic individuals it is important that the cup be made of unbreakable material and pleasant to bite on (such as thick plastic). The size of the cup should be such as to enable eye contact with the individual as she drinks. In instances where the person with RS is able to independently hold the cup, it is suggested that the cup be equipped with a mechanism controlling the amount of

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•

liquid drawn from a single sip (a holed cover or one with a mouthpiece). The individual with RS should be introduced to the possibility of using her hands while drinking (by using a cup with handles). A straw. If the individual with RS achieves good lip closure it is recommended to teach her to use a straw, which allows better consumption of liquids. Learning how to drink from a straw is an important stage. This ability can usually be acquired with relative ease: Use the individual's favorite drink (milkshake, cola, chocolate milk), use a flexible container, with a closed upper tube (the liquid is poured when the bottle is squeezed), the liquid is then pressed up the tube to the drinker’s mouth provoking her to sip it in. Kissing sounds may be made as audible hints for the individual to begin sucking. If a straw is used it should be of a type that won’t crush under the bite of the ataxic individual. A cup with a straw is recommended since it helps in stabilization of the shoulder girdle, the neck, and the head. A straw made out of thick and flexible plastic material can make it easier for the individual with RS to grip it with her lips.

Due to the complex integrative abilities needed for drinking out of a cup (co-control of the shoulder girdle, arms, trunk, head and mouth), the use a cup with a long straw, in a way that allows drinking without the need for using the hands is recommended. Drinking from a cup placed on the table (with a straw) is functional and it is believed that some individuals with RS will prefer this sort of device rather than investing the effort in learning how to drink. Such a device will enhance the independent abilities of the individual with RS, as well as improve her liquid intake. •

Spoons. A flat spoon will allow easy removal of food through the use of the upper lip. The spoon should be unbreakable (thick plastic) and pleasant to chew on (not metal). The size of the spoon should fit the size of the individual's mouth, and the length of the handle should fit the size of the feeder's hand. In some cases when the individual with RS feeds independently or with slight assistance, but lacks the ability to constantly hold the spoon, it is possible to add an upper semi circular strap to the handle of the eating utensil, in order to support the grip, and to enable the completion of a full feeding cycle without the spoon being dropped. The authors would like to caution against the frequent use of this technique which might prevent the individual with RS from taking responsibility for eating independently to the best of her ability. A heavy, solid thick-handled spoon will provide the individual with clear sensory input, thereby helping the apraxic\ataxic individual in handling the spoon and in progressing towards independent function. Since most individuals with RS have difficulty with complex motor abilities, such as the rotation of the forearm to both supination and pronation, an angled spoon will enhance the possibility of independent eating or at least aid the caregiver feeding the individual with RS. In some cases the motivation of the individual with RS to hold onto the spoon, thereby improving her hand grip, can be enhanced by either painting the handle of the utensil or attaching a colorful shiny object to it.

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Plates. Due to the generally poor manual abilities of individuals with RS, a plate with a high rim can prevent food spilling and will facilitate the scooping of food if the eater is independent or in need of slight assistance. Placement of the plate on a a non-slip rubber mat (such as Dycem ®, which prevents the plate from being pushed or moved during feeding), or a plate with an adhesive surface is recommended. This will prevent the tipping over of the plate that may occur either by the stereotypical hand movements of individuals with RS or an inaccurate hand reach in the case of an independent eater with RS. Due to the long duration of mealtime of individuals with RS the food may become cold by the end of the meal. Therefore the use of a double rimmed plate into which warm water can be poured is suggested. The use of this type of assistive utensil will enhance the individual with RS’s enjoyment for the duration of the meal. Since it is known that individuals with RS may be orally sensitive (14), keeping the food at a warm temperature may assist in cases where the individuals are sensitive to extreme temperatures (hot\cold). Such plates are found in most department stores selling baby equipment.

Placing the Utensils in the Mouth The following techniques are fundamental and are not unique for individuals with RS. These might be changed according to individual needs and specifications (i.e. if the individual with RS is fed through the use of a bottle or is placed in a tilted way due to the existence of contractures or decubitus (pressure sores). When feeding individuals with special needs the common practice is to insert the spoon towards the center of the mouth, above the tongue, to press down on the tongue with the spoon, to wait for lip closure over the spoon, and to then remove the spoon from the mouth in a straight horizontal plane. Removal of the spoon in this fashion will facilitate the scraping of the food off the spoon and into the mouth by the upper lip. This procedure is usually similarly executed with individuals with RS. In drinking, the cup should be placed on the lower lip and lifted in a way that will allow drops of liquid to enter the mouth when it opens.

The Recommended Amount of Food per Serving Due to the oral sensitivity of individuals with RS (14) and their poor oral coordination (6, 8, 33, 34), the amount of food placed in the mouth should be adapted according to the individual’s ability to cope with food in her mouth, taking into consideration the type of food, the support of the seating system, and the skill and efficiency of the feeder. The timing of servings could be important to enable proper coping with food by the individual with RS. It is important to evaluate the time the eater takes to clear her mouth after every serving and to act accordingly. The serving of food too quickly may induce vomiting and/or aspiration, while too slowly may be annoying or produce boredom, thus causing the individual to stop eating resulting in limited food consumption.

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The right amount of food should be more than what is needed to initiate the swallowing process but less than the amount the individual with RS can cope with, in between two intakes of air. Giving too little will make the feeding process too long both for the eater and the caregiver; giving too much will prevent the eater from chewing and swallowing properly, thereby causing the food to accumulate in the upper palate, or possibly leading to aspirations. The skilled caregiver will quickly learn what “the right personal amount” is. In order to deal with issues of staff turnover, in cases where "the right personal amount" is a critical issue it is advised that this sort of information be entered into a the personal diary or communication passport mentioned aerlier, including a photo entitled: "Spoon with correct amount of food".

Caregiver Intervention during Mealtime As a rule the intervention of the caregiver should aim at maximal independence on the part of the individual with RS and minimal assistance on the part of the caregiver. The assistance should be given according to the amount required by the individual with RS. An individual in need of substantial support can be helped by the "hand over hand" technique. On the other hand when there is need for minimal assistance only, this assistance can be provided through slight physical hints given at the elbow or shoulder level. It is sometimes possible for the individual with RS to achieve independent eating through continuous training. It is generally a gradual and slow process, progressing from total passivity to finger feeding and in some cases to independent eating with a spoon. Factors which may contribute to the development of independent eating skills include the development of a good rapport between the individual with RS and the feeder, together with the recognition of her abilities, of her sleep and wakeful hours throughout the day, and of her motivational factors. It is the belief of the authors that when the above mentioned factors are included within an intense intervention program, involving all the caregivers supporting the individual with RS, functional progress by the individual with RS can be achieved. On the other hand we must never forget that individuals with RS consume a diminished caloric intake (12) and therefore it is essential that they eat properly. Since appropriate food consumption is a matter of survival, a balance should be found between the amount of food consumed and independent eating. Therefore the caregiver should divide mealtimes into periods of feeding (for the sake of caloric intake) and periods of practice. As indicated above, communication is an essential aspect of eating; therapists and caregivers must remember to talk with the persons with whom they are interacting during mealtime. Responses through the use of communication strategies can be expected.

Environmental Considerations Due to the strong attraction held by individuals with RS for music (35-40), music can be used to create a relaxed atmosphere during mealtimes. It is advisable to play soft music in accordance with the individual preferences of the person with RS.

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Due to the significance of food for the individual with RS, mealtime can serve as an ideal active learning experience. In order to achieve the maximum gain, close attention should be paid to the individual with RS during mealtimes. Personal conversations among caregivers should be avoided at such times. A noisy eating environment might prevent successful communication between the caregiver and the individual with RS. Therefore steps should be taken by the caregiver to create a peaceful environment. The fluctuating nature of RS might affect the feelings, mood, and behavior of the individual with RS, thus causing a distraction during or around mealtime. It is important for the caregiver to be attentive and sensitive to possible distracting factors. The importance of the eating experience to this population (in terms of caloric intake, social and educational experiences, and food as a motivating factor) necessitates that care must be taken to ensure its positive value. Therefore in “bad times” efforts must be made both to detect the cause of this behavior and to find strategies for its resolution. An example of how the positive experience of mealtimes of the individual with RS can be maximized relates to the issue of smell. Because individuals with RS are often adversely affected by many different smells, different measures should be taken to ensure that the only aromas present during mealtimes are those of the actual food being eaten. An additional example with regard to environmental influence is the issue of color. Color is a highly potent environmental factor which can have an effect on both general feeling and mood. When considering environmental color and its effect on individuals with RS during mealtime, one must take into consideration whether or not we want the individual to look at her caregivers and the other individuals during mealtime, or at the flashy furniture and classroom walls. Individuals with RS have good peripheral vision (25). Movement at the edge of her visual field will draw the individual with RS's attention; therefore in order to ensure a quiet eating milieu, it is suggested that there be as few disturbances around the eating place as possible during mealtime. If the individual with RS is distracted and cannot fully participate in the eating experience, it is possible to consider moving her it to a quiet spot. Such a transfer will allow her the time and conditions she needs for a positive mealtime experience. Such a solution might enable the resolution of different “mealtime associated problems”. Despite the above, the therapeutic goal of the eating experience is full integration into community settings. Therefore the therapeutic staff’s final goal for individuals with RS is to facilitate their enjoyment of mealtime in a crowded, loud, and provoking environment such as a restaurant.

Conclusions Despite the fact that individuals with RS present a variety of difficulties, which may arise during and around mealtime, most of these problems can be resolved through the combination of a proper evaluation and a comprehensive prior knowledge of the different typical aspects related to this disorder. Due to the fluctuating nature of RS, evaluations of the individual and her eating environment should be on-going, in order to examine the therapeutic efficiency of previously taken measures. The complexity of RS, of the mealtime

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situation, and of the actual action of eating can easily hamper the smoothness of this experience. The application of knowledge and sensitivity on the part of therapists and caregivers can turn this from being a repetitive nightmare to being a positive experience for the individual with RS and her caregivers. The complexity of RS might challenge the caregivers and therapists with unanswered issues which remain outside the scope of the current article. In such situations the individual with RS and her family should be referred for consultation with experts in the field of feeding. Full resolution of these challenges might come from colleagues in the disciplines of occupational therapy, physical therapy, speech language pathology, nutrition, and gastroenterology.

References (1)

(2)

(3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13)

(14)

Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999;23(2): 185-8. Amir RE, Van Den Veyve IB, Schultz R, Malicki DM, Tran CQ, Dahle EJ et al. Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann Neurol 2000;47: 670-9. Hagberg B. Rett Syndrome: Clinical and biological aspects. London: Mac Keith Press, 1993. Engerstrom IW, Kerr A. Workshop on autonomic function in Rett Syndrome, Swedish Rett center, Frösön, Sweden. Brain Dev 1998;20:323-6. Lotan M. Management for Rett syndrome. Tel Aviv, IL: Rotem Publ, 2006 (Hebrew). Leonard S. The Australian Rett syndrome study inaugural report. Western Australia: Telethon Inst Individ Health Res., 2002. Evans MS, Klein DM. Pre feeding skills – a comprehensive resource for feeding development. Tucson, AZ: Therapy Skill Builders, 1987. Budden SS. Management of Rett syndrome: a ten year experience. Neuropediatr. 1995;26:75–7. Lotan, M, Zysman L. The digestive system and nutritional considerations for individuals with Rett syndrome. ScientificWorldJournal 2006;6:1737–49. Millar S. Personal Communication Passports: Guidelines for good practice. Edinburgh: CALL Centre, 2003. Personal Communication Passports. An internet site by Sally Millar, The CALL Centre. Information retrieved from site: http://www.communicationpassports.org.uk/ Motil K. Nutrition and weight management. Paper presented IRSA 12th Ann Conf. Boston, MA (24-27 May) 1996:622-11. Cass H, Reilly S, Owen L, Wisbeach A, Weekes L, Slonims V, Wigram T, Charman T. Findings from a multidisciplinary clinical case series of females with Rett syndrome. Dev. Med. Individual. Neurol 2003;45(5):325-37. Hunter K. The Rett Syndrome handbook. Washington, DC: Int Rett Syndr Assoc, 1999.

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(15) Thommessen M, Kase BF, Heiberg A. Growth and nutrition in ten girls with Rett Syndrome. Acta Pediatrica 1992;81:686-9. (16) Motil KJ, Schultz R, Brown B, Glaze DG, Percy AK. Altered energy balance may account for growth failure in Rett Syndrome. J Child Neurol 1994;9:315-9. (17) Werner D. Disabled village children. A guide for community health workers, rehabilitation workers, and families. Berkeley, CA: Hesperian Foundation, 1999. (18) Hunter K. Food allergies. Personal communication. (19) Personal communication (I). Thyroid, brassering, mucus and questions, received through the Rettnett March 13, 1997 from: [email protected]. (20) Personal communication (II): What's wrong with Haley? received through the Rettnett March 04, 1997 from: [email protected]. (21) Personal communication (III): What's wrong with Haley? received through the Rettnett March 05, 1997 from: [email protected]. (22) Krigger KW. Cerebral palsy: An overview. Am Fam Physician 2006;73:91-100. (23) Workinger MS. Cerebral palsy resource guide for speech-language pathologists. Clifton Park, NY: Thomson Delmar Learning, 2005. (24) Ayres JA. Sensory integration and the child, 5th ed. Los Angeles, CA: Western Psychol Serv, 1982. (25) Lindberg B. Understanding Rett syndrome. New York: Hogrefe Huber, 1991. (26) Wilson JR. The non-chew cookbook. Glenwood Springs, CO: Wilson Publ, 1985. (27) Holly G. (12.23.1996) Nutritional Link. Personal correspondence over the RettNett. [email protected]. (28) Kehler K. (4. 3.1997) What's wrong with Haley? Personal correspondence over the RettNett. [email protected]. (29) Weisz C. (3.5.1997) What's wrong with Haley? Personal correspondence over the RettNett. [email protected]. (30) Curtin M. (4.6.1997) Springtime illness. Personal correspondence over the RettNett. [email protected]. (31) Lane A. (11.10.1996) Ketogenic diet. Personal correspondence over the RettNett. [email protected]. (32) Pugh M, Stansfield S. Assessment of drinking equipment (cups and straws). DH Disability, undated. (33) Budden SS. Rett syndrome: habilitation and management reviewed. Eur. Individual. Adolesc. Psychiatry 1997; Suppl 1:103-7. (34) Motil KJ, Schultz RJ, Browning K, Trautwein L, Glaze DG. Oropharyngeal dysfunction and gastroesophageal dysmotility are present in individuals and women with Rett syndrome. J. Pediatr. Gastroenterol. Nutr 1999;29(1):31-7. (35) Merker B, Bergstrom-Isacsson M, Witt Engerstrom I. Music and the Rett disorder: The Swedish Rett Center survey. Nord. J Music Therapy 2001;10(1):42-53. (36) Rett A. Grundlagen der Musiktherapie und Music-Psychologie. Stuttgart: G Harrer, 1982. (German). (37) Wigram T. Assessment and treatment of a individual with Rett syndrome. In: Bruscia K, ed. Case studies in music therapy. Phoenexville, PA: Barcelona Publ, 1991.

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(38) Wigram T. A model of assessment and differential diagnosis of handicap in individualren through the medium of music therapy. In: Wigram T, Saperston B, West R, eds. The art and science of music therapy: A handbook. Chur, Switzerland: Harwood Acad Publ., 1995:181-93. (39) Wigram T. The effect of vibroacoustic therapy on clinical and non-clinical populations. Doctoral dissertation. St Georges Medical School, University of London. Cd-rom Music Therapy Info II. Witten-Herdecke University, 1996. (40) Wigram T, Cass H. Music therapy within the assessment process for a therapy clinic for people with Rett syndrome. Paper presented at the Rett Syndrome World Conference in Sweden, 1996.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter II

Ethics and Holistic Healthcare Practice Michael de Vibe∗1, Erica Bell2, Joav Merrick3,4,5, Hatim A. Omar5 and Søren Ventegodt 6 1

Lierskogen Health Center, Norway University Department of Rural Health, University of Tasmanian, Australia 3 National Institute of Child Health and Human Development 4 Office of the Medical Director, Division for Mental Retardation, Ministry of Social Affairs, Jerusalem, Israel 5 Adolescent Medicine and Young Parent Programs, J422, Kentucky Clinic, University of Kentucky, Lexington, USA 6 Quality of Life Research Center, Copenhagen K, Denmark 2

Abstract The paper aims to contribute to integrated discussion of ethics in holistic healthcare. Methods: Noting key aspects of the literature on ethics in holistic healthcare, the authors then focus on describing the working ethical statement for holistic healthcare practitioners produced for the International Society of Holistic Health (ISHH). Ethical principles, aims of holistic practice, and ethical guidelines are presented. The relationship of ethics to quality of care is outlined. Conclusions: The authors conclude that many of the ethical principles and guidelines, as well as expectations of quality and safety, that apply to mainstream healthcare, also apply to holistic practitioners. However, the multidisciplinary contexts of whole-of-patient healthcare present new challenges of application of these familiar ethical understandings.

∗

Correspondence: Michael de Vibe, MbBCh, Specialist in family medicine and systemic family therapy, Senior advisor, Norwegian Knowledge Centre for the Health Services, Postbox 7004, St.Olavs plass, N-0130 Oslo, Norway. E-mail: [email protected]

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Keywords: Medical ethics, holistic health care, CAM, medical practice.

Introduction Each patient carries with him his own doctor… They come to us without knowing this. We do our best when we give the doctor within each patient a chance to do its work. Albert Schweitzer (1875-1965) The aim is to support, nourish and remove obstacles for nature’s inherent healthpromoting and healing forces. Illness can be looked upon as a reaction to conditions we have placed ourselves in. Conditions inappropriate for maintaining health and well-being. Florence Nightingale (1820-1910)

The development of whole-of-patient healthcare has brought with it new discussions about the ethical obligations of practitioners delivering holistic healthcare (1). Though complementary and alternative medicine (CAM) treatments are being used in many western countries by up to half the population, but there has not been enough dialogue between mainstream health practitioners and CAM practitioners, about many issues of care delivery, including ethics (2,3). Ethical issues for physicians and allied health providers, who practice CAM are a related but quite distinct area, because these practitioners have been medically trained and operate in the legal and regulatory frameworks of mainstream medicine and health. Ethical issues for this group—the focus of this paper—have not been well explored in the published literature. However, we know that holistic healthcare involves a different conceptualisation of healing that, through its engagement with the whole patient (mind-body-spirit), creates quite different physician-patient relationships. These in turn raise new ethical considerations to do with vulnerabilities, ethical self awareness and trust (4). We also know that new treatments, such as touch therapy, whether integrated with mainstream approaches or not, also present new ethical considerations (5). Such ethical issues have been of interest to the International Society of Holistic Health (ISHH). This paper, developed by collaboration between holistic practitioners and researchers, offers information, content and implications of the ISHH guidelines. It aims to be useful to those wanting to reflect further on ethical practices in holistic healthcare. In a context where much modern medical and health practice is about integrative multidisciplinary approaches and inter-professional teams (6), and medical, nursing and allied health education increasingly engages with notions of what are ethical virtues (7), such matters are of interest to healthcare practitioners and educators generally. Ethics for health professionals has increasingly been conceptualised as being about an integrated set of knowledge, skills, and attributes such that the literature speaks of ethics as being about personhood and the evolution of the whole practitioner (8). This paper aims to contribute to this kind of integrated discussion of modern ethical healthcare.

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Definitions and Importance of Ethics Ethics are reflections and guidelines on how to act, while morals describe how we act. Ethics can be based on duty, on rights, on virtues, on consequence, on usefulness or on relations (9). The fundamental premise for all ethics is that every human being is equally valuable and demands the same respect and consideration. The main role of ethical guidelines is to protect those who cannot fully defend themselves and who cannot voice their demands or stand up for their rights. Ethical principles and guidelines are important, because they help encourage reflections on how to act. Unless human behaviour is audited against well-theorised and developed ethical statements, it is difficult for practice to be consistently ethical. Holistic healthcare practice involves a proactive approach to multidisciplinary treatments, often involving diverse teams of professionals. This can create new pressures and ethical decision-making situations for practitioners. Accordingly, the ‘whole-of-patient’ focus of holistic practice requires careful development of authentic and useful guidelines for practices that are not narrowly bio-medical.

Vision and Aims The International Society of Holistic Health (ISHH) is comprised of physicians, allied health professionals, and researchers, who have a commitment to developing high quality, whole-of-patient, integrative healthcare. The association has members across the world, in the Middle East, Europe, America, Asia, Australia, and elsewhere. This international group have been interested in and published on contemporary developments in healthcare that reflect our emphasis on multidisciplinary, holistic, innovative—and above all effective and ethical—care for patients. We undertake collaborative international research on healthcare practices that integrate bio-medical and other approaches to achieve quality, patient-centered care. We also organise conferences that are an international meeting place of all those interested in advancing practices in holistic healthcare. The aims of the ISHH are: 1. To promote holistic health awareness among health care providers, organisations and the general public 2. To foster and stimulate the highest quality of health care provision in all communities. Holistic health care is defined as the art and science of healing the whole person—body, mind and spirit, by prevention and treatment—to promote optimal health. The ISHH believes that health is a holistic concept, because it is impossible to be healthy without taking into account the physical, mental, social, environmental, and spiritual aspects of life. The fields of knowledge and experience that can inform this area are therefore vast. Accordingly, the ethical decision-making situations that can arise in holistic practice are many and varied. Yet we believe they can be guided by simple universal principles that can be agreed-upon by those in many cultures and countries.

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The ethical principles and guidelines endorsed by ISHH aim to help us fulfill another aspect of our vision: to build bridges between the various factions of medicine and healthcare providers that share a goal in creating high quality holistic healthcare services. This emphasis upon building bridges across different areas of practice, services, cultures, and countries is why our emphasis is on simplicity and clarity of ethical statements.

Key Ethical Principles for Holistic Practice Two key principles underline high quality holistic healthcare practices: 1. Do to others as you want to be done by 2. Ask if it would be okay if everybody acted the way you plan to act. The first principle is common to many world religions. It requires the practitioner to imagine being the patient and to ask yourself if the behaviour would be desirable if you were on its receiving end. The second principle comes from Kant’s writings. Kant suggests that the basis for immorality is to make an exemption for oneself (10). This principle invites you as practitioner to ask yourself if your behaviour would be good for society if it were universally adopted.

Aims of Holistic Practice The aims of holistic practice are fourfold: 1. 2. 3. 4.

Heal, help, and comfort the patient Support and strengthen the internal healing forces of each person Treat the person as a whole (bio-psycho-social-spiritual being) Focus on prevention when possible.

The first aim positions the health practitioner as a holistic helper of those experiencing illness and related hardships. The second aim focuses the attention of holistic healthcare on developing the capacities of healing of the patient, rather than acting upon the patient. The third aim emphasises the importance of whole-of-patient care and the interrelatedness of the different dimensions of being in any consideration of how best to meet the patient’s needs. The fourth aim emphasises the value of prevention, positioning holistic healthcare as being about proactive approaches to health: education for health, healthy behaviours, and so on. Together these aims suggest quite different relationships between the patient and practitioner than are suggested by either traditional bio-medical models or more modern corporate models of healthcare. In the holistic model the practitioner focuses on empowering the patient and delivers services that cannot be so easily commoditised—it is difficult to see how empathy as a basis for giving comfort, or an engagement with the spiritual dimensions of the patient as

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part of whole-of-patient approaches, could ever be authentically priced on the healthcare marketplace. If the holistic practitioner takes on different roles and responsibilities from those found in bio-medical traditions of care, or new corporate models of care, it follows that there will be ethical considerations in holistic care that are related, but not exactly the same, as those found in these two other models of healthcare. In developing ethical practices the holistic practitioner will want to be aware that holistic practice may involve applying universal ethical principles to new practice contexts. Recognising how a universal ethical principle— such as that treatment be evidence-based—is relevant to new practice contexts is an important part of developing deeper ethical awareness. This is a truism of learning generally: a generic knowledge or skill can only be internalised and reproduced in daily practice when it has been applied to enough diverse contexts to make it deeply understood.

Ethical Guidelines 1. The values and laws on which the practitioner should build holistic practices are: (1.1) (1.2) (1.3) (1.4) (1.5) (1.6) (1.7) (1.8)

compassion mutual trust respect for the patient’s integrity human rights truth and justice to the patient and society national laws informed consent confidentiality.

2. In delivering healthcare, the practitioner should: (2.1) (2.2) (2.3) (2.4) (2.5) (2.6) (2.7) (2.8) (2.9) (2.10) (2.11) (2.12)

give information regarding the purpose, content, duration, cost of treatment and complaint rules build the practice on evidence use methods that are validated use methods one can master use methods that do not harm place concern for the patient as paramount when trying out methods keep records (10 years) that patients can read conduct research, develop and test new methods of diagnosis and treatment to high standards of quality research practice monitor and evaluate results develop and improve one`s practice use one`s resources fairly where possible, develop the tool (oneself).

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3. The practitioner’s relationship to colleagues should: (3.1) (3.2) (3.3) (3.4) (3.5)

be respectful involve raising misconduct by other practitioners directly with them in a caring way; secondly with authorities not express criticism of colleagues in front of patients be transparent, sharing, and open, assuming informed consent in patient matters not involve inappropriate interference in, or prevention of, treatment given by others.

4. In relations with patients, the practitioner must not: (4.1) (4.2) (4.3)

(4.4) (4.5)

disrespect the patient’s right to choose (treatment, life or death) assist actively in ending life exploit or manipulate the patient economically, philosophically, religiously, sexually or in any other way (the consent of the patient does not free the practitioner from this duty) engage in a sexual relationship with the patient promise to cure the patient, or hinder the patient receiving help from others.

The first part of the guidelines focuses on broad values and laws that should govern holistic practice. The emphasis upon compassion suggests the way in which holistic care involves practitioner empathy for the patient, which is critical to an engagement with the whole patient. The second part of the guidelines emphasises that holistic practice is accountable, evidence-based, and rigorously developed. The third part of the guidelines emphasises high standards in collegial interactions in ways that serve the interests of rigorous and accountable healthcare services. The last and fourth part of the guidelines emphasise what the practitioner should not do in interactions with patients, consistent with other parts of the guidelines. Considered as a whole, these guidelines suggest that if holistic practice involves the integration of mainstream approaches and CAM to deliver whole-of-patient healthcare, such healthcare is not exempt from the high standards of rigour, accountability, transparency, and duty of care expected of practitioners everywhere. For example, when tailoring treatments from different disciplines to meet complex healthcare needs, the practitioner must be able to point at the evidence that informs decision-making about the appropriate treatments.

Ethics and Quality of Care Ethical healthcare practices and quality healthcare practices are related but different aspects of healthcare delivery. The personal ethics of the practitioner set the pre-conditions for quality healthcare at the micro-level of provider and patient; the quality of the care systems sets the macro pre-conditions for provider-patient interactions.

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Effective Efficient Safe

Service Quality Coordinated Involving users and giving them influence

Available and equitable

WHO and the Norwegian government

Provider practices that are ethical are also practices that aim for high quality. Holistic healthcare should aim to deliver services with the same quality aims as those set by the World Health Organisation (WHO), which have also been adopted by many countries in the world. The diagram below comes from the Norwegian National Strategy for Quality Improvement of Health and Social Services Norwegian National Strategy (11). It shows, in a picture, the ways in which service quality involves many ethical matters to do with safety, equity, accessibility, and user influence.

Conclusions In contrast to some representations of alternative therapeutic approaches as not involving, for example, a reliance on evidence-based approaches (12Kottow, 1992), the foregoing suggests that many of the principles and guidelines that apply to mainstream medicine apply to holistic healthcare. Expectations of quality and safety also apply. At the same time, in this paper, we do not give a simple ‘yes’ or ‘no’ answer to the question of whether ethical frameworks that apply to narrow bio-medical healthcare approaches apply to holistic healthcare. The health ethics literature suggests that one error to avoid in developing ethical statements is the assumption that frameworks developed for one health context can be simply applied to another (13). We take the view that holistic healthcare involves many common ethical principles and guidelines that can find new challenges of application in the multidisciplinary contexts of whole-of-patient care. Of course, most people from vastly different contexts of care can agree upon a set of common principles and guidelines if they are broad enough. The real challenges of obtaining real, in-practice agreement on ethics comes when practitioners need to make sound decisions about a familiar principle in an unfamiliar context. The meaning of ethics in holistic practice requires an effort of understanding precisely because holistic care opens up new contexts for the application of familiar ethical principles and guidelines. Thus, the restatement of familiar ethical principles and guidelines in ways that are nuanced to the contexts of holistic healthcare is important to developing understandings of how the former applies to the new contexts. This is the task that ISHH is engaged in as it develops these working principles and

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guidelines. Our work challenges healthcare educators to design undergraduate and continuing professional development courses that provide learners with opportunities to understand how familiar ethics principles and guidelines apply across diverse healthcare contexts. We believe that our work also extends a special challenge to holistic healthcare providers who want to address all aspects of the patient’s life: to apply the ethical standards to all aspects of one’s own life. Only then will we truly be able to live and work as we preach. And only then will we be able to touch the spirit, mind, and body of the patient in a way that allows healing to take place.

References (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14)

Slater L. Person-centredness: a concept analysis. Contemp Nurs 2006;23(1):135-44. Robotin MC, Penman AG. Integrating complementary therapies into mainstream cancer care: which way forward? Med J Aust 2006;185(7):377-9. Ernst E, Cohen MH, Stone J. Ethical problems arising in evidence based complementary and alternative medicine. J Med Ethics 2004;30(2):156-9. Geller G. A "holistic" model of the healing relationship: what would that require of physicians? Am J Bioethics 2006;6(2):82-5. Wardell DW, Engebretson J. Ethical principles applied to complementary healing. J Holistic Nurs 2001;19(4):318-34. Artnak KE. A comparison of principle-based and case-based approaches to ethical analysis. HEC Forum 1995;7(6):339-52. Sprengel A, Kelley J. The ethics of caring: a basis for holistic care. J. Holistic Nurs 1992;10(3):231-9. Keegan L, Keegan GT. A concept of holistic ethics for the health professional. J Holistic Nurs 1992;10(3):205-17. Buber M. Ich und du (I and thou). New York: Touchstone, 1966. Syse H. Veier til et godt liv Filosofiske tanker om hverdagslivets etikk. (Ways to a good life) Oslo: Aschehoug, 2006. (Norwegian). Norwegian National Strategy for Quality Improvement of Health and Social Services 2005-2015. http://www.ogbedreskaldetbli.no /237/IS-1162_E_5484a.pdf. Kottow MH. Classical medicine versus alternative medical practices. J Med Ethics 1992;18(1):18-22. McCarthy J. A pluralist view of nursing ethics. Nurs. Philosophy 2006;7(3):157-64.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter III

Domestic Violence and Small Children: Key Directions for Holistic Healthcare Erica Bell∗ University Department of Rural Health, University of Tasmanian, Australia

Abstract This analysis paper aims to identify key directions for developing holistic healthcare that is more responsive to the special needs of small children 0-5 exposed to domestic violence. It takes a ‘whole-of-patient’ as well as a ‘whole-of-systems’ approach to how health and allied health practitioners, service administrators, policy decision-makers, and researchers could work together to better meet the needs of these clients. Its focus is on mutually compatible health and allied health reforms, at the levels of research, practice, and policy. This analysis paper is based on select literature identified using the terms ‘children AND domestic violence’ in the databases SCOPUS and PUBMED. The emphasis was on papers for the period 1995-2006. Domestic violence is a prevalent social problem with known effects on small children that require early intervention if they are not to become more costly for the individual and society later. Much progress has been made, however, unless new approaches are energetically pursued, we may be facing another twenty years of program evaluations that do not give us the holistic evidence base needed for strong service development.

Keywords: Domestic violence, children, holistic health care, systems development.

∗

Correspondence: Erica Bell, PhD, Academic Research Leader and Research Fellow, University Department of Rural Health, University of Tasmania, Private Bag 103 Hobart, Tasmania 7000 Australia. tel: (03) 6226 6345; Fax: (03) 6231 6601; Email: [email protected]

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Erica Bell

Introduction Even in developed countries with relatively well-established healthcare data collection systems, it is difficult to know how many small children have been, and are being, exposed to domestic violence, and how many adolescents and adults were exposed to this violence in their earliest years. Australian data suggest that up to a quarter of young Australians (12 to 20 years) have been exposed to an ‘incident of physical or domestic violence against their mother or stepmother’ (1). One USA based study (2) estimated conservatively that ‘at least 10% to 20% of children were exposed to intimate partner violence yearly, with perhaps as many as one third exposed at some point during their childhood’ (p. 323). Notices posted in the United States offer the statistic that one woman is beaten every six seconds, with multiple studies indicating that about 20-25% of children report they have witnessed incidents of intimate partner violence (3). Rates of violence in the USA at least are highest among women and men in their twenties, indicating the high risk of young children being exposed (4). One American study identified that 10% of women seeking treatment for their children in an urban pediatric emergency department with children less than three years old reported being in abusive relationships over the last year, 28% reported childhood sexual abuse, and 52% reported histories of adult physical abuse (5). New Zealand research suggested that ‘partner abuse is most common among the young parents of small children’ and other studies confirmed that ‘young children and partner violence are concentrated together in the same population’ (6). These small clients present to health and welfare services most often accompanying their mothers, and they face service cultures that are often historically heavily oriented to the needs of women. Society has recognised and campaigned against domestic violence since colonial times (7), though in the USA and other western countries domestic violence rarely appeared in courts, and it was seen by the legal system as a private matter at least till the 1970s (8). Yet while concern over women affected by family violence has figured in public discourses in the last three decades, and shelters for women affected by domestic violence grew in number in the 1970s (9, 10), the concern about children has been later and more uneven (11, 12), though as we will see, it is now reflected in a growing body of research (13, 14). The literature on domestic violence covers many different settings, yet rarely focuses on practical directions for developing ‘whole-of-patient’ and ‘whole-of-systems’ approaches to better meeting the needs of these small clients. In practice, getting better responses to the needs of small children involves an engagement with many services and agencies: for example, anti-natal nursing and community healthcare services, pediatric hospital and general family practices, mental health and substance abuse services, ambulance services, emergency accommodation services, community counseling services, community education agencies, childcare centres and early education agencies, justice and child protection services, as well as central government agencies with administrative responsibilities for developing services, policy, and legislative frameworks. In Australia, as in many other countries, service fragmentation, a lack of good information sharing between agencies, and an emphasis on reactive child protection services rather than early intervention and protection is the common theme across different state reviews of services (15). As has been noted by a leading Australian commentator in this area,

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a key challenge for developing better responses to this health and social challenge lies in developing child-focus in a ‘whole-of-system’ approach that offers a holistic response to the child’s needs (16).

Methods This analysis paper is based on select literature identified using the terms ‘children AND domestic violence’ in the databases SCOPUS and PUBMED. The emphasis was on papers for the period 1995-2006, however, papers published earlier were not excluded if they appeared still relevant. The researcher selected papers on the basis of whether they were useful to identifying the special issues involved in healthcare responses to small children 0-5 years exposed to domestic violence. Studies relevant to pregnant women were included. The search methods used did not aim to produce a review describing the literature on domestic violence and small children. Rather, studies were selected on the basis of whether they offered insights into how health and allied health should be developed at the levels of research evidence, practice, and policy to better meet the needs of this client group.

Key Directions for a Whole-of-Patient, Whole-ofSystems Approach This section identifies key directions for developing a whole-of-patient, whole-ofsystems approach. A ‘whole-of-patient’ approach is a holistic approach that engages with the client’s bio-psycho-social well-being. A ‘whole-of-systems’ approach is an approach that mobilises multiple government, private, not-for-profit agencies across different sectors— from health, welfare, education, policing and so on—to deliver this ‘whole-of-patient’ approach. It is argued that while both the terms are different, it is difficult to have holistic responses to complex health needs without a whole-of-systems approach, precisely because holistic responses need facilitating in health systems that create the conditions for interprofessional and multidisciplinary.

Developing a Shared Community Ethos and Principles A shared culture and beliefs about non violence are critical to the capacity of a community and its practitioners to respond to the needs of small children exposed to domestic violence. Without this consensus it is difficult to overturn the ‘states of mind’ that allow children to pass unnoticed through health and allied health services, as suggested by the quotation below: I want to talk with you about the “unthinking, non-reflective space” that accompanies violence in the home and the profound impacts on a child of a parent’s state of mind in it’s own right (…)an absence of child focused thought can be perpetuated by the care-giving

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system and the legislation and policies that guide it. It is the overturning of such unthinking states of mind, in and out of the home, that so determines the nature of a child’s recovery from domestic violence (16). There is a growing body of literature defining domestic violence and the nature of the small child’s experience of this violence, including in-utero (1,2,11,14,17-23). Such research suggests that the lack of visibility of small children exposed to domestic violence may be linked to the fact that domestic violence is not simply ‘family’ violence. Children are involved in a wide range of domestic situations where violence may occur, as for example in ‘dating violence’ linked to teenage pregnancy. The existing research too often provides a poor basis for developing the visibility of small children exposed to domestic violence. This may be because it generally lacks a focus on the whole context of domestic violence, most notably in terms of its silence about men who commit the violence, but also other aspects of the violence. Researchers are afraid to bring heterogeneity to the field by exploring not only the role of men, but also, for example, female-initiated domestic violence, for fear of being seen to ‘blame the victim’ (3). Consequently, healthcare practitioners and the community generally do not have access to a body of knowledge that provides an authentic, well- contextualised basis for understanding and theorizing domestic violence. We know that domestic violence is overwhelmingly violence by men against women, with most studies, including those of public records, citing figures above 90% of reported cases (1,24-26). We also know that adult men who have been exposed to domestic violence as children are at higher risk of becoming perpetrators of domestic violence (16,27). Where domestic violence does occur it is most often part of a recurring pattern, a fact that is linked to the severity of outcomes for children (2,28,29). What is most certain is that domestic violence is a multi-dimensional situation shaped by a complex set of interacting multiple risk factors and chronic adversities (30). These will take a different form in different cultures and religions (10, 31). Developing a shared ethos and principles about domestic violence and small children exposed to it among healthcare practitioners will involve not simply better understandings of the anatomy of that violence—the what, where, and who of the violence—but also better understandings of the effects of exposure to violence on small children. While a considerable amount has been written about adolescents’ experiences of domestic violence, and its effects on them, there is relatively little literature on the impact on younger children (32). Studies that focus on accounts provided by children of domestic violence and its effects on them invariably focus on children ranging from 5 years into adolescence (20). Yet an emerging body of evidence about the effects of exposure to domestic violence on small children, including in utero, provides the beginnings of a foundation for developing community and practitioner understandings (17,33,34). The high-conflict behaviours of parents are known to have powerful effects on an individual’s adjustment in childhood, adolescence, and adulthood. The direct effects of such high-conflict behaviours relate to modelling of parental behaviour, failure to learn social skills, and physiological effects. Indirect effects relate to impaired parenting opportunities, relating to less father involvement and/or negative interactions with the father (21). Violence itself, particularly combined with other risk factors such as child abuse, poverty, and parental mental illness, has been shown in clinical and other research to be linked to pervasive effects on child development, ranging

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from mental health problems such as depression and anxiety, to lower levels of social competence, behavioural problems, and poorer academic and verbal functioning (2,11,14,35,36). In relation to cognitive development, studies refer to diminished neurocognitive functioning from environmental factors that work to suppress IQ and delay development (4,37). The literature also indicates, with less confidence (14), that family violence is linked to post-traumatic stress disorder (PTSD), and co-morbidities across different mental health symptom classes, particularly phobias and separation anxiety (38). More broadly, it is known that children’s emotional reactions to domestic violence are complex and intense and include feelings of fear, sadness, including self-harming reactions, anger, powerlessness, and loss of self-identity (20). The research also documents long-term negative effects on life satisfaction, self-esteem, psychological distress, and violence in one’s own relationships (1,21,39). Powerful arguments for intervening in children’s experience of domestic violence are suggested by studies that point to the inter-generational transmission of domestic violence—though any simplistic assumptions about its inevitability for all or even most children exposed to domestic violence are not supported (1,25,40). Considered together, this body of evidence provides strong support for the view that the effects of domestic violence begin at a very early age (16). The nature of the symptoms that small children will exhibit will include symptoms that are different from those exhibited by older children. One study notes that pre-school children are more likely to have physical symptoms following exposure to domestic violence such as sleeping difficulties, bedwetting, stomach aches, and asthma (37). Of course, these symptoms may also have their origin in other causes unrelated to domestic violence. An extensive review of the literature notes in relation to children that ‘no single pattern of immediate or short-term effects of exposure to domestic violence has been found’ (2). At the same time, the same study noted that ‘externalising behaviour problems such as aggression, disobedience, non-compliance, hostility, and oppositional behaviour were the most commonly observed patterns of response’ (2). Significantly, the literature notes that some children may appear to emerge from exposure to domestic violence ‘relatively unscathed’(2, 13). That is, small children affected by exposure to domestic violence may not exhibit obvious external signs. Part of the challenge of developing a shared ethos and principles for better holistic healthcare for small children exposed to domestic violence lies in the generally poor transfer of research into health policy into practice. Much of the research is diagnostic (on the nature and effects of domestic violence on small children) which means that developing statements of ethos and principles requires an additional effort of translation by service administrators and holistic health practitioners. The other problem is that the existing research does not generally appear to be very service-oriented i.e. it does not very often take a focus on what the findings of the study mean for practice in specific service settings for specific clients. Available statements of service ethos and principles in this area lie outside the corpus of scholarly research (28).

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Developing Better Evidence for Holistic Healthcare Practice Examination of the literature suggests some key areas where research evidence, policy, and practice need to be developed before holistic responses to small children affected by domestic violence are substantively improved.

Screening, Identification, and Assessment The screening, identification and assessment of small children exposed to domestic violence as they come into contact with different services is a key area. These terms have been used to mean the same, overlapping, or quite different things. However, they are not the same. ‘Screening’ refers to a broad range of inquiry processes that happen in heathcare service contexts—such as ‘screening’ for general psycho-social problems, or specifically for domestic violence (17). ‘Identification’ can be an outcome of effective screening and is associated with finding out if a child is being exposed to domestic violence. However, the term ‘assessment’ is often used to find out more about the situation and child’s needs, as a basis for making choices about appropriate intervention (13). In healthcare settings at least it has long been recognised that ‘it is likely that indirect observations alone are an insufficient means of screening’ (23). However, surveys of how acceptable women in primary healthcare find screening for domestic violence suggest that only between 43-85% find screening acceptable, and it has been argued that many practitioners also do not support it (41). This study argues that other than a modest increase found in identification and subsequent increased referral, there is little evidence that screening in healthcare settings at least actually results in positive outcomes such as decreased exposure to violence or at the very least does not cause harm to the women being screened (41). On the other hand, another study concludes that ‘concerns about lack of acceptance of maternal screening at pediatric visits seem to be unfounded. Screening may actually increase satisfaction with care’ (23). A further study found that many women do reveal domestic violence when screened in a pediatric healthcare setting (42). An Australian study of clinical presentation issues argued that while opportunistic screening is indicated, rather than screening of the whole population, it should be borne in mind that ‘women who have experienced partner abuse want to be asked about it and are more likely to disclose if asked in an empathetic, non-judgmental way. Doctors can make a difference’ (26). A still relevant point is made by a now out-of-date USA paper on domestic violence and the role of clinicians: One early theory suggested that identification in medical settings was difficult because battered women were reluctant to discuss the real cause of their injuries. Yet researchers have used simple interview techniques and questionnaires to uncover substantial rates of domestic violence in various medical settings, suggesting that identification was not so difficult after all. (9). By its very nature domestic violence can be difficult to discuss in any service setting. That some women in domestic violence situations conceal that fact through fear of losing custody of their children is well-documented (22,43,44). United Kingdom health literature

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suggests the very ‘private’ nature of domestic violence, urging health visitors to ‘be more proactive in their questioning techniques’ (45). There are related issues in this area such as how to handle a child’s confidences about domestic violence where parents have not reported such matters to a worker (2). The whole matter of identification of domestic violence also carries with it considerable duty of care issues: given the higher incidence of child abuse and neglect in domestic violence situations, professionals need to know and understand laws about reporting child abuse to child protection authorities (13). Those women that do seek help, often only when the violence has escalated, from health and welfare services for example, do not always receive appropriate support or protection, particularly accessing specialist services through referrals, including help for their small children (22,43). Black and Asian women experience particular challenges accessing services because of cultural and language barriers as well as discrimination (22,43). It has also been noted that professionals have difficulty identifying children who have been exposed to domestic violence, and may be uncertain about interpreting their problematic symptoms (13). In a study of children presented to urban pediatric emergency departments it was found that the children of women experiencing domestic violence ‘had no distinguishing complaints in the emergency department suggesting that there was violence in their families’ (5). Specific clinical issues to do with identifying young children exposed to domestic violence are not so well-researched. For example, and following on from the earlier point about PTSD, it has been noted that there is little research into the traumatic symptoms of exposure to domestic violence in very small children: ‘research on trauma symptoms in children younger than 6 who have experienced any traumatic effect is very minimal, perhaps due to problems in conceptualising traumatic symptomatology in young children’ (46). Yet as noted by Scheeringa and others (47) who reviewed the literature for post-traumatic stress disorder in children younger than 48 months, evidence of severe impairment can be found ‘in almost all such reports’. In connection with this, research has questioned the capacity of clinical tools for assessing post traumatic stress disorder in preschool age children exposed to domestic violence (46,47). Other studies of post traumatic stress disorder in children identify three clusters of symptoms: ‘re-enactment of the traumatic event; avoidance of cues associated with the event or general withdrawal; and physiological hyperactivity’ (48): Children with PTSD may present with a combination of problems including impulsivity, distractibility, and attention problems (due to hypervigilance), dysphoria, emotional numbing, social avoidance, dissociation, sleep problems, aggressive (often re-enactment) play, school failure, and regressed or delayed development (48). Recent years have seen important developments in the identification, and assessment of small children exposed to domestic violence, with principles and tools developed for use in healthcare settings (11,17,41). However, too often these tools do not have a strong evidence base behind them, with few exceptions, notably versions of the Conflicts Tactics Scale which is most commonly used. In any case, many such tools are largely for working with adult clients or older children in a context in which information collected about domestic violence in clinical health contexts is poorly standardized, leading to major validity problems (14,13,17,26-28, 33,46,49-51). There is a small body of literature about tools related

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specifically to the assessment of small children, such as the Child Behaviour Check List, however, this also shows how problematic their use can be with this age group (4,46). Clinical diagnostic and treatment guidelines have been developed by medical associations in different countries, and have been in use for some years. The trend is to move towards holistic screening, identification and assessment: a focus on multiple symptoms and needs presented by the small client, in ways that involve different professionals such as clinical specialists, mental health professionals and early childhood educators. While the literature emphasises the importance of such holistic processes leading to the development of support plans for children (52), this is far from a reality in many countries.

Interventions Holistic healthcare—in the new century quality multidisciplinary healthcare—is defined by its ability and willingness to combine a range of different elements of interventions to tailor-make treatments for individual clients that engage with their bio-psycho-social needs. In the case of small children, such approaches need to recognize that parents and their children have distinct but related needs (16). The first public strategy for domestic violence in the USA was convened in 1985, emphasising tools for intervention and prevention (9). America has had a National Directory of Domestic Violence programs (10). Good practice programs are also given on the websites of authorities in other countries, for example the Australian Domestic and Family Violence Clearinghouse (www.austdvclearinghouse.unsw.edu.au). However, in relation to small children there have not been uniform standards of care or comprehensively listed programs/interventions in many healthcare settings and countries around the world. The evidence base for effective interventions for small children is much poorer than the evidence base for the nature and effects of domestic violence (2). Researchers have observed a lack of ‘controlled outcome studies demonstrating the effects’ of such interventions for children (13) as well as for pregnant women (17). Another study, referring to the evidence for interventions in domestic violence more generally, noted that despite almost twenty years of program evaluations, their effectiveness is still questionable. These authors are, however, able to conclude that effective treatment programs focus on the safety of victims, educate perpetrators and victims, emphasise the need for participants to be responsible, and are properly linked to, and educate participants about, the criminal justice system (27). Holistic interventions in this area ideally take the form of mutually complementary health (including alternative and allied health such as alcohol and substance abuse), mental health, education, accommodation, employment, welfare, and safety interventions. These involve collaborative partnerships with all agencies delivering such services to address the child’s total situation. For example, positive action in supporting women to find work, including through a broad range of welfare-to-work supports (childcare, transportation, economic supports) are indicated for reducing not only poverty, but also domestic violence (53-56). Key strategies for facilitating this inter-agency collaboration can be as simple as the development of referral lists and posters, leaflets, and contact cards (43). Best practice also

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refers to the importance of a register of services and programs, or periodic publications of text describing these (52). Holistic service delivery models do exist. For example, the literature refers to a program in Boston, Massachusetts that involves an inter-agency approach to case management of child abuse cases involving domestic violence: teams of ‘CPS staff, police battered women’s advocates, batterers’ intervention providers, court personnel, hospital staff, and supervised visitation providers’ work together in a team to ‘use each other’s expertise to design effective case plans and to improve case practice’ (8). A multidisciplinary program in San Jose in California known as ‘The Family Violence Center’ has operated as a ‘one-stop-shop’ for families experiencing domestic violence or child abuse: it offers a range of services in one building, that include legal, mental health, and domestic violence services staff (8). Holistic approaches may include intervention programs for the perpetrator of the domestic violence (10,44). Therapies for small children exposed to domestic violence can involve group work, play therapy, visual and creative arts therapies, cognitive and educational strategies, family therapies, and other specific child-centered therapies (52). Group therapies are not so helpful for younger children for whom individual intervention with a strong focus on parent counselling is typical (13). The emphasis is upon making sure every child who needs it has access to age-appropriate intervention (20), though this is far from a reality in many countries. It is worth noting the emphasis in the literature on supporting mothers to help their children come to terms with domestic violence (20). One reviewer noted that at least two authors recommend that parents should receive parallel treatment and be aware of children’s group treatment (2). Psycho-dynamic approaches to treating preschooler-mother pairs have been developed by the Child Trauma Research project at the San Francisco General Hospital, which focuses upon strengthening abilities in healthy family functioning, with some positive evaluation outcomes (13). There is relatively little literature about best practice interventions targeting the pregnant woman, however, what exists focuses on multi-agency community team efforts aimed at supportive approaches to assessment and treatment of pregnancy complications, peer mothering, behavioural interventions, home visits, as well as interviewing techniques aimed at education intervention to support the woman to try to end the abuse—with inconclusive evidence of success (17, 33).

Discussion and Conclusions This paper suggests a number of directions for research, policy and practice, to develop a ‘whole-of-patient’ approach within a ‘whole-of-systems’ approach. The directions can be described in relation to research funding agencies, government agencies, and services. Research funding agencies can develop funding priorities that: •

value service-oriented research that has demonstrable, explicit value for service development such as

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•

•

• •

research that empirically validates holistic interventions for small children exposed to domestic violence, as well as research that develops new methodologies for managing the specific demands of research in this area, ethical and methodological research offering evidence-transfer models of practice, such as statements of ethos and principles that are tailored to the needs of different settings while preserving a core set of values and approaches research leading to practical tools for service delivery, such as better models of screening, identification, and assessment, empirically validated and designed for use with children younger than five in specific heath and allied health settings; such tools should be designed to develop holistic inter-professional approaches across services with clear links to inter-professional support plans tailor-made for individual children value research that focuses on the whole context of domestic violence, particularly as it relates to perpetrators and the needs of small children value research that support bio-psycho-social approaches to better understanding the clinical symptomatology of the effects of domestic violence on small children.

Government agencies can: •

•

drive the development of uniform standards of care and make available comprehensively listed programs and interventions relevant to different kinds of health and allied health settings, with an emphasis on holistic approaches drive holistic, inter-agency collaboration through policy directives, education programs modeling such collaboration, and related service performance measures

Medial and allied health education programs, both at undergraduate and continuing professional education levels can include components on the anatomy of domestic violence— the what, where, and who of the violence—as well as an emphasis on understanding the effects of exposure to such violence on small children. Services can: • • •

•

•

make inter-professional approaches to screening, identification, assessment, referral and case management a part of their vision and practice adopt mentoring relationships with other services, including those overseas, which have successfully established holistic models of service delivery in this area distribute materials to practitioners, particularly materials for referrals, guidelines, and information about age-appropriate interventions, and include an emphasis on domestic violence as it affects small children in professional development activities focus on the whole context of domestic violence as it affects small children and, where appropriate and in the best interests of the child, develop family-oriented practices focus on community education as it relates to small children affected by domestic violence.

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Domestic violence is a prevalent social problem with known effects on small children that require early intervention if they are not to become more costly for the individual and society later. Much progress has been made, however, unless new approaches are energetically pursued, we may be facing another twenty years of program evaluations that do not give us the holistic evidence base needed for strong service development.

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(4)

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(16) McIntosh J. Thought in the face of violence: a child's need. In: The way forward: children, young people and domestic violence. Melbourne, Victoria: Office Status Women, Commonwealth Gov, 2000. (17) Taft A. Violence against women in pregnancy and after childbirth: Current knowledge and issues in health care responses. Sydney: Aust. Domestic Family Violence Clearinghouse, 2002. (18) Richardson J, Coid J, Petruckevitch A, Chung WS, Moorey S, Feder G. Identifying domestic violence: cross sectional study in primary care. BMJ 2002;324:274-9. (19) Shepard MF, Elliott BA, Falk DR, Regal RR. Public health nurses' responses to domestic violence: a report from the enhanced domestic abuse intervention project. Public Health Nurs 1999;16(5):359-66. (20) McGee C. Childhood experiences of domestic violence. London: Jessica Kingsley, 2000. (21) Kelly J. Children's adjustment in conflicted marriage and divorce: a decade review of research. J Am Acad Child Adolesc Psychiatry 2000;39(8):963-73. (22) Humphreys C. Avoidance and confrontation: social work practice in relation to domestic violence and child abuse. Child Fam Soc Work 1999;4(1):77-87. (23) Parkinson GW, Adams RC, Emerling FG. Maternal domestic violence screening in an office-based pediatric practice. Pediatrics 2001;108(3):43-51. (24) Walby S, Allen J. Domestic Violence, Sexual Assault and Stalking: Finding from the British Crime Survey. pp. 1-129. London: Home Office Res Dev Stat Dir, 2004:1-129. (25) Johnson MP, Ferraro KJ. Research on domestic violence in the 1990s: making distinctions. J Marriage Fam 2000;62(4):948-63. (26) Hegarty K, Hindmarsh ED, Gilles MT. Domestic violence in Australia: definition, prevalence and nature of presentation in clinical practice. MJA 2000;173):363-7. (27) Romans SE, Poore MR, Martin JL. The perpetrators of domestic violence. MJA 2000;173):484-8. (28) Warshaw C. Identification, assessment and intervention with victims of domestic violence. In: Improving the health care response to domestic violence: A resource manual for health care providers. San Francisco: Fam Violence Prev Fund, 1998:48-86 (29) Hoyle C. Negotiating domestic violence: Police, criminal justice and victims. Oxford: Oxford Univ Press, 2000. (30) Vostanis P, Grattan E, Cumella S. Mental health problems of homeless children and families: longitudinal study. BMJ 1998; 316:899-902. (31) Ellison CG, Bartkowski JP, Anderson KL. Are there religious variations in domestic violence? J Fam Issues 1999;20(1):87-113. (32) Osofsky JD. The impact of violence on children. Future Children 1999;9(3):33-49. (33) Mayer L, Liebschutz J. Domestic violence in the pregnant patient: obstetric and behavioral interventions. Obstet Gynecol Survey 1998; 53(10):627-35. (34) Commonwealth Task Force on Child Development Health and Wellbeing: Consultation Paper: Towards the Development of a National Agenda for Early Childhood. Canberra: Commonwealth of Australia, 2003.

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(35) Huth-Bocks AC, Levendosky AA, Semel MA. The direct and indirect effects of domestic violence on young children's intellectual functioning. J Fam Violence 2001;16(3):269-90. (36) Feldman RS, Salzinger S, Rosario M, Alvarado L, Caraballo L, Hammer M. Parent, teacher, and peer ratings of physically abused and nonmaltreated children's behavior. J Abn Child Psychol 1995;23 (3):317-34. (37) Hester M, Pearson C, Harwin N. Making an impact: Children and domestic violence: A reader. London: Jessica Kingsley, 2000. (38) McCloskey LA, Walker M. Posttraumatic stress in children exposed to family violence and single-event trauma. J Am Acad Child Adolesc Psychiatry 2000;39(1):108-15. (39) Purvin DM. Weaving a tangled safety net: the intergenerational legacy of domestic violence and poverty. Violence Against Women 2003;9(10):1263-77. (40) Smith JP, Williams JG. From abusive household to dating violence. J Fam Violence 1992;7(2):153-65. (41) Ramsay J, Richardson J, Carter YH, Davidson LL, Feder G. Should health professionals screen women for domestic violence? Systematic review. BMJ 2002;325:314-26. (42) Siegel RM, Hill TD, Henderson VA, Ernst HM, Boat BW. Screening for domestic violence in the community pediatric setting. Pediatrics 1999;104(4):874-7. (43) Peckover S. 'I could have just done with a little more help': an analysis of women's help-seeking from health visitors in the context of domestic violence. Health Soc Care Community 2003;11(3):275-82. (44) Stanley N. Domestic violence and child abuse: developing social work practice. Child Fam Soc Work 1997;2:135-45. (45) Frost M. Health visitors' perceptions of domestic violence: the private nature of the problem. J Adv Nurs 1999;30(3):589-96. (46) Levendosky AA, Huth-Bocks AC, Semel MA, Shapiro DL. Trauma symptoms in preschool-age children exposed to domestic violence. J Interpers Violence 2002;17(2):150-64. (47) Scheringa M, Zeanah C, Drell M, Larrieu J. Two approaches to the diagnosis of posttraumatic stress disorder in infancy and early childhood. J Am Acad Child Adolesc Psychiatry 1995;34:191-200. (48) Perry B, Azad I. Posttraumatic stress disorders in children and adolescents. Curr Opinion Pediatrics 1999;11(4):310-6. (49) Sherin KM, Sinacore JM, Li XQ, Zitter RE, Shakil A. HITS: A short domestic violence screening tool for use in a family practice setting. Fam Med 1998;30(7):508-12. (50) Rosen D. "I just let him have his way": partner violence in the lives of low-income, teenage mothers. Violence Against Women 2004;10 (1):6-28. (51) Tolman RM, Raphael J. A review of research on welfare and domestic violence. J Soc Issues 2000;56(4):655-82. (52) Gevers L. Models of service for working with children and young people who have lived with domestic violence. Canberra: Commonwealth Aust, 1999. (53) Riger S, Staggs SL. Welfare reform, domestic violence, and employment. Violence Against Women 2004;10(9):961-90.

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(54) Gennetian LA. Welfare policies and domestic abuse among single mothers. Violence Against Women 2003;9(10):1171-90. (55) Scott EK, London AS, Myers NA. Dangerous dependencies: the intersection of welfare reform and domestic violence. Gender Soc 2002;16(6):878-97. (56) Moe AM, Bell MP. Abject economics: the effects of battering and violence on women's work and employability. Violence Against Women 2004;10(1):29-55.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter IV

Therapeutic Horseback Riding (Hippotherapy) for Individuals with Rett Syndrome: A Review with a Case Study Maciques Rodríguez Elaime1 and Meir Lotan ∗2,3,4 1

Cuban National Riding Rehabilitation Center,Havana, Cuba 2 Israel Rett Center, National Evaluation Team, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan 3 Zvi Quittman Residential Centers, Israel Elwyn, Jerusalem 4 Department of Physical Therapy, Ariel University Center, Samaria, Ariel, Israel

Abstract Individuals with Rett syndrome (RS) frequently present a constant ongoing need for therapeutic intervention. One of the therapeutic approaches suggested for this population is therapeutic horseback riding. Experience has shown that this type of intervention is extremely enjoyed by the individual with RS. The current article presents the possible benefits of applying Hippotherapy for individuals with developmental disabilities, the characteristics of RS compatible with this type of intervention and a case study describing the application of Hippotherapy for individuals with RS. It should be emphasized that the present article is not a research article, but rather a review of the literature on RS and therapeutic horseback riding, with a case study to illustrate the implementation of the theoretical background. The article presents clinical experience in these fields; therefore scientific generalization should be cautiously made. ∗

Correspondence: Meir Lotan, BPT, MScPT, Director, Therapeutic Department, Zvi Quittman Residential Center, Millie Shime Campus, Elwyn, POB 9011, IL-91090 Jerusalem. E-mail: [email protected]

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Keywords: Rett syndrome, hippotherapy, therapeutic horseback riding, equine assisted therapy.

Introduction Rett Syndrome (RS) is a complex neurological disorder resulting from a genetic fault in the X chromosome (1, 2), which occur mainly in females. It is considered to be the second most common cause, after Down syndrome, for multi-disabling disorder in females (3, 4). RS is characterized by reduced functional abilities, fine and gross motor skills, as well as verbal communicative abilities, along with the development of stereotypic hand movements, occurring after a period of apparently normal development. Individuals with RS often develop seizures, show disturbed breathing patterns with hyperventilation, along with periodic apnoea, scoliosis, growth retardation, apraxia and an ataxic gait pattern (5). The disorder affects all fields of daily function and throughout life. Due to the complex nature of RS, individuals showing this disorder are subjected to different intervention modes for long durations. In light of the vast array of intervention methods and approaches available today to the family with RS, a selection process based on knowledgeable decision making should be performed when deciding on an appropriate therapeutic intervention. One of the available therapeutic approaches for this population is therapeutic horseback riding which is enjoyed by 17.4% of individuals with RS in Australia (6). The present article presents therapeutic horseback riding (THR) as well as aspects of Rett syndrome, which may coincide with known benefits of THR.

Therapeutic Horseback Riding Animal Assisted Therapy (AAT) is a goal-directed intervention, in which an animal that meets specific criteria becomes an integral part of the treatment, which facilitates the healing process and rehabilitation of clients with acute or chronic disease (7). The use of horses in the realm of AAT is referred to as Therapeutic Horseback Riding (THR). Hippotherapy is a form of THR used by licensed health professionals to treat individuals who have impaired postural control and coordination (8). Therapeutic Horseback Riding is an alternative therapy for individuals with a variety of physical, emotional, cognitive, and social needs. Implementation of THR requires the proper positioning of the patient on the horse, after analyzing the patient’s response and by directing the horse’s movement accordingly, in order to achieve specific treatment goals. There is an array of different programs which utilize horses and horseback riding for therapeutic benefits. These interventional programs are also referred to as “Equine Assisted Therapy (EAT)” “Equine Facilitation Psychotherapy (EFP)” or “hippotherapy”.

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Terms Definition Therapeutic riding refers specifically to horseback riding lessons for people with special needs, in which the therapeutic benefits of riding are a result of acquiring riding skills. Because riding is such an enjoyable activity for so many people, therapeutic riding is also used as a quality-of-life-improving therapy for people with degenerative diseases, as well as a 'fun therapy' for individuals and adults alike. Therefore riding, like many other alternative therapies, may also be considered a form of recreational therapy. Other forms of equine assisted therapy include hippotherapy, in which a certified therapist uses the horse as a therapeutic tool and equine facilitated psychotherapy, in which a certified mental health professional utilizes the horse in various ways for therapeutic benefit. Hippotherapy is a therapeutic practice which uses the multidimensional movement of a horse to improve the neuromuscular function and sensory processing of the rider (9). Unlike other types of therapeutic riding (10), such as remedial educational vaulting, equine-assisted therapy, or recreational riding, Hippotherapy does not focus on improving riding skills, but rather on the achievement of specific therapeutic goals facilitated by the movement of the horse. Hippotherapy is a highly diverse, rapidly growing field. Although it is still termed as 'alternative, therapeutic intervention, horseback riding in general, and Hippotherapy specifically, has been recognized by many professionals as a very effective therapy for just about anyone (11).

Benefits Commonly Attributed to Hippotherapy According to the American Hippotherapy Association (12), conditions which can be modified or improved by Hippotherapy include: psychological (13), mental (issues related to arousal, motivation, and attention), physical (i.e. balance and posture, muscle tone and joints, spasticity reduction, movement coordination and mobility, motor planning) (14-18), social and cognitive skills (18-20), as well as sensorial (sensori-motor dysfunction) and communicational functioning (18). Individuals with RS are very different from one another, displaying a versatility of phenotypic expression. Therefore each and every one of them should be evaluated properly, along with having a specific intervention program individually tailored. Nevertheless, these individuals do show some commonalities which are suitable for intervention through the use of Hippotherapy. The achievement of such clinical aspects will be addressed theoretically, with proper case studies integrated into the text in the following section of the article. We believe that in order for the individual with RS to be therapeutically properly addressed and the intervention program skillfully delivered, the management program should take into account few aspects common to most individuals with RS. Therefore, the following section will present common aspects of individuals with RS and adjacent therapeutic possibilities by means of hippotherapy (the different characteristics of RS are lined up in alphabetical order).

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Attention Span Individuals with RS have short attention span (21), which may harm their ability to participate in, as well as gain from an educational interaction. In different populations, findings reveal that hippotherapy has contributed to the increasing of attention span and concentration (22-24). Such findings, if applied to individuals with RS, suggest possibilities for improved participation and educational achievement.

Balance, Posture, and Coordination When in motion, the individual with RS has to confront her unreliable sensory process, fear of movement, fluctuating muscle tone, on top of her poor muscular control, attributed to ataxia. The accumulation of such challenges inflicts severe functional limitations upon the individual with RS, therefore many of them will find it hard to handle tasks, such as ascending or descending staircases, walking on uneven terrains, running and more. Since hippotherapy has been found successful in improving the balance and posture in other populations (16, 25-27), it might show similar results for individuals with RS. As the horse moves, the rider is constantly thrown off-balance, and the task of the rider is to stay on the horse by controlling and coordinating postural response reacting to the motion of the horse (25). This exercise activates deep muscles not usually operated through conventional physical therapy. Because hippotherapy requires balance and good posture from all riders, students lacking good balance and posture will work on their balance issues from the very moment they mount. The three-dimensional rhythmical motion of the horse is very similar to the motion created in the human pelvis (25). When balance is set as a therapeutic goal, the instructor will often employ various exercises and riding styles which work on balance and posture in many different ways. Because hippotherapy can be adapted to each student's needs, exercises for balance are quite versatile. Exercises may begin simply by sitting on the horse; advance to walking and keeping balance while trotting. By selecting certain movements, speed, directions, gaits and physical characteristics of the horse, the skilled therapist can elicit versatile favorable responses (28). By placing the rider in different positions on the horse, different sets of muscles can be activated. Pausing and initiating movements of the horse, changing speeds and changing direction increase these benefits. When engaged in promoting advanced balance skills, the client can work on balance and posture through the use of exercises, such as grabbing rings while riding, riding with arms stretched out, riding with the eyes closed, riding backwards, etc. Challenging the rider enables him to improve his/her physical capabilities both on and off the horse. Improvement in balance and posture was found in two groups of individuals diagnosed with CP (cerebral palsy), due to hippotherapy (16, 25). Similar results were found by Biery and Kaufman (26) with a group of adolescents with intellectual disability.

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Body Scheme and Sensory Input Due to sensory imbalance of individuals with RS, it is presumed that their body scheme is awkward. This can be concluded from the Apraxia shown by many of the persons with RS and from their skewed midline (29, 30). Their fear of movement is probably caused by this same problem. Experiencing such sensory uncertainty on a continuous basis can lead to a sense of fear and insecurity. To reduce some of the anxiety accompanying the daily transfers of the individual with RS, it is recommended to apply intense proprioceptive input (deep pressure) to help the individual build up her sense of orientation (31,32). The movement of the horse is the key element in producing change in the rider (28). This type of movement is rhythmical, continuous, and is performed while the rider is actively stabilizing him/her self on the horse. Such an intervention program enables the therapist to change the client’s sensory perception causing her to change from activating “her entire upper body as one unit”, and achieve more isolated movements (28). Therefore, the sensory input received by the rider throughout the Hippotherapy session can organize her body scheme and help it mature, hopefully overflowing to other activities of daily living (ADL) of the individual with RS. In one session, the rider can be asked to both interpret sensory information she receives from the horse, instructor, or environment, and use this information in a fitting manner, according to her human, as well as animal companions. Lessons may focus on sensory information, such as various sensory intakes (i.e. motion, touch, smell, sound and sight).

Breathing Abnormalities Most individuals (84%) with RS present some form of breathing abnormality (33) such as apnea, hyperventilation, breath holding, and bloating. These incidents are apparent during waking hours alone (34). The underlying assumption is that the immature regulatory system supervising the breathing mechanism can supply the individual’s needs during sleep, while breathing irregularities are the outcome of the incapability of the system in coping with functional changes necessary during day-time activities (35). In a case study of an individual with RS included in a Hippotherapy program, the therapist observed that the individual “used the wrong muscles to breathe”. Changing the breathing pattern of the individual was set as one of the intervention goals, and during the sessions, the individual “was able to breathe normally while riding” (28).

Cognitive Function People with various cognitive and sensory disabilities can be treated with hippotherapy. Some such disorders include mental retardation, autism, brain damage, Down syndrome (36), developmental disorders such as RS, ADD/ADHD, dyslexia, learning disabilities etc. Due to fact that riding in general, along with hippotherapy, requires attention, reasoning skills and memory, hippotherapy enables the rider to build knowledge as time progresses. The instructor can gradually advance the rider from completing simple tasks, to acquiring

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complex skills which provide her with intellectual stimulation. Riding is a complex task, incorporating a huge amount of information in a small amount of time. It is believed that by cognitively challenging the individual with RS, advancements can also be made in this context.

Communication Skills Individuals with RS show the emotional and social need to communicate, but this need is coated by their disabilities (37), making their communicative acts difficult for the human environment to decipher. Nevertheless, when their motivation is high enough and the human surrounding attentive, the individual with RS is able to convey her needs and wants, thereby greatly improving her quality of life (38, 39). Hippotherapy has been found effective in improving the communication abilities (40, 41) and increasing verbal sounds (42), of other groups of clients. These abilities later transferred to the home environments (41). Therefore, it is possible to assume that this type of intervention will also yield positive results in the area of communication for individuals with RS.

Coordination and Motor Planning During THR, when involved in advanced riding, the control of the horse requires a lot of coordination in order to get the desired response. Since the horse provides instant feedback to every action by the rider, it is easy to know when you have given the correct cue. Repetition of patterned movements required in controlling a horse quickens the reflexes and aids in motor planning. Such a construct of repetitive actions with immediate response (feedback from the horse) is the ultimate interaction, perfectly compatible with the disparxic aspect of RS (32).

Emotional, Social and Psychological Aspects All Individuals with emotional, social and psychological disabilities may benefit from hippotherapy. This type of intervention is usually referred to as Equine Facilitated Psychotherapy (EFP), and is considered beneficial for a variety of mental and developmental issues including behavioural issues, attention deficit disorder, eating disorders, abuse issues, and depression (43). Relationships – Building a relationship with an animal can be very rewarding in many aspects; for a person with an emotional, social or psychological disability, the trust and loyalty an animal shows, illustrates to the rider how important these attributes are in personal relationships. Socialization - Horseback riding presents the rider with the opportunity to interact with others, as well as form meaningful relationships with the horse, not to mention with the instructor. Thus, through such interaction, socialization is stimulated (44).

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Empowerment and self-esteem - Horses may assist the rider to feel in control of the situation because a direct correlation exists between the rider’s action and the horse’s reaction. Self-esteem can be increased through acquiring new-found abilities which positively influence another being (44). In this way, the experience of riding a horse can empower the rider. Self-monitoring - Treatment of anxiety in particular is well-suited for Hippotherapy. Since individuals with RS are constantly in a state of an Under-active para-sympathetic system (45), they are continuously in a condition which entails a highly-strained being. The relaxed rhythmic movements of the horse, as well as the overall relaxed atmosphere of the ranch, may assist the individual with RS to relax and may even assist in self monitoring her internal autonomic system. These aspects of the riding experience are similar to other forms of animal assisted therapy and can generally improve the quality of life of the client (13). Since the individual with RS is seemingly developing normally at a young age, the reaction she experiences from the surrounding human environment is normal, thereby contributing to the development of a relatively mature emotional state (46). Therefore, one of the strongest attributes of these individuals is their emotional state. Due to the unsteady course of the Rett disorder, the individual experiences instability of her state, (expressed in constantly changing ill functioning of her body such as: repeated constipation, reduced ambulation, epilepsy and abnormal sleep patterns). This unstable situation may contribute to agitation, as well as other emotional episodes, often presented by individuals with RS. Since hippotherapy has been found to positively contribute to the emotional state of the riders (13,27), it may also contribute to the improvement of the emotional state of the individual with RS receiving hippotherapy.

Fear of Movement The fear of movement shown by individuals with RS has been described in the past (35) and may be caused by dysfunction of the vestibular system (47). As a consequence of this constant fear of movement, the individual becomes cautious, and the fluency of her everyday life is thereby interrupted. In her article, Graffman states that: “On her initial visit, Kara was completely unable to tolerate movement of the horse without being completely supported” (28). This description clearly presents the fear of movement common to many individuals with RS and yet, this situation was improved later on, in the progression of the sessions. It might be assumed that the repeated, controlled, and rhythmic movement of the horse, as well as the motivation of the individual with RS to continue and participate in hippotherapy, will allow her to get accustomed to external facilitation, and thereby reduce her fear of movement.

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Functional Improvement McGibbon and his associates (48) evaluated the effects of an eight-week program of hippotherapy on performance through the Gross Motor Function Measure (GMFM), energy expenditure during walking, and gait parameters in five individuals with spastic cerebral palsy. All five individuals demonstrated significant decrease in energy expenditure during walking and significant increase in the GMFM walk/run/jump subtest after Hippotherapy. Similar results were also found by other researchers (15,49-51). These improvements were found to maintain themselves seven weeks after the termination of the intervention program (14,49). In a case study of an individual with RS treated with hippotherapy, the author states an improvement in functional mobility on the floor of the client (28), thereby demonstrating that individuals with RS can gain functional improvements through Hippotherapy intervention.

Hand Use From about eight months up to four years of age, individuals with RS gradually loose most of their hand function (21). The assumption is that poor functional skills of individuals with RS are not derived from lack of ability rather from the combination of apraxia and lack of experience (52). Hence, despite hand functional loss, individuals with RS can and should be taught to acquire new hand skills (53). The use of adapted equipment, such as a saddle with hand grips, incorporated into the challenging mission of the rider to stay on the horse (25) may initiate long periods of hand gripping throughout the hippotherapy session. Another form of encouraging hand function is through positioning the rider on the moving horse when she is on all fours. To enhance the difficulty of such an exercise the use of reaching and purposefully grasping small stuffed animals could be introduced (28). Such training may hopefully carry over to other daily activities which require long periods of hand function, such as independent eating and drinking.

Muscles Tension and Joints Range of Motion The movement of the horse also requires good muscle tone and flexibility. The most obvious muscle regions which benefit from such exercise are the torso and buttocks as well the lower extremities. Muscles are strengthened by the increased usage of muscle action involved in riding. Even though riding is an exercise, it is perceived by the rider as enjoyable, and therefore the rider has an increased tolerance and motivation for long durations of exercise. Riding also effects smaller muscles and joints throughout the body since it is an activity which encourages participation of the entire body. Riders with low muscle tone and hyper flexible joint will work on strengthening and tightening the muscles. The therapeutic aim with riders showing high muscle tone is to work on relaxing the muscles through the rhythmic movements of the horse’s gait. The diverse gait pattern of the horse can be utilized

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to make the student aware of different muscle groups. The improvements in function can also be accomplished through the use of different positioning on the horse (for example, positioning a patient astride the horse facing sideways or backward helps improve balance and pelvis alignment. A prone position extends the trunk and neck, while lying supine stretches chest muscles and elicits a need to pull up into a sitting position). It is believed that as the rider learns different riding skills, muscle tone and flexibility are increasingly improved. The flexibility of Hippotherapy enables riders with very different needs to benefit from the same motion while learning similar skills.

Muscle Shortening Muscle shortening is common in individuals with RS with high muscle tone (54). Furthermore, individuals with RS who start with low muscle tone can gradually increase their muscle tone, therefore necessitating a change in intervention goals. Muscle shortening can be addressed by the applying hippotherapy. The warmth of the horse’s body, accompanied by the constant rhythmic movements of the horse, while maintaining an abducted position of the hips, can be suggested as a maintenance program against the shortening of the adductor muscles of the thigh.

Muscle Tone Spasticity is reduced by rhythmic motion (55), such as the motion of the horse. The warmth of the horse’s body may further contribute to relaxation, especially of the legs. Sitting astride a horse helps break up extensor spasms of the lower limbs. Holding the reins helps break flexor spasm patterns of the upper limbs. Many of the developmental vaulting positions enable breaking op pathological patterns or the reduction of spasticity. Fatigue also helps decrease spasticity by producing relaxation. Individuals with RS present abnormal muscle tone. Most individuals with RS change from very low muscle tone or even sever hypotonia, to high muscle tone (about 60%), including spasticity and/or rigidity (56). Such unbalanced muscle tone accompanying ataxia and apraxia will severely affect the individual posture and stability, thus severely harming her ability to function or self ambulate. These difficulties necessitate intensive therapy intervention. Since hippotherapy has been found in the past to reduce muscle tone in other population (16, 27), it is possible to speculate that similar beneficial results will be found for individuals with RS.

Osteoporosis/Osteopnia Osteoporosis occurs frequently in females with RS and has been reported in very young individuals. Patients with Rett syndrome have been found to have decreased bone mineral density compared to controls (57). The poor bony structure of theses individuals increases the

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risk of pathological fractures (58). It is expected that ambulatory individuals with RS will present better bone mineral density than non-ambulatory ones (59). These findings support the need for intensive locomotion programs for individuals with RS initiating at infancy and childhood. Due to the connection found between persons with osteoporosis and weak back musculature (60, 61), it is recommended that any activity program for osteoporosis prevention include back muscle exercise to enhance back strength. Since hippotherapy mainly exercises the torso, buttocks and lower extremities, it presents a unique opportunity for all individuals with RS (although especially for non-ambulatory ones) to practice active motion of their trunk. Another aspect of proper intervention in cases of osteoporosis is the use of proprioceptive dynamic posture training (PDPT) (62). Since the active motion of the horse is constantly producing dynamic postural changes, it is probable that Hippotherapy will yield positive results for the rider with RS in the area of bone mineral density, together with postural gains.

Postural Benefits The most obvious and the most immediately recognizable benefits of Hippotherapy are postural. Because riding is a physical activity, children and adults with special physical needs and various physical impairments can benefit from riding. Hippotherapy uses movement as a primary means of habilitation and was found to improve functional abilities of individuals with CP (15). Hippotherapy is assumed to benefit people with many different physical disabilities, such as muscular dystrophy, cerebral palsy, multiple sclerosis, amputation, paralysis, spina bifida, as well as anecdotal reports regarding similar outcomes for individuals with Rett syndrome (28, 63). Since the movement of the horse is the critical change-effecting factor in the rider (28) and since individuals with movement dysfunctions, such as individuals with RS, have limited experience in rhythmical movements and present postural abnormalities, such movements by the horse during hippotherapy constitute a driving force for change. The motion of the horse provides the client with an abundance of diverse practice conditions (25) which will hopefully influence the postural condition of the individual with RS.

Skeletal Deformities Over the years and with the progression of RS, some of the following skeletal problems might occur. •

Scoliosis – appears in 83% of individuals with RS while a deviation of the spine of at least 10 degrees may be detected in all other persons with RS (5)) An early diagnosis, followed by intense physical regime was found useful in regressing the spinal deformity in one person with RS (64), and such intervention may lead to prevention of surgery (65). Intense physical intervention is recommended in this situation by all experts in the field of RS (66-69). A pre-post investigation with a

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control group has revealed that hippotherapy brought on significant improvement in symmetry of muscle activity in muscle groups displaying asymmetry prior to hippotherapy in a group of children with developmental disabilities (70). It has also been reported that hippotherapy is beneficial for improving midline stability (40) and shows a positive effect on the quantity, as well as the quality of weight-bearing (71). It is hypothesized that the scoliosis presented by individuals with RS is caused in part by asymmetrical muscle activity (54), as well as by a skewed midline perception (29,30). Therefore, it is possible that riding a horse will enhance symmetrical muscle activity in the trunk muscles of individuals with RS, and moreover, that the use of asymmetrical positioning on the horse can cause opposite asymmetrical muscle activity of the trunk, thereby presenting a useful, yet enjoyable activity for the rider with RS diagnosed with asymmetrical postures and scoliosis. Hip instability - this orthopedic problem is not extremely common in ambulating individuals with RS, yet it tends to present itself more in non-ambulatory individuals (54). Hip instability and dislocation may be avoided through use of preventive measures, such as a daily standing program, manually keeping the joint in full range of motion, serial casting, and use of hydrotherapy to strengthen the muscle around the joint (72). The posture of the rider on the horse by itself is a preventive measure against hip dislocation, and since the rider is actively contracting her muscles around the hips and buttocks during the Hippotherapy session, she may prevent hip instability.

Stereotypical Hand Movements Manual mannerisms are apparent in all individuals diagnosed with RS and in actuality, constitute the trademark of this population. These movements are involuntary, do not include the use of objects (beside Angelman-type RS), and are not used for protection or as a response to a sensorial need (73). Voluntarily stopping the hand movement is usually very difficult for the individual with RS, although some can withdraw from those continuous movements for a short period on demand. It is speculated that the stereotypical movements are caused due to neuro/chemical imbalance in the Dopaminergic/Monoaminergic/Cholinergic systems (74,75). Despite the fact that in late stages of RS, the stereotypical movements subside, they can still be observed nonetheless (47). Reducing the stereotypical hand movements may be achieved through the use of adapted equipment, such as a saddle with hand grips, as well as through the use of challenging positioning (e.g. standing on all fours).

Hippotherapy for Individuals with Rett Syndrome Due to the specific characteristics of RS, the present section will address issues which should be taken into consideration when the trained hippotherapist initially meets the individual with RS.

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•

•

•

•

•

•

•

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The complex nature of RS necessitates that the experienced therapist at the ranch coordinate his/her therapeutic efforts with other members of the therapeutic team managing the individual with RS. The intervention itself is performed by a qualified instructor, although a thorough primary evaluation should be performed by a licensed physical, occupational or speech therapist. Such a primary evaluation enables the therapeutic team to set goals and select exercises, thereby meeting the specific needs of each client. The duration of the sessions should be adapted to the individual with RS, as it is possible that the individual will need a few shorter sessions to begin with (28), before getting used to being active for a whole 45-minute session. Safety equipment should always be included, incorporating equestrian helmets, Devonshire stirrups which are closed in the front in order to properly position feet and prevent them from sliding through, as well as the use of quick-release "peacock" stirrups which unhook if a rider falls. Due to the highly developed emotional state of individuals with RS (46), it is suggested that sessions be presented through creative exercises, keeping the interaction a fun experience. The complex nature of RS necessitates a multidisciplinary approach (76, 77). Hippotherapy sessions may be provided by a licensed therapists, physicians, clinical psychologists or students who volunteer at the ranch; nevertheless, they are all supervised by a qualified therapist. The epilepsy presented by individuals with RS (4,78) as well as the fluctuating muscle tone (56) are additional good reasons for an experienced handler to guide each horse, ready to aid the rider who loses her balance, or to assist in exercises and games. Due to lack of vocal communication by most individuals with RS, it is suggested that during the session the therapist/instructor constantly monitor the rider’s responses and instruct the handler to change the horse's direction and tempo accordingly, if found necessary. The paraprofessional team should keep careful progress evaluation on a regular basis and report regularly to family members, as well as to the referring physician. Due to the complex expression of RS and the many facets of its phenotypic expression, it is recommended that the Hippotherapy sessions incorporate more flexible therapeutic principles providing the individual with RS with versatile forms of intervention. Individuals with RS are famous for their functional and emotional fluctuations. During moments in an activity (yet sometimes even for hours or days) the individual with RS seems lost and disconnected “as if her mind is covered by a cloud" wrapped around her, separating her from the world (47). In some past cases, such a behavior was found to reduce the staff’s (caregivers and therapist alike) confidence in the individual’s abilities. This phenomenon is caused by numerous factors associated with this disorder (e.g. functional setbacks, irregular sleeping patterns, medication, etc.), and the therapist should have confidence in the fact that the individual will reconnect and return to her previous functional abilities.

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An Example The last part of this article present a case study of hippotherapy with an individual with RS, who received hippotherapy intervention at the Cuban National Riding Rehabilitation Center managed by the first author. Therefore, a short review of this center and its working procedures is presented.

The Cuban National Riding Rehabilitation Center The Cuban National Riding Rehabilitation Center has its facilities outside the city of Havana. It is conformed of four horses, specially trained for therapeutic riding. It also has six professional members: two psychopedagogists, one speech therapist, one physiotherapist and two riding trainers. In each therapy cycle, participate about 50 clients. These therapeutic cycles are determined by the proposed objectives for each patient, the therapeutic program, and the due dates for those objectives. Therapy organization is settled in the following way: autism, Down syndrome, and individuals with intellectual disability (ID) receive two sessions per week, and neurological originated syndrome, psychomotor retardation and Rett syndrome receive three times a week. The clients at the center receive a comprehensive program compiled with an assortment of games and educational, sport and art-related activities. Each session is usually 45 minutes in duration. In addition, the rehabilitation program suggested for individuals with RS at the Cuban National Riding Rehabilitation Center is a comprehensive supplementary program involving the primary caregivers (mostly parents), in their child’s treatment. The parents receive instructions to perform additional work with their children thus establishing a carry over of the achievements of the intervention program received at the center. Therapeutic sessions at the Cuban National Riding Rehabilitation Center are divided in three parts and evaluated by a standard instrument (see figure 1): •

•

•

First section: Waiting time/preparatory intervention. At this point, initial rapport with the individual is achieved, thereby enabling the therapist to evaluate the individual's mood and disposition during the daily activities. This initial contact can be established through music, water games, finger paint, puppets and other psychoeducational procedures. In case of individuals who present hyper tonicity, tone reduction intervention is introduced with the objective of relaxing the muscles and enhancing joint range of motion. Second section: Intermediate time. During this section of the intervention program, hippotherapy is presented in accordance with the individual program designed for each client. Third section: Riding time. This will permit the consolidation of the achievements reached in the previous sections. It is important that riding time not exceed 25 minutes, as to avoid muscular fatigue.

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WEEK 1

WEEK 2

WEEK 3

WEEK 4

WEEK 5

Approaching the horse Mounting the horse Balance Muscular tone Postural adjustments Interactions with the therapists Latency Interval between stimulus and response Eye contact with the therapists Intentional use of hands Communication attempts Enjoyment shown during the activity Figure 1. Semi subjective evaluation sheet used by the National Riding Rehabilitation Center. The chart follows the child development across his program and enables the evaluation of motor development; this chart was adapted and re-edited from a hippotherapy evaluation scale created by Isabel Salama.

Case Story In the case presented below the scale (figure 1) was used to evaluate initial state of each participant as well as to assess accomplishments and final results.

Clinical History Antecedents: wished pregnancy. GC was born through a normal delivery and normal birth weight. As an infant she had normal development for the duration of 15 months. She does not present/display epilepsy. Age at first signs: 15 month. Initial signs at RS: Some autistic behaviors are manifested by GC. These conducts were: the refrain from eye contact, social withdrawal, lack of motivation for, or interest in interactions with people or toys, loss of pre-acquired language, and appearance of stereotypical hand movements. During manual mannerisms her hands are kept at body middle line, her stereotypical movements include hand mouthing followed by thigh banging. Age at diagnosis of Rett syndrome: 2 years and 3 months. Genetic findings: GC was genetically diagnosed with RS (at the Genetic and

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Molecular Medicine Center, Pediatric Department of the University of Florence). She showed the MECP2 mutation at T158M site. A sleep laboratory examination was conducted during seven hours. The results showed epileptiform intercritic discharges of slow waves in the temporary left center, almost continuous during (Non-Rapid Eye Movements) NREM sleep and reduced during the REM sleep, as well as waking time. No medication is consumed. Physiotherapy initiated at the age of four years and still performed at present time. Age at initiation of therapeutic horse back riding intervention: six years of age. Observation: GC is a lovely girl; she enjoys contact with familiar people and differentiates between strangers and family. During her development, GC has never shown separation anxiety from her mother or relatives. She is usually in a good disposition, smiles when she feels fine, and enjoys activities mostly when she is surrounded by her peers. She enjoys water games, swinging on swings, walking around and when engaged in social happenings she shows socially accepted behavior. She has a special interest in music and dance, and when she dislikes a certain type of music, she shows it by crying. She responds to simple requests. She is able to vocalize some sounds mostly when she is upset, hungry or when the music stops, for example, she says "YA" when trying to express her dislike of something. GC is totally dependent in regards to ADL. During meal times, GC chews with good lip closure. She has no diaper control. On physical examination CG showed hypotonic muscle tone in the upper extremities and trunk and maintained distonic muscle tone in the lower extremities with a slight tendency towards spasticity. GC can independently walk, though she usually appears as aimlessly wondering. Her feet are inverted and supinated; therefore her weight bearing is performed on the lateral side of the feet. She sometimes walks with her eyes closed or facing the floor. She is not capable of overcoming obstacles, so mostly she tries to avoid them and therefore often trips. Due to poor protective reactions, GC may hurt herself when falling and therefore she is in need of constant monitoring when ambulating. When GC walks, she tends to recline her body backwards, nevertheless, she maintains her balance. GC is able to ascend and descend stairs with moderate assistance. When seated she shows a poor floppy posture. Transitions: GC is able to change from lying down to sitting (leaning through her left side without using her hands). From a sitting position on the floor, she needs assistance in order to achieve a standing position. At initiation of intervention, GC presented a minor left scoliosis of approximately 10 degrees. GC showed a short and fluctuating attention span. Therapeutic goals were to regulate muscular tone, to improve equilibrium reactions and to increase protective reactions. Intervention strategy: • • •

•

Looking for controlled "off balance" postures to provoke her reaction in order to achieve a correct positions on the horse. Changes of grazes of the passage with abrupt stops to activate proper equilibrium reactions. Work in fetal position to strengthen and stretch the lower back muscles, as well as work on the vestibular system, thereby enhancing balance and reducing spasticity. Work 10 minutes with back riding to achieve posture correction. Change between prone and supine positions to fortify truncal muscular strength

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Activities of weight transference to enhance activity and postural reactions. Manipulative and corrective exercises to reduce the development of scoliosis.

The results with GC were slow to emerge and could only be observed in the long run, a substantial part of her achievements wass due to the cooperation of her family with the training program. After six months of treatment we obtained better protective reactions, diminished falls to the ground, increased trunk muscular tone and achieving better posture in sitting, reduced stereotypical mannerism on the horse, due to hand usage for holding the reins during trot, increased functional hand use to grasp attractive objects while on the horse and reduced spasticity in lower limbs.

Conclusions The present article presented the use of THR (Therapeutic Horseback Riding) in general as well as hippotherapy specifically, as means for therapeutic intervention for individuals with RS. It is reiterated that this is not a research article but rather a review based on clinical experience in the realms of Rett syndrome and therapeutic horseback riding, therefore, scientific generalization is limited. Nevertheless, accumulating evidence suggests that hippotherapy is gradually shifting from being of the “non-traditional” therapeutic approaches to being a part of mainstream therapeutic intervention presented for individuals with developmental disabilities such as individuals with RS. Scientific evidence, as well as the authors’ experience imply that hippotherapy is a beneficial intervention for individuals with RS and may suggest physical, sensorial, and emotional as well as in social improvements, when applied in an organized goal oriented therapeutic intervention, thereby positively affecting the individual’s and family’s quality of life. The items evaluated reflect a significant improvement for the person in our case story, as well as for others with RS in the motor development of these individuals, postural improvements, gait, the ability to overcome obstacles, reduction of scoliotic curve, and reduction of challenging behaviors. We are satisfied with the results achieved within one year of intervention. For this one case study and for others with RS, who have been treated in our facility. These achievements would not have been possible without the help of the families, who received training in the handling of their child with RS and were directed by the therapy team on performing a home supplementary program.

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(39) Sigafoos J. Communication development and aberrant behavior in children with developmental disabilities. Educ. Training Ment. Retard Dev Dis 2000;35(2):168-76. (40) Sigafoos J, Woodyatt G, Keen D, Tait K, Tucker M, Roberts-Pennell D, Pittendreigh N. Identifying potential communicative acts in children with developmental and physical disabilities. Communication Disord Quart 2000;21(2):77-86. (41) Engel BT. The horse as a modality for occupational therapy. Occup Ther Health Care 1984;1:41-7. (42) Glazer HD, Clark MD, Stein DS. The impact of hippotherapy on grieving children. J Hospice Palliat Nurs 2004;6:171-5. (43) Lehrman J, Ross DB. Therapeutic riding for a student with multiple disabilities and visual impairment: A case study. J Visual Impair Blindness 2001;95:108. (44) Katcher AH, Wilkins GG. Animal-assisted therapy in the treatment of disruptive behavior disorder in children. In: Lundberg A, ed. The environment and mental health: A guide for clinicians. Mahwah, NJ: Laweence Erlbaum, 1998:193-204. (45) Taylor SM. Equine Facilitated Psychotherapy: An Emerging Field. A major paper submitted to the faculty of the program in Clinical Psychology of Saint Michael's College in partial fulfillment of the requirements for the degree of Master of Arts. Winooski Park Colchester: Vermont, December, 2001. (46) Engerstrom IW, Kerr A. Workshop on autonomic function in Rett Syndrome, Swedish Rett center, Frösön, Sweden. Brain Dev 1998;20:323-6. (47) Elefant C. Emotional/musical communication of children with RS. A lecture at an annual conference on RS. Ramat Gan, IL: Chaim Sheba Med Center, July 2005. (48) Lindberg B. Understanding Rett syndrome: A practical guide for parents, teachers and therapists. Toronto: Hognefe Huber, 1991. (49) McGibbon NH, Andrade CK, Widener G, Cintas HL. Effect of an equine-movement therapy program on gait, energy expenditure, and motor function in children with spastic cerebral palsy. Dev Med Child Neurol 1998;40(11):754-62. (50) Casady RL, Nichols-Larsen DS. The effect of hippotherapy on ten children with cerebral palsy. Pediatric Phys Ther 2004;16(3):165-72. (51) Would J. Improved gait in two children with cerebral palsy after hippotherapy: Two case reports. Sci Educ J Therapeut Riding 1998;51-58. (52) Would J. Improvements in walking and functional ability in children with cerebral palsy following hippotherapy: Research results. Int. Symposium, Amiens, France: University Picardie, August 2002. (53) Jacobsen K, Viken A, Von Tetchner S. Rett syndrome and aging: A case study. Disabil Rehabil 2001;23(3/4):160-6. (54) Piazza CC, Nederson C, Fisher W. Teaching self-feeding skills to patients with Rett Syndrome. Dev Med Child Neurol 1993;35:991-6. (55) Sponseller P. Orthopedic update in Rett syndrome. Rett Gazette 2001, spring:1,4-5. (56) Schalow G. Non-drug induced spasticity reduction achieved by coordination dynamic therapy in CNS injury. Electromyogr Clin Neurophysiol 2002;42(5):281-93. (57) Kerr AM. The future for Rett Syndrome girls. Int Rett Syndr Assoc Newsletter1992:134.

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(58) Haas RH, Dixon SD, Sartoris DJ, Hennessy MJ. Osteopenia in Rett syndrome. J Pediatr 1997;131(5):771-4. (59) Budden SS, Gunness ME Bone histomorphometry in three females with Rett syndrome. Brain Dev 2001;23(Suppl 1):S133-7. (60) Cepollaro C, Gonnelli S, Bruni D, Pacini S, Martini S, Franci MB, Gennari L, Rossi S, Hayek G, Zappella M, Gennari C. Dual X-ray absorptiometry and bone ultrasonography in patients with Rett syndrome. Calcif Tissue Int 2001;69:259–62. (61) Sinaki M, Khosla S, Limburg PJ, Rogers JW, Murtaugh PA 1993 Muscle strength in osteoporotic versus normal women. Osteoporos Int 1993;3:8-12. (62) Sinaki M, Itoi E, Wahner HW, Wollan P, Gelzcer R, Mullan BP, Collins DA, Hodgson SF Stronger back muscles reduce the incidence of vertebral fractures: A prospective 10 year follow-up of postmenopausal women. Bone 2002;30:836-41. (63) Sinaki M, Lynn SG. Reducing the risk of falls through proprioceptive dynamic posture training in osteoporotic women with kyphotic posturing: A randomized pilot study. Am J Phys Med Rehabil 2002;81:241-6. (64) Maciques R. Hippotherapy: A rehabilitating therapy for the Rett syndrome. A case study. Newsletter, UK Rett Assoc, 2004. (65) Lotan, M. Merrick J, Carmeli E. Scoliosis management in Rett syndrome. A case study. ScientificWorld Journal 2005;5:264-73. (66) Budden SS. Management of Rett syndrome: A ten-year experience. Neuropediatrics 1995;26(2):75-7. (67) Lotan M, Elefant C. Physiotherapy and music therapy for a girl with Rett syndrome. A dual treatment approach. Fysioterapeuten 2006;2: 15-20. (Danish). (68) Weeks L. Rett Syndrome. A lecture given at Sydney Australia, February, 1997. (69) Rossin L. Effectiveness of therapeutic and surgical intervention in the treatment of scoliosis in Rett syndrome. A seminar work, University of Duquesne, 1997:1-19. (70) McClure MK, Battaglia C, McClure RJ. The relationship of cumulative motor asymmetries to scoliosis in Rett Syndrome. Am J Occup Ther 1998;52:196-204. (71) Benda W, McGibbon NH, Grant KL. Improvements in muscle symmetry in children with cerebral palsy after equine-assisted therapy (hippotherapy). J Altern Complement Med 2003;9(6):817-25. (72) Bertoti DB. Effect of therapeutic horseback riding on extremity weight bearing in a child with hemiplegic cerebral palsy: A case report as an example of clinical research. Pediatr Phys Ther 1991;3:219-24. (73) Lotan M, Hadar-Frumer M. Hydrotherapy for individuals with Rett syndrome. A guidebook for hydrotherapists. Raanana, IL: Beit Issie Shapiro Publ, 2002. (Hebrew). (74) Lotan M, Roth D. The effect of hand vibrators on the hand stereotypes and function in Rett syndrome. Two case studies. Isr Physiother Quart 1996;52:23-6. (Hebrew) (75) Nomura Y, Segawa M. Motor symptoms of the Rett syndrome: abnormal muscle tone, posture, locomotion and stereotyped movement. Brain Dev 1992;14(Suppl): S21-8. (76) Matsuishi T, Yamashita Y, Kusaga A. Neurobiology and neurochemistry of Rett syndrome. Brain Dev 2001;23(Suppl 1):S58-61.

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(77) Cass H, Reilly S, Owen L, Wisbeach A, Weekes L, Slonims V, Wigram T, Charman T. Findings from a multidisciplinary clinical case series of females with Rett syndrome. Dev Med Child Neurol 2003;45(5):325-37. (78) Lotan M, Manor-Binyamini I, Elefant C, Wine J, Saraf E, Yoshei T. The Israeli Rett Syndrome Center. Evaluation and transdisciplinary play-based assessment. ScientificWorldJournal 2006;6:1302–13. (79) Nieto MA, Candau RS, Prieto P. Contribution to studies of seizures in Rett Syndrome analysis of critical forms of four cases. Rev Neurol 1995;23:1185-9.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter V

A Community in Transition: Incidence and Characterization of Injuries among Israeli Bedouin Children Presenting to the Primary Care Clinic Elissa Lane Freedman∗1, Zaid Afawi2, Joav Merrick3,4 and Mohammed Morad3,5 1

Department of Medicine, Maryland General Hospital, Baltimore MD, USA 2 Department of Neurology, Tel Aviv-Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 3 National Institute of Child Health and Human Development 4 Office of the Medical Director, Division for Mental Retardation, Ministry of Social Affairs, Jerusalem, Israel 5 Department of Family Medicine, Faculty of Health Sciences, Ben Gurion University of the Negev, Israel

Abstract Objectives: To review the incidence and character of minor trauma that presented to family practice clinic and associated demographic variables. Design: A retrospective data analysis was conducted using data collected from the CLICKS computerized medical records of primary care consultations at The Clalit Health System’s Shatal Clinic in Beer Sheva, Israel. A systematic sample of every tenth child was taken from the alphabetical listing of all Bedouin children between the ages of zero and fourteen, registered at the ∗

Correspondence: Elissa Newsome Freedman, MD, 6320 Greenspring Ave, Apt 405, Baltimore, MD 21209 United States. E-mail: [email protected]

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Elissa Lane Freedman, Zaid Afawi, Joav Merrick et al. clinic (n=156). Results: Of the 156 children sampled, 67 (42.9) had at least one injury and 31 (20.4) children had more than one childhood injury recorded in their medical record. Boys had a higher incidence of two or more childhood injuries compared to female children (23/80 (28.8) vs. 8/72 (11.1), p = .007). Girls had proportionally more injuries in early childhood with mean age at first injury 1.4 years younger for girls (4.0 ± 2.8 vs 5.4 ± 2.5, p=.035). Children of older parents in smaller families had more accidents. No significant association was found between family size or birth order and injury. Conclusions: Unintentional injuries have a huge morbidity and significant mortality world wide. The populations most vulnerable to the burden of injuries are found in the less developed societies. Current research has targeted at western society and the proven strategies for prevention inappropriate for the mechanisms of injury that are specific to the Bedouin culture. Further research is necessary to identify demographic characteristics and behaviors that are correlated with injury in Bedouin children. Chart review was not adequate for the study of demographic and SES factors affecting injury.

Keywords: Injury, childhood injury, injury prevention, family medicine, Bedouin, Israel.

Introduction Unintentional injuries are a leading cause of death in children between the ages of 1-14 years, observed worldwide in developed nations (1,2), however, mortality is only the tip of the iceberg (3). Emergency room visits are 233 times more common than injury related deaths (1). Numerous studies have shown that children from lower socioeconomic and minority backgrounds are at higher risk for unintentional injuries and their sequela (3). A Canadian study by Joffe et al (1) showed that 77% of all unintentional injuries admitted to the Pediatric Intensive Care Unit were potentially preventable, meaning that they resulted from a mechanism of injury, where a proven strategy could have significantly reduced injury. In 1983, the American Academy of Pediatrics introduced the Injury Prevention Program (TIPP), which outlined age appropriate safety awareness assessment and counseling with the goal of increasing parental safety practices. While these measures have been proven effective in dozens of studies in the US and Canada, they are culturally inappropriate for the dangers that threaten children in lesser developed societies. It is well documented that communities in transition are at greater risk for all sorts of morbidities. Wirsing (4) wrote that “traditional societies have long-lasting and stable relationships with their surroundings… As soon as such societies have extensive and continuous contact with industrialized societies…their adaptation is disrupted and their health jeopardized.” Across the Arab world, from the Atlantic to the Iberian Peninsula, the Bedouin - literally meaning "desert dweller" in Arabic - have lived as nomadic tribes since at least the fifth century CE. Over the past 50 years, these tribes have seen their world transformed as modernity engulfed even the world's most isolated communities. In the Southern region of Israel, in the Negev desert, a community that was nearly 45,000 people at the turn of the 20th century shrunk to 12,000 in 1948 after the Israeli War of Independence, which led many to seek shelter in neighboring countries. Today, the Bedouin population has grown to well over 100,000 and exists as a sizable cultural and religious

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minority among the Negev’s largely Jewish population (5). Their health needs have been largely overlooked in the planning of health care delivery by the state as a whole. However, they have drawn interest from the local academic community as they represent a unique opportunity to study a lesser developed community on a course toward modernity. The transition from nomadic life to permanent concrete housing exposes the families to new and unfamiliar dangers. In addition, Bedouin children still are exposed to familiar dangers of the traditional lifestyle such as burns. Bedouin are a cultural minority within the Arab population of Israel but still little research exists that specifically targets Bedouin. There is very limited data in the primary care setting to describe the kinds of injuries that Bedouin children experience and none to date that has considered socioeconomic and other demographic data as risk factors for injury among this population. More research on injuries has been done in the setting of the emergency department and while this yields a good review of the more serious injuries incurred, the iceberg metaphor applies here as well. A large scale retrospective study by Gofin et al (3) examined the nation wide differences between Arab and Jewish children presenting to the Emergency Department (ED) for unintentional injuries. Although Jewish children presented to the ED 1.5 times more often than Arab children, Arab children had an OR for hospitalization of 1.15, when compared to Jewish children. Arab children also had a mortality rate that was 3.2 times higher. It seems that there are numerous minor injuries that are treated in the primary care setting for every injury that requires an ED visit. Additionally, while treatment of many injuries occurs in the ED, the best opportunity for prevention strategy development and implementation lies in the primary care setting. The goals of this study were to estimate the incidence and characterize the injuries in the pediatric Bedouin population that presented to a Beer Sheva area family practice clinic. Family demographic data was examined to attempt to identify characteristics that may be associated with higher incidence of injury.

Methods Israel has six districts divided into 15 sub-districts. The Southern district is divided into two sub-districts, Beer Sheva and Ashkelon. The Beer Sheva sub-district encompasses 12,945 km2 and extends from the southern border of the West Bank (Judea and Samaria) to the tip of Eilat. The Beer Sheva sub-district geographically encompasses 58.5% of the State of Israel, but includes less than 10% of the population. The population of the Beer Sheva subdistrict, according to a 2005 Central Bureau of Statistics report was 550,200. There are seven municipalities in the Beer Sheva sub-district, 11 local authorities and eight regional authorities, five of which are Bedouin. The exact size of the Bedouin population is difficult to calculate because nearly 60% of the population is believed to live in unrecognized settlements. Various 2002 and 2003 Israeli government publications estimated the Bedouin population to be somewhere between 130,000-150,000 residents (6). Thus, the Bedouin population is about 30% of the general population.

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Elissa Lane Freedman, Zaid Afawi, Joav Merrick et al.

Assumptions about Possible Risk Groups In Israel, 17.0 percent of the families are “large families” with four or more children. However, among the Bedouin municipalities and regional authorities including Rahat, Tel Sheva, Segev Shalom, Arara BaNegev, Laqia, and Hura, the percent approaches and in some cases exceeds 60.0 percent (7). Given that a number of studies both in Israel and abroad have shown that parental supervision influences injury rates, perhaps children from larger families would have less supervision and therefore more injuries. It is believed and estimated that 20 percent of Bedouin marriages are polygamous, however, since polygamy is not legal in Israel, it is very difficult to determine exactly which marriages are polygamous. In some cases, the husband will undergo a perfunctory divorce with the first wife in order to add the second. Several North American studies have shown that single parent families have higher rates of injury. Perhaps Bedouin polygamous families, where the husband may be inconsistently present, also have these correlations with non-twoparent families leading to more injuries among the children. In Israel, all citizens are guaranteed health care in accordance with the 1995 Health Insurance Law. Provision of service is delegated by the government to four health funds. In the Beer Sheva sub-district, 68% of the general population belongs to the Clalit Health Fund. In Bedouin areas of the sub-district, the membership in Clalit approaches 90 percent (except in Arad where it is only 37 percent) (8). The Shatal Clinic is one of the primary care clinics that provide services as part of the Clalit Health Services in the area surrounding Beer Sheva, Israel. The population of this clinic is unique in that the clinic is located in the center of the city of Beer Sheva, but the majority of the registered patients are Bedouin that come from the surrounding unrecognized settlements. In February 2007, among the population under the age of 14, there were approximately 1,700 children registered to the clinic, 1,565 of whom were Bedouin.

Data Analysis A retrospective data analysis was conducted using data collected from the CLICKS computerized medical records of primary care consultations at the Clalit Health Fund Shatal Clinic in Beer Sheva, Israel. A systematic sample of every tenth child was taken from the alphabetical listing of all Bedouin children between the ages of 0-14 years, registered at the Shatal Clinic. The medical and demographic records for all selected children were then retrieved from the database and individually reviewed. For each of the selected cases, the medical chart was retrieved and the description of all prior injuries entered in its entirety to Excel worksheet. Demographic data including the date of birth, parents’ and siblings’ dates of birth, and birth order were retrieved from the administrative database. The data was later recoded for analysis with SPSS 14 software.

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Results The mean age of all children sampled was 8.2 ± 2.1 years on February 1st, 2007. Male children represented 83 (53.2%) of the sample. The mean age of the mothers at the delivery of the oldest sibling was 23.4 ± 4.4 years. On February 1st, 2007 the mean age of the mothers was 36.5 ± 6.9 years. The mean age of the fathers at the birth of the oldest sibling was 26.2 ± 7.1 years. On February 1st, 2007 the mean age of the fathers was 39.3 ± 8.4 years. For 53 (34.0%) children from the sample, no ID data was available for the father. Large families predominated in the sample with 102 (68.2%) families having more than four children and 45 (30.4%) families having eight or more children. The mean difference in age between the oldest sibling and the index child was 4.6 ± 3.8 years. The average difference in age between siblings was calculated by dividing the age difference between the oldest sibling and the index child by the birth order of the index child. In this sample the mean was 1.1 ± .68. years (see table 1). Of the 156 children sampled, 67 (42.9%) had at least one injury recorded in their clinic record. Other than older age of child and mother, no variables were found significant for having one injury recorded. (see table 2). Overall, 31 (20.4%) children had more than one childhood injury recorded in their medical record. The maximum number of childhood injuries in the sample was five. Interestingly, the age of the mother at the birth of her first child was greater in the children who have two or more injuries (25.8 ± 5.1 vs. 22.8 ± 4.1, p < .01). There was no statistically significant difference noted for two or more injuries based on father’s age, family size, birth order, or age difference between index case and oldest child (see table 3). Table 1. Demographics of all children by injury

<.01 .011 .3 8 6 6

NO INJURY Mean ± n SD 7.3 ± 4.3 88 35.3 ± 7.0 80 23.1 ± 4.1 80 28.2 ± 5.9 80 38.8 ± 9.4 54 26.6 ± 7.3 54

YES INJURY Mean ± n SD 9.6 ± 3.3 67 38.2 ± 6.3 61 23.9 ± 4.9 61 28.4 ± 6.1 61 39.8 ± 7.1 48 25.8 ± 5.9 48

TOTAL Mean ± SD 8.2 ± 4.1 36.5 ± 6.9 23.4 ± 4.4 28.2 ± 5.9 39.3 ± 8.4 26.2 ± 6.7

155 141 141 141 102 102

4

31.2 ± 8.7

54

30.1 ± 6.3

48

30.7 ± 7.7

102

7 1.0

4.7 ± 3.9 3.6 ± 1.9

88 83

4.5 ± 3.6 3.6 ± 2.2

65 64

4.6 ± 3.8 3.7 ± 2.0

153 147

.3

5.8 ± 2.3

83

6.2 ± 2.3

64

5.9 ± 2.3

147

6

1.2 ± .74

83

1.1 ± .61

64

1.1 ± .68

148

P

n

Age on February 1st, 2007 Mother’s age on February 1st, 2007 Mother's age at birth of first child Mother’s age at birth of index case Father’s age on February 1st, 2007 Father's age at birth of first child Father’s age at birth of index case Age difference between index and oldest Birth order of index child Number of children in the family Avg difference in age between siblings

Elissa Lane Freedman, Zaid Afawi, Joav Merrick et al.

74

Table 2. Characteristics of all children by injury history P .1 .2 .3 .9

.5

.001

NO INJURY N (%) 42 (51.2) 46 (63.0) 29 (64.4) 53 (54.1) 14 (66.7) 74 (55.2) 25 (55.6)

YES INJURY n (%) 40 (48.8) 27 (37.0) 16 (35.6) 45 (45.9) 7 (33.3) 60 (44.8) 20 (44.4)

TOTAL 83 (53.2) 73 (47.1) 45 (31.5) 98 (68.5) 21 134 45

58 (56.9)

44 (43.1)

102

28 (60.9)

18 (39.1)

46

55 (54.5)

46 (45.5)

101

23 (88.5) 18 (58.1) 21 (56.8) 26 (42.6) 88 (56.8)

3 (11.5) 13 (41.9) 16 (43.2) 35 (57.4) 67 (43.2)

26 31 37 61 155 (99)

Males Females Father not listed Father listed Oldest child Not oldest child Families that have 8 or more children Families that have less than 8 children Families that have more than 4 children Families that have 4 or fewer children Children age 0-3 Children age 4-6 Children age 7-10 Children age 11-14 Total

Table 3. Demographics of children with multiple injuries 1 or 0 Injuries P .003

Mean ± SD 7.8 ± 4.2

.001

22.8 ± 4.1

.070

27.8 ± 5.7

.001

35.5 ± 6.4

.7

26.9 ± 7.3

.3

31.0 ± 7.7

.7

39.3 ± 8.1

.2

6.1 ± 2.3

.3

4.8 ± 3.8

.2

3.8 ± 2.0

n

More than 1 Injury Mean ± n SD 10.2 ± 2.9 31

TOTAL

25.8 ± 5.1

29

30.0 ± 6.4

29

40.2 ± 6.8

29

26.2 ± 6.6

21

30.5 ± 7.9

21

40.1 ± 9.2

21

115 119

5.5 ± 2.3

30

Mean ± SD 8.2 ± 4.1 23.4 ± 4.4 28.2 ± 5.9 36.5 ± 6.9 26.2 ± 6.7 30.7 ± 7.7 39.3 ± 8.4 5.9 ± 2.3

4.0 ± 3.5

31

4.6 ± 3.8

151

115

3.3 ± 2.0

30

3.7 ± 2.0

155

121 110 110 110 78 78 78

n 152

Age on February 1st, 2007

139

Mother's age at birth of first child

139

Mother’s age at birth of index case

139

Mother’s age on February 1st, 2007

102

Father’s age at birth of first child

102

Father’s age at birth of index case

99

Father’s age on February 1st, 2007

155

Number of children in the family Age difference between index and oldest Birth order of index child

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Male children had a higher incidence of two or more childhood injuries as compared to female children (23/80 (28.8%) vs. 8/72 (11.1%), p = .007) (see table 4). They were, however, older on average than females at age of first recorded injury (5.4 ± 2.5 vs. 4.0 ± 2.8, p < .05) (see table 5). Though of borderline statistical significance, girls had a higher incidence of injury by age 6 compared to boys (9/16 (56.3) vs. 4/15 (26.7), p.095). In the oldest age group, boys age 11-14 years were more likely to have an injury and more likely to have more than 1 injury (see table 6-7). Overall, 31 (20.4%) children had more than one childhood injury recorded in their medical record. The maximum number of childhood injuries in the sample was five. Interestingly, the age of the mother at the birth of her first child was greater in the children who have two or more injuries (25.8 ± 5.1 vs. 22.8 ± 4.1, p < .01). There was no statistically significant difference noted for two or more injuries based on father’s age, family size, birth order, or age difference between index case and oldest child (see table 3). Male children had a higher incidence of two or more childhood injuries as compared to female children (23/80 (28.8%) vs. 8/72 (11.1%), p = .007) (see table 4). They were, however, older on average than females at age of first recorded injury (5.4 ± 2.5 vs. 4.0 ± 2.8, p < .05) (see table 5). Though of borderline statistical significance, girls had a higher incidence of injury by age 6 compared to boys (9/16 (56.3) vs. 4/15 (26.7), p.095). In the oldest age group, boys age 11-14 years were more likely to have an injury and more likely to have more than 1 injury (see table 6-7). Table 4. Characteristics of children with multiple injuries P .007 .8 .5 .3

.2

.016

More than 1 Injury n (%) 23 (28.8) 8 (11.1) 20 (21.1) 9 (19.6) 3 (15.0) 28 (21.2) 7 (15.9)

1 or 0 Injuries n (%) 57 (71.3) 64 (88.9) 75 (78.9) 37 (80.4) 17 (85.0) 104 (78.8) 37 (84.1)

80 72 95 46 20 132 45

23 (22.8)

78 (77.2)

102

12 (26.7)

33 (73.3)

45

18 (18.0)

82 (82.0)

100

1 (4.0) 3 (9.4) 10 (28.6) 17 (28.3) 31 (20.4)

24 (96.0) 29 (90.6) 25 (71.4) 43 (71.7) 121 (79.6)

25 32 35 60 152 (100)

TOTAL Males Females Father listed Father not listed Oldest child Not the oldest child Families that have 8 or more children Families that have fewer than 8 children Families that have 4 or fewer children Families that have more than 4 children Children age 0-3 Children age 4-6 Children age 7-10 Children age 11-14 Total

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76

Table 5. Injury history by gender P

Girls

Boys

Mean ± SD

N

Mean ± SD

n

.038

.56 ± 0.9

73

.92 ± 1.2

83

.035

4.0 ± 2.8

27

5.4 ± 2.5

36

Number of injuries in lifetime Age at 1st injury

Table 6. History of at least one injury by gender Cumulative, p

p

.7 .095 .052 .5 <.001

Girls No yes 13 2 (86.7) (13.3) 7 9 (43.8) (56.3) 8 8 (50.0) (50.0) 18 8 (69.2) (30.8)

n

p

15 16 <.001 16 26

No 10 (90.9) 11 (73.3) 13 (61.9)

Boys yes

8 (22.9)

1 (9.1) 4 (26.7) 8 (38.1) 27 (77.1)

N 11

Children age 0-3

15

Children age 4-6

21

Children age 7-10

35

Children age 1114

Table 7. History of two or more injuries by gender Cumulative, p

Girls p

.4. .5 036 .7 <.001

No 14 (93.3) 15 (93.8) 11 (68.8) 24 (96.0)

yes

N

1 (6.7)

15

1 (6.3)

16

p

.011

5 (31.3)

16

1 (4.0)

25

No 10 (100) 14 (87.5) 14 (73.7) 19 (54.3)

Boys yes

N

0

10

Children age 0-3

2 (12.5)

16

Children age 4-6

5 (26.3)

19

Children age 7-10

16 (45.7)

35

Children age 11-14

When examining the demographic data of small Bedouin families (four or fewer children) as compared to larger Bedouin families, the children in the smaller families were first injured over a year earlier than their counterparts in the large families (3.9 ± 2.1 vs. 5.2 ± 2.8, p=.05). Despite the younger age at injury, the number of injuries in children from the smaller families was not significantly different (0.89 ± 1.4 vs. 0.70 ± 0.91, p = .32) (see table 8). When we compare mothers of small families, those whose children had one or fewer injuries were a mean age of 24.3 ± 5.0 at the birth of their first child as compared with mothers whose child had 2 or more injuries (28.1 ± 6.5). When children are selected for a positive history of injury, children from small families reported more injuries than children from larger families (2.2 ± 1.4 vs. 1.5 ± .75, p < .01). They were also younger at age of first injury (3.9 ± 2.1 vs. 5.2 ± 2.9, p = .05) (see table 8).

Table 8. Demographics of all children by family size HISTORY OF 1 OR FEWER INJURIES

P

5 or more children Mean ± SD

HISTORY OF 2 OR MORE INJURIES

4 or less children p

n

Mean ± SD

n

5 or more children Mean ± SD

ALL CHILDREN

4 or less children P

n

Mean ± SD

n

5 or more children Mean ± SD

4 or less children n

Mean ± SD

n

<.001

8.8 ± 3.8

82

5.3 ± 4.2

33

.3

10.5 ± 2.6

18

9.4 ± 3.3

12

< .01

9.1 ± 3.7

101

6.3 ± 4.3

47

Age on February 1st, 2007

<.001

36.9 ± 4.9

78

32.2 ± 8.3

32

.8

40.0 ± 4.9

18

40.6 ± 9.3

11

< .01

37.6 ± 5.0

97

34.1 ± 9.3

45

Mother’s age on February 1st, 2007

.017

22.2 ± 3.6

78

24.3 ± 5.0

32

.053*

24.3 ± 3.5

18

28.1 ± 6.5

11

< .01

22.6 ± 3.6

97

25.1 ± 5.5

45

Mother's age at birth of oldest sibling

.3

28.2 ± 5.7

78

26.8 ± 6.0

32

.5

29.4 ± 6.0

18

31.0 ± 7.2

11

.5

28.4 ± 5.7

97

27.7 ± 6.5

45

Mother’s age at birth of index case

.039

40.4 ± 6.1

59

35.9 ± 12.2

19

.7

39.4 ± 7.3

11

40.9 ± 11.2

10

.086

40.2 ± 6.2

71

37.1 ± 11.8

31

Father’s age on February 1st, 2007

.18

25.3 ± 6.2

60

27.8 ± 9.6

19

.1

24.4 ± 6.2

11

29.6 ± 7.7

10

.048

25.1 ± 6.1

72

28.1 ± 8.7

31

Father’s age at birth of oldest sibling

<.001

5.9 ± 3.9

82

2.6 ± 2.2

33

.038

5.1 ± 3.9

18

2.7 ± 2.2

12

< .01

5.8 ± 3.9

101

2.6 ± 2.2

47

Age difference: index and oldest

<.001

4.4 ± 2.1

82

2.2 ± 1.0

33

.022*

3.9 ± 2.3

18

2.3 ± .9

12

< .01

4.3 ± 2.1

101

2.2 ± .95

47

Birth order of index child

.14

.35 ± 0.48

82

.21 ± 0.41

33

.081*

2.3 ± .6

18

2.9 ± 1.2

12

.3

.70 ± .91

101

.89 ± 1.4

47

Number of Injuries in lifetime

.063

10.5 ± 3.2

17

8.1 ± 2.8

9

Age oldest sibling at index’s injury 1

.5

5.3 ± 2.8

18

4.5 ± 2.1

10

Age at first injury

Elissa Lane Freedman, Zaid Afawi, Joav Merrick et al.

78

Younger children had burns more commonly than other age groups (mean age 3.8 ± 3.5 years). Falls resulting in lacerations, contusions and fractures were seen as children got older (7.2 ± 3.0). Children with burns, with one exception, were all under the age of five and 13 of the 18 burns reviewed involved injuries to the extremities. There was no indication in the charts, in nearly all cases, if the burns were from fire or scald. One child had an electrical burn. There were relatively few fractures reported - 4 from over 100 injury reports reviewed. There were 7 children who had injuries from stepping on either broken glass or a nail. Additionally, one child had a raisin lodged in his nose for over a month and another child had contusions after falling from a donkey (see table 9-11). Table 9. Type of injury Age

Injury #5

Injury #4

Injury #3

Injury #2

Injury #1

5.8 ± 3.0

1 (0.6)

4 (2.6)

11 (7.1)

29 (18.6)

67 (42.9)

Total Type of Injury

3.8 ± 3.5

1 (100)

0(0)

0 (0)

4 (13.8)

13 (19.4)

Burn

6.1 ± 2.7

0(0)

0(0)

0 (0)

6 (20.7)

12 (17.9)

Laceration

6.4 ± 3.1

0(0)

0(0)

8 (72.7)

14 (48.3)

17 (25.4)

Contusion

7.0 ± 0.0

0(0)

0(0)

0 (0)

1 (0.6)

3 (4.5)

Fracture

5.1 ± 3.5

0(0)

3 (75.0)

2 (18.2)

0 (0)

4 (6.0)

Insect or animal bite

7.1 ± 2.5

0(0)

0(0)

0(0)

2 (6.9)

5 (7.5)

Laceration and Contusion

0(0)

1 (25.0)

1 (9.1)

2 (6.9)

12 (17.9)

Other

9 ± 0.0

8 ± 3.4

7.5 ± 2.7

6.9 ± 3.1

4.8 ± 2.7

Age

Table 10. Mechanism of injury Age

Injury #5

Injury #4

Injury #3

Injury #2

Injury #1

5.8 ± 3.0

1 (100)

4 (100)

11 (100)

29 (100)

67 (100)

Total

n/a

1 (100)

0 (0)

6 (56.0)

17 (70)

32 (43)

Mechanism of Injury

3.8 ± 3.5

1 (100)

0 (0)

0 (0)

1 (5.9)

5 (15.1)

Burn

7.2 ± 3.0

0 (0)

0 (0)

4 (66.7)

11 ( 64.7)

14 ( 43.8)

Fall

n/a

0 (0)

0 (0)

0 (0)

1 ( 5.9)

3 (9.4)

Assault

n/a

0 (0)

0 (0)

0 (0)

2 (11.8)

5 (15.6)

Stepped on Something

n/a

0 (0)

0 (0)

2 (33.3)

2 (11.8)

5 (15.6)

Playing

9 ± 0.0

8 ± 3.4

7.5 ± 2.7

6.9 ± 3.1

4.8 ± 2.7

Age

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Table 11. Location of injury Burns

Injury #5

Injury #4

Injury #3

Injury #2

Injury #1

18

1 (0.6)

4 (2.6)

11 (7.1)

29 (18.6)

67 (42.9)

Total

18 (100)

1 (100)

2 (100)

9 (100)

26 (100)

63 (94.0)

Location of Injury

3 (16.7)

1 (100)

0

3 (33.3)

7 (26.9)

10 (15.9)

Head

6 (33.3)

0

0

2 (22.2)

4 (15.4)

17 (27.0)

Upper Limbs

7 (38.9)

0

1 (50)

3 (33.3)

11 (42.3)

25 (39.7)

Lower Limbs

1 (5.6)

0

1 (50)

1 (11.1)

1 (3.8)

4 (4.8)

Torso

0

0

0

0

3 (11.5)

6 (9.5)

Eye, Ear, Nose

1 (5.6)

0

0

0

0

1 (1.6)

Whole Body

3.8 ± 3.5

9 ± 0.0

8 ± 3.4

7.5 ± 2.7

6.9 ± 3.1

4.8 ± 2.7

Age

Discussion The Bedouin population of southern Israel is an example of a traditional society thrust into modernity over the past 50 years. While citizenship in a developed nation gives them access to the vast resources of modern medicine, they are still challenged to cope both with dangers of traditional life as well as the unforeseen and unpredictable threats of a rapidly changing society. Though the Bedouin community represents nearly 30 percent of the southern Israeli population, there is still limited data about their specific health needs.

Incidence and Clinic Utilization As reported by Gofin et al (3), Arab children are more likely than Jewish children to have visited another source of care prior to presenting to the ED after accidental injuries. This suggests that they presented to the primary care physician prior to being referred to the ED. If this is accurate, then the lifetime injury incidence of 43.2 percent might represent about 70 percent of all childhood injuries. This actually seems quite low. It seems that having childhood injuries is a right of passage. It is estimated by some sources that 1 in 4 children seek medical attention annually for injury. So by age 14, all children would have sought medical care for injury several times. Perhaps the population of Shatal Clinic underutilizes the clinic for injuries. A distinct characteristic of this population is that they live relatively distant from the clinic. They also have relatively low SES compared to Israelis as a whole and many families do not own a car. This would make it difficult to run to the clinic for every minor injury. If a family did feel that an injury was severe enough to need urgent attention, they might be more likely to choose to go directly to the ED. Further research should target home injuries that do not present to the clinic and also compare clinic and ED records.

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Parent Age, Family Size and Injury History While it was hypothesized that children from larger families would have more injuries, the opposite was found. Though not statistically significant overall, a trend can be seen that, in fact, children from larger families had fewer injuries. Among children from families with more than eight children, only 15.9 percent had more than one injury as compared to 26.7 percent among families with fewer than four children. It could be possible that experience teaches the mothers to prevent injury but then you would expect more injuries in lower birth order children. Or it could be that older siblings provide additional supervision. But additionally possible is that large families have, on average, less education and fewer resources. Therefore, the hardship of traveling to the clinic restricts their visits to only truly necessary trips and in that case, it may then warrant a direct trip to ED. Family size also correlated with age at which parents started families. Older parents with smaller families had children with more injuries. Perhaps this represents an outgrowth of our theory on utilization of the clinic: parents who are older when they start families, because they are more educated, and thus also have higher SES, and better access to transportation, and therefore bring in their children more often. Alternatively, it could be that if the parents are educated, they work and leave their children in the care of less capable supervision. Or, yet another possibility is that they were older when they started families because they were less marriageable because of some disability which delayed their childbearing and also undermines their parenting. Further research should be targeted at identifying the role of education of the parents in injury rates. It might also be enlightening to consider who is supervising children at the time of injury.

Gender In this study, boys were shown overall to have more injuries than girls. These findings correspond with the results of several other studies of Israeli Arab children showing rates 2 and 3 times higher for boys as well as many international studies that show that boys have higher rates of injuries than girls (3, 9, 10). However, the predominance of burns in girls, nearly all of whom were under age five years was documented by others (10). It is surprising given the well documented higher rates of injuries in boys. In the study by Morrongiello et al (11) it was shown that girls were more often injured while at play in “non play” areas such as the kitchen. The study also showed that boys were more often injured while misbehaving. Mothers that monitored children more closely, leaving them unattended for less time, had children with fewer injuries. The study also showed that parents adapted the level of supervision they gave to the perceived acceptability of their children’s behavior. Perhaps this explains why girls would have more burns. They are in the kitchen modeling their mother’s behavior or keeping her company and a short lapse of attention leads to them toppling over hot liquid or falling into the fire. Further research through interviews about the exact events surrounding burns could further elucidate this issue.

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Injury Distribution The most common injuries in this sample were contusions 47/112, lacerations 25/112 and burns 18/112. Unfortunately, mechanism was only documented in 50 percent of the injuries. Falls constituted 29/56 documented mechanisms and burns 18/56. As with other Israeli studies (3, 12-16), burns were found in the youngest age group. However in older children, they were rare in our sample. A 2003 study by Broides and Assaf (9) conducted in a Dimona health center presented the types of injuries that Bedouin children confronted in the home and the course of hospitalization that followed. They showed burns to be the most prevalent home accident. They also showed that the risk for burns was correlated with younger age. The recommendation was made to target prevention programs at maternal knowledge and safety measures.

Research Methodology The decision to do a chart review was based on the constraints of the time available for the project. Prior to the initiation of the data collection, the plan was to generate a report using the CLICKS data that listed all children under the age of 14 years who presented with an injury between January 1st, 2003 and December 31st, 2006. However, after attempting several times to generate the report, it seemed that the system was not capable of producing this data set. This could be because, on chart review, it became apparent that coding for injury was not always accurate. An American study (17) comparing accuracy of identification of injuries in the medical history showed that 78% of injuries could be found in the medical record as compared to 52% which were recalled by maternal interview. Perhaps due to the litigious culture of American health care, it could be that American medical records contain more details about the events. In this study it was nearly impossible in many cases to determine the events surrounding the injury. The decision to do a lifetime injury analysis was based on the small sample of children who have injuries every year. In 2006, only 16 children presented with injuries. In the initial study design, it was assumed that more information about socioeconomic status was contained in the medical record. In the end, it was not possible to consider income or education of the parents using this study design. The initial study included residence location and type, based on the design Zimmerman et al (18) used in a study on repeat Pediatric ED visits in New Brunswick, NJ, where street addresses were used to access SES. In this population, nearly all lived in unrecognized villages. Therefore, for most patients, their address was simply the nearest recognized settlement. The initial study design addressed polygamy. In one-third of the records, no information was available about the child’s father. The assumed explanation is that the children are only registered to the father from the mother that is the “legal wife”. If this were true, then no effect was seen on the rate of injury in children from these multi-parent families. However, omission of the father could also be just a clerical issue and therefore no real significance can be placed in the lack of significant differences in the injury rates.

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Conclusions Unintentional injuries have a huge morbidity and significant mortality world wide. The populations most at vulnerable to the burden of injuries are found in the less developed societies. Current research has been targeted at western society and the proven strategies for prevention are inappropriate for the mechanisms of injury that are specific to the Bedouin culture (19, 20). Further research is necessary to identify demographic characteristics and behaviors that are correlated with injury in Bedouin children. Chart review was not adequate for the study of demographic and SES factors affecting injury.

References (1) (2) (3) (4) (5)

(6)

(7) (8) (9) (10) (11) (12)

(13) (14) (15) (16)

Joffe AR, Lalani A. Injury admissions to pediatric intensive care are predictable and preventable: a call to action. J Intensive Care Med 2006;21(4):227-34. Gardner HG. Office-based counseling for unintentional injury prevention. Pediatrics 2007;119(1):202-6. Gofin R, Avitzour M, Haklai Z, Jellin N. Injury inequalities: morbidity and mortality of 0-17 year olds in Israel. Int J Epidemiol 2002;31:593-9. Wirsing R. The health of traditional societies and effects of acculturation. Curr Anthropol 1985;26(3):303-22. Morad M, Shvarts S, Merrick J, Borkan J. The influence of Israel Health Insurance Law on the Negev Bedouin population--a survey study. ScientificWorldJournal 2006;6:8195. Abu Asbeh K, Karakra A. Evaluation of the female Bedouin student scholarship program of the Center for Bedouin Studies and Development. Beer-Sheva: Ben Gurion Univ, 2006. Website: http://w3-new.bgu.ac.il/bedouin// Website: http://www.negev.co.il/statis/ eng/ch2.asp Website: http://www.negev.co.il/statis/tables /8001.htm Broides A, Assaf M. Home accidents in Arab Bedouin children in southern Israel. J Child Health Care 2003;7(3):207-14. Miron D. Shinnawi F, Meenes R, Avishai I, Sarid Y, Rotem M Childhood injuries in northern Israel—prevalence and risk factors. Harefuah 2003;142(8-9):579-82, 648. (Hebrew). Morrongiello BA, Ondejko L, Littlejohn A. Understanding toddlers’ in-home injuries: I. Context, correlates and determinants. J Pediatr Psychol 2004;29(6):415-31. Morad M, Hemmo-Lotem M, Kandel I, Hyam E, Merrick J. Burn injuries and adolescents in Israel. Int J Adolesc Med Health 2004;16(3):201-5. Ben Arieh AB, Danon YL. Epidemiological trends of pediatric emergency referrals in Israel. Isr Med Assoc J 2001;3(3):231-2. Brook U, Boaz M. Children hospitalized for accidental injuries: Israeli experiences. Patient Educ Couns 2003;51(2):177-82.

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(17) Goldman S, Aharonson-Daniel L, Peleg K, Israel Trauma Group(ITG). Childhood burns in Israel: a 7-year epidemiology review. Burns 2006;32(4):467-72. (18) Shani E, Ayalon A, Abu Hammad I, Sikron F. What picture is worth a thousand words? A comparative evaluation of a burn prevention programme by type of medium in Israel. Health Promot Int 2003;18(4):361-71. (19) Stone KE, Burrel L, Higman SM, McFarlane E, Fuddy L, Sia C, Duggan AK. Agreement of injury reporting between primary care medical record and maternal interview for children aged 0-3 years: implications for research and clinical care. Ambul Pediatr 2006;6(2):91-5. (20) Zimmerman DR, McCarten-Gibbs KA, DeNoble DH, Borger C, Fleming J, Hsieh M, Langer JC, Breckenridge MB: Repeat pediatric visits to a general emergency department. Ann Emerg Med 1996;28:467-73. (21) Hemmo-Lotem M, Merrick E, Endy-Findling L, Freh AA, Jinich-Aronowitz C, Korn L, Merrick J. Childhood injury prevention: intervention in the Bedouin city of Rahat. ScientificWorldJournal 2005;5:596-608. (22) Hemmo-Lotem M, Endy-Findling L, Jinch-Aronowitz C, Danon YL, Merrick J. Youth injury in Israel: an appeal for change. Int J Adolesc Med Health 2004;16(3):193-200.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter VI

Information Technology and Medical Education: A Survey of Perceived Computing Skills among Medical Students in Northern Nigeria Zubairu Iliyasu1, Isa S. Abubakar1, Mohammed Kabir1 and Muktar H. Aliyu 2∗ 1

Department of Community Medicine, Aminu Kano Teaching Hospital and Department of Community Medicine, Bayero University Kano, Nigeria 2 Department of Family and Community Medicine, Meharry Medical College, Nashville, TN, USA

Abstract The application of information communication technology (ICT) to medical education and health care is increasing worldwide. But little is known about the computer skills of medical students in developing countries. We investigated the knowledge, attitude and ICT skills of medical students of Bayero University Kano, Nigeria. A pretested, structured questionnaire was administered to 300 medical students in their preclinical and clinical years of study. Of the 300 medical students, 22.0% owned a personal computer and 32.3% had previous formal computer training. One hundred and sixty three (54.3%), 77 (25.7%) and 60 (20.0%) had good, fair and poor knowledge of computing respectively. There was a significant gender gap with male dominance of computer knowledge (85.9% vs. 67.4%) (P=0.0001). Also, computer ownership (95.4% vs.75.5%) (P=0.0001) and formal training (89.7% vs. 57.1%) (P=0.0001) positively influenced ∗

Correspondence: Muktar Aliyu, MD, DrPH, Department of Family and Community Medicine, Meharry Medical College, 1005 D.B. Todd Jr. Blvd., Nashville, TN 37208 United States of America. Tel: 615-327-5535; Fax: 615-321-2979; Email: [email protected]

86

Zubairu Iliyasu, Isa S. Abubakar, Mohammed Kabir et al. knowledge. Only 112(37.3%) students had positive attitude towards application of computing to medicine. This was positively affected by being male (45.4% vs. 20.0%) (P=0.0001), computer ownership (54.6% vs. 32.6%) (P=0.001) and formal training (50.5% vs. 31.0%)(P=0.001). Only 89(29.7%) of the students had good computing skills. The remaining 107 (35.7%) and 104(34.7%) students had fair and poor skills respectively. Computing skills were positively influenced by increasing years of study (74.4% vs. 56.8%) (P=0.04), computer ownership (95.5% vs. 57.0%) (P=0.0001) and formal training (85.6% vs. 55.7%) (P=0.0001). In conclusion, although most medical students had basic ICT knowledge, the level of self-assessed basic computing skills was low. Integration of ICT into the medical school curriculum could help enhance the ICT skills of future physicians in northern Nigeria.

Keywords: Information communication technology, attitude, skills, medical students, Nigeria.

Introduction The past decade has witnessed an explosive growth in the number of computers. By the end of 2000, there were over 414 million internet users with increasing use from Asia, Latin America and parts of Europe (1). That same year, the number of online indexable documents surpassed the one billion mark and keeps growing at 3.2 million new pages per day 1. This rapid development in computer technology and the wide availability of personal computers together with the internet, email, and various medical literature retrieval applications have changed both the study and the practice environments in medicine, as in other disciplines (2, 3). Medical schools in recent years have been faced with tremendous educational challenges caused by exponential growth of medical information and increasing sophistication and availability of technology (4, 5). With a rapid increase in student population, the available facilities used in the traditional methods of teaching are already overwhelmed with increasing student to teacher ratio (5, 6). Computer applications could therefore play an increasingly important role in fostering independent learning and compensation for the decreased lecture time via web-based learning. The internet can be used for teaching and learning in a variety of ways including online or live projection of lectures, e-mail for communication and video conferencing. The introduction of medical informatics as an integral part of medical school curricula allows tomorrow’s physicians to access, analyze and manage information so that they can make educated decisions on patient care (7). Medical students and doctors alike utilize information technology for computer based patients’ record system and data retrieval, word processing, presentation, data entry, storage and analysis, literature search, communication, telemedicine and evidence based medicine. The development of online databases allows medical professionals throughout the world immediate access to hundreds of e-journals. It is therefore important for all medical practitioners and medical students to be conversant with information and communication technology (6, 7). However, there is growing concern that the spread of information and communication technology has been skewed in favour of the developed countries. Gaps exist

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in terms of equipment, electricity and skills required to tap into the information superhighway. Medical schools present good opportunities to expose tomorrow’s doctors to the inevitable application of information and communication technology to medical practice and research. Research on medical students’ computing skills in developing countries are few and mostly originate from the western world, where informatics is well developed (8). There have been few studies on information technology use in medical education in Nigeria (9-11), most of which were conducted in schools located in the southern part of the country. The aim of this study was to investigate the knowledge, attitude and ICT skills of medical students at Bayero University Kano in northern Nigeria. The information may indicate the need for curricular modification aimed at enhancing the development of computer skills among students and integration of ICT into medical education.

Methods The Bayero University medical school is the 14th to be established in Nigeria and commenced training during the 1984/85 academic session. The school has 18 departments. The pre-clinical departments of anatomy, physiology and biochemistry are located in the old campus of the university. First year medical students receive lectures in the faculty of science together with other science students in the university. The clinical departments of the faculty are located in Aminu Kano Teaching Hospital, which is about 10 kilometers away. The total number of medical students (2nd to 6th year) in the faculty at the time of this study was 333. The number of students at the various levels was 102 in 2nd year, 69 in 3rd year, 70 in 4th year, 46 in 5th year and 46 in 6th year. The University information communication technology (ICT) center has over 100 computer workstations connected to the internet, available free of charge to matriculated students. The university central library has a network of computers that are also connected to the internet. The faculty of medicine has a computer laboratory with 50 computer stations that are also connected to the Internet, but was not functional at the time of conduct of this study. The teaching hospital has a cyber café with a set of 13 computers linked to the internet. The café serves doctors, interns, nurses, community health officers and medical students and charges a fee for its services. Upon entering medical school, students have variable levels of competence in the use of computers. In our institution, courses in basic computer skills (introduction to computers and internet, Windows, Microsoft office® applications, file management, and the basics of software programming) are available at the computer center, but are not mandatory. Most of the teaching staff have personal computers with only few having internet access in their offices. Staff members are encouraged to enroll in courses provided by the university to acquire ICT skills. The sample in this study consisted of students from the second to sixth year enrolled at the faculty of medicine at Bayero University Kano, Nigeria. The first-year students were excluded from the study because they were not yet involved in medical courses and it was difficult to contact them since they took courses taught by the faculty of science. We used a pre-tested structured questionnaire derived from previous survey tools (11-13). The

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questionnaire was in four parts. The first part captured sociodemographic information and previous formal computer training and ownership. The second part consisted of 20 true or false statements that assessed knowledge of different types of computers (microcomputerdesktop, laptop, palmtop etc), hardware (monitor, CPU, keyboard), peripherals (mouse, printers etc) and the internet. We also inquired about access to computing facilities on campus and at home. The third part of the questionnaire consisted of eight statements equally divided into 4 positive and 4 negative statements aimed at assessing attitude of respondents towards the application of computers in medicine. The fourth part assessed the respondent’s computing skills as used in previous studies (12, 14). Students’ self-reported skills were classified as poor (little or no computer skills), fair (able to do basic word processing and use the internet) and good (possess mastery of computing basics, including various software programs). A 5-point Likert scale was used to analyze attitude of students towards application of computers to medicine: strongly agree (5 points), agree (4 points), don’t know (3 points), disagree (2 points), strongly disagree (1 point). Attitude was measured by eight statements consisting of four positive and four negative statements. The negative statements were scored in the reverse direction. Data collection took place at the end of the second semester in the 2005-06 academic year. Students from the second, third (preclinical), fourth, and fifth year (clinical) were asked to complete the questionnaire. The questionnaires were distributed in appropriate lectures and retrieved immediately after completion. Participation in this study was voluntary, and all participants remained anonymous. Information on gender, age, and year of study was requested in the questionnaire. The institutional ethical committee approved the questionnaire and its administration.

Data Analysis All data analyses were performed using SPSS version 11.0 statistical software (15). Correct responses to the twenty knowledge questions were converted into percentages. Respondents with scores in the 0-39%, 40-69% and 70-100% range were considered as having poor, fair and good knowledge, respectively, as used in a previous study (14). A 5point Likert scale was used to analyze attitude of students towards application of computers to medicine. The maximum score for attitude questions was 40 and the minimum score was 8. Respondents who scored 24 and above were considered as having positive attitude, whereas those who scored below 24 were considered as having negative attitude towards computing. The Chi-square test was used to test for significance of association between categorical variables. To adjust for confounders, variables that were found to influence computing knowledge and skills on bivariate analysis were included in a multivariate logistic regression model. The level of statistical significance for all tests was set at p<0.05.

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Results An overall response rate of 90.1 percent (300 out of 333) was obtained. Individual class response rates for the second to the sixth year of study were 89.2 percent (n=91), 92.8 percent (n=64), 82.9 percent (n=58), 89.1 percent (n=41) and 100 percent (n=46), respectively. Out of 300 respondents, 68.3 percent (n=205) were males. Participants’ age ranged from 18 to 32 with a mean age of 23.7 ± 2.23 years (see table 1).

Computer Ownership and Training Sixty-six (22.0%) of the students owned a personal computer, but only 14 (21.2%) of them had internet access from their computers. One hundred and forty four (48.0%) of the students had access to a computer at home, with 37 (25.7%) of them connected to the internet. One hundred and forty (46.7%) students reported having access to computing facilities on the university campus while 227 (75.7%) used commercial cyber cafes. Ninetyseven (32.3%) of the students had a diploma or certificate in computer studies. Of these, only sixteen (16.5%) obtained training from the university ICT center. The majority 81 (83.5%) received training from private computing outfits. Table 1. Characteristics of medical students in Bayero University Kano, Nigeria 2006 Characteristics Level of study 2nd year 3rd year 4th year 5th year 6th year

Frequency (N=300) % 91 64 58 41 46

30.3 21.3 19.3 13.7 15.3

Age(years) <20 20-29 30

22 238 40

7.3 79.3 13.3

Gender Males Females

205 95

68.3 31.7

Computer ownership Owns a personal computer 66 Didn’t own a personal computer 234

22.0 78.0

Computer training Had formal computer training No formal computer training

32.3 67.7

97 (32.3) 203 (67.7)

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Computer Knowledge Correct responses to the 20 knowledge questions were converted into percentages and those scoring 0-39%, 40-69% and 70-100% were considered as having poor, fair and good knowledge respectively. Using these criteria, 163 (54.3%) of the respondents had good knowledge of computing, whereas, 77 (25.7%) and 60 (20.0%) had fair and poor knowledge of computing respectively (see table 2). There was a significant gender gap with male dominance among those with fairly good computer knowledge (85.9% vs. 67.4%) (OR=2.94, P=0.0001). Furthermore, computer ownership (95.4% vs.75.5%) (OR=6.76, P=0.0001) and formal training (89.7% vs. 57.1%) (OR=2.84, P=0.0001) positively influenced knowledge. These factors remained significant predictors of knowledge after adjusting for confounders as shown in table 5. Table 2. Knowledge of computing among medical students of Bayero University Kano, Nigeria, 2006

Poor

Knowledge F air

Good

2

Total

Gender Males Females Total

29(14.2) 31(32.6) 60(20.0)

65 (31.7) 12(12.6) 77(25.7)

111 ( 54.2) 52(54.7) 163(54.3)

205(68.3) 95(31.7) 300(100.0)

Age (years) <20 20-29 30 T otal

4(18.2) 50(21.0) 6( 15.0) 60(20.0)

5( 22.7) 54(22.7) 18(45.0) 77(25.7)

13(59.1) 134(56.3) 16(40.0) 163(54. 3)

22 (7.3) 238 (79.3) 40 (13.3) 300(100.0) 9.2

Level* Pre-clinical Cli nical Total

38( 24.5) 22(15.2) 60(20.0)

37(23.9) 40(27.6) 77(25.7)

80(51.6) 83(57.2) 163(54.3)

Computer ownership Owns a computer Doesn’ t own a computer Total

3(4.6) 57(24.5) 60(20.0)

14(21.2) 63(27.0) 77(25.7)

11(11.3) 66(32.5) 77(25.7)

Computer training Trained Not trained Total

10(10.3) 50(24.6) 60(20.0)

20.3

P V alue

0.0001

0.06

155(51. 7) 145(48.3) 300(100.0)

4.4

0.82

49(74.2) 114(48.5) 163(54.3)

66(22.0) 234(78.0) 300(100.0)

17.1

0.0001

76(78.4) 87(42.9) 163(54.3)

97(32.3) 203(67.7) 300(100.0)

33.4

0.0001

*Note: Pre-clinical = 2nd through 3rd year; Pre-clinical = 4nd through 5th year.

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Attitude towards Computing Using the criteria described in the methodology section, 112(37.3%) of the medical students had positive attitude towards computing and its application in healthcare and research. In contrast, 188 (62.7%) of them had negative attitude towards the application of computing in medicine. Table 3 shows that a significantly higher proportion of male students had positive attitudes compared to female students (45.4% vs. 20.0%) (OR=3.32, P=0.0001). Similarly, students who owned a computer were significantly more likely to have a positive attitude compared to those without a computer (54.6% vs. 32.6%) (OR=2.48, P=0.001). Additionally, previous computer training had a significant positive effect on attitude, whereby 50.5% of those with formal training had a positive attitude compared to 31.0% of those that had no such training. (OR=2.27, P=0.001). Table 3. Attitude of medical students towards application of ICT in medical education and practice, Bayero University Kano, Nigeria, 2006

Positive

Attitude Negative

93(45.4) 19(20.0) 112(37.3)

112 (54.6) 76(80.0) 188(62.7)

205(68.3) 95(31.7) 300(100.0)

Age (years) <20 20-29 30 Total

10(45.5) 82(34.5) 20(50.0) 112(37.3)

12(54.5) 156(65.5) 20(50.0) 188(62.7)

22 ( 7.3) 238 ( 79.3) 40 ( 13.3) 300 (100.0)

Level* Pre-clinical Cli nical Total

48(30.9) 64(44.1) 112(37.3)

107(69.0) 81(55.9) 188(62.7)

155(51.7) 145(48.3) 300(100.0)

Computer ownership Owns a computer Doesn’t own a computer Total

36(54.6) 76(32.6) 112(37.3)

30(45.5) 157(67.4) 187(62.7)

66(22.0) 234(78.0) 300(100.0)

Gender Males Females Total

Computer training Trained Not trained Total

49(50.5) 63(31.0) 112(37.3)

48(49.5) 140(68.9) 188(62.7)

Total

97(32.3) 203(67.7) 300(100.0)

*Note: Pre-clinical = 2nd through 3rd year; Pre-clinical = 4nd through 5th year.

2

P V alue

17.9 0.0001

4.2 0.12

6.3

0.18

10.6 0.001

10.7

0.001

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Table 4. Self-reported computing skills among medical students of Bayero university Kano, 2006 Poor Gender Males Females Total Age (years) <20 20-29 30 Total

Skills F air

70(34.2) 68 (33.2) 34(35.8) 39(41.1) 104(34.7) 107(35.7)

5(22.7) 8(36.4) 87(36.6) 83(34.9) 12(30.0) 16(40.0) 104(34.7) 107(35.7)

Good

Total 205(68.3) 95(31.7) 300(100.0)

3.2 0.21

9( 40.9) 68(28.6) 12(30.0) 89(29.7)

22 (7.3) 238 (79.3) 40 (13.3) 300(100.0)

2.7

0.61

14.5

0.04

67(43.2) 53(34.2) 37(25.5) 54(37.2) 104(34.7) 107(35.7)

35(22.6) 54(37.2) 89(29.7)

155(51.7) 145(48.3) 300(100.0)

Computer ownership Owns a computer Doesn’ t own a computer Total

3(4.6) 25(37.9) 101(43.4) 82(35.2) 104(34.8) 107(35.8)

38(57.6) 51(21.8) 89(29.4)

66(22.0) 234(78.0) 300(100.0)

14(14.4) 33(34.0) 90(44.3) 74(36.5) 104(34.7) 107(35.7)

P V alue

67 ( 32.7) 22(23.2) 89(29.7)

Level* Pre-clinical Cli nical Total

Computer training Trained Not trained Total

2

50(51.6) 39(19.2) 89(29.7)

97(32.3) 203(67.7) 300(100.0)

45.2 0.0001

40.2 0.0001

*Note: Pre-clinical = 2nd through 3rd year; Pre-clinical = 4nd through 5th year.

Table 5. Predictors of good ICT knowledge among medical students of Bayero University Kano, Nigeria, 2006 Predictor Age <20 20-29 30

Cr ude OR

Adj usted OR (95% CI)

P value

1. 0 1.20 0.79

Ref erent 0. 42 (0.08-2.15) 0.38 (0.10-1.42)

0.30 0.15

Sex F emale Male

1.0 2. 94

Referent 5.22 (2.60-10.50)

0.0001

Level Pre-clinical Clinical

1.0 1.82

Ref erent 1.45 (0.74-2.83)

0.28

Computer training No formal training Ha d formal training

1.0 2.84

Ref erent 4.37 (1.94-9.84)

0.0001

Computer ownership Di d not own a PC Owned a PC

1.0 6.76

Ref erent 6.80 (1.94-23.84)

0.003

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Table 6. Predictors of good IT skills among medical students of Bayero University Kano, Nigeria, 2006

Predictor Age <20 20-29 30

Cr ude OR

Adj usted OR (95% CI)

P value

1. 0 0.51 0.69

Ref erent 0. 31 (0.09-1.05) 0.38 (0.09-1.62)

0.06 0.19

Sex F emale Male

1.0 1. 47

Ref erent 1.97 (1.21-3.67)

0.04

Level Pre-clinical Clinical

1.0 2.22

Ref erent 1.90 (1.06-3.41)

0.03

Computer training No formal training Had formal training

1.0 4.72

Ref erent 6.22 (3.10-12.47)

0.0001

Computer ownership Di d not own a PC Owned a PC

1.0 15.95

Ref erent 13.73 (4.04-46.62)

0.0001

Computer Skills Table 4 shows that only 89(29.7%) of the students possessed good computing skills. Approximately 36% (n=107) and 35% (n=104) of the students students had fair and poor skills respectively. Computing skills were positively influenced by year of study, as clinical students had superior skills compared to their pre-clinical counterparts (74.4% vs. 56.8%) (OR=2.22, P=0.04). Similarly, computer ownership (95.5% vs. 57.0%) (OR=15.95, P=0.0001) and training (85.6% vs. 55.7%)(OR=4.72, P=0.0001) significantly predicted computing skills. These predictors remained significant after adjusting for confounding effects of other variables (see table 6).

Discussion Slightly more than half (54.3%) of the medical students in Bayero University had good knowledge of computing. This is higher than our earlier findings among health professionals (46.4%) in the affiliate teaching hospital-Aminu Kano Teaching Hospital (14). It is also higher than the findings of Arogundade et al (11), who reported good computer knowledge among 25% and 27% of medical students and doctors respectively in Ile-Ife, Nigeria. Similar results were obtained by Ajowun (58%) among first year clinical students in University of Ibadan, Nigeria (9). Higher values (89%) were obtained in the Netherlands-SEUSISS project

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(16). Furthermore, Raja et al (17) reported higher knowledge level of 84.5% among medical students in India. In the USA, Gay et al (18) reported good knowledge of computing among 60% of radiology residents in the University Hospital, New Jersey. The variations in the result may not be unconnected with the level of technological advancement in the various countries, level of personal computer ownership and access to computers. In addition, the different methods of assessment and timing of these studies could also be responsible for some of these differences. We observed that being male, owning a personal computer and having previous formal computer training positively influenced computer knowledge. Our findings concur with previous reports (19, 20). Computer ownership and training naturally provide stimulus for intellectual curiosity and usage. Gender differences may be due to the culturally induced reserved nature of our female medical students compared to the more adventurous nature of their male counterparts. Although digital disparities have diminished in the developed world, gaps still exist across gender and educational levels (19). This study found a low (22.0%) computer ownership rate among medical students in Kano. This is similar to the findings among medical students in Ile-Ife, Nigeria, where Arogundade et al reported that 26% of their students had personal computers (11). However, our findings contrast with an earlier report among health professionals in Aminu Kano Teaching hospital, where we found that 34.8% of the respondents owned a personal computer (14). The disparity in computer ownership is even more pronounced when our figures are compared with those reported for students in the developed countries. For instance, AsgariJirhadeh (21) reported that more than 50% of medical students of the University of Edinburgh, UK, owned a personal computer. Similarly, Jerant and colleagues (22) reported that 91%, 86% and 79% of faculty, students and residents in University of California, Davis, owned personal computers. A related survey of undergraduate dental students in Finland reported a personal computer ownership rate of 43% (23). The low computer ownership observed in the present study could be attributed to the lower income, slower technological development, and a perceived lack of felt need for computers among medical students compared with their colleagues in the developed countries. We also found that about 30% of our medical students had good computer skills. This level of skill is similar to the findings reported from other medical schools in Nigeria. For example, Ajuwon (9) found that only 42.6% of medical and nursing students could use a computer while about 60% had used the internet in the past. Ogunyade and Oyibo (7) discovered that 52% of their students were aware of Medline® on CD-ROM while only 24% had used it. In contrast to our findings, Odusanya and Bamgbala (10) in the University of Lagos, Nigeria reported that 80% of their final year medical and dental students had used the computer, but the use of software applications was very poor (19%). Our result is slightly higher than our findings among healthcare professionals in Kano Nigeria where 22.7% had good computer skills. Findings by Ajuwon and others (9) indicated that a higher proportion (42.6%) of the students in Ibadan could use a computer. In contrast, only 21% of medical students in Lagos (10) had adequate computer skills. Elsewhere in East Africa, Samuel and others (15) discovered that less than 60% of the respondents at Muhimbili University College, Tanzania had good computer skills. But Limta et al (24) and Raja (17) reported that 81.5% and 70% of their respondents judged themselves competent in ICT skills. This could

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be attributed to differences in personal computer rate and formal computer training between medical colleges in these countries. The perceived level of computing skill among our respondents is not surprising as there is no formal requirement to undertake basic computer training course before enrolling into our medical school. This is in stark contrast to students in Europe and other developed countries where most institutions provide basic computer appreciation courses to their students on matriculation. In this study, attitude of the medical students towards the use of computers was found to be positive in only 37% of our respondents (n=112). Attitude was also influenced by sex, personal computer ownership rate and formal computer training but not by the levels of the respondents. This is similar to the findings of Arogundade et al (11) in which only 39.9% of the respondents had good attitude and utilization habits. This is not unconnected to the relative underdevelopment with regards to information technology, low personal computer ownership rate and lack of computer training in the two institutions. Asgari-Jirhandeh and others (21) found that 62% of their respondents wanted a structured course as part of the medical school curriculum. Variations in attitude reflect differences in personality, lack of confidence, low utilization habits and fear of the new technology. The main limitation of the study was assessment of skills based on self-report without practical verification. Some students may score themselves higher than their actual computer skills. We were also unable to provide longitudinal information (such as changes in ICT skills over time) because of the cross-sectional design of our study. Our findings highlight the need to develop interventions that can improve ICT skills, as well as computer access, in order to bridge the digital divide for medical students in our institution. Students’ computer skills should be evaluated at the start of medical school and resources should be made available to ensure that all medical students achieve basic computer literacy. Medical school faculty need to be trained in computer technology, provided with relevant software and given access to experienced technical personnel to create an environment in which students will acquire and refine their computing skills. This will enable graduating physicians acquire IT skills required to grow professionally and provide the best medical care for their patients.

References (1) (2) (3) (4) (5)

Cole JI, Suman M, Schramm P, Lunn R, Lebo, H. The UCLA Internet report 2001: Surveying the digital future. J Educ Computing Res 2002;23,67-84. Evans RS, Classen DC, Burke JP. Evaluation of a computer assisted antibiotic dose monitor. Am Pharmacother 1999;33:1026-31. Evans RS, Pestoruk SL, Classen DC, Horn SD, Bass SB, Burke JP.Preventing adverse drug events in hospitalized patients. Ann Pharmacother 1994;28:523-7. Angaran DM. Telemedicine and telepharmacy. Current status and future implications. Am J Health-Syst Pharm 1999;56:1405-26. Ebbel M. Information at the point of care. Answering clinical questions. J Am Board Fam Prac 1999;12:225-35.

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Zubairu Iliyasu, Isa S. Abubakar, Mohammed Kabir et al. McGlade KJ, McKeveney CJ, Crawford VL, Brannigan P. Preparing tomorrow’s doctors; the impact of a special study module in medical informatics. Med Educ 2001;35:62-7. Ogunyade O, Oyibo WA. The use of CD-ROM MEDLINE by medical students of College of medicine, University of Lagos, Nigeria. J Med Internet Res 2003;5:7. McKinney WP, Bunton G. Exploring the medical applications of the internet; a guide for beginning users. Am J Med Sci 1993;306:114-44. Ajuwon GA. Computer and internet use by first year clinical and nursing students in a Nigerian teaching hospital. BMC Med Inform Decis Mak 2003;3:10. Odusanya OO, Bamgbala OA. Computing and information technology skills of final year medical and dental students at the College of Medicine University of Lagos. Niger Postgrad Med J 2002;9:189-93. Bello IS, Arogundade FA, Sanusi AA, Ezeoma IT, Abioye-Kuteyi EA, Akinsola A. Knowledge and utilization of IT among healthcare professionals and students of Ile-Ife, Nigeria. A case study of a University Teaching Hospital J Med Internet Res 2004;6:45. Forman LJ, Pomerantz SC. Computer assisted instruction: A survey on the attitudes of osteopathic medical students. J Am Osteopath Assoc 2006;106:487-94. Samuel M, Coombes JC, Miranda JJ, Melvin R, Young EJ, Azarmina P. Assessing computer skills in Tanzanian medical students. BMC Public Health 2004;4:37. Iliyasu Z, Abubakar IS, Kabir M, Abbas SM. Computing knowledge, attitude and skills among healthcare professionals in Aminu Kano Teaching Hospital, Nigeria. Niger J Med 2005;14:200-5. SPSS Base 10.0 for Windows User's Guide. Chicago, IL: SPSS, 1999. Haywood J. SEUSISS Project: Survey of European Universities Skills in ICT of Students and Staff http://www.intermedia.uib.no/seusiss/ results.html Accessed 14th December, 2006. Raja EE, Mahal R, Masih VB. An exploratory study to assess the computer knowledge, attitude and skills among nurses in healthcare setting of a selected hospital; Ludhiana, Punjab, India. Nurs J India 1999;12:226-7. Gay SB, De Angeles GA. Attitude of radiology residents towards personal computing: results of survey. Acad Radiol 1997;4:304-8. Stringer J, Moreno EA. A computer literacy requirement for medical students. Acad Med 1996;71:522. Losh SC. Gender, educational, and occupational digital gaps 1983-2002. Soc. Sci Comp Rev 2004;22:152-66. Asgari-Jirhandeh N, Haywood J. Computer awareness among medical students: a survey. Med Educ 1997;31:225-9. Jerant AF, Lloyd AJ. Applied medical informatics and computing skills of students, residents and faculty. Fam Med 2000;32:267-72. Virtanen JI, Nieminen P. Information and communication technology among undergraduate dental students in Finland. Eur J Dent Educ 2002;6:147-52. Lim TA, Wong WH, Lim KY. Perceived skills and utilization of IT in medical education among final year medical students, universiti Putra Malaysia. Med J Malaysia 2005;6:432-40.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter VII

Attitudes of First-Year Israeli Tourism and Hotel Management Undergraduate Students toward Persons with Disability: A Pilot Study Tagrid Morad ∗1, Zaid Afawi2, Joav Merrick3,4,5, Jemila Caplan Kester6 and Mohammed Morad7 1

Department of Hotel and Tourism Management, Ben Gurion University of the Negev, Israel 2 Department of Neurology, Tel Aviv-Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 3 National Institute of Child Health and Human Development 4 Office of the Medical Director, Division for Mental Retardation, Ministry of Social Affairs, Jerusalem, Israel 5 Kentucky Children’s Hospital, University of Kentucky, Lexington, USA 6 Department of Biology, City College, City University of New York, USA 3,7 Department of Family Medicine, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel

Abstract To explore the attitudes of undergraduate students of tourism and hotel management toward people with disabilities. Design: A survey of all first year students of the tourism and hospitality mangement department was completed using a short validated questionnaire with 15 topics reflecting the full range of attitudes toward the disabled.

