The Spectrum of Psychotic Disorders: Neurobiology, Etiology & Pathogenesis

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The Spectrum of Psychotic Disorders

The spectrum of psychotic disorders encompasses as many as 25 different etiologies, ranging from the primary psychoses through those secondary to medical conditions, drugs and medications, and sensory impairments. This book provides a one-stop, comprehensive review of these disorders, and gives quick comparisons for diagnostic decision-making to help with difficult differential diagnoses. Every chapter is uniformly structured to show comparisons between each disorder of presentation, course, and underlying neuropathology. Evidence for each etiology is also rated, indicating the confidence level the reader can place in the current findings. The international team of authors also examines data supporting a unitary neurobiological model of psychosis and the hypothesis that psychosis is a neurobiological syndrome similar to aphasia or apraxia. This book represents a paradigm shift in understanding, classifying, and diagnosing these disorders, providing directions for future research and treatment. It will be of great interest to psychiatrists and neuroscientists alike. Daryl Fujii is a Clinical Neuropsychologist based at the Hawaii State Hospital. Iqbal Ahmed is Professor of Psychiatry at the John A. Burns School of Medicine at the

University of Hawaii.

The Spectrum of Psychotic Disorders Neurobiology, Etiology, and Pathogenesis

Edited by

Daryl Fujii and Iqbal Ahmed

CAMBRIDGE UNIVERSITY PRESS

Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521850568 © Cambridge University Press 2007 This publication is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2007 eBook (EBL) ISBN-13 978-0-511-29480-8 ISBN-10 0-511-29480-8 eBook (EBL) ISBN-13 ISBN-10

hardback 978-0-521-85056-8 hardback 0-521-85056-8

Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this publication to provide accurate and up-todate information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this publication. Readers are strongly advised to pay careful attention to information provided by the manufacture of any drugs or equipment that they plan to use.

Contents

List of Contributors Preface Acknowledgements

Part I 1

ix xiii xv

Introduction Introduction: Is Psychosis a Neurobiological Syndrome?

3

Daryl E. Fujii and Iqbal Ahmed

Part II 2

Primary Psychotic Disorders Schizophrenia

15

Gerald Goldstein, Daniel N. Allen, and Gretchen L. Haas

3

Schizophrenia among Children and Adolescents

39

Jason Schiffman

4

Late-Life Schizophrenia

59

Katerine Osatuke, John W. Kasckow, and Somaia Mohamed

5

Schizoaffective Disorder

78

Daniel J. Abrams and David B. Arciniegas

6

Schizophreniform Disorder and Brief Psychotic Disorder: The Acute and Transient Psychoses

96

Andreas Marneros and Frank Pillmann

7

Delusional Disorder Theo Manschreck

v

116

vi

Contents

Part III

Mood Disorders

8

Psychosis in Bipolar Disorder

137

Deborah Yurgelun-Todd

9

Psychosis in Major Depression

156

Eric G. Smith, Philip R. Burke, Jessica E. Grogan, Susan E. Fratoni, Chelsea S. Wogsland, and Anthony J. Rothschild

Part IV

Neurodevelopmental and Genetic Disorders

10

Psychosis with Intellectual Disabilities

197

Colin P. Hemmings and Nick Bouras

11

Velo-Cardio-Facial Syndrome

218

Wendy R. Kates and Wanda Fremont

12

Psychosis in Autism

233

Angelina Kakooza-Mwesige, Laura Stoppelbein, and Dirk M. Dhossche

Part V 13

Central Nervous System Disorders Psychotic Disorder Due to Traumatic Brain Injury

249

Daryl E. Fujii, Nikki Panasci Armstrong, and Iqbal Ahmed

14

Schizophrenia-Like Psychosis and Epilepsy

262

Perminder Sachdev

15

Psychosis following Cerebrovascular Accident

285

James A. Bourgeois

16

Psychosis in Patients with Brain Tumors

302

Tamara Dolenc and Teresa Rummans

17

Psychosis Secondary to Infections

316

Sarah Reading and John T. Little

18

Psychosis Secondary to Inflammatory and Demyelinating Disease

337

Katherine H. Taber and Robin A. Hurley

Part VI 19

Substance Abuse and Medications Cannabis-Induced Psychosis Luis Alfonso Nu´n˜ez Domı´nguez

369

vii

Contents

20

Cocaine

382

Daryl E. Fujii and Erin Y. Sakai

21

Methamphetamine

392

Liz Jacobs and William Haning III

22

Medication-Induced Psychosis

406

Junji Takeshita, Diane Thompson, and Stephen E. Nicolson

Part VII

Neurodegenerative Disorders

23

Psychosis Secondary to Alzheimer’s Disease

455

Robert A. Sweet and James E. Emanuel

24

Dementia with Lewy Bodies

472

Sasha Ericksen and Debby Tsuang

25

Parkinson’s Disease

490

David L. Sultzer and George Webster Ross

Part VIII Sensory Impairments 26

Psychosis Associated with Sensory Impairment

513

Suzanne Holroyd

Part IX

Conclusion

27

Conclusion

535

Daryl E. Fujii and Iqbal Ahmed

Index

557

List of Contributors

Daniel J. Abrams University of Colorado School of Medicine Iqbal Ahmed University of Hawaii Daniel N. Allen University of Nevada, Las Vegas David B. Arciniegas University of Colorado School of Medicine

Susan E. Fratoni University of Massachusetts Medical School Wanda Fremont State University of New York, Syracuse

Nikki Panasci Armstrong University of Hawaii

Daryl Fujii Hawaii State Hospital

Nick Bouras Kings College London, United Kingdom

Gerald Goldstein VA Pittsburgh Healthcare System Pittsburgh, PA

James A. Bourgeois University of California, Davis Medical Center Philip R. Burke University of Massachusetts Medical School Dirk M. Dhossche University of Mississippi Medical Center Tamara Dolenc Mayo Clinic James E. Emanuel University of Pittsburgh Medical Center

ix

Sasha Ericksen University of Washington School of Medicine

Jessica E. Grogan University of Houston Gretchen L. Haas University of Pittsburgh William Haning III University of Hawaii Colin P. Hemmings South London and Maudsley NHS Trust, United Kingdom

x

List of Contributors

Suzanne Holroyd University of Virginia Robin A. Hurley VISN 6 MIRECC, Hefner VAMC, WFUSM, BCM Salisbury, North Carolina Elizabeth Jacobs University of Hawaii Angelina Kakooza-Mwesige Makerere University Medical School John Kasckow University of Cincinnati Wendy R. Kates State University of New York, Syracuse John T. Little Johns Hopkins University School of Medicine Theo Manschreck Harvard University Andreas Marneros Martin-Luther-Universita¨t Halle-Wittenberg, Germany Somaia Mohamed Cincinnati VA Medical Center Stephen E. Nicolson Massachusettes General Hospital Luis Alfonso Nu´n˜ez Domı´nguez Centro Me´dico, Navarra, Spain Katerine Osatuke VHA National Center for Organization Development