∗

Correspondence: Mohammed Morad, MD, Andarta 7, Apt 12, Beer Sheva, Israel. E-mail: [email protected].

98

Tagrid Morad, Zaid Afawi, Joav Merrick et al. Results: Of the 33/68 (48.5%) completed the questionnaire, while one was incomplete. 70% of the respondents demonstrated indepth understanding of the needs and rights of the disabled and the majority stressed their agreement with the need to make all places accessible without need for extra expenses by the disabled. Students believed that the presence of the disabled in the sphere of tourism had no negative effect on the industry image and use. While only half of the respondents feel comfortable in the presence of the disabled, 50% had reported that the disabled have the same abilities to enjoy and get excited as those without disabilities. Conclusions: Today students, future managers have to change their attitudes toward the disabled and most of the work has to be done during their academic studies and the educational system has to be responsible for such a change.

Keywords: Tourism, disability, attitudes, students, management, Israel.

Introduction Recently there has been an increased interest by academics and the tourism industry in the interaction between the disabled community and the tourism industry beyond the well documented issue of accessibility. Student attitudes have a direct impact on the quality of service experienced by the disabled consumer in the tourism industry. A negative attitude in the Israeli public could significantly affect the students and therefore worthwhile to explore the attitudes of the tourism student. In 2005, Israel had a population of approximately 600,000 disabled people, which constituted 10-15% of the total population. According to information from the Public Commission Inquiring into Proposed Disability Legislation for Israel in 1997 in was found that this population face discrimination and unequal access in many areas of life (1,2). One necessary step toward integration and full inclusion is a change in attitudes toward the disabled. In the Israeli multicultural society research has been focused since the 1960s on social attitudes with a great interest in demonstrating the impact of religion and culture on these attitudes (3-6). In 2004, Henry et al (6) showed that Israeli formal caring staff had higher sheltering and similarity scores but lower empowerment scores than staff in the United States. Using a public survey design, they showed that attitudes toward persons with disabilities in Israel were less than satisfactory, sharing the same interpersonal and intrapersonal processes that underlie similar attitudes in the United States. Israel has a great tourist heritage spanning centuries. Visitors are drawn to "the Holy Land" for both religious and historic reasons. Beyond these reasons, people are drawn to an attractive Mediterranean climate and its location, joining the East, West, North, and South. Visitors come alone, as families, or in groups to visit historic, religious, and scenic locations, or simply to visit friends and relatives. This small country can be accessed well by private car or by public transportation, making it a good destination for many disabled people. It is a land with a concentration of many valuable attractions. However, until recently disabled people was an ignored market segment of the tourism industry. With recent reports showing

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that this is a potentially profitable market (7), there is great interest in exploring the needs and expectations of disabled tourists. One barrier to the success of this demographic is the industry’s attitudes toward them. Apart from the well-studied accessibility issue (2,8), their needs have yet to be addressed. A change in the attitude of both the hospitality industry workers and the general Israeli public toward persons with disability is critical to shape health, quality of life, and satisfaction of disabled people (9). There are different models of intervention targeting student attitudes towards people with disabilities (10). As in the United States, the law in Israel must assure inclusion of people with disabilities in society. That could only be possible by eliminating barriers including the negative attitudes of employers, central and local government agencies, business owners, and other service providers who should fully comply with enacted laws (11). Changing attitudes of the public and hospitality staff may change behavior that affects the quality of services received by persons with disabilities which has a direct impact on their enjoyment of tourist attractions and leisure time. Tourism undergraduate students are the future managers of the tourism services and should learn to provide equal services to persons with and without disabilities. The increasing population of the disabled in society, the inclusion and integration movement, recent legislative changes in favor of the disabled, interest of tourism agencies to provide services for disabled clients, each require new educational activities and programs that target the attitudes of the students, who will become managers in the hospitality industry. One study examined the attitudes of management undergraduates toward persons with disabilities and expressed great concern about the attitudes of persons positioned in organization and how such attitudes could limit disabled people (12). It was shown that gender differences in these attitudes were diminishing and age was independent of these attitudes, but females showed lower scores than in studies elsewhere in the world. A change of attitudes toward the disabled community is therefore needed and despite the fact that this change is difficult, educators, managers, and organizations can take steps in the direction by valuing persons with disabilities (12). Some authors believe that the tourism industry for its own sake should tune its services based on relevant information from this population and therefore be sufficiently sensitive to the needs and expectations of the disabled persons (7). A change in attitude is imperative in order to improve the quality of life of people living in Israel with a disability and to reduce the impact of stigma and general negative attitudes. A recent public survey in Israel showed that 17.5% of respondents were convinced that disabled people were dangerous and annoying to the community (1). Among Israeli high school students, knowledge concerning disability was directly related to the presence of a disabled family member, but not to familiarity with disabled friends (4). Change is needed to make the shift to integration and inclusion in all aspects of life. For that to happen a shift to positive attitudes is a prerequisite for the success of the current reform of valuing disabled persons in Israel (1). In our study, we explore the attitudes of Israeli undergraduate tourism and hotel management students to determine the need for additional studies regarding their response to persons with disabilities. Previous studies have established the use of inventories and questionnaires to explore attitudes toward persons with disabilities (13, 14). We used analogies from the tourism industry to construct a simple questionnaire addressing the attitudes of students today, who will be future managers.

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Methods We used a modified questionnaire to explore the attitudes of a class of first year students at the BA program of tourism and hotel management at a major university in Israel.

The Questionnaire The developed questionnaire included 15 questions, including information on demographics, attitudes of the students toward the disabled, and their readiness to participate in programs that include disabled people. Items corresponded with the following items in the Scale of Attitudes towards Disabled Persons (SADP) (14): Competitive society, laws, adverse effect, living conditions, accident-prone, moral decisions, adjust, free public places, deviant personality and bizarre behavior. We distributed the questionnaire by hand to all students present in the class during a normal study day. There were no ethical issues to take into consideration and no conflict of interests.

Data Analysis The score we calculated from the sum of the values of all the variables in the Likert’s scales in the questionnaire.

Results Out of the complete study group of 68 students, 33 responded with full information, while one was questionaire was incomplete. The response rate was about 48.5%. The nonresponder group consisted of 34 students including 19 females and 15 males, 19 students aged 20-24 years (9 males and 10 females) and 15 aged 25-29 years (6 males and 9 females). Twenty-seven respondents were secular and none were Orthodox. Five were new emigrants from former Soviet Union and one from Argentina. Seventy nine percent of the responders were females, 73% were 20-24 years old, 24% 25-29 years old and 3% 18-19 years old.

Responses Of the responders 70% demonstrated an indepth understanding of the needs and rights of the disabled, and 55% thought that the disabled should not pay extra-expenses, while using sites or recreational and transport facilities. Sixty-one percent agreed that there is a need to make places, sites, and services accessible to the disabled and that it is not the responsibility of the disabled to make an extra effort to find information or places accessible to them. Seventy percent of the students answered that the presence of the disabled has no negative

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impact on the tourist site or on tourists visiting the site. About sixty percent were aware of the need for legislative measures to keep tourist sites and services accessible to people with disabilities. Only 49% of the students feel comfortable in the presence of the disabled, despite the fact that 49% of them believed that the disabled had the same abilites to enjoy and get excited as those without disability. Twenty five percent of the students reported that the disabled could function in many ways despite their physical disability, but only 18% of the respondents were ready to participate in research that focused on or included participants with disability. We did not use parametric methods to analyze the data, because variables addressing attitudes measured by Likert’s scales were nominal. Table 1 shows the study population demographics by response, while table 2 shows the mean scores by sex and age. Table 1. Demographics of students by response, sex and age

All 18-19 years old 20-24 years old 25-29 years old

All respondents

Male Respondents

Female Respondents 26 1

All nonrespondents 34 0

Male Nonrespondents 15 0

Female Nonrespondents 19 0

33 1

7 0

24

2

22

19

9

10

8

5

3

15

6

9

Table 2. Mean Score of response by sex, age group

Males Females 18-19 years old 20-24 years old 25-29 years old

Mean Score 18 19.2 12 15.37 20.62

Discussion Our study explored attitudes of first year students, future managers of the tourism industry in order to define needs for change, especially during their academic study and explore barriers to research, which include the disabled. There was a strong correlation between knowledge and positive attitudes, and an increase in age. Eighty five percent of pupils supported studies on disability in school and emphasized the need for teachers to be familiar with issues related to their disabled students. Watching TV and reading newspapers

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and youth periodicals provided for most of their knowledge about disability. Although attitudes may change with age, this still needs improvement. despite the minor role of school in shaping attitudes toward the disabled. A previous study of the attitudes of Israeli university students suggested that students with prior contact with disabled children had a more positive attitude toward the disabled than peers without exposure to such experience, and that their feelings were directly related to the length of exposure to a person with disability (15). This may lead us to the need to explore the experience of the studied group with disability. Students coming from a different cultural background and social values and norms were just recently part of the children’s community of Israel, exposed to secular and religious value systems shaping their attitudes and behavior toward people with disabilities. Despite the focus on the multicultural character of the Israeli society as one determinant of the attitudes, the role of media and educational system in changing attitudes was not a target of serious examination. Except for the health and welfare system, public places and governmental agencies, local and central services, business life has to change to accommodate the aspirations of the disabled living, immigrating, and touring in Israel. While negative attitudes endanger the health and wealth of the disabled, tourism is a positive method of improving the health and welfare of individuals with or without disabilities. This study showed that undergraduate students in the Tourism and Hotel management BA program at a major university had less positive attitudes toward disabled persons than their peers from other disciplines. These results were similar to those of first year students from other disciplines (16). Specific educational effort needs to be adopted in order to change this situation. As in other reports, this study showed gaps in knowledge, a possible loss of positive attitudes, and a lack of readiness to participate in activities with or for disabled people. More emphasis should be put on teaching disability issues in the curricula of BA programs in Tourism and Hotel Management.

Conclusions The faculty has to direct more attention to positively shaping the attitudes of their students toward persons with disability by involving students in more research on disability issues during their studies. This involvement will in turn affect their behavior later in their career. This behavior change is critical to the quality of life experienced by the disabled and their satisfaction with tourist services.

References (1) (2)

Vilchinsky N, Findler L. Attitudes toward Israel’s Equal Rights for People With Disabilities Law: A Multi-perspective approach. Rehabil Psychol 2004;49(4):309-16. Israeli A. A preliminary investigation of the importance of site accessibility factors for disabled tourists. J Travel Res 2002;41:101-4.

Attitudes of First-Year Israeli Tourism and Hotel Management… (3) (4)

(5) (6) (7) (8) (9)

(10)

(11)

(12) (13)

(14) (15)

(16)

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Chigier E, Chigier M. Attitudes to disability of children in the multi-cultural society of Israel. J Health Soc Behav 1965;9(4):310-7. Brook U, Galili A. Knowledge and attitudes of high school pupils toward children with special health care needs: An Israeli exploration. Patient Educ. Counseling 2000;40:510. Weisel A, Zaidman A. Attitudes of secular and religious Israeli adolescents towards persons with disabilities: a multi-dimensional analysis. Int J Disabil 2003;50(3):309-23. Henry DB, Duvdevany I, Keys CB, Balcazar FE. Attitudes of American an Israeli staff toward people with intellectual disabilities. Ment Retard 2004;42(1):26-36. Burnett J, Baker HB. Assessing the travel-related behaviors of the mobility-disabled consumer. J Travel Res 2001;40: 4-11. Daruwalla P, Darcy S. Personal and societal attitudes to disability. Ann Tourism Res 2005;32(3):549-70. Morad M, Morad T, Kandel S, Merrick J. Attitudes of Bedouin and Jewish physicians towards the medical care for persons with intellectual disability in the Bedouin community: A pilot study. ScientificWorldJournal 2004;4:649-54. Chenoweth L, Pryor J, Jeon Y.H, Hall-Pullin L. Disability-specific programme plays an important role in shaping students’ attitudes towards disablement and patients with disabilities. Learning Health Soc. Care 2004;3(2):83-91. Hernandez B, Keys C, Balcazar F, Drum C. Construction and validation of the Disability Rights Attitude Scale: Assessing attitudes toward the Americans with Disabilities Act. Rehabil Psychol 1998;43(3):203-18. Loo R. Attitudes of management undergraduates toward persons with disabilities. Rehabil Psychol 2001;46(3):288-95. Zsambok J, Hammer D, Rojahnn J. Put your money where your mouth is: direct and indirect measures of attitude toward community integration. Am. J. Ment. Retard. 1999;104(1):88-92. Antonak R, Livneh H. Measurement of attitudes towards persons with disabilities. Disabil Rehabil 2000;22(5):211-24. Rimmerman A, Hozmi B, Duvdevany E. Contact and attitudes toward individuals with disabilities among students tutoring children with developmental disabilities. J Intellect Devl Disabil 2000;25:13-8. Tervo R, Azuma S, Palmer G, Redinius P. Medical students’ attitudes toward persons with disability: A comparative study. Arch Physical Med Rehabil 2002;83:1537-42.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter VIII

All Causes and Violent Deaths of Children (0-14) in England and Wales 1974-2002 Compared to the Major Western Nations: Indicators of Improved Child Protection? Colin Pritchard∗ and Ann Sharples Institute of Health and Community Studies, Bournemouth University, Royal London House, Bournemouth, United Kingdom

Abstract In most Major Western Nations (MWN) there is considerable media criticism of failing to prevent the extremes of child abuse, namely a dead child. Testing whether services have prevented these extremes is trying to prove a `negative’, conversely measuring the `failure’ rate, children’s (0-14 years) deaths is a surrogate indicator of the level of societal child protection. Method: Utilising WHO mortality date, changes in all cause and violent-liked deaths in England and Wales were compared against the other nine MWN 3-year average per annum rates for 1974-76 v 2000-02. Violent-linked deaths included homicide, undetermined and accident and adverse event (AAE) deaths, thus accounting for any notional `hidden’ abuse deaths. Results: The current two highest rate of all cause children’s (0-14 years) deaths were in USA at 2539pm (death rates per million), representing a fall of 55% and England and Wales 1921pm, a fall of 65% , with ∗

Correspondence: Research Professor in Psychiatric Social Work, School of Health and Social Care, Bournemouth University, Rm 401b Royal London House, Christchurch Rd, Bournemouth BH1 3 LT, United Kingdom. Tel: 0044 2380 766487; E-mails: [email protected] or [email protected]

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Colin Pritchard and Ann Sharples the lowest Japan at 1297pm, a 65% fall and France 1600pm a decline of 64%. In the 1970’s England and Wales baby (<1 years) homicide rates were 2nd highest at 57pm, but fell to 17pm, a 74% fall, whereas the USA were now highest at 84pm, a 56% increase. Baby AAE deaths fell in every country, England and Wales falling from 341pm to 71pm, a 76% reduction. Both these results were significantly better than eight other MWN, although England and Wales baby undetermined deaths at 26pm, were high compared to the other MWN. Initially England and Wales’ children’s combined `violent-linked’ deaths were 203pm p.a., now 61pm, a 70% decline, with only Italy having lower rates. The highest rates were the USA at 185pm. We concluded that the major reductions in both all cause and violent-linked deaths should be a boost to the morale of front-line children’s service staff, especially in England and Wales and correct the erroneous public image. However there must be continuing concerns about USA children’s homicides.

Keywords: child abuse, deaths, prevention, international.

Introduction Since the time of Kempe et al seminal paper (1) the Major Western Nations (MWN) have appreciated that children are neglected and abused in all countries, and at the extremes, children die (1-4). In every MWN, here defined as those Western countries with populations greater than 16 millions, the death of an neglect or abused child often leads to the media castigating those children’s services concerned with protecting children (2,4,5). Consequently, the public’s perception is that front-line services are incompetent, rather than appreciating a child dying violently is relatively rare, indeed far less frequent than road deaths for example (4), though one fatally abused child is one too many. Nonetheless, in view of the considerable resources expended on children’s health and well being in the MWN (6), it is reasonable to ask, to what extent have the national child protection services (social services, health, police and education) (2), reduced the extent of neglect and abuse which leads to the extreme consequences over the last twenty years? There are of course major methodological difficulties in seeking to prove effectiveness along the continuum of neglect to the violent death of a child, as if the prevention was effective, then the event did not happen, the problem of trying to prove a negative. One answer is to reverse the question and not attempt to measure `success’ but instead, analyse `failure’, that is the violent deaths of children (0-14 years). This reflects the classic Durkheim idea that patterns of mortality infer much about society and recently UNICEF have argued that children’s (0-14 years) mortality rates reflect how well a nation is meeting the needs of its children (3). Thus we examine all causes of deaths of children (0-14 years) in the ten MWN between 1974-2002 and measure whether there were more or less violent-linked deaths of children over the period? The argument is that neglect/abuse deaths are treated as the tip-of-the-iceberg and a reduction in violent deaths infers that some form of intervention or policy change. Selfevidently, whilst the majority of neglected and abused children do not die, fatal outcomes can be taken as a major indicator of the extreme end of the neglect and abuse continuum, and can be indicative of how a nation meets the needs of its children. Moreover, focusing upon the

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violent deaths of children addresses public concerns and provides a baseline against which a society’s ability to protect it’s children can be shown to be either improving or deteriorating. All forms of violent deaths will be examined and to avoid the possibility that hidden abuse deaths have been missed and placed in mortality categories other than homicide (7), are analysed and include homicide, undetermined and accident and adverse event (AAE) deaths. The focus will be upon England and Wales, where the media criticism has been especially fierce (4) and Anglo-Welsh children’s (0-14 years) mortality be compared with the other nine MWN to explore how effective or ineffective was England and Wales in reducing children’s deaths compared to the other Major Western Nations(MWN). The study is essentially a hypothesis stimulating paper but two working null hypotheses are posed. One that changes in all cause and violent-related deaths of children will not indicate whether the Major Western Nations (MWN) are more effectively meeting the needs of their children over the period and second that changes in England and Wales’ children’s mortality will not be significantly different from the other MWN?’

Methods All data is drawn from the WHO mortality rates for 1974-76 and from the latest available standardised WHO mortality statistics for 2000-02 (8, 9). This enables a valid and reliable comparison of a country’s death rates per million (pm) of population over time to calculate a ratio of change, which compares the baseline (1974-76) with the index years, (2000-02). Hence it is the ratio of change, the difference between baseline and index years that is being measured and compared, not just the death rates. WHO children’s mortality rates are given for baby (under one year), infant (1-4 years) and child (5-14 years) (8,9) and we calculated a rate per million (pm) for these ages bands and an all children (0-14 years) mortality rate for all causes of deaths and all violent-related death, to avoid any possible hidden abuse deaths (7). The actual numbers and rates of child homicides are relatively low (4,8,9) and a few additional deaths in any one-year can distort the resulting ratio of change between single year end-points. Consequently 3-year average death rates for both males and females in the three children’s age bands baby (<1), infant (1-4) and child (5-14) are calculated, as well as an all Child (0-14) rate. It has been independently asserted that this approach successfully resolves the problems inherent in inter-national comparisons (10), as the ratio of change essentially measures a country against itself over time, which is similar to standard mortality ratios (SMR) (11) and it is these ratios that are used to compare between countries. This method has been used in a number of international studies of “problematic” deaths, using 3-year averages as comparative end-points (5, 12, 13). The baseline years are 3 year average annual death rates per million (pm) for 1974-76 and for the comparative index years 2000-02. Baseline and index years give end-points for comparison rather than rolling averages over a period, which would partly obscure the time points to be measured. The rationale for choosing 1974 was because whilst Kempe et al (1) raised the issue of child abuse earlier, it was not until the inquiry over the death of Maria Colwell in 1973, that England and Wales began to appreciate the ubiquity of the problem (5).

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Hence the baseline years of 1974-76 are compared with the latest available WHO data for the index years 2000-02. A few countries do not report rates up to 2002 so any comparisons with England and Wales will be modified accordingly e.g. the USA rates were for 1998-2000, Australia 1999-2001 and these will be matched with England and Wales averages for those years.

Hidden Abuse Deaths It has been argued that taking homicide rates as the only abuse-related deaths may miss hidden fatal abuse, which might be wrongly categorised in other mortalities, in particular “undetermined” deaths (7). Moreover, it is recognised that it is very hard to determine the accurate incidence of injuries to children, which are actually due to physical abuse (14,15). This means that any subsequent abused injured or disabled children dying might not appear in any mortality statistics, but they might appear in the undetermined category deaths. This is where though the child died violently it was not possible for the medical or legal authorities to determine whether it was accident, self-harm or assault (16). Undetermined deaths include “poisoning…(ranging from drugs to vapours and gases)…hanging…..suffocation…. drowning and submersion…firearms….undetermined intent in road crashes….blunt…falling...sharp objects….(coded Y10-35) …..and the sequel of earlier undetermined accidents” (coded Y 87-89) (16). It can be seen that all these types of death are a form of violence, but in each case “intent could not be determined”. Another possible depository of hidden abuse, could also be accidents and adverse events (AAE) deaths, and, might contain hidden abuse fatalities. There is some logic to this as AAE deaths, like child abuse, are known to be strongly associated with a range of poor psychosocio-economic circumstances (17-19). Thus in regard to accidents and adverse events (AAE) deaths, it might be inferred that an assailant may have hidden the abusive assault in a death and presented as an accident. However as this is highly unlikely in cases of confirmed motor vehicle deaths, which is a sub-category of undetermined deaths as suspicious road crashes (coded Y32), hence motor deaths are excluded from the AAE rates (16). The remaining subcategories in AAE are “poisonings, falls, fires, drowning, machines, firearms and other adverse events including late effects” (16). Whilst undetermined and AAE deaths are violent, whether they contain hidden abuse remains pure conjecture, but including them in the analysis ensures that all violent-linked deaths have been accounted for over the period. A minor point regarding the AAE rates - there were no AAE data available for the former East Germany in the 1970’s, so the `united’ German AAE baseline years have to be for 199092. Conversely, it might be argued however, that considering AAE and Undetermined deaths as possible abuse, is highly questionable, as it adds to the distress of grieving parents or the inadvertent miscarriages of justice, as exemplified in the problems surrounding “cot deaths” (5) so the greatest caution and circumspection is required. Nonetheless, only a rigorous examination of all forms of possible vViolent-related deaths of children (0-14 years), in which it might be possible that there was an assailant, will provide firm enough evidence to

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determine whether the policies, welfare provision and the children’s services of the MWN are contributing to the reduction of the extremes of child abuse. Child homicide being relatively low poses a problem when considering countries with small populations. This can make meaningful comparisons with larger countries questionable. Therefore, only countries for which there is reliable and consistent data, with populations in excess of 16 million are reviewed and designated `major’. However, because of their special circumstances, the former Warsaw pact countries, African, Asian and Latin American countries are not included in the analysis. The eligible MWN are Australia, Canada, England and Wales, France, Germany, Italy, Japan, the Netherlands, Spain and the USA. The period of review 1974-2002 crossed three `International Classification of Disease’ (ICD) editions (8th,9th,10th). However whilst some definitions of sub-categories may have changed, this was not the case with homicide and AAE (20). The undetermined category, widen slightly to include “legal” and the “results of war”, but this is unlikely to be relevant for children (0-14 years) in the ten countries under review. As all the data concerns only global mortality categories it is reasonable to compare these mortalities across these countries for the same time period. To place the results in context the numbers of violent-linked deaths in England and Wales and the USA will also be given. Only changes in national mortality rates of plus or minus 10% have clinical and practice significance, but as with previous studies "substantial" is defined here as a ratio of change outside 0.80-1.20, i.e. greater or lesser than 20% change (4,5,12), which is similar to standard mortality ratios (11). A series of chi square tests were undertaken to compare England and Wales with each of the other countries under review, with the statistical significant level of probability taken as <0.05, though statistical `trends’ are noted where the test falls just short of statistical significance (<0.07).

Results General finding: In every country in each age band boys were more often victims than girls. Moreover, baby (<1) rates were much higher than infant (1-4) rates, which in turn were higher than child (5-14) rates in every country. All causes of deaths (see table 1): In every country there were very substantial falls in all three age bands (>0.20, 20%+). Current baby (<1) deaths were highest in the USA at 7089pm, England and Wales 1957pm, but these rates represented falls over the period of 56% and 67% respectively. Lowest baby deaths were found in Japan 1195pm and France 1500pm, being falls 65% and 63%. All age (0-14) deaths were led by the USA at 2539pm, equivalent to a decline of 55% over the period, and England and Wales 1921pm a reduction of 67%, whilst again Japan at 1297pm and France 1600pm were the lowest, having reductions of 64% and 65%. Homicide: Baby (<1year) (see table 2). In the 1970’s period the highest baby homicide rate was in Japan at 89 per million (pm), followed by England and Wales 57pm, and Germany and the USA 54pm; the lowest were Italy and Spain at 6pm, then France 18pm. The highest current figures are USA at 84pm, Canada 37pm and Germany 34pm, the lowest being Italy 6pm, Spain 7pm and England and Wales 17pm.

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Infant (1-4): The infant rates fell in most countries and the current highest is now in the USA, 25pm, followed by Canada 9pm, all other countries have lower rates. Child (5-14) rates of child deaths were lower than infant rates and currently, only the USA reached double figures, 11pm, and most countries have rates less than 5pm. All age (0-14) rates: The 1970’s all age (0-14) children’s homicide rates ranged from Japan at 42pm, the USA 30pm and England and Wales at 24pm, the lowest being Spain 3pm and Italy 5pm and the Netherlands 10pm. Now the highest rate is in the USA at 40pm, Canada 16pm; the lowest being in Italy and Spain at 3pm followed by England and Wales at 8pm. Numbers: What do these rates mean in the actual numbers? In 1974-76 England and Wales baby rates transposed to an average of 35 pa (per annum) but by 2000-02 averaged 8 pa. Infant death numbers were 32 pa and are now 10 p.a. and child deaths averaged 26 pa and are now 19 pa. Thus England and Wales all children (0-14) average homicides fell from 93 pa to 37 pa an average` reduction in 56 homicides pa. In regard to USA numbers baby homicides were 171 rising to 331, infants were 306 increasing to 374 and child (5-14) 393 to 413. Overall in the 1970’s there were 870 US children’s homicides but by 2000 there were 1,118. Table 1. All Causes of Death rates of children by age and Ratios of change between 1974-76 v 1998-2002 (rates per million) Countries’ rates –Age Year 1974-76 v 19982002 USA Ratio 74-76 v 98-00 England & Wales Ratio 74-76 v 2000-02 Canada Ratio 74-76 v 98-00 Australia Ratio 74-76 v 1999-01

< 1yrs 1974 v 2002

1-4yrs 19746 v 2002

5-14yrs 1974 v 2002

0-14yrs 1974 v 2002

160027089 0.44 174205668 0.33 13898 – 5271 0.38 14751- 5248 0.36

716 – 338 0.47 737 – 257 0.35 746 - 239 0.32 748 - 291 0.39

3620.52 327 0.40 387 0.38 332 – 0.42

Netherlands Ratio 74-76 v 2000-02 Italy Ratio 74-76 v 1999-01 Spain Ratio 74-76 v 1999-01 Germany Ratio 74-76 v 1999-01 France Ratio 74-76 v 98-00 Japan Ratio 74-76 v 2000-02

108860.47 206480.24 166110.27 197460.23 124420.35 100550.34

669 – 0.41 612 – 0.32 772 – 0.35 758 – 0.34 681 – 0.36 844 – 0.39

317 – 0.43 335 – 0.41 365 – 0.46 360 – 0.36 366 – 0.39 304 – 0.43

5693 – 0.45 5958 – 0.33 5010 – 0.38 5277 1893 0.36 3957 – 0.47 7198 – 0.25 5916 – 0.28 6955 – 0.23 4486 – 0.36 37340.35

5170 4983 4558 4518 4413 3427

277 197 272 254 244 332

190 130 148 140

137 139 168 129 144 131

2539 1957 1886

1845 1773 1666 1634 1600 1297

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Table 2. Homicide rates and ratios of change s in the MWN 1974-76 v 2000-02 Rank ordered by all child ratios of change (rates per million) Country and Years Rank

Babies <1

Infants 1-4

Children 5-14

All Child

USA 1974-76 (1) 1998-2000 ratio

54 84 1.56

25 25 1.00

10 11 1.10

30 40 1.33

France 1974-76 (2) 1998-2000 Ratio

18 19 1.06

4 5 1.20

2 3 1.50

8 9 1.13

Netherlands 1974-76 (3) 2000-2002 ratio

23 28 1.22

3 3 1.00

3 2 0.67

10 11 1.10

Australia 1974-76 (4=) 1999-2001 ratio

29 28 0.97

8 9 1.13

5 4 0.80

14 14 1.00

Spain 1974-76 (4=) 1999-2001 ratio

6 7 1.17

2 2 1.00

1 1 1.00

3 3 1.00

Canada 1974-76 (5) 1998-2000 ratio

37 37 1.00

12 9 0.75

7 3 0.43

19 16 0.84

Germany 1974-76 (6) 1999-2001 ratio

54 34 0.63

5 6 120

5 3 0.60

21 14 0.67

Italy 1974-76 (7) 1999-2001 ratio

6 6 1,00

2 2 1.00

7 1 0.14

5 3 0.60

Eng & Wales 197476 1998-2000 1999-2001 (9) 2000-2002 Japan 1974-76 (10) 2000-2002 ratio

57 13 = 0.23 16 = 0.28 17 = 0.30

12 4 = 0.67 5 = 0.42 5 = 0.42

4 2 = 0.50 5 = 1.20 3 = 0.75

24 6 = 0.25 9 = 0.38 8 = 0.33

89 25 0.28

27 8 0.30

10 3 0.30

42 12 0.29

Ratios of Change 1974-6 Versus 2000-02 Baby (<1): There were marked changes over the period as baby homicide rates fell very substantially (>0.20), Japan’s ratio of change 0.28, was equivalent to a 72% decline, England and Wales ratio 0.30 and Germany ratio 0.63, reductions of 70% and 67% respectively. Conversely there were substantial increases in USA baby ratio of change, 1.56, a 56% rise and for the Netherlands a ratio 1.22, whilst Spain’s ratio of 1.17 reflected their low base rate moving from 6pm to 7pm homicides over the period.

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Table 3. Undetermined deaths and ratios of change. Rank ordered by all child ratios (rates per million) Country and years Netherlands 1974-76 (1) 2000-2002 Ratio Eng and Wales 1974-76 1998-2000 1999-2001 (2) 2000-2002 Canada 1974-76 (3) 1998-2000 Ratio Japan 1974-76 (4) 2000-2002 Ratio France 1974-76 (5) 1998-2000 Ratio Australia 1974-76 (6=) 1999-2001 ratio Italy 1974-76 (6=) 1999-2001 Ratio USA 1974-76 (8) 1998-2000 Ratio Germany 1974-76 (9) 1999-2001 Ratio Spain 1974-76 (10) 1999-2001 Ratio

Babies <1 2 12 6.00 16 40 =2.50 32= 2.00 26 = 1.63 5 11 2.20 14 16 1.14 17 11 0.65 7 2 0.29 4 1 0.25 33 16 0.48 25 11 0.44 0 0 xx

Infants 1-4 2 2 1.00 4 4 = 1.0 4 = 1.0 4 = 1.0 3 2 0.67 4 4 1.00 16 9 0.56 3 2 0.67 1 1 1.00 12 3 0.0.25 9 3 0.67 0 1 xx

Child 5-14 1 0 xx 3 3 = 1.0 3 = 1.0 3= 1.0 3 3 1.00 2 1 0.50 3 3 1.00 3 1 0.33 2 1 0.50 4 2 0.50 9 3 0.67 0 0 xx

All Child 0-14 2 5 2.50 8 16=. 2.00 13=1.63 11=1.38 4 5 1.20 7 7 1.00 12 8 0.67 4 2 0.50 2 1 0.50 16 7 0.44 14 6 0.43 0 1 xx

Infant (1-4): There were low rate of changes, which were not very meaningful in most countries, with the exceptions being Japan and England and Wales whose rates fell substantially, ratios of 0.30 and 0.42 respectively. Child (5-14): The latest rates of child deaths only reached double figures for Japan and the USA, so any changes were not statistically meaningful.

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All Age (0-14) Changes 1974-2002 The all age (0-14) homicide rates rose substantially in the USA, a ratio of 1.33, whereas there were notable falls in Japan 71%, England and Wales 67% and Germany 33%. Italy’s decline of 40% was from a low rate of 5pm down to 3pm. Undetermined Deaths (see table 3): Table 3 shows the undetermined rates and changes over the period. In the 1970’s the highest baby rates were the USA at 33pm and England and Wales at 16pm. Spain reported virtually none and the next lowest were the Netherlands 2pm and Italy 4pm. However, by 2000-02 England and Wales baby OECD rates rose to 26pm, which, apart from the Netherlands, was the only country to have an increase. The current undetermined rates were even lower for infant and child age bands, whilst no country reached 5pm for the child (5-14) age group in either period. Apart from England and Wales all age (0-14) rates currently at 11pm, no other country reached double figures. Numbers: The numbers of baby rates in England and Wales were and average of 9 pa, but rose to17 pa and all children averaged 39 pa in the 1970s, but increased to 46 pa, and extra seven a year. In the USA baby undetermined numbers fell from 102 pa to an average of 64 and all children declined from 398 to 177 pa, a reduction of 211. Accidents and Adverse Events (AAE) (See Table 4) Every country had substantial falls in AAE mortality over the period, The highest current baby AAE rates were in the USA 221pm, a ratio of 0.72, equivalent to a fall of 28%, and Japan at 147pm, down 68%. The lowest latest baby AAE rates were in the Netherlands at 55pm, with a ratio 0.20, followed by Germany 57pm, ratio 0.32, and England and Wales 74pm, a ratio of 0.24. All age (0-14) AAE rates averaged 72pm in the 10 MWN, with the highest being the USA at 138pm, ratio of 0.57, Australia 84pm, ratio 0.35 and France and Japan at 83 pm., ratios of 0.21 and 0.31 respectively. The lowest all age AAE rates were found in England and Wales 42pm, a ratio of change of 0.25, Germany 42pm, ratio 0.40 (1990-2001) and the Netherlands 49pm, with a ratio 0.26. Numbers: In 1974-76 England and Wales Baby AAE deaths were 257 pa, but by 2000-02 averaged 41 pa. All age (0-14) England and Wales AAE deaths averaged 943 pa, but are now down to 167 pa an 88% reduction. In the USA baby AAE fell from 1381 down to 685 and all age AAE declined from an average of 8,308 to 3,426 pa, a 59% reduction. Combined violent-related death rates (0-14) (see table 5): The combined violent-linked deaths of children (0-14) (homicide, OECD and AAE) in the MWN show that they declined very substantially (>20%) in every country between 1974-2002. The highest current rate was in the USA at 185pm, a ratio of change 0.64, followed by Japan at 102pm, a 0.32 ratio and Australia at 100pm, a ratio of 0.32. The lowest rates were found in Italy at 54pm, England and Wales 61pm and Spain 67pm, being falls equivalent to 65%, 70% and 70% falls respectively. Numbers: The numbers of violent-linked deaths in England and Wales initially averaged 1,075 pa, but by 2000-02 averaged 250 pa, a 77% reduction. In contrast, the numbers of deaths in the USA were 8,400 pa falling to 4,634 pa were equivalent to a reduction of 45%.

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International Comparisons of Violent-Linked Deaths (See Table 6) A series of Chi Square tests compared the changing patterns of mortality in England and Wales with each of the other countries. Table 6 shows the results. Homicide: England and Wales had a significantly greater reduction for baby homicides than every country except Japan. The all age England and Wales rates were significantly better than Australia (trend), Canada, France (trend), the Netherlands and the USA. Table 4. All accidents and adverse events 1974-2002 by rank ordered by all child ratios (rate per million) Country and years Babies <1 Infant 1-4 USA 1974-76 309 264 (1) 2000 221 120 Ratio 0.72 0.46 Germany 1990-92# 181 121 (2) 1999-2001 57 58 Ratio 0.32 0.48 Australia 1974-76 317 271 (3) 1999-2001 125 88 Ratio 0.39 0.32 Italy 1974-76 193 132 (4) 1999-2001 82 37 Ratio 0.43 0.28 Japan 1974-76 454 255 (5) 1998-2002 147 64 Ratio 0.32 0.25 Canada 1974-76 342 247 (6=) 1998-2000 119 54 Ratio 0.35 0.22 Spain 1974-76 376 165 (6=) 1999-2001 81 68 Ratio 0.22 0.41 Netherlands 1974-76 273 181 (8) 2000-2002 55 53 Ratio 0.20 0.29 England & Wales74-76 314 111 1998-2000 66 = 0.21 29 = 0.26 1999-2001 71= 0.23 26 = 0.23 (9) 2000- 2002 74= 0.24 28=0.25 France 1974-76 862 207 (10) 1998-2000 123 75 Ratio 0.14 0.36 # There were no earlier figures for the DDR and FDR.

Child 5-14 160 73 0.46 63 32 0.51 136 40 0.29 114 32 0.28 85 37 0.44 192 53 0.28 119 41 0.35 108 38 0.35 88 12 = 0.14 11 = 0.13 24=0.27 128 52 0.41

All Child (0-14) 244 138 0.57 122 49 0.40 241 84 0.35 146 50 0.34 265 83 0.31 260 75 0.29 220 63 0.29 187 49 0.26 171 36=0.21 36 =0.21 42=0.25 399 83 0.21

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Table 5. Total violent-linked (Homicide, Undetermined, AAE) Children (0-14) rates and ratios of changes in the MWN 1974-76 v 2000-02, rank ordered by highest rates (rates per million) Country and Years Rank

Homicide

Undetermined

AAE

Total

USA (3) 1974-76 (1) 1998-2000 Ratio

30 40 1.33

16 7 0.44

244 138 0.57

290 185 0.64

Japan (2)1974-76 (2) 2000-2002 Ratio

42 12 0.29

7 7 2.00

265 83 0.31

314 102 0.33

Australia (5) 1974-76 (3=) 1999-2001 ratio

14 14 1.00

4 2 0.50

241 84 0.35

259 100 0.39

France (1) 1974-76 (3=) 1998-2000 Ratio

8 9 1.13

12 8 0.67

399 83 0.21

419 100 0.24

Canada (4) 1974-76 (5) 1998-2000 ratio

19 16 0.84

4 5 1.20

260 75 0.29

283 96 0.34

Germany ((9)1974-76 (6) 1999-2001 ratio

21 14 0.67

14 6 0.43

122 49 0.40

157 69 0.44

Spain (6) 1974-76 (7) 1999-2001 ratio

3 3 1.00

0 1 xx

220 63 0.29

223 67 0.30

Netherlands (8) 1974-76 (8) 2000-2002 ratio

10 11 1.10

2 5 2.50

187 49 0.26

199 65 0.33

Eng and Wales (7) 1974-76 1998-2000 1999-2001 (9) 2000-2002 Italy (10) 1974-76 (10) 1999-2001 ratio

24 6 = 0.25 9 = 0.38 8 = 0.33 5 3 0.60

8 16 = 2.00 13= 1.63 11= 1.38 2 1 0.50

171 36 = 0.21 36= 0.21 42= 0.25 146 50 0.34

203 58=0.29 58=0.29 61=0.30 153 54 0.35

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Table 6. England and Wales baby and all children deaths compared with other MWN 1974-76 v 2000-02, P values Countries Ratios of Change Australia Canada France Germany Italy Japan Netherlands Spain USA

Homicide All Baby - Child <0.001 <0.06t <0.0001 <0.03 <0.003 - <0.07t <0.03 n.sig <0.04 n.sig n.sig n.sig <0.001 <0.05 <0.03 n.sig. <0.0001 <0.001

OECD All Baby - Child n.sig n.sig n.sig n.sig n.sign.sig <0.03+ - n.sig n.sig n.sig n.sig n.sig <0.02 n.sig n.sig n.sig <0.01+ - n.sig

AAE All Baby Child <0.0001 <0.01 <0.001 <0.001 n.sig. n.sig <0.09t - <0.01 <0.0001 <0.03 <0.001 <0.07t n.sig n.sig n.sig n.sig <0.0001 <0.0001

All chi square tests 1 d/f. + indicates England and Wales changes greater than the other country, otherwise England and Wales rates declined significantly more than the other country.

Undetermined deaths: Whilst infant and child undetermined rates were not very high England and Wales baby rates had increased significantly more than Germany and the USA. Conversely, the Netherlands rates rose significantly more than England and Wales. However, there were no significant differences for all child rates between any of the other countries and England and Wales. Accident and adverse effects: England and Wales baby AAE rates declined significantly more than every country except France, the Netherlands and Spain. England and Wales all child (0-14) AAE rates had significantly bigger reductions than Australia, Canada, Germany (trend), Italy, Japan and the USA.

Discussion Like all studies on aggregated data, this study can tell us nothing about individuals. In addition, there is the inherent problem of international variations in recording. However, by utilising WHO data, and focusing upon ratios of change, the method used has been said to have largely resolved these problems (10). Notwithstanding the above, the results are reasonably reliable in providing an indicator of changing trends of the deaths of children in England and Wales and the other Major Western Nations. The main limitation, however, is that whilst we can map the changes effectively, we do not know the extent to which the various types of policy and practice interventions’ may have contributed to the reductions. Various changes in policies, health and social care practices and welfare provision will have been a factor in the general improvements, as well as the direct practice contributions of the Child Protection Services. Hence, we must interpret the results with caution. However, it is known that amongst the MWN reviewed, the proportion of Gross Domestic Product (GDP) devoted to health by England and Wales was the lowest of

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the ten countries under review (6). Whilst this has recently reached the European Union average, the other MWN have spent considerably more on health than England and Wales over the past 20 years (5,6). This needs to be borne in mind when considering the likely contribution of the Child Protection Services in England and Wales, as say compared to health alone. Nonetheless, it is accepted that these results cannot show explicitly which of the various societal responses to children’s needs made the greatest contribution and must be interpreted cautiously. The first null hypothesis that changes in all causes and violent-linked deaths in the MWN would not show that they have more effectively met the needs of their children, by reducing child deaths, can be rejected as every nation more than substantially reduced both types of mortality. The second null hypothesis can be rejected as England and Wales had statistically significantly bigger reductions than most of the other MWN for all cause deaths in regard to Australia, Canada, France, Japan, Netherlands and the USA, as the Anglo-Welsh rates reduced significantly more than these countries. However, Germany, Italy and Spain had bigger reductions in all cause deaths than England and Wales. In regard to the violent-linked deaths the hypothesis can also be rejected in regard to baby homicide for every country except Japan and for Baby AAE for every country except France, the Netherlands and Spain, but not for baby undetermined deaths as Germany and the USA had significantly better results over the period. In England and Wales and the other countries, all cause and violent-linked deaths have never been lower but in regard to the combined violent-linked deaths, only Italy had currently lower all children’s rate 54pm to 61pm than England and Wales. It is reiterated that UNICEF (3) have argued that the extent of children’s injuries and deaths are a reflection of the degree to which a society meets the needs of its children. This theme is pursued in the UN `Millennium Goals’ (21), hence the importance of examining, over time, children’s mortality statistics, even in the Major Western Nations.

Do Undetermined or AAE Contain Many Hidden Abuse Deaths? When an earlier epidemiological study had shown an improvement in England and Wales homicides (22) it was argued that this was largely to due to there being un-reported abuserelated deaths, hidden in the undetermined and, possibly AAE deaths (7). In reviewing the sub-types of death within undetermined deaths poisoning by drugs or gases, drowning, falls etc numbers of baby death in England and Wales rose from 9 to 16 per annum, which might give rise to a degree of suspicion. Taking a suspicious perspective and assume that most undetermined baby, along with the homicides, were `abuse-related’ and therefore the responsibility of the Child Protection Services, the overall fall in the numbers of baby violent-related deaths more than matches majority of the other MWN. Perhaps therefore, the children’s services in England and Wales might be given some credit for these reductions? However, to assume that undetermined deaths are `abuse’ related without knowing the facts carries other problems, such as inadvertently castigating grieving parents of children

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dying from an undetermined or an accidental death, which at worst could contribute to a miscarriage of justice (5). Whilst such mortality categories may contain un-recognised, `abuse-related’ deaths, on these results it seems unlikely that there were many undiscovered `assailants’ hidden in these deaths in all the countries reviewed. There were two results that were unexpected, which raise questions which this study can not answer. In the 1970s England and Wales were amongst the worst of the MWN for violent-linked deaths of children but are now the second lowest. Furthermore, they have significantly seen bigger falls in all causes of deaths than six of the nine other MWN. Such achievements over the period might counter the public image of failing children’s services not just in England and Wales but in most of the other MWN. Conversely, the substantial increases in USA homicides was a surprise as this occurred within a declining adult homicide rate (5,8,9). Transposing these USA rates into numbers, the combined violent-related deaths of US children averaged 4,634 pa, exceeding many national catastrophes!

Conclusions The extent of the improvement in children’s violent-linked deaths in the majority of the Major Western Nations, especially in England and Wales, is a positive outcome, especially as the media appears to imply that matters have never been worse, despite earlier evidence of continued improvements over the years (4,5,22), culminating in this latest and most detailed analysis. This erroneous perception may well contribute to an undermining of the morale of frontline staff. Moreover, politics can be played with high profile children’s deaths. A former British Director of Social Services when hearing about earlier encouraging results said “ I am really pleased about the results but don’t shout too loudly or the elected members will hear and cut the budget”. To be fair, it does seem that within the competing demands for Social Service Department resources, children’s services have received a degree of protection. This may have proved to be a factor in the England and Wales results being better than those of America as there is evidence that during the Regan and first Bush years of precidency, there were serious cuts in a range of services related to children (23,24), whereas relatively the Anglo-Welsh children’s services have a degree of continued priority. As in all countries, children’s services are multi-disciplinary, consisting of social workers, pediatricians, health visitors, GP’s, police (2), and, increasingly, teachers (25). Whilst these results must be treated cautiously, yet as the media readily blames poor social work for the tragedies, without in anyway being complacent, social work’s contribution to what has been achieved should be a boost to the families with whom they work and the morale of front-line staff. Though self-evidently, improved economies and medical care will have contributed to these reduction in deaths, but so too will the children’s services. The death of any child however is a tragedy, especially when it was violent-linked and it is imperative not to forget that these figures are not just numbers, but can often represent the inhumane treatment of children. Nonetheless, perhaps Western societies can acknowledge

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these achievements, especially in England and Wales, of steady progress, in which with increasing effectiveness, children are protected from the extremes of abuse.

References (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13)

(14) (15) (16) (17) (18) (19)

Kempe CH, Silverman FN, Steele BF, Droegemueller W, Silver HK. The battered child syndrome. JAMA 1962;181(1):17-24. Kooijman K, Wattam C. Moving towards effective child maltreatment prevention strategies in Europe. Brussels: CAPCAE, 1997. UNICEF. Child deaths by injury in rich nations. Florence: Innocenti Res Centre, Report 2, 2001. Pritchard C, Butler AW. Child homicide in the USA 1974-97: An international comparison-grounds for concern? J Fam Violence 2003;18:341-50. Pritchard C. The child abusers: Research and controversy. Buckingham: Open Univ Press, 2004. US-DHHS. Health, United States, 2006. Washington, DC: US Dept Health Human Serv., 2006. Creighton J. Children’s homicide: an exchange. Br J Soc Work 1993;23(4):643-4. WHO. Annual health statistics (1974,1975,1976). Geneva: World Health Org., 1979. WHO. Annual health statistics. Geneva: World Health Org, 2005 (www3.who.int/whosis/mort/table1). Shah A, De T. Suicide in the elderly: A review. Int J Psychiatr Clin Pract. 1998;2(1):318. Gladen BC, Rogen WJ. On graphing rate ratios. Am J Epidemiol 1983;10:905-8. Pritchard C, Amunalla S. Suicide and undetermined deaths in 17 predominately Islamic countries: A source of `hidden’ suicides. Psychol Med 2007;37:421-30. Pritchard C, Sayer T. Estimating potential extra-family child homicide assailants in the UK and their homicide rate. Perception of risk and the need for debate. Br J Soc Work 2007, in press. Barnes PM, Norton CM, Dunstan FD, Kemp AM, Sibert JR. Abdominal injury due to child abuse. Lancet 2005;366(9481):187-8. Sibert RJ, Payne EH, Kemp AM, Barber M, Rolfe K, Butler I. The incidence of severe physical child abuse in Wales. Child Abuse Neglect 2002;26(3):267-76. WHO. International classification of diseases, 10th ed. Geneva: World Health Org, 1992. Lipman E, MacMillan H, Boyle M. Childhood abuse and psychiatric disorders among single and married mothers. Am J Psychiatry 2001;158(1):73-7. Moore A. Changing patterns of childhood mortality in Wolverhampton. Arch Dis Childhood 2005;90(7):687-91. Subramanian SV, Chen JT, Rehkopf DH, Waterman PD, Krieger N. Racial disparities in context: A multi-level analysis of neighbourhood variations in poverty and excess mortality among Black populations in Massachusetts. Am J Public Health 2005;95:375.

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(20) US-DHHS. Comparability of cause of death between ICD-9 and ICD-10: Preliminary estimates. Washington, DC: US Dept Health Human Serv, Nat Vital Stat., Report 49, 2005. (21) UN. UN millennium development goals report: Keeping the promise 2015. Geneva: United Nations Org, 2006. (22) Pritchard C. Indicators of effective child protection? A re-analysis of international child data 1973-93. A reply to Lindsey, Trocme and Macdonald. Br J Soc Work 1996;26:545-63. (23) Mishra R. Globalisation and the welfare state. Cheltenham: Edward Elgar, 1999. (24) McFate K, Lawson R, Wilson JW. Poverty, inequality and the future of social policy. New York, Sage, 1995. (25) Williams R, Pritchard C. Breaking the cycle of educational alienation. Buckingham: Open Univ Press, 2006.

Section II: Environment and Mood

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter IX

Childhood Obesity and Depression: Connection between these Growing Problems in Growing Children Gloria M. Reeves ∗1,2, Teodor T. Postolache2 and Soren Snitker3 1

Child and Adolescent Psychiatry Division, Department of Psychiatry 2 Mood and Anxiety Program, Department of Psychiatry 3 Endocrinology, Diabetes, and Nutrition Division, Department of Medicine, University of Maryland School of Medicine. Baltimore, MD, USA

Abstract Depression and obesity have been recognized as major public health issues in youths. Although they have traditionally been compartmentalized as separate physical and emotional health conditions, evidence suggests interactions and common pathways between them, implying that successful treatment should ideally target shared underlying mechanisms. The purpose of the present article is to review the pediatric diagnostic criteria for depression and obesity, highlight similarities in their clinical presentation, identify common pathways and underlying mechanisms, describe their developmental trajectories, and suggest areas for future study to guide development of innovative prevention and treatment initiatives.

Keywords: pediatric depression, pediatric obesity, inflammation, serotonin.

∗

E-mail address: [email protected]. Correspondence: Gloria M Reeves, MD, University of Maryland School of Medicine, 701 W Pratt Street, Baltimore, MD 21201, United States

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Introduction Obesity and depression, conditions which have until recently been considered “adult” health problems, are now recognized as common conditions among youths. Recent data from the National Health and Nutrition Examination Survey estimate 17% of youths ages 2-19 years old to be overweight [1] compared to just 5% a few decades ago. Depression also impacts a large population of youths. Prevalence of major depressive disorder has been estimated to be 2% of children and 4-8% of adolescents [2]. Note that in the following, “children” generally means up to 12 years of age, while “adolescents” are 13 years and above. The word “youths” is used when referring collectively to both groups. The high prevalence of these individual conditions is alarming given the health and socioeconomic burdens associated with these problems, and the limited efficacy of current treatment interventions. The Surgeon General has highlighted both pediatric obesity and depression as major public health issues in recent reports. In the 2000 report on children and mental health, the Surgeon General emphasized that recurrence of childhood depression episodes is common and depression “may leave behind psychological scars that increase vulnerability throughout early life.” In 2003, the Surgeon General testified on “The Obesity Crisis in America” that the annual cost of obesity in the US in 2000 was 117 billion dollars, and that obesity epidemics have been followed by pediatric epidemics of type 2 diabetes and hypertension (http://www.surgeongeneral.gov/reportspublications.html#calls). While psychosocial and medication interventions are increasingly used to target childhood depression, the limited effectiveness of standard interventions is concerning. The state-of-the-art Treatment of Adolescents with Depression Study (TADS) reported that only 37% of adolescents treated with intensive, combination medication and psychotherapy treatment achieved remission at 12 weeks [3]. Similarly, lifestyle and medication interventions for childhood obesity have failed to curb the growing epidemic of pediatric overweight, leading to the increased use of invasive bariatric surgery for morbidly obese adolescents [4]. For the most part obesity and depression have been compartmentalized as separate health problems of a physical and emotional nature, respectively [5]. However, the fact that depression and obesity have shared symptoms such as sleep problems, sedentary behavior and dysregulated food intake, is not a mere coincidence but appears to be related to shared pathophysiological mechanisms. If this conceptual framework is correct, it implies that successful treatment for the comorbid conditions of obesity and depression should ideally target shared underlying mechanisms. The purpose of the present article is to review the pediatric diagnostic criteria for depression and obesity, highlight similarities in their clinical presentation, review common pathways or other connecting mechanisms, describe their developmental trajectories, and suggest areas for future study with the eventual goal of improved therapeutic and preventive modalities.

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Diagnoses of Childhood Depression and Obesity Obesity and depression are diagnosed differently in children compared to adults. Depression criteria include depressed mood, anhedonia, fatigue, feelings of guilt or worthlessness, thoughts of death, as well as changes in sleep, appetite, or psychomotor activity. Problems with sleep, appetite, and psychomotor activity can occur in either direction, i.e. individuals may experience insomnia or hypersomnia; anorexia or increased appetite; psychomotor retardation or agitation. The Diagnostic and Statistical Manual IV text revised (DSM IV TR) criteria for a major depressive episode stipulate that five of nine possible depression criteria must be present for most of the time over a two week period, must be present most of the time, one of the criteria must include either depressed mood or diminished interest or pleasure (anhedonia), and the symptoms must be a change from prior functioning. There are two differences in how depression is diagnosed in youths compared with adults. Mood may be irritable, instead of depressed or anhedonic, and youths may meet symptom criteria if they fail to make expected gains in growth rather than experience weight loss from decreased appetite. In younger children diagnosis is challenging because of difficulty eliciting internalizing symptoms (e.g. feelings of hopelessness or guilt) Subtypes of major depressive disorder include atypical, melancholic, postpartum, catatonic, or chronic depression features. Atypical depression describes individuals who experience mood reactivity plus two of the following symptoms: weight gain/increased appetite, hypersomnia, heavy, leaden feelings in arms or legs (leaden paralysis), and long standing pattern of interpersonal rejection sensitivity; whereas melancholic depression describes individuals with prominent anhedonia and three or more of the following symptoms: anorexia/weight loss, worsening depression in morning, early morning awakening, excessive guilt, marked psychomotor retardation or agitation. Similar to adults, a mixed presentation of depression is more prevalent than any of the specifier types. In a clinical sample of over 1,000 youth aged six to 19 years old with major depressive disorder, 15% of youths met criteria for atypical depression, with 21% of youths with symptoms of hypersomnia [6]. Melancholic depression is more prevalent in adolescents compared with prepubertal children [7]. In the TADS study, 14% of youths met criteria for melancholic depression, and melancholic features were associated with poorer response to depression intervention[8]. Strictly speaking, “obesity” means excess of body fat. However, for practical reasons, clinical recommendations are based on the body mass index (BMI), which is calculated as the weight divided by the height squared, in metric units, i.e., kg/m2. Because the numerator of the BMI is body weight, which also includes non-fat, or lean mass, some have argued that BMI should only be used as a screening tool, not a diagnostic tool [9]. In adults, cutoff points for BMI are 25 kg/m2 and 30 kg/m2 (labeled “overweight” and “obesity”, respectively). In children, however, normal growth patterns dictate the use of age- and sex-specific cutoff points. The presently accepted BMI-for-age growth curves were published by the Centers for Disease Control and Prevention (CDC) in 2000 and are based on United States national surveys from 1963-1994, i.e., before the current rise in obesity gained momentum [10]. As a function of age, BMI exhibits a downward trajectory from infancy through age 6 years, whereupon an upward trajectory takes over. According to the CDC, children at or above the

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85th but below the 95th percentile are considered “at risk for overweight” and those at or above the age- and sex- specific 95th percentile are considered “overweight”. This terminology makes sense because BMI is a measure of weight and not fatness, making it is possible (although extremely rare) that some children, especially adolescent boys, may be miscategorized if a high BMI percentile is equated with obesity. However, an expert panel convened by the American Medical Association has proposed labeling the 85th percentile “overweight” and 95th percentile “obese”, concerned that avoidance of the term “obese” would lead to under-treatment (http://www.ama-assn.org/ amednews/site/free/hlsd0709.htm, accessed 11/19/2007). Methods exist to estimate body fat content from skinfold thickness and, more precisely, by radioimaging techniques, but there are no criteria to interpret their results in terms of what constitutes a pathological amount of body fat. Therefore, this paper will use the terms “obesity” and “overweight” interchangeably.

Similarities in Clinical Presentation of Childhood Obesity and Depression Those meeting the diagnostic criteria for depression are a heterogeneous population with differences in individual symptoms (e.g. sleep change can be insomnia or hypersomnia) as well as differences in combinations of symptoms (i.e. irritable or depressed mood is the only required symptom in the combinations). In this section, we review specific depression symptoms (both type of symptom and direction of impairment, e.g. insomnia) that may serve as links between childhood obesity and depression and possible targets for intervention for both disorders. Sleep Sleep problems are a prominent and difficult to treat feature of adolescent depression. In the TADS study of over 400 adolescents with a primary diagnosis of major depressive disorder, change in sleep was the most prevalent residual depression symptom in both youths whose depressive episode remitted as well as those whose depression failed to remit at 12 weeks [11]. Adolescents with depression have prolonged sleep latency compared with nondepressed adolescents [12]. Prolonged sleep latency is important because it is associated with increased risk of depression recurrence among youths [13]. In children ages 7-17 years old with major depressive disorder, insomnia was associated with active suicidality, measured by presence of suicidal thoughts and plan [14]. Obesity, too, has connections to sleep problems. Overweight children are at increased risk for sleep apnea and obesity hypoventilation syndrome, which are associated with daytime somnolence and decreased nighttime sleep [15]. A cross section sample of 383 youths ages 11-16 years old studied using objective activity monitoring (wrist accelerometer) indicated that overweight youths experienced less total sleep time than non-obese youths, although there were no significant differences between the groups in measures of sleep disturbance [16]. Relationship between sleep and obesity may be mediated at least in part by insulin resistance. In a study of obese children, insulin resistance was associated with shorter sleep duration by polysomnography [17]. In healthy, young adults, short term partial sleep deprivation (4 h per night) results in increased insulin resistance [18] As early as 1999, it was

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proposed that sleep loss could explain the increased prevalence of diabetes and other cardiovascular factors in individuals with low socioeconomic status, possibly mediated through sympathoadrenal dysregulation [19]. While decrease in sleep is not a consistent feature of either depression or obesity, and in fact sleep may be increased in atypical depression, sleep deprivation may contribute to a worsening of both obesity and depression. As sleep deprivation is associated with increased hunger [20] and decreased insulin sensitivity, this symptom is likely to exacerbate or at least sustain obesity. Insomnia is also associated with increased suicidality in depressed patients. In other words, undertreated sleep problems in obese depressed children decreases chances of sustained recovery from depression and increases suicidal risk. It is unclear if individuals with depression are more vulnerable to the psychological distress caused by insomnia or if insomnia and depression severity are linked to underlying dysfunction in neurotransmitter systems that regulate both mood and sleep, e.g. serotonin system. Another system that is disrupted in sleep deprivation and may be of importance for both obesity and depression is the hypothalamic-pituitary-adrenal axis (see below) [21]. An area for future research is to determine the threshold for sleep deprivation to have an impact on either mood or obesity in children at different stages of growth, i.e. differences in developmental sleep needs, and in non-depressed versus depressed children. However, it must be emphasized that it has not been irrefutably demonstrated that sleep deprivation is an independent risk factor for depression. Sleep is an appealing target for both depression and obesity interventions. Sleep can be measured objectively, there are both pharmacologic and behavioral options (e.g. sleep hygiene, relaxation techniques) to target sleep problems, and insomnia is associated with less social stigma that either depression or obesity.

Sedentary Behavior Human locomotion behavior can be summarized in various ways. One way is to look at total amount of activity over a specific period (e.g. 24 h) as quantified by movement detection or its associated energy expenditure, which can be calculated with the use of indirect calorimetry. Another way is to look at time spent at various levels of intensity, typically segmented as sedentary, light, moderate, and vigorous. Time spent in sedentary activity, sometimes reduced to time spent watching TV, is sometimes a stronger correlate of obesity than total amount of activity or time spent in moderate/vigorous activity. In a prospective study of three year old children, TV viewing and physical activity measures at age 3 were better predictors of BMI at age 6 than eating habits [22] despite the fact that eating habits were assessed with great accuracy using direct observation by trained observers in the child’s community environment. TV viewing has been identified as the strongest connection between a specific behavior and childhood obesity [23]. The relationship between sedentary behavior and obesity is not explained solely by reduced physical activity. In a population of adolescent females, correlation between percentage body fat and internet viewing time persisted even after controlling for physical activity [24]. A core feature of depression is decreased interest and motivation for activity. Lack of activity does not need to cause weight gain to have an adverse effect on metabolism. In a

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study of adolescents, we found that independently of each other, body composition and physical activity were determinants of insulin sensitivity [25]. Reports of interpersonal problems and feelings of ineffectiveness on the Children’s Depression Inventory correlated with sedentary behavior in young adolescents, ages 11-13 years old [26]. With recent technology advances, there are expanded options for sedentary activity including video games, internet activity, and 24 hours of daily TV programming. Among a community sample of approximately 1,500 youth aged 10-17 years old who used the internet, 30% of youth with major depressive symptomatology (five depression criteria plus functional impairment) used the internet for at least 3 hours a day, compared with 14 % of youths with minor depressive symptomatology (3 depression criteria) and 12% of youths with no depressive symptoms [27]. Increased sedentary behavior may also contribute to worsening depression and obesity, as well as directly link these two conditions. Depression may cause increased sedentary activity secondary to depressed mood, fatigue, and decreased motivation. The combination of decreased physical activity and/or increased appetite can lead to unhealthy weight gain. Thoughts, mood, and behavior are linked conceptually in the cognitive behavioral model of depression. Interventions targeting one of these components are expected to impact the other two. For example, increased play time with peers may improve mood as well as thoughts of self-esteem (“other kids like to play with me”). Many sedentary activities are considered pleasurable by children, i.e. playing a favorite video game. However, exclusive pursuit of sedentary activities promotes social isolation as well as decreased physical activity. Increased sedentary behavior is also likely to sustain or worsen obesity unless there is significant reduction in food intake. Thus, reduction in sedentary activity may help improve obesity by increased energy expenditure and improve mood by increased social interaction/support. In summary, the relation between obesity, depression, and inactivity is multidirectional. Inactivity is a cause of obesity. Depression may be a cause of inactivity and therefore promote obesity. Those with a large body have greater difficulty exercising and derive less pleasure doing so; the resultant inactivity may promote depression. An environmentally induced decrement in physical activity may lead to both obesity and depression through discrete or convergent pathways. It is likely that a comprehensive approach addressing all three issues directly will be clinically superior to one that only addresses one. However, sometimes it may be necessary to address obesity first (a clinical parallel would be the common notion that one can not even start meaningful treatment of depression in severely anorexic patient without addressing malnutrition first).

Appetite and Food Intake Food intake is of importance in a discussion of obesity because obesity arises as a result of imbalance between energy intake and expenditure. One of the vegetative symptoms associated with depression is changes in appetite. Appetite is defined as the desire to eat. These changes can go in either direction (i.e., anorexia or hyperphagia), however, in this context we will concentrate on hyperphagia. In a community sample of adolescents with major depressive disorder followed prospectively, both increased appetite and depressed

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mood were significantly associated with recurrence of depression in adulthood [28], suggesting that increased appetite is a central feature of depression. In addition to general changes in appetite, food cravings, i.e., a strong desire for certain categories of food, may also develop during depressive episodes. An example of depression with food cravings is winter seasonal depression, which is characterized by worsening of mood during late fall and winter and remission of mood symptoms in the spring and summer. Individuals with seasonal depression report increased carbohydrate craving during the depressive episode [29]. The weight gain also associated with the depressive episodes is likely a consequences of the food cravings. Swedo et al. [30] estimate that seasonal affective disorder affects 1.7 – 5.5% of youths ages 9-19 years old based on a community study of over 2,000 youth. Key symptoms that discriminated between 60 subjects from this sample with seasonal affective disorder and 60 comparison subjects were "feel worst," "eat most," "sleep most," and being "most irritable" in the winter, i.e., both increased appetite and sleep during winter months was reported in youths with seasonal mood changes compared to youths without seasonal changes [30]. Obese and non-obese children differ in terms of physiologic factors that regulate food intake and satiety. Leptin is a peptide secreted by adipocytes (fat cells) which acts upon receptors in the hypothalamus, a center for satiety/appetite regulation. Increased leptin secretion is associated with decreased appetite. Obese youths compared with non-obese youths have higher levels of leptin, suggesting central and peripheral leptin insensitivity [31]. After weight loss in obese youths, leptin levels have been shown to decrease, i.e. normalize [31,32]. Ghrelin is another peptide hormone that roughly speaking has the opposite effects of leptin. It stimulates appetite and is increased in experimental sleep deprivation, possibly contributing to explain the connection between sleep and obesity [20]. Ghrelin is correlated to behavioral food intake traits in children, and may therefore explain some genetic predisposition to obesity [33]. Both leptin and ghrelin are changed by sleep curtailment in laboratory studies of adults [20], reemphasizing the multidirectional relations between affect, body composition, and sleep. Similar to sleep and other phenomena discussed here, appetite is related to obesity and depression in an inconsistent fashion, likely resulting from both obesity and depression being conditions with heterogeneous etiology. Notably, however, among psychiatric diagnoses, appetite change is an exclusive symptom criteria of depression, not included in the diagnosis of anxiety, trauma, or psychotic disorders. Not even eating disorder diagnostic criteria include change in appetite. Rather, these disorders are defined by extreme changes in actual food intake, including binging and deliberate avoidance of food intake, suggesting that the normal relationship between appetite and food intake is impaired. In depression, increased appetite does not always result in increased food intake, although presumably increased hunger may result in greater emotional distress if an individual feels deprived of food intake needed to achieve feeling of satiety. In summary, both obesity and depression have tie-ins with appetite and food intake that are incompletely understood.

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Negative Self Image Depressive episodes are characterized by feelings of guilt and shame. In a clinic-referred population of depressed youths ages 11-20 years old, feelings of guilt, self-blame, and failure were more prominent in females than males [34], consistent with cognitive theories holding that greater vulnerability to depression in females compared with males may be due in part to a negative self-attribution style. Symptoms of guilt were endorsed more frequently along with externalizing behavior problems in children compared with adolescents in a clinical sample of over 1,000 children [35]. Also obesity is associated with a negative self image, although the negative association between self esteem/self image and obesity first reported in clinical samples appears to be less robust in community samples [36]. Demographic characteristics have been identified as important moderators of the relationship between obesity and self-esteem. Weight cycling [37], gender [36], and culture have been identified as possible moderators between the relationship of depression and obesity. In a community sample of 2,813 Australian youths, body dissatisfaction mediated most of the relation in females [38]. Cultural factors also appear to influence this relationship. In a non-clinical referred sample of overweight and at risk children, depression was significantly associated with body size dissatisfaction in Caucasian but not African American children [39]. Thus, self-esteem is moderated by demographic characteristics such as gender in both conditions: obesity and depression. White females may be particularly vulnerable to low self-esteem due to obesity; studies of body image and depression may focus on this group. Hindering research and clinical applications, excessive feelings of guilt and decreased self-esteem may be more difficult to assess than the above neurovegetative symptoms, since these are abstract concepts and identification of these symptoms needs to take into account gender and cultural differences in how they may be expressed. From a clinical perspective we posit that it may be possible to obtain a synergistic therapeutic effect by addressing obesity and depression as well as feelings of insufficience. While the presumption is typically that interventions that alleviate obesity and depression can improve self-esteem and feelings of guilt, interventions that target these negative feelings initially may conversely improve adherence to weight loss and depression treatments by reducing incapacitating feelings that interfere with motivation and energy to change, as well as self-perception that one can benefit from change.

Obesity and Depression: Shared Underlying Pathway? While the above discussion suggests possible links between obesity and depression with specific depressive symptoms, and thus possible targets for interventions, the following section reviews possible underlying pathways between depression and obesity to identify possible targets for both prevention and intervention. Increased inflammation and altered stress system may be a common link between obesity and depression. Obesity is considered a pro-inflammatory state. Animal and human studies have shown that obesity increases adipose tissue expression and secretion of proinflammatory cytokines, and treatments that reduce obesity or insulin resistance have a

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moderating effect of reducing inflammation [40]. Levels of pro-inflammatory cytokine IL-6 have been shown to be higher in a population of overweight children compared to normal weight controls [41], and levels of C-reactive protein, a biomarker for inflammation and cardiovascular disease risk, were significantly higher in a community sample of otherwise healthy overweight youths compared to non-overweight youths [42]. Similarly, there is growing evidence from adult studies that depressive episodes are associated with dysregulation of inflammatory system. Pro-inflammatory cytokines IL-6 and tumor necrosis factor alpha have been shown to be higher in psychiatric inpatients with major depressive disorder compared with normal controls [43], and in patients with treatment refractory depression compared with normal controls as well as euthymic individuals who were previously treatment refractory [44]. While cerebrospinal fluid IL-6 levels did not differ between adults with major depressive disorder and age-and gender- matched controls [45], significant diurnal elevations in plasma IL-6 levels and shift in its circadian rhythm were found in depressed adults compared with controls who were tightly matched by gender, age, BMI, and menstrual cycle phase, all variables that affect IL-6 levels [46]. Increases in IL-6 after interferon alpha treatment of hepatitis C has also been associated with significant depression side effects [47]. In children, a negative association between IL-6 and depression scores has been found in youths post hematopoietic stem cell transplantation [48]. Early morning IL-6 levels 24 hours post motor vehicle accident predicted diagnosis of posttraumatic stress disorder (PTSD) in pediatric patients [49], suggesting that IL-6 has profound cerebral effects. Centering on the hypothalamic-pituitary-adrenal (HPA) axis, Gold and Chrousos [50] developed a comprehensive model that posits two subtypes of depression as either upregulation (melancholic) or downregulation (atypical) of the stress system by changes in the HPA axis and sympathetic arousal, which also relate to changes in immune response. In the atypical depression model, decreased sympathetic activity and HPA axis activity result in increased sleep and appetite as well as reduced concentration and energy level; a reverse of functioning triggered by arousal state (“fight or flight”), triggered by sympathetic stimulation and corticotrophin releasing hormone mediated glucocorticoid secretion. Metabolic effects of HPA downregulation would include decreased insulin sensitivity and dyslipidemia, as well as increased fat mass. As mentioned earlier, insulin resistance is also a consequence of physical inactivity, possibly illustrating one of the several converging pathways that may explain the frequent co-occurrence of obesity and depression. Immune effect from HPA down-regulation would be relatively increased inflammation, whereas, HPA up-regulation in melancholic depression would be associated with decreased appetite and sleep, and relative immunosupression. Charmandari et al. [51] identified developmental issues related to this model [51], and emphasized that early childhood stress or trauma may have more long lasting effects on dysregulation of the stress system, causing hyperreactivity of the stress system, and impaired glucocorticoid negative feedback. While this model identifies a clear link between depression states and obesity, mixed depression states are much more common in childhood than either extreme subtype. In addition, the relationship between the stress system and depressive symptoms is likely to be affected by psychiatric comorbidity, particularly the high comorbidity between depression and anxiety disorders in youths. A clinical implication of the findings regarding insulin resistance, an important risk factor for type 2 diabetes, could be

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that one needs to be mindful about using medications that increase insulin resistance (like atypical neuroleptics) in treatment of depressed youth with obesity. Current treatment for pediatric depression also highlights the possible role of serotonin in the relationship between obesity and depression. The serotonin selective reuptake inhibitors (SSRI’s) are the most commonly prescribed medications for pediatric depression treatment. Serotonin has been linked with mood states, appetite, and sleep regulation. The connection between serotonin and food intake is related to appetite, food intake and food preference. Carbohydrate intake, unlike protein consumption, increases serotonin levels. Preference for carbohydrates by individuals with winter seasonal depression may be driven by underlying decreases in serotonin during mood episodes [52]. Seasonal changes in serotonin transporter gene expression have been shown in adults with seasonal depression [53]. SSRI agents are also used in the treatment of binge eating behaviors. A possible relationship between serotonin and HPA axis stress response has been identified by studying differences in the promoter region of the serotonin transporter gene. Girls who were homozygous for the short allele in the promoter region of the serotonin transporter gene have higher cortisol response to a stressor than girls with one long allele [54]. Also, treatment with mediators of inflammation, for clinical [55,56] and experimental goals [57,58] results in symptoms of depression and anxiety. For example, nearly 45% of patients treated with a high dose of IFN-α became depressed [59]. A relationship between depression/suicidal ideation and cytokine treatment is further suggested by the cessation of depressive symptoms when cytokine treatment was discontinued [60]. It has been reported that certain cytokines, such as IL-1, IL-2, and IFN- γ, induce the expression of the enzyme indoleamine-2,3-dioxygenase which shifts tryptophan (TRP) metabolism from serotonin synthesis toward the kynurenin (KYN) pathway (and the production of neurotoxic compounds) resulting in TRP depletion [61, 62]. TRP availability is the rate-limiting step in the synthesis of serotonin, and its reduced availability is associated with the induction of a depressive relapse in vulnerable patients [63,64]. It has been consistently shown in patients with cancer and hepatitis, that treatment with IFN-α or IL-2 is associated with significant decreases in TRP, increases in KYN, and decreases in the TRP/KYN ratios [65]. Moreover, the decrease in TRP, the increase in KYN, and the decrease in TRP/KYN ratio have been correlated with the severity of depression [66]. Antidepressant treatment attenuates Interferon-α induced depressive symptoms [59], suggesting that mediators of inflammation induce, trigger or exacerbate depression, rather than merely inducing nonspecific sickness behavior. In summary, obesity is a pro-inflammatory state. The fact that inflammation causes depression may make obesity a risk factor for depression.

Obesity and Depression: Developmental Trajectories Emerging longitudinal studies have investigated the complex relationship of obesity and depression over development. In a prospective study of over 9,000 youth, depressed mood significantly predicted obesity at one year follow up, even controlling for baseline BMI, age, race, gender, socioeconomic status, and parental obesity [67]. Although a limitation of the study is that weight and height were determined by self report, this fact is unlikely to explain

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the finding. A longitudinal study of a large birth cohort from Northern Finland assessed measures of obesity at ages 14 and 31 years old, along with measures of depression at age 31 years [68]. Adolescent obesity was associated with adulthood depression. Additional studies have investigated relationship between weight and mood changes over time to characterize the relationship between obesity and depression. Anderson et al. [69] assessed weight, height, depression, and anxiety in a community sample of youths at four time points over a 20 year time period. To take into account developmental considerations, weight changes were expressed in terms of body mass index z score changes and mental health outcome was measured using different structured assessments appropriate for age; e.g. psychopathology in children was assessed using parent and child report, whereas depression and anxiety in young adults was assessed using self report only (the BMI z score is a continuous measure of relative weight which corresponds with growth chart percentiles). Gender differences were identified in association between weight and anxiety. In females, anxiety was associated with higher BMI z score, whereas there was no significant relationship between weight and anxiety in males. Relationship between depression and weight also appeared to be modified by gender. In males, depression was associated with lower BMI z scores in childhood, but no significant relationship between weight changes and depression over development. In females, early childhood depression was associated with higher BMI z scores and higher weight gain than non-depressed females over development. Self report data from a cohort of almost 4,000 female college students indicated that women who reported weight cycling over a ten year period were more likely to report physician diagnosed depression and substance abuse than women who either reported weight loss, weight gain, or no significant changes in weight [70]. These longitudinal studies illustrate the role of gender in moderating the relationship between obesity and depression, which is consistent with the notion that these are heterogeneous conditions. The studies also suggest that, for specific clinical populations, intervention for one condition may also contribute to prevention of the other condition over development.

Conclusions Investigation of the complex relationship between obesity and depression is challenged by many factors. First, the heterogeneity of depression. Different types of depression (e.g. atypical depression, reactive depression) and differences in depression phenomenology over development (childhood, adolescence, adulthood) make it difficult to conclude clear overarching association and interaction between depression and obesity. Also, depression may change over development from a unipolar mood disorder (depression episodes only) to a bipolar mood disorder, with depressive, manic, or mixed mood episodes. As the developmental course of bipolar disorder typically presents with episodes of depression before occurrence of mixed or manic states, studies of prepubertal youths with major depression are likely to include youths who will go on to develop bipolar disorder later in adolescence or adulthood. It is unclear if acute weight changes have a different association with depressive disorders from that of chronic obesity, as suggested by increased

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psychopathology in patients with weight cycling and binge eating. Also, obesity in otherwise healthy individuals may have less impact on mood symptoms than obesity in individuals with co-occurring hypertension, diabetes, or other obesity related illnesses. Comparison of different, more homogeneous subtypes of depression or obesity will aid in future investigation of these complex relationships. Gender differences appear to moderate differences between obesity and depression. It would be interesting to assess if gender differences are consistent in populations of prepubertal youth, where cultural pressures, hormonal changes, and differences in body fat distribution are less pronounced. However, changes in weight status with depression interventions, particularly non-medication interventions, are often not reported. It is unclear, for example, if cognitive behavioral therapy focused on depression treatment results in weight loss, and if these reductions may occur independent of mood improvement. Another example would be light treatment in seasonal depression. Given the propensity toward carbohydrate craving and weight gain during winter months, the impact of light therapy on weight as well as whether or not weight changes are associated with mood changes would inform obesity treatment in this depressed population. Anxiety disorders are the most common psychiatric comorbid illnesses across the lifespan. However, there are significant developmental differences in the type of anxiety comorbidity (e.g. separation anxiety versus panic disorder) experienced by children, adolescents, and adults. Therefore, new investigation may elucidate how different anxiety disorders modulate the relationship between depression and the stress response. Finally, longitudinal studies can be used to further identify childhood predictors of adult onset obesity and depression as well as factors that influence persistence of childhood obesity and depression into early adulthood. Understanding of the developmental sequence of factors that influence risk of these conditions is critical for planning timing and targets for prevention.

Acknowledgements Drs. Snitker and Reeves were supported by NIH 1K12RR023250-01. Drs. Postolache and Snitker were supported by R34MH073797.

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[48] Munitz-Shenkar D, Krulik T, Peretz C, Shiloh R, Elhasid R, Toren A, Weizman A. Psychological and cytokine changes in children and adolescents undergoing hematopoietic stem cell transplantation. Eur Neuropsychopharmacol 2007; 17(1): 5863. [49] Pervanidou P, Kolaitis G, Charitaki S, Margeli A, Ferentinos S, Bakoula C, Lazaropoulou C, Papassotiriou I, Tsiantis J, Chrousos GP. Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident. Psychoneuro-endocrinology 2007; 32(8-10): 991-9. [50] Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Molecular Psychiatry 2002;7(3):254-275. [51] Charmandari E, Kino T, Souvatzoglou E, Chrousos GP. Pediatric stress: hormonal mediators and human development. Horm Res 2003;59(4):161-79. [52] Wurtman RJ, Wurtman JJ. Brain serotonin, carbohydrate-craving, obesity, and depression. Obesity Res 1995;477S-480S. [53] Willeit M, Sitte HH, Thierry N, Michalek K, Praschak-Rieder N, Zill P, Winkler D, Brannath W, Fischer MB, Bondy B, Kasper S, Singer EA. Enhanced serotonin transporter function during depression in seasonal affective disorder. Neuropsychopharmacology 2008; 33(7): 1503-13. [54] Gotlib IH, Joormann J, Minor KL, Hallmaver J. HPA Axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol Psychiatry 2008; 63(9):847-51. [55] Ademmer K, Beutel M, Bretzel R, Jaeger C, Reimer C. Suicidal ideation with IFNalpha and ribavirin in a patient with hepatitis C. Psychosomatics 2001; 42(4): 365-7. [56] Capuron L, Ravaud A, Dantzer R. Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alpha-2b therapy. J Clin Oncol 2000; 18(1): 2143-51. [57] Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, and Pollmacher T. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001; 58(5): 445-52. [58] Pollmacher T, Haack M, Schuld A, Reichenberg A, Yirmiya R. Low levels of circulating inflammatory cytokines—do they affect human brain functions? Brain Behav Immun 2002; 16(5):525-32. [59] Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, Greiner K, Nemeroff CB, Miller AH. Paroxetine for the prevention of depression induced by high-dose interferon alpha. N Engl J Med 2001; 344(13):961-6. [60] Capuron L, Dantzer R, Miller AH. Neuro-immune interactions in psychopathology with the example of interferon-alpha-induced depression. J Soc Biol 2003a; 197(2):151-6. [61] Schwarcz R. The kynurenine pathway of tryptophan degradation as a drug target. Curr Opin Pharmacol 2004; 4(1):12-7.

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[62] Wichers MC, Maes M. The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J Psychiatry Neurosci 2004;29(1):11-7. [63] Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990;47(5):411-8. [64] Delgado PL, Price LH, Miller HL, Salomon RM, Aghajanian GK, Heninger GR, Charney DS. Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients. Arch Gen Psychiatry 1994;51(11):865-74. [65] Bonaccorso S, Marino V, Biondi M, Grimaldi F, Ippoliti F, Maes M. Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus. J Affect Disord 2002;72(3):237-41. [66] Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH. Interferon-alpha induced changes in tryptophan metabolism: relationship to depression and paroxetine treatment. Biol Psychiatry 2003b; 54(9): 906-14. [67] Goodman E, Whitaker RC. A prospective study of the role of depression in the development and persistence of adolescent obesity. Pediatrics 2002; 110(3): 497-504. [68] Herva A, Laitinen J, Miettunen J, Veijola J, Karvonen JT, Laksy K, Joukamaa M. Obesity and depression: Results from the longitudinal Northern Finland 1966 Birth Cohort Study. Int J Obes (Lond) 2006 Mar;30(3):520-7. [69] Anderson SE, Cohen P, Naumova EN, Jacques PF, Must A. Adolescent obesity and risk for subsequent major depressive disorder and anxiety disorder: prospective evidence. Psychosom Med 2007;69(8):740-7. [70] Wyshak G. Weight change, obesity, mental health, and health perception: self-reports of college educated women. Prim Care Companion J Clin Psychiatry 2007;9(1):48-54.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter X

Asthma and Mood Disorders Anupama Kewalramani ∗1, Mary E. Bollinger1 and Teodor T. Postolache2 1

Department of Pediatrics, Division of Allergy/Pulmonology, University of Maryland School of Medicine, Baltimore, MD, USA 2 Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

Abstract The high rate of comorbidity of asthma and mood disorders would imply the possibility of potential shared pathophysiologic factors. Proposed links between asthma and mood disorders include a vulnerability (trait) and state connection. Vulnerability for both asthma and mood disorders may involve genetic and early developmental factors. State-related connections may include obstructive factors, inflammatory factors, sleep impairment, psychological reactions to chronic medical illness, as well as exacerbation of asthma in individuals with chronic stress. Treatment for asthma may also exacerbate mood disorders. New research suggests involvement of the central nervous system in asthma and allergy. Further characterization of clinical, psychological, cellular and molecular interconnections between asthma and mood disorders is needed to better evaluate and treat these patients. A close collaboration between mental health professionals and allergists could result in improved symptom control, quality of life, overall functioning and ultimately, decreased mortality.

∗

E-mail address: [email protected] Corresponding author: Anupama Kewalramani, MD, University of Maryland School of Medicine, Department of Pediatrics, Division of Allergy / Pulmonology, 737 W. Lombard Street, Suite 314, Baltimore, MD 21201 United States.

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Keywords: asthma, major depression, mood disorders, suicide, anxiety disorders, inflammation, sleep.

Introduction Mood disorders, including major depressive disorder, dysthymic disorder and bipolar disorder, are common in the United States (US). Approximately 20.9 million American adults (9.5% of people ages 18 and older in a given year) have a mood disorder. Major depressive disorder is the leading cause of disability in the US for ages 15 to 44 years [1]. They are among the most expensive medical conditions and cost the US economy over $83 billion in 2000 [2]. Depressive disorders may affect children and adolescents of all ages, with an onset as early as preschool [3]. Suicide, the eleventh leading cause of death in the US representing over 32,000 deaths, occurs most often in depressed individuals. Anxiety, including panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and phobias frequently co-occur with depressive disorders. Approximately 40 million American adults ages 18 and older have an anxiety disorder [1]. These disorders are among the most common psychiatric conditions in children and adolescents, affecting more than 10% of the youth in the general population [3]. A chronic physical condition, such as asthma is described as one that interferes with daily functioning for more than 3 months a year and/or may cause prolonged hospitalizations [4]. Many of these conditions start in childhood, but then continue into adulthood because they are incurable. Hence, throughout a person’s life, he or she may experience exacerbations of a chronic physical condition similar to flares that can occur with mood disorders and anxiety disorders. Many medical conditions can present or be associated with psychiatric symptoms. Sometimes these psychiatric symptoms can be so prominent that they can overshadow the underlying pathophysiologic process that accounts for them. Patients with a chronic medical illness and comorbid depression or anxiety report significantly more medical symptoms compared to those without depression or anxiety. Research points to a bidirectional effect between depression/anxiety and severity of the medical illness. Depression and anxiety are associated with lower adherence rates to personal care regimens and increased morbidity in patients with chronic medical illness, which may lead to increased symptoms. Mood disorders and anxiety may lead to a keen awareness of physical symptoms. An exacerbation of physical symptoms and resulting functional impairment can exacerbate episodes of depression or anxiety. In turn, an exacerbation of these symptoms can worsen the physical symptoms associated with the medical illness [5]. Chronic physical conditions are also associated with higher-than-expected rates of suicidal ideation [6]. Asthma is a prototypical chronic physical condition that has been linked with mood disorders and anxiety. It is one of the most common chronic health problems in the US and is characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and underlying inflammation. The interaction of these factors influences the clinical manifestations, severity of disease and the response to treatment [7]. According to the Centers for Disease Control and Prevention (CDC), an estimated 7.7% of the US population (22.2 million) have asthma, including 6.5 million children. Approximately

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4,000 Americans die each year from asthma. Asthma accounted for 1.8 million emergency room visits and approximately 500,000 hospitalizations in 2004 [8]. In 1998, the cost of asthma was approximately $12.7 billion in the US [9]. A number of studies have investigated the interaction between asthma and mood disorders, such as depression, anxiety and suicidal ideation. These are common comorbid conditions with potential shared pathophysiology, impacted by treatment choices, adherence and level of control. A number of studies are ongoing to further investigate this relationship.

Prevalence of Depression and Anxiety in Asthma Asthma was previously thought to be a psychosomatic disease because of the episodic nature in which symptoms would suddenly appear without warning or apparent cause. Emotional causes were frequently thought to lead to asthma exacerbations [10]. Several clinical studies have found patients with asthma have higher rates of depressive and anxiety symptoms than healthy controls. Studies also suggest that asthma is associated with increased likelihood of suicidal ideation [6]. In 2000, Zielinski et al. [11] performed a literature search and reviewed eight studies specifically directed at the prevalence of depressive symptoms in children and adults with asthma. All eight studies indicated that depressive symptoms were more common in children and adults with asthma than in the general population. However, only one of the eight actually looked at the prevalence of major depressive disorder in asthma patients so no conclusion with respect to the rate of formal mood disorders in asthma patients could be made [11]. Eisner et al. [12] studied 743 adults with asthma who were recruited after a hospitalization for asthma. They looked at depressive symptoms based on the Center for Epidemiologic Studies Depression Scale and found that these subjects had an 18% prevalence rate of depressive symptoms [12]. Goodwin et al. [13] found that German adults 18 to 65 years old with physician diagnosed current (previous 4 weeks) and lifetime severe and non-severe asthma had a significantly higher likelihood of any anxiety disorder. Mental disorders were assessed using the German National Health interview and Examination Survey-Mental Health Supplement (GHS-MHS) [13]. Suicidal ideation and suicidal attempt have been shown to be more prevalent among asthmatic adults and this was independent of a major depression diagnosis [5]. Adolescents and young adults similarly have been found to have higher rates of depressive and anxiety disorders. Goodwin et al. prospectively examined the likelihood of depressive and anxiety disorders in a birth cohort of over 1,000 young people with asthma studied to the age of 21 years. At ages 18 and 21 years, participants were questioned about their experience with depressive and anxiety symptoms since the previous assessment, using the Composite International Diagnostic Interview (CIDI). Asthma in adolescence and young adulthood was associated with increased likelihood of major depression, panic attacks and any anxiety disorder [14]. Adolescents frequently take risks with their health, such as drug use. The Youth Risk Behavior Survey (YRBS) assesses health risk behaviors in high school students in the US. Bender recently reported that the survey found high school students with asthma report higher rates of depressive symptoms such as feeling sad or hopelessness (45.3 vs. 29.3%) than their non-asthmatic peers. He also found that they considered suicide at a

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higher rate than their non-asthmatic peers (31% vs. 16.2%) and the suicide attempt rate was twice the national population rates [15]. Asthma is the most common chronic illness in children accounting for most hospitalizations in pediatrics [8]. Inner city children with asthma tend to have a higher burden of disease. Goodwin et al. studied a sample of 74 patients 5 to 11 years old who were screened for mental disorders with the National Health’s Diagnostic Interview Schedule for Children (DISC) Predictive Scale (DPS) while in the waiting room of an inner city asthma clinic. They found almost 26% of patients had a probable depressive or anxiety disorder [16]. Morrison et al. studied 46 patients ages 6 to 17 years who presented to the Children’s Medical Center Asthma Clinic which primarily treats children from low-income families. Eighty-six percent of the children were on medium or high doses of inhaled corticosteroids for their asthma and 41% had mild to moderate airway obstruction even on inhaled steroids. Thirty percent of patients had Children’s Depression Rating Scale, Revised (CDS-R) scores consistent with likely, very likely, or almost certain depressive disorder [17]. Most studies have depended upon patient self-report of asthma and although the diagnosis of asthma depends primarily on the history, spirometry provides an objective measure of lung function in these patients. Few studies have investigated the association between asthma based on spirometry and depression or anxiety. Goodwin et al. found that adults with obstructive lung disease had significantly lower scores on the overall General Well-Being scale and a higher odds of depressive symptoms compared to subjects with no lung function abnormalities. There was no association seen with anxiety symptoms. It should be noted, however, that there was no information available for subjects’ specific respiratory conditions [18]. Lavoie et al. confirmed the diagnosis of asthma with spirometry and found rates of depressive and anxiety disorders in asthmatic adults (20% and 23%, respectively) to be twice as likely as the general population [19]. Meanwhile, Rimington et al. found only weak correlations between anxiety and depression with 2 spirometry measures [peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1)] [20]. The impact of depression and anxiety has been investigated in relation to asthma symptoms. Richardson et al. conducted a large population-based sample of adolescents with asthma (767 youth aged 11 to 17) and found that those with an anxiety or depressive disorder reported significantly more asthma symptom days in the previous 2 weeks than those without anxiety or depressive disorders. Youth with >1 DSM-IV anxiety and depressive disorder and asthma had significantly more asthma symptom days over the prior 2 weeks than those with asthma alone [21]. For adults recently hospitalized with asthma, depressive symptoms were associated with poorer asthma-related health status, greater severity of asthma, poorer asthma-specific quality of life, and poorer physical health status [12]. Rimington et al. measured the effect of anxiety and depression using the Hospital Anxiety and Depression (HAD) scale on asthma symptoms as measured by the Asthma Quality of Life Questionnaire (AQLQ) in 114 adults from general practitioner practices. Anxiety and depression were strongly correlated with severity of asthma symptoms [17]. Martinez-Moragon et al. investigated possible determinants of dyspnea in 153 adult patients with different levels of severity of asthma using spirometry, dyspnea scales, and the Beck Depression Inventory (BDI). Independent of the severity of obstruction that the patients demonstrated, patients showed more dyspnea when they had higher levels of anxiety and depressive symptoms [22].

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Anxiety and depression were shown to increase complaints of respiratory troubles in asthma patients, even when no quantitative differences in measured respiratory function were present. [23]. Few studies have evaluated whether depression or anxiety treatment affects a patient’s asthma. Brown et al. conducted a randomized, double-blind, parallel-group, placebocontrolled trial of citalopram in 90 depressed adults followed in an asthma clinic. Multiple visits were conducted and at each visit, the Hamilton Rating Scale for Depression (HSRD), Inventory of Depressive Symptomatology-Self Report (IDS-SR30), Asthma Control Questionnaire (ACQ), and Asthma Quality of Life Questionnaire (AQLQ) were administered in addition to an assessment of oral corticosteroid use. HSRD scores decreased in both groups. Although there were no significant differences between the citalopram and placebo groups in change in ACQ or AQLQ scores, the citalopram group had significantly fewer follow-up assessments in which they required systemic corticosteroids compared to placebo group [24]. In an attempt to establish which diagnosis comes first in asthmatic patients, Solis, et al. [25] collected data on patients with both asthma and major depression. They found that asthma heralded the onset of the first depressive symptoms in 62% of patients while depression preceded asthma in 24% and both presented at the same time in 14% of participants [25]. It has been difficult to establish a link between asthma and depression/anxiety. Goodwin et al. suggested that the presence of specific personality factors, like neuroticism, could explain the association between mental and physical disorders. In a 2006 study, the group investigated the importance of neuroticism in those with allergy and depression. Over 3,000 adults between 25 and 75 years of age underwent the Midlife Development in the United States (MIDUS) Survey that involved a telephone interview and 2 mailed questionnaires. Multiple logistic regression analyses were used to investigate the association between depression and allergy and the role of neuroticism in these relationships. Among their male subjects they found that higher neuroticism was associated with a significantly increased likelihood of allergy. After adjusting for demographics, depression, and neuroticism, neuroticism remained significantly associated with increased likelihood of allergy. Among females, there was a significant relationship between allergy and depression but this was independent of the effects of neuroticism [26].

Pathophysiologic Connection between Asthma and Mood Disorders Asthma is a chronic inflammatory disorder which involves airway hyperresponsiveness and bronchial obstruction. These factors lead to symptoms and signs such as cough, dyspnea, wheezing, and chest tightness. Although symptoms are easily appreciated, the fundamental pathophysiology of asthma is underlying airway inflammation, which can be present without overt symptoms. Immune responses are regulated by T lymphocytes. Naïve CD4+ T cells can either develop into Th1 (T helper type 1) cells or Th2 cells. Th1 cells are primarily involved in

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response to infection; whereas, Th2 cells are primarily involved in the allergic response. Asthma is a disorder of the conducting airways characterized by Th2 cell mediated inflammation and increased mediator release. Asthma begins early in life often in response to viral infections and in addition, in response to allergen exposure. Allergens are recognized by the immune system and taken up by antigen presenting cells (APCs). After the antigen is broken down into short polypeptides, APCs present them to T lymphocytes. For those predisposed to an allergy phenotype and in the presence of allergy-promoting cytokines, such as IL-4 and IL-13, T helper cells will develop into Th2 cells. These Th2 cells induce B lymphocytes to undergo a class switch from immunoglobulin M (IgM) to allergen-specific IgE, levels of which are increased in atopic asthma. IgE molecules will bind to receptors on effector cells, such as mast cells, basophils and eosinophils, in the respiratory mucosa leading to sensitization. Once the allergen is encountered again, it will cross-link IgE molecules and induce the effector cells to degranulate and release a host of mediators. Mediators including histamine, tryptase, cytokines, leukotrienes, and prostaglandins induce asthma symptoms [27]. For years, psychological stress has been thought to play an important role in asthma as these patients tend to have higher levels of stress and negative emotions such as panic, fear, irritability and depression. Evidence indicates that emotional stress may exacerbate the physical symptoms of atopic disorders such as asthma [3]. Some data suggest that psychological stress may shift the Th1/Th2 cytokine balance towards type 2 and cause an immune dysregulation with more allergic or asthmatic reactions during periods of high stress. Psychological stress activates the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system, leading to an increase in cortisol and catecholamine secretion. Cortisol and catecholamines can suppress Th1 cytokines such as IL-12 and IFN-γ which may then shift the immune response toward a Th2 phenotype [28]. This dysregulation is believed to play a role in the pathogenesis of asthma and allergic diseases with increased levels of IL-4, IL-5, and IL-13 in cells obtained from asthmatic patients and may further aggravate existing inflammation after an inhaled antigen exposure [29]. Liu et al. [30] conducted an antigen challenge on 20 college students with mild asthma during both a low-stress phase and a stress phase. The low-stress phase was conducted during mid-semester or at least 2 weeks after final examinations while the stress phase took place during the final examination week. Questionnaires assessed for anxiety and depression. Sputum samples were collected before the challenge, and at 6 hours, 24 hours and 7 days post-challenge. Sputum eosinophils and eosinophil derived neurotoxin levels were significantly increased at 6 hours and 24 hours post-challenge and were enhanced during the stress phase. IL-5 generation was also increased at 24 hours during stress and correlated with increased sputum eosinophils. The investigators suggested that stress can act as a cofactor to increase eosinophilic airway inflammatory responses to antigen challenge and in this way increases asthma severity. It should be noted, however, there was no significant deterioration in lung function or increase in reported asthma symptoms associated with these inflammatory changes [30]. Stress management should be routinely recommended for asthmatics. Smyth et al. investigated adults with mild to moderate severe asthma and stress and found that asthmatics who wrote about their most stressful experience from the past had improvements in lung function and decreases in self-reported distress levels [31].

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Asthma is frequently associated with noctural symptoms and a decrease in lung function. Nocturnal cough and dyspnea are associated with cyclic shifts in airway inflammation and hyperresponsiveness. A survey study conducted in 1988 of 7,729 asthmatics found 74% of these patients awoke once a week with asthma symptoms. In the same study, 40% of the subjects actually reported symptoms every night. Sleep disturbances can manifest as difficulty in sleep onset and early arousals, sleep apneas [23,32], less time spent in the stages of deep sleep, and microarousals [32]. Microarousals can be especially frustrating, as the individual may not even realize he is awakening from sleep, yet will still experience significant negative effects to the same extent as with the other noticeable disturbances. Impaired sleep leads to daytime fatigue, difficulty in concentration, reduced productivity, worsened mood, and, in general, a lower quality of life. Sleep impairment itself can also exacerbate or bring about depression in vulnerable individuals [33]. Moreover, the functional impairment induced by asthma may reduce participation in physical, social, and outdoor activities, the last of which means decreased exposure to natural light. All of these factors can be depressogenic. In addition, anxiety is associated with the inherent uncertainty of asthma and its attacks [34]. Interestingly, several reports have posited that hypercapnia can result in changes in activity in the locus coerulus, leading to increased anxiety [35,36].

Asthma Pharmacotherapy and Effects on Mood Disorders Pharmacotherapy for asthma is divided into controller medications which are taken on a daily basis and rescue medications which are used for treatment of acute exacerbations. These medication regimens need to be monitored closely for adverse events, such as exacerbations of depression or anxiety symptoms. Rescue medications include short acting beta-adrenergic agonists (SABAs), anticholinergics, and systemic corticosteroids. Controller medications include inhaled corticosteroids (ICS), leukotriene modifiers, long-acting beta-adrenergic agonists (LABAs), cromones, methylxanthines and immunomodulators [7]. Inhaled corticosteroids are the most potent and most effective long-term antiinflammatory medication available for treatment of asthma. Oral corticosteroid (OCS) bursts, such as prednisone and prednisolone, are frequently prescribed for patients with acute asthma exacerbations. Corticosteroids inhibit cytokine, prostaglandin and leukotriene production, prevent inflammatory cell activation and migration, and decrease microvascular leakage, in addition to enhancing the action of β-adrenergic receptors on airway smooth muscle. Systemic corticosteroids have been associated with depression, mania and psychosis. Brown et al. evaluated adults receiving at least seven days of a minimum of 40 mg of prednisone for asthma exacerbations. Patients were assessed before, during and after systemic corticosteroid therapy with the HRSD, the Young Mania Rating Scale (YMRS), the Brief Psychiatric Rating Scale (BPRS), and the Internal State Scale (ISS). They found significantly increased manic symptoms compared to baseline. Patients with depression actually showed a decrease in symptoms compared to those without depression. These changes resolved with discontinuation of the steroids. Some suggest that mood changes seen with corticosteroids may be due to improvement in the symptoms of the physical condition; however, in this

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study, changes in mood measures did not show significant associations with changes in peak expiratory flow readings in a subset of patients [37]. Some patients with difficult to control severe persistent asthma on maximal medical therapy may require chronic oral steroids. Chronic steroid use seems to be associated with an increase in depressive symptoms [31]. Brown et al. conducted a small follow-up study on 13 patients with either asthma or rheumatologic conditions, 6 of whom were on chronic prednisone. The HRSD, YMRS, and BPRS were administered. The prednisone treated group had higher scores on psychiatric measures than those not on chronic steroids [38]. ICS are considered the mainstay of chronic asthma management. There are concerns about the long-term safety of such medications; however, their bioavailability is significantly less than that of oral corticosteroids and numerous studies have demonstrated the relative safety of ICS in children and adults. However, if they are used at high doses for an extended period of time (i.e., years) and accompanied by frequent OCS bursts, similar adverse effects may be seen as with chronic OCS therapy [7]. For this reason, those patients with moderate and severe persistent asthma may require adjunct therapy that may also serve as steroid sparing agents, such as leukotriene modifiers, LABAs, chromones, theophylline, and omalizumab. The impact of these medications on comorbid depressive and anxiety disorders in patients with asthma have not been extensively studied. Leukotriene modifiers, including inhibitors of leukotriene production and leukotriene receptor antagonists, affect a specific component of the inflammatory process. Leukotrienes affect bronchoconstriction, mucus secretion, and the activation and infiltration of inflammatory cells in the airway. Leukotriene modifiers have been shown to decrease rescue medication use, decrease symptoms including nighttime awakenings and improve lung function. When combined with ICS, montelukast has shown to significantly increase lung function [7]. Montelukast, a leukotriene receptor antagonist, has been rarely been associated with dream abnormalities, hallucinations, drowsiness, psychomotor hyperactivity (including irritability, agitation, aggressive behavior, restlessness, and tremor), insomnia, depression, and suicidal thinking [39]. Bronchodilators are important medications for acute and chronic management of asthma. Inhaled SABAs are preferred for acute asthma exacerbations. Side effects include tachycardia, tremor, and hypokalemia. They have been proven safe and effective in all age groups; however, if used regularly instead of as-needed, they may be associated with diminished control of asthma and increased bronchial reactivity [40]. Salmeterol and formoterol are the two LABAs approved for use in asthma in the US. They are only used in conjunction with ICS and when they are used as adjuncts, they decrease the risk of exacerbations requiring OCS, significantly improve lung function, and increase symptomfree and rescue medication-free days. They can also produce similar side effects to SABAs [7]. The chromones, cromolyn and nedocromil, are mast cell stabilizers that are alternatives, but not preferred, for mild persistent asthma. They inhibit early- and late-phase response to allergen and can be used as preventive treatment prior to exercise or unavoidable exposure to known allergens. They are the safest medications for asthma available, but because of frequent dosing, adherence is often an issue [7].

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Theophylline is a phosphodiesterase inhibitor which has some bronchodilator effects and at low doses, some possible anti-inflammatory effects. It is approved for patients 5 years and older and is used for mild persistent asthma and as an adjunct to ICS in moderate and severe persistent asthma. Its use has diminished in recent years due to its potential side effects such as seizures, insomnia, anxiety, and tachyarrhythmias. Because of its narrow therapeutic range, frequency of concomitant illnesses that change its kinetics, and many drug interactions that affect its clearance, it is essential to monitor blood levels [40]. Research is being conducted on the use of immunomodulators for asthma. Omalizumab is FDA approved for the treatment of moderate to severe persistent asthma in patients 12 years and older who have proven allergen sensitivity. It is a monoclonal antibody that selectively binds to free IgE. It prevents IgE from binding to the high-affinity receptors on mast cells and basophils and, hence, prevents release of mediators that can cause airway inflammation and bronchial hyperreactivity. Postmarketing surveys have identified anaphylaxis in an estimated 0.2 percent of treated patients, which resulted in an FDA black box warning. As it is an injectable medication, there are frequent reports of injection site pain [7]. No effects on depression or anxiety have been reported.

Ongoing Research and Preliminary Clinical Implications Evidence suggests a high rate of co-occurrence of depression/anxiety and asthma for children, adolescents and adults. More research is needed to establish the link between these conditions. More studies are also needed to determine whether concurrent treatment of depression and anxiety in asthma patients improves asthma symptoms. It is equally important for mental health providers to screen their mood disorder patients for symptoms of asthma such as persistent cough, shortness of breath, or wheezing and primary care providers to screen their asthma patients for depressive and/or anxiety symptoms. Since, during times of high pollen counts in the spring, mood worsens [41,42] and the suicide rate is increased [43,44] we recommend paying attention to environmental pollen counts. They can, thus, identify possible periods of increased vulnerability for decompensation and suicide attempts for patients with comorbid allergy and mood disorders. This is particularly important, as molecular and cellular mediators of allergy have been identified in the brain in response to allergic sensitization and exposure [45,46]. Moreover, Th2 cytokines gene expression has been found to be increased in the brains of victims of suicide as compared with controlled subjects who died from other causes [47]. A functional imaging study has identified a neuroanatomical substrate for the interaction between emotion and asthma symptom exacerbation in the subgenual anterior cingulate cortex and insula [48]. It is important to mention that in the subgenual anterior cingulate cortex in patients with recurrent major depression a reduction of gray matter thickness has been previously reported, across episodes of illness [49,50]. Appropriate evaluation and treatment of patients with comorbid asthma and mood disorders is not only important to maintain lung function and respiratory-related quality of life, but it may also negatively impact the mood disorder if not recognized and treated

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appropriately. It is equally important for primary care providers and asthma specialists to recognize the association between asthma and mood disorders and screen their patients for depression and anxiety. Patients exhibiting psychiatric symptoms should be referred to mental health services. Comprehensive treatment of patients with psychiatric symptoms due to a medical condition may require multi-disciplinary care involving primary care, mental health, and specialty care personnel. If underlying depression or anxiety is not considered, this may lead to unnecessary medication changes and testing, poor adherence, higher rate of symptoms, higher medical costs and potentially higher mortality.

Acknowledgements The authors thank Sarah Zimmerman for her substantial contribution to this manuscript and Joseph Soriano for his editorial help.

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[11] Zielinski TA, Brown ES, Nejtek VA, Khan DA, Moore JJ, Rush AJ. Depression in Asthma: Prevalence and Clinical Implications. Prim Care Companion J Clin Psychiatry 2000; 2(5):153-8. [12] Eisner MD, Katz PP, Lactao G, Iribarren C. Impact of depressive symptoms on adult asthma outcomes. Ann Allergy Asthma Immunol 2005; 94(5):566-74. [13] Goodwin RD, Jacobi F, Thefeld W. Mental disorders and asthma in the community. Arch Gen Psychiatry 2003; 60(11):1125-30. [14] Goodwin RD, Fergusson DM, Horwood LJ. Asthma and depressive and anxiety disorders among young persons in the community. Psychol Med 2004; 34(8):1465-74. [15] Bender BG. Depression symptoms and substance abuse in adolescents with asthma. Ann Allergy Asthma Immunol 2007; 99(4):319-24. [16] Goodwin RD, Messineo K, Bregante A, Hoven CW, Kairam R. Prevalence of probable mental disorders among pediatric asthma patients in an inner-city clinic. J Asthma 2005; 42(8):643-7. [17] Morrison KM, Goli A, Van Wagoner J, Brown ES, Khan DA. Depressive symptoms in inner-city children with asthma. Prim Care Companion J Clin Psychiatry 2002; 4(5):174-7. [18] Goodwin RD, Chuang S, Simuro N, Davies M, Pine DS. Association between lung function and mental health problems among adults in the United States: findings from the First National Health and Nutrition Examination Survey. Am J Epidemiol 2007;165(4):383-8. [19] Lavoie KL, Bacon SL, Barone S, Cartier A, Ditto B, Labrecque M. What is worse for asthma control and quality of life: depressive disorders, anxiety disorders, or both? Chest 2006;130(4):1039-47. [20] Rimington LD, Davies DH, Lowe D, Pearson MG. Relationship between anxiety, depression, and morbidity in adult asthma patients. Thorax 2001; 56(4):266-71. [21] Richardson LP, Lozano P, Russo J, McCauley E, Bush T, Katon W. Asthma symptom burden: relationship to asthma severity and anxiety and depression symptoms. Pediatrics 2006;118(3):1042-51. [22] Martinez-Moragon E, Perpina M, Belloch A, de Diego A, Martinez-Frances M. Determinants of dyspnea in patients with different grades of stable asthma. J Asthma 2003;40(4):375-82. [23] Janson C, De Backer W, Gislason T, Plaschke P, Bjornsson E, Hetta J, Kristbjarnarson H, Vermeire P, Boman G. Increased prevalence of sleep disturbances and daytime sleepiness in subjects with bronchial asthma: a population study of young adults in three European countries. Eur Respir J 1996; 9(10):2132-8. [24] Brown ES, Vigil L, Khan DA, Liggin JD, Carmody TJ, Rush AJ. A randomized trial of citalopram versus placebo in outpatients with asthma and major depressive disorder: a proof of concept study. Biol Psychiatry 2005;58(11):865-70. [25] Solis OL, Khan DA, Brown ES. Age at onset of major depression in inner-city adults with asthma. Psychosomatics 2006;47(4):330-2. [26] Goodwin RD, Castro M, Kovacs M. Major depression and allergy: does neuroticism explain the relationship? Psychosom Med 2006; 68(1):94-8.

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[27] Lilly CM. Diversity of asthma: evolving concepts of pathophysiology and lessons from genetics. J Allergy Clin Immunol 2005;115(4 Suppl):S526-31. [28] Chrousos GP. Stress, chronic inflammation, and emotional and physical well-being: concurrent effects and chronic sequelae. J Allergy Clin Immunol 2000;106(5 Suppl):S275-91. [29] Frieri M. Neuroimmunology and inflammation: implications for therapy of allergic and autoimmune diseases. Ann Allergy Asthma Immunol 2003;90(6 Suppl 3):34-40. [30] Liu L, Coe C, Swenson C, Kelly E, Kiu H, Busse W. School examination enhance airway inflammation to antigen challenge. Am J Respir Crit Care Med 2002;165:10627. [31] Smyth JM, Stone AA, Hurewitz A, Kaell A. Effects of writing about stressful experiences on symptom reduction in patients with asthma or rheumatoid arthritis: a randomized trial. JAMA 1999; 281(14):1304-9. [32] Craig TJ, Teets S, Lehman EB, Chinchilli VM, Zwillich C. Nasal congestion secondary to allergic rhinitis as a cause of sleep disturbance and daytime fatigue and the response to topical nasal corticosteroids. J Allergy Clin Immunol 1998;101(5):633-7. [33] McEwen BS. Sleep deprivation as a neurobiologic and physiologic stressor: Allostasis and allostatic load. Metabolism 2006;55(10 Suppl 2):S20-3. [34] Levenson JL, ed. The American Psychiatric Publishing Textbook of Psychosomatic Medicine. Arlington, Va: Am Psychiatr Publ, 2005. [35] Carr RE. Panic disorder and asthma: causes, effects and research implications. J Psychosom Res 1998;44(1):43-52. [36] Zaubler TS, Katon W. Panic disorder in the general medical setting. J Psychosom Res 1998;44(1):25-42. [37] Brown ES, Suppes T, Khan DA, Carmody TJ 3rd. Mood changes during prednisone bursts in outpatients with asthma. J Clin Psychopharmacol 2002;22(1):55-61. [38] Brown ES, Vera E, Frol AB, Woolston DJ, Johnson B. Effects of chronic prednisone therapy on mood and memory. J Affect Disord 2007;99(1-3):279-83. [39] Singulair [package insert]. Whitehouse, NJ: Merck, 2007. [40] Braman SS, Hanania NA. Asthma in older adults. Clin Chest Med 2007;28(4):685-702, v. [41] Guzman A, Tonelli LH, Roberts D, Stiller JW, Jackson MA, Soriano JJ, Yousufi S, Rohan KJ, Komarow H, Postolache TT. Mood-worsening with high-pollen-counts and seasonality: a preliminary report. J Affect Disord 2007;101(1-3):269-74. [42] Postolache TT, Lapidus M, Sander ER, Langenberg P, Hamilton RG, Soriano JJ, McDonald JS, Furst N, Bai J, Scrandis DA, Cabassa JA, Stiller JW, Balis T, Guzman A, Togias A, Tonelli LH. Changes in allergy symptoms and depression scores are positively correlated in patients with recurrent mood disorders exposed to seasonal peaks in aeroallergens. Scientific World Journal 2007; 7:1968-77. [43] Timonen M, Viilo K, Hakko H, Sarkioja T, Meyer-Rochow VB, Vaisanen E, Rasanen P. Is seasonality of suicides stronger in victims with hospital-treated atopic disorders? Psychiatry Res 2004; 126(2):167-75. [44] Postolache TT, Stiller JW, Herrell R, Goldstein MA, Shreeram SS, Zebrak R, Thrower CM, Volkov J, No MJ, Volkov I, Rohan KJ, Redditt J, Parmar M, Mohyuddin F, Olsen

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In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XI

Jet Lag: A Modern-Day Malaise Tatiana Menick1, Joseph J. Soriano2 and Teodor T. Postolache ∗1,2,3 1

St Elizabeths Hospital, Residency Training Program, Washington DC, USA Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA 3 Institute for Sports Chronobiology, Washington DC, USA

Abstract Jet lag, a circadian rhythm sleep disorder associated with transmeridian travel, is the result of many factors, the most important being misalignments between the light-dark cycles of origin and destination, and between the social demands at the place of destination and internal, biological, representations of day and night which govern our abilities to fall asleep, stay alert and perform. Most of the time, sleep deprivation compounds the misalignment effects. The demands and duration of the trip, as well as the direction and number of time zones crossed and prior vulnerability to jet lag should determine if and how to treat jet lag. Treatment options include simple measures involving bright light exposure and avoidance, bright light treatment, timed meals, and exercise, and, sometimes, melatonin, short-acting hypnotics, and alertness promoting beverages and pharmacological agents. Given the long-term health implications of circadian rhythm sleep disorder, and their impact on individuals and society, further research and more effective treatments are needed.

∗

E-mail address: [email protected] Correspondence: Teodor T Postolache, MD, Mood and Anxiety Program (MAP), Department of Psychiatry, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF Building Room 502, Baltimore, MD 21201, USA Tel: 410-706-2323.

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Keywords: Jet lag, applicative chronobiology, transmeridian travel, bright light treatment, circadian rhythm sleep disorders, melatonin.

Introduction “The past is a foreign country; they do things differently there.” The words of novelist L.P. Hartley (1895-1972) described the folkways of rural England at the turn of 20th century, but they are equally true of our more distant forebears. They spent more time outdoors than we do, had little in the way of artificial illumination, and traveled at the speed of the march, the horse and the sail. Rapid transmeridian travel, unknown 100 years ago, is now a common experience. We may travel faster these days, but our physiologies are rooted in our ancestors’ world. Our contemporary environment, characterized as it is by microclimates with artificial light and temperature control, is a novelty in human experience; and we have learned that living in a 24-hour society, with a round-the-clock economy of shift work and frequent jet travel, has its price. Both jet lag and shift work are highly prevalent in industrialized countries and have health and safety implications for both the individuals involved and for the public. Jet lag syndrome and shift work sleep disorder are circadian rhythm sleep disorders resulting in a constellation of symptoms such as sleepiness, difficulty initiating and maintaining sleep, and peaks and troughs of alertness and mental performance, all of which become out of sync with the environmental demands. The overall clinical presentation is influenced by a combination of physiological, behavioral, and environmental factors. The long-term health implications of shift work and, in particular, jet lag are not widely recognized.

The Circadian System Circadian Rhythms Biological rhythms having a period of approximately 24 hours are called circadian (from the Latin words circa, meaning “about,” and dies, meaning “day”). The human circadian system orchestrates rhythmicity in the human body and drives normal sleep-wake and restactivity phases. Circadian rhythms are part of normal human physiology and behavior, and almost every bodily function has been shown to exhibit a circadian rhythm. Many human health parameters show a circadian variation: body temperature has an evening maximum and late night-early morning minimum. The blood levels of hormones can also change, depending on the time of day. Cortisol and testosterone are highest in the morning, while insulin, gastrin, and renin are highest in the early evening. Growth hormone, prolactin, and melatonin are at their highest at night [1]. The suprachiasmatic nuclei (SCN), located in the hypothalamus above the optic chiasm, are generators of normal circadian rhythmicity and are known as the circadian or biological clock. The pineal gland, retina, and retinohypothalamic tract also influence the circadian

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rhythm [2]. Also known as the “master oscillator,” the SCN serves as pacemaker, setting electrophysiological neuronal activity and hormonal rhythms. These, in turn, send information to peripheral, so-called “slave,” oscillators in the organism. Under constant conditions, circadian rhythms are consistent and have a period slightly longer than 24 hours, with the result that certain physiological and behavioral rhythms occur at a later clock time each day. Is circadian rhythmicity produced by the SCN neurons or the network of those neurons? Strong evidence supports the former. In each of the SCN neurons, the transcription/translation of “clock genes” and the complex feedback from their protein products generate a rhythm with a period of approximately, but not equal to, 24 hours. The circadian rhythm in gene transcription/translation is converted into a rhythm in neuronal firing by tying the levels of ion channels, receptors, or transmitters to the rhythmically transcribed genes [3]. Downstream from the SCN, information about internal day (rapid firing) or internal night (slow firing) is transmitted to the paraventricular nucleus of the hypothalamus. Then, via multisynaptic pathways, the SCN inhibits the melatonin secretion in the pineal gland via a ßadrenergic receptor. Melatonin closes the feedback loop, activating, via blood and cerebrospinal fluid (CSF), its receptors in the SCN.

Zeitgebers or “Time Givers” The SCN also times circadian rhythms to the environment. The most important aspect of this external synchronization is the “entrainment,” or synchronization of the SCN-generated rhythms to the 24-hour period of rotation of the Earth. Environmental factors that influence the SCN are known as zeitgebers or “time givers”.

Light Is the Main Zeitgeber Various rhythmic environmental stimuli are known to entrain circadian clocks [4]. Lightdark cycles are the most important environmental entraining agents for circadian rhythms because they are the most consistent from day to day. However, other environmental stimuli, such as temperature, physical activity, or feeding, may also play important roles for entrainment. Human circadian clocks adjust internal time to the external time primarily by way of light input through the retina [5]. Input for entrainment comes primarily through specialized retinal ganglion cell photoreceptors, which connect via the retinohypothalamic tract to the SCN. The neural pathway that extends from the SCN to the pineal gland involves a multisynaptic link via the superior cervical ganglion (SCG). Melatonin, secreted by the pineal gland, closes the feedback loop by acting on melatonin receptors in the SCN. Light as a circadian phase shifting agent. The effect of light on the human circadian clock depends on the time at which it is presented. The relationship between the time of light exposure and the direction of magnitude of phase shift can be quantified and analyzed by deriving a phase response curve (PRC). For PRC studies, a demanding protocol called

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“constant routine” is necessary to minimize the masking effects of sleep, food and water intake, and posture on circadian rhythms. In a room with dim light, and under the direction of an attending technician, the subject is kept awake in half supine position for as long as 50 hours. Food, water and any medications are given day and night at short even intervals. In majority of entrained individuals, the point of minimum body temperature occurs at 45am. Bright light prior to the minimum body temperature phase delays circadian rhythms, After the minimum of body temperature minimum phase, light advances circadian rhythms [6]. For more detailed information on PRC, the reader is directed to the review by Postolache and Oren [4]. Melanopsin and blue light. Melanopsin, present in the majority of retinal ganglion cells, is an important novel circadian photoreceptor. Melanopsin is photosensitive to shortwavelength or blue light, which, according to several studies, appears to have stronger circadian effects [7].

Pathophysiology of Jet Lag Acute jet lag. Jet lag is caused by a misalignment between the circadian clock’s internal timing and the new external, environmental light-dark, day-night cycle. The exact symptoms of jet lag, and their severity and duration, depend on the individual, the direction of travel, and the number of time zones crossed. Symptoms may include sleep impairment, general malaise, poor mental concentration, loss of motivation, and increased incidence of headache, irritability, and gastrointestinal disturbance. Sleep impairment usually manifests itself as an inability to fall asleep or maintain sleep at the destination’s local nighttime. Sleep impairment adds another component to daytime sleepiness, already present due to misalignment. Jet lag is typically worse when traveling east than when traveling west [8]. The unadjusted rhythm is phase-delayed relative to local time after an eastward flight, and phaseadvanced after a westward flight [1]. Since the circadian clock has a period slightly longer than 24 hours [9], it has a natural tendency to phase delay. Thus, phase delays proceed easier and more rapidly than phase advances, and this is one important reason why it is more difficult to adjust for eastward travel. As the body contains multiple oscillators, one hypothesis of jet lag is based not on the desynchronization between the SCN and the external light-dark cycle, but on the desynchronization between central and peripheral oscillators [10]. In other words, while the central oscillators are adjusting somewhat faster to the timing of the destination using local zeitgebers, the peripheral oscillators take a significantly longer time. This might explain why the symptoms of jet lag often persist beyond the duration necessary for the entrainment of common circadian markers such as melatonin, cortisol, or temperature rhythms. Chronic jet lag. Many people, such as pilots and flight attendants, are exposed chronically to changes in meridian time. Temporal lobe atrophy and spatial cognitive deficits have been associated with a short recovery period after transmeridian flights in flight attendants [11]. Specifically, the volume of the temporal lobe and hippocampus-dependent memory deficits were compared in two flight attendant groups (each composed of 10 healthy,

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22-to-28-year-old women with five years in service). One group had recovery periods of fewer than five days, while the other was given 14 days or more to recover. Magnetic resonance imaging (MRI) revealed that the group with the short recovery period (fewer than five days) had smaller right temporal lobe structures. Visual spatial memory tests identified impairments in hippocampus-dependent memory. In addition, the reduction in the right temporal lobe volumes was associated with higher cortisol levels [11].

Light and Jet Lag Treatment Compared to naturalistic models, which involve a lot of variability due to the heterogeneity of travel-related behavior, jet lag is much easier to study in the laboratory, where the sudden change in light exposure can be easily simulated, circadian markers monitored, and treatment interventions tested. In the lab, an appropriately timed light exposure, combined with light avoidance or melatonin administration, accelerates adaptation to the new time zone [12]. In a study of 15 healthy young men in a laboratory simulation of a trip from Montreal to London (an eastward flight across five time zones), light exposures scheduled during the advancing portion of the PRC were effective in synchronizing the biological night and day to the sleep-wake rhythms in the new destination [13]. In a recent laboratory study by Eastman et al. [14], circadian rhythms were advanced at home by light exposure before an eastward flight as a strategy to prevent or reduce jet lag. The sleep schedule of 26 young healthy adults was gradually advanced one or two hours per day for three days, with intermittent morning bright light exposures (one-half hour of approximately 5000 lux and one-half hour of less than 60 lux) for 3.5 hours. According to this proactive approach, a large-enough phase advance before flight, close to the number of time zones to be crossed can, theoretically, eliminate jet lag. Instead, the traveler would arrive with circadian rhythms already set to the new zone. The goal of the preflight schedule, then, is to advance circadian rhythms as much as possible, while keeping them aligned with the advancing sleep schedule. However, for the great majority of us, such preflight gradual adjustment is not practical. Field studies of light exposure after flights are few and inconclusive. Exposure and avoidance of light. Both light exposure and light avoidance are effective circadian shifters. Appropriately timed light exposure and light avoidance are crucial in the treatment and prevention of jet lag. One common mistake transmeridian travelers make is to get indiscriminate exposure to light at the destination in order to adapt to the new time zone rapidly. In fact, knowing when to avoid light at certain times is important to prevent worsening of the jet lag. For instance, if someone travels from New York to Paris and arrives at 8 AM in Paris, there is a six-hour lag between the internal biological clock and the external clock time in Paris. If one is exposed to bright light at 8 AM in Paris, that light is not a stimulus for the SCN at 8 AM (Paris time) but rather at 2 AM (the internal time). According to the light PRC, this is the region of maximum phase delays, and now, one can experience an eight-hour jet lag instead of a six-hour jet lag. To avoid this, light exposure should be avoided or minimized before the temperature minimum (between 10 AM and 11 AM Paris time). After that period, bright light exposure is highly recommended and it will cause

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circadian phase-advance. Light can be avoided by the use of eyeshades, window shades, or sunglasses [4]. The sunglasses should be dark (but not so dark as to make driving more dangerous) and should filter out or reflect blue light, which is the most potent stimulating spectral band of melanopsin receptors. There is a schedule of recommended times for avoidance of and exposure to bright light when crossing time zones, eastbound or westbound, but the schedules are often difficult to apply in general conditions. For more complete schedules, consult Postolache et al. [10]. For simplicity, one can remember that bright light should be avoided several hours before temperature minimum (Tmin) with eastern travel and several hours after Tmin with Western travel. Consultants could estimate the temperature minimum on the first day at the new destination (Tmin2) as Eastward travelTmin2=Tmin (of origin) +number of time zones crossed and Westward travelTmin2=Tmin (of origin) -number of time zones crossed. Natural light. Natural sunlight contains the blue-green wavelengths that may be optimal for the chronotherapeutic effects of light. Hazards include ultraviolet radiation, which can cause skin cancer and cataracts, and blue wavelengths, which can cause retinal damage. Artificial light treatment. Light boxes, light visors, sunrise clocks, dawn simulators, and face masks have all been used to treat jet lag. Mini light boxes, which are small and portable, use light-emitting diodes (LEDs). Currently, narrow-spectrum, short-wavelength blue-green, and blue light devices provide more potent melatonin suppression and circadian shifting and shorter periods of exposure compared to the more traditional light boxes, which produce white cool or full spectrum light. Bright light treatment is considered generally effective and a safe intervention. The most commonly reported side effects are headache, eyestrain, feeling “wired,” and nausea. If these symptoms are moderate or severe, and persist after decreased duration of light exposure, discontinuation is recommended. Initially, it was believed that only bright light could shift circadian rhythms in humans. Now we know that even room light has shifting potential especially with extended exposure. Thus, the traveler should be mindful of the potential detrimental exposure to room light at the place of destination. In contrast, one should brighten the room when the exposure to brighter light is adequate.

Melatonin for Jet Lag In humans, as in most vertebrates, melatonin is synthesized primarily from serotonin in the pineal gland. It is often called the “hormone of darkness” since it is secreted during the “internal” nighttime. Melatonin has a role in diverse physiological functions: it is centrally involved in sleep regulation; it is considered the body’s chronological pacemaker; and it has potential antioxidant, oncostatic, and immunomodulatory properties. As a chronobiotic molecule, melatonin has shown to be valuable in treating various circadian rhythm sleep disorders, including jet lag or shift-work sleep disorder. As mentioned earlier, when melatonin is given during the evening, it phase-advances the circadian clock; when administered during the sleep period or in the morning, it shows maximal phase delays of the circadian clock. The timing of melatonin administration is critical for the optimal treatment of jet lag. One study by Waterhouse et al. [12] proposed a

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schedule for use of melatonin on the first day after time-zone transitions. Arendt et al. [15], in a review of 10 years of studies using melatonin, found that subjective assessments of jet lag symptoms declined by half with melatonin treatment, compared to placebo. The recommended regime was 5 mg melatonin taken in the evening three days before traveling and upon arriving using the same dose taken at local bedtime for four days after a flight [15]. In a laboratory study by Revell and Eastman [16], preflight melatonin and light administration were shown to phase-advance circadian rhythm by 2.5 hours. Smaller doses (0.5 mg) were recommended, since doses of 3 mg resulted in increased sleepiness. Takahashi et al. [17] studied six subjects who took eight-hour eastward flights from Tokyo to Los Angeles. Entrainment by phase advancing was seen in all subjects under a regime of 3 mg melatonin for three days after the flights. Five days after the flights, entrainment was almost complete. Melatonin is sold and marketed as a dietary supplement in the United States and it is not approved for the treatment of any disorder by the US Food and Drug Administration. The most common mistakes made in melatonin utilization include consuming it at the wrong time and using higher doses, more adequate for sleep induction rather than circadian shifting. If melatonin is taken indiscriminately as a sleep inducer, it can cause circadian shifts in an unwanted direction. Smaller doses (0.5-1 mg) are recommended and sufficient for phase shifting in jet lag.

Symptomatic Interventions In addition to the interventions specifically targeting the pathophysiology of jet lag, additional interventions target symptomatic improvement. The most common symptoms patients complain of are insomnia and daytime sleepiness. For insomnia, melatonin, synthetic melatonin receptor agonists (which are awaiting clinical studies for jet lag), and short-acting hypnotics at regular doses are often used. For improved alertness, caffeine as beverage or pill, and modafinil are interventions that are sometimes recommended. Hypnotics For the majority of patients the inability to fall asleep at the adequate time when traveling eastward is the most salient symptom of jet lag, the most bothersome and the one for which they seek treatment. For these patients, a successful restoration of the ability to sleep equates to a successful treatment of jet lag, even if alertness deficits and other jet lag symptoms persist after treatment with hypnotics. In addition, in patients with bipolar disorder, one night of sleep loss represents a major potential trigger for an “upward switch,” increased cycling, and loss of therapeutic control. In a recent study, travelers crossing five to nine time zones during transatlantic flights were given 10 mg of zolpidem (non-benzodiazepine hypnotic) or placebo for three consecutive nights, starting with the first nighttime sleep after travel. Zolpidem resulted in improved sleep quality, longer total sleep time, and a reduced number of awakenings compared to placebo. The most common side effects were headaches [18]. Other hypnotics that are not expected to work beyond 8 hours of sleep include temazepam (15 mg at bedtime), zaleplon (10 mg at bedtime), and eszopiclone (3 mg at bedtime). It is important to keep in

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mind that all hypnotics can have adverse effects and are recommended only for short-term symptomatic treatment. We discourage the use of hypnotics with longer duration of action for the treatment of jet lag, such as trazodone (Desyrel) or older generation antihistamines (diphenhydramine), which can affect cognitive functioning. In addition, a very important consideration is to think about the expected duration of sleep. If the remaining duration of sleep is less than 8 hours, we recommend not to use eszopiclone or zolpidem extended release, but the regular, non-extended release zolpidem. For the induction of very short sleep of several hours and for sleep maintenance difficulties after eastward travel, we often recommend zaleplon, considering its very short half time. With the newer generations of hypnotics, cognitive side effects represent areas of concern, and the individual response of a particular patient needs to be determined prior to prescribing these agents to be selfadministered for jet lag in a remote location.

Caffeine Caffeine is one of the most frequently used psychostimulant drugs worldwide and has been reported to improve subjective alertness and alleviate the deleterious effects of sleep deprivation. The actions of caffeine, a naturally occurring methylxantine most commonly found in coffee, tea, cola, and chocolate, have effects on various physiologic systems. The effects of caffeine on sleep and circadian rhythm are most likely mediated through the antagonism of adenosine A1 and A2a receptors [19]. Caffeine is often consumed at different times of day and night to alleviate the consequences of sleep deprivation, jet lag, and shift-work. In a recent study by Beaumont et al.. [20], a new slow-release formulation of caffeine (SRC), at a dosage of 300 mg twice a day, was shown to maintain performance and alertness during 32-hour sleep loss after rapid eastward transmeridian travel, with no side effects. Nevertheless, this alerting effect of SRC seemed to have residual effects on recovery sleep: feeling of sleepiness and sleep latencies were higher than in baseline conditions, and subjects who took SRC woke up earlier, slept less, and experienced more awakenings compared to subjects who took melatonin during the first night. Further studies on jet lag and administration of SRC will be required to elucidate its effects on recovery sleep. Reported side effects of caffeine include increased anxiety, locomotor agitation, diuresis, and tachycardia. The use of the new slow-release formulation of caffeine can reduce these adverse effects.

Modafinil (Provigil) Modafinil is currently FDA approved for excessive daytime sleepiness secondary to shift work, and as an add-on in obstructive sleep apnea. In a recent study, treatment with 200 mg modafinil resulted in a decrease in extreme sleepiness and a modest improvement in sustained-attention performance in patients with shift-work disorder [21]. However, patients treated with modafinil continued to show evidence of excessive sleepiness and, consequently,

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impaired performance during the night shift. Headaches were the most common side effect. Another laboratory study examined modafinil’s effects on sleep, cognitive performance, and mood during simulated shift work [22]. Participants received a single oral modafinil dose (0, 200, or 400 mg) one hour after waking following a day shift, and one hour after waking following a night shift, for three days. The shifts were alternated three times. Therapeutic doses of modafinil showed an attenuation of mood and cognitive performance impairments during night shift, while the larger dose administered during day-shift work caused sleep disruptions. These findings may have some significance in possible treatments of individuals in occupations where abrupt changes in work shifts are common. There have been no reports on treating jet lag with modafinil. Modafinil is a forbidden medication for competitive athletes due to its performance enhancing properties.

Exercise It is not exactly known if and how exercise can cause chronobiological effects in humans. However, there is convincing evidence to suggest a phase- shifting effect of exercise, especially confirmed for phase delay, rather than phase advance. Factors such as the intensity, specific kind, and duration of exercise, as well as interaction between exercise and light, have to be studied in order to provide any evidence-based approach or recommendation to travelers [23].

Discussion Research directions may include a) testing light, melatonin, and light avoidance in naturalistic paradigms; b) studying light of different wavelengths for jet leg, allowing exposure to smaller intensities of light, and also filtering certain wavelengths using adequate sunglasses; c) using melatonin receptor antagonists and wake promoting agents for jet leg; d) understanding interaction between multiple pace makers in creating jet lag; and e) understanding vulnerability to jet lag, in other words, why some people report a lot of symptoms, while others, very few. Patients with mood disorders are particularly vulnerable to the effects of sleep loss, which may exacerbate symptoms of depression and hypomania/mania, increase mood lability and cycling, and precipitate episodes of major mood disorders. Also, many patients with mood disorders have preexisting circadian abnormalities [24] that can compound the effects of jet lag. Consulting for jet lag in patients for mood disorders, when anticipating transmeridian travel in a patient with preexisting psychiatric illness the context, is very important, as well as his/her history of prior response to transmeridian travel. Individuals with a tendency to phase advance will do well traveling eastward, while those with a phase delay will adjust better when traveling west. Patients with bipolar disorder, especially those with rapid cycling and poor therapeutic control, are at increased risk. A written recommendation for the employer to assist the employee with minimize transmeridian travel is a first step. If frequent travel is

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currently an occupational imperative for those patients, a recommendation for change in job or profession may be required. Bipolar patients and those with recurrent major depression should be counseled against becoming flight attendants, and obviously against becoming commercial pilots. If the planned stay is short, the schedule at the destination flexible, and the performance upon return essential, it is desirable to try to keep the schedule of activity and of dark and light exposure of the place of origin. Window shades and/or sunglasses (dark or orange, i.e. filtering blue light) and alternation of bright light are recommended to avoid adjusting to the new time zone. When adjusting rest activity to local time is imperative or impossible to avoid, and the trip itself very important, shifting light-dark exposure, sleepwake, and rest-activity by one hour per day before the trip is recommended, when feasible. For that purpose, 30-minute exposure to bright light is useful for eastward travel upon awakening and for westward travel in the late afternoon or evening. In most cases, however, the treatment of jet lag starts on the day of departure. To fast-start entrainment in the majority of patients who are neither phase delayed or advanced (thus having their temperature minimum between 4 and 5 AM) traveling east, we recommend melatonin 0.5-1 mg in the afternoon of the departure (4-6 PM time of departure). At destination, on the first day, we strongly recommend bright light avoidance before (4 AM + number of time zones crossed AM) and bright light exposure after (4 AM + number of time zones crossed), then moving the time separating light avoidance and exposure earlier every day. Traveling west, we recommend bright light in the afternoon of departure (4-5 PM departure time) and, at the location of destination, avoidance of bright light in the early morning upon awakening for several days. Short acting hypnotics are useful for sleep induction for eastward travel, while ultrashort acting hypnotics may be useful for sleep maintenance with westward travel. Alerting medications may be useful in patients with a severe mismatch between occupational demands and alerting resources, and may include caffeine and modafinil. All these interventions are off-label, as the treatment of jet lag awaits larger and more definitive trials, which is well-deserved considering the increasing number of individuals exposed to transmeridian travel. All alerting medications may add to the potential mania-inducing capacity of sleep deprivation in patients with bipolar disorder. We recommend purposeful timing for exercise and meals, in the direction of the desired adjustment. Independent of crossing meridians, general air travel advice includes: wearing loose clothes and shoes, drinking plenty of fluids, avoiding alcohol and caffeinated beverages, investing in a noise reduction headset, having eye shades available, walking for 10 minutes every 90 minutes, and moving legs for three minutes every 15 minutes when awake. In addition, we would advise traveling patients with mood disorders to reduce tasks and expectations during the first several days of the trip and using a decongestant if symptoms of rhinitis are present prior to travel, in order to avoid an obstructive sleep impairment factor secondary to cabin environment. Patients are reminded not to forget their medications, and to put needed medications in carry-on luggage, in case flight schedules are altered. Bipolar patients should be advised not to sacrifice sleep duration under any circumstance, and to use short-term hypnotics more readily to secure the regular duration of sleep. Finally, we recommend that the treating consultant be available for brief phone consultations, anticipating possible time windows of contact, as well as clearly discussing the patient concrete situations when the patient will have to seek local professional attention.

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Acknowledgements Dr. Postolache has received unrestricted research funds from Apollo Health (American Fork, UT, USA), a research grant from LiteBook (Alberta, Canada), and is supported by a grant from the National Institutes of Health to study prediction of response to bright light treatment and its metabolic effects (1R34MH073797-01A2: PI Postolache). Additional support has been received from St. Elizabeths Hospital Psychiatry Residency Training. We thank Sarah Zimmerman and Manana Lapidus, MD for their contributions to the final form of the manuscript.

References [1] [2] [3] [4] [5]

[6] [7] [8] [9] [10]

[11] [12] [13] [14] [15]

Dunlap JC, Loros JJ, DeCoursey PJ. Chronobiology: Biological timekeeping. Sunderland, MA: Sinauer, 2004. Richardson GS. The human circadian system in normal and disordered sleep. J Clin Psychiatry. 2005;66 Suppl 9:3-9;42-3. Ko CH, Takahashi JS. Molecular components of the mammalian circadian clock. Hum Mol Genet 2006;15(2):R271-7. Postolache TT, Oren DA. Circadian phase shifting, alerting, and antidepressant effects of bright light treatment. Clin Sports Med 2005;24(2):381-413, xii. Czeisler CA, Richardson GS, Zimmerman JC, Moore-Ede MC, Weitzman ED. Entrainment of human circadian rhythms by light-dark cycles: a reassessment. Photochem Photobiol 1981;34(2):239-47. Khalsa SB, Jewett ME, Cajochen C, Czeisler CA. A phase response curve to single bright light pulses in human subjects. J Physiol 2003; 549(Pt 3):945-52. Rea MS, Bullough JD, Figueiro MG. Phototransduction for human melatonin suppression. J Pineal Res 2002; 32(4): 209-13. Boulos Z, Campbell SS, Lewy AJ, Terman M, Dijk DJ, Eastman CI. Light treatment for sleep disorders: consensus report. VII. Jet lag. J Biol Rhythms 1995;10(2):167-76. Czeisler CA, Duffy JF, Shanahan TL et al.. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 1999; 284 (5423): 2177-81. Postolache TT, Hung TM, Rosenthal RN, Soriano JJ, Montes F, Stiller JW. Sports chronobiology consultation: from the lab to the arena. Clin Sports Med 2005; 24(2): 415-56, xiv. Cho K. Chronic 'jet lag' produces temporal lobe atrophy and spatial cognitive deficits. Nat Neurosci 2001;4(6):567-8. Waterhouse J, Reilly T, Atkinson G. Jet-lag. Lancet 1997; 350(9091):1611-6. Boivin DB, James FO. Phase-dependent effect of room light exposure in a 5-h advance of the sleep-wake cycle: implications for jet lag. J Biol Rhythms 2002;17(3):266-76. Eastman CI, Gazda CJ, Burgess HJ, Crowley SJ, Fogg LF. Advancing circadian rhythm before eastward flight: a strategy to prevent or reduce jet lag. Sleep 2005;1:33-44. Arendt J, Skene DJ, Middleton B, Lockley SW, Deacon S. Efficacy of melatonin treatment in jet lag, shift work, and blindness. J Biol Rhythms 1997; 12(6): 604-17.

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[16] Revell VL, Eastman CI. How to trick mother nature into letting you fly around or stay up all night. J Biol Rhythms 2005; 20(4):353-65. [17] Takahashi T, Sasaki M, Itoh H et al.. Re-entrainment of circadian rhythm of plasma melatonin on an 8-h eastward flight. Psychiatry Clin Neurosci 1999; 53(2): 257-60. [18] Jamieson AO, Zammit GK, Rosenberg RS, Davis JR, Walsh JK. Zolpidem reduces the sleep disturbance of jet lag. Sleep Med 2001; 2(5):423-30. [19] Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 1999;51(1):83-133. [20] Beaumont M, Batejat D, Pierard C et al.. Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel. J Appl Physiol 2004;96(1):50-8. [21] Czeisler CA, Walsh JK, Roth T et al.. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med 2005;353(5):476-86. [22] Hart CL, Haney M, Vosburg SK, Comer SD, Gunderson E, Foltin RW. Modafinil attenuates disruptions in cognitive performance during simulated night-shift work. Neuropsychopharmacology 2006; 31(7):1526-36. [23] Atkinson G, Edwards B, Reilly T, Waterhouse J. Exercise as a synchroniser of human circadian rhythms: an update and discussion of the methodological problems. Eur J Appl Physiol 2007; 99(4): 331-41. [24] Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar disorders and recurrent depression, 2nd Ed. New York: Oxford Univ Press, 2007.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XII

Mindfulness Meditation in Patients with Mood Disorders. Feasibility, Safety and Efficacy: An Empirical Review Kalina Boteva∗ Division of Consultation Liaison Psychiatry, Department of Psychiatry, University of Maryland Medical Systems, Baltimore, Maryland, USA

Abstract Since 1979, when mindfulness-based stress reduction (MBSR) was first introduced at a mainstream medical center, there has been a rapidly growing interest in the science and clinical applications of mindfulness meditation. MBSR is efficacious in improving quality of life and decreasing symptoms of depression in a wide variety of medical patient populations. Mindfulness-based cognitive therapy (MBCT) incorporates elements of mindfulness meditation and cognitive therapy and was specifically designed for relapse prevention in depression. The objective of this study is to review the feasibility, safety, and efficacy of mindfulness based interventions in patients with mood disorders. Systematic searches for clinical studies were conducted on several databases and one relevant website. Fifteen articles met criteria for inclusion in this review. MBCT is feasible for patients with major depressive disorder (MDD), bipolar affective disorder (BAD), and history of suicidal thinking or behavior. The intervention has a low dropout rate and high degree of acceptability. MBCT is probably efficacious for decreasing the risk of relapse in patients with three or more depressive episodes. Preliminary evidence suggests that MBCT might be helpful in reducing symptoms of depression in moderately to severely depressed patients with MDD or BAD, in reducing anxiety and depressive symptoms in bipolar patients, and in possibly decreasing cognitive vulnerability to suicidality. MBSR is less well studied in mood disorder patients. MBCT and possibly ∗

Correspondence: Kalina Boteva, MD, Box 349, Department of Psychiatry, UMMS, 22 S Greene Street, Baltimore, MD 21201 USA. Tel: 410-328-6091; E-mail: [email protected]

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Kalina Boteva MBSR have a potential as clinically valuable interventions in the treatment of mood disorders. Further research into their efficacy, feasibility, and safety is recommended.

Keywords: mindfulness meditation, mindfulness based cognitive therapy, mindfulness based stress reduction, mood disorders, depression.

Introduction Mindfulness meditation is part of millennia-old Eastern contemplative tradition developed to understand the mind and the human condition by means of systematic, first person inquiry into the nature of mental phenomena. Over the years there have been countless subjective accounts of increased sense of vitality, well-being, inner peace, and happiness, as a result of sustained mindfulness practice [1,2]. As early as fifth century mindfulness of breathing was universally emphasized as an intervention for those who are especially prone to compulsive thinking [3]. Through the ground-breaking work of Jon Kabat-Zinn [4], the practice of mindfulness was brought into mainstream clinical medicine in the form of Mindfulness-Based Stress Reduction (MBSR), which was designed as a program for treatment of chronic pain [5]. Since its introduction in 1979, MBSR has been studied in patients with a range of different health conditions: cancer [6-9], heart disease [10,11], organ transplantation [12,13], HIVinfection [14], fibromyalgia [15-17]. In a meta-analysis of studies including pain, cancer, heart disease, depression, and anxiety patient populations, Grossman et al report that MBSR leads to improvement in a wide spectrum of clinical outcomes [18]. Overall, both controlled and uncontrolled studies showed similar effect size of about 0.5, which was consistent across the spectrum of outcome measures: quality of life, depression, anxiety, coping style, medical symptoms, sensory pain, physical impairment [18]. Mindfulness-Based Cognitive Therapy (MBCT) combines mindfulness meditation training with some elements of cognitive therapy and was specifically developed as a treatment for the prevention of depressive relapse [19). Two randomized controlled trials demonstrated that MBCT significantly reduced the risk of depressive relapse in patients with 3 or more past depressive episodes [20,21]. The first of the two studies as well as studies of MBSR in a variety of other patient populations have been reviewed in a meta-analysis by Baer 2003 [22]. Similar to the findings of Grossman et al [18], Baer reports that, in spite of significant methodological flaws, the current literature suggests that mindfulness-based interventions may help to alleviate a variety of mental health problems and improve psychological functioning [22]. In another review paper Toneatto and Nguyen report that the beneficial effect of MBSR on depression and anxiety is equivocal [23]. When active control groups were used, MBSR did not show an effect on depression and anxiety [23]. Toneatto and Nguyen [23], Grossman et al [18], and Baer [22] have all reviewed research studies reporting outcomes in a broad range of patient populations as well as healthy volunteers. A question still remains as to the role of mindfulness-based interventions when offered specifically to patients with clinical diagnosis of depression or other mood disorders.

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The purpose of this study is to review the empiric research on the feasibility, safety, and efficacy of mindfulness-based clinical interventions in the treatment of patients with mood disorders.

Definition of Mindfulness An operational, working definition of mindfulness is: the awareness that emerges through paying attention on purpose, in the present moment, and nonjudgmentally to the unfolding of experience moment by moment [24]. It is a kind of nonelaborative, nonjudgmental, presentcentered awareness in which each thought, feeling, or sensation that arises in the field of attention is acknowledged and accepted as it is [25]. This definition of mindfulness is explicitly based on the descriptions of mindfulness in the modern vipassana (contemplative insight) tradition of Theravada Buddhism. A prominent Vipassana scholar describes mindfulness as nonconceptual awareness, or “bare attention”, which does not label or categorize experience. “Mindfulness is present-time awareness … It stays forever in the present … If you are remembering your second-grade teacher, that is memory. When you then become aware that you are remembering your second-grade teacher, that is mindfulness” [3]. Recently, a two-component model of mindfulness has been proposed [25]: The first component has to do with self-regulation of attention so that attention is maintained on immediate experience, thereby allowing for increased recognition of mental and sensory phenomena in the present moment. This component of mindfulness requires: a) sustained attention, i.e. the ability to maintain a state of vigilance and uninterrupted present-time awareness of immediate experience over some period of time; b) an element of remembering of what the task at hand is, and c) skills of switching attention, i.e. the ability to bring the attention back to the present-time awareness when the mind loses track of the unfolding subjective experience in the present and drifts into memories about the past or planning for the future. The second component of mindfulness is adopting a particular orientation towards one’s experience that is characterized by friendly curiosity, openness, acceptance, and nonjudgment. This requires making a commitment, or setting up an intention to maintain an even-mindedness, an attitude of non-grasping and non-aversion (i.e. equanimity) towards all of one’s experiences. All thoughts, feelings, and sensations that arise in the field of awareness are seen as relevant and therefore subject to observation. Mindfulness is ostensibly cultivated in the process of mindfulness meditation. One of the basic formal meditation practices is awareness of breathing- as in awareness of the full course of each inhalation and exhalation or awareness of the body sensations related to the process of respiration. In addition to the breath, one may include in the field of meditative awareness body sensations from particular regions, movement, a sense of the body as a whole, sound, an emotional state, or the thought process itself. In a formal practice one may chose to focus on one meditative object to the exclusion of others, or may "just sit" with awareness of whatever comes up in the field of attention, not looking for anything in particular to focus on- a practice sometimes called "choiceless awareness". In essence, attending to any object in the field of mental phenomena could serve as a method of cultivating direct moment-to-moment

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awareness. What is important is the quality of intention and commitment to practice, and not the "technique" one is using or what one is paying attention to [4].

Mindfulness-Based Stress Reduction (MBSR) MBSR is the first mindfulness-based clinical program of its kind that was introduced at a mainstream medical center in 1979 and was originally developed for the management of chronic pain [5]. The program is an 8-10 week course, which patients attend once a week for 2-3.5hours [4,5,26]. During the sixth week of the program there is an all-day (7.5 hours) silent retreat. The formal mindfulness meditation methods thought in an MBSR program are as follows: body scan meditation (a supine meditation focusing on sensations from the body as it is being attended to in a systematic way from head to toe); gentle Hatha yoga (practiced with mindful awareness of the body during movement and yoga postures); sitting meditation (mindfulness of breath, body, feelings, thoughts, emotions, and choiceless awareness); walking, standing, and mindful eating meditations. In addition, MBSR participants are encouraged to cultivate mindfulness in everyday life by practicing informally deliberate awareness of routine activities and events such as eating, weather, driving, walking, awareness of interpersonal communications, as well as awareness of pleasant and unpleasant events throughout the day. For the entire duration of the course participants commit to and are expected to complete daily home assignments including a minimum of 45 minutes a day of formal mindfulness practice and 5-15 minutes of informal practice, six days per week. During the group sessions there are ample opportunities for individual and group dialogue and exploration of hindrances to mindfulness and development and integration of mindfulness-based self-regulatory skills and capacities. The MBSR program is highly experiential and the patients are active participants in the curriculum in the context of a collaborative relationship with the MBSR provider. Self-responsibility is an important element of the program and it is repeatedly emphasized that internal resources for selfhealing can only be developed by sustained work on the part of the individual [5]. Before the first group meeting there is a 2-hour group orientation session, or one-hour individual assessment/interview. Sometimes there are individual post-program exit interviews. In summary, the total in-class contact is about 30 hours, total home assignments: minimum of 42-48 hours, total individual interview time: 1.5-2.0 hours, and total group orientation time: 2.0 hours [26].

Mindfulness-Based Cognitive Therapy (MBCT) MBCT is a manualized clinical intervention combining the practices and perspectives of mindfulness meditation with elements of cognitive therapy. MBCT consists of eight weekly group meetings (or classes), one individual interview before the start of the weekly group meetings, and a varying number of follow-up meetings in the year following the 8-week program [19]. The patients are expected to have daily formal meditation practices for the duration of the 8-week program, as well as to complete various homework assignments. The

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focus of sessions 1-4 is learning to pay attention, on purpose, in each moment, without judgment. This is taught, first, in reference to parts of the body, and, second, with reference to the breathing. Participants are taught to recognize how the mind frequently wanders from one topic to another and how this wandering can allow negative thoughts and feelings to occur. The focus of sessions 5-8 is wider awareness of thoughts, feelings, body sensations and action tendencies. Participants learn to recognize whenever a negative thought or a feeling arises, then to acknowledge it, and then to consider how best to respond to it. They may chose to deal with the negative thoughts or feelings directly, by seeing them simply as thoughts or feelings and observing them as they pass through the field of attention. Or participants may choose to deal with a difficult emotional state by noting the part of the body it affects and bringing awareness and breathing to that part of the body. Participants also learn how to use "breathing space". This involves learning to step out of automatic pilot, then to move through a three part practice, each part taking about one minute: a) awareness of current thoughts, feelings and body sensations; b) narrowed focus on sensations of breathing; and c) wider awareness of the whole body. Finally, participants are encouraged to become more aware of their own unique warning signs of developing depression, and to plan specific actions for when this may occur. See also Baer [22] and The Melbourne Academic Interest Group [27] for conceptual reviews of mindfulness-based clinical interventions.

Methods Summary of the Search Strategy A comprehensive search for clinical research was carried out. Systematic searches were conducted on several databases, secondary citations were sought from relevant reviews, and one relevant website was also included in the search. Databases searched: CINAHL, MEDLINE, PreMEDLINE, PsychINFO, PubMed. All searches were conducted September 1-26, 2007. Website searched: Center for Mindfulness in Medicine, Health Care, and Society at the University of Massachusetts Medical School: (http://www.umassmed.edu/cfm/index.aspx?linkidentifier=idanditemid=3376)Search terms: The basic search terms for mindfulness-based clinical interventions were: meditation, mindfulness-based stress reduction, mindfulness-based cognitive therapy. The term meditation was combined with each of the basic search terms for mood disorders: mood, affective, depression, depressive, dysthymia, bipolar, manic. When researching the CINAHL database it was the term mindfulness meditation (not meditation) that was combined with the search terms for mood disorders.

Selection Criteria ·

Types of studies: All clinical studies, including controlled trials, uncontrolled trials, observational studies and case reports were identified for possible inclusion in this review.

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·

·

Types of participants: Only studies where participants were specifically ascertained to meet clinical diagnostic criteria for current or lifetime mood disorder were selected for inclusion. Types of intervention: Studies of clinical interventions based on Mindfulness-based stress reduction or Mindfulness-based cognitive therapy were selected for inclusion. Excluded are studies of yoga practices and styles that were not specifically based on mindfulness approach, and studies that involved multiple interventions delivered to the same participants. Studies of Dialectical-Behavioral Therapy which incorporates some elements of mindfulness are beyond the scope of this review ((except one case report [40] describing specifically the use of mindfulness within the DBT approach that was included in the review)). Types of outcome measures: The clinical studies identified by the search strategy were not specifically screened for inclusion based on types of outcome measures.

Data Collection and Analysis Studies were selected for inclusion in this review by applying the inclusion/exclusion criteria to each of the unique citations identified by the database and website searches. The following information was extracted from the clinical studies under review: sample size, clinical diagnoses of patients, research design, description of the active and control intervention (when applicable), duration of follow-up, outcome measures, main results, reports of potential adverse effects. Methodologically, the studies were appraised using the following criteria: method of randomization, concealment of allocation and level of blinding (if relevant), baseline comparison of characteristics, method of dealing with missing values, loss to follow-up/withdrawals, and reporting on measures of compliance.

Results The database searches resulted in a total of 1,036 non-unique citations for initial screening (this number does not include potential articles identified on the CFM website or secondary citations identified from relevant reviews). Of all citations 15 clinical studies met criteria for inclusion in this review [20,21,28-40]. The rest of the clinical studies identified by the search strategy that were not included in the review, fit in the following three categories: 1) Studies in which the intervention was mindfulness-based, however the subjects were not specifically ascertained to meet diagnostic criteria for mood disorder 2) Studies in which (mindfulness) meditation was part of a more complex intervention including other components 3) Studies of meditation or other interventions that were not mindfulness-based. Please refer to table 1 for summary of the 15 studies included for review.

Table 1. Summary of studies of mindfulness-based interventions in patients with mood disorders Study

Sample

Randomized studies Barnhofer N=34 et al. 2007 Age 18-65 4 MBCT patients withdrew before and 2 dropped out after the start of the intervention; 6 TAU patients lostto follow-up

Ma and Teasdale 2004

N=75 Age 18-65 AND N=50 never depressed controls matched for age and gender 6 MBCT patients dropped out

Inclusion Criteria

Design

Intervention

Control group

Previous episode of major depression with suicidal ideation, currently in recovery for at least 8 weeks

Participants randomized to MBCT in addition to TAU or TAU alone

n=16 MBCT plus TAU Following the manual of Segal et al adapted for suicidal depression including discussions of thoughts and feelings specific for suicidality

n=18 TAU

DSM-IV diagnosis of recurrent MDD now in remission, off antidepressants preceding 12 weeks, baseline HRSD-17 <10

Randomization by strata to MBCT in addition to TAU or TAU alone Stratification based on the severity of last depressive episode and number of previous episodes Follow-up at 3 months for a year after the 8week treatment phase

MBCT plus TAU Following the manual of Segal et al. After the initial 8week phase, two follow-up meetings were scheduled at intervals of 1 and 6 months

TAU

Outcome measure(s) BDI-II PANAS EEG pre- and post- an 8-week treatment period

Relapse/recurrenc e of major depressive episode (SCID at baseline, upon completion of MBCT, and every 3 months for one year) 17-item HAM-D BDI MOPS (at baseline) Life Events (specific for the time when patients were diagnosed with relapse during follow-up)

Results

Methodological appraisal

Significant pre to postdecreases in asymmetry scores in the TAU group (for prefrontal area F4/F3 P=0.003, for area F8/F7 P=0.001) No significant pre to post EEG changes in the MBCT group

R-adequate, CA and BA not reported Baseline: MBCT and TAU groups similar on gender, BDI, age of onset of first episode, proportion of patients using antidepressants MBCT group significantly older and tended to have more previous episodes CH: not reported Attrition: Results based on the 10 MBCT and 12 TAU completers R, CA, BA: adequate Baseline characteristics: TAU and MBCT groups were similar on all baseline measures CH: not reported Attrition: intent-to-treat analysis; no significant differences between completers vs. dropouts except for number of previous depressive episodes (5 of the 6 dropouts had only two). The difference in dropout rate between those with 2 and those with three or more was significant

Patients with >/=3 prior depressive episodes had significantly less hazard of relapse/recurrence in MBCT group compared with TAU p=0.001, hazard ratio = 0.278 (CI 0.130-0.597); 36% of MBCT vs. 78% of the TAU group had a relapse (h value of 0.88 indicating a large effect size A positive linear relationship between number of previous episodes and risk of relapse was found in the TAU group, but not in the MBCT group MBCT was more effective in preventing relapse not preceded by life events

Table 1. Continued Study Teasdale et al. 2000

Sample N=145 patients recruited at 3 sites Age 18-65 13 of 76 MBCT patients dropped out

Teasdale et al. 2002

N=100 subset from Teasdale et al 2000

Inclusion Criteria DSM-III-R diagnosis of recurrent MDD; off antidepressants preceding 12 weeks, baseline HRSD-17 <10

Design

Intervention

Control group n=69 TAU

Outcome measure(s) Relapse/Recurrence of major depressive episode, 17-item HRSD BDI All assessments were performed at baseline, upon completion of MBCT training, and every two months thereafter for one year

n=76 MBCT plus TAU After the initial 8week phase, four follow-up meetings were scheduled at intervals of 1, 2, 3 and 4 months

As in Teasdale et al 2000

Randomization within strata at each site to MBCT plus TAU or TAU alone, 8-week treatment phase and a 1y follow-up phase Stratification based on recency of recovery from last depressive episode and number of previous depressive episodes As in Teasdale et al 2000

n=52 MBCT plus TAU

n=49 TAU

N=45 Subset from Teasdale et al 2000 Mean age=44 (SD=9.5)

As in Teasdale et al 2000

As in Teasdale et al 2000

n=21 completers MBCT plus TAU

n=20 completers TAU

4 patients dropped out

Methodological appraisal

Patients with >/=3 prior depressive episodes had significantly less hazard of relapse/recurrence in MBCT group compared with TAU p<0.01, hazard ratio = 0.473 (CI 0.2670.836); 40% of MBCT participant had a relapse vs. 66% in the TAU group (h value of 0.53 indicating a medium effect size)

R, CA, BA: adequate Baseline: similar for marital status, education, social class, previous treatment of depression, severity of depressive symptoms. MBCT group differed from TAU on age and age was used as a covariate on all comparisons CH: not reported Attrition: reasons for drop out not stated, intent-to treat analysis

MACAM At 22 weeks after the start of MBCT

Metacognitive awareness significantly greater following MBCT than TAU (p<0.02)

HRS-D AMT at baseline (time 1) and about 4 months following the end of treatment (time 2)

Significant increase in proportion of specific memories (p=0.03) and decrease in proportion of categorical memories (p=0.03) at time 2 in the MBCT group

R, CA, BA: adequate Baseline: MBCT similar to TAU except for age, age was used as a covariate CH: not reported Attrition: analysis on completers R, CA, BA: adequate Baseline: MBCT group not different from TAU on age, number of years of education, number of previous depressive episodes CH: not reported Attrition: analysis on completers only

13 MBCT patients dropped out Williams et al. 2000

Results

Table 1. Continued Study Williams et al. 2007

Sample N=68 Age 18-65

Non-randomized studies Kenny and N=50 Williams Age 17-61 2007

Kingston et al. 2007

N=19 Age 20-62

Inclusion Criteria At least one prior episode of major depression (MDD or BAD) accompanied with suicidal ideation, currently in recovery

Control group n=35 (27 unipolar and 8 bipolar) waitlist controls plus TAU

Outcome measure(s) BDI-II BAI

MBCT plus TAU Based on Segal et al 2002

None

MBCT plus TAU, based on Segal et al 2002 manual Design 1: n=8 Design 2: n=19

TAU Design 1: n=11

BDI (pre and post MBCT) Likert scale rating of the importance of MBCT for patients (max=10) BDI RUM at pre-, midpoint, post-, and 1-month follow-up

Design

Intervention

Random allocation to MBCT plus TAU or waitlist control plus TAU

n=33 (24 unipolar and 9 bipolar) MBCT plus TAU based on Segal et al 2002

DSM-IV MDD or BAD, depressed phase, continuous, active symptoms of depression at the start of MBCT BDI>10

Within subject comparisons before and after MBCT

DSM-IV recurrent depressive disorder with 3 or more prior depressive episodes, residual depressive symptoms (baseline BDI 13-45) 2 patients BPAD-II, 9 with history of deliberate self-harm

MBCT plus TAU or TAU alone based on consecutive referrals Within subject pre-to post MBCT comparisons after the patients initially assigned to TAU completed MBCT

Results

Methodological appraisal

Significant difference in level of depression post MBCT compared to waitlist controls Significantly lower anxiety scores in bipolar patients post MBCT compared to waitlist bipolar patients No difference in anxiety scores post MBCT for unipolar patients

R, CA: adequate, BA: not reported Baseline: no difference between MBCT and waitlist bipolar patients and between bipolar and unipolar patients on age, gender, current occupation CH: not reported Attrition: missing follow up data on 5 MBCT and 8 waitlist participants, reasons for dropout not reported

Significant decrease of mean BDI pre to post (p<0.0001) in both moderately and severely depressed patients; BDI for all 5 bipolar patients decreased post MBCT Mean Likert scale for MBCT=8.5 SD=1.5 Significantly lower BDI and RUM for both MBCT and TAU groups post 8-week treatment period; Significantly lower BDI post MBCT compared to TAU (p<0.05) Trend toward greater reduction in RUM postMBCT compared to TAU (p=0.063) .Significantly lower BDI post for all patients who completed MBCT (p<0.05)

R, CA, BA: none, control group-none, Baseline characteristics: descriptive as there is no comparison group; CH: not reported; Attrition: one of 50 did not complete MBCT, reason for dropout unclear R, CA: none, BA: not reported Baseline: MBCT and TAU groups similar on age, gender, baseline BDI CH: not reported Attrition: 6 dropouts (reasons not provided), 3 missing data (reasons explained). Analysis performed on the 19 patients who completed five or more MBCT sessions

Table 1. Continued Study

Sample

Ramel et al. 2004

N=23 Mean age 50.87 SD=8.87

Weiss et al. 2005

N=31 Age 22-75

Inclusion Criteria DSM-IV lifetime mood disorder, 50% met criteria for a lifetime anxiety disorder 26% with current major depressive episode (MDD or BAD)

DSM-IV diagnoses of depression and anxiety disorders

Design

Intervention

Control group

Design 1: within subject comparison before and after MBSR Design 2: 11 MBSR completers matched to 11 wait-list controls

MBSR Modeled after Kabat-Zinn 82

Design 1: no control group Design 2: wait-list controls matched by age, gender, and baseline BDI to a subset of patients who completed MBSR intervention

Non-randomized controlled trial Group allocation based on patient preference

n=15 opted to learn MBSR (MBSR group). Training consisted of eight 1hour individual sessions, the first and last devoted entirely to MBSR, the intervening 6 divided between MBSR and individual therapy homework: 30 minutes a day 6 days a week

n=16 opted to continue with standard psychotherapy (psychotherapy only or PO group)- once a week for 1hour of routine individual psychotherapy.

Outcome measure(s) BDI STAI DAS RSQ Before and after MBSR

GSI of the Symptom Checklist-90-R; 100-point selfidentified goal scale; Number and rate of therapy sessions sought by clients for 2 months prior and 6 months after the study period; Rate of termination of therapy

Results

Methodological appraisal

Significant decrease postMBSR in: BDI (p<0.024), STAI-trait (p<0.02), RSQrumination (p<0.001), DASapproval (p<0.05) Changes in rumination remained significant after controlling for changes in BDI, STAItrait, and DAS-approval (p<0.004) Completers had significantly less RSQ-rumination postMBSR (p<0.005) compared to matched controls

R: none, CA, BA: not reported, Baseline: wait-list controls similar to the matched MBSR completers on age, gender, baseline BDI Matched MBSR completers had higher baseline rumination CH: low, assessed retrospectively after MBSR, average total home practice 11.46 hr or 1.4 hr per week, SD=15.35 hr Attrition: 2 dropouts to n=23 of which 5 attended <4 sessions, analysis was on the n=23 “treated” sample R, AC, BA: none; Baseline: MBSR and PO groups similar for age, marital status, education, total number and rate of therapy sessions prior to intervention, and GSI. MBSR group with significantly greater distance from goal attainment than the PO group; CH: not assessed during the MBSR training Attrition: none during active and control intervention, 4 of 15 MBSR participants did not return the follow-up questionnaire at 6 months

Significant improvement on all measures in both MBSR and PO groups The MBSR group showed Significantly greater gains on the goal achievement measure (p=0.008) and a higher rate of termination of therapy (p=0.016) in the MBSR compared to the PO group At 6 months F/U 11 of 15 MBSR participants were still meditating, rated importance of MBSR very highly and reported lasting improvements in energy level, activity, and coping ability

Table 1. Continued Study

Sample

Qualitative studies Finucane N=13 and Mercer Age 18-65 2006

Mason and Hargreaves 2001

N=7 Age 24-59

Smith et al 2007

N= 38 Age 65-88, mean 70.5; 8 dropped out after starting MBCT, 7 more lost to follow up, at the end of follow-up complete data available for 25 patients

Inclusion Criteria

Design

Recurrent depressive disorder by ICD10 or depression and anxiety with at least two prior depressive episodes, at least mild symptoms of depression Baseline BDI>14 DSM-III-R Diagnosis of depression on at least two occasions

Qualitative analysis 3 months post MBCT and some pre- to post comparisons on level of depressive and anxiety symptoms

At least three episodes of MDD baseline BDI-II 19 or less Some co-morbid anxiety disorders, pain, or physical illness

Qualitative within subject comparisons before and after MBCT

Qualitative analysis immediately postMBCT n=4 and 12-30 months postMBCT n=3

Intervention MBCT Following Segal et al 2002 with shortening of some meditation practices: body scan was reduced from 40 to 30 minutes and the guided sitting meditation from 40 to 25 minutes MBCT

MBCT Based on prepublication version of manual by Segal et al 2002 Mindful yoga adapted for older people

Control group

Outcome measure(s)

Results

Methodological appraisal

None

BDI-II BAI before and 3 months after MBCT Semi-structured qualitative interview 3 months after MBCT

Majority of MBCT participants found course enjoyable and beneficial, increased ability to relax, improved mood, sleep, self awareness, and new ways to work with negative thoughts and emotions Mean BDI-II and anxiety decreased pre to post MBCT

R, CA, BA, control group: none Baseline comparisons: N/A CH: not reported Attrition: 2 participants did not complete post-interview, reasons provided

None

Themes emerging from clinical interviews

R, CA, BA: none Baseline comparisons: N/A CH, Attrition: not reported

None

BDI-II Thematic analysis of clinical interviews before, 2 weeks after, and 12-13 months post-MBCT

Initial expectations important for later therapeutic gain, group important in facilitating change, increased mindfulness skills, greater ability to observe one’s problems, which gives more choice in how to respond Positive link suggested between consistency of homework practice and the process of change Common themes: increased awareness, acceptance, control, less ruminations, more enjoyment and getting along better with others Most patients found that the course either improved their lives in major ways or definitely helped them, 27 of 29 would definitely recommend MBCT to a depressed friend Mean BDI-II decreased slightly post MBCT and further at 13 months

R, AC: none, BA: attempted by having a psychologist naïve to MBCT perform interviews Baseline comparisons: N/A CH: assessed retrospectively at the 1y follow-up- most participants maintained frequent mindfulness practice and expected to continue Attrition: reasons for dropout provided

Table 1. Continued Study Case studies Williams and Swales 2004

Williams et al. 2006

Sample N=2

N=1

Inclusion Criteria History of suicidal thinking Patient 1: BPD, eating disorder, parasuicidal behaviors Patient 2: history of multiple overdoses and violent behavior towards her siblings Recurrent suicidal ideation and prior suicide attempt, depression, active alcohol and drug use

Design

Intervention

Control group

Outcome measure(s)

Results

Methodological appraisal

Case study

Use of mindfulness approach in the context of DBT

None

Subjective report of personal experience

Patient 1 was able to utilize “breathing space” as one approach of tolerating escalating suicidal thoughts and affects, increasing her capacity to focus on more active problem-solving Patient 2: Becoming more aware of both her own judgmental thoughts (and those of her relatives) enabled her to interrupt the chain of events frequently leading to parasuicidal behavior in the past

R, CA, BA: none Baseline comparisons: N/A CH: not reported Attrition: N/A

Case study

MBCT Based on Segal et al 2002 modified slightly for work with potentially suicidal patients

None

Subjective report of personal experience MAAS

After initial difficulties, some increased ability to observe her negative thoughts without experiencing strong emotional reactions At the end of the course the patient had reported improved relationship with her daughter, reduced intake of drugs and alcohol, and had described the course as a “life-changing experience” MAAS increased post MBCT

R, CA, BA: none Baseline comparisons: N/A CH: not assessed Attrition: N/A

MBCT- Mindfulness-Based Cognitive Therapy, MBSR- Mindfulness-Based Stress Reduction, CBT- Cognitive Behavioral Therapy, DBT- Dialectical Behavioral Therapy, TAU- Treatment As Usual, DSM-III-R- Diagnostic and Statistical Manual of Mental Disorders-III-Revised, ICD-10 International Classification of Diseases, MDD- Major Depressive Disorder, BAD- Bipolar Affective Disorder, Sch- Schizophrenia, SA- Substance Abuse, BPD- Borderline Personality Disorder, ADMsAntidepressant Medications, BDI- Beck Depression Inventory, HRSD, HRS-D or HAM-D- Hamilton Rating Scale for Depression, STAI- Spielberg State-Trait Anxiety Inventory, BAI- Beck Anxiety Inventory, PANAS- Positive and Negative Affect Schedule: State Version, GSI- Global Severity Index, MOPS- Measure of Parenting Style, MACAM- Measure of Awareness and Coping in Autobiographical Memory, AMT- Autobiographical Memory Test, RUM- Rumination Scale, MAAS- Mindful Attention Awareness Scale, DAS- Dysfunctional Attitude Scale, RSQ- Response Style Questionnaire, VA- Veterans Administration, R- Randomization, CAConcealment of Allocation, BA- Blinding of Assessors, CH- Compliance with homework, N/A – Not Applicable

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Overview of Clinical Studies Randomized Controlled Trials The study by Teasdale et al [20] was the first study that examined the efficacy of MBCT in relapse prevention in depression. In this study 145 patients, in remission or in recovery from recurrent major depression (i.e., at least two previous episodes), were randomized to continue with treatment as usual (TAU) or TAU plus MBCT. Patients were stratified on two baseline variables- recency of recovery from last depressive episode (0-12 months vs. 13-24 months) and number of previous depressive episodes (2 vs. 3 or more) and were randomized by strata within each site. Eighty-six percent of the patients were in the asymptomatic range of the Hamilton Rating Scale of Depression at baseline. In an intent-to-treat analysis MBCT significantly reduced the risk of depressive relapse/recurrence during a one-year follow-up period in patients with three or more episodes of depression. The relapse rate of 66% in the TAU group was reduced to 37% in patients with three or more depressive episodes, an effect of moderate size. For patients with only two previous episodes, MBCT did not reduce relapse/recurrence. As discussed by the authors, it is not clear if the observed benefits of MBCT could be attributed to the specific skills taught by the program versus nonspecific factors, such as therapeutic attention and/or group participation. In the study of Ma and Teasdale [21] a different patient sample of 75 recovered recurrently depressed patients were randomized within strata to TAU or TAU plus MBCT in a design that was similar to Teasdale et al [20]. Stratification was based on severity of last episode (above and below the median) and number of previous depressive episodes (2 vs. more than 2). Replicating the previous findings, in intent-to-treat analysis, MBCT participants with three or more depressive episodes had a significantly lower risk of relapse/recurrence of major depression in the one-year follow-up period compared to TAU participants (relapse rates were 78% in the TAU group and 36% in the MBCT group). MBCT was not effective in preventing relapse in patients with 2 prior depressive episodes. Ma and Teasdale also explored possible differences between patients with 3 or more depressive episodes vs. patients with only 2 prior episodes. Relapses were more often associated with significant life events in the group with 2 prior depressive episodes. This group also reported less childhood adversity and later onset of first depressive episode than the 3-or-moreepisode group. MBCT was more effective in preventing relapses not preceded by life events. In the study of Teasdale et al [28] 100 recovered or remitted recurrently depressed patients recruited at two treatment centers were randomized to TAU or TAU plus MBCT. This patient sample was part of the larger randomized control trial published previously by Teasdale et al [20]. See above for overview of that study reporting outcome data on the total three-center trial. Teasdale et al [28] reported for the first time on the effects of MBCT on post-treatment metacognitive awareness- a measure that is related to likelihood of depressive relapse in vulnerable individuals. Metacognitive awareness refers to the way that negative thoughts and feelings are experienced as they arise. It refers to the extent to which thoughts are experienced just as thoughts (mental events) rather than aspects of self or true facts. The study reports significantly greater metacognitive awareness (p<0.02) following MBCT

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treatment than TAU. These data might indicate that as a result of MBCT patients develop wider, decentered perspective towards negative thoughts and feelings and this affects whether mild states of depression will escalate to more severe and persistent depressive relapse. In the study of Williams et al [29] 45 recovered or remitted recurrently depressed patients recruited at one treatment site were randomly allocated to receive TAU, or TAU plus MBCT. This patient sample was part of the larger randomized control trial reported by Teasdale et al [20]. Williams et al [29] reported for a first time on the effect of MBCT on the specificity of autobiographical memory. It has been shown previously that overgenerality in autobiographical memory is associated with more negative outcomes in depressed patients. The study reports significant increase in proportion of specific memories four months postintervention in the MBCT group (p=0.03) compared to TAU group. Also, there was a significant decrease in categorical memories in MBCT compared to TAU participants 4 months post-intervention (p=0.03). The study of Williams et al [30] was a preliminary randomized control trial specifically designed to examine the immediate effect of MBCT on between-episode anxiety and depressive symptoms in patients with a history of serious suicidal depression that were currently in remission. Sixty eight participants, who met criteria for MDD or BAD, were randomly allocated to treatment with MBCT or waitlist control condition. Both unipolar and bipolar patients allocated to MBCT showed reduction of depressive symptoms relative to waitlist condition. Bipolar patients receiving MBCT had significantly lower anxiety scores post-intervention compared to waitlist bipolar patients. There was no difference in level of anxiety symptoms for unipolar patients (MBCT and waitlist) pre- or postinterventon. Limitations of the study: as pointed out by the authors, analysis was based on a small sample, limiting power. The study was not designed specifically to demonstrate a difference between unipolar and bipolar patients and did not include a measure of manic symptoms. The study preferentially included patients with a history of suicidal ideation so findings may not generalize to patients who do not have such symptoms. Barnhofer et al [31] investigated the immediate effects of MBCT on prefrontal cortical asymmetry in patients with previous history of suicidal depression, who were now in remission. Twenty-two patients were randomly assigned to TAU or TAU plus MBCT. Resting electroencephalogram (EEG) was measured before and after an 8-week course of treatment. The TAU group showed significant deterioration towards decreased relative leftfrontal activation, indicating decreases in positive affective style, while there was no significant change in the MBCT group. The findings suggest that MBCT may help individuals at high risk for suicidal depression to retain a balanced pattern of brain activation immediately following an 8-week intervention. However, it is not clear if these findings will persist over a longer follow-up period. Also, at this time it is not clear if the lack of decrease of left-frontal activation in MBCT participants actually relates to lack of worsening of suicidal thinking or to actual decrease in rates of depressive relapse. Another limitation of the study, pointed out by the authors, is that it assessed prefrontal asymmetry only during resting state and not following mood challenge, which would have provided information on potential state effects.

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Non-Randomized Studies Kenny and Williams [33] studied 50 patients who met DSM IV criteria for either MDD (n=45) or BAD depressed phase (three patients with BAD I and two with BAD II), and were still actively symptomatic at the start of the MBCT course (baseline BDI>10). Thirty-two of the 50 patients at baseline also reported thoughts of death and suicide. Within subject comparisons are reported for BDI scores before- and after MBCT intervention. There was a significant change of mean BDI pre (24.3 SD=9.8) to post (13.9 SD=9.7) p<0.0001. In the “moderate” depression group (baseline BDI <24, n=26) mean BDI pre (17.2 SD=4.3) fell to a post-intervention of 11.5 SD=7.8 (moderate effect size of 0.9). In the “severe” depression group (baseline BDI 25 or above, n=24) mean BDI fell from 33.2 SD=6.4 pre- to 17.1 SD=11.2 post-intervention (large effect size of 1.8). Four patients became worse during the intervention, for 2 of them change was “meaningful” based on Jacobson-Truax calculation. One other patient had to be hospitalized just after the course started for agitated depression, subsequently his BDI decreased from 49 to 19. Mean rating (SD) of subjective importance of MBCT on a Likert scale (Max=10) was 8.5 (SD=1.5). In a separate analysis the 32 patients with suicidal ideation were compared to patients who did not report such symptoms. Mean BDI for suicidal patients at baseline was significantly higher than the score for patients without suicidal thoughts (p=0.003). Following treatment BDI scores declined in both groups. Post-treatment BDI scores decreased for all five patients with BPAD who participated in the MBCT course. As authors themselves point out, there is no control group and the change observed in participants cannot be conclusively ascribed to MBCT treatment. Four patients became worse in the course of the intervention and this raises the question of possible adverse effects and how to best monitor/report these in future studies. The patients in this study were fairly severely symptomatic and had not fully responded to standard pharmacological and cognitive-behavioral treatments prior to beginning the MBCT training, therefore patients might have been much more motivated in comparison with symptomatic patients for whom MBCT is offered earlier in the course of treatment. In a mixed-model complex design Kingston et al [35] studied the effects of MBCT on level of depression (BDI) and rumination in a sample of 19 recurrently depressed patients who still experienced residual depressive symptoms (baseline BDI ranged 13-25). Diagnostically most patients met criteria for recurrent MDD; two of the patients were diagnosed with BAD II. Nine patients had a history of deliberate self-harm. Design 1 consisted of consecutive referrals of patients to TAU plus MBCT, or TAU alone. In design 2, the TAU group proceeded to complete MBCT training, and within-subject pre- to postcomparisons were reported for all completers. The main findings for design 1 are as follows: BDI and rumination for both MBCT and TAU groups significantly decreased over the 8week treatment period. Immediately post-treatment MBCT group had significantly decreased BDI compared to TAU (p<0.05). There was a trend toward greater reduction in rumination post-intervention for the MBCT group compared to TAU (p=0.063). Reduction of BDI correlated with a reduction in rumination as measured by RUM (a rumination scale). Design 2: BDI scores decreased significantly pre- to 1-month follow-up for all patients who completed MBCT (p<0.05). The patients initially assigned to TAU that completed MBCT later, did not differ from the patients who completed MBCT at the beginning of the study. At

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1 month follow-up the majority of patients were using some skills learned from the MBCT program. Study limitations: this is a preliminary, non-randomized study, with small sample, relatively brief follow-up, with no active/placebo control groups. Ramel et al [36] studied 23 patients with active or remitted depression and anxiety disorders referred from both a VA (Veterans Administration) and a University health care system. From the VA system patients were referred for a mental or physical health concern (mood, anxiety symptoms or chronic pain). The patients recruited from the University system were enrolled in other medication or psychotherapy treatment studies for depression. After enrollment in this study patients were assessed with DSM-IV SCID by a research clinician. All patients met criteria for a lifetime mood disorder, 50% met lifetime criteria for one or more anxiety disorders, 26% met criteria for current major depressive episode as part of either MDD or BPAD. The first analysis included within-subject comparisons for 23 patients before and after completing MBSR. In the second between-subject analysis 11 wait-list control patients who met the same inclusion criteria were matched to 11 MBSR completers on age, gender, baseline BDI. The within-subject analysis revealed significant decrease postMBSR in BDI (p<0.024), STAI-trait (p<0.02), RSQ-rumination (p<0.001), and DASapproval (p<0.05). Changes in rumination remained significant after controlling for changes in BDI, STAI-trait, and DAS-approval (p<0.004). Additional analyses demonstrated no significant difference in changes in rumination and dysfunctional attitudes before and after MBSR between currently and formerly depressed patients. However currently depressed patients showed significantly greater decline in BDI (p<0.05), STAI-state (p<0.05), and STAI-trait (p<0.02) post-MBSR, compared to formerly depressed patients. When patients with 2 prior depressive episodes were compared to patients with 3 or more episodes, there was a trend (p=0.067) towards smaller reduction in trait anxiety symptoms. Between-subject analysis demonstrated no significant difference between the 11 MBSR completers and the 11 matched wait-list controls on BDI, STAI, or DAS post-intervention. MBSR completers had significantly less RSQ-rumination post-intervention (p<0.005). Some of the study limitations raised by the authors are: small sample, therefore negative findings may simply reflect lack of statistical power to detect significant differences. Allocation to MBSR or wait-list control condition was not randomized therefore causality between the MBSR intervention and observed outcomes may not be inferred. Twenty-two percent of treated sample, 18% of the matched completers, and 27% of the matched wait-list patients changed their medications or psychotherapy between the baseline and follow-up assessment. These changes were not accounted for in the statistical analysis. Since patients with both depression and anxiety diagnoses were studied together, it is not clear if the primary clinical diagnosis/co-morbidity confers a differential response to MBSR. Weiss et al [38] studied the usefulness of MBSR as adjunct to outpatient psychotherapy in 31 patients with DSM-IV depression and anxiety, referred from an outpatient psychotherapy practice. The study was not randomized; allocation to the active intervention group (MBSR training in addition to psychotherapy) or control group (psychotherapy only or PO group) was based on patients’ preference. Fifteen patients opted to learn MBSR. The training consisted of eight 1-hour individual sessions, the first and last devoted entirely to MBSR, the intervening six sessions divided between MBSR and individual therapy. Participants were asked to practice meditation at home for 30 minutes a day six days a week

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and were provided sample meditation tapes. Global Severity Index of the Symptom Checklist-90-R (indicative of level of psychological distress) was assessed one week before and at the completion of the study period. At the beginning of the study patients were asked to specify an important goal of therapy and to rate themselves on a 100-point scale indicating distance from their goal. At the end of the study patients were asked again to complete selfrating on the same measure. Another outcome reported in the study was the number and rate of therapy sessions sought by clients for two months prior and 6 months after the study period as well as the rate of termination of therapy altogether. Both MBSR and PO groups showed significant improvement on all measures at the end of the intervention period. The MBSR group showed significantly greater gains on the goal achievement measure (p=0.008), and a higher rate if termination of therapy (p=0.016) compared to the PO group. At six months post-intervention 11 of the 15 MBSR participants who returned a follow-up questionnaire indicated they were still meditating, and reported lasting improvements in energy level, activity, and coping ability. These 11 participants rated the importance of MBSR in their lives very highly- mean rating 9.1 (SD=0.94) from a maximum of 10. Study limitations: patient sample consisted of patients with both depression and anxiety disorders and it would have been helpful to investigate if the different clinical diagnoses conferred differential response to MBSR. Also, in the absence of specific assessment of depressive and anxiety symptoms, it is not clear if the higher termination rate reported by MBSR participants is in fact related to clinical improvement. Three MBSR participant and one PO patient were treated with antidepressants and it s not clear if these additional treatments might have contributed to the observed outcomes.

Qualitative Studies Finucane and Mercer [32] studied 13 patients with recurrent depression or recurrent depression and anxiety with active, at least mild symptoms of depression (baseline BDI>14) in a routine primary care setting. Mean baseline BDI was 43, range 29-58. Semi-structured qualitative interviews were conducted three months after completing the MBCT program. The qualitative data indicated that mindfulness training was both acceptable and beneficial for the majority of patients. For many of the participants being in a group was an important validating experience, and most felt the course was too short and a follow up was essential. More than half of patients continued to apply mindfulness techniques three months after finishing the course. A quantitative analysis of depression and anxiety scores pre- and postintervention showed a significant decrease of both depression (p=0.001) and anxiety (p=0.030) scores after MBCT. Limitations: as acknowledged by the authors, this is a small study with no control group and no randomization of participants. The study assessed the immediate effects of MBCT training and it is not clear if there might be any long-term changes post-intervention. The author who led the MBCT group had no prior experience of running MBCT groups and, when considering the importance of group factors in effecting a therapeutic change, a question arises as to the specificity of the intervention delivered in this study. Additional point to consider is that 5 of the 11 patients completing the intervention continued to experience moderate to severe levels of depression or anxiety three months later

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and this raises the question of possible “side effects” of the intervention and whether it may lead, at least in certain patient, to worsening symptoms. Mason and Hargreaves [35] reported a qualitative study of seven patients with DSM III recurrent major depression (on at least two occasions), recruited from adult mental health service, diagnosed by a member of the service. In the first phase of the study four patients were interviewed following MBCT training. In addition, three further interviews were conducted with participants who had completed MBCT between 12 and 30 months previously, and who attended a monthly MBCT practice group. One of the major themes emerging from the clinical interviews was the importance of initial expectations for later insight and therapeutic gain. Patients with highest expectations paradoxically experienced fewest positive effects from MBCT. Overall only one patient did not report a therapeutic gain from MBCT. All participants highlighted the importance of the group in facilitating change. Other themes were “coming to terms” with one’s negative experiences and a shift in attitude towards acceptance, flexibility, and “living in the moment”- a process participants felt continued after the conclusion of the course. For participants who reported therapeutic gains, all described one or more points of discovery or insight which they felt were significant. The majority reported listening to meditation tapes to be calming and relaxing experience and a positive link was suggested between consistency of homework practice and the process of change. Participants also described increased mindfulness skills in meditation, yoga, and breathing spaces, thought differed in their degree of success with different skills. For some, the practice of mindfulness introduced a “distance” from negative experiences, which allowed participants to consider options and exercise a choice in responding in a particular situation. Some patients also reported developing increased awareness of “warning bells”personal indications of worsening mood, and as a result taking action to prevent further progression of low mood/depression. Limitations of the study: It is not clear if the patients were still actively symptomatic or in recovery/remission from their last depressive episode at the start of MBCT and whether there was any change in symptoms over time. Also, in assessing the safety of MBCT, it would have been important to know if the one person who did not report therapeutic gain actually became clinically worse over time. Smith et al [37] report a qualitative study of 38 elderly patients (mean age 70.5 years, range 65-88 ) with at least three past episodes of unipolar major depression and co-morbid anxiety disorders, pain, or another physical illness, who were referred for MBCT by local health care professionals. Patients with more significant depressive symptoms (BDI-II >19) were excluded from the study. Clinical interviews and BDI-II assessment were performed before, two weeks after, and 12-13 months after completing the MBCT training. The MBCT course followed a pre-publication manual by Segal et al [19] with some modifications. Mindful yoga was adapted for older individuals and the instructions for the formal walking meditations were shifted slightly from focusing specifically on the walking itself to a broader, more open focus. Several common themes emerged from the clinical interviews: increased awareness, acceptance, control, less ruminations, more enjoyment and getting along better with others. Some patients felt they had changed in fundamental ways such as “feeling more alive” and “more of a whole person”. Pre-course confidence of continued mindfulness practice was very high for some participants and for many there was a positive relationship between expectations and actual practice over time. Most people found that the course either

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improved their lives in major ways or definitely helped them, the proportion finding mindfulness of major benefit increased over the year following the course, 27 of 29 participants would definitely recommend MBCT to a depressed friend. Mean BDI-II decreased slightly post MBCT and further at 13 months. Some patients became more depressed in the follow-up period. Study limitations: no standardized measures of the comorbid anxiety and physical illness.

Case Studies In a case study of two patients with suicidal thoughts or behaviors Williams and Swales [40] reported specifically on the use of mindfulness within a Dialectical Behavior Therapy (DBT) approach. Patient 1 (treated in an inpatient DBT program) presented with borderline personality disorder, eating disorder, and parasuicidal behaviors; patient 2 had a history of multiple overdoses and violent behavior towards her siblings. In addition to mindfulness approaches, a variety of other problem-solving and dialectical strategies were utilized in the overall management of both cases. After practicing awareness of breathing in one session, patient 1 had reported she does not feel so overwhelmed by her negative thoughts. With further practice the patient was able to utilize this as one approach of tolerating escalating suicidal thoughts and affects, increasing her capacity to focus on more active problem solving. Patient 2 was able to learn the mindfulness skill of being non-judgmental. Becoming aware of both her own judgmental thoughts (and those of her relatives) enabled her to interrupt the chain of events that had frequently led to parasuicidal behavior in the past. Williams et al [39] reported a case study of the usefulness of MBCT in one patient with recurrent suicidal ideation and a prior suicide attempt, depression, active alcohol and drug use. The MBCT intervention was modified slightly for work with potentially suicidal patients. There was an increased emphasis on early identification of relapse and creation of action plans, detailed planning for what to do and whom to call in case of suicidal crisis/emergency. Increased emphasis was given to more externally focused and grounding meditation practices. Examples of suicidal cognitions were explicitly introduced and discussed in class. Subjectively the patient had reported initial difficulties with strong body sensations during the body scan meditation and a strong desire to stop the practice altogether. Eventually, “staying with” these difficulties has lead to an insight about how easily body sensations are judged and labeled and how strong is the pull away from unpleasant sensations. Later, during an exercise of imagining thoughts as passing images on a movie screen or leaves floating on a river, the patient had discovered that when observed with sustained attention the thoughts no longer provoked emotional reactions. The patient’s attitude towards her thoughts changed from fear and sadness to friendly curiosity. She was more able to attend to negative thoughts about herself without getting sucked in. At the end of the course the patient had reported improved relationship with her daughter, reduced intake of drugs and alcohol, and had described the course as extremely important for her and “life-changing experience”. Her score on the Mindful Attention and Awareness Scale (MAAS), measuring the person’s level of mindfulness, had increased from 36 to 56. Further questions raised by the authors are whether the subjective changes reported by this one

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patient generalize to other patients with suicidality and whether changes in MAAS scores are associated with changes in suicidal reactivity and possibly decreased number of suicide attempts in the future.

Summary Patient Populations The 15 clinical studies reviewed here report on the usefulness and feasibility of MBCT and MBSR in patients with major depressive disorder, bipolar affective disorder, and history of suicidal thinking and behavior, who were studied at different phases of their illness and different stages in their lives. Teasdale et al [20], Ma and Teasdale [21], and Ramel et al [36] studied patients in remission or recovery of major depression. Patients with active/residual symptoms of recurrent major depression were part of the patient sample in the studies of Kenny and Williams [33], Kingston et al [34], Ramel et al [36], Finucane and Mercer [32]. Elderly patients with recurrent depression and medical co-morbidities were subjects in the study of Smith et al [37]. Patients with bipolar affective disorder were studied in remission [30] or while actively symptomatic during a depressive phase of their illness [33,34,36]. Some of the studies recruited patients with serious suicidal ideation or behavior- as part of major depression currently in remission [30,31,34], as part of bipolar disorder currently in remission [30], or as part of depression/borderline personality disorder [39,40]. Clinical Outcomes Decreased risk of relapse/recurrence in patients with three or more prior depressive episodes, who were currently in remission/recovery, for a year following MBCT, was reported by two randomized studies [20,21]. Both studies had a large and clearly specified sample of formerly depressed patients, used a treatment manual, and demonstrated that MBCT is superior to TAU, therefore supporting a "probably efficacious" designation for the role of MBCT in reducing depressive relapse in patients with 3 or more depressive episodes. If additional studies conducted by independent investigators confirm this finding, or show that MBCT is equivalent or superior to another treatment in preventing depressive relapse, MBCT will qualify for “well established” designation. Reduced overgeneralized autobiographical memory and increased metacognitive awareness following MBCT training in two subsets of patients from the study of Teasdale et al [20], were reported by Williams et al [29] and Teasdale et al [28]. These findings are clinically relevant as in previous studies overgeneral autobiographical memory and reduced metacognitive awareness has been associated with vulnerability to depression. Significant decreases in left frontal activation as measured by EEG in the treatment-as-usual group but not in the MBCT group were reported by Barnhofer et al in patients with suicidal depression currently in recovery [31]. These findings suggest that MBCT may help individuals at high risk for suicidal depression to retain a balanced pattern of brain activation immediately following an 8-week intervention. In another study of patients with history of suicidal depression, Williams et al [30] report significant difference in level of depression in MBCT participants post-intervention compared to waitlist controls. Both case studies of patients with

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suicidal thoughts or behavior by Williams and Swales [40] and Williams et al [39] provided a detailed account on how mindfulness practices increased the patients capacity to observe and tolerate highly emotionally charged negative or suicidal thoughts without acting on them. Significant decrease of depressive symptoms post MBCT was reported by Kenny and Williams in a study of patients with recurrent major depression or bipolar affective disorder who were actively symptomatic at baseline [33]. The decrease of depressive symptoms was more pronounced in the “severe” depression group in comparison to “moderate” depression group. Significant decrease of depressive symptoms immediately post-MBCT was reported also by Kingston et al in another study of patients with residual depressive symptoms [34]. The qualitative studies by Finucane and Mercer [32], Mason and Hargreaves [35] and Smith et al [37] indicated that mindfulness training was both acceptable and beneficial for majority of patients in reducing depressive symptoms. Williams et al [30] specifically reports outcomes for patients with bipolar affective disorder who were in remission at the beginning of MBCT- bipolar patients receiving MBCT had significantly lower anxiety and depression scores post-intervention compared to waitlist bipolar patients. For patients with bipolar illness with active symptoms of depression at baseline, there was a reduction of depressive symptoms immediately post-MBCT [33]. MBSR was the active intervention in two studies [36,38]. Ramel et al report significant decrease of depression, trait anxiety, and rumination following MBSR training [36]. In the study of Weiss et al MBSR was offered individually to patients with depression and anxiety. The study reports that the MBSR group showed significantly greater gains on the goal achievement measure, and a higher rate of termination of therapy compared to the psychotherapy only group [38]. Safety In the 15 studies under review no serious adverse events specifically attributable to MBCT or MBSR were reported. Subjective reports indicate that, early in the course of the interventions, some patients go through challenging and sometimes negative experiences [30,35], thus raising the question of possible early side effects of the mindfulness practices. Most patients find their way in working through these challenging experiences and eventually derive benefits from the practices. However it would be important for future studies to report on these potential early side effects in a more systematic way. In the study of Kenny and Williams four patients became worse in their BDI scores during the MBCT intervention, for two of them change was assessed as “meaningful” [33]. Although the patients claimed that the program was important to them, and the rise of BDI scores was due to their normal mood fluctuations, further research needs to take into account the possibility of adverse effects. At this time it is not clear how to distinguish between intervention side effects and worsening of depressive symptoms as part of illness trajectory. In the study of Weiss et al 47% of patients who chose to learn MBSR in the context of their individual psychotherapy terminated therapy within the 6 months following MBSR, compared to only 6% of patients who did not choose to learn MBSR [38]. Responses from follow-up questionnaires have supported the authors’ interpretation that these findings indicate an increased sense of agency and self-directedness in the patients who terminated, rather than a negative outcome. It would still be prudent, however, to consider possible break-up in the therapeutic relationship as a potential reason for premature termination of treatment. In the study of Smith et al some patients became more

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depressed in the one year follow-up period [37], bringing up the question of potential longerterm side effects of MBCT. Again, it is not clear how to distinguish between intervention side effects and natural progression of depression, especially considering the high degree of morbidity and mortality in this patient sample of elderly individuals. The study of Kenny and Williams [33] raises another consideration: sometimes the improvement of depressive symptoms in patients with BAD heralds worsening of manic symptoms, therefore it would be important to monitor prospectively for emergence of manic symptoms, even when mindfulness interventions are offered to bipolar patients in the depressive phase of their illness. An important safety consideration raised by Williams et al [39] is that, in working with high suicide risk or otherwise actively symptomatic patients, it is important to insure that participants have a clear sense of whom they can contact in case of psychiatric emergency. MBCT instructors do not interact with patients in the capacity of psychotherapists, and MBCT is currently viewed as an approach to staying well, rather than an active treatment. In summary, safety considerations to be addressed in future studies are: 1) Reporting in a systematic way on the early negative experiences in some participants as a result of the mindfulness practices, 2) Distinguishing between possible long-term adverse effects and the natural progression of illness, 3) Insuring that participants have a safety plan on whom to call in case of psychiatric emergency.

Conclusions Mindfulness-Based Cognitive Therapy is feasible in a wide range of patients with mood disorders: 1) Adults and elderly patients with recurrent major depression who are either actively symptomatic, or in a state of recovery/remission after their last depressive episode, 2) Patients with bipolar affective disorder who are either in remission, or in the depressive phase of their illness, 3) Patients with a history of suicidal thinking or behavior. MBSR is feasible in patients with MDD and possibly depressed phase of BAD. Both interventions have a low dropout rate and high degree of acceptability even for patients whose symptoms worsened during the study period. No serious adverse events specifically attributable to MBCT or MBSR were reported. MBCT is probably efficacious for decreasing the risk of depressive relapse in patients with three or more depressive episodes. The evidence for the positive effects of MBCT in reducing symptoms of depression in moderately to severely symptomatic patients with major depression or BAD is preliminary at this time. Preliminary is also the evidence of the immediate effect of MBCT on reducing anxiety and depressive symptoms in bipolar patients with suicidal ideation or behavior, and in possibly decreasing cognitive vulnerability to suicidality. MBSR is less well studied in patients with mood disorders. Preliminary evidence is encouraging that MBSR might reduce symptoms of depression, trait anxiety, and rumination in patients with depression and anxiety and that MBSR may be used as an adjunctive treatment to individual psychotherapy.

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These findings, albeit preliminary, indicate that mindfulness-based approaches have a potential as clinically valuable interventions in the treatment of mood disorders. Further research into their efficacy, feasibility, and safety is recommended.

Acknowledgements The author was a Psychosomatic Medicine Fellow at the Division of Consultation/Liaison, Department of Psychiatry, University of Maryland Medical Systems, Baltimore, Maryland, from July 1, 2006 to June 30, 2007 and is now in private practice. The author wishes to thank Drs. Mark Ehrenreich and J. Mark G. Williams for valuable feedback on this paper.

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Lama D, Cutler HC. The art of happiness: A handbook for living. New York: Riverhead, 1998. [2] Ricard M. Happiness: A guide to developing life's most important skill. First English Language edition. New York: Little Brown, 2006. [3] Wallace BA. The attention revolution: unlocking the power of the focused mind. Boston: Wisdom Publ, 2006. [4] Kabat-Zinn J. Full catastrophe living: Using the wisdom of your body and mind to face stress, pain, and illness. Fifteenth anniversary Ed. New York: Bantam Dell, 2005. [5] Kabat-Zinn, J. An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: theoretical considerations and preliminary results. Gen Hosp Psychiatry 1982;4:33-47. [6] Carlson LE, Garland SN. Impact of mindfulness-based stress reduction (MBSR) on sleep, mood, stress and fatigue symptoms in cancer outpatients. Int J Behav Med 2005; 12(4):278-85. [7] Carlson LE, Speca M, Patel KD, Goodey E. Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress and levels of cortisol, dehydroepiandrosterone sulfate (DHEAS) and melatonin in breast and prostate cancer outpatients. Psychoneuro-endocrinol 2004; 29(4):448-74. [8] Speca M, Carlson LE, Goodey E, Angen M. A randomized, wait-list controlled clinical trial: the effect of a mindfulness meditation-based stress reduction program on mood and symptoms of stress in cancer outpatients. Psychosom Med 2000;62(5):613-22. [9] Smith JE, Richardson J, Hoffman C, Pilkington K. Mindfulness-Based Stress Reduction as supportive therapy in cancer care: systematic review. Adv Nurs 2005;52(3):315-27. [10] Robert McComb JJ, Tacon A, Randolph P, Caldera Y. A pilot study to examine the effects of a mindfulness-based stress-reduction and relaxation program on levels of stress hormones, physical functioning, and submaximal exercise responses. J Altern Complement Med 2004;10(5):819-27.

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[11] Tacon AM, McComb J, Caldera Y, Randolph P. Mindfulness meditation, anxiety reduction, and heart disease: a pilot study. Fam Community Health 2003;26(1):25-33. [12] Kreitzer MJ, Gross CR, Ye X, Russas V, Treesak C. Longitudinal impact of mindfulness meditation on illness burden in solid-organ transplant recipients. Prog Transplant 2005;15(2):166-72. [13] Gross CR, Kreitzer MJ, Russas V, Treesak C, Frazier PA, Hertz MI. Mindfulness meditation to reduce symptoms after organ transplant: a pilot study. Adv Mind Body Med 2004; 20(2):20-9. [14] Robinson FP, Mathews HL, Witek-Janusek L. Psycho-endocrine-immune response to mindfulness-based stress reduction in individuals infected with the human immunodeficiency virus: a quasiexperimental study. J Altern Complement Med 2003; 9(5):683-94. [15] Grossman P, Tiefenthaler-Gilmer U, Raysz A, Kesper U. Mindfulness training as an intervention for fibromyalgia: evidence of postintervention and 3-year follow-up benefits in well-being. Psychother Psychosom 2007; 76(4):226-33. [16] Sephton SE, Salmon P, Weissbecker I, Ulmer C, Floyd A, Hoover K, Studts JL. Mindfulness meditation alleviates depressive symptoms in women with fibromyalgia: results of a randomized clinical trial. Arthritis Rheum 2007; 57(1):77-85. [17] Kaplan KH, Goldenberg DL, Galvin-Nadeau M. The impact of a meditation-based stress reduction program on fibromyalgia. Gen Hosp Psychiatry 1993;15(5):284-9. [18] Grossman P, Niemann L, Schmidt S, Walach H. Mindfulness-based stress reduction and health benefits. A meta-analysis. J Psychosom Res 2004;57(1):35-43. [19] Segal, Z.V., Williams, J.M. and Teasdale J.D. Mindfulness-based cognitive therapy for depression: A new approach to preventing relapse. New York: Guilford, 2002. [20] Teasdale JD, Segal ZV, Williams JM, Ridgeway VA, Soulsby JM, Lau MA. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. J Consult Clin Psychol 2000; 68(4): 615-23. [21] Ma SH, Teasdale JD. Mindfulness-based cognitive therapy for depression: replication and exploration of differential relapse prevention effects. J Consult Clin Psychol 2004;72(1):31-40. [22] Baer RA. Mindfulness training as clinical intervention: a conceptual and empirical review. Clin Psycol Sci Pract 2003;10:124-43. [23] Toneatto T, Nguyen L. Does mindfulness meditation improve anxiety and mood symptoms? A review of the controlled research. Can J Psychiatry 2007;52(4):260-6. [24] Kabat-Zinn J. Mindfulness-based interventions in context: past, present, and future. Clin Psycol Sci Pract 2003;10:144-56. [25] Bishop SR, Lau M, Shapiro S, Carlson L, Anderson ND, Carmody J, Segal ZV, Abbey S, Speca M, Velting D, Devins G. Mindfulness: a proposed operational definition. Clin Psychol Sci Prac 11:239-241, 2004. [26] Santorelli SF, Kabat-Zinn J, eds. Mindfulness-based stress reduction (MBSR) structure, methods, and key program characteristics. Published in Mindfulness-based stress reduction professional training resource manual: Integrating mindfulness meditation into medicine and health care. Worcester, MA: Center Mindfulness Med Health Care Society, 2006.

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[27] Allen NB, Chambers R, Knight W; Melbourne Academic Mindfulness Interest Group. Mindfulness-based psychotherapies: a review of conceptual foundations, empirical evidence and practical considerations. Aust NZ J Psychiatry 2006;40(4):285-94. [28] Teasdale JD, Moore RG, Hayhurst H, Pope M, Williams S, Segal ZV. Metacognitive awareness and prevention of relapse in depression: empirical evidence. J Consult Clin Psychol 2002;70(2):275-87. [29] Williams JM, Teasdale JD, Segal ZV, Soulsby J. Mindfulness-based cognitive therapy reduces overgeneral autobiographical memory in formerly depressed patients. J Abnorm Psychol 2000;109(1):150-5. [30] Williams JM, Alatiq Y, Crane C, Barnhofer T, Fennell MJ, Duggan DS, Hepburn S, Goodwin GM. Mindfulness-based Cognitive Therapy (MBCT) in bipolar disorder: Preliminary evaluation of immediate effects on between-episode functioning. J Affect Disord 2007 Sep 18 [Epub ahead of print] [31] Barnhofer T, Duggan D, Crane C, Hepburn S, Fennell MJ, Williams JM. Effects of meditation on frontal alpha-asymmetry in previously suicidal individuals. Neuroreport 2007;18(7):709-12. [32] Finucane A, Mercer SW. An exploratory mixed methods study of the acceptability and effectiveness of Mindfulness-Based Cognitive Therapy for patients with active depression and anxiety in primary care. BMC Psychiatry 2006;6:14. [33] Kenny MA, Williams JM. Treatment-resistant depressed patients show a good response to Mindfulness-based Cognitive Therapy. Behav Res Ther 2007;45(3):617-25. [34] Kingston T, Dooley B, Bates A, Lawlor E, Malone K. Mindfulness-based cognitive therapy for residual depressive symptoms. Psychol Psychother 2007;80(Pt 2):193-203. [35] Mason O, Hargreaves I. A qualitative study of mindfulness-based cognitive therapy for depression. Br J Med Psychol 2001;74(Pt 2):197-212. [36] Ramel W, Goldin PR, Carmona PE, McQuaid JR. The effects of mindfulness meditation on cognitive processes and affect in patients with past depression. Cognit Ther Res 2004; 28(4): 433-55. [37] Smith A, Graham L, Senthinathan S. Mindfulness-based cognitive therapy for recurring depression in older people: a qualitative study. Aging Ment Health 2007; 11(3): 346-57. [38] Weiss M, Nordlie JW, Siegel EP. Mindfulness-based stress reduction as an adjunct to outpatient psychotherapy. Psychother Psychosom 2005; 74(2):108-12. [39] Williams JM, Duggan DS, Crane C, Fennell MJ. Mindfulness-based cognitive therapy for prevention of recurrence of suicidal behavior. J Clin Psychol 2006;62(2):201-10. [40] Williams JM, Swales M. The use of mindfulness-based approaches for suicidal patients. Arch Suicide Res 2004;8(4):315-29.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XIII

Thinking Outside of the Light Box: Applications of Cognitive-Behavioral Theory and Therapy to Seasonal Affective Disorder Kelly J. Rohan∗ and Yael I. Nillni University of Vermont, Psychology Department, Burlington, VT, USA

Abstract The purpose of this paper is to review: 1) current evidence that constructs proposed in cognitive and behavioral theories of depression have relevance to winter seasonal affective disorder (SAD) and 2) the results of preliminary randomized clinical trials testing the acute and long-term efficacy of cognitive-behavioral therapy (CBT) for SAD, alone and in combination with adjunct light therapy, as compared to solo light therapy. Research supports that factors related to a cognitive vulnerability to depression as well as low rates of response-contingent positive reinforcement in the winter and learned emotional and psychophysiological reactivity to light-relevant stimuli are operative in SAD and may represent a point of intervention via a SAD-tailored CBT. Preliminary randomized clinical trials suggest that CBT for SAD is acutely efficacious and may be prophylactic with regard to preventing winter depression recurrence. To advance the theoretical understanding of the psychopathology SAD, we advocate for an integrative biological-psychological conceptualiz-ation of SAD and for multi-disciplinary research to study interactive biological-psychological mechanisms in SAD onset and maintenance. To advance the treatment of SAD, we advocate for a greater focus on testing long-term outcomes in SAD treatment research. In contrast to establishing only acute treatment ∗

E-mail address: [email protected] Correspondence: Kelly J Rohan, PhD, University of Vermont, Psychology Department, John Dewey Hall, 2 Colchester Avenue, Burlington, VT 05405-0134, United States.

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Keywords: Seasonal affective disorder, cognitive-behavioral theory, cognitive-behavioral therapy.

Introduction The majority of theories for seasonal affective disorder (SAD) etiology propose a biological mechanism that interacts with low light availability to contribute to the onset and maintenance of winter depression [1]. There are several reasons why SAD has been conceptualized as a largely “biological” subtype of depression, including a reflection of the theoretical orientation of the original pioneers in the field and a large clinical trials literature supporting the efficacy of bright light therapy in acute SAD treatment [2]. Because the relation between latitude and SAD is stronger in the U. S. and less significant in other countries [3] and because biological models for SAD have yielded inconsistent findings, researchers have suggested that psychological factors may interact with biological factors in SAD episode maintenance, severity, and recurrence. The purpose of this paper is to review [1] evidence that cognitive and behavioral factors are relevant to understanding SAD and [2] results from preliminary randomized clinical trials testing the efficacy of cognitive-behavioral therapy on acute and long-term SAD outcomes. In conclusion, we advocate for a more comprehensive, multi-dimensional approach to conceptualizing and treating SAD, including cognitive and behavioral as well as biological factors; and we propose several directions for future research.

Dual Physiological-Psychological Vulnerability to SAD The dual-vulnerability model provides a broad theoretical framework within which to examine a role for psychological factors in SAD. Young developed the dual-vulnerability model based on a study in which individuals with SAD retrospectively reported onset of fatigue, hypersomnia, and increased appetite first, followed by the other symptoms of depression [4]. Young and colleagues [4] hypothesized that the temporal pattern of symptom onset suggests different mechanisms underlying these symptom clusters. Specifically, Young’s dual vulnerability hypothesis [4,5] proposes that individuals with SAD have both: (1) a physiological vulnerability to experience the “physiological” symptoms of SAD (e.g., core vegetative symptoms such as fatigue, hypersomnia, and increased weight/appetite) during fall and winter and (2) a psychological vulnerability to develop the cognitive, affective, and behavioral symptoms of depression (e.g., difficulty concentrating, loss of interest, depressed mood, social isolation) in reaction to physiological symptoms.

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The original formulation of the dual-vulnerability model did not specify the content of the psychological vulnerability to SAD. That is, what psychological processes, specifically, confer an increased risk of SAD? To date, the majority of the research on psychological factors in SAD has examined cognitive and behavioral factors. This growing body of research suggests that the psychological vulnerability to SAD may represent a cognitive-behavioral vulnerability and provides a rationale for using cognitive-behavioral therapy as a treatment for SAD.

Evidence for Negative Cognitions in SAD According to cognitive models, situations do not directly determine emotional responses. Instead, cognitive processes (e.g., an individual’s interpretation and appraisal of experiences) mediate the impact of events on mood state and behavior. Cognitive theories of depression are diathesis-stress models whereby an underlying cognitive vulnerability to depression (the diathesis) interacts with an occasion setter (the stress) to contribute to depression onset. Although there are a variety of cognitive theories of depression, they are conceptually similar enough to be considered together as a generic cognitive vulnerability-stress model [6]. According to Beck’s cognitive model [7,8], depression results when negative cognitive schemas containing dysfunctional attitudes are activated by a stressful life event. Examples of dysfunctional attitudes include: “If I do not do as well as other people, it means I am an inferior person;” “If I fail partly, it is as bad as being a complete failure;” and “Being isolated from others is bound to lead to unhappiness” [9]. Several studies have examined dysfunctional attitudes in SAD. In cross-sectional studies, currently depressed individuals with SAD and individuals with nonseasonal major depression reported similar levels of dysfunctional attitudes with both depressed groups endorsing more dysfunctional attitudes than nondepressed controls [10], and, SAD patients in a current depressive episode reported higher endorsement of dysfunctional attitudes than never-depressed controls [11]. In a longitudinal comparison of women with SAD history (i.e., met DSM-IV criteria for a lifetime diagnosis of Major Depressive Disorder, Recurrent with Seasonal Pattern and experienced Major Depressive Episodes over the past two consecutive winters) and control women with no history of depression assessed in fall (October/November), winter (January/February), and summer (June/July), the groups did not differ on dysfunctional attitudes in any season; however, women with SAD reported more dysfunctional attitudes in fall and winter than in summer [12]. Taken together, these results suggest that elevated dysfunctional attitudes may be a state marker of winter depression. That is, when SAD patients are symptomatic, negative core beliefs containing dysfunctional attitudes may become activated and contribute to depressogenic information-processing. According to Beck’s model, when negative cognitive schemas are activated, brief moment-to-moment spontaneous thoughts in conscious awareness (i.e., automatic thoughts) are correspondingly negative and contribute to maintaining negative emotional states. Currently depressed individuals with SAD and individuals with nonseasonal major depression reported similar levels of automatic negative thoughts with both groups reporting

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more negative automatic thoughts than nondepressed controls [10]. Women with a SAD history endorsed significantly more frequent automatic negative thoughts than controls across a fall, winter, and summer assessment, and the SAD history group demonstrated increased automatic negative thought frequency in winter relative to fall or summer [12]. Together, these studies suggest a somewhat pervasive pattern of automatic negative thoughts in SAD that peaks when clinical depression manifests. Rumination in response to sadness, or repetitively focusing attention on dysphoric mood and its consequences, has been proposed as a cognitive vulnerability to depression [13]. Among women with a history of SAD, ruminative coping, as assessed in the fall, predicted the severity of SAD symptoms prospectively reported at an assessment during the subsequent winter [12]. A study using prospective daily reports of coping behaviors among SAD patients in the fall found that rumination frequency predicted severity of the subsequent winter episode [14]. Given that these studies used rumination at an asymptomatic baseline assessment to prospectively predict SAD symptoms in the next winter, frequent rumination may represent a cognitive vulnerability to SAD. Hopelessness theory proposes that a negative attributional style (i.e., a tendency to attribute negative events to global and stable factors) contributes to the development of hopelessness and depression [15]. A cross-sectional comparison found that individuals with SAD evidenced a similar negative attributional style as compared to individuals with nonseasonal depression [16]. In summary, the research reviewed above suggests that the same factors proposed to represent a cognitive vulnerability to depression (i.e., dysfunctional attitudes, rumination, and negative attributional style; 6) are, at the very least, operative in SAD and may be relevant to the pathogenesis of SAD.

Evidence for Behavioral Factors in SAD Behavioral models of depression propose that behavioral disengagement (i.e., a low rate of response-contingent positive reinforcement contributes to depression and may explain the anhedonia common in depression [17,18]. This model may have relevance to SAD. Women with SAD history engaged in fewer pleasant events (i.e., potentially enjoyable activities) than never-depressed controls during winter, had a lower frequency of pleasant events in winter than in either summer or fall, and had less frequent pleasant events in fall than in summer [12]. Women with a SAD history reported greater enjoyment in pleasant events in summer than in winter or fall. This overall pattern suggests a progression of decline, beginning with diminished capacity for enjoyment in the fall leading to less time spent on pleasant events in the winter. Presumably, both biological and psychological theories of SAD are diathesis-stress models, conceptualizing light deprivation as the “stress” (i.e., the seasonally-linked environmental factor that triggers depression onset in SAD-vulnerable individuals). Whereas biological models propose that this stressor triggers an underlying biological mechanism, a more behavioral approach focuses on classical and operant conditioning. Learned associations between depressive behavior and environmental stimuli signaling low light availability and winter season may play a role in SAD. Women with SAD history reported a

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greater exacerbation of baseline depressed mood state after exposure to photographs of outdoor scenes with an overcast sky as compared to scenes depicting a sunny sky and scenes of indistinguishable light intensity (i.e., outdoor scenes that did not include the sky; 12]. In addition, women with a history of SAD reported an improvement in mood after exposure to scenes with a sunny sky relative to nondepressed controls. Because these within- and between-group differences were robust across assessments in the fall, winter, and summer seasons; a consistent pattern of emotional reactivity to light-relevant stimuli may be a trait marker of SAD. A second study suggests that this reactivity may also apply to season-relevant stimuli. In a cross-sectional comparison of currently depressed individuals with SAD and with nonseasonal depression, both groups reported a greater exacerbation of depressed mood following a video depicting winter scenes as compared to never-depressed controls [19]. However, the SAD group uniquely evidenced increased psychophysiological responses (i.e., more frequent significant skin conductance responses and greater skin conductance response magnitude) during the winter video compared to the other two groups. In an effort to determine whether stimulus light intensity (sunny or overcast sky) or seasonal cues (summer with green leaves, fall with autumn foliage, and winter with bare trees) is more closely related to emotional responding, Tierney Lindsey, Rohan, and Roeckelin [20] compared currently depressed individuals with SAD to never-depressed controls on emotional responses to outdoor photographs that varied both dimensions. Among SAD participants, light intensity was a more salient cue than season in determining facial expression of emotion based on surface facial EMG responses in the corrugator muscle (i.e., brow-pursing); however, both light and season cues affected self-reported mood state. Controls’ facial expressions and subjective mood states did not differ by stimulus light intensity or seasonal content. Taken cumulatively, these studies suggest that emotional and psychophysiological reactions to light- and season-relevant stimuli may be a unique feature of SAD, possibly learned via classical and/or operant conditioning.

Why Apply Cognitive-Behavioral Therapy (CBT) to SAD? Young and colleagues suggested that psychotherapy may be an appropriate intervention to target the psychological vulnerability to SAD [4]. As reviewed above, SAD is associated with negative cognitions (e.g., dysfunctional attitudes, negative automatic thoughts, rumination, and a negative attributional style), a low rate of response-contingent positive reinforcement in the wintertime, and emotional and psychophysiological reactivity to environmental stimuli signaling low light availability and the winter season. Whether or not these factors constitute a psychological vulnerability to develop SAD is not known. However, regardless of their onset etiological significance, these cognitive and behavioral factors are correlated with SAD and may represent an appropriate point of intervention. The most plausibly-matched intervention to target these factors is a SAD-tailored cognitive-behavioral therapy.

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Cognitive therapy for depression is a structured, time-limited, active, and present-focused treatment [21]. Cognitive therapy involves a behavioral activation component designed to activate depressed patients, enabling them to extract positive reinforcement from their environments [22]. The majority of cognitive therapy focuses on teaching patients to recognize and correct situation-specific, negative automatic thoughts and to identify and modify core depressive schemas [21]. Extensive literature documents the efficacy of cognitive therapy as a treatment for nonseasonal depression [23,24,25]. Importantly, cognitive therapy for depression appears to confer benefits that extend beyond the point of treatment termination [23,26]. Several studies have found that depressed patients who demonstrated a clinical response to cognitive therapy had a reduced risk of depression relapse as compared to patients who initially responded to antidepressant medications [27,28,29,30]. In addition to reducing the more proximal risk of relapse, a recent trial found that patients who had recovered from the treated episode with cognitive therapy demonstrated a reduced risk for a wholly new depressive episode onset (i.e., recurrence) relative to patients who had recovered from the initial episode with pharmacotherapy [28]. If these long-term outcomes for cognitive therapy generalize to SAD, the treatment could represent an effective approach to long-term SAD management.

Why Is a Psychological Treatment for SAD Needed? Light therapy is the established and best available acute SAD treatment. A recent quantitative analysis of eight trials comparing light therapy to credible controls concluded that light therapy is associated with significant reductions in depression severity for SAD in the initial winter [2]. A pooled analysis of light therapy studies [31] concluded that 53% of individuals with SAD overall and 43% of moderate to severe SAD cases meet remission criteria by the end of a light therapy trial. The rationale for light therapy draws from a purely biological conceptualization of SAD, with regard to correcting circadian phase [32]. Available clinical practice guidelines for SAD recommend at least 30 minutes of bright light therapy daily from onset of first symptom through spontaneous springtime remission during every fall/winter season [33]. Data on over 600 SAD patients treated at the NIMH Seasonal Studies Program between 1981 and 2001 suggest that an untreated fall/winter major depressive episode persists for an average 4.9±1.4 months before spontaneous springtime remission (personal communication, Norman E Rosenthal, MD, May 2005). Therefore, daily light therapy would be necessary for, on average, about 5 months of the year. Light therapy is limited for at least three fundamental reasons. First, a substantial minority of SAD patients overall (47%) and the majority (57%) of moderate to severe cases do not reach the recommended clinical endpoint of remission over a supervised light therapy trial [31]. This is problematic because treating depression to full remission has become the recommended treatment goal in contrast to striving only for improvement, which leaves residual symptoms that impair functioning and increase the risk of depression relapse [34]. Second, even when successful, light therapy leaves residual symptoms. Due to its predictable pattern of major depression recurrence in fall/winter and full remission in spring/summer,

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SAD affords unique opportunities to examine how closely treatment effects approximate the “natural” remitted state as opposed to scale-derived remission criteria. Taking advantage of this, Postolache et al [35] found that the degree of improvement associated with light therapy is incomplete relative to mood status following spontaneous remission in the summer, indicating persistent residual symptoms. As the third and most important limitation, longterm compliance with light therapy is lower than hoped. To our knowledge, no study (except for our group’s preliminary clinical trials) has ever conducted a planned, prospective followup of SAD patients treated with light therapy. However, a retrospective followup survey of SAD patients treated at the NIMH between 1981 and 1985 revealed that only 41% of patients continued regular use of light therapy [36]. When queried as to why they discontinued using light therapy, perceived “ineffectiveness” and “inconvenience” were the two most commonly cited reasons. After light therapy, antidepressant medications are widely regarded as the second line of treatment for SAD [33]. Several recent clinical trials provide evidence that antidepressant medications are efficacious for acute SAD treatment relative to pill placebo. Most recently, three double-blind, placebo-controlled trials using a total of 1,042 adults with a history of SAD initiated bupropion HCL extended release tablets or pill placebo prior to the onset of clinically significant SAD symptoms in the fall (September to November) and followed participants until treatment was discontinued following a 2-week taper that began the fourth week of March [37]. The proportion of depression recurrences was significantly lower in buproprion than in placebo across the three studies: 19% vs. 30%, 13% vs. 21%, and 16% vs. 31%, respectively. For all three studies combined, the overall proportion of depression recurrences at the end of treatment was significantly lower for those on buproprion (16%) than for those on placebo (28%). Based on these findings, in June 2006, the Food and Drug Administration (FDA) approved buproprion for prevention of depressive episodes in patients with a history of SAD. Light therapy and medications, like most treatments, are palliative treatments that work by suppressing symptoms and, therefore, need to be continued with regularity over time. For SAD, this equates to daily treatment throughout the typically symptomatic months each fall/winter season indefinitely. However, available data suggest that the majority of SAD patients are not willing/able to comply with light therapy over subsequent fall/winter seasons. Light therapy is established as acutely efficacious for SAD, but noncompliance with the treatment over time leaves patients vulnerable to subsequent winter depressive episodes. No study to date has assessed compliance with or clinical outcomes for medication treatments for SAD over subsequent winters. However, if the data on long-term compliance with medications for major depression generalize to SAD, the outlook is not good. In a recent review of antidepressant medication adherence [38], 50% of major depression patients had discontinued their medications after 3 months. Due to these limitations, light therapy and antidepressant medications are unlikely to fully meet the clinical demands afforded to the public by SAD. Therefore, the development of supplementary or alternative treatments is clearly warranted. Ideally, alternative treatments would be time-limited (i.e., acute treatment completed in a discrete period vs. daily treatment every fall/winter indefinitely), easier to implement in the long-run relative to 3-5 months of daily light therapy or medications each year, and have more durable effects than light therapy

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or medications (i.e., effects that endure beyond the cessation of acute treatment to prevent the annual recurrence of depression). We propose that cognitive-behavioral therapy holds promise in fulfilling these criteria.

The CBT for SAD Protocol We have conceptualized and developed a manual for a cognitive-behavioral treatment protocol to intervene at the level of a psychological vulnerability to SAD [39]. The rationale addresses the role of environmental changes as well as cognitions and behavior in the onset and maintenance of symptoms. Our SAD-tailored version of CBT uses traditional cognitive therapy elements such as behavioral activation and cognitive restructuring to improve coping with winter. Accordingly, behavioral activation seeks to develop wintertime interests and schedule pleasant events to counteract disengagement. Some cognitive restructuring focuses on challenging negative thoughts and core beliefs related to the winter season, light availability, and weather. A relapse-prevention component addresses early identification of negative anticipatory thoughts about winter and SAD-related behavior changes, using the CBT skills learned to cope with subsequent winter seasons, and development of a personalized relapse-prevention plan to enhance CBT’s durability. Although cognitive therapy is typically administered for 12-20 sessions, SAD necessitates an intensified version. With winter lasting just 3 months, SAD patients may spontaneously remit with the arrival of spring if CBT is conducted weekly over 20 weeks. Therefore, our protocol employs 1½-hour CBT sessions twice a week over 6 weeks (total of 12 sessions). For practical reasons, we have been conducting CBT for SAD in group therapy format with 4-8 participants per group.

Preliminary Efficacy Studies Initially, we conducted a small sample, uncontrolled feasibility trial to obtain preliminary data on the efficacy of our CBT for SAD treatment, published as the first trial of a psychotherapy treatment for SAD [40]. In an analysis of the 23 treatment completers, solo CBT, solo light therapy, and the CBT-plus-light therapy combination were associated with comparable and significant pre to posttreatment improvements in SAD symptoms over the 6week trial. Next, we conducted the first controlled trial of CBT for SAD [41]. This study randomized 61 SAD patients, 54 of whom completed the 6-week treatment phase. In both the intent-to-treat (ITT) and completer samples; CBT, light therapy, and their combination significantly and comparably improved acute SAD symptoms relative to a concurrent waitlist control on blind interviewer- and patient-rated measures. The proportion of participants classified as remitted was statistically larger in combination treatment (73-79%) relative to the wait-list (20-23%). In both studies, our light therapy condition posttreatment outcomes virtually replicated results from prior trials. Both our feasibility study and our randomized controlled trial included a next winter followup to examine the comparative durability of these treatment effects during the subsequent winter season (i.e., January or February during the next winter season after the

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initial winter of study treatment completion). At the end of the acute treatment phase in both pilot studies, we routinely provided all participants with a referral list including contact information for light therapy companies around the world and for local mental health providers. Participants who were randomized to CBT, light therapy, or combined treatment and who had not dropped out of the study by the end of acute treatment phase were invited to return to the laboratory for a naturalistic followup visit during the next winter. We did not assess wait-list controls at the next winter because they were treated with light therapy after the wait. We conducted an intent-to-treat (ITT) analysis using all participants randomized to CBT, light therapy, and combination treatment across our pilot studies (N = 72; 42). We used multiple imputation to estimate next winter outcomes for the 17 individuals who dropped out during treatment, were withdrawn from protocol, or were lost to followup. The CBT (5.8%) and combination treatment (5.2%) groups had significantly smaller proportions of winter depression recurrences than the light therapy group (39.2%). CBT, alone or combined with light therapy, was also associated with significantly lower blind interviewer- and patientrated depression severity at 1-year as compared to light therapy. The observed 1-year differences between initial treatment with CBT, with or without adjunct light therapy, and initial treatment with solo light therapy (i.e., a 33% difference in depression recurrence and a 6- to a 7-point difference in continuous depression scores) are large and very clinically meaningful. Among completers who provided 1-year data, all statistically significant treatment group differences persisted after adjustment for ongoing treatment with light therapy, antidepressants, and psychotherapy. Therefore, the observed treatment group differences during the next winter do not appear to be secondary to ongoing treatment use. Only 4 participants reported any ongoing light therapy the next winter, and only 2 of them (both initially treated with combination treatment) reported using light therapy at a frequency, duration, and treatment length that would be expected to confer therapeutic benefits [33]. In summary, the results of two pilot studies suggest that CBT for SAD is efficacious as an acute SAD treatment. Our results strongly suggest that any differences between solo CBT and light therapy at posttreatment are quite small and that it would not be cost-effective to power subsequent studies to detect these observed differences (i.e., a 10-11% difference in the proportions remitted and differences of less than 2-points on continuous depression scores). Given that central public health challenge in the management of SAD is prevention of depression recurrence each fall/winter season, we argue that long-term treatment outcomes are more important than acute treatment effects. Although SAD episode recurrence is probabilistic (i.e., a full threshold major depressive episode does not necessarily recur in every fall/winter season for all individuals with SAD history), our preliminary data suggest that initial treatment with CBT may still be prophylactic compared to the best available treatment, light therapy. Initial treatment with CBT was associated with fewer recurrences and less severe symptoms during the subsequent winter season relative to initial treatment with solo light therapy. If these findings are replicated in a larger, more definitive study and by other laboratories, CBT could represent a more effective and practical approach to longterm SAD management than what current clinical practice guidelines recommend: daily light therapy during the symptomatic months each year indefinitely.

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Conclusions and Directions Future work stands to advance both the theory and treatment of SAD. On the theoretical level, a unidimensional etiological focus is unlikely to explain the psychopathology of SAD. Although it would be parsimonious if a single etiology (i.e., a genetically-mediated circadian phase advance in response to short photoperiods) was revealed as the uniform underlying cause of all SAD cases; the heterogeneity in symptom presentation [43], within- and between-individual year-to-year variability in timing and severity of depressive episode onset [44], individual differences in the long-term course of SAD including the possibility of developing into nonseasonal major depression [45], and individual differences in response to different treatments suggest that the psychopathology of SAD is complex and that there may be multiple pathways to SAD. Therefore, we advocate for a more comprehensive, multidimensional approach to conceptualizing SAD that incorporates a role for both biological and psychological factors. Recent work on the dual-vulnerability model holds promise as an integrative biologicalpsychological model of SAD onset and maintenance. In a prospective longitudinal study of SAD patients, Young and Azam [14] found that the frequency of ruminative behaviors in the fall interacted with fall vegetative symptoms, but not with fall cognitive/affective symptoms, to predict the severity of vegetative symptoms during the subsequent winter. In a prospective study of individuals with vegetative winter symptoms but not diagnosed SAD, cognitive vulnerabilities assessed in the summer when asymptomatic (i.e., endorsement of dysfunctional attitudes following a sad mood prime, rumination frequency, and low selfesteem and worthlessness dimensions of negative attributional style) predicted cognitive and affective symptom severity when assessed the following winter [46]. These studies suggest that a cognitive vulnerability to experience the cognitive/affective symptoms of depression may interact with a biological vulnerability to experience vegetative symptoms in the fall/winter to explain the full symptom profile of SAD. Multidisciplinary collaborations are needed to explicitly study the interaction of biological and psychological mechanisms in SAD. Regarding future treatment directions, we propose that SAD treatment outcome research should expand its dominant focus on demonstrating acute treatment efficacy over a 2- to 8week trial in an initial winter to include a longer-term focus on outcomes after the initial fall/winter season of study. Only the latter approach reflects the recurrent nature of the disorder. Keeping SAD patients well over time and preventing the recurrence of these debilitating symptoms each year is the most significant public health challenge related to SAD. At a minimum, we propose that a next winter followup be included in study designs. For SAD, the development of prophylactic treatments that keep working after treatment is discontinued to eliminate or offset underlying processes that lead to wholly new onsets in the future (i.e., prevent recurrence) would be particularly advantageous. The development of innovative methods for promoting compliance with more palliative treatments such as light therapy and antidepressant medications would also be helpful. Regarding CBT for SAD specifically, although the approach holds potential promise as a prophylactic treatment for SAD; our results require replication in a larger, more definitive study and by other laboratories before widespread dissemination of CBT for SAD as a

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prophylactic treatment can be recommended. Studies of the generalizability of CBT’s effects to other populations (e.g., children and adolescents, other latitudes, and more racially and ethnically diverse individuals) are also needed. Future research should also explore mechanisms underlying CBT’s acute and long-term effects. Studying acute mechanisms could identify theoretically-relevant, treatment-specific mechanisms and highlight important maintenance factors for SAD (e.g., if improvements in cognitive vulnerability factors uniquely drive the acute antidepressant response in CBT as compared to other treatments). Researching long-term mechanisms may clarify whether CBT’s durability results via modifying causal processes that contribute to SAD risk or via the acquisition of compensatory skills.

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Sohn C-H, Lam RW. Update on the biology of seasonal affective disorder. CNS Spectr 2005;10(8):635-46. [2] Golden RN, Gaynes BN, Ekstrom RD, Hamer RM, Jacobsen FM, Suppes P, Wisner KL, Nemeroff CB. The efficacy of light therapy in the treatment of mood disorders: A meta-analysis of the evidence. Am J Psychiatry 2005; 162(4): 656-62. [3] Mersch PP, Middendorp HM, Bouhuys AL, Beersma DGM, van den Hoofdakker RH. Seasonal affective disorder and latitude: A review of the literature. J Affect Disord 1999;53(1):35-48. [4] Young MA, Watel LG, Lahmeyer HW, Eastman CI. The temporal onset of individual symptoms in winter depression: Differentiating underlying mechanisms. J Affect Disord 1991;22(4):191-7. [5] Young MA. Integrating psychological and physiological mechanisms of SAD: The dual-vulnerability model. Biolog Rhythms Bull 1999;1:4-6. [6] Hankin BL, Abramson LY. Development of gender differences in depression: An elaborated cognitive vulnerability-transactional stress theory. Psychol Bull 2001;127(6):773-96. [7] Beck AT. Depression: Clinical, experimental, and theoretical aspects. New York: Hoeber, 1967. [8] Beck AT. Cognitive therapy and the emotional disorders. New York: Int Univ Press, 1976. [9] Weissman AN, Beck AT. Development and validation of the Dysfunctional Attitude Scale. Paper presented at the annual meeting of the Association for the Advancement of Behavior Therapy, 1978, Chicago. [10] Hodges S, Marks M. Cognitive characteristics of seasonal affective disorder: A preliminary investigation. J Affective Disord 1998;50(1):59-64. [11] Golden RN, Dalgleish T, Spinks H. Dysfuntional attitudes in seasonal affective disorder. Behav Res and Ther 2006; 44(8):1159-64. [12] Rohan KJ, Sigmon ST, Dorhofer DM. Cognitive-behavioral factors in seasonal affective disorder. J Consult Clin Psychol 2003;71(1):22-30.

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[13] Nolen-Hoeksema S. Sex differences in unipolar depression: Evidence and theory. Psychol Bull 1987;101(2):259-82. [14] Young MA, Azam O. Ruminative response style and the severity of seasonal affective disorder. Cognit Ther Res 2003; 27(2): 223-33. [15] Abramson LY, Metalsky GI, Alloy LB. Hopelessness depression: A theory-based subtype of depression. Psychol Rev 1989; 96(2):358-372. [16] Levitan RD, Rector NA, Bagby RM. Negative attributional style in seasonal and nonseasonal depression. Am J Psychiatry 1998;155(3):428-30. [17] Lewinsohn PM. A behavioral approach to depression. In: Friedman RJ, Katz MM, eds. The psychology of depression: Contemporary theory and research. Washington, DC: John Wiley and Sons, 1974:157-78. [18] Lewinsohn PM, Hoberman HM, Teri L, Hautzinger M. An integrative theory of depression. In: Reiss S, Bootzin RR, eds. Theoretical issues in behavior therapy. Orlando: Academic Press, 1985:331-59. [19] Sigmon ST, Whitcomb-Smith S, Boulard NE, Pells JP, Hermann BA, Edenfield TM, LaMattina SM, Shartell JG. Psychophysiological reactivity to seasonal stimuli in seasonal affective disorder. Cognit Ther Res in press. [20] Tierney Lindsey K, Rohan KJ, Roecklein KA. Surface facial electromyography reactions to light- and season-relevant stimuli in seasonal affective disorder. Manuscript under review. [21] Beck AT, Rush JA, Shaw BF, Emery G. Cognitive therapy of depression. New York, NY: Guilford Press, 1979. [22] Jacobson NS, Dobson KS, Truax PA, Addis ME, Koerner K, Gollan JK, Gortner E, Prince SE (1996). A component analysis of cognitive-behavioral treatment for depression. J Consult Clin Psychol 1996; 64(2):295-304. [23] Gloaguen V, Cottraux J, Cucherat M, Blackburn IM. A meta-analysis of the effects of cognitive therapy in depressed patients. J Affect Disord 1998;49(1):59-72. [24] Hollon SD, Shelton RC, Davis DD. Cognitive therapy for depression: Conceptual issues and clinical efficacy. J Consult Clin Psychol 1993;61(2):270-5. [25] U. S. Department of Health and Human Services. Depression in primary care: Treatment of Major Depression. Rockville, USA: AHCPR Publications, 1993. [26] Hollon SD, Stewart MO, Strunk D. Enduring effects for cognitive behavior therapy in the treatment of depression and anxiety. Annu Rev of Psychol 2006;57:285-315. [27] Blackburn IM, Eunson KM, Bishop S. A two-year naturalistic follow-up of depressed patients treated with cognitive therapy, pharmacotherapy and a combination of both. J Affect Disord 1986;10(1):67-75. [28] Hollon SD, DeRubeis RJ, Shelton RC, Amsterdam JD, Salomon RM, O'Reardon JP, Lovett ML, Young PR, Haman KL, Freeman BB, Gallop R. Prevention of relapse following cognitive therapy vs medications in moderate to severe depression. Arch Gen Psychiatry 2005; 62(4)2:417-22. [29] Evans MD, Hollon SD, DeRubeis RJ, Piasecki JM, Grove WM, Garvey MJ, Tuason VB. Differential relapse following cognitive therapy and pharmacotherapy for depression. Arch Gen Psychiatry 1992; 49(10):802-8.

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[30] Simons AD, Murphy GE, Levine JL, Wetzel RD. Cognitive therapy and pharmacotherapy for depression: Sustained improvement over one year. Arch Gen Psychiatry 1986;43(1):43-8. [31] Terman M, Terman JS, Quitkin F, McGrath P, Stewart J, Rafferty B. Light therapy for seasonal affective disorder: A review of efficacy. Neuropsychopharma-cology 1989;2(1):1-22. [32] Terman JS, Terman M, Lo ES, Cooper TB. Circadian time of morning light administration and therapeutic response in winter depression. Arch Gen Psychiatry 2001;58(1):69-75. [33] Lam RW, Levitt AJ. Clinical guidelines for the treatment of seasonal affective disorder. Vancouver, BC: Clinical and Academic Publishing, 1999. [34] Thase ME (2003). Achieving remission and managing relapse in depression. J Clin Psychiatry 2003;64(Suppl 18):3-7. [35] Postolache TT, Hardin TA, Myers FS, Turner EH, Barnett RL, Matthews JR, Rosenthal NE. Greater improvements in the summer than with light treatment in winter in patients with seasonal affective disorder. Am J Psychiatry 1998;155(11): 1614-6. [36] Schwartz PJ, Brown C, Wehr TA, Rosenthal NE. Winter seasonal affective disorder: A follow-up study of the first 59 patients of the National Institute of Mental Health Seasonal Studies Program. Am J Psychiatry 1996;153(8):1028-36. [37] Modell JG, Rosenthal NE, Harriett AE, Krishen A, Asgharian A, Foster VJ, Metz A, Rockett, CB, Wrightman DS. Seasonal affective disorder and its prevention by anticipatory treatment with Buproprion XL. Biol Psychiatry 2005;58(8):658-67. [38] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353(5): 48797. [39] Rohan KJ. Coping with the seasons: A cognitive-behavioral group treatment for seasonal affective disorder. Unpublished manual, 2000. [40] Rohan KJ, Tierney Lindsey K, Roecklein KA, Lacy TA. Cognitive-behavioral therapy, light therapy, and their combination in treating seasonal affective disorder. J Affect Disord 2004;80(2-3): 273-83. [41] Rohan KJ, Roecklein KA, Tierney Lindsey K, Johnson LG, Lippy RD, Lacy TJ, Barton FB. A randomized controlled trial of cognitive-behavioral therapy, light therapy, and their combination for seasonal affective disorder. J Consult Clin Psychol 2007;75(3):489-500. [42] Rohan KJ, Roecklein KA, Lacy TJ, Vacek PM. (submitted). Winter depression recurrence one year after cognitive-behavioral therapy, light therapy, or combination treatment. [43] Rosenthal NE, Sack DA, Gillin C, Lewy AJ, Goodwin FK, Davenport Y, Mueller PS, Newsome DA, Wehr TA. Seasonal affective disorder: A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984; 41(1):72-80. [44] Young MA, Meaden PM, Fogg LF, Cherin EA, Eastman CI. Which environmental variables are related to the onset of seasonal affective disorder? J Abnorm Psychol 1997;106(4): 554-62. [45] Lam RW, Tam EM, Yatham LN, Shiah I-S, Zis AP. Seasonal depression: The dual vulnerability hypothesis revisited. J Affect Disord 2001;63(1-3);123-32.

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[46] Enggasser JL, Young MA. Cognitive vulnerability to depression in seasonal affective disorder: Predicting mood and cognitive symptoms in individuals with seasonal vegetative changes. Cognitive Therapy and Research 2007;31(1):3-21.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XIV

Prepartum Depressive Symptoms Correlate Positively with C-Reactive Protein Levels and Negatively with Tryptophan Levels: A Preliminary Report Debra A. Scrandis1, 2, Patricia Langenberg 3, Leonardo H. Tonelli1, Tehmina M. Sheikh1,4, Anita C. Manogura5, Laura A. Alberico2, Tracey Hermanstyne1, Dietmar Fuchs6, Hugh Mighty5, Jeffrey D. Hasday7, Kalina Boteva8 and Teodor T. Postolache ∗1,4,8 1

Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA 2 Department of Family and Community Health, University of Maryland School of Nursing, Baltimore, MD, USA 3 Epidemiology and Preventive Medicine, University of Maryland, Baltimore, MD, USA 4 St. Elizabeth’s Hospital, Psychiatry Residency Training Program, Washington, DC, USA 5 Department of Obstetrics and Gynecology, University of Maryland School of Medicine Baltimore, MD, USA, 6 Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria 7 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA 8 University of Maryland/Sheppard Pratt Psychiatry Residency Program, Baltimore, USA ∗

E-mail address: [email protected] Correspondence: Teodor T Postolache, MD, Mood and Anxiety Program (MAP), Department of Psychiatry, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF Building Room 502, Baltimore, MD 21201 USA. Tel: 410-706-2323;

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Abstract Prepartum and postpartum depression have negative, and sometimes devastating, effects on women and their families. As inflammatory processes are related to depression in general, we hypothesized that inflammatory perturbations, prepartum and postpartum, contribute to triggering and worsening of symptoms of peripartum depression. We conducted a longitudinal preliminary study on 27 women at high risk for developing postpartum depression measuring SIGH-SAD scores at three time points: 35-38 weeks gestation, 1-5 days postpartum, and 5-6 weeks postpartum. Serum C-reactive protein and interleukin-6, both markers of inflammation, as well as tryptophan, kynurenine, and the kynurenine/tryptophan ratio, as consequences of inflammation and pathophysiological steps towards depression, were measured at each time point. C-reactive protein levels were found to be positively related to atypical and total depression scores in the prepartum period and with atypical depression scores in the early postpartum period. Tryptophan was found to be negatively associated with total depression scores in the prepartum, as well. These findings warrant further investigation that could lead to novel interventions to decrease poor outcomes from peripartum depression.

Keywords: Prepartum depression, postpartum depression, atypical depression, inflammation, C-reactive protein, tryptophan, tryptophan depletion, kynurenine.

Introduction Peripartum, or perinatal, depression includes the well known postpartum depression, the very common postpartum blues, and the less known and recognized prepartum depression. Yet, prepartum depression, which occurs in 8.5 to 11% of women [1], has a potentially detrimental impact not only on the mother, but also on the offspring, including an increased risk of spontaneous preterm birth [2,3], poor fetal growth [4-6], and infant temperament reactivity [7]. Often times, prepartum depression is undiagnosed due to common pregnancy symptoms, such as fatigue, weight gain, and sleep problems, that are similar to major depression criteria. Prepartum depression is also a high risk factor for the development of postpartum depression [8], a disorder with negative consequences of impaired mother-child interactions [9], chronic depression [10], suicide [11], and, rarely, infanticide [12]. In fact, about 10-12% of postpartum depression has a prepartum onset [13,14]. Activation of the immune system and production of cytokines has been proposed as a potential mechanism that may promote depressive states [15]. Administration of certain cytokines to patients for therapeutic purposes and induction of cytokines experimentally in healthy subjects can result in depression [16-19]. Maternal immune system changes during pregnancy include evidence of immune system activation, immune system suppression, and immunological tolerance [20-23]. These changes are, in great part, physiological. For instance, for a viable pregnancy, the maternal immune system must tolerate paternal-derived fetal antigens. In contrast, the mother physiologically requires a more vivid immune response in preparation for delivery, considering the associated massive tissue trauma and exposure to bacterial microorganisms. Consistent with their biological functions, measured cytokines

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levels are higher in women at the end of term, compared to non-pregnant women [24]. After delivery, there is even greater immune activation, with increased serum concentrations of several inflammatory markers such as interleukin-6 (IL-6), IL-6 receptor (IL-6R), IL-1 receptor antagonist, and decreased levels of leukemia inhibitory factor receptor [24]. A previous study showed that women who were more depressed in the early postpartum had significantly higher serum concentrations of IL-6 and IL-6R [24], suggesting a potential involvement of this cytokine in postpartum depression. There are several potential biological mechanisms connecting inflammatory processes with mood dysregulation. One of them is the serotonin dysfunction secondary to the activation of the enzyme indoleamine 2,3 dioxygenase (IDO) by cytokines, resulting in tryptophan depletion and production of compounds such as kynurenine (KYN) [25]. Tryptophan (TRP) is the precursor of serotonin (5HT), which plays an important role in major depression and other mood disorders. Studies have found that TRP depletion is correlated with inducing depressive symptoms, particularly in patients with a history of major depressive episode and/or recently medicated or partially remitted symptoms [26-28]. In an alternative enzymatic pathway via IDO, TRP can be metabolized to KYN and, thus, less TRP is available to be metabolized to 5HT [29]. There is evidence that plasma tryptophan concentrations in women at the end of term and after delivery are lower than plasma tryptophan concentrations in non-pregnant, healthy women [30,31] and that plasma tryptophan concentrations decrease with the duration of pregnancy [32]. Moreover, the decrease in the plasma KYN/TRP ratio is significantly more pronounced in women with high levels of depressive symptoms in the early postpartum period [33]. Not only could tryptophan depletion result in depression in vulnerable postpartum women, but metabolites of kynurenine are potentially toxic compounds. The putative mechanism connecting decrease in KYN/TRP ratio and inflammation is the activation of IDO by pro-inflammatory cytokines released during inflammation. We thus hypothesized that there is a relationship between inflammatory markers, TRP, KYN, and the KYN/TRP ratio, and symptoms of depression in prepartum and postpartum women.

Methods In this preliminary study, twenty-seven women were recruited from two Mid-Atlantic obstetric clinics and one birthing center and evaluated for depression, inflammatory markers, and KYN/TRP ratio at three time points: 35-38 weeks gestation (prepartum), 1-5 days postpartum (early postpartum), and 5-6 weeks postpartum (late postpartum). Participants signed informed consent after a full explanation of the study, and were evaluated to sign consent, as approved by the Institutional Review Board of the University of Maryland Baltimore. Screening The obstetricians and midwives completed an inclusion-exclusion criteria checklist for all pregnant women at their clinics. Women were excluded if they had any autoimmune disorders, if they abused alcohol, opiates, cocaine, psychostimulants, marijuana, or sedatives

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during current pregnancy, if they had a lifetime diagnosis of psychotic illness including a history of psychotic depression or infanticide, a lifetime diagnosis of alcohol, phencyclidine, hallucinogen, cannabis, opiate, cocaine, or stimulant dependence, if they had any active infections, or were using antidepressant medications during the current pregnancy. Women interested in participating were screened with the mood disorder, substance abuse screen, and psychotic screen modules of the Structured Clinical Interview Diagnostic for DSM-IV TR (SCID) [34] for inclusion criteria and to confirm no exclusion criteria. As we wanted to study women who were more likely to develop postpartum depression, we included women who scored positive for factors predicting postpartum depression. As such, women were included if they were at least 18 years of age and had a lifetime history of major recurrent mood disorders, an anxiety disorder symptomatic during pregnancy, or at least one of the stressful social situations known to be high risk factors for postpartum depression during the past year: death of a loved one, separation from partner/boyfriend/husband, loss of job, and/or moving from household.

Procedure The Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder (SIGH-SAD) [35] was used to measure severity of depression in study participants. Trained raters asked participants 29 questions at 3 different times: 35-38 weeks gestation (prepartum), days 1-5 postpartum (early postpartum), and weeks 5-6 post-partum (late postpartum). This scale includes typical depressive symptoms and atypical depressive symptoms. Ten milliliters of venous blood was drawn from each participant in the prepartum, early postpartum and late postpartum for C-reactive protein (CRP), IL-6, TRP, and KYN. After centrifugation at 3,000 rpm for 10 minutes, serum was separated and frozen at -70 degrees Celsius. IL-6 and CRP were measured by two antibody ELISAs in the University of Maryland Cytokines Core Laboratory (www.cytokines.com) using paired antibodies and standards from 0.08 mcg/mL and 1.5 pg/mL for CRP (Dako, Glostup, Denmark) and IL-6 (Pierce/Endogen, Rockville, IL, USA) respectively. Levels of IL-6 and CRP were calculated from a standard curve using the SoftPro software package (Molecular Devices, Sunnyvale, CA, USA). TRP and KYN measurements were done using HPLC on reversed phase [36]. Serum samples were diluted with potassium phosphate buffer containing L-nitro-tyrosine as internal standard and were deproteinized with trichloroacetic acid. After injection of 100 µL, separation was performed on a reverse phase C18 column (Lichrocart, Merck, Darmstadt, Germany) using sodium acetate buffer (15 mmol/L, pH 4.0) with 3% acetonitril and a flow rate of 0.9 mL/min at a temperature of 25°C and a Varian ProStar liquid chromatography system with autosampler Model 400 (Varian, Palo Alto, CA, USA). L-kynurenine was monitored by its UV-absorption at 360 nm (UV-detector SPD-6A, Shimadzu, Japan), tryptophan by detection of its natural fluorescence at 285 nm excitation and 365 nm emission wavelengths (ProStar fluorescence-detector Model 360, Varian). Peaks were identified by comparing their retention time to those of an albumin-based calibrator containing 10 µmol/L L-kynurenine and 100 µmol/L L-tryptophan which was prepared like the serum samples. To estimate IDO activity, KYN/TRP was calculated.

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Data analysis Initial descriptive analyses included examining distributions of all variables for outliers and extreme skewness. Two outliers were identified and all analyses conducted both with and without them; results were very similar. Analyses presented are without outliers. Means and standard deviations were calculated for all depression scores and biomarkers. Statistical comparisons across the three time periods were made using repeated measures (mixed model) regression analyses to account for within-subject correlation. Associations of biomarkers with depression scores were estimated with mixed model regression analyses as well.

Results Twenty nine women were recruited for the study. Two women dropped out after one measurement, leaving 27 women who completed the study. A majority of the sample was African American (85%), never married (74%), and multiparous (63%). The mean age was 23.2 years (SD = 6.6 years). According to the SCID results, 52% percent of the sample had no past or current mood disorder. Eight women had past history of major depression and two had current depression during their pregnancy (see Table 1). Table 1. Demographics of the sample (n=27) Demographics Race Marital Status

Level of Education

Parity Psychiatric Diagnosis

Category

% (n)

African American White Married Never married Other Less than high school High School graduate Part college Graduate 2 year college or more Primiparous Multiparous

85% (23) 15% (4) 22% (6) 74% (20) 0.03% (1) 19% (5) 48% (13) 19% (5) 15% (4) 37% (10) 63% (17)

Major Depression recurrent, (current episode )

0.1% (2)

Major Depression Recurrent (past episode)

30% (8)

Depressive Disorder Not Otherwise Specified

11% (3)

Depression Scores Total depression scores were higher in the prepartum (M = 11.4, SD = 6.9) than the early postpartum (M= 9.3, SD = 6.6) and the late postpartum (M = 7.9, SD = 4.6). Atypical

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depression scores were significantly higher in the prepartum (M = 4.9, SD= 3.3) than the early postpartum (M = 3.5, SD = 2.7) and the late postpartum (M = 3.5, SD = 3.1) (p = .04, Table 2).

Inflammatory Markers CRP and atypical depression scores prepartum were positively correlated (r = .59, p=.005). For every one mcg/mL increase in CRP, there was a 0.13 point increase in atypical scores (p=.02) and a 0.18 point increase in total depression score (p=0.03, Table 3).

Table 2. Means of total and atypical depression scores, C-reactive protein, Interleukin-6, Tryptophan, Kynurenine, and Kynurenine/Tryptophan ratio (n =27)

Total Depression Scores

Atypical Depression Scores

C-Reactive Protein (μg/L)

Interleukin 6 (pg/mL)

Kynurenine/ Tryptophan ratio µmol/mmol Tryptophan (μmol/L)

Kynurenine (μmol/L)

Prenatal Early Postpartum Late Postpartum Prenatal Early Postpartum Late Postpartum Prenatal Early Postpartum Late Postpartum Prenatal Early Postpartum Late Postpartum Prenatal Early Postpartum Late Postpartum Prenatal Early Postpartum Late Postpartum Prepartum Early Postpartum Late Postpartum

Mean 11.4* 9.3 7.9 4.9* 3.5 3.5 20 41.2** 15.5 10.2 60.4** 11.9 32.8 34.2 34.8 44.9 44.2 50.0# 1.4 1.4 1.7#

SD 6.9 6.6 4.6 3.3 2.7 3.1 15.3 20.4 18.6 7.4 77.3 10.1 7.3 11.3 8.6 9.5 7.8 7.0 0.4 0.3 0.5

* significantly higher than postpartum values, p<0.06. ** significantly higher than pre- and late postpartum values, p<0.001. # significantly higher than pre- and early postpartum values, p<0.005. Comparisons of means from mixed model analyses, adjusting for repeated measures on participants.

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Table 3. Associations of biomarkers with depression scores prepartum, early postpartum, and late postpartum, from repeated measures regression analyses (n=27) Independent Variable

C-Reactive Protein Prepartum Early Postpartum Late Postpartum Tryptophan Prepartum Early Postpartum Late Postpartum Kynurenine Prepartum Early Postpartum Late Postpartum Interleukin 6 Prepartum Early Postpartum Late Postpartum

Total Depression Scores Coefficient P value

Atypical Depression Scores Coefficient P value

0.176 -0.098 -0.002

0.03 0.09 0.98

0.126 -0.060 0.011

0.002 0.03 0.75

-0.277 0.049 -0.112

0.04 0.77 0.53

-0.077 0.037 0.005

0.27 0.67 0.95

-4.29 -0.47 -3.87

0.22 0.90 0.17

-0.53 1.85 -0.05

0.77 0.34 0.97

-0.093 0.007 -0.133

0.60 0.68 0.35

0.089 0.003 -0.088

0.32 0.75 0.23

CRP was negatively associated with total and atypical depression scores in the early postpartum, but there was no association in the late postpartum. There were no significant relationships between IL-6 and total or atypical depression scores at any time points. Tryptophan TRP was significantly higher in the late postpartum (M = 50.0, SD = 7.0) than the prepartum (M = 44.9, SD = 9.5) (p = .002) and the early postpartum (M = 44.2, SD = 7.8) (p <.001). KYN was also significantly higher in the late postpartum (M = 1.7, SD = 0.5) than the prepartum (M =1.4, SD = 0.4) and the early postpartum period (M = 1.4, SD = 0.4) (p =.004). The KYN/TRP ratio was lower in the prepartum period (M = 32.8, SD = 7.3) than the early postpartum period (M = 34.2, SD = 11.3) and the late postpartum (M = 34.8, SD = 8.6). However, changes over time in KYN/TRP ratio scores were not significant. TRP was significantly negatively associated with total depression score in the prepartum period, but not in other time periods. Neither KYN nor the KYN/TRP ratio was associated with depression scores.

Discussion This is the first study, to our knowledge, to examine the relationship between inflammatory markers and peripartum depression, separately for typical and atypical symptoms. In fact, we identified associations with biological markers only with atypical and total depression scores, and we did not find any association with typical depression scores. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) [37] lists “with atypical features” as a specifier of major depression. To be

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diagnosed with this identifier, the person must have mood reactivity, such as mood brightening in response to actual or potential positive events, and two or more of these symptoms: significant weight gain or appetite, hypersomnia, leaden paralysis, and interpersonal rejection sensitivity. Women are more likely to have atypical symptoms than men [38-41]. However, it is not unusual for women in their third trimester to experience fatigue or sleepiness secondary to sleep disturbance due to fetal movement and difficulty breathing, and weight gain due to pregnancy. In the present study, any weight gain due to pregnancy (weight gain 1-2 lbs/week) was not counted in the depression scores so as to determine depressive symptoms versus normal physiological changes. Many studies do not assess atypical symptoms for major depression in the prenatal or postpartum period; therefore it is hard to determine the incidence in the prenatal period [42]. The only finding consistent with the hypothesized relationship between inflammation and mood dysregulation was the positive relationship between depressive symptoms, both atypical and total, and CRP. Elevated CRP was found in another sample of non-pregnant women with remitted major depressive disorder [43] and a mostly female sample of currently depressed patients [44]. In response to tissue injury or stress, pro-inflammatory cytokines (TNF-α, IL-1beta, IL-6) are released from macrophages. These cytokines induce the release of certain acute phase proteins, such as CRP, into the plasma. CRP, produced mainly by the liver, is a more stable measure of inflammatory process than other, more transient, markers, such as IL-6. Of interest also was the observed negative association of TRP with total depression scores in the prepartum period. Our results are consistent with the previously reported TRP degradation occurring during gestation and improved during the postpartum period [45]. Inflammation has been found to contribute to TRP depletion via activation of the IDO metabolic pathway [25]. Subsequently, reduced tryptophan levels lead to decreased synthesis of serotonin in the brain. The KYN/TRP ratio in our study was elevated in the early postpartum compared to the prepartum period, although slightly and nonsignificantly. This is not inconsistent with a recent study in which TRP increased and KYN/TRP decreased in women who did not report symptoms of postpartum blues, and showed no change in women with postpartum blues [46]. Our study had several limitations. Despite being at risk, many of the women did not develop postpartum depressive symptoms and, thus, our hypothesis needs to be reevaluated in larger cohorts or in case control paradigms in other studies where serum or plasma have been preserved. As mentioned, we measured IL-6 and not other pro-inflammatory cytokines such as TNF α and IL-1. In this preliminary study, our sample was small (n = 27), thus generalization of our findings is limited. Lastly, we acknowledge that depressive symptoms, especially atypical symptoms, may overlap with sickness behavior symptoms. Other important biological markers, such as cytokines or hormones have not been measured.

Conclusions This study adds to the very limited literature on prenatal depression and to the growing body of literature linking mediators of inflammation with depression. Confirming and

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expanding our results in larger samples, and identifying pathophysiological mechanisms which may contribute to perinatal depression, may result in identifying new treatment targets and finding novel interventions, leading to better health, symptomatic relief, and improved quality of life in women and their children.

Acknowledgements Supported from seed funds from the University of Maryland School of Medicine to Dr. Postolache. Dr. Postolache was also supported by grant R21 MH075891-01A1 (PI Postolache, co PI Tonelli) from NIMH , and is a mentor on the 5 K12 HD42489-03, and NIH grant for Maryland’s Organized Research Effort in Women’s Health, program where Dr. Tonelli was the recipient of a BIRCWH scholar award, and Dr. Langenberg is the PI. Additional support has been provided by the St. Elizabeth Hospital Psychiatry Residency Training Program (Drs. Postolache and Sheikh), and by the University of Maryland/Sheppard Pratt Psychiatry Residency Program (Dr. Boteva). The authors are also grateful for the support by the University of Maryland General Clinical Research Center Grant M01 RR 16500, General Clinical Research Centers Program, National Center for Research Resources (NCRR), NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institutes of Health, or of the University of Maryland School of Medicine or School of Nursing.

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[26] Delgado P, Price L, Miller H et al. Serotonin and the neurobiology of depression: Effects of tryptophan depletion in drug-free depressed patients. Arch Gen Psychiatry 1994;51(11):865-74. [27] Moore P, Landolt H, Seifritz E et al. Clinical and physiological consequences of rapid tryptophan depletion. Neuropsychopharmacology 2000;23:601-22. [28] Moreno F, Heninger G, McGahuey C, Delgado P. Tryptophan depletion and risk of depression relapse: A prospective study of tryptophan depletion as a potential predictor of depressive episodes. Biol Psychiatry 2000;48(4): 327-9. [29] Byrne G, Lehmann L, Kirschbaum J, Borden E, Lee C, Brown R. Induction of tryptophan degradation in vitro and in vivo: A gamma-interferon-stimulated activity. J Interferon Res 1986;6(4):389-96. [30] Maes M, Ombelet W, Verkerk R, Bosmans E, Scharpe S. Effects of pregnancy and delivery on the availability of plasma tryptophan to the brain: Relationships to delivery induced immune activation and early postpartum anxiety and depression. Psychol Med 2001; 31(5):847-58. [31] Fuchs D, Schrocksnadel H, Baier-Bitterlich G, Dapunt O, Wachter H. Activated cellular immunity and decreased serum tryptophan in healthy pregnancy. Adv Exp Med Biol 1996; 398:149-53. [32] Schrocksnadel H, Baier-Bitterlich G, Dapunt O, Wachter H, Fuchs D. Decreased plasma tryptophan in pregnancy. Obstet Gynecol 1996 1996; 88(1): 47-50. [33] Maes M, Verkerk R, Bonaccorso S, Ombelet W, Bosmans E, Scharpe S. Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation. Life Sci 2002; 71: 1837-48. [34] First M, Spitzer R, Gibbon M, Williams J. Structured Clinical Interview for DSM-IV TR Axis 1 Disorders- Non patient version. Vol 11/2002 version. New York: Biometrics Res Dept, New York State Psychiatr Inst, 2002. [35] Williams J, Link M, Rosenthal N, Amira L, Terman M. Structured interview guide for the Hamilton depression rating scale seasonal affective disorder version: New York: NY State Psychiatr Inst, 1992. [36] Widner B, Werner E, Schennach H, Wachter H, Fuchs D. Simultaneous measurement of serum tryptophan and kynurenine by HPLC. Clin Chem 1997; 43: 2424-6. [37] American Psychiatr Assoc. Diagnostic and statistical manual of mental disorders: Text revised. 4th ed. Washington, DC: Am Psychiatr Assoc, 2000. [38] Posternak M, Zimmerman M. Symptoms of atypical depression. Psychiatry Res 2001;104:175-81. [39] Moskvina V, Farmer A, Jones I et al. Sex differences in symptom patterns of recurrent major depression in siblings. Depres Anxiety 2007 Oct 12. [EPub ahead of print]. [40] Angst J, Gamma A, Sellaro R, Zhang H, Merikangas K. Toward validation of atypical depression in the community: results of the Zurich cohort study. J Affect Disord 2002;72(2):125-38. [41] Benazzi F. Prevalence and clinical features of atypical depression in depressed outpatients: A 467 case study. Psychiatry Res 1999;86:259-65.

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[42] Kammerer M, Taylor A, Glover V. The HPA axis and perinatal depression. Arch Womens Ment Health 2006;9(4):187-96. [43] Kling MA, Alesci S, Csako G et al. Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A. Biol Psychiatry 2007;62(4):309-13. [44] Lanquillon S, Krieg J, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 2000; 22(4):370-9. [45] Schrocksnadel K, Widner B, Bergant A, Neurauter G, Schrocksnadel H, Fuchs D. Tryptophan degradation during and after gestation. Adv Exp Med Biol 2003;527: 77-83. [46] Kohl C, Walch T, Huber R et al. Measurement of tryptophan, kynurenine and neopterin in women with and without postpartum blues. J Affect Disord 2005; 86: 135-42.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XV

Mood Changes after Brief Exposure to Chemosensory Stimuli in Patients with Seasonal Affective Disorder Solomon S. Williams1, Norman E. Rosenthal2, Avery N. Gilbert3, John W Stiller4, Todd A. Hardin5, and Teodor T. Postolache ∗6 1

Central Texas Veterans Health Care System, Temple, TX, USA 2 Department of Psychiatry, Georgetown University, Washington DC 3 Synesthetics Inc, Montclair, NJ, USA 4 Neurology Consultation Service, St Elizabeths Hospital, Washington, DC, USA 5 National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 6 Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

Abstract As previous reports related olfaction to both mood and seasonality in humans, and as previous studies suggest that lemon odor may influence mood and behavior, we hypothesized that brief exposure to the scent of lemon would alter mood in patients with seasonal winter depression. Twenty-four patients with seasonal affective disorder (17 females and 7 males, aged 43±10 years) were briefly exposed to lemon and a control odor (fir tree) using a cross-over randomized nested design. Mood change following exposure to lemon scent was compared to mood change following exposure to fir tree ∗

E-mail address: [email protected] Correspondence: Teodor T Postolache, MD, Director, Mood and Anxiety Program (MAP), Department of Psychiatry, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF Building Room 930, Baltimore 21201 USA. Tel: 410 706 2323.

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Solomon S. Williams, Norman E. Rosenthal, Avery N. Gilbert et al. using Wilcoxon nonparametric tests. There was a significant, although small, difference between change in mood after sniffing lemon odor (improvement) versus after sniffing fir odor (worsening) {Wilcoxon matched- pair signed rank test, Z = -2.58, N = 23, p = 0.01}. Studies evaluating potential antidepressant or antidepressant-augmenting effects of odorants will require longer repetitive exposures., , and randomized placebo controlled trials, Our limited conclusion is that even very brief exposure to chemosensory stimuli may influence mood reports in patients with seasonal depression.

Keywords: Seasonal Affective Disorder; Depression, Chemosensory environment, Odorant hedonics, Olfactory stimulation

Introduction A number of reports suggested that odors may affect mood, cognition, and behavior. For example, regular exposure to pleasant odor elevates mood in males [1] and females at midlife [2]. Stimulation with lemon odor, but not with other odors, reduces the immobility time in rats following forced swimming paradigm, a model for testing antidepressant activity [3]. This suggests that certain odors may have specific effects on depressive-like behaviors. Given that even brief odor exposure can alter mood [4], we tested the hypothesis that oneminute exposure to lemon odor would elevate mood in patients with seasonal affective disorder (SAD), who have been previously reported to have a greater olfactory acuity than control subjects [5].

Methods Twenty-four human subjects who met criteria for SAD [6] and the DSM-IV criteria for a past major depressive episode [7] were enrolled. All subjects provided informed consent. Subjects’ average age was 43±10 years and included 17 females and 7 males. Subjects were tested when depressed and while off medication between December 1 and March 20. A minimal level of depression (“typical score” > 13 or “typical score” > 11 with a total score > 19) assessed by the Structural Clinical Interview Guide for the Hamilton Depression Rating Scale, SAD version {SIGH-SAD} [8] was required on the day of the study to ensure that all subjects were currently depressed. All but one woman was pre-menopausal. The protocol was approved by the intramural Institutional Review Board of the National Institute of Mental Health (NIMH). Exclusion criteria were current smokers, subjects with other axis I psychiatric diagnoses, history of psychosis, those medically ill, those with history of head injury and those with a history of allergy to cosmetics. If acute upper respiratory symptoms occurred, the testing was postponed for at least two weeks. Subjects were told that the study was to explore the relationship between depression and pleasantness of odor and were specifically instructed to focus attention on the following qualities of odors: pleasantness, familiarity, and intensity.

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Olfactory Stimuli Odorants provided by Dragoco, Inc. (Totowa, NJ), included fragrance raw materials diluted in dipropylene glycol to approximately equal odor intensity as assessed by professional perfumers. The stimuli were lemon (Italian) and fir tree (Canadian). The latter was chosen as a control odor because in a battery of thirty odors, an unrelated sample of subjects described lemon and fir as raising therapeutic expectations associated with a sense of well being. The stimuli were presented bi-rhinally for a minute each, with a two minute interval between odors. A nested randomized order of presentation ensured that lemon and fir had an equal chance of being presented as the first or as the second odor. Stimuli were prepared by dipping fragrance filter papers (Orlandi, Farmingdale, NY) to a depth of 2.5 cm in the odorant solution. The filter strips were brought into the testing room in glassine envelops with minimal delay between odorant preparation and presentation. Testing occurred at the NIMH clinical center in a well ventilated room with controlled temperature and humidity. When presenting the stimuli, the test administrator held the scented end of the filter strip as close to the subject’s naris as possible without touching it. The subject was asked to sample the odor by sniffing naturally, and then to rate the intensity, pleasantness, and familiarity of the odor. Ratings were made on 100-mm visual analogue scales [9] labeled with descriptors at both ends. Patients marked the horizontal line at the spot that best described their assessment of the odor. The scales were anchored with descriptors based on life-time experiences. Anchors for the pleasantness scale were “most unpleasant ever” and “most pleasant ever”; for the familiarity scale “most unfamiliar” and “most familiar”; and for the intensity scale “undetectable” and “most intense ever.”

Mood Self-Ratings Subjects rated their mood immediately before and one minute after the administration of each odor on visual analogue scales [10]. Three dimensions of mood were used: happy, relaxed, and energetic. The happiness scale was anchored with “most unhappy mood ever” and “happiest mood ever”; the relaxation scale with “most tense” and “most relaxed”; and the energy with “most tired ever” and “most energetic ever.”

Statistical Analysis The basic unit of analysis was the difference between the pre-exposure and post-exposure mood rating for each odor. Because the difference data were not normally distributed, nonparametric statistical method was used to compare the change in mood with exposure to lemon versus fir.

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Results Mood change results are summarized in figures 1, 2, and 3. There was a significant difference in mood changes after sniffing lemon (improvement) versus change in mood after sniffing fir (worsening), [Wilcoxon matched-pair signed-rank test, Z = -2.58, N =23, p = 0.01]. One subject was unable to rate her mood. Similar significant differences were seen in relaxation (Z = -2.33, p = 0.02) and energy (Z = -2.33, p = 0.02). Following adjustment for multiple comparisons, difference in the happiness change remained statistically significant (p = 0.03) while the relaxation and energy changes approached significance (p = 0.06). The lemon odor was judged more pleasant (71 mm) than fir (41 mm) (Wilcoxon test, Z = -4.05, N =24, p < 0.0001). The odors did not differ in intensity or familiarity. The relationship between perceived odor pleasantness and mood change was then examined. A median split on the pleasantness rating of each odor was used to categorize subjects as relative high raters (those who rated the odor as more pleasant) or relative low raters (those who rated the odor as less pleasant). Mood change scores of high raters and low raters were then compared. The results are summarized in figures 2 and 3. The mean relaxation rating of lemon high raters improved after sniffing, while lemon low raters showed little change. The group difference was statistically significant (Z = -1.97, p < .05). A similar pattern of group difference was evident for happiness (Z = -1.85, p = .063) and energy (Z = 1.52, ns). The mean relaxation rating of fir high raters changed little after sniffing fir; low raters became less relaxed (Figure 3). The group difference was statistically significant (Z = -2.30, p < .05). A similar result was found for energy (Z = -2.03, p<.05) and for happiness (Z = 1.81, p = .07).

Discussion A one-minute exposure to lemon odor was associated with a rapid small elevation of mood in depressed SAD patients when compared to mood changes with a control odor (fir tree). In healthy subjects, brief odor exposure has been shown to produce small, transient, but statistically significant alterations in mood [4, 11, 12]. Our study demonstrates divergent changes in mood with two odors, after a short duration of exposure in depressed patients under laboratory conditions. Our results add to existing evidence that lemon odor may have mood-altering properties. For example, in an animal model for testing the efficacy of antidepressants—the forced swim paradigm—lemon scent reduced immobility time and potentiated the effect of imipramine in reducing depressive-like behaviors [3]. Exposure to citrus fragrance reduced the antidepressant dose required to maintain remission in a group of depressed patients [13]. This clinical result was accompanied by alteration in humoral and immunological parameters, including reduction in cortisol level, reduction in the CD4/8 ratio, and improved NK cell activity. Also, application of lemon balm to the arms and face reduced verbal and nonverbal aggression, and improved quality of life in a group of patients with severe dementia [14].

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Possibly, the response of SAD patients to very short exposure to odors may be related to previously reported heightened olfactory acuity in SAD patients [5]. Consistent with this is the finding that SAD patients report more discomfort following exposure to certain odors as compared to other groups [15].

Figure 1. Mean change in self-rated happiness, relaxation, and level of energy in depressed SAD patients (n=23) following one minute of odor exposure.

Considering that both seasonality and depression have been associated with alterations in olfactory perception, it will be of interest to compare olfactory hedonic responses in patients with seasonal vs. nonseasonal depression. Evidence suggests that the mood elevating effect of odors may be related to their adjudged pleasantness. For example, fragrance administration results in a significant reduction in anxiety in patients who judge the fragrance to be pleasant [16]. Compared to unpleasant odors, pleasant odors elicit a greater percentage of happy memories [17]. The subjects in our study rated lemon as more pleasant-smelling than fir. Therefore, it is useful to ask whether this difference in perceived pleasantness might, by itself, account for the differential impact on mood. When patients were grouped according to their relative pleasantness ratings for each odor, a consistent pattern emerged. The group with higher odor pleasantness ratings exhibited mood changes in a positive direction, and the group with lower odor pleasantness ratings showed negative mood changes (see Figures 2 and 3). This suggests that the perceived pleasantness of an odor can modulate its effect on mood.

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Figure 2. Mean change in self-rated mood after one-minute exposure to lemon odor in depressed SAD patients (n=23) categorized by hedonic rating. A median split on the pleasantness rating was used to categorize subjects as relative high raters (those who rated the odor as more pleasant) or relative low raters (those who rated the odor as less pleasant). Mood change scores of high raters and low raters were then compared.

Figure 3. Mean change in self–rated mood after one minute of exposure to fir odor in depressed SAD patients (n=23) categorized by hedonic rating. A median split on the pleasantness rating was used to categorize subjects as relative high raters (those who rated the odor as more pleasant) or relative low raters (those who rated the odor as less pleasant). Mood change scores of high raters and low raters were then compared.

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However, when comparing only patients who rated the odor pleasant in both absolute and relative terms, lemon produced a much larger positive mood change than did fir. Thus, odor pleasantness by itself could not account entirely for the present results. This is in agreement with other investigators who have found that mood change is independent of an observer’s perception of odor qualities [11]. Moreover, chemical signals can alter mood without being consciously detected and perceived as odors [18]. The overlap of cortical areas mediating olfactory and emotional functions could potentially underlie the effect of olfactory stimulation on mood [1]. Exposure to a relatively unpleasant odor activates both amygdala and orbito-frontal cortex whereas exposure to a relatively more pleasant odor does not activate the amygdala but activates the orbito-frontal cortex [19], a region also involved in the modulation of affective and behavioral manifestations of depression [20]. As a substantial percentage of the amygdala neurons in rodents respond to olfactory stimulation by being tonically inhibited [21], another possible mechanism may be deactivation of the amygdala, a brain region that has an increased activity in depression and may contribute to mediation of depressive affect and behavior [20, 22]. Future avenues of research may explore the augmentation potential of olfactory stimulation, as it has been reported that improvement with conventional light treatment in depressed SAD patients is not as complete as the spontaneous remission occurring in summertime [23]. Our study was limited to a single one-minute odor exposure. Future studies, with longer exposure periods and longer post-exposure assessment intervals, would be useful in determining how large a mood effect is possible and how long it might be sustained. In designing research protocols in affective disorders, it might be useful to consider that exposure to certain olfactory stimuli, even for a very short time, may significantly, even if minimally, alter self report of mood. Considering that pleasantness of the stimuli appears to be related to mood-altering effects of odors, intermittent brief exposure to odorants may be more potent in altering mood, mood perception, and appraisal than longer exposures, as longer exposure to odorants results in habituation and desensitization which further impede accurate appraisal of the hedonic qualities of odorants. Finally, our results support possible mood influences of chemosensory macro- and microenvironments.

Acknowledgements We thank Mulon Luo, Ludy Yi, and Zac Buchman for their contribution to data collection and management. We are grateful to Drs. Erick Turner and Jeffrey Matthews for patient follow-up, and Dr. Ronald Barnett, Frances Myers, RN, MSN, Holly Lowe, MSW, and Kathleen Dietrich, RN for screening and rating subjects. We thank Drs. Ling Han and Lulu Jimma, and Charles No, for olfactory testing, and Sarah Zimmerman for her contribution to the final form of the manuscript. Supported initially by NIHM intramural (PI Rosenthal) and afterwards by the DC Department of Mental Health (Drs. Postolache, Williams, and Stiller) and the Mood and Anxiety Program of the University of Maryland (Dr. Postolache).

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Schiffman SS, Suggs MS, Sattely-Miller EA. Effect of pleasant odors on mood of males at midlife: comparison of African-American and European-American men. Brain Res Bull 1995;36:31-7. Schiffman SS, Sattely-Miller EA, Suggs MS, Graham BG. The effect of pleasant odors and hormone status on mood of women at midlife. Brain Res Bull 1995; 36:19-29. Komori T, Fujiwara R, Tanida M, Nomura J. Potential antidepressant effects of lemon odor in rats. Eur Neuropsycho-pharmacol 1995;5:477-80. Baron RA. The sweet smell of…helping: Effects of pleasant ambient fragrance on prosocial behavior in shopping malls. Personality and Social Psychology Bulletin 1997; 23:498-503. Postolache TT, Wehr TA, Doty RL, Sher L, Turner EH, Bartko JJ, Rosenthal NE. Patients with seasonal affective disorder have lower odor detection threshold than control subjects. Arch Gen Psychiatry 2002; 59(12): 1119-22. Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK, Davenport Y, Mueller PS., Newsome DA, Wehr TA. Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984; 41: 72-80. American Psychiatric Association. DSM-IV: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: Am Psychiatr Assoc, 1994. Williams JB, Links MJ, Rosenthal NE, Terman ME. Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD). New York: New York Psychiatr Inst, 1988. Ayabe-Kanamura S, Saito S, Distel H, Martinez-Gomez M, Hudson R. Differences and similarities in the perception of everyday odors: A Japanese-German cross-cultural study. Ann NY Acad Sci 1998; 855:694-700. Aitken RC. Measurement of feelings using visual analogue scales. Proc R Soc Med 1969;62:989-93. Chen D, Haviland-Jones J. Rapid mood change and human odors. Physiol Behav 1999; 68:241-50. Lehrner J, Eckersberger C, Walla P, Potsch G, Deecke L. Ambient odor of orange in a dental office reduces anxiety and improves mood in female patients. Physiol Beh 2000;71:83-6. Komori T, Fujiwara R, Tanida M, Nomura J, Yokoyama M. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodula-tion 1995;2:174-80. Ballard CG, O'Brien JT, Reichelt K, Perry EK. Aromatherapy as a safe and effective treatment for the management of agitation in severe dementia: the results of a doubleblind, placebo- controlled trial with Melissa. J Clin Psychiatry 2002; 63:553-8. Nawab SS, Miller CS, Dale JK, Greenberg BD, Fried TC, Chrousos GP, Strause SE, Rosenthal NE. Self reported sensitivity to chemical exposure in five clinical populations and healthy controls. Psychiatry Res 2000; 95:67-74. Redd WH, Manne SL, Peters B, Jacobsen PB, Schmidt H. Fragrance administration to reduce anxiety during MR imaging. J Magn Reson Imaging 1994;4:623-6.

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[17] Ehrlichman H, Kuhl SB, Zhu J, Warrenburg S. Startle reflex modulation by pleasant and unpleasant odors in a between- subjects design. Psychophysio-logy 1997;34:726-9. [18] Jacob S, McClintock M. Psychological state and mood effects of steroidal chemosignals in women and men. Horm Behav 2000; 37:57-78. [19] Zald DH, Pardo JV. Emotion, olfaction, and human amygdala: amygdala activation during aversive olfactory stimulation. Proc Natl Acad Sci USA 1997; 94:4119-24. [20] Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional anatomical study of unipolar depression. J Neurosci 1992;12: 3628-41. [21] Jesberger JA, Richardson JS. Brain output dysregulation induced by olfactory bulbectomy: an approximation in the rat of major depressive disorder in humans. Int J Neurosci 1988;38:241-65. [22] Drevets WC. Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res 2000;126, 413-31. [23] Postolache TT, Hardin TA, Myers FS, Turner EH, Yi LY, Barnett RL, Matthews JR, Rosenthal NE. Greater improvement in summer than with light treatment in winter in patients with seasonal affective disorder. Am J Psychiatry 1998;155:1614-6.

In: Child Health and Human Development Yearbook - 2008 ISBN: 978-1-60692-979-7 c 2009 Nova Science Publishers, Inc. Editor: Joav Merrick

Chapter XVI

M OOD O SCILLATIONS AND C OUPLING B ETWEEN M OOD AND W EATHER IN PATIENTS WITH R APID C YCLING B IPOLAR D ISORDER

1

Steven M. Boker1, Ellen Leibenluft2, Pascal R. Deboeck3, Gagan Virk 4,5 and Teodor T. Postolache5

Department of Psychology, The University of Virginia, Charlottesville, Virginia, USA Chief, Section on Bipolar Spectrum Disorders, Emotion and Development Branch, Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, MD 3 Department of Psychology, The University of Notre Dame, Notre Dame, Indiana, USA 4 St. Elizabeths Hospital, Residency Training Program, Washington DC Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD 2

5

Abstract Rapid Cycling Bipolar Disorder (RCBD) outpatients completed twice–daily mood self–ratings for 3 consecutive months. These ratings were matched with local measurements of atmospheric pressure, cloud cover, and temperature. Several alternative second order differential equation models were fit to the data in which mood oscillations in RCBD were allowed to be linearly coupled with daily weather patterns. The modeling results were consistent with an account of mood regulation that included intrinsic homeostatic regulation as well as coupling between weather and mood. Models were tested first in a nomothetic method where models were fit over all individuals and fit statistics of each model compared to one another. Since substantial individual differences in intrinsic dynamics were observed, the models were next fit using an ideographic method where each individual’s data were fit separately and best–fitting models identified. The best–fitting within–individual model for the largest number of individuals was also the best–fitting nomothetic model: temperature and the first derivative of temperature coupled to mood and no effect of barometric pressure or cloud cover. But this model was not the best–fitting model for all individuals, suggesting that there may be substantial individual differences in the dynamic association between weather and mood in RCBD patients. Heterogeneity in the parameters of the differential equation model of homeostatic equilibrium as well as the coupling of mood to an inherently unpredictable (i.e., nonstationary) process such as weather provide an alternative account for reported broadband frequency spectra of daily mood in RCBD. 1 E-mail address: [email protected]. Correspondence: Steven M. Boker PhD, Associate Professor, Department of Psychology, The University of Virginia, PO Box 400400, Charlottesville, VA 22904, USA

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Keywords: Rapid Cycling Bipolar Disorder, Dynamical Systems, Differential Equations, Linear Oscillator, Mood Regulation

Introduction Since admissions for mania may be related to weather [1, 2] and exposure to light may have mood–altering effects in bipolar disorder patients [3], the present study examines the relationship between weather and mood in patients with rapid cycling bipolar disorder (RCBD). Patients with RCBD, who by definition, experience four or more major affective episodes per year [4], represent an important population for studying a potential relationship between mood and weather because significant mood changes occur over a relatively short interval of time. From a theoretical standpoint, the evaluation of a possible relationship between weather and mood would contribute to our knowledge of mood regulation and dysregulation. Clinically, the severity of RCBD and its challenging management warrant the effort to define the environmental factors that might contribute to the frequent shifts observed in the mood of these patients. This would allow the estimation of short term prognosis, the anticipation of situations of increased vulnerability, and the design of secondary and tertiary prophylactic measures [5]. The present study examines the relationship between daily self–reported mood ratings from a sample of RCBD patients and three weather variables: temperature, sky cover, and atmospheric pressure. A relationship between affective states and temperature has been suggested in multiple studies, although the relationship has not been replicated consistently [6, 5]. Sky cover was chosen because of the antidepressant effect of light and its potential for stabilizing or destabilizing RCBD patients depending on the timing of the exposure [7]. Evidence that atmospheric pressure is involved in mood regulation is less direct, but there are indications that atmospheric pressure affects neurotransmitters implicated in mood regulation. Temperature Neurotransmitters involved in mood regulation are also involved in thermoregulation. It has been shown that injection of either dopamine or 5–HT in a small dose causes a fall in core in rats at about 17 degrees Celsius [8]. During cold exposure, the levels of NE increase many–fold [9]; NE is released from peripheral nerve endings and exerts thermoregulatory response through alpha adrenergic receptors on smooth muscles and beta adrenergic receptors on skeletal muscles. Malberg et al. [10] showed a different core temperature and 5–HT neurotoxicity profiles after administration of fenfluramine at different ambient temperatures. They demonstrated that FEN treated rats at hypo– or hyperthermic temperatures showed a large depletion in 5–HT and 5HIAA, the metabolite of serotonin. Ghosh et al. [11] showed higher environmental temperature-induced increases in body temperature involving serotonin in the GABA–mediated interaction of the opioidergic system. Blanc et al. [12] showed variation of dopamine and noradrenaline levels in response to stress. According to them, there was an increase in NE or DA in response to the cold wind stress and these two affect the level of other amine levels. O’Shea et al. [13] studied the effect of MDMA on dopamine and serotonin levels at various ambient temperatures in rats. They noticed a difference in the response to the same dose of MDMA at different temperatures. It was seen that MDMA produced a greater increase in dopamine levels at higher temperatures than at lower temperatures. Also, MDMA produced a greater thermogenic response at higher ambient temperatures as compared to lower ambient temperatures. Finally, there is some recent neuroimaging evidence of the effect of temperature on affect. Sung

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et al. [14], using brain fMRI reported that warm stimulation results in increased activation of regions related to affective/emotional awareness and processing. The study concluded that appropriate thermal stimulation induces mood states and activates emotion/affect related regions of the brain. Sky Cover One reason to suspect sky cover as a potential predictor of mood regulation is the evidence from seasonality. Changes in photoperiod are followed by changes in temperature, sunlight, humidity, etc. Winter depression and photoperiodism [15] are phenomena of which many people are aware. However, it is less widely known that the majority of incidents of depression are during spring, and successful suicides are more frequent in spring than in other seasons. In fact, one of the most highly replicated findings in psychiatric epidemiologic research is the seasonal spring peak in suicide [16], an ultimate and tragic result of mental illness. A peak in spring was reported for depression exacerbation, admissions for depression, and ECT use [17, 18, 19, 20, 21, 22]. Admissions for bipolar depression also peak in April [23, 24]. Photoperiod, changes in photoperiod, and light intensity have been proposed as possible driving forces for peaks of suicide and depression [25]. However, upon careful scrutiny, the peak times of suicide occurrence (April and May, reviewed by Altamura et al. [26]) do not match the peak of photoperiod (centered on the Summer Solstice in late June) or the time when photoperiodic changes are at their greatest (centered on the Spring equinox in March) [27, 28, 29, 30, 31]. Atmospheric Pressure There are several indirect reasons why atmospheric pressure may play a role in mood regulation. Several studies report that atmospheric pressure may influence serotonin metabolism, a major neurotransmitter involved in mood regulation and dysregulation. For instance, atmospheric pressure has been reported to explain a portion of the variance in platelet [3H]Paroxetine binding in normal volunteers [32], and in the ratio between the serotonin precursor L-tryptophan and the sum of the amino acids known to compete for the same cerebral uptake mechanism [5]. Furthermore, a negative correlation was shown between air pressure and CSF 5-HIAA [33], but this finding was not replicated at a second location with different climatic conditions [34].

Dynamical Systems and Mood Gottschalk et al. [35] studied daily mood ratings from a group of 7 bipolar patients and reported that mood in patients with bipolar disorder was not cyclic for extended periods of time based on evidence from power spectrum analysis. While Gottschalk et al. [35] concluded that this was evidence of deterministic chaos, Krystal and Greenside [36] noted that many processes other than deterministic chaos can lead to the broadband spectra and low correlation dimensions reported by Gottschalk and colleagues. In fact, many nonstationary processes including linear processes coupled to exogenous nonstationary processes can masquerade as low dimensional chaos, as measured by methods such as spectral analysis and correlation dimension [37, 38]. If mood and weather were coupled, and given the demonstrated nonstationarity of weather [39, 38], one plausible explanation for the reported broadband spectra of daily mood ratings would be a linear homeostatic emotion regulation process with coupling to exogenous influences such as weather. We compare the fit of several models of this form to daily mood rating and weather data. Modern state space techniques [40, 41, 42, 43] can estimate the parameters of models that

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are linear in their differential form, but exhibit phase resetting either due to intrinsic dynamics or coupling to exogenous influences. The method we chose uses differential equation models estimated through state space techniques to represent continuous patterns of change within systems (intrinsic dynamics) and between systems (coupling) [44, 45, 46]. Differential equation models allow the expression of effects within the system in terms of the instantaneous rates of change of variables as well as in terms of the values of the variables themselves [47, 48]. Suppose mood is a variable that has a homeostatic equilibrium value, a value around which daily mood fluctuates. We could then consider daily mood as a displacement from this equilibrium value. A differential equation model for mood might include a prediction about how the displacement of mood from its equilibrium is related to the derivative of the mood with respect to time, that is how rapidly the mood is changing at that same moment. A model for cyclic fluctuations in mood would include a relationship between the displacement of mood and the second derivative of mood with respect time, that is how rapidly mood was accelerating or decelerating in its change. One of the simplest physical systems that exhibits cyclic behavior is a pendulum. A pendulum swings with a particular frequency that is related to the length of the pendulum and will come to rest over an interval of time that is related the friction inherent in the pendulum’s pivot point. If we make a few simplifying assumptions that the friction is constant and that there are no other influences on the pendulum’s trajectory, a linear differential equation can describe the pendulum with friction: the damped linear oscillator [49]. The equation for the damped linear oscillator can be expressed as a linear regression formula where the acceleration of the pendulum is the outcome variable and the position and velocity of the pendulum are the predictor variables. If xt is the displacement of the pendulum from equilibrium,then (1) x¨ = ηxt + ζ ˙x + et , where xt is the value of the displacement from equilibrium at time t, ˙x is the first derivative, and ¨ x is the second derivative with respect to time. This results in two main parameters: η is related to the square of the frequency of the oscillation of the system and ζ is related to the amount of damping (friction) in the system. These two have appealing substantive interpretations. The frequency parameter from the linear oscillator equation represents the fundamental frequency with which a particular RCBD patient’s mood would tend to cycle if she or he were isolated from external influences. The damping or friction parameter from the equation represents how rapidly a patient would return to a euthymic state if they were influenced by a single event and then isolated from external influences. One way to think of the dynamic relationships between variables in dynamical systems terms is as coupling between the variables. For instance, imagine a pendulum. Attached to the mass of this pendulum is a spring that can be used to push or pull the mass from its prescribed trajectory. The push or pull of the spring can affect the pendulum in many different ways. The spring can modulate either the frequency or damping of the pendulum, or both. Consequently, the trajectory of the pendulum could become quite intricate overtime, particularly if the push or pull on the spring changes with time. Differential equation models can formalize and test these ideas by comparing how well alternative models account for data from the pendulum (mood) and the spring (weather). Due to the irregularity of weather patterns [39, 50, 51], the effects of weather on mood over extended periods of time may appear to be highly complex. This, however, does not preclude the use of local linear approximations of the derivatives of weather variables with respect to time to examine how they may act as an external influence on mood. These models need not account for patterns of weather, but in order to be useful, they should account for the degree to which changes in weather variables can account for changes in mood. In addition to the effect of the exogenous weather variables, we wish to understand how much of the variability in mood might be accounted

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for by an intrinsic dynamic — to what extent changes in mood can be accounted for by an intrinsic self–regulatory process. Even if all external influences on mood were perfectly understood, the long term trajectory of daily mood may not be able to be predicted, that is to say, mood might exhibit sensitive dependence on initial conditions. However, even if the time–varying trajectory of daily mood turns out to be some deterministic nonlinear or stochastic nonstationary process, it is still possible to gain an understanding of the dynamics of daily mood over short intervals of a few days by using local linear approximations of the derivatives. Furthermore, we are interested in how weather variables may be related to daily mood dynamics. We wonder whether coupling between weather and mood involves a direct effect of the displacement of weather from its mean on the displacement of mood from its mean. Or perhaps the displacement of a weather variable from its mean value or the rate of change in the weather variable modulates the frequency or damping parameters of mood. In the analyses below, we test hypotheses about the relationship between weather and the dynamics of fluctuations of daily mood in a sample of RCBD patients.

Methods A clinical sample of 15 RCBD patients rated their mood every morning and evening for 3 months. In addition, a variety of weather variables were recorded each day for the same period. Four variables were chosen to study the coupling between mood and weather: the twice–daily mood rating, the barometric pressure, the percentage of sky cover, and the mean temperature for each day on which a measurement was obtained. Three models were fit to these data in order to explore the potential for understanding the cycling of mood in RCBD as a dynamical system and to test the degree of coupling between such a system and the three indicators for weather. Three additional models tested the coupling of each of the weather variables one at a time with the mood of RCBD patients. Subjects Fifteen patients diagnosed with rapid cycling bipolar disorder (7 Bipolar I, 8 Bipolar II) participated in the experiment. The patients had all been on stable medication (see Table 1) for at least three consecutive months. Eleven patients were female and 4 were male and their mean age was 42.2. Fourteen patients were Caucasian while the remaining patient was Asian. The patients all lived in the Washington, DC area: 2 in the District of Columbia, 7 in Northern Virginia and 6 in Maryland. All participants were outpatients followed at the outpatient research clinic for patients with rapid cycling bipolar disorder at the National Institute of Mental Health (NIMH). All patients met the criteria for bipolar illness as established by a Structural Clinical Interview for DSM-III-R [52, 53]. In addition, patients reported having had at least four major affective episodes within the past year, including at least one each among major depression and hypomania (or mania). We excluded patients with substance abuse or dependence within the past year, and those that met criteria for borderline or antisocial personality disorder by the Structural Clinical Interview for DSM–III–R Personality Disorders (SCID–II) [54]. Patients signed informed consent.

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Table 1. Age, sex, diagnoses, and medication for the 15 patients that participated in the study. Diagnoses Comorbid Axis I

Patient

Age

Sex

Bipolar

Medication

1

33

F

I

2

32

F

II

Simple Phobia Agoraphobia

Carbamazepine Fluoxetine

3

43

F

II

Simple Phobia

Lithium

Valproate Bupropion

Phenelzine 4

54

F

I

Panic Disorder

Lithium, Calproate Sertraline

5

43

F

II

Social Phobia, OCD Panic Disorder

Carbamazepine, Clonazepam Levothyroxine, Phenelzine

6

47

M

I

Valproate, Nortriptyline Tranylcypromine

7

39

M

I

Lithium, Bupropion Carbamazepine

8

50

F

I

Social Phobia, OCD Panic Disorder

Valproate Tranylcypromine

9

40

F

II

Social Phobia

Lithium, Fluoxetine Levothyroxine

10

47

F

I

Simple Phobia

Lithium, Venlafaxine Clonazepam

11

38

F

I

Lithium, Doxepin Propranolol

12

45

M

II

Lithium

13

48

M

I

Lithium, Bupropion Levothyroxine

14

40

F

II

Lithium Fluoxetine

15

37

F

I

Social Phobia

Levothyroxine Sertraline

RCBD Mood Oscillations with Coupling to Weather

235

Procedure Patients completed daily mood self–ratings twice a day, once shortly after awakening and once just before bedtime. Patients rated their mood on a 100mm line with 0 representing “most depressed I’ve ever felt” and 100 representing “most manic I’ve ever felt”. Patients were able to view their previous responses. The region less than 35 was labeled “depressed”, from 35 to 65 was labeled “euthymic” and greater than 65 was labeled “hypomanic/manic”. In addition patients completed a sleep log with a 15 minutes resolution every day. During the clinic visits, the patients were rated using the Structured Interview Guide for the Hamilton Rating Scale for Depression: Seasonal Affective Disorder Version (SIGH–SAD) [55] to measure the typical and atypical depressive symptoms while the Hypomania Interview Guide (HIGH–SAD) [56] was used to measure hypomanic/manic symptoms. Data were gathered during the spring, summer and fall of 1993 and 1994. Each patient was studied for three consecutive months beginning as early as April and as late as September. Weather variables for the Washington DC metropolitan area were obtained from the National Climatic Data Center as measured at Dulles Airport. Barometric pressure was collected as a daily average based on eight observations per day at 3 hour intervals. Barometric pressure was measured in units of .001 inches of Mercury and was rescaled to units of .1 inches of Mercury for purposes of the analysis. Sky cover was measured as the daily average cloud cover from midnight to midnight, with data values varying from 0.0 representing clear for the entire 24 hour period to 100.0 representing completely overcast. Daily mean temperature was collected as a daily average based on eight observations per day at 3 hour intervals, rounded to the nearest degree Fahrenheit. Models The process by which differential equation models were fit to these data involved four main steps. First optimal analysis intervals, ( τ), were estimated individually for each subject. Second, local linear approximations to the first and second derivatives of each variable were estimated for each available triplet of occasions of measurement separated by the chosen analysis interval. Third, covariances between all the variables and their derivatives were calculated. Finally, seven competing structural equation models were fit to the covariance matrices and the results compared. Since there may be important categorical differences between the patients in this population, we chose to estimate the derivatives in two different ways. First, we use a nomothetic approach in which the grand mean of all of the individual analysis intervals is calculated and used to estimate derivatives for all patients and occasions. The covariances between these derivatives are then used to fit the seven candidate models to the population. Second, we used an ideographic approach in which each patient’s estimated optimal analysis interval was used to fit all seven models to that patient’s repeated observation data. In this approach we do not aggregate over patients, but rather compare which models are best–fitting within patient. We expand on each of these modeling steps below, starting with an explanation of local linear approximation (LLA) of derivatives. We then present the damped linear oscillator model and discuss the estimation of the analysis interval. Finally we discuss alternative models for coupling daily mood with weather variables. Local Linear Approximation of Derivatives In order to fit a differential equation model to data, the data must be in the form of approxima-

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tions to the instantaneous first and second derivatives of the variable at each occasion of measurement. Local linear approximation can be used to estimate parameters of continuous time differential equations models [45]. Suppose the variable M is measured on three successive occasions separated by an interval of time ∆t and resulting in the measurements M1 , M2 and M3. A local linear approximation for the first derivative of M at the second occasion of measurement is given by the average of the two slopes between M1 and M2 and between M2 and M3 , M˙ 1+τ ≈

M1+2τ − M1 , 2τ∆t

(2)

where in this case τ = 1 because M1 , M2 and M3 are successive occasions of measurement and ∆t is the interval of time between measurements. When many occasions of equal interval measurement exist, alternating measurements in a sequence (for instance M1 , M3 and M5) could also be used, in which case τ = 2 would be used in the Equation 2. Similarly, the local linear approximation for the second derivative of M at the second occasion of measurement can be calculated from the same triplet of scores M1, M2 and M3 as the change in the slopes with respect to time, M¨ 1+τ ≈

M1+2τ − 2M1+τ + M1 . τ2 ∆t 2

(3)

For this analysis, we assumed that the within–subject mean value of the mood variable estimated the equilibrium value for each subject. We thus subtracted the within–subject mean values for each variable so as to express the mood variable as an estimated displacement from equilibrium. We did not standardize the mood or weather variables. Damped Linear Oscillator Model of Daily Mood A linear second order differential equation for a damped linear oscillator model of mood can be expressed as, (4) M¨ t = ζM˙ t + ηMt + et , where Mt represents the value of mood self–report mood at time t, η is related to the frequency of oscillation, ζ estimates the damping and et is the residual in estimating M¨ t . A plot of the trajectory resulting from this equation, given example parameter values for η and ζ and initial conditions at t = 0, is shown in Figure 1. Although Equation 4 is a linear regression equation, the interpretation of its parameters is quite different. A normal linear regression model would estimate some expected growth line or expected growth curve. This differential equation regression model estimates an expected oscillation and damping given some set of initial conditions. In Figure 1 there are no exogenous influences on the variable M except at time t = 0. Of course, initial conditions may be change over time due to exogenous influences on mood. Thus, an individual’s observed trajectory is some mixture of these exogenous influences and the intrinsic self–regulation in response to the exogenous input. When the model in Equation 4 is fit to repeated observations from an individual, it estimates how the individual self–regulates in response to exogenous input. Thus, this model does not describe a particular trajectory for a particular person, instead it describes a family of trajectories that would be expected in response to a distribution of possible exogenous influences. In order to fit this model, the first and second derivatives for mood M were calculated using linear approximation as described above. Estimation bias in the damped linear oscillator model

RCBD Mood Oscillations with Coupling to Weather

237

0.1 0.0 -0.1 -0.2

DeviationDisplacement of A from its mean

0.2

Damped Spring X zeta=.25 eta=2 x(0)=.1 dx(0)/dt=.2

0

50

100

150

200

Occas ion Samples of Meas urement

Figure 1. A time series generated by a damped linear oscillator differential equation model of mood as in Equation 4.

parameters has been shown to depend on the selection of the parameter τ, the interval of time between observations used to estimate the derivatives [45]. Therefore, individual values of τ were estimated for the mood data of each individual using the fixed–window surrogate R2 technique [57, 58]. This technique uses surrogate data analysis [59] to automate a plot–based method developed by Boker and Nesselroade [45] for low bias within–individual parameter estimation of damped linear oscillator models. Fixed–window analysis was used to estimate τ due to the possibility of relatively long frequencies relative to the time over which samples were collected; plots of results from the surrogate technique and the plots described by Boker and Nesselroade [45] were also examined for patterns uncharacteristic of damped linear oscillators. Values for τ were estimated for the morning and evening mood data separately and compared as a within–individual check of the data. Analysis of data using the fixed–window surrogate technique begins by calculating the explained variance from fitting equation 4 to the observed time series of an individual, using LLA to estimate the first and second derivatives with a range of τ values. Boker and Nesselroade [45] have shown that plots of the explained variance versus τ tend to an approach asymptote as the ideal value for τ is approached. The black, wide line in Figure 2 shows a typical plot of the explained variance versus τ for an oscillating system. A resampling technique called surrogate data analysis is then used to establish at what values of τ the observed explained variance is greater than would be expected by chance [59]. The original time series is randomly shuffled to create multiple surrogate data sets. Random shuffling of the original time series produces time series with the same distributional characteristics as the original data (e.g. mean, variance), but all meaningful relationships related to time are removed. Equation 4 is then fit to each surrogate data set in the same manner as the original data set. The results from the surrogate data analysis, depicted as thin, gray lines in Figure 2, can be used to estimate the

Steven M. Boker, Ellen Leibenluft, Pascal R. Deboeck et al.

0.4 0.0

0.2

R^2

0.6

0.8

1.0

238

2

4

6

8

10

12

14

tau Figure 2. Plot of variance explained (R2 ) versus τ. The bold, black line represents the results from an original time series. Grey lines represent results from the analysis of surrogate data sets.

explained variance that would be expected by chance if the observed time series had no time–based relationships. At each value of τ the proportion of surrogate data sets that produced an explained variance smaller than the original data set can be calculated (range: 0 to 1). The proportion versus τ data is used to select the first value of τ that explains an unusual amount of variance. This is done by generating one–half square–waves (i.e. pulses) ranging from 0 to 1, with the first half of the pulse equal to 0. Pulses of varying lengths are then fit to the data, with the mean squared difference between each pulse and the proportion data calculated for each pulse length. The minimum mean squared difference is selected as the best indicator of the transition from low to high proportions, and is therefore related to the asymptote of the R2 versus τ graph. The ideal values for τ, which have been shown to be nearly unbiased in the range of 15 to 95 observations per cycle, occurs at the first value equal to 1 of the pulse with the minimum mean squared difference. After estimating an optimal time delay, τ for each subject, each triplet of values for which there were no missing data was used. Thus each subject, with twice daily measurement, might contribute as many as 2(N − 2τ) observations, or fewer if some occasions were missing. The analysis used all possible within–subject triplets for which three values existed. A path diagram representing the linear oscillator model from Equation 4 (Model A) is depicted in Figure 3. This diagram follows the conventions of RAM diagrams [60, 61] in which squares represent measured variables, circles represent unmeasured variables, single headed arrows represent regression coefficients and double headed arrows represent variance and covariance components. The box labeled M represents the mood variable, the box labeled dM represents the first derivative of mood and the box labeled d2M represents the second derivative of the mood variable. The variances of M and dM are represented by the double headed arrows labeled VM and VdM , the regression coefficients ζ and η are represented by the corresponding single headed arrows, and the residual variance for d2M is represented by Ve . The weather variables in Model A (shown in Figure 3) are represented by the six boxes labeled

RCBD Mood Oscillations with Coupling to Weather

239

Model A

B

dB

M Vm

S

!

dS

d2M

e

T

∀

dT

dM VdM

Ve

Figure 3. Path diagram of Model A. This model hypothesizes intrinsic oscillation of mood conforming to a damped linear oscillator, but no coupling between weather and mood.

B for barometric pressure, dB for change in barometric pressure, S for percentage of sky cover, dS for change in percentage of sky cover, T for mean temperature and dT for change in mean temperature. Note that in Model A there are no connections between the weather variables and the mood variables, thus Model A tests the hypothesis that the mood oscillator is not predicted by these weather variables. All weather variables were allowed freely covary, since we do not want to explicitly model the relationships between weather variables. This structural model was then fit using the Mx software [62] to provide estimates of the coefficients that are closest to the observed covariances between the three variables of mood in the maximum likelihood sense. By comparing the differences in fit indices for each of these models we can test hypotheses that one model is preferred over another individually within each patients’ data. It should be noted that there are no degrees of freedom in the linear oscillator portion of the model, so there is no potential contribution of misfit from the linear oscillator model of mood. However, there are two methods that can be used to help understand how well the linear oscillator portion of the model is accounting for the observed data. First, the explained variance R2 for the d2M can be calculated as the proportion of original variance of d2M that does not appear as Ve. In addition, a index can be derived by multiplying the estimated η parameter by the squared delay value, (τ∆t)2, used for analysis. With oscillating systems η(τ∆t)2 tends to depart from the value −2, when τ∆t is not 1/4 or 3/4 the period (wavelength) of the oscillator [63]. In the case of the current data, measurements are one day apart, so ∆t = 1. We will estimate the optimum delay value of τ given the data; this estimation procedure is described in a subsequent section. We will refer to the three variables M, dM, and d2M along with the single headed and double headed paths that connect them as the mood oscillator. We use this descriptive term since the algebraic form of these variables and their connections is equivalent to the damped linear oscilla-

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tor from Equation 4. The remaining models test various hypotheses concerning the relationship between weather and mood. Linear Oscillator Model of Mood Coupled to Weather The covariances between the 9 variables (Mood and its first and second derivatives, and Barometric Pressure, Sky Cover and Mean Temperature and their respective first derivatives) are predicted by the six structural equation models represented by the path diagrams in Figure 4. Each model tests a different hypothesis concerning the observed covariances between the weather variables and the mood oscillator. Model B

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Models B, C, and D in Figure 4 test three hypotheses concerning the structure of the covariance between the weather variables and the mood oscillator. Model B tests the hypothesis that the weather variables act directly as part of the mood oscillator by predicting the second derivative of the mood (d2M) directly. Models C and D, respectively, test if there is a direct effect of weather variables on the displacement of mood from equilibrium (M) or the first derivative ( dM) of mood. Note that when the effects of weather on the second derivative are mediated through M or dM in Model C or D, the estimated parameter values for η and ζ will not change relative to those estimated in Model A. On the other hand when Model B is estimated, the estimates for the coefficients η and ζ will partially depend on the values estimated for the regression coefficients connecting the weather variables to d2M. Thus a preference for Model B over Models C and D would suggest that the parameters for the mood oscillator interacted with exogenous influences and might be considered to have state–like characteristics, whereas a preference for Model C over Model B would indicate that

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the estimated parameters for the mood oscillator were more stable, endogenous, trait–like parameters. Models E, F, and G in Figure 4 test the hypothesis that only one weather variable dominates in its effect on the regulation of the mood oscillations. Models E, F, and G are in some sense complementary to Models B, C, and D in that Models E, F, and G test hypotheses about what does the regulation and Models B, C, and D test hypotheses about how the regulation happens. This model construction strategy may be useful in a wide variety of contexts where relevant theory posits coupling between variables. Note that all six of these models have the same number of degrees of freedom, but are not nested. Thus, direct likelihood ratio difference tests are inappropriate, but the AIC fit statistic may be used.

Results Descriptive statistics for the four variables used in the present analyses are displayed in Table 2. Most patients are missing only a few observations, however one patient is missing 36% of the total possible observations (patient 14). Recall that since a full non–missing triplet of data is needed to estimate the derivatives, there will be fewer observations actually included in the analysis. Due to the large proportion of missing observations, patient 14 was dropped from further analyses. Table 2. Descriptive statistics for Mood, Barometric Pressure, Sky Cover and Temperature for all 15 subjects.

Subj. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Observations Total Missing Days AM/PM 92 11/10 92 2/3 92 0/0 92 0/2 92 5/10 92 0/0 92 0/0 92 9/18 91 0/1 92 8/8 92 0/1 92 1/2 91 4/15 92 34/33 92 9/20

Mood Mean(SD) AM PM 47.1(9.7) 46.8(10.5) 44.5(15.0) 48.0(11.3) 46.1(15.5) 45.8(15.7) 45.1(15.3) 45.9(16.5) 43.9(20.1) 57.5(19.7) 48.5(13.1) 45.9(11.4) 41.1(8.1) 48.6(10.9) 43.4(13.0) 40.5(12.4) 60.3(20.4) 53.0(24.0) 25.9(13.0) 32.9(9.8) 50.4(17.7) 52.5(17.2) 37.6(5.2) 38.1(5.6) 38.6(21.5) 53.8(27.7) 17.6(18.4) 16.7(18.3) 44.4(11.9) 42.2(9.0)

Barometer (0.1 in.) Mean(SD) 296.9(1.0) 296.5(1.3) 296.9(1.0) 296.8(1.2) 296.8(1.0) 296.8(1.0) 296.9(1.0) 296.9(1.0) 297.6(1.9) 296.8(1.2) 297.2(1.5) 296.5(1.3) 296.6(1.6) 296.9(1.0) 296.8(1.2)

Sky Cover (%) Mean(SD) 57(28) 61(27) 57(28) 64(27) 54(27) 54(27) 57(28) 57(28) 63(31) 64(27) 60(29) 61(27) 58(28) 57(28) 64(27)

Temp. (o F) Mean(SD) 75.8(8.0) 72.0(10.4) 75.7(8.0) 76.7(5.5) 76.8(6.2) 76.8(6.2) 75.7(8.0) 75.7(8.0) 56.3(12.6) 76.7(5.5) 67.2(12.0) 72.0(10.4) 65.6(10.6) 75.8(8.0) 76.7(5.5)

Data from three example patients are plotted in Figure 5. These examples were chosen to illustrate the individual differences shown in patterns in the mood trajectory. For instance, patient 6 shows strong and regular cycles in his/her mood trajectory, whereas the mood trajectory of patient 13 only hints at the possibility of a long frequency cycle, and any underlying cyclicity in patient 1 is not immediately apparent to the eye. It may also be useful to note that the Barometric Pressure and

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Temperature variables appear to have fewer high frequency components than the Sky Cover variable. The Temperature variable however shows clear trends over time, which are not as apparent in the Barometric Pressure and Sky Cover variables. Mood for Subject 6

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Within–Individual Estimation of τ Previous simulations have indicated that the best estimates of the η and ζ parameters in damped linear oscillator models occur when the interval between the three measurements used to approximate the derivatives (τ) is an optimum value [45]. If the interval between the measurements is too small then error variance tends to be compounded in the approximation of the derivatives, whereas if the measurement interval is too long, the variance in the second derivative approaches zero and thus there is little or no residual variance that can be predicted with external variables. Surrogate data analysis can be used to select values for τ which lead to low bias paramater estimates of the damped linear oscillator model [57, 58]. This surrogate R2 technique examines the variance explained by models using different τ values and selects the value for τ that occurs as the variance explained asymptotes. The asymptote in the explained variance has been identified as an optimal point for the selection of τ for oscillating systems with substantial error variance [45]. For the present analysis, the fixed–window surrogate R2 technique was fit to the morning and evening data separately, for each individual. The estimated τ values are shown in Table 3. Table 3. Estimated τ values for morning and evening data. Subj. τ AM τ PM

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Of the 14 patients, only three showed large differences between their morning and evening data: patients 5, 7, and 9. Thus, the estimated self–regulating dynamic for 11 of the 14 patients exhibited similar frequency properties in two interleaved samples. This suggests that it is unlikely that these estimates are due to random fluctuations. Furthermore, lower values of τ tend to be associated with time series with either a very weak signal and a large proportion of error variance, or even no signal at all. Based on a large scale simulation, Deboeck and Boker [58] suggest that when the estimated optimal analysis interval τ > 4, data are unlikely to primarily consist of error variance. The grand mean of all patients’ was µ(τ) = 9.18, providing converging evidence that variability in daily mood is unlikely to be attributable to random fluctuations. For the nomothetic analysis below, derivatives were estimated using the integer value of the grand mean µ(τ) = 9. For the ideographic analyses, derivatives for each participant were estimated using the within–individual mean of the morning and evening τ values listed in Table 3. For both nomothetic and ideographic analyses, time between successive observations ( ∆t) was specified as 1/7, so that the estimated estimated parameters are scaled in terms of weeks. This scaling ensured that the variance of M and its derivatives spanned only few orders of magnitude. Variances spanning more than three orders of magnitude can be problematic for SEM estimation routines due to rounding precision. The weather variables are not being explicitly modeled as outcomes and therefore did not require equivalent attention for the selection of τ. Derivatives for all three weather variables were calculated using a τ equivalent to one day. Time scaling of the weather derivatives, ∆t was specified as 1/7 in order to maintain the time scaling used in the mood derivatives.

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Nomothetic Modeling Results We first fit the seven damped oscillator models to the covariance matrix calculated from data from all 14 patients. Since the data were largely complete for all included subjects, this approach allows us to provide estimates of mean values for the parameters of each model and to evaluate differences between models across all subjects. The results of fitting these models to the aggregated covariance matrix are presented in Table 4. The mean frequency parameter is essentially invariant p across models, η = −1.09, resulting in a mean period of λ = 2π −1/η + .25ζ2 = 6.01 weeks. The mean damping parameter, 0.02 ≤ ζ ≤ 0.05, was small and positive, indicating that exogenous influences tended to be amplified into larger fluctuations as time elapsed. Model A (AIC=41.74), in which weather is presumed to have no effect on mood fluctuations, and Model G (AIC=41.84), in which barometric pressure alone is couple to mood, are the two worst fitting models. The two best–fitting models are Model B (AIC=16.20), in which the weather variables predict the second derivative of mood, and Model F (AIC=6.02), in which temperature alone is used to predict all of the mood variables. Table 4. Estimated parameters from fitting the seven damped linear oscillator models for mood. η ζ B→M B → dM B → d2M dB → M dB → dM dB → d2M T →M T → dM T → d2M dT → M dT → dM dT → d2M S→M S → dM S → d2M dS → M dS → dM dS → d2M N R2 -2LL AIC DOF

Model A -1.092 0.039

Model B -1.093 0.027

Model C -1.092 0.039 0.608

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-0.026 0.739 -0.188 -0.645

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0.080 0.170 0.031 -0.071 0.022 0.410 0.068 -0.309 0.067 0.193 1749 0.617 77.74 41.74 18

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1749 0.623 30.02 6.02 12

0.292 0.102 -0.271 0.092 0.180 -0.215 1749 0.619 58.63 34.63 12

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Discussion of Nomothetic Results Given that the model hypothesizing no effect of weather on mood fluctuations fit substantially worse than all but one of the other models, it is concluded that it is unlikely for there to be no coupling between weather and mood fluctuations in these RCBD patients. However, the small number of subjects limits the generalizability of this conclusion to the population of all individuals diagnosed with RCBD. The two best–fitting models, Model B and F come from two complementary categories of models. Model B tests a hypothesis about which type of regulation best accounts for the data. Model B allows regulation of the second derivative, and thus it is concluded that the regulation of mood coupled to weather is likely to be state–like in that there are likely to be time–dependent frequency and damping of an individual’s observed trajectory over time. Model F excludes the effect of all weather variables but temperature. Thus, it is concluded that in relation to the other weather variables in these data, temperature better accounts for the observed mood fluctuations in these RCBD patients. Each of the seven models accounted for approximately 62% of the variance in the second derivative of daily mood. While this R2 might at first glance seem high, in previous simulations [45] when the true model was known to be a damped linear oscillator with invariant parameters, R2 values exceeded 0.75 even when substantial noise (i.e., measurement error) was present. Thus, we conclude that either (a) there are substantial individual differences in the parameters of the model, (b) there are within–person time varying parameters to the model, (c) there are other exogenous influences to which mood is coupling, or (d) there exists a better dynamical systems model to account for self regulation within these data. There is evidence from the τ estimation results in Table 3 that substantial individual differences exist in the period of oscillation for these patients. Thus, constraining the parameter values to a sample average in a nomothetic analysis may obscure reliable individual differences in the self– regulation of mood. Ideographic Modeling Results We next fit the seven models to each individual in order to estimate individual differences. Covariance matrices for each individual were calculated based on the individual τ values shown in ˙ M) ¨ range from 60 to 168, with the median Table 3. The number of complete data triplets (i.e. M, M, person having 126 triplets. The results from Model A are first considered. Individual values of η(τ∆t)2 range from −2.190 to −1.108, with a median value of −1.534. The departure of these values from −2 for many individuals suggests that underlying signal is behaving as would be expected for a damped linear oscillator [63]. Substantial individual differences in both the frequency ( η) and damping (ζ) parameters for the damped linear oscillator model of mood were observed. Patients’ frequency parameters range from a relatively rapid frequency of η = −7.46 (16.1 days) to slow frequencies of η = −0.26 (85.6 days). The median participant frequency was 34.8 days ( η = −1.59). The individual differences in the damping parameter ζ range from ζ − 0.49 to ζ = +0.42, with a median ζ of −0.04. A negative damping parameter indicates that these individuals’ oscillators are likely to reduce in amplitude over time. All seven models were then fit to each individual’s data. The AIC fit statistics for each of these models, for each individual, are summarized in Table 5. The last column in this table identifies

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Table 5. AIC fit statistics for each individual, for all seven models. The best–fitting model within individual is shown in the final column, and the mean and median result within model are shown in the last two rows. Patient 01 02 03 04 05 06 07 08 09 10 11 12 13 15 Mean Median

Model A AIC -7.320 49.717 6.089 21.603 1100.123 -9.409 -15.669 21.197 30.171 9.568 91.726 78.980 -1.126 1.756 98.386 15.383

Model B AIC -1.389 39.181 -2.994 13.545 29.785 -6.754 -9.406 26.009 27.394 13.337 45.161 71.430 -11.490 11.639 17.532 13.441

Model C AIC -2.323 41.689 9.764 21.140 238.277 -6.269 -9.959 18.525 15.309 -3.953 46.329 83.442 8.066 -8.470 32.255 12.537

Model D AIC -10.972 18.476 4.603 8.032 293.169 -5.986 -11.860 -2.563 17.839 12.371 92.175 17.472 1.057 1.410 31.087 6.317

Model E AIC -1.207 43.820 13.915 3.332 63.344 -14.725 -10.028 14.399 20.237 10.349 87.890 81.301 4.893 4.420 22.996 12.132

Model F AIC -6.419 37.838 13.594 25.962 6.755 -1.146 -9.334 12.003 3.296 -13.782 20.458 5.835 -9.924 -9.203 5.424 4.566

Model G AIC -0.884 37.029 -8.485 20.259 361.488 -4.092 -13.185 7.286 34.249 17.839 84.801 84.392 4.550 9.687 45.352 13.763

Best Model D D G E F E A D F F F F B F – –

the best–fitting model based on AIC, while the last two rows show mean and median AIC values within each model. The pattern of results for the mean AIC values are similar to those shown in the nomothetic results, with Models B and F displaying the best fit. However the median results seem to suggest that Models D and F are the best–fitting models. Examination of results within individual suggest that substantial individual differences exist. The data of six individuals seems to be best fit by model F, the model that seemed to emerge as best from the nomothetic results, where temperature and its first derivative influences the damped linear oscillator model of mood. However model D, where weather variables affect the first derivative of mood, provides the best fit for three individuals. The data from two individuals are best fit by model E, where barometer and its first derivative affect the oscillator model. Data from one of each of the other three individuals are best fit by models A, B, and G. No single model provides the best fit for the majority of individuals in this sample. In addition to examining which model fits best, one can also consider how weather variables may influence the mood oscillator. In models A, C, and D the estimated η and ζ parameters will be the same, but in the remaining four models the parameters of the mood oscillator will be affected by weather. We can compare the estimated values of η and ζ in models A and F, for instance, by calculating the change in parameter values within individual from one model to the other. The change in frequency ranges from −0.75 days to 3.04 days, with a median value of 0.10 days. These differences are relatively small compared to the range of frequency values estimated in Model A, which was 16.1 days to 85.6 days. The change in ζ ranges from −0.120 to 0.148, with a median value of −0.008. For some individuals these changes are of moderate magnitude compared to the range of ζ values estimate in Model A, which was −0.49 to 0.42. Similar results are observed for the change in η and ζ parameters for the other models where the mood oscillator was affected by weather variables.

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Discussion of Ideographic Results This analysis examined the within–subject variability in self–report mood measured at daily intervals over a span of 90 days. A set of models that interpret this intraindividual variability using a state space estimated second order differential equation were fit to these data and measures of goodness–of–fit were compared. Individual results were not well characterized by a single model. While six of the individuals seemed to be best characterized by Model F, where temperature and its first derivative affect the mood oscillator, the remaining eight individuals were best characterized by a variety of models which included all models except model C. These differences could be due to a variety genetic and environmental influences, including possibly the effect of different medications or the existence of certain RCBD sub-types. Ideographic analyses with a larger sample of individuals would be required to address the sources of individual differences in best–fitting models. These results do suggest that averaging over all individuals may result in misleading conclusions for some individuals, as not all subgroups may be well represented; this seems to be the case with RCBD patients. When self–report mood was modeled as a damped linear oscillator, there were marked individual differences in the values for the frequency and damping parameters of the mood oscillator. In addition to different frequencies of oscillation, substantial individual differences in the damping (or friction) parameter of the estimated mood oscillator were observed. Some subjects were estimated to have a relatively large negative value for this parameter and thus show damping in their mood oscillator, which could be interpreted as resiliency or a tendency to return to homeostasis after an exogenous influence. However other individuals were estimated to have positive values for their damping parameter and thus show amplification in their mood oscillator, a tendency to amplify small exogenous effects into large changes in mood — dysregulation to homeostasis. The individuals with positive damping parameters exhibit behavior that would also be consistent with a deterministic chaotic process. Models B, E, F, and G all allowed for the possibility that weather, or certain components of weather, may affect the parameters of the hypothesized mood oscillator. Comparing changes in the frequency and damping parameters of these models to Model A, only small changes in the frequency of oscillation were observed for most individuals, relative to the range of observed frequencies. The damping parameter, however, showed the potential for moderately large changes for some individuals, relative to the range of observed damping estimates. This suggests that if and when weather variables do have an effect on the mood oscillator of RCBD patients, the greater effect is not on how quickly they transition from one affective state to the next but on how the regulation to homeostasis may change over time.