Frank Pillmann Martin-Luther-Universita¨t Halle-Wittenberg, Germany Sarah Reading Johns Hopkins University School of Medicine Anthony J. Rothschild University of Massachusetts Medical School and UMass Memorial Healthcare, Inc. Teresa Rummans Mayo Clinic Perminder Sachdev University of New South Wales, Australia Erin Y. Sakai Beth Israel Deaconess Medical Center Jason Schiffman University of Hawaii Eric G. Smith University of Massachusetts Medical School and UMass Memorial Healthcare, Inc. Laura Stoppelbein University of Mississippi Medical Center David L. Sultzer University of California at Los Angeles and VA Greater Los Angeles Healthcare System Robert A. Sweet University of Pittsburgh Medical Center Katherine H. Taber VISN 6 MIRECC, Hefner VAMC, WFUSM, BCM Salisbury, North Carolina

xi

List of Contributors

Junji Takeshita University of Hawaii

George Webster Ross VA Pacific Islands Healthcare System

Diane Thompson Queen’s Medical Center

Chelsea S. Wogsland University of Massachusetts Medical School

Debby Tsuang University of Washington School of Medicine

Deborah Yurgelun-Todd Harvard Medical School and McLean Hospital

NaN

Preface

Psychotic disorders of different etiologies have interested both clinicians and researchers, but for different reasons. People with psychosis have been some of the most challenging for clinicians to treat due to the severity and chronicity of symptoms. One potential problematic aspect of treatment is differential diagnosis as psychosis can result from numerous etiologies and many patients have more than one risk factor. A review of the presentation, course and progression, and optimal treatment strategies would certainly be useful for clinicians in making these determinations. For researchers and theoreticians, secondary or ‘‘organic’’ psychotic disorders can provide clues to underlying neurobiological mechanisms of schizophrenia or psychosis in general. Unfortunately, thus far, this potential avenue of research has not been adequately explored. One problem is that the literature on the ‘‘so called’’ secondary psychotic disorders is not readily available for study or review. There are many different etiologies, thus amassing this disparate literature would take a concerted effort. In addition, much of the information on ‘‘organic psychosis,’’ particularly for the obscure etiologies, is provided in case studies or case series, many in difficult-to-find journals. We believe these problems in access to information have prevented researchers from mining this rich resource. The purpose of this book is to address the needs of both clinician and researcher by providing comprehensive reviews of psychotic disorders of different etiologies in one handy resource. For clinicians faced with difficult and fascinating differential diagnoses, this compendium allows quick comparisons useful for diagnostic decision-making. For researchers and theoreticians interested in the neurobiology of schizophrenia and psychosis, we compare and contrast the current data in searching for clues on the neurobiological essence of psychosis. Specifically, we examine the hypothesis that psychosis is a neurobiological syndrome similar to aphasia or apraxia.

xiii

xiv

Preface

There are two unique organizational features of our book. First, each chapter is uniformly structured to aid in comparison of the presentation, course, and underlying neuropathology between each disorder. Second, authors have rated the level of evidence for each etiology indicating the confidence level the reader can place in the current findings. We hope you find this book useful in your practice and research.

NaN

Acknowledgements

There are many people we would like to acknowledge in the making of this book. First, we would like to thank all the contributing authors for their efforts, expertise, and taking time out of their busy schedules to collaborate with us. Second, we would like to thank the researchers who have trodden the path of organic psychosis and inspired us to continue the exploration. These people include: Kenneth Davison and Christopher Bagley, pioneers in compiling information on secondary psychotic disorders; Alwyn Lishman for piquing everyone’s interest in organic psychiatry; and Jeffrey Cummings for his seminal ideas in the neuropsychiatry of psychosis. With this book, we hope to carry the torch in this area of study. Third, we would like to thank the individuals who have facilitated our research over the years: librarian Lisa Anne Matsumoto who special ordered many of our journal articles; and administrative assistant Sharon Lai for her multiple contributions. We would also like to thank Erin Sakai and Cale Palmer for their assistance in compiling and rating the data in the chapters. Last, but not least, we would like to thank our families, without whose love, support, and patience our work could not have been accomplished. Daryl would like to thank his beautiful wife Sam, two eggies Dylan and Cody, loving parents Earl and Judy Fujii, big brother Jay and his family, Naomi and Jarin, grandparents Kenneth Ito and the late Mildred Ito and Shizuko Fujii. Ike would like to thank numerous colleagues, and students who have helped shape his ideas over the years, his co-author Daryl for his years of collaboration and for the active exchange of ideas which led to the writing of the book, and for being the force behind getting these ideas out into the public domain. Finally, he would like to thank his lovely wife Lisa, for her love and enduring support, and his two daughters Yasmin and Jihan for their love and the joy they have provided.

xv

Part I

Introduction

1

Introduction: is psychosis a neurobiological syndrome? Daryl E. Fujii1 and Iqbal Ahmed2 1 2

Hawaii State Hospital University of Hawaii

Psychosis is a state in which the individual experiences a severe disconnection from reality. The most common symptoms associated with psychotic disorders are delusions and hallucinations. Delusions are false beliefs about experiences, oneself, or the environment that cannot be altered in the face of contradictory evidence. An example would be delusions of persecution in which the individual believes that others are tormenting, ridiculing, or intending to harm him or her. Hallucinations involve false perceptions in any sensory modality without insight into their pathological nature. The most common hallucination is auditory, which is generally experienced as ‘‘hearing voices.’’ Other symptoms associated with psychotic disorders include negative symptoms such as restricted emotional expression (flat affect), sparse language output (alogia), poor initiation and persistence of goal-directed behaviors (avolition), disorganized thoughts, speech, or behaviors, or a severe decrease in reactivity to one’s surroundings (catatonia) (American Psychiatric Association, 2000). Psychosis has many etiologies. The Diagnostic and Statistical Manual-IV Text Revision (DSM-IV TR) (American Psychiatric Association, 2000) distinguishes between primary psychotic disorders and those due to other etiologies. Primary psychotic disorders include schizophrenia, delusional disorders, schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder. By contrast, psychosis can be due to a general medical condition such as Dementia of the Alzheimer’s Type (DAT) or traumatic brain injury (TBI), a psychoactive substance such as amphetamines or cannabis, or secondary to a mood disorder such as major depression. The following are brief descriptions of the DSM-IV TR diagnostic criteria for each disorder:

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The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Daryl E. Fujii and Iqbal Ahmed

Diagnostic criteria for schizophrenia A. Two or more of the following symptoms are present: (1) delusions, (2) hallucinations, (3) disorganized speech, (4) grossly disorganized or catatonic behavior, and (5) negative symptoms. B. Dysfunction in social, academic, or occupational achievement. C. Continuous signs of the illness persist for at least six months. D. Exclusion of schizoaffective or mood disorder as an etiology. E. Exclusion of substance use or a general medical condition as an etiology. F. If a premorbid pervasive developmental disorder exists, hallucinations and delusions are present for at least a month to warrant and additional diagnosis of schizophrenia.

Diagnostic criteria for psychotic disorder due to a general medical condition A. Prominent hallucinations or delusions are present. B. There is evidence that the psychotic symptoms are a direct consequence of a general medical condition. C. Psychotic symptoms are not better accounted for by another mental disorder. D. Psychotic symptoms do not occur exclusively during the course of a delirium.

Diagnostic criteria for substance-induced psychotic disorder A. Prominent hallucinations or delusions are present. B. There is evidence that the psychotic symptoms develop within a month of substance intoxication or withdrawal, or the substance is etiologically related to the psychosis. C. Psychotic symptoms are not better accounted for by another mental disorder. D. Psychotic symptoms do not occur exclusively during the course of a delirium. There exists a curious dichotomy in DSM-IV TR criteria between the primary psychotic disorders and Psychotic Disorders Due to a General Medical Condition (PDDGMC) and Substance-Induced Psychotic Disorders (SIPD). In both PDDGMC and SIPD, diagnosis is based on the presence of psychotic symptoms (criterion A) within the context of either a medical condition or substance use (criterion B), while ruling out schizophrenia or delirium as the

5

Introduction: is psychosis a neurobiological syndrome?