Conclusions Two main conclusions emerge from analyses present in the current study. The first conclusion is that there appears to be substantial heterogeneity in this sample of RCBD patients. There were substantial individual differences in the parameters estimated by the mood oscillator model, differences that may have diagnostic value. One potential source of this heterogeneity could be overlap genes, such as proposed by Potash [64]. Further research is required to determine whether the techniques and models presented here will prove to differentiate RCBD patients into diagnostically useful categories, to anticipate periods of increased vulnerability to dysregulation, or to provide predictive power in short term prognosis. Taken together, the observed heterogeneity in dynamics indicates that averaging over individuals is likely to obscure rather than reveal the mood regulatory

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processes at work in these individuals. Such a view of adaptive heterogeneity in combination with deterministic dynamics is similar to the views proposed by Yeragani et al. [65]. The second main conclusion is that there is evidence that weather may be coupled to mood regulation in RCBD patients in several different ways. In the largest category of individuals, thermoregulation appears to be the primary source of coupling between mood and weather. A second type of coupling observed in these individuals is one in which one of the three weather variables tended to change the estimated damping parameter, the measure of homeostatic regulation. Thus it may be that weather, in particular heat, may both affect mood directly as well as affecting the way that mood is regulated. This indication of potential nonstationarity in the parameters of the model needs to be further explored. The model presented here has parameters that are fixed over time within subjects. Our analyses suggest that a better model would estimate the direct effect of weather on regulation using time–varying coefficients. There are many possible explanations for an association between weather and regulation of mood. For instance, in better weather people may be more likely to spend time outdoors. This may result in increased activity and exercise. Increased outdoor time may also increase exposure to light as a positive consequence or to allergens as a negative consequence. Increased indoor time may increase exposure to viruses as well as reduce exercise and lower exposure to light. So, while weather and mood may be associated, this does not mean that there is necessarily a direct effect of weather on mood. The current analyses did not test any of these potential mediating or moderating influences. Both frequency and damping are appealing ways to conceptualize aspects of mood regulation or dysregulation [66]. Frequency of oscillation of mood is an intuitive notion. But damping as a parameter of mood regulation has not received similar attention. Note that our model allows for exogenous inputs to the system that can drive it away from equilibrium. For instance, weather may be one exogenous influence that contributes to mood being pushed away from homeostasis. The effect of these exogenous influences mean that any one person’s modeled oscillations will likely never damp entirely to equilibrium. Exogenous variables other than weather, such as emotional stressors, challenges, threats, sleep loss, and other unpredictable outside influences on mood, may serve to push mood away from homeostatic equilibrium. Our modeling results are inconsistent with a hypothesis that the observed variability in mood is simply due to noise. If it were, then the most likely preferred model would have been Model A and the most likely estimated optimal τ would have been 1 or 2. In contrast, we only found one individual whose preferred model was Model A and only one other individual whose optimal τ was 2. An explanation consistent with our results is that exogenous random shocks, i.e, nonstationary effects are coupled to a homeostatic regulatory system. The effect of these nonstationary coupled influences would likely be a broadband spectrum of mood, such as reported by Gottschalk et al. [35], even if the regulatory mechanism were linear such as in the analyses reported here. Accounting for the physiological bases of these mechanisms of mood regulation and dysregulation remains an open and active field of inquiry. Clearly, new samples with more subjects and more observations per subject are called for in order to help determine the extent to which our findings in the current sample generalize to the population. In addition, seasonal effects and sleep may covary with mood — future studies should consider varying the time of year of sampling as well as collecting sleep data. We believe that the methods and results presented here offer an opportunity to refine the focus of psychopharmacological research into mood regulation and to test the outcomes of competing theoretical mechanisms.

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Author Notes This work was supported in part by the National Institute of Mental Health Intramural Research Program. This study was approved by the Institutional Review Board of the NIMH. Dr. Boker is supported by NIH Grant R29–AG14983 and NSF Grant BCS–0527485. Dr. Postolache is supported by two grants: R21 MH075891-01A1 and R01MH074891, both from the National Institute of Mental Health (PI: Teodor T. Postolache). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation or National Institutes of Health. We also gratefully acknowledge the help of Susana Feldman–Naim and Joseph Soriano, MS.

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[39] P. Grassberger. Do climate attractors exist? Nature, 323:609–612, 1986. [40] S. M. Chow, N. Ram, S. M. Boker, F. Fujita, and G. Clore. Capturing weekly fluctuation in emotion using a latent differential structural approach. Emotion, 5(2):208–225, 2005. [41] Johan H. L. Oud and Robert A. R. G. Jansen. Continuous time state space modeling of panel data by means of SEM. Psychometrica, 65(2):199–215, 2000. [42] J. H. L. Oud. Continuous time modeling of reciprocal relationships in the cross-lagged panel design. In S. M. Boker and M. J. Wenger, editors, Data Analytic Techniques for Dynamical Systems, pages 87–130. Lawrence Erlbaum Associates, Mahwah, NJ, 2007. [43] Wei Wu, Yun Gao, Elie Bienenstock, John P. Donoghue, and Michael J. Black. Bayesian population decoding of motor cortical activity using a Kalman filter. Journal of the American Statistical Association , 18(1):80–118, 2006. [44] S. M. Boker and John Graham. A dynamical systems analysis of adolescent substance abuse. Multivariate Behavioral Research , 33(4):479–507, 1998.

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[62] Michael C. Neale, S. M. Boker, G. Xie, and Hermine H. Maes. Mx: Statistical modeling, 2003. VCU Box 900126, Richmond, VA 23298: Department of Psychiatry. 6th Edition. [63] S. M. Boker and E. S. Covey. Two recent advances in estimating and testing differential equations models. Paper presented to the Annual Meeting of the Society of Multivariate Experimental Psychology, 2002. [64] J. B. Potash. Carving chaos: genetics and the classification of mood and psychotic syndromes. Harvard Review of Psychiatry, 14(2):47–63, 2006. [65] V. K. Yeragani and V. Sree Hari Rao. Patterns of oscillatory behavior in different human systems: a special reference to psychiatry and techniques to quantify such patterns. Bipolar Disorders, 8:421–422, 2006. [66] J. C. Sprott. Dynamical models of happiness. Nonlinear Dynamics, Psychology, and Life Sciences, 9(1):23–36, 2006.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XVII

The Body Speaking of Blues and Worries: Fibromyalgia in Children and Adolescents Lynn Hugger, Zinoviy Gutkovich∗ and Harriet Knapp North Shore-Long Island Jewish Healthcare System, Derner Institute for Advanced Psychological Studies, Adelphi University, Garden City, NY, USA Private Practice, Manhasset, NY , USA St. Luke’s-Roosevelt Hospital, Division of Child Psychiatry; Child and Family Institute New York, NY , USA

Abstract Fibromyalgia is a poorly understood pain disorder that can become disabling. Much less is known about fibromyalgia in children and adolescents and this paper will add to this body of literature. Recognition and treatment of children and adolescents provides an important opportunity to prevent illness from becoming a way of life. Fibromyalgia, is a pain disorder that can become a way for the body to speak what the mind does not know. The authors clinical experience indicates that fibromyalgia symptom severity can exist on a continuum from mild to severely disabling and those unconscious conflicts can move fibromyalgia from a mild pain disorder to a chronically disabling condition. It requires bridging the mind and body, both in understanding the mechanisms of the disorder and in guiding the treatment. The authors elucidate physiological and psychological mechanisms for this complex syndrome as well as a model for treatment intervention with children and adolescents. In doing so, they make bridges between literatures of medicine, neuropsychology, cognitive behavioral therapy and psychoanalytic theories; ∗

E-mail address: [email protected] Correspondence: Zinoviy Gutkovich, MD, St Luke’s- Roosevelt Hospital, St. Luke’s Division, Department of Psychiatry, Division of Child Psychiatry; Child and Family Institute; 411 west 114 Street New York, NY 10025, USA. Tel: 212-523-4885; Fax 212-523-3064;

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Lynn Hugger, Zinoviy Gutkovich and Harriet Knapp thereby paralleling the treatment process which moves from the physical through different layers of psychological depth. They provide a detailed clinical discussion of a young girl with a complex case of fibromyalgia that illustrates an application of this type of clinical theorizing applied to an individual and family treatment on an inpatient psychiatric unit.

Keywords: Children, adolescents, fibromyalgia, psychiatry, disability, pain.

Introduction A 15 year old girl (called N for this paper) stares at Dr. Hugger, daring her to offer help. Dr. Hugger senses at once that she is on the firing line. The mother of the girl explains that Dr. E. (a rheumatologist) referred her to Dr. Hugger as she specializes in the treatment of fibromyalgia, but frankly she also can not really understand how a psychologist could be of any help. N. tells Dr. Hugger that she frequently has significant pain in her back, legs, hands and feet and feels tired all the time. They have been to many doctors and seem to experience relief in at least receiving a diagnosis, although they have no idea what the diagnosis means and are upset that there is no pill that will make the pain and fatigue go away. The authors are also typically mildly uncomfortable, as each patient with fibromyalgia presents its own unique picture and are well aware of how poorly understood this diagnosis is and how poorly understood the treatment is. We have learned to find a place for this lurking fear that comes with working with what is known and knowing that there is more to learn. Each time we are aware that we take a step into that space between the known and the unknown as patient, parent and therapist work to figure out why this particular person developed fibromyalgia and how we can get the symptoms to remit. In our head we hear the reassuring words of former patients who tell us (only after they are no longer in pain) that the pain was magnified by stress and becomes intermittent and of little consequence once they become psychologically stronger. One teenager, who had been incapacitated by her fibromyalgia pain, captured this best when she smiled and said “let’s not even talk about the pain anymore – it’s just not that important – you know it’s so related to stress.” The authors hope to add to the literature that will bring us closer to understanding this complex condition as there are no empirical studies examining the efficacy of combining a psychoeducational, cognitive-behavioral, psychodynamic and psychopharmacological treatment approach in a step-wise fashion, depending on the complexity of the case. In our experience many patients may benefit from this type of approach. This paper explores the intersection between the physical symptoms of fibromyalgia and the psychological stressors that exacerbate the symptoms. It examines the intersection between the physiology of this pain disorder and how this physiology overlaps the physiology of depression and anxiety, thereby explaining how stress amplifies the symptoms of fibromyalgia. We also explore the psychological mechanisms that block successful coping and contribute to the internalization of the stress, a key factor in converting the symptoms from minor inconvenience to debilitating interference in life. As in many disorders, the complex cases more vividly display these facets of the disorder. A complex case will be

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discussed in detail to illustrate the relationship between mind and body in the understanding and treatment of fibromyalgia.

Mind and Body The separation of mind and body in western philosophy has an impact on our approach to how we understand the human condition. This can be seen vividly in our understanding of fibromyalgia – a pain disorder that illustrates the inextricable interconnection between the mind and body [1]. As the current interest in pain disorders demonstrates [2,3] scientists and clinicians are delving into uncharted waters as we struggle to understand and treat these disabling conditions. Scientists, clinicians, and patients must be willing to stand in the space between the known and the unknown in order to study, give and receive treatment for fibromyalgia. Fibromyalgia in particular demonstrates the mind-body connection because it is principally a diagnosis of exclusion – that is, all known medical conditions that could account for the symptoms (in children, mainly those of pain and fatigue) must be excluded. Chiong [4] defines disease as a condition caused by an identifiable pathogen. There is no evidence of disease or deterioration (i.e. tissue damage) of any part of the body yet the patient will be significantly affected by their pain (and often fatigue) [1]. The authors have psychologically treated or supervised the psychological treatment of many children and adolescents with fibromyalgia. Their stories are compelling, convincing and similar. Underwood [5] captured the dilemma in her title “Fibromyalgia: Not All in Your Head,” as for years these symptoms were dismissed. Underwood reported approximately 6 million people in the United States who suffer from this condition and Anthony and Schanberg [6] reported an estimated occurrence in 6% of school age children. Fibromyalgia in children and adolescents have been reported in the United States, Israel, Finland and Mexico [1]. Interestingly the authors have found that a combination of lifestyle changes and a psychological approach that combines cognitive behavioral and psychoanalytic concepts can result in remission of the symptoms for many patients. It has been our observation that less complex cases, i.e. those with minor impairment in functioning at times respond to lifestyle and cognitive behavioral interventions; however, some less complex cases as well as the more complex cases require a psychoanalytically informed treatment and in some cases psychiatric medication. Like many conditions, symptom severity exists on a continuum. It has been our impression that when the symptoms become more disabling unconscious psychological factors are present, warranting a psychodynamic treatment. It is our belief that it is particularly important to identify and treat fibromyalgia in children and adolescents because this allows the individual to develop a self concept and identity that can include this condition without feeling overwhelmed, sick and debilitated by it. It can prevent the development of an identity as one who is “sick” because through the treatment process the person becomes empowered in learning how to cope with fibromyalgia. Pain coupled with fatigue can become increasingly disabling until it becomes chronic. If uninterrupted, pain reinforces the reasons for degradation of functioning, with subsequent lifestyle changes [7]. Ford [8] describes somatization as “illness as a way of life.” It is critical to interrupt this

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vicious cycle as early as possible, preventing a chronic depression due to feeling powerless, weak and feeling resigned to a life with chronic pain and fatigue.

Diagnosis Fibromyalgia is a musculoskeletal diagnosis with the key criteria of widespread pain of at least three month duration, in the absence of an underlying medical condition and with normal laboratory studies [6]. It is a diagnosis of exclusion i.e. musculoskeletal pain is not due to other illnesses (e.g. rheumatoid arthritis, Lyme disease, osteoarthritis). It is still defined as a rheumatologic disease by the American College of Rheumatology (ACR). The criteria for children include 5 out of 11 designated tender points where ligaments, tendons, and muscle attach to bone [1]. Other symptoms commonly seen in juvenile primary fibromyalgia syndrome include: headaches, stomach irritability, and/or impaired concentration [6]. All of these authors referred to the criteria set forth by Yunus and Masi [9] for fibromyalgia in children. It should be noted, however; that fibromyalgia can co-exist with other disorders and that both authors have treated children and adolescents who had comorbid diagnoses of juvenile rheumatoid arthritis and systemic lupus erythematosus, for example. The rheumatologist would diagnose fibromyalgia, if there was pain that did not typically occur in the co-morbid condition and the criteria for fibromyalgia was met (in particular the positive tender point exam).

Physiology of Pain It would be important to review the current understanding of the physiology of pain as it pertains to fibromyalgia. Pain is a sensory and a subjective experience. Pain is a perception that is a function of brain behavior and a dynamic interplay between the self and others. “Pain receptors are also called nociceptors … Any type of stimulus, provided that it be sufficiently intense, seems to be adequate for stimulating nociceptors in the skin and mucosa. In contrast, only marked changes in pressure and certain chemicals can stimulate nociceptors in the viscera.” [10]. In this section we will address the brain behavior, as it is currently understood. Dobbs [3] discusses Stephen Waxman’s (chair of neurology at Yale) work on neuropathic pain. Waxman is quoted as saying that “virtually all chronic pain is neuropathic pain.” He discusses “…malfunctions in the sensory nerve fibers running from tissue to brain.” He goes on to discuss a hyperexcitability of sensory neurons causing a sustained pain signal. Carmichael [2] in an article discussing pain and its pathways reports how “…doctors believe a continuous flood of pain signals to the brain may cause long-term changes in the nervous system that can lead to ongoing pain, even if the original injury has healed.” In this same article the impact of gender is discussed and she reports that “women have up to twice as many nerve fibers in the skin as men do, so they feel some types of pain more intensely,” meaning that a female’s intense pain is most likely worse than a man’s intense pain. This finding is important as there are more females diagnosed with juvenile fibromyalgia [6], (which is true for adult cases as well) and sexism in medicine and psychiatry has most likely

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contributed to some of the misunderstandings of fibromyalgia, such as it being part of hysteria or histrionic behavior thereby trivializing of the condition [11]. Carmichael [2] reports growing evidence that fibromyalgia “… is in part a brain disorder that sets the pain pathways afire.” Thernstrom [12] discussed the findings of Dr. Sean Mackey’s work at the Neuroimaging and Pain Lab at Stanford University, where subjects who were experiencing chronic pain could see their brain activity on a functional MRI machine. Volunteers were asked to try to increase and decrease their pain while watching the areas of the brain involved in pain perception and modulation, using a more direct method for biofeedback, illustrating the ability to control one’s experience of pain. “Much chronic pain is thought to involve either an overactive pain-perception circuit or an underactive pain modulation circuit” [12]. Thernstrom discussed how pain is activated by stress and modulated by belief. “The brain will shut down pain if it believes it has been given pain relief, even when it hasn’t (the placebo effect), and it will augment pain if it believes you are being hurt, even if you aren’t (the nocebo effect)[12].” In neuroimaging studies, fake opiates have been shown to cause the brain to release endogenous opiates (endogenous endorphins) [12]. It is a short leap to connect the impact an environment might have in magnifying pain, or containing pain. It confirms the use of many pain management techniques that involve distraction, it also confirms the importance of parents learning to find and walk the line between support and amplification – no easy process for a parent. We have observed that pain in one’s child is very compelling for a parent. It can be very difficult for a parent to contain their own anxiety, doubt and skepticism about the medical establishment and simultaneously become clear about their role in that complex process of separation and individuation inherent in the growth and development of maturing children, especially as they try to respond to their child who is often in tears and withdrawing from their daily activities. For example, there is a vast difference for a parent to say to a child “do the best you can, your pain will ease up soon” and “come lie down, stay home and rest, I am so worried about you.” The importance of containing anxiety rather than building it is crucial in pain management with children [13]. Further, parental assistance in helping their child decrease negative cognitions about their pain and being careful not to magnify the child’s distress have been found to contribute to improved functioning [14]. The pain literature is beginning to more clearly intersect the stress/trauma literature. Dreifus [15] interviewed Dr. Elizabeth Blackburn, a biochemistry professor at the University of California, San Francisco and a winner of the 2006 Albert Lasker Award for Basic Medical Research. Dr. Blackburn discussed the effect of stress on chromosomes that impacts premature aging. She also discussed the adverse impact of stress on the immune system, heart and lower gut. Dr. Blackburn found the protective caps at the end of chromosomes called telomeres are restored by an enzyme called telomerase. She found that stress wears down the telomeres and reduces telomerase. Dr. Blackburn worked with Dr.Elissa Epel, a psychologist who studies chronic stress. Dr. Blackburn found shortened length of the telomeres and reduced amount of telomerase on the tips of chromosomes in two groups exposed to chronic stress compared to findings in a matched non-stressed group. One comparison involved mothers with normal, healthy children and mothers of a child with a chronic illness; the other comparison involved caregivers of people with dementia. The significance of these studies is

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that it clearly depicts the impact of chronic stress on the chromosomes of the body. Living with chronic pain is a chronic stressor – similarly there are studies that indicate, such as Thernstom’s sited above, that pain can be exacerbated by one’s environment. This is part of the vicious cycle of fibromyalgia pain – stress wears the person down making them more vulnerable to fibromyalgia and then the pain and fatigue become part of the stress as well. Fibromyalgia has been associated with stress, anxiety and depression. Abeles et al [16] reviewed the literature on the pathophysiology of fibromyalgia and concluded that “…evidence is accruing that psychiatric illness (for example, anxiety, somatization, and posttraumatic stress) predisposes to the development of the syndrome.” They review studies that report associations between serotonin, dopamine, and cortisol and pain, anxiety and depression in fibromyalagia patients. They also report on the benefits of antidepressants in the treatment of fibromyalgia. The trauma literature helps us understand the other piece in this puzzle – how does stress contribute to the onset of fibromyalgia? Dr. Bessel van der Kolk [17] discussed the connection between traumatic stress and psychobiology in his aptly titled chapter called “The Body Keeps the Score.” Van der Kolk [17] discusses the role of “…stress responsive neurohormones, such as the catecholamines (e.g., epinephrine and norepinephrine), serotonin, hormones of the hypothalamic-pituitary-adrenal (HPA) axis (e.g., cortisol and other glucocorticoids, vasopressin, oxytocin), and endogenous opioids.” These neurotransmitters are known to affect the autonomic nervous system – in particular epinephrine and norepinephrine are associated with increase muscle tension needed for the “fight or flight” response. They are also associated with hypermotility of the intestines and increased acid in the stomach, which may explain the nausea and stomach upset that many fibromyalgia patients experience. The chronic muscle tension may explain in part the connection between stress and muscle pain reported in fibromyalgia patients [10]. The physiological response to stress combined with the sleep disturbance that is commonly associated with anxiety and depression is a contributing factor to the fatigue that is so commonly reported. These factors may cause or amplify the pain. The pain also often disturbs sleep, which becomes an added stressor and enters the vicious cycle of pain, fatigue, and stress. Blackburn-Munro [18] also found an association between the HPA axis, chronic pain and depression.

Therapeutic Work The initial visit to a psychologist for the treatment of fibromyalgia is typically filled with skepticism. The patients and their parents have often been to many doctors in order to find out what is causing their child’s chronic pain and other symptoms such as extreme fatigue, upset stomach, headaches, and difficulty concentrating (commonly referred to as fibro fog). Patients are often relieved to be given a diagnosis, as that at least validates their symptoms and self experience which has typically been challenged by doctors, school officials, family members and peers. This relief, expressed to me by many patients, may also represent the importance of having ones experience organized in a meaningful way. Prior to the diagnosis the symptoms are frightening, not necessarily related to each other and seems to leave patients feeling psychologically disorganized. Thus the diagnosis serves as a step towards

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validation and integration of the patient’s experience. However, at the same time they are often frustrated that there is no magic pill to cure it. Thus it is often out of desperation that the patient agrees to see a psychotherapist for treatment and this presents the therapist with the first challenge – establishing a working therapeutic alliance. In order to do this a space where the mind and body can meet must be created, thereby allowing for a dialogue about the patient’s physical experience and thoughts and the therapist’s thoughts. In order to work effectively the therapist must be willing to acknowledge all of the “maybes” in the search for relief, the therapist has to be willing to take these immeasurable physical complaints at face value and enter the patient’s subjective world. This is not unlike other psychological therapies and medical conditions, but somehow there is an expectation with physical symptoms that there should be more hard core proof of their existence and the absence of this lurks in the treatment relationship as well as most of the other relationships in the patient’s life. In order to work effectively the therapist must be able to believe the patient without this type of proof. We remind the patient that there are other medical conditions that are affected by stress yet create physical distress, such as headaches, ulcers and irritable bowel syndrome. In the first session we typically take a thorough history of when the pain began always looking for sources of stress that preceded the development of the pain – the stress could be physical or psychological. If the patient is generally able to manage various aspects of their life successfully and there was a clear physical stressor, like mononucleosis or a debilitating virus that induced a long period of fatigue, basic lifestyle adjustments that fortify the recovery process will often help the patient recover. However often there is a variety of complex stressors such as struggling in school due to learning disabilities, unresolved issues pertaining to sexual abuse, excessive perfectionism combined with increased academic and/or family pressures to achieve, and/or fears about separation and individuation as they step out into the peer group and school life. These are just a few of the many different stressors that we have seen in the patients we have worked with. There also appears to be common personality traits that we have found in the patients who develop fibromyalgia. Most noticeably there is a tendency to minimize and deny emotions and the impact that events in their life can have on them. This may account for the findings that although “patients with fibromyalgia have increased rates of depression…most patients with fibromyalgia are not clinically depressed and fibromyalgia is therefore an independent but overlapping entity” [16]. Superficial inquiry with most of the fibromyalgia patients that the authors have evaluated would agree with that finding; however, more in depth inquiry would not. A brief case example will illustrate this. One of the authors (LH) was working with an 8 year old girl diagnosed with fibromyalgia that was severely interfering with her ability to attend school and function in many areas of her life. In session she would rarely speak of upsetting events, yet Dr. Hugger knew that her family was under significant stress. One night there was a violent event that occurred at the home. Due to the crisis Dr. Hugger met with the patient’s sister individually as well. The 12 year old sister, who did not have fibromyalgia, immediately began to tell the author what had occurred the night before. Her story was a coherent narrative that integrated events and her emotional reactions to these events. In contrast, her sister, who had fibromyalgia, came into her individual session, smiled at Dr. Hugger and assured her that nothing in particular had occurred last night and she was

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perfectly fine. An inability to acknowledge and integrate one’s emotional reaction to life events is a common personality trait and can be understood as a defensive process. Van der Kolk [17] in his work on Post Traumatic Stress Disorder (PTSD) notes that “chronic physiological arousal, and the resulting failure to regulate autonomic reactions to internal or external stimuli, affect people’s capacity to utilize emotions as signals.” He goes on to say that “after having been chronically aroused, without being able to do much to change this level of arousal, persons with PTSD may (correctly) experience just having feelings as being dangerous” [17]. Although Van der Kolk is discussing PTSD, it has long been suggested in the literature that stress is also a subjective experience and what traumatizes one person may not traumatize another. The early work on the Type A personality and cardiac conditions noted similar neurobiological pathways [19] and Masud Khan [20] developed the concept of cumulative stress as it occurs in the parent/child relationship and the impact it has on the developing child. As will be seen, the cumulative stress that Khan refers to is quite relevant to our case presentation. Not knowing one’s emotions and the impact it can have on memory has been referred to in the psychodynamic literature as dissociation and has an 85 year old history dating back to the work of Janet in 1909 [21]. We have found that as the patient integrates the split off emotions related to their particular stressor, they are then freed to find more successful solutions (i.e. to family conflict, learning disabilities, peer group ostracisms etc.) which thereby decreases the stress and appears to decrease the pain. Therapeutic work typically begins where the patient is at – by examining lifestyle habits that are closely related to the physical symptoms. This requires a psychoeducational and cognitive behavioral approach developed by DeGotardi et al.[22] (and referred to below) and becomes a steppingstone to a psychodynamic therapy. The information obtained in the evaluation has provided the therapist with the source of the stressors in the patient’s life and can now be re-introduced as the less threatening area of lifestyle is examined and worked with. This allows for connections between mind and body in small steps. The physiology of stress and fatigue is explained to the patient to help them understand that these can cause the pain, headaches, stomach upset, and poor concentration that these patients typically experience. Sleep habits are examined and ways to improve their sleep quality are recommended. Recommendations commonly include: creating regular sleep and waking times which fosters consecutive cycles of REM and Stage IV sleep, learning ways to relax prior to bedtime which contributes to fewer instances of waking at night, decreasing caffeine use, and eliminating naps (which interfere with the consecutive sleep cycles needed at nighttime for restorative sleep). Sleep diaries are typically used to help the patient identify their habits and take corrective action. Often when examining the patient’s difficulty falling asleep, the patient begins to speak about their worries and anxiety that keep them awake. This is another important opportunity to begin incorporating psychodynamic work because it is this same patient who typically denied having any concerns in the evaluation. Thus one can begin to provide a path for the patient to begin to talk about their concerns which is a step towards finding the denied and split off emotional experiences that many patients and sometimes family systems embrace. Nutrition is examined as poor eating can contribute to fatigue.

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Time management is examined as schedule overload contributes to stress and fatigue. Learning to eat properly and manage time wisely are new skills for teenagers as prior to (approximately) age 11 parents typically regulated the younger child’s time, nutrition, sleep routines and bedtimes. As children enter Middle School they are given more freedom and typically minimize or do not attend to these important areas of health. While exploring these areas it is also common to begin to understand the patient’s personality – concerns about school work and entering the competition for getting into college contributes to schedule overload and extreme anxiety related to high academic achievement and many extracurricular activities. Fears about being accepted by the peer group are common. As teenagers struggle to clarify their identity peer group stability can waiver as friends change and competition for popularity ensues. Pain management techniques are also utilized. These include use of heat, showers, stretching, and identifying activities that distract from pain and are utilized to decrease the pain and empower the patient. The authors utilize an approach that is eclectic and incorporates knowledge of physiology, neurobiology, cognitive behavioral techniques and psychodynamic interventions informed by psychoanalytic theories. This allows us to work from surface issues where “the body is speaking” to the underlying psychological conflicts and mechanisms that the patient is either unaware of or has minimized in a need to deny their emotional life (i.e. their fears and worries). The authors’ backgrounds inform our approach as Dr. Gutkovich is a physician, who specializes in child psychiatry and Dr. Hugger was a certified child and adolescent psychiatric clinical nurse, who became a clinical psychologist, specializing in child and adolescent treatment. Thus we both feel comfortable exploring and integrating the physical and the psychological aspects of human experience. Our training also includes many orientations and we therefore draw upon many theories in helping our patients. We have found this flexibility allows us to match the patient and the patient’s dilemma to the theory that is most useful at any given clinical moment. It is our experience that the patient’s symptoms represent an unconscious complex psychological process and we hope to illustrate how psychoanalytic theory and psychodynamic intervention is critical in empowering the patient to learn to live adaptively with fibromyalgia.

Case Story As this paper is a joint effort, for purposes of clarity, it may be useful to discuss our roles in the following case presentation. Dr. Gutkovich was the treating therapist and managed medication as well. He will be referred to in the case presentation as the treating psychiatrist. When faced with challenges in the treatment, he called in Dr. Harriet Knapp, an esteemed psychoanalyst. Dr. Knapp had participated in writing the original manuscript. She recently passed away and therefore could not continue her work on this paper. Based on the treatment of many children and adolescents with fibromyalgia, Dr. Hugger will provide her thoughts about the theoretical underpinnings for understanding the psychological mechanisms and treatment interventions that helped to make this treatment successful. In addition, it is important to note that the following case is not a typical case of fibromyalgia. This case was selected because it does illustrate the complexity of mind-body

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interactions and demonstrates deeper psychological processes that can be a component of fibromyalgia symptomatology, i.e. how psychological stress can become experienced as physical pain, fatigue, stomach aches, headaches, all of which are not conversion symptoms. As discussed earlier in this paper, psychological stress can physiologically manifest itself in physical symptoms. We have found that it is common for patients with fibromyalgia to minimize or deny their emotional stress, except as it relates directly to the physical symptoms of fibromyalgia, even when there are significant stressors occurring in the patient’s life, indicating the use of dissociative processes (not to be confused with dissociative disorder). Shapiro [23] also noted similar mechanisms in her work with an adolescent girl with fibromyalgia. A Conversion Disorder would be at the extreme end of this type of denial or mind/body split. It is rare for a patient with fibromyalgia to require inpatient psychiatric hospitalization. It is also not typical for patients with fibromyalgia to have a co-morbid diagnosis of Conversion Disorder. As will be seen in this case, Karen does have a co-morbid diagnosis of a Pain Disorder Associated with both Psychological Factors and a General Medical Condition (fibromyalgia) as well as a Conversion Disorder. Karen (a pseudonym) is a 10 year old girl whose pain began four months earlier following a fractured toe and two bouts of bronchitis with shortness of breath. Prior to this, her parents reported that Karen was a well adjusted girl who studied dancing for many years and academically was placed in a class for gifted children the previous year. Her persistent and worsening pain led to a series of medical evaluations and eventuated in a diagnosis of fibromyalgia. Karen was referred to an outpatient fibromyalgia program however during the assessment process Karen became upset by the psychiatrist’s questions about possible sexual abuse causing her to withdraw from the program. Karen next saw an outpatient psychotherapist who utilized a cognitive behavioral approach to help Karen develop better coping skills. However her symptoms worsened and she was brought to the emergency room by her parents after screaming in pain for 72 hours. She was initially hospitalized on a pediatric medical unit in order to fully evaluate her complaints and confirm the diagnosis of fibromyalgia. The treating psychiatrist was called in for a consultation while Karen was on the pediatric unit because of Karen’s non-stop screaming and moaning. Calling a psychiatrist was strongly opposed by Karen’s parents as they believed all her psychological symptoms were due to fibromyalgia. Although most evaluations occur on an outpatient basis, it was the magnitude of Karen’s complaints that resulted in hospitalization. It is extremely important to rule out other causes for the symptoms of fibromyalgia, as there are many other illnesses with similar symptoms that must be eliminated. It is not uncommon for patient’s to see many doctors before the diagnosis of fibromyalgia is made. It should be noted that Karen was initially diagnosed with fibromyalgia at an outpatient clinic by a Pediatric Rheumatologist, after being seen by numerous other doctors. Approximately four months later, Karen was admitted to a pediatric unit where a different Pediatric Rheumatologist also diagnosed Karen with fibromyalgia. The standard method for making this diagnosis in the pediatric population is to use the criteria, discussed earlier in this paper, developed by Yunis and Masi. The treating psychiatrist reviewed all of the medical records. During the treating psychiatrist’s first encounter with Karen, he asked her to rate her pain on a scale from 0 to 10; and she replied that when the pain first started four months prior it

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was “10,” since then it had become progressively worse. She said it never improved and pain medications did not help. Her speech was very intense and dramatic. When he entered the room to speak to Karen, he asked mom to step out and Karen started screaming as if in fear, “Not alone!” Her reaction raised the thought of a possible history of sexual abuse or conversion symptoms. When the treating psychiatrist later asked to speak to Karen’s mother alone, Karen reacted with rage; pointing a finger at her mother and screaming: “You have ten minutes.” This resembled the behavior that the treating psychiatrist often saw in children with eating disorders, for example, and the control through anger and intimidation they often exercised with their parents. Karen alternated between a controlling anger and an uncontrolled pathetic screaming in anguished pain. On a later interview the treating psychiatrist was told a “secret” by Karen that she lost 20 pounds. She asked him not to share this secret. Comorbid body image and eating disorder issues contributed to the complexity of Karen’s psychological problems. As a first step, the treating psychiatrist tried to continue medication treatment on the pediatric unit. He continued Elavil (frequently used in pain disorders and initially prescribed by the pediatrician) and added Paxil to address the patient’s anxiety. Due to Karen’s extreme levels of anxiety, Ativan was also used as a temporary measure to decrease anxiety because Elavil and Paxil typically take three to four weeks to reach maximum effectiveness. Subsequently Paxil and Elavil were discontinued due to ineffectiveness. Prozac was prescribed with good results and a low dose of Risperidone was prescribed to address Karen’s distorted thinking, especially when stressed. Ativan was changed to Klonopin with some relief of anxiety; Klonopin was eventually discontinued as it became unnecessary, most likely because the Prozac began to take effect. During the next two weeks on the pediatric unit Karen became unable to walk, needed a wheelchair to ambulate and began to urinate on herself. The pediatricians and the treating psychiatrist felt that the major work at this point was psychiatric and she was transferred, with strong protests from her parents, to the child psychiatry unit. Initially, the treating psychiatrist utilized some behavioral interventions in order to motivate Karen to give up some of her regressive behavior. Family visits were contingent on: attendance in school, compliance with physical therapy, and increased independence in hygiene. This behavioral plan contributed to progress in all of these areas. The treating psychiatrist also asked a staff psychologist trained in hypnosis to hypnotize Karen in order to see if she could walk while in a trance; however, Karen could not be hypnotized. The treating psychiatrist felt strongly that there were unconscious conflicts with some features of conversion disorder (leg paralysis) causing Karen’s behavior. He contacted Dr. Knapp, a psychologist with high expertise in psychoanalytic and family therapy to consult on the case in order to obtain an additional view of the psychodynamics of Karen and her family. Walking the line between the emotional and physical spheres of human experience places the therapist in murky waters at the beginning of treatment. Willingness to enter these waters in the face of convincing physical symptoms and an extremely resistant family and patient is challenging as there is always some doubt that the therapist has to put aside in order to create a psychological space for exploration. Aron [24] discusses “opening up psychic space for self-reflection and mentalization” as an important therapeutic strategy that can move a treatment from relations of complementarity (where the patient and therapist are in

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opposition) to relations of mutuality (where the patient and therapist are working together). This is essential to the treatment of people with fibromyalgia as the patient has to feel understood and respected by the therapist and the therapist has to believe and respect the patient’s physical and psychological experience. We have found that fibromyalgia patients are extremely sensitive to attitudes of disbelief on the part of the therapist. Further exploration revealed that family dynamics were significantly involved in Karen’s illness and treatment failure; therefore, family therapy was initiated. Stern [25] examines the analytic relationship and refers to the “grip of the field,” this phenomenon can be applied to all relationships including the patient’s family. In child and adolescent treatments it is often essential to work with the family and we have found it quite helpful to apply concepts typically utilized to examine the analyst-patient relationship to the understanding of family relationships. The presence or absence of many of the non-interpretive functions of the analytic relationship applies to healthy emotional life in the family. Functions such as providing a holding environment where the patient can experience different aspects of the self in a safe, non-hostile environment (Winnicott’s holding environment [26]) and the importance of parents containing anxiety so that it does not become overwhelming are two examples. Slochower [26] compares the analytic environment to the evolving maternal metaphor and elaborates on Winnicott’s holding environment metaphor and Bion’s containing function as well as the work of other psychoanalysts in describing the similarities between the mother/analyst. This type of thinking influenced the treating psychiatrist as he began an exploration of Karen’s family life with an eye for assessing these functions in Karen’s family. Something has made it necessary for Karen to be unable to symbolize her emotional experience (i.e. it remained unformulated and outside of conscious experience). As in the analytic relationship, important clues will be found in the enacted experience of family life. Stern [25] noted that “enacted experience, and thus dissociated states as well, cannot be symbolized and therefore do not exist in any other explicit form than enactment itself. Enacted experience is unformulated experience.” He goes on to note that “enactment ends in the achievement of internal conflict, which occurs when the two dissociated states, one belonging to each participant in the enactment, can be formulated inside the consciousness of one or the other of the two psychoanalytic participants” [25] or we would add family members. Stern goes on to explain that in enactment all of the people involved are unable to simultaneously hold in consciousness the tolerable experience and the dissociated one. Once they can hold these in consciousness, the two states that form the conflict can be negotiated and worked through. We do not suggest that all cases of fibromyalgia are necessarily related to conflicts within the family as we have observed many psychological stressors not related to family life (such as learning disabilities or peer group problems) can also be related to the disabling amplification of fibromyalgia symptoms; however, family dynamics can play a significant role for many children and adolescents and in all cases parents need to find ways to support their child without amplifying the disability. We do believe that overwhelming emotional experience that leaves the individual unable to think, unable to process their experience with the subsequent dissociation and internalization of the stress is a critical psychological mechanism that underlies some cases of fibromyalgia, usually the more complex ones, and may be understood as enacted experience – i.e. the body speaks.

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Karen presented the treating psychiatrist with diagnostic challenges. Karen was diagnosed with fibromyalgia by two rheumatologists associated with different hospitals; part of her pain was associated with this condition. However she exhibited symptoms that were not part of fibromyalgia, such as leg paralysis, excessively regressed behavior such as loud screaming and urinating on herself. Karen had a complete medical evaluation while on the Pediatric Unit ensuring that another medical condition could not account for these symptoms. Karen’s intense fear of walking strongly indicated that she was not intentionally producing or feigning this symptom and therefore Karen met the criteria for a co-morbid diagnosis of Conversion Disorder [27]. Karen did not meet the criteria for Somatization Disorder as her symptoms did not occur over a period of several years and she did not have any sexual symptoms or gastrointestinal symptoms. Dr. Knapp’s background in psychoanalysis and family therapy was important in helping Karen and her family as she understood how to work with resistance and that it represented a defense for unconscious conflicts. Shapiro [23] in her work with an adolescent patient with fibromyalgia also recognized the importance of initially respecting the patient’s needed defense of denial. Shapiro observed that “premature confrontation or interpretation, even if correct, forces the patient and/or family to mobilize other defenses, or to seek other treatment, often in a biomedical venue” [23]. Dr. Knapp knew to start with Karen’s physical symptom and looked to build bridges (as Shapiro [23]discussed) between the mind and body. Early in Karen’s treatment on the psychiatric unit, Karen and her parents were brought in and introduced to Dr. Knapp for a consultation/case conference. Dr. Knapp asked Karen what happened that she could not walk. Karen explained that because of the pain she grew tired and could not walk. Dr. Knapp asked if she could walk, where would she walk. Karen’s mood changed noticeably and she replied with great animation that she would go to Ireland, the home of her father’s family. It was a country she had never visited but could picture with precision in her mind. She spoke of the streets of Dublin as if she walked on those streets. In her fantasized journey she demonstrated a vivid imagination and more importantly, identification and closeness with her father. During that period she was animated and lively without a hint of illness at which point her mother intervened, remarking how happy Karen had been until her illness. This intrusion set Karen to commence her moaning which quickly escalated to uncontrolled screams about her pain. She could not be engaged any further and her screaming disrupted the ability of the interviewer to talk to her parents. The chief psychologist on the unit said quietly but firmly that if she could not stop she would be taken out of the room until she could control herself. She didn’t and was removed by a nurse who wheeled her into the hall. Karen’s closeness to her father and wish to know him better, as her fantasized walk demonstrated, provides an important link between the trigger for her fibromyalgia symptoms and her unconscious conflicts. The onset of her symptoms followed a fractured toe and shortness of breath due to bronchitis. Her father had similar medical symptoms as he had shortness of breath due to asthma and a chronic limp. In addition Karen later revealed in her individual therapy fears concerning her mother’s health due to smoking thus Karen’s symptom of shortness of breath was connected to anxiety about the safety of her two main attachment figures. Dr. Knapp began to explore with the parents how they viewed Karen’s illness. Mom insisted Karen was a perfect child until she developed fibromyalgia. Karen’s parents viewed

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fibromyalgia as the cause of all the disagreeable aspects of Karen’s behavior. Karen’s mother said angrily that she saw no reason for her to be on a psychiatric unit as her illness was physical. Dr. Knapp stated that physical illness becomes intensified under conditions of stress, and that Karen seemed frightened of something, and that she avoided any talk of growing up. She reminded mom that Karen was a pubescent girl at which point mom reacted with a sharp awakening that she just recalled that Karen seemed panicked at the sight of her first pubic hair. She was concerned and anxious about her changing body and was fearful of growing up. This was a turning point in the treatment as it was the first time the parents joined in connecting the physical and the emotional experience of Karen. Karen was unable to tell the treating psychiatrist or Dr. Knapp about her internal conflicts because she had dissociated them. Karen and her therapists were being drawn into “the grip of the field” and were working to wiggle there way out of it, patient and family in hand. The treating psychiatrist, as well as the staff of the unit, was forced into responding to Karen’s tantruming behavior with action, as seen by imposing a psychiatric hospitalization or by removing Karen from the room. Karen’s present language utilized action and amplification of her fibromyalgia pain to symbolize her thoughts and therefore her therapists needed to join in this form of communication. However, the treating psychiatrist was aware that one of their goals was to begin to create meaning and give words to these actions and somatic expressions. The therapist and patient put forth hypotheses and exploration reveals which ones are most relevant. In this way a dialogue is created between patient and therapist that is in the tradition of the relational view of psychoanalysis where there is mutual recognition and coconstruction of experience. By doing this the external conflict between Karen and her therapists can gradually become an internal conflict which can then be resolved through therapeutic work. In this case in particular where Karen’s autonomy was usurped by the treating psychiatrist, regaining this aspect of the therapeutic relationship was going to be difficult but essential to progress. Karen was wheeled back into the consultation room as she had calmed down. Further inquiry about family dynamics revealed issues of competitiveness and conflict at home. As the parents began to openly discuss these conflicts, Karen was given psychological permission to begin to consciously explore and thereby verbally symbolize her own feelings and reactions. This is one avenue for unformulated experience becoming formulated or consciously organized into a coherent narrative that then allows for further therapeutic work. Knowing that conflict in the parent’s marriage is often a contributing factor to the problems of children, the treating psychiatrist explored this area with Karen’s parents. Their willingness to reveal and begin to explore their significant marital conflict was another step towards a weakening of the family’s defensive system of denial and minimization and took admirable courage on the part of the parents. Karen’s father would leave home when angry with his wife. Karen’s mother expressed her anger in a powerful, nonverbal style, e.g. by raising her eyebrows and Karen fully understood the anger expressed by this gesture. In Karen’s individual sessions with the treating psychiatrist, she began to reveal that she often assumed the painful role of peacemaker between her parents out of her fear of them separating. Karen’s increased trust in the treating psychiatrist developed in her individual work and had a positive impact on family sessions. Issues from the individual treatment tended to spill over into the family sessions. Children are very attuned to marital conflict as

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well as the moods of their parents and in chronically stressed families this most likely contributes to a state of hyperalertness in the more aware or sensitive child. It is this state of hyperalertness that is associated with the physiology of stress [17]. Mom unconsciously colluded with Karen’s regressive behavior. She reacted with anger at Karen’s abusive and aggressive actions and paradoxically beamed at Karen’s “spiritedness.” On the surface mom appeared to support Karen and thus verbalized that she did not wish to do anything that would “break her spirit” (i.e. limit setting, including use of the seclusion room). Mother’s emotional confusion could also be seen in her comment that “maybe Karen would be better off in a wheelchair – happy – than unhappy, walking with a broken spirit.” Unconsciously Karen’s anger and regressive behavior served multiple purposes for this family. This pattern of family interaction has serious implications for the emotional health of the children. Lyons-Ruth and Jacobvitz. [28] studied attachment styles of children and associated this kind of controlling, fear inducing behavior with disorganized attachment style. The authors note that “in the absence of adequate caregiving regulation of fearful arousal, various intersubjective, intrapsychic, and physiological compensatory mechanisms are set in motion, resulting in maladaptive, contradictory, or controlling behavioral and mental organizations” [28]. The open ended spirit of a psychodynamic treatment allows for the unexpected discovery of unconscious sources of anxiety. It was therefore important for Karen to be seen in individual therapy as well as family therapy because individual sessions allow for a private, safe place to play with possibilities about one’s emotional and psychological experience affording the patient an opportunity to make meaning and integrate their behavior, life experiences and emotional life, all of which are critical to an integrated sense of self. One example of this occurred when the treating psychiatrist asked Karen “what is your worst fear? What would be worse than being paralyzed for the rest of your life and being in a wheelchair?” She responded with striking promptness “if my mother doesn’t stop smoking the same thing will happen to her that happened with my grandfather”. Crying, Karen told the treating psychiatrist how her grandfather lost his voice and had a tube put into his throat due to his cancer. Considering Karen’s often violent and aggressive behavior, particularly towards her mother, this was an unexpected reply. It mirrored mother’s defensive attempt to keep Karen “spirited” while becoming enraged at Karen for any hostility, and thus indicated the extent of Karen’s ambivalent relationship with her mother as well as the confusing messages prevalent within the family. Another step was made towards helping Karen to acknowledge her dependency needs and find a more appropriate way to have them met. By two months into her hospitalization Karen had developed increased trust in her relationship with the treating psychiatrist and they began to explore Karen’s fear of standing. Together, they agreed to help Karen master this fear by using a device recommended by the Physical Medicine department called a stander. A stander is a machine that provides a supportive cage that makes it impossible to fall. The treating psychiatrist’s offer to provide the stander and Karen’s willingness to use it allowed this to be a nonconfrontational approach that helped Karen feel emotionally understood and simultaneously move towards a return to independent functioning. When individual therapy is provided in conjunction with family therapy there can be a rich opportunity for the recognition of unconscious needs in the individual and change in the family that can alter the

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developmental course for all family members, including the identified patient. Karen and her family were helped to symbolize their emotional experience through words instead of actions. Karen’s fibromylagia was most likely precipitated by the stress related to her role in the family, her developmental needs, intensity of the conflict in this particular family and her heightened emotional sensitivity. At the age of 10, children in our society are faced with an increased pressure to separate and individuate. Karen’s body was physically changing, she was at the end of elementary school, and the social, academic and developmental pressures that are inherent in the move towards middle school often place children from conflicted families under considerable stress. Loewald [29] eloquently discusses the complexities of this developmental phase. In particular he emphasized the importance of a home environment where the child can reject the parents as libidinal objects (psychological parricide) in order for one’s own autonomy, superego and nonincestuous object relations to evolve. Karen’s overstimulating relationship with her father, which was unconsciously encouraged by her parents due to their own conflict, combined with Karen’s developmentally appropriate emotional dependency on her parents placed Karen in unconscious psychological conflict. Her parents were unable to provide a psychologically safe space which Karen could step into as she matured and responded to the developmental demands of individuation and separation. Karen’s fibromyalgia became part of a vicious cycle. The symptoms, which may have been a result of the stress Karen lived with combined with the developmental demands of her age, also allowed Karen to regress thereby precluding mastery of the developmental challenges related to her age. Karen’s infantile behaviors inadvertently increased her stress at home, in school and with her peer group. This is one way that fibromyalgia takes on a life of its own. Karen’s symptoms acted to distract the family from their marital issues as the family coalaced around helping Karen. Karen’s passive father began carrying her into the shower, which gratified her wish to remain a little girl close to her father and unconsciously served as an Electra conquest. Within the peer group Karen became ostracized as she experienced girls envying her placement in classes for gifted children and they began siding against her. The intense competition and complex social interactions common to this age group is often a source of anxiety. Children with greater intrapsychic conflict will most likely have greater difficulty managing this stress. The illness allowed Karen to avoid school with all the peer problems of competitiveness, friendships and academic stresses. In addition it is common for families with children in this age group to have aging grandparents. Both of Karen’s grandparents used wheelchairs. Aging grandparents was most likely a stressor for Karen and her parents as imbedded in this process are anxieties related to mortality, loss and separation that can destabilize a vulnerable family and child. At the same time, this provided a model for Karen’s conversion symptoms, i.e. her leg paralysis. It became apparent that Karen and her family were functioning at a borderline level. Characteristics of people who function in the borderline range include “extreme anxiety, intense reactivity, potential for disorganizing regression, lack of self- and object constancy and the profound fears that coexist with their deep needs for attachment” [30]. Thus their ability to negotiate the stress that life presents was limited and contributed to the severe symptomatology of this particular child who had fibromyalgia. The symptoms of fibromyalgia became another maladaptive vehicle for the expression of anxiety and conflict within the family. Evidence for this level of functioning was seen in the significant levels of

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splitting that occurred in response to conflict between mother and father, Karen’s threatening and demanding behavior to her parents as well as in Karen’s response to the staff on the pediatric and psychiatric unit. It was therefore consistent with this level of functioning when at the beginning of Karen’s hospitalization she reacted with screaming and threats of self harm as an attempt to intimidate others into obeying her demands. This was due to her defensive use of splitting, i.e. viewing others as well as her own needs in all or nothing terms. Splitting inevitably leads to high levels of anxiety as the individual frequently feels extremely vulnerable and simultaneously limits ones ability to effectively problem solve. Khan [20] described the cumulative trauma due to “the strain and impingements from the failure of mother’s [or parent’s, our addition] role as protective shield ...” and the adverse impact this has on the gradual integration of a sense of self and the development of “proper differentiation and growth of internal psychic structures” [20]. As the family, individual and milieu treatment progressed, Karen and her family began to more openly discuss the problems in the family. Family members at different points dared to speak what others were afraid to speak and in this way helped each other to begin to symbolize their emotional experience, decreasing the need to dissociate, and allow for more adaptive solutions within the family and for Karen. In order to break through the unconscious collusion of “not speaking” about conflict in the family the treating psychiatrist insisted that Karen’s siblings be included in some of the family sessions. Consistent with the family’s need to deny conflict, Karen’s mother initially objected to including the siblings, saying that they had enough exposure to Karen’s “crazy” behavior and that she needed to protect them. However, this proved to be a crucial therapeutic intervention. Karen’s older brother began the session by openly speaking about the burden that Karen’s illness placed on the family. This sparked an onslaught of accusations and verbal attacks between Karen and her mother culminating in the mother saying “I can only take so much. You are not going to put me down in front of my son!” At this point the treating psychiatrist took a risky step by asking “Are these children going to live in the different homes?” “Yes!” mom responded unexpectedly, “If she continues to act this way she goes to a group home!” A moment of dead silence followed. Father and Karen were shocked. Then father looked at his wife and said, “No - she is coming home. And she is coming home walking.” The family split with father and daughter on one side and mother and son on the other became illuminated. Later during this session the mother became more able to acknowledge her own insecurities and fear of losing control which opened the way for therapeutic work where alignments and generational boundaries within the family could be reorganized. In retrospect it is interesting to note how the treating psychiatrist’s possible solution, reflected by him being unconsciously drawn into the family’s use of splitting as a solution, speaking the language of the family, yet posing this as a challenging question, helped this family to relinquish such extreme solutions to conflict as it implied other solutions were possible. This session explicated what Terr [31] refers to as “moments in psychotherapy” - sessions that lead to critical change. It also demonstrated the back and forth movement from positions of less reflectivity (what Klein refers to as a paranoid-schizoid position) to positions where feelings can be verbalized, reflected upon, and there becomes an increased capacity to recognize each others subjectivity (what Klein refers to as the depressive position) [32]. Therapy progresses as the individual, and in this case family members as well, are more able to recover from the paranoid schizoid position and

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return to the depressive position on their own. In this way, the family environment becomes safer and allows for increased self reflection and mentalization, core components of healthy emotional functioning [33]. After this session there was a noticeable improvement in Karen’s walking, culminating in a moment when she threw the walker away and walked. Karen also began to ask for home visits, whereas previously she expressed fear of living at home. A therapeutic agreement made at the beginning of Karen’s hospital stay made these visits contingent on her being able to walk. She was discharged about three weeks after she began walking. During those three weeks there was a gradual transitioning back to home and her previous school. A slight limp also disappeared by the time of discharge. The entire hospitalization was approximately three months. Highlights of Karen’s treatment were selected in order to illustrate how the symptoms of fibromyalgia can become exacerbated by unconscious psychological processes. We also wanted to illustrate the importance of using a psychoanalytically informed treatment in working with a child and family to alleviate the magnification of fibromyalgia symptomatology. The treating psychiatrist’s work with Karen and her family terminated at discharge and she and her family returned to her previous psychologist who continued treatment with a new perspective. She was also referred to an outpatient psychiatrist for continued medication treatment. It is important to note that Karen’s pain did not completely go away by the end of her hospital stay; however, it no longer had any significant interference in her life. To quote Karen: “I still have pain but it doesn’t hurt me anymore.” Two years after discharge from the hospital, Karen continued to do very well and eventually her pharmacotherapy and then psychotherapy were discontinued due to her sustained full recovery. By the time of discharge from her outpatient treatment, Karen no longer had pain. This has occurred with other fibromyalgia patients we have treated, although some patients report that the pain will flare up during periods of physiological or psychological stress. Other patients live with the pain but no longer experience it as disabling. For some patients, fibromyalgia need not be disabling once the patient fully understands how to effectively manage it and the unconscious forces associated with the stressor become conscious, freeing the patient to find more adaptive psychological solutions.

Conclusion The authors have presented literature describing the physiological intersection of mind and body. As we join in the search for satisfactory treatments for juvenile primary fibromyalgia syndrome, one pathway may be a treatment that utilizes psychoeducation, cognitive behavioral, psychodynamic and psychopharmacology treatments, depending on the complexity of the particular individual’s stressor(s).

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Acknowledgements This paper is in memory of Harriet Knapp Ph.D. who was unable to complete this paper due to her untimely death. The authors would like to thank Dr. Sheldon Weintraub, Chief Psychologist of the Child Inpatient Ward for his invaluable suggestions throughout the treatment process. Authors thank the psychiatry residents: Drs. David Margulis and Innessa Indictor whose sensitive care assisted in the healing process; the work of the nursing staff, in particular Maureen Daly, RN, Margaret O’Brien, LPN, Jacqueline Presti, RN, and Karen’s teacher, Marion Savio. Dr. Hugger would like to thank Drs. Emily Klass and Pamela Degotardi (Psychologists); and Drs. Norman Illowaite, Beth Gottlieb and Anne Eberhardt (Pediatric Rheumatologists) for sharing their knowledge with her about fibromyalgia in the pediatric population. The work and ideas presented in this paper represent the thoughts of the authors and not the institutions with which they are affiliated.

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[2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

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Kashikar-Zuck, S, Graham, TB, Huenefeld, MD, Powers, SW. A review of biobehavioral research in juvenile primary fibromyalgia syndrome. Arthritis Care Res 2000;13(6):368-97. Carmichael, M. The changing science of pain. Newsweek 2007 June 4:40-47. Dobbs D. The pain gate. Scientific American MIND 2007;18(2):48-55. Chiong W. Diagnosing and defining disease. JAMA 2001;285:89-90. Underwood A. Fibromyalgia: not all In your head. Newsweek 2003; May 19:53. Anthony KK, Schanberg, LE. Juvenile primary fibromyalgia syndrome. Curr Rheumatol Reports 2001;3:1523-74. Gatchel RJ. Comorbidity of chronic pain and mental health disorders: biopsyhcosocial perspective. Am Psychol 2004;59(8):795-805. Ford CV. Somatization and fashionable diagnoses: illness as a way of life. Scand J Work Environ Health 1997;23 (Suppl 3): 7-16. Yunus M, Masi A. Juvenile primary fibromyositis syndrome Arthritis Rheumatol 1985;28:138-45. Anthony CP, Kolthoff, NJ. Textbook of anatomy and physiology, 8th ed. St Louis: Mosby, 1971. Grzesiak RC, Ury GM, Dworkin RH. Psychodynamic psychotherapy with chronic pain patients. In: Gatchel RJ, Turk D, eds. Psychological approaches to pain. New York: Guilford, 1996:148-78. Thernstrom M. My pain, my brain. New York Times Magazine 2006 May 14, 50-55. McGrath PA, Hillier LM. Controlling children’s pain. In: Gatchel RJ, Turk DC, eds. Psychological approaches to pain. New York: Guilford, 1996:331-70. Reid GJ, McGrath PJ, Lang BA. Parent-child interactions among children with juvenile fibromyalgia, arthritis, and healthy controls. Pain 2005;113:201-10.

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[15] Dreifus C. Finding clues to aging in the fraying tips of chromosomes. New York Times 2007 July 3; Science Times:F2. [16] Abeles AM, Pillinger MH, Solitar BM, Abeles M. Narrative review: The pathophysiology of fibromyalgia. Ann Internal Med 2007;146(10):726-34. [17] Van der Kolk BA. The body keeps the score: Approaches to the psychobiology of posttraumatic stress disorder. In: Van der Kolk BA, McFarlance, AC, Weisaeth, eds. Traumatic stress: The effects of overwhelming experience on mind, body and society. New York: Guilford, 1996:214-41. [18] Blackburn-Munro G. Hypothalamo-pituitary-adrenal axis dysfunction as a contributory factor to chronic pain and depression. Curr Pain Headache Report 2004;8:116-24. [19] Freidman M, Rosenman RH. Type A behavior and your heart. New York: Knopf, 1974. [20] Khan MMR. The privacy of the self. New Yopk: Int Univ Press, 1974. [21] Van der Kolk BA. Trauma and memory. In: Van Der Kolk BA, McFarlance, AC, Weisaeth, editors. Traumatic stress: the effects of overwhelming experience on mind, body and society. New York: Guilford, 1996:279-302. [22] Degotardi PJ, Klass ES, Rosenberg BS, Fox DG, Gallelli KA, Gottlieb BS. Development and evaluation of a cognitive-behavioral intervention for juvenile fibromyalgia. J Pediatric Psychol 2006; 31(7):714-23. [23] Shapiro B. Building bridges between body and mind: The analysis of an adolescent with paralyzing chronic pain. Int J Psychoanal 2003;84:547-61. [24] Aron L. Analytic impasse and the third: clinical implications of intersubjectivity theory. Int J Psychoanal 2006;87:349-68. [25] Stern D. The eye sees itself. Dissociation, Enactment and the achievement of conflict. Contemp Psychoanal 2004; 40(2): 197-237. [26] Slochower J. Holding and the evolving maternal metaphor. Psychoanal Rev 1996; 83(2):195-218. [27] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: APA, 1994. [28] Lyons-Ruth K, Jacobvitz D. Attachment disorganization: unresolved loss, relational violence, and lapses in behavioral and attentional strategies. In: Cassidy J, Shaver PR, eds. Attachment: theory, research and clinical applications. New York: Guilford, 1999: 520-54. [29] Loewald H. The waning of the Oedipus complex. J Am Psychoanal Assoc 1979; 27: 751-75. [30] Psychodynamic Manual (PDM) Task Force. Psychodynamic Diagnostic Manual. Silver Spring, MD: Alliance Psychoanal Org, 2006. [31] Terr LC, McDermott JF, Benson RM, Blos P Jr, Deeney JM, Rogers RR, Zrull JP. Moments in psychotherapy. J Am Acad. Child Adoles Psychiatry 2005;44(2):191-7. [32] Fonagy P, Gergely G, Jurist EL, Target M. Affect regulation, mentalization, and the development of the self. NY: Other Press, 2002. [33] Seligman S. Mentalization and metaphor, acknowledgment and grief: forms of transformation in the reflective space. Psychoanal Dialogues 2007;17(3):321-44.

Section III : Environment and Suicide

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XVIII

The Antisuicidal Efficacy of Lithium: A Review of the Clinical Literature and the Underlying Pharmacology Colleen E. Kovacsics, Harish K. Goyal, Koshy J. Thomas and Todd D. Gould ∗ Department of Psychiatry, Mood and Anxiety Disorders Program, University of Maryland School of Medicine, Baltimore, Maryland, USA

Abstract The results of a large number of studies suggest the efficacy of lithium in the prevention of suicide. These studies include retrospective, prospective, and discontinuation studies, as well as comparison studies with other medications. Despite this extensive clinical data, it remains unclear what molecular mechanisms underlie the antisuicidal efficacy of lithium. Lithium has a number of undesirable side effects that often limit its clinical use. Determining the molecular mechanisms that underlie the therapeutic effects of lithium is a critically important task. It may be possible to develop a novel drug that mimics the efficacy of lithium in the prevention of suicide, but possesses a more limited side effect profile than lithium. We review molecular effects of lithium that may be related to its antisuicidal efficacy, focusing particularly on serotonin neurotransmission.

Keywords: Prevention, suicide, lithium, neuroscience, serotonin.

∗

Correspondence: Todd D Gould, MD, 685 West Baltimore Street, MSTF 934D, Department of Psychiatry, Mood and Anxiety Disorders Program, University of Maryland School of Medicine, Baltimore, Maryland USA 21201 United States. Tel: 410-706-5585; Fax: 410-706-0751; E-mail: [email protected]

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Introduction In addition to the loss of life, suicide has widespread implications on society, health care, surviving family members, caregivers, and economic measures. According to the Centers for Disease Control and Prevention (CDC), National Center for Injury Prevention and Control data, suicide is the 11th leading cause of death in the United States with an annual suicide rate of 11.1 per 100,000 individuals, thus accounting for 1.4% of all deaths in United States (1). When examining subcategories of the U.S. population, the rate of suicide (per 100,000 individuals) is highest among white males [19.6] followed by non-white males [9.3]. A similar pattern is observed in females with whites showing higher rates than non-whites [5.1 compared to 2.4]. Within specific ethnic groups, the highest rates are seen in Native Americans [12.9] and black males [9.0], with lower rates evident in Asian/Pacific Islanders [5.6], Hispanics [5.3], and black females [1.8]. The prevalence of suicide is highest in the 4554 year age group, followed closely by people 75 years and older. Women attempt suicide about three times more frequently than men but men commit suicide about 3.7 times more often than women, and men represent 78.8% of all U.S. suicides (1). The number of suicide attempts is far higher than completed suicides and it is often difficult to determine exact figures for these behaviors. Suicidal behavior is common in psychiatric illnesses with an especially high prevalence in affective disorders. For example, patients suffering from bipolar disorder have a rate of suicide that is 20 times greater than that of the general population. Variables that can be associated with risk of suicide in patients with mood disorders include substance and alcohol abuse, family history of suicide, co-morbid anxiety, gender, history of lifetime episodes of depression, rapid cycling bipolar disorder, number of previous hospitalizations, and season of the year (2-14). A considerable challenge to both researchers and clinicians is to understand the extent to which pharmacological interventions can be useful in preventing suicide. So far in clinical practice, interventions such as close clinical supervision, psychotherapy, early hospitalization, and electroconvulsive therapy have generally shown limited efficacy for decreasing the long-term risk of suicidal behavior (14, 15). Extensive research has been undertaken on a variety of psychotropic medications to observe their anti-suicidal properties in psychiatric patients. These medications include lithium, valproic acid and other anticonvulsants, antidepressants, and typical and atypical antipsychotics, particularly clozapine. As we will discuss, a number of studies have observed a significant reduction in suicidal behavior with long-term lithium treatment. Additionally, there is evidence in favor of a reduction in suicide in schizophrenic patients treated with clozapine (15, 17, 18). Anticonvulsant drugs, which are commonly prescribed for mania, lack substantial evidence that they have long-term protective effects against suicidal behavior (19-21). Studies of antidepressants, though not reviewed in this article, are inconclusive about their antisuicidal properties and are an area of intense investigation. Antidepressants have been shown in some randomized placebo controlled trials to be effective in reducing suicidal ideation (22, 23) but there is also data that suggests antidepressants may induce suicidal ideation (15, 24-27). Overall, there is limited data supporting an effect of antidepressants in reducing suicidal acts (19, 28-30).

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Historical Studies of Anti-Suicidal Efficacy The efficacy of lithium in the treatment of mania was first reported in the medical literature by John Cade in his open trials and later Mogens Schou demonstrated that lithium was superior to placebo in the acute treatment of mania (31,32). Controlled data on the prophylactic mood stabilizing actions of lithium dates back to 1970 when Basstrup, Schou, and colleagues conducted a placebo controlled study and demonstrated the significant mood stabilizing effect of maintenance lithium therapy in bipolar and recurrent unipolar disorder patients (33). In 1974, Prien and colleagues conducted two randomized, placebo controlled studies that first suggested a decreased rate of suicide with lithium therapy. The first study involved 205 bipolar patients who were randomly assigned to lithium or placebo before discharge from the hospital following remission of an acute manic episode and the second study consisted of 44 bipolar and 78 unipolar patients, who were randomly assigned to lithium, imipramine or placebo following discharge from the hospital after treatment for acute depression. There were two suicides in the placebo groups and none in lithium groups, suggesting that lithium may have antisuicidal properties (34). An open study conducted in 1977 examined the efficacy of lithium in subjects with major affective disorder (35). The authors observed no suicides in the 123 subjects on lithium but 3 suicides in the subjects not taking lithium. Poole and colleagues looked at suicidal attempts in affective disorder subjects before and during lithium treatment (36). There were three times more suicide attempts before lithium therapy compared to during lithium treatment, which suggested that lithium may be reducing suicidality. In the early 1980s limited data was available regarding the antisuicidal effect of longterm prophylactic lithium treatment. Hanus and Zapletalek in 1984 observed a significant reduction in the number of suicidal acts in a high risk affective disorder population of 99 patients during a 5 year period of lithium treatment. This was evidenced by 4 suicidal attempts during lithium treatment compared to 25 attempts preceding the lithium treatment (37). In 1992, Muller-Oerlinghausen conducted a study on 68 manic-depressive patients with a previous history of a suicide attempt, and found that long term lithium treatment significantly decreased the risk of suicidal behavior (38). As mentioned in the introduction, the risk for suicide is much higher in white men and elderly populations (39,40). To investigate lithium’s antisuicidal potential and whether it varies with age and sex, Kessing and colleagues conducted an observational study and found that continued lithium treatment was associated with reduced rate of suicide regardless of sex, age and severity of illness using nationwide registers of all deaths and all prescribed medication in Denmark. The study also found that the rate of suicide decreased further with increasing numbers of lithium prescriptions (41).

Lithium Discontinuation Studies It has been suggested that the positive effects of lithium treatment, especially possible antisuicidal properties, may remain insignificant until after long-term treatment (38,42-46).

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Additionally, the results of some studies suggest that abrupt termination of lithium treatment leads to a high susceptibility for suicide (19,47-52). Tondo and colleagues in 1998 conducted a study on 310 bipolar disorder patients who were observed for an average of 8.3 years before and 6.4 years during lithium treatment (47). They also followed 185 patients who discontinued lithium treatment for an average of 3.7 years and compared the rate of suicidal acts before, during and after lithium treatment. Analysis of the results showed that the rate of suicidal acts per 100 patient-years before, during and after lithium treatment was 2.30, 0.355 and 3.51 respectively. This suicide risk was relatively high within the year of discontinuation [7.11 per 100 patient years] as compared to later years [2.29 per 100 patient years] and was even more than prior to starting lithium treatment [2.30 per 100 patient years] (47).

Antisuicical Efficacy of Lithium Compared to Anticonvulsants In recent years, anticonvulsant medication use for bipolar disorder has markedly increased as compared to lithium (53,54). Since bipolar disorder patients have a high risk of suicide it is important to find out whether these anticonvulsant medications provide protection against suicide in these high risk patients and if so, whether these medications are better than lithium. Theis-Flechtner and colleagues in 1996 conducted a randomized, prospective multicenter study on 378 patients suffering from bipolar, unipolar and schizoaffective disorders. Subjects were randomized for at least two years to lithium, carbamazepine, or amitriptyline. No suicidal acts were observed in the lithium group but substantial risk was seen in the other groups, as evidenced by 5 attempted and 4 completed suicides in the carbamazepine group and 5 completed suicides in a group that contained patients who had discontinued their randomized medication during the study period (21). In a large retrospective cohort study of 20,638 health maintenance organization members suffering from bipolar disorder, Goodwin and colleagues found that the risk of death from suicide was 2.7 times higher during treatment with valproic acid than during treatment with lithium. Additionally, non-fatal suicidal behavior resulting in hospitalization and attempts diagnosed in the emergency room were reduced with lithium therapy. In this study the results for carbamazepine were also similar to valproic acid qualitatively but were less significant, which may be related to the small carbamazepine sample size (20). Collins and McFarland reported a retrospective study in 2007 using data from Oregon’s Medicaid program. Subjects had a diagnosis of bipolar disorder and had received at least 1 dose of lithium, valproic acid, gabapentin, or carbamazepine. Only subjects receiving a monotherapy were included. The study compared rates of attempted and completed suicide in the subjects receiving each medication. Overall, the lowest rates of both attempted and completed suicide were found in the lithium treatment group. When comparing lithium to valproic acid, the authors found that there was a statistically significant increase in suicide attempts in subjects taking valproic acid as compared to those taking lithium. The only statistically significant result found in regards to completed suicide indicated that lithium led to a decreased risk of suicide when compared to gabapentin (55).

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Meta-Analyses In recent years several meta-analyses have been published that support the efficacy of lithium in preventing suicidal behavior. Cipriani and colleagues in 2005 conducted a metaanalysis of randomized controlled trials and found lithium to be more effective in reducing risk of suicide, deliberate self harm, and overall mortality than placebo, anticonvulsants or antidepressants in subjects with a mood disorder (56). Reduction in the risk of suicide was reflected by a decrease in all-cause mortality, as the cause of most of the deaths was suicide. The proportionate reduction of both suicide and all-cause mortality also suggested that there was no increase in fatalities due to lithium toxicity (56). Baldessarini and colleagues, analyzing open clinical trials in addition to several randomized studies in a 2006 metaanalysis, found that the risk of completed suicide in bipolar disorder patients decreased by 8.4 times with long term lithium treatment compared to the patients without lithium treatment. Additionally they found the risk of suicide attempts decreased by an average of 3.4. In this meta-analysis, Baldessarini also reported on the lethality of suicidal acts (ratio of attempts/suicides) and found that with lithium treatment, there were fewer fatalities per suicide attempt, indicating decreased lethality of suicidal acts (incidence ratio of attempted to completed suicide was 2.5 times higher with lithium versus without lithium) (57). To address whether lithium has a role in reducing suicide in recurrent major depressive disorder, similar to what is seen with bipolar disorder, Guzzetta and colleagues conducted a meta-analysis in which they reviewed 8 studies involving 329 major depressive disorder patients with an average exposure time of 4.56 years with lithium and 6.27 years without lithium. Risk of suicidal behavior was found to be 88.5% lower with lithium treatment (16).

Evidence of an Independent Antisuicidal Effect Current data suggests that long term lithium treatment significantly reduces suicidal behavior. One possibility is that lithium provides protection against suicide by prevention of recurrence of depressive episodes (3,5,11). However, the fact that traditional antidepressants do not appear to have a significant antisuicidal profile argues against this possibility. Furthermore, Ahrens and Muller-Oerlinghausen reported a reduction in suicidal acts in both responders and non responders to long term prophylactic lithium treatment, suggesting that lithium may act as an independent antisuicidal agent irrespective of its effect on affective disorders. Specifically, the analysis relied upon a retrospective study of 167 high risk recurrent affective disorder patients drawn from the main International Group for the Study of Lithium-treated patients (IGSLI) study, who had a history of one or more suicide attempts before starting lithium prophylaxis. They divided the sample into 3 groups: excellent lithium responders who experienced no further affective episodes during treatment time, poor lithium responders who showed no reduction in affective episodes or not less than 50% of number of episodes from pre-lithium treatment state, and moderate responders which consisted of the remainder of the sample. Though the clinical response to prophylactic lithium therapy was different, a statistically significant reduction in suicide attempts was observed in all three groups.

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This suggests that lithium might be exerting an antisuicidal effect even in patients whose mood does not improve (58, 59).

Evidence against Lithium and Study Limitations Although the majority of studies conducted provide evidence in favor of lithium being an effective antisuicidal agent in affective disorders, there is not complete agreement. For example, Coryell and colleagues suggested that confounding biases such as a patient’s adherence with treatment and lower risk of suicidal behavior could lead to artifactually positive results (60). In a case control design using data from the NIMH Collaborative Depression Study, patients who completed or attempted suicide were compared. They did not find any significant protective effects of lithium (60). In a small study of 140 private practice patients with bipolar disorder treated for a minimum of 6 months, Yerevanian and colleagues found no difference in incidence of suicide between patients who were on lithium and those who were on anticonvulsant medications, chiefly valproic acid (61). They extracted the data from patient charts and compared the incidence of completed suicides, number of suicide attempts, and number of hospitalizations for suicidal ideation or behavior per 100 patient years of either “on” or “off” lithium or anticonvulsant mood stabilizer monotherapy. Analysis of the results indicated that only one completed suicide occurred (the patient was in an “off” period of lithium treatment at the time) and that incidence of nonlethal suicidal behavior was not different during treatment with lithium or an anticonvulsant. A possible reason for the low number of suicides and apparent lack of an antisuicidal effect of lithium is that the quality of patient care and strength of therapeutic alliance is relatively higher in private practice, and the severity of illness is relatively lower (61,62). Overall, there are certain limitations of studies that use suicide as a final outcome measure. Conducting randomized clinical trials to determine suicide risk has ethical implications. The relatively low incidence of suicide and attempted suicide even in high risk populations limits the power of studies (63). For example, in 2005 Born and colleagues reported a retrospective chart review of 128 patients on lithium and anticonvulsant medications at a university clinic in Germany; there were no suicide attempts/suicide deaths during an average follow up of 1 year (62). Since suicide is a rare event epidemiological studies that include suicide as an outcome require large sample sizes and lengthy follow up periods (64). Furthermore, since suicide may not be the primary outcome of interest of studies, suicidal acts of less severity may be underreported (16,57). On the other hand, the subjects from studies conducted mainly in lithium clinics or specialist university clinics generally exhibit severe psychiatric illness or are non-responsive to treatment, thus making it difficult to generalize the results of such studies to the general population (64-66). Therefore, the rate of suicide and the effect of lithium on suicide may vary according to disease severity, intensity of care, and strength of therapeutic alliance (41,67). In regards to meta-analyses, the trials which fail to show the superiority of lithium compared to placebo or to other medications may not be published (56). Also the available data is often subject to certain limitations such as lack of control for multiple medication use, the influence of noncompliance, and treatment discontinuation.

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Adverse Effects of Lithium Due to the data discussed in the preceding sections the efficacy of lithium as a pharmacological intervention for the prevention of suicide is mostly accepted. However, lithium is not an ideal medication. Due in part to its narrow therapeutic window, lithium can cause many side effects that often affect a patient’s adherence to treatment. The optimum therapeutic range of lithium is a serum level in the range of 0.5 – 1.2 mM and severe toxicity generally occurs at the level of 2 mM or more. However mild adverse effects can occur even if the serum lithium level is in the therapeutic range. It can affect many organ systems (68,69). Patients who are on long term lithium treatment can develop renal complications such as nephrogenic diabetes inspidus with polydipsia and polyuria as a result of tubular or glomerular dysfunction (70). Thyroid impairment is another well known side effect of long term lithium therapy that manifests as hypothyroidism. Lithium-induced hypothyroidism is more likely in women than in men and may be accompanied by raised serum calcium and magnesium concentration (69,71). Lithium is considered a teratogenic drug (category D). It can cross the placenta easily, so it is contraindicated in the first trimester of pregnancy. It has been suggested that it is associated with Ebstein’s anomaly in fetus, but from a follow up study of 60 babies born to mothers who had taken lithium during the first trimester, Mogens Schou concluded that there was no increased frequency of either physical or mental abnormalities in the children (72). The current data on lithium’s association with Ebstein’s anomaly is equivocal; however lithium may cause skeletal and craniofacial dysmorphism and abnormal vasculogenesis (73). Mild toxicity may manifest as abdominal discomfort, nausea, vomiting, diarrhea, vertigo, blurred vision, sleepiness, dizziness, muscle weakness, fine tremors or drowsiness. Signs and symptoms of mild toxicity can occur at the start of treatment but they frequently disappear as the therapy stabilizes. As toxicity increases, the patient may have excessive thirst, polyuria followed by increased drowsiness, confusion, hyper-reflexia, fasciculations, seizure, basal ganglia dysfunction manifesting as parkinsonism and choreoathetoid movements, cerebellar signs such as ataxia, nystagmus and eventually coma or even death (46). Thus, lithium has a very narrow therapeutic index, is dangerous in overdose, and can be used purposely to commit suicide in patients at high risk of suicide. However the use of lithium to commit suicide is rare, which may be due to its antisuicidal effects (16,57). In summary, lithium has a number of side effects. The ones that most commonly lead to its discontinuation, and are often unrelated to dose, include metallic taste, confusion, tremors, dryness of skin, polyuria, polydipsia, weight gain, hypothyroidism, and diabetes inspidus. Despite the therapeutic benefits of lithium for the treatment of mania, depression, and suicide, it remains unclear how lithium exerts these effects. Without a clear understanding of how lithium works, it has been impossible to develop a next generation of lithium mimetic compounds that effectively reproduce the therapeutic benefits of lithium without the undesirable side effects. In the next section we review some of the molecular targets of lithium as well as secondary actions of select intracellular signaling pathways. We then describe the effects of lithium on serotonergic neurotransmission, which is perhaps the most likely mechanism by which lithium may exert its antisuicidal effects.

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Molecular Targets and Signaling Pathways Initial Direct Targets of Lithium Lithium inhibits the activity of some enzymes through competition for magnesium (7476). At high concentrations, lithium inhibits the activity of a number of enzymes. However, at human therapeutic concentration (0.6 - 1.2 mM), only a few are recognized as being more than modestly inhibited. Defined by John York and colleagues in 1995, lithium inhibits a group of at least four related phosphomonoesterases, which are a group of magnesium dependent, lithium sensitive phosphatases that, in mammals, currently includes inositol polyphosphate 1-phosphatase (IPPase), inositol monophosphate phosphatase (IMPase), fructose 1,6-bisphosphastase (FBPase), and bisphosphate nucleotidase (BPNase) (77). All members of this small group contain a conserved amino acid sequence motif, Asp-Pro-(Ile or Leu)-Asp-(Gly or Ser)-(Thr or Ser), and have a common core tertiary structure that binds metal ions and participates in catalytic functions of the enzyme (77). Of these enzymes, IPPase, IMPase, and FBPase were originally identified as containing this conserved structure (77), whereas BPNase was identified subsequently based upon its common sequence (78). Lithium also inhibits the metabolic enzyme phosphoglucomutase (PGM) (79-82) and a kinase that functions as an intermediary in numerous intracellular signaling pathways, glycogen synthase kinase-3 (GSK-3) (83, 84). Much of the research effort concerning the mood stabilizing effects of lithium has focused upon IMPase and GSK-3 as possible therapeutically relevant targets of lithium inhibition based predominantly upon the roles these enzymes play in neurological functions (for review see (85)). It is likely that lithium exerts its initial biochemical effects on the activity of cellular enzymes, which modulates the activity of signaling pathways, and ultimately results in physiological effects such as changes in the release of, and/or response to, neurotransmitters.

Signaling Pathways Modulated by Lithium Lithium has been documented to alter the activity of a number of signaling pathways. The majority of research studies have focused on cyclic AMP and phosphoinositol mediated signaling, and more recently neurotrophic signaling cascades. Lithium appears to have complex effects on cyclic AMP mediated signaling, with the preponderance of the data demonstrating an elevation of basal Adenylate Cyclase (AC) activity, and an attenuation of receptor-stimulated responses in both preclinical and clinical studies (see (86) for an excellent review). Thus, a number of independent research laboratories have found that lithium decreases receptor-mediated activation of AC (86,87). These extensive cellular findings are consistent with an animal model where cholera toxin (a stimulator of the G proteins, Gs and Golf) induces hyperactivity when injected into the nucleus accumbens of rats. Cholera toxin induced hyperactivity was decreased by lithium administration, consistent with decreased Gs and/or Golf activity during lithium treatment (88). However, there is also evidence to suggest an increase in basal cyclic AMP activity (see (86) for a review of this

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literature). Thus, the literature describing the effect of lithium on G proteins suggests that lithium both increases basal activity and inhibits stimulated AC. As mentioned, IPPase and IMPase (enzymes that are involved in recycling of inositol-1, 4, 5-triphosphate (IP3) back to PIP2) are directly inhibited by lithium (89). The fact that lithium Inhibits these enzymes led to the inositol depletion hypothesis of lithium’s action, which suggests that lithium, via inhibition of IMPase, decreases the availability of myoinositol, and thus the amount of PIP2 available for G-protein mediated signaling events that rely upon this pathway (90). The inositol depletion hypothesis led to a number of studies, both in cultured cells and animal models, which suggest that the PI pathway may be involved in the pathophysiology or treatment of bipolar disorder (91). Protein Kinase C (PKC) is a primary target of 1,2-diacylglycerol (DAG), an enzyme regulated by activity of the phosphoinositol (PI) signaling pathway, and as such there has been extensive research in regard to the action of lithium on the PI pathway. PKC is an omnipresent enzyme, highly enriched in the brain, where it plays a major role in regulating both pre- and postsynaptic aspects of neurotransmission (92). Chronic lithium treatment decreases the level of PKC isozymes α and ε (93-95) in cells and treated rodents. The precise mechanism by which lithium exerts these isozyme-selective actions is unknown, but there is evidence that it is due to lithium’s inhibition of IMPase (91,93). Further supporting the effect of lithium on PKC, lithium decreases the levels and phosphorylation of a major PKC substrate, myristoylated alanine rich C kinase substrate (MARCKS), following chronic treatment in rats (96). In cultured cells, it was found that this effect appears to be dependent on low media inositol concentrations, thus implicating lithium’s inhibition of IMPase and/or IPPase as a causative factor (91,97). Neurotrophins are a family of regulatory factors that mediate the differentiation and survival of neurons, as well as the modulation of synaptic transmission and synaptic plasticity. It is beyond the scope of this review to discuss all the various neurotrophin signaling pathways and lithium’s action on them. However, as one example, many of the effects of neurotrophins are mediated by the ERK MAP kinase signaling pathway, and the effects of activation of this pathway are observed on effectors and transcription/translation of neurotrophic molecules such as bcl-2 and brain derived neurotrophic factor (BDNF). Lithium, at therapeutically relevant concentrations, has been shown to activate the ERK MAP kinase cascade in human neuroblastoma SH-SY5Y cells (98) and in the rodent brain (99). A downstream target of the MAP kinase cascade is ribosomal S-6 kinase (Rsk), which phosphorylates the cAMP response element binding protein (CREB) and this leads to induction of bcl-2 and BDNF gene expression. Treatment of rats with therapeutically relevant concentrations of lithium results in an increase in the activation or Rsk, and CREB, and an increase of bcl-2 levels in frontal cortex (100-102). Lithium has also been shown to increase the expression of BDNF in rodent brain (103). Consistent with its effects on neurotrophic signaling cascades, lithium has been demonstrated to be neuroprotective in animal models of ischemia and Huntington’s disease. Furthermore, lithium promotes neurogenesis in the hippocampus of rats, increases the regeneration of CNS axons (104), and is neuroprotective in many cell culture models (see (105,106). Evidence suggests that the neuroprotective effect of lithium in cortical neurons requires BDNF expression (107).

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The therapeutic mechanism of lithium action thus likely involves an initial inhibition of the function of lithium-inhibitable enzymes. This inhibition then modifies the function of intracellular signaling pathways, modifying extracellular receptor-mediated signal transduction as well as the transcription of proteins resultant from activation of transcription factors. These changes ultimately result in physiological effects, such as neuroprotection (as discussed above), changes in hormones, and modulation of neurotransmitter systems. The full discussion of these effects requires a separate review article, and the interested reader is referred to the following excellent reviews (85,108-110). As discussed below, there is extensive evidence implicating the serotonergic system in suicide. For this reason, we focus our discussion of the downstream effects of lithium on the serotonergic neurotransmitter system.

Serotonin Neurotransmission A Possible Target for the Antisuicidal Effects of Lithium While lithium has a number of physiological effects and modulates a number of different neurotransmitter systems, we focus here on lithium’s action on the serotonergic system. The rationale for this focus is multifold. Since the emergence of the monoamine hypothesis of depression, serotonin has been implicated in the pathophysiology and treatment of depression. Many antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs), act by increasing neurotransmission of this monoamine. Partly because suicide is typically associated with depression, many investigators have explored alterations in the serotonin system in suicide. However, as discussed in the introduction, antidepressants such as SSRIs that have robust actions on serotonin neurotransmission do not appear to be particularly efficacious in the prevention of suicide, and some studies suggest that this class of medications may actually increase the risk of suicide. The observation that lithium may exert its antisuicidal effects independent of its mood stabilizing effects suggests the possibility of unique antisuicidal and mood stabilizing targets of the drug (58, 59). The results of numerous studies suggest both completed and attempted suicides are associated with an overall decrease in serotonergic transmission. While not all studies are in complete agreement, the majority show that 5-hydroxyindoleacetic acid (5-HIAA), the metabolite of serotonin (5-hydroxytryptamine, or 5-HT), is decreased in the cerebral spinal fluid (CSF) of individuals who have attempted suicide (111-113). Additionally, 5-HT was observed to be decreased in the CSF of suicide victims (114). The number of 5-HT transporter binding sites appears to be decreased in the prefrontal cortex of individuals who have committed suicide (115,116). Other changes in the serotonin system that have been found in relation to suicide include an increase in both 5-HT1A and 5-HT2A receptors (115, 117). These results point to the possibility that serotonergic transmission is altered in individuals who attempt and commit suicide (118,119). Furthermore, studies have identified modifications of the serotonin system that are associated with suicide independently of depression (118). These data thus suggest that while both depression and suicide are associated with alterations in serotonin neurotransmission, the specific serotonin pathways

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affected as well as the associated molecular changes are distinct. It is therefore likely that treatments for depression and suicide, that both may target serotonin neurotransmission, may do so via distinct mechanisms. Preclinical studies observing changes in the serotonin system induced by lithium have yielded mixed results. Often different results are found in different brain regions, or with different doses and durations of lithium treatment. The preclinical studies discussed in this section all involved either mice or rats. We describe studies as either short-term (five days or less) or long term (greater than two weeks) of lithium administration. When administered short term, lithium appears to have no effect on 5-HT levels in the frontal cortex (120-122), but increases 5-HT levels in the hippocampus and whole brain (120,121). While long term lithium administration did not change 5-HT levels in different cortical regions (123), levels were decreased in the hypothalamus and brainstem (124). Eight days of lithium treatment led to elevated 5-HT levels in the limbic forebrain structures and hemishpheres (whole brain minus limbic forebrain and striatum) (125). Also following long term administration, both basal and stimulated serotonin release was found to be increased in the hippocampus, but no change in release was observed in the cortex (126). When examining the metabolite 5-HIAA, varied results have been found. Long term lithium treatment was shown to lead to both increases and no changes in the whole brain 5-HIAA and a decrease in the cingulate cortex 5HIAA (123, 125, 127). Overall, lithium may increase the levels of serotonin or serotonin metabolites in particular brain regions in the rodent, but may also have an effect to decrease serotonin levels in other brain regions such as the hypothalamus and brain stem. The studies on 5-HIAA are inconclusive; it is important for more studies to be conducted to determine the exact effects lithium has on serotonin and 5-HIAA levels in the brain. The 5-HT transporter acts to remove serotonin from the synapse and transports it back inside presynaptic neurons. Short term lithium administration has been reported to have no effect on the amount of uptake sites present in the rodent brain (128). Administration of lithium long term was also shown to have no effect on the number of transporter sites in the cortex or to increase uptake sites in the cerebral cortex, lateral hypothalamus, brain stem, corpus striatum, and hippocampus (123,128, 129). Tryptophan is a precursor to 5-HT and long term lithium administration leads to an increase in both the brain levels and uptake of tryptophan, while short term lithium has been shown to have no effect on brain levels of tryptophan (130-133). Tryptophan hydroxylase is the rate limiting enzyme of serotonin synthesis, and both short and long term lithium administration has been shown to decrease this enzyme’s activity in the midbrain (134). Overall it appears that short term lithium administration has limited effect on the serotonin transporter or tryptophan levels, but one study shows that it may decrease the activity of tryptophan hydroxylase. With long term treatment lithium appears to have limited effect on serotonin transporter levels, decreases tryptophan hydroxylase activity, and increases both the levels and uptake of tryptophan. Many distinct serotonin receptors have been characterized thus far, but most studies have focused on the 5-HT1 and 5-HT2 types. With short term administration lithium seems to have no effect or leads to an increase in the number of 5-HT1A receptors (135,136), while long term lithium can have no effect or can decrease the number and mRNA signal of these receptors in various brain regions (123,137-141). One study suggests that long term lithium increases the number of low affinity 5-HT1B receptors and decreases the number of high

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affinity receptors as measured with 5-HT and [3H]8-OH-DPAT competition assays (123). This change would lead to a decrease in receptor sensitivity. In the hippocampus, frontal cortex, and choroid plexus, long-term lithium led to no change in 5-HT1B receptor density (137). Two studies have found that long term lithium administration shows no effect on 5HT2 receptor density in a variety of brain regions (142,143). Electrophysiological experiments are another method that has been used to investigate the effects of lithium on the serotonin system and studies using this method have focused on short term lithium treatments. Short term lithium has been shown to increase the effect of stimulating the ascending 5-HT pathway, which leads to a decrease in the firing activity of dorsal hippocampal neurons (136,144). Lithium did not change the response to 5-HT itself, the firing rate of neurons, or effectiveness of manipulations that alter 5-HT autoreceptors, suggesting that the actions of lithium may be on the release of serotonin or some other alternative mechanism (136, 144). Lithium has also been shown to augment the effects of antidepressants on the firing of dorsal hippocampal pyramidal neurons (135). As suicide is uniquely human behavior, it is obviously not possible to recreate the behavior in animals. However, it may be possible to study the relevance of the neurobiological underpinnings of suicide (endophenotypes) in animals (145-147). To date, few studies have linked the actions of lithium on serotonin to animal models of impulsivity and aggression that may be related to suicide (148). There is evidence that the behavioral effects of lithium in mouse models of antidepressant efficacy may be mediated in part through actions of lithium on serotonin neurotransmission. The mouse forced swim test is an animal model of antidepressant efficacy (149). When a subactive dose of lithium was administered prior to a subactive dose of the 5-HT1A agonist gepirone, or other serotonin agonists, immobility time was reduced in the forced swim test (149,150). This additive mechanism is likely to be mediated largely by the serotonergic system, as antidepressants specific for dopaminergic and noradrenergic transmission are not affected by lithium in this model (150). A similar effect of 5-HT1A agonists to potentiate the effect of lithium has also been observed in the tail suspension test, another model of antidepressant efficacy (151). There is also evidence that the lithium may act through 5-HT1B receptors, since the 5-HT1B receptor agonist, anpirtoline, also augmented the effects of lithium in the forced swim test (152). There are also serotonin-mediated behaviors present in rodent on which the effects of lithium have been studied. The 5-HT1A receptor agonist (8-OH-DPAT) produces two different behavioral effects: hypothermia and a movement syndrome referred to as the serotonin syndrome. It has been proposed that the hypothermia is the result of the agonist’s actions at presynaptic receptors while the serotonin syndrome results from postsynaptic actions (153). The hypothermic response in mice can be attenuated with 14 days of lithium treatment, but in rats 3 or 14 days of lithium does not change this response (143,154). A possible reason for this discrepancy is that the rats had plasma lithium levels below the therapeutic range (reported as 0.4mmol/L)(154). The serotonin syndrome induced by 8-OHDPAT consists of stereotyped and observable motor behaviors including forepaw treading, head weaving, tremor, flat posture, and hindlimb abduction (154,155). The results of two studies in rats indicate that both 3 and 14 days of lithium treatment result in enhancement of this syndrome (154,155). The results of these studies using 8-OH-DPAT suggest that lithium

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may differentially affect the cellular response following stimulation of presynaptic and postsynaptic 5-HT1A receptors. Several studies indicate these 5-HT1A receptors can be differentially regulated by drug treatments and are coupled to different G proteins (156). Several other behaviors in rodents have a proposed serotonergic mechanism. These include head twitches in mice and wet dog shakes in rats. Both of these behaviors are hypothesized to be mediated by 5-HT2 receptors. In mice, head twitch behavior can be induced by the 5-HT precursor 5-hydroxytryptophan (5-HTP) and carbidopa or by the agonist 5-methoxy-N, N-dimethyltryptamine (5 MeODMT). This behavior is decreased by both 3 and 14 days of lithium treatment (143). In rats, wet dog shakes can be induced by (± )-DOI, a 5HT2A receptor agonist, and long term lithium treatment was shown to decrease this behavior (157). Lithium appears to decrease the sensitivity of the 5-HT2 receptors in both mice and rats. Another behavioral measure is that of hyperlocomotion, induced by the 5-HT receptor agonist, RU24969. At short and long term doses, lithium does not effect this hyperlocomotion syndrome in mice (143). It is important to keep in mind that the effects of lithium on these models do not imply that they are models of suicidal behavior, but simply provide evidence for the role of serotonin in mediating some of the behavioral effects of lithium. However, the complex effect lithium appears to have on 5-HT mediated behaviors may be related to its antisuicidal effects. Additionally, effects opposite those observed with other depression treatments such as SSRIs, could be important for lithium’s unique antisuicidal or antimanic properties. The results of these preclinical in vivo studies are complemented by cell culture studies of lithium’s effects on serotonin. When lithium was added to cortical membrane preparations, the only change seen in 5-HT receptors was a decrease in 5-HT1B receptor density (158). Hippocampal slices showed a decrease in 5-HT release when lithium was applied at a low dose; at a higher dosage lithium inhibited the regulation of 5-HT release that 5-HT exerts through autoreceptors (159). In agreement with these results, brain slices from rats that had received short term treatment with lithium in vivo showed a decrease in stimulation induced 5-HT release when lithium was applied in vitro (160). Overall, lithium appears to have various effects on the different components of the serotonin system. Lithium likely leads to increases in serotonin levels and serotonin release in certain brain regions such as the hippocampus and decreases in other areas, possibly including the hypothalamus and brainstem. The increase observed with lithium could potentially counteract the decrease in serotonin observed in the forebrain of individuals who died of suicide (118). The literature also suggests that lithium decreases the activity of tryptophan hydroxylase, which would be expected to lead to a decreased serotonin production, and could possibly be a cellular response to regulate lithium-induced increases in serotonin. This is consistent with the findings of Bach-Mizrachi and colleagues that tryptophan hydroxylase protein and mRNA is increased in the dorsal raphe nucleus of individuals who died of suicide compared to controls (161, 162). While the mechanism of this increase is unknown, it is likewise hypothesized to be due to compensation for altered (in this case decreased) serotonin (161). Although this enzyme may be decreased, its substrate, tryptophan, appears to be increased in both levels and uptake with lithium administration. It is unclear what effect, if any, lithium has on regulating 5-HT receptors. Electrophysiological studies suggest that lithium increases serotonin neurotransmission. Lithium appears to

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augment the actions of antidepressants and serotonin agonists in the mouse forced swim test and tail suspension tests models of antidepressant efficacy. The studies described above employed various doses and treatment lengths and looked at different components in different brain regions. It will be important in future studies to conduct comprehensive experiments that examine lithium’s effects at various dosing levels and in specific brain regions. Although lithium does appear to alter serotonergic transmission, there is much research that needs to be done in order to clarify these effects and to determine their relevance to the antisuicidal effects of lithium. As supported by literature suggesting limited, if any, antisuicidal efficacy of SSRIs, future pharmacological approaches to help prevent suicide by targeting the serotonin system will likely not act simply by increasing intrasynaptic levels of serotonin, but rather by a more complex mechanism that is relevant to only a subset of neurological circuits that rely upon serotonin neurotransmission.

Conclusions Suicide is a leading cause of death. There is more evidence for lithium preventing the occurrence of suicide than for any other medication. However, it is unknown by what mechanism lithium exerts its antisuicidal effects. Concerns inherent in the use of lithium include undesirable side effects ranging from weight gain to hypothyroidism and also its narrow therapeutic window that requires continual monitoring. The potential benefits of a lithium mimetic drug would include a reduction in side effects and a potential increase in efficacy. Lithium has a number of direct and indirect targets and the actions of lithium on these may be related to its therapeutic actions. However, there is a tremendous need for more research on the role of these targets in the therapeutic actions of lithium.

Acknowledgements We very much appreciate the comments of Helene Bach-Mizrachi, Columbia University.

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In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XIX

Suicidality in the Juvenile Justice Environment Srirangam S Shreeram∗ and Aditi Malik 1

Psychiatry Residency Training Program, St. Elizabeths Hospital, Washington, DC, USA

Abstract This article provides an overview of the prevalence, risk factors, and screening instruments for suicidal thoughts and suicidal behaviors in the juvenile delinquent population. Factors specific to the juvenile justice environment and their interactions with suicidality in adolescents are examined. Methods: A search of the MEDLINE and SearchMedica Psychiatry databases was conducted for articles published since 1980 in the areas of suicide and suicidal behavior in the juvenile offender population as well as the general adolescent population. Results: Several studies reported an increased rate of suicide and suicidal behavior in juvenile delinquents as compared to the general adolescent population. Risk factors can be grouped in four major categories Demographic factors –female gender, race (Native American >Hispanic>White>Black); Psychiatric illness- mood disorders, substance abuse, conduct disorder, history of suicidal behavior; Psychological factors- impulsivity, history of sexual abuse; Environmental factors- housing with adults, room confinement, locked sleeping rooms, short term facility. Conclusion: The environment (juvenile detention) is but one of several factors that might explain the increased rate of suicides in juvenile facilities. A continuum of universal screening at intake, adequate psychiatric treatment including medication management and therapy, appropriate facility level changes, adequate housing, staff training and restricted use of confinement are likely to be very helpful.

∗

Correspondence: Srirangam S Shreeram, MD, Psychiatry Residency Training Program, St. Elizabeths Hospital, 2700 ML King Ave SE, Barton Hall 2nd Floor, Washington DC 20032, USA. E-mail: [email protected]

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Keywords: Suicide, suicidal thoughts, suicide attempts, juvenile justice, delinquents, Juvenile Delinquency, risk factors, screening instruments.

Introduction A juvenile offender or juvenile delinquent is a person, who has been adjudged to have committed an act of juvenile delinquency. Youths are referred to the juvenile court through different sources such as law enforcement, social services, schools, parents and victims. Of the youth that are referred to the juvenile court about 60% are formally processed (“petitioned”), while the rest are informally handled. About 60% of the youth petitioned to juvenile courts are judged to be delinquent. Over half of adjudicated delinquent youth are placed on probation and over one quarter are placed in residential facilities. Other sanctions include community service, restitution, referral to another agency, or waiver to the adult criminal court (1). At any processing point, a juvenile may be held in detention centers or reception centers (short-term facilities) to await adjudication or further processing. Less than a fifth of all juvenile delinquency cases result in detention between referral and disposition (1). Juveniles are usually detained if they are believed to be a threat or to be at risk if returned to the community, or if there are concerns that they may not appear at an upcoming hearing. The fact that black youth are nearly twice as likely to be detained as white youth (1) is an indication that social factors play a role in determining which youth are detained. Determination of which juvenile remains in the community and who is incarcerated is often made on the basis of the offense. Serious offenses like murder and rape warrant automatic detention for the safety of the society. However, environmental factors such as socioeconomic status, family functioning, the availability of social supports, community resources and alternative placements frequently determine whether a juvenile is detained or remains in the community. Even after adjudication, the court-ordered release of juveniles into the community or placement into long-term facilities is determined, among other factors, by the social environment that is available to the juvenile in the community. The fundamental difference between the juvenile justice system for youth and the criminal justice system for adults is that rehabilitation is considered to be the primary goal for youth. Suicide is the third leading cause of death among females and the fourth among males among 15-19 year-olds, in the general population worldwide (2). In the United States, suicide is the third leading cause of death among those aged 15-24 years in the general population (3). A report on 7-year follow-up of 118 formerly incarcerated delinquent youth of both sexes, seven had died before their 25th birthdays (4). The authors of this report calculated that the mortality rate of the sample works out to be approximately 58 times the national average for individuals in their age group. Suicide risk of juvenile offenders is estimated to be three to five times that of the general adolescent population (5-7). The risk of suicidal ideation and suicidal behaviors is also very high among juvenile offenders. In a study of youth incarcerated in 39 detention facilities across the United States 22% had seriously considered suicide, 20% had a plan to commit

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suicide, 16% had made at least one suicide attempt, and 8% had been hurt in a suicide attempt in the previous year (8). Some studies have even shown that the methods used for suicide attempts by incarcerated adolescents tend to be more violent than those of young people in the general population (9). Hence, suicide attempts and death by suicide among confined juvenile offenders is a major public health concern. The higher risk for suicide among confined adolescents could be due to risks inherent to this high-risk population (10). In a US national study of juvenile suicides in confinement, all suicides in youth detention centers occurred within the first four months of detention, with 40% of the suicides occurring within the first 72 hours (11). This suggests that the events preceding incarceration and the stress associated with incarceration may contribute to the increased suicide rates among confined youth. Thirdly, an increased risk for suicidality may also be conferred, in part, by the environment of juvenile justice facilities (6). In this review we examine the environmental effects of the juvenile justice confinement, as well as the interaction of such effects with risk factors inherent to these high-risk youth, on suicidality. It should be noted that the factors that make these youth “high risk” are as much a function of the pre-detention environment as they are individual attributes. While not minimizing the importance of the pre-detention environment, this review focuses on studies of suicidality in detained juveniles. However, evidence was also gathered from studies of suicidality in youth with any juvenile justice involvement. All suicide-related thoughts and behaviors including suicidal ideation, attempted suicide, and completed suicide are considered. Finally, we discuss the measures that can be taken to diminish the risk for youth suicide in juvenile justice facilities.

Methods We conducted a search of the MEDLINE and SearchMedica Psychiatry databases for articles that had been published since 1980 on suicide in the juvenile offender population as well as articles on adolescent suicide. Terms used in the search were “delinquent(s),” “suicide delinquents”, “suicide adolescents”, “mood disorder delinquents” and “Juvenile Delinquency [MeSH]”. Manual reviews of articles’ reference lists identified additional studies which were reviewed.

Results Demographic Risk Factors Demographic factors associated with suicidality in juvenile detainees have been the focus of many studies.

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Race In a survey of 1801 minors in 39 short-term and long-term facilities randomly selected from across rural and urban areas of the United States, North American Natives were the most likely to report suicidal ideation and attempts (29%), followed by whites (25%), Hispanics (15%), Asian Americans (12%), and African Americans (8%) (8). Adjusting for other risk factors such as substance use, gang membership, and sexual abuse, white youth were at twice the risk for suicidal ideation, and white/Native American youth were at more than twice the risk for suicide attempts. The rate of completed suicide for white juveniles between the ages 7–17, during 1981-1998, averaged nearly twice the rates for black youth and Asian youth (12). The same survey found that the rate of suicide in Native American youth was double that of white youth. Although the suicide rate was higher in white youth as compared to black youth, the suicide rate for black males increased 240% between 1981 and 1994, while the rate for white males increased 40%.

Gender Thompson and others found that although male gender was significantly associated with suicidal ideation and suicidal attempts among the general population of adolescents, delinquency was more strongly associated with suicidal ideation in girls than in boys (10). The authors speculate that delinquency is more normative for boys than girls and suggests that girls who engage in delinquent behaviors may differ more from their less delinquent female counterparts on a range of variables predicting poor functioning than delinquent boys differ from their counterparts. Among confined delinquents as well, a higher risk for suicidal ideation and suicidal attempts has been found among females (8). Female delinquents in the juvenile justice system have significantly higher rates of psychopathology (13,14), child maltreatment, other traumatic experiences, and familial risk factors (14) than delinquent boys. Many of these are risk factors for suicidal behaviors in female adolescents and young adults (15). Although, girls are more likely to consider and even attempt suicide, boys’ attempts were more lethal (16). A retrospective study of all suicides among young people in Quebec found that female juvenile delinquents had a much higher relative risk for suicide than male juvenile delinquents (5).

Psychiatric Illnesses as Risk Factors Among all adolescents, the strongest and most consistent risk factor for suicidal behavior is mental illness (17). This relationship is consistently observed in all studies of clinical populations and in studies using “psychological autopsy” techniques. Several studies document the risk of mental health disorders in the youth in juvenile justice system to be 60%-70% of the population (18,19). Lack of adequate community-based programs for disturbed youth has been suggested as one of the reasons for many of these young people being detained for minor offences (20). In a study of 1,829 youths detained in Chicago’s

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Cook County Detention Center, Teplin and others, found that about half of teens in juvenile detention have two or more psychiatric disorders and substance abuse disorders (18).

Mood Disorders A lifetime diagnosis of mood disorder is associated with the history of suicide attempts in prisoners and incarcerated adolescents (21,22). In a review of mood disorders among juvenile offenders, Ryan and Redding have suggested that situational depression among detained adolescents might be as treatment-responsive as endogenous depression (23). Adolescents who become depressed or whose depression becomes worse when they are put in correctional settings may be more prone to impulsive suicide attempts than depressed adolescents in community settings, thus making the identification and treatment of mood disorders in the incarcerated juvenile population all the more important. In a review of adolescent suicide risk factors Brent found depression to be the single most common mental disorder associated with suicide among adolescents (24). Teplin and others found high rates of depression and dysthymia among detained youth (17.2% of males, 26.3% of females), which are much higher than general population rates (18).

Disruptive Disorders Many of the youths in the juvenile justice system have a diagnosis of conduct disorder (CD). Disruptive disorders have been reported to be a risk factor for suicide in different psychological autopsy studies (25,26). CD was found to be associated with suicide, especially in older adolescent males with comorbid substance abuse and mood disorder. In a study done with 271 Russian male delinquents with CD, Ruchkin and others found that these youth have higher rates of suicidal ideation and attempts (27). Thirty four percent of the youth reported a lifetime history of suicidal ideation or attempts. Comorbid diagnoses of separation anxiety disorder or ADHD in the CD youths increased the risk of suicidal ideation or attempts. Attention deficit hyperactivity disorder (ADHD) also seems to increase the risk for suicide, especially among younger males with more severe comorbid conditions such as conduct disorder and depression (28). In another study of 428 homeless adolescents a positive intercorrelation was found between suicidality (measured with lifetime suicidal ideation and suicide attempts), internalizing disorders (lifetime diagnoses of major depressive episode and post-traumatic stress disorder), and externalizing disorders (indicated by lifetime diagnoses of conduct disorder, alcohol abuse, and drug abuse) (29).

Substance Abuse Substance use disorders, and even one-time substance abuse (30), are known risk factors for suicide in adolescents. Among older adolescents, substance use disorders may confer a higher risk for attempted suicide (31). Substance abuse/dependence disorders are more

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common in attempters than ideators (32), suggesting that the substance use may facilitate suicide attempting. When used before incarceration, hallucinogens, sedative/hypnotics, narcotics, stimulants, inhalants, and alcohol, but not cannabis, have been associated with a history of suicide attempts in juvenile delinquents (33,22). The Teplin et al study of youths detained in Chicago’s Cook County Detention Center found that half of the males and almost half of the females met diagnostic criteria for a substance abuse disorder (18). In a Swedish study, Moeller and Hell (34) administered SCID-1 and Psychopath Checklist (PCL-R) to 102 inmates aged 17-27 years and found that 82% met criteria for substance dependence and 29% had made at least one suicide attempt. Similarly, Sanislow and others (35) found that, even after controlling for depression, substance abuse remained significantly associated with suicide risk scores among detained youths.

Past Suicidal Attempts Past attempts and ideations are a very significant predictor of future suicidality (22). Diagnostically those who attempt suicide are very similar to those who complete suicide (17). However attempted suicides in adolescents are approximately 1,000 times more common than are completed suicides (36). More than 70% of the victims of completed suicides in juvenile confinement had a history of suicidal behavior (11).

Learning Disabilities Approximately 30 to 50% of children in the juvenile justice system have learning disabilities (LD). Youth with LD are adjudicated at about twice the rate as non-learning disability youth, and have greater recidivism and parole failure (37). In a prospective study of 188 students recruited from six public high schools at age 15 who were then followed for a mean of 3.3 years, youth with reading disabilities were three times more likely than typical readers to consider or attempt suicide (38). Follow-up interviews also showed that students with reading disabilities were more likely to experience suicidal thoughts or attempts. This association persisted after accounting for psychiatric disorders and school drop-out. We were unable to find any published links between learning disorders and suicide risk in juvenile delinquent population.

Psychological Risk Factors Suicide has been thought of as a coping mechanism, in which suicidal or self-destructive thoughts result from interaction between an individuals defense mechanisms and his/her external circumstances. One of the models of suicidal behavior proposes that life stressors are not enough to produce such violent behavior; rather, other factors have to be inherently present for these individuals to take this desperate step. A study assessing suicidality and psychopathology using in 271 incarcerated male juvenile delinquents in a facility in Northern

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Russia found that specific personality traits create vulnerability to stressors, which under the influence of situational factors may lead to suicidal thoughts and acts (27).

Impulsivity Sanislow and others compared 81 adolescents in a short-term juvenile detention center with a matched group of 81 adolescent psychiatric inpatients (35). Results of this study reflected that even after controlling for depressed mood, impulsivity added significantly to the suicide risk variance among the detainee population but not for the inpatient psychiatric population. They speculated that detained youngsters, lacking their habitual impulsive outlets, resort instead to suicidal behaviors. Rohde and others, in a study of 555 delinquents in county juvenile detention center, reported that impulsivity was associated more with current suicidal ideation in female delinquents (22). Based on this finding they suggested that treatment modalities and preventive interventions should be more gender specific.

Sexual Abuse In a study of confined youth, Morris and others found that youth who reported a history of sexual abuse had a 43% incidence of suicidal ideation and a 35% incidence of one or more suicide attempts, whereas youth who reported no history of sexual abuse had an 18% suicidal ideation rate and a 12% rate of suicide attempts (8).

Environmental Risk Factors Placing youth who are psychologically ill-prepared to tolerate stress in the immensely stressful detention situations often results in youth resorting to suicidal behaviors (6).

Locked Sleeping Rooms Gallagher and Dobrin (39) reported that the odds of reporting a death by suicide was seven times higher in the facilities that locked the delinquents in the sleeping rooms for any amount of time compared to facilities that did not lock the sleeping rooms. The authors speculated that the most plausible reason for this finding could be increased opportunity for committing suicide without intervention.

Short Term Facility Teens entering the juvenile justice system are frequently placed temporarily in short-term facilities to be screened for future placements into the most appropriate settings. Rates of

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suicide in such short-term facilities are higher than in other kinds of juvenile placements (39). Since these facilities have high turnover, the staff has less time to get familiar with the detainee. Also detainees in short-term facilities have usually recently experienced an acute situation. Additive effect of these factors leads to higher suicide risk in the adolescents in these facilities (35).

Juveniles in Adult Facilities Flaherty studied suicides in a thousand jails and juvenile detention centers and found that the suicide rate of juveniles in adult jails is 7.7 times higher than that of juvenile detention centers (40). A more recent report on prison suicides completed by the British Prison Reform Trust found that, while people aged 15 to 21 made up only 13 percent of the prison population, 22 percent of all suicide deaths was in this age group (41).

Room Confinement Data from a national survey of juvenile suicide in confinement appeared to show a strong relationship between juvenile suicide and room confinement (11). Out of the 110 juvenile suicides between 1995 and 1999, 62 percent of victims had a history of room confinement prior to their deaths and 50 percent of victims were in room confinement status at the time of their deaths. Room confinement in these cases was usually being used as a punitive measure. Parent and others also found that suicidal behavior was more common in youth who were restricted from being with their peers (42). Almost 77% of all youth in the justice system are residing in facilities that allow isolation. In a recent report on solitary confinement in Arizona prisons and jails, two out of the three juveniles who committed suicide in the Arizona Department of Juvenile Corrections in 2002 had been locked in their cells, one for over a week (43).

Protocols to Address Risk for Suicidality in Confined Youth Several protocols have been proposed to address suicidal behaviors in juvenile facilities (44). The American Academy of Child and Adolescent Psychiatry has published Practice Parameter for the Assessment and Treatment of Youth in Juvenile Detention and Correctional Facilities, which includes fourteen recommendations (45). It recommended that all youths in a juvenile detention be screened at entry and be continually monitored for suicide risk factors and behaviors (as part of an overall behavioral, emotional, and substance use screen). Recent or current suicidal ideation or attempts should require additional evaluation by a mental health clinician. Such youths referred for further clinical assessment should be assessed for risk for future violence against self and others. A clearly defined clinical role as opposed to the role as an agent of the court or the state is essential for mental health professionals to be effective. At the same time, clinicians working in the juvenile justice system should be fully

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aware of the operations of the system, open themselves to cross-training with the security staff, be vigilant about their own personal safety, and be alert to malingering, secondary gain, and other manipulative behaviors of the youths. Staff should be with suicidal youths continuously when such youths are housed in single rooms. Juvenile facilities should study the causes of high staff turnover and soften the effects of such turnover by increased staff training (42).

Screening Instruments Since a history of risky behavior helps predict risk, instruments to screen for suicidal behaviors are considered to be an essential tool for identifying youths with the highest risk for future suicidal behaviors. The Beck Scale for Suicidal Ideation, and the Suicidal Ideation Questionnaire screen for suicidal thinking. The Suicide Probability Scale is designed to assess the probability of engaging in suicide related behaviors. Beck Depression Inventory, and the Hopelessness Scale for Children are used to screen for other known risk factors for suicidal behaviors. Most of these instruments were constructed for adults and have not been tested for validity in adolescents (46). Screening for suicide within the first few to 24 hours of the youth’s contact with the juvenile justice system is usually done for safety reasons (47). After initial screening, a full clinical assessment along with diagnosis and treatment planning should be done by licensed clinicians. Wasserman and others contend that follow-up screening and evaluation at discharge from detention are also essential to promote continuity of care and to ensure appropriate links with the mental health system (47). The Massachusetts Juvenile Justice System developed a screening instrument, the Massachusetts Screening Instrument-Second Version (MAYSI-2), which is now used by justice systems nationwide (13). This instrument has 52-items structured to screen for mental, emotional, or behavioral problems, and also has specific questions to screen for suicidality. The sensitivity for this scale is 65%-75% and its specificity is 70%-90%. The MAYSI-2 requires no more than 10 minutes to administer, relies on youth self-report, is easy to read, and requires no clinical expertise to administer score or interpret. The voice format of the MAYSI-2 may be even better than the paper format because it may reduce incomplete data and increase reporting of stigmatized behaviors and because of its ability to automatically generate scored reports and aggregate data (48). Kaczmarek and others tested the reliability and validity of a new instrument for assessing suicidality in adjudicated delinquents, the Suicide Screening Inventory (SSI) (49). SSI is a 14-item interview, which was evaluated, based on data from 442 adolescents, primarily male, between the ages of 12 and 20. Two estimates of reliability indicated moderate internal consistency. In addition, a moderate correlation (r= .53) between the SSI and the Reynolds’s Adolescent Depression Scale suggested convergent validity. Expert ratings of the instrument's utility also provided content validity evidence. Descriptive data were collected on four youth who made suicide attempts. Elevated scores among these select cases provided some evidence for consequential validity.

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Another instrument, which was developed by Galloucis and Francek is the Juvenile Suicide Assessment (JSA) (50). The JSA needs to be completed by a licensed mental health professional. The JSA assesses a variety of risk factors including psychosocial and environmental. The JSA has been used by authors in clinical work and despite its face validity this instrument had not been empirically validated. Reasons for Living Inventory (RFL) is designed to evaluate possible reasons for not committing suicide and it is a self-report measure (51). A slightly modified version of the RFL was administered to two samples of adolescents, one from a general high school population, and one from a population of juvenile delinquents receiving psychological treatment in a correctional facility (52). It was found that young people who have more reasons for staying alive are less likely to have suicidal thoughts or behaviors. Evidence of convergent validity emerged via correlations of RFL subscales with depression, hopelessness, and other suicide inventories. Evidence of construct validity emerged in the RFL subscales related to suicidal thoughts and behaviors. As such, the scale is one of the few instruments that assess protective factors or beliefs buffering against suicidal behavior, rather than focusing on risk factors. Other versions of the RFL include the Brief RFL (BRFL), the RFL for Adolescents (RFL-A) and the Brief RFL for Adolescents (BRFL-A). Some suicide screening instruments for adolescents that report information on sensitivity and specificity are: Columbia Suicide Screen (CSS), Risk of Suicide Questionnaire (RSQ), Suicidal Ideation Questionnaire (SIQ), Suicidal Ideation Questionnaire JR (SIQ-JR), Diagnostic Predictive Scales (DPS), Suicide Risk Screen (SRS), Suicide Probability Scale (SPS). Most of these instruments have not been tested in juvenile justice systems.

Psychosocial Interventions Early intervention for youth showing antisocial behavior can avoid juvenile detention and its attendant risks. Instead of removing youth from their home environment, communitybased treatments address problems where they develop, and establish long-term support mechanisms necessary to sustain progress. Multisystemic Therapy (MST) is a cost-effective community-based services approach to treatment of serious antisocial behavior. The main focus of MST is to promote parent involvement and friendships with prosocial peers, to remove offenders from deviant peer groups, and to promote future employability and financial success by school and vocational interventions. MST has shown to cause decrease in delinquency and incarceration in various studies (53). Other community-based programs have been successful in decreasing delinquency and associated risk behaviors, and are more cost-effective and beneficial than incarceration. Wraparound Milwaukee is a Countyoperated health maintenance organization that helps the juvenile justice youth by providing them the option of community care as an alternative to residential treatment or psychiatric hospitalization. Another example is a State program in Ohio in which four State agencies put together funds to promote local efforts to help bring about a coordination of juvenile justice system, mental health and substance abuse services to decrease incarceration and improve access of mental health services for the delinquent youth (54).

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Among the psychological treatments that have been tried in juvenile justice facilities, cognitive behavior therapy has been the most widely studied and has been shown to reduce substance abuse, episodes of violence, and recidivism (55). Ovaert and others evaluated the efficacy of a structured group therapy for posttraumatic stress disorder (PTSD) in incarcerated male juveniles and found significant reductions in self-reported PTSD symptoms, especially in youth with trauma related to gang and community violence (56). In a randomized controlled trial of 93 nonincarcerated adolescents recruited from a county juvenile justice department with comorbid major depression and conduct disorder, recovery rates for the cognitive behavioral treatment group were 39 percent, compared with 19 percent for the life-skills tutoring control group. However, group differences in recovery rates of major depressive disorder at six- and 12-month follow-up and differences in conduct disorder both post-treatment and during follow-up were insignificant (57).

Substance Use Treatment The risk of suicidal behavior in adolescents with CD was found to be considerably increased by comorbid alcohol dependence among adolescents admitted to psychiatric inpatient care (58). Since substance use disorders are risk factors for suicidality in the juvenile justice population (18,34) screening for substance use at intake, continuous monitoring, and treatment of substance use disorders are recommended (45). There are few reports about substance abuse treatment and its outcome within juvenile justice facilities. However, a community intervention called Multisystemic therapy (MST) has been examined for treatment of substance abuse or dependence in a study that included 118 juvenile offenders. Participants were randomly assigned to receive MST versus usual community services. Results showed that MST reduced alcohol, marijuana, and other drug use by 50% at 6 months post-treatment follow up (59). Several agencies work together to implement rehabilitation programs for delinquent youth in detention facilities and in the community. Substance Abuse and Mental Health Services Administration (SAMHSA) and the Office of Juvenile Justice and Delinquency Prevention (OJJDP) work in coalition by funding National Institute of Corrections to help court and juvenile justice leaders to improve treatment and services for juvenile offenders with co-occurring disorders (60).

Medication Treatment There has been a limited amount of research into the use of medications in treating psychiatric conditions in juvenile delinquents and virtually no studies that have shown a decrease in risk of suicidality with medication treatment in this population. The following section reviews studies of medications to treat the most common psychiatric conditions that are associated with suicidality in the juvenile justice youth, namely conduct disorder, substance abuse disorders and mood disorders. Among the mood disorders bipolar disorder diagnosis has soared in the youth. The number of American children and adolescents treated for bipolar disorder increased 40-fold

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from 1994 to 2003 (61). Bipolar disorder is a significant risk factor for suicide, especially among boys and when it is comorbid with substance use disorder (62). In adults with bipolar disorder, lithium may be effective in reducing suicide rates during long-term treatment of bipolar disorder (63,64). Although the currently available evidence for lithium’s anti-suicide effect is in adults, the possibility of a similar effect in adolescents should be considered. Aggressive tendencies and substance use may contribute to suicidality in some adolescents. Lithium has been shown to be useful in treating children and adolescents who exhibit aggression (65), as well as in reducing substance use in teens comorbid for bipolar disorder and substance use disorder (66). Fluoxetine is the only selective serotonin reuptake inhibitor (SSRI) that is currently FDA-approved for use in adolescents for the treatment of major depressive disorder. There have been randomized controlled trials supporting the use of fluoxetine in the general adolescent population (67,68), and at least one open trial supporting its use in drug-dependent delinquents (69). In October 2003 concerns arose about a modest increase in suicidal thinking among SSRI-treated children and adolescents (70). The subsequent placement of a black box warning on the labeling of all antidepressants has been associated with dramatic reductions in diagnosis and treatment of pediatric depression with antidepressant medications (71,72). Increases in suicide rates of children in the US and Netherlands have added to concerns about the potential for harm that might arise due to the decreased use of SSRIs in the pediatric population (73). A recent metaanalysis of published and unpublished randomized controlled trials of second-generation antidepressants including SSRIs in adolescents and children with depressive and anxiety disorders found that the benefits of treatment with these medications were much greater than the risks of suicidality (74). While there was increased suicide risk with SSRI treatment when all depressive and anxiety disorder indications were analyzed together, this risk was no longer statistically significant when each indication such as major depressive disorder, obsessive compulsive disorder (OCD), and non-OCD anxiety disorders were separately analyzed. An earlier review concluded that first generation antidepressants such as tricyclic antidepressants are not the first line of treatment for adolescents since their efficacy in treating adolescents is not proven and also because of their narrow therapeutic index and potential lethality (75). Disruptive disorders such as CD have been associated with suicide in adolescents (26). Stimulant medications have been shown to have positive effects on the symptoms of CD even after controlling for their effects on improving attention and hyperactivity (76). The use of stimulant medications in juvenile justice populations is however fraught with concerns about misuse. Suicidal behavior among youth with disruptive disorders might arise from impulsivity that is frequently seen in these disorders. Atypical antipsychotics are the consensus treatment recommendation for impulsive aggression that does not respond to adequate treatment of the underlying psychiatric conditions (77). Post-traumatic stress disorder (PTSD) is reported to be common in juvenile detainees (78). A preliminary study found that quetiapine may benefit symptoms associated with PTSD in juvenile detainees (79). However, to date there are no published controlled trials of quetiapine for PTSD in adolescents or adults, and given the potential for major side sideeffects with quetiapine, caution should be exercised before considering this medication for treatment of PTSD. In a rare controlled medication trial among adolescent boys in a juvenile

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justice facility, valproate at dose of 1000 mg/day was shown to improve aggression, hyperarousal and anger, particularly in the presence of PTSD. All the 61 subjects in the study met criteria for CD, and over half were comorbid for attention deficit hyperactivity disorder (80).

Discussion To our knowledge, there are no studies that have systematically sampled youth in the general population as well in juvenile facilities to study the environmental influences of risk factors for suicidality. However, a study that examined mortality data from a national survey of juvenile justice facilities and compared them with data from the general population found that, after adjusting for period at risk, there was a 200% increase in risk of death from suicide among adolescents in juvenile justice facilities as compared to the general population of adolescents (6). Unfortunately this last study did not report on the individual characteristics of the suicide victims and hence adjusted risk for the demographic and other predictors of suicide in this population are not available. There is a wide variation in the severity of offence for which youth enter the juvenile justice system and are detained. Youth may be detained for property offenses such as burglary or arson, public order violations such as weapons offenses, drug law violations, or person offenses including homicide and forcible rape. Although the risk factors for suicidality in such widely different youth may well be unique, there are no currently available studies on risk factors of suicidality that discriminate between youth with history or relatively minor offenses from those with more serious offenses. Native American and white adolescents seem to be the most at risk for suicidal ideation, suicidal attempts, and completed suicide (8) although black youth seem to show the largest increase in rates recently (12). The relationship of gender to suicidal risk seems less clear although there are indications that female delinquents are at a higher risk for not only suicidal ideation and attempts, but also completed suicide. However, a majority of victims of completed suicides were male (11), which is explained by the overwhelming male preponderance among confined juveniles. There are some studies that have shown an association between psychiatric diagnoses and suicidality among confined juveniles (22,3335), and others that show that the rate of psychiatric disorder diagnoses is high among juveniles in confinement (18), and that mood, conduct, and substance use disorders are associated with suicidality in the general adolescent population (25,26,30-32). In addition, impulsivity (35) and history of sexual abuse (8) have also been specifically associated with suicidal risk among confined juveniles. It is important to recognize, that demographic and illness characteristics attributable to the individual adolescents occur in the context of several environmental risk factors in the community. Family factors such as poor parental supervision and ineffective discipline practices, peer factors such as gang membership and association with delinquent peers, community factors such as exposure to violence and drug dealing, and school factors such as truancy and poor academic achievement contribute to delinquency and detention (81). Although these factors have not been specifically associated with suicidality among juvenile

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offenders, they highlight the importance of environmental influences on events leading up to detention of juvenile offenders. Among environmental risk factors within detention facilities, placement in short-term facilities, room confinement, being in a facility that locks sleeping rooms, and housing with adults have all been shown to be associated with increased risk for suicidality. Detained youth are at an increased risk for suicide as compared to adolescents in the general population (6,7). This increased risk could be related to the environmental factors inherent to detention facilities such as separation from support group, punitive measures, and learned aggression. It could equally well be related to environmental factors in the community which led to detention being chosen as the option rather than supervised community placement. For example, lack of reliable adult supervision, chaotic family situations, and exposure to violence in the community environment are common reasons for intake staff to recommend detention instead of supervised release into the community. While it is premature to draw any conclusions about causal factors, these environmental factors are likely to be as important as the individual demographic and illness characteristics in explaining the increased rate of suicide found in detained juveniles. At least in the case of short-term facilities, the possible contribution of a third factor that could be “causal” for both the detention and the suicidal ideation has been suggested. This third factor is the crisis that led to detention, which could also be the cause of stress for the youngster. The environmental aspect of the increased suicidality risk seen in short-term facilities is that the staff in short-term facilities may have less time to get familiar with the detainees because of the high turnover rate in such facilities (39). Juvenile delinquency may turn out to be a variable that predicts suicidal risk independent of other demographic and psychological variables. Using the National Longitudinal Study of Adolescent Health Thompson and others prospectively studied the associations between delinquency at ages 12-17 years and suicidal behaviors 1 and 7 years later (10). They found delinquency to be associated with an increased risk for suicidal ideation and suicidal attempts, even after controlling for demographic variables and other risk factors such as depression, self-esteem, problem drinking, impulsivity, and religiosity. It has been suggested that some youth who are suicidal choose to commit “suicide by homicide”. These youth intentionally place themselves in dangerous situations involving the police or gangs and get themselves killed in the process. Homicides are the second leading cause of death among 1524 year olds. Youth involved with the juvenile justice system have a mortality rate that is more than 4 times the general population rate, and 95 % of these deaths are due to homicide (82). There is little systematic research available on the effectiveness of protocols that have been advocated for dealing with suicidal risk in the juvenile justice system. Current recommendations are based on consensus of expert opinion. A consensus conference of a nationally recognized group of expert mental health assessment researchers and expert juvenile justice practitioners identified the need to have evidence-based scientifically sound screening instruments that are sensitive in detecting emergent risk of potential harm to self or others (47). The consensus statement noted that, given the realities of staffing and context, instruments that are simple to administer are likely to be the most useful in juvenile justice facilities. The Massachusetts Youth Screening Instrument-2 (MAYSI-2) was developed for

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use in the juvenile justice system, to be routinely administered within the first few days of admission (13). This time frame is particularly important given the findings of a US national survey of youth suicides in confinement which found that all juvenile detention center suicides occurred within the first four months of confinement, with over 40% occurring within the first 72 hours (11). The fact that MAYSI-2 has been tested in different states is a welcome development since it will gather evidence that will inform practice in this area (13,83,84). Universal screening of all youth within 24 hours of being admitted to juvenile facilities is particularly important since it is the only process measure that has been linked to lower odds for suicidal attempts (85). Screening adolescents on an ‘as needed’ basis was associated with higher odds of suicidal attempts as compared to not screening at all (85). In addition to screening for risk of imminent danger, overall mental health screening is necessary to detect disorders that have been shown to be risk factors for suicide in the juvenile justice population. The voice format of the Diagnostic Interview Schedule for Children (voice DISC) has been used in juvenile facilities for the purpose of overall mental health screening (19). A comparison of the voice DISC to the MAYSI-2 found that, although there was an overlap in the identification of individuals by these two screening instruments, the voice DISC identifies a portion of youth with mental health needs that are not identified by the MAYSI-2 (84). This suggests that the voice DISC, which yields reliable diagnostic information, may have role in screening for service needs that is separate from the role of MAYSI-2 as a screening instrument for emergent risk (imminent danger) (84). Research on persons who have been confined or incarcerated raises several ethical considerations which have discouraged the conduct of controlled trials of medications in such settings. Doing research with confined youth involves many procedural problems. Besides their status as minors, the fact that these youth are detained against their will raises concerns that research participation may be perceived as coerced. That many of the confined adolescents do not have involved parents or guardians to provide consent for research participation is another impediment (86). The presence of emotional disorders in these confined youth adds another layer of complexity since the investigator has to work with challenges such as defining vulnerability, and determining extent of autonomy (87). Establishment of an ethical framework within which these sorely needed trials can be conducted should play an important part of any future initiatives in this area. A recent survey of 3500 juvenile justice residential facilities in the United States, only 53 were found to have received voluntary accreditation for facility health care from the National Commission on Correctional Health Care (88). The authors point out that juvenile facilities have been provided a single set of standards for a diverse system with tremendous variation across and within facility types. The development of specific standards for different kinds of facilities and the requirement that all juvenile facilities be compliant with such standards should be a goal for the future. According to a study by the Government Accountability Office, over 12,700 children, mostly adolescent males, were given up by their families to the juvenile justice system because they could not afford or access mental health services these children needed (89). Reforms in the mental health service systems for these children can be achieved redefining bureaucratic practices, improving funding and redirecting more of that funding from

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institutional to community-based care, and educating the public about how untreated mental illness affects behavior (90).

Conclusions While it appears that the environment (juvenile detention) may be one of the contributors to the increased frequency of suicidal attempts and completed suicides among adolescents in confinement, there is a complex interaction of inter-related factors that also contribute. Certain demographic and psychological variables have been shown to be associated with suicidal behavior and suicides in juvenile detainees. Conduct disorder, substance use disorders, and mood disorders, all of which have been shown to be more prevalent in the juvenile detainees are all risk factors for suicidal behavior and suicide. Several instruments to screen juvenile detainees for suicidal thoughts exist, and many protocols have been published for juvenile facilities to follow in order to minimize suicides. Universal screening of all adolescents for suicidal thoughts within 24 hours of entering juvenile facilities seems to reduce the risk of suicidal behaviors. The importance of getting information about current medications, substance use history, and service use history, in ensuring that psychotropic medications are continued without interruption, and detoxification or other services are appropriately provided should not be minimized. Effort should be directed towards developing standards for healthcare including mental healthcare that are more specific for different kinds of juvenile justice facilities, which should be provided incentives to seek accreditation based on these standards. More studies are needed to systematically evaluate suicide prevention protocols for their effectiveness in preventing suicides in juvenile facilities.

Acknowledgements The authors would like to acknowledge the guidance and expert input of Alan A. Abrams, MD, JD

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(20) Skowyra K, Cocozza JJ. A blueprint for change: Improving the system response to youth with mental health needs involved with the juvenile justice system. Delmar, NY: Nat Center Ment Health Juvenile Justice, 2007. (21) Biggam FH, Power KG. A comparison of the problem-solving abilities and psychological distress of suicidal, bullied, and protected prisoners. Crim Justice Behav 1999;26:196–216. (22) Rohde P, Seeley JR, Mace DE. Correlates of suicidal behavior in a juvenile detention population. Suicide Life Threat Behav 1997;27: 164–75. (23) Ryan EP, Redding RE. A review of mood disorders among juvenile offenders. Psychiatric Services 2004;55(12):1397-1407. (24) Brent DA. Risk factors for adolescent suicide and suicidal behavior: mental and substance abuse disorders, family environmental factors, and life stress. Suicide Life Threat Behav 1995;25(suppl):52–63. (25) Brent DA, Perper JA, Moritz G et al. Psychiatric risk factors for adolescent suicide: a case-control study. J Am Acad Child Adolesc Psychiatry 1993;32:521-9. (26) Shaffer D, Gould MS, Fisher P et al. Psychiatric diagnosis in child and adolescent suicide. Arch Gen Psychiatry 1996;53:339-48. (27) Ruchkin VV, Schwab-Stone M, Koposiv RA et al. Suicidal ideations and attempts in juvenile delinquents. J Child Psychol Psychiatry 2003;4:1058–66. (28) James A, Lai FH, Dahl C. Attention deficit hyperactivity disorder and suicide: a review of possible associations. Acta Psychiatr Scand 2004;110(6):408-15. (29) Yoder KA, Longley SL, Whitbeck LB, Hoyt DR. A dimensional model of psychopathology among homeless adolescents: Suicidality, internalizing, and externalizing disorders. J Abnorm Child Psychol 2007 Jul 25; [Epub ahead of print] (30) King RA, Schwab-Stone M, Flisher AJ, Greenwald S, Kramer RA, Goodman SH et al. Psychosocial and risk behavior correlates of youth suicide attempts and suicidal ideation. J Am Acad Child Adolesc Psychiatry 2001;40(7):837-46. (31) Borowsky IW, Ireland M, Resnick MD. Adolescent suicide attempts: Risks and protectors. Pediatrics 2001;107(3):485-93. (32) Gould MS, King R, Greenwald S, Fisher P, Schwab-Stone M, Kramer R, Flisher AJ, Goodman S, Canino G, Shaffer D. Psychopathology associated with suicidal ideation and attempts among children and adolescents. J Am Acad Adolesc Psychiatry 1998;37(9):915-22. (33) Putnins AL. Recent drug use and suicidal behavior among young offenders. Drug Alcohol Rev 1995;14:151–8. (34) Moeller AA, Hell D. Affective disorder and ‘psychopathy’ in a sample of younger male delinquents. Acta Psychiatr Scand 2003; 107:203-7. (35) Sanislow C, Grilo C, Fehon D, Axelrod S, McGlashan T. Correlates of suicide risk in juvenile detainees and adolescent in-patients. J Am Acad Child Adolesc Psychiatry 2003;42(2):234-40. (36) Grunbaum JA, Kann L, Kinchen SA. Youth risk behavior surveillance: United States, 2001. MMWR Report 51(SS4) 2002:1–62. (37) Larson KA. A research review and alternative hypothesis explaining the link between learning disability and delinquency. J Learning Disabil 1988;21(6):357-63.

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(38) Wake Forest University Baptist Medical Center. Reading disabilities put students at risk for suicidal thoughts and behavior and dropping out of school. ScienceDaily 2006 Nov 3. Retrieved October 27, 2007, from http://www.sciencedaily.com/releases/ 2006/11/061101151341.htm (39) Gallagher CA, Dobrin A. Facility-level characteristics associated with serious suicide attempts and deaths from suicide in juvenile justice residential facilities. Suicide Life Threat Behavior 2006;36: 569-82. (40) Flaherty MG. An assessment of the national incidence of juvenile suicide in adult jails, lockups and juvenile detention centers. Community Research forum, prepared for the US Dept Justice. Urbana-Champaign, IL: Univ Illinois, 1980. (41) The rising toll of prison suicide. London: Prison Reform Trust, 1997. (42) Parent D, Leiter V, Kennedy S, Livens L, Wentworth D, Wilcox S. Conditions of confinement: Juvenile detention and corrections facilities. Washington, DC: Office Juvenile Justice Delinquency Prev, US Dept Justice, 1994. (43) Isaacs C, Lowen M. American Friends Service Committee. Solitary confinement in Arizona, 2007. www.afsc.org/az http://www.afsc.org/az/documents/buried-alive.pdf (44) Roush DW. Desktop guide to good juvenile detention practice. Research report funded by the Office of Juvenile Justice and Detention, 1996. Accessed on September 16, 2007 at http://www.njda.msu.edu/publications/desktop_guide_detention.pdf (45) American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of youth in juvenile detention and correctional facilities. J Am Acad Child Adolesc Psychiatry 2005;44:10. (46) Gutierrez PM.. Integratively assessing risk and protective factors for adolescent suicide. Suicide Life Threat Behav 2006;36:129-35. (47) Wasserman GA, Jensen PS, Ko SJ, Cocozza J, Trupin E, Angold A, Caufman E et al. Mental health assessments in juvenile justice: Report on the consensus conference. J Am Acad Child Adolesc Psychiatry 2003;42(7):752-61. (48) Hayes MA, McReynolds LS, Wasserman GA. Paper and voice MAYSI-2: format comparability and concordance with the voice DISC-IV. Assessment 2005;12(4):395403. (49) Kaczmarek TL, Hagan MP, Kettler RJ. Screening for suicide among juvenile delinquents: Reliability and validity evidence for the Suicide Screening Inventory (SSI). Int J Offender Ther Comparative Criminol 2006;50:204-17. (50) Galloucis M, Francek H. The juvenile suicide assessment: An instrument for the assessment and management of suicide frisk with incarcerated juveniles. Int J Emergency Ment Health 2002;4(3):181-99. (51) Linehan MM, Goodstein JL, Nielsen SL, Chiles JA. Reasons for staying alive when you are thinking of killing yourself: The reasons for living inventory. J Consult Clin Psychol 1983;51(2):276-86. (52) Cole DA. Psychopathology of adolescent suicide: hopelessness, coping beliefs, and depression. J Abnorm Psychol 1989;9:248-55. (53) Henggeler SW. Treating serious antisocial behavior in youth: The MST approach. Washington, DC: US Dept Justice, Office Juvenile Justice Delinquency Prev, 1997.

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(54) Cocozza J, Skowyra K. Youth with mental health disorders: Issues and emerging responses. Office Juvenile Justice Delinquency Prev J 2000;7(1):3-13. (55) Bray C. Cognitive behavioral curricula in correctional settings: A review of literature. Minneapolis, MN: Univ Minnesota Press, 2000. (56) Ovaert LB, Cashel ML, Sewell KW. Structured group therapy for posttraumatic stress disorder in incarcerated male juveniles. Am J Orthopsychiatry 2003;73(3):294-301. (57) Rohde P, Clarke G, Mace DE et al. Efficacy/effectiveness study of cognitivebehavioral therapy for adolescents with comorbid major depression and conduct disorder. J Am Acad Child Adolesc Psychiatry 2004;43:660–8. (58) Ilomäki E, Räsänen P, Viilo K, Hakko H. Suicidal behavior among adolescents with conduct disorder--the role of alcohol dependence. Psychiatry Res 2007;150(3):305-11. (59) Henggeler SW, Pickrel SG, Brondino MJ. Multisystemic treatment of substance abusing and dependent delinquents: Outcomes, treatment fidelity, and transportability. Ment Health Serv Res 1999; 1:171-84. (60) Bilchik S. Mental health disorders and substance abuse problems among juveniles. Washington, DC: US Dept Justice, Office Juvenile Justice Delinquency Prevention, 1998. (61) Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry 2007;64(9). (62) Hyman SE. Mood disorders in children and adolescents: a NIMH perspective. Biol Psychiatry 2001;49:962–9. (63) Muller-Oerlinghausen B, Muser-Causemann B, Volf J. Suicides and parasuicides in a high-risk group on and off lithium long-term medication. J Affect Disord 1992;25:261– 70. (64) Schou M. Suicidal behavior and prophylactic lithium treatment of major mood disorders: a review of reviews. Suicide Life Threat Behav 2000;30:289–93. (65) Malone RP, Delaney MA, Luebbert JF, Cater J, Campbell M. A double-blind placebocontrolled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000;57(7):649-54. (66) Geller B, Cooper TB, Sun K, Zimerman B, Frazier J, Williams M, Heath J. Doubleblind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry1998;37(2):171-8. (67) Emslie GJ, Rush J, Weinberg WA, Kowatch RA, Hughes CW, Carmody T, Rintelmann J. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997;54:1031-7. (68) Emslie GJ, Heiligenstein JH, Wagner KD, Hood SL, Ernest DE, Brown E, Nilsson M, Jacobson JG. Fluoxetine for acute treatment of depression in children and adolescents: A placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2002;41:1205-15. (69) Riggs PD, Mikulich SK, Coffman LM, Crowley TJ. Fluoxetine in drug-dependent delinquents with major depression: an open trial. J Child Adolesc Psychopharmacol 1997;7(2):87-95.

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(70) Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry 2006;63(3):332-9. (71) Libby AM, Brent DA, Morrato EH, Orton HD, Allen R, Valuck RJ. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry 2007;164(6):884-91. (72) Nemeroff CB, Kalali A, Keller MB, Charney DS, Lenderts SE, Cascade EF, Stephenson H, Schatzberg AF. Impact of publicity concerning pediatric suicidality data on physician practice patterns in the United States. Arch Gen Psychiatry 2007;64(4):466-72. (73) Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RMC, Mann JJ. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 2007;164:135663. (74) Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 2007;297(15):1683-96. (75) American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with suicidal behavior. J Am Acad Child Adolesc Psychiatry 2001;40(7 Suppl):24S-51S. (76) Klein RG, Abikoff H, Klass E, Ganeles D, Seese LM, Pollack S. Clinical efficacy of methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder. Arch Gen Psychiatry 1997;54(12):1073-80. (77) Pappadopulos E, Macintyre Ii JC, Crismon ML, Findling RL, Malone RP, Derivan A, Schooler N, Sikich L, Greenhill L, Schur SB, Felton CJ, Kranzler H, Rube DM, Sverd J, Finnerty M, Ketner S, Siennick SE, Jensen PS. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part II. J Am Acad Child Adolesc Psychiatry 2003;42(2):145-61. (78) Steiner H, Garcia IG, Matthews Z. Posttraumatic stress disorder in incarcerated juvenile delinquents. J Am Acad Child Adolesc Psychiatry 1997;36(3):357-65. (79) Stathis S, Martin G, McKenna JG. A preliminary case series on the use of quetiapine for posttraumatic stress disorder in juveniles within a youth detention center. J Clin Psychopharmacol 2005;25(6):539-44. (80) Steiner H. Valproate and related compounds in the treatment of conduct disorder. 45th Ann Meet Am Acad Child Adolesc Psychiatry, Anaheim, October 1998. (81) Redding RE. Characteristics of effective treatments and interventions for juvenile offenders. Juvenile Justice Fact Sheet. Charlottesville, VA: Inst Law Psychiatr Public Policy, Univ Virginia, 2000. (82) Teplin LA, McClelland GM, Abram KM, Mileusic D. Early violent death among delinquent youth: a prospective longitudinal study. Pediatrics 2005;115:1586-93. (83) Archer RP, Stredny RV, Mason JA, Arnau RC. An examination and replication of the psychometric properties of the Massachusetts Youth Screening Instrument - Second Edition (MAYSI-2) among adolescent in detention. Assessment 2004;11(4):1-13.

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(84) Wasserman GA, McReynolds LS, Ko SJ, Katz LM, Cauffman E, Haxton W et al. Screening for emergent risk and service needs among incarcerated youth: Comparing the MAYSI-2 and Voice DISC-IV. J Am Acad Child Adolesc Psychiatry 2004;43(5):629-39. (85) Gallagher CA, Dobrin A. The association between suicide screening practices and attempts requiring emergency care in juvenile justice facilities. J Am Acad Child Adolesc Psychiatry 2005;44(5):485-93. (86) Federal Policy for the Protection of Human Subjects: Notices and Rules, part 2, Vol 56, No. 117 (18 June 1991), 56 Federal Register. 28002-32. (87) Hoagwood K, Jensen PS et al, eds. Ethical issues in mental health research with children and adolescents. Mahwah, NJ: Lawrence Erlbaum Assoc, 1996. (88) Gallagher CA, Dobrin A. Can juvenile justice detention facilities meet the call of the American Academy of Pediatrics and National Commission on Correctional Health Care? A national analysis of current practices. Pediatrics 2007;119:e991-e1001. (89) Ashby CM. General Accounting Office (GAO), testimony before the Senate Committee on Governmental Affairs, July 17, 2003, “Child Welfare and Juvenile Justice: Several Factors Influence the Placement of Children Solely to Obtain Mental Health Services,”GAO-03-865T; accessed on October 15, 2007 at www.gao.gov/atext/d03865t.txt. (90) Koppelman J. Mental health and juvenile justice: Moving toward more effective systems of care. Washington DC: National Health Policy Forum, 2005.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XX

Mood Disorders and Suicide in the Correctional Population: The Importance of Recognizing Comorbidity Alan A Abrams∗, Maheen Patel, Tyler Jones, Yu-Fei Huang, Nesibe Soysal, Lobna Ibrahim, Constance N Flanagan, Cessare Scott, KyleeAnn Stevens, Gavin Rose and Alan Newman Georgetown University Hospital, Department of Psychiatry, Forensic Psychiatry Fellowship Program, Washington, DC, USA

Abstract The identification or recognition of mental disorders in the Criminal Justice System (CJS) is fraught with difficulties. Some obstacles are merely definitional, e.g. delimiting where the boundaries of Impulse Control Disorder NOS or Paraphilia NOS might exist. More significant hurdles are the reliance on inaccurate self-report, persistent substance induced altered CNS functioning in many detainees, and the atypical presentation of individual psychiatric disorders in persons with multiple comorbidities, combined with troubled and deviant life histories. Identification and treatment of mood disorders in the CJS is presently an area requiring further development through studies on the multiply comorbid, both in and out of custody. Recent studies on pediatric mood disoders suggest that there may be a subgroup that end up in the CJS as they get older. Predicting suicide in the criminal justice system is similarly difficult because of the low specificity of predictive methods. Many inmates have multiple risk factors, and multiple psychiatric

∗

Correspondence: Alan A Abrams, MD, JD, Kober-Cogan Hall, 6th floor, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC, 20007 United States. E-mail: [email protected]

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Keywords: Suicide, affective, mood, prisoner, comorbidity, substance abuse.

Introduction The accuracy and reliability of attempts to estimate the exact proportion of the Criminal Justice System (CJS) population which experiences any particular mental disorder is highly uncertain. A recent publication of the Bureau of Justice Statistics (BJS) reported that more than half of people in custody have psychiatric problems (1). The meaning and implications of such a “statistic” are unclear. Inmates or detainees in the CJS do not represent an unbiased sample from the general population. They differ in gender (i.e. more males), IQ (lower), frequency of substance misuse (higher), ethnicity (fewer European-American whites) and socioeconomically (lower SE Index). Women and girls in the CJS appear to differ even more from their counterparts in the general population. The CJS population also likely differs from the general population in the distribution and frequency of psychiatric disorders. Nonetheless this is a population of real interest to psychiatry because of the large number of Americans who have involvement with the CJS. Emerging areas of interest in both general psychiatry and correctional psychiatry are the correlations between impulsivity, attachment disorders, aggression, mood disorders and suicide (2,3). Studies of the persisting comorbidities of ADHD, severe mood dysregulation, Oppositional Defiant Disorder, substance use disorders and narrow or broad phenotype bipolar disorder in adults will compliment the current research into the occurrence and effects of these comorbidities in children (4). Many of these adults will be involved in the CJS. Unfortunately, reliable studies of the mental health problems and diagnoses of persons in the CJS are rare, because of the essential need to verify self reported symptoms and history with collateral documentation, and the lack of a nosology that accounts for multiple developmental and biological comorbidities. The vast majority of studies on psychiatric disorders in the CJS are either retrospective chart reviews or surveys primarily reliant on subject self-report (1). Self-report and chart review are likely to suffer from both over-reporting and under-reporting, with little ability to identify the actual diagnoses without collateral information.

The Criminal Justice System For those readers not familiar with the CJS, the distinction between jail and prison is typically that people detained in jails are awaiting trial, awaiting being sent to prison, or serving a sentence generally under 12 months, while people in prison are generally postconviction serving sentences longer than 12 months, or returned to custody for parole violations. People considered as involved with the Criminal Justice System could include a very wide ranging of populations: from minors, patients in forensic hospitals, people on local

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probation, in jail, in prison, in military detention facilities, on parole, in sexually violent predator programs, dangerous offender commitments, and in immigration detention. Even within the same institution or program there are differing environments - from minimum security, banked reporting, special housing units, to condemned row - that would reasonably have different rates of suicide or psychiatric disorders. This is a diverse set of many subpopulations, in multiple microenvironments and including unique individuals, all contributing to the variance from the general population. Nonetheless, because of the increasing overlap of populations between mental health and criminal justice, it is a worthwhile endeavor to understand the possible role of mood disorders and suicide in the overall CJS population.

The Problem of Symptom Self Reporting and Substance Induced Symptoms Any definite statement beyond the fact of mood disorders among those involved in the CJS is difficult. A number of sources of distortion come into play, making accurate diagnoses in the CJS problematic. In the CJS the self-reporting of symptoms or past history is frequently viewed as having benefits (e.g. access to treatment, special programs and medications) or negative consequences (e.g., disqualification from camp programs, see e.g. Pennsylvania v. Yeskey (5)). Both willful overreporting and underreporting are common obstacles to accurate assessment of mental disorders in the CJS. Further, surveys of mental disorders in the CJS may only consider “serious” mental illnesses as dictated by the Supreme Court’s decision in Estelle v. Gamble (6). The suggestion from a number of epidemiological studies is that somewhere between 5% to 20% of the prison population has a major mental illness (7-10). This is at best a very rough working approximation, depending most particularly how substance induced disorders are categorized. Many detainees have abused stimulants, some to the extent of full dependence. In the BJS 2006 study over 40% of men and 50% of women identified with mental problems had used cocaine, methamphetamine or other stimulants within the month prior to arrest (1). In that study, well over 40% identified with mental disorders were also identified with either substance abuse or dependence (1). If stimulant related symptoms are not recognized, these detainees may well fit “criteria” for Bipolar I or Paranoid Schizophrenia. The role of polarized litigation, and spirited advocacy with both sides offering up “experts” and studies to prove their points has further obscured reliable information in this area. (11). The BJS 2006 study Mental Health Problems of Prison and Jail Inmates is perhaps among the best surveys of mental health disorders in the CJS in the United States (1). It attempted to address some of the methodological problems involved with sampling, consistency of evaluation technique, and inconsistent standards for diagnosing. Unfortunately because of its reliance on detainee self-report, and its failure to distinguish symptoms of drug intoxication or withdrawal from “endogenous” mental disorders, it must be viewed as primarily a survey of drug induced or influenced CNS symptoms, providing no ability to distinguish those from non-substance induced mental disorders. The authors of the BJS survey used a modified structured clinical interview for the DSM-IV (modified SCID). However, as the authors

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report: “The surveys did not assess the severity or duration of the symptoms, and no exclusions were made for symptoms due to medical illness, bereavement, or substance use.” The respected NCCHC (National Commission on Correctional Health Care) offered the following mental health epidemiology to Congress in 2002: “On any given day, between 2.3 and 3.9 percent of inmates in State prisons are estimated to have Schizophrenia or other psychotic disorder, between 13.1 and 18.6 percent Major Depression, and between 2.1 and 4.3 percent Bipolar Disorder (manic episode). A substantial percentage of inmates exhibit symptoms of other disorders as well, including between 8.4 and 13.4 percent with Dysthymia, between 22.0 and 30.1 percent with an anxiety disorder, and between 6.2 and 11.7 percent with Posttraumatic Stress Disorder” (12). In 1999, the Federal Bureau of Justice Statistics, drawing on a survey in 1997 of adult prisoners, estimated that 16 percent of state and federal adult prisoners and a similar percentage of adults in jails were mentally ill (13). Estimates of the percent of mentally ill individuals entering the jail or prison system who have a comorbid or co-ocurring drug-abuse or alcohol problem range from 70 to 85%. This may reflect a similar prevalence among the general CJS population for substance use disorders. In marked variance, in the 2006 Federal Bureau of Justice Statistics survey, it was reported that more than two-fifths of State prisoners (43%) and more than half of jail inmates (54%) self-reported symptoms that met the criteria for Bipolar Disorder, manic. The BJS also reported that about 23% of State prisoners and 30% of jail inmates self-reported symptoms of major depression. An estimated 15% of State prisoners and 24% of jail inmates self-reported symptoms that met the criteria for a psychotic disorder. Overall the 2006 report estimated that 56% of State prisoners, 45% of Federal prisoners, and 64% of jail inmates had mental health problems (1). This large degree of variance of estimation appears largely due to the effect of reliance on self-report for diagnoses, and the failure to consider the role of substance induced disorders. It is our experience that the more that individuals have multiple psychiatric comorbidities and medical disorders, the more the DSM categories blur. The present nosology for the symptoms of mood, perceptual and behavioral dysfunction among the wide variety of brain damaged and life damaged individuals remains a frontier requiring expansion. Other comorbidities, particularly complex PTSD related to childhood sexual abuse and revictimization must be considered. In the BJS 2006 study a quarter of detainees with psychiatric problems reported prior sexual or physical abuse. When women were separated out nearly 70% reported prior sexual or physical abuse. (1). A study in England done by Dyer showed that two thirds of women in prison showed symptoms of at least one neurotic disorder such as depression, anxiety, and phobias (14). Additionally 14% suffer from severe psychosis such as schizophrenia or delusional disorders, compared to less than 1% in the general population. 40% of women in prison reported attempting suicide during their lifetime. It is also our experience that very few people in prisons do not have either an Axis I or Axis II disorders, and more typically multiple Axis I and II diagnoses, and often psychiatrically relevant Axis III disorders. Whether these disorders are recognized, diagnosed

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or treated are highly dependent on social policy, financial constraints, limited resources, peer pressures, information flow, and the clinical interest within the particular institution. Whatever the actual statistics in any given institution, based on any given standard or methodology, it is apparent that persons with a history of mood disorders are arrested, convicted and incarcerated. The absence of reliable diagnostic information makes it risky to speculate whether there is an increased incidence of mentally ill prisoners compared to the past. Most observers believe that the incidence of severe mental illness in the CJS is markedly increased (15). If comorbid mood disorders and substance-induced disorders are included, it is likely that the increasing use of potent neurotoxic agents (LSD, PCP, cocaine, methamphetamine, MDMA), which began in the 1960’s, has contributed to a very significant increase in CJS detainees with mental disorders. The role of de-institutionalization is more speculative since deinstitutionalization was historically occurring at the same time as the explosive growth in neurotoxic substance use. It is unclear, even if there was greater capacity in the public mental health institutions, whether this would the alter the increasing overlap of systems, given that most jurisdictions do not provide for involuntary treatment based on substance use disorders. The opposite phenomena, i.e. the diversion of the criminal justice population into the mental health system is just beginning to be implemented and studied.

Comorbidity in the CJS Population The National Comorbidity Study, the STEP-BD and other more modern prospective studies have highlighted the importance of co-ocurring disorders in adult mood disorders. (16,17). This is nowhere more apparent than in the CJS. In the National Comorbidity Study, there were a number of high correlations involved mood disorders and externalizing disorders: bipolar disorder (major depressive episode with mania/hypomania); comorbid mania/hypomania and attention-deficit/hyperactivity disorder; and comorbid substance disorders (both alcohol abuse and dependence with drug abuse and dependence). High levels of comorbidity were seen in a small number of subjects but accounted for nearly 60% of all instances of the conditions (16). An important contributor to the seeming excess of persons with multiple co-morbidities in the CJS is that persons with deficits in a lack of inhibitory controls, increased aggressivity, or otherwise impaired executive or attentional systems, are entering the CJS. Mood disorders are highly comorbid with substance use disorders and ADHD suggesting that the frequency of impaired inhibition, evident during a manic episode, may be more pervasive and detrimental (17,18). Even just considering the “dual diagnosis” concept of comorbidity, meaning a single mental disorder with co-occurring substance abuse, the 2006 BJS study found that “among inmates who had a mental health problem, local jail inmates had the highest rate of dependence or abuse of alcohol or drugs (76%), followed by State prisoners (74%), and Federal prisoners (64%).” Drugs other than alcohol were more frequently abused in preference to alcohol (1). The recent work by the STEP-BD studies has shown the ubiquity of comorbidity in those who suffer from mood disorders (18). The current debate regarding the overlap between mood disorder symptoms, impulsivity, suicide, hyperactivity, and personality disorder

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symptoms further complicates our understanding of multiple comorbidities in the CJS (19). Additionally the understanding of the importance of complex PTSD (based primarily on extensive childhood neglect and abuse) in the development of mood and personality disorders adds additional layers of comorbidities (20). It is our experience that when full collateral records are collected and complete “forensic” interviews are performed, there is extensive syndromal and subsyndromal comorbidity with mood disorders in this population including fetal alcohol syndrome, head injuries, learning disorders, borderline intellectual functioning, ADHD, Conduct Disorder, Oppositional Defiant Disorder, early onset of abuse of multiple substances, cognitive impairments, various forms of PTSD including experiencing childhood sexual abuse, re-victimization and witnessing violence toward others, other anxiety disorders, impulse control disorders, HIV and Hepatitis C exposure, personality disorders and conditions signified by “V” codes. Hopefully the findings of the STEP-BD studies, studies of sex workers, the natural history of substance abusers and more comprehensive studies of persons at each stage and institution in the CJS will lead to a better recognition of the importance of comorbidities and mood disorders in the CJS populations. Childhood onset Bipolar Disorder, both narrow and broad phenotypes, can be highly comorbid with ADHD (60.6% and 86.7%, respectively) or misdiagnosed as ADHD (2). The high comorbidity with substance use disorders and behavioral problems often leads these people to be diagnosed as substance abusing antisocials or Cluster B patients. Consideration of early onset Bipolar is rare, at least until a detainee has a mood episode in custody. Example 1: Mr. C, a 25-year-old unmarried white male, had severe behavior, emotional and attention problems in elementary and junior high school, but was not diagnosed with ADHD or any other psychiatric disorder or ever treated. After dropping out of high school, he began using hallucinogens, amphetamines, marijuana and alcohol. He had his first psychotic episode while “partying” in Mexico. This was diagnosed as substance induced psychosis. Three years later he had what appeared in retrospect to be another manic episode during which he began a fight with a merchant. He was charged and convicted of assault; because of the drug history no mental state defense was offered. While in prison Mr. C had another manic episode which landed him in administrative segregation. He was identified as possibly mentally ill on screening, and further evaluation reached the opinion that he suffered Bipolar I Disorder. Initially involuntary treatment with antipsychotics was necessary, but Mr. C eventually accepted treatment with mood stabilizers. The recent STEP-BD statistics in the general population illuminate these issues in the CJS. 87 of the nearly 1,000 subjects with Bipolar Disorders in the STEP-BD study met criteria for a lifetime diagnosis of comorbid ADHD (17). Effective treatment of comorbid ADHD and Bipolar disorders needs to address and differentiate to the extent possible both disorders (18). However mental problems are tabulated, it is clear that life in custody is more difficult for those with mental disorders adding adjustment disorders to the preexisting comorbidities. The BJS 2006 study found that compared to those who denied psychiatric symptoms, the mentally ill in state prison custody were more likely to have a violent offense in their background, had longer mean maximum sentences, served longer terms, were more likely to

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be injured in a fight, and committed more rule violations. About one third of the inmates in state prison, who were identified by the BJS methodology were receiving or had received mental health care since their reception into state prison (1).