cause of the psychosis (criteria C and D). Thus in these two diagnostic categories, the etiology of psychotic symptoms is ‘‘known,’’ while other mental disorders must be ruled out as the cause. By contrast, for primary psychotic disorders, diagnosis is based upon the presence of psychotic symptoms (criteria A and F), the severity and duration of illness (criteria B and C), and ruling out other etiologies (criteria D and E). Thus unlike PDDGMC or SIPD in which the clinician must establish an etiology to make a diagnosis, for the primary psychotic disorders, the etiological concern of the clinician is to rule out other etiologies as causative. If this can be accomplished, then it is assumed that psychosis is due to schizophrenia. The DSM-IV TR nomenclature for psychosis illustrates a major criticism of the classification scheme in general. Unlike general medical disease models, psychiatric diagnoses are often based upon symptom clusters rather than tied to etiology (Pichot, 1994). Indeed, on a practical level, the symptom-based nosology of the DSM-IV TR frequently results in diagnostic dilemmas for clinicians as the presentation of primary and other psychotic disorders are often very similar. For example, the modal patient with psychosis due to cocaine or methamphetamine use, seizure disorder, or TBI generally resembles a patient with schizophrenia, paranoid type (Fujii & Ahmed, 2002a; Post & Kopanda, 1976; Sachdev, 1998; Sato, Numachi & Hamamura, 1992). In addition, studies have found that there is no symptom specific to schizophrenia. Even the once hypothesized schizophrenic marker, Schneiderian First Rank Signs (Schneider, 1959), can be found in bipolar disorder and psychotic disorders of other etiologies (Gonzalez-Pinto et al., 2003; Marneros, 1988; Sato et al., 1992). The following hypothetical case illustrates how similar presentations and different criteria (etiology versus severity/duration of symptoms) can cause problems with differential diagnoses. Let’s say Fred, a 25-year-old male without a previous history of psychosis, comes to the ER for paranoid delusions and auditory hallucinations. He has used methamphetamine daily over a five-year period and is currently intoxicated with methamphetamine. In this case, his diagnosis would most likely be methamphetamine-induced psychosis as the onset of psychosis can clearly be tied to his drug use. By contrast, let’s say that Fred continues to experience paranoid delusions six months after abstinence. According to the methamphetamine literature, it is not uncommon for long-term users to remain symptomatic six months after discontinuing their use (Sato et al., 1992). However, according to DSM-IV TR differential diagnosis recommendations, in this case schizophrenia would have to be considered as the diagnosis due to duration of illness, even if there is no family history of schizophrenia and there is a known potential etiology.

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Daryl E. Fujii and Iqbal Ahmed

Conversely, let’s say that Fred’s cousin has been diagnosed with schizophrenia. Fred’s family predisposition may suggest that he suffers from a primary psychotic disorder. On the other hand, studies have reported that a family history of schizophrenia is a risk factor for substance-induced psychosis such as hallucinogens and cannabis (Tsuang, Simpson, & Kronfold, 1982). Given the fact that monozygotic twins have only a 50% concordance rate for schizophrenia (Gottesman, 1991), environmental events such as the use of methamphetamine may be required to trigger schizophrenia in a genetically vulnerable individual. Thus, in this case, is methamphetamine an environmental factor that triggers the onset of schizophrenia or is it the etiology of the psychosis? How can you rule out which etiology is causative? To further cloud matters, what if Fred were 45 years old instead of 25? Would this affect which etiology is more salient? What if Fred sustained a previous head injury with a seven-day loss of consciousness three months prior to the onset of his delusions and hallucinations? Would the head injury be the etiology of psychosis, the trigger of a schizophrenia episode, a coincidental occurrence, or perhaps a contributing factor to a psychosis? What if he didn’t lose consciousness? In such a case, it would be extremely difficult to rule out schizophrenia, TBI, or methamphetamine as being the primary etiology of the psychosis, rule outs being an essential criterion for each DSM-IV TR category of psychotic disorder. Unfortunately, these issues are not uncommon as about 50% of people who are diagnosed with schizophrenia also have a substance abuse problem (Regier et al., 1990), whereas up to 40% have sustained head injuries (for a review see Fujii, 2005). In such cases, studies have shown that patients who meet criteria for GMC and SIPD are often diagnosed with schizophrenia (Fujii & Ahmed, 2002a; Shaner et al., 1998). Again going back to the DSM-IV TR, diagnostic issues arise because the presentation of schizophrenia is not unique, as no symptom is pathognomonic of the illness. Similarly there is not a definitive biological marker to designate the presence of schizophrenia. Instead, diagnosis is primarily based upon the presence and severity of psychotic symptoms in which no other etiology can be identified. Furthermore, although researchers agree that genetic factors are more important than environmental factors in the transmission of schizophrenia, more than 60% of people with schizophrenia have no family history (Gottesman, 1991). A diagnosis of schizophrenia essentially does not tell us anything about the etiology of the psychosis. Indeed, many speculate that schizophrenia is a heterogeneous illness with more than one etiology (Schroder et al., 1995; Seaton, Goldstein, & Allen, 2001). Due to the inherent problems in DSM-IV TR nomenclature for psychotic disorders, we offer a different conceptual approach. We argue that the separate

7

Introduction: is psychosis a neurobiological syndrome?

categories (primary and other) of psychotic disorders may be a distinction without a difference, as many GMC and SIPD appear to affect the same neurochemical systems and have similar neuropathology to schizophrenia (Fujii & Ahmed, 2004). Schizophrenia has consistently been associated with abnormalities in mesial temporal, frontal areas, and frontal-temporal connectivity (McCarley et al., 1999; Berman & Meyer-Lindenberg, 2004), as well as the dopaminergic system projecting from the ventral tegmental area to the striatum (for a review see Thompson, Pogue-Geile, & Grace, 2005). Among the most common medical etiologies associated with secondary psychosis include disorders affecting temporal structures such as DAT, TBI, and temporal lobe epilepsy (Wragg & Jeste, 1989; Sachdev, 1998; Fujii & Ahmed, 2002a). Similarly, substances that directly affect the transmission of dopamine such as cocaine, methamphetamine, and anti-Parkinsonian medications have been found to induce psychoses in users (Cummings, 1991; Post and Kopanda, 1976; Sato et al., 1992). Furthermore, in many GMC and SIPD a family history of schizophrenia is a risk factor (Sachdev, Smith, & Cathcart 2001; Tsuang et al., 1982). With other neurological syndromes, lesions to specific areas of the brain are associated with concomitant behavioral, emotional, and cognitive sequelae regardless of etiology (Mesulam, 2000). For example, subcortical lesions generally present with cognitive slowing, deficits in attention and concentration, executive functioning, visuospatial skills, and memory, with more problems in retrieval versus memory encoding and storage problems. There is an absence of aphasia, apraxia, and agnosia, and apathy, depression, or personality changes (Lezak, Howieson, & Loring, 2005). Severity of injury is also important for presentation and may be more important than actual etiology in determining presentation. This principle was demonstrated in a study comparing the effects of anoxia versus TBI that found cognition is more closely associated with severity of injury than with etiology (Hopkins, Tate, & Bigler, 2005). In addition, there is emerging evidence indicating that neuropathology resulting in associated sequelae occur in other ‘‘psychiatric’’ disorders such as depression. For example, Hickie et al. (2005) reported that reduced hippocampal volumes in depression are associated with deficits in visual and verbal memory. Given that schizophrenia is a brain disease, why shouldn’t the same principles apply to psychosis? We propose an alternate conceptualization of psychosis. We argue that psychosis is a neurobiological syndrome similar to aphasia and apraxia. Affected structures include frontal systems that would include the frontal-striatal-thalamiccerebellar axis as well as the frontal-striatal-hippocampal axis, and the dopaminergic projections to these areas. Altering this circuit to a significant degree by any

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Daryl E. Fujii and Iqbal Ahmed

means including drugs, disease, trauma, or normal developmental brain changes can result in psychotic symptoms. Our conceptual framework for developing a psychotic disorder is as follows (Fujii & Ahmed, 2002b): 1. Psychosis is associated with abnormal functioning of frontal systems, temporal lobes, and the dopaminergic projections to these areas. 2. All individuals are at risk for developing a psychosis. Contributing factors include: a. genetic predisposition. b. environmental factors. i. damage sustained through trauma, disease, substance abuse. ii. effects of experience on neuronal structures and neurochemical release. c. neuronal and biochemical changes during normal human development. 3. Psychosis will develop when a threshold of damage or changes to frontal systems, temporal structures, and dopaminergic projections is attained. In this framework, anyone would be vulnerable to developing a psychosis once a threshold of damage or changes to the affected structures is reached. For example, if there is a strong genetic predisposition, the onset of psychosis may be inevitable after neuronal pruning during adolescence/early adulthood, or may be expedited with onset in adolescence by an early mild head injury or marijuana abuse. Conversely, for a person with no genetic vulnerability, psychosis may occur in middle age only after multiple head injuries and long-term methamphetamine dependence, or in late life after the onset of DAT. In both cases, life experiences that increase stress or stress response that would in turn increase the amount of dopamine in the brain would also contribute to the initial onset of psychosis or exacerbation of illness. This framework is consistent with the diathesis
stress model of schizophrenia which hypothesizes that the disorder results from an interaction between a biological predisposition and an environmental trigger (Zubin & Spring, 1977). Our model, however, differs in several key aspects: (1) it applies a similar conceptualization to psychotic disorders in general, (2) it specifies and expands potential environmental factors beyond the pre- and perinatal periods, and (3) it also incorporates the effects of normal life-cycle neurological changes in conceptualization beyond young adulthood. Our model is also consistent with newer models of vulnerability for schizophrenia focusing on endophenotypes. For example, Weiser, van Os, & Davidson (2005) argues that impaired cognition is present in both patients with schizophrenia and their first degree relatives more frequently than in the normal population. These broad vulnerabilities, or endophenotypes, are believed to be genetically transmitted. In our conceptual framework,

9

Introduction: is psychosis a neurobiological syndrome?

we argue that vulnerabilities such as impaired cognition can also result from environmental factors. For a more in-depth discussion of the model see Fujii & Ahmed (2002b).

Examining the hypothesis One purpose of the book is to examine the Fujii & Ahmed (2004) hypothesis that psychosis is a neurobiological syndrome. A neurobiological syndrome exists if the following criteria are met: 1. A constellation of symptoms is reliably associated with neuropathology in a circumscribed structural location or neural circuit. 2. Similar neurobiological disturbances (location or neural circuit) secondary to different etiologies would result in similar cognitive or behavioral symptoms. 3. Smaller amounts of similar neurobiologic disturbances are associated with milder symptoms. 4. Additional symptoms such as cognitive, mood, psychiatric, or other associated neurological symptoms are related to other networks simultaneously being affected by underlying neurochemical or neuropathologic processes. 5. Aside from treating the underlying disease process, treatment for the associated symptoms of a neurobiological disorder of different etiologies is similar. This hypothesis will be examined by comparing and contrasting the characteristics of psychotic disorders of different etiologies. If psychosis is a neurobiological syndrome, then psychotic disorders of different etiologies should affect common brain structures and neurochemical systems, and should also overlap in symptoms and presentation. Each chapter will review the literature on a psychotic disorder of a specific etiology. Data in the following areas will be reviewed: (1) epidemiology, (2) age of onset, (3) presentation (positive and negative symptoms, neuropsychological deficits, emotional disorders), (4) course and progression including latency from initial insult to presentation of psychotic symptoms and prodrome, (5) suspected neuropathology, (6) suspected neurochemical pathology, (7) genetic factors, (8) other risk factors, and (9) treatment. In addition, the data for each area will be rated on the quality of evidence according to the Centre for Evidence-Based Medicine Levels of Evidence Grades of Recommendation System criteria (see Appendix at the end of chapter for criteria). This rating is included to inform the reader of the current status of evidence for a specific etiology of psychosis. The data will be evaluated qualitatively for similarities and differences of the aforementioned nine areas between the different etiologies of psychosis. By comparing this information we hope to gain insight into which brain areas are associated with psychosis and patterns in development, presentation,

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Daryl E. Fujii and Iqbal Ahmed

and treatment. These qualitative impressions will be described section by section in the concluding chapter. REFERENCES American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision. Washington, DC: American Psychiatric Association Press. Berman, K. F. & Meyer-Lindenberg, A. (2004). Functional brain imaging studies in schizophrenia. In Neurobiology of Mental Illness, ed. D. S. Charney & E. J. Nestler. New York: Oxford University Press, pp. 311
23. Cummings, J. L. (1991). Behavioral complications of drug treatment of Parkinson’s disease. Journal of the American Geriatric Society, 39, 708
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94. Fujii, D. E. & Ahmed, I. (2002a). Characteristics of psychosis due to traumatic brain injury: An analysis of case studies in the literature. Journal of Neuropsychiatry and Clinical Neurosciences, 14, 130
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67. Shaner, A., Roberts, L. J., Eckman, T. A., et al. (1998). Sources of diagnostic uncertainty for chronically psychotic cocaine abusers. Psychiatric Services, 49, 684
90. Thompson, J. L., Pogue-Geile, M. F., & Grace, A. A. (2005). Developmental pathology, dopamine, and stress: A model of the age of onset of schizophrenia symptoms. Schizophrenia Bulletin, 30, 875
900. Tsuang, M. T., Simpson, J. C., & Kronfold, Z. (1982). Subtypes of drug abuse with psychosis. Archives of General Psychiatry, 39, 141
7. Weiser, M., van Os, J., & Davidson, M. (2005). Time for a shift in focus in schizophrenia from narrow phenotypes to broad endophenotypes. British Journal of Psychiatry, 187, 203
5. Wragg, R. E. & Jeste, D. V. (1989). Overview of depression and psychosis in Alzheimer’s disease. American Journal of Psychiatry, 146, 577
87. Zubin, J. & Spring, B. (1977). Vulnerability: A new view of schizophrenia. Journal of Abnormal Psychology, 86, 103
26.

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Appendix Descriptors of Oxford Centre for Evidenced-based Medicine Levels of Evidence Criteria (May 2001) www.cebm.net/levels_of_evidence.asp

Level 1a 1b 1c 2a 2b 2c 3a 3b 4 5

Differential dx/symptom prevalence SR with consistency of prospective cohort studies Prospective cohort studies with 1
5 years follow up All or none case studies SR with consistency in 2b rated studies or better Retrospective cohort studies, or those with follow up 51 year Ecological studies SR with consistency of 3b rated studies or better Nonconsecutive cohort studies or studies with very small samples Case-series or superseded reference standards Expert opinion without explicit critique

Treatment SR with consistency of RCTs Individual RCT with a narrow confidence interval All or none single case studies with AB design SR with consistency in 2b rated studies or better Individual cohort study with poor RCT and follow up Outcomes research and ecological studies SR with consistency of case controlled studies Individual case controlled study Case-series and poorly controlled cohort and case-controlled study Expert opinion without explicit critique

SR ¼ systematic review; RCT ¼ randomized control clinical trial Grades of Recommendation

A B C D

Findings based upon consistent level 1 studies Findings based upon consistent level 2 or 3 studies or extrapolated* from level 1 studies Findings based upon level 4 studies or extrapolated* from level 2 and 3 studies Findings based upon level 5 evidence or inconsistent/inconclusive studies at any level

*Extrapolation ¼ findings taken from studies in which the findings are not the primary focus of the study

Part II

Primary Psychotic Disorders

2

Schizophrenia Gerald Goldstein1, Daniel N. Allen2, and Gretchen L. Haas3 1

VA Pittsburgh Healthcare System University of Nevada, Las Vegas 3 University of Pittsburgh 2

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B A B B B B C C C

Introduction Schizophrenia is a chronic psychotic disorder that has apparently existed throughout recorded history. First called ‘‘dementia praecox’’ by Emil Kraepelin, it was renamed by Eugen Bleuler early in the twentieth century to schizophrenia, or more exactly ‘‘the schizophrenias.’’ While the dramatic manifestations of the disorder made it recognizable from antiquity, there was some disagreement as to its identification and it was not until the reforms of DSM-III (the third Diagnostic and Statistical Manual of the American Psychiatric Association) that a consensus was formed regarding criteria for diagnosing the disorder, and its reliable diagnosis was largely achieved. Psychosis has several aspects including the classic symptoms of delusions and hallucinations, impairment of reality testing, and a severity level that substantially interferes in coping with the demands of life. Schizophrenia has all of these aspects and 15

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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so the current (DSM-IV) diagnostic criteria include the symptoms of delusions and hallucinations in addition to disorganization of speech and behavior and the negative symptoms of affective blunting and impairment of purposive behavior, presence of social/occupational dysfunction, and duration of at least six months. There are variations in the pattern of symptoms reflected in the clinical subtypes of paranoid, disorganized, catatonic, undifferentiated, and residual schizophrenia. In this chapter we provide an overview of schizophrenia as the classic disorder defined in DSM-IV which will be contrasted in this book with other psychotic disorders.