Adjustment Disorders and Environmental Stressors The environmental stressors contributed by the particular CJS institutions to mood disorders are only just being studied. Negative life events, humiliation, threats of physical and emotional abuse, and sentence length appear to contribute to adjustment disorder with depression and suicidiality. The effects of exposure to punitive segregation, restrictions on contact with outside support systems, overcrowding, sexual assaults, sensory isolation, boredom, hopelessness due to harsh sentencing or parole practices, and exposure to aggressive “control” further distinguish the CJS population from the general population, as well as one particular institution from another. Among fifty percent of those who commit suicide experienced acute stressors at the time of the suicide with a majority having a history of chronic stressors (21,22). Inmates diagnosed with AIDS have been found to have been found to be at an increase risk of suicide due to potential hopelessness, victimization, and threats by other inmates (23,24). Many factors are significant in the link between personality disorders, violence risk and comorbid mood disorders including impulsivity, affect lability and hostility. There are associations with personality disorders and childhood history of abandonment, cruelty and humiliation which may be exacerbated or reexperienced by entry into the CJS and could serve to further increase the risk for violent behavior or revictimization and development of adjustment disorders. Anxiety experienced by inmates particularly upon admission to jail or prison or just before release from prison also is a contributing factor to acute adjustment disorders. During the intake process to jail, the high-risk period for suicide and attempted suicide is in the first 24 to 48 hours (25). Although this has not been observed to be the case with prisons, the first 30 days at most reception centers are generally assessed to be the most vulnerable time to those individuals with a prior history of suicide attempts (26). With respect to the actual physical environment, most suicide attempts take place in maximum-security facilities, in single cells, or isolation (27, 28). A study of sexual coercion in prison noted that approximately 20 percent of subjects are reportedly pressured or forced into sexual contact with another person; one third of these individuals experience thoughts of suicide (29). US prisons house a disproportionate number of HIV-infected inmates, often of color, who become infected prior to incarceration. Mood Disorders, most especially depression, are common in patients with HIV. They occur throughout the spectrum of the illness and range from mild to severe. This marks a long cascade of associations and co-morbidities as these same mood disorders often are co-morbid with other psychiatric disorders, substance use and complications of HIV infection. The high risk behaviors of substance abuse, violence, unprotected sex and the like are associated with the transmission of HIV and are related to, and perhaps emerge from; isolation, depression, low self-esteem, marginalization, and sexual

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abuse. It is easy to suppose these are same issues faced by many in the CJS. Additionally, HIV infection alone is associated with high rates of suicide and many of the same factors that are high risk for HIV transmission are associated with increased risk for suicide (24). In the CJS the inundation of risk factors are worsened by failure to recognize and treat, as a whole, the myriad of problems faced by those with HIV and comorbid mood disorders. It has been estimated that about 33% of persons with hepatitis C virus (HCV) spend time in a correctional facility each year. Several psychiatric comorbidities exist with HCV, as expected, substance use disorders are most common, but mood, anxiety and psychotic disorders are also frequently encountered (30). The risk of psychiatric comorbidity is complicated by the use of interferon treatment for HCV. The risk of depressive disorders is as high as 37% even without immunosuppressive therapy. The risk for treatment-emergent depression after interferon therapy has been reported as 10% to 40% (31). The presence of severe psychiatric illness is important to establish as it may present a significant contraindication to interferon therapy. In 2003, Kraus et al (32) studied 104 patients, 84 of whom received interferon and found increased depression, anger and hostility as features of the group. Additionally, clinically relevant emotional distress was evident in 58% of those treated with interferon. HCV comorbid mood disorders require aggressive treatment and because poor compliance is associated with worsening mood the need for effective detection, monitoring and treatment is highlighted. The vast majority of research on mental health issues related to incarceration in the United States have been done on males. Perhaps this is due to the fact that the number of women incarcerated is significantly lower than that of men and this may be a population that is overlooked. Although the number of incarcerated males has doubled in recent decades, it should be noted that the overall number of women have tripled as well. Separation from family and children is more often reported as a severe stressor by women compared to men. This would lend directly to the need for more studies aimed at this population. The effect of the CJS environment on the civilian employees is poorly studied. The detailed self-report by Ted Conover regarding his psychological metamorphosis during his first year as a Correctional Officer at Sing-Sing, and the occurrence of suicides among CJS employees, suggest this would be a useful investigation (33).

Mood Disorders and Treatment in the Criminal Justice System The significance of the high level of comorbidities in the mentally disordered detainees is that the recognition of mood disorders becomes far more complex. (34,35). There is always the risk that one comorbid condition will obscure the inquiry into mood disturbances. A recently published review of over 60 international surveys estimated a 6-month prevalence of major depression in 10% of men and 12% of women in custody (10). There are prevalent patterns of mood disorders that occur from temperamental substrates (36). Affective dysregulation or “rage” that is often seen and attributed to personality disorders may be a part of unstable temperament that predisposes an inmate to mood disorders or is an under-recognized mood disorder (4). It is common that detainees are pejoratively dismissed

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because of the co-occurrence of Axis II disorders. Borderline Personality Disorder (BPD) and other Cluster B Personality Disorders are common comorbid conditions in the CJS and require effective treatment strategies across multiple domains (37). Adequate treatment of, for example, ADHD and Bipolar Disorder often requires treatment of both co-morbidities (18). Most CJS facilities have an understandable reluctance to treat ADHD with abusable stimulants or use bupropion because of fears of abuse or selling of prescribed medications. Psychological treatment or stable support groups may not be available in short-term detention facilities because of high transience rates. There are many obstacles to effective or safe use of mood stabilizers or antidepressants. Laboratory facilities in CJS institutions may not be able to do tests of plasma levels, the supervision of detainee medication adherence can be difficult, scheduling conflicts or indifference can cause missed appointments to have blood drawn that are not rescheduled, and medication visits to review laboratory tests may be infrequent. Inmates often have an “aspirin model” of medication treatment - use more if you feel bad, skip prescribed treatments if you feel normal, causing irregular serum levels. Jails and prisons may not have adequate cooling or ventilation systems, or provide easy access to drinking water. Prisons in the south and southwest have to additionally contend with problems of high ambient temperatures during the long summer months. Lithium can accumulate to toxicity if inmatepatients become dehydrated in high ambient temperature. Medications with anticholingeric activity, stimulants, and neuroleptics can make inmate-patients more susceptible to heat related pathologies because of dehydration and limitations on cooling mechanism. Deaths of inmates on various psychotropics have lead to “heat medication” regulations in some states (39). While these regulations play a useful role in limiting relatively rare morbidity, they also lead inmates to reject psychotropics to avoid heat medication restrictions (40). As noted above infections with Hepatitis C or other causes of liver damage, can lead to toxicity with drugs requiring hepatic metabolism or causing hepatic damage. The CJS is a culture that is suspicious of claims of self-harm or psychiatric disorders. At its worst, it is a culture that expects that it should induce depression and feelings of loss in the detainees and inmates, and that these are the “just desserts” of punishment. Social policies must balance the wish to punish and deprive offenders with the requirement of constitutionally adequate and humane medical treatment. (6). The institutional culture often balances on the side of deprivation. Social policies must also balance the needs of detainees who are guaranteed access to mental health care for serious illnesses with the fact of large numbers of uninsured non-offenders in the community who have no access to mental health care.

Suicide in CJS institutions The World Health Organization has stated: “Suicide is often the single most common cause of death in correctional settings” (41). As seen in the Figure 1 below, suicide rates (per 100,000) detainees have been falling over the past twenty years in both jails and prisons. Suicide rates vary widely between specific CJS institutions. Jails have a substantially higher suicide rate than prisons. Small jails have a much higher suicide rate than large jails

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(42). The Bureau of Justice Statistics also tracks suicides at the time of arrest, prior to detention. A significant portion of jail suicides occur in the first three days after booking. However suicides also occur at the scene of the arrest. Two-thirds (67%) of arrest-related suicides occurred at the scene of the attempted arrest, and typically involve attempted arrests for violent crimes.

Figure 1. Decrease of grades of suicide. BJS, suicide and homicide rates in state prisons and jails. August 2005, NCJ 210036 (42).

The vast majority of crime scene arrest suicides occur by firearms, while those suicides that occur at booking and early detention are by hanging. (43). Studies suggest that it is the very young prisoners (below age 21) who are especially at risk; juvenile offenders placed in adult detention homes with almost an eight times greater rate of suicide versus those placed in juvenile detention facilities. During the intake process to jail, the high-risk period for suicide attempts and completions is in the first 24 to 48 hours. Although this has not been observed to be the case with prisons, the first 30 days at most reception centers are generally assess to be the most vulnerable time to those individuals with a prior history of suicide attempts. Substance intoxication at or near the time of detention increases the risk of selfharm. About half of those detainees who commit suicide experience acute stressors at the time of the suicide, with a majority having a history of chronic stressors. For example, inmates diagnosed with AIDS have been found to have been found to be at an increase risk of suicide due to potential hopelessness, isolation, victimization, and threats by other inmates (14). Some of the demographics of persons at risk for suicide are similar to factors in the general population. The strongest predictor for suicide risk is a prior suicide attempt or prior deliberate self-harm. Theories attributing culture as a risk factor have been controversial.

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However, general statistics show that although African-Americans continue to be overrepresented in the penal populations, they also have the lowest rate of suicide attempts and completion compared to their white counterparts. Older white (non-Hispanic) males both in or out of custody have excessive morbidity from suicide. In both jail and prison, the suicide rate among Hispanics is quite a bit lower than other whites, and the suicide rate among African-Americans is even lower than both non-Hispanic and Hispanic whites. White jail inmates six times more likely to commit suicide than black inmates and three times more likely than Hispanic inmates. However jail inmates under age 18 years have significantly higher suicide rates than in the general population, reported as 101 per 100,000 (42). The role of disciplinary segregation in promoting suicide remains controversial, though the majority of studies find it to be a negative factor (28). Two examples from the author’s experience will illustrate the spectrum of the obstacles to eliminating completed suicides in the CJS. Slight modification have been made. Example 2: Mr. A was a 40-year-old unmarried African American facing a life term, who had just received notice from his attorney that his very last appeal was denied. Immediately after receiving this news, he was transferred to a maximum security facility. The receiving institution was not notified of this. Mr. A did not mention this news to any of his acquaintances or to his cell mate. His prior screening for mental illness two years earlier was negative. On reception screening he denied any problems or risk factors. The first Sunday following the news that his appeal was denied, Mr. A waited until his cellmate left for church, made an excuse why he was not going, then jammed the door lock with paper to hinder the cell being opened, put a pre-made noose around the upper bunk frame, tied a rope around his waist and hands so that he couldn’t rescue himself at the last minute, and proceeded to hang himself. A search of his cell after the suicide revealed a suicide note with grandiose comparisons between his situation and Jesus being crucified. Example 3: Mr. B, a 25 year old white male, was in administrative segregation because of threats against him. Mr. B had been convicted of lewd and lascivious with a child. Threats included a variety of violence, both sexual and physical. Two days before his suicide, Mr. B requested sick call for a throat swap and an HIV test. The reason for this sudden request was not fully explored. The tests were scheduled for later that week. The next day he requested a meeting with a mental health counselor, but did not indicate any urgent need, or reason for the request, and this was also delayed. Mr. B hung himself, and left a note indicating that he had been raped by his cellmate and feared that he was infected with HIV. The Death in Custody Reporting Act of 2002 (44) will continue to improve the monitoring of suicides in the CJS. The BJS report indicated that the suicide rate in local jails fell from 129 per 100,000 inmates in 1983 to 47 per 100,000 in 2002. State prison suicide rates also dropped in that comparison from 34 per 100,000 state prisoners to 14 per 100,000 in 2002 (42). Specific suicide prevention programs, and improved mental health care, likely account for much of this improvement (45,46). These programs consist of: training custody staff in the recognition of inmates with depression or otherwise at risk for self harm; promoting an attitude among all staff that suicide must be prevented; destigmatizing mental

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health care among inmates and staff; early screening of detainees for prior history of suicide attempts, suicidal ideation and mental illness; and increased referral of inmates thought to be at risk, for more extensive mental health screening. General guidelines have been developed for screening detainees who may be at higher risk for self-harm. Prediction of suicide is difficult because of the low specificity of identifying risk factors. When prisoners are at risk for suicide nothing less than systematic risk assessment will do, because of the multidimensional nature of suicidal behavior. Risk assessment of individuals should be repeated over time as conditions change. Individual risk factors remain only weakly predictive. At the individual level while the identification of risk factors is important, it is also crucial that emphasis is placed on identifying individuals with specific vulnerability factors and poor coping skills, who are placed in high risk situations. In keeping with the general theme of this review, many of the screening guidelines are tabulations of co-morbidities combined with history and demographics from suicides in the general population. Co-morbidities that need to be considered include adjustment disorders, impulse control disorders, personality disorders, substance use disorders, anxiety disorders, particularly PTSD and of course affective disorders. The adjustment disorders uniquely associated with detention, e.g. loss of an appeal, being targeted for assault, being placed in segregated housing, loss of outside social contact, which lead to pervasive hopelessness, must be specifically investigated, as shown in the two examples. There are numerous studies in the general population relating low levels of CNS serotonin, aggression, and suicide (47). These associations are born out in the CJS. Violent offenders in both local jails (92 per 100,000) and State prisons (19 per 100,000) had suicide rates over twice as high as those of nonviolent offenders (31 and 9 per 100,000 respectively) (42). In one well designed study of 220 cases of jail and prison suicide from Austria, the most important predictors of suicide in pre-trial detainees and sentenced prisoners were single-cell accommodation (i.e. being isolated in a cell by oneself), known previous suicide attempt, receiving psychiatric medication while in custody, and that the last offence of a highly violent nature (27).

Conclusions A prevalent perception is that detainees in the CJS, as a group, are different from the civilian population, and that this difference is part and parcel of their failure to conform to social norms. Psychiatry is only recently recognizing the relationship of failure of behavioral inhibition to newly defined forms of mood disorders and their comorbidities (48). Nearly all of these studies are the result of the emerging interest in childhood bipolar disorders. Accurate and reliable studies of persisting mood disorders and comorbidities in adults are needed to compliment the pediatric studies. Disentangling and treating the contributions of inattention, hyperactivity, mood dysregulation, and oppositional defiance may reduce their combined contribution to the eventual violation of social norms. The CJS will likely be the most productive locus for studying adults with persisting childhood mood disorders and comorbidities.

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Substance intoxication or withdrawal, particularly from stimulants, can mimic symptoms of mania, hypomania, mixed episode or major depression. These symptoms are generally time limited. However stimulants and other drugs can also induce more persistent mood disorders, that require treatment. Understanding and addressing co-morbidities, along with the adjustment disorders attendant on detention or involvement in the CJS, are essential elements for programs to further reduce the hopefully downward trend in suicide in the CJS. The understanding of most justice systems as “adversarial” is essential to effective improvement of mental health care in that environment. Entry screening devices, while perhaps satisfying court ordered improvement or internal initiatives, are highly unreliable in the absence of more independent verifications. There are conflicting motives on either side for the efforts needed to achieve diagnostic accuracy. These screening devices often then begin a cycle of reification, and reinforcement where little new information is added and questionably accurate diagnoses are repeated as established. Additionally financial restraints lead screening agents to only look for constitutionally required serious conditions. Concerns about advantages or additional deprivations lead subjects to shape the information that is shared. Peer pressures further shape the subjects reporting of problems or symptoms. Mood disorders short of MDD with psychotic features or Bipolar I with psychotic features are recognized with degrees of variation. Time pressures, lack of training about the importance of comorbid disorders, concerns with only “serious” disorders, and other factors lead CJS mental health clinicians to stop after a single diagnoses on Axis I or II. Knowing that effective treatment will not be allowed or possible in the CJS further discourages clinicians from looking for the full range of co-morbidities affecting the subjects in the CJS. As correctional psychiatry becomes a more mature subspecialty, mental health workers will come to appreciate the Gordian knot created by the multiple co-morbidities in the detainees in the CJS. Despite all the obstacles related to studies in the CJS, accurate research into the role of childhood mood disorders and comorbidities in leading to adult criminality is essential. Men and women both must be included in these studies to enrich the understanding of the different presentation of mood disorders in boys and girls. Finally, the complexity of the subject population in the CJS, and its growing importance as a population that must receive constitutionally adequate mental health care, will make it an important part of psychiatric training in the years to come.

References (1) (2) (3)

Bureau of Justice Statistics. Special Report: Mental Health Problems of Prisons and Jail Inmates. US Department of Justice. September 2006. (NCJ 213600). Carlson GA. Who are the children with severe mood dysregulation, a.k.a. “Rages”? Am J Psychiatry 2007;164:8. Newcorn JH, Halperin JM, Miller CJ. Comorbidity of attention deficit disorders with oppositionality and aggression. In: Brown TE, ed. Attention-deficit disorders and comorbidities in children, adolescents and adults. Washington, DC: Am Psychiatr Press, 2000:171–208.

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Alan A Abrams, Maheen Patel, Tyler Jones et al. Leibenluft E, Charney DS, Towbin KE, Bhangoo RK, Pine DS. Defining clinical phenotypes of juvenile mania. Am J Psychiatry 2003;160:430-7. Pennsylvania Dept of Corrections v. Yeskey, 524 U.S. 206 (1998). Estelle v. Gamble, 429 U.S. 97, 104 (1976). Fryers T, Brugha T, Grounds A, Melzer D. Severe mental illness in prisoners. BMJ 1998;317:1025-6. Teplin L. The Prevalence of severe mental disorder among male urban jail detainees: Comparison with the epidemiologic catchment area program. Am J Public Health 1990;80(6):663-9. Lamb HR, Weinberger LE. Persons with severe mental illness in jails and prisons: A review. Psychiatr Serv 1998;49:483-92. Fazel S, Danesh J. Serious mental disorder in 23,000 prisoners: A systematic review of 62 surveys. Lancet 2002; 359(9306):545-50. Metzner JL. Class action litigation in correctional psychiatry. J Am Acad Psychiatry Law 2002;30(1):19-32. National Commission on Correctional Health Care. The health status of soon-to-bereleased inmates. A report to congress. Volume 1. Chicago, Ill: Nat Comm Correct Health Care, March 2002. Ditton PM. Bureau of Justice Statistics. Special report: Mental health and treatment of inmates and probationers. Washington, DC: US Dept Justice, July 1999. (NCJ 174463). Rickford D. Troubled inside: Responding to the mental health needs of women in prison. London: Prison Reform Trust, 2003. Torrey, EF. Jails and prisons - America’s new mental hospitals. Am J Public Health 1995;85(12):1611-3. Kessler RC, Chiu WT, Demler O, Walters E. Prevalence, severity, and comorbidity of 12-Month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:617-27. Nierenberg AA et al. Clinical and diagnostic implications of lifetime attentiondeficit/hyperactivity disorder comorbidity in adults with bipolar disorder: Data from the first 1000 STEP-BD participants. Biol Psychiatry 2005;57:1467-73. Patel, M. Comorbid ADHD and affective disorders. Presentation at Georgetown University Hospital Grand Rounds, June 2007. Swann AC, Dougherty DM, Pazzaglia PJ, Pham M, Steinberg JL, Moeller FG. Increased impulsivity associated with severity of suicide attempt history in patients with bipolar disorder. Am J Psychiatry 2005;162:1680-7. Romans SE, Potter K, Martin J, Herbison P. The mental and physical health of female sex workers: a comparative study. Aust NZ J Psychiatry 2000;35:75-80. Gore, SM. Suicide in prisons. Reflection of the communities served, or exacerbation of risk? Br J Psychiatry 1999;175:50-5. He XY, Felthous AR, Holzer CE et al. Factors in prison suicide: One year study in Texas. J Forensic Sci 2001;46:896-901. Alegria M, Vera M, Freeman DH, Robles R et al. HIV infection, risk behaviors, and depressive symptoms among Puerto Rican sex- workers. Am J Public Health 1994;84:2000-2.

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(24) Herfkens K. Depression, neurocognitive disorders, and HIV in prisons. HIV Educ Prison Project NEWS 2001;4(1):1-8. (25) DuRand C, BurtkaGJ, Federman EJ et al. A quarter century of suicide in a major urban jail: implications for community psychiatry. Am J Psychiatry 1995;152:1077-80. (26) White TW, Schimmel DJ, Frickey R. A comprehensive analysis of suicide in federal prisons: a fifteen-year review. J Correction Health Care 2002;9:321-45. (27) Fruehwald S, Matschnig T, Koening F et al. Suicide in custody: Case - control study. Br J Psychiatry 2004;185:494-8. (28) Way BB, Sawyer DA, Barboza S, Nash R. Inmate suicide and time spent in special disciplinary housing in New York State Prison. Psychiatr Serv 2007;58:558-60. (29) Struckman-Johnson C, Struckman-Johnson D, Rucker L et al. Sexual coercion reported by men and women in prison. J Sex Res 1996;33:67-76. (30) Yovtcheva SP, Rifai MA, Moles JK, Van der Linden BJ. Psychiatric comorbidity among hepatitis C-positive patients. Psychosomatics 2001;42(5):411-5. (31) Dieperink E, Ho SB, Thuras P, Willenbring ML. A prospective study of neuropsychiatric symptoms associated with interferon-alpha-2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 2003;44(2):104-12. (32) Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J Clin Psychiatry 2003;64(6):708-14. (33) Conover T. Newjack: Guarding Sing Sing. New York: Vintage, 2001. (34) Abrams A. Treatment issues in prisons, jails, and correctional and forensic settings CME Bipolar Disord Impulse Disord Spectrum Letter 2004 Aug 10:3. (35) Herrman H, McGorry P, Mills J, Singh B. Hidden severe psychiatric morbidity in sentenced prisoners: an Australian study. Am J Psychiatry 1991;148(2):236-9. (36) Skodol AE, Stout RL, McGlashan TH et al. Co-occurrence of mood and personality disorders: a report from the collaborative longitudinal personality disorders study (CLPS). Depress Anxiety 1999;10(4):175-82. (37) Akiskal HS. Subaffective disorders: dysthymic, cyclothymic and bipolar II disorders in the "borderline" realm. Psychiatr Clin North Am Clin 1981;4(1):25-46. (38) Trestman RL. Behind bars: personality disorders. J Am Acad Psychiatry Law 2000;28(2):232-5. (39) Coleman v. Wilson, 912 F. Supp. 1282 (E.D. Cal., 1995). (40) Abrams A, Davis SJ. Court mandated restrictions on medicated mentally ill state inmates. California Meeting ADA, Poster Presentation, Am Coll Legal Med, San Diego, March 30, 2000. (41) Department of Mental Health. Preventing suicide: A resource for prison officers. Geneva: World Health Organization, 2000. (42) Bureau of Justice Statistics. Special report. Suicide and homicide in state prisons and local jails. Washington, DC: US Dept Justice, 2005. (NCJ-210036). (43) Mumola CJ. Bureau of Justice Statistics. Special report: Arrest-related deaths in the United States, 2003-2005. Washington, DC: US Dept Justice, October 2007. (NCJ 219534). (44) The Death in Custody Reporting Act of 2002 (Public Law 106-297).

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(45) Hayes LM. National study of jail suicides: seven years later. Psychiatric Quart 1989;60(1):7–29. (46) Hayes LM. Prison suicide: An overview and guide to prevention. Washington, DC: US Dept Justice, Nat Inst Corrections, 1995. (47) Asberg M. Neurotransmitters and suicidal behavior. The evidence from cerebrospinal fluid studies. Ann N Y Acad Sci 1997;836:158-81. (48) Rich BA, Schmajuk M, Perez-Edgar KE, Fox NA, Pine DS, Leibenluft E. Different psychophysiological and behavioral responses elicited by frustration in pediatric bipolar disorder and severe mood dysregulation. Am J Psychiatry 2007;164(2):309-17.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXI

Suicide in the Muslim World Farooq Mohyuddin∗ Psychiatry Residency Training Program, St. Elizabeth’s Hospital, Washington, DC, USA

Abstract Suicide is a cause of significant mortality and morbidity around the world. There has been research on the various risk factors and protective factors for suicide. One protective factor that has been of interest is the possible negative correlation between religion, religiosity/moral objections to suicide and suicide rates. There are several reports that the rate of suicide is lower in Muslim majority countries (Islamic countries). The various hypotheses about the lower suicidal rate include the impact of the Quran’s injunction against suicide, the prospect of an eternal life in hell, the social integrative and regulative benefits of religion, and underreporting of suicide due to stigma/criminal penalties. Despite the disagreement on the causal factors many of the studies have suggested that Muslims are at a lower risk for suicide compared to other populations. Some of this data comes from studies of Muslims in countries with mixed religious population. Scarcity of research about the incidence of suicide in Muslim majority countries precludes a definitive conclusion. This is a preliminary review of the subject with a key objective of pointing out directions for future research and the clinical implications. We will discuss the state of current knowledge about Islam as a possible protective factor against suicide.

Keywords: Muslims, suicide, risk factors, protective factors, religion.

∗

Correspondence: Farooq Mohyuddin, MD, Director Psychiatry Residency Training Program, St. Elizabeths Hospital, Barton Hall, 2700 Martin Luther King Junior Ave SE, Washington DC 20032, United States. Tel: 202-645-8777; E-mail: [email protected]

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Introduction Suicide is a major health problem worldwide. According to the WHO statistics, up to a million people commit suicide per year around the world. The number of suicidal attempts may be ten to twenty times higher (1). The impact of this major health problem on society in terms of pain and suffering, financial, medical and psychosocial consequences makes it imperative to study suicidal behavior with an aim to devise better predictive and preventive strategies. The risk factors that have been linked to increased risk of suicide include psychiatric illness, comorbid drug and alcohol abuse, childhood trauma (physical or sexual abuse), family history of suicide, current suicidal ideation, history of suicide attempts, acute stressors, history of head injury or neurological illness and accessibility to lethal means (2). The rates of suicide vary greatly in different countries around the world (3). A better understanding of the factors producing this variation can go a long way towards predictive and protective efforts. The impact of sociological factors on the rates of suicide has long been a topic of interest. The need for sociological studies has arisen from the lack of accuracy in predicting and preventing suicide in individual patients due to considerable interindividual variability in patients who attempt or complete suicide. It has been difficult to devise randomized controlled trials to study suicide prevention for several reasons. These include ethical concerns, medico-legal problems and the inability to design a methodologically significant study with enough statistical power to be able to definitively identify risk factors and protective factors. To a certain degree sociological studies circumvent these problems by studying the general population and thus identifying the factors that may be associated positively or negatively with suicide rate. While these studies provide some guidance to the clinician in assessing suicide risk, their limitation is the difficulty in translating the risk in the population to risk in an individual patient. Although some of the positive or negative suicidal risk factors have been studied extensively, the impact of religion and particularly Islam did not receive much attention until recently. Historically the religious influence on suicide has been understood in the terms of Durkheim’s (1897) classical work on suicide (4). The traditional view held by Durkheim of the social integrative and regulative function of religion has undergone major developments, including Stack’s (5) religious commitment theory and Pescosolido’s (6,7) religious network theory. According to Durkheim, the subordination of individual needs to the collective needs of society produces integration through shared religious beliefs which in turn counteracts suicidal thoughts (4). Stack proposed that it is the content of life-preserving religious beliefs that provides the protective effect on suicide, and not the number of beliefs, as proposed by Durkheim (5,8). Pescosolido, in her religious networks theory, focuses on the contexts and social networks providing integration and protection against suicide (6,7). The earlier literature about religious influence on suicide was focused on differences between Protestants and Catholics in suicidal attempts or completions. Durkheim concluded that Catholicism was a denomination with many shared beliefs and therefore was more protective against suicide as compared to Protestantism (4). However, this view has been challenged with studies demonstrating that when other variables were controlled Catholicism’s relationship to suicide rates as compared to

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Protestantism disappeared (8). There have been further developments of the traditional view studying the protective effect of religion as modified by social, historical and cultural factors (7). Research in specific denominations or groups in the Christian faith has demonstrated the beneficial effects of religion (9). There are studies which point out the negative correlation of suicide and religious commitment. Hilton et al (10) in a comparison of age matched males in the US, reported 2.5 to 3 times higher rates of suicide in 20-34 year olds compared to religiously active males in the Church of Latter Day Saints. In their study of protective factors against suicidal behavior in depressed adults with a history of childhood abuse, Dervic et al (11) reported an inverse correlation between suicidal ideation and moral objections to suicide or religiosity. It appears that any study of the protective effects of religion will need to take into account regional differences, education, religiosity, secularization and urbanization and its impact on the integrative effects of religion. The impact of religious differences has also been studied in non-Christian majority countries. The review of epidemiological data from Israel by Morad et al (12) reported that the rates of suicidal behavior were lower in Arab children and adolescents when compared to the Jewish population (12). Another review by Lester also points out that suicide rates are lower in the Muslim population as compared to other religions (13). Religious views of suicide range from outright intolerance to relative tolerance. Suicide is mentioned in the Bible and Talmud without moral injunctions (14,15). However, we find that very early in predominantly Christian nations suicide came to be regarded as a grave sin and was penalized not only with religious but material sanctions (4). The criminalization of suicide in majority Christian countries was evident until a couple of centuries ago. The influence of Dante's vision that the lowest reaches of hell were reserved for people that committed suicide may also be a factor in the society’s view of suicide (16). In Hinduism the traditional view of suicide has been evolving in the Vedic Scriptures as described by Ladha et al (17). It was tolerated in the earlier Vedic traditions. Later, however, the Upashinads condemned suicide and denied salvation. Among Muslims there is a general consensus on the Quranic view of suicide as a sin. It expressly forbids Muslims from killing themselves (18). There has also been a tradition of not awarding traditional funeral rites to people who complete suicides in many religions. Majority of religions consider suicide to be a sinful act. Some cultures have historically had tolerance and ambivalence towards suicide, e.g. feudal Japan’s acceptance of suicide by samurai warriors or in the early Greek city-states where suicide was only a crime if committed without prior approval by the state. There have been several published studies suggesting that the suicidal rates in Muslims may be lower in comparison to other religions (12,13,19-23). In some Islamic countries the reported suicide rates may be as low as 1 per million (24). This article is an attempt to review the state of current knowledge of the relationship between Islam and suicide rates. This article is focused on suicidal intent as it pertains to medical and clinical aspects. The discussion of militant and political perspective of suicide with intent to harm others is beyond the scope of this article and will be discussed in a future article.

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Methods Two major databases PubMed and PsychINFO were searched using the search terms Islam, Muslims and suicide. The abstracts were reviewed and full text articles that were considered relevant to the subject were obtained. The relevance of the articles was based on comparison of suicide rates between people from different religions/sects.

Results There are several studies addressing the incidence of suicide or suicidal thoughts as influenced by religious differences. An early study looking at Islam and suicide performed by Simpson and Conklin (20) examined different socioeconomic variables in 71 nations and concluded that the percentage of Muslims in a population was one of the four factors which was significantly negatively correlated to the suicide rate. There has been difficulty in compiling the statistics of suicide in Islamic countries since many of the predominantly Muslim nations have not reported mortality data to the World Health Organization for more than a decade. However many researchers have attempted to overcome this by various methods. Lester collected data directly from different countries for suicide rate and the percentage of Muslims in each country (28). This data did not show a significant impact of the percentage of Muslims in the population on suicide rates. He also reported an inverse relationship between percentage of Muslims in the former Soviet Union states and suicide rate in the early 1990s (29). Another method by which the lack of data has been addressed is studying the suicide rate in Muslims living in countries with other religious majorities. Meer’s study in South Africa reported the percentage of Muslims in the Indian population who completed suicide was 4.8% compared to their share of the population which was 16% (21). In an interesting study, Lester calculated suicide rates in England and Wales for immigrants from the Indian subcontinent with the data from Soni Raliegh. The suicide rates were almost two fold for immigrants from India, a majority Hindu country, compared to immigrants from Pakistan and Bangladesh, majority Muslim countries (13). Ong and Leng reported a significantly lower rate of completed suicide in Malays (Muslims) in Malaysia as compared to Chinese and the Indians (22). Other notable studies include the Morad et al (12) review of suicide behavior among Arab adolescents which concluded that suicide has a lower incidence in the Arab Muslim population as compared to the Jewish adolescents. It was also observed in this review that there has been an increase in suicide in Arab adolescents over the last 10 years. The difference among Arab and Jewish populations in Israel decreased but still persisted when unexplained causes of death were added to the total number of suicides for both populations. The difference among these two populations was also noted by Levav et al in their 1989 study (23). They noted that in addition to religion there were certain other differences in these two populations which could impact rates of suicide. For example, the non-Jewish population was less urbanized, less educated, and proportionately more people tended to live in groups

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rather than in isolation. These and other studies studying suicidal rates within a country have pointed to a low rate of suicide in the Muslim population (13, 20-22). There are also some reports contradicting the protective effects of Islam on suicide. Lester has concluded that the rate of attempted suicide does not appear to be lower in Muslims as compared to non-Muslims (13). A recent study by Pritchard and Amanullah (24) analyzed the rates of suicide and undetermined deaths in 17 Islamic countries and compared the rates with the suicide rate in the United Kingdom. The conclusion from their study was that the rates in Islamic countries vary widely and the significantly higher rates of other violent deaths (as defined by WHO), especially in Middle Eastern countries could be masking the deaths from suicide (24). Kamal and Loewenthal reported that in a survey of young Muslims and Hindus living in the United Kingdom Muslims endorsed moral, survival and coping beliefs and total reasons of living more strongly as compared to Hindus, there was no difference however, between the two groups in suicidal thoughts, plans or behaviors (26).

Discussion The review of the current state of knowledge about suicide in the Muslim world has revealed a lack of consensus about Islam being a protective factor against suicide. The conflicting reports in the available literature preclude a definitive statement that the suicide rates in Muslims are lower when compared to other religions. One of the reasons for the lack of consensus could be the heterogeneity of this population. Muslims are spread around the world belonging to different regional, ethnic, cultural groups and religious sects. To study them together as a homogenous population may neglect the impact of other important sociological factors on suicide. This is evident by the disparity in reported suicide rates in Muslim majority countries (24). However, these studies also allow an opportunity for teasing apart religion from climate, socioeconomic factors or diet. In the following discussion, we shall summarize the various studies reviewed, the conclusions reached by authors in these studies and the various hypotheses proposed to explain the findings. There have been several studies which have reported a lower rate of suicide in various religious groups, particularly Islam (10-13,19-23). Some of these studies have attempted to minimize the impact of the regional variation by comparing suicide in different religious populations within the same country (12,13,21-23). This has the advantage of controlling for cultural norms, legal issues, geographical factors and social factors since many of these may be shared across different religious groups within the same country. A limitation of some of these positive studies has been the lack of officially reported data from many of the Muslim countries. This has been addressed methodologically by studying the differences across religions in countries with better reporting of data. In Lester’s 2006 review of suicide and Islam the comparison of immigrants from India, Sri Lanka, Bangladesh and Pakistan demonstrated a significantly higher rate of suicide for immigrants from India, a majority Hindu country, as compared to immigrants from Pakistan and Bangladesh, majority Muslim countries (13). This review is significant because the immigrants from these countries share many of the cultural and regional characteristics, with the major difference being religion. It is noteworthy that the reported rate for immigrants from Pakistan was higher than the

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reported suicide rate in the country of origin, Pakistan. The higher rate may be attributed to more accurate reporting, suggesting that the reporting of suicides may be impacted by the religious and social views. On the other hand, this increase could also be attributed to immigration, thus raising the question of social and cultural factors increasing the risk of suicide in a population. This demonstrates the complexity of the interactions that can increase or decrease the risk of suicide in any given population, therefore making it hard to calculate the impact of any one factor when studying suicide. In reviewing these positive studies, we can include various hypotheses proposed to explain the lower reported rates of suicide in Muslim populations. These include the impact of suicide being expressly forbidden in Quran (18), the view of afterlife as an eternity in hell after suicide, the social stigma against suicide that is present in many predominantly Islamic countries towards suicide, the criminalization of suicide in some Islamic countries making it an undesirable act, and the possibility of underreporting. To this list, we can suggest adding other factors that may influence the suicide rates and have been reported in other religions; the degree of religiosity, moral objections to suicide and degree of social cohesion. (10,11,25,26). In contrast to these studies there have been reports which suggest that the actual rate of suicide may be the same across different religions and lack of accurate data may give the perception that the rates of suicide are lower in Muslims (24). Pritchard and Amanullah’s analysis (24) suggested the possibility of hidden suicides which may be reported as other violent deaths or other unexplained deaths in many Muslim countries. They also pointed out that the rates of suicide in former Soviet Islamic republics were higher than the rate of suicide in the United Kingdom. There are many possible reasons for underreporting suicides in Islamic countries which include social and religious taboos as well as the possibility of legal action in some countries. One of the major risk factors for suicide is having a psychiatric disorder. The incidence of major psychiatric disorders is generally not related to countries or ethnicity, therefore raising the possibility that the incidence of suicide may be the same across different parts of the world. It is evident by these conflicting reports that we need more research to quantify any protective effect that Islam may have towards suicide. The complexity of the interactions between various protective and risk factors and the paucity of data at present limit our ability to quantify the effect. One of the primary requirements for any future research on this topic is the collection of better data, especially in countries where suicide data has not been reported for a long time. The direction of future research should also include an exploration of the possible causes of variations in suicide rates between the former Soviet Islamic countries and other Islamic countries. The impact of decades of totalitarian rule on social cohesion and religiosity may need to be factored in when studying former Soviet republics. Future studies should to be designed to weigh the regional and sectarian differences in concluding the suicide risk. The importance of religion in the lives of believers particularly in societies where it is a dominant force and the different ways in which it could impact health outcomes has been the subject of a number of studies. In terms of clinical significance, one has to be careful not to assume that suicide risks may be lower in individual Muslim patients. Clinicians should be attuned to the influence of religion in their patients lives.

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Evaluating this may be useful in engaging the patients who score high in religiosity. For clinicians working with patients at risk, it is important to learn about the patient's beliefs, religious view of suicide and the strength of the belief in afterlife. This could potentially benefit the patients by utilizing the religious beliefs and moral objections to suicide in the service of suicide prevention. Focusing on life promoting beliefs could be one of the interventions to reduce suicidality in hopeless and depressed patients. This could be extended to improve coping skills and optimistic attitudes. The role of clergy as gatekeepers could potentially be helpful in a suicide prevention program. Involving the Imams in educating the Muslim population, as well as in acting as screeners for potential risk could be helpful. The role of screening for suicidal risk in the community has been shown to reduce suicidal risk in some settings (27). The clinician can also emphasize that in many cases depression or other mental conditions represent factors that can overwhelm free will, and as such, patients need to seek help from trained professionals. Obviously, working together with the Muslim clerics to increase awareness in community and to destigmatize mental illness and suicide is an important goal, one which can have far reaching implications. Finally, studying suicide across cultures is expected to increase our general understanding of what is universally human and what is specific for certain ethnic, social and economical configurations, ultimately allowing application of what is learned in one culture to increase the protection against suicide in all of us. Considering that suicide is a universally shocking, extremely painful, and guilt inducing event for the immediate social environment of the victim in all cultures, and that it reaches public health dimensions, transcultural research efforts may ultimately result in more subtle and effective suicide prevention practices.

References (1) (2) (3) (4) (5) (6) (7) (8) (9)

World Health Organization. Figures and facts about suicide http://www.who.int/mental_health/media/en/382.pdf. Mann JJ. A current perspective of suicide and attempted suicide: Ann Intern Med 2002;136:302-11. World Health Organization: www.who.int/whosis Durkheim E. Suicide. A study in sociology. Glencoe, IL: Free Press, 1951 (original 1897). Stack S. The effects of religious commitment on Suicide: A cross- national analysis. J Health Soc Behav 1983;24:362-74. Pescosolido B, Wright E. Suicide and the role of the family over the life course. Fam Perspect 1990;24:41-60. Pescosolido B. The social context of religious integration and suicide. Sociol Quart 1990;31:337-57. Stack S. Suicide: A 15-Year review of sociological literature. Suicide Life Threat Behav 2000;30:2. Pescosolido B, Georgianna S. Durkheim, suicide and religion. Am Sociol Rev 1989;54:33-48.

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(10) Hilton S, Fellingham G, Lyon J et al Suicide rates and religious commitment in young adult males in Utah. Am J Epidemiol 2002; 155:413-9. (11) Dervic K, Grunebaum M, Burke A, Mann JJ, Oquendo M et al. Protective factors against suicidal behavior in depressed adults reporting childhood abuse. J Nerv Ment Dis 2006;194:971-4. (12) Morad M, Merrick E, Schwarz A, Merrick J. A review of suicide behavior among Arab adolescents. Scientific World Journal 2005;5:674-9. (13) Letser D. Suicide and Islam. Arch Suicide Res 2006;10:77-97. (14) Barraclough BM. The Bible suicides. Acta Psychiatr Scand 1992; 86(1):64-9. (15) Koch HJ. Suicides and suicide ideation in the Bible: An empirical survey. Acta Psychiatr Scand 2005;112:167-72. (16) Alighieri D. La divina commedia. Munich: Bremer Presse, 1921. (17) Ladha K, Bhat S, D’souza P. Suicide attempts in a general hospital in India. Acta Psychiatr Scand 1996;94:26-30. (18) Sarhill N, Legrand S, Islambouli R et al. The terminally ill Muslim: Death and dying from a Muslim perspective. Am J Hospice Palliat Care 2001;18:251-5. (19) Ineichen B. The influence of religion on the suicide rate: Islam and Hinduism compared. Ment Health Religion Culture1998;1(1):31-6. (20) Simpson M, Conklin G. Socio-economic development, suicide and rligion: A tst of Durkheim's teory of rligion and sicide.Soc Forces 1989;67:945-64. (21) Meer F. Race and sicide in South Africa. London: Routledge Kegan Paul, 1976. (22) Ong S, Leng YK. Suicidal behavior in Kuala Lumpur, Malaysia. In: Peng KL, Tseng Wa, eds. Suicidal behavior in Asia-Pacific Region. Singapore: Singapore Univ Press, 1992:176-98. (23) Levav I, Aisenberg E. Suicide in Israel. Acta Psychiatr Scand 1989; 79:468-73. (24) Pritchard C, Amanullah S. An analysis of suicide and undetermined deaths in 17 predominantly Islamic countries contrasted with the UK. Psychol Med 2007;37:421-30. (25) Dervic K, Oquendo M, Grunebaum M, Ellis S, Burke A, Mann JJ et al. Religious affiliation and suicide attempt. Am J Psychiatry 2004; 161:2303-8. (26) Kamal Z, Lowenthal K. Suicide beliefs and behavior among young Muslims and Hindus in the UK. Ment Health Religion Culture 2002, 111-8. (27) Knox K, Litts D, Talcott G, Feig J, Caine E et al. Risk of suicide and related adverse outcomes after exposure to a suicide prevention programme in the US Air Force: Cohort Study. BMJ 2003; 327:1376-8. (28) Lester D. Patterns of suicide and homicide in the World. New York: Nova Sci, 1996. (29) Lester D. Suicide in post-Soviet Central Asia. Central Asian Survey 1999;18:121-4.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXII

Ethnic Differences in Adolescent Suicide in the United States Theodora Balis∗ and Teodor T. Postolache Mood and Anxiety Program, Department of Psychiatry, Baltimore, University of Maryland Medical Center, Baltimore, MD, USA

Abstract Suicide is the third-leading cause of death for adolescents between 15 and 24 years of age in the United States and its rate has been increasing. Factors that contribute to rate of, risks for, or protection against depression and suicide may be different for people from cultures with different values and health beliefs. Although typically seen as affecting Caucasians more than other groups in the U.S., the rates of suicide among African Americans, Latinos, and others have been increasing. 87 studies were reviewed looking at rates for suicide/suicidal ideation, risk factors for suicide, protective factors/coping mechanisms, service delivery/barriers to care, and specific treatment or management of suicidal thoughts for adolescents from different ethnic groups in the U.S. The following ethnic groups in the U.S. were compared: African American, Latino, Asian American, Native American/Alaskan Native, and Hawaiian American. Although studies report conflicting rates, most studies still show an overall higher risk for suicide among Caucasian youth than any other group. Rates for suicide are growing for African American teens (perhaps more in boys), Latino teens (especially Latina girls), Asian American youth, Native American youth, Alaskan Native youth, and Hawaiian American youth. Details about these differences are discussed along with recommendations for clinicians working with youth at risk for suicide from minority cultures in the U.S.

∗

Correspondence: Theodora Balis, MD, Assistant Professor, University of Maryland Medical Center, Department of Psychiatry, Mood and Anxiety Program, 685 West Baltimore St., MSTF Building Suite 500, Baltimore, Maryland 21201, USA. E-mail: [email protected]

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Keywords: Adolescent, culture, depression, ethnicity, suicide, United States.

Introduction The United States has experienced great changes in ethnic mix over the past 20 years and the growing diversity in the population needs to be considered when talking about suicide in the U.S. (1). Factors that contribute to risks for or protection against depression and suicide may be different for cultures with different values and health beliefs. Although typically seen as affecting Caucasians more than other groups in the U.S., the rates of suicide among African Americans and Latinos, among others, have been increasing (2,3). Understanding the reasons for this change and how to treat people from non-majority ethnic groups is a growing need in healthcare. Some definitions may be helpful in understanding the issues. Culture can be defined as a pattern of human behavior that includes customs, communication, beliefs, values, and views about life in a religious, ethnic, or social group (4). Many cultural groups fall under the categories of ethnicity, religion, sexual orientation, and other social groupings. Ethnicity, specifically considered in this paper, usually implies a geographic origin and can be defined as an individual’s sense of belonging to a group of people sharing a common origin and history. Cultural competence includes sensitivity toward diverse groups and awareness of factors that impact on minority groups and immigrants like: the stress of migration, acculturation, history, poverty, language barriers, discrimination, prohibitions, values, beliefs, and spirituality that can affect health care. In order to provide the best care to people from minority groups, it is important to understand basic concepts about different cultures such as how illness is defined in that culture, the specific values and beliefs that influence understanding of illness, family connections, and social networks, and how to build a therapeutic alliance with someone from a different culture. As for the definition of suicide, studies vary in what exactly is reported when discussing suicide. The term suicide in the literature usually means completed suicide, but sometimes it is difficult to distinguish what is termed “suicide” from completed suicide, attempted suicide, performing other self-injurious behavior, planning suicide, and having suicidal thoughts. There is a great deal of data about general lifetime rates and risk factors for suicidal thoughts, plans, attempts, and completion. Data from the National Comorbidity Survey, 1999 showed that in the U.S., the prevalence of suicide ideation is 13.5%, for plan is 3.9%, for attempt is 4.6%, and, of the attempters, 39% reported it was a serious attempt [5]. Females were more likely to have suicidal thoughts (OR 1.7) and more than twice as likely to attempt suicide (OR 2.2) compared to males (5). They found that having any DSM III-R disorder, especially mood disorder, Post Traumatic Stress Disorder (PTSD), non-affective psychosis, substance abuse disorder, antisocial personality disorder, female gender, and being a nonstudent with 12 or fewer years of education increased the odds of attempting suicide [5]. Analysis of coroner data in a major city between 1998 and 2001 found that the suicide rate was 14.8 per 100,000 (6). This data showed that about half of those people who committed suicide had a mental illness and 26% had history of substance abuse. The leading risk factors

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were age, psychosocial stressors, poor health, and access to firearms (6). Studies looking at methods of suicide for adults across ethnicities show that Latinos were more likely than other groups to use firearms, implementing them in 1.8% of suicides, while Asian American and Native Americans were less likely to use firearms, in only 0.6% (7). Use of firearms in completed suicide has increased across ethnic groups, including African Americans and Latinos. Men are more likely to use more violent means of suicide and although women are more likely to use poisons for suicide, firearm use by women is also increasing [8]. Asian Americans (Chinese and Japanese Americans) were more likely to use hanging as a method of suicide, though again it was found that firearm use was increasing (8). It is unclear if the same patterns exist in adolescents. Genetic studies show that there are genetic factors involved in the etiology of suicidal thoughts and behavior. In fact, multiple genes may play a role. The serotonergic system has shown the most evidence, but there is new evidence also implicating the noradrenergic and dopaminergic systems (9). A study by Thalmeier showed that genes involved in cell proliferation, development of the CNS, cell–cell communication, and signal transduction may play a specific role in suicidal behavior (10). Focusing on adolescence in particular, since 1999, suicide has been considered the thirdleading cause of death for people between the ages of 15 and 24 in the U.S. (1). According to the National Comorbidity Survey, if lethality is ignored, the highest risks for suicidal ideation, plans, and attempts are in the late teens and early twenties (5). From 1900 to 1955, the suicide rate for 15-24 year-olds was about half that for the combined rate for all U.S. age groups. Between the mid-1950s and 1980, however, the rate almost tripled (11). The CDC, as quoted in Bechtold, reported that this increase in suicide rate among U.S. adolescents has coincided with an overall reduction in suicide rates in people older than 30 years of age, making the adolescent increase even more noteworthy and concerning (11,12). There have been multiple studies examining motivations, risk factors, protective factors, and treatments for depression and suicide in American youth. There is also growing research looking at how suicide differs across cultures in the U.S. and internationally. This paper will examine factors influencing suicide and suicidal ideation in adolescents from various ethnic groups in the U.S. in an attempt to further the understanding of how to prevent suicide across cultures. This paper will not examine suicide thoughts or behaviors in non-ethnic cultural groups, nor ethnic groups outside the U.S. Comparisons will be made only for broader ethnic groups in the U.S.

Methods A search was made on PubMed, MEDLINE, CINAHL, and Medscape between the years 1975 and 2007. It was anticipated that the literature prior to 20 years ago would be sparse and less relevant to the clinical work of today. Only papers published in English were collected. Studies examining suicide internationally were excluded. Articles were categorized according to the ethnic group examined: general study on ethnicity and suicide, or studies specifically on African American, Asian, Caucasian, Latino,

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Native American, and/or Native Hawaiian youth. These groupings were selected since most studies established comparisons based on such delineations. Where more than one group was compared, the article was considered for each group. It was decided to focus on these groups in this overview as most studies grouped subjects according to these general racial groups. Where studies looked at specific Latino groups (i.e., Mexican, Argentinean, etc.), the article was considered for Latino subjects in general. Studies were then grouped according to whether they examined general rates, risk factors, protective factors/coping mechanisms, use of mental health services, or treatments for depression and suicide in youth in America. A total of 87 articles were reviewed that looked at suicide and suicidal thoughts in youth from minority groups in the U.S. The following search words were used: Adolescent, culture, depression, ethnicity, suicide, United States, children.

Results 87 studies were reviewed. Most studies compared African American, Latino, Native American, and Caucasian subjects and a few studied Asian American and Native Hawaiian subjects. 14 studies looked at general rates, risks, and treatments for suicide/suicidal ideation across cultures. 43 studies examined risk factors for suicide and 12 examined protective factors/coping mechanisms. 9 studies looked at service delivery/barriers to care or treatment/management of suicidal thoughts for any ethnic group. Of the 17 articles studying African Americans, 14 were surveys, 1 was a chart review, one was a literature review, one looked at mortality data, one was a book, and one was a case controlled study. Of the 26 articles studying Latinos, 19 were surveys, four looked at mortality data, and three were a literature reviews. Of the 12 articles studying Asian Americans, 8 were surveys, one was a literature review, one interviewed subjects using DSM criteria, one was a case-control study, and one was a medical record review. Of the 25 articles looking at Native Americans/Alaskan Natives, 16 were surveys, three reviewed mortality data, two were case studies, three were literature reviews, and one was participatory action research. There were three articles that studied Native Hawaiians and all were done by survey. There were 9 articles about ethnicity and suicide in youth in general and of those, two were reviews, one was a chapter, and six were surveys.

General Studies of Adolescents and Suicide in the US Data from the National Comorbidity Survey, 1999 showed that of the 5,877 respondents aged 15-54 years, 13.5% reported lifetime suicidal ideation, 3.9% plan, and 4.6% attempt (5). A large study in Boston found from reports of students that 20% of Boston Public high school students were frequently depressed, 20% had suicidal thoughts at one time, and 10% actually attempted suicide (13). In that study, males were more likely to complete suicide, but females were twice as likely to attempt suicide (13). Another study by Roberts et al. in 1997

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similarly found that suicidal thoughts in adolescents from a lower status group were more prevalent for older females, but it was older males who made more attempts (14). National mortality data has been used to look at methods of suicide used by adolescents in the US. A study by Shepherd and Klein-Schwartz in 1998 researched the epidemiology of poisoning deaths by adolescents in the U.S. and found that, although most poisoning victims were Caucasian males, females were most likely to use poisoning as a means of suicide and the death rate was highest in 15-19 year-olds (15). Younger adolescents (10-14 year-olds) appear to use drugs other than alcohol to commit suicide and inhalants seem to be used more by older adolescents (15-19 year-olds) in suicides and accidental deaths (16). Another study found that the most common method of suicide for adolescents is by firearms and the increases in suicide rate in adolescents attributable to firearms far exceeds increases attributable to any other method of suicide (17). General risk factors for suicide attempts and suicidal thoughts in adolescents include depression, drug/alcohol use, family history and friends’ history of suicide attempt, female gender, lower education, school dropout, lower socioeconomic status, history of environmental stress, history of sexual abuse/physical abuse, and parental conflict (18). One study analyzed data from the CDC National Youth Risk Behavior Survey in 2001 and found that ethnicity, gender, being offered drugs at school, and being abused by a boyfriend/girlfriend were risk factors (19). Other studies have found that similar risks including mood disorders, prior suicide attempts, social alienation, substance abuse, and family hardships contribute to adolescent suicide (20). Another study looked at differences between male and female adolescents and found that “daily hassles and negative life events” were related to suicidal ideation in males, but depression and low social support were related to suicidal ideation in females (21). Alcohol and drug use is a significant risk factor across cultures for U.S. adolescent suicide (22). Alcohol use has been reported to make adolescent females 3 times more likely and males 17 times more likely to attempt suicide (23). A small study of more affluent youth found that suicide attempts and suicide completion were likely to occur around holidays and attempts peaked at the end of the school year (24). Post Traumatic Stress Disorder (PTSD) has also been shown to be a significant risk factor for suicide ideation and possibly attempts in adolescents (25). Children from lowincome backgrounds are at particular risk and rates as high as 14.5% for suicidal ideation have been reported in children starting at 9-10 years (26). In that study, suicidal ideation was associated with past experience of violence, symptoms of distress in response to exposure to violence, as well as depression (26). Another study showed that disaster related stress, like exposure to hurricanes, can also increase risk of suicidal thoughts in adolescents (27). In further considering the demographics and risks of adolescent suicide, there are several variables that should be considered: gender, early versus later pubescence, geographic area, socioeconomic status, and ethnicity. Regarding gender, suicide rates in the U.S. for adolescent boys are about 5 times higher than those for adolescent girls (11,28). This male predominance may not be the same when ethnicity is considered, however. Regarding age, completed suicide is less common prior to the age of 12 years and is most common during the early 20s (11,28). Regarding geography, suicide in adolescents seems to be higher in western states, including Alaska (11).

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Rew (18) studied 10,059 students from the 7th, 9th, and 11th grades in Connecticut and compared Caucasian, African American, and Latino students. She found that stress, physical and sexual abuse, family and friend attempted suicide, “internalizing and externalizing behaviors,” reduced social connectedness and religiosity were associated with suicide attempt. Many adolescents with depression and even suicidal thoughts do not pursue treatment. A study by Pirkis showed that less than one-third of all adolescents who seriously considered suicide received counseling (29). Logistic regression showed that those who were more likely to get counseling were female, 13 years old or younger, depressed, had made a previous attempt, and/or had a physical exam in the last year (29). One method of suicide prevention is identification of those at higher risk and attempting to minimize those factors that contribute to that increased risk. Research has shown that reducing access to means of suicide can significantly reduce the risk (28). Limitation of access to alcohol and drugs, as well as access to firearms, may have a positive impact on youth suicide. Recognizing those communities where access to firearms and access to illicit substances is more prevalent could help to target more vulnerable youth. Treating psychiatric disorders that are common to those attempting/completing suicide is also important. In particular, treating affective disorders and substance abuse disorders, common in adolescents, could thus reduce rates of suicide. Encouraging other behaviors, like engaging in physical activity, may also be beneficial. Another study found that adolescents, both Caucasian and Latino, who engaged more in physical activity (i.e.: physical education class) were less likely to report feeling sad, having suicidal thoughts, and making suicide plans (30). One treatment method used to address the problem of adolescent suicide is the Signs of Suicide program. This is a school-based program that combines psychoeducation with a curriculum that helps raise awareness of suicide and contributing factors with a brief screening tool for depression and suicidal behavior (31). Asteline and DeMartino studied the program in 2004 and found that the SOS program resulted in the adolescents having greater knowledge about depression and suicide and have a lower likelihood of making a suicide attempt (31). When gender was examined, girls were more likely to have suicidal thoughts and attempt suicide in the last three months, but have greater knowledge about depression and suicide, be more likely to intervene on behalf of friends, and be more likely to seek help (31).

African American Adolescents and Suicide Suicide has typically been seen as something that affects Caucasians more than other groups in the U.S., but the rate of suicide among African Americans has been increasing (2). In 1999, the National Comorbidity Survey for lifetime suicide attempts found that African Americans, compared with Caucasian Americans, were somewhat less at risk, with an odds ratio of 0.6 for suicidal thoughts, 0.7 for suicide attempt, 0.7 for suicide plan/planned attempt, and 0.8 for impulsive attempt without a plan (5). Data from the CDC, as well as a study by Roberts et al. (32), found similar results. Considering African American adults, data from the National Survey of American Life was used to examine the prevalence of suicidal thoughts

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and attempts for African Americans across the lifetime (3). They found that the prevalence of suicidal ideation was 11.7% and the prevalence of suicide attempt was 4.1% for African Americans. When data from specific ethnic/gender subgroups were looked at, Caribbean men had the highest rates of attempts (3). Interestingly, this study found that risk factors for attempts were youth, having one or more DSM-IV disorder, residing in the Midwest, and being less educated (3). African American women have specific risk factors, and one study reported these to include “psychological distress,” substance abuse, PTSD, relationship difficulties, poor social support, childhood abuse, and abuse by her partner (33). Roberts studied data taken from Teen Health 2000 with 4,175 adolescents aged 11-17 years looking at lifetime attempts, thoughts, and plans found similar results (32). Most of the literature indicates a lower risk for suicide attempts in general, as well as past year attempts, for African American youth compared with Caucasian youth (32). The exception may be a study with young African American males, which found that they were as likely as young Caucasian males to commit suicide (32). African American youth often grow up in economically disadvantaged neighborhoods in the U.S. with higher prevalence of poverty, discrimination, high school dropout, teen pregnancy, and single parent households. These stresses may contribute to the prevalence of depression and suicide. One study found that parental conflict made African American adolescents 6.4 times more likely to attempt suicide (23). Depression, behavior disorders, and drug and alcohol use are also risk factors for suicide attempt and suicidal thoughts in this group (34). Lower levels of family cohesion and adaptability were also found to be linked to an increased rate for suicide attempt in low-income African American adults (35), but it is unclear if this is also the case with youth. Alcohol is a major risk factor for suicide across cultures, although it is Caucasian adolescents who have been more likely to have used alcohol before they commit suicide (23). Depression is a major risk factor for African American adolescents as well, and depression in African American adolescent females has been found to be associated with an even greater risk of suicide compared with males in this group (23). African American adolescent males appear to commit suicide more frequently than females (36,37). Attempts have been made to understand the higher rate for suicide in young African American males and an article by Willis et al. (36) has theorized that “postmodernity loosens the bonds between the individual and society, thereby increasing the vulnerability to depression, related pathologies (such as substance abuse), and suicide.” They and others argue that young African American males are more exposed to such stresses and the usual social institutions that provide support in the African American culture have been unable to be as effective in maintaining that support currently (36,37). A study by Vega (38) looking at suicidal behavior in Latino, African American, and Caucasian boys found that low self esteem, depressive symptoms, and belittling by teachers and parents were higher for African American and Latino boys. Interestingly, deviancy-delinquency was higher for Caucasian boys (38). There are well-documented problems with underdiagnosis of depression in African Americans in general, but it is unclear how much this plays a role in adolescent suicide in this population. A study by Kung et al. compared 22,957 deceased adolescents from the 1993 U.S. National Mortality Followback Survey and found that suicide in Caucasian adolescents

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was associated with depression, marijuana abuse, heavy drinking, use of mental health services, and firearm use; on the other hand, suicide in African American adolescents was associated only with marijuana use, use of mental health services, and firearm availability (39). Diagnosis of depression was not found to be correlated. It is unclear what role the wellknown underdiagnosis of depression in African Americans plays in this finding. The literature has attempted to identify protective factors for African Americans that may contribute to the overall lower risk of suicide. Harris and Molock found that strong family support and family cohesion were related to fewer episodes of depression and suicidal thoughts in African American college students (40). Wingate et al. argues that living in the South is the protective factor to suicidal ideation (41). Some studies indicate that minorities like African Americans are protected from suicide as a result of social factors including links to the church, close social ties, and family cohesion (42-44). It has been suggested that religion has an impact as a protective factor because involvement in the church “encourages social connection, self esteem, and may provide meaning to one’s life” (44-46). Studies have shown that it is personal devotion and orthodox religious beliefs that are strong protective factors and that these are protective for both African Americans and Caucasians (47,48). It was corroborated by Walker and Bishop that religiosity was related to lower suicidal thoughts for both African American and Caucasian college students (49). Yet another study found that reduction in suicidal behavior is associated with religious coping; this association was prevalent only when also associated with decreased fatalism (50). Morrison and Downey found that black college students reported significantly more reasons for living and had higher scores for moral objections to suicide than Caucasians, suggesting that religiosity may decrease suicidal behavior (51). Another study sites protective factors of spirituality, hope, support from family and friends, self efficacy, coping ability, and effectiveness of obtaining resources (52). It is important to consider how racial disparities influence treatment of psychiatric disorders in minority groups. A study of mental health service use found that African American adolescents were 65% as likely to report the use of mental health treatment when experiencing suicidal thoughts (53). The study by Asteline and DeMartino (31) on the use of SOS program in schools also compared how students responded to the SOS program according to ethnicity. Caucasian students were more knowledgeable about suicide and depression, but African American students were less likely to have suicidal thoughts and attempts and less likely to get help compared with Caucasian and Latino youth (31). The question of how to increase the low rate of African American youth receiving psychiatric treatment for suicidal thoughts remains largely unanswered in the literature.

Latino Adolescents and Suicide In 1999, the National Comorbidity Survey for lifetime suicide attempts found that Hispanic Americans, compared with Caucasian Americans, had higher risk for suicidal thoughts, plan, and impulsive attempt (odds ratio of 1.2 for suicidal thoughts, 1.2 for suicide plan, and 1.7 for impulsive attempt without plan), though risk was not elevated for general suicide attempt or planned attempt (0.9 for suicide attempt, 1 for planned attempt) (5).

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Roberts et al. found no difference between Caucasians and Mexican Americans on lifetime attempts or on suicidal thoughts, plans, or attempts in the past year (32). One of the limitations to this study, however, is that they did not control for suicide intent or for lethality of attempt (32). Controlling for intent and lethality of attempt may dramatically lower estimates of the prevalence of suicide attempts. Information about severity and lethality varies from study to study, which may account for the different rates. Latino adolescents may have different rates than Latino adults, although there is some difference of opinion about risk for Latino adolescents in the U.S. Another study compared suicide rates between Latino and Caucasian adolescents and found that the suicide rate was 9.0/100,000 for Latinos and 11.9/100,000 for Caucasians (54). The Vega study (38) looking at suicidal behavior in Latino, African American, and Caucasian boys found that Latino boys had a 7.8% higher rate of suicide attempt than the other groups. Another study (55) looked at 1,786 high school students and found no significant difference in suicide plans or attempts in the past year between Latinos and Caucasian Americans. Another issue is that Latinos often express mood symptoms differently, usually expressing them as somatic complaints. Thus, identifying at risk patients may be more challenging. Suicide rates may be greater depending on gender for Latin American youth. One study with 10,059 students from 7th, 9th, and 11th grades in Connecticut found that suicide attempts were higher among Hispanic Latina girls (19.3%) compared to Latino boys, all Caucasian adolescents, and all African American adolescents (18). The reasons for this are unclear. This is corroborated, however, by a study in 2005 with data from the CDC which found that 14.9% of Hispanic female adolescents attempted suicide compared with 9.3% of Caucasian female youth and 9.8% of African American female youth (19). Razin et al. (56) found that Latino adolescent girls who attempted suicide had poorer school performance, suffered early losses (like that of their biological fathers), and the attempt was often precipitated by interpersonal conflicts with mother or boyfriend. Their mothers tended to have a more tumultuous relationship with their daughters, have made suicide attempts themselves in the past, be less likely to be born in the U.S., rely more on public assistance, and be less medically healthy (56). Rew found significant relationships between recent suicide attempts and environmental stress, history of sexual abuse, history of physical abuse, family history of suicide attempt, and friend’s history of suicide attempt for this group (18). One study found different results, however, when they looked at 3,310 12-19 year olds and found that, although Latina teens had higher rates of alcohol use and depression than their peers, there were no differences in risk for suicidal behaviors in female youth comparing Caucasian, Latina, and African American female groups (57). Attempts have been made to understand the reason for the possible increased risk for Latina girls. Zayas found that the process of acculturation might be related to the higher risk (16). According to Zayas’ research, the increased risk for suicide attempt in Latina girls may be related to the traditional gender roles for girls in that culture, ethnic identity, and resulting adolescent-parental conflict (16). In traditional Latino culture, girls are expected to conform to the female gender role of not expressing anger, fulfilling multiple obligations to parents and the family (16). However, the cultural expectations of how these girls would also resolve the additional normal adolescent struggles of dating, sexuality, and peer pressure and how this would differ from other teens in the U.S. culture may add to their stress (16).

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Regarding method of suicide, Razin et al. (56) found that Latino adolescents who attempted suicide were more likely to do it in an impulsive and non-lethal way, and to attempt by overdose. As discussed for African American youth, Latino youth also commonly grow up in economically disadvantaged neighborhoods in the U.S. This is a major contributor to several factors that affect many economically disadvantaged groups like poverty, discrimination, high school dropout, teen pregnancy, and single parent households. These stresses, in addition to unique stresses for immigrants, like the stress of acculturation, may contribute to risks for depression and suicide in particular for Latino youth (38). Depressive symptoms, family problems, low acculturation, and problems with other coping have been related to suicidal ideation in Latino adolescents (58,59). According to Canino a “fatalistic worldview and passive coping style” have been found to be more prevalent in groups from lower socioeconomic levels (2,60). She goes on to say that depression and suicidal behavior is related to the Mexican cultural tendency towards a passive coping style and fatalism (external control) (2,60). This belief in external control may weaken other coping styles (2).. However, adolescents in Mexico do not have as high rate of suicide as Mexican American adolescents (11.5% vs. 23.4%) (61,62). This suggests that there are multiple factors that contribute to the differences in suicide rates among Caucasians and Mexican Americans. How SES, education, acculturation, and culture combine in this population needs to be further evaluated. Protective factors would include factors that specifically decrease risks described above. Effective acculturation may be a protective factor to depression and suicide. Effective acculturation depends on how an individual melds their culture of origin with the new culture and this can include both pride in their culture of origin while still incorporating positive and useful aspects of the new culture. Another study found that a strong ethnic affiliation and pride is associated with less drug use (63). Although not directly tested, this may also impact suicide. Another study looking at acculturation found that speaking English was associated with lower rates of depression and suicidal thoughts in a group of Latino youth (64). As with African American youth, religion is a protective factor for Latino youth. It was found that the influence of religion, church attendance, and religiosity were protective factors against suicidal ideation for Latinos (65). A study of mental health service use found that when experiencing suicidal thoughts, Latino adolescents were 55% as likely to report the use of mental health treatment compared with Caucasians (53). Treatment for Latino adolescents should take into account the differences in language, values, health beliefs, and attitudes about mental health and suicide particular to the Latino culture. A study by Heiman et al. showed that having an outpatient mental health clinic located within the Mexican-American community with an informal atmosphere, minimal administrative procedures, bilingual and bicultural staff, focus on preventative care, and publicity that minimizes the stigma of mental illness were effective measures for engagement and treatment of this population (66).

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Asian Adolescents and Suicide Data is sparse for Asian Americans and suicide, although there is more about suicide in Asians outside the U.S. A study by Hesketh (67) on Chinese adolescent suicide in China found that, of the 1,576 middle school children surveyed, 16% reported suicidal ideation, 9% reported a suicide attempt, and about 33% reported severe depression. Risk factors included female gender, poor academic performance, depression, and rural residence (67). It is unclear if similar rates and risks would be found in Chinese adolescents in the U.S. Some studies have attempted to look at this. Available U.S. studies show that Asian Americans are less likely than Caucasians to seek mental health treatment (68). Identifying Asian people, adolescents in particular, with mood disorders may be better done in primary care settings as Asians often express depressive and anxiety disorders in somatic ways. A study looking at rates of depression in primary care found that the prevalence of MDD among Chinese Americans was 19.6% and this is comparable to prevalence of depression in Caucasians (69). As for Asian adolescents, Choi et al. studied Korean youth aged 11-13 years and found that there was significant correlation between depression and somatic symptoms (70). Another study, however, postulated that Asian Americans, specifically Chinese American adolescents, have lower rates of depression and suicide than Caucasian adolescents because cultural factors contribute to immunity to depression in this group (71). Further work on prevalence of mood disorders and suicidal behavior is needed in this group. Stresses seen in other minority immigrants like acculturation, alienation, discrimination, acculturation gap between the child and parents, and identity confusion may also contribute to risks in this group (72). Lau et al. (72) studied 285 youth ages 4-17 years, who received outpatient mental health care at the Asian Pacific Family Center in California. They found that older age, lower acculturation, and parent-child conflict were associated with increased risk of suicide (72). The article by Lau et al. studied whether suicide in Asian American youth was related to difficulties with acculturation like alienation, discrimination, and identity confusion, and intergenerational conflicts when parents disapproved of how the children adopted U.S. cultural norms (72). They found risk factors were the same for males and females and included depression, age (older youth), and parental conflicts (72). Importantly, they found that there was a relationship between lower acculturation with parent-child conflict and suicide behavior risk for these youth (72). They believed that these youth may have more collectivist/family-harmony values that make them more at risk (72). Others corroborate that risk factors like depression and parental conflicts increase the risk for suicidal behavior in Asian-American youth (23). Others have found that depression with hopelessness is a major cognitive factor affecting suicidal ideation for male and female Asian international students in the U.S. (73). A number of studies have shown relationship between poor academic performance in addition to parent-child conflict as major risk factors specific for Asian American youth (74). Depression may also be more likely diagnosed in Asian girls than boys (68), but there are limited studies looking at this. Coping mechanisms for depression may be different for Asian Americans than for Caucasian Americans. A study with Korean and Filipino Americans found that they appraised stressors as more challenging than Caucasians, but were more likely to use coping

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skills like religious coping, problem-solving, distancing, escape-avoidance, and accepting responsibility (75). A study by Zhang in 1996 compared US and Chinese college students and found that religiosity and family cohesion are protective against suicidal thoughts (76). Asian Americans are much less likely than Caucasians to use mental health services and multiple factors may contribute to this. Asian youth have been found to be the least likely to receive counseling for suicidal thoughts (29). Patient factors such as cultural view of mental illness, stigma of having a mental illness, and the appropriate management of emotional stresses, clinician factors such as understanding how to engage and treat people from this group, as well as system factors such as access to care may contribute to this lower likelihood for Asian Americans to get help. Screening for depression and suicide in a primary care center may be an effective way to reduce risk for suicidal thoughts and behaviors for Asian American youth. Reducing stigma may be more easily accomplished in this setting and provide a better opportunity to treat depression, a major risk factor for suicide. Another useful venue may be school-based screening and treatment as difficulties in school performance have repeatedly been shown to be related to suicide in Asian youth in particular.

Native American/Alaskan Native Adolescents and Suicide Suicide among Native Americans/Alaskan Natives(AI/AN) is growing, though studies vary greatly as to the rates of suicide. Some studies report rates as high as 20 times the national average and some report rates below the national average (11). The increased rate may prove especially true for adolescents aged 15-24 years of age, however (11,77,78). The 1988 Indian Health Service Adolescent Health Survey found that 15% of children in grades 6-12 reported making a suicide attempt and over 50% of those made multiple attempts (79). The national trend across cultures in the U.S. for male preponderance for suicide is higher in Native Americans (11,77). A study looking at fatal injuries across ethnic groups in the U.S. found that Native Americans/Alaskan Natives between the ages of 10 and 19 years had higher rates of fatal injuries, suicide, and motor vehicle deaths (78). Reasons for this are unclear. “Suicide clustering” (also called “suicide contagion”), higher in adolescents as a whole, is also a significant factor to consider in the Native American adolescent population (11). Bechtold described a cluster of nine adolescent males from a single tribe who committed suicide within seven weeks of each other (11). All were committed by hanging. This “contagious” behavior may be more prevalent in small, relatively closed communities like Native American reservations (11). Risk factors for suicide in Native American adolescents have been reported to be female gender, history of mental health problems, weekly consumption of hard liquor, having a family history of or friend who attempted suicide, a history of physical or sexual abuse, alienation from family and community, and poor self-perception of health (79). Other studies corroborate that substance abuse (prevalence of 9% in Native American adolescents vs. 3.8% of Caucasian adolescents) is associated with suicide in American Indian youth (80). Because of the increased prevalence of substance abuse in Native American youth, this may be an even more important risk factor to consider for them. They also found that poverty, unemployment, welfare dependency, family adversity, and family/parental deviance (i.e.,

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parental violence) were also associated with increased rates of suicide (80). Another study by Novins et al. (81) cites that risk factors for suicidal thoughts and behaviors also include psychiatric illness, antisocial behavior, substance abuse, parental conflicts, family history of attempted suicide, friend attempting suicide, father not living at home, loss of cultural supports, and weak ethnic identity. They hypothesized that risk would differ across tribes. They found that for Pueblo youth, a more closely knit tribe, risk factors most associated with suicidal thoughts/behaviors were depressed affect, friend attempted suicide, and lower social support (81). For the Southwest tribe, also with strong family and community ties, risk factors of antisocial behavior, father not living at home, and stressful life events correlated most with suicidal thoughts/behavior (82). This tribe has strong cultural prohibitions about suicide or even thinking about death so the youth with suicidal behavior were thought to be quite outside the cultural norm (81). The Northern Plains tribe, who emphasize individualistic values, had risk factors of depression and low self-esteem (81). There has not been much research on protective factors for Native Americans/Alaskan Natives. One study found that protective factors against suicidal thoughts for this group of adolescents were positive school experience, caring family relationships, and supportive tribal leaders (82). Another by Garroutte found that a commitment to cultural spirituality was a specific protective factor (83). Treatment that focuses on reducing risk factors like substance abuse and access to fire arms, that treats mood/anxiety and antisocial behavior disorders in a culturally informed way, and that comprehensively tries addresses poverty, family disruption, and limited access to care, is imperative for Native American youth. Treatment that is culturally informed has been attempted and Gary et al. (82) found that culturally competent clinicians who address the issues of limited access to care, poverty, family conflicts, and school failure can be most effective with engaging Native American adolescents. Interventions involving school and family as well as community elders and minimizing media coverage of suicide may also be advisable (11).

Native Hawaiian Adolescents and Suicide There has been a significant increase in suicide attempts in Hawaiians in recent years (84). 3,094 high school students in Hawaii were surveyed by Yuen et al. in 2000 and it was found that the rate of suicide attempts for Hawaiian youth was 12.9% whereas the rate for non-Hawaiians was 9.6% (85). Risk factors for suicide were also studied by Yuen et al. They found that predictors of suicide attempts for Hawaiian youth included Hawaiian cultural affiliation, depression, substance abuse, educational level, and “main wage earner’s” educational level (85). Predictors of suicide attempts for non-Hawaiians included depression, aggression, and substance abuse (85). Another study by Nishimura et al. corroborated that substance abuse was a major risk factor for Hawaiian teens for suicidal ideation, plans, and attempts (86). The study by Nishimura et al. (86) looked at a school based program to help decrease substance abuse, a major risk factor in Hawaiian adolescent suicidal behaviors. They used school and community based programs to teach adolescents about the consequences of

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alcohol use. This program was found to be helpful in addressing alcohol use and thus suicidal behaviors.

Limitations Some of the limitations of the current research are that the definition of suicide versus suicidal thoughts or attempts is not adequately delineated. The literature often groups together many ethnic groups in broader categories like “Latino” and “Asian” and “Caucasian” when these groups are made up of quite different populations. Another limitation is that culture is not uniform so that people labeled as being from the same ethnic group like “African American” may be quite diverse. Additionally, there is very little research about what is specific to the various cultures that influences not just suicide rates, but methods, risks, protective factors, and intrapsychic processes that contribute to suicidal behavior.

Discussion It is difficult to identify effects from culture specifically versus effects from more general factors like socioeconomic level, education, acculturation, and geographic location (urban vs. rural, western states vs. eastern). A deeper understanding of specific cultural values and health beliefs may be the key to disentangling this problem. Until more definitive research is available, consulting knowledgeable colleagues about how to provide culturally sensitive care is important. Addressing risk factors is the first step to decreasing suicide in minority youth. Similar risk factors across ethnicities include mood and anxiety disorders, substance abuse disorders, lower socioeconomic and educational level, access to firearms, and family stresses. There are differences in prevalence and impact of some of these risk factors and in how to address them for each ethnic group in a culturally informed way. Risk factors that differ across ethnic groups include perhaps increased risk for African American and Latino adolescents from single parent households, possibly more of an impact from parent-child conflicts for Asian American and Native American adolescents, likely greater impact of poor school performance for Asian American adolescents, and perhaps a greater impact of friend suicide for Native American adolescents. Identifying protective factors may be equally important in reducing suicide across ethnicities for adolescents. In general, involving family, and important figures like spiritual leaders, extended family, and teachers can be quite helpful. For African Americans, Latinos, and Native Americans, spirituality and religiosity are important protective factors that may be enhanced by encouraging support and collaboration between mental health providers and spiritual leaders. For Asian Americans, addressing the strong family and community bonds and the value placed on education by including the family in treatment may be beneficial. Understanding the health beliefs held by each ethnic group is also important in planning treatment. Keeping in mind that mental illness may be manifested by somatic complaints is

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important to consider for Latino and Asian adolescents. Understanding the stigma placed on calling something a psychiatric disorder is important for all groups discussed, especially for Asian Americans.

Conclusion Culture guides human thought, emotion, values, health beliefs, social and family interactions, and provides mechanisms for dealing with major life challenges, including illnesses (87). Finding ways to help adolescents from different ethnic groups to develop effective coping strategies to stressful life situations that take into consideration the values and coping strategies of their community at large is important to the treatment of psychiatric disorders in minority groups. There is a need for increased awareness in schools and in psychiatric and primary care settings of the needs of those from minority groups. Consulting teachers and clinicians who are also from the specific minority group can be quite useful. There is also a need to have a willingness to collaborate with community supports that are important to patients from minority backgrounds like religious leaders and family members.

Acknowledgements The authors thank Johanna Cabassa, Joseph Soriano and Sarah Zimmerman for their help with the final review and formatting of the manuscript. Drs. Balis and Postolache are supported by R21 MH075891-01A1 from the National Institute of Mental Health (PI Postolache). Dr Postolache’s work on suicide was additionally supported by R01MH074891 (PI Postolache) and by an Independent Investigator Award from NARSAD and by the American Foundation for Suicide Prevention.

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(59) Hovey JD. Acculturative stress, depression, and suicidal ideation among Central American immigrants. Suicide Life Threat Behav 2000;30(2):125-39. (60) Farris B, Glenn N. Fatalism and familism among Anglos and Mexican-Americans in San Antonio. Sociol Soc Res 1976;60:393-402. (61) Mirowsky J, Ross CE. Mexican culture and its emotional contradictions. J Health Soc Behav 1984;25(1):2-13. (62) Swanson JW, Linskey AO, Quintero-Salinas R, Pumariega AJ, Holzer CE3rd. A binational school survey of depressive symptoms, drug use, and suicidal ideation. J Am Acad Child Adolesc Psychiatry 1992;31(4):669-78. (63) Marsiglia FF, Kulis S, Hecht ML, Sills S. Ethnicity and ethnic identity as predictors of drug norms and drug use among preadolescents in the US Southwest. Subst Use Misuse 2004; 39(7):1061-94. (64) Roberts RE, Chen YW. Depressive symptoms and suicidal ideation among Mexicanorigin and Anglo adolescents. J Am Acad Child Adolesc Psychiatry 1995;34(1):81-90. (65) Hovey JD. Religion and suicidal ideation in a sample of Latin American immigrants. Psychol Rep 1999;85(1):171-7. (66) Heiman EM, Burruel G, Chavez N. Factors determining effective psychiatric outpatient treatment for Mexican-Americans. Hosp Community Psychiatry 1975;26(8):515-7. (67) Hesketh T, Ding QJ, Jenkins R. Suicide ideation in Chinese adolescents. Soc Psychiatry Psychiatr Epidemiol 2002;37(5):230-5. (68) Abright AR, Chung H. Depression in Asian American children. West J Med 2002;176(4):244-8. (69) Yeung A, Chan R, Mischoulon D, Sonawalla S, Wong E et al. Prevalence of major depressive disorder among Chinese-Americans in primary care. Gen Hosp Psychiatry 2004;26(1):24-30. (70) Choi H, Stafford L, Meininger JC, Roberts RE, Smith DP. Psychometric properties of the DSM scale for depression (DSD) with Korean-American youths. Issues Ment Health Nurs 2002; 23(8):735-56. (71) Chen IG, Roberts RE, Aday LA. Ethnicity and adolescent depression: the case of Chinese Americans. J Nerv Ment Dis 1998; 186(10): 623-30. (72) Lau AS, Jernewall NM, Zane N, Myers HF. Correlates of suicidal behaviors among Asian American outpatient youths. Cultur Divers Ethnic Minor Psychol 2002;8(3):199213. (73) Yang B, Clum GA. Life stress, social support, and problem-solving skills predictive of depressive symptoms, hopelessness, and suicide ideation in an Asian student population: a test of a model. Suicide Life Threat Behav 1994;24(2):127-39. (74) Lee MT, Wong BP, Chow BW, McBride-Chang C. Predictors of suicide ideation and depression in Hong Kong adolescents: perceptions of academic and family climates. Suicide Life Threat Behav 2006;36(1):82-96. (75) Bjorck JP, Cuthbertson W, Thurman JW, Lee YS. Ethnicity, coping, and distress among Korean Americans, Filipino Americans, and Caucasian Americans. J Soc Psychol 2001;141(4):421-42. (76) Zhang J, Jin S. Determinants of suicide ideation: a comparison of Chinese and American college students. Adolescence 1996;31(122): 451-67.

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(77) Ogden M, Spector MI, Hill CAJr. Suicides and homicides among Indians. Public Health Rep 1970;85(1):75-80. (78) Bernard SJ, Paulozzi LJ, Wallace DL. Fatal injuries among children by race and ethnicity--United States, 1999-2002. MMWR Surveill Summ 2007; 56(5):1-16. (79) Grossman DC, Milligan BC, Deyo RA. Risk factors for suicide attempts among Navajo adolescents. Am J Public Health 1991; 81(7):870-4. (80) Costello EJ, Farmer EM, Angold A, Burns BJ, Erkanli A. Psychiatric disorders among American Indian and white youth in Appalachia: the Great Smoky Mountains Study. Am J Public Health 1997;87(5):827-32. (81) Novins DK, Beals J, Roberts RE, Manson SM. Factors associated with suicide ideation among American Indian adolescents: does culture matter? Suicide Life Threat Behav 1999;29(4):332-46. (82) Gary FA, Baker M, Grandbois DM. Perspectives on suicide prevention among American Indian and Alaska native children and adolescents: a call for help. Online J Issues Nurs 2005;10(2):6. (83) Garroutte EM, Goldberg J, Beals J, Herrell R, Manson SM. Spirituality and attempted suicide among American Indians. Soc Sci Med 2003;56(7):1571-9. (84) Colucci E, Martin G. Ethnocultural aspects of suicide in young people: a systematic literature review part 1: Rates and methods of youth suicide. Suicide Life Threat Behav 2007;37(2):197-221. (85) Yuen NY, Nahulu LB, Hishinuma ES, Miyamoto RH. Cultural identification and attempted suicide in Native Hawaiian adolescents. J Am Acad Child Adolesc Psychiatry 2000;39(3):360-7. (86) Nishimura ST, Goebert DA, Ramisetty-Mikler S, Caetano R. Adolescent alcohol use and suicide indicators among adolescents in Hawaii. Cultur Divers Ethnic Minor Psychol 2005;11(4):309-20. (87) Griffith E, Delgado A, Foulks E et al. Suicide and ethnicity in the United States. Committee on Cultural Psychiatry, Group for the Advancement of Psychiatry. Report no 128. New York: Brunner Mazel, 1989.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXIII

Allergen Specific IgE: No Relationship with Prior History of Suicide Attempts and Instability in Patients with Recurrent Mood Disorders Teodor T. Postolache ∗1, Darryl W. Roberts2, Patricia Langenberg3, Olesja Muravitskaja1, John W. Stiller4, Robert G. Hamilton5 and Leonardo H. Tonelli1 1

Mood and Anxiety Program (MAP), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA 2 Organizational Systems and Adult Health, University of Maryland School of Nursing, Baltimore, MD, USA 3 Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD, USA 4 Neurology Service and the Residency Training Program, St Elizabeths Hospital, Washington, DC, USA 5 Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

∗

Correspondence: Teodor T Postolache, MD, Mood and Anxiety Program (MAP), Department of Psychiatry, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF Building Room 502, Baltimore 21201 USA. Tel: 410-706 2323; Email: [email protected]

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Abstract Suicide and decompensation of mental illness peaks in spring and to a lesser extent in fall. Several recent studies reported that suicide and decompensation peaks coincided with spring and fall aeroallergen peaks. Allergic symptoms occur as the result of a complex biochemical cascade initiated by IgE antibodies (sensitization) and allergens (triggers). Animal models have shown molecular/neurochemical changes in the brain as well as relevant behavioral changes associated with this IgE mediated biochemical cascade. These factors suggest that seasonal allergy could precipitate suicidality and mood instability. In the current study, we compared the prior suicide attempt and decompensation history in allergen sensitive and nonsensitive persons diagnosed with mood disorders. Patients with Major Depressive Disorder or Bipolar I or II Disorder (n=80) completed several instruments (Columbia Suicide History Form, Beck Scale of Suicidal Ideation and Beck Suicide Intent Scale). Serum was screened for allergenspecific IgE antibody. t-Test analysis was used to compare the history of suicide attempts and instability between the two groups, aeroallergen positive and negative. Further, we compared the ratio of attempts and decompensations during the allergy season to suicides in both groups occurring during the rest of the year. There were no statistical differences in any measurement performed between the psychologically ill and well groups. In contrast to previous studies that found an association between completed suicide and allergen exposure or prior history of allergy, the current study found no association between number or timing of prior suicide attempts and markers of allergic sensitization in patients with recurrent mood disorders.

Keywords: Environment, allergen, mood disorders, suicide, psychiatry.

Introduction Suicide attempts and completed suicides are common results of decompensation among persons with bipolar disorder (BPD) and major depressive disorder (MDD). Spring is the most common season for depression exacerbation, hospital admissions for depression, and electroconvulsive therapy (ECT) use (1-7). In addition, hospital admissions for bipolar depression also peak in April (8,9). Studies conducted in several countries located in both hemispheres have revealed a strong relationship between spring decompensation and increases in suicide (6,10,11). There is also a less robust, and less replicated, fall peak in suicides that is worthy of investigation. To date, no studies have adequately explained the spring and fall peaks in either decompensation or suicide. The most commonly considered cause of this relationship is a suspected association between suicide and photoperiod, changes in photoperiod, and light intensity (12,13). Closer examination, however, reveals that spring suicide occurrence peaks in April and May and fall suicide occurrence peaks in October and November (14-17). This occurs particularly among women (16,18,19). However, photoperiod is longest around the Summer Solstice in late June and photoperiodic changes peak around the spring equinox in March and the fall equinox in September (13,20-24).

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Seasonal aeroallergens such as pollen from deciduous trees (e.g., maple, elm, oak) and weeds (e.g. ragweed), peak in early spring (April and May) and late fall (October and November), respectively. The highest incidence of allergic rhinoconjunctivitis occurs during spring peaks of atmospheric tree-pollen (25-27). Tree pollen allergies affect 10-30% of adults 25, while ragweed induced hayfever affects more than 25% of adults (28). The prevalence of sensitization to these allergens far exceeds the prevalence of either BPD or MDD (12). Timonen et al (29,30) reported that atopy is more prevalent in patients with depression and with those persons who have a family history of depression. Allergic disease results from a hypersensitivity to otherwise harmless environmental substances. Allergen sensitization can be assessed by measuring specific IgE antibodies directed against allergens in serum. In sensitized individuals, allergen exposure causes the immune system to release cytokines. Similar cytokines given during treatment and research studies have induced depression and, occasional, suicidal thoughts (31,32). Recent epidemiologic and clinical studies have shown a relationship between the timing of seasonal peaks in mood decompensation and suicide and peaks in aeroallergens. Timonen et al (29,30,33) and Marshall et al (34) recently reported a strong association between allergic disease and depression. In a recent study (35) we found a significant relationship between worsening mood and pollen exposure in pollen sensitive but otherwise healthy college students. We also reported an increased incidence of suicide during and after peak pollen periods (19). An increased suicide rate could be associated not only with exposure to allergens, but also with a previous diagnosis of allergic disease (36). Additional support for the relationship between decompensation of mood disorders, suicide, and aeroallergen-induced inflammation comes from postmortem studies of the human brain, where increased markers of allergic inflammation have been found in suicide victims. Upper respiratory immune responses to intranasally instilled bacterial lipopolysaccharides (which increases TNF-alpha transcription in the brain) may act as a mediator for depressive-like symptoms in rats (37). In Brown Norway rats that were sensitized and exposed to tree pollen, the brains of the rats expressed higher levels of inflammatory markers (e.g. interleukin-5, interleukin-6, and interleukin-13) than did brains from saline-exposed control rats (38). In consideration of the relationship between allergen-induced upper respiratory inflammation, depression, and suicide, we hypothesized that sensitization to seasonal allergens might be associated with a higher level of mood instability and with a higher number of lifetime suicide attempts in persons with MDD or BPD. Therefore, in the current study, we have tested whether there is a temporal relationship between seasonal allergen exposure, the presence of IgE antibodies specific to those seasonal allergens, and seasonal mood instability in persons with MDD and BPD. We expected that seasonal allergen sensitive individuals with MDD and BPD would exhibit a higher Instability Index and Suicide Attempt Index during the atmospheric tree pollen period (in spring) or ragweed pollen period (in late summer-early fall), depending on individual’s sensitivities, than those present in similarly diagnosed non-allergic controls.

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Methods We recruited a convenience sample (n=80) of patients with MDD and BPD, who had a history of suicide attempts from a variety of sources including inpatient psychiatric facilities, private psychiatrists’ offices, hospital-based clinics, and stand-alone clinics. Inclusion and exclusion criteria are summarized in table 1. Charts were prescreened as approved by the Institutional Review Board of the University of Maryland School of Medicine. A staff member approached patients who met the entrance criteria to request permission for us to interview them. Patients were then given informed consent and the Mini-Mental State Exam (MMSE) (39), on which they had to score > 27 for inclusion. Table 1. Study inclusion/exclusion criteria

1. 2.

3.

Inclusion criteria Aged 18-65 Clinical diagnosis of MDD, BPD I, or BPD II made at least two years before enrollment (NOTE: Diagnosis verified by Structured Clinical Interview for the DSM-IV 40 ) Lifetime history of at least one nonambiguous suicide attempt

1. 2. 3. 4. 5. 6.

Exclusion criteria Clinical diagnosis of schizophrenia or schizophreniform disorder Cognitive disorder (or MMSE<28) Diagnosis and treatment of asthma within two years of enrollment Current treatment with medications that could interfere with IgE levels (e.g., corticosteroids) History of parasite infections History of bronchopulmonary aspergellosis

Table 2. Characteristics of participants in total and by Phadiatop status

Variable Gender (%) Male Female Race (%) White Black Hispanic Other Diagnosis (%) MDD Bipolar I Bipolar other History of Psychotic symptoms during mood dd episodes (%) Tree pollen positive (%) Ragweed positive (%) Phadiatop positive (%)

Total n=81

Phadiatop status Positive Negative n=33 n=48

43.2 56.8

51.5 48.5

37.5 62.5

0.21

59.3 34.6 2.5 3.7

39.4 54.6 3.0 3.0

72.9 20.8 2.1 4.2

0.02

38.3 60.5 1.2

39.4 57.6 3.0

37.5 62.5 0.0

0.46

75.3 12.4 8.6 40.7

78.8 30.3 21.2 --__

72.9 0.0 0.0 --__

0.55 0.0001 0.0008

p value

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Selection into the sensitized test group or non-sensitized control group was made based on the results of the allergen-specific IgE analysis (described in Instruments section), with both the participant and rater being masked to the IgE antibody results. Demographics of participants in both groups are presented in table 2.

Periods of High Pollen The pollen periods were selected in a semi-arbitrary manner after initially reviewing the airborne pollen concentrations from local pollen counting stations enrolled in the Aeroallergen Monitoring Network of the American Academy of Allergy Asthma and Immunology. Due to our location in the Southern mid-Atlantic region, the tree- and ragweedpollens windows followed those expected based on historical data: April through May for tree pollen and September through October for ragweed pollen.

Data Collection and Instruments Raters who were trained in psychiatric testing techniques guided the subjects through a rigorous 90-minute interview, which consisted of a series of semi-structured and structured interview instruments. These instruments included the Structured Clinical Interview for the DSM-IV for Axis I Disorders (SCID) (40) to verify a diagnosis. Since the primary purpose of the SCID was as an advanced screening tool, we selected only those modules, which related to mood, psychotic and substance use disorders. An additional benefit of the SCID was its excellent history module that provided a useful timeline and comparison tool for verification of information collected with subsequent tools. Only patients who “passed” the SCID continued on to the remaining modules. The first evaluation instrument in the interview was the Columbia Suicide History Form (CSH) (41). This instrument is a semistructured interview that is used to document prior lifetime suicide attempts, including indicators of lethality. The resulting data identifies ambiguous from actual suicide attempts. Raters then employed the retrospective self-version of the NIMH Life Chart Methodology (LCM) (42). This instrument documents mood episodes, the number of suicide attempts and ER admissions during the past two years. This instrument, combined with the lifetime history given during the SCID, permitted researchers to establish a definitive picture of the participants’ seasonal patterns of decompensation and suicidality. This outcome of these instruments produced an Instability Index (INIX) and a Suicide Attempt Index (SAI). The INIX was calculated from the LCM and the SCID timeline by the following equation: (admissions ≥ 5 days x 5) + (admissions < 5 days x 3) + (ER w/o admission x 2) participant's age

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The SAI was calculated from the CSH and the SCID timeline, with adjustments from the SIS, using the following equation: # of actual suicide attempts participant’s age After the interview, a Registered Nurse collected serum for IgE antibody analysis. The Multi-allergen screen (Phadiatop, Kalamazoo, MI) was selected for the primary multiallergen screening assay for IgE antibody since it detects IgE antibodies specific for a panel of 15 aeroallergens that elicit the majority of aeroallergen related allergic disease. Results of this analysis are highly predictive of an individual’s predisposition to manifest rhinitis and other aeroallergen induced allergic symptoms. The Phadiatop results were reported as positive or negative. Its diagnostic sensitivity ranges from 75-95% and its diagnostic specificity ranges from 85-95% 43. The Phadiatop screen positive sera underwent a subsequent specific IgE antibody analysis for individual specificities including oak, beech, maple, elm, birch, ash, sycamore, poplar, and ragweed pollen using the Pharmacia ImmunoCAP 250 (Kalamazoo, MI). Analyses were performed in the Johns Hopkins Dermatology Allergy and Clinical Immunology (DACI) Reference laboratory using a positive/negative cut-off threshold of 0.35 kIU/L (44).

Statistical Analysis Categorical variables for patient characteristics were summarized by proportions and percents, and Phadiatop positive and negative groups were compared by Pearson chi-square tests. Phadiatop positive and negative groups were compared on prior suicide history (number of suicide attempts / age) and prior stability (considering attempts, admissions, and ER visits) using t-tests. Similarly, the positive and negative groups were compared on the ratio of spring to the entire year suicides, and the same ratio for hospital and ER admissions, with t-tests.

Results No statistical differences were observed between the two sensitized and non-sensitized groups involving either the overall or the spring ratios. Differences between the groups were not close to statistical significance, with all p-values > 0.38 (see table 3). These data failed to support the working hypothesis that either the number or timing of past suicide attempts or the instability measures were associated with aeroallergen sensitization as identified by a positive serological IgE antibody status.

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Table 3. Comparisons of aeroallergen sensitive and non-sensitive groups on suicide attempts and instability index Phadiatop status Variable Suicide attempt index mean (SD) Ratio spring suicide attempts mean (SD) Instability index mean (SD) Ratio spring instability mean (SD)

p value*

Total n=81

Positive n=33

Negative n=48

0.113 (0.102)

0.105 (0.091)

0.119 (0.109)

0.56

0.226 (0.340)

0.186 (0.292)

0.254 (0.370)

0.38

0.072 (0.062)

0.072 (0.064)

0.073 (0.061)

0.96

0.379 (0.408)

0.359 (0.429)

0.394 (0.398)

0.72

* p values from t-test comparisons.

Discussion The conclusions of the present study contrast with those of recent studies suggesting a relationships between either the seasonality of suicide and allergen exposure (19), the seasonality of suicide and a prior history of allergic disease (45), and a prior history of allergic disease (36). The current study data do not support relationship between the presence of allergen sensitization and number and timing of prior suicide attempts. Our negative findings may be a result of several factors: First, the study design may have had limited power with a reasonably small sample size of 80 subjects. While a larger sample size may have provided more power for examining differences in the prevalence rates between allergic and non-allergic subjects, the required size to potentially see a significant difference, based on the differences observed in this study, could exceed 5,000 subjects, which, practically, is not achievable in clinical samples. Second, the study included patients on psychotropic medications, and those with comorbid substance abuse and personality disorders. These factors may have counteracted the measurable effect of the allergic response on suicidality. Subjects taking psychotropic medications, however, were not excluded from the study for several reasons. It would have resulted in the study recruitment falling short of the study’s goals. Moreover, patients who are medication free but have a history of major affective disorders and suicide attempts do not represent the typical patient population. Additionally, it would have been ethically questionable to request that participants discontinue prescribed medications for any period in

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order to participate in a study of this nature, particularly considering a large proportion of individuals were recruited from an inpatient hospital setting. With this in mind, patients with personality disorders and substance abuse are more likely to have histories of ambiguous suicide attempts. Furthermore, patients from these groups might use the hospital and ER more frequently than would patients with BPD or MDD who do not have these comorbidities (46,47). However, because personality disorders and substance use disorders are frequently comorbidities with MDD and BPD (48-50), including these diagnoses in the study increased our overall generalizability of the findings. Suicide attempts are the strongest predictor of completed suicide (51). However, a recent study by Lindqvist and colleagues (52) supports the conclusion of previous studies suggesting that persons who attempt suicide are significantly different in suicidal intent from those who complete suicide. To address the temporality of suicide attempts, we asked participants to provide a timeline of their lifetime suicide attempts, hospitalizations, and ER visits. Because corroboration with medical records could not be accomplished, the history may not be temporally accurate. Another potential limitation was our reliance on a self-reporting instrument to ascertain information on attempted suicides, as accurate identification of “attempted” suicide is particularly difficult to determine from a personal history in part because of the associated stigma and tendency to avoid a hospital admission when possible. Finally, it is possible that the level of aerosolized allergen exposure of depressed or suicidal individuals with allergic disease was insufficient to induce a significant cytokine elevation to alter the subject’s psychological state. Aerosolized pollen levels vary widely throughout the day and across seasons and they are dependent on natural phenomena such as the amount of rainfall, wind conditions and microenvironment variation. To confirm this negative relationship, a future study on the relationship between suicide attempts and allergic sensitization should ideally be prospective with larger recruitment and a more strictly defined group of subjects. The self-reported clinical data should then be corroborated with collateral sources of information. However, it appears that a greater yield would probably result from focusing on how completed suicide and suicide risk factors other than the number and timing of prior suicide attempts might relate to the presence of allergic disease and the exposure to aeroallergens. For that purpose, information on severity of allergic symptoms and measuring markers of inflammation may be as or more important than allergen specific IgEs.

Acknowledgements Supported by a NARSAD Independent Investigator Award to Dr. Postolache.

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(38) Leonardo H. Tonelli, Gagan Virk, Belzora Joppy, Teodor T. Postolache Experimentally-induced allergy to tree pollen induces depressive-like behavior and mast cell activation in the brain of female rats. Biol Psychiatry 2006;59:1S-264S. (39) Folstein MF, Folstein SE, McHugh PR. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):189-98. (40) First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I-Version 2.0). New York: Biometr Res Dept, New York Psychiatr Inst, 1995. (41) Oquendo MA, Echavarria G, Galfalvy HC et al. Lower Cortisol Levels in Depressed Patients with Comorbid Post-Traumatic Stress Disorder. Neuropsychopharmacol 2003;28(3):591-8. (42) Denicoff KD, Ali SO, Sollinger AB, Smith-Jackson EE, Leverich GS, Post RM. Utility of the daily prospective National Institute of Mental Health Life-Chart Method (NIMHLCM-p) ratings in clinical trials of bipolar disorder. Depress Anxiety 2002;15(1):1-9. (43) Wood RA, Phipatanakul W, Hamilton RG, Eggleston PA. A comparison of skin prick tests, intradermal skin tests, and RASTs in the diagnosis of cat allergy. J Allergy Clin Immunol 1999;103(5 Pt 1):773-9. (44) Hamilton RG, Adkinson NFJr. Clinical laboratory assessment of IgE-dependent hypersensitivity. J Allergy Clin Immun 2003;111(2 Suppl):S687-S701. (45) Timonen M, Viilo K, Hakko H et al. Is seasonality of suicides stronger in victims with hospital-treated atopic disorders? Psychiatr Res 2004;126(2):167-75. (46) Paris J. Half in love with easeful death: the meaning of chronic suicidality in borderline personality disorder. Harvard Rev Psychiatry 2004;12(1):42-8. (47) Sansone RA. Chronic suicidality and borderline personality. J Personal Disord 2004;18(3):215-25. (48) Kessler RC. The epidemiology of dual diagnosis. Biol Psychiatry 2004;56(10):730-7. (49) Farabaugh A, Mischoulon D, Fava M, Guyker W, Alpert J. The overlap between personality disorders and major depressive disorder (MDD). Ann Clin Psychiatry 2004;16(4):217-24. (50) Schiavone P, Dorz S, Conforti D, Scarso C, Borgherini G. Comorbidity of DSM-IV Personality Disorders in unipolar and bipolar affective disorders: a comparative study. Psychol Rep 2004;95(1):121-8. (51) Suominen K, Isometsa E, Suokas J, Haukka J, Achte K, Lonnqvist J. Completed suicide after a suicide attempt: a 37-year follow-up study. Am J Psychiatry 2004;161(3):562-3. (52) Lindqvist D, Nimeus A, Traskman-Bendz L. Suicidal intent and psychiatric symptoms among inpatient suicide attempters. Nord J Psychiatry2007;61(1):27-32.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXIV

Acute Stress Promotes Aggressive-Like Behavior in Rats Made Allergic to Tree Pollen Leonardo H. Tonelli ∗1, Akina Hoshino2, Morgan Katz,1, and Teodor T. Postolache3 1

Laboratory of Behavioral Neuroimmunology, Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA 2 Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA 3 Laboratory of Experimental Chronobiology, Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

Abstract It has been reported that allergies are associated with depression and possibly suicide in women. Aggression is an important behavioral component that predisposes depressed individuals to suicidal acts. In the present study we examined the relationship between allergies and aggression to determine a potential contribution of allergies in factors of risk for suicidal behavior. Because stress plays a critical role in the manifestation of clinical symptoms of allergies and also in suicidal behavior, we also studied the role of acute stress. Female inbred Brown Norway rats known for their susceptibility to respiratory allergies were sensitized and challenged with a mixture of tree pollen and evaluated in the resident-intruder test for detection of aggressive behaviors. They were also subjected to acute stress by sessions of inescapable forced swimming and reevaluated in the resident intruder test. Animals made allergic to tree pollen and subjected ∗

Correspondence: Dr Leonardo H. Tonelli, PhD. Assistant Professor, 685 West Baltimore Street, MSTF Building, Room 502, Baltimore MD, 21201 USA: E-mail: [email protected]

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Leonardo H. Tonelli, Akina Hoshino, Morgan Katz et al. to acute stress displayed increased aggressive-like behavior as compared with controlsaline treated animals or to their own aggressive scores previous to the stress session. These results suggest that allergies and stress increases aggressive-like behavior, indicating that these conditions may be important factors promoting altered emotional reactivity with the potential to influence suicidal behavior.

Keywords: neuroimmune, intranasal, Brown Norway, inbred, female, resident-intruder.

Introduction Suicide is a very complex behavior that is associated with different factors including among others, socioeconomic, demographic and genetic (1-3). One of the most important risk factors for attempted and completed suicide is suffering from a mental disorder, and major depression is the most common psychopathology that has been consistently associated with suicidal behavior (1,4-6). Other mental disorders include bipolar disorder, borderline personality disorder, substance abuse and schizophrenia (1,5,6). Certain personality traits are important factors that contribute to increase the risk for suicidal behavior in depressed individuals including impulsivity neuroticism and aggression (6-10). Studies about the contribution of these traits in increasing the risk for suicide in individuals suffering from major depression concluded that aggression, but not impulsivity or neuroticism, is the trait with clinical relevance that better predicts increased suicide risk in people with depression (11). Thus, an aggressive state in depressed individuals significantly increases risk for suicidal behavior; it has been said that to be able to kill oneself, one should be “ready to die and ready to kill”. Moreover, based on the fact that only a relative small percentage of psychiatric patients attempt suicide, it has been hypothesized that a secondary stressor in people at high risk is likely to act as a precipitant for suicidal behavior (1). The interaction of a stressor such as an acute psychosocial crisis in psychiatric patients with a predisposition for suicidal behavior (the stress-diathesis model) explains and also predicts the occurrence of suicidal behavior (1,12). Epidemiological studies show that depression and suicide manifest in the population with marked oscillations on their incidence. An increased rate of depression as measured by hospitalization has been documented during early spring followed by an increase incidence in suicide rates during late spring (13). It is important to note that the spring peak in suicide is more prominent for violent suicides than for non violent suicides (14). The reasons for these seasonal patterns in disease fluctuation are highly debated. Several additional epidemiological studies reported that in women, suffering from an atopic condition increases the risk for depression (15,16) and seasonality of completed suicide (17) and that seasonal aeroallergen exposure may be related with suicide completion (18). Based on these associations, we have previously hypothesized that seasonal allergies may be a factor contributing to increased incidence in suicide during spring, particularly in women (18,19). However, the behavioral traits that may be influenced by allergies leading to depression and suicide are unknown. Moreover, the interactions of these factors during a stressful situation have not been explored.

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To determine if seasonal allergies influence behavioral traits that may contribute to suicidal behavior in females, we evaluated in the resident intruder test female rats made allergic to tree pollen. The resident intruder test is used to detect aggression based on elements of rat behavior expressed during social encounters (20,21). To explore the contribution of an acute stressful event in this paradigm, we introduced in this model inescapable forced swim sessions known to induce learned helplessness in rodents (22,23).

Methods Allergy to Pollen Inbred Female Brown Norway (BN/NHhsd) rats (n = 18) were obtained from HarlanSprague Dawley (Indianapolis, IN). This strain was selected based on their susceptibility to develop respiratory allergic reactions after repeated exposure with an antigen (24,25). They were sensitized by repeated intranasal instillations with a mixture of equal parts of tree pollen (oak, cedar, maple and birch) (Greer Laboratories, Lenoir, NC) dissolved in saline (250 mg/ml pollen mixture) for 5 consecutive days. The animals were slightly anesthetized with isofluorane in induction chambers and at the moment of awakening were administered with 100 µl per nostril of saline solution or pollen mixture. The animals received an intranasal dose at day 15 after the last administration to boost the immune reaction. The rats were challenged 7 days later after the boosting administration for 5 consecutive days with the same solutions. Control animals were treated with saline under the same schedule. Allergic animals developed mild allergic symptoms evidence by watery runny nose.

Stress Exposure Groups of rats (n = 9) consisted of control saline and pollen treated animals evaluated on a first session of resident intruder test on day five of the challenge with tree pollen. Five days later control and pollen treated rats were subjected to acute stress exposure by forced swimming in a vertical glass cylinder (diameter 22.5 cm and height 60 cm) containing 35 cm of water maintained at 25?C for 15 min. Twenty-four hours later the animals were re-tested in the resident intruder test. All animal procedures were approved by the Institutional Animal Care and Use Committee of the University of Maryland, Baltimore.

Resident Intruder Test Resident and intruder rats were separated 21 days before testing. Rats were housed in Plexiglas cages with standard food pellets and water available ad libitum in a room at a constant temperature of 23º C. All animals were maintained on a 12:12 L:D cycle (lights on at 07:00 hr) and each rat remained in its original cage throughout the experimental procedures. Resident intruder tests were performed between 10:00 AM - 12:00 PM each day.

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The resident rat remained in its original home cage placed in the testing area for ten minutes prior to intruder entry to ensure the resident was fully acclimated to its surroundings. An unfamiliar intruder was taken from a separate cage and placed in the resident cage to begin the test. Tests were videotaped from a horizontal angle with a Sony Mini DV camcorder in sessions of ten minutes. Aggressive behavior was measured by two observers both during the test, and re-scored on video after the test. Behavior that was considered aggressive was measured solely from the resident directed towards the intruder and was scored based on the number of aggressive actions that occurred. After the ten-minute test, the intruder was removed from the cage and returned to its original cage. Data was analyzed with a one way ANOVA followed by Neuman-Keuls as post hoc comparisons. Statistical significance was set at alpha 0.05.

Results Identification of Agonistic Behaviors in Female Brown Norway Rats Based on the descriptions of DeBold and Miczeck, 1984 (26) and Blanchard 1982 (27) and Mitchell 2005 (20,21) the following agonistic behaviors were identified in all groups and conditions tested: a) Lunging toward the intruder b) placing paws on intruder's back c) pursuing or following the intruder d) cornering (backing intruder into a corner of the cage). The following agonistic behaviors were not identified in any group or condition tested: a) bite, b) boxing c) nipping. Additional behavioral categories identified included exploration (locomotion and rearing) and investigation (nose to nose sniff, genitalia sniff) and maintenance (grooming, digging). The relative percentage of these behaviors during the 10 minutes test is shown in table 1.

Stress-Induced Aggressive-Like Behavior in Rats Allergic to Tree Pollen Based on the consideration that all of the agonistic behaviors identified correspond to the same category of low intensity aggressive behaviors, the frequency of each individual agonistic behavior for each animal was summarized giving a total aggression count corresponding to the 10 minutes of test. The analysis of variance ANOVA for total aggression counts showed a significant difference between groups [F (1, 20) = 12.66; p < 0.0001]. Post hoc analysis showed that animals made allergic to tree pollen and subjected to the stress session had increased aggression scores compared with the rest of the groups (Figure 1). No differences were found for pollen treated animals with respect to control if they were not subjected to the stressor.

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Table 1. Mean percentage values ± standard error mean of different behavioral categories identified during 10 minutes of an encounter with an unfamiliar intruder conspecific in control saline rats or rats sensitized and challenged with tree pollen. The relative time spent on each behavior was grouped according to the motivational state as follow: locomotion and rearing (Exploration); nose to nose sniff and genitalia sniff (Investigation); lunging toward the intruder, placing paws on intruders back, pursuing or following the intruder and backing intruder into a corner of the cage (Aggression); grooming and digging (Maintenance); (adapted from Mitchell, 2005 (20))

** p < 0.0001. Figure 1. Total number of aggressive behaviors (lunging toward the intruder, placing paws on intruders back, pursuing or following the intruder and backing intruder into a corner of the cage) identified during 10 minutes of an encounter with an unfamiliar intruder conspecific in control saline rats or rats sensitized and challenged with tree pollen. Before Stress: animals tested before acute stress session. After Stress: animals tested after an acute stressor consisting of 15 minutes of inescapable forced swimming.

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Discussion The present study showed that allergies increase low intensity aggressive-like behaviors only when they interacted with an acute stressor. Since acute stressors are unpredictable in nature, the present results lead us to speculate that seasonal allergies are a necessary, yet not sufficient factor that may contribute to increase the risk for suicidal behavior during spring via increased aggressive behavior. Moreover, the present study analyzes only one aspect of the full spectrum of behavioral risk factors for suicide, the contribution of allergic processes in depression, anxiety, impulsivity, and other suicide risk factors including alterations in sleep patterns have not been investigated. Studies on patterns of aggressive behaviors displayed by female out-bred Norway rats indicates that high intensity aggressive behaviors in female rats are rare and that they may represent defensive behaviors towards the intruder rather than offensive actions (26-28). However, these behaviors which include striking bites towards the face have been documented and they were not observed in the present study. As mentioned earlier, all the aggressive postures observed are considered to be of low intensity aggression (26-28). This has been documented previously for the resident-intruder test in male inbred Brown Norway rats (29). Whether or not these features represent aggressive traits in humans with any relevance for suicidal behavior is only speculation. In any case, the present data shows that acute stress during an allergic process clearly influences agonistic behaviors as evidenced by the doubling of these encounters that represent altered social interactions. Altered social interactions are recognized as characteristic of pre-suicidal states in humans, and the inability to cope with a stressful situation is a hallmark of many mental disorders (23). Several mechanisms may explain how allergies influence aggressive-like behaviors. One of them is through the effect that cytokines released during an allergic process may have on rage and aggression. It has been reported that certain cytokines such as interleukin-1ß (IL-1ß) administered in several brain regions potentiates rage and aggression in cats (30). Moreover, the authors showed that interleukin-2 may suppress or enhance defensive rage in cats depending on the region of the brain in which it was administered (31). Another study demonstrated that peripheral administration of IL-1ß inhibits inter male agonistic behavior in a dose dependent manner (32). Conversely, it has been shown that mice deficient for interleukin-6 display high degrees of aggressive behavior (33). In humans, hostility, physical and verbal aggression has been positively correlated with tumor necrosis factor-alpha expression in stimulated monocytes (34). Although studies on the behavioral effects of the major cytokines involved in allergic inflammation have received little attention, it is possible that these cytokines including interleukin-4, 5 and 13 among others may modulate aggressive behavior through interactions with cytokines such as IL-6, IL-1ß and TNF-α. Despite the fact that immune challenge and cytokine administration have been shown capable of modifying components of aggressive behaviors, in the present study the manifestation of aggressive-like behaviors was not seen in allergic animals but only after they have been exposed to an acute stressor. This is an important consideration because it may point to an important mechanism of neuro-immune interaction that have been consistently reported in the literature. It is known that the relationship between stress and allergic conditions is reciprocal where stress worsens atopic disorders (35,36) and atopic disorders

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influence emotional reactivity (37,38). The core physiology of this reciprocal connection involves the hypothalamic-pituitary-adrenal (HPA)-axis that can both modulate immune function through the effects of glucocorticoids, and its activity can be modulated by immune function through the effects of cytokines (39-41). In addition, activation of mast cells by corticotrophin-releasing factor (CRF), that is also a potent activator of the HPA-axis, has been proposed as a contributing mechanism (36). Therefore, nasal allergies induced by tree pollen may lead to a similar situation to that we have recently reported in which inflammation in the nasal cavities produces a sub-syndromal state of sickness increasing cytokine expression and priming the HPA-axis to release large amounts of glucocorticoids under stress such as forced swimming (42) and potentially influencing later behavioral responses.

Conclusions In conclusion, altered agonistic behaviors were observed in female rats made allergic to tree pollen and subjected to acute stress. This relationship may represent an important factor of altered emotional reactivity and its behavioral expression in individuals that suffer from both atopic and mood disorders. Further studies are necessary to fully characterize and determine the mechanisms of this association.

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(24) Steerenberg PA, Dormans JA, van Doorn CC, Middendorp S, Vos JG, van Loveren H. A pollen model in the rat for testing adjuvant activity of air pollution components. Inhal Toxicol 1999; 11(12):1109-22. (25) Motta A, Peltre G, Dormans JA, Withagen CE, Lacroix G, Bois F, Steerenberg PA. Phleum pratense pollen starch granules induce humoral and cell-mediated immune responses in a rat model of allergy. Clin Exp Allergy 2004;34(2):310-4. (26) DeBold JF, Miczek KA. Aggression persists after ovariectomy in female rats. Horm Behav 1984;18(2):177-90. (27) Blanchard DC, Blanchard RJ. Ethoexperimental approaches to the biology of emotion. Ann Rev Psychol 1988;39:43-68. (28) DeBold JF, Miczek KA. Sexual dimorphism in the hormonal control of aggressive behavior of rats. Pharmacol Biochem Behav 1981;14 Suppl 1:89-93. (29) Berton O, Ramos A, Chaouloff F, Mormde P. Behavioral reactivity to social and nonsocial stimulations: a multivariate analysis of six inbred rat strains. Behav Genet 1997;27(2):155-66. (30) Zalcman SS, Siegel A. The neurobiology of aggression and rage: role of cytokines. Brain Behav Immun 2006;20(6):507-14. (31) Bhatt S, Zalcman S, Hassanain M, Siegel A. Cytokine modulation of defensive rage behavior in the cat: role of GABAA and interleukin-2 receptors in the medial hypothalamus. Neuroscience 2005; 133(1):17-28. (32) Cirulli F, Pistillo L, de Acetis L, Alleva E, Aloe L. Increased number of mast cells in the central nervous system of adult male mice following chronic subordination stress. Brain Behav Immun 1998; 12(2):123-33. (33) Alleva E, Cirulli F, Bianchi M, Bondiolotti GP, Chiarotti F, De Acetis L, and Panerai AE. Behavioural characterization of interleukin-6 overexpressing or deficient mice during agonistic encounters. Eur J Neurosci 1998;10(12):3664-72. (34) Suarez EC, Lewis JG, Krishnan RR, and Young KH. Enhanced expression of cytokines and chemokines by blood monocytes to in vitro lipopolysaccharide stimulation are associated with hostility and severity of depressive symptoms in healthy women. Psychoneuroendocrinology 2004;29(9):1119-28. (35) Vig RS, Forsythe P, Vliagoftis H. The role of stress in asthma: insight from studies on the effect of acute and chronic stressors in models of airway inflammation. Ann N Y Acad Sci 2006;1088:65-77. (36) Theoharides TC, Kalogeromitros D. The critical role of mast cells in allergy and inflammation. Ann N Y Acad Sci 2006;1088:78-99. (37) Hashizume H, Takigawa M. Anxiety in allergy and atopic dermatitis. Curr Opin Allergy Clin Immunol 2006;6(5):335-9. (38) Buske-Kirschbaum A, Hellhammer DH. Endocrine and immune responses to stress in chronic inflammatory skin disorders. Ann N Y Acad Sci 2003;992:231-40. (39) Mastorakos G, Ilias I. Interleukin-6: a cytokine and/or a major modulator of the response to somatic stress. Ann N Y Acad Sci 2006;1088:373-81. (40) Dunn AJ, Swiergiel AH, and de Beaurepaire R. Cytokines as mediators of depression: what can we learn from animal studies? Neurosci Biobehav Rev 2005;29(4-5):891-909.

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(41) Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 2006; 6(4):318-28. (42) Tonelli LH, Holmes A, Postolache TT. Intranasal Immune Challenge Induces SexDependent Depressive-Like Behavior and Cytokine Expression in the Brain. Neuropsychopharmacology 2007.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXV

Changes in Severity of Allergy and Anxiety Symptoms Are Positively Correlated in Patients with Recurrent Mood Disorders Who Are Exposed to Seasonal Peaks of Aeroallergens Teodor T. Postolache ∗1, Patricia Langenber2, Sarah A. Zimmerman1, Manana Lapidus, 1, Hirsh Komarow, 3, Jessica S. McDonald1,4, Nancy Furst1,4, Natalya Dzhanashvili1, Debra Scrandis1,, Jie Bai 1, Bernadine Postolache4, Joseph J. Soriano1, Bernard Vittone4, Alvaro Guzman1, Jong-Min Woo1,5, John Stiller1,6, Robert G. Hamilton7 and Leonardo H. Tonelli1,8 1

Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA 2 Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD, USA 3 Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 4 National Center for the Treatment of Phobias, Anxiety and Depression, Washington, DC, USA 5 Department of Psychiatry, Seoul Paik Hospital, Inje University School of Medicine, Seoul, Korea

∗

Correspondence: Tel: 410-706-2323; Email: [email protected]

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Neurology Consultation Service, St. Elizabeth’s Hospital, Washington, DC, USA Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 8 Behavioral Neuroimmunology, Mood and Anxiety Program, Department of Psychiatry, University of Maryland, Baltimore, MD, USA

7

Abstract Considering clinical and animal evidence suggesting a relationship between allergy and anxiety, we hypothesized that, from low to high aeroallergen exposure, changes in anxiety symptom scores in patients with primary mood disorders will correlate with changes in allergy symptom scores. We also anticipated that sensitization to tree pollen, as determined by allergen specific IgE antibodies, will predict a greater worsening of anxiety during exposure to tree pollen. 51 patients with unipolar or bipolar disorder (age: 19-63 years, 65% female) were recruited. Tree- pollen IgE positive subjects (12) were included as the experimental group and patients negative to a multi-allergen serological test (39) were included in the control group. Self reports of anxiety and allergy symptoms were obtained once during the peak airborne pollen counts and once during the period of low airborne pollen counts, as reported by two local pollen counting stations. Using linear regression models, we confirmed a significant positive association between allergy scores and anxiety scores (p<0.04); however, the IgE specific tree pollen positivity was not significantly associated with changes in anxiety scores. Because changes in anxiety scores relate to changes in depression scores, the relationship between allergy and anxiety involves states rather than only traits, and as such, our results lead to future efforts to uncover potential anxiety triggering, exacerbating or perpetuating role of allergens in vulnerable individuals.

Keywords: anxiety, depression, allergen, allergy, rhinitis, atopy, allergen specific IgE, tree pollen.

Introduction Allergic disease is a prevalent condition, with approximately 50% of the American population sensitized to at least one allergen (NHANES II and III) (1). Worldwide, a peak in suicide in the spring is consistently observed in epidemiologic research studies (2-8). In the fall, a second, smaller peak in suicides has also been observed, although it has been less well replicated (7,9-12). Such seasonal peaks in suicide correspond temporally with the peaks in aeroallergens that are measured in the environment. The spring peak is contemporaneous with high airborne tree pollen counts, and the fall peak with high weed counts, particularly ragweed in the United States. We have preliminarily reported an association between peaks in airborne tree pollen and springtime peaks in nonviolent suicide in women. While depression is the disorder most frequently associated with suicide (14), anxiety has also been found to independently contribute to increased suicide risk (15,16). Comorbid

Changes in Severity of Allergy and Anxiety Symptoms Are Positively Correlated… 391 anxiety further increases the risk of suicide (17), especially when comorbid with bipolar disorder (18) or depression (19-21). In fact, comorbid depression and anxiety also peaks in the spring and again in the fall, with the seasonality of comorbidity greater than that of depression alone (21). Comorbid anxiety and depression symptoms are also commonly reported in allergic patients (22). We have recently found a preliminary association between symptoms of upper airway inflammation and depression (23) and between the seasonality of mood and self-reported mood sensitivity to high pollen counts (24). Additionally, in an animal model intended to examine the effects of allergic sensitization to tree pollen on depressive symptoms, we found significant anxiety-like behavior across trials in the sensitized animals following exposure to tree pollen (25). In individuals with allergic sensitization, when mast cell bound IgE antibody is crosslinked by specific allergens, an activating signal is transduced which results in mast cell degranulation and the release of inflammatory mediators and cytokines. Clinical investigation suggests that Th2-type lymphocytes are predominantly activated in allergic diseases. Th2 cells are characterized by their production of IL-4, IL-5, and IL-13. Cytokines, administered in amounts below the threshold necessary to induce “sickness behaviors,” have been shown to induce anxiety, depression, and cognitive disturbances in healthy subjects (26). An increase in cytokine levels in the blood has been hypothesized as one potential catalyst for the decompensation of depression (27-29). Cytokine-treated patients may also experience an increase in depressive symptoms, including suicidal ideation and attempted suicide (30-33). Even a low dose of cytokine-promoting endotoxins such as lipopolysaccharides (LPS), can trigger depressive symptoms along with anxiety without bringing about other sickness behaviors (26). Certain cytokines released during LPS-induced inflammation are also released during the allergic response. For instance, mast cell degranulation releases TNF-α (34), the administration of which has been shown in animal models to be anxiogenic (33). We have seen that sensitization and subsequent exposure to tree pollen (25) and intranasal LPS administration (35) induce anxiety-like behaviors in sensitized rodents. Additionally, we have reported increased gene expression of cytokines involved with allergic inflammation (36) in the orbital cortex of suicide victims, where histopathological changes in suicide victims have been previously reported (14). We hypothesized that a) that during the intervals of high tree pollen, the anxiety level should be greater in individuals who are sensitized, that is IgE antibody positive, to tree pollen allergens., and b) the changes in anxiety scores between the high and low pollen periods will be positively correlated with changes in allergy symptoms.

Methods This is an auxiliary hypothesis driven analysis of data collected for a primary study on changes in depression and allergy symptoms. The protocol has been approved by the Institutional Review Board at the University of Maryland School of Medicine. We recruited 51 participants, 18 to 65 years of age with a past clinical diagnosis of Major Depressive Disorder or Bipolar Disorder, by means of radio and newspaper advertisements. Recruitment

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took place at two sites, Baltimore and Washington, DC, between September 2006 and June 2007. A pre-screening interview was performed by telephone for all subjects in order to exclude those with any major medical illness, previous psychotic disorder, winter-type seasonal affective disorder, drug or alcohol dependence, or current or intended pregnancy during the course of the study. We obtained informed consent following a thorough explanation of the study. A semistructured questionnaire was administered that was designed to measure the comprehension of the consent, before continuing any study procedures. At this time, participants were further screened with a questionnaire and they provided a blood specimen to determine the presence of aeroallergen specific IgE antibodies as an indicator of allergic sensitization. The subject’s serum was initially analyzed with a widely used multi-allergen screen, Phadiatop, ImmunoCAP 250, Phadia, Uppsala, Sweden, that detects IgE antibodies specific for any of 15 common weed, grass, tree, mite and pet epidermal aeroallergens, including the principal seasonal allergen specificities relevant to the hypothesis of our study [37]. To verify each subject’s specific sensitization to spring pollen, tree, and/or fall, ragweed, aeroallergens, serum from each Phadiatop positive subject was then reanalyzed for IgE antibody to individual allergens using the ImmunoCAP 250. Quantitative levels of IgE antibody specific for the trees ash, beech, birch, elm, maple, poplar, sycamore, oak and the weed ragweed pollen allergens. IgE antibody results > 0.35 kUa/L were considered a positive result, indicative of the presence of IgE antibody to that allergen specificity in the blood (38). Patients were additionally screened with a Structural Clinical Interview for DSM-IV (SCID) (39) using the mood disorders, substance abuse, and psychotic disorders modules. For inclusion in the study, the individual had to have unipolar or bipolar depressive disorder. Patients were excluded if they had an active substance abuse or dependence or a psychotic disorder as assessed by the SCID. Exclusion of subjects with substance abuse was considered important because, in addition to directly altering mood states, the drugs can directly alter mediator release from effector cells of allergic inflammation and potentially reduce peripheral blood cytokine levels. In addition, the use of intranasal corticosteroids or montelukast led to exclusion because of the locus of their action and its potential for reducing cytokine levels. Anti-histamines and decongestants, however, are not known for their central effects on the allergic cascade, instead acting to relieve symptoms of allergic reaction, and therefore their use was not a criterion for exclusion. Based on the results of the blood tests, patients were subdivided into IgE -positive or sensitized subjects in the test group and Phadiatop-negative subjects who were considered the control group. The participants and the raters were masked to the specific IgE results or group assignment throughout the course of the study. Data on daily airborne pollen counts were obtained from two local, official pollencounting stations in Washington, DC and Baltimore that are recognized by the AerobiologyAeroallergen Monitoring Network of the /American Academy of Allergy Asthma and Immunology (AAAAI). Pollen data from these counting stations were e-mailed to the study center daily and, starting in February 2007, the data from these stations were recorded daily on the AAAAI website (www.aaaai.org). A research assistant entered and verified the aeroallergen data and matched the genus of tree pollen counts to the specificity of the IgE in

Changes in Severity of Allergy and Anxiety Symptoms Are Positively Correlated… 393 the blood of each study subject. The periods of high or low levels of atmospheric tree pollen concentrations were identified as after January 15 and before July 1st of 2007. The pre-pollen interval began when the subject’s first tree pollen allergen count exceeded 10 grains/m3. The cut-off pollen count, which identified a peak tree pollen period, was = 90 grains/m3. The actual timing of the first visit was designed to be one of convenience. For some participants, their low tree pollen period visit preceded the peak tree pollen season, and for others it followed the peak tree pollen period.

Anxiety and Allergy Rating Examinations Anxiety symptoms were measured with the Burns Anxiety Inventory (BAI) (40), a selfreported questionnaire often used in a clinical setting. The severity of five symptoms of allergic disease, namely sneezing; rhinorrhea; itchy nose, throat or palate; itchy, watery, or red eyes; and nasal congestion, were measured using the Allergy Symptom Severity Assessment (ASSA)(41). The ASSA is also a self-reported instrument, using a scale from 0 to 4, where 0 is no symptoms; 1 is mild symptoms but no discomfort; 2 is moderate symptoms with discomfort but no interference in functioning; 3 is severe symptoms with discomfort such that it interferes with functioning; and 4 is severe symptoms such that medical attention is required. For the primary study on depression, patients were also evaluated using the Structured Interview Guide for the Hamilton Depression Rating Scale – Seasonal Affective Disorder Version (SIGH-SAD)(42).

Data Management and Analysis Preliminary analysis included descriptive methods in which the study data were characterized with a mean and standard deviation for continuous variables, and percentage of positivity for categorical variables. The IgE anti-tree pollen positive group data were compared to the negative group data using Student’s t-test and chi-square analysis. Differences in the measures of allergic disease or anxiety symptoms during the low and high pollen periods were computed using the BAI scores and the ASSA data. Linear regression analysis was performed to identify significant associations between a change in ASSA and the BAI scores. These measures were adjusted for factors including gender, and the order of the low pollen and high pollen interviews. A second model included IgE tree pollen specific IgE antibody positivity. In a third, more parsimonious model, the ASSA score was replaced by nasal congestion alone. Posthoc, change in the total SIGH-SAD depression score was added to the model to assess whether depression mediates the association between allergy and anxiety, and medication use was considered for inclusion in the models. Statistical analysis was performed using SAS version 9.1 software.

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394

Results To date, 51 individuals completed the study. Of these, 12 individuals (24%) were positive for tree pollen specific IgE (IgE+) and 39 (76%) were IgE antibody negative for tree pollen (IgE-). From this sample, 78.4% of the participants had their low pollen interview during their second visit, i.e., preceding their high pollen interview on the third visit. For IgE+ individuals, 41.7% had their low pollen interview before their high pollen interview. For IgE- individuals, 89.7% had their low pollen interview before their high pollen interview. Table 1 presents these characteristics of the participants as well as their demographic information. Table 1. Characteristics of study participants, all combined, and by IgE Tree Pollen Positivity Total Variable

N=51

IgE Tree Pollen Positive Yes, N=12 (24%)

No, N=39 (76%)

p value*

Age, mean (SD)

45.4 (11.1)

41.8 (13.1)

46.5 (10.4)

0.20

Gender male (%)

35.3

41.7

33.3

0.60

Caucasian

76.5

66.7

79.5

0.47

African-American

21.6

33.3

18.0

Hispanic

2.0

0.0

2.6

Low pollen

80.0

81.8

79.5

0.86

High pollen

95.7

90.9

97.2

0.36

Low pollen

20.3 (15.6)

22.8 (17.6)

19.6 (15.2)

0.55

High pollen

20.7 (17.2)

24.1 (23.9)

19.7 (14.8)

0.57

41.7

89.7

0.0004

Race (%)

Allergy symptoms (%)

Burns Anxiety Score, mean (SD)

Low pollen visit before high pollen visit 78.4 (%)

*p values from comparisons of tree positives and negatives, t-test comparing means, and chi-square comparing proportions.

During the low pollen period, 80.0% of all participants reported experiencing allergic symptoms, with 81.8% of IgE+ and 79.5% of IgE- groups reporting symptoms. During the high pollen season, 95.7% of all participants reported allergic symptoms, with 90.9% of IgE+ and 97.2% of IgE- reporting symptoms. During the low pollen season, the average of all participant BAI scores was 20.3±15.6 (mean±SD). The average BAI score for IgE+ individuals during that period was 22.8±17.6 (mean?SD), and for IgE- individuals it was 19.6±15.2 (mean±SD). During the high pollen season, the average of all participant scores was 20.7±17.2 (mean±SD). The average score for IgE+ individuals in that period was 24.1?23.9 (mean±SD); however, there was no significant difference with the BAI score of IgE-individuals, which then averaged 19.7 ±14.8 (mean±SD). Table 1 reports average

Changes in Severity of Allergy and Anxiety Symptoms Are Positively Correlated… 395 participant scores on the BAI and ASSA by IgE status as well as combined. Table 2 lists the medications used for all participants and by tree pollen specific IgE antibody status. The linear regression analyses revealed a significant association between the ASSA score and an increase in the BAI score (p=0.04; table 3). One interpretation of the regression coefficient is that, after adjustment for gender and visit order, an increase by one unit was observed between a high versus low pollen ASSA score was associated with an increase of 1.14 in the BAI score. In a second model, the IgE specific tree pollen positivity was not significantly associated with the BAI score and, in a multivariable model, did not affect the significance of the ASSA relationship with the BAI score. Table 2. Medication usage for tree positive vs. tree negative participants

Tree pollen negative (n = 39) Tree Positive (n = 12) Total (n = 51)

Antidepressants

Mood Stabilizers

Anxiolytics

Antipsychotics

Thyroid Hormones

% 90

n 35

% 28

n 11

% 26

n 10

% 18

n 7

% 21

n 8

Sleep Medication s % n 13 5

75

9

25

3

8

1

25

3

8

1

8

1

86

44

27

14

22

11

20

10

18

9

12

6

Table 3. Results from linear regression models for associations of change in Allergy Symptom Severity Score (Model 1) and IgE Tree positivity (Model 2) with change in Burns Anxiety Score, adjusted for gender and order of visit. In Model 3, nasal congestion replaced the allergy symptom score Burns Anxiety Score (High - Low Pollen Score) Model 1

β

Independent Variable

SE

Model 2

Model 3

p-value*

β

SE

p-value* β

SE

p-value*

3.67

0.63

Allergy Symptom Score (high - low pollen)

1.14

0.54

0.04

1.15

0.54

0.04

-

Gender male

2.04

3.64

0.58

1.40

3.66

0.70

1.76

5.93

4.88

0.23

-

13.87

4.87

0.01

9.52

4.26

0.03

7.67

3.78

0.05

IgE Tree Positive (Yes vs  No) Low pollen visit before high

10.99

Nasal congestion

-

4.27

0.01

-

* p-value for coefficient from linear regression model.

Finally, in a third model, the presence of nasal congestion, considered independent of the ASSA score, was associated with a significant 7.67 unit increase in the BAI score, adjusted for gender and visit order. Posthoc, when we included the SIGH-SAD score of depression in

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the model, it was highly significantly associated with the BAI score and the ASSA score lost significance. When use of either anxiolytic or antidepressant medication was added to models, neither was significantly associated with the BAI score. A significant association (p=0.0004) was observed for the order of the visits with change in the BAI score, such that those individuals whose low pollen visit preceded the high pollen visit showed a greater increase in the BAI score. Such order effects were taken into account in the linear regression analysis.

Discussion In the present study, we have confirmed one of our two hypotheses. Change in the severity of allergic symptoms was positively correlated with changes in the severity of anxiety symptoms. This is consistent with previous research suggesting a connection between allergic inflammation and anxiety (22,25,43,44)]. On the other hand, we did not find, as we had hypothesized, a link between specific IgE antibody status and anxiety scores, possibly as a result of the low number of participants who were positive for tree pollen specific IgE antibody. The results of the present study should, however, be interpreted with caution, considering several limitations. First, as this was an addition to our main depression study, we did not use the anxiety disorder module in the SCID to diagnose anxiety disorders. Second, we used the presence of pollen specific IgE antibody as an indicator of sensitization, but we did not quantify the magnitude of the sensitization. We preferred, instead, to use the specific IgE test rather than puncture skin tests because psychotropic medications may have anti-histaminic effects that could have interfered with the interpretation of the skin test. The order of high pollen and low pollen interviews was not randomized. The post-pollen season may not represent a low pollen period in the same way as the pre-pollen season given the presence of grass pollen at the later time. Further limitations may lie in the instruments used to assess allergic and anxiety symptoms. Both the Allergy Symptoms Severity Assessment and the Burns Anxiety Inventory are self-reports. This may lead to concern regarding whether and to what extent individual features, such as neuroticism, may have altered both self-ratings and thus contributed a spurious relationship. However, data from a recent study specifically examining the role of neuroticism in affecting the association between allergy symptoms and depression have indicated that its contribution is absent in women and small in men (45). We can speculate as to several possible mechanisms mediating a relationship between the severity of anxiety symptoms and allergic symptoms. First, the psychological effects of being ill, as well as impairments of sleep secondary to nasal obstruction or inflammation may affect mood. Second, cytokines may lead to a mood disturbance via the expression of the enzyme indoleamine-2,3-dioxygenase, which shifts the synthesis of tryptophan from serotonin to kynurenin (13,43,46). The resultant acute tryptophan depletion results in decreased brain serotonin, which may contribute to both depression and anxiety. Third, cytokines released during allergic inflammation may affect the brain directly, via nerves, surrounding tissue, or

Changes in Severity of Allergy and Anxiety Symptoms Are Positively Correlated… 397 via regions that do not have a blood brain barrier, such as the circumventricular organs. Other explanations for the behavioral change may exist. The amygdala, in mediating the fear response, is associated with anxiety through its connection to the hippocampus, which controls contextual conditioning, and the prefrontal cortex (PFC), responsible for extinction. Anxiety results when the context of fear-inducing circumstances is misconstrued or when the fear response does not become extinct even in the presence of innocuous circumstances (47). The PFC ordinarily inhibits and suppresses activity in the amygdala, often through the regulation of the hippocampus (48). However, the PFC also receives inputs from the systems, involved in the regulation of behavioral, autonomic, and endocrine responses, to which the amygdala projects. In this way, emotional stimuli serve to stimulate the PFC more than do other stimuli, resulting in a reciprocal process (49). Thus, the PFC, which usually allows for responses to stimuli to be changed as necessary, when damaged or inhibited prevents a response other than fear from occurring even when circumstances may not be noxious (48). It is possible that the orbital cortex and its regulation of the amygdala may be affected by cytokine expression, leading to a decrease in amygdala inhibition and an increase in anxiety. We have observed increased gene expression in the cytokines involved in allergic reactions in that region of the brain in victims of suicide (36). Cytokines may also be involved in changes in the hypothalamic-pituitary-adrenal (HPA) axis, as well as in the production of corticotropin-releasing hormone (CRF), adrenocorticotropic hormone (ACTH), and cortisol or corticosterone (26,44,50,51). A sustained increase in activity in the HPA axis is associated with severe anxiety (14). A recent study using an animal model has (44) indicated that the degranulation of mast cells, a central cellular element of the anti-parasitic and allergic response, was necessary to see an increase in activity in the PVN and central amygdala. The former is responsible for hypothalamic secretion of ACTH and activation of the sympathetic autonomic nervous system; the latter for the release of CRF and its consequent stress response. In addition, Breese et al. found that cytokines might lead to a physiological change in GABAA receptor functioning, possibly serving to limit the activity of its agonists, often anxiolytic (51). Allergen-induced peripheral inflammation could also be linked with inflammatory processes in the brain underlying observable anxiety-like behaviors (44,52). The percentage of individuals reporting upper respiratory symptoms (more than 75% during low pollen symptoms and more than 90% during high pollen season), exceeded the expected prevalence estimate based on the proportion of subjects who were IgE antibody positive. It is likely that non-allergic upper respiratory symptoms contributed to these results. Non-IgE mediated allergic rhinitis is triggered by environmental conditions and substances other than allergens which include changes in the weather, irritants, or pollutants (53). Alternatively, it has been recently shown that some individuals may have a ‘local form’ of allergy disease involving IgE produced only in the nasal mucosa. They develop nasal symptoms in the absence of detectable serum IgE or a positive skin test to prevalent environmental allergens (54). Finally, exogenous proteases from pollens and other aeroallergens may cause inflammation by mechanisms other than IgE activation of effector cells, possibly acting on molecules such as protease-activated receptors (PARs) (55-57).

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We are lacking convincing evidence that such a mechanism is, indeed, operative in rhinitis. In any case, our results, which are consistent with our animal data (35,52), indicate that anxiety symptoms are correlated with upper respiratory inflammatory symptoms. The relationship between anxiety and allergy scores became non-significant when we adjusted for depression scores for covariates. This suggests that the depression and anxiety scores are highly intercorrelated, with anxiety symptoms as a component of the depressive syndrome, or indicative of comorbidity between anxiety and depression. On the other hand, the relationship between depression scores and allergy symptom scores remained significant after adjustment for anxiety symptoms. These data suggest that the relationship between allergic disease and depression is a major phenomenon, and seemingly more robust than the one between allergic disease and measures of anxiety. However, our animal model data point towards a more consistent association between anxiety-like behaviors rather than depressivelike behaviors and with sensitization and exposure to tree pollen allergen (35,52). To further analyze this triangular relationship between allergy, depression, and anxiety, we will continue our research with primary anxiety disorders and primary non-comorbid mood disorders. Despite its preliminary nature, the current study is conceptually important. One could suppose that the relationship between allergic disease and anxiety, or depression, represents mainly common vulnerabilities, possibly genetic or developmental. However, identifying a relationship between changes in allergy symptoms and changes in depression symptoms strongly suggests a relationship that affects states rather than traits. This concept, which leads to an investigation of the causality, triggering, precipitation, and exacerbation of anxiety disorders is important for designing potential preventive and curative interventions. Additional research is necessary to confirm our currently reported relationship between changes in self-reported allergy symptoms and anxiety symptoms, with better instruments for measuring anxiety and more precise measurements of allergic inflammation. Studies in humans and animals, involving immunological and psychotropic interventions, will be essential for mechanistic and therapeutic understanding and may contribute to the generation of novel targets and interventions for anxiety symptoms and disorders.

Acknowledgements Supported by grant R21 MH075891-01A1 from the National Institute of Mental Health (Principal Investigator: Teodor T. Postolache), by research funds from the Johns Hopkins University Dermatology Allergy and Clinical Immunology (DACI) Reference Laboratory and by the University of Maryland General Clinical Research Center Grant M01 RR 16500, General Clinical Research Centers Program, National Center for Research Resources (NCRR), NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of Mental Health or the National Institutes of Health. The authors thank Ms. Belzora Joppy for help with recruitment, and the staff of the GCRC/ University of Maryland for their overall contribution.

Changes in Severity of Allergy and Anxiety Symptoms Are Positively Correlated… 399

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Changes in Severity of Allergy and Anxiety Symptoms Are Positively Correlated… 401 (33) Ademmer K, Beutel M, Bretzel R, Jaeger C, Reimer C, Clemens J. Suicidal ideation with IFN-alpha and ribavirin in a patient with hepatitis C . Psychosomatics 2001;42(4):365-7. (34) Schwartz LB. Mast cells and basophils. Zweiman B, Schwartz LB, ed. Inflammatory Mechanisms in Allergic Diseases. New York, NY: Marcel Dekker, 2002:3-42. (35) Tonelli LH, Holmes A, Postolache TT. Intranasal Immune Challenge Induces SexDependent Depressive-Like Behavior and Cytokine Expression in the Brain. Neuropsychopharmacology 2007 Jun 27. [EPub ahead of print] (36) Tonelli LH, Stiller J, Rujescu D, Giegling I, Schneider B et al. Elevated cytokine espression in the orbitofrontal cortex of victims of suicide. Acta Psychiatr Scand 2007 Dec 13. [EPub ahead of print]. (37) Hamilton RG, Adkinson NFJr. Clinical laboratory assessment of IgE-dependent hypersensitivity. J Allergy Clin Immunol 2003; 111(2 Suppl):S687-701. (38) Hamilton RG, Adkinson NFJr. In vitro assays for the diagnosis of IgE-mediated disorders. J Allergy Clin Immunol 2004;114(2):213-26. (39) First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I-Version 2.0). New York: Biometr Res Dept, New York Psychiatr Inst, 1995. (40) Burns DD. The feeling good handbook. New York, NY: Plume, 1999. (41) Howarth PH, Stern MA, Roi L, Reynolds R, Bousquet J. Double-blind, placebocontrolled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis. J Allergy Clin Immunol 1999; 104(5):927-33. (42) Williams JB, Link MJ, Rosenthal NE et al. Structured Interview Guide for the Hamilton Rating Scale - Seasonal Affective Disorder Version (SIGH-SAD). New York: New York State Psychiatric Institute, 1988. (43) Cuffel B, Wamboldt M, Borish L, Kennedy S, Crystal-Peters J. Economic consequences of comorbid depression, anxiety, and allergic rhinitis. Psychosomatics 1999;40(6):491-6. (44) Costa-Pinto FA, Basso AS, Russo M. Role of mast cell degranulation in the neural correlates of the immediate allergic reaction in a murine model of asthma. Brain Behav Immun 2007; 21(6):783-90. (45) Goodwin RD, Castro M, Kovacs M. Major depression and allergy: does neuroticism explain the relationship? Psychosom Med 2006; 68(1):94-8. (46) Wichers MC, Maes M. The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J Psychiatry Neurosci 2004;29(1):11-7. (47) LeDoux JE. Fear and the brain: where have we been, and where are we going? Biol Psychiatry 1998;44(12):1229-38. (48) Sotres-Bayon F, Cain CK, LeDoux JE. Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex. Biol Psychiatry 2006;60(4):32936. (49) LeDoux JE. The emotional brain, fear, and the amygdala. Cell Mol Neurobiol 2003;23(4-5):727-38.

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(50) Kusnecov AW, Goldfarb Y. Neural and behavioral responses to systemic immunologic stimuli: a consideration of bacterial T cell superantigens. Curr Pharm Des 2005;11(8):1039-46. (51) Breese GR, Knapp DJ, Overstreet DH, Navarro M, Wills TA, Angel RA. Repeated Lipopolysaccharide (LPS) or Cytokine Treatments Sensitize Ethanol WithdrawalInduced Anxiety-Like Behavior. Neuropsychopharmacology 2007 Jun 06. [EPub ahead of print] (52) Tonelli LH, Virk G, Joppy B, Postolache TT. Experimentally-induced allergy to tree pollen induces depressive-like behavior and mast cell activation in the brain of female rats. Biol Psychiatry 2006;59(1S-264S):755. (53) Sanico A, Togias A. Noninfectious, nonallergic rhinitis (NINAR): considerations on possible mechanisms. Am J Rhinol 1998; 12(1):65-72. (54) Rondon C, Romero JJ, Lopez S, Antunez C, Martin-Casanez E, Torres MJ et al. Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis. J Allergy Clin Immunol 2007;119(4):899-905. (55) Widmer F, Hayes PJ, Whittaker RG, Kumar RK. Substrate preference profiles of proteases released by allergenic pollens. Clin Exp Allergy 2000;30(4):571-6. (56) Bagarozzi DAJr, Travis J. Ragweed pollen proteolytic enzymes: possible roles in allergies and asthma. Phytochemistry 1998; 47(4):593-8. (57) Reed CE. Inflammatory effect of environmental proteases on airway mucosa. Curr Allergy Asthma Rep 2007;7(5):368-74.

Section IV: Obesity and Adolescents

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXVI

Obesity and Sport Participation Dilip R. Patel∗ and Donald E. Greydanus Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, Kalamazoo Center for Medical Studies, Kalamazoo, MI, USA

Abstract Obesity is increasingly prevalent in adolescents with significant lifelong medical complications. The exact prevalence of obesity among adolescent athletes is not known; however, there is research that suggests obesity prevalence varies by the type of sports. A few studies suggest that youth sport participation can be an effective tool in the management of obesity in children and youth. Regular physical activity and sport participation that is fun is strongly recommended. This discussion considers the role of sports in helping obese adolescents and also what physical activity is recommended. It is concluded that sports participation can be an important part of effective management of obese youth and setting the stage for a lifelong pursuit of physical activity to control and/or reduce obesity in the adolescent and adult population.

Keywords: Adolescent, obesity, sports, management, human development.

Introduction The prevalence of obesity is estimated to be 20% in the United States and other developed countries (1-8). Over the past 25 years there has been a 75% relative increase in ∗

Correspondence: Professor Dilip R Patel, MD, Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, Kalamazoo Center for Medical Studies, 1000, Oakland Drive, Kalamazoo, MI 49008 United States. E-mail: [email protected]

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obesity in American adolescents. The number of adolescents who are overweight or obese has doubled during the same period in children between 6 and 11 years of age and tripled in adolescents between 12 and 17 years of age. The exact prevalence of overweight and obesity in adolescents regularly participating in various sports is not known. In a recent study, Malina et al looked at the prevalence of overweight and obesity among participants between ages 9 and 14 years in American football. The cross-sectional study of 653 participants found that overall 45% of participants were overweight and 42.6% were obese (9). The prevalence of overweight and obesity was highest among early maturing boys, and relatively higher in offensive and defensive linemen. The authors concluded that the prevalence of overweight and obesity was relatively higher among young football players compared to national samples of American boys (9). These adolescents are at a higher risk for becoming obese adults. The very nature of American football in which a high value is place on large body mass of players is a risk factor for overweight and obesity among these adolescents. The long term adverse effects of obesity on health have been well documented in published literature. The causes of increased prevalence of obesity in children and adolescents are multi-factorial that includes a complex interplay of genetic and environmental factors (10-12). A sedentary lifestyle and lack of regular physical activity are major factors contributing to the increasing prevalence of obesity. The role of sports participation in the management of obesity in adolescents is now considered.

Role of Sport Participation in Prevention and Treatment of Obesity Lifestyle modification is an essential component of management of obesity. In order to effectively loose weight the adolescent needs to expend more calories than what he or she consumes. Appropriate dietary modification combined with regular physical activity has been shown to be effective in achieving steady weight loss over a long period of time; however, the role of behavior modification therapy, pharmacotherapy, and bariatric surgery in the treatment of adolescent obesity is not clear at this time (13-23). Role of regular physical activity in weight management and other benefits of exercise have been well known (see table 1)(24). Structured exercise programs have been shown to have a favorable impact on body composition of adolescents, especially when combined with reduced total caloric intake. One study has shown than obese children improve their lipid profiles if placed on a low fat diet and exercise program of moderate intensity (i.e., heart rate at 60-80% of maximum) for eight weeks with progressively increased duration of activities such as aerobic dancing, swimming, walking, or jogging (25). Programs that include regular exercise tend to have lasting effects on weight reduction and may prevent later development of obesity. Reasons for adolescents not engaging in regular physical activities are many and include lack of opportunity at school, exercise related injuries, inappropriate exercises, and psychosocial environment that is conducive to sedentary as well as isolated lifestyle (26). Obesity itself may play a role in discouraging exercise because of some inherent biomechanical and physiological factors that impede exercise performance (27). Obese adolescents often have increased friction between their thighs, arms, and torso. They also

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may have suboptimal level of pulmonary function because of the need to move a heavier body mass and increased need for oxygen relative to more thin adolescents. These factors may affect effective participation in certain activities such as running and jumping. Excessive weight may also impose demands on weigh bearing exercises. Korsten-Reck et al looked at motor abilities and aerobic fitness of obese children (28). Data were collected on 49 obese children ages 8-12 years and compared with age-matched control group before and after an intervention program that consisted of a combination of organized sports, behavior therapy, and nutritional counseling. Before the intervention program, aerobic capacity of obese subjects was found to be significantly below the control group. Similarly the obese subject performed relatively poorly on motor abilities measured by medicine-ball toss. Table 1. Positive effects of exercise Decrease • Body mass • Percentage body fat • Visceral fat • Blood pressure (arterial) • Triglycerides • LDL cholesterol Increase • Insulin sensitivity • HDL cholesterol • Physical fitness • Self esteem The investigators noted that following intervention, performance in motor abilities improved and the difference in strength between obese and control group decreased (28). Weintraub et al have evaluated the feasibility, acceptability, and efficacy of an afterschool team sports program for reducing weight gain in low-income overweight children in a trial called the Stanford Sports to Prevent Obesity Randomized Trial (SPORT) (29). The subjects were children in 4th and 5th grade with BMI at or above the 85th percentile. The intervention consisted of participation in after-school soccer play and the reference group intervention consisted of health education program. The study found that all 21 participants in soccer group had decreased BMI at 3 and 6 months and increased levels of physical activity at three months (29).

Recommendations for Sports Fun activities whether they are part of organized sports or not should be recommended to all adolescents (16,30-32). Children and adolescents generally do better with exercise if the

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fun aspect is emphasized in contrast to the health benefits. Such activities may include walking, dancing, cycling, swimming, and other aerobic activities (see table 2). A variety of different activities should be encouraged and tried while activities should be periodically changed. Children and adolescents should be actively and regularly encouraged to engage in regular physical activities. School-based programs should be strongly encouraged. Sport participation and physical activity should be viewed as a lifelong recommendation while such activities as golf, tennis, swimming, and running should be encouraged. Parents should consistently encourage their children and adolescents to engage in various physical activities on a regular basis. Appropriately supervised weight training is safe and children as well as adolescents should be allowed to participate in such programs. A summary of recommended activities is provided in table 3.Adolescents should generally participate in physical activities of moderate intensity for 30 minutes daily. Sport participation should be tailored to the abilities of the child or adolescents. For examples, obese adolescents may be taller and stronger than some of their peers and may do better at sports requiring strength and or height such as throwing events, football or basketball. A number of obese adolescents may prefer water sports because adipose tissue provides more buoyancy in water and tends to hide their increased size. Parents should consistently encourage their children and adolescents to engage in various physical activities on a regular basis. Appropriately supervised weight training is safe and children as well as adolescents should be allowed to participate in such programs. A summary of recommended activities is provided in table 3.Adolescents should generally participate in physical activities of moderate intensity for 30 minutes daily. Sport participation should be tailored to the abilities of the child or adolescents. Table 2. Aerobic activities for obese youth (31). Used with permission Indoor activities tailored for aerobic exercise • Dance • Treadmill • Rowing machine • Stationary bike • Others Outdoor activities for aerobic exercise • Jogging • Bicycling • Long distance running • Roller blading • Power walking • Others

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Table 3. Recommendations for physical activity for obese children/youth (27,31). Used with permission Overweight Children: <150% IBW; >85-95 percentile BMI • Aerobic Activities: Weight bearing: • Brisk walking • Treadmill or stair climber • Field sports, roller blading, hiking • Racquetball or tennis • Martial arts • Skiing, jump rope • Indoor sports: swim, dance, play tag, aerobic dance Obese Children: 150-200% IBW; >95-97 percentile BMI • Aerobic activities: Non-weight bearing • Swimming • Cycling • Strength or aerobic circuit training • Arm-specific aerobic dancing • Arm ergometer (crank) • Interval walking with rest as necessary; gradually work up to longer walks with fewer rest stops Severely Obese Children: >200% IBW; >97 percentile BMI Weekly supervision by trained exercise professional Only non-weight-bearing aerobic physical activity: • • • • •

Swimming Recline biking Arm ergometer Seated (chair) aerobics Seated or lying circuit training

For examples, obese adolescents may be taller and stronger than some of their peers and may do better at sports requiring strength and or height such as throwing events, football or basketball. A number of obese adolescents may prefer water sports because adipose tissue provides more buoyancy in water and tends to hide their increased size.

Conclusions Obesity is increasingly prevalent in children and adolescents with significant lifelong medical complications. The exact prevalence of obesity among athletes is not known, though some studies suggest that it varies by the type of sports. American football players have been

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shown to have higher prevalence of overweight and obesity. The role of exercise and increased physical activity in general as an essential component of management of obese youth is well accepted; however, the role of sport participation in the management of obesity is not so clear. A few studies suggest that youth sport participation can be an effective tool in the management of obesity. Regular physical activity and sport participation is that is fun is strongly recommended.

References (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14)

(15) (16) (17)

Rowlett JD Obesity in the adolescent. In: Greydanus DE, Patel DR, Pratt HD, eds. Essential adolescent medicine. New York: McGraw-Hill Med Publ, 2006:651-65. Dietz WH. Overweight in childhood and adolescence. N Engl J Med 2004;350:855-7. Eneli I, Davies HD. Epidemiology of childhood obesity. In: Davies HD, ed. Obesity in childhood and adolescence. Westport, CT: Praeger, 2008:3-23. Kohn M, Booth M. The worldwide epidemic of obesity in adolescents. Adolesc Med 2003;14:1-9. World Health Organization. Obesity: Preventing and managing the global epidemic. Geneva: WHO, 1997. Kiess W, Boettner A. Obesity in the adolescent. Adolesc Med 2002;13:181-90. Livingstone MB. Epidemiology of childhood obesity in Europe. Eur J Pediatr 2000;159(Suppl): S14-S34. Seidell JC. Obesity: A growing problem. Acta Paediatr 1999;88 (Suppl) 46-50. Malina RM, Morano PJ, Barron M, et al. Overweight and obestiy among youth participants in American football. J Pediatr 2007;151:378-82. Strauss RS, Knight J. Influence of the home environment on the development of obesity in children. Pediatrics 1999;103:127. Hill J, Peters J. Environmental contributions to the obesity epidemic. Science 1998;280:1371-4. Hofmann AD. Obesity. In: Hofman AD, Greydanus DE, eds. Adolescents medicine, 3rd ed. Stamford, CT: Appleton Lange, 1997:663-82. Guide to clinical preventative services, 3rd ed. Report of the US Preventative Services Task Force. Philadelphia, PA: Lippincott Williams Wilkins, 2002:219-29. Lowry R, Galuska DA, Fulton JE, et al. Physical activity, food choice and weight management goals and practices among US. college students. Am J Prev Med 2000;18:18-27. Hill JO, Trowbridge FL, eds. Symposium on the causes and health consequences of obesity in children and adolescents. Pediatrics 1998;101(3:Suppl):497-574. Greydanus DE, Bhave S. Editorial. Obesity in adolescence. Indian Pediatrics 2004;41:545-50. Berkowitz RI, Wadden TA, Tershakovec AM, Cronquist JL. Behavioral therapy and sibutramine for the treatment of adolescent obesity. A randomized controlled trial. JAMA 2003;289:1805-12.

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(18) Yanovski SZ. Pharmacotherapy for obesity. Promise and uncertainty. N Engl J Med 2005;353:2187-9. (19) Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002;346:591-602. (20) Sugerman HJ, Sugarman EL, DeMaria EJ, et al. Bariatric surgery for severely obese adolescents. J Gastrointest Surg 2003;7:102-8. (21) Barlow SE: Bariatric surgery in adolescents: for treatment failures or health care system failures? Pediatrics 2004;114:252-3. (22) Steinbrook R. Surgery for severe obesity. N Engl J Med 2004;350:1075-9. (23) Himes JH, Dietz WH. Guidelines for overweight in adolescent preventive services: Recommendations from an expert committee. The Expert Committee on Clinical Guidelines for Overweight in Adolescent Preventive Services. Am J Clin Nutr 1994;59(2):307. (24) Berkey CS, Rockett HRH, Gillman MW, et al. One-year changes in activity and inactivity among 10- and 15-year old boys and girls: Relationship to change in body mass index. Pediatrics 2003; 111:836-43. (25) Becque M, Katch V, Rocchini A, et al. Coronary risk incidence of obese adolescents: Reduction by exercise plus diet intervention. Pediatrics 1988;81:605-12. (26) Amisola RB, Jacobson MS. Physical activity, exercise, and sedentary activity: relationship to the causes and treatment of obesity. Adolesc Med 2003;14:23-35. (27) Sothern MS. Childhood and adolescent obesity: Exercise as a modality in the treatment of childhood obesity. Pediatric Clin North Am 2001;48:1-17. (28) Korsten-Reck U, Kaspar T, Korsten K, et al. Motor abilities and aerobic fitness of obese children. Int J Sports Med 2007;28(9):762-7. (29) Weintraub DL, Tirumaldi EC, Haydel F, et al. Team sports for overweight children: The Standford Sports to Prevent Obesity Randomized Trial (SPORT). Arch Pediatr Adolesc Med 2008; 162(3):232-7. (30) Watts K, Jones TW, Davis EA, Green D. Exercise training in obese children and adolescents. Sports Med 2005;35(5):375-92. (31) Greydanus DE, Bricker LA, Patel DR. The benefits of sports participation in childhood and adolescents to prevent obesity in adolescents and adults. Asian J Ped Pract 2006;9(4):1-7. (32) Eneli I, Mantinan KD. Managing the overweight child In: Fitzgerald HE, Mousouli V, eds. Obesity in childhood and adolescence. Westport, CT: Praeger, 2008:191-225.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXVII

Obesity and Hypertension in Adolescents Alfonso D. Torres∗ and Colette A. Gushurst Pediatric Nephrology, Pediatrics and Human Development Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, Michigan, United States of America

Abstract The link between obesity and hypertension is examined in this discussion. Underlying mechanisms include increase in sympathetic activity, sodium balance, renal tubular sodium reabsorption, glomerular filtration rate (GFR) and development of insulin resistance. The role of leptin is examined in the development of hypertension in obese adolescents. Also considered in this review are the definitions of hypertension and principles of management for obese youth with hypertension. Pharmacologic agents used for management of hypertension include diuretics, alpha blockers, beta blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin-2 receptor blockers (ARBs), and long acting calcium channel blockers. The importance of weight control, caloric restriction, and exercise in the management of obesity in youth is also stressed.

Keywords: Adolescents, obesity, hypertension, management.