Epidemiology Although the lifetime morbid risk of schizophrenia is generally considered to be approximately one percent, prevalence estimates (the number of cases at risk within a defined population over a defined period of time) vary by several-fold. Such variation stems from several factors including variation in definition, variation in the geographic location of the base population, and differences in the case-finding method and diagnostic procedures. Point prevalence, the estimated number of active (i.e., symptomatic) cases on a given date, ranges from 1.4 to 4.6 per 1000 (Jablensky, 2000) and is likely to underestimate true prevalence. Such error can be attributed, in part, to the episodic course of the disorder, with the common inter-episode remission of positive symptoms contributing to underdetection of psychoses. The lack of insight into illness that is a common characteristic of psychosis also likely contributes to under-reporting of symptoms in community-based surveys. Estimates of incidence (the number of first-episode cases in a defined population per year) tend to be more reliable than estimates of prevalence
particularly when based on a common, clearly operationalized definition of onset (e.g., first contact with clinician, first hospitalization, etc.). However, given that schizophrenia is being treated on an outpatient basis more often than ever before, incidence estimates based on hospital admission are likely to underestimate the true values and to reflect an increasing lag time between onset of symptoms and admission to hospital. Variations in the definition or diagnostic criteria for schizophrenia also contribute to variance in incidence estimates. Studies using restrictive criteria are likely to yield lower incidence rates than those using broader definitions (Haas & Castle, 1998). When first contact rates are reported using the more restrictive criteria (e.g., DSM-III-R or ICD10) within a single region (e.g., the United Kingdom), estimates range from 0.08 to 0.14; using the same criteria for a similar region, but controlling for migration and mortality within

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a given district, the estimated prevalence is likely to be higher, as in the study of Jeffreys et al. (1997) in which it is 0.21. Increased mortality has also been reported. Individuals with schizophrenia experience an approximate 20 percent reduction in life compared to the general population (Brown, Inskip, & Barraclough, 2000), with greater mortality in males than females. Increased mortality is caused by a number of factors, including environmental influences such as homelessness, increased death from natural causes, suicide, and accidental death. The lifetime risk for suicide in patients with schizophrenia is estimated to be 5
10% (depending upon how risk is assessed) and is significantly higher than observed in the general population. Increases in mortality also result from comorbid conditions such as cardiovascular disease, diabetes, hypertriglyceridemia, human immunodeficiency virus, and hepatitis (Goff et al., 2005). However, the most common comorbid condition is substance abuse, with up to 65% of patients with schizophrenia having lifetime diagnoses of substance use disorders (Mueser et al., 1990b). While incidence of schizophrenia is consistent across many countries, some subgroups appear particularly susceptible to the disorder, with one of the most striking examples coming from some migrant samples who exhibit markedly increased incidence. An early report by Hemsi (1967) noted that African- and Caribbean-born migrants to the United Kingdom exhibited a high incidence of schizophrenia, a finding which has since been repeatedly demonstrated even in late onset cases (Mitter et al., 2005). Similar findings have also been reported in other countries as well (Cantor-Grace, Zolkowska, & McNeil, 2005), although the cause remains unclear. Environmental factors and in particular psychosocial stress resulting from impoverishment, discrimination, and acculturation have been suggested as major contributing factors (Cantor-Grace et al., 2005; Sharpley et al., 2001), although the direct effects of these factors have not been clearly demonstrated.

Age of onset The onset of the active phase of schizophrenia most commonly occurs in the 20s, although onset can occur in childhood, early adolescence, or in later adulthood. Earlier age of onset is generally associated with poorer outcome (Haas & Garrett, 1998). However, little difference in symptomatology has been noted between early and late onset cases. Older onset may be associated with increased incidence of paranoid delusions and auditory hallucinations (Jeste et al., 1997). Earlier onset cases show greater negative symptoms and disorganization (Kirkpatrick et al., 2000). Differences in age of onset have also been consistently reported between

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males and females with schizophrenia, with females typically experiencing onset three to five years later than males (Haas & Castle, 1998). Males also have poorer premorbid adjustment and more severe deterioration prior to disease onset (Haas & Garrett, 1998). Mitter et al. (2005) found that for schizophrenia-like syndromes that were very late in onset in British-born patients, age of onset for women was approximately 80 years of age, while males had an average age of onset of 75. It has been suggested that at least for some of these late onset cases, schizophrenia symptoms may actually be a prodrome to the development of a degenerative dementia, such as Alzheimer’s disease, although this is probably true for only a subgroup of these patients as most exhibit a pattern of neurocognitive decline consistent with a non-progressive illness (Jeste et al., 1997). Operational definitions of age at onset of illness have been based on the emergence of positive symptoms in large part because of their greater salience and, hence, greater reliability, in dating. Nonetheless, it is recognized that subtle forms of behavioral dysfunction commonly emerge well before that time. Presentation Schizophrenia typically presents with an acute onset of florid symptoms during late adolescence or early adulthood. The initial episode, generally referred to as the ‘‘first break’’ or ‘‘first episode’’, can be most broadly characterized as a loss of contact with reality. Initial symptoms are typically dramatic and include delusions, hallucinations, incoherent speech, and/or disorganized behavior. Social functioning or capacity for independent self-care is substantially reduced and, in most cases, the individual needs to be hospitalized, at least briefly. However, with widespread use of antipsychotic medications and improved case management, it is more typical for patients to be hospitalized for brief periods of time, followed by referral to outpatient treatment while remaining on medication. Over the years, the presentation and conceptualization of schizophrenia have changed. First, with the advent of antipsychotic medications, the severity and duration of the positive symptoms have been reduced in treated cases. Second, the prevalence of certain of the symptoms such as catatonia and so-called ‘‘first-rank’’ symptoms (Schneider, 1957) has decreased. What Kurt Schneider proposed as a set of pathognomonic symptoms that included prominent hallucinations and delusions of mind control (i.e., thought withdrawal, thought insertion, and thought broadcasting) do not occur with sufficient frequency to be given prominence in current diagnostic criteria. Based on recent epidemiologic studies, the most recent version of the DSM (DSM-IV) includes only prominent hallucinations as one of the core criteria for the diagnosis.

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With the introduction of antipsychotic medication, the course of the disorder has changed in certain respects. When the active or acute symptoms have been stabilized on medication, hallucinations are less prominent, delusions tend to be less profound, and speech can become relatively normal. A reduction in the severity of positive symptoms is often accompanied by enhanced ability to maintain self-care; as a result, patients who are compliant with their medication regime can be maintained without inpatient treatment for long periods of time, if not indefinitely. For reasons that are not clear, the nature and prevalence of the so-called ‘‘subtypes’’ of schizophrenia have changed since the advent of the use of antipsychotic medication in the early phase of illness, with the catatonic and disorganized subtypes less common and an increase in the residual subtype. The negative symptoms, which are now recognized as prominent features of some forms of the disorder in the most recent version of the DSM are not readily amenable to pharmacological treatment and do not change dramatically. They include affective blunting, social withdrawal, lack of volition, poverty of speech, and a variety of cognitive deficits. An extensive literature has emerged devoted to characterizing the cognitive deficits and, recently, seeking their correlates in brain structure and function. Cognitive deficits may be reduced with medication, or increase with stress. Many authorities view these deficits as core features of the disorder or endophenotypic markers of the underlying genetics of schizophrenia and, within the last decade, the condition has been more commonly viewed as a cognitive disorder with prominent behavioral features and neurocognitive substrates. Over several decades, various theories have emerged stressing deficits in such cognitive processes as abstract and logical reasoning, memory, social cognition, and attention. Although not formally part of the diagnostic process, cognitive testing is now a well-established procedure for characterization of schizophrenia, and numerous tests have been developed or utilized for that purpose. Many clinicians use intelligence tests and various neuropsychological tests to evaluate cognitive functioning and to provide recommendations for treatment and rehabilitative interventions. This clinical practice has been supported by a wealth of laboratory studies using experimental methods for investigation of various aspects of cognition in schizophrenia. With regard to clinical presentation, two problems have created substantial controversy in this area. The first of these focuses on what has become known as the ‘‘general deficit syndrome.’’ In the search for a general underlying deficit, numerous efforts have been made to identify some specific cognitive deficit that could account for thought disorder
the changes in the formal organization of speech and thinking that are a common feature of schizophrenia. Formal ‘‘thought disorder’’ is manifest as incoherent or loosely organized speech,

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illogical reasoning, oddities of speech such as neologisms, or idiosyncratic associations based on the concrete characteristics of words. When present, such abnormalities of speech and thought tend to persist throughout the course of illness. Beginning in the 1940s, prominent leaders in the field of psychopathology proposed that the underlying deficit in schizophrenia was an impairment of ‘‘abstract attitude’’, as demonstrated by remarkably concrete reasoning on interview, and impaired performance on tests of abstract reasoning. Other explanations stressed the presence of essential or ‘‘core’’ features such as illogical thinking (e.g., syllogistic reasoning), a loss of ego boundaries, and an impairment of body image that led to an inability to separate the self from the outside world, or an inability to distinguish between internal and external events. Several research groups studied attention with reaction time experiments, showing that individuals with schizophrenia could not maintain or flexibly shift across complex concepts or cognitive ‘‘sets.’’ Based on the mounting empirical literature within the then active field of experimental psychology, leaders in the field asserted that individuals with schizophrenia consistently did more poorly than normal control subjects on any cognitive task offered (Chapman & Chapman, 1978). As a consequence of this controversial, but persuasive argument, the presumptive underlying abnormality of cognition became known as the ‘‘general deficit syndrome.’’ In light of the yet controversial but widely accepted notion of a generalized deficit in schizophrenia, investigators who conduct research on cognition in schizophrenia are now required to demonstrate dissociation between performance on different cognitive tasks, ideally equated for difficulty level, to demonstrate that the findings reflect a specific deficit and/or a previously unidentified aspect of thought in schizophrenia that is not a part of a general deficit syndrome. Nonetheless, at present, there appears to be no consensus concerning a single cognitive deficit that characterizes all of schizophrenia. Rather, the heterogeneity across the cognitive test performance profiles of individuals with this disorder indicates that not all individuals with schizophrenia present the same level or pattern of cognitive problems. There is, indeed, substantial variation in performance across individuals, ranging from normal function in some areas of cognition to severely impaired performance that may be undistinguishable from the behavior of elderly individuals with dementing illnesses such as Alzheimer’s disease. One may encounter individuals with fluent and intelligible speech, apparently good reasoning abilities, and no evidence of failures in memory or maintenance of attention, but one may also see individuals with very little intelligible speech, and inability to maintain attention or solve relatively simple reasoning problems. While it is unusual to find superior or normal performance across all tests, near normal performance in general, with superior performance

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sometimes achieved on individual tests is sometimes found. On the other end of the spectrum, some patients with schizophrenia may demonstrate significant impairment on all tests given. Thus, we now speak of ‘‘cognitive heterogeneity’’ in schizophrenia, and while cognitive dysfunction is typically observed among the majority of individuals with the disorder, in contemporary practice, evidence of cognitive performance problems is not used to characterize the disorder, and is not used to make the diagnosis. Efforts have been made to attribute this variability in cognitive functioning to factors other than schizophrenia, often involving demographic and individual difference factors such as age, education, premorbid capabilities, alcohol or drug abuse, or the presence of another illness that impairs brain function. In brief, cognitive heterogeneity in schizophrenia is not readily explained by extraneous factors. Hence, there continues to be an ongoing, unresolved debate as to whether the cognitive heterogeneity reflects variability in general severity of the dysfunction or meaningful subtypes of schizophrenia.

Course and progression Early behavioral abnormalities such as failure to achieve normal developmental milestones, functional decline during adolescence or early adulthood, or transient psychotic symptoms often precede the constellation of symptoms that meet diagnostic criteria for schizophrenia. Thus, the course of schizophrenia includes a premorbid phase (occurring before the active ‘‘malignant’’ phase of illness), and this is often followed by a prodromal phase (marked by onset of subtle symptoms and/or behavioral changes that precede the active phase) in advance of the active symptoms or acute phase of illness. Decades of research on the premorbid period show a robust association between premorbid social, occupational/educational achievement and the longer-term clinical course of schizophrenia, including treatment response, rate of relapse, and level of social and occupational functioning (Fenton & McGlashan, 1987; Gittelman-Klein & Klein, 1969). Whether premorbid functioning influences the individual’s adaptation to the disorder or whether there is some direct relationship between premorbid adjustment and a specific etiologic or pathophysiologic subtype is not known and remains a focus of scientific investigation. Because of the proposed neurodevelopmental origin of schizophrenia (Weinberger, 1987), adjustment prior to the onset of the disorder in the premorbid state has received renewed attention in recent years. Premorbid abnormalities have been identified in academic and social functioning (Allen et al., 2001), motor and intellectual abilities (Aylward, Walker, & Bettes, 1984;

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Bilder et al., 1992; Caspi et al., 2003), and affective responsivity (Walker, Lewine, & Neumann, 1996). These premorbid deficits exhibit significant associations with specific clinical and neurobiologic aspects of the disorder, such as neuroanatomical abnormalities (Walker et al., 1996), neurocognitive functioning (DeQuardo et al., 1994; Levitt et al., 1996; Silverstein et al., 2003), age of symptom onset (Gittelman-Klein & Klein, 1969; Haas & Sweeney, 1992), positive and negative symptoms (Kelley et al., 1992), social skills (Mueser et al., 1990a), intellectual functioning and educational attainment (Allen et al., 2001; Aylward et al., 1984; Bilder et al., 1992), haloperidol treatment response (van Kammen et al., 1996), and disability and long-term outcome (Fleischhaker et al., 2005). Longitudinal studies of children at elevated genetic risk for schizophrenia indicate a statistical relationship between increasing symptoms and poorer adjustment prior to onset of schizophrenia (Dworkin et al., 1991), along with a stability in positive and negative symptom profile from late childhood to adulthood in some who later go on to develop schizophrenia (Cannon & Mednick, 1993). Because premorbid adjustment is not a unitary construct, efforts have been made to determine those abnormalities that are unique to schizophrenia, and those that may be indicators of more general risk for later development of mental illness. Two areas of premorbid functioning that have been examined extensively include premorbid intellectual functioning and premorbid psychosocial functioning. In the absence of longitudinal data, indices of premorbid intellectual functioning have been derived using a number of techniques, such as current patterns of performance on ‘‘hold’’ versus ‘‘non hold’’ subtests from intelligence tests (Bilder et al., 1998), achievement test performance (Kremen et al., 1996), or regression analyses of demographic variables (Vanderploeg, Schinka, & Axelrod, 1996). Premorbid psychosocial functioning is typically determined using scales based on information derived from interviews and ratings that incorporate patient self-reports, family member reports, and available academic, medical, and other pertinent records. One such instrument, the Cannon-Spoor Premorbid Adjustment Scale (PAS) (Cannon-Spoor, Potkin, & Wyatt, 1982), has been widely used to retrospectively collect information concerning academic and social domains of childhood, adolescent, and adulthood functioning. Support for the partial independence of these two domains has been generated through a series of factor analytic studies, most recently using confirmatory factor analysis (Allen et al., 2001). Their validities have been further demonstrated via investigations of their partially independent patterns of association with biological, outcome, symptom, and IQ variables, as well as comparisons between clinical and non-clinical populations (Allen et al., 2001; Cannon et al., 1997; van Kammen et al., 1996).