∗

Correspondence: Alfonso D Torres, MD, Pediatric Nephrology Director, Michigan State University/Kalamazoo Center for Medical Studies, 1000 Oakland Drive, Kalamazoo, MI 49008-1284 United States. Tel: 269-3376450; Fax: 269-337-6474; E-mail: [email protected]

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Introduction World health organization (WHO) data indicates that one billion individual are overweight and over 300,000 obese. Epidemiologic data reveal that the prevalence rates of obesity are increasing not only in the industrialized nations but also in developing countries. The number of overweight and obese adults in the United States of America (USA) has dramatically increased in the last 20 years. Approximately 60 % of USA males and 51% of the USA females are overweight or obese (1). Of particular concern is the relatively new phenomenon of increasing prevalence in overweigh and obesity in children and adolescents. This is an alarming problem observed in industrialized as well as developing countries and in the urban centers more than in the rural areas. Overweight was reported in 40.9% of Mexican-American adolescents (12-19 years of age) 40.9% while obesity was noted in 22.9%; males had a higher prevalence of overweight and obesity than females (2). In Pavia, northern Italy, the percent of overweight and obese boys were 20.9% and 4% while percentages of overweight and obese girls were 14.7% and 1.1% respectively (3). In Pune, India the prevalence of overweight base on BMI was 27.5% in boys and 20.9 % in girls; hypertension was present in 12% of the overweight boys and in 9.75% of girls while the prevalence of hypertension increased with the increase in BMI (4). In Lausanne Switzerland, of 2507 children studied with a mean standard deviation (SD) age 12.3 (0.5) years, 2.2 % were found to be hypertensive; of the hypertensive children, 16.1% of the boys and 12.4% of the girls were overweight or obese based on the CDC criteria of BMI > 85th percentile (5). In a study in Poland (city of Lodz), involving 25,309 children and adolescents between 7-18 years of age, the mean prevalence of overweight was 15.1%; 13.2% of the girls and 17% of the boys were found to be overweight.6 Obesity was found in 4.4% of the boys and in 2.9 % of the girls (6). Prehypertension was found in 11.1% and hypertension in 4.9 %; hypertension was more prevalent in the younger group ages 7-13 years than in the older group's age 14-19 years (6). Similar observations have been made in Germany, China, and other countries. In the United States the prevalence of obesity increased from 5% to 13% in boys and from 5% to 9% in girls between 1996-1970 and 1988-1991 respectively (7). In the United States, disparity exists in childhood and adolescent prevalence of obesity between regions and states of the Country (7). South and central regions of the United States have an obesity prevalence of 18% while the mountain region has the lowest prevalence of 11.4% (7). Children in West Virginia, Kentucky, Tennessee, Texas, and North Carolina all have an adjusted obesity prevalence >18.3%; this is over twice the odds of been obese than their Utah counterparts who have an adjusted prevalence of 10.4% (7). Socioeconomic status, neighborhood, social capital, television viewing, recreational computer use, and physical activities account for 55% of the regional and states differences in the prevalence of obesity (7). Substantial differences exist in the prevalence of overweight and obesity among different ethnic groups. African-American women and Mexican-American of both sexes have the highest prevalence of overweight in the United States today. However, the "epidemic" proportions of overweight and obesity can not be explained on the basis of familial or genetic

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factors alone. As a consequence of technologic advances over the past 30 years in agriculture, industry, communications, transport, commerce and medicine have brought changes in lifestyle all over the world, promoting a sedentary, self gratifying lifestyle in large number of children and adolescents. Education about appropriated nutrition and the importance of participation in physical activities has lagged behind (8). Overweight and obesity are not variations of normal growth of children and adolescents, but that of illnesses requiring intervention. Excessive weight gain is an important risk for comorbidities involving multiple organ systems: endocrine, cardiovascular, gastrointestinal, pulmonary, orthopedic, neurologic, dermatologic, and psychosocial. Clinical manifestations of overweight and obesity are many, including those listed in table 1. Based on the current prevalence of adolescent obesity in the United States, the prevalence of obesity in 35-years-olds will be in the range of 30% to 37% in men and 34% to 44% in women by the year 2020. A total increase in the number of patients with cardiovascular diseases is also expected to occur. Deaths secondary to coronary heart disease will increase in number and will occur in younger individuals as they approach middle age (9). Table 1. Complications of obesity Hypertension Type 2 Diabetes Cardiovascular diseases Cerebrovascular diseases Sleep apnea Back pain Osteoarthritis Non-alcohol-related fatty liver infiltration Kidney diseases Malignancies Psychosocial disturbances

Recently a meta-analysis epidemiologic study involving 247 published papers indicated that there was a strong positive association between BMI and risk for kidney disease outcomes (10). The authors concluded that 24.2% and 33.9% of kidney diseases among American men and women respectably (versus 13.8% in men and 24.9% in women in other industrialized countries) could be related to overweight and obesity (10). Obesity by itself is clearly linked to glomerulomegaly and to a secondary form of focal segmental glomerulosclerosis, likely on the bassis of a hyperfiltration mechanism (11).

Obesity and Hypertension The relationship between obesity and hypertension is well documented in children and adolescents, with blood pressure following an almost linear correlation though time;

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hypertension develops more often in those individuals that have been obese for over five years. Obesity is clearly related to type-2 diabetes mellitus and systemic arterial hypertension. Type 2 diabetes mellitus and hypertension are major risk complications of the development of coronary heart disease and chronic renal disease. Abundant clinical observations indicated that hypertension improves with reduction of body weight. Animal experimental observations that are highly reproducible demonstrate predictable elevation in blood pressure in association with high fat diets in dogs and rabbits as well as obese human beings (12).

How Obesity Induces Hypertension? Experimental data in obese animals and clinical observations in obese humans are associated with hemodynamic, neurohumoral, and renal changes that include increased arterial pressure, heart rate, and cardiac output. There is increase in sympathetic activity, sodium balance, renal tubular sodium reabsorption, glomerular filtration rate (GFR), and development of insulin resistance (13). Endothelial dysfunction and carotid intimal thickening are also observed in children and adolescents with obesity and hypertension. The increase in cardiac output observed in obese individuals is not necessarily directed to the increased adipose tissue. The change in blood flow is more likely due to general vasodilation induced by increase metabolic rate in many organs given the increase in organ size; this vasodilation is probably mediated by nitrous oxide (NO) produced by the endothelium and seems to occur early, before the development of vascular disease. Increase heart rate early in obesity seems to be mediated by diminution of the parasympathetic tone in the heart, rather than change in sympathetic activity (14). There are many studies however, linking obesity with hypertension and the role of the sympathetic nervous system activity in this relationship (15). Ethnicity may be an important factor to consider given the fact that sympathetic nervous system activity as well as propensity to obesity and hypertension differ with different ethnic groups. In obesity, sympathetic nerve system activity is increased in skeletal muscle, as detected by microneurography that measures muscle sympathetic nerve activity; this technique has shown consistent elevation of such nerve activity in obesity (16). One detrimental effect is to increase sympathetic activity to the peripheral vasculature resulting in vasoconstriction with time. Pharmacologic inhibition of the sympathetic nervous system(SNS) with alpha and beta blockers reduces blood pressure to a greater extent in obese than in lean individuals. Examination of norepinephrine spillover in obesity has shown regional hyperactivity in the kidneys. Increase SNS activity in the kidneys cav lead to sodium retention and abnormal hemodynamics resulting in increased blood pressure. Patients with obesity-associated hypertension present with positive sodium balance and expanded extracellular volume. In normal subjects, expanded extracellular volume triggers mild increase in blood pressure, resulting in a significant sodium excretion by the kidney and restoration of normal volume. This phenomenon is known as "pressure natriuresis" and functions as a physiologic back-up system for preservation of the extracellular volume. In hypertensive obese individuals, pressure natriuresis is impaired, requiring higher blood pressure to excrete a sodium load. In experimental obese animals, sympathetic renal denervation attenuates renal sodium retention

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associated with high fat diet. Several other potential mechanism have been implicated in the activation of the SNS in obesity associated hypertension, including hyperinsulinemia, increase levels of free fatty acids, impaired baroreceptor reflexes, obstructive sleep apnea, and cytokines release from adipocytes. Visceral obesity is a high risk for obstructive sleep apnea that is often seen in association with hypertension. These patients have an increased peripheral chemoreflex response to hypoxia resulting in activation of the SNS. There is also a clear link between visceral fat accumulation and SNS activity and hypertension is mediated through the visceral fat production of leptin. Leptin is a protein produced mainly by visceral adipose tissue that acts in the central nervous system. Leptin plasma concentration is elevated in obese humans (17). One of the leptin pathways in the hypothalamus involves stimulation of the pro-opiomelacortin neurons in the arcuate nucleus that then send projections to the paraventricular nucleus and lateral hypothalamus releasing amelanocyte-stimulating hormone (a-MSH) which is an agonist for acting on melanocortin receptors 3/4 (MC3/4-R). These neurons projections act on the nucleus of the solitary tract in the midbrain affecting changes in appetite, SNS activity, and blood pressure (18). Currently leptin secreted by adipocytes is the main factor linking obesity with increased sympathetic nerve system activity and hypertension (19). It is well known that the kidney contains all the elements for intrinsic activation of the renin-angiotensin-aldosterone system (RAAS). The intrarenal RAAS seems to be involved in hypertension associated with visceral obesity despite the fact that there is sodium retention and expansion of the extracellular volume. Possible explanations for the activation of renin secretion may involve activation of the sympathetic renal nerves and decrease sodium delivery to the macula densa due to increase sodium reabsorption early in the proximal tubule and the loop of Henle. In addition, increased renal pressure induced by visceral and intrarenal fat can stimulate renin secretion as seen in the peg kidney. Increase activity of RAAS causes efferent arteriole vasoconstriction and may result in hyperfiltration and nephrosclerosis. Aldosterone has direct mineralocorticoid receptor agonist effects resulting in increased sodium reabsorption in the cortical collecting duct and increasing blood pressure. Additionally, aldosterone is considered to promote fibrosis in organs such as the heart. Mineralocorticoid blockers are useful in the management of obese hypertensive patients. The view that overweight and obesity represent simply a mater of caloric deposits is obsolete; we are learning that the adipose tissue is a very complex biologic system with surprising number of functions interacting with other organ systems including those listed in table 2. Adipose tissues are the source of numerous hormones, cytokines, growth factors, and complement factors that promote inflammation. Endothelial dysfunction eventually leads to promotion of vascular wall stiffness and is correlated with increase in carotid intimal-medial wall thickness (20). A recently published epidemiologic meta-analysis involving 247 published papers from 1980 to 2006 demonstrated that compared with normal individuals, overweight and obese persons had significantly higher risk for kidney disease.21 The pooled relative risks (RRS) were 1.4 (1.30-1.50) for overweight and 1.83 (1.78-2.17) for obesity (21). The association between obesity and kidney disease was stronger in women with RR=1.92 (1.78-2.07) than in men with RR=1.49 (1.36-1.63) (21). This study indicated that there is a positive association between BMI and risk for kidney disease outcomes.

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The authors concluded that 24.2% and 33.9% of kidney diseases among men and women respectively in the United States versus 13.8% in men and 24.9% in women in other industrialized countries could be related to overweight and obesity (10). Table 2. Interactions of adipose tissue Central and Peripheral Nervous systems Endocrine system Cardiovascular system Musculoskeletal system Renal system Immune system

Definitions of Hypertension in Children and Adolescents The Fourth Report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents uses blood pressure percentiles based upon demographic data from the National Health and Nutritional Examination Surveys (NHANES), taking in consideration information on gender, age, height, and blood pressure measurements on three separated occasions (21). Table 3 lists hypertension definitions. Both systolic and diastolic blood pressures are of equal importance and the higher value determines the severity of the hypertension. The blood pressure should be measured in at least three different occasions to establish the diagnosis of hypertension. Stage 1 hypertension (see table 3) allows more time for evaluation. Treatment may be initiated with no pharmacologic approach that includes lifestyle modification such a weight loss, diet, and exercise. Stage-2 hypertension (se table 3) is more likely to be secondary hypertension and requires more rapid evaluation as well as initiation of pharmacologic intervention. Table 3. Definitions of hypertension 1. 2. 3. 4.

Normal - systolic and diastolic blood pressure < 90 percentile Prehypertension – Systolic and/or diastolic blood pressure >90th percentile but < 95th percentile, or if BP exceeds 120/80 mmHg even if <90th percentile Stage 1 Hypertension – Systolic and/or diastolic BP between the 95th percentile and 5 mmHg above the 99th percentile. Stage 2 Hypertension – Systolic and/or diastolic BP > 99% percentile + 5mmHg.

Treatment of Hypertension in Obese Adolescents The treatment of the hypertensive obese adolescent is based on the same principles of treatment as used for management of other causes of hypertension. It is important to obtain a

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comprehensive history including a family history. The physical examination should be aimed to find possible secondary causes of hypertension that can be amenable to specific therapy, resulting in the cure or amelioration of the hypertension. Appropriate laboratory studies (see table 4) are helpful in investigating secondary forms of hypertension. Secondary forms of hypertension are more common in preadolescent children. Essential hypertension is more often seen in families with positive histories for hypertension and obesity. The cornerstone of management of hypertension secondary to obesity is body weight reduction and limiting caloric intake is necessary. Behavior modification is also very important. Better results are obtained by caloric restriction, behavior changes, and regular exercise (22). The experience for weight reduction with pharmacologic agents is limited and in general not recommended in the United States for adolescents. There are reports of a few small series of morbidly obese adolescents with BMI > 40 Kg/ M² that have treated surgically for weight reduction (23). However, lifestyle modification with behavior changes and exercise continues to be the best management option for most patients, particularly prehypertensive and stage 1 hypertensive adolescents. Adolescents with stage 1 hypertension should be monitored every few months. If the hypertension becomes more severe or symptomatic, stage 2 hypertension is diagnosed, and pharmacologic treatment is indicated. Table 4. Selective list of key laboratory tests in hypertension evaluation Urinalysis Creatinine Urea nitrogen Electrolytes Others

Pharmacologic Therapy for Obese Hypertensive Adolescents Several classes of medication are able to successfully control elevated blood pressure in adolescents as listed in table 5. The decision to utilize a specific medication however, requires consideration of the potential undesirable side effects, including metabolic consequences. It is well known that diuretics decrease blood pressure and offer cardiovascular protection in many hypertensive patients and are recommended as the fist line therapy for hypertensive adults. However in obese patients, there is an increase in the fasting blood glucose (FBG) levels in patients that were started on treatment with thiazides for hypertension. The magnitude of change in FBG and the development of new onset diabetes mellitus after thiazide initiation have been associated with increase in BMI and base line FBG (24). Additionally, diuretic use is associated with electrolyte disturbances, particularly hypokalemia, hyponatremia, and abnormalities in uric acid metabolism. The experience with beta blockers for the treatment of hypertension in pediatrics is extensive. In the older adult population, beta blockers are particularly beneficial after myocardial infarction. However, beta blockers make glucose control more difficult; they are also associated with increased lipid levels and make it more difficult for the individual to loss

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weight. In younger obese individuals, other metabolically more neutral alternatives for treatment of hypertension are available. Increasing experience in the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin-2 receptor blockers (ARBs) is accumulating in the treatment of hypertensive adolescents and in children. In general, these medications are well tolerated by adolescents. Precautions are necessary in those adolescents with decrease renal function because for the risk of aggravating the decreased glomerular filtration rate and the development of hyperkalemia. Table 5. Medications for treatment of hypertension in adolescents Diuretics Alpha blockers Beta blockers Angiotensin converting enzyme inhibitors (ACE inhibitors) Angiotensin-2 receptor blockers (ARBs) Long acting calcium channel blockers

These drugs are effective in controlling the elevated blood pressure, and because most are long acting medications, compliance is better. One drawback with these medications is the possibility of development of angioedema, a rare but serious complication. Another important consideration is their use in the adolescent female at risk of becoming pregnant given the teratogenic effects of ACEs and ARBs in the fetus. Long acting calcium channel blockers are used for different forms of hypertension and are well tolerated in adolescents. They are associated with less metabolic abnormalities than diuretic or beta blockers (25). The dihydropyridine calcium channel blocker, amlodipine, induces tachycardia and ankle edema that are of no clinic consequence; gum hypertrophy is also noted. Recent publications seem to indicate that that long term thiazide diuretics can increase fasting blood glucose and BMI levels and predispose to development of diabetes mellitus in hypertensive patients (24,25). These studies indicate that the selection of antihypertensive medications is important to prevent or diminish the undesirables metabolic consequences that may be induced in susceptible individuals by certain medications.

Conclusions Overweight and obesity in adolescents is now a global problem affecting developed and developing societies around the world. It is predictable that childhood and adolescent obesity will translate into adulthood obesity and its consequent morbidities including hypertension, hyperlipidemia, as well as type 2 diabetes mellitus and cardiovascular diseases. The causes of overweight and obesity in children and adolescents are the result of excessive caloric intake and concomitant decline in levels of physical activity in association with various socioeconomic, cultural, and genetic factors. There are populations that are at higher risk than others to be affected by these factors, including Asian Pacific Islanders, Australian

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Aborigine, African American Hispanics, and Native Americans; however no populations are exempt. Adolescent hypertension is one of the co-morbidities of obesity that can be detected, prevented, and treated. The diagnosis of hypertension in adolescents in the United States is based on the recently published guidelines (21). The cornerstone in the treatment of obesityassociated hypertension in adolescents is weight reduction by decreased caloric intake, behavior modification, and exercise. Organized physical activities and sport programs at schools and/or in the community in important in this regard. When pharmacologic therapy becomes necessary the prescribing physician needs to become familiar with the different antihypertensive medications as well as their side effects noted in obese diabetic patients, in those with cardiovascular diseases, and in patients with diminished kidney function. The best approach to the management of the obese "epidemic" is prevention and in this regard, health education of the population at large is critical.

References (1)

Jensen MD. Obesity. In: Goldman L, Ausiello D, eds. Cecil medicine, 23rd ed. Philadelphia, PA: Saunders Elsevier, 2008:1643-52. (2) Forrest KY, Leeds MJ. Prevalence and associated factors of overweight among Mexican-American adolescents. J Am Diet Assoc 2007;107(10):797-800. (3) Turconi G, Guarcello M, Maccarini L, Bazzano R, Zacardo A, Roggi C. BMI values and other anthropometric and functional measurements as predictors of obesity in selected group of adolescents. Eur J Nutr 2006;45(3):136-43. (4) Rao S, Kanade A, Kelkar R. Blood Pressure among overweight adolescents from urban school children in Pune, India. Eur J Clin Nutr, 2007;61(5):633-41. (5) Chiolero A, Cachat F, Burnier M, Paccaud F, Bovet P. Prevalence of hypertension in schoolchildren based in repeated measurements and association with overweight. J Hypertension 2007;25(11):2209-17. (6) Ostroswska-Nawarycz L, Nawaricz T. Prevalence of excessive body weight and high blood pressure in children and adolescents in the city of Lodz. Kardiol Pol 2007;65(9):1079- 87. (7) Singh GK. Kogan MD, VanDick PC. Multilevel analysis of state and regional disparities of children and adolescents obesity in the United States. J Community Health 2007;34:222-5. (8) Pazmino P A, Pazmino A K, Diabetic renal failure in Texas: Influence of ethnicity and household income. Tex Med 2003;99:57-65. (9) Bibbins-Domingo K, Coxon P, Pletcher MJ, Lightwood J, Goldman L. Adolescent overweight and future adult coronary heart disease. N Engl J Med 2007;357:2371-9. (10) Wang Y, Chen X, Song Y, Caballero B, Cheskin LJ. Association between obesity and kidney disease: A systemic review and meta-analysis: Kidney Int 2008;73:19-33. (11) Kambham N, Markowitz GS, Valeri AM, et al. Obesity and related glomerulopathy: An emerging epidemic. Kidney Int 2001;59:1498-1509.

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(12) Hall JE Brands MW, Dixon WN, et al Obesity induced-hypertension: Renal function and systemic hemodynamics. Hypertension 1993;22:292-9. (13) Messereli FH, Christie B, DeCarvalho JG, Obesity and essential hypertension: Hemodynamics, intravascular volume, sodium excretion, and plasma renain activity. Arch Intern Med 1981; 141:81-5. (14) Vaz M, Jennings G, Turner A, et al. Regional sympathetic nervous activity and oxygen consumption in obese normotensive human subjects: Circulation 1997;96:3423-9. (15) Lambert E, Staznicky M, Esler M, Dawood T, Hotchkin E, Lambert G. Differing patterns of sympathoexitation in normal-weight and obesity related hypertension. Hypertension 2007;50(50):862-8. (16) Corry DB, Tuck ML. Obesity, hypertension and sympathetic nerve system activity. Curr Hypertens Rep 1999;1(2):119-26. (17) Haynes WG, Interaction between leptin and sympathetic system activity in hypertension. Curr Hypertens Rep 2000;2(3):311-8. (18) John E. Hall, Alexander A da Silva, Elizabeth Brandon, et al. Pathophysiology of obesity induced hypertension and target organ damage. In: Lip GYH, Hall JE, eds. Comprehensive hypertension. Philadelphia, PA: Mosby Elsevier, 2007:441-68. (19) Francischetti EA, Genelhu VA. Obesity-hypertension: An ongoing pandemic. Int J Clin Pract. 2007;61(2):269-80. (20) Sorof JM, Turner J, Martin DS, et al. Cardiovascular risks factors and sequelae in hypertensive children identified by referral versus school base screening. Hypertension 2004;43:214-8. (21) The Fourth Report on diagnosis, evaluation and treatment of high blood pressure in children and adolescents. Bethesda, MD: Nat Heart Lung Blood Inst Health. Pediatrics 2004;114:555-76. (22) Rocchini AP, Cutch V, Anderson J, Becker D, Martin M, Mark C. Blood pressure in obese adolescents, effect of weight loss. Pediatrics 1998;82(1):16-23. (23) Widhalm K, Dietrich S, Prager G, Silberhummer G, et al. Bariatric surgery in morbidly obese adolescents: A 4-year follow-up of ten patients. Int J Pediatr Obes 2008;3(suppl 1):78-82. (24) Siegel D, Meier J, Maas C, Lopez J. Swislocki AL. The effect of body mass index on fasting blood glucose after initiation of thiazide therapy in hypertensive patients. Am J Hypertension. 2008; [Epub ahead of print]. (25) Gupta AK, Dahlof B, Dobson j, Sever PS, Wedel H, Poulter NR; on behalf of ASCOT Investigators. Determinants of new-onset diabetes Among 19,251 hypertensive patients randomized in the ASCOT-BPLA Trial and relative influence of antihypertensive medication. Diabetes Care 2008; [Epub ahead of print].

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXVIII

Hyperandrogenism and Obesity: Ominous Co-Morbidities Amit M. Deokar, Shawn J. Smith, Amanda J. Goodwin and Hatim A. Omar Division of Adolescent Medicine, Department of Pediatrics, University of Kentucky, Lexington, KY, USA

Abstract This review has a two-fold objective. One, it addresses the association of hyperandrogenism and obesity and the complex metabolic derangements that are part of the problem. Clinical management of these co-morbidities is challenging and complex. Second, this article will aid health care providers with the key features to an early diagnosis and intervention to decrease the morbidities in the short as well as long term. Method: Systematic review of articles and information on the topic of interest that were published in the last 15 years. Conclusion: Obesity and hyperandrogenism are integral parts of Metabolic Syndrome/Polycystic Ovarian Syndrome (PCOS)/Hyperandrogenism, Insulin resistance, and Acanthosis Nigricans (HAIR-AN). With the childhood obesity epidemic, the metabolic syndrome and the associated abnormalities are routinely seen in clinical practice and these have a tremendous economic burden on the society and the quality of life.

Keywords: Adolescence, obesity, metabolic syndrome, hyperandrogenism, polycystic ovarian syndrome, hyperandrogensim, insulin resistance, acanthosis nigricans.

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Introduction Obesity in children and adolescents has increased at an alarming rate in the last two decades. Over the years, researchers have acquired a better understanding about the strong association of obesity in metabolic syndrome (MS, previously known as metabolic syndrome X) (1). Patients with MS have various metabolic abnormalities that can include abnormal glucose and insulin ratio, insulin resistance, high blood pressure, altered lipid profile, prothrombotic and pro-inflammatory state. Teenagers with MS are predisposed to long term morbidities, such as early coronary artery disease, hepatic steatosis, type 2 diabetes, and stroke (1). Evidence suggests that an overweight teenager has an 80 percent chance of continuing to be overweight in the adult life (2). Approximately 17 percent of children aged 2-19 years are considered overweight based on a survey by National Health and Nutrition Examination Survey of 2003-2004 (3). As noted earlier, the rate of obesity has doubled in adolescents, who are in the 12-19 year age group (4). The prevalence of obese and overweight children may be different depending on the gender and ethnicity. For example, the obesity rates are higher in African Americans, Hispanic Americans, males, and those living in the southern states (2). The definition of obesity varies in adolescents when compared to adults due to different proportion of body fat in boys and girls at different ages (5). Body Mass Index (BMI) is a reliable tool to assess obesity, because it is easy to obtain and correlates well with the body fat (6). Any adolescent with a BMI of 30 kg/m2 or 95th percentile for gender and age falls in the overweight category. They are considered at risk of being overweight if their BMI is between 85th and = 95th percentile. In the US, the economic burden of direct and indirect healthcare cost due to obesity and co-morbidities is estimated to be well over $ 117 billion annually. As the obesity rates have doubled and tripled respectively in children and adolescents, so have the health care costs (7). This impacts the healthcare burden directly. Obesity and hyperandrogenism (HA) are strongly associated in patients who have been diagnosed to have polycystic ovarian syndrome (PCOS)/HA/MS. This article addresses their relationship with one another and specific management options. A subset of (PCOS) includes hyperandrogenism, insulin resistance and acanthosis nigricans, abbreviated as HAIR-AN (8,9). Historically PCOS was described based on findings of multiple cysts in the ovaries, irregular or no menstrual periods, and hirsuitism. However, absence of ovarian cysts does not rule out this syndrome (10). Women with high androgen levels have associated HAIR-AN features in about 5-10 percent of cases (11). The onset of PCOS/HAIR-AN may occurs in adolescent years and the diagnosis is likely to be delayed until early adulthood (8,9).

Pathophysiology As PCOS/HAIR-AN is being studied more over the last two decades, different theories have been proposed to explain the features of the syndrome, including obesity. The primary problem in HA appears to be due to an altered hypothalamo-pituatary-ovarian axis. The anovulation and thus abnormal or absence of menstrual periods is from a persistent leutenizing hormone (LH) surge and its high concentration in the blood. There is also an

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increased GnRH surge as the negative feedback from estrogen and progesterone is ineffective due to relative hypothalamic insensitivity. The LH surge results in increased production of androgens. The level of follicle stimulating hormone (FSH) is less when compared to the LH resulting in decreased enzymatic (aromatase) conversion of androgen to estrogen and thus anovulation. Another key association of HA is hyperinsulinsm. This is due to peripheral insulin resistance, which can result in a hyperglycemic state. The level of sex hormone binding globulin (SHBG) is decreased due to the high insulin levels and consequently there is a rise in the free testosterone level (8). Insulin also increases the androgen production by directly stimulating the theca cells (12). Both hyperinsulinism and HA predispose an individual to have an athrogenic lipid profile. Total cholesterol, triglycerides (TG) levels are also elevated. Increased activity of the enzyme lipase affects the cholesterol metabolism and could result in a decreased level of the high density lipoprotein-cholesterol (HDL-C) (13). Another postulated mechanism for HAIR-AN is a genetic mutation of the insulin receptor (tyrosine kinase domain) (9). Effects of HA can be multi-fold. Even though increased androgen production in women is associated with obesity, one study in 2002 by Gapstur et al (14) in obese men have found to have lower testosterone and dehydroepiandroterone sulfate (DHEAS) levels. High androgen levels in children and adolescents are linked to precocious puberty, accelerated bone growth, height, features of PCOS, and are more commonly seen in obese subjects compared to non-obese. In pre-pubertal obese children the level of DHEAS is often elevated (14). Recently, researchers have looked at the effects of proteins like adiponectin, resistin, leptin, and TNF-a on the fat metabolism, peripheral insulin resistance, and energy expenditure (15). Resistin is produced by the mature visceral and subcutaneous adipocytes and influences insulin sensitivity. Adiponectin and leptin, also secreted from the adipocytes, have similar roles (16). A recently published study by Shin et al (17) suggested obesity as an inflammatory process due to findings of increased levels of C-reactive protein (CRP) and TNF found in obese children. The adiponectin level was found to be much lower concentration in these children. Retinol Biding Protein 4 (RBP4) is present in omental and subcutaneous fat and is expressed more in women with PCOS (18). The high levels of androgen and features of metabolic syndrome have shown to normalize in post-menarche obese adolescents after weight reduction (19).

Diagnostic Criteria A standard list of the diagnostic criteria for MS in children and adolescents is still lacking. However, a modified diagnostic criteria for children using the NCEP criteria and data from the National Health and Nutrition Examination Survey (NHANES, 1988-94) is widely used. The National Cholesterol Education Program (NCEP) and the Adult Treatment Panel III (ATP III) include at least 3 of 5 of the following criteria for the diagnosis of MS in adults (1,2,20,21).

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Abnormal lipid panel: Hypertriglyceridemia (>150 mg/dl) and low HDL-C (<40mg/dl in males and <50 in females). High fasting glucose level. Hyperglycemic state is defined as fasting glucose level of 100 mg/dl or more. Elevated blood pressure, systolic, diastolic, or both using reference ranges. From example, blood pressure of >135/85 mmHg is considered abnormal. Increased waist circumference/abdominal girth. BMI is fairly reliable in assessing obesity in children. High insulin resistance (criterion in children). The World Health Organization (WHO) criteria required elevated insulin or glucose level (>110mg/dl) in addition to at least two of the following:[2] Abdominal obesity Waist size >94 cm or waist to hip ratio of >0.9 Triglycerides > 150 mg/dl or HDL <35 mg/dl Blood pressure >140/90 mmHg.

HAIR-AN is a clinical diagnosis and includes the following, in addition to criteria mentioned above (9): (a) Acne, hirsuitism, temporal balding, clitoromegaly, and deepening of voice (suggestive of high androgen level). (b) Acrochordons (skin tags), acanthosis nigricans (usually found on the neck, axillae, and back). These are suggestive of insulin resistance and altered hormonal levels.

Suggested Workup Anthropometric measurement, vital signs, with a complete history and physical exam (including genital) is recommended. A detailed family, past medical, and medication history should also be documented. Laboratory data that may be useful includes, fasting levels of insulin, glucose (complete metabolic panel to assess liver and renal function), lipid panel, glucose/insulin ratio, HgA1c, and AM cortisol level. Oral glucose tolerance test (2 hour) is also recommended to document hyperglycemic state. One test that has high sensitivity and specificity is the euglycemic hyperinsulinemic clamp. This may be impractical in a clinical setting due to the time consuming and complex nature of the test (9). A thorough endocrine evaluation should include thyroid function tests, serum prolactin, DHEA-S, am 17hydroxyprogesterone (17-OHP), SHBG level, and free and total testosterone. IGF-1 level may be helpful in a suspected growth hormone producing tumor (22). In order to establish the diagnosis of PCOS, the presence of multiple ovarian cysts is not necessary. Likewise, an abdominal/pelvic ultrasound detection of multiple ovarian cysts does not confirm that diagnosis either. Occasionally a computed tomography (CT) or an MRI of the abdomen/pelvis may be necessary in situations where there are progressive signs of hyperandrogenism (22).

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Outcome Metabolic syndrome (PCOS and HAIR-AN subset) in children can lead to potentially complicated short and long term medical problems. This exhaustive list includes but is not limited to the following (6): • • • •

•

Distorted body image and perception Low self-esteem and depression Acne Obesity associated problems like snoring, obstructive sleep apnea, disordered sleep, gastro esophageal reflux disease (GERD), gall stones, joint pain, exercise intolerance, features of diabetes, coronary artery disease, and skin changes, etc. Amenorrhea (predisposing to subsequent inadequate bone mineralization) and possibly infertility.

Treatment Options The timeframe for the diagnosis of metabolic syndrome/HAIR-AN to the outcome of the treatment varies from patient to patient and can be often protracted. A multidisciplinary approach is often required to address the metabolic as well as the psychological stressors associated with this syndrome. reatment should be geared toward specific metabolic abnormalities as well (6,9,23). It is important for the healthcare provider to be aware of the concerns that teenagers may have when it relates to cosmetic appearance. At a psychological developmental stage where bodily appearance plays an important role in a teenager’s life, skin related problems such as acanthosis nigricans, acne, and hirsuitism may be quite troubling (22). This can affect their self-esteem directly. Health care providers should have a low threshold for referring these teenagers to counseling services.

Lifestyle Modification Although compliance can play a big role with this approach, it is considered one of the most favored and successful mode of treatment in obese patients, who also have HA (22). Weight loss can dramatically improve the ovarian function and decrease the levels of androgens (24). Different dietary changes such as caloric restriction of carbohydrates or fat with increased protein intake have been previously studied. There is no sufficient data available if restriction of carbohydrates is better than that of fat intake. It is therefore prudent to use the expertise of a dietician or nutritionist who can work with obese/overweight individuals.

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Medication Management Typically, in addition to the lifestyle modification, medical treatment may include a combination of one or more of these therapies such as anti androgens, insulin-sensitizing agents, combined hormonal contraceptives, bariatric surgery, and complementary and alternative medicine treatment options. As part of a multidisciplinary approach, psychological counseling is very crucial.

Insulin-Sensitizing Agents Biguanide: Metformin (trade names such as Glugophage®, Rhiomet®), a pregnancy category B drug, has traditionally been used in type 2 diabetes mellitus (DM). From a glycemic stand point, Metformin interferes with the hepatocyte mitochondrial respiratory oxidative process and decreases gluconeogenesis. This however, is not a complete blockade of gluconeogenesis. It also facilitates the glucose transport in tissues such as the skeletal muscles, by activating the enzyme tyrosine kinase (TK) on the insulin receptors and enhancing the glucose transporter system. Some of this action is also on the adipocytes. It also acts against the gluconeogenic effects of glucagon. Metformin is particularly useful in obesity associated with HA. Due to its insulin lowering effect, there is a consequent decrease in the free and total testosterone and an increase in the estradiol level (25). This has a beneficial effect on ovulation, hirsuitism and acne. As obesity is strongly associated with cardiovascular morbidity and mortality, metformin has an added benefit of being cardioprotective. It has shown to decrease the free fatty oxidation, which helps improve the insulin sensitivity as well. It may also help lower the total cholesterol (TC), very low density lipopoprotein cholesterol (VLDL-C), low density lipoprotein cholesterol (LDL-C), and increase the high density lipoprotein cholesterol (HDLC). It also lowers the platelet aggregation and adhesion, and decreases the levels of tissue plasminogen inhibitor 1 and von Willebrand factor. This has a positive effect on homeostasis (26). It can induce vascular relaxation and reduce the oxidative stress (25,26). A combination of flutamide (an androgen receptor blocker) and metformin with an addition of drosperinone (a 4th generation progesterone) has shown to decrease abdominal fat (27). Usual side effects from metformin may include gastrointestinal symptoms such as nausea, flatulence and diarrhea. These may be reduced by taking it with food. Treatment may be started with a single daily dose, preferably at a lowest possible dose. It may then be increased to a twice daily dose. It is not recommended to go over the maximum dosage of 2.25 grams/day (25). One must be aware of the potential toxicity from metfromin that includes lactic acidosis in rare situations. Metformin is fairly safe for the mother and baby during pregnancy and lactation (28). Thiazolidinediones: Rosiglitazone is an insulin sensitizing agent, whose action on the peroxisome proliferator-activated receptor (PPAR ) on the adipocytes improves glucose transport into the cell by increasing the adiponectin secretion (29). In studies done earlier on overweight women with PCOS, there was a decrease in the insulin resistance and return of ovulation as indicated by regular menses. The SHBG level also shows an increase that helps

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with the ovulation. Some of the side effects include weight gain and cardiac failure in susceptible individuals (30).

Regulation of the Hormonal/Androgen Imbalance and Use of Oral Contraceptives Combination birth control pills (BCP’s) are the cornerstone in the treatment of HA. Their mechanism of action includes the following: • • •

Increase the SHBG production and level: This allows a reduction of free testosterone. Suppress LH: Decreases androgen production from the ovaries. Anti-minerelocorticoid activity: Certain progestins such as Drosperinone have low androgenic activity and are generally preferred in HA. The brand name contraceptives Yasmin® and Ortho-Tri-Cyclen® contain Drosperinone.

The effects of combination BCP’s include normalization of menses and a decrease in acne and hirsuitism (22). In addition to the above, other pharmacologic agents have been tried in HA states are cyproterone acetate, finastreride, glucocorticoid, such as prednisone (patients with late onset congential adrenal hyperplasia (CAH) having PCOS features), and spironolactone.

Surgical Options Bariatric Surgery: A decrease in obesity-related morbidity has been well documented in individuals that have undergone Roux-en-Y gastric bypass surgery. Although this is an optional procedure that has been evaluated mostly in morbidly obese adults, the guidelines are quite conservative for the adolescent population. Morbidly obese teenagers, who have failed the non-surgical approach may be considered for a gastric bypass surgery. Other justifications in addition to the above includes a BMI of 40 kg/m2 or more, physical and psychosocial co morbidities from obesity (31). Bariatric surgery intended to result in weight loss can positively impact obesity, PCOS, and reverse anovulation. The risks from obesity during pregnancy in morbidly obese teens is also decreased by the procedure (31). A 1 to 2 year wait post operatively for becoming pregnant is usually recommended. As there can be potential complications from this surgical procedure, careful multidisciplinary evaluation for the need for surgery is needed.

Complementary and Alternative Medicine Alternative approaches in the treatment of PCOS have been recently gaining popularity. In view of side effects from the traditional medical and surgical treatment, researchers have

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looked at the benefits of acupuncture, a traditional form of Chinese medicine. Acupuncture has been shown to modulate neuro-endocrine systems that results in lowering of the increased sympathetic tone in individuals with PCOS. By releasing ß-endorphins the technique of acupuncture can directly influence the HPA axis and lower the cortisol and LH levels (32). As a result, its beneficial effects on metabolic, ovulation, and other neuro-endocrinal endogenous systems can positively influence the features of PCOS/HA. Other forms of alternative medicine such as homeopathy, Ayurveda, diet supplements, and hypnotherapy have been tried to treat obesity in adults with some encouraging results even though some are not very convincing (33).

Federal/State Program The CDC (Center for Disease Control and Prevention), the Division of Nutrition and Physical Activity (DNPA) and the health departments of 28 states have established the Nutrition and Physical Activity Program to Prevent Obesity and Other Chronic Diseases (NPAO) since 1999 using the social ecological model (34). Healthcare providers are encouraged to contact their individual health departments to learn more about the program, where available.

Conclusions Metabolic syndrome, hyperandrogenism, and PCOS are integral part of complex metabolic abnormalities that have a great impact on the health and general well-being of an individual. The diagnosis is often late and this adds to the economic burden from obesity related problems. The following key points will aid the healthcare provider with the timely diagnosis of HA/MS/PCOS and appropriate interventions. • • • • •

•

Healthcare provider awareness of obesity in childhood and adolescence. Utilizing diagnostic criteria and/or clinical diagnosis of PCOS/HA/MS. One may refer to the NCEP, NHANES, ATP III, WHO diagnostic criteria. A complete history, including that of the individual, family, past, and medications. Complete physical exam. As noted earlier, the diagnosis of HAIR-AN is clinical. Laboratory and radiological work up. The list includes fasting insulin, glucose (complete metabolic panel to assess liver and renal function), lipid panel, glucose/insulin ratio, HgA1c, and AM cortisol level. Oral glucose tolerance test (2 hour), thyroid function tests, serum prolactin, DHEA-S, am 17-hydroxyprogesterone (17-OHP), SHBG level, free and total testosterone, IGF-1 level are also recommended. Management that includes medical, surgical, lifestyle modification techniques, and appropriate referrals to other sub-specialty providers for addressing associated co morbidities. Keeping in mind that some patients may desire to utilize alternative and complimentary medicine options as well.

Hyperandrogenism and Obesity •

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Multidisciplinary approach that includes, the primary care provider, sub-specialist, social worker, nutritionist, and counselor/psychologist.

References (1) (2)

(3)

(4)

(5)

(6) (7) (8)

(9)

(10) (11) (12)

(13)

Kranz S, Mahood LJ, Wagstaff DA. Diagnostic criteria patterns of US children with metabolic syndrome: NHANES 1999-2002. Nutrition J 2007;6:38. Strasburger VC, Braverman PK, Rogers PD, Holland-Hall CM. Adolescent medicine: A handbook for primary care, 1st ed. Philadelphia, PA: Lippincott Williams Wilkins, 2005. CDC. Prevalence of overweight among children and adolescents: United States, 20032004. 2007 [cited 2008 05/16/2008]; Health E-Stat. National Center for Health Statistics. Centers for Disease Control.]. Available from: http://www.cdc.gov/nchs/products/ pubs/pubd/hestats/overweight/overwght_child_03.htm National Association of Children's Hospitals and Related Institutions (NACHRI). Childhood Obesity Statistics and Facts. 2007 [cited 2008 05/16/2008]; Available from: http://www.childrenshospitals.net/AM/Template.cfm?Section=HomepageandTEMPLA TE=/CM/ContentDisplay.cfmandCONTENTID=34357. CDC. Defining overweight and obesity, 2007 [cited 2008 05/14/2008]; Definition for children and teens]. Available from: http://www.cdc.gov/nccdphp/dnpa/obesity/ defining.htm Krebs NF, Himes JH, Jacobson D, Nicklas TA, Guilday P, Styne D. Assessment of child and adolescent overweight and obesity. Pediatrics 2007;120(Suppl 4):S193-228. Stein CJ, Colditz GA. The epidemic of obesity. J Clin Endocrinol Metab 2004;89(6):2522-5. McCartney CR, Prendergast KA, Chhabra S, Eagleson CA, Yoo R, Chang RJ, et al. The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism. J Clin Endocrinol Metab 2006;91(5):1714-22. Rager KM, Omar HA. Androgen excess disorders in women: the severe insulinresistant hyperandrogenic syndrome, HAIR-AN. ScientificWorldJournal 2006;6:11621. Mukhtar I Khan DMK, ,. Polycystic ovarian syndrome. 2006 [cited 2008 05/14/2008]; Available from: http://www.emedicine.com/med/topic2173.htm Barbieri RL, Hornstein MD. Hyperinsulinemia and ovarian hyperandrogenism. Cause and effect. Endocrinol Metab Clin North Am 1988;17(4):685-703. McCartney CR, Blank SK, Prendergast KA, Chhabra S, Eagleson CA, Helm KD, et al. Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls. J Clin Endocrinol Metab 2007;92(2):430-6. Valkenburg O, Steegers-Theunissen RP, Smedts HP, Dallinga-Thie GM, Fauser BC, Westerveld EH, et al. A more atherogenic serum lipoprotein profile is present in

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(14)

(15) (16)

(17)

(18) (19)

(20)

(21)

(22) (23)

(24)

(25) (26) (27)

(28)

Amit M. Deokar, Shawn J. Smith, Amanda J. Goodwin et al. women with polycystic ovary syndrome: a case-control study. J Clin Endocrinol Metab 2008;93(2):470-6. Gapstur SM, Gann PH, Kopp P, Colangelo L, Longcope C, Liu K. Serum androgen concentrations in young men: a longitudinal analysis of associations with age, obesity, and race. The CARDIA male hormone study. Cancer Epidemiol Biomarkers Prev 2002;11(10 Pt 1):1041-7. Zou CC, Liang L, Hong F. Relationship between insulin resistance and serum levels of adiponectin and resistin with childhood obesity. Indian Pediatrics 2007;44(4):275-9. Hendler I, Blackwell SC, Mehta SH, Whitty JE, Russell E, Sorokin Y, et al. The levels of leptin, adiponectin, and resistin in normal weight, overweight, and obese pregnant women with and without preeclampsia. Am J Obstet Gynecol 2005;193(3 Pt 2):979-83. Shin JY, Kim SY, Jeung MJ, Eun SH, Woo CW, Yoon SY, et al. Serum adiponectin, C-reactive protein and TNF-alpha levels in obese Korean children. J Pediatr Endocrinol Metab 2008;21(1):23-9. Stanley T, Misra M. Polycystic ovary syndrome in obese adolescents. Curr Opin Endocrinol Diabetes Obes 2008;15(1):30-6. Wabitsch M, Hauner H, Heinze E, Bockmann A, Benz R, Mayer H, et al. Body fat distribution and steroid hormone concentrations in obese adolescent girls before and after weight reduction. J Clin Endocrinol Metab 1995;80(12):3469-75. de Ferranti SD, Gauvreau K, Ludwig DS, Neufeld EJ, Newburger JW, Rifai N. Prevalence of the metabolic syndrome in American adolescents: Findings from the Third National Health and Nutrition Examination Survey. Circulation 2004;110(16):2494-7. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: Findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med 2003;157(8):821-7. Harwood K, Vuguin P, DiMartino-Nardi J. Current approaches to the diagnosis and treatment of polycystic ovarian syndrome in youth. Horm Res 2007;68(5):209-17. McClanahan KK, Omar HA. Navigating adolescence with a chronic health condition: a perspective on the psychological effects of HAIR-AN syndrome on adolescent girls. ScientificWorldJournal 2006;6:1350-8. Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84(4):1470-4. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002;137(1):25-33. Bailey CJ. Metformin--an update. Gen Pharmacol 1993;24(6):1299-309. Ibanez L, De Zegher F. Flutamide-metformin plus an oral contraceptive (OC) for young women with polycystic ovary syndrome: switch from third- to fourth-generation OC reduces body adiposity. Hum Reprod 2004;19(8):1725-7. Goldenberg N, Glueck C. Medical therapy in women with polycystic ovarian syndrome before and during pregnancy and lactation. Minerva Ginecol 2008;60(1):63-75.

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(29) Majuri A, Santaniemi M, Rautio K, Kunnari A, Vartiainen J, Ruokonen A, et al. Rosiglitazone treatment increases plasma levels of adiponectin and decreases levels of resistin in overweight women with PCOS: a randomized placebo-controlled study. Eur J Endocrinol 2007;156(2):263-9. (30) Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 2007;370(9593):1129-36. (31) Miller RJ, Xanthakos SA, Hillard PJ, Inge TH. Bariatric surgery and adolescent gynecology. Curr Opin Obstet Gynecol 2007;19(5):427-33. (32) Stener-Victorin E, Jedel E, Manneras L. Acupuncture in polycystic ovary syndrome: current experimental and clinical evidence. J Neuroendocrinol 2008;20(3):290-8. (33) Pittler MH, Ernst E. Complementary therapies for reducing body weight: a systematic review. Int Journal Obes 2005;29(9):1030-8. (34) Hamre R, et al. CDC’s state-based nutrition and physical activity program to prevent obesity and other chronic diseases. July 2006 January 17, 2008 [cited 2008 06/24/08]; Available from: http://www.cdc.gov/nccdphp/dnpa/obesity/state_programs/pdf/NPAO_ Performance_Report_2005.pdf

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXIX

Bariatric Surgery and Adolescent Obesity Tara B. Mancl and Alan A. Saber∗ Minimally Invasive Surgery, Bariatric Surgery and Surgery Program, Michigan State University College of Human Medicine, MSU/Kalamazoo Center for Medical Studies, Kalamazoo, MI, USA

Abstract Obesity is the most prevalent metabolic disorder in the United States with adolescents and children being the fastest growing segment of the population affected by this disorder. The initial management of obesity entails modification of diet and exercise as well as a trial of medications. Unfortunately, this usually has unsatisfactory results; as a result, bariatric surgery has been used in the adult population and seems to offer improved long term results. Because the results have been quite favorable in the adult population, specialists are also looking at bariatric surgery for the adolescent population. This appears to be a safe approach in conjunction with diet and exercise and it offers improved long term results. This article discusses the use of bariatric surgery in obese adolescents.

Keywords: Adolescence, obesity, surgery, treatment.

∗

Corrrespondence: Alan A Saber, MD, FACS, Associate Professor of Surgery, Michigan State University College of Human Medicine, Chief, Minimally Invasive Surgery and Bariatric Surgery, Surgery Program, MSU/Kalamazoo Center for Medical Studies, 1000 Oakland Drive, Kalamazoo MI 49008-1284 United States. Tel: 269-337-6230; Fax: 269-337-6441; E-mail: [email protected]

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Introduction Obesity is the most prevalent metabolic disorder in the United States, with children and adolescents being the fastest growing affected segment of the population (1). The prevalence of obesity has steadily trended upward over the past three decades; approximately two-thirds of adults in the United States are overweight and one-third are obese (2). This trend is paralleled in the child and adolescent population with an estimated 25% of children being overweight or obese, a percentage which has doubled over the last 30 years (3). Up to 77% of obese children grow up to be obese adults (1). There are also differences noted in incidence of obesity among different racial and ethnic groups; the percentage of childhood obesity tends to be higher in the Hispanic and African American communities (4,5). The epidemic of childhood obesity is not limited to the United States; for example, childhood obesity is also increasing in China, among other countries (6). Definition, risk factors, consequences, and non-surgical management of obesity in adolescents are reviewed elsewhere in this journal issue. This discussion focuses on bariatric surgery. Bariatric surgery has proven to be effective in adults with morbid obesity in both the improvement of long term weight management as well as improvement or resolution of medical comorbid conditions (7). Given these results, bariatric surgery is becoming increasingly popular in the obese adolescent population. The number of bariatric procedures in adolescents increased five-fold between 1997 and 2003 (8). In 2003, approximately 1,000 adolescents underwent bariatric surgery; this, however, represents a small percentage of the total number of bariatric procedures that are performed (9). The long term follow-up of adolescent patients undergoing bariatric surgery is limited, and thus, this is an area in which additional research is necessary (10,11).

Bariatric Surgery The literature regarding bariatric surgery in adolescents is sparse. (see table 1). Most studies have a sample size of 50 patients or less and there are limited retrospective studies prior to 2000 (9). In 1991, the NIH developed criteria for weight loss surgery in adults; however, the upper and lower limits of age remain an area of controversy and currently guidelines do not exist for the age group of under age eighteen. In adults, a patient with a BMI >40 without medical comorbidities, or BMI > 35 with comorbidities, who has failed multiple nonsurgical efforts, meets the guidelines for operative intervention (9). A recent task force has been created by the American Pediatric Surgery Association to look at this issue in children and to address whether these patients, given already increased rates of rebellion and noncompliance, will have similar outcomes to adults (8). Early studies show that bariatric surgery in adolescents appears to have acceptable results and appears to be the only successful long lasting method for reliable weight loss in severely obese adolescents (12).

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Table 1. Literature Review of bariatric surgery in adolescents RYGBP = Roux en Y Gastric Bypass, AGB = Adjustable Gastric Band Author

#

Procedure

Age

Sex

Pre-op Weight NA

Post-op Weight NA

Followup (mo) 36

Soper, et al. [16] 1975

25

18

NA

Anderson, et al. [17] 1980

41

22 RYGBP 3 HGP 33 RYGBP 8 HGP

17

Rand, et al. [18] 1994

34

Greenstein, et al. [19] 1995 Strauss, et al. [20] 2001 Dolan, et al. [21] 2003 Sugerman, et al. [22] 2003

14

30 RYGBP 4 VGP 14 VGP

Complications

NA

238% IBW

187% IBW

60

17

NA

NA

66% EWL

72

3 deaths 6 wound infection 1 abscess 3 hernias 2 stomal stenosis NA

17

NA

NA

NA

61

NA 5 iron deficiency 3 folate deficiency 1 slipped band 1 leaking port

NA

10

10 RYGBP

<17

NA

148 kg

94.4 kg

12

17

17 AGB

17

NA

44.7 BMI

30.2 BMI

25

33

1 HGP 2 VGP 30 RYGBP

16

19F 14M

52

NA

NA

Stanford, et al. [23] 2003 Angrisani, et al. [24] 2005 Schilling, et al. [8] 2008

4

4 RYGBP

18

NA

55.1

87% EWL

4-22

58

58 AGB

17

NA

46.1 BMI

29.7 BMI

84

3 band erosion 2 psychological

431

386 RYGBP 36 GP 7 Other

16

307F 124M

NA

NA

NA

9 Pulmonary 12 Hemorrhage 3 OR take back

Till, et al. [25] 2008

1

1 SG

16

F

43.1 BMI

29 BMI

12

None

HGP = Horizontal Gastroplasty, VGP = Vertical Banded Gastroplasty. GP = Gastroplasty, IBW = Ideal Body Weight, EWL = Excess Weight Loss. SG = Sleeve Gastrectomy, mo = months, M = Male, F= Female. SBO = Small Bowel Obstruction.

1 PE 5 wound infection 3 stomal stenosis 4 marginal ulcers 1 SBO 6 hernias NA

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A unique feature to consider in adolescents is the attainment of linear growth and physiologic maturity. For adolescents who have reached a majority of their linear growth, there is little reason to suspect that bariatric surgery will adversely affect growth. Girls achieve this usually by age 13, and boys usually achieve this by age 15 years. Girls usually have reached physiologic maturity approximately two years after menarche. Measures to detect physiologic maturity include bone age with nomograms to help determine the appropriate age for bariatric surgery (13). The rationale for bariatric surgery in adolescents is to prevent or alter the adverse health consequences. The current indications for bariatric surgery as endorsed by the American Pediatric Surgical Association, include: failure of at least six months of organized, medically supervised weight loss attempts, and attained physiologic maturity; severe obesity (BMI >40) with comorbidities or BMI >50; commitment to psychologic and medical evaluation; avoidance of pregnancy for 1 year postoperatively; capability of adhering to nutrition guidelines; and demonstration of adequate decisional capacity and supportive family environment (9). Contraindications to bariatric surgery include substance abuse, psychiatric diagnosis that would make adherence to postoperative diet and medications difficult, medical causes of obesity, unwillingness to comprehend surgical procedures as well as medical consequences, and refusal to participate in lifelong medical surveillance (9). Offering bariatric surgery based on severe obesity with resultant comorbidities, however, may lead to higher complication rates and less weight loss. The American Society of Bariatric Surgery does not support a strict BMI cutoff of 40 for obese adolescents and promotes bariatric surgery earlier without the need for pre-existing comorbidities and currently supports the same criteria used for morbidly obese adults (11). The two most common procedures performed in the adolescent population are adjustable gastric banding and gastric bypass. The placement of the adjustable gastric band is performed by creating a small gastric pouch by placing a silastic constricting belt around the upper part of the stomach, with an internal balloon connected to a reservoir placed subcutaneously to allow for adjustments (see figure 1)(14). The Roux-en-Y gastric bypass is performed by creating a small proximal gastric pouch of about 20 cc, which emptied into a portion of the jejunum in a Roux En Y fashion (see figure 2)(14). Gastric bypass surgery has multiple weight loss mechanisms. There is a restrictive element from the creation of a small gastric pouch to decrease food intake; there is also a malabsorptive element from the decreased absorption of free fatty acids, vitamins, and minerals. This is particularly relevant in females who wish to get pregnant later in life, as malabsorption is detrimental to fetal growth. Postoperative bariatric patients are at increased risk for malnutrition and require lifelong surveillance for nutritional deficiencies. Current guidelines recommend two chewable vitamins with supplemental calcium and iron for menstruating females.

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Figure 1. Adjustable gastric band.

Outcomes The mortality rate after placing the gastric band is 0.1%. Gastric perforation is a complication occurring about 0.2%-3.5% in the adult population and the rates are based on a learning curve. Stomach slippage is a common complication as well as stomach obstruction, occurring in about 10%. Erosion and gastric necrosis are also possible complications, but occur in less than 1% (14). The complications after gastric bypass occur in about 10% of cases. Anastomotic leak is the most concerning complication; imaging in this situation is difficult and early operative exploration is often the best way to manage this clinical scenario (14). Limited data exists about the outcomes of bariatric surgery in adolescents. Limited experience suggests that thus far, bariatric surgery is safe and effective. Tsai recently reported complications among adolescent and adult populations as similar in bariatric surgery patients (15). The most complications included death, wound infection and dehiscence, incisional hernias, abscess, and stomal stenosis. Schilling et al reviewed the KID (Kids Inpatient Database) and found that the most commonly performed procedure among adolescents is the gastric bypass procedure. The adjustable band is second most commonly performed procedure in children; it, however, is currently not approved by the FDA for adolescents under the age of 18 years and insurance carriers do not usually cover this procedure (8).

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However there are current debates comparing gastric bypass versus adjustable banding (8). Favorable arguments for the Lap Band include potential reversibility, potential avoidance of nutritional defects, and low incidence of morbidity and mortality (8). The concern for placing a laparoscopic adjustable band is the lack of long-term outcomes, the concerns for the longevity of the device, and concerns for high failure and reoperative rate (8). According to Schilling’s study, the average age of adolescent patients undergoing bariatric procedures was 16 years of age, with no one under age 12 years (8). The majority of patients were female. Most patients report an improved quality of life and a significant psychosocial impact. No studies have indicated an adverse impact on physical or sexual maturation.

Conclusions The trends in bariatric surgery in the adolescent population appear to have favorable outcomes, although large randomized, prospective trials are nonexistent. The unique features of the adolescent population suggest that bariatric surgery in this population should be performed at centers that specialize in bariatric surgery. As more patients undergo this procedure, more long term data will be available, but at present, bariatric surgery seems to offer the best long term results for weight loss.

References (1) (2) (3)

(4) (5)

(6) (7) (8)

(9)

De Silva NK, Helmrath MA, Klish WJ. Obesity in the adolescent female. J Pediatr Adolesc Gynecol 2007;20(3):207-13. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA 2002; 288(14):1723-7. Wang Y. Cross-national comparison of childhood obesity: the epidemic and the relationship between obesity and socioeconomic status. Int J Epidemiol 2001;30(5):1129-36. Ogden CL, Carroll MD, Curtin LR, McDowell MA, et al. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 2006;295(13):1549-55. Dwyer JT, Stone EJ, Yang M, et al. Prevalence of marked overweight and obesity in a multiethnic pediatric population: findings from the Child and Adolescent Trial for Cardiovascular Health (CATCH) study. J Am Diet Assoc 2000; 100(10):1149-56. Luo J, Hu FB. Time trends of obesity in pre-school children in China from 1989 to 1997. Int J Obes Relat Metab Disord 2002; 26(4):553-8. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA. 2004; 292(14):1724-37. Schilling PL, Davis MM, Albanese CT, et al. National trends in adolescent bariatric surgical procedures and implications for surgical centers of excellence. J Am Coll Surg 2008;206(1):1-12. Xanthakos SA, Daniels SR, Inge TH. Bariatric surgery in adolescents: an update. Adolesc Med Clin 2006;17(3):589-612.

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(10) Helmrath MA, Brandt ML, Inge TH. Adolescent obesity and bariatric surgery. Surg Clin North Am 2006;86(2):441-54. (11) Kane TD, Garcia VF, Inge TH. Bariatric Surgery in Adolescents. In: Schauer PR, Brethauer S, Schirmer BD, eds. Minimally invasive bariatric surgery. New York: Springer, 2007:419-27. (12) Inge TH, Krebs NF, Garcia VF, et al. Bariatric surgery for severely overweight adolescents: concerns and recommendations. Pediatrics. 2004;114(1):217-23. (13) Inge TH, Zeller M, Garcia VF, Daniels SR. Surgical approach to adolescent obesity. Adolesc Med Clin 2004;15(3):429-53. (14) Pories WJ. Bariatric Surgery. In: Fischer JE, Bland KI, Callery MP, et al, eds. Mastery of surgery. Philadelphia, PA: Lippincott Williams Wilkins, 2006. (15) Tsai WS, Inge TH, Burd RS.Bariatric surgery in adolescents: recent national trends in use and in-hospital outcome.Arch Pediatr Adolesc Med. 2007;161(3):217-21. (16) Soper RT, Mason EE, Printen KJ, Zellweger H. Gastric bypass for morbid obesity in children and adolescents. J Pediatr Surg 1975; 10(1):51-8. (17) Anderson AE, Soper RT, Scott DH.Gastric bypass for morbid obesity in children and adolescents.J Pediatr Surg 1980;15(6):876-81. (18) Rand CS, Macgregor AM. Adolescents having obesity surgery: a 6-year follow-up. South Med J 1994;87(12):1208-13. (19) Greenstein RJ, Rabner JG.Is Adolescent gastric-restrictive antiobesity surgery warranted? Obes Surg 1995;5(2):138-44. (20) Strauss RS, Bradley LJ, Brolin RE.Gastric bypass surgery in adolescents with morbid obesity. J Pediatr 2001;138(4):499-504. (21) Dolan K, Creighton L, Hopkins G, Fielding G.Laparoscopic gastric banding in morbidly obese adolescents. Obes Surg 2003;13(1):101-4. (22) Sugerman HJ, Sugerman EL, DeMaria EJ, et al. Bariatric surgery for severely obese adolescents. J Gastrointest Surg 2003;7(1):102-8. (23) Stanford A, Glascock JM, Eid GM, et al. Laparoscopic Roux-en-Y gastric bypass in morbidly obese adolescents. J Pediatr Surg 2003; 38(3):430-3. (24) Angrisani L, Favretti F, Furbetta F, et al. Obese teenagers treated by Lap-Band System: The Italian experience. Surgery 2005; 138(5):877-81. (25) Till HK, Muensterer O, Keller A, et al. Laparoscopic sleeve gastrectomy achieves substantial weight loss in an adolescent girl with morbid obesity. Eur J Pediatr Surg 2008;18(1):47-9.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXX

Endocrinologic Issues in Obesity Manmohan Kamboj∗ Pediatrics and Human Development, Michigan State University College of Human Medicine, Division of Pediatric Endocrinology, Pediatrics Program,Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, MI, USA

Abstract There has been a profound increase in the prevalence of obesity over the last 20 to 30 years causing the coining of the term “obesity epidemic” in children, adolescents and adults. It is believed to be due to a complex interaction of social and environmental factors in the overall lifestyle pattern. The increased rate of obesity is seen to be associated with increasing incidence of type 2 diabetes mellitus in adolescents, along with perturbations of the other endocrine axes, as well as, higher risk of long term complications. It is therefore of the utmost importance that concerns about overweight and obesity be addressed from early childhood and adolescence to avoid resultant significant morbidity and/or mortality.

Keywords: BMI, Body Mass Index, obesity, diabetes mellitus, endocrinology.

∗

Correspondence: Manmohan Kamboj, MD, Associate Professor, Pediatrics and Human Development, Michigan State University College of Human Medicine, Division of Pediatric Endocrinology, Pediatrics Program, Michigan State University, Kalamazoo Center for Medical Studies, Kalamazoo, MI 49008-1284 United States. Tel: 269-337-6450; Fax: 269-337-6474; E-mail: [email protected]

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Introduction Obesity has become a significant health problem worldwide over the last few years. The prevalence of obesity has reached epidemic proportions both in the pediatric as well as adult populations. Obesity in children and adolescents correlates directly to obesity in adulthood. This high prevalence of obesity is leading not only to an increased incidence of a multitude of medical problems, but also increasing the financial burden on the health systems all over the world.

Definition Obesity and overweight have been defined in a variety of ways by different institutions. For the purposes of the following discussion, the definitions considered in this article are a Body Mass Index (BMI) of 25-29.9 kg/m2 is considered overweight and BMI > 30 kg/m2 is labeled obese in adults.1 For children and adolescents definitions of the Institute of Medicine label BMI between 85th to 95th percentile for age and sex as overweight and BMI values >95th percentile are classified as obesity. The Centers for Disease Control and Prevention (CDC) labels both these categories as ‘risk for overweight’ and ‘overweight’ respectively (13).

Incidence and Prevalence Approximately 17.1 % of children and adolescents in the US were overweight while 33.6% were overweight or at risk for overweight in 2003-2004 (4). The prevalence of overweight/obesity increased from 5% to 17.1% in adolescents (12-19 years of age) between 1976-1980 and 2003-2004 (4). Prevalence of obesity is more common among Native Americans, non-Hispanic blacks, and Mexican Americans than in whites.4 The risk of obesity increases if one of the parents is obese.

Medical Conditions Associated with Obesity Obesity in childhood and adolescence is associated with morbidity involving multiple body systems. These include abnormalities of the endocrine, cardiovascular, gastrointestinal, dermatological, pulmonary, neurologic, and psychosocial systems. Many of these effects are primarily caused by metabolic dysfunction while others may be due more to the physical impairment caused by obesity. Although the medical dysfunction is multi-systemic with function of each system closely linked to the other, only the endocrine dysfunction is discussed in this chapter.

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Endocrine Dysfunction in Obesity Obesity can cause alteration in functioning of most endocrine axes leading to disturbances of growth and pubertal development, thyroid, adrenal, gonadal as well as parathyroid function. Metabolic function in context of insulin and glucose metabolism is a major concomitant of obesity. These disturbances predispose the individual to develop hyperinsulinemia, insulin resistance, impaired glucose tolerance, and ultimately type 2 diabetes mellitus. The coexistence of insulin resistance and dyslipidemias with obesity is referred to as the dysmetabolic syndrome (or Syndrome X). Obesity together with hyperandrogenemia may predispose to the development of the polycystic ovarian syndrome (PCOS). Hyperandrogenism and PCOS are discussed elsewhere in this edition.

Disturbances of the Insulin and Glucose Metabolism The spectrum of disturbances seen in the glucose and insulin metabolism include insulin resistance and hyperinsulinemia with normal glucose tolerance, insulin resistance and hyperinsulinemia with impaired glucose tolerance (IGT), and type 2 diabetes mellitus (type 2 DM). The relationship of obesity, BMI, IGT and type 2 DM has been well illustrated in a study where 25% of children and 21% of adolescents with BMI >95th percentile for sex and age were found to have IGT, while 4% of these adolescents had type 2 DM (5). Insulin resistance (IR) is defined as a subnormal glucose response to a given concentration of insulin. IR is found to be an easy and good predictor of IGT. Various methods have been devised to study IR including the fasting glucose to insulin ratio (FGIR), the homeostasis model assessment of insulin resistance (HOMA), and the quantitative insulin sensitivity check index (QUICKI) (6-8). In routine clinical practice fasting glucose and insulin levels are commonly done. However, it is also important to evaluate the post-prandial response with a two hour oral glucose tolerance test (OGTT) with fasting and two hour postprandial glucose as well as insulin level determinations. The diagnostic criteria for normoglycemia, IGT and frank diabetes mellitus are outlined in table 1 by the American Diabetes Association (ADA) (9). An important clinical marker of IR in children and adolescents is acanthosis nigricans (AN) which is a velvety dark pigmentation seen at the nape of the neck and flexural folds of the body. Nevertheless, there is an ongoing controversy about whether or not AN should be considered a reliable clinical marker for hyperinsulinemia in overweight children (10,11). With the increasing prevalence of type 2 DM in children and adolescents, it becomes increasingly important to be able to differentiate between the two major types of diabetes mellitus, namely type I DM and type 2 DM; this is an issue that may not be as straight forward as previously believed. The important differentiating features are listed in table 2. The increasing prevalence of type 2 DM children and adolescents is noted to closely parallel the obesity curve. Varying incidences of new onset, non-autoimmune diabetes mellitus (with a majority of patients having type 2 DM) in children and adolescents have been reported to be between 8-45 % (12).

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Management Early diagnosis of IGT and type 2 DM is very important for early initiation of interventional strategies resulting in early and improved glycemic control. This would lower the incidence of chronic complications. Recommendations have been made by the American Diabetes Association for testing guidelines in high risk individuals as outlined in table 3 (13). The spectrum of obesity – IR – IGT – type 2 DM is a clear example of prevention being the cornerstone of intervention strategies. The key to prevention of type 2 DM remains addressing the root concern of obesity by early introduction of life-style modifications. These include reduced caloric intake coupled with initiation of structured exercise/activity programs. Exercise regimens improve insulin sensitivity, metabolic profile, and cardiovascular functioning independent of weight loss (14). Daily caloric intake is lowered by making quantitative and qualitative modifications in daily food intake by decreasing portion sizes and making healthy food choices. Moderate intensity exercise as 30 minutes/day for seven days a week has been recommended for everyone while 60 minutes have been advised for weight loss (14,15). Pharmacologic agents are being extensively investigated for prevention and treatment of obesity. Medications available include orlistat and sibutramine but lack long term study information regarding benefits and side effects in children and adolescents. Metformin has increasingly been used in this group of patients to improve insulin sensitivity. A small, randomized study in adolescents reported metabolic improvement and a small decrease in BMI, while lifestyle modifications were noted to be more effective than metformin in preventing progression from IGT to type 2 DM (16,17). Newer options being investigated include topiramate, Peptide YY, rimonabant, and magnesium. Unfortunately not enough long term studies have been done to justify their use in children and adolescents (18). Once obese patients develop type 2 DM, pharmacologic therapeutic agents need to be added to the lifestyle modifications which should be continued. Metformin remains the most common oral hypoglycemic agent used in adolescents. Other oral hypoglycemic agents available and used extensively in adults are not used in children and adolescents very commonly. Insulin may also have to be added to the treatment regimen if adequate glycemic control is not achieved with oral medications. A list of the commonly available hypoglycemic agents is available in table 4 (19).

Effect of Obesity on Other Endocrine Axes Effect of Obesity on Growth Axis Although obesity is associated with accelerated growth, obese patients are noted to have low growth hormone (GH) levels (20). Both the spontaneous growth hormone levels as well as stimulated GH levels are low (21-23). Interestingly the IGF-1 levels are normal or even elevated inspite of low growth hormone levels. The mechanism for this complex interaction is not clear. Multiple mechanisms have been proposed for low growth hormone levels including decreased synthesis and increased clearance of growth hormone; others include an increase in the somatostatinergic tone causing inhibition of GH secretion, or a compromised

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response to growth hormone releasing hormone (GHRH)(24,25). Possible explanations for normal IGF-1 levels offered include increased hepatic IGF-1 production by high insulin levels, adipose tissue being a source of IGF-1 production, and the effect of some obesity related factors possibly leptin (26).

Effect of Obesity on Thyroid Axis Hypothyroidism may cause obesity and an important point to remember in this regard is that exogenous obesity is associated with accelerated growth while obesity due to hypothyroidism is associated with poor growth.21. There is controversy regarding the effect of obesity on thyroid function. Overall, it is believed that the hypothalamic-pituitary-thyroid axis is generally intact and normal in obesity. A retrospective study noted a 20% incidence of TSH elevation in obese patients versus an incidence of 0.3% in non-obese patients, in the face of normal free T4 levels and negative antithyroid antibodies (27). At present there is no consensus on role of thyroid hormone replacement in this subgroup of patients with apparent subclinical or compensated hypothyroidism (21).

Effect of Obesity on Puberty and Reproductive Function Obesity can interfere with the hypothalamic-pituitary-gonadal (HPG) axis function causing disruption of pubertal development. Obesity in boys may be associated with delay of pubertal development and maturation (28-30). On the other hand, obesity in girls may be associated with early puberty and early menarche (29,30). Interference with the HPG axis may cause low FSH, high LH, and high LH:FSH ratios with elevated estrogen levels, presenting clinically with disturbances and irregularity of menstrual function (20,31). There may be early adrenarche, PCOS, hirsutism, and infertility (32,33). Free testosterone levels are generally normal, although total testosterone and SHBG levels are low.

Effect of Obesity on Adrenal Axis In the face of the ongoing obesity epidemic, complex interactions of obesity including the hypothalamic-pituitary-adrenal axis (HPA axis) and the central complex mechanisms of appetite control, are areas of active research work. Over activity of the components of the HPA axis result in hypercortisolemia and cause Cushing’s syndrome. These patients exhibit central obesity and increased cortisol levels with disruption of the normal diurnal rhythm. The majority of adolescents with simple, exogenous obesity are believed not to have significant perturbations of the HPA axis. There is increased cortisol secretion rate with normal diurnal rhythm, normal dexamethasone suppression and normal 24 hour free urine cortisol (for body surface area) levels. Recent studies however highlight the role of adrenocortical dysregulation as a major player in causing insulin resistance and obesity (34). The enzyme 11βHSD1 present in the liver and adipose tissue regenerates active cortisol from

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inactive cortisone. Multiple studies have explored the role of dysregulation of 11βHSD1 in adipose tissue in the pathogenesis of insulin resistance and obesity (35, 36).

Effect of Obesity on Parathyroid/Vitamin D Axis Abnormalities of the mineral metabolism in calcium, parathyroid, and vitamin D homeostasis are seen in obesity (37). These changes have suggestions of secondary hyperparathyroidism with elevated parathyroid hormone levels, normal calcium levels, and increased urine calcium levels (31). A recent study looked at vitamin D and parathyroid hormone level status in obese children before and after weight loss. PTH levels were positively, and 25 hydroxy vitamin D levels were negatively related to the weight status; these changes were believed to be consequences rather than the cause of overweight (38).

Conclusions The incidence of obesity is rapidly increasing at epidemic proportions in the adolescent age group. Obesity is associated with multi-systemic pathophysiologic alterations leading to a wide array of complications. The endocrine system is one of the systems which is extensively involved with changes in its multiple axes as mentioned in this discussion. It is therefore essential that clinicians recognize and manage obesity early emphasizing life-style modifications to prevent long-term morbidity and mortality.

Acknowledgements The author thanks Dr Martin Draznin for his critical review of the manuscript and Ms Amy Esman for her expert administrative assistance.

References (1)

(2)

(3)

Department of Health and Human Services, Centers for Disease Control and Prevention. Atlanta, GA: Centers for Disease Control and Prevention; updated 2007 November 17; cited 2008 February 13. Available from: http://www.cdc.gov/nccdphp/dnpa/obesity/ Institute of Medicine of the National Academies. Washington DC: National Academy of Sciences; 2008; updated 2006 April 7; cited 2008 February 13. Available from: www.iom.edu/cms/22593.aspx Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents, 1999-2000. JAMA 2002;288:1728-32.

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Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 2006;295:1549-55. Sinha R, Fisch G, Teague B, Tamborlane WV, Banyas B, Allen K et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 2002;346:802-10. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9. Keskin M, Kurtoglu S, Kendirci M, Atabek ME, Yazici C. Homeostasis model assessment is more reliable than the fasting glucose/insulin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescents. Pediatrics 2005;115:500-3. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85:2402-10. American Diabetes Association. Screening for type 2 diabetes. Diabetes Care 2004; 27(Suppl 1):S11-4. Nguyen TT, Keil MF, Russell DL, Pathomvanich A, Uwaifo GI, Sebring NG. Relation of acanthosis nigricans to hyperinsulinemia and insulin sensitivity in overweight African American and white children. J Pediatr 2001;138:474-80. Stuart CA, Gilkison CR, Smith MM, Bosma AM, Keenan BS, Nagamani M. Acanthosis Nigricans as a risk factor for non-insulin dependent diabetes mellitus. Clin Pediatr (Phila) 1998;37:73-9. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000;23:381-9. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2004;27 Suppl 1: S15-35. Jakicic JM. Exercise in the treatment of obesity. Endocrinol Metab Clin North Am 2003;32:967-80. Cummings S, Parham ES, Strain GW; American Dietetic Association. Postion of the American Dietetic Association: weight management. J Am Diet Assoc 2002;102:114555. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. Freemark M, Bursey D. The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics 2001;107:E55. Thearle M, Aronne LJ. Obesity and pharmacologic therapy. Endocrinol Metab Clin North Am 2003;32:1005-24. Kamboj MK. Diabetes on the college campus. Pediatr Clin North Am 2005;52:279305.

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(20) Gungor N, Arsalanian S. Nutritional disorders. Integration of energy metabolism and its disorders in childhood. In: Sperling M, ed. Pediatric endocrinology, 2nd ed. Philadelphia, PA: Saunders Elsevier, 2002:689-724. (21) Boston BA. Obesity. In: Kappy MS, Allen DB, Geffner ME, eds. Principles and practice of pediatric endocrinology. Springfield, IL: Charles C Thomas, 2005:577-606. (22) Vanderschueren-Lodeweyckx M. The effect of simple obesity on growth and growth hormone. Horm Res 1993;40:23-30. (23) Bowers CY. A new dimension on the induced release of growth hormone in obese subjects. J Clin Endocrinol Metab 1993;76:817-8. (24) Maccario M, Grottoli S, Procopio M, Oleandri SE, Rossetto R, Gauna C, et al. The GH/IGF-I axis in obesity: Influence of neuro-endocrine and metabolic factors. Int J Obes Relat Metab Disord 2000;24(Suppl 2):S96-9. (25) Veldhuis JD, Iranmanesh A, Ho KK, Waters MJ, Johnson ML, Lizarralde G. Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man. J Clin Endocrinol Metab 1991;72:51-9. (26) Woelfle JF, Harz K, Roth C. Modulation of circulating IGF-I and IGFBP-3 levels by hormonal regulators of energy homeostasis in obese children. Exp Clin Endocrinol Diabetes 2007;115:17-23 . (27) Stichel H, L’Allemand D, Grüters A. Thyroid function and obesity in children and adolescents. Horm Res 2000;54:14-9. (28) Wang Y. Is obesity associated with early sexual maturation? A comparison of the association in American boys versus girls. Pediatrics 2002;110:903-10. (29) Laron Z. Is obesity associated with early sexual maturation? Pediatrics 2004;113:171-2. (30) Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME. Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics 2001;108:347-53. (31) Kokkoris P, Pi-Sunyer FX. Obesity and endocrine disease. Endocrinol Metab Clin North Am 2003;32:895-914. (32) L’Allemand D, Schmidt S, Rousson V, Brabant G, Gasser T, Grüters A. Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche. Eur J Endocrinol 2002;146:537-43. (33) Ibañez L, Potau N, Virdis R, Zampolli M, Terzi C, Gussinyé M et al. Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1993;76:1599-603. (34) Roberge C, Carpentier AC, Langlois MF, Baillargeon JP, Ardilouze JL, Maheux P. Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity. Am J Physiol Endocrinol Metab 2007;293:1465-78. (35) Stewart PM, Boutlon A, Kumar S, Clark PM, Shackleton CH. Cortisol metabolism in human obesity: impaired cortisone – cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab 1999;84:1022-7. (36) Weigand S, Richardt A, Remer T, Wudy SA, Tomlinson JW, Hughes B, et al. Reduced 11beta-hydroxysteroid dehydrogenase type 1 activity in obese boys. Eur J Endocrinol 2007;157:319-24.

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(37) Glass AR. Endocrine aspects of obesity. Med Clin North Am 1989;73:139-60. (38) Reinehr T, de Sousa G, Alexy U, Kersting M, Andler W. Vitamin D status and parathyroid hormone in obese children before and after weight loss. Eur J Endocrinol 2007;157:225-32.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXXI

Psychological Issues in Obesity Helen D. Pratt∗ Division of Behavioral and Developmental Pediatrics, Pediatrics Program Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, MI, USA

Abstract Obesity has been deemed a public health epidemic, which carries with it high financial and psychological stakes, social consequences, and ethics of public, mental, and medical health care research pushing for all adolescents, who are “obese” to lose weight. This article reviews the psychological aspects of overweight in adolescents. No single factor has been shown to cause obesity; most researchers agree that the causes of obesity are multifaceted and complicated. Adolescents who are overweight may experience the deleterious effects of obesity on psychological functioning. Concepts of beauty, perceptions of body image and satisfaction all contribute to the psychological attitudes and beliefs about personal value, worthiness, self image, body satisfaction, and dieting. Not all adolescents who are at-risk-for-overweight or are overweight are unhealthy. Clinicians should consider that just as they warn the obese about the risks of obesity, they must expend as much energy evaluating the risks of successful weight loss. They must also remember that there are other standards of beauty and body size among ethnic groups and other cultures. The weight for height by body type tables that are used to calculate BMI should be changed to reflect the body types and fat distributions of Latinoand African-Americans.

Keywords: Adolescents, obesity, psychology, impact of overweight, human development.

∗

Correspondence: Helen D Pratt, PhD, Pediatrics Program, MSU/KCMS, 1000 Oakland Dr, Kalamazoo, MI 49008 United States. Tel: 269 337-6450; Fax 269-337-6474; E-mail: [email protected]

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Introduction Obesity has been deemed a public health epidemic which carries with it high stakes financial, psychological, and social consequences (1, 2). Approximately 14% of adolescents (ages 12 to 19 years) are overweight (3, 4). The CDC reported the cost of care for overweight adolescents has not been calculated (3) however, costs for adult obesity were estimated to be approximately 100 billion dollars for which sixty percent of those costs are for inpatient, outpatient, and laboratory services (2,4,5). Although the literature supports that the costs for obesity add a burden to the costs of health care, the profits from the obesity industry are rarely discussed. Treatment of obesity in the United States has produced a 46 billion dollar weight loss industry; promoters of weight loss products and bariatric surgery focus on the negative emotions of being “fat” and concentrate on poor physical health, social isolation and rejection, and feelings of sadness and depression (4). Table 1. Factors that influence risk and prevalence of obesity Individual

Familial

• Age • Certain medical

• Genetic susceptibility • Social Economic Status (SES)

conditions Sedentary life styles Physical inactivity Diet high in calories Diet low in nutrient dense foods • Smoking cessation • Food is seen as entertainment versus sustenance • Increase use of TV, video games, computers

(higher SES for non Hispanic Caucasians, lower SES for African-Americans and youth of Hispanic-ancestry • Race/ethnicity • Family history o Eating patters o Food choices o Attitudes about obesity or “fat” o Eat out more often o Have fewer family meals

• • • •

Contextual Schools:

• Physical education no longer mandatory in schools

• Vending machines high calorie dense food choices are money makers for schools and do not support goals of providing healthy nutrition in meals and snacks • Cafeteria foods often high calorie foods that offer little choice to select balanced foods Communities • Limited access to safe places to engage in physical activity • Access to fresh fruit and vegetables limited • Cost higher for healthier foods in urban areas

Ethiology No single factor has been shown to cause obesity (see table 1)(2,4,5). Several controversial views have been put forth to account for increases in weight in children or adolescents.5, 6 Current views hold that when children and adolescents gain weight, many

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complementary changes have simultaneously increased the individual’s energy intake and decreased his/her energy expenditure (see table 2)(5,7). Table 2. Changes in behavior that influence risk and prevalence of obesity • Exercise is no longer a part of one’s daily functioning and must be artificially introduced.

• Youth have difficulty incorporating physical exercise

• •

• • •

into normal, everyday mandatory activity (walking to school; playing in safe areas in their communities in the out of doors) Youth have little control over what they have access to eat at home and school Youth, especially minority youth are subjected to targeted marking of high fat low nutrition low fiber foods Most fast food and restaurant have changed to larger portion sizes Food is viewed as and used for entertainment or as therapy View that one can eat drink as much as one wishes to have a good time and have fun.

Obesity in the Adolescent Population The term “obese” is no longer applied to children or adolescents; instead, the terms “at risk of overweight” and “overweight” are designated by the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, as appropriate descriptions that are not based on health outcomes or risk but take into account the age and gender of an individual (7). These terms are defined in other articles of this issue on obesity.

Social Consequences of Obesity Obesity puts adolescents at risk for physical health problems and negatively impacts their social and psychological health. Adolescents also have an increased likelihood they will experiencing feelings of cultural isolation as a result maladaptive family, peer, and healthcare provider experiences (see table 3)(2,4,8-13). Adolescent females who see themselves as overweight are prone to dieting, exercising to lose weight, using pills, and vomiting to lose weight. Caucasian female adolescents are almost two times more likely than AfricanAmerican females to a) perceive themselves as overweight and b) engage in unhealthy weight management practices (14). The stigma of obesity is so strong that adolescents may face biases in all aspects of their lives (11,14,15).

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Psychological Aspects of Obesity Adolescents who are overweight may experience the deleterious effects of obesity on psychological functioning (see table 3)(12,13). Psychological aspects of overweight during adolescence include how an adolescent a) thinks about him or herself, b) views the feedback about him or her, and c) how that feedback is interpreted; these issues all combine with the adolescents’ temperament and cultural environment. An adolescent’s views of self-image, values about body-shape, body-mass, beauty, and weight begin to develop during childhood and are shaped within the context of his or her cultural environment (10,11,14). Prior to age 11 years, children are primarily influenced by their families and intimate environment. As their world expands, adolescents’ perceptions of how others view them become increasingly more important. These factors (family and cultural environments) have great influence over how a person develops his or her views of self perception and attitudes about body size, weight, body fat, and beauty; however, peers, teachers, physicians, and the media can exert significant influence such that they can provide negative factors that can often exacerbate an adolescent’s psychological (i.e., cognitive, affective, and social) distress.16 Peers, teachers, and the media can also provide protective factors to promote or sustain an adolescent’s psychological well being (10,14,16). Table 3. Associated psychological outcomes for overweight and obesity in adolescents •

•

perpetrating or being a victim of bullying behavior o boys reported more overt victimization o girls • reported more problems with − intimate peer relations with other girls • refusal to spend time with subject • silent treatment • refusal to sit near subject at lunch or in class • verbal teasing • have less supportive and more antagonistic friendships • are less likely to date than their peers • have fewer opportunities to develop intimate romantic relationships • may experience more self-consciousness and anxiety depression and low selfesteem. Obese boys and girls reported being more dissatisfied with their dating status compared with average-weight peers.

Adolescents are usually resilient and can overcome harsh environmental events with family and community support. Despite this resilience, adolescents are still vulnerable from a developmental point of view; they lack a history of interpersonal relationship successes to offset negative views about obesity expressed by family members and peers. Based on

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feedback from their cultural environment, adolescents develop their views of who they are, discover why they are unique, and determine their strengths and weaknesses. Based on these discoveries they develop healthy or unhealthy self-esteem and negative or positive perceptions of their value and self-worth. If that environment provides negative feedback, the adolescent may develop poor self esteem, unhealthy self image, and develop body dissatisfaction. The combination of these negative cognitive emotions and multiple sources of insults (i.e., family, peers, health care providers, and the media) regarding obesity result in negative affective states that can erode the adolescent’s ability to be resilient. Adolescents need protection and nurturance from parents, other family members, and peers to withstand these negative situations. Without this support they can develop profound sadness, distress, or even depression as a result of harassment, bullying, and peer rejection (10,11,15).

Perceptions of Beauty Standards of beauty in Western cultures and in the United States in particular, exclude many adolescents who do not exemplify the “thin ideal.” Thinness is associated with attractiveness, fitness, worthiness, access (i.e., friendship, dating, and special favors) and health; in contrast, obesity/overweight is associated with unattractiveness, poor health, being food-obsessed, being physically unfit, being lazy, not having will power or self-control, and potentially costing society an unfair share amount of money for health care (2,10,12,13,17). These negative views of overweight may result in social biases which may expose the adolescent to stigmatizing experiences and promote unhealthy weight loss practices (7). Such biases can help overweight youth become victims of peer rejection, harassment or bullying. Although not the common outcome of obesity bias, some overweight youth become perpetrators of harassment or bullying (11). Yet, in some cultures where the “Western Ideal” has not been adopted, there is greater acceptance of higher body weights. Fatness or plumpness may be considered a sign of beauty or is accepted without bias (17). Adolescents, especially ethnic girls (African-, Asian, Hispanic-, Native-Americans, and Alaskan/Pacific Island Native-Americans) are keenly aware of differences between Western standards of beauty and their own physical characteristics; perhaps this is why they tend to describe beauty in terms of personality traits instead of physical attributes (i.e., intelligence, social skills, altruism, grooming, and having a good sense of humor) (18). Caucasian adolescents are more likely to attempt to diet to lose weight, engage in compensatory behaviors (i.e., purging, excessive exercise, calorie restriction). African American girls perceive beauty as flexible, fluid, and as exceeding physical characteristics. They judged beauty on the basis of how one moved rather than how much one weighed -- even in light of society’s beliefs and media portrayals of the “western ideal as the standard of beauty (18). Youth who express biases and prejudices about overweight adolescents can learn to have more positive views of their overweight peers if they receive education directed at the causes of obesity (15). Based on exposure to peer views of overweight as positive and not a moral defect, others can view youth who have larger body types, as healthy and not representing examples of medical or psychological pathology.

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Body Dissatisfaction Individuals who do not like the physical characteristics of their bodies can be said to experience some aspect of body dissatisfaction (i.e., height, weight, size, and shape of face, nose, or mouth, eye shape or color, type of hair, others). Body dissatisfaction as used when talking about the issue of obesity is generally focused on a more narrow aspect of body mass, and how fat is deposited over the body. Body dissatisfaction may be pervasive among adolescents and not just a problem of obesity. Robinson, et al (19) compared body dissatisfaction between 6th and 7th grade American females (African-, Asian- and CaucasianAmerican) and found that even adolescents who are very lean/short/tall, will report body dissatisfaction. They further found that BMI was the strongest independent predictor of increased body dissatisfaction for all subjects (19). The researcher concluded that AfricanAmerican girls had the highest body satisfaction. Girls with high body satisfaction were more likely to report parental and peer attitudes that encouraged healthy eating and exercising to be fit versus dieting (19). Baskin, Aluwalia and Resnicow (18) offered that the positive body images of African American girls need not be viewed as problematic or abnormal. In fact, it could be argued that majority culture has a dysfunctional view of body image and obesity. Body dissatisfaction may result in an adolescent developing a low self-esteem, feeling bad about his or herself, questioning his or her personal value and uniqueness, and feeling bad about his or her physical characteristics. Such negative cognitions can lead to adolescents developing a poor self image.

Self Image In a recent survey approximately 35% described themselves as being overweight (Males25% and females-38%)(6). Research on body image with African- and Caucasian-American concluded that media influences on self-perceptions of body images are different for each group. When exposed to mainstream media, Caucasian subjects reported poorer body image, while African American subjects did not. When exposed to African American media Caucasian subjects reported no impact. African American subjects who were also exposed to African American oriented television had healthier body image while viewing mainstream television. Ethnic identity also predicted healthier body image among black women (20).

Relationship between Overweight and Depression The psychological correlates between overweight and depression with the resulting consequences are not well understood (21-23). An adolescent’s relative weight is associated with depressive symptoms for girls (but not boys) and was stronger among adolescents in lower grades (23). A recent study concluded that the behavioral, cognitive, physiological, and social mechanisms that form the pathway between obesity and depression is bidirectional (23,24).

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Depression and obesity in teens have been linked to family income, educational level, and socioeconomic status. Researchers found about a third of the cases of depression and obesity among those teens could be attributed to being from families with low incomes or having parents with low levels of education. Lower parental education was associated with 40 percent of depression and 39 percent of obesity among these teens.21-23 Obesity rates are about 50% higher in families below the poverty line when compared to youth whose family income is at or above it. These rates are higher for ethnic females (i.e., African Americans, Hispanics and Native Americans) than among Caucasian-Americans (21-23).

Impact of Weight Re-Gain after Treatment Although adolescents may successfully lose weight, they may suffer other negative side effects post intervention or post surgery which includes unhealthy eating and physical activity obsessions (24). A search of web based publications shows that questions regarding the development of addictive behaviors (i.e., gambling, sex addition, and other impulse control disorders) resulting from bariatric surgery. A review of the literature using First Search, Medline, and Psych Info did not yield any empirical studies linking bariatric surgery, weight loss, and the development of impulse control disorder symptoms. A meta-analytic review of 64 obesity prevention programs yields that 21% produced significant prevention effects that were typically pre- to post treatment intervention effects (25). Larger effects emerged for programs that targeted children and adolescents (vs. preadolescents) and females. The researchers concluded that effective prevention had the following components: a) the programs were relatively brief; b) they solely targeted weight control versus other health behaviors (e.g., smoking); c) they had been evaluated during pilot trials; and d) the participants self-selected into the intervention. Other factors, including mandated improvements in diet and exercise, sedentary behavior reduction, delivery by trained interventionists, and parental involvement, were not associated with significantly larger effects (25).

Controversies That Impact the Psychology of Obesity Fleck and Petersmarch (4) questioned the right of public health and medical organizations, physicians, and other health care clinicians to push or encourage adolescents to “lose weight.” The authors contended that dieting and weight loss carry with them their own health risks. They also reminded clinicians that patients should set their own goals, even if that means they chose not to lose weight. Many health care professionals inform their patients about the risks of being overweight, but do not discuss the risks of their recommended interventions. For example, clinicians do not discuss complications that often result from weight loss (i.e., gall stones), nor do they present the risks of extreme weight loss interventions (i.e., starvation, severe food restriction, and bariatric surgery). Some health and psychological risks may exceed the risks of being overweight for some patients. Therefore, they ask physicians to adhere to their ethical duty to “do no harm” (4).

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Other researchers (23,25) also support Flech Petersmarch’s findings (4) that most patients do not maintain their weight loss post intervention, and may regain the lost weight; the increase in weight gain can result in the adolescent experiencing increased negative physical and psychological outcomes. Weight regain can result in the adolescent feeling like he or she is a failure, especially after accepting the negative aspects about their obesity from the agency, health care professional or surgeons who have helped them to be successful in weight loss. The adolescent who loses weight works hard not to be a representative of the negative stereotypes and works hard to please the clinical and weight loss professionals who help them with their efforts. Not only may the adolescent experience feelings of personal failure because of the weight re-gain, but now they have the added burden of no longer meeting the expectations of those professionals. Another issue concerning the ethics of interventions to address overweight involves issues with minority populations. Fat distribution for African- and Latino-Americans is different than for their non-Hispanic Caucasian. The tables of ideal weights derived from non-Hispanic populations are not applicable to African- and Latino Americans.14 Research suggests that Latino American appeared to tolerate higher body weights without an adverse impact on their mortality experience and therefore, support the notion that new tables should be derived from prospective data specific to African- and Latino-American populations (18). Assessment and treatment interventions should also take into account the cultural and ethnic issues related to providing health care that meets the general and specific needs of these populations (4).

Conclusions Adolescent overweight has significantly increased over the past 20 years while most researchers agree that the causes of obesity are multifaceted and complicated; however the exact causes of the significant increases in the prevalence of overweight have not been clearly identified. Some researcher offers that many changes in the adolescent’s physical activity, types and quality of foods they ingest, and use of food as entertainment contribute to the overall problem of overweight and obesity. In a society where thinness is one of the signs of beauty and health, being overweight can contribute to psychological distress in adolescents who are not thin. It is important that clinicians remember that there are other standards of beauty and body size among ethnic groups and other cultures. Psychopathology (i.e., depression, sadness, feelings of isolation, and sense of rejection) that has been associated with overweight has not been shown to result from just being overweight. Researchers have found that these affective states can also be present in adolescents without the presence of overweight or obesity. Problems with self-image, body satisfaction, self-esteem also occur during adolescence with those who are both too thin (males), too short, or who do not look like the “thin ideal” of the perfect body. The relationship between depression and overweight has been show to be bidirectional. Clinicians must consider that even though overweight is associated with a number of adverse consequences, treatment to lose weight and actual weight loss also have adverse consequences. Further, not all overweight individuals are unhealthy or exhibiting medical or

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mental pathology. The acceptance of Western ideals of thinness as the only form of beauty can create conflicting cultural demands for people who do not fit this body type.

References (1) (2)

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(4)

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Dietz WH, Robinson TN. Overweight children and adolescents. N Engl J Med 2005;352:2100-9. Gortmaker SL, Must A, Perrin JM, Sobol AM, Dietz WH. Social and economic consequences of overweight in adolescence and young adulthood. N Engl J Med 1993;329(14):1008-12. CDC. Prevalence of overweight among children and adolescents: United States, 1999-2002. National Health and Nutrition Examination Survey. Hyattsville, MD: US Department of Health and Human Services, CDC, National Center for Health Statistics, 2007. Available http://www.cdc.gov/nchs/products/pubs/pubd/hestats/overwght99.htm Fleck LM, Petersmarch KA. Ethical Considerations related to obesity intervention. In: Davies HD, Fitzgerld HE, ed. Obesity in childhood and adolescence: Understanding development and prevention, vol 2. Westport, CT: Praeger, 2008:271-303. Center for Disease Control and Prevention, University of North Carolina at Chapel Hill School of Public Health. North Carolina Institute for Public Health. Public Health Grand Rounds: The epidemic of obesity: Personal choice or environmental consequence? 2002. http://www.publichealthgrandrounds.unc.edu/obesity/webcast.htm. Fitzgibbon ML, Stolley MR. Environmental changes: May be needed for prevention of overweight in minority children. Pediatric Ann 2004;33(1):45-49. Center for Disease Control and Prevention. CDC Growth Charts: United States - Body mass index-for-age percentiles: Boys and girls ages 2 to 20 years.3rd, 5th, 10th, 25th, 50th, 75th, 85th, 90th, 95th, 97th percentiles. National Health and Nutrition Examination Survey. Hyattsville, MD: US Department of Health and Human Services, CDC, National Center for Health Statistics, 2000. Available at http://www.cdc.gov/nchs/data/nhanes/growthcharts/set1/chart03.pdf http://www.cdc.gov/nchs/data/nhanes/growthcharts/set1/chart04.pdf Gordon-Larsen P, Adair LS, Popkin BM. The relationship of ethnicity, socioeconomic factors, and overweight in US adolescents. Obes Res 2003;11(1):121-9. Pearce MJ, Boergers J, Prinstein MJ. Adolescent obesity, overt and relational peer victimization, and romantic relationships. Obes Res 2002;10(5):386-93. Erermis S, Cetin N, Tamar M, Bukusoglu N, Akdeniz F, Goksen D. Is obesity a risk factor for psychopathology among adolescents? Pediatr Int 2004;46(3):296-301. Puhl RM, Latner JD. Stigma, obesity, and the health of the nation's children. Psychol Bull 2007;133(4):557-80. Griffiths LJ, Wolke D, Page AS, Horwood JP the ALSPAC Study Team. Obesity and bullying: different effects for boys and girls. Arch Dis Child 2006;91:121-5. Eisenberg ME, Neumark -Sztainer D, Story M. Associations of weight-based teasing and emotional well-being among adolescents. Arch Pediatr Adolesc Med 2003;157(8):733–8.

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(14) Neumark-Sztainer D, Story M, Faibisch L. Perceived stigmatization among overweight African-American and Caucasian adolescent girls. J Adolesc Health 1998;23(5):26470. (15) Puhl RM, Schwartz MB. Brownell KD. Impact of perceived consensus on stereotypes about obese people: A new approach for reducing bias. Health Psychol 2005;24(5):51725. (16) Fulkerson JA, Strauss J, Neumark-Sztainer D, Story M, Boutelle K. Correlates of psychological well-being among overweight adolescents: The role of family. J Consul Clin Psychol 2007;75(1):181-6. (17) Kelly AM, Wall M, Eisenberg ME, Story M, Neumark-Sztainer D. Adolescent girls with high body satisfaction: who are they and what can they teach us? J Adolesc Health 2005;37(5):391-6. (18) Baskin ML, Ahluwalia HK, Resnicow K. Obesity intervention among AfricanAmerican children and adolescents. Pediatr Clin North Am 2001;48(4):1027-39. (19) Robinson TN, Killen D, Litt IF, Hammer LD, Wilson DM, Haydel F, Hayward D, Taylor CB. Ethnicity and body dissatisfaction: Are Hispanic and Asian girls at increased risk for eating disorders. J Adolesc Health 1996;19(16):384-93. (20) Schooler D,Ward ML, Merriwether A, Caruthers A. Who’s that girl: Television’s role in the body image development of young white and black women. Psychol Women Q 2004;28(1):38-47. (21) Kostanski M, Fisher A, Gullone E. Current conceptualization of body image dissatisfaction: have we got it wrong? J Child Psychol Psychiatry 2004; 45(7):1317-25. (22) Cunningham MR, Roberts AR, Barbee AP, Druen PB, Wu CH. Their ideas of beauty are, on the whole, the same as ours: Consistency and variability in the cross-cultural perception of female physical attractiveness. J Personality Soc Psychol 1995;68:26179. (23) Needham BL, Crosnoe R. Overweight status and depressive symptoms during adolescence. J Adolesc Health 2005;36(1):48–55. (24) Markowitz S, Friedman M A, Arent SM. Understanding the relation between obesity and depression: causal mechanisms and implications for treatment. Clin Psychol Sci Pract 2003;15(1):1-20. (25) Stice E, Shaw H, Marti CN. A meta-analytic review of obesity prevention programs for children and adolescents: The skinny on interventions that work. Psychol Bull 2006;132(5):667-91.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXXII

Overweight Children and Adolescents: Impact on Psychological and Social Development Kimberly K. McClanahan, Marlene B. Huff and Hatim A. Omar∗ Division of Adolescent Medicine, Department of Pediatrics, Kentucky Children’s Hospital, University of Kentucky, Lexington, KY, USA

Abstract The global epidemic of childhood and adolescent overweight has become a major public health concern. Not only are these youth more likely to become obese as adults, and thus more prone to obesity-related diseases than their non overweight peers, they are also likely to suffer emotional and social effects associated with overweight. Overweight in youth has been linked to depression, low self-esteem, eating disorders, negative body image, and stigma. It appears to be bi-directional in nature, with overweight sometimes predicting certain psychological effects and psychosocial issues sometimes predicting overweight. Effective assessment and treatment of psychological and mental health issues in overweight youth will help overweight youth deal more effectively with their social and psychological milieus. Additionally, interventions for mental health concerns may have the added health benefit of increasing weight loss, thus decreasing obesityrelated disease for which the overweight adolescent is prone.

∗

Correspondence: Hatim Omar, MD, FAAP, Professor of Pediatrics and Obstetrics/Gynecology, Chief, Adolescent Medicine and Young Parent programs, J422, Kentucky Clinic, University of Kentucky, Lexington, KY 40536 United States. Tel: 859-323-6426 ext. 311; Fax: 859-257-7706; E-mail: [email protected]

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Keywords: Overweight, obesity, adolescence, mental health, psychological development, human development.

Introduction Adolescence is defined most simply by the word ‘change’--physical, cognitive, emotional, and social. As physical and cognitive changes occur, so do changes in the domains of emotional/psychological development and social interaction/relationships. Psychological health and social adequacy are important components of mental health, but adolescence brings with it unique challenges, and interruption of development within any domain may occur. Disruptions in emotional and social development can be influenced by many things, including physical and/or medical problems (1). Obesity has become one of the most common diseases and disease-associated conditions in the United States (US) and other countries. In the year 2000, it was estimated that obesity would soon surpass tobacco smoking as the leading cause of preventable death in the United States (2) and it has also been suggested that today’s young people may, on average, live less healthy and ultimately shorter lives than their parents due to overweight and obesity; in fact, this epidemic may reverse the modern era’s steady increase in life expectancy (3,4). Further, it has been estimated that as this century progresses, more people will die from the complications of overnutrition than of starvation (5). Pinhas-Hamiel (6) noted that “life-stylerelated diseases are no longer the exclusive domain of adult medicine.” Furthermore, overweight has a bi-directional relationship with mental and psychological health in that psychosocial factors have been shown to predict overweight, but overweight also impacts psychosocial factors such as psychological development and social functioning (7,8). Overweight in children and adolescents is usually defined as a body mass index (BMI) equal to or greater than the 95th percentile, compared to pediatric population reference data when plotted on the appropriate age and gender chart; children and adolescents with a BMI between the 85th and 95th percentile are considered to be at risk for overweight, according to the Centers for Disease Control and Prevention (CDC); the CDC does not use the term obesity for children and adolescents. Most overweight preadolescent children and at least 70% of overweight adolescents will remain obese into adulthood (9), significantly increasing the chances of obesity-related disease as well as psychological complications associated with overweight (7,8). Between 1980 and 2002, overweight prevalence tripled in children and adolescents ages 6 to 19 years (10-12). Comparing results obtained from the 1999-2000 National Health and Nutrition Examination Survey (NHANES) to results from the NHANES survey in 20032004, 13.9% vs. 17.1%, respectively, of US children and adolescents were overweight. For female children and adolescents, the percentage overweight increased from 13.8% in 19992000 to 16.0% in 2003-2004; for male children and adolescents, the increase went from 14.0% to 18.2% during the same time period (11). More than 10% of school age children are overweight worldwide with the Americas reporting rates as high as 32% (9). According to the 2005 Youth Risk Behavior Survey, a national probability sample of 9th – 12th graders which

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assesses risk behaviors and risk factors (13), approximately 16% of students in the US were at risk for overweight, and 13% were already overweight. Childhood and adolescent overweight has some endogenous causes, but when those causes are ruled out, then behavioral and psychological factors, rather than biological ones, are primarily responsible for the upward trend in adolescent overweight.14 Behavioral factors such as lack of physical exercise, sedentary behavior, and poor dietary choices have been cited as common risk factors for weight gain, although psychological and mental health factors also factor into the equation (14,15).

Psychosocial Risks for Adolescents In the realm of psychological and social development, today’s youth often face challenges in mental health and wellness as they progress from childhood to adolescence to adulthood. Over the past 20 years, the proportion of pediatric patient visits in general pediatric practices with psychosocial problems has increased from 7% to 19% (16). According to the 1999 US Surgeon General’s report on children’s mental health, 13% of children and adolescents have anxiety disorders, 6.2% have mood disorders, 10.3% have disruptive disorders, and 2% have substance use disorders, for a total of 20.9% having one or more mental health or substance abuse disorders (1). Of those needing active mental health interventions, 11% were found to have significant functional impairment and 5% were found to have extreme functional impairment (1). Other research has found that 27% of children ages 9, 11, and 13 years of age have mental impairment, and 20% have a diagnosable mental health condition (17). Further, suicide is the third leading cause of death in the US for children ages 15-24 years and suicide attempts reach a peak during the midadolescent years (1,18,19) highlighting the psychological vulnerability adolescents experience. Many children and adolescents have both physical and mental disorders, and it has been found that the majority of children and adolescents with medical problems have higher levels of mental disorders (20), suggesting that having a chronic health condition, such as overweight, may increase the likelihood of mental health issues and concerns. In fact, one recent study found serious adverse consequences of overweight on health-related quality of life (HRQOL) in a clinical sample of severely overweight (BMI: 34.7) children and adolescents 5 to 15 years of age (21).

Psycho-Social Risks for Overweight Adolescents Depression Several studies have documented a clear correlation between depression and overweight in adolescents (22-24). Goodman et al (25) have shown in a nationally representative, longitudinal study of over 9,000 adolescents that depressed mood in non overweight individuals is associated with the development of overweight at one year and worsening overweight in baseline overweight participants, suggesting that depression may precede

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overweight. Other studies using community samples of overweight versus non overweight adolescents have found no differences in depressive symptoms between the two groups (26). Swallen et al (27) found a statistically significant relationship between BMI and general physical health in adolescents from age 12 to 20 years, but only young adolescents (12-14 years) evidenced a deleterious impact on emotional health as reported by depression and/or low self esteem. Several studies, including a recent one by Daniels (22), failed to confirm a relationship between overweight and symptoms of depression in adolescents. Thus, the relationship between depressive symptoms and overweight in children and adolescents is not completely clear, although depression appears to play a role in the mental health of a certain subpopulation of overweight adolescents.

Self-Esteem Studies on self-esteem in overweight children and adolescents also report inconsistent results. Some studies have shown moderately lower self-esteem in overweight children and adolescents than their non overweight peers (28, 29), while others have shown no difference between population-based groups of overweight children and their non overweight peers (30,31). Studies also show that overweight females are at greater risk for self-esteem problems because body image is so important to self-image (28), perhaps because girls are expected to be thin, beautiful, flawless, sexy, cookie-cutter images of the super models and actresses they attempt to emulate. In clinical populations, there is a clear relationship between overweight and self-esteem in children and adolescents, with more heavily overweight children having lower self-esteem (31). One hypothesis is that clinically referred children represent a subgroup of overweight children associated with especially low self-esteem (15).

Eating Disorders The age of onset for 85% of all eating disorders is between 11 and 20 years (32) and eating disorders have been found to be associated with overweight in adolescents (33). Overweight youth are stigmatized (34), predisposing them to unhealthy dieting practices and attempts to lose weight. Britz et al (35) reported that the rate of eating disorders was six times higher in an overweight patient group than a population-based control group. The disorders included bulimia nervosa, eating disorders not otherwise specified, and anorexia nervosa. Sixty percent of females and 35.5% of males reported binge eating episodes.

Body Image Overweight in adolescents has been associated with negative body image (7). Overweight children as young as age five can develop a negative body image (36). A consistently replicated finding is that overweight children and adolescents have a more negative body image than their peers (37). A 1994 study by Grilo et al (38) demonstrated that

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“the greater the frequency of being teased about weight and shape while growing up, the more negative one’s appearance is regarded, and the greater the degree of body dissatisfaction in adulthood” (p. 448). Studies have shown that overweight girls appear to have a more negative body image than overweight boys (29).

Stigmatization Stigmatization of overweight children and adolescents is significant and has long been a part of western culture (39). Studies have shown that children as young as three years of age begin to have negative attitudes toward overweight and obesity. When given different methods for assessing stigmatizing attitudes, these children ascribe negative characteristics to overweight targets, including mean, ugly, stupid, and sloppy, compared to non overweight targets (40). These trends tend to worsen as children get older (41). Such stereotypes are born out in real-life when studies show that US women who were overweight adolescents become adults with lower educational attainment, lower paying jobs, higher rates of poverty, and less likelihood of marriage in comparison to thinner women (42,43). Stigma associated with overweight thought to be greater for girls than for boys (27). Overweight impacts adolescents’ relationships due to increased vulnerability to weightrelated teasing and social isolation. Overweight adolescents may be socially marginalized among their peers and experience more weight-related stigmatization by peers and family members (7,44). Overweight youth have greater difficulty in gaining admission to college, although there is no indication that they are less apt to be able to complete the course work (39).

Evaluation of Mental Health Overweight adolescents should be thoroughly evaluated to identify any psychological conditions that may affect the course of medical treatment for weight loss or other medical co-morbidities (15). However, most pediatric health care providers are not trained to assess mental health issues and may have limited experience in daily practice in addressing mental health related problems. Other factors, including limited visit time and lack of established office strategies (24), may also contribute to the lack of detection of the psychological and psychosocial factors leading to overweight or originating from it. Additionally, pediatricians may directly or indirectly express “fatism,” which may contaminate the relationship with their young patients, and is particularly true with younger, overweight patients where parentbashing or blaming is common (15). Jonides et al (45) reporting results of a questionnaire to pediatricians asking about the routine evaluation of various psychological and emotional factors including self-esteem, eating disorders, concern about weight, family dynamics and history of abuse, showed that by far not every provider asks and elaborates on all of those important factors. Friedman (46) suggested that pediatricians are in an ideal position to detect psychological issues in young people, and they should be better trained to probe for and recognize signs of major mental

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illnesses. Weitzman and Leventhal (47) concluded that the pediatric practice setting is an optimal environment for behavioral health screening if the currently available tools are used effectively. However, training is lacking in these areas. Given that most providers specializing in adolescent overweight are not trained in mental and behavioral health evaluations, having a team of providers, including mental health providers familiar with evaluation of and treatment options for various mental and behavioral health conditions in adolescents, would add significant value to the team caring for this particular patient subset. Evaluation and treatment of underlying psychological and behavioral problems by a health care provider trained in adolescent mental health will aid in the reduction of obesity-related psychological co-morbidity in adolescents.

Suggestions for Mental Health Evaluation There is no consensus recommendation for the evaluation of mental health in overweight adolescents, and there are no studies comparing different methods for psychiatric assessment of affected children (15). An expert committee recommendation on overweight evaluation and treatment by Barlow and Dietz (48) suggested that asking the right questions in “objective, non accusatory language” would help establish a basis of trust between family and provider, which is key to long-term, successful management. Additionally, the use of well-validated instruments for evaluation is important. A thorough psychiatric, psychological and family history regarding the patient needs to be taken. As rapport is established, questions regarding the patient’s weight, concerns about weight, weight gain or loss, eating issues, and psychosocial issues associated with being overweight (e.g., friendships, teasing, depression, low self-esteem) need to be broached. It is also important to assess readiness for change. When dealing with an adolescent, the family context is important, and the entire family must have some readiness for change for any to occur. Paper and pencil assessment instruments can be useful in the initial assessment of psychological variables associated with overweight. As noted earlier, no specific guidelines have been established, but the following instruments are suggested as a potential assessment packet which assesses depressive symptoms, behaviors across a variety of domains, eating issues, and acute and characterological psychological concerns. A summary of the suggested instruments may be seen in table 1. In order to assess level of depression, the Children’s Depression Inventory (CDI), a 27item, symptom-oriented scale for children ages 6 -17 years (49) may be utilized. The CDI is a highly reliable and valid measure (50) and has been used effectively in several studies with overweight children (51,52). Since the CDI is a self-report measure, it can be supplemented by a parent-completed Child Behavior Checklist (53) in order to obtain corroborating or conflicting data from parents. Issues regarding eating can be measured through completion of a version of the Eating Attitude Test (54,55). This is a 6-point, forced choice, self-report inventory that measures dieting behaviors, food preoccupation, anorexia, bulimia, and concerns about being overweight. Versions for teenagers and younger children (chEAT), have demonstrated concurrent and predictive validity as well as reliability (55). Finally, for

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overall symptom assessment, younger children (9-12 years) can complete the Millon Preadolescent Clinical Inventory (M-PACI), and adolescents (13-19 years) can complete the Millon Adolescent Clinical Inventory (MACI). Both instruments are designed to quickly and accurately identify psychological problems and determine both emerging personality patterns and acute psychological symptoms. Table 1. Psychological assessment instruments for overweight adolescents Instrument

Children’s Depression Inventory (CDI) Child Behavior Checklist (CBCL) Children’s Eating Attitude Test (chEAT)

Age Group (yrs) 6-17

6-18

7-14

Millon Preadolescent Clinical Inventory (MPACI)

9-12

Millon Adolescent Clinical Inventory (MACI)

13-19

Measures

Method of report

Symptoms of depression

Selfreport

Child's activities, social relations, and school performance Diet behaviors, food preoccupation, anorexia, bulimia, concerns about overweight Emerging personality patterns and acute psychological symptoms Emerging personality patterns and acute psychological symptoms

Parent report

Selfreport

Selfreport

Selfreport

Addressing mental health by correct and timely assessment and intervention can be of significant importance in improving the outcome of obesity-related problems in adolescents. Also, the correct diagnosis and therapy of mental health problems, if associated with overweight, can improve weight management and decrease medical complications.

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Conclusions Overweight, obesity, and obesity-related diseases have become major problems in the developed and developing world in recent years. Adolescents are a high risk group for developing overweight, and most overweight teenagers will be unsuccessful in their attempts, should they make any, to lose weight; they move on to become an overweight or obese adult with the concomitant risk for medical disease. Along with obesity-related disease states, overweight adolescents are also likely to suffer from some psychosocial effects of overweight, such as depression, low self-esteem, eating disorders, negative body image, and stigmatization from peers, thus increasing the probability of obesity-related mental health comorbidities. The public health agenda with regard to overweight and obesity has shifted the focus toward primary prevention of overweight. Primary prevention is certainly the strategy for which to strive, but secondary and tertiary prevention are more reasonable strategies at this time since overweight and its potential complications are more prevalent than ever and need to be addressed aggressively and comprehensively. To improve obesity-related morbidity and mortality in this age group, providers involved in their care need to develop a better understanding and increased focus on mental health in addition to physical health. One strategy is a comprehensive team approach, including a mental health specialist who not only addresses those issues in the patient and family but also teaches the pediatric provider better strategies for initial screening.

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(44) Jonides L, Buschbacher V, Barlow SE. Management of child and adolescent obesity: psychological, emotional, and behavioral assessment. Pediatrics 2002;110(1 Pt 2):21521. (45) Friedman RA. Uncovering an epidemic - screening for mental illness in teens. N Engl J Med 2006;355(26):2717-9. (46) Weitzman CC, Leventhal JM. Screening for behavioral health problems in primary care. Curr Opin Pediatr 2006;18(6):641-8. (47) Barlow SE, Dietz WH. Obesity evaluation and treatment: Expert committee recommendations. The Maternal and Child Health Bureau, Health Resources and Services Administration and the Department of Health and Human Services. Pediatrics 1998;102(3):E29. (48) Kovacs M. The Children's Depression Inventory (CDI). Psychopharmacol Bull 1985;21:995-8. (49) Knight D, Hensley VR, Waters B. Validation of the Children's Depression Scale and the Children's Depression Inventory in a prepubertal sample. J Child Psychol Psychiatry 1988;29:853-63. (50) Sheslow D, Hassink S, et al. The relationship between self-esteem and depression in obese children. Ann NY Acad Sci 1993;699:289-91. (51) Wallace WJ, Sheslow D, Hassink S. Obesity in children: A risk for depression. Ann NY Acad Sci 1993;699:301-3. (52) Achenbach TM, Ruffle TM. The Child Behavior Checklist and related forms for assessing behavioral/emotional problems and competencies. Pediatr Rev 2000;21:26571. (53) Garner DM, Garfinkle PE. The eating attitudes test: An index of the symptoms of anorexia nervosa. Psychol Med 1979;9:273-9. (54) Maloney MJ, McGuire JB, Daniels SR. Reliability testing of a children's version of the Eating Attitude Test. J Am Acad Child Adolesc Psychiatry 1988;27:541-3.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXXIII

Pharmacotherapy for Obese Adolescents Donald E. Greydanus∗, Cynthia Feucht, and Dilip R. Patel Pediatrics and Human Development, Michigan State University College of Human Medicine and Ferris State University College of Pharmacy, Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, MI, USA

Abstract This discussion reviews various medications currently used and being studied for weight loss induction in adults and adolescents. The search for medication to induce weight loss was stimulated by the US FDA’s 1959 approval of phentermine, a sympathomimetic amine, for short-term weight loss despite limited research supporting its claims of causing weight loss. In addition to noradrenergic products like phentermine, other reviewed medications include herbal products (such as Korean herbal formula based on Taeumjowi-tang), sibutramine (mixed noradrenergic-serotonergic chemical), orlistat (lipase inhibitor), metformin (biguanide), rimonabant (CB1-selective cannabinoid receptor antagonist), and others. Only two non-amphetamine-related medications are FDA-approved for adolescents: sibutramine for those 16 years of age and older, and orlistat for those 12 years of age and older. Pharmacotherapy for morbidly obese adolescents should only be used as part of a comprehensive weight loss program that involves diet, exercise, and behavioral modification. The side effects of these products should always be considered as well as the potential for serious adverse events.

∗

Correspondence: Donald E. Greydanus, MD, Professor, Pediatrics and Human Development, Michigan State University College of Human Medicine, Pediatrics Program Director, Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, MI 49008-1284 United States. Tel: 269-337-6450; Fax: 269-3376474; E-mail: [email protected]

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Introduction Obesity has become a well-known concern among children, adolescents, and adults throughout the world (1-10). Pharmacotherapy has been shown to be effective in the treatment of obesity in some adults, however, their use in most youth is often limited at this time to those in research protocols (5,11-21). The actual safety, effectiveness, and long-term consequences of these medications for obese youth are unknown at this time (2). The use of anti-obesity medication should be in association with a comprehensive weight reduction program that emphasizes behavioral modification, appropriate diet, and an exercise program (15,22-28). Pharmacologic management is typically used in obese youth when changes in lifestyle have not worked, medical complications have developed (i.e., hypertension, obstructive sleep apnea, others) and before bariatric surgery is offered (3,7,15,21,28,29). Weight loss is usually modest, from 2 to 10 kilograms, and usually noted in the first six months of use. Only two non-amphetamine-related antiobesity agents, sibutramine and orlistat, are US Food and Drug Administration (FDA) approved for use under the age of 18: sibutramine for those ≥ 16 years of age and orlistat for those ≥ 12 years of age (5,6). This article reviews various medications used in the management of adolescent obesity.

Over-The Counter (OTC) Herbal Agents Various forms of phenylpropanolamine, caffeine, and ephedrine are adrenergic medications which have been used as “weight-loss drugs.” They have limited, if any real benefit and with their cardiovascular risk profile, they should be avoided (2,5,30). Phenylpropanolamine (PPA) is from the phenethylamine family of drugs and has been used as a decongestant and appetite suppressant. On November 6, 2000, the US Food and Drug Administration (FDA) issued a public health advisory against PPA because of increased risk of hemorrhagic cerebrovascular accidents in 18 to 49 year old female users and requested manufacturers to stop marketing products containing PPA (31). The FDA noted that the risk was low but the event itself was extremely serious. Yoo and associates from Korea have advocated the short-term effectiveness and safety of a traditional Korean herbal formula (based on Taeumjowi-tang) in children (average age of 11 years)(32). Korean herbal formula is the most popular herbal weight loss product in Korea advocated for use in obese youth and adults (32). It consists of a mixture of various seeds, stalks, berries, nuts, and roots as listed in table 1. One of its ingredients is Ephedra sinica (species of ephedra or Ma Huang) that contains alkaloids of ephedrine and pseudoephedrine. Other herbal or supplement products contained ephedrine (from Ma Huang) and caffeine (from green tea, kola nut or guarana). Ephedrine has been related to reports of sudden death along with some abuse potential. In 1997 the FDA warned against the use of herbal “PhenFen” (ephedra and Hypericum perforatum)(33). More than 800 adverse events related to ephedra had already been reported (33). In 2001, it was demonstrated that ephedra accounted for 64% of all adverse reactions communicated to poison control centers in relation to herbal products (33). On April 12, 2004, the FDA banned over-the-counter dietary supplements with

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ephedrine alkaloids (ephedra)(33). With the ban on ephedra products, many supplements changed their products to be ephedra-free, utilizing a variety of herbal supplements including caffeine and Citrus aurantium (bitter orange). Other herbal products used without proof of weight loss efficacy and safety include chromium picolinate, chitosan, l-carnitine, Yerba mate, Hoodia, Garcinia cambogia and others (2,5,7,34). Table 1. Components of the Korean formula based on taeumjowi-tang 1. Seeds a) Coix lacryma-jobi (Job’s tears; also found in the US) b) Raphanus sativus (Japanese radish also found in the US) c) Pinus koraiensis (Korean pine found in parts of Asia) 1. Stalks (Ephedra sinica) (see text) 2. Berries (Schisandra chinensis; woody vine with clusters of red berries found in China, Russia, and Korea) 3. Nuts (Castanea crenata) (Japanese or Chinese chestnut) 4. Roots a) Liriope platyphylla (flowering plant in Asia, especially China) b) Acorus calamus (plant called “Sweet Flag” found in North America, Europe, and Asia; many medicinal uses claimed) c) Pelargonium grandiflorum (Andrews) (large flowery, shrubby plant that is native to South Africa and is a popular house plant)

Noradrenergic Products Amphetamines can lower weight, but lead to severe cardiac and mental health problems, including addiction. They are neither recommended nor approved for use as weight loss products. A number of noradrenergic medications have been tried, and phentermine emerged after receiving FDA approval in 1959 as an appetite suppressing drug. There are limited studies noting the efficacy of this sympathomimetic amine and it has limited use in adolescents because of its Schedule IV DEA classification, its potential for addiction, its structure and side effects being similar to amphetamine, and the lack of evidence for safety and long-tem efficacy. Its link with “Fen-Phen” as noted elsewhere, has led to its reduced use as a weight loss agent, certainly in adolescents. Several phentermine products are available including Adipex P® and Ionamin®. It is recommended for those individuals with a BMI > 30 kg/m2 or > 27 kg/m2 in the presence of other risk factors such as hypertension, diabetes mellitus, etc. These should only be used for short-term (up to 12 weeks) in those > 16 years of age and in combination with other weight loss measures (such as diet and exercise plans). Other schedule III noradrenergic drugs approved by the FDA for short-term use to induce weight loss include benzphetamine (Didrex®), and phendimetrazine (Bontril®).2 Diethylpropion (Tenuate®) is a schedule IV noradrenergic agent also FDA-approved for short-term weight loss in adults (17). Benzphetamine is FDA-approved in adolescents ≥ 12

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years of age and diethylpropion in adolescents >16 years of age; both are for short-term use only. These sympathomimetic amines have many side effects including cardiovascular (hypertension, valvular disease), gastrointestinal (diarrhea, constipation, nausea), and sleep dysfunction (insomnia, restlessness).7 Noradrenergic products should be avoided in individuals with cardiovascular disease, moderate to severe hypertension, pulmonary hypertension, hyperthyroidism, and patients with a history of drug abuse.

Serotoninergic Agents Serotoninergic medications stimulate the release of serotonin from nerve endings, inhibit serotonin reuptake or do both. The result is enhanced serotonin effect at the postsynaptic nerve endings of the brain. Fenfluramine was noted to decrease hunger (and satiety), decrease carbohydrate craving, and decrease binging. Historically, it was marked as Pondimin® (mixed dextro- and levo-fenfluramine) as well as Redux® (dexfenfluramine). The popular “Phen-Fen” diet (phentermine and fenfluramine) had great success at weight loss with sustained benefit seen up to 3 ½ years with continued use, but discontinuation of the medication was frequently associated with a relapse in weight (2,22). Therefore, these drugs were used for longer periods of time in the 1990s, and at least in some studies, were associated with cardiac valvulopathy. The FDA withdrew fenfluramine from the market on September 15, 1997 due to findings indicating 30% of patients taking these products had abnormal echocardiograms despite no symptoms (35). Significantly, fenfluramine and dexfenfluramine have both been associated with pulmonary hypertension, albeit rare. The FDA did not request that phentermine be removed from the market.

Mixed Noradrehergic-Serotonergic Product The FDA (Food and Drug Administration) has approved the use of sibutramine (Meridia) for the treatment of obesity in adults (17,20,36,37). Sibutramine (DEA Schedule IV) inhibits the reuptake of norepinephrine, serotonin, and to some degree dopamine, thus, it increases the concentrations of these neurotransmitters in the brain resulting in such effects as reduced appetite. This centrally-acting drug appears to be well-tolerated in most adult patients with a 5% to 10% loss of initial body weight in adults that is sustained in 8 of 10 research studies (5). However, a dose-related increase in heart rate and blood pressure has been described which can be of clinical significance in some patients (20,37-40). No valvulopathy has been demonstrated to date. It is given as a dose of 10 mg (5 mg to 15 mg) per day and can be given for up to 2 years. Research has noted limited weight loss in adolescents (average of 3 kilograms more than controls and reduction of body mass index up to 5.6 kg/m2) but not beyond six months of use (4,14,20,26-28,38-41). The FDA has approved sibutramine for weight loss management in patients 16 years of age and older (6). Research has also noted that sibutramine can be of benefit for children with hypothalamic obesity and exogenous obesity (42). Side effects and contraindications for use of sibutramine are listed in table 2.

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There is the potential for drug interactions since sibutramine is metabolized by cytochrome P450 3A4 substrate. Caution should be utilized when combining with agents that can increase the effect of sibutramine (i.e. clarithromycin, nefazadone, verapamil) or decrease the effect of sibutramine (i.e. phenytoin, carbamazepine, rifampin). Table 2. Side effects and contraindications for Sibutramine (Meridia) A. Side effects 1. Dry mouth 2. Headache 3. Dizziness 4. Insomnia 5. Anxiety 6. Depression 7. Suicidality 8. Nausea 9. Constipation 10. Asthenia 11. Increase in pulse (usually minor) 12. Increase in blood pressure (usually minor) B. Contraindications 1. Avoid in selected heart disease patients 2. Avoid in patients with poorly controlled hypertension 3. Avoid in patients with severe renal or hepatic dysfunction 4. Avoid in patients with a history of substance abuse 5. Avoid in patients with narrow-angle glaucoma 6. Do not use during or within 2 weeks of monoamine oxidase inhibitors (MAOIs) 7. Do not use with serotonergic agents (SSRIs, triptans, tramadol) 8. Do not use in patients with anorexia or bulimia

Lipase Inhibitor Orlistat (Xenical) is an inhibitor of lipase (gastric and pancreatic) and has been effective in decreasing weight in clinical trials of adults and adolescents by inducing a dose-dependent fat malabsorption (5,14,17,20,25,43,44). It blocks about 30% of dietary fat with the 120 mg prescription and 25% with the 60 mg dose (44,45) and can be used in adolescents as well as adults (15,25). Orlistat can also induce improved lipid levels, glucose levels, insulin sensitivity, and blood pressure (5,15,45). In a 16 week trial of adults receiving orlistat in combination with a low fat, reduced calorie diet , the orlistat group lost 1.15 kg more than those in the placebo group (46). In addition, a reduction in BMI up to 4.09 kg/m2 has also been observed (20). In contrast, some research notes no benefit for this drug in obese

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adolescents (47). The FDA has approved its sale as an over-the-counter drug (Alli®) at half the prescription dose for weight loss with the appropriate dieting measures (44). Orlistat can lead to gastric upset, dyspepsia, abdominal pain, flatulence, steatorrhea, malabsorption, fecal urgency, fecal incontinence, and reduced absorption of fat-soluble vitamins (A, D, E, and K)(7,44,48). Orlistat (Xenical®) is given in a dosage of 120 mg three times a day with meals. A multivitamin containing fat soluble vitamins should be given daily and at least 2 hours before or after taking orlistat. It was approved by the FDA in 2003 for use in weight management of obese youth ≥12 years of age (6). However, its side effects have led to its limited acceptance by youth. The effects of orlistat on growing youth is unknown (6). It is contraindicated in individuals with chronic malabsorption syndrome and cholestasis. It can increase warfarin’s anticoagulant effect due to decreased absorption of vitamin K and may interfere with the absorption of various drugs (46). Another drug, Acarbose (Precose®), inhibits pancreatic alpha-amylase and intestinal alpha-glucoside hydrolase. This results in a delay of ingested carbohydrates leading to reduced postprandial blood glucose concentrations. It can be helpful for obese children and adolescents with evidence of hyperinsulinemia and is used to treat type 2 diabetes mellitus. Side effects include gastrointestinal upset, flatulence, diarrhea, and symptomatic lowering of blood glucose, when used in combination with a sulfonylurea or insulin. It is initiated at an oral dose of 25 mg three times a day with meals and gradually increased as tolerated. Adult maintenance doses are 50 to 100 mg three times daily.

Metformin Metformin (Glucophage, Glumetza, Fortamet, Riomet) is a biguanide that is a glucosesensitizing drug and has been FDA-approved since 1994 to treat type 2 diabetes mellitus. It increases the sensitivity of various tissues (muscle, liver, fat) to the uptake and action of insulin. It reduces hepatic gluconeogenesis as well as improving cell membrane movement of glucose in tissues (adipose tissue and skeletal muscle)(5). It has also been used to treat polycystic ovary syndrome (PCOS) which is associated with hyperinsulinemia and hyperandrogenism. Metformin acts to improve insulin sensitivity by reducing insulin levels and decreasing symptoms associated with PCOS (49-51). In PCOS it may lead to better regularity of menstrual cycles, lower levels of androgens, and improved ovulation (49). Ovulation may also improve because of reduction in weight. Metformin has been used to treat adults with morbid obesity as well as the metabolic syndrome and can also promote weight loss in non-obese individuals (5,7,52). In a trial of 9 to 18 year old males in Australia, 1 gram of metformin twice a day resulted in an average weight loss over six months of 4.35 kg (53). The dose in adolescents (10-16 yrs) is 500 mg twice a day and if treating diabetes mellitus type 2, increase the dose by 500 mg a week to a maximum of 2 grams per day. Side effects (seec table 3), often dose-related, tend to improve with time. One in every 30,000 patients on metformin develops lactic acidosis with a 50% mortality rate and occurrence is more common in patients with renal insufficiency. Though metformin offers some promise for use in overweight adolescents, more research is needed (20,29,52).

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Table 3. Side effects and contraindications for metformin (Glucophage, others) A. Side effects 1. Nausea 2. Emesis 3. Indigestion 4. Abdominal discomfort 5. Flatulence 6. Diarrhea 7. Lactic acidosis 8. Malabsorption of vitamine B12 B. Contraindications 1. Avoid in patients with renal insufficiency (Scr >1.5 mg/dl in men and 1.4 mg/dl in women) 2. Avoid in patients with congestive heart failure requiring pharmacologic management 3. Avoid in patients with liver disease or hypoxia 4. Avoid in patients who are critically ill

Rimonabant Rimonabant is a new drug that is a CB1-selective cannabinoid receptor antagonist/inverse agonist and is used in Europe as part of a diet and exercise plan for management of obesity in adults (7,21,54,55). It has also been used and studied in different countries as a smoking cessation product and for management of other addictions (56,57). It leads to a dose-dependent decrease in appetite, decrease in triglycerides, and an increase in HDL level with no impact on LDL levels (58). In February, 2006 rimonabant received an approval letter from the FDA for obesity management in adults but not for smoking cessation due to concerns over safety. The endocannabinoids are important modulators during stress conditions as well as in anxiety, phobias, depression, and posttraumatic stress disorder (58). Concern has been raised over possible worsening for depression and suicidality with a noted relative risk of 1.5-2.5 for psychiatric events in the four Rimonabant in Obesity trials.58 On June 13, 2007, the FDA Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously to not approve rimonabant for obesity due to high risk of serious psychiatric effects, high drop-out rates from the studies, and need for more long-term data (58). Further research is needed to clarify these ongoing issues.

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Other Medications A number of medications (see table 4) have been studied but not proven to be effective and/or safe for adults or adolescents with obesity. Fluoxetine (Prozac) is an antidepressant medication (selective serotonin reuptake inhibitor) with apparently limited weight loss results (59). Other antidepessants that have been used because of their anorexic effects include sertraline (Zoloft) and bupropion (Wellbutrin) (see table 4). However, SSRIs and bupropion are approved for use in the treatment of depression and other mental health disorders in adults but not for obesity (2,60). A number of anticonvulsants (i.e., topiramate, zonisamide) have been studied in research protocols and used off-label for obesity in adults due to their appetite-suppressing effects (17). Octreotide is a somatostatin receptor analog that has been shown to cause weight loss in pediatric patients with hypothalamic obesity (7). Table 4. Medications or chemicals studied but not proven benefical or safe in obesity Treatment 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Bupropion (antidepressant) Cholecystokinin Ciliary neurotrophic factor Glucagon-like peptide-1 (exenatide) Leptin (neuropeptide produced by adipose tissue) Neuropeptide Y Selective Serotonin Reuptake Inhibitors (SSRIs: fluoxetine, sertraline) Somatostatin receptor analog: octreotide (for hypothalamic obesity) Synthetic ß-3 agonists Topiramate (anticonvulsant) Zonisamide (anticonvulsant)

Conclusions Pharmacologic therapy of obesity is recommended only in conjunction with a comprehensive weight loss program that involves diet, exercise, and behavioral modification. The sympathomimetic amine, phentermine, was the first FDA approved product for shortterm weight loss in adults in 1959. Since then, other amines with FDA-approval for shortterm use in adults include benzphetamine, phendimetrazine, and diethylpropion. The only products that are FDA-approved for long-term use in obese adults are sibutramine (mixed noradrenergic-serotonergic product) and orlistat (lipase inhibitor). Sibutramine is FDA approved for adolescents as young as 16 years of age and orlistat is FDA approved down to 12 years of age. Other drugs under research for use in obese adults include metformin (a biguanide used to treat diabetes mellitus type 2 and the metabolic syndrome in adolescents as well as adults),

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rimonabant (a CB1-selective cannabinoid receptor antagonist), and select antidepressants as well as select anticonvulsants with appetite-suppressant effects (see table 3). Attention to the potential side effects of these products is important to consider. Long-term safety of these drugs remains unknown and awaits future research to elucidate. Herbal products have long been popular for weight loss and while ephedra is no longer available, many products now contain caffeine, Citrus aurantium, and a variety of other supplements and herbs. A lack of standardization, supportive research, and the potential for side effects make these products less than desirable as a treatment alternative.

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(55) Pi-Sunyer FX, Arrone LJ, Heshmati HM, et al. Effect of rimonabant, a cannabinoid-1receptor blocker on weight and cardiometabolic risk factors in overweight or obese patients. JAMA 2006;295:761-75. (56) Huestis MA, Gorelick DA, Heishman SJ, et al. Blockage of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatr 2001;58(4):322-8. (57) Maldonado R, Valverde O, Berrendero F. Involvement of the endocannabinoid system in drug addiction. Trends Neurosci 2006; 29(4):225-32. (58) US Food and Drug Administration. FDA Briefing Document; NDA 21-888 (rimonobant). Available from: http://www.fda.gov/ohrms/dockets/ac/07/briefing/20074306b1-fda-backgrounder.pdf (59) Fluoxetine (Prozac) and other drugs for treatment of obesity. Med Lett Drugs Ther 1994;36(936):107. (60) Greydanus DE, Calles J, Patel DR. Pediatric and adolescent psychopharmacology : A primer for the pediatrician. Cambridge: Cambridge Univ Press, 2008.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXXIV

Eating Disorders in Adolescents with Obesity Vinay N. Reddy∗ Pediatrics and Human Development, Michigan State University College of Human Medicine, Pediatrics Program, MSU/Kalamazoo Center for Medical Studies, Kalamazoo, MI, USA

Abstract Although obesity is not classified as an eating disorder, there are associations between obesity and anorexia nervosa, bulimia nervosa, and binge eating disorder. This article reviews some of these associations. For example, a proportion of patients with anorexia nervosa eventually become bulimic and some of these patients eventually become overweight, while anorexia is often seen in a previously obese patient who loses weight successfully and then cannot stop losing weight or continues to try to lose weight even after reaching an otherwise normal weight range. There are possible genetic components for obesity as there are for anorexia nervosa and bulimia nervosa, but there are also associations with the family environment, particularly with family dietary habits. Obese patients should be screened for the presence of an eating disorder, especially bulimia nervosa and binge eating disorder. Obese patients who successfully lose weight should also be carefully observed for the possible development of anorexia nervosa. Principles of management are also reviewed.

Keywords: Adolescence, obesity, eating disorders, management. ∗

Correspondence: Vinay N. Reddy, MD, Assistant Professor, Pediatrics and Human Development, Michigan State University College of Human Medicine, Pediatrics Program, MSU/Kalamazoo Center for Medical Studies. 1000 Oakland Drive, Kalamazoo, Michigan 49008-1284 United States. Tel: 269-337-6450; Fax: 269-3376474; E-mail: [email protected]

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Introduction Anorexia nervosa, bulimia nervosa, and binge eating disorder are all classified as eating disorders by the American Psychiatric Association Manual of Mental Disorders (DSM-IV TR)(1). Obesity is often not regarded as an eating disorder per se and differs from the DSMIV eating disorders in that distortion of body image, a hallmark of and a diagnostic criterion for anorexia nervosa and for bulimia nervosa, is not common in obese patients. However, there are many connections between obesity and the eating disorders, and especially close associations between obesity and bulimia nervosa as well as between obesity and binge eating disorder. The term anorexia nervosa (Greek: “nervous loss of appetite”) is used to describe patients with self-restriction of food intake, increased physical activity, psychological disturbance including distorted self-perception of appearance, severe weight loss, and, in females (2,3). In contrast, bulimia nervosa (Greek: “nervous ravenous hunger”) is “an irresistible urge to overeat, followed by self-induced vomiting or purging” (4), which may or may not be associated with weight loss; in fact, many adolescents with bulimia nervosa are not underweight, and some are obese or morbidly obese. Anorexia nervosa and bulimia nervosa were described in DSM-III and -III-R (5,6), while the diagnostic criteria were made more specific in DSM-IV (1) with subtyping of anorexia nervosa patients into “restrictors” and “binge/purgers;” in addition, more stringent criteria was applied for “binge eating” in the definition of bulimia. DSM-IV also includes a category of “eating disorders not otherwise specified” (acronym: EDNOS). This category includes patients with “binge eating disorder”, a term used to describe marked binge eating or overeating with significant associated distress, but not followed by purging or other compensation for excessive food intake. Excessive weight is not a required criterion for the diagnosis of binge eating disorder, or of bulimia nervosa, but many patients with binge eating disorder are overweight, as are a smaller but still significant proportion of patients with bulimia nervosa.

Epidemiology About 0.5-2% of females will meet all of the criteria for diagnosis of anorexia nervosa during their lifetimes. Some patients have only some of the clinical features of anorexia but are still sufficiently ill to require medical treatment for its complications. Bulimia nervosa is much more common with a lifetime prevalence of bulimia of 1-3% (7-9). Both anorexia nervosa and bulimia nervosa predominantly affect females. Males are also seen with both disorders, but the ratio of affected females to affected males is about 10-20:1 for anorexia and about 10:1 for bulimia. The higher incidence of eating disorders in females may be related to societal and cultural pressures regarding appearance, as considered later in this discussion.

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Risk Factors Eating disorders are by their nature biological, psychological, social, and developmental. They are diseases of affluence, in that they occur in societies where food is plentiful and yet in which “thinness” is valued over “fatness”. In such societies people, especially the young, constantly receive both overt and covert messages that fat is bad and “the thinner is the winner” (a phrase that appears on many so-called “pro-ana” or pro-anorexic Web sites). Many eating disorder patients start wanting to lose weight because of specific stimuli of this type; often a patient starts to lose weight after critical remarks about her weight or appearance from family, teachers (especially physical education or health teachers), peers, or romantic interests, or after disorders related to excess weight are diagnosed in family or friends. This can also occur in the previously obese. A small but non-negligible percentage of obese people who try to lose weight by dietary restriction and increased exercise, and who reach a normal weight and BMI, “overshoot” and continue to lose weight until they meet the diagnostic criteria for anorexia. Conversely, a proportion of patients with anorexia nervosa “recover” from their anorexia but then meet the diagnostic criteria for bulimia nervosa; many of these patients are overweight or obese. As with anorexia nervosa and bulimia nervosa, there is evidence for a genetic component to obesity. Candidate genes have been identified, including genes coding for leptin receptors. Leptin is produced by fatty tissue and appears to be the transmitter involved in feedback regulation of weight (10) and obesity has been induced in experimental animals deficient in these candidate genes. As with anorexia and bulimia, the familial component is most likely environmental as well as genetic, and the environmental component includes the immediate family’s dietary habits and is quite significant in itself.

Clinical Features Bulimia and anorexia have many risk factors in common, as do bulimia and binge eating disorder. Abnormally low body weight excludes the diagnosis of bulimia, and many bulimic patients are also obese; however, excess concern with body image and weight is a diagnostic criterion for bulimia. As many as 30% of those with bulimia have a prior history of anorexia; bulimia, like anorexia, tends to run in families (11). Childhood and parental obesity are more common in those with bulimia than in the general population or in patients with non-eatingdisorder-related psychiatric problems, in contrast to those with anorexia nervosa; also, criticism by family and friends regarding diet and habitus are more common in patients with bulimia (12,13). Anxiety, mood disorders, personality disorders, and substance abuse are also more common in those with bulimia than in other groups (11); in particular, up to 75% of patients with bulimia also have or have had an affective disorder (14) and as many as 37% of those with bulimia meet DSM-IV criteria for the diagnosis of borderline personality disorder (15). A history of abuse, particularly sexual abuse, in childhood is associated with the later development of eating disorders, particularly bulimia. Many theories have been advanced as to the mechanisms, including development of a disassociative coping style, poor self-esteem

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and self-hatred, and attempts to reexert control over the patient’s own life (16,17). Adolescents with bulimia also seem to have a higher incidence of novelty-seeking behavior and impulsivity, and an increased incidence of self-injurious behavior including selfmutilation, substance abuse, and suicidal behavior (18), which is consistent with the association between bulimia and borderline personality disorder. Bulimia usually develops in early adulthood or late adolescence, in contrast to the association with puberty seen in anorexia. Disordered eating in bulimia typically begins during or after a period of dieting, when a patient comes to believe that it is possible to cut caloric and nutritional absorption by purging after eating; however, many patients begin bingeing before making other diet changes (19). Emetics such as ipecac are sometimes used to purge, but more often patients learn to induce vomiting with their fingers or with objects such as toothbrush handles, and with practice patients learn to vomit voluntarily without adjuncts. Others use laxatives or enemas in an attempt to increase stool output, reduce weight, and hopefully decrease absorption of nutrients, or take diuretics to lose weight acutely; they do not understand that these measures simply redistribute fluid. Bulimic (and anorexic) diabetics have been known to stop their own insulin to cause hyperglycemia leading to hyperglucosuria and osmotic diuresis, while some with bulimia and anorexia have resorted to stimulants or thyroid hormone to induce weight loss. As bulimia develops, the initial feeling of control over weight and the satisfaction of eating large amounts of food without gaining weight decreases. Hunger after purging leads to “compensatory” bingeing, and a vicious cycle develops, made worse by other provocations to binge such as anxiety, depressed mood, boredom, and use of alcohol and other substances that reduce inhibition. Certain “forbidden” foods may also trigger binges. Binges tend to occur while alone, and patients may hoard food for later bingeing in privacy. As with anorexia, bulimic patients will go to great lengths to conceal their disordered eating behavior from family and friends. The amount of food ingested may be massive (i.e., >10,000 kcal in a single binge), but may also be no larger than a normal meal and distinguished from normal eating only by the patient’s perceived loss of control during the meal.

Assessment The high prevalence of eating disorders in adolescents makes screening patients for signs and symptoms imperative; such screenings should involve obese adolescents as well. An obese patient may be even more at risk for development of an eating disorder, and may already have bulimia nervosa or binge eating disorder. The reported mortality rates for those with anorexia exceeds that for bulimia, but a bulimic patient may appear relatively normal physically with no outward signs of potentially lethal metabolic derangements. Patients in the early stages of anorexia, especially if they are or have recently been overweight, may not yet show the stigmata of chronic malnutrition.

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Table 1. Screening questions for patients with disordered eating (adapted from Sigman) (20) For the patient: • • • • • •

Are you dieting now? Do you diet often? Are you comfortable with your weight and appearance? Do you want it to change? Do you think about food and food choices often? Do you wish you could think about it less? Do you do things to control your weight that you wish you didn’t have to do as often? Do you feel in control of the way you eat?

For the parents: • • • •

Has the way your child has been eating changed? Is your child overly concerned about weight or food choices? Have you noticed any compulsive weight control behaviors, such as dieting, excessive exercise, or frequent weighing? Has your child been eating fewer meals with the family than in the past?

When taking a history, initial screening questions for disordered eating are noted in table 1 (20). Diagnosis of an eating disorder in an obese patient may be complicated by the patient’s and physician’s desire to maintain or reduce her current weight and diet. When working with an obese patient, it is important to watch for and avoid “undershoot” of weight; similarly it is important to avoid “overshoot” of weight in treating an anorexic patient, both to maintain a good therapeutic relationship and to avoid the possible development of frank obesity. The physician’s own attitude toward obesity is a potential pitfall in caring for the obese patient, and may itself contribute to the development of an eating disorder. The negative reaction to obese people seen in their peers is, consciously or not, shared by many of clinicians, and to treat these patients effectively the physician must set these reactions aside. Also, as with the eating disorders, treatment of obesity may be lengthy and drawn-out, complicated by socioeconomic factors affecting both patients and their families; these issues may make it difficult for these adolescents to improve their diet and exercise. Simply helping the adolescent patient to maintain a stable weight may be more feasible than trying to achieve actual weight loss.

Treatment There are many aspects in common in the management of patients with anorexia nervosa or with bulimia nervosa. The psychological aspects of treatment are especially similar. The

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treatment of obesity, which inevitably involves recommended or imposed dietary restriction, may in fact trigger anorexia or bulimia. For example, in the World War II-era study by Keys (21,22) volunteer subjects who were subjected to severe dietary restriction for several months continued to restrict their own intake for some time after the imposed restriction was lifted; also, a similar phenomenon is seen in some -- but not all -- obese persons who develop clinical features of anorexia after losing an appropriate amount of weight. The patient with an eating disorder is treated most effectively by a team approach whether the youth is in an outpatient or as an inpatient setting (23,24). The multifactorial nature of eating disorders makes it unlikely that any one person will have all the therapeutic and medical skills an eating disorders patient needs to be treated effectively. The core of a typical treatment team includes a physician, a psychotherapist, and a dietitian. The physician is responsible for the patient’s medical supervision, including overall regulation of nutrition and medication, monitoring of symptoms, physical findings as well as laboratory studies, and management of such complications as malnutrition, refeeding, and purging. Often a pediatrician or internist works in partnership with a psychiatrist, since the latter is more familiar with psychotropic agents including their uses and side effects. Subspecialists in adolescent medicine and pediatric hospitalists are often well-versed in eating-disorder management. The therapist concerns herself with the psychological and social aspects of the patient’s eating disorder, as well as concurrent and contributing problems such as obsessivecompulsive disorder or prior abuse. A clinical psychologist or a psychiatric social worker experienced in working with adolescents with eating disorders and their families is recommended. Family therapy and parent coaching are also important in treating adolescents with eating disorders, since these adolescents live in the context of their families. Some therapists can provide both individual and family therapy, or collateral therapy in which the patient is seen separately from the parents by the same provider; however, in other situations, separate individual and family therapists may be required. Cognitive-behavioral therapy (CBT) has been shown in randomized controlled trials to be effective in the treatment of bulimia nervosa, and is felt by some to be the psychotherapy of choice in those patients, whether conducted on an individual or a group basis (25-28). Dialectical-behavioral therapy, which combines CBT with principles derived from Zen Buddhism, is a frequently-used modality for patients with borderline personality disorder (BPD) and has been found effective in treating patients with BPD and bulimia nervosa or binge eating disorder (29,30). Although the medical aspects of refeeding need close medical supervision, a dietitian is also an essential part of the team. Her role includes not only helping to determine patients’ nutritional needs, but educating patients and their families on the role of specific nutrients, assisting in planning menus, and addressing the adolescent patient’s beliefs, attitudes, and misconceptions about various foods. As with other members of the team, a dietitian who has experience working with adolescents with eating disorders is desirable, but dietitians without such experience can be helpful in communication with other, more experienced professionals on the patient’s team. A social worker can contribute to treatment in ways other than providing direct therapy to the patient and family. She or he can assist in resolving conflicts between the patient and

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family, and can help identify patient/family needs and locate other management resources. A recreational therapist or child-life specialist can be very valuable in helping patients improve their social interactions and with learning relaxation techniques. The majority of eating disorder patients, and in particular most bulimic patients, can be managed as outpatients. Anorexic patients are hospitalized more often than bulimic patients in part because of physiologic changes that accompany chronic malnutrition. Table 2 provides indications for admission. Table 2. Hospital admission indications for eating disorder patients • • • • • •

Body weight that is dangerously low or has dropped rapidly Electrolyte disturbances, including hypokalemia and hypophosphatemia Symptomatic bradycardia or orthostatic hypotension, or signs of heart failure Risk of self-injury (suicide, or ED behaviors that have potential for physical injury) Concomitant medical or psychiatric conditions requiring hospitalization Failure of outpatient treatment to arrest the progress of the disease

Medical Management Eating disorder patients and those who treat them have a common goal, that is, they all want the patient to “eat healthy”. The difference between patients and therapists is in the definition of “healthy eating.” One feature of eating disorders is distortion of the patient’s view of what healthy eating really involves. The modern Western world values thinness, and society is continuously bombarded with messages extolling thinness and denigrating fatness. The effects of societal pursuit of thinness are magnified in obese patients, for whom frequent weight-based criticism may trigger an eating disorder. As a result, many ED patients learn to fear fat and to avoid fat intake at all costs, not realizing that fatty acids are essential to many physiological functions, from hormone production to nerve-fiber myelination. Providing nutrition to an ED patient is a matter of helping the adolescent patient maintain a healthy weight range and to do so with as little food-related anxiety as is possible. In an obese patient this may require initial weight reduction, while simultaneously helping the patient avoid “undershoot”. The ultimate goal is for the patient to reach and maintain good health in a healthy weight range. The concept of a range must be emphasized, since the patient will focus on a particular number as a goal and feel that she has failed if her weight is above or below that number. The healthy range, or goal range, is that in which she has normal physical, endocrine, metabolic, and reproductive functioning. The latter is one factor used in choosing a healthy weight range for a patient. It is common to choose a goal weight range corresponding to 10-15 percentiles below the anorexic patient’s height percentile, based on National Center for Health Statistics standard growth charts. This may be appropriate for a formerly obese patient who is now anorexic. For an adolescent patient who presents with obesity, an appropriate goal range may be at or above the mean for age and/or height, especially since weight loss of 10-15 pounds is

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associated with improvement in other physiologic markers such as blood pressure and glucose regulation. Even before admission, cardiac dysrhythmias due to electrolyte imbalance are the most concerning complication of anorexia and bulimia nervosa. Electrolyte imbalances are most often due to purging, whether by vomiting (which results in both potassium loss and hypochloremic metabolic alkalosis), laxative abuse (leading to metabolic acidosis because of bicarbonate loss in stools), or excessive use of diuretics (also leading to metabolic alkalosis). Prolonged QT intervals are also often seen in ED patients; the mechanism for this is unclear but may be related to deficiency of magnesium and/or potassium. Prolonged QT intervals may also be a contraindication to many medications that might otherwise be useful in these patients. Abuse of ipecac for purging may result in skeletal and cardiac myopathy due to toxic effects of emetine. Excessive vomiting, regardless of how it is induced, may cause upper gastrointestinal trauma ranging from a Mallory-Weiss tear to rupture of the esophagus or stomach.

Counseling and Therapy Since eating disorders are biopsychosocial in nature, individual therapy and family therapy are essential to recovery and to preventing relapse. This is true for inpatients and outpatients, and therapy for these two groups is largely similar. Psychotherapy, including individual, family, and group therapy, should begin as soon as possible after diagnosis, and is generally started or restarted almost immediately after inpatient medical admission; it is, of course, the mainstay of residential therapy for eating disorder patients. Initial therapy for patients hospitalized for severe malnutrition may consist of little more than supportive counseling, coupled with basic explanations of the disease and its effect on the patient that can be repeated and varied as necessary.

Psychotropic Medications Psychotropic medications have also been used to treat patients with eating disorders, especially in bulimia nervosa where the use of selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine is supported by randomized controlled trials. However, the salutary effect of SSRIs in these patients is not as great, or as long-lasting, as that of CBT, and it appears that the most effective treatment for bulimia is the combined use of CBT and an SSRI (26,31).

Conclusions Although obesity is not classified as an eating disorder, there are associations between obesity and the DSM-IV-defined eating disorders. Many patients with binge eating disorder

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are overweight, as are a smaller but still significant proportion of patients with bulimia nervosa. Anorexia nervosa, for which abnormally low body mass is a diagnostic criterion, is not immediately associated with obesity. However, a proportion of patients with anorexia nervosa eventually become bulimic and some of these patients eventually become overweight, while anorexia is often seen in a previously obese patient who loses weight successfully and then cannot stop losing weight or continues to try to lose weight even after reaching an otherwise normal weight range. There are possible genetic components for obesity as there are for anorexia nervosa and bulimia nervosa, but there are also associations with the family environment, particularly with family dietary habits. Bulimia runs in families, and both childhood and parental obesity are more common in patients with bulimia compared with the general population. Bulimia often begins after a period of dieting when a patient starts thinking that purging after eating will result in weight loss, then worsens when post-purging hunger leads to “compensatory” bingeing which is then followed by further purging. Obese patients should be screened for the presence of an eating disorder, especially bulimia nervosa and binge eating disorder. Obese patients who successfully lose weight should also be watched for the possible development of anorexia nervosa.

References (1)

American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed, text revision. Washington, DC: APA, 2000. (2) Gill W. Anorexia nervosa (apepsia hysterica, anorexia hysterica). Trans Clin Soc London 1874;7:22-28. (3) Silverman J. Sir William Gill (1819-1890). Limner of anorexia nervosa and myxoedema. An historical essay and encomium. Eat Weight Disord 1997;2(3):111-6. (4) Russell G. Bulimia nervosa: an ominous variant of anorexia nervosa. Psychol Med 1979;9(3):429-48. (5) American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd ed. Washington, DC: APA, 1980. (6) American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd revised ed. Washington, DC: APA, 1987. (7) Quintero-Parraga E, Perez-Montiel A, Montiel-Nava C, Pirela D, Acosta M, Pineda N. Eating behavior disorders. Prevalence and clinical features in adolescents in the city of Maracaibo, Zulia State, Venezuela. Invest Clin 2003;44:179-93. (8) Kendler K, MacLean C, Neale M, Kessler R, Heath A, Eaves L. The genetic epidemiology of bulimia nervosa. Am J Psychiatry 1991;148:1627-37. (9) Garfinkel P, Lin E, Goering P, Spegg C, Goldbloom D, Kennedy S, et al. Bulimia nervosa in a Canadian community sample: prevalence and comparison of subgroups. Am J Psychiatry 1995;152:1052-8. (10) Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372(6505):425-32.

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(11) Klump K, Kaye W, Strober M. The evolving genetic foundations of eating disorders. Psychiatr Clin North Am 2001;24(2):215-25. (12) Fairburn C, Doll H, Welch S, Hay P, Davies B, O'Connor M. Risk factors for bingeeating disorder: A community-based case-control study. Arch Gen Psychiatry 1998;55:425-32. (13) Fairburn C, Welch S, Doll H, Davies B, O'Connor M. Risk factors for bulimia nervosa: A community-based case-control study. Arch Gen Psychiatry 1997;54:509-17. (14) Brewerton TD, Lydiard RB, Herzog DB, Brotman AW, O'Neil PM, Ballenger JC. Comorbidity of axis I psychiatric disorders in bulimia nervosa. J Clin Psychiatry 1995;56:77-80. (15) Sansone RA, Levitt JL, Sansone LA. The prevalence of personality disorders among those with eating disorders. Eat Disord 2004;13(1):7-21. (16) Smolak L, Murnen S. Meta-Analytic Examination of the relationship between child sexual abuse and eating disorders. Int J Eat Disord 2002;31:136-50. (17) Rayworth B, Wise L, Harlow B. Childhood abuse and risk of eating disorders in women. Epidemiology 2004;15:271-8. (18) Paul T, Schroeter K, Dahme B, Nutzinger D. Self-injurious behavior in women with eating disorders. Am J Psychiatry 2002;159:408-11. (19) Haiman C, Devlin M. Binge Eating before the onset of dieting: A distinct subgroup of bulimia nervosa? J Eat Disord 1999;25:151-7. (20) Sigman G. Eating disorders in children and adolescents. Ped Clin North Am 2003;50:1139-77. (21) Keys A. The residues of malnutrition and starvation. Science 1950;112(2909):371-3. (22) Taylor HL, Keys A. Adaptation to caloric restriction. Science 1950;2904(2899):215-8. (23) Rome E, Ammerman S, Rosen D, Keller R, Lock J, Mammel K, et al. Children and adolescents with eating disorders: The state of the art. Pediatrics 2003;111:e98-e108. (24) Joy E, Wilson C, Varechok S. The multidisciplinary team approach to the outpatient treatment of disordered eating. Curr Sports Med Rep 2003;2(6):331-6. (25) Walsh B, Wilson G, Loeb K, Devlin M, Pike K, Roose S, et al. Medication and psychotherapy in the treatment of bulimia nervosa. Am J Psychiatry 1997;154(4):52331. (26) Fairburn C, Harrison P. Eating disorders. Lancet 2003;361:407-16. (27) Lundgren J, Danoff-Burg S, DA. A cognitive-behavioral therapy for bulimia nervosa: An empirical analysis of clinical significance. Int J Eat Disord 2004;35(3):262-74. (28) Mitchell J, Pyle R, Pomeroy C, Zollman M, Crosby R, Seim H, et al. Cognitivebehavioral group psychotherapy of bulimia nervosa: importance of logistical variables. Int J Eat Disord 1993;14(3):277-87. (29) Safer D, Telch C, Agras W. Dialectical behaviou therapy for bulimia nervosa. Am J Psychiatry 2001;158(4):632-4. (30) Telch C, Agras W, Linehan M. Dialectical behavior therapy for binge eating disorder. J Consult Clin Psychol 2001;69(6):1061-5. (31) Greydanus DE, Calles J, Patel DR: Pediatric and adolescent psychopharmacology: A primer for the pediatrician. Cambridge: Cambridge Univ Press, 2008.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXXV

Sexuality and Obesity in Adolescence Helen D. Pratt∗1, Donald E. Greydanus1 and Kazue Ishitsuka2 1

Division of Behavioral and Developmental Pediatrics, Pediatrics Program, Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, MI, USA 2 Division of Child and Adolescent Psychiatry, Tokyo Metropolitan Umegaoka Hospital, Setagaya-ku, Tokyo, Japan

Abstract Adolescence is a critical period of growth and development in an individual’s maturation from puberty to adulthood. A key component of normal adolescence is the process of healthy sexual development that is influenced by an inevitable passage through the stages of maturation from infancy to adulthood. Primary care clinicians should understand and appreciate the importance of sexuality in the lives of their adolescent patients. Obesity is one of the factors that influences sexuality in adolescents. The purpose of this paper is to succinctly discuss the relationship between obesity and adolescent sexuality. In this regard, it is vital to examine whether obesity alone can derail healthy adolescent sexual development. Not all overweight adolescents experience severe negative outcomes because of their obesity. However, for those who do experience negative sexuality issues, the sensitive and caring clinician can help direct them to helpful resources to address these critical issues.

Keywords: obesity, sexuality, adolescence, human development.

∗

Correspondence: Helen D Pratt, PhD, Pediatrics Program, MSU/KCMS, 1000 Oakland Dr, Kalamazoo, MI 49008 United States. Tel: 269 337-6450; Fax 269-337-6474; E-mail: [email protected]

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Introduction Adolescence is a critical period of growth and development in an individual’s maturation from puberty to adulthood (1,2). The hallmark of adolescence is the process of puberty, a profound neurobiological/psychological event in the life of each child that prepares the way for eventual adulthood. The onset of puberty is often accompanied by acts of daydreaming, fantasizing, feelings of confusion, fears about the future, peer rejection, strong emotions, and strong physiological reactions to a variety of stimuli. These accompaniments are a part of the continued process of human sexual development (see table 1) (3). A key component of healthy sexual development involves how the adolescent moves through the stages of maturation from infancy to adulthood (see table 2) (4-12). As adolescents matriculate through puberty into adulthood they generally will come to terms with their own sexuality. Table 1. Components of sexuality biologic sex (XX or XY) Gender identity Gender role behavior Behaviors associated with masculinity or femininity and androgyny Sexual orientation: • Physical and emotional attractions to individuals • Heterosexual, gay lesbian or bisexual Cultural environment Family inter- and intra- personal intimacy Peer inter- and intra- personal relationships and intimacy Personal Physical Health Mental Health • Emotional • Intellectual Psychosocial Health Exposure to Interpersonal Violence or Abuse Perceptions of Attractiveness to others Body Image (positive negative view of physical attributes) Self esteem (negative/positive views of value/worthiness) Body Satisfaction/Dissatisfaction Sexual Activity • Masturbation • Mutual Masturbation Petting/Kissing Sexual Intercourse

Growing up during adolescence brings with it a number of inevitable stresses and obstacles without the potential burden of additional issues, such as obesity. It is important to

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examine whether obesity alone can derail healthy adolescent sexual development. Research shows that not all obese adolescents grow up to be maladjusted. Obese adolescents are sexual individuals as can be readily observed by simply watching and counting the number of pregnant young women in any area of the United States. Many of the psychosocial outcomes of obesity are also common psychosocial outcomes of adolescence itself. Table 2. Factors that may impede development of healthy sexuality in adolescents Cognitive factors • Poor self esteem • Negative body image • Body dissatisfaction • Negative perceptions of physical characteristics • Poor intimate peer relationships • Feeling overweight or fat Physical factors • Delayed physical or mental development • Being overweight • Being physically different from peers Exposure to violence or trauma • Sexual molestation • Sexual assault • Rape • Being harassed physically or sexually • Dating violence • Constant exposure to sexual media content. Unwanted pregnancy Sexually transmitted diseases Physical disabilities or chronic illness

Additionally, physiological and biological processes of adolescence may promote or predispose to the condition of being overweight or obese in females.13 Since obesity is one of the factors that influences sexuality in adolescents, the purpose of this discussion is to consider the relationship between obesity and the development of sexuality in adolescents.

Defining Sexuality Sexuality begins at conception and the physiologic components to sexuality are evident at an early age (see table 1)(4-12). Sexuality is comprised of the interactions between a complex set of individual, family, environmental, peer, and community variables as well as processes. Sexuality is affected by various family, legal, ethical, moral, and religious issues. An individual’s personal history of exposure to violence (i.e., rape, abuse, molestation) can have a significant impact on that adolescent’s sexuality. Factors such as hormonal problems,

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body dissatisfaction, poor self image, and interest in sexual activity also impact an individual’s sexuality (13). A person’s sexuality is based on his or her body image. Body image, a vital component of sexuality, is influenced by factors that include: a) attitudes about intimacy, b) perceptions about attractiveness, c) views about peer reactions to his or her physical characteristics, d) mental depiction of his or her personal body size and e) the feelings concerning those characteristics (2, 13).