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Deterioration in premorbid academic functioning may be unique to schizophrenia, while premorbid social deterioration may be a more general feature of severe affective and psychotic illnesses. For example, using the PAS, Cannon et al. (1997) found poor premorbid social adjustment in schizophrenia and bipolar disorder, whereas only the schizophrenia group exhibited impaired academic adjustment. A number of studies have also reported deterioration in academic performance or academic achievement test scores that become increasingly severe during late adolescence for individuals who later go on to develop schizophrenia (Allen et al., 2005; van Oel et al., 2002). In a direct comparison of the course of academic and social premorbid adjustment across age periods, Allen et al. (2005) found that while deterioration is present across both academic and social functioning prior to the onset of schizophrenia, premorbid academic functioning is particularly susceptible to deterioration, most notably in later adolescence as the onset of the active phase of clinical symptoms becomes imminent. This accelerated decline in premorbid academic functioning appears to occur well before the onset of the clinical manifestations of schizophrenia. The cumulative findings also suggest that academic dysfunction or deterioration in childhood or early adolescence is a unique premorbid marker for schizophrenia. Although speculative, such developmental deficits may reflect neurodevelopmental abnormalities that may have a particularly profound effect on basic cognitive functions necessary for adequate performance in academic environments. Prospective studies of offspring at genetic risk for schizophrenia may contribute to better understanding and recognition of the earliest stages of schizophrenia, as well as investigation of genotypic variation and/or variation in the neurobiologic substrates of the psychopathology. The long-term course of schizophrenia is quite variable, with an episodic course for some and chronic, unremitting courses for others. Review of the evidence from international follow-up studies indicates that the five patterns of course and outcome now incorporated into DSM-IV have good empirical support (Jablensky, 2000). Whereas some individuals with an episodic course experience full symptom remission between episodes, others have incomplete remission and yet others experience continuous, unremitting symptoms. Based on the cumulative evidence from prospective longitudinal studies conducted in various regions of the world, it is commonly recognized that the course is without abnormally progressive loss of cognitive function. Although once conceived as an early onset form of dementia (dementia praecox), it is now generally accepted that schizophrenia is not a progressive deteriorative disease of the central nervous system. Neuropsychological cross-sectional studies of age differences in schizophrenia have largely found an absence of more rapid decline in individuals with schizophrenia than in normal controls (Goldstein & Zubin, 1990). The typical course of

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schizophrenia is now thought to be relatively stable with periods of relapse. Positive symptoms may return after substantial remission associated with medication. The reasons for these relapses are partially understood and have mainly to do with failures of medication compliance. Substance abuse and onset of severely stressful life events may be factors, but sometimes relapse occurs without medication nonadherence, substance abuse, or stress
apparently because of some not well understood neurobiological cycle. Neurobiological changes that precede clinical relapse have been identified.

Suspected neuropathology and neurochemical abnormalities While neuropathology and neurochemistry have traditionally been viewed as separate disciplines, this distinction has diminished recently, in part, because of significant advances in molecular biology. In the past, neuropathology has largely involved examination of tissue at autopsy or in conjunction with brain biopsy. Neurochemistry once largely involved the study of biochemical assays, via analysis of blood, cerebral spinal fluid, and urine. It is becoming increasingly possible to do neuropathology studies in living people through advanced imaging techniques that can identify specific tissue abnormalities. It is probably fair to say that traditional neuropathological/neuroanatomic approaches have not been productive in schizophrenia. Autopsy studies have shown areas of tissue abnormality throughout the brain without any clear identification of an area or structure particularly relevant to understanding the etiology of schizophrenia. Neuropathologic examination of tissue has not identified any characteristic pathology in the sense that schizophrenia is not a neoplastic, infectious, vascular, traumatic, or other form of pathological disorder. The closest we come is that it may be related to developmental anomalies, but that possibility is better evaluated with different approaches. Regarding neurochemistry, we have gone through an era of the dopamine hypothesis that turned out to be productive. Briefly, the dopamine hypothesis proposes that an abnormality in the mesolimbic dopaminergic system is a key agent in the pathogenesis of schizophrenia. Evidence for this view came largely from the beneficial effects of drugs that block dopamine receptors. While this hypothesis and other related ones were quite heuristic at their time, new developments in neuroscience have allowed for examination of the underlying molecular biology. Starting with the structural or visible neuropathological findings, there is abundant evidence of brain abnormalities in schizophrenia. Both postmortem and in vivo neuroimaging studies have demonstrated structural changes.

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MRI studies report finding enlarged lateral and third ventricles, decreased (mainly grey matter) brain volume, reductions in volume of the temporal cortex
particularly the hippocampus and the superior temporal gyrus
and reduced size of the prefrontal cortex. By far the most commonly reported neuropathological finding in schizophrenia is enlarged ventricles. However, functional and structural neuroimaging studies have also identified more specific abnormalities in frontal-striatal and temporo-limbic regions, including cortical grey matter volume reductions (Ananth et al., 2002; Gur et al., 2000a; Gur et al., 2000b; Harvey et al., 1993; Sullivan et al., 1998). Frontal lobe regions that have been shown to be functionally or structurally abnormal include the dorsolateral prefrontal cortex (Gur et al., 2000a; Ragland et al., 1998; Weinberger et al., 1992), medial prefrontal cortex and anterior cingulate (Ananth et al., 2002; Haznedar et al., 1997), frontal eye fields (Sweeney et al., 1998), and orbital frontal cortex (Gur et al., 2000a; Malaspina et al., 1998). Abnormalities have also been reported for the superior temporal gyrus (Menon et al., 1995; Shenton et al., 1992; Sullivan et al., 1998), and medial temporal lobe structures (Arnold et al., 1995; Bogerts et al., 1990; Suddath et al., 1989; Suddath et al., 1990). In chronic schizophrenia subjects with a more severe course, and especially males, there appears to be a progressive loss of frontal and posterior, superior temporal grey matter. The question is what produced these changes? One approach has come from magnetic resonance spectroscopy (MRS), an MRIrelated procedure that assesses brain metabolism at a molecular biology level. An initial answer proposed by Pettegrew et al. (1991) was that these morphometric changes reflected a reduction in neuropil secondary to exaggerated synaptic pruning with resultant loss of synapses. Reduction in neuropil would be expected to increase neuronal density, and in fact stimulated by this suggestion increases have been reported in pyramidal cell density in schizophrenia (Selemon, 2004). These findings support the occurrence of neuropil and synaptic loss in schizophrenia. Reductions have also been seen in dendritic spines from cortical pyramidal cells in the frontal cortex (Garey et al., 1998; Glantz & Lewis, 2001) and elsewhere in the cerebral cortex. Thus, the reduction in cortical volume could result from loss of neuropil and synapses and reflect an exaggeration of the normal synaptic pruning which occurs during adolescence. Numerous lines of evidence support a neurodevelopmental role in schizophrenia. Recently, there has been some suggestion that in addition to developmental abnormalities there may be neurodegenerative processes occurring, at least in some schizophrenia patients (Lieberman, 1999; Mathalon et al., 2001), and that this progression may contribute to the cognitive decline observed in some patients (Flashman and Green, 2004; Lieberman, 1999).

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In two longitudinal MRS-cognitive studies, chronic schizophrenia subjects were found to have reduced NAA/PCrþCr in the left hemisphere compared to recent-onset schizophrenia subjects and controls (Molina et al., 2005). The other revealed decreased NAA in the anterior cingulate gyrus in schizophrenia subjects as a function of age and duration of illness (Ende et al., 2000). NAA (N-Acetyl-Aspartate) is a metabolite that is widely recognized as being an indicator of neuronal integrity and is reduced with neuronal loss. The possibility has been raised that antipsychotic medication may produce at least some of these structural alterations, but current evidence suggests that is not the case. To summarize, schizophrenia is now thought to be a neurodevelopmental disorder characterized by initiation of an abnormal pruning process that destroys a substantially more than normal number of neurons. The process appears to involve an abnormality in membrane phospholipid metabolism that produces decreased synthesis of membranes primarily affecting synapses. This process manifests itself as abnormal synaptic pruning of the type that takes place normally in adolescence, at least in non-human primates. 31P MRS (phosphorous spectrum) studies with schizophrenia participants have consistently found alterations of membrane phospholipid metabolism, while 1H MRS (hydrogen spectrum) studies have demonstrated loss of neuronal cells evidenced by reduced NAA. The process appears to involve a cycle of membrane breakdown reflected in the increase of a metabolite called phosphodiester (PDE) followed by attempts at repair reflected in elevation of phosphomonoester (PME). Dopamine becomes involved in this process because of an agent called dopamine-cAMP-regulated phosphoprotein (DARPP) that is involved in phosphorylation of membrane channels and receptors, apparently involved in cell repair. There is the possibility that some individuals with schizophrenia, in addition to these developmental abnormalities, sustain a neurodegenerative process in later life. This group may constitute what has been described as ‘‘Kraepelinian’’ or ‘‘Very Poor Outcome’’ Schizophrenia.