Defining Obesity The term “at risk for overweight” is defined by the Centers for Disease Control and Prevention (CDC), when an adolescent’s age- and sex specific body mass index (BMI) is over the 85th percentile, but below the 95th percentile (14). “Overweight” has been defined by the CDC as a sex- and age-specific BMI at or above the 95th percentile based on revised CDC growth charts. The classic formula for calculating BMI is weight in kilogram devided by height in meter squared (BMI=kg/m2).

Sexuality Development Beginning in infancy, youth discover their bodies first through internal and external sensations. Next, they learn how their specific actions/reactions cause changes in their environments. A combination of their ability to process these sensations and the resulting cause and effect relationships in their environments help to shape aspects of their sexuality. Early experiences with sexuality include the activities of daily living (i.e., feeding, changing diapers, bathing, nurturing, and soothing). How an infant is held, how gentle the care giver is when the child is bathed, how the genitalia are handled when a diaper is changed are all events that help the child and youth develop body image and feelings of value. The infant who has caregivers who can interpret her needs, and responds to those needs in a manner that nurtures or soothes, is learning about her self and how to get her needs met. The infant who sees the caregiver smile and talk in a soothing nature is learning to see themselves as able to make others happy. The child that grows with these same levels of care begins to develop self-confidence, enjoys others, and behaves in a way that encourages others to see them as lovable and valuable. For example, infants learn to associate sensory inputs of warmth and satiation with suckling (breast or nipple), ingesting nutrients, visual cues, touch, and smells. While gazing into the eyes of their caregivers as they are held firmly and gently against a warm body and are fed, the infant begins to link these sensory experiences with satiation which sets the early feelings of pleasure. As the infant matures and experiences these basic senses (i.e., cognitive, visual, emotional, sensory, and kinesthetic), and gets his or her needs met in a timely fashion, that infant will learn how to get access to pleasurable events and avoid or minimize negative events. This infant learns to control his or her environment and develops a healthy sense of

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self and is one step closer to having the requisite components of healthy sexuality for a lifetime. The same process continues through adolescence. The adolescent who learns to love himself, to be flexible in his view of others, to be patient with others, and to know how to be comforted and soothed by stable caregivers will be better able to adjust to the stresses of growing up as well as the rejection and conflict that may occur with peers. Through this process youth also learn about the function, roles, sensations, and emotions connected to their body parts. Youth are naturally curious about sexuality and often experiment widely, especially during mid-adolescence. They become keenly aware of their bodies, the accompanying sensations to stimuli that occur in their bodies, and their associations to their sense of sexually. Adolescents may find some sensations they experience to be more pleasurable than others. They are attracted to some types of individuals and may fear or reject other types of people. These feelings of attraction are refined as youth grow and their exposure to pleasurable and aversive stimuli is broadened. Female adolescents generally become more self conscious about their bodies as they make the critical journey through puberty. As their bodies develop breasts and their hips become full, female adolescents may become concerned about being fat and may fear being objects of sexual harassment (15). Males who do not develop masculine characteristics are more likely to be more self conscious about their bodies (15). Youth are often concerned about being too thin or too short. Female adolescents may be concerned about not developing large enough breasts or having breasts that are too small; male adolescents may be more concerned about musculature and penis size (16). Other gender differences in sexuality development include developmental milestones. For example, females tend to develop most of their self esteem based on their physical attractiveness. This attitude corresponds roughly with Erikson’s developmental task of “identity vs role confusion” in which she attempts to integrate her many roles, including that of being a sexual person, into a healthy self-image within the context of peer pressure and role models. Males base their sense of self-esteem on their ability to accomplish things. This corresponds with Erikson’s developmental task of “industry vs inferiority” wherein he tries to develop a sense of self worth by refining skills (16). Being different than one’s peers is a major contributor to body dissatisfaction (15). Expressions of sexual behaviors such as affection are initially learned in the adolescent’s family. This family sets the rules, mores, and level of acceptance for what expressions of sexuality (sexual behavior [such as masturbation, kissing, hugging], emotions, and affection are acceptable or unacceptable. As the adolescent’s environment broadens to include others (i.e., communities, schools, and peer groups) they learn more about sexuality and may have specific physiological responses to the emotion of affection and arousal. Adolescents may become concerned about whether their cognitions, emotions, and physiological reactions make them heterosexual or homosexual, especially if they are experiencing feelings of strong emotions towards a same sex person. Youth may also become confused by some of the thoughts they have about themselves and others. They are often hypersensitive to feedback from others about their physical characteristics, physical performance, and social skills (especially from peers). These experiences of hypersensitivity are normal and natural

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processes of normal maturation during adolescence, along with oral language and physical awkwardness. Adolescents who develop low self-esteem, negative body image, doubts involving future self-sufficiency, and questions about their value may become easy prey for peers who criticize and bully others for their own advantage (17). They may seek intimate relationships that are not mutually satisfying and healthy. Some of these youth may engage in high risk behaviors as a means of gaining peer approval, acceptance, and affection.2 As the individual moves into puberty, cognitive processes begin to focus on body image issues as growth patterns begin to accelerate rapidly and body contours change dramatically (2). Female sexuality researchers and educators in sexuality often note considerable differences in how both sexes view sexuality (2). Several studies on adolescent body and self esteem found that issues such as BMI, acne, and height each are related to an adolescent having lower self esteem and seeing themselves as being less sexually attractive. Although African Americans females in one study had more favorable body self esteem than Caucasians, they had higher BMIs. Additionally BMI was associated with overall body esteem and weight concerns but not with feelings of sexual attractiveness (15,17,18). Males tend to learn their early concepts of sexuality in the context of social relationships. American males may learn early in their development to define masculinity as synonymous with such destructive concepts as dominance, competition, performance, and achievement. Males lacking extended contact with their fathers for appropriate role model patterns are especially vulnerable to such misogynic cues from the media. Males are taught from early life and throughout life to be more distrustful and insecure than females. Males are taught to control their sexual thoughts in regard to males and to use homophobia as a guiding principle. Males are more likely to carry negative attitudes about their bodies from their childhood throughout adolescence and adulthood. Though males tend to masturbate earlier than females, they are more likely to avoid group masturbation due to societal homophobic attitudes. The issue of whether or not females engage in group masturbation was not addressed in our review (2).

Self-Esteem and Sexuality Self esteem refers to how an individual feels about his or her physical attributes and instrumental effectiveness. Adolescents develop healthy self esteem that is positive and selfsustaining for a lifetime when they have been nurtured and reared in a cultural environment that has consistently taught them from infancy through adolescence that they are worthy, have intrinsic value, and are competent in all areas of life, including sexual realms. Females tend to develop most of their self esteem based on physical attractiveness or how pretty they are. Males tend to develop their self esteem based on their instrumental effectiveness or based on their ability to accomplish things (16). The female adolescent’s self esteem is based on how happy they are with their bodies which translates into how attractive they may see themselves. During early adolescence, girls tend to base their body dissatisfaction on how well their physical attributes match or do not match those of their age appropriate peers. One researcher found that among their American

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subjects, Latinos and Asians, who were among the leanest 25 percent of girls, reported significantly more body dissatisfaction than did Caucasians (15). Caucasian girls who were shorter in height and Asian girls who were taller in height than their peers were also more likely to be unhappy with their body type (15,19). Adolescents who have learned to be satisfied with their bodies are less likely to experience body dissatisfaction even if their body mass index increases (20).

Impact of Obesity on Sexuality Overweight adolescents may be viewed as unattractive and assumed to be sexually maladjusted. They may also develop poor self esteem, poor self image, unhealthy or unrealistically negative body images, and ineffective social skills. Overweight adolescents and those who view themselves as being overweight may experience social rejection, harassment, and mental health problems. There are no substantial clinical data at this point to support the psychological theory that obesity is a defense against sexuality (18,21). Research supports the concept that overweight adolescents are more victimized, date less, and are less satisfied with their dating status than are their non-overweight peers (17). Because adolescents rely on their peers for the development and maintenance of their selfimage, self-acceptance, and sense of belonging, the rejection that obese youth experience from their peers can have devastating effects on their overall social and psychological health (17). Being overweight can result in an adolescent (except for African American females) experiencing negative social and psychological health through maladaptive peer experiences (17,22). Studies of the impact of adolescent obesity and sexual activity were not found in our literature search. However, one study on the topic with adult males concluded that significantly obese adult males found that they had a) body image dissatisfaction, b) lacked desire for sexual activity, c) lacked erotic fantasies and d) lacked motivation in sexual advances.23 Extreme (morbid) obesity in an adolescent might present problems that interfere with the actual physical expression of sexuality. These youth may have difficulty consummating the act of sexual intercourse. They may feel inadequate compared with “normal” peers and therefore may feel a need to perform well sexually. This performance pressure may predispose to sexual dysfunction (25). In order to gain peer acceptance and approval overweight or obese adolescents may become involved in high risk sexual activities to prove that they are normal and able to engage in the sexual activities they see modeled in the media by their thin peers. However, this same reaction can occur in adolescents who have physical disabilities, mental illness, chronic illness, or poor social relationships from various causes.

Conclusions Primary care clinicians should understand and appreciate the importance of sexuality in the lives of their adolescent patients. All of the critical components to healthy child and

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adolescent development are equally important to the development of healthy sexuality. Sexuality is a critical part of normal growth and development. Adolescents need knowledgeable health care professionals who can a) help parents understand what healthy sexuality is about, and b) supplement parental teaching about human sexuality in a confidential and sensitive manner. Obesity impacts healthy sexuality development if it impedes an adolescent’s body image, self esteem, self confidence, self worth, and emotional health as well as peer relations. Not all overweight adolescents experience severe negative outcomes because of their obesity. But for those who do experience negative sexuality issues, the sensitive and caring clinician can help direct them to appropriate resources to address these issues. The clinician who is not biased against obesity and remains non judgmental while presenting helpful information on human sexuality is more likely to have an adolescent patient who is in compliance with recommended medical regimes.

References (1)

(2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14)

Lewis M. Overview of infant, child and adolescent development. In: Wiener JM, ed. Textbook of child and adolescent psychiatry, 2nd ed. Washington, DC: Am Psychiatr Press, 1997:39-66. Greydanus DE. National Institute of Health conference on disability through the lifespan. Peers and sexuality. Bethesda, MD, 21-22 Jul 2003. Pratt HD, Greydanus DE. Normal psychological development. In: Greydanus DE, Patel DR, Prat HD, eds. Behavioral pediatrics vol I. New York: Universe, 2006:5-36. Piaget J. Intellectual evaluation from adolescence to adulthood. Hum Dev 1972;15:112. Piaget J, Inhelder B. The psychology of the child. New York: Basic Books, 1969. Piaget J. The language and thought of the child. New York: Harcourt Brace, 1932. Flaherty T. Maria Montessori (1870-1952). Women's intellectual contributions to the study of mind and society. http://www.webster.edu/~woolflm/montessori.html Freud S. The origin and development of psychoanalysis. Am J Psychol 1910;21:181218. Freud S. Collected works. Standard edition. London: Hogarth, 1954. Boeree CG. Personality theories. 1997. http://www.ship.edu/~cgboeree/perscontents.html Erikson EH. Childhood and society, 2nd ed. New York: WW Norton, 1963. Erickson E. Identity, youth and crisis. New York: WW. Norton, 1968. Greydanus DE, Patel DR, Pratt HD,eds. Essential adolescent medicine. New York: McGraw-Hill Med, 2006. Center for Disease Control and Prevention. CDC growth charts: United States - Body mass index-for-age percentiles: Boys and girls ages 2 to 20 years.3rd, 5th, 10th, 25th, 50th, 75th, 85th, 90th, 95th, 97th percentiles. National Health and Nutrition Examination Survey. Hyattsville, MD: US Department of Health and Human Services, CDC, National Center for Health Statistics. 2000. Available at

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(16) (17) (18) (19)

(20) (21) (22) (23) (24) (25)

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http://www.cdc.gov/nchs/data/ nhanes/growthcharts/set1/chart03.pdf http://www.cdc.gov/nchs/data/nhanes/growthcharts/set1/chart04.pdf Kornblau IS, Pearson GC, Breitkopf CR. Demographic, behavioral, physical correlates of body esteem among low income female adolescents. J Adolesc Health 2007; 41(4):566-70. Dorian L, Garfinkel PE. Culture and body image in Western society. Eat Weight Disord 2002;7(1):1-19. Pearce MJ, Boergers J, Prinstein MJ. Adolescent obesity, overt and relational peer victimization, and romantic relationships. Obes Res 2002;10(5):386-93. Grabe S, Hyde JS, Lindberg SM. Body objectification and depression in adolescents: the role of gender shame, and rumination. Psychol Women Q 2007;31:164-75. Robinson TN, Killen JD, Litt IF, Hammer LD, Wilson DM, Haydel, et al. Ethnicity and body dissatisfaction: Are Hispanic and Asian girls at increased risk for eating disorders. J Adolesc Health 1996; 19:384-93. van den Berg P, Neumark-Sztainer D. Fat ‘n happy 5 years later: Is it bad for overweight girls to like their bodies? J Adolesc Health 2007;41(4):415-7. Bess BE. Human sexuality and obesity. Int J Mental Health 1997; 26(1):61-7. Nichter M. “Fat talk”: What girls and their parents say about dieting. Cambridge, MA: Harvard Univ Press, 2000. Jagstaidt V, Golay A, Pasini W. Relationships between sexuality and obesity in male patients. New Trends Exp Clin Psychiatry 1997;13(2):105-10. Pearce MJ, Boergers J, Prinstein MJ. Adolescent obesity, overt and relational peer victimization, and romantic relationships. Obes Res 2002;10:386-93. Greydanus DE, Pratt HD, Baxter T: Sexual dysfunction and the primary care physician. Adolesc Med State Art Rev1996;7(1):9-26.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXXVI

Concepts of Contraception for Adolescents with Obesity: Pathways of Judicial Moderation Donald E. Greydanus∗1, Hatim A. Omar2 and Artemis K. Tsitsika3 1

Pediatrics and Human Development, Michigan State University College of Human Medicine, Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, MI, USA 2 Adolescent Medicine and Young Parents Program, University of Kentucky, Kentucky Clinic, Lexington, KY, USA 3 Adolescent Health Unit, Second Department of Pediatrics, University of Athens-Greece, Children’s Hospital, Athens, Greece

Abstract All sexually active youth, whether obese or normal weight, should be offered counselling regarding contraception and appropriate contraceptive methods. However, obese youth who are sexually active may be less likely than their normal weight peers to use contraceptives correctly. Methods of contraception for obese adolescents are reviewed in this discussion. Combined oral contraceptives (COCs) and the contraceptive patch have higher failure rates in obese versus normal weight females, though failure rates are lower than noted with barrier contraceptives. The risk for venous thrombosis is higher in obese youth on COCs. Progestin-only pills and the levonorgestrel intrauterine system appear to be safe and effective methods in obese females. Depotmedroxyprogesterone acetate, intravaginal ring, and implants are also considered. ∗

Correspondence: Professor Donald E Greydanus, MD, Pediatrics and Human Development, Michigan State University College of Human Medicine, Pediatrics Program Director, Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, MI 49008-1284 United States. Tel: 269-337-6450; Fax: 269-3376474; E-mail: [email protected]

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Keywords: Adolescence, sexuality, obesity, contraception.

Introduction Sexually active adolescents whether chronically ill or not, should be offered contraception if they are not willing to accept abstinence (1-7). Adolescents who are obese are at risk for unwanted pregnancy with its well-known risks and thus, should also be offered safe and effective contraceptives. However, overweight or obese females are less likely to use contraception than their normal weight peers, despite their higher risk for pregnancy-related complications (8). This chapter reviews contraception in obese youth. In general, contraception is much safer than risks posed because of obesity and pregnancy. Effective methods that the clinician should consider include combined oral contraceptives, mini-pills, depo-medroxyprogesterone aceate, intravaginal ring, implantable contraception, and levonorgestrel intrauterine device (see table 1). Barrier methods are not generally effective in youth. Table 1. Contraceptive methods Abstinence Combined Oral Contraceptives (COCs) Contraceptive patch Mini-pills (Progestin-only pills; POPs) Emergency contraceptives Injectable Contraceptives Depo-Provera® (Depo-medroxy-progesterone acetate Lunelle® (estradiol cypionate and medroxyprogesterone acetate) Implants Norplant I (withdrawn from the US market in 2000) Implanon (one rod system with etonogestrel) Jadelle (Norplant II: two silastic rods with levonorgestrel) Intravaginal ring (NuvaRing) Intrauterine Devices Progestasert® IUD (with progesterone) ParaGard® (Copper T380A IUD) Mirena® (IUD with levonorgestrel) Vaginal barrier contraceptives Cervical cap (Prentif Cavity-rim®) Condoms (male) Contraceptive sponge (vaginal) Diaphragm Female condom (Reality®) Spermicides (vaginal)

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Combined Oral Contraceptives (COCs) Females with obesity have some decreased efficacy with COCs due to higher basal metabolic rates, higher hepatic metabolism of enzymes, and drug sequestration that is higher in adipose tissue; however, efficacy is higher than noted with barrier methods (9-13). There are over 145 brands of combined oral contraceptives (COCs) used throughout the world, which generally contain both synthetic estrogen and synthetic progestin. In the United States, birth control pill brands are various combinations estrogen and progestin. The usual estrogen is ethinyl estradiol as the estrogen, though a few brands use mestranol. Various progestins are used including norgestrel, levonorgestrel, ethynodiol diacetate, norethindrone acetate, norethindrone, desogestrel, norgestimate, norethynodrel, drospirenone, and gestodene (not available in the US). The pill has been shown to be a safe and effective contraceptive for reproductive women – especially for those of the adolescent age group. Thus, motivate adolescent females who are obese can still be encouraged to use the COC despite the reported higher failure rates, mainly because of the overall efficacy of COCs and the known adverse pregnancy outcomes. Current recommendations are to begin with a monophasic pill, which has 30-35 mcg of estrogen and 0.15 to 1.5 mg of progestin, or a triphasic pill. Triphasic pills are also recommended due to their low dose of estrogen and progestin. Careful monitoring and selection of patients for birth control pill use will reduce complications of the pill to a considerable extent. Contraindications to oral contraception are reviewed in table 2. Sexually active youth who are on combined oral contraceptives are advised to use condoms as well. Table 2. WHO medical eligibility categories for OCPs. Used with permission (3) Category one (no restrictions)

• • • • • • • • • •

Antibiotics Benign breast disease Benign ovarian tumors Cervical ectropion Dysmenorrhea, Endometriosis Epilepsy Family history of breast cancer Gestational trophoblastic disease (benign or malignant) Headaches (mild)

History of ectopic pregnancy or abortion (postabortion after first or second trimester),

• • • • • • •

History of gestational diabetes Increased STD risk Iron deficiency anemia Irregular menstrual bleeding Obesity Ovarian or endometrial cancer Past pelvic surgery

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Pelvic inflammatory disease Postpartum at or over 21 days Thyroid disorders (as hypo/hyperthyroidism, simple goiter) Varicose veins Various infections :malaria, tuberculosis, others) Sexually transmitted diseases Viral hepatitis carrier

Category two (caution)

• • • • • • • • • • • • •

Cervical cancer Diabetes mellitus (uncomplicated) Headaches (severe and if they start after beginning OCPs) Hypertension at 140-159/100-109 mm Hg Major surgery without prolonged immobilization Migraine headaches without focal neurologic involvement. Patients who have a hard time taking the OCP correctly: drug or alchohol abuse mental retardation persistent history as poor OCP takers severe psychiatric disorders Sickle cell disease or sickle C disease Undiagnosed breast mass

Category three (Usually no OCP given)

• • • • •

Gallbladder disease Lactating (6 weeks to 6 months), Less than 21 days postpartum Medications that interfere with OCP efficacy Undiagnosed abnormal vaginal/uterine bleeding.

Category four (OCP contraindicated) Breast cancer • Cerebrovascular accident (active or history) Complicated structural heart disease (with pulmonary hypertension, atrial fibrillation or history of subacute bacterial endocarditis)

• •

Coronary (or ischemic) heart disease (active or history) Deep vein thrombosis or pulmonary embolism (active of history)

Diabetes mellitus (complicated with retinopathy, neuropathy, nephropathy) Headaches (including migraine headaches) with focal neurologic symptoms Hypertension (severe: (160+/110+ mm Hg or with vascular complications)

• Lactation under 6 weeks postpartum Liver disease (including liver cancer, benign hepatic adenoma, active viral hepatitis, severe cirrhosis) • Pregnancy, complicated Surgery (involving the lower extremities and/or prolonged immobilization

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Ortho Evra Patch The contraceptive patch provides contraceptive efficacy similar to COCs but may have an increased risk for cardiovascular complications due to delivery of increased hormonal levels in contrast to oral COCs (14). As noted with the birth control pill, obesity (weight over 90 kg [198 pounds]) leads to reduced contraceptive efficacy, but still levels better than noted with barrier contraceptives (12,13,15,16). Dermatitis can occur as well with patch technology. Females with a history of skin allergy or exfoliative dermatological disorders may not be good candidates for the patch. There is also an increased incidence in breast symptoms, though most are reported to be mild or moderate (14,17). Causes of increased risk of contraceptive failure include having the patch on over seven days, patch detachment, and failure to start a new patch after seven days of being off the patch.

Contraindications to OCPs The World Health Organization has published a list of medical eligibility guidelines to provide clinicians with guidelines for COC use in those with various chronic illnesses that place users at increased risk of complications (see table 2) (18,19). Those in WHO Category 1 have no restrictions to OCP use, while those in Category 2 present with some increased risk, though the risks of pregnancy exceed them. Category 3 conditions have risks that are further increased, such that the pill is not used unless risks for pregnancy are even higher and no alternative contraceptive is available. Conditions found in Category 4 present risks that are so high that OCPs are not prescribed.

Cardiovascular Complications Research has indicated an increased risk of cardiovascular complications in females on COCs (7,20,21). Obese females on birth control pills have an increased risk for pulmonary emboli, thrombophlebitis, and vascular thromboses. Some studies note a greater incidence of myocardial infarction and subarachnoid hemorrhage as well (21). An absolute OCP contraindication is a past history of venous thrombosis (VT) and the risk of VT is more significant for the adolescent or young adult than arterial thrombosis. Significant obesity is a VT risk factor and the risk is increased in obese COC users (12,13,22). Cardiovascular deaths from venous and arterial complications in non-smoking females aged 20-24 years is 2-6 per million per year. There is a 3-6 fold increased risk factor for VT development in COC users and the risk for VT is higher with desogestrel versus levonorgestrel (7,20). The VT risk in the general population is 0.8 per 10,000 women per year, 3-4 for those on COCs, and 6-12 for females who are pregnant or postpartum (20,23,24). Most who develop venous thrombosis do not have identified VT risk factors. Table 3 lists screening questions to use when considering OCPs for contraception. In general, if there is no overt positive family history for VT, one does not need to screen for factor V Leiden or other prothrombotic mutations.

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The pill should be stopped before situations arise requiring prolonged bed rest as with some surgeries. Hypertension and hyperlipidemia may be complications of obesity. Blood pressure should be regularly checked since it may rise in some patients.25 If there is a family or personal history of hyperlidemia, OCPs may still be prescribed if low-density lipoprotein (LDL)levels remain < 160 mg/dl and triglycerides < 250. COCs are not recommended for adolescents (obese or not) if they have congestive heart failure, cardiac shunts, or low output heart disorders.5,26. Table 3. Screening questions about personal/family history of thromboembolism 1. Is there a history of blood clots in legs or lungs in close family members, including uncles and aunts? 2. Have any of your close family members been in the hospital for leg/lung blood clots? 3. Have you and/or close family members ever taking blood thinners? 4. What were the circumstances that led to blood clot (s), as for example while as a result of traveling by airplane?

Diabetes Mellitus Diabetes mellitus may be a complication of or occur incidental of obesity. Current evidence suggests that combined oral contraceptives are safe for obese females with wellcontrolled diabetes mellitus types 1 and 2 (12). COCs do not worsen the metabolic status in diabetic females (12,13,27). Care is needed because of concern over worsening metabolic status due to progestins and increased risk for thromboembolic events due to estrogen (28). COCs should not be offered if they are in poor metabolic control or have hypertension, nephropathy, or retinopathy. Other contraceptive methods that are safe and effective in females with diabetes include progestin-only pills and the intrauterine device (IUD) (13). There may be an increase in recurrent, treatment-resistant vaginal yeast infections in diabetic youth with an IUD (28). The use of depo-medroxyprogesterone acetate or levonorgestrel implant may worsen the metabolic status in diabetic females.

Migraine Headaches Caution is advised when prescribing the birth control pill to an individual with a history of migraine headaches and the COC should be stopped if the migraine aura or headache pattern worsen on COCs (1-4). If the individual has a history of severe migraines or migraines with prolonged auras (as with the hemiplegic or ophthalmoplegic types) the pill should not be given. If the migraine headache and/or the aura worsen while on the pill, it should be stopped immediately. Careful monitoring is advised when placing women with migraines on the pill. It is not known if obesity presents a greater risk for migraine-related cerebrovascular accidents that may be increased by the COCs or patch.

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Table 4. Management of some oral contraceptive related problems PROBLEM Acne

MANAGEMENT Anti-acne measures and medications

Acute/Chronic monilial vaginitis

Anti-fungal agents (as fluconazole); persistent infections: Look for underlying factors, as diabetes mellitus, other endocrinopathies, use of antibiotics, infected male genital tract, others. Oral nystatin may reduce gastrointestinal reservoir; use anti-fungal agents for a protracted period of treatment.

Breakthrough bleeding

Usually a transient condition; ensure patient is taking the pill each day; higher estrogen pill or supplemental estrogen may help; evaluate for underlying pathology

Suspected pregnancy

COCs are not teratogenic but should be stopped as soon as the pregnancy is identified.

Weight gain or edema

Use a lower estrogen pill

Other Conditions Females with active liver disease should not be placed on OCPs. The effect of obesityrelated NASH (nonalcoholic steatohepatitis) on COCs not clear at this time. Youth with obesity may be at risk for depression and no obesity-related complications with SSRIs are reported. Tricyclic antidepressants can reduce estrogen levels with increased BTB but not reduced contraceptive efficacy. St. John’s wart is used to treat depression and can lead to increased break-through bleeding and anecdotal reports of reduced OC efficacy (1-4). Some females with obesity are at increased risk for fungal infections and some anti-fungal agents are potent hepatic enzyme inducers with resultant decreased contraceptive efficacy; these agents include griseofulvin, ketoconazole and itraconazole. Other drugs can interfere with contraceptive efficacy, such as rifampin. Table 4 lists management principles for miscellaneous side effects of COCs.

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Progestin-Only Pills (POPs) (Mini-Pills) POPs contain 0.35 mg of norethindrone (Micronor®; Nor-Q.D®) and 0.075 mg of norgestrel (Ovrette®). Obesity may be associated with reduced contraceptive efficacy (13). POPs are typically used in those individuals having disorders where estrogen may be contraindicated – such as sickle cell anemia, cyanotic heart disease, severe hypertension, diabetes mellitus, and others (see table 2). Some clinicians have not recommended the minipill for teenagers because of its increased pregnancy rate as well as frequent breakthrough bleeding and amenorrhea noted in some females on the mini-pill (1-4). POPs are avoided in those with a history of ectopic pregnancy and those taking certain medications (as anticonvulsants, griseofulvin and rifampin). There is no increase in VT in obese females on progestin-only pills (12,13).

Depot-Medroxyprogesterone Acetate (DMPA) The main injectable contraceptive available in the US is depomedroxy-progesterone acetate (Depo-Provera®). It is given in a dose of 150 mg intramuscularly every three months and DMPA has a better contraceptive efficacy than the COC with a failure rate of 0.3%. No decreased contraceptive efficacy is noted in obese females versus normal weight females (13). Its mechanism of action includes an induction of a low FSH/LH level, low LH surge, production of an atrophic endometrium, and thickening of the cervical mucus. Side effects include irregular menses, amenorrhea, acne, breast tenderness, weight gain (with bloating), decrease in bone density, decrease in high-density lipoprotein levels, and some behavioral changes such as irritability and depression. It is useful where a highly effective contraceptive is needed and where the side effects of an estrogen-type contraceptive must be avoided. Thus, it has been used for individuals with cyanotic heart disease, sickle-cell anemia, thrombophlebitis, and others. Internationally, psychotic and retarded individuals who are at risk for pregnancy have been prescribed this injectable contraceptive. It is considered to be a very effective hormonal contraceptive for obese females, despite the reported change in body composition towards fatness and central redistribution of fat following its use. Another injectable contraceptive, Lunelle® (5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate [MPA/E2C]), was approved by the FDA in 2000. Estrogen is added to allow a better menstrual period rhythm than seen with Depo-Provera. Less weight gain is noted and overall adverse effects are similar to COCs (29). Lunelle® is given intramuscularly every 28-30 days and it has a high contraceptive efficacy rate (30). One study noted that there was a weight gain of 0.9 kg to 1.8 kg if the female weighed under 68 kg versus a weight gain of 1.4 to 3.6 kg if over 68 kilograms (30). There is no overt contraindication in females with obesity.

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Emergency Contraceptives Emergency contraceptives (EC) are among the most controversial and under prescribed contraceptive methods (seee table 5)(31). Obesity is not a contraindication to use of ECs. Anti-emetics can be given to prevent the frequent occurrence of nausea and emesis that occurs with high dose estrogen; thus, an antiemetic should be taken an hour before taking these pills. In 1999, the US Food and Drug Administration (FDA) approved of Plan B®, a progestin-only method with two tables of 0.75 mg of levonorgestrel. The first tablet is taken immediately and the second tablet is taken two hours later. Because Plan B® contains no estrogen, nausea and vomiting is uncommon and there is no need to obtain a pregnancy test before administation. Thus, Plan B may be better tolerated than those with estrogen (32). Though the official recommendation is that they must be used within three days of coitus, they may be effective in pregnancy prevention within five days. Table 5. Emergency contraceptives • • • • • •

Ovral® : 2 tablets followed by 2 tables in 12 hours Lo/Ovral®, Nordette® or Levlen® : 4 tabs and 4 more in 12 hours Plan B®: levonorgestrel, 0.75mg followed by 0.75 mg in 12 hours Preven® Emergency Contraceptive Kit Ovrette®: 20 tabs and 20 more in 12 hours TriPhasil® or Tri-Levlen® (yellow tabs only): 4 tabs, and 4 more in 12 hours

NuvaRing® (Vaginal Ring) This is a soft, flexible, transparent vaginal ring made of a ethylene vinyl acetate copolymer; it has an outer diameter of 54 mm and a cross-section of 4 mm (2,4). There are two steroid reservoir cores that provide a daily hormonal release of 15 mcg of ethinyl estradiol and 120 mcg of etonogestrel (an active metabolite of desogestrel) (30,33). Side effects include extended withdrawal bleeding, vaginal discomfort, nausea, headache, nervousness, acne, breast tenderness, leukorrhea, reduced libido, and slight weight gain. There is an increased risk of thrombotic diseases (34). There is usually less irregular bleeding than seen with COCs. Extremely overt weight females may have trouble inserting the ring. Obesity itself does not effect the contraceptive efficacy of the NuvaRing and it is considered as one of the most effective hormonal contraceptive methods for obese females.

Implanon® Norplant® was the first implantable contraceptive developed and was very effective as a contraceptive. It contains six silastic levonorgestrel-containing rods; however, it was withdrawn from the United States market in 2000 (2,4). The Jadelle® implant (Norplant II) contains two silastic rods with levonorgestrel and Implanon® contains one rod (vinyl

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ethylene acetate polymer) with etonogestrel (7,35). Both Jadelle® and Implanon® are approved by the FDA for three years and are not contraindicated in obesity, though both may induce some weight gain. Though obese females have been found to have lower serum etonogestrel levels, there is no reduced efficacy noted with Implanon in obese female (13,36).

Intrauterine Device (IUD) There are three IUDs which currently are used in the United States: Progestasert IUD®, the ParaGard® (Copper T380A) and the Mirena IUD (2,4,37-39). Previous controversial IUD links with pelvic inflammatory disease (PID) have limited its application to adolescents. However, the IUD is an excellent contraceptive method with no contraindication in obese women. The Mirena® IUD (Levonorgestrel-containing IUD; LNG-IUD) was FDA-approved in 2001 for five years and contraindications are active PID, prosthetic heart valves, history of subacute bacterial endocarditis, and distorted uterine cavity. The most common side effect is menstrual bleeding; there is increased bleeding and spotting during the first 3-6 months after insertion that usually decreases after this time. Obese females have an increased incidence of dysfunctional uterine bleeding and endometrial hyperplasia, making the Mirena IUD a good contraceptive choice for obese females needing contraception (12). No reduced contraceptive efficacy has been noted because of obesity (13,40). In diabetic patients, an increase in vaginal yeast infections should be taken under consideration.

Conclusions Contraceptive efficacy is reduced in obese females on the combined oral contraceptive and the contraceptive patch; however, the efficacy is still above that noted with barrier contraceptives. COCs are safe with obese females with diabetes mellitus if they are in good control and do not have nephropathy, retinopathy, neuropathy, or hypertension. Progestinonly pills are safe in obese females but decreased contraceptive efficacy is noted in all females on this contraceptive method. Obesity is not a contraindication to use of depomedroxyprogesterone acetate, IUD, and intravaginal ring. The mini-pill and levonorgestrel IUD may be the safest for obese females needing contraception (12).

References (1) (2) (3)

Greydanus DE, Patel DR, Rimsza ME. Contraception in the adolescent: An update. Pediatrics 2001;107(3):562-73. Greydanus DE, Patel D. Contraception in the adolescent: Preparation for the 1990's. Med Clin North Am 1990;74(5):205-24. Greydanus DE. Contraception. In: Greydanus DE, Patel DR, Pratt H, Bhave S, eds. Course manual for adolescent health. Kalamazo, MI: Michigan State Univ Coll Hum Med, 2002:309-24.

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(12)

(13) (14) (15) (16)

(17)

(18) (19) (20) (21) (22)

(23) (24)

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Greydanus DE, Rimsza ME, Matytsina L. Contraception for college students. Pediatr Clin North Am 2005;52:135-61. Gittes EB, Strickland JL. Contraceptive choices for chronically ill adolescents. Adolesc Med 2005;16(3):635-44. Rimsza ME. Contraception in adolescents. In: Greydanus DE, Patel DR, Pratt DH, eds. Essentials of adolescent medicine. New York: McGraw-Hill Med Publ, 2005:27. Klein JD, Barratt MS, Blythe MJ, et al. Contraception and adolescents. Pediatrics 2007;120:1135-48. Chuang CH, Chase GA, Bensyl DM, Weisman CS. Contraceptive use by diabetic and obese women. Women’s Health Issues 2005; 15:167-73. Holt VL, Cushing-Haugen KL, Kaling JR. Body weight and risk of oral contraceptive failure. Obstet Gynecol 2002; 99(5 Pt 1): 820-7. Holt VL, Scholes D, Wicklund KG, et al. Body mass index, weight, and oral contraceptive failure risk. Obstet Gynecol 2005;105(1):46-52. Brunner Huber LR, Hogue CJ, Stein AD, et al. Body mass index and risk for oral contraceptive failure: a case-cohort study in South Carolina Ann Epidemiol 2006;16(8):637-43. ACOG Practice Bulletin. Use of hormonal contraception in women with coexisting medical conditions. Clinical Management Guidelines for Obstetrician-Gynecologists. Obstet Gynecol 2006;107:1453-72. Teal SB, Ginosar DM. Contraception for women with chronic medical conditions. Obstet Gynecol Clin North Am 2007;34:113-26. Sicat BL. Ortho Evra, a new contraceptive patch. Pharmacotherapy 2003; 23:472-80. Ortho Evra. A contraceptive patch. Med Lett 2002; 44:8. Zieman M, Guillebaud J, Weisberg E, et al. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril 2002;77(2 Suppl):S13-8. Sibai BM, Odlind C, Meador ML, et al. A comparative and pooled analysis of the safety and tolerability of the contraceptive patch (Ortho Evra/Evra). Fertil Steril 2002;77(Suppl 2):S19-26. World Health Organization. Medical eligibility criteria for contraceptive use, 2ed. Geneva: WHO, Reprod Health Res, 2000. World Health Organization. Medical eligibility criteria for contraceptive use, 2ed. Geneva: WHO, Reprod Health Res, 2002. Vandenbrouke JP, Rosing J, Bloemenkamp KWM, et al.: Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001;344:1527-35. Sheldon T. Venous thromboembolism and oral contraceptives. BMJ 324:869, 2002. Sidney S, Petitti DB, Soff GA, et al. Venous thromboembolic disease in users of lowestrogen combined estrogen-progestin oral contraceptives. Contraception 2004;70(1):310. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999;353:125865. Kujovich JL. Hormones and pregnancy: thromboembolic risks for women. Br J Haematol 2004;126:443-54.

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(25) Mottram Hall Guidelines. Evidence-guided prescribing of the pill. Carnforth: Parthenon Publ, 1996. (26) Heroux K. Contraceptive choices in medically ill adolescents. Semin Reprod Med 2003;21(4):389-98. (27) Garg SK, Chase HP, Marshall G, et al. Oral contraceptives and renal and retinal complications in young women with insulin-dependent diabetes mellitus. JAMA 1994;271:1099-1102. (28) Owens K, Honebrink A. Gynecologic care of medically complicated adolescents. Pediatr Clin North Am 1999;46:631-42. (29) Freeman S. Contraceptive efficacy and patient acceptance of Lunelle. J Am Acad Nurs Pract 2002;14:241-346. (30) Keder LM. Tips for clinicians: New developments in contraception. J Pediatr Adolesc Gynecol 2002;15:179-81. (31) Trussell J, Ellertson C, Steward F, et al. The role of emergency contraception. Am J Obstet Gynecol 2004;190(Suppl 4):S30-8. (32) Emergency contraception OTC. Med Lett 2004;46:10-11. (33) Mulders TM, Dieben TO, Bennick HJ. Ovarian function with a novel combined contraceptive vaginal ring. Hum Reprod 2002; 17:2594-9. (34) Murphy NA, Elias ER. Council on children with disabilities. Sexuality of children and adolescents with developmental disabilities. Pediatrics 2006;118:398-403. (35) Glasier A. Implantable contraceptives for women: effectiveness, discontinuation rates, return of fertility, and outcome of pregnancies. Contraception 2002;65:29-37. (36) Huber J, Wenzl R. Pharmacokinetics of Implanon: an integrated analysis. Contraception 1998;58(6 Suppl):85S-90. (37) Arias RD. Compelling reasons for recommending IUDs to any woman of reproductivde age. Int J Fertil 2002;47:87-95. (38) A progestin-releasing intrauterine device for long-term contraception. Med Lett 2001;43:7-8. (39) Baldaszti E, Wimmer-Puchinger B, Loschke K. Acceptability of the long-term contraceptive levonorgestrel-releasing intrauterine system (Mirena): a 3-year follow-up study. Contraception 2003;67:87-91. (40) Mansour D. Implications of the growing obesity epidemic on contraception and reproductive health. J Fam Plann Reprod Health Care 2004;30(4):209-11.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXXVII

Nutrition and Adolescent Obesity Vinay N. Reddy∗ Pediatrics and Human Development, Michigan State University College of Human Medicine, Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, MI, USA

Abstract The prevalence of obesity has increased to epidemic proportions in the United States in recent years. Obesity in the Western world is a disease of poverty that is seen much more often in minority populations. Obesity-related illnesses, such as type II diabetes, are now seen frequently in adolescents and even in younger children. Caloric intake has increased in adolescents over the last two decades along with changes in dietary composition fueled by advertisements of unhealthy foods by various food producers. Nutritional modification is an essential part of any weight-loss program. This article discuss various diet changes that are important to reverse this current trend of increasing obesity in all populations and ages. Highly-restrictive diets should be reserved only for the morbidly obese child or for those with obesity-related problems such as sleep apnea.

Keywords: Nutrition, obesity, diabetes, diet.

∗

Correspondence: Vinay N. Reddy MD, Assistant professor, Pediatrics and Human Development, Michigan State University College of Human Medicine, Michigan State University/Kalamazoo Center for Medical Studies, 1000 Oakland Drive, Kalamazoo, Michigan 49008-1284 United States. Tel: 269-337-6450; Fax: 269-3376474; E-mail: [email protected]

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Introduction In recent years the prevalence of obesity has increased steadily in the United States, and the rate of increase has itself increased, especially over the last 25 years (1-5). Although one might expect obesity to be more prevalent among people of higher socioeconomic status with better nutritional access, the converse is true; indeed, the prevalence of obesity in much of the developed world increases with poverty. In the United States obesity is much more prevalent among American Hispanics (21.8%) and African-Americans (21.5%) than among Caucasians (12.3%), with a prevalence of 26.6% among teenage and preteen African-American females (1,6-8). Obesity-related illnesses, such as type II diabetes mellitus, previously observed only in later adulthood, are being seen more often in adolescence and sometimes in the preteen years. Many problems with treatment of obesity arise from obesity risk factors (9). Health-care professionals and the general publicassume that increases in adolescent’s caloric intake, coupled with decreases in their physical activity, are responsible for the increased prevalence of obesity. However, published data from the United States shows that caloric intake among children over the last three decades remained relatively constant from the 1970s until the late 1980s. From then until 2000, caloric intake increased among adolescent females, especially white and black females, with larger increases toward the end of this period (10). Similarly, the United States Department of Agriculture data shows decreased average caloric intake for the general United States population from the mid-1960s to 1991, followed by an increase in the mid-1990s (11). These trends do not explain the steady and accelerating increase in prevalence of obesity over the past thirty years, nor do they fit the observed increases in prevalence among ethnic groups, especially Hispanics. Many experts conclude that decreased physical activity and the resulting fall in caloric consumption have contributed to the recent increase in obesity, and that physical activity has decreased due to the rapid increase in television watching since the 1960s, and more recently to the even more rapid increase in adolescent’s use of the internet, both of which are physically sedentary activities. Many studies of risk factors for obesity in adolescents have shown significant associations between obesity and television watching, although some studies did not support this conclusion (11-18). Increased television watching is associated with increased BMI (19,20), increased food consumption (21) and decreased fruit and vegetable consumption (22). Other contributing factors for children in urban areas may include use of cars or mass transit rather than walking (17) and inability to play safely outdoors due to neighborhood crime in association with low socioeconomic status (23,24). Significantly decreased physical activity has been observed among female college freshmen within 5 months after starting college; this gain is accompanied by a significant decrease in caloric intake along with significant increase in body-weight parameters, suggesting suggests that decreased activity was a major contributor to this weight gain (25). Unfortunately, there is little data available on how children’s or adolescent’s physical activity and caloric consumption have changed over the years, and there is evidence that decreased physical activity occurs after obesity develops, rather than before (26). Changes in dietary carbohydrate and fat intake are also blamed for the increased prevalence of obesity. Excessive fat intake by some persons, especially those predisposed to

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obesity, certainly seems to lead to obesity. Although fat-laden foods -- especially fast foods -have been strongly linked to the development of obesity in the media, fat consumption by children has decreased over the last 30-35 years (10,27). Carbohydrate consumption, on the other hand, has increased over the same time period and seems to be related to the emphasis seen in recent years on decreasing dietary fat intake, which has resulted in fat calories being largely replaced by simple carbohydrate calories (28). Calcium intake has decreased due to the substitution of soft drinks and non-citrus fruit juices for milk, which is perceived to be a source of fat. Many parents believe that fruit juices and fruit drinks are “healthier” than milk because they contain nutrients found in the source fruits. However, the actual nutritional value of fruit juices is quite low, especially for clear juices such as those from apples and grapes which are little more than flavored sugar water in which grape juice is 1/7 sugar by weight (29,30). Carbohydrate composition of foods is commonly classified using the glycemic index (31), which is in general higher for simple sugars and starches (e.g., potatoes, refined grains, and many fruit juices), lower for whole grains and legumes, and lowest for non-starchy fruits and vegetables. High glycemic-index diets have been associated with obesity (32) and type II diabetes mellitus (33) in adults; these associations may hold in children and adolescents, but this has not yet been confirmed. Also, postprandial hyperinsulinemia is associated with weight gain, and low glycemic-index diets appear to decrease postprandial hyperinsulinemia, while also being associated with weight loss in obese patients (9). Unfortunately, foods high in fat and/or refined carbohydrates taste good, especially to children and adolescents. They are also less expensive and more convenient than more nutritionally valuable foods, especially in the Western world; this may explain why economically disadvantaged children in the United States are more likely to be obese. Attempts to replace high-fat, high-carbohydrate foods in school lunch programs have been met with protests from children and adolescents served by those programs, who would much rather eat nachos and pizza (6). The media affects children’s dietary choices as well as their activity levels. Saturday-morning children’s television is largely financed by brand-name advertising for fast-food chains and food manufacturers, and much of that advertising is for high-fat, high-sugar, and high-salt foods. A similar pattern is seen in food-related advertising on prime-time television, and young children prefer the taste of food in fast-food chain packaging to the identical food in plain wrappers, especially if they have multiple TV sets in their homes and/or if they eat fast food frequently (34). A 1999 analysis of the percentage of advertising for each food group in the USDA Food Guide Pyramid (35) showed a massive overemphasis on high-calorie foods (fats, oils, sweets, and grain-based foods), with only 12% of food advertising promoting vegetables and fruits (36). There is an inherited component to obesity as well. Many genetic syndromes are associated with obesity, as are endocrine disorders such as Cushing’s disease and hypothyroidism (37,38). Hypothyroidism does not appear to be a primary cause of massive obesity, although modest weight loss is noted with treatment (39). However, much of the familial component of obesity seems to be environmental. Obesity in children and adolescents has been associated with both maternal and paternal obesity (18,40-42). Although this may be partly genetic and, in the case of maternal obesity, partly due to gestational influences, socioeconomic factors shared by parents and children are certainly responsible as

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well; examples include lack of physical activity and indulgence in fast foods and other highfat, high-carbohydrate food. In some countries, although not in Western countries, adolescents have been found to underestimate their body weight significantly, especially when they are overweight or obese (43). This is in contrast to the overestimation seen in anorexia nervosa and bulimia nervosa, but appears to be related to cultural norms and their effect on self-image. Obesity has also been associated with social factors, including low family income and lower cognitive stimulation at home (44). This may explain in part racial and ethnic differences in the prevalence of obesity, although some of these differences persist when corrected. A history of neglect and/or abuse, especially sexual abuse, is also associated with obesity (45, 46).

Nutritional Treatment Even a brief look at the media reveals multitudes of weight-loss programs, diets, and medical treatments for obesity. Some of them may actually work, at least for a while, at least in adults, and at least until deleterious effects or lack of long-term relief are seen. The story of damage produced by fenfluramine should be remembered in this regard, as reviewed elsewhere in this issue on obesity. Obese children and adolescents are more difficult to treat. Social and economic considerations, especially family issues, must be addressed, and the entire family must make the required lifestyle changes (47). The goals of treatment must also be realistic. Many patients expect the same results seen in the before-and-after advertisements for weight-loss programs; however, weight loss of that extent is often not possible without medication and/or surgery. However, moderate weight loss -- 5-10% of weight at presentation, for example -- can produce significant improvement in blood pressure, glucose, and lipids (48). It may be most practical, and beneficial especially to the growing child or teenager to maintain weight at a particular range rather than to seek actual weight loss. Also, early treatment is of benefit even in young children, both to avoid childhood complications (e.g., sleep apnea, orthopedic disease) as well as adult complications (e.g., type 2 diabetes, coronary vascular disease) and to avoid or lessen the psychosocial consequences of obesity. Dietary modification, combined with increased and regular physical activity, is a cornerstone of therapy for obesity. These interventions work best when they take place simultaneously (49). Diet changes should be made by the entire family and emphasize increasing consumption of healthy foods that include vegetables, whole fruits, and whole grains while avoiding highfat, high-simple-carbohydrate foods such as juices, sweetened drinks, fats (especially saturated fats), and refined carbohydrates (sweets, baked goods containing white flour and/or simple sugars). Many dietary modification plans are based on the USDA Food Guide Pyramid,35 which is easier to follow for most children and families than counting calories with every meal. Table 1 lists simple and realistic strategies for diet modification (50). One program, the “Traffic Light Diet” (52) uses simple categories (Red Light [avoid], Yellow Light [approach-with-caution], and Green Light [at-all-you-want]; it also provides a list of foods in each of the major food groups (grains, fruits/vegetables, dairy, and meat, with a fifth miscellaneous category). This program teaches children and families to make healthy

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food choices. When used in combination with exercise and behavioral modification, this diet program has produced long-term weight loss in children (53). Table 1. Simple and realistic strategies for diet modification (50) • • • • • •

Reducing consumption of specific high-calorie foods, such as candy or potato chips, without entirely eliminating them from the diet. Replacing high-calorie snacks such as cookies or baked goods with low-calorie alternatives such as fruits. Reducing portion sizes when preparing meals, and when eating out. Eating out less often, and choosing low-calorie foods such as vegetables instead of high-calorie foods such as French fries. Limiting drinks containing large amounts of sugar, including fruit juices (even 100% juices are high in simple sugars) and soft drinks. Eating meals as a family as frequently as possible (this helps children and their parents support each other in implementing the above strategies, and has been shown to be of benefit in adolescents51 as well as in younger children).

Regular meals, especially breakfast, also seem to be important in prevention of obesity. Cross-sectional studies have shown an inverse relationship between regularly eating breakfast and development of obesity. One recent prospective study shows a direct association between breakfast frequency and carbohydrate as well as fiber intake; it also noted an inverse and dose-related relationship between breakfast frequency and BMI, although these relationships have not yet been shown to be causal (54). Severely obese patients, such as the morbidly obese or those with acute obesity-related problems such as sleep apnea, may need more restricted diets such as those high in protein (i.e., 1.5 to 2.5 g/kg/day) and very low in calories (i.e., 600-900 kcal/day) with extremely limited carbohydrate as well as fat intake and a minimum water intake of 1.5 liters per day. These diets are usually deficient in essential vitamins and in some minerals, which must be provided by appropriate supplements. Close monitoring by the physician and nutritionist is essential when using these diets to ensure compliance by the patient and family as well as to avoid, detect, and treat potential medical complications (55-57). Exercise is important, but cannot by itself reduce weight (58). Since ability to exercise decreases with increased BMI, regular exercise must begin before morbid obesity renders the patient immobile (59). There are many approaches possible to increasing physical activity and reducing a sedentary lifestyle; examples include increased activity at school during lunch and recess, walking or bicycling to school, enrollment in summer schools or summer camps (60) and reducing television viewing (13,21,61). Psychotherapy may also be helpful in selected cases (62) and inpatient treatment may be especially useful when family support for treatment is lacking. A combination of dietary changes, organized and supervised exercise, and cognitive-behavioral therapy in a 10-month (one school year) inpatient program resulted weight loss at discharge that was sustained 14 months after discharge (63). If diet modification and increased exercise do not yield weight stabilization or weight loss, further investigation should address the extent and severity of obesity co-morbidities. Pharmacologic

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treatment may be considered at this stage as an adjunct to continued diet and exercise, as reviewed elsewhere in this issue on obesity.

Conclusions The prevalence of obesity has increased to epidemic proportions in the United States in recent years. Factors behind this problem include some increase in caloric intake stimulated by the good taste of high-fat and high-carbohydrate foods along with strong advertising for these unhealthy foods by their producers. Nutritional modification is an essential part of any weight-loss program. Diet changes, which should be made by the patient’s entire family for best results, include adding more vegetables, whole fruits, and whole grains to the diet while avoiding high-fat and high-simple-carbohydrate foods such as juices, sweetened drinks, fats (especially saturated fats), and refined carbohydrates. Reducing consumption of specific high-calorie foods such as candy and potato chips, replacing high-calorie snacks with lowcalorie ones, limiting high-sugar drinks, eating smaller portions, eating more often at home, and eating meals as a family are simple and realistic strategies for reducing caloric intake. Eating regular meals, especially breakfast, may also help avoid obesity. Highly-restrictive diets should be reserved only for the morbidly obese child or teenager and for those with obesity-related problems such as sleep apnea.

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(2) (3) (4) (5) (6) (7)

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(28) Cavadini C, Siega-Riz A, Popkin B. US adolescent food intake trends from 1965 to 1996. Arch Dis Child 2000;83:18-24. (29) United States Department of Agriculture Nutrient Data Laboratory. (30) Wagner PM. Grapes into wine. New York: Alfred A Knopf, 1976: 105. (31) Ludwig D, Eckel R. The glycemic index at 20 y. Am J Clin Nutr 2002;76(suppl):264S5. (32) Brand-Miller J, Holt S, Pawlak D, McMillan J. Glycemic index and obesity. Am J Clin Nutr 2002;76(suppl):281S-5. (33) Willett W, Manson J, Liu S. Glycemic index, glycemic load, and risk of type 2 diabetes. Am J Clin Nutr 2002;76(suppl):274S-80. (34) Robinson TN, Borzekowski DLG, Matheson DL, Kraemer HC. Effects of fast food branding on young children's taste preferences. Arch Pediatr Adolesc Med 2007;161(8):792-7. (35) United States Departments of Agriculture and Health and Human Services. Nutrition and your health: Dietary guidelines for Americans, 4th ed. Washington, DC: US Dept Agriculture, 2000. (36) Byrd-Bredbenner C, Grasso D. A comparative analysis of television food advertisements and current dietary recommendations. Am J Health Studies 1999;15:169-80. (37) Snyder E, Walts B, Perusse L, Chagnon Y, Weisnagel S, Rankinen T, et al. The Human Obesity Gene Map: The 2003 Update. Obes Res 2004;12(3):369-439. (38) Jones K. Smith's recognizable patterns of human malformation, 5th ed. Philadelphia, PA: WB Saunders, 1997. (39) Styne D, Schoenfled-Warden N. Obesity. In: Rudolph C, Rudolph A, eds. Rudolph's pediatrics, 21 ed. New York: McGraw Hill, 2003:2136-42. (40) Ramos de Marins V, Almeida R, Pereira R, de Azevedo Barros M. The relationship between parental nutritional status and overweight children/adolescents in Rio de Janeiro, Brazil. Public Health 2004;118(1):43-9. (41) Savva S, Kourides Y, Epiphanou-Savva M, Tonaritis M, Kafatos A. Short-term predictors of overweight in early adolescence. Int J Obes Relat Metab Disord 2004;28(3):451-8. (42) Power C, Parsons T. Nutritional and other influences in childhood as predictors of adult obesity. Proc Nutr Soc 2000;59:267-72. (43) Al-Sendi A, Shetty P, Musaiger A. Body weight perception among Bahrain adolescents. Child Care Health Dev 2004;30(4):369-76. (44) Strauss RS, Knight J. Influence of the home environment on the development of obesity in children. Pediatrics 1999;103(6):e85. (45) Lissau I, Sorenson T. Parental neglect during childhood and increased risk of obesity in young adulthood. Lancet 1994;343(8893):324-7. (46) Zametkin AJMD, Zoon CKBS, Klein HWBS, Munson SBA. Psychiatric Aspects of Child and Adolescent Obesity: A Review of the Past 10 Years. J Am Acad Child Adolesc Psychiatry 2004;43(2):134-50. (47) Strauss R. Childhood obesity. Ped Clin North Am 2002;49(1):175-201.

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(48) Goldstein D. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord 1992;16(6):397-415. (49) Fulton J, McGuire M, Casperson C, Dietz W. Interventions for weight loss and weight gain prevention among youth: Current issues. Sports Med 2001;31(3):153-65. (50) Mullen MC, Shield J, eds. Childhood and adolescent overweight: The health professional's guide to identification, treatment and prevention. Chicago, IL: Am Diet Assoc, 2004. (51) Neumark-Sztainer D, Eisenberg ME, Fulkerson JA, Story M, Larson NI. Family meals and disordered eating in adolescents: Longitudinal findings from project EAT. Arch Pediatr Adolesc Med 2008;162(1):17-22. (52) Epstein L. Family-based behavioural intervention for obese children. Int J Obes Relat Metab Disord 1996;20(Suppl 1):S14-S21. (53) Epstein LH, Valoski A, Wing RR, McCurley J. Ten-year outcomes of behavioral family-based treatment for childhood obesity. Health Psychol 1994;13(5):373-83. (54) Timlin MT, Pereira M, Story M, Neumark-Sztainer D. Breakfast eating and weight change in a 5-Year prospective analysis of adolescents: Project EAT (Eating Among Teens). Pediatrics 2008;121(3):e638-45. (55) Hirsch J, Hudgins L, Leibel R, Rosenbaum M. Diet composition and energy balance in humans. Am J Clin Nutr 1998;67(3):551S-5. (56) St. Jeor ST, Howard BV, Prewitt TE, Bovee V, Bazzarre T, Eckel RH. Dietary protein and weight reduction: A statement for healthcare professionals from the nutrition committee of the council on nutrition, physical activity, and metabolism of the American Heart Association. Circulation 2001;104(15):1869-74. (57) Willi S, Oexmann M, Wright N, Collop N, Key L. The effects of a high-protein, lowfat, ketogenic diet in adolescents with morbid obesity composition, blood chemistries, and sleep abnormalities. Pediatrics 1998;101:61-6. (58) Saris W. Exercise with or without dietary restriction and obesity treatment. Int J Obes Relat Metab Disord 1995;19(Suppl 4):S113-6. (59) Speiser PW, Rudolf MCJ, Anhalt H, Camacho-Hubner C, Chiarelli F, Eliakim A, et al. Childhood obesity. J Clin Endocrinol Metab 2005;90(3):1871-87. (60) Jago R, Baranowski T. Non-curricular approaches for increasing physical activity in youth: a review. Prev Med 2004;39(1):157-63. (61) Robinson TN. Reducing children's television viewing to prevent obesity: A randomized controlled trial. JAMA 1999;282(16):1561-7. (62) Eliakim A, Kaven G, Berger I, Friedland O, Wolach B, Nemet D. The effect of a combined intervention on body mass index and fitness in obese children and adolescents - a clinical experience. Eur J Pediatr 2002;161:449-54. (63) Braet C, Tanghe A, Decaluwe V, Moens E, Rosseel Y. Inpatient treatment for children with obesity: Weight loss, psychological well-being and eating behavior. J Pediatr Psychol 2004;29(7):519-29.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXXVIII

Dermatologic Aspects of Obesity Donald Hare∗ Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, MSU/Kalamazoo Center for Medical Studies, Kalamazoo MI, USA

Abstract Obesity presents special challenges for skin care and is associated with several conditions that need careful attention. Among the conditions reviewed here include acanthosis nigricans, papillomatosis of Gougerot and Carteaud, polycystic ovary syndrome, striae distensae, Cushing disease, and Cushing syndrome in relation to their dermatologic aspects. Various treatment modalities reviewed include bathing, soaps, cleansers, shampooing, emollients, topical corticosteroids, topical antibacterials, antifungals, and topical retinoids.

Keywords: Dermatology, obesity, child health, treatment.

Introduction Obesity in adolescents presents special challenges for skin care and is associated with several conditions that need careful attention. First, this article considers basic dermatologic anatomy and physiology followed by mention of some basic research perspectives regarding ∗

Correspondence: Donald Hare, MD, Associate Professor, Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, MSU/Kalamazoo Center for Medical Studies, 1000 Oakland Drive, Kalamazoo MI 49008-1284 United States. Tel: 269-337-6450; Fax: 269-337-6474; E-mail: [email protected]

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clinical dermatologic conditions. Then the discussion reviews dermatologic conditions including acanthosis nigricans, papillomatosis of Gougerot and Carteaud, polycystic ovary syndrome, striae distensae, Cushing disease, and Cushing syndrome in relation to their dermatologic aspects. Various treatment modalities reviewed include bathing, soaps, cleansers, shampooing, emollients, topical corticosteroids, topical antibacterials, antifungals, and topical retinoids.

Anatomy and Physiologogy The skin has the largest surface area of the body and in the obese individual, the area gradually increases with body size. When obesity starts in childhood as it usually does, the skin increases in growth at a normal pace; however, if weight gain is rapid, at some point stretching may occur resulting in striae or stretch marks which may leave atrophic lines. These may be permanent or may heal and disappear. The skin is a dynamic organ. The epidermis provides mechanical, physical (e.g. U-V), chemical, and immunological protection from the external environment maintaining a homeostatic internal environment for the body. The subcutaneous fat layer provided protection from cold and heat. The inner layer of the epidermis is the stratum spinosum. The basal layer is a factory of metabolism providing Vitamin D and antibody production. Oil glands provide lubrication and sweat glands help with heat regulation. The dermis which meshes with the epidermis through the rete peges consist of fibroblasts and collagen and is a tough protective layer. The subcutaneous layer underneath is a vascular layer that contain the fat cells that dynamically produce the endocrine leptin which when called upon along with gastric grehlin controls appetite to maintain a balanced intake of fuel. The color of the skin depends on many factors. Melanocytes in the stratum spinosum are increased in numbers in dark skinned people but are also stimulated to increase in numbers in areas around the neck, axillae, and other areas in obesity and are a marker for insulin resistance and type 2 diabetes mellitus.

Current Research Perspectives The agouti gene defect causes obesity and yellow coat color in mice. In these mice, the agouti-signaling protein α133 amino acid peptide is over abundant in many tissues. This protein inhibits the binding of melanocyte stimulating hormone (MSH) to its receptor in the skin (melanocortin-1 receptor) and therefore, reduces melanin pigmentation in the stratum spinosum (1). The agouti gene defect then could explain the increase in melanocyte stimulating hormone and increase in melanin pigmentation as seen in acanthosis nigricans. When transgenic mice are developed deleting the melanocortin-4 receptor, the mice become hyerphagic and obese (2). When melanocortin-3 receptors are deleted mice also become obese. Leptin is actively produced in fat cells and it signals the brain to reduce food intake. Defects in leptin receptors have been shown in the mouse model to increase fat mass. These

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hormones and their receptors in the skin and subcutaneous tissue as well as other parts of the body are part of the complex metabolic disorder that is responsible for obesity and insulin resistance. Leptin deficient mice (OB or LEP gene) have hyperphagia, insulin resistance, and hyperinsulinemia. The study of the human genome has advanced rapidly and may identify many gene defects responsible for obesity and may lead to new therapies to identify and treat these gene disorders. Children born with an absence of leptin have been identified. They gain rapidly after birth with a voracious appetite (3,4). People with leptin mutation defects have been identified and have been treated successfully with recombinant leptin. It has been suggested that obese children and youth should have leptin levels to compare with the normal. One child with leptin deficiency was treated with recombinant leptin and lost 16.4 kg of adipose tissue over a 12-month period (5). Leptin used for obese adults with normal leptin levels has resulted in some weight loss. Issues regarding such medication as sibutramine, octreotide and metformin therapy are discussed elsewhere. Selected specific dermatologic disorders are now considered.

Acanthosis Nigricans (AN) AN is a cutaneous disorder characterized by light brown to black veruccous or papillomatous lesions that may appear in any part of the body, but characteristically in the neck, axillae, and in the groin. It may be seen on the knuckles, the perineum, and the breasts. It may appear in childhood or adolescence as a marker for insulin resistance and it is found in various ethnic groups as noted in table 1. AN may be rarely associated with malignancy. Therapy for AN is not very successful. It seems to be related to circulating peptides, Cpeptide or other unknown factors associated with insulin resistance. Good management of the metabolic syndrome or type 2 diabetes seems to improve the AN in patients with these problems (6,7). Table 1. Percentage appearance of acanthosis nigricans in ethnic groups -

Adolescents of European origin – 0.5% Adolescents of Hispanic origin – 6.0% Adolescents of African American origin – 13.0% Adolescents of Native American origin – 40%

Confluent and Reticulate Papillomatosis of Gougerot and Carteaud This condition can be confused with AN. There is black papillomatosis but no true hyperpigmentation. It appears around the neck and chest. It will not wash off with soap and water but will come off with alcohol. It responds to the tetracycline class of antibiotics.

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Polycystic Ovary Syndrome (PCOS) This is another disorder of insulin resistance with obesity that must be recognized in the adolescent female. It is associated with ovulatory dysfunction and hyperandrogenism. There are increased testosterone and adrenocorticosteroid levels and it is the most common cause of sterility in women PCOS has life long implications for increased risk of infertility, metabolic syndrome, type 2 diabetes mellitus, and possible cardiovascular disease. It is a syndrome and not a disease and must be considered in adolescent females with hirsuitism, acne vulgaris, menstrual irregularities, and obesity. Many cases are atypical and a diagnosis may be challenging because some features will be present and others will not (8).

Striae (Striae Distensae) Stretch marks are linear depressions of the skin that are initially pink and later become white, shiny, and atrophic. They are seen in areas subject to stretching such as the lower back, buttocks, thighs, breast, abdomen, inguinal areas, and shoulder. They develop in 35% of girls and 15% of boys between 9 and 16 years at a time when the adrenal gland is producing an increased amount of glucocorticoids. They appear at times of rapid growth, obesity, adolescence, and pregnancy. They seem to be due to stress induced rupture of connective tissue damage to collagen as well as elastin and healing is slowed by glucocorticoid activity. Cushing’s disease and prolonged use of potent topical steroids aggravate the healing, although in time the striae become less noticeable. In one report, retinoic acid 0.1% cream once per day for eight weeks improved and even faded pink striae (9). Breast and hip striae showed the best results. Pulsed dye laser treatment has produced good results in the inflammatory (rubra) stage, and this treatment should be limited to experienced dermatologists because some skin types result in hyperpigmentation (9).

Cushing’s Disease and Cushing’s Syndrome Cushing’s disease is a disorder of overproduction of adrenal cortical hormones from pituitary and hypothalamic overstimulation. Cushing’s syndrome is most commonly due to the iatrogenic use of steroid drugs usually systemic but rarely topical. All causes of Cushing’s syndrome, except due to exogenously administered corticosteroids, produce signs of combined adrenocortical and androgen excess. A study of 36 children and adolescents with pituitary Cushing’s disease had features as noted in table 2 (10).

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Table 2. Features of pituitary Cushing’s disease in 36 children and adolescents (10) Striae Acne Hirsutism Acanthosis nigricans Ecchymosis Hyperpigmentation Fungal infections

77.7% 58.3% 63.7% of 22 girls 27.7% 27.7% 16.6% 11.1%

New onset acne (steroid acne) and/or hirsuitism may be the presenting complaint. Hyperpigmentation of the striae is associated with the generalized hyperpigmentation due to adrenocorticotrophic hormone (ACTH) excess and the melanocyte stimulating hormone (MSH) excess as in Addison’s disease. The glucocorticoids also cause a change in the distribution of fat to the cheeks (moon faces), the buffalo hump, the abdomen, and buttocks while sparing the extremities. This is an example of the influence of the endocrine system on the distribution of body fat. Glucocorticoids cause fine downy hair on the sides of the face but the androgens cause true sexual hair excess in pubic and face as well as the mid-chest and abdominal areas. Other cutaneous features of glucocorticoid excess are due to superinfection with organisms that normally colonize the skin. Tinea versicolor may appear; oral and vaginal candida may also be seen. Fungal infections of the nails may present early. Perleche at the corners of the mouth and intertrigo with candida may appear at the neck, axillae, under the breasts, and in the groin. Glucocorticoids cause distinct perifollicular pustules on the back, upper arms, chest, and face. They are all at the same stage of development and present like a folliculitis; this is called “steroid acne.” These dermatologic problems require usual management but may be difficult to treat until endocrinologic management is also started (10).

Treatment Bathing, Soaps and Cleansers Principles of bathing and skin cleansing do not differ for the obese patient and daily bathing and shampooing is not necessary because the skin is self cleansing. However, daily bathing and shampooing is not harmful and is a ritual in American life. Soap should be mild with a low alkaline pH for sensitive skin but for normal skin any soap that pleases the patient should be acceptable. Soapless cleansers such as Aquanil or Cetaphil are useful as moisturizers for sensitive skin such as eczema. This should be put on the skin before towel drying. After the bath topical steroids should be put on the skin before the emollient for eczema. Retinoids and other potent medications for acne vulgaris should be applied only after the skin is dry because of the rapid absorption of wet skin. Eczema and xerosis present with itching problems that start the scratch-itch cycle in itchy and dry skin. Pramoxine topical and

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Pramosone have been helpful but not as helpful as topical corticosteroids. Benadryl has been used at bedtime but is not as effective as the newer non-sedating antihistamines. Loratadine is approved to age 3 and Cetirizine to age 2 years.

Shampooing Daily shampooing may not be necessary but is not harmful. Medicated shampoos used for dermatitis should be applied before the bath and left on for 15-20 minutes after the bath before rinsing.

Emollients The best skin emollient is petrolatum or mineral oil. These may not be comfortable in hot weather and may aggravate acne vulgaris when creams and lotions are used. They are important for dry skin especially in cold weather. Lanolin and vegetable oils may be more sensitizing.

Soaks and Bathing Intertrigo and Staphylococcal pyoderma may require wet compresses for cleansing using dilute chlorhexidine, 2% acetic acid or a 1:40 aluminum acetate (Domeboro) solution. Betadine is not recommended because of iodine absorption from damaged skin. The wet skin after a soothing soak will absorb medications such as Bactroban, Lotrimin, and corticosteroids better when indicated. Poison ivy contact dermatitis responds well to astringent soaks followed by steroid creams or ointments. Intertriginous dermatitis found in the folds of the skin in the neck, groin, axillae, and beneath the folds of the breasts respond well to this plan.

Topical Corticosteroids Topical cortiocosteroids have been used since 1952 for the treatment of atopic dermatitis and soon after for other inflammatory dermatoses in children and adolescents. They have an immediate and delayed effect on cytokines and immune mediated as well as inflammatory skin conditions. Hydrocortisone was first used as a low potency medication. Its potency has been increased by fluorination, methylation, and acetylation with more potent products being developed as a result. The lowest strength that will clear the eruption in the shortest time should be used. For lesions on the face, skin folds, and diaper areas, use a low potency cream or ointment such as hydrocortisone 1%. For problems that are moderately severe or for thickened dry lesions, use a mid or high potency cream or ointment for a short time and follow with a moisturizing cream or lotion. Continuous use for longer than 4-6 weeks is not

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recommended because tachyphylaxis can develop. For chronic eczema, intermittent use is much more effective and patients can be given pulsed on and off treatment with a calcineurin inhibitor or moisturizing cream. Prolonged use will cause dermal atrophy, striae, and petechiae. These skin changes will resolve if discontinued after 4 weeks. Striae will not disappear. Prolonged use of medium to high potency steroids will affect the adrenal-pituitary axis and Cushing’s syndrome will develop though this is rare with topical steroids. Peri-oral dermatitis is made worse by steroid preparations. The treatment of scabies or tinea with corticosteroids will improve initially only to return with vigor.

Antibacterials and Antifungals The skin of the obese person is subject to an increased risk for intertrigo with the problem of moist skin folds, increased friction, increased sweating, and rubbing from tight clothing. The female has an increased risk for vulvo-vaginitis and leucorrhea. There is an increased risk for the metabolic syndrome and type 2 diabetes mellitus which leads to monilial infections. The skin may be colonized and infected with Staphylococcal aureus while Pseudomonas may be contracted from hot tubs. Folliculitis in the bearded area as well as areas on the legs from shaving may develop. Skin cultures are indicated to identify resistant organisms and plan appropriate systemic treatment if needed. Topical 1% Clotrimizole or 2% Miconazole cream or vaginal tablets can be used. They are effective for dermatophytes and yeasts. Staphylococcal or streptococcal impetigo of the face may be treated with mupirocin three times daily for 7-10 days. Nasal carrier for streptococcus is common and can be eliminated in 2-4 days with mupirocin ointment but recurrences are expected in 2-4 months. Trimethoprim/sulfamethoxazole is effective, but there is a risk of Stevens-Johnson’s Syndrome or hemolytic reaction with G-6-PD deficiency. Nizoral 2% (ketoconazole) cream or shampoo is useful for problems with topical fungal or candida infections; its use systemically is fraught with risks of prolonged QT and sudden death from ventricular tachycardia. Onychomycosis is common in the older adolescent and is easier to prevent than to treat. Good foot care, frequent bathing, careful drying beneath the toes, the use of foot powder such a Tinactin and appropriate nail care is essential. If fungal nail infection develops, topical nail treatment with ciclopirox or fluconazole is safer but less effective than systemic Sporonox. Tinea corporis, tinea cruris, tinea pedis, and tinea versicolor are common problems in which fungal cultures and KOH preps confirm the correct diagnosis. Patients with tinea corporis do not need to be excluded from school but wrestlers can spread it. Keeping the area dry and application of antifungal powder or cream such as Nystatin is usually effective. Rarely a systemic antifungal may be needed in which griseofulvin is safer and preferred over ketaconazole. A dermatophytid reaction may occur as an immune reaction in the hands, arms, legs, and trunk, while skin testing shows a positive reaction to dermatophytes. Tinea versicolor responds to topical Selenium sulphide shampoo or Ketaconozole shampoo. If persistent, fluconazole (Diflucan) 400 mg is given in one dose that may be repeated if necessary. Candidal infections should be looked for as mycelial forms or budding yeasts on KOH preparation or cultures on Sabouraud’s media.

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It is seen as vulvovaginitis or oral candida infection, including moist areas at the corner of the mouth. Treat with Nystatin, clotrimozole, or if persistent, Diflucan 150 mg (one dose) in the older child or adolescent. If these infections persist, check for underlying HIV infection.

Retinoids There is no published evidence that obesity is related to more or less trouble with acne vulgaris than the average patient; however, when acne occurs, retinoids may be clinically useful. The biologic action of this medication is targeted to intracellular receptors with stimulation of cellular growth, apoptosis, and control of skin cytokines. The newer synthetic retinoids, adapalene and tazarotene, have more selective retinoid receptor interactions than Retin-A (retinoic acid). Retinoids have a comedolytic action and are effective with benzoyl peroxide topical management. Pomade acne consists of multiple closed comedones on the forehead of patients using various hair oils. Topical azelaic acid is effective for inflammatory acne vulgaris but may cause hypopigmentation in dark skinned patients. Systemic antibiotics may be needed for more severe cases of acne and these include tetracycline, erythromycin, minocycline, and doxycycline. Tetracycline is probably the safest for long term use if effective for the selected patient. Topical preparations of benzoyl peroxide and either erythromycin or clindamycin are often helpful. The estrogenic role of oral contraceptive medications may suppress androgens and may be helpful, although depomedroxyprogesterone acetate may aggravate acne.

Genetic Disorders Associated with Obesity Families often enquire regarding a genetic cause for the obesity problem. Obesity as a genetic disorder is rare but frequently seen in conditions listed in table 3 (12). Table 3. Genetic disorders associated with obesity (11-13) Albright Hereditary osteodystrophy (Intracutaneous ossification from infancy or childhood) Bardet-Biedl Syndrome (Laurence-Moon Biedl’s Syndrome) (12) Borjeson-Forsman Lehman Syndrome Carpenter Syndrome Cohen Syndrome Grebe Syndrome 45 X0 Syndrome Prader Willi S. (acanthosis nigricans) Killian Teschler-Nicola S. (Tetrosomy 12p) (streaks of hyperpigmentation)

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Many dermatologic features may be present in these syndromes. Skin fibroblasts are affected with streaks of hyperpigmentation in KTN Syndrome. If suspected a genetic referral is indicated (11)

Conclusions Dermatologic conditions in children and adolescents with obesity can be challenging conditions for patients and clinicians alike. This discussion considers a variety of skin conditions, including acanthosis nigricans, papillomatosis of Gougerot and Carteaud, polycystic ovary syndrome, striae distensae, Cushing disease, and Cushing syndrome in relation to their dermatologic aspects. Various treatment modalities are also reviewed include bathing, soaps, cleansers, shampooing, emollients, topical corticosteroids, topical antibacterials, antifungals, and topical retinoids. Complex and resistant cases should be referred to dermatologic colleagues.

References (1)

Lu D, Willard D, Patel IR, et al. Agouti protein is an antagonist of the melanocyte stimulating hormone receptor. Nature 1994; 371:799-802. (2) Vaisse C, Clement K, Duzant E, et al. Melanocyte-4 receptor mutations are frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000;106(2):253-62. (3) Montague CT, Farouki IS, Whitehead JP, et al. Congenital leptin deficiency is associated with early onset obesity in humans. Nature 1997; 387:903-8. (4) Farouki IS, Yeo GS, Keogh JM, et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin-4 deficiency. J Clin Invest 2000;106(2):185-7. (5) Farouki IS, Jebb, SA , Langmack G, et al. Effects of recombinant leptin therapy in a child with congested leptin deficiency. New Eng J Med 1999;341(12):879-84. (6) Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis nigricans. N Engl J Med 1976;294:739. (7) Stuart CA, Gilkison CR, Smith M. Acanthosis nigricans as a risk factor for non-insulin dependent diabetes mellitus. Clin Pediatrics 1998;37:73-80. (8) Rosenfield RL. Current concepts of polycystic ovary syndrome. Bailliere’s Clin Obstet Gynecol 1997;11:307. (9) Marcus J, Horan, DB, Robinson JK. Tissue expansion, past, present and future. J Am Acad Dermatol 1990;23:813-25. (10) Stratakis C, Mastorakos G, Mitsiades NS, et al. Skin manifestations of Cushing’s disease in children and adolescents before and after the resolution of hypercortisolemia. Ped Dermatol 1998;15(4):253-8. (11) Schachner LA, Hansen RC. Pediatric dermatology. New York: Mosby 2003.

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(12) Slarotinek, AM, Stone EM, Mykytyn K, et al. Mutations in MKKS cause Bardet-Biedle syndrome. Nat Genet 2000;26:15-6. (13) Greydanus DE, Feinberg AN, Patel DR, Homnick DN. The pediatric diagnostic examination. New York: McGraw-Hill Med Publ, 2008.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XXXIX

Down Syndrome and Obesity Joav Merrick∗1,2,3,4 and Isack Kandel1,5 1

National Institute of Child Health and Human Development, Office of the Medical Director, Division for Mental Retardation, Ministry of Social Affairs, Jerusalem 3 Interuniversity College for Health and Development, Castle of Seggau, Graz, Austria 4 Kentucky Children’s Hospital, University of Kentucky, Lexington, KY, USA 5 Faculty of Social Sciences, Department of Behavioral Sciences, Ariel University Center of Samaria, Ariel, Israel 2

Abstract Obesity in childhood has particular concern, because if it continues into adulthood, the result will be increased morbidity and decreased life expectancy. An increase in obesity in the general population in the developed world has been documented in recent years. This trend is also seen in persons with intellectual disability and in particular in persons with Down syndrome (DS). Persons with DS are prone to obesity already at an early age and several studies have shown a high prevalence in this population compared to persons with intellectual disability without DS and the general population. Persons with DS have a low resting metabolic rate and low dietary intake of individual nutrients and therefore exercise and vitamin-mineral supplement diet must be instituted in this population to prevent or minimize obesity and its adverse consequences.

Keywords: Obesity, overweight, intellectual disability, developmental disability, mental retardation, Down syndrome.

∗

Correspondence: Professor Joav Merrick, MD, MMedSci, DMSc, Medical Director, Division for Mental Retardation, Box 1260, IL-91012 Jerusalem, Israel. E-mail: [email protected]

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Introduction Obesity in childhood and adolescence presents a challenging and sometimes frustrating problem in clinical practice. Obesity is of particular concern, because of the health risk associated with it, such as hypertension, hyperlipidemia, hypertriglyceridemia, diabetes mellitus, coronary heart disease, pulmonary and renal problems, surgical risks and degenerative joint disease. The prevalence of overweight among children and adolescents in the United States has increased between 1980 and 2004 (1). Height and weight measurements were obtained from 8,165 children and adolescents as part of the 2003-2004 and 2005-2006 National Health and Nutrition Examination Survey (NHANES)(1). During 2003-2006, 11.3% (95% confidence interval [CI], 9.7%-12.9%) of children and adolescents 2-19 years were at or above the 97th percentile of the 2000 BMI-for-age growth charts, 16.3% (95% CI, 14.5%-18.1%) were at or above the 95th percentile, and 31.9% (95% CI, 29.4%-34.4%) were at or above the 85th percentile.

Studies of Obesity in Persons with Intellectual Disability Polednak and Auliffe in 1976 studied (2) 161 adults in an institution for people with intellectual disability (ID) in Canada (aged 18-73 years, 108 males, 53 females) and found that 20.4% of the males and 17.0% of the females were obese. The frequency of obesity was higher, but not statistically significant, in moderate ID than mild or severe ID. Burkart et al in 1985 (3) reviewed the literature and found that obesity was a prevalent problem in the population of persons with ID with a higher incidence among females than males. A study from Northern Finland (4) in 1991 calculated the BMI at the age of 20 for all the 132 survivors (83%) out of the 159 persons born in that region with ID in 1966. Reliable information for 112 cases (84.8%) did not deviate significantly from the average Finnish population at age 20-29 years. 41.5% with mild ID (IQ 35-70) and 28.6% with severe ID (IQ less than 35) were of ideal weight (BMI 20-24), while 9.8% of all the persons studies were moderately obese (BMI greater than 30) and 7.1% severely obese (BMI greater than or equal to 32). 91% of the severe obese cases lived with their parents and did not participate in any occupational therapy or work. 29.5 % of the persons studied were underweight (BMI less than 20) and most of these cases were with severe ID. Takeuchi (5) studied 20,031 pupils and students at special schools in Japan. The degree of obesity was computed as actual weight devided standard weight times 100. Standard weight was the average weight for the child's sex, age and height. 11.1% of males and 14.5% of females were obese and 2.5 % of males and 3.1% of females were severely obese. Frey and Rimmer (6) studied 210 adults with ID residing in a residential setting in United States and one in Germany. Mean age was 31.7 years. Skinfold measurements were used to estimate percent body fat (PBF) and height and weight were used to compute BMI. PBF was significantly higher among females and persons in institutional settings had significantly

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lower BPF and BMI levels than persons in the family setting. PBF and BMI levels were significantly higher in persons from the United States than Germany. Another study from Rimmer et al (7) studied 364 adults (mean age 36.8 years) from four residential settings (state institution, private community facility (ICF/MR), private group home and living with family) in Illinois. The rates of obesity were higher among females (58.8% versus 27.5%), persons with severe ID had the lowest overall rates of obesity (29.4% versus 53.2 for moderate and 46.5% for mild) and the institutional group had the lowest incidence of obesity (16.5%, 50.0% for ICF/MR, 40.9 % for group home and 55.3% for natural family). A total of 27.5% of males and 58.5% of females were obese, higher than the national data for the general population in the United States. In a study from Israel (8)of persons with ID aged 40 years and older living in residential care centers (2,282 persons) we found that the mean BMI was 25.7 and 35% classied as overweight. 45.7% with mild ID, 45.1% with moderate, 27.1% with severe and 15% with profound ID had a BMI over 27. A recent large study of of 1,119 adults with ID aged 20 years and older (9) from the United Kingdom Leicestershire Learning Disability Register, who participated in a programme of universal health checks and home interviews with their carers, looked at weight and hight and compared the observed and expected prevalences of body mass index categories in the ID and general populations using indirect standardisation for age. They found (9) in those aged 25 years and older, that the standardised morbidity ratio (SMR) for obesity was 0.80 (95% CI 0.64-1.00) in men and 1.48 (95% CI 1.23-1.77) in women. The SMR for underweight was 8.44 (95% CI 6.52-10.82) in men and 2.35 (95% CI 1.72-3.19) in women. Among those aged 20 years and older, crude prevalences were 20.7% for obesity, 28.0% for overweight, 32.7% for normal weight and 18.6% for underweight. Obesity was associated with living independently or with family, ability to feed/drink unaided, being female, hypertension, Down syndrome and the absence of cerebral palsy. From the above studies it seems that a disproportionate high number of persons with ID display obesity and especially females. It also seems that living arrangements and environment plays an important role in obesity rates for this population.

Studies of Obesity in Persons with Down Syndrome A study Children's Hospital in Philadelphia (10) on 730 children with Down syndrome (DS) showed a tendency to overweight beginning in late infancy and throughout the remainder of the growing years. The percentage of children with overweight increased to 50 % of the girls by the third year of life and 50 % of the boys by early childhood. The percentage of children, who were overweight fluctuated to 18 years, but the percentage above the 85th percentile of weight per height always was greater than 30 %. A study from Australia (11) determined the resting metabolic rate of children with DS living at home (11 males, 7 females aged 10-14 years) and found a depressed rate compared to normal values for children of similar age. These findings seems to support the theory of "metabolic sluggishness" as a contributing factor to the etiology of obesity in children with

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DS and therefore a nutritional energy-controlled diet with daily physical activity could work against obesity in DS. Bell and Bhate (12) from Northumberland in the United Kingdom studied 183 adult persons (58 with DS) with ID living in the community. They found that 70.58% of males and 95.83% of females with DS and 49.29 % males and 62.96 % females with non-DS retardation were overweight and obese compared to 40% of males and 32% of females from the general population. A study from the University of Illinois at Chicago (13) with 283 adults with Down syndorme (146 males, 137 females, aged 15-69 years) living with family or group home found that 45% of males and 56% of females were overweight with BMI levels higher in the family setting than at the group homes. A Japanese study from 2000 (14) with 325 school children with Down syndrome aged 618 years showed obesity for the children with DS compared to the average Japanese child (34.3% and 7.47% respectively). Obesity started to increase in the obese group around age 7 year and the obese group tended to have greater intake of sweets, juice and total foods in their preschool days, but unexpectedly had been physically more active in their primary school days. A detailed method was used to identify all adults with ID in Leicestershire, United Kingdom (15), which included medical examination and measurement of height and weight. For each person with Down syndrome, an individual matched for gender, age and accommodation type was identified. Data was obtained for 247 matched pairs and it was found that women with Down syndrome had lower mean height and weight, but greater mean BMI than the matched pairs. Men with Down syndrome had a lower mean height and weight, but there was no statistical difference in BMI compared to the matched pairs. Using World Health Organization categories of BMI, women with Down syndrome were more likely to be overweight or obese than their matched pairs (odds ratio=2.17). Men with Down syndrome were more likely to be in the overweight category than their matched pairs, but were less likely to be obese (odds ratio=0.85). Looking at the physical activity of children with DS researchers from Wake Forest University School of Medicine in Winston Salem, NC, United States (16) studied 28 children with DS compared with their siblings (n = 30), between 3-10-years (mean +/- SD 7.1 +/- 2.1 years). Physical activity was measured over seven days. The children with DS were younger (6.6 vs. 7.1 years) and heavier (BMI 18.4 vs. 16.7) than their siblings (p < 0.05). Children with DS accumulated less vigorous-intensity activity than their siblings (49.5 vs. 68.6 minutes per day; p = 0.04) and for shorter bouts (2.5 vs. 5.1 minutes per bout; p < 0.01), but spent similar time in moderate physical activity and low-intensity physical activity. Physical activity should therefore be encouraged in this population from an early stage in life (16,17).

Conclusions Obesity is a major public health problem in the population of persons with intellectual disability and especially in the persons with Down syndrome. Obesity limits the capacity of the child and adolescent with Down syndrome to participate in recreational and sports

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activities and obesity also have social adverse consequences. The management of obesity in children with DS is complicated due to their low resting metabolic rate and low dietary intake of individual nutrients, but exercise and a vitamin-mineral supplement diet should be efforts in the right direction to minimize obesity and its adverse effects.

References (1) (2) (3) (4) (5) (6) (7)

(8)

(9)

(10)

(11) (12)

(13) (14)

Ogden CL, Carroll MD, Flegal KM. High body mass index for age among US children and adolescents, 2003-2006. JAMA 2008;299(20):2401-5. Polednak AP, Auliffe J. Obesity in an institutionalised adult mentally retarded population. J Ment Defic Res 1976;20(1):9-15. Burkart JE, Fox RA, Rotatori AF. Obesity of mentally retarded individuals: prevalence, characteristics and intervention. Am J Ment Defic 1985;90(3):303-12. Simila S, Niskanen P. Underweight and overweight cases among the mentally retarded. J Ment Defic Res 1991;35(2):160-4. Takeuchi E. Incidence of obesity among school children with mental retardation in Japan. Am J Ment Retardation 1994;99(3):283-8. Frey B, Rimmer JH. Comparison of body composition between German and American adults with mental retardation. Med Sci Sports Exerc 1995;27(10):1439-43. Rimmer JH, Braddock D, Fujiura G. Prevalence of obesity in adults with mental retardation: Implications for health promotion and disease prevention. Ment Retardation 1995;31(2):105-10. Merrick J, Davidson PW, Morad M, Janicki MP, Wexler O, Henderson CM. Older adults with intellectual disability in residential care centers in Israel: health status and service utilization. Am J Ment Retard 2004;109(5):413-20. Bhaumik S, Watson JM, Thorp CF, Tyrer F, McGrother CW. Body mass index in adults with intellectual disability: distribution, associations and service implications: a population-based prevalence study. J Intellect Disabil Res 2008;52(Pt 4):287-98. Cronk C, Crocker AC, Pueschel SM, Shea AM, Zackai E, Pickens G, Reed RB. Growth charts for children with Down syndrome: 1 month to 18 years of age. Pediatrics 1988;81(1):102-10. Chad K, Jobling A, Frail H. Metabolic rate: A factor in developing obesity in children with Down syndrome ? Am J Ment Retardation 1990;95(2):228-35. Bell AJ, Bhate MS. Prevalence of overweight and obesity in Down syndrome and other mentally handicapped adults living in the community. J Intellect Disabil Res 1992:36(4):359-64. Rubin SS, Rimmer JH, Chicoine B, Braddock D, McGuire DE. Overweight prevalence in persons with Down syndrome. Ment Retardation 1998;36(3):175-81. Kawana H, Nonaka K, Takaki H, Tezuka F, Takano T. [Obesity and life style of Japanese school children with Down syndrome]. Nippon Koshu Eisei Zasshi 2000;47(1):87-94. [Japanese].

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(15) Melville CA, Cooper SA, McGrother CW, Thorp CF, Collacott R. Obesity in adults with Down syndrome: a case-control study. J Intellect Disabil Res 2005;49(Pt 2):12533. (16) Whitt-Glover MC, O'Neill KL, Stettler N. Physical activity patterns in children with and without Down syndrome. Pediatr Rehabil 2006;9(2):158-64. (17) Sayers Menear K. Parents' perceptions of health and physical activity needs of children with Down syndrome. Downs Syndr Res Pract 2007;12(1):60-8.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XL

Environment and School Transportation: A Review of Evidence from Health and Equity Perspectives Important in Obesity Prevention Chanam Lee∗ and Xuemei Zhu Department of Landscape Architecture and Urban Planning, College of Architecture, Texas AandM University, College Station, TX, USA

Abstract Obesity rates among children around the world have reached an epidemic level. Having an option to walk or bike to school is important for mobility, health and equity purposes. However, fewer students are walking or biking to school today than a generation ago, and fewer students live within a walkable distance to schools. This review highlights the existing evidence from multiple disciplines on health and equity issues related to school transportation. It then assesses the literature dealing with the built environmental correlates of walking or biking to school. Travel distance and safety were found to be the strongest predictors of walking or biking to school. Studies suggested that about one-half to one mile (0.8-1.6 km) between home and school was generally considered walkable. Other factors such as roadway conditions, sidewalk continuity, bike lane availability, signals, lighting, and neighborhood design appeared important but with some inconsistencies in the findings. Many commonly reported environmental barriers were related to transportation infrastructure, such as high-volume and high-speed roadways, unsafe street crossings, and railroads. Compared with distance, safety and transportation infrastructure, neighborhood characteristics such as density, land use, and ∗

Correspondence: Chanam Lee, PhD, Department of Landscape Architecture and Urban Planning, College of Architecture, Texas AandM University, W014D Williams Administration Building, College Station, TX 77843-3137 USA. Tel: 1-979-845-7056; Fax; 1-979-862-1784; E-mail: [email protected]

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Chanam Lee and Xuemei Zhu overall street patterns appeared less significantly associated with school transportation. This review revealed evidence supporting the link between school transportation and the built environment. It also discovered many remaining questions for future research, such as interactions and causalities between personal and environmental factors, environmental influences from multiple spatial scales, and differences between objective and perceived measures.

Keywords: School transportation, walking, bicycling, obesity, physical activity, environment.

Introduction This review paper discusses health and equity issues related to school transportation and the environment. The focus is on the roles of built environments in promoting or deterring physically active commuting to school. Increased automobile dependency and sedentary lifestyle have contributed to many public health problems such as obesity and diabetes. Obesity rates have reached an epidemic level across all age, race, gender and income groups. Childhood obesity is of significant concern because of its lifelong consequences involving many comorbidities. Walking or biking to school can help incorporate routine physical activity into children’s daily life and therefore fight against obesity. However, fewer students are walking or biking to school today than a generation ago, due to many personal and environmental barriers. Leading environmental deterrants include dangers from traffic and crime, long distances between homes and schools, and poor infrastructure conditions. In addition to the health benefits, creating a supportive environment for walking and biking is also important for mobility and equity purposes. Walking and biking are more important and more common travel modes for lower income populations than for higher income groups. However, lower income people often bear greater risks while walking or biking, because their neighborhoods tend to have more traffic crashes and crimes, and more automobile-emitted pollutants. This paper reviews the existing evidence from multiple disciplines concerning the personal and environmental correlates of school transportation. It emphasizes the public health implications of walking or biking to school as healthy physical activities and as ways to establish lifelong habits of active living. After summarizing the current state of knowledge on the topic, it concludes with discussions about future research needs to fill in the remaining gaps.

School Transportation and Health Physical Activity and Health Without reversing the current trend of unhealthy lifestyles and health disparity, the advances in modern medicine may no longer be sufficient to add quality and length to human

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lives. Physical activity holds particular significance as the most powerful tool to prevent and manage chronic diseases such as obesity, asthma, hypertension, type 2 diabetes, cardiovascular diseases, and depression (1) and to reduce healthcare costs (2). Benefits of physical activity among children and adolescents are even greater with additional developmental and health benefits, such as stress management and improved academic performance (3-5). Play activities are important for children’s social developments (6,7). According to the Surgeon General’s Report on Physical Activity and Health (1), even moderate-intensity daily activities such as walking for 30 minutes or jogging for 15 to 20 minutes can be beneficial to health for people of all ages. This report recommends at least 30 minutes of physical activity on five or more days per week. Despite the many proven health benefits, more than half of US adults are not sufficiently active to meet this recommendation and 26% are not active at all (1). Physical activity levels and the opportunities for children to be active have continued to decrease over the past several decades. This decline is due to increased parental safety concerns related to traffic and crime, reduced physical education classes offered at schools, greater dependency on automobiles for commuting to schools, and shift in the forms of play from active to sedentary. An observation study found that children from low-income families spent about 58% of their free playtime in sedentary behaviors (8). About 14% of young people in the US engage in no regular physical activity (9). Enrollment in physical education classes among high school students has reduced from 42% in 1991 to 25% in 1995 (9). Among children aged 9 to 13 years, only 38.5% engaged in organized sports but 77.4% reported performing some free-time physical activity in a week (10). Physical activities decrease dramatically during the teen years (11,12). Looking specifically at school transportation, children who walk or bike to school reduced from 42% in 1969 to 16% in 2001 (13). During the same period, students living within one mile from schools, generally considered a walkable distance, decreased from 34% to 21% (13). This prevalence of physical inactivity and sedentary lifestyle has contributed to the recent obesity epidemic. Childhood obesity has tripled over the past two decades and adult obesity has doubled since 1980, reaching over 30% (13). Physically active commuting to school alone may not be sufficient to bring about the health benefits related to physical activity. However, physical activity habits are formed early in childhood, and walking and biking are the most attractive, accessible, and feasible forms of physical activity. Walking was found to be the most preferred type of physical activity among primarily Mexican American 7th grade students from San Antonio, Texas, followed by rollerskating/blading and running (14). Walking is the most preferred physical activity among adults as well (15, 16). In addition, a study of 9-year-old Danish children found that walking to or from school was a good indicator of overall physical activity among children (17). Another US study among the 5th-grade students found that walking to or from school was associated with 24 additional minutes of moderate to vigorous physical activity per day (18). Utilitarian transportation behaviors such as walking and biking are especially important, because they are sustainable, lifestyle activities. They serve dual purposes as transportation modes and healthy exercises (19). As travel modes, they are affordable, environmentally clean, and efficient and reliable in covering short distances (20). As part of lifestyle intervention programs, they are more likely to induce long-term lifestyle changes, to be

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effective for currently sedentary people, and to be more cost effective than structured interventions (21-23). Further, if even a small proportion of automobile trips can be replaced by nonmotorized modes, additional environmental benefits will be significant through reduced air pollution and reduced land consumption (24). As outdoor activities, walking and biking can potentially bring added health benefits through the exposure to pleasant natural settings, which is shown to facilitate recovery from daily stresses (25, 26). However, one may question if walking is rigorous enough to actually lower the risks of developing chronic diseases. Although the scientific evidence is not as extensive as that available for overall physical activity, empirical studies have shown that walking alone without other physical activities can and does bring health benefits such as improved cardiovascular, respiratory, and metabolic fitness (27-29). Sesso and colleagues found that walking more than 10 city blocks everyday resulted in a 33% reduction in cardiovascular disease risks (30).

Physical Activity, Health and Built Environments Multiple factors influence people’s decision to engage in physical activity, including personal, social, and physical environmental factors. Adding to the strong empirical knowledge on the roles of personal and social correlates, a recent and growing body of studies now confirms the significance of the physical environment. As the prevalence of physical inactivity has reached an epidemic proportion, environmental approaches that target large populations at a time and target lifestyle changes are gaining increasing support (31,32). Previous studies have shown that the designs and uses of built environments (e.g., sidewalks, street network patterns, shops, recreational facilities, and other destinations) and the related environmental characteristics (e.g., safety, lighting, traffic, and aesthetics) are associated with physical activity, walking, and other transportation behaviors (33-41). A study conducted in Seattle, Washington, showed that if neighborhood environments are supportive, people can meet the recommended amount of physical activity by neighborhood walking alone (40). In addition, studies suggest that built environments can influence diet behaviors. People living closer to a supermarket are likely to eat more fruits and vegetables. Availability and cost of food, especially healthy food, vary by the neighborhood’s socioeconomic status. The poor, especially those living in inner-city areas, pay more for their food and have fewer grocery stores nearby (42). A study of Chicago schools showed that three to four times more fast food restaurants were located within 1.5 kilometers (0.93 miles) from schools than what would be expected without considering the school locations (43). This increased accessibility may trigger increased consumption of unhealthy, energy-dense fast food by school-aged children. The health implications of the built environment have become increasingly important in this highly urbanized society where the majority of the population’s everyday experiences are dominated by human-built elements. Cumulative scientific evidence now lets us believe that the built environment does and can make people sick. It does so by exposing people to toxins and hazards. For example, proximity to high-volume streets has been shown to have a role on asthma diagnosis and hospitalization (44). Recent trends in land use and infrastructure developments appear to foster unhealthy lifestyles such as poor diet and sedentary behaviors,

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as discussed earlier. Unfortunately, however, the exact mechanism through which the built environment interacts with human behaviors and health is not clearly understood. Built environments are the physical settings for youth activities and development. Urban development patterns in the US since World War II have been dominated by automobileoriented infrastructure with divided land uses. Urban landscapes have been shaped to make it easier for people to adopt unhealthy lifestyles than healthy ones. Young people are especially vulnerable to their surrounding environments, because they do not have control over the types of environment in which they live, learn, or play. Children have limited mobility due to their limited physical capacity and their lack of access to private automobiles. Therefore, the magnitude of impact by the given and proximal environments on children is much greater compared to that on adults with greater physical capacity and mobility options.

Equity in School Transportation Elimination of health disparity is one of the two overarching goals in Healthy People 2010 (45). The burden of chronic diseases is not equally distributed among different subpopulations. Among the many alarming facts, up to 80% of Hispanic populations are overweight or obese and they are twice as likely to have diabetes than non-Hispanic whites (46). Type 2 diabetes is the most common comorbidity of obesity among children, estimated to result in the reduction of 15 to 27 years in life expectancy (47), and undiagnosed cases are much more prevalent among minorities than among whites (48). Over 38% of Hispanics with diagnosed diabetes do not have any healthcare coverage, compared with only 12.4% for whites and 19.8% for African Americans (48). Hispanics and African Americans, as well as those living in rural and underserved areas, tend to have much higher risks for being overweight or obese and have limited access to healthcare services (49). The current cost of obesity, in Texas for example, is about $500 per person per year and is expected to double by 2040. Compared with those of normal weight, obese people spend 36% more for their healthcare and 77% more for their medication (50). The economic burdens of obesity, diabetes, and other health problems are greater among those with lower socioeconomic status. Physical activity levels differ across different population groups. Minorities, females, low-income groups, and rural residents report the highest rates of inactivity, and these differences emerge in early childhood (51,52). About 50% of Hispanic and 47% of black adolescent females engage in regular vigorous physical activity, compared to 60% among white counterparts (53). Females are generally less active than males. A study reported that only 36.3% of non-Hispanic black females and 42.3% of Hispanic females engaged in regular physical activity, compared to 49.7% among non-Hispanic whites (54). Gender differences are also shown in environmental influences on outdoor physical activity. While distance to the closest open play area was important for boys, violent crime was a key consideration for girls (14). In addition, rural residents are more sedentary according to leisure-time physical activity than urban residents, and they face more personal barriers to physical activity (52). Rural children or adolescents walk or cycle less than their urban counterparts (55) and are more likely to be obese or overweight (56). Another key factor is income, which is often strongly correlated with ethnicity and education. Residents of low-income neighborhoods

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were 36% less likely to be vigorously active than were those from high-income areas (35). Children from lower income families were more likely to be inactive and overweight (35,57). Lower income neighborhoods were generally perceived less walkable, and students from lower-income schools consumed more baked foods, chips, sodas, and candies, compared to those from higher income neighborhoods (58). They also spent more time watching television and sitting in front of the computer (58). Another study conducted in Cincinnati, Ohio, reported that poverty rate among young children was positively associated with proximity to fast food restaurants (59). While health problems, especially those related to physical inactivity, are more common among minority and low-income populations, their access to physical activity resources tends to be more limited (60). Even if these resources are available, they often suffer from poor quality and maintenance, crime and gang activities, and pollution (61-63). It should be noted that the issues of disparity are related to multiple, interrelated dimensions, including socioeconomic and environmental dimensions. For example, while children in inner-city or lower income communities may rely more on freely available public parks and streets for their outdoor play activities (64), the availability and the quality of such facilities in these communities are usually far worse than those available in higher-income, suburban neighborhoods. Consequently, inner-city children are shown to report lower levels of physical activity (57) and higher rates of obesity. Further, children from low-income and minority communities are more likely to suffer from poor pedestrian infrastructure conditions and safety problems (65), but may be forced to walk because they are deprived of other mobility options. Lower income parents are more likely to report unpleasant walking conditions and to perceive dangers from crime, drug dealers, and violence (66). Schools with high percentage of low-income or minority students were exposed to more traffic, which can increase exposure to polluted air and traffic dangers (67). In general, empirical studies on the environmental or spatial disparities related to health and physical activity behaviors are limited (68). Most existing studies focus on simple comparisons of prevalence rates among different income, age, gender, or ethnic groups. Further, the different attitude and perceptions toward walking and physical activity across different subgroups should be considered. Bostock states that while utilitarian physical activity such as walking is encouraged for everyone as healthful activity, the reality of people’s daily living may tell a different story (69). For instance, for mothers with young children from low-income families who have no other means to run daily errands, walking will come with the added pressure and labor demand, performed in deprived, unsafe, and polluted environments. In cases like this, the mental stress and physical fatigue, as well as increased risks for respiratory diseases, may outweigh the benefits of walking as healthy exercise.

Correlates of Walking and Biking to School A limited but growing body of literature has explored the multilevel correlates of walking and biking to school behaviors, including personal, social, and physical environmental factors (see table 1). Although it is too early to draw conclusions on exactly

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what variables play what roles, some important patterns are discovered from the literature. In general, smaller and more compact neighborhood schools located centrally in neighborhoods that have safe and connected street system appear supportive of students’ walking and biking to school. Kouri’s work found that older schools (built before 1983), which were primarily small neighborhood schools, had four times more students walking to school, compared to newer schools (71). The related issue of school siting emerged as a key factor predicting the travel distance and mode choice (70). Contradictory to what is shown to be desirable for walking and biking, current trend in school developments, however, shows a pattern toward larger schools farther away from the students’ homes. These schools are often located near high-volume arterials and highways, making it unsafe or even impossible to walk or bike to school. Personal correlates of walking or biking to school are many. Overall, boys are more likely to walk or bike to school than are girls (72-75). Younger elementary school children walked more than older elementary school students in two US studies (73,74). However, another Australian study reported a reverse association (75) and a few other studies reported insignificant results (72,76,77). It appears that Hispanic and African American children and children with lower socioeconomic status walk more (72,78,79), but, again, insignificant results have also been reported (73,74, 77). Parents’ education levels were insignificant in four studies (72-74,76). The child’s level of independence, the parents’ perceived benefits of active commuting, and having the father as the responsible parent had a positive correlation with walking or biking to school (75). In contrast, convenience of driving was a negative factor (74). Other factors such as parents’ marital status (73,75) and car ownership (75,77,78,80) have yielded inconsistent results. A growing number of studies have shed light on the environmental attributes that may encourage or deter children to walk or bike to school (see table 1). These variables cover the environmental attributes at both the larger neighborhood level and the detailed microscale level. First of all, distance and safety are definitely two of the most important environmental correlates of walking or biking to school. In a national survey by the Centers for Disease Control and Prevention (CDC), parents reported long distances, traffic dangers, and crime as the topmost barriers to walking to school (81). Empirical studies have also confirmed the importance of both objective and perceived measures of distance and safety. For walkable distances, studies report about one-half to one mile (0.8-1.6 km) between home and school to be the maximum threshold for walking to school (74,75,77,82), although this threshold will likely vary depending on the children’s personal characteristics and the environmental conditions. Safety concerns were related to traffic and crime, and the parents’ perceptions played especially significant roles (74-76). While the actual crash rates have declined over the years, the perceived fear of traffic crashes has not. The CDC survey found that about one third of the parents reported traffic danger to be a barrier to walking to school (81). Along the same line, fear of abduction seems to encourage automobile use for school transportation (83,84).

Table 1. Built environmental correlates of walking or biking to school Class

Variable

Travel Distance

Travel time (distance) Route directness Route directness for 5-6 year old Route directness for 9-12 year old Neighborhood safety for child to walk/bike to/from school alone

Safety

Neighborhood safety for playing Safety concerns Safety concerns about strangers Crime Traffic dangers School

School size (enrollment)

Age of school (built before 1983) School locations (urban vs. suburban) School Environment Population density (Residents + jobs) density Land-use mix Abandoned buildings in surroundings Windows facing streets in surroundings Roadway Conditions Intervention: replacing 4-way stops with traffic signals Intersection density Dead end density Street width Block length Speed humps Street lighting No light/crossings Street tree coverage

Measure Typea O, PP O O O PP PP CP PP PP, CP PP PP, CP PP O O O O O O O O O O O O O O O O O PP O

Associationb

Source

(−) (×) (×) (−) (×) (−) (×) (−) (×) (−) (×) (−) (−) (×) (+) (×) (+) (×) (×) (+) (×) (+) (+) (×) (−) (+) (×) (×) (−) (−) (×)

(74, 75, 77, 78, 80-82, 87) (77) (82) (82) (74) (88) (73) (76) (82) (81) (82) (75, 81) (79) (78, 80, 87) (89) (18) (79) (78, 80, 87) (78, 80, 87, 88) (88) (88) (85, 86) (77) (79) (77) (88) (88) (88) (88) (82) (78, 87)

NonMotorized Facility

Neighborhood

Barriers

Others a

Interventions: sidewalk gap closures Interventions: new sidewalks and sidewalk gap closure Interventions: crossing improvement Interventions: development of bicycle facility in areas with low pre-existing bicycle travel Sidewalk coverage Bike lane or paved shoulder coverage Neighborhood locations in central cities, suburbs, or small cities/towns vs. rural areas Neighborhood locations in urban vs. suburban areas Neighborhood aesthetics Access to local stores (within 20-min walk) Access to biking/walking facilities Walkability in high-income neighborhood Walkability in low-income neighborhood High-speed road barriers (> 30 mph) Major road barriers Busy road barriers Railroad track barriers Steep road barriers for 5-6 year old Steep road barriers for 9-12 year old Need to cross several roads Limited public transport Not having many other children around Multi-level interventions including engineering improvement

O O O O

(+) (+) (×) (×)

(85, 86) (85, 86) (85, 86) (86)

O O O PP

(×) (+) (×) (+)

(88) (78, 80, 87) (78, 80, 87) (73)

O PP PP PP O O PP O O O O O PP PP PP O

(×) (+) (+) (+) (+) (×) (−) (×) (−) (−) (−) (×) (×) (×) (−) (+)

(88) (76) (76) (76) (76) (76) (88) (77) (82) (77) (82) (82) (82) (82) (82) (90)

O, objective measures; PP, parents’ perceptions; CP, children’s perceptions. b (+), positive association; (−), negative association; (×), no association with walking or biking to school.

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Sidewalk and other street characteristics have significant impacts on walking or biking to school, although insignificant results have also been reported (see table 1). These factors include sidewalk and bike lane availability, sidewalk continuity, traffic signals, street crossings, slope, and lighting (73,78,80,82,85,86). While the majority of the previous studies are cross-sectional, a small number of longitudinal studies identified certain environmental interventions to be effective, including sidewalk gap closures at locations with moderate or heavy pre-existing walking/biking traffic and the replacement of four-way stops with traffic signals (85,86). Compared with the roles of distance, safety, and infrastructure conditions, the influence of neighborhood characteristics such as density, land use, and street patterns appeared somewhat weaker with less consistent results (77-80). Neighborhood locations in rural areas were found to be negatively correlated with active school travel, consistent with findings from the physical activity literature (73). Table 1 shows that the research on built environmental correlates on walking or biking to school behaviors is a work in progress, with inconsistent results and missing variables. Also lacking are systematic comparisons between objective and perceptual measures and investigation into the interrelations between different environmental factors as well as between environmental and personal factors.

Discussion This paper discussed several important public health and social equity issues related to school transportation and the roles of the built environment. Existing literature was reviewed identifying specific environmental correlates of walking or biking to school behaviors and confirming the importance of the built environment in promoting or detering these behaviors. It should be noted that this paper did not review exhaustively all published literature on this topic, and focused on selected empirical studies published in peer-reviewed journals. The scope of the reviews and discussions in this paper was to cover the broad categories of themes emerged from the literature. Despite these limitations, several important findings are emerged from the literature reviewed in this paper and major gaps in the current knowledge on this topic are identified. First, school siting is the foremost important factor in assessing walkability because it determines the distance that students have to travel and therefore the mode choice. It is clearly shown that beyond certain distance thresholds (between one half to one mile), walking is not considered a viable travel option. Parallel to the strategies to promote locating or keeping schools near residential neighborhoods and urban centers, policies such as minimum acreage requirements and financial incentives for new school constructions require re-examination. Second, along with distance, safety is another key factor in children’s school transportation. A national survey reported that traffic-related dangers were the second most common barriers reported by parents of 5- to 18-year-old children, followed by distance (81). Although other previous studies reported some inconsistency in the roles of safety (76,82, 88), safety still demands full attention in both research and promotion efforts. The “perception” of safety, rather than the factual crime or crash data, and the “perception” of

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physical barriers, such as high-volume and high-speed roadways and unsafe street crossings, seem crucial. Findings suggest that several improvements in the built environment may contribute to increase safety perceptions, including traffic-calming devices, signalized crossings, continuous sidewalks, and increased surveillance in areas around schools and along the major home-to-school routes. It is encouraging that most of these interventions are considered feasible. However, comprehensive cost-benefit analyses of these options, considering both the short-term and the long-term costs and benefits, seem necessary to guide future research and intervention efforts. Third, school transportation has potentially significant equity implications. We know that people of lower socioeconomic status walk more for transportation purposes, but they do so in poorly maintained and unsafe environments. Green and colleagues found that schools with higher percentage of minority and low-income students are exposed to more traffic and air pollution when they walk to school (67). Many advocates are promoting walking and walkable communities, as a way to incorporate healthy physical activities into people’s daily routines and to reduce reliance on automobiles. However, walking for children and for lower income populations may not be perceived positively as a healthful activity but rather as a socially stigmatized activity for persons of lower socioeconomic status who do not own a car (69). This is especially true when they are forced, rather than they choose, to walk. For certain populations, walking can add significantly to the already intensive labor demand of their job or other daily burdens. Cumulative findings suggest that the environments where people do walk are less safe and less walkable than the environments where people do not walk. Future research and promotion efforts should consider social equity aspects related to walking or biking to school behaviors. Fourth, this review identified multi-level factors associated with walking or biking to school, confirming that school transportation is not an independent individual choice but is decided by multiple household-related and environmental characteristics. Among the nonenvironmental factors, parental characteristics were found to be the key determinants of children’s school transportation. Future promotion efforts can be more effective if they target parents as well as children. Also importantly, more research is needed to understand the complicated interactions among the environmental, policy, and personal (children and family) factors that influence children’s school transportation. Further, the literature showed that the necessary conditions required for children to be able to walk or bike to school vary depending on the characteristics the students and their parents. A study by Kerr et al. showed that the objectively measured walkability of a neighborhood was important in high-income neighborhoods but not in low-income neighborhoods (76). Future efforts targeting active commuting to school should consider the different needs of and concerns for the specific target students and parents. Several additional gaps in the previous literature are identified from this review. More work is needed to understand diverse environmental settings (e.g., urban, suburban, and rural settings) and the differences in the roles of specific environmental features in school transportation behaviors. Further, what and how different environmental conditions influence school travels across different groups of children (e.g., by age, gender, ethnicity, and income) are still unclear. From the methodological perspective, many school transportationenvironment research remains descriptive or observational. Longitudinal experimental

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research necessary to investigate causal relationships is rare in this area of research, because of the technical difficulty and ethical concerns involving children. Boarnet further suggests that children represent an important population for studying environment-physical activity relationships because they do not select where to live, and therefore the problem of selfselection bias is resolved or reduced (91). Although truly experimental research is not feasible, quasi-experimental studies can be designed, which can add valuable insights into the currently fragmented picture in understanding school transportation behaviors.

Conclusions Boarnet’s studies are two of the few such studies that we found, and more longitudinal studies are needed, perhaps taking advantage of the natural experiments (intervention programs) that are being increasingly planned (85, 86). Finally, future research should also consider the additional roles of streets as venues for play activities for children, especially those who do not have parks or private yards to play in. Despite the growing number of empirical studies on this topic, this area of research is still in its early stage of development with many questions waiting to be answered. The “what” questions relating to correlates are beginning to be revealed, but the “why” and “how” questions about school travel choices remain largely unanswered.

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In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XLI

Insights into Bangkok Elementary Students’ Food Choice on School Days Chulanee Thianthai∗ Department of Sociology and Anthropology, Chulalongkorn University, Bangkok, Thailand.

Abstract Research has focused on adolescent’s food choice with the hope of finding key factors preventing obesity. We aimed to specifically spot relevant key factors that influence Bangkok children, aged 9-11 years old, their food buying preferences and behaviors in schools. Nutritional anthropological research methodology namely, participant observation, in-depth interviews, and buying and eating behaviors-related observation questionnaires were carried out among 27 participating elementary schools in Central Bangkok. This research aimed to discover detailed factors associated with individuality, sociality, environmental, and external influence over children’s food choices. First, individuality factors associated to children’s food choices involved the amount of daily allowance, children’s food preferences, students’ perception towards food ability in correlation with the frequency of school breaks, and children’s rationale of food prices (reasonable/affordable range). Second, sociality factors concerned how individual(s) have shaped children’s knowledge of food, food-related beliefs, and individual(s) that accompany/are present at the moment when children are buying foods. Third, environmental factors discovered were the location, distance, and quality of where food is being sold, shelving/how food is being displayed, and the availability of food knowledge the school displayed/provided for their students. Last, external factors ∗

Correspondence: Assistant Professor Dr. Chulanee Thianthai, Department of Sociology and Anthropology, Faculty of Political Science, Chulalongkorn University, Patumwan, Bangkok 10330, Thailand. Tel: (662) 2187292; Fax: (662) 218-7300; E-mail: [email protected] or [email protected]

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Chulanee Thianthai identified the variety of mass media channels, which triggered children to desire new food items, were tested and shown no influence over children’s food choice on school days. In conclusion, the insights gained can enlighten ways in which in-depth understanding of children’s food choice and behaviors can be obtained in order to create a more efficient and culturally suited future obesity prevention plan.

Keywords: Bangkok children, children’s food choice, children’s eating habits/patterns, children’s food preference, nutritional anthropology, child obesity, obesity prevention/ strategy.

Introduction Today’s health scientists are focusing on the importance of children’s nutritional-related habits, because of the increasing rate of child obesity. It has been proven that children’s nutritional eating habits will have a strong influence over their adult years (1). Children, especially those who live in urban areas, are being bombarded by unhealthy food alternatives, such as high calorie, sugary, and fattening foods. Not only do these unhealthy food alternatives not provide the essential nutrients a child needs, but the sense of fulfillment from eating these types of foods also reduces the child’s appetite to want other nutrient enriched foods, particularly vegetables and fruits. Many studies have been conducted to stress how children’s unhealthy eating habits can cause obesity, diabetic type 2, high blood pressure, dental disease, and heart failure (2-4). However, many societies believe that a part of these unhealthy eating habits have been built up due to the support of mass media influence (5,6). Recent literatures have found that there are multiple factors that contribute to children’s food choice and eating behaviors. These factors were such as family influence, given health information, availability and accessibility, exposure to new food types, food environment, socioeconomic status, and cultural beliefs (7-9). Not only do these factors shape children’s food choice and eating behaviors, but they are also factors that will instigate modifications in those choices and behaviors (7). However, not all of these factors may apply to certain populations. Moreover, due to variation in children’s food choice and eating behaviors from society to society, researchers should not limit their examination to only the above factors. Therefore, in order to gain realistic insights on obesity prevalence, researchers should focus on a particular societal circumstance. Using Thai society as an example, the World Health Organization has showed that in just over a period of two years, the prevalence of obesity among Thai children aged 5-to-12 years old had risen from 12.2% to 15-16% (10). Another recent research has proven that children who live in Bangkok have a higher risk of being obese than those who live in the rural areas (11). In supporting the latter research result, another research found that 1 out of 4 Thai children who attended well-known schools within Central Bangkok district were obese (12). In order to efficiently create a health program that specifically targets on reducing the obesity rate among children who live in urban areas, like Bangkok, one needs to gain cultural insight dimension and have an in-depth understanding of why and how urban children’s food choice appear to be that way. Thus, this research proposes to identify the main influential factors

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affecting Bangkok children and young adolescents’ food choice on their school days through illustrative insights.

Methods The fieldwork data was obtained from intensive fieldwork in Bangkok from mid 2006 to 2007. Bangkok, known as Krung Thep, the capital of Thailand, was selected to be the most appropriate setting for this research. Bangkok is known for having the best educational institutions, which attracts students from different regions in Thailand, enabling the researcher to receive students with various socio-economic backgrounds. In addition, students in Bangkok were the group that has been bombarded with a greater variety of food through mass media influence. Having Bangkok students as the target population also permits the researcher to examine whether or not their food choices during their school hours involved Western and international variety of foods and to what extent. Through permission from 27 public elementary schools located in Central Bangkok, the researcher was able to observe and participate in food buying and selling-related activities of elementary school children, aged 9-11 years old, during their school hours on school days. This age group was selected, because they just started their own decision making in spending their allowance on food and they are among the most at risk group for obesity. Moreover, this study was able to capture the majority of children’s food choice behaviors because it covers five days out of the week when they must make their own decisions.

Procedures and Research Techniques The data collection started with the process of mapping out and defining the boundary of Central Bangkok. The research team then visited over 50 public elementary schools in Central Bangkok and explained the research objectives. Out of 50 elementary schools, 27 were willing to participate in this research. The researchers then visited these schools and observed the children, while buying and eating during the school hours (08:00-16:00). Observation records were kept and found it to be interesting in the form of field notes. After several months of utilizing systematic observation, the researchers moved on to participate in children’s food related activities at school. For example, they assisted school teachers and food vendors to sell food and beverages during the school hours, helped teachers make foodrelated posters to hang in the cafeterias, and facilitated the children to form lines for buying food. Through the methodology of participant observation, the researchers were able to gain essential firsthand experience needed for building a realistic buying and eating behaviorsrelated observation questionnaire. The questionnaire was composed of three parts: 1) school information and drawing of physical site where foods were sold in schools; 2) demographic questions of who were being observed, at what time, and where and 3) sets of closed-end and opened-end questions needed for further in-depth interviews with students. At least 20 students per school, who portrayed the characteristics being articulated and showing

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regularity in buying foods and beverages during school hours were selected for in-depth interviews. Observation and participation in children food buying and selling-related activities were limited to when they buy foods of any type or form within the school courtyard during school hours. The activities related to food buying inside and outside of the schools after school hours were excluded. Their food choices that we observed were mainly the types of foods that they bought other than what their school provided for their lunch.

Data Analysis The researcher used the data gained from participant observation field notes and the first and second parts of the questionnaire to examine and highlight the pattern of children’s food choice in each school. The data obtained through the third part of the closed-ended questions were calculated with the help of Statistical Package for the Social Sciences (SPSS) and the output was shown in percentages, whereas the data drawn from open-ended questions were used to cross-check with the data gained from participant observation and to further clarify what has been the children’s perspective.

Results The following are findings that revealed detailed factors associated with the four areas of examination: individual, social, environmental and external factors believed to have influence over food choice patterns.

Individual Factors Individuality involved factors that were mainly created by the children themselves, which contributed to their food choice behaviors. Individual factors were the amount of children’s daily allowance, children’s food preference, children’s perception towards food availability in correlation with the frequency of school breaks, and children’s rationale of food prices (reasonable/affordable range) factors. The amount of money Bangkok children received per day to spend on buying food and beverages on school days was on average $0.60 cents (equivalent to 20 Baht). With this amount of money, children can only afford certain quality and quantify of food. For example, in this study the average number of food items bought per day was 1-2. Food preference was being tested in terms of what were Bangkok children’s most favorite food items (listed in order): Fried food (i.e. fried chicken wings, french fries, fried sausages, and fried wontons), ice cream, chips/snacks in small packages, food items that represent meals (i.e. a one dish meal such as rice and curry or noodles), various kinds of milk products, and types of flour related foods (wafer, bread, cookies, and sandwich). From the observation and in-depth interviews, this research found that children were highly fond of

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sweet-tasting beverages such as soda pops and Thai ice tea and ice coco drinks and smoothies. Also through the in-depth interviews, the study has found that milk was categorized not as a beverage, but rather seen as a food item. Children’s perception towards food availability in correlation with the frequency of school breaks revealed that lunch time was the peak time for them to buy food and beverages in schools. Almost every child in this study bought food and beverages after they ate their school-provided meals. From the in-depth interviews, the research has found that Bangkok children defined food-buying-and-eating activities as their leisure time. Children’s rationale of what is the reasonable food price was $0.20-0.30 cents (equivalent to 5-10 baht) per item. Every food item at this price range was in the small size packaging.

Socail Factors Sociality concerns other individual(s)/source(s) that have shaped and contributed to children’s food choices and eating patterns. Examples of these individuals were parents, teachers, friends, food and beverages sellers. Thus, the social category we found in this study covered individual(s)/source(s) that had influenced food knowledge, food-related beliefs, and individual(s) that accompanied or was present at the moment when children were buying foods. Individual(s)/source(s) that had influenced these Bangkok children’s food knowledge and food-related beliefs (ranked in order) were their elementary school teachers, parents and television commercials. Although television commercials were mentioned as one of the sources that influenced food choice, it had only shaped their perception of what was good and nutritious food, but had no impact on their food buying decisions. Individual(s) that Bangkok children wanted to accompany or be present with when they buy food was their friends. Friends usually accompany friends to buy food in a group of 1-2 friend(s) at a time. However, this study revealed that there were no influence related to the choice of food and beverages they buy at this age.

Environmental Factors Environment is being defined as factors that were created by physical things that surrounded children on school days. Thus, environmental factors found involved the location, distance, and quality of where food was sold, food display, ice cream commercial food pricing posters displayed above the ice cream freezers, and the availability of food knowledge the school displayed/provided for their students. The location where food was sold in schools usually came in the form of student union shops, food stands located inside school cafeterias and outdoor food stands within the school gate and food vending machines. This study found that the location and distance were correlated to the decision-making of children when they want to buy food, that is children often go to buy foods at the closest location to their classrooms. Listed in order that shows

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this correlation between the closest distance and where food were most bought by these children were food stands in school cafeterias, student union shops, outdoor food stands and food vending machines. Regarding the quality of where food is being sold we found that in schools with only elementary level, only one venue was provided for selling foods during break time. In contrast, in schools that have both elementary and high school level, children would have more variety in choosing places to buy food. From the in-depth interviews, the ideal quality food place was defined as a place that sells a variety of foods. Moreover, the food sold there should be fresh, clean and delicious. The ice cream commercial food pricing posters displayed above the ice cream freezer had an influence on food choice only to a certain extent, that is to help them know the price and make their decision if they can afford it or not and provide them with easier access to quickly grab the right kind of ice cream in the freezer by memorizing the packaging. In every school we visited, the food sold most were often displayed and shelved at a distance that is easy for the children to grab and gain access to (leveling to student’s reachable height or placed towards the front of the table where food is sold). When we collected our data, the most popular food was fried foods and small package chips/snacks, located as easy access. The types of food knowledge these elementary schools displayed/provided for their students came in the form of posters that provided nutritional food facts and hygienic facts relating to proper hand washing before eating, broadcasting on school radio, and leaflets/handouts in the school library. The most popular food knowledge displayed was the five food group posters. Rarely have the researchers witnessed a link between the children’s food choice and information from these media.

External Factors External category included influences outside of the school arena. Externality largely was identified as the variety of mass media channels (what children read in books and magazines and/or watch on television commercials), which triggered them to desire new food items. The study showed that there was little influential factors dominated by what children read in books and magazines or watch on television commercials that cause them to desire new food items. This is maybe due to the fact that the variety of foods sold in schools were limited and the way in which they can buy the types of food they really like through what they read/see on commercials can be more apparent on the weekends. Through the in-depth interviews we found that at this age, children would mainly buy food on their school days based on the delicious taste of the food, the color of the food, the attractive packaging and the free stuff that came with the food.

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Conclusions In conclusion, the insights gained provided in-depth details of Bangkok children’s food choices on school days. As we can see, participant observation of buying and eating behaviors, questionnaires, and in-depth interviews served as amazing tools that can provide insight into what really has an influence over our children. These factors are not isolated from one another, but rather associated to one another in shaping Bangkok children’s decisionmaking and food habits. Building upon this information would help in constructing a more efficient future obesity prevention plan in schools. For example, if a greater variety of food stalls that provide reasonable prices (not exceeding their daily allowance), fresh, delicious, clean, and healthy foods are needed to be located near children’s classrooms and at places they can easily access. This change can alter and improve their decision-making and behaviors with regard to food. Meanwhile, there is an urgent need to reduce the consumption of fried foods and sweet beverages that are not nutritious in Bangkok elementary schools. The reduction can be made through limiting the amount of these types of foods as well as making it more difficult to buy these foods in schools. The types of food knowledge these elementary schools displayed near food shops or broadcast during the lunch time (which is the peak time when children would buy foods) should also cover information on negative health consequences resulting from eating high fattening and high calorie foods, namely fried foods and sweet beverages. Displaying food facts and harmful consequences relating to their current food buying behaviors would have a stronger impact on their food selections. It is refreshing to learn that mass media and negative peer influences have very little influence over these children’s food choices on school days. We suggest that there is room for healthy foods to make its way into Bangkok elementary schools. Moreover, the data gained from this research can also act as a foundation to create healthy food alternatives for elementary school children in Bangkok. Such research methodologies can easily be applicable in other cultures to improve the study of child obesity.

Acknowledgements The author wishes to thank the students, teachers, and participating schools, the Thailand Research Fund (TRF) Grant and Commission of Higher Education for making this study possible, Dr. Chitr Sitthi-Amorn in contributing valuable comments, and Raksaya Aunsnunta for her constructive editing skills.

References (1) (2)

Healthy eating in childhood persists into older age. Nurs Standard 2006;20:17. Unhealthy foods bulk of school vending machine choices. Nation’s Health 2004;JuneJuly:7.

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Deborah JA. Approaches to the study of children, food and sweet eating: a review of the literature. Early Child Dev Care 2005;175: 407-17. (4) Holffer J. Child obesity can lead to heart problems. New York Amsterdam News 2005;November: 38. (5) Lewis MK, Hill AJ. Food advertising on British children’s television: a content analysis and experimental study with nine-year olds. Int J Obes 1998;22:206-14. (6) Krisberg K. Food marketing toward youth contributing to unhealthy choices. Nation Health 2006;January/February:19. (7) Cooke, L. The development and modification of children's eating habits. Nutrition Bull 2004;29(1):31-5. (8) Huon GF, Wardle J. Improving children's eating patterns: intervention programs and underlying principles. Aust J Nutr Dietetics 1999;56(3):156-65. (9) Green J, Waters E, Haikerwal A, O'Neill C, Raman S, Booths ML, Gibbons K. Social, cultural and environmental influences on child activity and eating in Australian migrant communities. Child Care Health Dev 2003;29(6):441-8. (10) Obesity and overweight. Accessed 2008 Jun 08.URL: http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/ (11) Chaiamnuan P. A personal documentary report on how to prevent and cure obesity in Thai population. Bangkok: Natl Defense Coll Thailand, 2002. (12) Neannui P. Tooth decay: A little problem that is not little. In: Brain Bank for Health. Bangkok: Office Natl Economic Soc Dev Board, 2004:242-8.

In: Child Health and Human Development Yearbook-2008 ISBN: 978-1-60692-979-7 Editor: Joav Merrick © 2009 Nova Science Publishers, Inc.

Chapter XLII

Israeli Adolescents and Obesity Mohammed Morad1,2, Isack Kandel2,3, Jason Ahn2,4, Brian Seth Fuchs2,4 and Joav Merrick∗ 2,5 1

Department of Family Medicine, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel 2 National Institute of Child Health and Human Development, Office of the Medical Director, Division for Mental Retardation, Ministry of Social Affairs, Jerusalem, Israel 3 Faculty of Social Sciences, Department of Behavioral Sciences, Ariel University Center of Samaria, Ariel, Israel 4 Harvard Medical School, Boston, MA, USA 5 Kentucky Children’s Hospital, University of Kentucky, Lexington, KY, USA

Abstract Childhood and adolescent obesity are risk factors for poor health later in life as well as decreased life expectancy. This short communication reviews literature on obesity in Israel and examines several recent studies, which have clearly demonstrated rising rates of childhood and adolescent obesity similar in magnitude to those trends observed in other Westernized nations. It is incumbent upon relevant authorities within Israel to reverse these trends so as to prevent the long-term adverse health consequences associated with childhood and adolescent obesity. We recommend initiating a national educational campaign to promote exercise and healthy eating. This campaign would target children and adolescents and would rely upon evidence based guidelines for diet and exercise.

∗

Correspondence: Professor Joav Merrick, MD, MMedSci, DMSc, Medical Director, Division for Mental Retardation, Box 1260, IL-91012 Jerusalem, Israel. E-mail: [email protected]

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Keywords: Obesity, overweight, adolescence, Israel.

Introduction Obesity is recognized as an important risk factor for many chronic diseases, such as cardiovascular disease, diabetes and cancer. Children who are overweight are at an even greater risk of developing such diseases, because of their extended exposure to the harmful effects of excessive weight; and there is often an accelerated onset of chronic disease within this population. In addition, children who are overweight are more likely to suffer from impaired physical, psychological, and social development. In this short communication we examine recent research on obesity among Israeli children and adolescents.

Research Findings from Israel We conducted a Medline search from 2000 for papers relevant to this review (search entry was adolescence and overweight and Israel). Because Israel has large number of army recruits each year who are given physical exams, researchers were able to conduct a population-based study of Israeli Jewish males prior to army enrollment (1). This study provided valuable information for two body mass index (BMI) reference points: a national reference (NR), and an ethnic-specific reference (ER). This study included 109,570 Jewish males 17 years of age. Weight, height and blood pressure values were recorded, and BMI was calculated. The 85th percentile of BMI was used as a lower limit for defining overweight status for NR and ER. Hypertension prevalence among recruits was used as a biomarker to confirm the reliability of the ER when discrepancies in classification between the two references were found. Compared to the NR, three ethnic groups had a BMI distribution shifted to the left (light sub-population) and five had a BMI distribution shifted to the right (heavy sub-population). In the light subpopulation, 7% of the recruits who were classified as normal weight by the NR were considered overweight by the ER and had a hypertension rate similar to that of those defined as overweight by both references (3.1 per 1,000). In the heavy sub-population, 4% of the subjects who were classified as overweight by NR and normal by ER had hypertension rates similar to that of those defined as normal weight by both references (2.7 per 1,000), and significantly lower than that of those classified as overweight by both references (10.8 per 1,000). Type 2 diabetes has been increasing even among children and adolescents during the past decade. A case report (2) of a boy (14 years) and two girls (16.5 and 17 years) and a larger study (3) of 22 children and adolescents linked extreme obesity (BMI 39-47) with acanthosis nigricans, elevated diastolic blood pressure, hirsutism, menstrual disorders and insulin resistance as part of this metabolic syndrome. One study of a weight management program included 177 obese children (6-16 years); this longitudinal, non-randomised study compared three and six month combined dietarybehavioural-exercise interventions with matched control. The researchers demonstrated

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that body weight and BMI were reduced (P<0.05) and physical endurance was improved (P<0.0005) by the three month intervention. Obese children who were given six months of intervention were able to successfully maintain their weight loss and further improved their physical endurance time. In contrast, the obese children who did not participate in the structured intervention gained weight and increased their BMI. Gender, pubertal status, and the degree of obesity had no influence on BMI changes, but children of normal weight parents demonstrated significantly greater weight loss than children of obese parents (4). An innovative long-term follow-up (seven years) study, which focused on educating the parents of 50 obese children rather than only the children, evidenced a larger treatment effect compared with the conventional approach of treating only children. Inadequate dietary habits can result in iron deficiency, as shown in a study of 321 children and adolescents who were treated in Israel between 1999 and 2001 (6). Iron deficiency was common in this sample of overweight and obese children, and the prevalence of this deficiency was significantly greater among obese children compared with their normal-weight counterparts. This result was confirmed by another study (7) which demonstrated an elevated risk of vitamin B12 deficiency in obese children. One recent study investigated the correlation between early postnatal weight gain and obesity in Arab adolescents (8). Growth records were examined from the first 24 months of life. Eighty eight obese and 214 non-obese 12 year-old Arab children were evaluated in this study. Height and weight at birth were comparable for the obese and non-obese adolescents, while the rate of breastfeeding was significantly lower in the obese group (p < 0.01), suggesting that breastfeeding had a protective effect. The evidence also indicated that obese adolescents had a small but significant weight gain at four (p = 0.002) and 12 (p = 0.01) months of age relative to their non-obese counterparts. Furthermore, weight gain during the first two months of life and feeding pattern were independent predictors of BMI at the age of 12.

Israel Compared to Europe and the United States Israel participated in a cross-sectional, nationally representative school-based survey in 1997-1998 (991 Israeli students participated out of a total of 29,242 boys and girls, 13 to 15 years) by means of identical data collection methods (9). The following countries participated in this study: Austria, Czech Republic, Denmark, Flemish Belgium, Finland, France, Germany, Greece, Lithuania, Ireland, Israel, Portugal, Slovakia, Sweden and the United States. The United States evidenced the highest prevalence of overweight children and Lithuania the lowest. In the United States 12.6% of 13-year-old boys were overweight, 10.8% of 13year-old girls, 13.9% of 15-year-old boys, and 15.1% of 15-year-old girls. In contrast, in Israel 3.5% of 13-year-old boys were overweight, 4.8% of 13-year-old girls, 6.8% of 15-yearold boys, and 6.2% of 15-year-old girls (9). Relative rankings among countries were similar if BMI at or above the 85th percentile were used for comparisons. Although the differences were less dramatic if weight at the 85th percentile was used as a definition of obesity, this

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approach evidenced the highest prevalence of overweight children in the United States, Ireland, Greece and Portugal (9).

Recent Studies of Army Conscripts A recent study included 76,732 adolescents, 32,402 (42.2%) females and 44,330 (57.8%) males aged 17 years at the draft examination (10). Among 17-year-old Israeli conscripts 4.1% of males were obese, and 3.3% of females were obese. The prevalence of individuals categorized as borderline overweight was 12.4% for males and 11.4% for females. Prevalence of hypertension and type 2 diabetes was greater in males than females (P<0.001, 0.015), but for both sexes rates of hypertension and type 2 diabetes were significantly higher among conscripts with BMI>30 kg/m2. Females with BMI>30 kg/m2 were found to be less likely to have completed 10 years of education, but there was no similar difference found among male conscripts. This study found a relatively low prevalence of obesity, but a high prevalence of individuals who were categorized as borderline overweight; Obesity was positively correlated with hypertension and type 2 diabetes and negatively correlated with level of educational attainment. Another cross-sectional population-based study conducted from 1996 to 2002 on 560,588 Israeli army recruits 16.5 to 19 years of age determined the prevalence of hypertension and obesity and assessed the relationships between prehypertension, body mass index (BMI), sex and age. These researchers demonstrated that mean systolic BP (SBP) and diastolic BP (DBP) were significantly higher in male subjects than female subjects; 56.8% of males and 35.8% of females were categorized as prehypertensive. There was also a statistically significant positive association between mean SBP and DBP, age and BMI. Moreover, the prevalence of prehypertension was significantly higher in obese subjects; 10.9% of males were overweight and 3.3% were obese, while 11.1% of females were overweight and 3.2% were obese (11).

Health Related Quality of Life Health-related quality of life (HRQOL) has also been studied in 182 children and adolescents from community pediatric clinics and a hospital-based obesity clinic (12). Compared with normal weight children, obese children reported significantly lower HRQOL in physical, social and school domains (P<0.01). Dividing the HRQOL results into BMI quartiles demonstrated that scores for emotional and school domains were similar between moderately obese children and normal weight children. Only children in the 4th quartile, with severe obesity, evidenced significantly lower scores. Parents of obese children perceived their children's HRQOL scores to be lower than what was reported by the children themselves.

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Conclusions Recent studies have clearly demonstrated rising rates of childhood and adolescent obesity similar in magnitude to those trends observed in other Westernized nations. It is incumbent upon relevant authorities within Israel to reverse these trends so as to prevent the longterm adverse health consequences associated with childhood and adolescent obesity. We recommend initiating a national educational campaign to promote exercise and healthy eating. This campaign would target children and adolescents and would rely upon evidence based guidelines for diet and exercise.

References (1)

Lusky A, Lubin F, Barell V, Kaplan G, Layani V, Lev B, Wiener M. Body mass index in 17-year-old Israeli males of different ethnic backgrounds; national or ethnic-specific references? Int J Obes Relat Metab Disord 2000;24(1):88-92. (2) Pinhas-Hamiel O, Koren I, Vardi P. [Type 2 diabetes among adolescents in Israel]. Harefuah 2000;138(3):186-9, 271. [Hebrew] (3) Kerem N, Guttmann H, Hochberg Z. The autosomal dominant trait of obesity, acanthosis nigricans, hypertension, ischemic heart disease and diabetes type 2. Horm Res 2001;55(6):298-304. (4) Eliakim A, Kaven G, Berger I, Friedland O, Wolach B, Nemet D. The effect of a combined intervention on body mass index and fitness in obese children and adolescents - a clinical experience. Eur J Pediatr 2002;161(8):449-54. (5) Golan M, Crow S. Targeting parents exclusively in the treatment of childhood obesity: long-term results. Obes Res 2004;12(2):357-61. (6) Pinhas-Hamiel O, Newfield RS, Koren I, Agmon A, Lilos P, Phillip M. Greater prevalence of iron deficiency in overweight and obese children and adolescents. Int J Obes Relat Metab Disord 2003;27(3):416-8. (7) Pinhas-Hamiel O, Doron-Panush N, Reichman B, Nitzan-Kaluski D, Shalitin S, GevaLerner L.Obese children and adolescents: a risk group for low vitamin B12 concentration.Arch Pediatr Adolesc Med. 2006 Sep;160(9):933-6. (8) Shehadeh N, Weitzer-Kish H, Shamir R, Shihab S, Weiss R. Impact of early postnatal weight gain and feeding patterns on body mass index in adolescence. J Pediatr Endocrinol Metab 2008;21(1):9-15. (9) Lissau I, Overpeck MD, Ruan WJ, Due P, Holstein BE, Hediger ML. Health Behaviour in School-aged Children Obesity Working Group.Body mass index and overweight in adolescents in 13 European countries, Israel, and the United States. Arch Pediatr Adolesc Med 2004;158(1):27-33. (10) Bar Dayan Y, Elishkevits K, Grotto I, Goldstein L, Goldberg A, Shvarts S, Levin A, Ohana N, Onn E, Levi Y, Bar Dayan Y. The prevalence of obesity and associated morbidity among 17-year-old Israeli conscripts. Public Health 2005;119(5):385-9.

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(11) Israeli E, Schochat T, Korzets Z, Tekes-Manova D, Bernheim J, Golan E. Prehypertension and obesity in adolescents: a population study. Am J Hypertens 2006;19(7):708-12. (12) Pinhas-Hamiel O, Singer S, Pilpel N, Fradkin A, Modan D, Reichman B. Health-related quality of life among children and adolescents: associations with obesity. Int J Obes (Lond) 2006;30(2):267-72.

About the Editor Joav Merrick, MD, DMSc, is professor of child health and human development affiliated with Kentucky Children’s Hospital, University of Kentucky, Lexington, United States and the Zusman Child Development Center, Division of Pediatrics, Ben Gurion University of the Negev, Beer-Sheva. The medical director of the Division for Mental Retardation, Ministry of Social Affairs, Jerusalem and the founder and director of the National Institute of Child Health and Human Development, Israel.

About the National Institute of Child Health and Human Development in Israel (NICHD-IL) The National Institute of Child Health and Human Development (NICHD) in Israel was established in 1999 as a virtual institute under the auspices of the Medical Director, Ministry of Social Affairs in order to function as the research arm for the Office of the Medical Director. During the years many activities have became focused in the south of Israel due to an affiliation with the Division for Community Health and the School of Continuing Medical Education at the Faculty of Health Sciences (FOHS) at the Ben Gurion University of the Negev (BGU). We established on the BA level a full course on “disability” at the Recanati School for Allied Professions in the Community and also on the MA level a course on “aging with disability” The mission of a National Institute for Child Health and Human Development in Israel is to provide an academic focal point for the scholarly interdisciplinary study of child life, health, public health, welfare, disability, rehabilitation, intellectual disability and related aspects of human development. Nationally the NICHD works in collaboration with the Faculty of Health Sciences, Ben Gurion University of the Negev, Department of Physiotherapy, Sackler School of Medicine, Tel Aviv University, Department of Physiotherapy, Haifa University, Department of Education, Bar Ilan University, Ramat Gan, Faculty of Social Sciences and Health Sciences, Ariel University Center, Samaria in Ariel. Internationally with the Department of Disability and Human Development, College of Applied Health Sciences, University of Illinois at Chicago, Strong Center for Developmental Disabilities, Golisano Children's Hospital at Strong, University of Rochester School of Medicine and Dentistry, New York, Division of Neuroscience, Department of Psychiatry, Columbia University, New York, Centre for Chronic Disease Prevention and Control, Health Canada, Ottawa, Chandler Medical Center and Children’s Hospital, Section of Adolescent Medicine, University of Kentucky, Lexington, Institute for the Study of Disadvantage and Disability, Atlanta, Quality of Life Research Center, Copenhagen, Denmark, Nordic School of Public Health, Gottenburg, Sweden and School of Social Work, Chinese University, Hong Kong.

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These national and international collaborations have resulted in many research projects and publications in peer-reviewed international journals (7).

Index A AAT, 48 ABC, 294, 484 abdomen, 426, 532, 533 abduction, 288, 551 abnormalities, xxi, 4, 6, 56, 135, 144, 148, 153, 163, 227, 283, 419, 420, 423, 424, 427, 430, 444, 527 abortion, 509 absorption, 438, 480, 490, 533, 534 abstinence, 508 abusive, 34, 45, 108, 269 academic, xiv, 37, 71, 87, 88, 98, 101, 261, 263, 270, 313, 357, 365, 547, 579 academic performance, 357, 547 academics, 98 Acanthosis nigricans, 533, 537 access, 36, 41, 79, 80, 81, 86, 87, 88, 89, 94, 95, 98, 310, 315, 325, 331, 349, 352, 358, 359, 360, 454, 455, 457, 500, 520, 525, 549, 550, 558, 568, 569 accessibility, 31, 98, 99, 102, 340, 558, 559, 564 accidental, 79, 82, 118, 351 accidents, xiii, 70, 82, 108, 114, 476, 512 accommodation, 34, 40, 334, 542 accountability, 30 accounting, xiv, 105, 144, 239, 278, 306 accreditation, 315, 316 acculturation, 82, 348, 355, 356, 357, 360 accuracy, 81, 127, 215, 324, 335, 340 ACE inhibitors, xxi, 413 acetate, xxiii, 210, 507, 508, 509, 512, 514, 515, 516, 534, 536 acetic acid, 534 acetylation, 534

achievement, 14, 49, 50, 176, 183, 187, 263, 266, 274, 313, 502 acid, 210, 260, 278, 280, 282, 284, 286, 296, 297, 419, 530, 532, 534, 536 acidosis, 481 acne, 427, 428, 429, 502, 513, 514, 515, 532, 533, 534, 536 acne vulgaris, 532, 533, 534, 536 ACR, 258 ACTH, 300, 397, 533 action research, 350 activated receptors, 397 activation, 147, 148, 153, 180, 186, 198, 200, 208, 209, 214, 216, 227, 231, 250, 284, 285, 286, 295, 296, 298, 377, 385, 397, 400, 402, 417 active transport, 557, 561 activity level, 521, 547, 549, 557 acupuncture, 430 acute, xvi, xx, 48, 133, 147, 148, 193, 194, 198, 199, 200, 201, 202, 203, 214, 218, 220, 279, 294, 298, 307, 320, 329, 332, 340, 379, 380, 381, 383, 384, 385, 387, 396, 468, 469, 523 acute asthma, 147, 148 acute stress, xx, 329, 332, 340, 379, 381, 383, 384, 385 Adams, 44, 136 adaptability, 353 adaptation, 70, 159 addiction, 477 adductor, 55 adenoma, 510 adenosine, 162 adequate housing, xviii, 301 adhesion, 428 adipocytes, 129, 417, 425, 428 adiponectin, 425, 428, 432, 433

582

Index

adipose, 130, 408, 409, 416, 417, 418, 447, 480, 482, 509, 531 adipose tissue, 130, 408, 409, 416, 417, 418, 447, 480, 482, 509, 531 adiposity, 432, 450, 524, 559 adjudication, 302 adjustment, 36, 44, 150, 159, 164, 201, 222, 328, 329, 334, 335, 395, 398 administration, 88, 159, 160, 162, 205, 221, 223, 226, 230, 284, 287, 289, 292, 296, 298, 299, 381, 384, 391, 484 administrative, 34, 72, 328, 333, 356, 448 administrators, xii, 33, 37 adolescence, xi, xxii, xxiii, 36, 133, 135, 143, 349, 363, 399, 410, 411, 430, 432, 443, 444, 456, 460, 461, 462, 464, 465, 471, 483, 484, 490, 497, 498, 499, 501, 502, 504, 520, 524, 525, 526, 531, 532, 540, 572, 575 adolescent boys, 126, 312, 351 adolescent female, 127, 136, 351, 353, 364, 420, 440, 509, 520, 532, 549 adolescent patients, xxiii, 436, 440, 497, 503 adrenal gland, 532 adrenal hyperplasia, 429 adrenocorticotropic hormone, 397 adult, xxi, 34, 36, 39, 118, 124, 131, 134, 144, 151, 184, 258, 292, 302, 308, 314, 319, 326, 327, 332, 335, 346, 387, 405, 419, 421, 424, 435, 439, 444, 454, 464, 470, 472, 478, 503, 511, 522, 525, 526, 542, 543, 547, 557, 564 adult obesity, 454, 472, 526, 547 adult population, xxi, 405, 419, 435, 439, 444 adulthood, xxiii, xxiv, 36, 129, 133, 134, 142, 143, 399, 420, 424, 444, 461, 464, 465, 467, 490, 497, 498, 502, 504, 520, 526, 539, 557 adverse event, xiv, xxiii, 105, 107, 108, 114, 147, 187, 188, 475, 476 advertisements, xxiii, 391, 519, 522, 526 advertising, 521, 524, 570 advocacy, 325 aerobic, 406, 407, 408, 409, 411 aerobic exercise, 408 aerobics, 409 aesthetics, 548, 553 affective dimension, 250 affective disorder, xv, xvi, xvii, 129, 136, 138, 167, 186, 187, 188, 193, 194, 203, 204, 205, 206, 217, 219, 220, 225, 226, 227, 250, 278, 279, 281, 282, 291, 292, 293, 294, 334, 336, 352, 373, 375, 377, 392, 489

affective states, 230, 457, 460 Africa, xi, 94, 342, 346, 375, 477 African American, xix, 130, 211, 304, 333, 347, 348, 349, 350, 352, 353, 354, 355, 356, 360, 362, 363, 364, 421, 424, 436, 449, 457, 458, 459, 483, 502, 503, 531, 549, 551 African American women, 353, 363, 364 African-American, xxii, 215, 226, 333, 363, 394, 414, 453, 454, 455, 462, 520, 560 agent, 157, 281, 282, 308, 428, 446, 477 agents, xv, xxi, 132, 148, 155, 157, 162, 163, 294, 296, 327, 335, 413, 428, 446, 476, 479, 492, 513 aggression, xx, 37, 222, 288, 312, 314, 324, 334, 335, 359, 379, 380, 381, 382, 384, 387 aggressive behavior, xx, 148, 269, 379, 382, 383, 384, 386, 387 aging, 65, 259, 270, 274, 579 agonist, 288, 289, 299, 417, 481 agriculture, 415 aid, xxi, 17, 18, 58, 134, 423, 430, 468 AIDS, xi, 329, 332 air, 6, 7, 20, 88, 90, 164, 231, 387, 548, 550, 555, 557 air quality, 557 air travel, 164 airflow obstruction, 142 airway hyperresponsiveness, 145 airway inflammation, 145, 147, 149, 152, 387, 391 airways, 146 akathisia, 292 alanine, 285 Alaska, 351, 366 Alaskan Native, xix, 347, 350, 358, 359 Alberta, 165 albumin, 210 alcohol, 40, 164, 178, 185, 209, 278, 305, 311, 320, 326, 327, 328, 340, 351, 352, 353, 355, 360, 362, 363, 364, 366, 392, 415, 490, 531 alcohol abuse, 278, 305, 327, 340, 364 alcohol dependence, 311, 320, 392 alcohol use, 351, 353, 355, 360, 362, 366 alcoholism, 291 aldosterone, 417 alertness, xv, 155, 156, 161, 162 alienation, 120, 351, 357, 358 alkaline, 533 alkaloids, 476, 477 alkalosis, 494 ALL, 77 allele, 132

Index allergens, xix, xx, 148, 248, 368, 369, 376, 390, 391, 392, 397, 399 allergic inflammation, 369, 384, 391, 392, 396, 398 allergic reaction, 11, 153, 381, 392, 397, 401 allergic rhinitis, 152, 376, 397, 401 allergy, xv, xix, xx, 11, 141, 145, 146, 149, 151, 152, 153, 220, 368, 376, 377, 387, 390, 391, 393, 395, 396, 397, 398, 400, 401, 402, 511 allograft, 216 alpha, xxi, 131, 138, 139, 191, 216, 230, 296, 369, 382, 400, 413, 416, 432, 480 alpha blocker, xxi, 413 alternative, 26, 31, 32, 40, 48, 49, 63, 199, 209, 229, 232, 235, 288, 302, 310, 318, 428, 430, 483, 511 alternative hypothesis, 318 alternative medicine, 26, 32, 428, 430 alternatives, 148, 420, 523, 564, 569 alters, 296 altruism, 457 aluminum, 534 ambivalence, 341 ambivalent, 269 ambulance, 34 amelioration, 419 amenorrhea, 514 American Academy of Pediatrics, 70, 322 American culture, 353 American Diabetes Association (ADA), 337, 445, 446, 449 American Heart Association, 527 American Indian, 358, 366 American Indians, 366 American Psychiatric Association (APA), 226, 252, 274, 472, 488, 495 Americans with Disabilities Act, 103 amine, xxii, 230, 297, 475, 477, 482 amines, 478, 482 amino, 231, 284, 298, 530 amino acid, 231, 284, 298, 530 amphetamine, xxii, 298, 475, 476, 477 amphetamines, 328 amplitude, 245 amputation, 56 Amsterdam, 204, 570 AMT, 174, 178 amygdala, 225, 227, 397, 401 amylase, 480 amyloid, 218 analog, 482 analysis of variance, 382

583

anaphylaxis, 149 anatomy, 36, 42, 87, 273, 529 androgen, 424, 425, 426, 428, 429, 432, 532 androgens, 425, 427, 428, 450, 480, 533, 536 androgyny, 498 anemia, 509, 514 anger, 37, 265, 268, 269, 312, 330, 355 angioedema, 420 angiotensin converting enzyme, xxi, 413, 420 animal models, 285, 288, 296, 299, 391 animal studies, 387 animals, xx, 54, 288, 380, 381, 382, 383, 384, 391, 398, 416, 489 anorexia, xxiii, 125, 128, 466, 468, 469, 473, 479, 487, 488, 489, 490, 491, 494, 495, 522 anorexia nervosa, xxiii, 466, 473, 487, 488, 489, 491, 495, 522 ANOVA, 382 antagonism, 162 antagonist, xxii, 148, 209, 475, 481, 483, 486, 537 antagonistic, 456 antagonists, 148, 163 anterior cingulate cortex, 149 anthropological, xxiv, 563 anthropology, 564 antibiotic, 95 antibiotics, 513, 531, 536 antibody, xx, 149, 210, 368, 371, 372, 391, 392, 393, 394, 395, 396, 397, 530 anticoagulant, 480 anticonvulsant, 280, 282, 482 anticonvulsants, 278, 281, 294, 482, 483, 514 antidepressant, xvii, 139, 165, 198, 199, 202, 203, 210, 220, 222, 226, 230, 286, 288, 290, 292, 297, 298, 299, 312, 320, 321, 386, 396, 482 antidepressant medication, 198, 199, 202, 210, 312, 396, 482 antidepressants, 173, 174, 183, 201, 222, 260, 278, 281, 286, 288, 290, 292, 299, 312, 331, 483, 494, 513 antigen, 146, 152, 381 antigen presenting cells (APCs), 146 antihistamines, 162, 534 antiobesity, 441, 476 antioxidant, 160 antipsychotics, 278, 312, 321, 328 antisocial behavior, 310, 319, 359 antisocial personality disorder, 233, 348

584

Index

anxiety disorder, 131, 134, 139, 142, 143, 144, 148, 151, 176, 177, 182, 183, 184, 210, 305, 312, 326, 328, 334, 357, 360, 396, 398, 400, 465 anxiolytic, 396, 397 APCs, 146 apnea, 51, 415 apoptosis, 536 Appalachia, 366 appetite, 10, 125, 128, 129, 131, 132, 136, 137, 194, 214, 417, 447, 476, 477, 478, 481, 482, 483, 530, 531, 564 application, xii, xiii, xviii, 5, 12, 22, 25, 31, 47, 85, 87, 88, 91, 222, 256, 345, 516, 535, 556, 558 apraxia, 4, 48, 54, 55 Arab world, 70 ARBs, xxi, 413, 420 Argentina, 100 argument, 106 Ariel, 3, 47, 539, 571, 579 Arizona, 308, 319 Army, 574 arousal, 49, 131, 262, 269, 501 arrest, 4, 325, 332, 493 arson, 313 arterial hypertension, 416 artery, 424, 427 arthritis, 273 ash, 372, 392 Asia, 27, 86, 346, 477 Asian, xix, 39, 109, 233, 278, 304, 346, 347, 349, 350, 357, 358, 360, 361, 365, 411, 421, 457, 458, 462, 484, 503, 505 Asian American, xix, 304, 347, 349, 350, 357, 358, 360, 361, 365 Asian Americans, 304, 349, 350, 357, 358, 360, 361 aspirate, 10 aspiration, 5, 6, 10, 11, 16, 19 aspirin, 331 assault, 108, 328, 334, 499 assessment, xxii, 5, 24, 38, 39, 40, 41, 42, 44, 67, 70, 94, 95, 134, 143, 145, 170, 182, 183, 184, 196, 221, 225, 264, 314, 319, 321, 325, 334, 377, 401, 445, 449, 463, 468, 469, 483 assignment, 392 assumptions, 37, 232 asthma, xv, 37, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 267, 370, 376, 387, 401, 402, 547, 548, 558 astringent, 534 asymmetry, 57, 173, 180, 191

asymptomatic, 179, 196, 202 ataxia, 4, 50, 55, 283 Athens, 507 athletes, xxi, 163, 405, 409 Atlantic, 70, 209, 371 atmosphere, 20, 53, 356 atmospheric pressure, 229, 230, 231, 251 atopic asthma, 146 atopic dermatitis, 387, 534 atopic eczema, 376 atopy, 369, 376, 386, 390 ATP, 425, 430 atrial fibrillation, 510 atrophy, 158, 165, 535 attachment, 267, 269, 270, 324 attacks, 11, 17, 143, 147, 271, 291 attention, xii, 3, 7, 8, 12, 13, 21, 28, 39, 49, 50, 51, 52, 61, 79, 80, 102 Attention deficit hyperactivity disorder (ADHD), 51, 305, 324, 327, 328, 331, 336 attention problems, 39, 328 attitudes, xiv, xxii, 91, 96, 97, 98, 99, 100, 101, 102, 103, 136, 182, 195, 196, 197, 202, 203, 266, 345, 356, 364, 453, 456, 458, 467, 472, 473, 492, 500, 502, 561 attractiveness, 457, 500, 502 attractors, 251 attribution, 130 atypical, xvi, xviii, 125, 127, 131, 133, 138, 208, 210, 212, 213, 214, 217, 235, 278, 323, 532 aura, 512 Australia, 22, 25, 27, 33, 34, 44, 48, 63, 66, 108, 109, 111, 112, 113, 114, 115, 116, 117, 480, 525, 541 Austria, 207, 334, 539, 573 autism, 51, 59 autobiographical memory, 180, 186, 191 autoimmune, 152, 209, 445 autoimmune diseases, 152 autoimmune disorders, 209 automobiles, 547, 549, 555 autonomic nervous system, 260, 397 autonomy, 268, 270, 315 autopsy, 304, 305, 385, 386 autosomal dominant, 575 availability, xxiv, xxv, 10, 86, 132, 194, 196, 197, 200, 217, 285, 302, 354, 363, 545, 550, 554, 559, 563, 564, 566, 567 aversion, 169

Index avoidance, xv, 39, 126, 129, 155, 159, 163, 164, 358, 438, 440 awareness, 6, 26, 27, 29, 70, 96, 142, 169, 170, 171, 174, 177, 179, 184, 185, 186, 191, 195, 231, 345, 348, 352, 361, 430 axon, 296 axons, 285

B B lymphocytes, 146 babies, 283, 294 bacterial, 208, 369, 402, 510, 516 Bahrain, 526 bananas, 17 Bangladesh, 342, 343 bariatric surgery, xxi, 124, 406, 428, 435, 436, 437, 438, 439, 440, 441, 454, 459, 476 baroreceptor, 417 barrier, xxiii, 99, 397, 507, 508, 509, 511, 516, 551 barriers, xix, xxiv, 39, 99, 101, 347, 348, 350, 545, 546, 549, 551, 553, 554 basal ganglia, 283 basal layer, 530 basal metabolic rate, 509 base rate, 111 basic research, 529 basketball, 408, 409 basophils, 146, 149, 401 battered women, 38, 41 Bayesian, 251 bcl-2, 285, 296 BDNF, 285 Beck Depression Inventory (BDI), 144, 173, 174, 175, 176, 177, 178, 181, 182, 183, 184, 187 behavior modification, 406, 419, 421 behavior therapy, 204, 310, 407, 496 behavioral aspects, 556 behavioral assessment, 473 behavioral change, xix, 368, 397, 514 behavioral effects, 288, 289, 384 behavioral manifestations, 225 behavioral medicine, 189 behavioral modification, xxiii, 475, 476, 482, 523 behavioral problems, 309, 328, 468 behavioral theory, 194 behaviours, 28, 36, 299, 385, 399 Belgium, 376, 573 beliefs, xix, xxii, xxv, 35, 195, 200, 310, 319, 340, 343, 345, 346, 347, 348, 356, 360, 361, 364, 453, 457, 492, 560, 563, 564, 567

585

bending, 6, 17 beneficial effect, 168, 341, 428, 430 benefits, xiii, xix, 47, 48, 49, 50, 56, 63, 179, 187, 190, 198, 201, 260, 283, 290, 312, 325, 339, 406, 408, 411, 430, 446, 483, 484, 546, 547, 548, 550, 551, 555 benign, 509, 510 benzodiazepine, 161 benzoyl peroxide, 536 bereavement, 326 Bessel, 260 beta blocker, xxi, 413, 416, 419, 420 beverages, xv, 155, 164, 565, 566, 567, 569 bias, 236, 237, 243, 457, 462, 556 Bible, 341, 346 bicarbonate, 494 bilingual, 356 binding, 22, 62, 149, 231, 251, 285, 286, 295, 296, 297, 425, 530 binding globulin, 425 binge eating disorder, xxiii, 487, 488, 489, 490, 492, 494, 495, 496 bingeing, 490, 495 bioavailability, 148 biochemistry, 87, 259, 295 biofeedback, 259 biological markers, 213, 214 biological models, 194, 196 biological processes, 499 biomarker, 131, 572 biomarkers, 211, 213 biomolecules, 294 bipolar, xv, xx, 133, 142, 161, 163, 167, 171, 175, 180, 186, 187, 188, 191, 230, 231, 233, 249, 250, 251, 278, 279, 280, 281, 282, 285, 290, 291, 293, 294, 295, 297, 311, 320, 324, 327, 334, 336, 337, 338, 368, 375, 377, 380, 386, 390, 391, 392, 399, 400 bipolar disorder, xx, 133, 142, 161, 163, 186, 191, 230, 231, 233, 249, 251, 278, 280, 281, 282, 285, 290, 291, 293, 294, 295, 311, 320, 324, 327, 334, 336, 338, 368, 377, 380, 386, 390, 391, 400 bipolar illness, 187, 233 birth, xiii, 60, 70, 72, 73, 74, 75, 76, 77, 80, 133, 143, 208, 215, 429, 509, 511, 512, 525, 531, 573 birth control, 429, 509, 511, 512 birth weight, 60 births, 215 bivariate analysis, 88 black women, 458, 462

586

Index

blame, 6, 36, 130 blaming, 467 bleeding, 7, 509, 510, 513, 514, 515, 516 blindness, 165 blocks, 479, 548 blood, 149, 156, 157, 210, 331, 387, 391, 392, 393, 397, 415, 416, 417, 418, 419, 420, 421, 422, 424, 426, 478, 479, 480, 494, 512, 522, 527, 564, 572 blood clot, 512 blood flow, 416 blood glucose, 419, 420, 422, 480 blood monocytes, 387 blood pressure, 407, 415, 416, 417, 418, 419, 420, 422, 426, 478, 479, 494, 512, 522, 572 blood thinners, 512 body composition, 128, 129, 136, 406, 484, 485, 514, 543 body dissatisfaction, 130, 457, 458, 462, 467, 500, 501, 502, 505 body esteem, 502, 505 body fat, 125, 127, 134, 407, 424, 456, 533, 540 body image, xxii, 130, 265, 427, 453, 458, 462, 463, 466, 470, 472, 488, 489, 499, 500, 502, 503, 504, 505 Body Mass Index (BMI), xxii, 9, 125, 127, 131, 132, 136, 407, 409, 411, 414, 415, 417, 419, 420, 421, 422, 424, 426, 429, 436, 437, 438, 443, 444, 445, 446, 453, 458, 464, 465, 466, 477, 479, 489, 500, 502, 520, 523, 540, 541, 542, 572, 573, 574, 575 body size, xxii, 130, 453, 456, 460, 500, 530 body temperature, 156, 158, 230 body weight, 125, 416, 419, 421, 433, 457, 460, 472, 478, 485, 489, 522, 525, 573 bonds, 353, 360 bone, 55, 66 bone age, 438 bone density, 514 bone growth, 425 borderline, 75, 185, 186, 233, 270, 328, 337, 377, 380, 489, 492, 574 borderline personality disorder, 185, 186, 377, 380, 489, 492 Borderline Personality Disorder, 178, 331 boredom, 19, 329, 490 Boston, 22, 41, 64, 189, 350, 362, 450, 571 boys, xix, 75, 80, 109, 137, 304, 311, 335, 347, 353, 355, 357, 363, 406, 411, 414, 424, 438, 447, 450, 456, 458, 461, 467, 532, 541, 549, 551, 573 bradycardia, 493

brain, xix, 51, 149, 153, 166, 180, 186, 214, 217, 225, 231, 258, 259, 273, 285, 287, 289, 295, 296, 297, 298, 299, 300, 326, 368, 369, 377, 384, 396, 397, 400, 401, 402, 478, 530 brain activity, 259 brain damage, 51, 326 brain stem, 287 brainstem, 287, 289 Brazil, 526 breakfast, 523, 524 breast cancer, 509 breast mass, 510 breastfeeding, 573 breathing, 4, 6, 48, 51, 168, 169, 171, 178, 184, 185, 214 Brief Psychiatric Rating Scale (BPRS), 147 British children, 570 broadband, 229, 231, 248 bronchial asthma, 151 bronchial hyperresponsiveness, 142 bronchioles, 6, 7, 11 bronchitis, 264, 267 bronchoconstriction, 148 bronchodilator, 149 Brussels, 119 Buddhism, 169, 492 budding, 535 buffalo, 533 buffer, 210 buildings, 552 bulimia, xxiii, 466, 468, 469, 479, 487, 488, 489, 490, 491, 492, 494, 495, 496, 522 bulimia nervosa, xxiii, 466, 487, 488, 489, 490, 491, 492, 494, 495, 496, 522 bullying, 456, 457, 461 bupropion, 199, 234, 331, 482 burglary, 313 burn, 78, 83 burning, 9 burns, 71, 78, 80, 81, 83 bypass, 429, 438, 439, 440, 441

C caffeine, 161, 162, 164, 166, 262, 476, 483 calcium, xxi, 283, 413, 420, 438, 448 calcium channel blocker, xxi, 413, 420 California, 41, 94 caloric intake, 9, 10, 16, 20, 21, 406, 419, 420, 421, 446, 520, 524 caloric restriction, xxi, 413, 419, 427, 496

Index calorie, 9, 454, 457, 479, 521, 523, 524, 564, 569 calorimetry, 127 CAM, 26, 30 cAMP, 285 Canada, 63, 70, 109, 110, 111, 112, 114, 115, 116, 117, 165, 540, 579 Canberra, 43, 44, 45 cancer, 32, 132, 138, 168, 189, 216, 269, 400, 509, 510, 572 cancer care, 32, 189 candida, 533, 535, 536 candidates, 511 cannabis, 210, 305 capacity, 35, 39, 164, 178, 185, 187, 188, 196, 262, 271, 298, 327, 407, 438, 542, 549 caps, 259 carbohydrate, 129, 134, 136, 138, 478, 520, 521, 522, 523, 524 carbohydrates, 132, 427, 480, 521, 522, 524 cardiac dysrhythmia, 494 cardiac output, 416 cardiovascular disease, 131, 415, 420, 421, 478, 532, 547, 548, 558, 572 cardiovascular function, 446 cardiovascular morbidity, 428 cardiovascular protection, 419 cardiovascular risk, 476 caregiver, 7, 8, 10, 11, 14, 17, 18, 20, 21, 500 caregivers, xii, 3, 5, 8, 10, 13, 15, 20, 21, 22, 58, 59, 259, 278, 500, 501 caregiving, 10, 269 Caribbean, 353 carrier, 535 case study, xiii, 47, 51, 54, 59, 62, 65, 66, 96, 185, 217 casting, 57 catalyst, 391 cataracts, 160 catastrophes, 118 catatonic, 125 catecholamines, 146, 260 category d, 108 Catholics, 340 cation, 296 cats, 384 Caucasian, xix, 130, 233, 347, 348, 349, 350, 351, 352, 353, 354, 355, 357, 358, 360, 365, 394, 454, 455, 457, 458, 459, 460, 462, 483, 502, 503, 520 causal relationship, 556 causality, 182, 398

587

cavities, 385 cell, 131, 138, 146, 147, 153, 157, 222, 285, 289, 296, 333, 334, 349, 377, 387, 391, 400, 401, 402, 428, 449, 480, 510, 514 cell culture, 285, 289 cellular immunity, 217 Center for Disease Control and Prevention, 430, 461, 504 Center for Epidemiologic Studies Depression Scale, 143 Centers for Disease Control (CDC), 125, 142, 150, 278, 290, 444, 448, 455, 464, 500, 504, 551, 556, 557 Central America, 365 Central Asia, 346 central nervous system, xv, 141, 387, 417 central obesity, 447 cerebral cortex, 287, 297 cerebral palsy, 50, 54, 56, 63, 64, 65, 66, 541 cerebrospinal fluid, 131, 157, 297, 338 cerebrovascular, 476, 512 cerebrovascular accident, 476, 512 certificate, 89 cervical, 6 Chad, 543 channel blocker, 420 channels, xxv, 157, 564, 568 chaos, 231, 251, 253 chemicals, 258, 482 chemokines, 387 chewing, 11, 12, 16, 17, 20 Chicago, 96, 579 chicken, 15, 566 child abuse, xiv, 36, 39, 41, 44, 45, 105, 106, 107, 108, 109, 119 Child Behavior Checklist, 468, 469, 473 child development, 36, 60 child maltreatment, 119, 304 child protection, xiv, 34, 39, 105, 106, 120 child welfare, 317 childbearing, 80 childbirth, 44 childcare, 34, 40 child-centered, 41 childhood history, 329 childhood sexual abuse, 34, 326, 328 China, 357, 414, 436, 440, 477 Chinese, 579 Chinese medicine, 430 Chi-square, 88

588

Index

chitosan, 477 chloride, 298 chocolate, 11, 16, 18, 162 cholera, 284, 295 cholestasis, 480 cholesterol, 407, 425, 428 choreoathetoid movements, 283 choroid, 288 chromium, 477 chromosome, 22, 48, 63 chromosomes, 259, 274 chronic disease, 48, 433, 547, 548, 549, 572 chronic illness, 144, 259, 499, 503, 511 chronic pain, 168, 170, 182, 189, 258, 259, 260, 273, 274 chronic stress, xv, 141, 259, 329, 332, 387 chronically ill, 508, 517 chronobiology, 156, 165 CINAHL, 171, 349 Cincinnati, 550 circadian, xv, 131, 137, 155, 156, 157, 158, 159, 160, 161, 162, 163, 165, 166, 198, 202, 250 circadian clock, 157, 158, 160, 165 circadian rhythm, xv, 131, 137, 155, 156, 157, 158, 159, 160, 161, 162, 165, 166, 250 circadian rhythmicity, 156, 157 circadian rhythms, 157, 158, 159, 160, 165, 166, 250 cirrhosis, 510 citalopram, 145, 151 citizens, 72 citizenship, 79 citrus, 222, 226, 521 Citrus aurantium, 477, 483 civilian, 330, 334 CJS, xviii, 323, 324, 325, 326, 327, 328, 329, 330, 331, 333, 334, 335 classes, 37, 170, 270, 419, 547 classical, 196, 197, 340 classification, 119, 253, 477, 572 classroom, 15, 21 classrooms, 567, 569 clients, xii, 33, 34, 37, 39, 40, 48, 52, 59, 99, 176, 183 climatic factors, 251, 376 clinical assessment, 308, 309 clinical depression, 196 clinical diagnosis, 168, 182, 391, 426, 430 clinical presentation, xv, 38, 123, 124, 156 clinical symptoms, xx, 379

clinical trial, xvi, 189, 190, 193, 194, 199, 216, 281, 282, 292, 320, 377, 433, 479 clinical trials, xvi, 193, 194, 199, 281, 282, 292, 377, 433, 479 clinically significant, 199 clinician, xxiii, 182, 308, 340, 345, 358, 377, 497, 504, 508 clinicians, 38, 65 clinics, 72, 209, 282, 370, 574 clonidine, 299 cloning, 495 closure, 6, 18, 19, 61, 553 clozapine, 278, 291 clustering, 358 clusters, 39, 194, 477 CME, 337 CNS, xviii, 65, 203, 285, 291, 296, 299, 323, 325, 334, 349 cocaine, 209, 325, 327 COCs, xxiii, 507, 508, 509, 511, 512, 513, 514, 515, 516 codes, 328 coding, 81, 489 coercion, 329, 337 coffee, 162 cognition, 220 cognitive, xi, xv, xvi, xvii, 37, 41, 48, 49, 51, 128, 130, 134, 138, 158, 162, 163, 165, 166, 167, 168, 170, 171, 172, 181, 188, 190, 191, 193, 194, 195, 196, 197, 198, 200, 202, 203, 204, 205, 206, 216, 255, 256, 257, 262, 263, 264, 272, 274, 310, 320, 328, 357, 376, 377, 391, 400, 456, 457, 458, 464, 496, 500, 502, 522, 523, 560 cognitive behavior therapy, 204, 310 cognitive behavioral therapy, xvii, 134, 255 cognitive deficit, 158, 165 cognitive deficits, 158, 165 cognitive development, 37 cognitive function, 37, 162 cognitive impairment, 328 cognitive models, 195 cognitive performance, 163, 166 cognitive process, 191, 195, 502 cognitive therapy, xv, 167, 168, 170, 171, 172, 190, 191, 198, 200, 204 cohesion, 344, 353, 354, 358, 363 cohort, 133, 143, 215, 217, 250, 280, 375, 517, 525 coitus, 515 collaboration, xv, 26, 40, 42, 141, 360, 579 collagen, 530, 532

Index collateral, 324, 328, 374, 492 College Station, 545, 559 college students, 133, 146, 354, 358, 363, 364, 365, 369, 410, 517 colleges, 95 collusion, 271 coma, 283 combined oral contraceptives, 508, 509, 512 commerce, 415 commercial, 89 commercials, 567, 568 common symptoms, 161 communication, xiii, xxv, 8, 14, 15, 16, 20, 21, 23, 52, 58, 64, 65, 85, 86, 87, 96, 198, 268, 348, 349, 492, 571, 572 communication abilities, 52 communication strategies, 20 communities, 27, 70, 336, 352, 358, 436, 455, 501, 550, 555, 561, 570 community, 21, 23, 34, 35, 36, 41, 42, 45, 70, 79, 87, 98, 99, 102, 103, 127, 128, 130, 131, 133, 136, 151, 217, 302, 304, 305, 310, 311, 313, 314, 315, 331, 337, 345, 356, 358, 359, 360, 361, 364, 421, 456, 466, 495, 496, 499, 541, 542, 543, 574 community service, 302, 311 community support, 361, 456 community-based services, 310 co-morbidities, xxi, 37, 186, 327, 329, 331, 334, 335, 421, 423, 424, 467, 470, 523 comorbidity, xv, 131, 134, 141, 150, 324, 327, 328, 330, 336, 337, 391, 398, 470, 471, 549 compassion, 29, 30 compatibility, 5 compensation, 86, 289, 488 competence, 37, 87, 348 competition, 263, 270, 284, 288, 294, 295, 502 competitiveness, 268, 270 complement, 417 complementarity, 265 complex interactions, 447 complexity, 21, 22, 137, 256, 263, 265, 272, 315, 335, 344, 560 compliance, 37, 172, 199, 202, 265, 282, 330, 420, 427, 504, 523 complications, xxi, xxii, 11, 41, 283, 329, 405, 409, 416, 429, 439, 443, 446, 448, 459, 464, 469, 470, 476, 488, 492, 508, 509, 510, 511, 512, 513, 518, 522, 523

589

components, xxiii, 42, 128, 165, 172, 238, 242, 247, 272, 289, 384, 387, 447, 459, 464, 487, 495, 499, 501, 503 composition, xxiii, 519, 521, 527 compounds, xv, 132, 155, 209, 283, 321 comprehension, 392 computed tomography, 426 computer skills, xiii, 85, 87, 88, 94, 95, 96 computer technology, 86, 95 computer use, 414 computers, 86, 87, 88, 89, 94, 95 computing, xiii, 85, 87, 88, 89, 90, 91, 92, 93, 95, 96 concealment, 172 concentration, 50, 98, 131, 147, 158, 258, 262, 283, 284, 417, 424, 425, 445, 575 conception, 499 conceptual model, 362 conceptualization, 198, 462 concordance, 319 concrete, 71, 164 conditioning, 397 condom, 508 conduct disorder, xviii, 301, 305, 311, 320, 321, 328 conductance, 197 confidence, 37, 58, 95, 184, 504, 540 confidence interval, 540 confidentiality, 29 confinement, xviii, 301, 303, 306, 308, 313, 314, 316, 319 conflict, 36, 100, 266, 268, 270, 271, 274, 351, 353, 355, 357, 501 conflict of interest, 100 confounders, 88, 90 confrontation, 44, 267 confusion, 269, 283, 357, 498, 501 congestive heart failure, 481, 512 conjecture, 108 Connecticut, 352, 355 connective tissue, 532 conscious awareness, 195 consciousness, 266 consensus, 35, 165, 312, 314, 319, 341, 343, 447, 462, 468 consent, 5, 29, 30, 209, 220, 233, 315, 370, 392 consolidation, 59 constipation, 7, 17, 53, 478 constraints, 81, 327 construct validity, 310 construction, 241, 268 consulting, 360

590

Index

consumption, xii, 3, 18, 19, 20, 132, 358, 422, 520, 521, 522, 523, 524, 525, 548, 559, 569 contact dermatitis, 534 content analysis, 570 continuity, xxiv, 252, 309, 545, 554 contraceptives, xxiii, 428, 429, 507, 508, 509, 511, 512, 515, 516, 517, 518 control condition, 180, 182 control group, xx, 57, 168, 175, 176, 177, 181, 182, 183, 311, 371, 390, 392, 407, 466 controlled research, 190 controlled studies, 279 controlled trials, xvii, 168, 171, 199, 220, 278, 281, 292, 294, 312, 315, 321, 340, 492, 494 contusions, 78, 81 conversion, 264, 265, 270, 295, 425, 450 conversion disorder, 265 conviction, 324 Cook County, 304, 306 cooling, 331 Copenhagen, 25, 558, 579 Coping, 178, 205, 357 coping strategies, 361 copolymer, 515 corn, 11 coronary artery disease, 424, 427 coronary heart disease, 415, 416, 421, 540 correlation, xix, xxv, 53, 101, 127, 211, 231, 309, 339, 341, 357, 415, 465, 563, 566, 567, 568, 573 correlations, 72, 144, 310, 324, 327, 472 cortex, 149, 153, 225, 287, 362, 391, 397, 401 cortical asymmetry, 180 cortical neurons, 285, 296 corticosteroid therapy, 147 corticosteroids, xxiv, 144, 145, 147, 152, 370, 392, 529, 530, 532, 534, 535, 537 corticosterone, 397 corticotrophin releasing hormone, 131 corticotropin, 397 cortisol, 132, 136, 138, 146, 158, 159, 189, 215, 216, 222, 260, 397, 426, 430, 447, 450 cosmetics, 220 cost-effective, 201, 310 costs, 150, 424, 454, 493, 547, 555 cough, 7, 145, 147, 149 coughing, 6, 10 counseling, 34, 70, 82, 352, 358, 363, 407, 427, 428, 494 country of origin, 344

coupling, 229, 231, 232, 233, 235, 239, 240, 241, 245, 248 course work, 467 courts, 34, 302 covariate, 174 coverage, 359, 549, 552, 553 covering, 547 CPS, 41 CPU, 88 craniofacial, 283 crash rates, 551 craving, 129, 134, 136, 138, 478 C-reactive protein, xvi, 131, 208, 210, 212, 218, 425, 432 CREB, 285 credit, 117 CRH, 138 crime, 43, 332, 341, 520, 546, 547, 550, 551, 554, 557, 559 crimes, 546 criminal justice, xviii, 40, 43, 44, 302, 323, 325, 327 criminal justice system, xviii, 40, 302, 323 criminality, 335 critical period, xxiii, 497, 498 critically ill, 481 criticism, xiv, 30, 105, 107, 489, 493 cross-cultural, 226, 462 cross-sectional, 95, 195, 196, 197, 406, 554, 559, 573, 574 cross-sectional study, 406 CRP, 210, 212, 213, 214, 425 CSF, 157, 231, 251, 286, 297 CSS, 310 Cuba, 47 cues, 14, 39, 197, 500, 502 cultural beliefs, 564 cultural differences, 130 cultural factors, 341, 344, 357 cultural norms, 343, 357, 522 cultural values, 360 culture, xiii, 35, 70, 81, 82, 98, 130, 331, 332, 345, 348, 350, 355, 356, 360, 365, 366, 458 curiosity, 94, 169, 185 curriculum, xiv, 86, 95, 170, 352 cyanosis, 6 cyanotic, 514 cycles, xv, 59, 155, 157, 165, 241, 262, 480 cyclic AMP, 284 cycling, 130, 133, 134, 161, 163, 230, 233, 249, 278, 291, 408, 557, 558

Index cyproterone acetate, 429 cysts, 424, 426 cytochrome, 479 cytokine, 131, 132, 137, 138, 146, 147, 153, 209, 216, 374, 384, 387, 391, 392, 397, 401 cytokines, 130, 131, 132, 138, 146, 149, 208, 209, 210, 214, 216, 369, 376, 384, 385, 387, 391, 396, 397, 417, 534, 536 cytoprotective, 296 Czech Republic, 573

D daily living, 51, 500, 550 dairy, 16, 17, 522 damping, 232, 233, 236, 244, 245, 247, 248 danger, 5, 16, 315, 551, 560 Darcy, 103 data analysis, xiii, 69, 72, 237, 243, 252 data collection, 34, 81, 225, 565, 573 data set, 81, 237, 238 database, 72, 171, 172 dating, 36, 45, 262, 355, 456, 457, 503 DBP, 574 death, xiv, xix, 30, 70, 105, 106, 107, 108, 110, 113, 117, 118, 120, 125, 142, 181, 210, 273, 278, 280, 283, 290, 302, 303, 307, 313, 314, 321, 331, 342, 347, 349, 351, 359, 364, 377, 399, 433, 439, 464, 465, 470, 476, 535, 558 death rate, xiv, 105, 107, 113, 351 deaths, xiv, 70, 105, 106, 107, 108, 109, 110, 112, 113, 116, 117, 118, 119, 142, 278, 279, 281, 282, 308, 314, 317, 319, 337, 343, 344, 346, 351, 358, 362, 437, 511 debt, 136 decay, 570 deciduous, 369 decision making, 14, 48, 565 decisions, 10, 31, 86, 100, 561, 565, 567 decoding, 251 decongestant, 164, 476 defects, 440, 450, 531 defense, 267, 306, 328, 503 defense mechanisms, 306 defenses, 267 deficiency, 437, 494, 509, 531, 535, 537, 573, 575 deficit, 52, 305, 312, 318, 321, 327, 335, 336 deficits, 158, 161, 165, 327 definition, 44, 63, 169, 190, 230, 348, 360, 424, 488, 493, 573 degenerative disease, 49

591

degenerative joint disease, 540 degradation, 138, 214, 217, 218, 257 degrees of freedom, 239 dehiscence, 439 dehydration, 6, 331 dehydroepiandrosterone, 189 dehydrogenase, 450 deinstitutionalization, 327 delinquency, 304, 310, 313, 314, 317, 318, 353 delinquent behavior, 304 delinquents, xviii, 301, 303, 304, 305, 306, 307, 309, 310, 311, 312, 313, 316, 317, 318, 319, 320, 321 delivery, xix, 26, 30, 41, 42, 60, 71, 73, 208, 209, 217, 347, 350, 417, 459, 511 demand, 14, 57, 550, 555 dementia, 222, 226, 259 demographic characteristics, xiii, 70, 82, 130, 216 demographic data, 71, 76, 418 demographics, 100, 101, 145, 332, 334, 351, 362 denervation, 416 denial, 264, 267, 268 Denmark, 25, 210, 279, 385, 573, 579 density, xxiv, 55, 288, 289, 428, 514, 545, 552, 554 Department of Agriculture, 520, 526 Department of Education, 579 Department of Health and Human Services, 135, 204, 448, 461, 473, 504, 558 Department of Justice, 335 deposits, 417 depressants, 395 depressed, xvi, xx, 125, 126, 127, 128, 130, 131, 132, 134, 135, 137, 139, 142, 145, 167, 173, 175, 177, 179, 180, 181, 182, 185, 186, 188, 191, 194, 195, 196, 197, 198, 204, 209, 214, 217, 220, 222, 223, 224, 225, 235, 261, 291, 292, 305, 307, 341, 345, 346, 350, 352, 359, 374, 379, 380, 400, 465, 490, 541 depressive disorder, xv, 124, 125, 126, 128, 131, 133, 134, 135, 136, 137, 139, 142, 143, 144, 151, 153, 167, 175, 177, 186, 214, 218, 227, 281, 291, 292, 311, 312, 330, 365, 368, 377, 386, 392 depressive symptomatology, 128 depressive symptoms, xvi, 128, 130, 131, 132, 137, 138, 143, 144, 145, 148, 151, 167, 174, 175, 180, 181, 184, 187, 188, 190, 191, 209, 210, 214, 215, 216, 235, 336, 353, 363, 365, 386, 387, 391, 400, 458, 462, 466, 468, 471 depressive-like, 153, 220, 222, 369, 377, 398, 400, 402

592

Index

deprivation, xv, 126, 127, 129, 152, 155, 162, 164, 196, 331 derivatives, 232, 233, 235, 236, 237, 240, 241, 243 dermatitis, 534, 535 dermatologic, xxiv, 415, 529, 531, 533, 537 dermatologists, 532 dermatology, 537 dermatophytes, 535 dermatophytid, 535 dermatoses, 534 dermis, 530 desensitization, 225 desert, 70 desire, xxv, 128, 185, 430, 491, 503, 564, 568 desynchronization, 158 detachment, 511 detainees, xviii, 303, 307, 312, 314, 316, 318, 323, 324, 325, 326, 327, 330, 331, 332, 334, 335, 336 detection, xx, 127, 136, 210, 226, 330, 379, 426, 467 detention, xviii, 301, 302, 303, 304, 307, 308, 309, 310, 311, 313, 314, 316, 317, 318, 319, 321, 322, 325, 331, 332, 334, 335 detoxification, 316 developed countries, xii, 34, 86, 94, 95, 405 developed nations, 70 developing countries, xiii, 85, 87, 414 developmental delay, xi developmental disabilities, xiii, 5, 47, 57, 62, 64, 65, 103, 518 developmental disorder, 51 developmental factors, xv, 141 developmental milestones, 501 deviation, 56 dexamethasone, 447 diabetes, xxiii, 124, 127, 131, 134, 283, 416, 419, 420, 422, 424, 427, 433, 443, 445, 449, 477, 480, 482, 483, 509, 512, 513, 514, 516, 518, 519, 520, 521, 522, 526, 531, 537, 540, 546, 547, 549, 559, 572, 574, 575 diabetes mellitus, 416, 419, 420, 443, 445, 449, 477, 480, 482, 512, 513, 514, 516, 518, 537, 540, 559 diabetic patients, 421, 516 diacylglycerol, 285 Diagnostic and Statistical Manual of Mental Disorders, 178, 213 diagnostic criteria, xv, 123, 124, 126, 129, 172, 306, 425, 430, 445, 488, 489 diarrhea, 283, 428, 478, 480 diastolic blood pressure, 418, 572 diathesis-stress model, 195, 196

diet, xxi, xxii, xxiv, xxv, 9, 10, 12, 16, 17, 23, 136, 343, 411, 417, 418, 430, 435, 438, 457, 459, 475, 476, 477, 478, 479, 481, 482, 489, 490, 491, 519, 522, 523, 524, 525, 527, 539, 542, 543, 548, 571, 575 dietary, xxiii, xxiv, 161, 406, 427, 465, 476, 479, 484, 487, 489, 492, 495, 519, 520, 521, 522, 523, 526, 527, 539, 543, 572, 573 dietary fat, 479, 521 dietary habits, xxiii, 487, 489, 495, 573 dietary intake, xxiv, 539, 543 dieting, xxii, 453, 455, 458, 459, 466, 468, 480, 490, 491, 495, 496, 505 diets, xxiv, 17, 416, 519, 521, 522, 523, 524 differential diagnosis, 24 differentiation, 271, 285, 560 digital divide, 95 dimorphism, 387 diodes, 160 diphenhydramine, 162 direct observation, 127 directives, 42 disability, xxiv, 50, 52, 59, 63, 80, 98, 99, 101, 102, 103, 142, 256, 266, 306, 318, 504, 539, 540, 542, 543, 579 disabled, xiv, 97, 98, 99, 100, 101, 102, 108 disabled students, 101 disaster, 351 discharges, 61 discipline, 313 disclosure, 364 discomfort, 14, 223, 283, 393, 481, 515 discrimination, 39, 98, 348, 353, 356, 357 diseases, xxii, 146, 415, 418, 463, 464, 470, 489, 515 dislocation, 57 displacement, 232, 233, 236, 240 disposition, 9, 59, 61, 302 dissatisfaction, 130, 458, 462, 499, 503 dissociation, 39, 262, 266 distraction, 21, 259 distress, 14, 37, 108, 137, 146, 259, 261, 351, 365, 456, 457, 488 distribution, 134, 236, 324, 432, 460, 533, 543, 572 diuretic, 419, 420 diuretics, xxi, 413, 419, 420, 490, 494 divergence, 524 diversity, 348 divorce, 44, 72 dizziness, 283 doctors, 86, 87, 93, 96, 256, 258, 260, 264

Index dogs, 416 domestic violence, xii, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 dominance, xiii, 85, 90, 502 donkey, 78 doors, 455 dopamine, 230, 249, 250, 260, 478 dopaminergic, 288, 349 doping, 484 dosage, 162, 289, 428, 480 dosing, 148, 290 Down syndrome, xxiv, 48, 51, 59, 539, 541, 542, 543, 544 down-regulation, 131, 296 draft, 574 dream, 148 drinking, 5, 18, 19, 23, 54, 164, 314, 331, 354 drinking water, 331 dropouts, 173, 175, 176 drowning, 108, 117 drowsiness, 148, 283 drug abuse, 305, 327, 478 drug addict, 486 drug addiction, 486 drug dealing, 313 drug history, 328 drug interaction, 149, 479 drug therapy, 294 drug treatment, 289, 386 drug use, 143, 178, 185, 311, 318, 351, 356, 362, 365 drugs, 108, 117, 162, 178, 185, 278, 286, 292, 299, 320, 327, 331, 335, 351, 352, 363, 392, 420, 476, 477, 478, 480, 482, 484, 486, 513, 532 Dry mouth, 479 drying, 533, 535 DSM, 125, 144, 173, 174, 175, 176, 177, 178, 181, 182, 184, 195, 210, 213, 217, 220, 226, 233, 252, 325, 326, 336, 348, 350, 353, 365, 370, 371, 377, 386, 392, 401, 488, 489, 494 DSM-II, 174, 177, 178, 488 DSM-III, 174, 177, 178, 488 DSM-IV, 144, 173, 175, 176, 182, 195, 210, 213, 217, 220, 226, 325, 336, 353, 370, 371, 377, 386, 392, 401, 488, 489, 494 durability, 200, 203 duration, xv, 9, 12, 15, 17, 19, 29, 58, 59, 60, 126, 155, 158, 160, 162, 163, 164, 170, 172, 201, 209, 222, 250, 258, 326, 406 dynamical system, 232, 233, 245, 251

593

dynamical systems, 232, 245, 251 dyslexia, 51 dyslipidemia, 131 dysmetabolic, 445 dyspepsia, 480 dysphoria, 39 dyspnea, 144, 145, 147, 151 dysregulated, 124 dysregulation, 127, 131, 138, 146, 209, 214, 227, 230, 231, 247, 248, 324, 330, 334, 335, 338, 447, 450 dysthymia, 171, 305 dysthymic disorder, 142

E eating, xii, xxii, xxiii, xxv, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 52, 54, 127, 129, 132, 134, 136, 137, 170, 178, 185, 262, 265, 458, 459, 462, 463, 466, 467, 468, 470, 472, 473, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 505, 523, 524, 527, 563, 564, 565, 567, 568, 569, 570, 571, 575 eating behavior, xxv, 132, 137, 472, 490, 527, 563, 564, 565, 569 eating disorders, xii, xxii, 3, 52, 265, 462, 463, 466, 467, 470, 472, 483, 487, 488, 489, 490, 491, 492, 493, 494, 496, 505 ecological, 430 economic development, 346 economic status, 302 economically disadvantaged, 353, 356, 521 economics, 46, 150 ectopic pregnancy, 509, 514 ectropion, 509 eczema, 533, 535 edema, 420, 513 educated women, 139 education, xi, xiii, v, 3, 28, 34, 35, 40, 41, 42, 80, 81, 85, 87, 91, 96, 106, 150, 211, 415, 425, 569, 579 educational attainment, 467, 574 educational institutions, 565 educational system, xiv, 98, 102 educators, 26, 32, 40, 99, 502 eggs, 11 elastin, 532 elderly, 119, 184, 188, 279 elderly population, 279 elders, 359 electricity, 87 electroencephalogram (EEG), 64, 173, 180, 186

594

Index

electrolyte, 419, 494 electrolyte imbalance, 494 electromyography, 204 electrophysiological study, 298 elementary school, xxv, 270, 551, 556, 557, 560, 561, 563, 565, 567, 568, 569 eligibility criteria, 517 emboli, 511 emergency departments, 39, 71 EMG, 197 emission, 7, 210 emotion, 149, 153, 197, 231, 251, 361, 387, 501 emotional, xi, xii, xv, xvi, xx, xxii, 3, 37, 39, 48, 52, 53, 58, 62, 64, 123, 124, 129, 138, 146, 152, 169, 171, 178, 185, 193, 195, 197, 203, 215, 216, 225, 231, 248, 261, 262, 263, 264, 265, 266, 268, 269, 270, 271, 308, 309, 315, 328, 329, 330, 358, 363, 365, 376, 380, 385, 397, 400, 401, 461, 463, 464, 466, 467, 473, 498, 500, 504, 560, 574 emotional abuse, 329 emotional disorder, 203, 315 emotional distress, 129, 330 emotional experience, 262, 266, 268, 270, 271 emotional health, xv, 123, 269, 466, 504 emotional reactions, 37, 178, 185, 261 emotional responses, 195, 197 emotional state, xii, 3, 53, 58, 169, 171, 195 emotional stimuli, 397 emotional well-being, 461 emotions, 170, 177, 261, 262, 457, 498, 501 empathy, 28, 30 employability, 46, 310 employees, 330 employers, 99 employment, 40, 45 empowered, 257 empowerment, 98 encoding, 22, 62 endocarditis, 510, 516 endocrine, xxii, 136, 190, 397, 415, 426, 430, 443, 444, 445, 448, 450, 493, 521, 530, 533 endocrine disorders, 521 endocrine system, 430, 448, 533 endocrinology, 138, 443, 450 endogenous depression, 305 endometrial cancer, 509 endometrial hyperplasia, 516 endometrium, 514 endophenotypes, 288, 299 endorphins, 259, 430

endothelium, 416 endotoxins, 391 endurance, 573 enemas, 490 energy, xxii, 23, 54, 65, 127, 128, 130, 131, 176, 183, 221, 222, 223, 425, 450, 453, 455, 524, 527, 542, 548 engagement, 13, 26, 28, 30, 34, 356 England, vi, xiv, 105, 107, 109, 110, 111, 112, 113, 114, 116, 117, 118, 119, 156, 326, 342 enrollment, 182, 370, 523, 552, 572 entertainment, 454, 455, 460 environment, xi, xviii, xxiv, 7, 8, 15, 21, 51, 52, 53, 65, 95, 127, 156, 157, 164, 220, 259, 260, 266, 270, 301, 303, 310, 314, 316, 330, 335, 363, 390, 406, 410, 456, 457, 468, 498, 500, 501, 502, 526, 541, 546, 548, 549, 554, 555, 557, 558, 560, 561, 564 environmental change, 200 environmental characteristics, 548, 555 environmental conditions, 397, 551, 555 environmental effects, 303 environmental factors, xxi, xxiv, xxv, 37, 156, 230, 251, 302, 314, 406, 443, 546, 554, 555, 563, 567 environmental influences, xxiv, 247, 313, 546, 549, 570 Environmental Protection Agency, 561 environmental stimuli, 157, 196, 197 enzymatic, 209, 425 enzyme inhibitors, 420 enzymes, 284, 285, 286, 402, 509 eosinophils, 146 Ephedra, 476, 477, 484 epidemic, xxi, xxii, xxiii, xxiv, 124, 410, 414, 421, 423, 431, 436, 440, 443, 444, 447, 448, 453, 454, 461, 463, 464, 473, 483, 518, 519, 524, 545, 546, 547, 548 epidemics, 124 epidemiology, 83, 326, 351, 362, 377, 495, 557 epidermis, 530 epiglottis, 6 epilepsy, 4, 53, 58, 60 epinephrine, 260 equilibrium, 61, 229, 232, 236, 240, 248 equipment, 10, 13, 17, 19, 23, 54, 57, 58, 87 equity, xxiv, 31, 545, 546, 554, 555, 556, 560 erosion, 437 esophageal, 6 esophagus, 6, 7, 494 esthetics, 5

Index estimating, 236, 238, 253 estradiol, 428, 508, 509, 514, 515 estrogen, 425, 447, 509, 512, 513, 514, 515, 517 ethanol, 402 ethical concerns, 340, 556 ethical issues, 26, 100 ethical principles, xii, 25, 28, 29, 31 ethical standards, 32 ethics, xii, xxii, 25, 26, 27, 30, 31, 32, 453, 460 ethnic background, 575 ethnic groups, xix, xxii, 278, 347, 348, 349, 358, 360, 361, 414, 416, 436, 453, 460, 520, 531, 550, 572 ethnicity, 292, 324, 344, 348, 349, 350, 351, 354, 366, 421, 424, 454, 461, 549, 555, 559 ethylene, 515, 516 etiology, 129, 194, 202, 349, 541 Europe, 27, 86, 95, 119, 410, 477, 481, 558, 573 European, 96, 117 European Union, 117 evening, 138, 156, 160, 164, 233, 237, 243 evidence, xii, 29, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 41, 42, 43, 62, 86, 108, 118 evolution, 26 examinations, 146 excitation, 210 excitotoxicity, 296 exclusion, 169, 172, 209, 210, 257, 258, 370, 392 excretion, 416, 422 excuse, 333 execution, 5, 12 exercise, xv, xxi, xxii, xxiv, xxv, 12, 50, 54, 56, 137, 148, 155, 163, 164, 184, 185, 189, 248, 406, 407, 409, 410, 411, 413, 418, 419, 421, 427, 435, 446, 457, 459, 475, 476, 477, 481, 482, 489, 491, 523, 539, 543, 550, 557, 571, 572, 575 exercise performance, 406 experimental design, 64 expert, 26, 135, 314, 316, 411, 448, 468 expertise, 41, 265, 309, 427 exposure, xv, xvii, xx, 36, 37, 38, 39, 42, 43, 102, 146, 147, 148, 149, 155, 157, 159, 160, 163, 164, 165, 197, 208, 215, 219, 220, 221, 222, 223, 224, 225, 226, 230, 248, 271, 281, 313, 314, 328, 329, 346, 351, 368, 369, 373, 374, 380, 381, 390, 391, 398, 457, 499, 501, 548, 550, 560, 564, 572 extensor, 55 external environment, 530 external influences, 233 externalizing, 130, 305, 318, 327, 352

595

externalizing behavior, 130, 352 externalizing disorders, 305, 318, 327 extinction, 397, 401 eye contact, 7, 8, 14, 17, 60 eyes, 50, 61, 393, 500

F face validity, 310 facial expression, 197 facilitators, 13 factorial, 406 failure, xi, xiv, xxiii, 4, 23, 36, 39, 105, 106, 130, 195, 249, 262, 266, 271, 306, 325, 326, 330, 334, 429, 438, 440, 460, 507, 509, 511, 514, 517 failure to thrive, 4 faith, 341 false statement, 88 familial, 291, 304, 317, 385, 414, 489, 521 family conflict, 262, 359 family environment, xxiii, 272, 318, 438, 487, 495 family functioning, 41, 302 family history, 278, 340, 351, 355, 358, 369, 419, 449, 468, 511, 512 family income, 459, 522 family interactions, 361 family life, 266 family meals, 454 family medicine, 25, 70 family members, 15, 58, 260, 266, 270, 271, 278, 361, 456, 457, 467, 512 family relationships, 266, 359, 363 family support, 354, 363, 523 family system, 262 family therapy, 25, 265, 266, 267, 269, 492, 494 family violence, 34, 37, 45 fast food, 455, 521, 522, 526, 548, 550, 559 fasting, 419, 420, 422, 426, 430, 445, 449, 485, 559 fasting glucose, 426, 445, 449, 559 fat, xxii, 125, 129, 131, 407, 417, 424, 425, 427, 428, 432, 453, 454, 458, 472, 479, 480, 489, 493, 499, 501, 514, 520, 521, 522, 523, 524, 525, 527, 530, 533 fat soluble, 480 fatalism, 354, 356 fatalistic, 356 fatalities, 108, 281 fatality rates, 362 fatigue, 59, 125, 128, 147, 152, 189, 194, 208, 214, 256, 257, 260, 261, 262, 263, 264, 376, 550 fats, 17, 521, 522, 524

596

Index

fatty acids, 417, 438, 493 FBG, 419 FDA, xxii, 149, 162, 199, 292, 312, 321, 439, 475, 476, 477, 478, 480, 481, 482, 485, 486, 514, 515, 516 fear, 36, 37, 38, 50, 51, 53, 95, 146, 185, 256, 265, 267, 268, 269, 271, 272, 397, 401, 493, 501, 551 fear response, 397 fears, 261, 263, 267, 270, 331, 498 fecal, 7 fee, 87 feedback, 52, 131, 157, 189, 425, 456, 457, 489, 501 feeding, xii, 3, 4, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 22, 65, 157, 500, 573, 575 feelings, 21, 37, 102, 125, 128, 130, 169, 170, 171, 173, 179, 226, 262, 268, 271, 331, 454, 455, 460, 498, 500, 501, 502 feet, 58, 61, 256 females, xii, xvii, xxiii, 3, 4, 22, 48, 55, 66, 67, 75, 99, 100, 107, 127, 130, 133, 136, 145, 219, 220, 258, 278, 302, 304, 305, 306, 350, 351, 353, 357, 364, 381, 414, 426, 438, 455, 458, 459, 466, 488, 499, 501, 502, 503, 507, 508, 509, 511, 512, 513, 514, 515, 516, 520, 532, 540, 541, 542, 549, 574 femininity, 498 fertility, 518 fetal, 61, 208, 214, 216, 328, 438, 517 fetal alcohol syndrome, 328 fetal growth, 208, 438 fetus, 215, 283, 420 fiber, 455, 523 fibers, 258 fibroblasts, 530, 537 fibromyalgia, xvii, 168, 190, 255, 256, 257, 258, 260, 261, 263, 264, 266, 267, 270, 272, 273, 274 fibrosis, 417 fidelity, 320 Filipino, 357, 365 filtration, xxi, 413, 416, 420 Finland, 94, 96, 133, 139, 257, 375, 376, 386, 399, 540, 557, 573 fire, 78, 80, 359 firearms, 108, 332, 349, 351, 352, 354, 360, 362, 363 fires, 108 first generation, 312 fitness, 407, 411, 457, 525, 527, 548, 556, 557, 575 flare, 272 flatulence, 428, 480 flexibility, 54, 55, 184, 263 flexible joint, 54

flexor, 55 flight, 131, 158, 159, 161, 164, 165, 166, 260 floating, 185 flood, 258 flow, 6, 144, 148, 210, 327, 416 flow rate, 210 fluctuations, 58, 187, 232, 233, 243, 244, 245 fluid, 131, 137, 157, 286, 297, 338, 457, 490 fluorescence, 210, 294 fluorination, 534 fluoroscopy, 5 fluoxetine, 292, 312, 320, 482, 494 focal segmental glomerulosclerosis, 415 focusing, xviii, 106, 116, 170, 184, 196, 277, 310, 374, 564 folate, 437 follicle, 425 follicle stimulating hormone (FSH), 425, 447, 514 folliculitis, 533 food, xii, xxiii, xxiv, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 124, 128, 129, 132, 158, 381, 410, 428, 438, 446, 454, 455, 457, 459, 460, 468, 469, 488, 489, 490, 491, 493, 519, 520, 521, 522, 525, 526, 530, 548, 550, 558, 559, 563, 564, 565, 566, 567, 568, 569, 570 Food and Drug Administration (FDA), 161, 199, 476, 478, 484, 485, 486, 515 food intake, 5, 17, 124, 128, 129, 132, 438, 446, 488, 526, 530 football, 406, 408, 409, 410 Ford, 257, 273 forebrain, 287, 289, 298 forensic, 324, 328, 337 forensic settings, 337 Fox, 274, 338, 543, 557 fractures, 56, 66, 78 fragmentation, 34 France, xiv, 63, 65, 106, 109, 111, 112, 113, 114, 115, 116, 117, 573 free will, 345 freedom, 239, 241, 263 Freud, 504 friction, 232, 247, 406, 535 friendship, 457 frontal cortex, 225, 285, 287, 288, 298 fructose, 284 fruit juices, 521, 523 fruits, 521, 522, 523, 524, 548, 564 frustration, 338 fuel, 530

Index fulfillment, 65, 564 functional changes, 51 functional imaging, 149 functional MRI (fMRI), 231, 259 funding, 41, 311, 315 funds, 72, 165, 215, 310, 398 fungal, 513, 535 fungal infection, 513 fungal nail infection, 535

G G protein, 284, 289 G-6, 535 GABA, 230 gait, 48, 54, 62, 63, 65 gambling, 459 games, 58, 59, 61, 128, 454 Gamma, 217 ganglia, 283 ganglion, 157, 158, 296 gangs, 314 gases, 108, 117 gastrectomy, 441 gastric, 135, 429, 438, 439, 440, 441, 479, 480, 530 gastrin, 156 gastrointestinal, 158, 267, 415, 428, 444, 478, 480, 494, 513 gender, xiii, xviii, 76, 85, 88, 90, 94, 99, 130, 131, 132, 133, 134, 173, 175, 176, 182, 203, 258, 278, 301, 304, 307, 313, 324, 348, 351, 352, 353, 355, 357, 358, 393, 395, 418, 424, 455, 464, 501, 505, 542, 546, 550, 555 gender differences, 99, 134, 203, 501 gender gap, xiii, 85, 90 gender role, 355 gene, 132, 149, 157, 285, 297, 391, 397, 495, 530, 531 gene expression, 132, 149, 285, 391, 397 gene promoter, 297 General Accounting Office, 322 general practitioner, 144 generalizability, 203, 245, 374 generalization, xiii, 47, 62, 214 generalized anxiety disorder, 142 generation, xxiv, 146, 162, 312, 398, 428, 432, 545, 546 generators, 156 genes, 157, 247, 349, 489 genetic factors, 349, 415, 420 genetic syndromes, 521

597

genetics, 152, 253, 297 Geneva, 119, 120, 337, 410, 517 genome, 531 geography, 351 Georgia, 455, 559 Germany, 108, 109, 111, 112, 113, 114, 115, 116, 117, 210, 282, 414, 540, 557, 573 gestation, xvi, 208, 209, 210, 214, 218 gestational diabetes, 509 Ghrelin, 129 Gibbs, 83 gifted, 264, 270 girls, xiii, xix, 23, 65, 70, 75, 80, 109, 132, 137, 270, 304, 324, 335, 347, 351, 352, 355, 357, 411, 414, 424, 431, 432, 447, 450, 456, 457, 458, 461, 462, 466, 467, 471, 502, 504, 505, 525, 532, 533, 541, 549, 551, 572, 573 girth, 426 gland, 157 glass, 78, 381 glaucoma, 479 globulin, 425 glomerulopathy, 421 glucagon, 428 glucocorticoids, 260, 385, 532, 533 gluconeogenesis, 428, 480 glucose, 295, 419, 420, 422, 424, 426, 428, 430, 445, 449, 479, 480, 494, 522, 559 glucose metabolism, 445 glucose regulation, 494 glucose tolerance, 426, 430, 445, 449 glucose tolerance test, 426, 430, 445 glucoside, 480 glutamate, 296 glycemic index, 521, 526 glycogen, 284, 295 glycogen synthase kinase, 284, 295 glycol, 221 goal attainment, 176 goal-directed, 48 goals, 10, 14, 17, 48, 49, 51, 55, 58, 61, 71, 120, 132, 268, 373, 410, 454, 459, 522, 549 Gore, 336 government, 34, 35, 41, 43, 71, 72, 99 Government Accountability Office, 315 government policy, 43 G-protein, 285 grades, 151, 332, 352, 355, 358, 458 grading, 377 grain, 521

Index

598

grains, 393, 521, 522, 524 grandparents, 270 grants, 249 grape juice, 521 grapes, 521 graph, 238 grass, 392, 396 gray matter, 149 Greece, 507, 573, 574 green tea, 476 grief, 274 Gross Domestic Product (GDP), 116 grounding, 185 group therapy, 200, 310, 320, 494 group work, 41 groups, xix, xx, xxii, 9, 50, 52, 55, 57, 78, 98, 124, 126, 145, 148, 158, 168, 173, 175, 176, 181, 183, 195, 197, 201, 223, 259, 278, 279, 280, 281, 310, 331, 341, 342, 343, 347, 348, 349, 350, 352, 354, 355, 356, 358, 360, 361, 368, 371, 372, 373, 374, 382, 394, 414, 416, 436, 453, 460, 466, 489, 494, 501, 520, 522, 531, 546, 549, 550, 555, 572 growth, xxiii, 5, 9, 10, 23, 48, 86, 125, 127, 133, 135, 208, 215, 236, 259, 271, 296, 327, 415, 417, 425, 426, 438, 445, 446, 447, 450, 493, 497, 498, 500, 502, 504, 530, 532, 536, 540 growth factor, 296, 417 growth factors, 417 growth hormone, 426, 446, 450 growth rate, 9 GSK-3, 284 guidance, 316, 340 guidelines, xii, xxv, 25, 26, 27, 28, 30, 31, 40, 42, 198, 201, 205, 294, 334, 421, 429, 436, 438, 446, 468, 472, 511, 526, 571, 575 guilt, 125, 130, 345 gut, 259

H habituation, 225 Haifa, 579 hallucinations, 148 haloperidol, 298 handicapped, 543 handling, xii, 3, 5, 8, 14, 16, 18, 62 hands, 12, 16, 18, 60, 61, 256, 333, 535 hanging, 108, 332, 349, 358 happiness, 168, 189, 221, 222, 223, 253 harassment, 457, 503 hardships, 28, 351

harm, 29, 38, 50, 108, 175, 181, 271, 281, 312, 314, 331, 332, 333, 334, 341, 357, 459 harmful effects, 9, 572 harmony, 357 Harvard, 253, 377, 505 Hawaii, 359, 366 hazards, 548 HDL, 407, 425, 426, 428, 481 HEA, 63 head, 6, 7, 11, 12, 13, 18 head injuries, 328 head injury, 220, 340 headache, 158, 160, 512, 515 healing, 26, 27, 28, 32, 48, 64, 170, 273, 532 Health and Human Services, 135, 204, 448, 473, 526 health care, xiii, xxi, xxii, 26, 27, 33, 44, 71, 72, 81, 85, 103, 150, 182, 184, 190, 278, 315, 329, 331, 334, 335, 348, 357, 411, 423, 424, 453, 454, 457, 459, 460, 467, 468, 471, 504 health care costs, 424 health care professionals, 184, 459, 504 health care system, 182, 411 health education, 26, 42, 407, 421 health effects, 527 health information, 564 health problems, 37, 44, 124, 142, 469, 473, 549, 550 health services, 35, 43, 150, 310, 315, 350, 354, 358, 471 health status, 144, 336, 543 healthcare, xii, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 91, 94, 96, 316, 348, 424, 427, 430, 455, 527, 547, 549 healthy eating, 569 hearing, 118, 302 heart, 150, 168, 190, 259, 274, 406, 415, 416, 417, 421, 422, 433, 471, 478, 479, 481, 493, 510, 512, 514, 516, 527, 540, 564, 570 heart disease, 168, 190, 415, 416, 479, 510, 514, 575 heart failure, 433, 493, 564 heart rate, 406, 416, 478 heart valves, 516 heat, 248, 263, 331, 530 heavy drinking, 354 Hebrew, 22, 64, 66, 82, 575 hedonic, 223, 224, 225 height, xxii, 9, 13, 15, 125, 132, 381, 408, 409, 418, 425, 453, 458, 493, 500, 502, 503, 540, 541, 542, 568, 572 helmets, 58

Index helper cells, 146 hematopoietic, 131, 138 hematopoietic stem cell, 131, 138 hemiplegic, 66, 512 hemisphere, 250, 375 hemodynamic, 416 hemodynamics, 416, 422 hepatitis, 131, 132, 137, 138, 139, 330, 337, 400, 401, 510 hepatitis c, 510 hepatitis C, 131, 137, 138, 139, 330, 337, 401 hepatocyte, 428 herbal, xxii, 475, 476, 484 herbs, 483 Hesperian, 23 heterogeneity, 36, 133, 159, 202, 247, 248, 343 heterogeneous, 126, 129, 133, 537 high affinity receptors, 288 high blood pressure, 418, 421, 422, 424, 564 high density lipoprotein, 425, 428 high fat, 416, 417, 455, 569 high risk, xvi, 6, 34, 180, 186, 208, 210, 279, 280, 281, 282, 283, 303, 329, 334, 380, 417, 446, 470, 481, 502, 503 high school, 99, 103, 143, 211, 306, 310, 328, 350, 353, 355, 356, 359, 547, 568 high-density lipoprotein, 514 higher-income, 550 high-fat, 521, 522, 524 high-risk, 292, 303, 320, 329, 332 high-speed, xxiv, 545, 555 highways, 551 hip, 57, 374, 426, 456, 532 hippocampal, 288, 296, 299 hippocampus, 158, 285, 287, 288, 289, 296, 297, 298, 300, 397 hips, 14, 55, 57, 501, 523, 524 hirsutism, 447, 485, 572 Hispanic, xviii, 137, 301, 333, 354, 355, 362, 363, 364, 370, 394, 424, 436, 444, 454, 457, 460, 462, 485, 505, 531, 549, 551 Hispanic origin, 531 Hispanic population, 460, 549 Hispanics, 278, 304, 333, 364, 421, 459, 520, 549 histamine, 146 HIV, xi, 168, 328, 329, 333, 336, 337, 536 HIV infection, 329, 336, 536 HIV test, 333 holistic, xii, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 38, 40, 42, 43

599

holistic approach, 35, 42 holistic care, 29, 30, 31, 32 Holland, 431 homeless, 44, 305, 318 homeostasis, 247, 248, 428, 445, 448, 450 homework, 170, 176, 177, 178, 184 homicide, xiv, 105, 107, 108, 109, 110, 111, 113, 117, 118, 119, 250, 313, 314, 332, 337, 346, 375, 386, 399 homicide rate, xiv, 106, 108, 109, 110, 111, 113, 118, 119, 332 homicide rates, xiv, 106, 108, 110, 111, 113, 332 homogenous, 343 Hong Kong, 365, 579 hopelessness, 125, 143, 196, 310, 319, 329, 332, 334, 357, 362, 365 hormonal control, 387 hormone, 129, 131, 156, 160, 226, 397, 417, 424, 425, 426, 432, 446, 447, 448, 450, 451, 490, 493, 530, 533, 537 hormones, 137, 156, 189, 214, 260, 286, 417, 531, 532 horse, xiii, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 61, 62, 63, 64, 65, 66, 156 horses, 48, 59, 63 hospital, 34, 41, 87, 93, 94, 96, 152, 250, 272, 279, 290, 346, 368, 370, 372, 374, 375, 377, 385, 386, 399, 441, 512, 574 hospitality, xiv, 97, 99 hospitalization, 71, 81, 143, 264, 268, 269, 271, 272, 278, 280, 310, 380, 493, 548 hospitalizations, 142, 143, 144, 278, 282, 374, 558 hospitalized, 82, 95, 144, 181, 264, 320, 493, 494 hospitals, 267, 324, 336 host, 146, 388 hostile environment, 266 hostility, 37, 269, 329, 330, 384, 386, 387 household, 45, 210, 421, 555 households, 353, 356, 360 housing, xviii, 71, 301, 313, 325, 334, 337 HPA, 131, 132, 138, 218, 260, 385, 397, 430, 447 HPA axis, 131, 132, 218, 260, 397, 430, 447 HPLC, 210, 217 HRS, 174, 178 human, xi, 14, 15, 27, 29, 50, 51, 52, 53, 64, 130, 138, 156, 157, 165, 166, 168, 190, 216, 220, 226, 227, 250, 253, 257, 263, 265, 284, 285, 288, 300, 345, 348, 361, 369, 376, 386, 405, 416, 422, 450, 453, 464, 495, 497, 498, 504, 526, 531, 546, 548, 577, 579

600

Index

human behavior, 288, 348, 549 human brain, 138, 216, 369, 376 human condition, 168, 257 human development, xi, 138, 405, 453, 464, 497, 577, 579 human experience, 156, 263, 265 human genome, 531 human immunodeficiency virus, 190 Human Kinetics, 556 human rights, 29 human subjects, 165, 220, 422 humane, 331 humans, xvi, 138, 160, 163, 216, 219, 227, 250, 376, 384, 398, 400, 416, 417, 449, 527, 537 humidity, 221, 231, 249 humiliation, 329 hurricanes, 351 husband, 72, 210 hydrocortisone, 534 hydrolysis, 295 hygiene, 127, 265 hygienic, 568 hyperactivity, 39, 148, 284, 295, 298, 305, 312, 318, 321, 327, 334, 336, 416 hyperandrogenism, xxi, 423, 424, 426, 430, 431, 450, 480, 532 hyperarousal, 312 hypercapnia, 147 hyperglycemia, 490 hyperinsulinemia, 417, 445, 449, 480, 521, 531 hyperinsulinism, 425 hyperkalemia, 420 hyperlipidemia, 420, 512, 540 hypermotility, 260 hyperparathyroidism, 448 hyperplasia, 429, 516 hyperreactivity, 131, 149 hypersensitive, 17, 501 hypersensitivity, 369, 377, 401, 501 hypersomnia, 125, 126, 194, 214 hypertension, xxi, 124, 134, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 471, 476, 477, 478, 479, 510, 512, 514, 516, 540, 541, 547, 572, 574, 575 hypertensive, 414, 416, 417, 418, 419, 420, 422 hyperthyroidism, 478, 510 hypertriglyceridemia, 540 hypertrophy, 420 hyperventilation, 48, 51 hypnosis, 265 hypnotherapy, 430

hypnotic, 161 hypokalemia, 148, 419, 493 hyponatremia, 419 hypophosphatemia, 493 hypopigmentation, 536 hypothalamic, 127, 131, 146, 249, 260, 385, 397, 425, 447, 478, 482, 485, 532 hypothalamic-pituitary-adrenal axis, 127, 447 hypothalamic-pituitary-adrenal axis (HPA axis), 447 hypothalamus, 129, 156, 157, 287, 289, 387, 417 hypothermia, 288 hypothesis, 107, 117, 136, 158, 194, 205, 214, 220, 239, 240, 241, 245, 248, 285, 286, 295, 318, 372, 391, 392, 466 hypothyroidism, 283, 290, 447, 521 hypotonia, 55 hypoxia, 417, 481 hysteria, 259

I iatrogenic, 532 Iberian Peninsula, 70 ICD, 109, 120, 177, 178 ice, 10, 566, 567, 568 ICT, xiii, 85, 87, 89, 91, 92, 94, 95, 96 identification, xviii, 16, 38, 39, 40, 42, 81, 130, 185, 200, 267, 305, 315, 323, 334, 352, 366, 374, 400, 471, 527 identity, 37, 257, 263, 355, 357, 359, 365, 458, 498, 501 IDS, 145 IFN, 132, 138, 146, 401 IgE, vii, xix, xx, 146, 149, 367, 368, 369, 370, 371, 372, 377, 390, 391, 392, 393, 394, 395, 396, 397, 401, 402 IGF, 426, 430, 446, 450 IGF-1, 426, 430, 446 IGF-I, 450 IGT, 445, 446 IL-1, 132, 146, 209, 214, 384, 391 IL-13, 146, 391 IL-2, 132 IL-4, 146, 391 IL-6, 131, 209, 210, 213, 214, 384 illicit substances, 352 Illinois, 43, 319, 541, 542, 579 illumination, 156 images, 185, 458, 466 imagination, 267 imaging, 149, 159, 226, 250, 439

Index imbalances, 494 immigrants, 342, 343, 348, 356, 357, 365 immigration, 325, 344 immobilization, 510 immune activation, 209, 217 immune function, 226, 385 immune reaction, 381, 535 immune response, 131, 146, 190, 208, 369, 387 immune system, 17, 146, 208, 259, 369 immunity, 9, 137, 357, 400 immunoglobulin, 146 immunological, 208, 222, 398, 530 immunomodulatory, 160 immunosuppressive, 330 immunotherapy, 137 impaired glucose tolerance, 445, 449 impaired glucose tolerance (IGT), 445 impairments, 56, 159, 163, 396 impetigo, 535 implants, xxiii, 507 implementation, xiii, 47, 71 Impulse Control Disorder, xviii, 323 impulsive, 297, 299, 305, 307, 312, 352, 354, 356, 386 impulsiveness, 386 impulsivity, xviii, 39, 288, 301, 307, 312, 313, 314, 324, 327, 329, 336, 380, 384, 490 in situ, 426 in transition, 70 in utero, 36 in vitro, 217, 289, 387 in vivo, 217, 289, 295 inactivation, 22, 63 inactive, 448, 550 inattention, 334 incarceration, 303, 305, 310, 329, 330 incentives, 316, 554 incidence, xiii, xix, xxii, 39, 66, 69, 71, 75, 79, 108, 119, 158, 214, 249, 281, 282, 307, 319, 327, 339, 342, 344, 362, 369, 375, 380, 399, 411, 436, 440, 443, 444, 446, 447, 448, 449, 488, 490, 511, 516, 540, 541 incisional hernia, 439 inclusion, xv, 98, 99, 167, 171, 172, 182, 209, 210, 370, 392, 393 income, 45, 81, 94, 144, 351, 353, 363, 385, 407, 421, 459, 505, 522, 546, 547, 549, 550, 553, 555, 559, 560 incomes, 459 increased access, 548

601

incurable, 142 independence, 14, 20, 265, 551 index case, 73, 74, 75, 77 India, 94, 96, 342, 343, 346, 414, 421 Indian, 342, 358, 362, 410, 432, 484 Indian Health Service, 358 Indiana, 229 Indians, 342, 366 indication, 6, 78, 248, 302, 312, 467 indicators, 10, 233, 366, 371 indices, 239 indirect effect, 45 indirect measure, 103 individual character, 313 individual characteristics, 313 individual differences, 202, 229, 241, 245, 246, 247 individualistic values, 359 individuality, xxv, 563 inducer, 161 induction, xxii, 132, 161, 162, 164, 208, 285, 381, 475, 514 industrialized countries, 156, 415, 418 industrialized societies, 70 industry, xiv, 98, 99, 101, 415, 454, 501 ineffectiveness, 128, 199, 265 inequality, 120 infancy, xxiii, 45, 56, 125, 497, 498, 500, 502, 536, 541 infants, 110, 111, 112, 500 infection, 146, 168, 330, 336, 437, 439, 535, 536 infections, 5, 146, 210, 331, 370, 510, 512, 513, 516, 533, 535, 536 inferiority, 501 infertility, 427, 447, 532 inflammation, xvi, 123, 130, 131, 132, 137, 142, 145, 146, 147, 149, 152, 208, 209, 214, 369, 374, 384, 385, 387, 391, 392, 396, 397, 398, 417 inflammatory, xv, xvi, 130, 131, 132, 137, 138, 141, 145, 146, 147, 148, 149, 208, 209, 213, 214, 216, 218, 369, 376, 387, 391, 397, 398, 424, 425, 510, 516, 532, 534, 536 inflammatory cells, 148 inflammatory disease, 510 inflammatory mediators, 391 inflammatory response, 146 information and communication technology, 86 information communication technology, xiii, 85, 87 information sharing, 34 information technology, 86, 87, 95, 96 Information Technology, v, 85

602

Index

informed consent, 29, 30, 209, 220, 233, 370, 392 infrastructure, xxiv, 545, 546, 548, 549, 550, 554 ingest, 460 inguinal, 532 inhalation, 6, 169 inheritance, 537 inherited, 521 inhibition, 284, 285, 286, 296, 298, 300, 327, 334, 397, 416, 446, 490 inhibitor, xxii, 137, 149, 312, 428, 475, 479, 482, 494, 535 inhibitors, xxi, 132, 148, 286, 292, 413, 420, 479 inhibitory, 209, 327 initial state, 60 initiation, 5, 61, 81, 418, 419, 422, 446 injection, 149, 210, 230 injunction, xix, 339 injuries, xiii, 38, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 108, 117, 358, 366, 406 injury, xiii, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 119, 214, 220, 258, 290, 340, 493 inmates, xviii, 306, 323, 326, 327, 329, 331, 332, 333, 336, 337 innate immunity, 388 inositol, 284, 285, 295, 296 insecurity, 51 insertion, 9, 516 insight, 169, 184, 185, 387, 564, 569 insomnia, 125, 126, 127, 148, 149, 161, 478 instability, xix, 53, 57, 368, 369, 372, 373 institutionalization, 327 institutions, 95, 273, 327, 329, 331, 444, 565 instruction, 96 instructors, 188 instruments, xviii, xix, 301, 309, 310, 314, 315, 316, 368, 371, 396, 398, 468, 469 insulin, xxi, 126, 127, 128, 130, 131, 136, 156, 413, 416, 423, 424, 425, 426, 428, 430, 431, 432, 445, 446, 447, 449, 450, 479, 480, 485, 490, 518, 530, 531, 532, 537, 559, 572 insulin resistance, xxi, 126, 130, 131, 136, 413, 416, 423, 424, 425, 426, 428, 432, 445, 447, 449, 450, 485, 530, 531, 532, 537, 572 insulin sensitivity, 127, 128, 131, 136, 425, 428, 432, 445, 446, 449, 479, 480 insults, 457 insurance, 439 integration, 21, 23, 30, 87, 98, 99, 103, 170, 261, 271, 340, 345 integrity, 29

intellectual disabilities, 103 intellectual functioning, 45, 328 intelligence, 457 intensity, 127, 163, 197, 220, 221, 222, 231, 270, 282, 368, 382, 384, 406, 408, 446, 542, 547 intentions, 299 interaction, xxi, 8, 15, 50, 52, 58, 98, 128, 133, 142, 149, 153, 163, 202, 216, 230, 249, 269, 303, 306, 316, 380, 384, 443, 446, 464 interactions, xv, xviii, xxiv, 30, 36, 60, 123, 136, 138, 149, 208, 264, 270, 273, 301, 344, 361, 380, 384, 447, 479, 493, 499, 536, 546, 555 interdisciplinary, 579 interference, 30, 256, 272, 393 interferon, 131, 137, 138, 139, 216, 217, 330, 337, 400, 401 intergenerational, 45, 357 interleukin, xvi, 137, 138, 208, 209, 216, 369, 384, 387, 400 interleukin-1, 369, 384, 400 interleukin-2, 216, 384, 387, 400 interleukin-6, xvi, 137, 208, 209, 369, 384, 387 internal biological clock, 159 internal consistency, 309 internal environment, 530 internal time, 157, 159 internalised, 29 internalization, 256, 266 internalizing, 125, 305, 318, 352 International Classification of Diseases, 178 international students, 357 internet, 22, 63, 86, 87, 88, 89, 94, 96, 127, 128, 136, 317, 520 Internet, 87, 95, 96 internist, 492 interpersonal communication, 170 interpersonal conflict, 355 interpersonal conflicts, 355 interpersonal relations, 456 interpretation, 135, 187, 195, 236, 267, 363, 395, 396 interrelatedness, 28 interrelations, 554 intertrigo, 533, 535 interval, 221, 230, 232, 235, 236, 237, 243, 393 intervention, xii, xvi, xvii, xxi, 4, 5, 12, 14, 16, 20, 33, 34, 38, 40, 41, 43, 44, 47, 48, 49, 51, 52, 54, 55, 56, 58, 59, 61, 62, 64, 66, 83, 99, 106, 125, 126, 130, 133, 160, 167, 168, 170, 172, 173, 176, 180, 181, 182, 183, 185, 186, 187, 190, 193, 197,

Index 255, 263, 271, 274, 283, 307, 310, 311, 407, 411, 415, 418, 423, 436, 446, 449, 459, 460, 461, 462, 469, 527, 543, 547, 555, 556, 570, 573, 575 intervention strategies, 446 interview, 38, 81, 83, 143, 145, 170, 177, 217, 265, 309, 325, 370, 371, 372, 392, 394 interviews, xxv, 80, 170, 177, 183, 184, 306, 328, 393, 396, 541, 563, 565, 566, 567, 568, 569 intimacy, 498, 500 intimidation, 265 intoxication, 325, 332, 335 intracellular signaling, 283, 284, 286 intraindividual variability, 247 intramuscularly, 514 intravascular, 422 intrinsic, 229, 232, 233, 236, 239, 252, 417, 502 intrinsic value, 502 invasive, 124, 441 inventories, 99, 310 iodine, 534 ion channels, 157 ions, 284 IQ, 37, 43, 324, 540 Ireland, 267, 318, 573, 574 iron, 437, 438, 573, 575 iron deficiency, 437, 573, 575 irritability, 146, 148, 158, 258, 514 irritable bowel syndrome, 261 ischemia, 285 ischemic, 510, 575 ischemic heart disease, 575 Islam, xix, 339, 340, 341, 342, 343, 344, 346 Islamic, xix, 119, 339, 341, 342, 343, 344, 346 isolation, 128, 194, 308, 329, 332, 343, 454, 455, 460, 467 isozyme, 285, 296 isozymes, 285, 296 Israel, ix, xii, xiii, xxv, 3, 4, 25, 47, 69, 70, 71, 72, 79, 82, 83, 97, 98, 99, 100, 102, 103, 257, 341, 342, 346, 539, 541, 543, 571, 572, 573, 575, 577, 579 ISS, 147 Italy, xiv, 106, 109, 110, 111, 112, 113, 114, 115, 116, 117, 414 ITT, 200, 201

J jails, 308, 319, 324, 326, 331, 332, 333, 334, 336, 337

603

JAMA, 119, 134, 152, 273, 291, 321, 361, 410, 440, 448, 449, 470, 471, 484, 485, 486, 518, 524, 527, 543, 557, 559, 561 Japan, xiv, 106, 109, 110, 111, 112, 113, 114, 115, 116, 117, 210, 341, 376, 497, 540, 543 Japanese, 226, 349, 477, 542, 543 jejunum, 438 Jerusalem, 3, 25, 47, 69, 97, 539, 571, 577 jet lag, xv, 155, 156, 158, 159, 160, 161, 162, 163, 165, 166 jobs, 467, 552 joint pain, 427 joints, 12, 49, 54 judgment, 169, 171 Jun, 401, 402, 570 Jung, 137 junior high school, 328 jurisdictions, 327 justice, xviii, xix, 29, 34, 40, 43, 44, 108, 118, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 319, 322, 324, 325, 327, 335, 560 juvenile delinquency, 302 juvenile delinquents, xviii, 301, 304, 305, 306, 310, 311, 316, 318, 319, 321 juvenile detention facilities, 332 juvenile justice, xviii, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 319, 322 juvenile rheumatoid arthritis, 258 juveniles, 302, 303, 304, 308, 311, 313, 314, 319, 320, 321

K Kalman filter, 251 Kant, 28 Kentucky, 25, 97, 414, 423, 463, 507, 539, 571, 577, 579 ketogenic, 527 kidney, 415, 416, 417, 418, 421 kidneys, 416 killer cells, 400 killing, 319, 341 kinase, 284, 285, 295, 296, 425, 428 kinematics, 64 kinesthetic, 500 kinetics, 149 King, 291, 301, 318, 339, 364, 400, 558, 559 KOH, 535 Korea, 389, 476, 477

Index

604 Korean, xxii, 357, 365, 432, 475, 476, 477, 484 kynurenine pathway, 138

L labeling, 126, 312 labor, 550, 555 laboratory studies, 129, 258, 419, 492 lack of confidence, 95 lack of control, 11, 282 lactation, 428, 432 lactic acid, 428, 480 land, xxiv, 98, 545, 548, 549, 554, 557 land use, xxiv, 545, 548, 549, 554, 557 landscapes, 549, 558 language, 12, 22, 23, 39, 60, 63, 137, 268, 271, 348, 356, 468, 502, 504 language barrier, 39, 348 laparoscopic, 440 laptop, 88 laser, 532 latency, 126 Latin America, 86, 109, 355, 365 Latino, xix, xxii, 347, 348, 349, 350, 352, 353, 354, 355, 356, 360, 361, 453, 460, 503 law, 99, 302, 313 law enforcement, 302 laws, 29, 30, 39, 99, 100 laxatives, 490 LDL, 407, 428, 481, 512 lead, xvi, xx, 6, 7, 13, 51, 56, 102, 126, 128, 142, 143, 145, 150, 184, 185, 194, 195, 202, 208, 214, 231, 243, 258, 271, 282, 283, 287, 288, 289, 306, 328, 331, 334, 335, 384, 385, 390, 396, 397, 416, 427, 438, 458, 477, 480, 513, 521, 531, 570 leakage, 147 learned helplessness, 381 learners, 32 learning, 14, 18, 21, 29, 51, 55, 86, 171, 257, 259, 261, 262, 266, 306, 318, 328, 417, 439, 493, 500, 556 learning disabilities, 51, 261, 262, 266, 306 legal issues, 343 legislation, 36, 561 legislative, 34, 99, 101 legumes, 521 leisure, 99, 549, 559, 567 leisure time, 99, 559, 567 leptin, xxi, 129, 136, 413, 417, 422, 425, 432, 447, 450, 489, 530, 531, 537 lesions, 531, 534

leukemia, 209 leukotriene modifier, 147, 148 leukotrienes, 146 libido, 515 life course, 345 life cycle, 385 life expectancy, xxiv, xxv, 464, 470, 539, 549, 571 life experiences, 269 life satisfaction, 37 life stressors, 306 life style, 454, 543 lifespan, 134, 504 lifestyle, xxi, 71, 124, 257, 261, 262, 406, 415, 418, 419, 428, 430, 432, 443, 446, 449, 476, 522, 525, 547, 548, 557 lifestyle changes, 257, 522, 547, 548 lifestyles, 546, 548, 549 life-threatening, 11 lifetime, 76, 77, 79, 81, 143, 172, 176, 182, 195, 210, 278, 291, 305, 326, 328, 336, 348, 350, 352, 353, 354, 361, 369, 371, 374, 488, 501, 502 light-emitting diodes, 160 likelihood, 143, 145, 179, 239, 241, 352, 358, 455, 465, 467 Likert scale, 88, 175, 181 limitation, 95, 116, 132, 180, 199, 340, 343, 360, 374 limitations, xii, 3, 11, 50, 182, 183, 185, 199, 214, 282, 331, 355, 360, 396, 554 linear, xx, 173, 231, 232, 233, 235, 236, 237, 238, 239, 240, 243, 244, 245, 246, 247, 248, 252, 390, 395, 396, 415, 438, 532 linear regression, xx, 232, 236, 390, 395, 396 links, xv, 42, 126, 130, 141, 306, 309, 354, 516 lipase, xxii, 425, 475, 479, 482 lipid, 406, 419, 424, 425, 426, 430, 479 lipid profile, 406, 424, 425 lipids, 522 lipopolysaccharide, 387 lipopolysaccharides, 369, 391 lipoprotein, 425, 428, 431, 512 liquid chromatography, 210 liquids, 16, 18 liquor, 358 listening, 184 literacy, 95, 96 literature, xii, xiii, 4, 25, 26, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 47, 86 lithium, vii, xviii, 234, 249, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291,

Index 292, 293, 294, 295, 296, 297, 298, 299, 300, 311, 312, 320 Lithuania, 573 litigation, 325, 336 liver, 214, 295, 331, 415, 426, 430, 447, 480, 481, 510, 513 liver cancer, 510 liver damage, 331 liver disease, 481, 513 living arrangements, 541 living conditions, 100 LNG, 516 local authorities, 71 local government, 99 location, xxv, 14, 81, 98, 162, 164, 231, 360, 371, 558, 561, 563, 567 lockups, 319 locomotion, 56, 66, 127, 382, 383 locus, 147, 334, 392 London, 22, 24, 44, 45, 46, 63, 105, 159, 249, 251, 319, 336, 346, 495, 504 long distance, 546, 551 long period, 54, 261, 406 longevity, 440 longitudinal studies, 132, 133, 134, 554, 556 longitudinal study, 44, 133, 202, 321, 399, 400, 465 long-term, xv, xvi, xxv, 37, 147, 155, 156, 183, 188, 193, 194, 198, 199, 201, 202, 203, 258, 278, 279, 288, 292, 294, 296, 302, 303, 310, 311, 320, 440, 448, 468, 476, 481, 482, 518, 522, 523, 547, 555, 571, 573, 575 Los Angeles, 23, 161, 375, 556 loss of appetite, 488 loss of control, 490 losses, 355 love, 10, 377, 501 low fat diet, 406 low-density, 512 low-density lipoprotein, 512 lower-income, 550 low-income, 45, 144, 351, 353, 363, 407, 547, 549, 550, 553, 555, 559, 560 low-intensity, 542 loyalty, 52 LPS, 391, 402 LSD, 327 LSI, 23 lubrication, 530 luggage, 164 lung, 5, 11, 144, 146, 147, 148, 149, 151, 512

605

lung disease, 144 lung function, 144, 146, 147, 148, 149, 151 lungs, 512 lupus erythematosus, 258 luteinizing hormone, 432 lying, 7, 55, 61, 409 lymphocytes, 146, 216, 391 lymphokine-activated killer, 400

M machines, 108, 454, 567 macrophages, 214 magnesium, 283, 284, 295, 446, 494 magnetic resonance, 250 mainstream, xii, xv, 25, 26, 30, 31, 32, 62, 167, 168, 170, 458 maintenance, xvi, 55, 162, 164, 193, 194, 200, 202, 203, 279, 280, 293, 310, 382, 383, 480, 485, 503, 550 major depression, 133, 137, 142, 143, 145, 149, 151, 164, 173, 175, 179, 184, 186, 187, 188, 190, 195, 198, 199, 202, 208, 209, 211, 213, 217, 227, 233, 297, 300, 311, 320, 326, 330, 335, 380, 385, 386, 400 major depressive disorder, xv, 124, 125, 126, 128, 131, 135, 136, 137, 139, 142, 143, 151, 153, 167, 186, 214, 218, 227, 281, 291, 311, 312, 365, 368, 377, 386 malabsorption, 438, 479, 480 malabsorptive, 438 maladaptive, 136, 269, 270, 455, 503 malaise, 158 malaria, 510 Malaysia, 96, 342, 346 males, xvii, 89, 100, 107, 130, 133, 219, 220, 226, 278, 302, 304, 305, 306, 315, 324, 330, 333, 341, 346, 348, 350, 351, 353, 357, 358, 414, 424, 426, 460, 466, 480, 488, 502, 503, 540, 541, 542, 549, 572, 574, 575 malignancy, 531 malignant, 509 malingering, 308 Mallory-Weiss tear, 494 malnutrition, 6, 9, 10, 128, 438, 490, 492, 493, 494, 496 maltreatment, 119 mammals, 284 management, xiv, xviii, xix, xxi, xxiii, 22, 23, 41, 42, 49, 64, 66, 87, 97, 98, 99, 100, 102, 103, 146, 148, 150, 170, 185, 198, 201, 225, 226, 230, 259,

606

Index

263, 301, 319, 347, 350, 358, 405, 406, 410, 413, 417, 418, 419, 421, 423, 424, 435, 436, 449, 455, 468, 469, 470, 476, 478, 480, 481, 483, 484, 487, 491, 492, 493, 513, 531, 533, 536, 543, 547, 572 management practices, 455 mania, 147, 163, 164, 230, 233, 249, 250, 278, 279, 283, 290, 291, 293, 327, 335, 336, 375, 400 manic, 133, 147, 171, 180, 188, 235, 249, 250, 279, 292, 294, 295, 326, 327, 328, 375, 399 manic episode, 279, 294, 326, 327, 328 manic symptoms, 147, 180, 188 manic-depressive illness, 295, 375, 399 mapping, 565 marginalization, 329 marijuana, 209, 311, 328, 354, 486 marital conflict, 268 marital status, 174, 176, 375, 551 market, 98, 478, 508, 515 market segment, 98 marketing, 476, 570 marriage, 44, 268, 467 marriages, 72 Maryland, 69, 123, 141, 155, 167, 189, 207, 209, 210, 215, 219, 225, 229, 233, 277, 347, 367, 370, 376, 379, 381, 389, 390, 391, 398 masculinity, 498, 502 masking, 158, 343 mass media, xxv, 564, 565, 568, 569 Massachusetts, 41, 119, 171, 309, 314, 317, 321 mast cell, 146, 148, 149, 153, 377, 385, 387, 391, 397, 400, 401, 402 mast cell stabilizer, 148 mast cells, 146, 149, 385, 387, 397 mastery, 88, 270 maternal, xi, 38, 81, 83, 208, 215, 266, 274, 517, 521 matrix, 244 maturation, xxiii, 440, 447, 450, 497, 498, 502 meals, xv, 8, 12, 14, 155, 164, 454, 480, 491, 523, 524, 527, 566, 567 measurement, xx, 211, 217, 233, 235, 236, 238, 243, 245, 368, 426, 542 measures, xv, xxiv, 5, 21, 42, 57, 70, 81, 101, 103, 107, 126, 127, 133, 144, 148, 155, 168, 172, 173, 176, 183, 185, 200, 211, 212, 213, 230, 247, 278, 303, 314, 356, 372, 393, 398, 416, 468, 477, 480, 490, 513, 546, 551, 553, 554 meat, 17, 522 media, xiv, xxv, 102, 105, 106, 107, 118, 285, 345, 359, 456, 457, 458, 499, 502, 503, 521, 522, 535, 564, 565, 568, 569

median, 179, 222, 224, 245, 246, 300 mediation, 225 mediators, 132, 138, 146, 149, 214, 387, 391 Medicaid, 280, 293 medical care, 79, 95, 103, 118, 449 medical school, xiv, 86, 87, 94, 95 medical student, xiii, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96 medicine, xi, xiii, xvii, 25, 26, 28, 31, 32, 70, 79, 86, 87, 88, 91, 96, 168, 189, 190, 255, 258, 407, 410, 415, 421, 428, 430, 431, 464, 483, 484, 492, 504, 517, 546 meditation, xv, 167, 168, 169, 170, 171, 172, 177, 182, 184, 185, 189, 190, 191 Mediterranean climate, 98 Medline, xviii, 94, 96, 171, 301, 303, 349, 459, 572 melancholic, 125, 131, 138 melanin, 530 melanocyte stimulating hormone, 530, 533, 537 Melanocytes, 530 melatonin, xv, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 189 melatonin receptor agonists, 161 membership, 72, 304, 313 memorizing, 568 memory, 51, 152, 158, 169, 180, 186, 191, 262, 273, 274 memory deficits, 158 men, xi, 34, 36, 136, 159, 214, 226, 227, 258, 278, 279, 283, 325, 330, 337, 353, 364, 386, 396, 415, 417, 418, 425, 432, 481, 525, 541 menarche, 425, 438, 447 menstrual cycle, 131, 480 mental development, 499 mental disorder, xviii, 144, 151, 217, 226, 274, 305, 323, 324, 325, 327, 328, 336, 380, 384, 465, 495 mental health, xv, xxii, 34, 37, 40, 41, 49, 65, 124, 133, 139, 141, 149, 150, 151, 168, 184, 201, 273, 304, 308, 309, 310, 314, 315, 316, 317, 319, 322, 324, 325, 326, 327, 329, 330, 331, 333, 335, 336, 350, 354, 356, 357, 358, 360, 362, 363, 364, 463, 464, 465, 466, 467, 468, 469, 470, 471, 477, 482, 503 mental health professionals, xv, 40, 141, 308 mental illness, xix, 36, 231, 292, 304, 315, 325, 327, 333, 334, 336, 345, 348, 356, 358, 360, 368, 385, 468, 473, 503 mental impairment, 465 mental retardation, 51, 510, 539, 543 mental state, 328

Index mentor, 215 mentoring, 42 Merck, 152, 210 Mercury, 235, 242 meridian, 158 messages, 15, 269, 489, 493 messenger RNA, 299 meta-analysis, 43, 168, 190, 203, 204, 216, 281, 292, 321, 385, 415, 417, 421, 433, 440 metabolic, xxi, xxiv, 136, 137, 165, 214, 284, 294, 416, 419, 420, 423, 424, 425, 426, 427, 430, 431, 432, 435, 436, 444, 446, 450, 480, 482, 490, 493, 494, 509, 512, 531, 532, 535, 539, 541, 543, 548, 572 metabolic acidosis, 494 metabolic alkalosis, 494 metabolic disorder, xxi, 435, 436, 531 metabolic dysfunction, 444 metabolic rate, xxiv, 416, 509, 539, 541, 543 metabolic syndrome, xxi, 423, 424, 425, 427, 431, 432, 480, 482, 531, 532, 535, 572 metabolism, 127, 132, 139, 216, 231, 297, 298, 331, 419, 425, 445, 448, 450, 509, 527, 530 metabolite, 230, 286, 287, 515 metabolites, 209, 287, 295, 297 metacognitive, 179, 186 metal ions, 284 metallic taste, 283 metamorphosis, 330 metaphor, 71, 266, 274 metformin, xxii, 428, 432, 446, 449, 475, 480, 481, 482, 484, 485, 531 methamphetamine, 325, 327 methylation, 534 methylphenidate, 321 metric, 125, 240 metropolitan area, 235, 362 Mexican, 350, 355, 356, 363, 365, 414, 421, 444, 485, 547 Mexican Americans, 355, 356, 444 Mexican-Americans, 365 Mexico, 257, 328, 356 mice, 287, 288, 289, 297, 299, 384, 387, 530, 531 microdialysis, 298 microenvironment, 374 microenvironments, 225, 325 microorganisms, 208 microvascular, 147 midbrain, 287, 417 Middle East, 27, 343

607

middle-aged, 558 midlife, 226 midwives, 209 migraine, 510, 512 migraine headache, 510, 512 migrant, 570 migration, 147, 348 mild asthma, 146 militant, 341 military, 325 milk, 11, 18, 521, 566 Millennium, 117 mind-body, 26, 257, 263 mineralization, 427 mineralocorticoid, 417 minerals, 438, 523 Minnesota, 320 minorities, 354, 549 minority, xix, xxiii, 70, 71, 198, 347, 348, 350, 354, 357, 360, 361, 363, 455, 460, 461, 519, 550, 555 minority groups, 348, 350, 354, 361 minority students, 550 minors, 303, 315, 324 mirror, 7, 15 miscarriage, 118 miscarriages, 108 misconceptions, 492 misleading, 247 mitochondrial, 428 mitogen, 296 mitogen-activated protein kinase, 296 MMSE, 370 mobility, xxiv, 49, 54, 103, 545, 546, 549, 550 Modafinil, 162, 166 modalities, xxiv, 124, 307, 529, 530, 537 modality, 14, 63, 65, 411, 492 modeling, 42, 80, 229, 235, 248, 251, 252, 253 models, xix, xx, 28, 29, 41, 42, 99, 159, 194, 195, 196, 229, 231, 232, 233, 235, 236, 237, 239, 240, 241, 243, 244, 245, 246, 247, 253, 285, 288, 289, 290, 296, 299, 306, 368, 386, 387, 390, 391, 393, 395, 396, 466, 501 moderators, 130, 471 modernity, 70, 71, 79 modulation, 225, 227, 259, 285, 286, 296, 387 modules, 210, 371, 392 molecular changes, 287 molecular mechanisms, xviii, 277 molecules, 146, 285, 397 momentum, 125

608

Index

money, 103, 454, 457, 566 monoamine, 286, 298, 479 monoamine oxidase, 298, 479 monoamine oxidase inhibitors, 479 monoclonal, 149 monoclonal antibody, 149 monocytes, 384, 387 mononucleosis, 261 monotherapy, 280, 282 montelukast, 148, 392 mood change, xvii, 129, 133, 134, 147, 219, 222, 223, 225, 226, 230, 267 mood disorder, xv, xviii, xix, xx, 133, 141, 142, 143, 149, 152, 153, 163, 164, 167, 168, 169, 171, 172, 173, 176, 182, 188, 189, 203, 209, 210, 211, 278, 281, 291, 293, 295, 300, 301, 303, 305, 311, 316, 318, 320, 323, 324, 325, 327, 329, 330, 334, 335, 348, 351, 357, 368, 369, 385, 390, 392, 398, 400, 465, 489 mood states, 132, 197, 231, 392 morale, xiv, 106, 118 morals, 27 morbidity, xiii, xix, xxii, xxiv, 70, 82, 142, 151, 182, 188, 331, 333, 337, 339, 428, 429, 440, 443, 444, 448, 468, 470, 472, 539, 541, 575 morning, 125, 131, 138, 156, 159, 160, 164, 205, 233, 237, 243, 521 mortality, xi, xiii, xiv, xv, xix, xxii, 70, 71, 82, 105, 106, 107, 108, 109, 113, 114, 117, 118, 119, 141, 150, 188, 270, 281, 293, 294, 302, 313, 314, 339, 342, 350, 351, 428, 439, 440, 443, 448, 460, 470, 472, 480, 490 mortality rate, 71, 106, 107, 109, 302, 314, 439, 480, 490 mothers, 34, 41, 45, 46, 73, 76, 80, 119, 259, 283, 355, 550, 560 motion, 6, 50, 51, 55, 56, 57, 59, 269 motivation, 18, 49, 52, 53, 54, 60, 127, 128, 130, 158, 503 motives, 335 motor behavior, 288 motor function, 8, 63, 65 motor skills, 48 motor vehicle accident, 131, 138 mouse, 88, 288, 290, 299, 386, 495, 530 mouse model, 288, 530 mouth, 6, 7, 11, 12, 16, 17, 18, 19, 103, 458, 533, 536 movement, 7, 10, 12, 13, 48, 49, 50, 51, 53, 54, 56, 57, 65, 66, 99, 127, 169, 170, 214, 271, 288, 480

MPA, 514 MRI, 159, 259, 426 mRNA, 287, 289, 296, 300 MS, 22, 23, 135, 165, 226, 249, 317, 318, 364, 411, 424, 425, 430, 450, 471, 517, 543, 557, 560 MSW, 225 mucosa, 146, 258, 397, 402 mucus, 23, 148, 514 multicultural, 98, 102 multidimensional, 49, 249, 334 multidisciplinary, xii, 22, 25, 26, 27, 31, 35, 40, 41, 58, 67, 427, 428, 429, 496 multiple factors, 356, 358, 564 multiple sclerosis, 56, 64 multivariate, 88, 387 murder, 302 murine model, 153, 401 muscarinic receptor, 296 muscle, 4, 8, 12, 13, 14, 15, 49, 50, 54, 55, 56, 57, 58, 61, 66, 147, 197, 258, 260, 283, 416, 472, 480 muscle strength, 12, 14 muscle weakness, 283 muscles, 12, 50, 51, 54, 55, 57, 59, 61, 66, 295 muscular dystrophy, 56 musculoskeletal, 258 musculoskeletal pain, 258 music, 20, 23, 24, 59, 61, 66 music therapy, 23, 24, 66 Muslim, vii, xix, 339, 341, 342, 343, 344, 345, 346 mutation, 22, 61, 63, 425, 531 mutations, 22, 62, 511, 537 mutuality, 266 myelination, 493 myocardial infarction, 419, 511 myo-inositol, 285, 296 myopathy, 494

N narcotics, 305 Nash, 337 nation, 71, 79, 106, 117, 461, 472 national, xxv, 29, 106, 107, 109, 118, 125, 136, 144, 302, 303, 308, 313, 314, 319, 322, 345, 358, 375, 385, 406, 440, 441, 464, 541, 551, 554, 560, 571, 572, 575, 580 National Academy of Sciences, 448 National Institutes of Health (NIH), 134, 150, 165, 215, 219, 249, 389, 398, 436, 483 National Science Foundation, 249 National Strategy, 31, 32

Index Native American, xviii, xix, 278, 301, 304, 313, 347, 349, 350, 358, 359, 360, 421, 444, 459, 531 natural, 15, 147, 158, 188, 199, 210, 328, 374, 501, 541, 548, 556 nausea, 160, 260, 283, 428, 478, 515 neck, 6, 11, 12, 13, 17, 18, 55, 426, 445, 530, 531, 533, 534 necrosis, 131, 384, 439 negative attitudes, 99, 102, 467, 502 negative body image, xxii, 463, 466, 470, 502, 503 negative consequences, 208, 325 negative emotions, 146, 454 negative experiences, 184, 187, 188 negative life events, 351 negative mood, 223 negative outcomes, xxiii, 180, 497, 504 negative peer influences, 569 negative relation, 374 neglect, 39, 106, 328, 343, 522, 526 neonates, 216 nephropathy, 294, 510, 512, 516 nephrotoxicity, 294 nerve, 6, 230, 258, 296, 416, 417, 422, 478, 493 nerve fibers, 258 nerve growth factor, 296 nerves, 396, 417 nervous system, 258, 416 nervousness, 515 Netherlands, 93, 109, 110, 111, 112, 113, 114, 115, 116, 117, 312, 557 network, 87, 137, 157, 216, 340, 348, 548 neurobiological, 262, 288, 498 neurobiology, 139, 217, 263, 297, 387 neuroblastoma, 285 neurochemistry, 66 neurogenesis, 285 neuroimaging, 230, 259 neuroleptics, 132, 331 neurologic symptom, 510 neurological disorder, 48 neurons, 157, 225, 258, 285, 287, 288, 300, 417 neuropathic pain, 258 neuropathy, 510, 516 neuropeptide, 482 Neuropeptide Y, 482 neuroprotection, 286, 296 neuroprotective, 285, 296 neuropsychology, xvii, 255 neuroscience, 277 neurotic, 326

609

neuroticism, 145, 151, 380, 396, 401 neurotoxic, 132, 327 neurotoxicity, 230, 249 neurotransmission, xviii, 277, 283, 285, 286, 288, 289, 299 neurotransmitter, 127, 231, 286 neurotransmitters, 230, 260, 284, 478 neurotrophic, 284, 285, 296, 482 New Jersey, 94 New York, 23, 32, 97, 120, 150, 159, 166, 189, 190, 203, 204, 217, 226, 252, 255, 273, 274, 337, 346, 366, 375, 377, 386, 401, 410, 441, 472, 483, 504, 517, 524, 526, 537, 538, 556, 557, 570, 579 New Zealand, 34 newspapers, 101 Newton, 136 next generation, 283 Nielsen, 292, 319, 385 Niger, 96 Nigeria, v, xiii, 85, 86, 87, 89, 90, 91, 92, 93, 94, 96 nitrogen, 419 nitrous oxide, 416 Nixon, 299 NMR, 294, 295 nocebo, 259 noise, 164, 245, 248 nomothetic approach, 235 non-clinical, 24, 130 non-clinical population, 24 non-insulin dependent diabetes, 449, 537 nonlinear, 233 non-Muslims, 343 non-obese patients, 447 nonparametric, xvii, 220 non-random, 182, 572 nonverbal, 222, 268 non-violent, 376 noradrenaline, 230, 250 norepinephrine, 260, 300, 416, 478 normal, xxiii, 6, 9, 48, 53, 60, 66, 100, 125, 129, 131, 156, 165, 187, 214, 216, 231, 236, 258, 259, 331, 355, 415, 416, 417, 422, 432, 445, 446, 447, 448, 455, 487, 489, 490, 493, 495, 497, 501, 503, 504, 507, 508, 514, 530, 531, 533, 541, 549, 572, 573, 574 normal development, 48, 60 normalization, 429 norms, 102, 334, 343, 357, 365, 522 North America, 63, 72, 303, 477 North Carolina, 414, 461

Index

610

Norway, xx, 25, 369, 379, 380, 381, 382, 384, 559 NOS, xviii, 323 not-for-profit, 35 Notre Dame, 229, 252 novelty, 156, 490 nuclei, 156, 300 nucleus, 157, 250, 284, 289, 299, 300, 417 nucleus accumbens, 250, 284 null hypothesis, 117 nurse, 263, 267 nurses, 44, 87, 96 nursing, 26, 32, 34, 94, 96, 273 nurturance, 457 nutrient, 454, 564 nutrients, xxiv, 490, 492, 500, 521, 525, 539, 543, 564 nutrition, 22, 23, 263, 415, 433, 438, 454, 455, 492, 493, 527 nutritional deficiencies, 438 nuts, 11, 476 nystagmus, 283

O obese patients, 419, 427, 446, 447, 485, 486, 488, 493, 521, 523 obesity epidemics, 124 obesity hypoventilation syndrome, 126 obesity prevention, xxv, 459, 462, 564, 569 objectification, 505 obligations, 26, 355 observations, xii, 38, 235, 236, 237, 238, 241, 243, 248, 414, 416 obsessive-compulsive disorder (OCD), 142, 234, 312, 492 obsolete, 417 obstetricians, 209 obstruction, 144, 145, 396, 439 obstructive lung disease, 144 obstructive sleep apnea, 162, 417, 427, 476 occupational, 12, 22, 58, 64, 65, 96, 164, 540 occupational therapy, 22, 64, 65, 540 odds ratio, 352, 354, 542 odorants, xvii, 220, 225 odors, 220, 221, 222, 223, 225, 226, 227 OECD, 113 Oedipus, 274 Oedipus complex, 274 offenders, 302, 305, 310, 311, 313, 318, 321, 331, 332, 334

Office of Juvenile Justice and Delinquency Prevention (OJJDP), 311, 316, 317 office-based, 44 Ohio, 310, 550 oil, 10, 534 oils, 521, 536 older adults, 152, 558 older people, 177, 191, 558 olfaction, xvi, 219, 227 olfactory, 220, 223, 225, 227 olfactory bulb, 227 olive, 10 olive oil, 10 omission, 81 online, 86, 136 online interaction, 136 openness, 169 operant conditioning, 196, 197 opiates, 209, 259 opioids, 260 opposition, 266 oppositional behaviour, 37 Oppositional Defiant Disorder, 324, 328 optic chiasm, 156 optimal health, 27 oral, xix, xxiii, 6, 8, 10, 12, 13, 16, 17, 19, 145, 148, 163, 339, 344, 432, 445, 446, 480, 502, 507, 509, 511, 513, 516, 517, 533, 535, 536 oral contraceptives, xxiii, 507, 517 oral hypoglycemic agents, 446 orbitofrontal cortex, 153, 362, 401 organ, 168, 190, 283, 415, 416, 417, 422, 530 organism, 157 organization, 59, 99, 280, 310, 414 organizations, 99, 269, 459 orientation, 10, 51, 169, 170, 194, 363, 498 Orlistat, 479, 480, 485 orthodox, 354 orthopaedic, 64 orthostatic hypotension, 493 oscillation, 232, 236, 239, 245, 247, 248 oscillations, 229, 241, 248, 380 oscillator, 157, 232, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 252 osmotic, 490 ossification, 536 osteoarthritis, 258 osteodystrophy, 536 osteoporosis, 56 OTC, 476, 485, 518

Index Ottawa, 579 outcome of interest, 282 outliers, 211 outpatient, 182, 189, 191, 233, 264, 272, 293, 320, 356, 357, 365, 454, 492, 493, 496 outpatients, 135, 151, 152, 189, 217, 229, 233, 400, 493, 494 ovarian cysts, 424, 426 ovarian tumor, 509 ovariectomy, 387 ovaries, 424, 429 ovary, 432 overeating, 488 overload, 263 overnutrition, 464 overproduction, 532 over-the-counter, 476, 480 overtime, 232 ovulation, 428, 430, 480 ownership, xiii, 85, 88, 90, 93, 94, 95, 551 oxidation, 428 oxidative, 428 oxidative stress, 428 oxide, 416 oxygen, 407, 422 oxygen consumption, 422 oxytocin, 260

P pacemaker, 157, 160, 165 Pacific, 278, 346, 357, 421, 457 Pacific Islanders, 278, 421 Pacific Region, 346 packaging, 521, 567, 568 pain, xvii, 7, 149, 168, 170, 177, 182, 184, 189, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 267, 268, 272, 273, 274, 340, 415, 427, 480 pain management, 259 Pakistan, 342, 343 palliative, 199, 202 pancreatic, 479, 480 pandemic, 422 panic attack, 143, 291 panic disorder, 134, 142 paralysis, 56, 125, 214, 265, 267, 270 parameter, 232, 236, 237, 239, 240, 244, 245, 246, 247, 248, 319, 321 parameter estimation, 237 parasite, 370 parasympathetic, 416

611

parathyroid, 445, 448, 451 parathyroid hormone, 448, 451 paraventricular, 157, 417 paraventricular nucleus, 157, 417 parent involvement, 310 parental involvement, 459 parent-child, 357, 360 parenting, 36, 80 parents, xi, xiii, 5, 8, 11, 17, 34, 36, 39, 40, 41, 59, 64, 65, 70, 72, 80, 81, 108, 117, 259, 260, 263, 264, 265, 266, 267, 268, 270, 271, 302, 315, 353, 355, 357, 444, 457, 459, 464, 468, 491, 492, 504, 505, 521, 523, 540, 550, 551, 553, 554, 555, 567, 573, 575 Paris, 159, 377, 385 Parkinson, 44 parkinsonism, 283 parole, 306, 324, 329 paroxetine, 139, 216, 251 participant observation, xxv, 563, 565, 566, 569 particles, 7 partnership, 492 partnerships, 40 passive, 13, 270, 356 paternal, 208, 521 pathogenesis, 146, 196, 216, 448 pathogens, 388 pathologists, 12, 23 pathology, 11, 22, 457, 461, 513 pathophysiological, xvi, 124, 208, 215 pathophysiological mechanisms, 124, 215 pathophysiology, 137, 139, 143, 145, 152, 161, 260, 274, 285, 286, 295, 401 pathways, xv, 123, 124, 128, 130, 131, 157, 202, 258, 262, 283, 284, 286, 417, 557 patient care, 28, 31, 86, 282 patient-centered, 27 Paxil, 265 PC12 cells, 296 PCL-R, 306 PCP, 327 pedestrian, 550, 561 pedestrians, 560 pediatric, xv, xviii, 34, 38, 39, 43, 44, 45, 71, 82, 83, 123, 124, 131, 132, 136, 150, 151, 264, 265, 271, 273, 292, 312, 320, 321, 323, 334, 338, 440, 444, 450, 464, 465, 467, 468, 470, 482, 492, 538, 574 pediatric patients, 131, 292, 320, 482 pediatrician, 265, 486, 492, 496

612

Index

peer, 41, 45, 261, 262, 263, 266, 270, 310, 313, 327, 355, 455, 456, 457, 458, 461, 498, 499, 500, 501, 502, 503, 504, 505, 554, 569, 580 peer group, 261, 262, 263, 266, 270, 310, 501 peer rejection, 457, 498 peer relationship, 499 peers, xxii, xxiii, 8, 61, 102, 128, 143, 260, 308, 310, 313, 355, 408, 409, 456, 457, 463, 466, 467, 470, 489, 491, 499, 501, 502, 503, 507, 508 PEF, 144 pelvic, 426, 509, 516 pelvic inflammatory disease, 516 pelvic ultrasound, 426 pelvis, 14, 50, 55, 426 penalties, xix, 339 pendulum, 232 penis, 501 Pennsylvania, 325, 336 peptide, 129, 446, 482, 530, 531 percentile, 126, 407, 409, 414, 418, 424, 444, 445, 464, 493, 500, 540, 541, 572, 573 perception, xxv, 51, 57, 106, 118, 130, 139, 223, 225, 226, 258, 259, 334, 344, 358, 427, 456, 462, 488, 525, 526, 554, 563, 566, 567 perceptions, xxii, 45, 365, 453, 456, 457, 499, 500, 544, 550, 551, 553, 555 perfectionism, 261 perforation, 439 performance, 42, 54, 64, 156, 162, 164, 166, 355, 357, 358, 360, 406, 407, 469, 501, 502, 503, 547 perinatal, 208, 215, 218 perineum, 531 periodic, 41, 48 peripheral, 418 peripheral blood, 392 peripheral nerve, 230 peripheral oscillators, 158 permit, 59 persistent asthma, 148, 149 personal, xiii, xxii, xxiv, 6, 8, 15, 16, 17, 20, 30, 52, 85, 86, 87, 89, 94, 95, 96, 142, 178, 184, 198, 308, 354, 374, 453, 458, 460, 472, 498, 499, 500, 512, 546, 548, 549, 551, 554, 555, 570 personal communication, 16, 198 personal computers, 86, 87, 94 personal history, 374, 499, 512 personal relations, 52, 498 personal relationship, 52, 498

personality, 95, 100, 145, 261, 262, 263, 306, 327, 329, 330, 334, 337, 373, 374, 377, 380, 457, 469, 489, 496 personality disorder, 327, 329, 330, 334, 337, 373, 374, 377, 489, 496 personality factors, 145 personality traits, 261, 306, 380, 457 personhood, 26 persons with disabilities, 98, 99, 103 Perth, 525, 557 perturbations, xvi, xxii, 208, 443, 447 petechiae, 535 pets, 64 PFC, 397 pH, 210, 533 pharmacologic agents, 419, 429 pharmacological, xv, 155, 181, 278, 283, 290 pharmacology, 299 pharmacotherapy, 198, 204, 205, 272, 293, 406 pharynx, 6 phencyclidine, 210 phenomenology, 133 phenotype, 146, 299, 324, 432 phenotypes, 22, 63, 328, 336 phenotypic, 11, 49, 58 phenytoin, 479 Philadelphia, 410, 421, 422, 431, 441, 450, 470, 483, 526, 541 philosophy, 257 phobia, 399 phone, 164 phosphatases, 284 phosphate, 210, 295 phosphodiesterase, 149 phospholipids, 295 phosphorylates, 285 phosphorylation, 285 photographs, 197 photoperiod, 231, 368 photoperiodism, 231 photoreceptor, 158 photoreceptors, 157 physical abuse, 34, 108, 326, 351, 355 physical activity, xxi, 56, 127, 128, 136, 157, 352, 363, 405, 406, 407, 408, 409, 410, 420, 433, 454, 459, 460, 488, 520, 522, 523, 524, 525, 527, 542, 544, 546, 547, 548, 549, 550, 554, 556, 557, 558, 559, 561 physical attractiveness, 462, 501, 502 physical education, 352, 489, 547

Index physical environment, 329, 548, 550, 558 physical exercise, 455, 465 physical fitness, 525 physical health, 144, 182, 336, 454, 455, 466, 470 physical therapist, 12 physical therapy, 22, 50, 64, 265 physical well-being, 152 physicians, xiv, 26, 27, 32, 43, 58, 86, 95, 103, 456, 459, 484 physiological, xvii, 6, 36, 39, 137, 156, 157, 160, 194, 203, 208, 214, 217, 249, 255, 260, 262, 269, 272, 284, 286, 397, 406, 458, 493, 498, 499, 501 physiological arousal, 262 physiological factors, 406 physiology, 87, 156, 256, 258, 262, 263, 269, 273, 385, 529 physiotherapy, 12 pilot studies, 201 pilot study, 66, 103, 136, 189, 190 pilots, 158, 164 pineal, 156, 157, 160 pineal gland, 156, 157, 160 pituitary, 131, 146, 260, 274, 385, 397, 447, 532, 533, 535 PKC, 285, 296 placebo, xvii, 145, 151, 161, 182, 199, 220, 226, 259, 278, 279, 281, 282, 292, 294, 320, 401, 433, 479, 485 placenta, 283 planning, 10, 16, 49, 52, 71, 134, 169, 185, 309, 348, 360, 492, 557, 558 plasma, 131, 137, 139, 166, 209, 214, 217, 249, 288, 298, 331, 400, 417, 422, 433, 449 plasma levels, 331, 400, 433 plasminogen, 428 plastic, 17, 18 plasticity, 285 platelet, 231, 251, 428 platelet aggregation, 428 play, 20, 39, 41, 67, 80, 86, 128, 146, 157, 196, 231, 266, 269, 284, 302, 315, 325, 331, 349, 364, 406, 407, 409, 427, 466, 520, 547, 549, 550, 551, 556 pleasure, 125, 128, 500 plexus, 288, 298 pneumonia, 11 poison, 476 poison control centers, 476 poisoning, 108, 117, 351, 362 poisons, 349 Poland, 414

613

police, 41, 106, 118, 314 policy makers, 362 politics, 118 pollen, xx, 149, 152, 153, 369, 370, 371, 372, 374, 375, 376, 377, 379, 381, 382, 383, 385, 386, 387, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 402 pollutants, 397, 546 pollution, 387, 548, 550, 555 polycystic ovarian syndrome, 423, 424, 432, 445 polycystic ovary syndrome, xxiv, 432, 433, 480, 485, 529, 530, 537 polydipsia, 283 polygamy, 72, 81 polymer, 516 polymorphism, 297 polypeptides, 146 polysomnography, 126, 135 polyuria, 283 poor, xi, xiii, xvi, xxv, 13, 19, 36, 37, 50, 54, 55, 61, 85, 88, 90, 93, 94, 108, 118, 135, 150, 158, 163, 208, 262, 281, 304, 313, 330, 334, 349, 353, 357, 358, 360, 447, 454, 457, 458, 465, 489, 500, 503, 510, 512, 546, 548, 550, 559, 571 poor health, xxv, 349, 457, 571 POPs, 508, 514 population group, 549 Portugal, 573, 574 Positive and Negative Affect Schedule, 178 positive attitudes, 91, 99, 101, 102 positive correlation, 551 positive mood, 225 positive reinforcement, xvi, 193, 196, 197, 198 positive relation, 184, 214 positive relationship, 184, 214 post traumatic stress disorder, 39 Post Traumatic Stress Disorder (PRSD), 37, 39, 45, 131, 138, 142, 260, 262, 274, 305, 310, 320, 321, 348, 351, 363, 481 postmenopausal, 66 postmenopausal women, 66 postmortem, 297, 369 postoperative, 438 postpartum, xvi, 125, 208, 209, 210, 211, 212, 213, 214, 216, 217, 218, 510, 511 postpartum depression, xvi, 208, 209, 210, 216 postpartum period, xvi, 208, 209, 213, 214 postsynaptic, 285, 288, 297, 298, 299, 478 post traumatic stress, 37, 39, 45, 131, 138, 142, 260, 262, 274, 305, 310, 320, 321, 348, 351, 363, 481

614

Index

posture, 10, 11, 13, 14, 49, 50, 55, 56, 57, 61, 62, 63, 66, 158, 288 Potash, 247, 291 potassium, 210, 494 potato, 523, 524 potatoes, 521 poverty, xi, xxiii, 36, 40, 45, 119, 348, 353, 356, 358, 359, 459, 467, 519, 520, 550 poverty line, 459 poverty rate, 550 powder, 535 power, 64, 180, 182, 189, 201, 231, 247, 282, 340, 373, 457 PPA, 476 preadolescents, 365, 459 precipitation, 398 preclinical, 88, 284, 287, 289 pre-clinical, xiii, 85, 87, 93 precocious puberty, 425 prediction, 165, 232 predictive validity, 468 predictor variables, 232 predictors, xxiv, 90, 93, 127, 134, 313, 334, 359, 365, 385, 421, 526, 545, 573 prednisone, 147, 152, 429 preeclampsia, 432 pre-existing, 438, 553, 554 preference, 132, 176, 182, 240, 327, 402, 564, 566 prefrontal cortex, 153, 286, 297, 397, 401 prefrontal cortex (PFC), 397 pregnancy, 36, 41, 44, 60, 208, 209, 210, 211, 214, 216, 217, 283, 353, 356, 392, 428, 429, 432, 438, 499, 508, 509, 511, 513, 514, 515, 517, 532 pregnancy test, 515 pregnant, 35, 40, 41, 44, 209, 214, 216, 420, 429, 432, 438, 499, 511 pregnant women, 35, 40, 209, 214, 216, 432 premature adrenarche, 450 preschool, 39, 45, 142, 542, 556, 558, 559 preschool children, 559 pressure, 6, 11, 12, 19, 51, 229, 230, 231, 233, 235, 239, 244, 251, 258, 270, 355, 407, 416, 417, 418, 419, 420, 421, 422, 424, 426, 478, 479, 494, 501, 503, 512, 522, 550, 564, 572 pressure sore, 19 presynaptic, 287, 288, 297, 300 preventative care, 356 prevention, xiii, xv, xviii, xix, xxv, 12, 27, 28, 30, 40, 43, 56, 70, 71, 81, 82, 83, 106, 119, 123, 130, 133, 134, 135, 136, 138, 159, 167, 168, 179, 190,

191, 199, 200, 201, 205, 277, 281, 283, 286, 291, 293, 294, 316, 324, 333, 338, 340, 345, 346, 352, 362, 366, 421, 446, 459, 461, 462, 470, 483, 515, 523, 527, 543, 559, 564, 569 preventive, 57, 124, 148, 292, 307, 317, 340, 398, 411 prices, xxv, 563, 566, 569 primary care, xiii, 44, 59, 69, 71, 72, 79, 83, 136, 149, 150, 183, 191, 204, 216, 357, 358, 361, 365, 431, 473, 484, 505 primary caregivers, 59 primary school, 542, 560, 561 primates, 250 priming, 385 prior knowledge, 21 priorities, 41 prisoners, 305, 318, 326, 327, 332, 333, 334, 336, 337 prisons, 308, 326, 329, 331, 332, 334, 336, 337 privacy, 274, 490 private, 34, 35, 39, 45, 89, 98, 189, 269, 282, 370, 541, 549, 556 private practice, 189, 282 proactive, 27, 28, 39, 159 probability, 109, 309, 464, 470 proband, 376, 386 probation, 302, 325 probe, 467 problem behavior, 364 problem drinking, 314 problem-solving, 5, 13, 178, 185, 318, 358, 365 problem-solving skills, 365 producers, xxiii, 519, 524 production, 132, 147, 148, 208, 209, 218, 289, 391, 397, 402, 417, 425, 429, 447, 493, 514, 530 productivity, 147 professional development, 32, 42 profit, 35 profits, 454 progesterone, 425, 428, 508, 514 progestins, 429, 509, 512 prognosis, 230, 247 program, xii, xxii, xxiii, 9, 20, 33, 40, 41, 43, 49, 51, 54, 55, 56, 57, 59, 60, 62, 65, 82, 100, 102, 168, 170, 179, 182, 183, 185, 187, 189, 190, 215, 264, 280, 310, 325, 336, 345, 352, 354, 359, 406, 407, 430, 433, 475, 476, 482, 519, 522, 523, 524, 561, 564, 572 programming, 87, 128 pro-inflammatory, 130, 132, 209, 214, 218, 424

Index prolactin, 156, 426, 430 proliferation, 216, 349 promote, xxv, 27, 128, 208, 309, 310, 417, 456, 457, 480, 499, 554, 557, 571, 575 promoter, 132, 297 promoter region, 132 property, 313 prophylactic, xvi, 193, 201, 202, 230, 250, 279, 281, 291, 294, 320, 375, 399 prophylactic agents, 294 prophylaxis, 249, 281, 292, 293, 294 Propranolol, 234 prosocial behavior, 226 prostaglandin, 147 prostaglandins, 146 prostate, 189 prostate cancer, 189 proteases, 397, 402 protection, xiv, xix, 34, 39, 57, 105, 106, 118, 120, 280, 281, 340, 345, 347, 348, 457, 530 protective factors, xix, 310, 319, 339, 340, 341, 347, 349, 350, 354, 356, 359, 360, 456 protective role, 363 protein, xvi, 22, 62, 132, 157, 208, 285, 289, 295, 296, 417, 427, 523, 527, 530, 537 protein family, 295 protein kinase C, 295, 296 protein kinases, 296 proteins, 214, 218, 284, 286, 289, 296, 425 proteolytic enzyme, 402 Protestants, 340 pro-thrombotic, 424 protocol, 157, 200, 201, 220, 391 protocols, 225, 308, 314, 316, 476, 482 provocation, 402 proximal, 198, 417, 438, 549 Prozac, 265, 482, 486 Pseudomonas, 535 psychiatric diagnosis, 438 psychiatric disorder, xviii, 119, 304, 306, 313, 323, 324, 325, 328, 329, 331, 344, 352, 354, 361, 472, 496, 510 psychiatric disorders, xviii, 119, 304, 306, 323, 324, 325, 329, 331, 344, 352, 354, 361, 472, 496, 510 psychiatric illness, 163, 260, 278, 282, 330, 340, 359 psychiatric morbidity, 337 psychiatric patients, 278, 380 psychiatrist, 263, 264, 265, 266, 267, 268, 269, 271, 272, 492 psychiatrists, 43, 293, 370

615

psychoanalysis, 267, 268, 504 psychoanalytic theories, xvii, 255, 263 psychobiology, 260, 274 psychological development, 427, 464, 504 psychological distress, 37, 127, 183, 318, 353, 460 psychological health, 455, 464, 503 psychological problems, 265, 469 psychological processes, 195, 252, 264, 272 psychological stress, 146, 256, 264, 266, 272, 427 psychological stressors, 256, 266, 427 psychological variables, 314, 316, 468 psychological well-being, 137, 462, 527 psychologist, 177, 256, 259, 260, 263, 265, 267, 272, 431, 492 psychology, 150, 204, 453, 504 psychometric properties, 321 psychopathology, xvi, 133, 134, 138, 193, 202, 304, 306, 317, 318, 380, 461 psychopathy, 318 psychopharmacological, 248, 256 psychopharmacology, 272, 295, 486, 496 psychoses, 250, 292, 375, 399 psychosis, 147, 220, 326, 328, 348 psychosocial factors, 464, 467 psychosocial stress, 349 psychosomatic, 143 Psychosomatic, 152, 189 psychostimulants, 209 psychotherapy, 49, 63, 124, 176, 182, 187, 188, 191, 197, 200, 201, 271, 272, 273, 274, 278, 492, 496 psychotic, 129, 210, 253, 292, 326, 328, 330, 335, 371, 392, 514 psychotropic drug, 291, 400 psychotropic drugs, 291, 400 psychotropic medications, 278, 316, 373, 396 pubarche, 450 pubertal development, 445, 447 puberty, xxiii, 431, 447, 450, 490, 497, 498, 501, 502 public, xi, xii, xiv, xv, xxii, 27, 34, 36, 40, 98, 99, 100, 102, 106, 107, 118, 123, 124, 156, 199, 201, 202, 303, 306, 313, 315, 327, 345, 355, 453, 454, 459, 463, 470, 471, 472, 476, 525, 542, 546, 550, 553, 554, 557, 560, 565, 579 public health, xi, xii, xv, xxii, 123, 124, 201, 202, 303, 345, 453, 454, 459, 463, 470, 471, 472, 476, 525, 542, 546, 554, 557, 560, 579 public schools, 560 puerperium, 216, 217 Puerto Rican, 336

Index

616 pulmonary embolism, 510 pulmonary hypertension, 478, 510 pulse, 238, 479 pulses, 165, 238 punishment, 331 punitive, 308, 314, 329 pupils, 101, 103, 540 PVN, 397 pyramidal, 288

Q QT interval, 494 qualitative research, xii quality of life, xv, xxi, 16, 52, 53, 62, 99, 102, 141, 144, 147, 149, 151, 167, 168, 189, 215, 222, 423, 440, 465, 471, 472, 574, 576 quality of service, 98, 99 quality research, 29 quartile, 574 Quebec, 304, 317 questioning, 39, 458 questionnaire, xiii, xiv, 5, 85, 87, 88, 97, 99, 100, 176, 183, 392, 393, 467, 565, 566 questionnaires, xxv, 38, 88, 99, 145, 187, 563, 569 quetiapine, 312, 321 quinine, 299

R race, xviii, 132, 301, 362, 364, 366, 432, 450, 471, 546, 559 racial groups, 350 radiation, 160 radio, 391, 568 radiological, 430 rain, 22, 64, 65, 66 rainfall, 374 Raman, 570 random, 5, 11, 243, 248 range, xii, xiv, xxiii, xxv, 3, 12, 36, 38, 40, 41, 57, 59, 88, 97, 108, 118, 149, 168, 179, 183, 184, 188, 237, 238, 245, 246, 247, 270, 283, 288, 304, 326, 329, 335, 341, 415, 487, 493, 495, 522, 563, 566, 567 rape, 302, 313, 499 raphe, 289, 299, 300 rat, 227, 249, 295, 296, 297, 298, 299, 300, 381, 387 rating scale, 217 ratings, 45, 223, 229, 230, 231, 235, 309, 377, 396

rats, xx, 153, 220, 226, 230, 250, 284, 285, 287, 288, 289, 298, 299, 300, 369, 377, 379, 381, 383, 384, 385, 386, 387, 400, 402 raw materials, 221 reactivity, xvi, xx, 125, 138, 148, 186, 193, 197, 204, 208, 214, 270, 380, 385, 387 reading, 101, 306 reality, 40, 41, 550 reasoning, 51 reasoning skills, 51 reception, 302, 329, 332, 333 receptor agonist, 288, 289, 417 receptors, 6, 129, 146, 147, 149, 157, 160, 162, 230, 258, 286, 287, 288, 289, 297, 298, 299, 300, 387, 397, 417, 428, 485, 489, 530, 536 recidivism, 306, 310 reciprocal relationships, 251 recognition, xviii, 20, 136, 169, 268, 269, 323, 328, 330, 333 recovery, 36, 127, 158, 162, 173, 174, 175, 179, 184, 186, 188, 261, 272, 311, 494, 548 recreation, 558 recreational, 49, 100, 414, 493, 542, 548, 558 recurrence, xvi, 7, 124, 126, 129, 135, 136, 173, 174, 179, 186, 190, 191, 193, 194, 198, 200, 201, 202, 205, 281, 293 recycling, 285 red meat, 17 redistribution, 514 reduction, xiv, xv, 49, 55, 59, 62, 65, 106, 109, 110, 113, 114, 118, 128, 136, 149, 152, 159, 164, 167, 168, 171, 172, 175, 180, 181, 182, 187, 189, 190, 191, 222, 223, 278, 279, 281, 290, 349, 354, 406, 416, 419, 421, 425, 429, 432, 459, 468, 476, 478, 479, 480, 485, 493, 527, 548, 549, 569 refining, 501 reflection, 117, 194, 272 reflectivity, 271 reflexes, 52, 417 reforms, xii, 33 refractory, 131 regeneration, 285, 296 regional, 71, 72, 341, 343, 344, 414, 416, 421 regression, xx, 88, 145, 211, 213, 232, 236, 238, 240, 270, 352, 390, 393, 395, 396 regression analysis, 393, 396 regression equation, 236 regular, 5, 16, 58, 161, 162, 164, 199, 215, 220, 241, 262, 293, 406, 408, 419, 428, 522, 523, 524, 547, 549

Index regulation, 129, 131, 132, 160, 169, 229, 230, 231, 236, 240, 241, 245, 247, 248, 269, 274, 289, 296, 388, 397, 489, 492, 494, 530 regulations, 331 regulators, 321, 450 regulatory framework, 26 rehabilitation, 23, 48, 59, 302, 311, 579 Rehabilitation Center, 47, 59, 60 rehabilitation program, 59, 311 reinforcement, xvi, 193, 196, 197, 198, 335 rejection, 125, 214, 454, 457, 460, 498, 501, 503 relapse, xv, 132, 167, 168, 173, 174, 179, 180, 185, 186, 188, 190, 191, 198, 200, 204, 205, 217, 250, 293, 375, 478, 494 relapses, 179 relatives, 61, 98, 178, 185, 376, 386 relaxation, 17, 55, 127, 189, 221, 222, 223, 428, 493 relevance, xvi, 193, 196, 288, 290, 342, 380, 384 reliability, 309, 319, 324, 468, 473, 572 religion, xix, 98, 339, 340, 341, 342, 343, 344, 345, 346, 348, 354, 356 religions, 28, 36, 341, 342, 343, 344 religiosity, xix, 314, 339, 341, 344, 345, 352, 354, 356, 358, 360, 364 religious belief, 340, 345, 354 religious beliefs, 340, 345, 354 religious groups, 343 REM, 61, 262 remission, 124, 129, 139, 173, 179, 180, 184, 186, 187, 188, 198, 205, 222, 225, 257, 279 renal, xxi, 137, 283, 413, 416, 417, 420, 421, 426, 430, 479, 480, 481, 518, 540 renal disease, 416 renal failure, 421 renal function, 137, 420, 426, 430 renin, 156, 417 rent, 305 replication, 190, 202, 321 research design, 172 research funding, 41 researchers, xii, xxii, 26, 27, 33, 38, 54, 194, 278, 314, 342, 371, 424, 425, 429, 453, 459, 460, 502, 542, 564, 565, 568, 572, 574 reservoir, 438, 513, 515 residential, 16, 302, 310, 315, 317, 319, 494, 540, 541, 543, 554, 558 residues, 496 resilience, 456

617

resistance, xxi, 126, 130, 131, 136, 267, 413, 416, 423, 424, 425, 426, 428, 432, 445, 448, 449, 450, 485, 530, 531, 532, 537, 572 resistin, 425, 432, 433 resolution, 21, 22, 235, 436, 537 resources, xi, xxiii, 29, 79, 80, 95, 106, 118, 164, 170, 302, 327, 354, 363, 493, 497, 504, 550, 561 respiration, 64, 169 respiratory, xx, 5, 6, 7, 10, 13, 144, 145, 146, 149, 220, 369, 379, 381, 397, 398, 428, 548, 550 respiratory problems, 13 responsibilities, 29, 34 responsiveness, 298 restaurant, 21, 455 restaurants, 548, 550, 558, 559 restitution, 302 restructuring, 200 retardation, 48, 51, 59, 125, 542 retention, 210, 416, 417 retina, 156, 157 retinohypothalamic tract, 156, 157 retinoic acid, 532, 536 retinoids, xxiv, 529, 530, 536, 537 Retinol, 425 retinopathy, 510, 512, 516 Rett syndrome, xii, 3, 4, 7, 9, 22, 23, 24, 47, 48, 55, 56, 59, 60, 62, 63, 64, 65, 66, 67 re-victimization, 328 Reynolds, 294, 309, 362, 401 rheumatoid arthritis, 152, 258 rheumatologist, 256, 258, 273 rhinitis, 150, 164, 372, 390, 398, 402 rhinorrhea, 393 rhythm, xv, 155, 157, 158, 447, 514 rhythmicity, 156 rhythms, 156, 157, 158, 159, 160, 165, 166, 250 ribosomal, 285 rice, 6, 566 rigidity, 55 Rimonabant, 481 rings, 50 risk assessment, 334 risk behaviors, 143, 310, 336, 465 risk factors, xviii, xix, xxv, 36, 71, 82, 210, 301, 303, 304, 305, 308, 309, 310, 311, 313, 314, 315, 316, 317, 318, 323, 330, 333, 334, 339, 340, 344, 347, 348, 349, 350, 351, 353, 357, 359, 360, 361, 362, 364, 374, 380, 384, 400, 436, 465, 471, 477, 485, 486, 489, 511, 520, 571

Index

618

risks, xix, xxii, 143, 293, 303, 310, 312, 344, 347, 348, 349, 350, 351, 356, 357, 360, 417, 422, 429, 453, 459, 483, 508, 511, 517, 535, 540, 546, 548, 549, 550 rodents, 225, 285, 287, 289, 296, 299, 381, 386, 391 rods, 508, 515 rolling, 12, 107 romantic relationship, 456, 461, 505 Rome, 496 room temperature, 250 Rouleau, 385 routines, 243, 263, 555 Royal Society, 251 rubber, 19 rumination, 176, 181, 182, 187, 188, 196, 197, 202, 505 rural, 156, 303, 357, 360, 414, 549, 553, 554, 555, 558, 559, 564 rural areas, 414, 553, 554, 559, 564 rural communities, 558 Russia, 306, 477 Russian, 305

S sacrifice, 164 sadness, 37, 185, 196, 454, 457, 460 safety, xii, xv, xxiv, 25, 31, 40, 45, 70, 81, 148, 156, 167, 169, 184, 188, 189, 267, 292, 302, 308, 309, 401, 476, 477, 481, 483, 484, 517, 525, 545, 547, 548, 550, 551, 552, 554, 560, 561 SAI, 371, 372 saline, 369, 380, 381, 383 salt, 17, 521 salts, 292 sample, xiii, 69, 72, 73, 75, 81, 87, 125, 126, 128, 130, 131, 133, 135, 136, 144, 172, 176, 179, 180, 181, 182, 183, 186, 188, 200, 211, 214, 221, 230, 233, 245, 246, 247, 248, 280, 281, 282, 302, 317, 318, 324, 363, 364, 365, 370, 373, 394, 436, 464, 465, 472, 473, 495, 573 sampling, 248, 325 sanctions, 302, 341 SAS, 393 satisfaction, xxii, 37, 38, 99, 102, 453, 458, 460, 462, 490, 556 saturated fat, 522, 524 SBA, 526 SBP, 574 scabies, 535 scaling, 243

scheduling, 331 schemas, 195, 198 schizoaffective disorder, 280, 291 schizophrenia, 153, 178, 291, 325, 326, 370, 380, 400 schizophrenic patients, 278 Schmid, 558 scholarship, 82 school failure, 39, 359 school performance, 355, 358, 360, 469 school work, 263 science, 24, 27, 87 scientists, 257, 564 sclerosis, 56, 64 SCN, 157, 158, 159 scoliosis, 15, 48, 57, 61, 62, 66 scores, xvi, xx, 88, 98, 99, 101, 131, 133, 144, 145, 148, 152, 173, 175, 180, 181, 183, 186, 187, 201, 208, 211, 212, 213, 214, 222, 224, 236, 306, 309, 354, 380, 382, 390, 391, 393, 394, 396, 398, 400, 574 search, xviii, xxii, 35, 86, 143, 171, 172, 261, 272, 301, 303, 333, 342, 349, 350, 459, 475, 503, 572 search terms, 171, 342 searches, xv, 167, 171, 172 Seasonal Affective Disorder (SAD), xvi, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 208, 210, 219, 220, 222, 223, 224, 225, 226, 227, 235, 252, 392, 393, 395, 401 seasonal pattern, 250, 371, 375, 380, 399 seasonality, xvi, 152, 219, 223, 231, 250, 373, 375, 376, 377, 380, 386, 391, 400 Seattle, 548 secret, 265 secretion, 129, 130, 131, 137, 146, 148, 157, 397, 417, 428, 446, 447, 450 secular, 100, 102, 103 secularization, 341 security, 308, 325, 329, 333 sedative, 305 sedatives, 209 sedentary, 124, 127, 128, 136, 406, 411, 415, 459, 465, 520, 523, 546, 547, 548, 549, 557 sedentary behavior, 124, 127, 128, 136, 459, 465, 547, 548 sedentary lifestyle, 406, 523, 546, 547 seed, 215 seeds, 476 segregation, 328, 329, 333 seizure, 283

Index seizures, 17, 48, 67, 149 selecting, 50 selective serotonin reuptake inhibitor, 137, 286, 312, 482, 494 selectivity, 296 self, xx, 53, 92, 106, 130, 133, 145, 170, 221, 226, 324, 325, 390, 407, 458, 466, 469, 496, 498, 502 self esteem, 130, 353, 354, 457, 466, 499, 501, 502, 503, 504 self image, xxii, 130, 453, 457, 458, 500, 503 self monitoring, 53 self worth, 501, 504 self-confidence, 500 self-consciousness, 456 self-control, 457 self-efficacy, 363 self-esteem, xxii, 37, 53, 128, 130, 137, 202, 314, 329, 359, 427, 456, 457, 458, 460, 463, 466, 467, 468, 470, 472, 473, 489, 501, 502 self-identity, 37 self-image, 456, 460, 466, 501, 503, 522 self-mutilation, 490 self-perceptions, 458 self-reflection, 265 self-regulation, 169 self-report, xviii, 88, 95, 137, 139, 144, 146, 197, 309, 310, 311, 323, 324, 325, 326, 330, 374, 391, 393, 396, 398, 468 self-reports, 139, 396 self-worth, 457 SEM, 243, 251 sensation, 12, 16, 169 sensations, 13, 169, 170, 171, 185, 500, 501 sensitivity, 7, 11, 14, 16, 17, 19, 22, 125, 127, 128, 131, 136, 149, 214, 226, 270, 288, 289, 298, 309, 310, 348, 372, 391, 407, 425, 426, 428, 432, 445, 446, 449, 479, 480 sensitization, xix, xx, 146, 149, 368, 369, 372, 373, 374, 390, 391, 392, 396, 398 sensory experience, 500 sentences, 324, 328 sentencing, 329 separation, 37, 61, 134, 210, 257, 259, 261, 270, 305, 314 sequelae, 152, 422 series, 22, 67, 109, 114, 237, 238, 242, 243, 252, 264, 321, 371, 419 serotonergic, xxii, 283, 286, 288, 289, 290, 297, 299, 300, 349, 362, 475, 479, 482

619

serotonin, xviii, 123, 127, 132, 137, 138, 139, 160, 209, 214, 217, 230, 231, 249, 260, 277, 286, 287, 288, 289, 292, 297, 298, 299, 300, 312, 334, 396, 478, 482, 494 serotonin syndrome, 288, 299 sertraline, 482 serum, 138, 209, 210, 214, 216, 217, 218, 283, 331, 369, 372, 392, 397, 426, 430, 431, 432, 516 service provider, 99 service quality, 31 services, xiv, 28, 30, 31, 34, 35, 38, 39, 40, 41, 42, 43, 72, 87, 99, 100, 102, 105, 106, 109, 117, 118, 302, 310, 311, 316, 317, 354, 410, 411, 427, 454, 549, 558 SES, xiii, 70, 79, 80, 81, 82, 356, 454 settlements, 71, 72 severe asthma, 143, 146 severe stress, 330 severity, xvii, 4, 7, 9, 36, 127, 132, 142, 144, 146, 151, 158, 173, 174, 179, 194, 196, 198, 201, 202, 204, 210, 230, 250, 255, 257, 279, 282, 313, 326, 336, 355, 374, 375, 387, 393, 396, 399, 418, 523 sex, 95, 101, 125, 234, 279, 328, 329, 336, 362, 375, 399, 425, 431, 444, 445, 459, 471, 498, 500, 501, 540, 574 sex steroid, 431 sexism, 258 sexual abuse, xviii, 34, 261, 264, 265, 301, 304, 307, 313, 326, 328, 330, 340, 351, 352, 355, 358, 489, 496, 522 sexual activities, 503 sexual activity, 500, 503 sexual assault, 329 sexual behavior, 501 sexual contact, 329 sexual development, xxiii, 497, 498, 499 sexual dysfunction, 505 sexual harassment, 501 sexual intercourse, 503 sexual orientation, 348 sexuality, xxiii, 355, 497, 498, 499, 500, 501, 502, 503, 504, 505, 508 sexually transmitted diseases (STD), 499, 509, 510 shame, 130, 505 shape, 99, 335, 456, 458, 467, 500, 564 shaping, 102, 103, 569 sharing, 30, 34, 98, 273, 348 shelter, 70 shocks, 248 short period, 57

620

Index

shortness of breath, 149, 264, 267 short-term, xxii, 37, 135, 162, 164, 287, 298, 299, 302, 303, 307, 313, 331, 475, 476, 477, 482, 555 shoulder, 12, 18, 20, 532, 553 shoulders, 7, 11, 14 shunts, 512 siblings, 72, 73, 77, 80, 178, 185, 217, 271, 542 Sibutramine, 478, 479, 482, 484, 485 sickle cell anemia, 510, 514 side effects, xviii, xxiii, 131, 148, 149, 160, 161, 162, 184, 187, 277, 283, 290, 419, 421, 428, 429, 446, 459, 475, 477, 478, 480, 483, 492, 513, 514 sign, 209, 457 signal transduction, 286, 296, 349 signaling, 196, 197, 284, 285, 295, 296, 297, 530 signaling pathway, 283, 284, 285, 286, 296 signaling pathways, 284, 285 signalling, 295 signals, xxiv, 225, 258, 262, 530, 545, 552, 554 signs, 37, 60, 145, 171, 283, 363, 426, 460, 467, 490, 493, 532 similarity, 98 simple goiter, 510 simulation, 159, 243 simulations, 243, 245 Singapore, 346 SIS, 372 sites, 100, 174, 286, 287, 297, 298, 354, 392, 489 skeletal muscle, 230, 416, 428, 480 skewness, 211 skills, xiii, 8, 9, 20, 22, 26, 36, 48, 49, 50, 52, 54, 55, 65, 85, 86, 87, 88, 92, 93, 94, 95, 96, 169, 170, 177, 179, 182, 184, 200, 203, 263, 264, 311, 334, 345, 358, 365, 457, 492, 501, 503, 569 skills base, 95 skin, xxiv, 160, 197, 258, 283, 376, 377, 387, 396, 397, 399, 426, 427, 511, 529, 530, 531, 532, 533, 534, 535, 536, 537 skin cancer, 160 skin conductance, 197 skin conductance responses, 197 skin disorders, 387 skin tags, 426 sleep, xv, xxiv, 20, 39, 51, 53, 61, 124, 125, 126, 127, 129, 131, 132, 135, 136, 141, 142, 147, 151, 152, 155, 156, 158, 159, 160, 161, 162, 163, 164, 165, 166, 177, 189, 208, 214, 235, 248, 249, 260, 262, 263, 384, 396, 417, 427, 476, 478, 519, 522, 523, 524, 527 sleep apnea, xxiv, 126, 147, 417, 519, 522, 523, 524

sleep deprivation, xv, 126, 127, 129, 155, 162, 164 sleep disorders, 156, 160, 165 sleep disturbance, 126, 151, 152, 166, 214, 260 sleep-wake cycle, 165 sleeve gastrectomy, 441 Slovakia, 573 smiles, 61 smokers, 220 smoking, 267, 269, 459, 464, 481, 511 smoking cessation, 481 smooth muscle, 147, 230 smoothness, 22 SMR, 107, 541 snoring, 427 SNS, 416, 417 soccer, 407 social attitudes, 98 social capital, 414 social care, 116 social category, 567 social class, 174, 559 social cohesion, 344 social competence, 37 social context, 345, 560 social development, 464, 465, 547, 572 social environment, 302, 345 social factors, 302, 343, 354, 522 social group, 348 social institutions, 353 social isolation, 128, 194, 454, 467 social network, 340, 348 social norms, 334 social phobia, 234 social policy, 120, 327 social problems, 38 social relations, 469, 502, 503 social relationships, 502, 503 social services, 1, 32, 106, 118, 302 social situations, 210 social skills, 36, 457, 501, 503 social support, 302, 351, 353, 359, 362, 363, 364, 365 social withdrawal, 60 social work, 44, 45, 118, 431, 492 social workers, 118 socialization, 52 society, xi, xii, xiii, 28, 29, 33, 43, 70, 79, 82, 98, 99, 100, 102, 103, 106, 117

Index socioeconomic, 70, 71, 81, 124, 127, 132, 136, 342, 343, 351, 356, 360, 380, 385, 420, 440, 459, 461, 491, 520, 521, 548, 549, 550, 551, 555, 559, 564 socioeconomic status, 81, 127, 132, 136, 351, 440, 459, 520, 548, 549, 551, 555, 559, 564 sociological, 340, 343, 345, 376 sociology, 345 sodium, xxi, 210, 299, 413, 416, 417, 422 soft drinks, 521, 523 soft palate, 6 software, 72, 87, 88, 94, 95, 210, 239, 393 solutions, 262, 271, 272, 381, 557 somatic complaints, 355, 360 somatic symptoms, 357 somatization, 257, 260 somatostatin, 482 somnolence, 126 sounds, 8, 11, 18, 52, 61 South Africa, 342, 346, 375, 477 South Carolina, 517, 560, 561 Soviet Union, 100, 342 soy, 11 Spain, 109, 110, 111, 112, 113, 114, 115, 116, 117 spastic, 54, 65 spasticity, 12, 13, 49, 55, 61, 62, 65 spatial, xxiv, 158, 165, 546, 550, 558 spatial memory, 159 species, 476 specific heat, 42 specificity, xviii, 153, 180, 183, 294, 309, 310, 323, 334, 372, 392, 426 spectral analysis, 231 spectroscopic methods, 294 spectrum, 160, 168, 231, 248, 291, 329, 333, 384, 445, 446 speculation, 384 speech, 4, 12, 22, 23, 58, 59, 63, 265 speed, xxiv, 4, 7, 50, 63, 156, 545, 553, 555 spheres, 265 spina bifida, 56 spine, 15, 56 spiritual, 27, 28, 360 spirituality, 348, 354, 359, 360 spirometry, 144 sports, xxi, 405, 406, 407, 408, 409, 411, 484, 542, 547 sputum, 146 Sri Lanka, 343 SRIs, 286 SRS, 310

621

SSI, 309, 319 stability, 11, 12, 13, 55, 57, 263, 296, 372 stabilization, 12, 13, 14, 18, 295, 298, 523 stabilizers, 148, 293, 295, 296, 328, 331 stable asthma, 151 staffing, 314 stages, xxiii, 57, 127, 147, 186, 490, 497, 498 STAI, 176, 178, 182 standard deviation, 211, 393, 414 standard error, 383 standardization, 483 standards, xxii, 29, 30, 32, 40, 42, 210, 315, 316, 325, 361, 449, 453, 457, 460 starch, 387 starch granules, 387 starches, 521 starvation, 459, 464, 496 statistical analysis, 182 Statistical Package for the Social Sciences (SPSS), 72, 88, 96, 566 statistics, 107, 108, 117, 119, 229, 241, 245, 246, 316, 327, 328, 333, 340, 342, 558 steatorrhea, 480 stenosis, 437, 439 stereotypes, 66, 460, 462, 467 stereotypical, 9, 15, 19, 57, 60, 62 steroid, 148, 431, 432, 515, 532, 533, 534, 535 steroid cream, 534 steroid creams, 534 steroid hormone, 432 steroids, 144, 147, 532, 533, 535 stiffness, 417 stigma, xix, xxii, 99, 127, 339, 344, 356, 358, 361, 374, 455, 463 stigmatization, 462, 467, 470 stigmatized, 309, 466, 555 stimulant, 210, 312, 325 Stimuli, vi, 219, 221 stimulus, 94, 159, 197, 258 stochastic, 233 stomach, 7, 37, 258, 260, 262, 264, 438, 439, 494 storage, 86 strain, 271, 381 strains, 387 strategic, 299 strategies, xiii, 20, 21, 40, 41, 64, 70, 82, 119, 185, 274, 331, 340, 361, 446, 467, 470, 483, 522, 523, 524, 554 strawberries, 11 strength, 56, 61, 66, 282, 345, 407, 408, 409, 534

622

Index

stress, xv, xx, 37, 39, 45, 130, 131, 132, 134, 136, 138, 141, 146, 150, 167, 168, 171, 172, 189, 190, 191, 195, 196, 203, 214, 215, 230, 250, 256, 259, 260, 261, 262, 263, 264, 266, 268, 269, 270, 272, 274, 303, 307, 312, 314, 318, 321, 348, 351, 352, 355, 356, 363, 365, 379, 380, 381, 382, 383, 384, 385, 386, 387, 397, 428, 481, 532, 547, 550, 556, 564 stressful life events, 359 stressors, 248, 256, 261, 262, 264, 266, 306, 329, 332, 340, 349, 357, 384, 387, 427 stretching, 263, 530, 532 striae, xxiv, 529, 530, 532, 533, 535, 537 striatum, 250, 287 stroke, 424 structural equation model, 235, 240 students, xiii, xiv, xxiv, xxv, 50, 58, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 133, 143, 146, 306, 318, 350, 352, 354, 355, 357, 358, 359, 363, 364, 365, 369, 410, 465, 517, 540, 545, 546, 547, 550, 551, 554, 555, 563, 565, 567, 568, 569, 573 subacute, 510, 516 subarachnoid hemorrhage, 511 subcutaneous tissue, 531 subgroups, 247, 353, 495, 550 subjective, 60, 161, 162, 168, 169, 181, 185, 197, 258, 261, 262 subjective experience, 169, 258, 262 subjectivity, 271 substance abuse, xviii, 34, 40, 133, 151, 210, 233, 251, 292, 301, 304, 305, 310, 311, 318, 320, 324, 325, 327, 328, 329, 348, 351, 352, 353, 358, 359, 360, 373, 374, 380, 392, 438, 465, 479, 489 substance disorders, 327 substance use, 291, 304, 305, 308, 311, 313, 316, 324, 326, 327, 328, 329, 330, 334, 371, 374, 465 substances, 6, 328, 352, 369, 397, 490 substitution, 521 substrates, 296, 330 suburban, 550, 552, 553, 555, 559 suburbs, 553 suffering, 11, 278, 280, 340, 380, 484 sugar, 17, 521, 523, 524 sugars, 521, 522, 523 suicidal behavior, xviii, xx, 191, 251, 278, 279, 280, 281, 282, 289, 291, 293, 294, 301, 302, 304, 306, 307, 308, 309, 310, 311, 314, 316, 317, 318, 321, 334, 338, 340, 341, 346, 349, 352, 353, 354, 355,

356, 357, 359, 360, 362, 363, 365, 379, 380, 381, 384, 385, 490 suicidal ideation, xix, 132, 142, 143, 150, 173, 175, 178, 180, 181, 185, 186, 188, 278, 282, 291, 292, 302, 303, 304, 305, 307, 308, 313, 314, 318, 321, 334, 340, 341, 347, 349, 350, 351, 353, 354, 356, 357, 359, 362, 363, 364, 365, 385, 391, 400 suicide attempters, 297, 377, 386 suicide attempts, xx, 149, 150, 186, 278, 279, 280, 281, 282, 290, 292, 293, 301, 302, 304, 305, 307, 309, 318, 319, 321, 329, 332, 333, 334, 340, 351, 352, 353, 354, 355, 359, 361, 362, 363, 366, 368, 369, 370, 371, 372, 373, 374, 385, 399, 400, 465 suicide rate, xix, 149, 278, 303, 304, 308, 311, 312, 316, 331, 333, 334, 339, 340, 341, 342, 343, 344, 346, 348, 349, 351, 355, 356, 360, 369, 376, 380 sulfate, 189, 425 sulfonylurea, 480 summer, 129, 195, 196, 197, 198, 202, 205, 227, 235, 331, 369, 523 Sun, 320 sunlight, 160, 231 superego, 270 superiority, 282 supervised release, 314 supervision, 72, 80, 278, 313, 314, 331, 409, 492 supplemental, 438, 513 supplements, 10, 430, 476, 483, 523 supply, 51 suppression, 43, 160, 165, 208, 216, 447 suprachiasmatic, 156 suprachiasmatic nuclei, 156 suprachiasmatic nuclei (SCN), 156 Supreme Court, 325 surface area, 447, 530 Surgeon General, 124, 465, 547, 556 surgeons, 460 surgeries, 512 surgery, xxi, 56, 411, 422, 429, 433, 435, 436, 438, 439, 440, 441, 459, 509, 510, 522 surgical, 66, 429, 430, 436, 438, 440, 484, 540 surgical intervention, 66 surprise, 118 surveillance, 318, 364, 438, 471, 555 survey design, 98 survival, 20, 285, 296, 343, 559 surviving, 278 survivors, 540 susceptibility, xx, 280, 379, 381, 454 swallowing, 5, 6, 7, 9, 10, 11, 16, 20

Index sweat, 530 Sweden, 22, 24, 64, 65, 392, 573, 579 sweets, 521, 522, 542 switching, 169 Switzerland, 24, 414 symmetry, 57, 66 sympathetic, xxi, 7, 53, 131, 146, 397, 413, 416, 417, 422, 430 sympathetic nervous system, 146, 416 symptom, xv, xvii, xx, 37, 125, 126, 127, 129, 141, 144, 148, 149, 151, 152, 153, 161, 194, 198, 202, 217, 255, 257, 267, 390, 395, 398, 468 symptomatic treatment, 162 synapse, 287 synaptic plasticity, 285 synaptic transmission, 285 synchronization, 157 syndrome, xii, xvii, xxiv, 3, 4, 7, 9, 22, 23, 24, 47, 48, 51, 55, 56, 59, 60, 62, 63, 64, 65, 66, 67, 119, 126, 156, 205, 226, 255, 258, 260, 272, 273, 288, 289, 299, 398, 424, 427, 430, 431, 432, 433, 445, 447, 480, 485, 529, 530, 532, 535, 537, 538, 542 synergistic, 130 synthesis, 132, 214, 216, 287, 298, 396, 446, 558 systemic lupus erythematosus, 258 systems, xi, xii, 14, 30, 33, 34, 35, 41, 57, 102, 127, 162, 232, 239, 243, 253, 283, 286, 299, 309, 310, 315, 322, 327, 329, 331, 335, 349, 397, 415, 417, 418, 430, 444, 448

T T cell, 145, 216, 402 T lymphocytes, 145 tachycardia, 148, 162, 420, 535 Tanzania, 94 target population, 565 targets, 71, 126, 130, 134, 215, 283, 284, 286, 290, 296, 398, 467, 564 task force, 436 taste, 16, 136, 521, 524, 526, 568 tau, 238 tea, 162, 567 teachers, 64, 65, 101, 118, 353, 360, 361, 456, 489, 565, 567, 569 teaching, 10, 86, 87, 93, 96, 102, 198, 504 team sports, 407 technician, 158 technological advancement, 94 technology, xiii, 85, 86, 87, 95, 96, 128, 511 Technology Assessment, 215

623

teenagers, 263, 364, 427, 429, 441, 468, 470, 514 teens, xix, 304, 312, 347, 349, 355, 359, 362, 429, 431, 459, 473 teeth, 11, 12, 17 Tel Aviv, 22, 64, 69, 97, 579 telemedicine, 86 telephone, 145, 392 television, 414, 458, 520, 521, 523, 525, 526, 527, 550, 567, 568, 570 television commercial, 567, 568 television viewing, 414, 523, 525, 527 telomerase, 259 telomeres, 259 temperament, 208, 215, 330, 456 temperature, 12, 19, 156, 157, 158, 159, 160, 164, 210, 221, 229, 230, 231, 233, 235, 239, 244, 245, 246, 247, 249, 331, 381 temporal, 158, 165, 194, 203, 369, 426 temporal lobe, 158, 165 tendons, 258 Tennessee, 414 tension, 260 teratogenic, 283, 420, 513 terminally ill, 346 testimony, 322 testosterone, 156, 425, 426, 428, 429, 430, 447, 532 tetracycline, 531, 536 Texas, 219, 336, 414, 421, 545, 547, 549, 559 Thai, 564, 567, 570 Thailand, 563, 565, 569, 570 theory, 38, 80, 196, 202, 203, 204, 241, 250, 263, 274, 340, 375, 399, 503, 541 therapeutic, xii, 10, 16, 21, 31, 47, 48, 49, 50, 54, 58, 59, 61, 62, 63, 64, 66 therapeutic agents, 446 therapeutic approaches, xii, 31, 47, 48, 62 therapeutic benefits, 48, 49, 201, 283 therapeutic change, 183 therapeutic goal, 10, 21, 49, 50 therapeutic practice, 49 therapeutic relationship, 187, 268, 491 therapeutics, 295, 299 therapists, 5, 11, 20, 22, 58, 64, 65, 268, 492, 493 thiazide, 419, 420, 422 thiazide diuretics, 420 thiazolidinediones, 433 thinking, xvi, 148, 167, 168, 178, 180, 186, 188, 265, 266, 309, 312, 319, 359, 495 Thomson, 23, 216 threat, 302

624

Index

threatening, 262, 271 threats, 79, 248, 271, 329, 332, 333 three-dimensional, 50, 295 threshold, 127, 136, 201, 226, 372, 391, 427, 551, 554 throat, 269, 333, 393 thromboembolic, 512, 517 thromboembolism, 512, 517 thrombophlebitis, 511, 514 thrombosis, xxiii, 507, 510, 511, 517 thrombotic, 424, 515 thyroid, 426, 430, 445, 447, 490 time consuming, 426 time frame, 314 time periods, 211, 213 time series, 237, 238, 243, 252 timing, xx, 7, 19, 94, 134, 158, 160, 164, 202, 230, 368, 369, 372, 373, 374, 393 tinea corporis, 535 tinea cruris, 535 tinea pedis, 535 tinea versicolor, 535 tissue, 12, 130, 208, 214, 257, 258, 396, 408, 409, 416, 417, 418, 428, 447, 448, 480, 482, 489, 509, 531, 532 TNF, 214, 369, 384, 391, 425, 432 TNF-alpha, 369, 432 TNF-α, 384 tobacco, 464 tobacco smoking, 464 toddlers, 82 Tokyo, 161, 497 tolerance, 54, 208, 341, 426, 430, 445, 449 tomato, 11 tonic, 298 Topiramate, 482 total cholesterol, 428 totalitarian, 344 tourism, xiv, 97, 98, 99, 100, 101, 102 tourist, 98, 99, 101, 102 toxic, 209, 494 toxic effect, 494 toxicity, 281, 283, 331, 428 toxin, 284, 295 toxins, 548 toys, 60 tracking, 11 trade, 428 tradition, 168, 169, 268, 341 traditional gender role, 355

traffic, 546, 547, 548, 550, 551, 552, 554, 555 training, xiii, xviii, 10, 20, 54, 56, 62, 66, 85, 87, 88, 89, 90, 91, 93, 94, 95, 168, 174, 176, 181, 182, 183, 184, 186, 187, 190, 263, 301, 308, 333, 335, 364, 408, 409, 411, 468 trait anxiety, 182, 187, 188 traits, xx, 129, 380, 381, 384, 385, 390, 398 trajectory, 125, 187, 232, 233, 236, 241, 245 transatlantic flights, 161 transcript, 296 transcription, 157, 285, 286, 369 transcription factor, 286 transcription factors, 286 transduction, 295 transfer, 6, 12, 21, 37 transference, 62 transformation, 274 transgenic, 530 transgenic mice, 530 transition, 70, 71, 238, 247, 431 transitions, 161 translation, 37, 157, 285 transmission, 37, 285, 286, 288, 290, 329 transparency, 30 transparent, 30, 515 transplant, 190 transplant recipients, 190 transplantation, 131, 138, 168 transport, 100, 415, 428, 553, 558, 560 transportation, xxiv, 40, 80, 98, 545, 546, 547, 548, 551, 554, 555, 557, 558, 560, 561 transportation infrastructure, xxiv, 545 trauma, xiii, 39, 45, 69, 129, 131, 208, 259, 260, 271, 311, 340, 494, 499 traumatic experiences, 304 travel, xv, 103, 155, 156, 158, 159, 160, 161, 162, 163, 164, 166, 546, 547, 551, 553, 554, 556, 560, 561 treatment programs, 40 treatment-resistant, 512 tree cover, 552 trees, 197, 369, 392 tremor, 148, 288 trend, xxiv, 40, 80, 114, 116, 181, 182, 335, 358, 436, 465, 519, 539, 546, 551 TRF, 569 trial, xxi, 145, 151, 152, 176, 179, 180, 189, 190, 198, 200, 202, 205, 216, 226, 291, 311, 312, 320, 324, 334, 407, 410, 435, 479, 480, 484, 485, 527, 557

Index tribal, 359 tribes, 70, 359 trichloroacetic acid, 210 tricyclic antidepressant, 312 tricyclic antidepressants, 312 triggers, xix, 196, 368, 416 triglycerides, 407, 425, 426, 481, 512 truancy, 313 truism, 29 trust, 26, 29, 52, 268, 269, 468 tryptophan, xvi, 132, 138, 139, 208, 209, 210, 214, 216, 217, 218, 231, 287, 289, 298, 300, 396 Tryptophan, vi, xvi, 207, 208, 209, 212, 213, 217, 218, 249, 287 TSH, 447 tuberculosis, 510 tubular, xxi, 283, 413, 416 tumor, 131, 384, 426 tumor necrosis factor, 131, 384 tumors, 509 turnover, 16, 20, 298, 307, 309, 314 tutoring, 103, 311 type 2 diabetes, xxii, 124, 131, 420, 424, 428, 433, 443, 445, 449, 480, 522, 526, 530, 531, 532, 535, 547, 574 type 2 diabetes mellitus, xxii, 420, 428, 443, 445, 480, 530, 532, 535 type II diabetes, xxiii, 519, 520, 521 tyrosine, 210, 298, 425, 428

U ultrasonography, 66 ultrasound, 426 ultraviolet, 160 uncertainty, 51, 147, 411 undergraduate, xiv, 32, 42, 94, 96, 97, 99, 102 undergraduates, 99, 103 underlying mechanisms, xv, 123, 124, 203 underreported, 282 unemployment, 358 unhappiness, 195 UNICEF, 106, 117, 119 uniform, 40, 42, 202, 360 uninsured, 331 United Kingdom, 38, 105, 343, 344, 541, 542 United Nations, 120 university students, 102 urban areas, 303, 454, 520, 564 urban centers, 414, 554 urbanization, 341

625

urbanized, 342, 548 uric acid, 419 urine, 447, 448 US Department of Health and Human Services, 461, 504, 558 USDA, 521, 522 users, 86, 96 Utah, 346, 414

V vaginitis, 513, 535 validation, 103, 203, 217, 261 validity, 39, 309, 310, 319, 468 valproic acid, 278, 280, 282, 296, 297 values, xix, 9, 29, 30, 42, 93, 100, 102, 116, 172, 212, 232, 235, 236, 237, 238, 240, 243, 244, 245, 246, 247, 347, 348, 356, 357, 359, 360, 361, 372, 373, 383, 394, 421, 444, 456, 493, 541, 557, 572 variability, 159, 202, 232, 243, 247, 248, 252, 340, 462 variable, 43, 87, 142, 232, 233, 235, 236, 238, 241, 242, 314 variables, xiii, 69, 73, 88, 93, 100, 101, 131, 179, 205, 211, 230, 232, 233, 235, 236, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 252, 304, 314, 340, 342, 351, 372, 393, 496, 499, 551, 554, 556 variance, 231, 237, 238, 239, 243, 245, 307, 325, 326, 382 variation, 156, 230, 249, 250, 251, 290, 297, 313, 315, 335, 340, 343, 374, 375, 399, 400, 472, 564 variety of domains, 468 vascular disease, 416, 522 vascular wall, 417 vasculature, 416 vasculogenesis, 283 vasoconstriction, 416, 417 vasodilation, 416 vasopressin, 260 vegetable oil, 534 vegetables, 454, 521, 522, 523, 524, 548, 564 vein, 510 velocity, 232 Venezuela, 495 ventilation, 331 ventricular tachycardia, 535 ventrolateral prefrontal cortex, 297 venue, 267, 358, 568 verapamil, 479 Vermont, 65, 193

626

Index

versatility, 49 vertebrae, 6 vertebrates, 160 vertigo, 283 vestibular system, 53, 61 victimization, 328, 329, 332, 456, 461, 505, 560 victims, 40, 44, 109, 149, 152, 153, 286, 292, 297, 300, 302, 306, 308, 313, 351, 362, 369, 377, 386, 391, 397, 401, 457 Victoria, 44 video games, 128, 454 viewing patterns, 525 village, 23 violence, xii, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 108, 274, 308, 310, 313, 314, 328, 329, 333, 351, 359, 364, 499, 550, 560 violent, xiv, 105, 106, 107, 108, 109, 113, 115, 117, 118, 178, 185, 251, 261, 269, 297, 302, 306, 321, 325, 328, 329, 332, 334, 343, 344, 349, 362, 376, 380, 386, 549 violent behavior, 178, 185, 306, 329 violent crime, 332, 549 violent crimes, 332 violent offenders, 297 viral hepatitis, 400, 510 viral infection, 146 virus, 139, 190, 261, 330 viruses, 248 viscera, 258 vision, 21, 28, 42, 283, 341 visual field, 21 vitamin B1, 573, 575 vitamin B12, 573, 575 vitamin B12 deficiency, 573 vitamin D, 448, 451, 530 vitamin K, 480 vitamins, 438, 480, 523 VLDL, 428 vocational, 310 voice, 15, 27, 269, 309, 315, 319, 426 volunteers, 259 vomiting, 6, 7, 19, 283, 455, 488, 490, 494, 515 vulnerability, xv, xvi, 124, 130, 141, 149, 155, 163, 167, 186, 188, 193, 194, 195, 196, 197, 200, 202, 203, 205, 206, 230, 247, 306, 315, 334, 353, 465, 467 vulnerability to depression, xvi, 130, 186, 193, 195, 196, 206, 353

W waking, 51, 61, 163, 262 Wales, vi, xiv, 105, 107, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 342 walking, xxiv, 50, 54, 61, 65, 164, 170, 184, 267, 269, 271, 272, 406, 408, 409, 455, 520, 523, 545, 546, 547, 548, 550, 551, 552, 553, 554, 555, 557, 558, 560, 561 war, 109 warfarin, 480 Warsaw, 109 Washington, 22, 64, 119, 120 water, 7, 19, 59, 61, 158, 249, 331, 381, 408, 409, 521, 523, 531 wavelengths, 160, 163, 210 weakness, 283 wealth, 102 weapons, 313 web, 64, 86, 459 web-based, 86 websites, 40 weight changes, 133, 134 weight control, xxi, 131, 413, 459, 491 weight gain, 17, 125, 127, 128, 129, 133, 134, 208, 214, 283, 290, 407, 415, 429, 460, 465, 468, 514, 515, 516, 520, 521, 527, 530, 573, 575 weight loss, xxii, 125, 129, 130, 133, 134, 136, 406, 418, 422, 429, 436, 438, 440, 441, 446, 448, 451, 453, 454, 457, 459, 460, 463, 467, 472, 475, 476, 477, 478, 480, 482, 483, 484, 485, 488, 490, 491, 493, 495, 521, 522, 523, 527, 531, 573 weight management, 22, 406, 410, 436, 449, 455, 469, 470, 480, 572 weight reduction, 406, 419, 421, 425, 432, 476, 493, 527 weight status, 134, 448, 472 Weinberg, 135, 320 welfare, xi, 34, 35, 39, 40, 45, 46, 102, 109, 116, 120, 317, 358, 579 welfare reform, 46 welfare state, 120 welfare system, 102 well-being, xi, 26, 35, 137, 152, 168, 190, 430, 461, 462, 527 wellness, 465 West Bank, 71 Western countries, 26, 34, 106, 522 Western culture, 457, 467 Western societies, 118

Index wheat, 11 wheelchair, 265, 269 wheezing, 145, 149 whole grain, 521, 522, 524 wind, 230, 374 windows, 164, 371 wine, 526 winter, xvi, xvii, 129, 132, 134, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 205, 219, 227, 392 wintertime, 197, 200 wisdom, 189 withdrawal, 39, 60, 293, 325, 335, 485, 515 women, xi, xvi, xx, 23, 34, 35, 36, 38, 39, 40, 41, 44, 45, 46, 66, 133, 153, 159, 190, 195, 196, 197, 208, 209, 210, 211, 214, 215, 216, 218, 226, 227, 258, 278, 283, 325, 326, 330, 335, 336, 337, 349, 363, 364, 368, 375, 379, 380, 386, 387, 390, 396, 399, 414, 415, 417, 418, 425, 428, 431, 432, 433, 467, 472, 481, 496, 509, 511, 512, 516, 517, 518, 532, 541, 542, 558, 559 word processing, 86, 88 workers, 23, 99, 118, 328, 335, 336 World Health Organization (WHO), xiv, 31, 105, 107, 108, 116, 119, 331, 337, 340, 342, 343, 345, 410, 414, 426, 430, 509, 511, 517, 542, 558, 564 worldview, 356 wound infection, 437, 439

X X chromosome, 22, 48, 63 X-linked, 22, 62 X-ray, 5, 66

Y yeast, 295, 512, 516 yield, xii, 3, 52, 56, 374, 459, 523 young adults, 126, 133, 143, 151, 304, 317, 361, 399, 471 young men, 136, 159, 432 young women, 432, 499, 518 younger children, xxiii, 36, 41, 125, 468, 519, 523

Z Zeitgeber, 157 Zen, 492 Zoloft, 482

627