Genetic factors The currently most favored view concerning the basis for these neurobiological phenomena is that they are genetic in origin. There has been an enormous amount of genetic research in schizophrenia ranging from earlier population or family descriptive studies of twins to state-of-the-art laboratory investigations. Probably the best conceptualization of the current status of the field has been made by Weinberger who has written that there are currently several

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promising candidate genes. They are catechol O-methyltransferase (COMT), dysbindin-1, neuregulin 1 (NRG1), metabotropic glutamate receptor 3 (GRM-3), glutamate decarboxylase 1, and disrupted in schizophrenia 1 (DISC1). COMT has probably been the most extensively studied. It affects prefrontal function by altering the regulation of dopamine activity in the brainstem. GRM-3 plays a similar role by affecting glutamate synapses. DISC1 affects hippocampal function, and dysbindin-1 appears to have a general influence on cognitive capacity. These genes are characterized as ‘‘susceptibility genes’’ that may influence development of the schizophrenic phenotype. A detailed description of these and other genes and their possible relations to schizophrenia are presented in an extensive review by Harrison & Weinberger (2005). While the most extensive work has been done with COMT, there is a particularly interesting susceptibility gene from the standpoint of the MRS derived abnormal synaptic pruning theory. It is called neuregulin 1 (NRG1) and is of interest because of its role as a growth factor involved in neuronal migration, axon guidance, synaptogenesis, glial differentiation, and myelination. Harrison and Weinberger conclude that the various candidate or susceptibility genes converge on schizophrenia risk through influencing ‘‘synaptic plasticity and the development and stability of cortical microcircuitry’’ (Harrison & Weinberger, 2005, p. 1). The neuropathological or neuroanatomic and neurochemical conceptualization of schizophrenia as illustrated by studies of visible structural abnormalities such as enlarged lateral ventricles and by the ‘‘dopamine hypothesis’’ are in large part outdated and have been replaced by advanced methodologies in microbiology, neuroimaging, and genetics. This work has not yet led to any definitive conclusions about the specific biology of schizophrenia, although there is abundant evidence of abnormalities in synaptic transmission and microcircuitry in the brain
abnormalities that are apparently influenced by multiple genetic factors, involving numerous genes and gene interactions.

Treatment Pharmacological, somatic, behavioral, and rehabilitative treatments have been developed for schizophrenia over the years, although medication is currently considered an essential component of any treatment program. While it is a chronic disorder, it is probably not productive to characterize it as incurable. It is clearly treatable, and does not resemble incurable illnesses such as certain forms of cancer or dementia in which no form of treatment has any effect on outcome. Remission clearly occurs in schizophrenia, and sometimes

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may exist to the extent that individuals with the disorder have been described as indistinguishable from normal community dwellers. Historically, the use of somatic treatments preceded the advent of the pharmacological treatments, but sometimes they may be used concurrently. They include hydrotherapy, electroconvulsive (shock) therapy (ECT), insulin shock therapy, and psychosurgery. These methods are rarely used in contemporary treatment. The development of new drugs to treat schizophrenia have been a boon to interventions for the disorder, with the most recent strides made in the development of what have been variously referred to as ‘‘atypical,’’ ‘‘second generation,’’ or ‘‘novel’’ antipsychotics (Arnt & Skarsfeldt, 1998). Unlike their predecessors, which were primarily dopamine antagonists, these novel antipsychotics have affinity for serotonergic 5-HT2 receptors and a1 adrenoceptors, in addition to dopamine D2 receptor affinity. Clozapine was the first in this new generation of medications, followed by risperidone, olanzapine, sertindole, and more recently quetiapine. Novel APDs have been shown to produce less extra-pyramidal side effects (EPS) and decrease negative symptoms, including neurocognitive deficits, when compared to traditional antipsychotics, potentially because of their combined serotonergic and dopaminergic affinities. Serotonergic neurons inhibit functioning of the dopaminergic system in midbrain structures, where the dopaminergic system originates (Kelland, Freeman, & Chiodo, 1990), as well as in the striatum and forebrain, including the prefrontal cortex (Ashby et al., 1990). Antagonism of the serotonergic system decreases inhibition of the dopaminergic system which, in turn, may account for the reduction in EPS (striatum) and reduction in negative symptoms (prefrontal cortex) noted following treatment with novel antipsychotic agents (Kapur & Remington, 1996). A major challenge to pharmacological treatment has been the patient who does not respond to these medications. This condition has been described as treatmentresistant schizophrenia, and some years ago attempts were initiated to find new drugs to deal with this difficulty. The most widely studied of these drugs is clozapine, which was shown to be effective with patients who did not respond to the conventional antipsychotic medications. Clozapine has since been established as having third-line status to be used only when there is no response to two other antipsychotic medications. The reason for this policy is that use of clozapine has been associated in some cases with the development of agranulocytosis. Recent research has shown that some of the other atypical medications are superior to haloperidol when used with treatment-resistant patients. Current treatment of schizophrenia in general now includes use of one of the atypical medications, with use of haloperidol or other ‘‘first generation’’ antipsychotics being substantially less common.

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Recent emphasis has been placed on evidence-based treatments whose effectiveness is supported by research. In the case of schizophrenia, Drake et al. (2000) have listed several such areas including (1) use of medications; (2) illness self-management; (3) case management in the community; (4) family psychoeducation; (5) supported employment; (6) substance abuse treatment. There is a developing field of intensive case management in which the patient is followed and appropriate interventions are made from hospitalization through life in the community. One of the first published controlled clinical trials of a psychosocial intervention tested the efficacy of individual analytically oriented psychotherapy for schizophrenia; patients were assigned to one of five treatment regimens: individual psychotherapy alone, antipsychotic medication alone, the combination of the two, ECT, and ‘‘milieu’’ treatment. The contrast between psychotherapy with pharmacotherapy and the psychotherapy with a no-medication placebo showed no independent or incremental benefit of analytically oriented psychotherapy as compared to somatic therapies at either the termination of inpatient treatment or at 3
5 years following treatment termination (May, Tuma, & Dixon, 1981). Empirical findings on contemporary psychosocial interventions for schizophrenia indicate that they have variable efficacy depending on several key factors. Interventions that have empirical support can be conceptualized and organized in terms of four key dimensions: (1) the phase of illness (i.e., early acute versus the later, more stable phase of illness); (2) the specific focus or goals of treatment (e.g., enhancement of compliance with treatment, increasing socialization, versus reduction of positive symptoms); (3) the format of delivery (e.g., individual-, group-, or family-based); and (4) the theoretical model and the related intervention techniques (e.g., behavioral versus cognitive-behavioral). A brief review of the current literature on efficacy of psychosocial treatments for schizophrenia follows. Early phase of illness

Particularly relevant to the treatment of the early phase of schizophrenia is psychoeducation. In general, psychoeducational interventions aim to inform the patient (and significant others) regarding the nature of the disorder, the intended impact of medications and their possible side effects, early warning signs of relapse or recurrence, and other issues particularly pertinent to the transition from acute and intensive care to community-based care. Psychoeducational intervention alone is unlikely to have an impact on treatment adherence, although mixed modality (family and individual) approaches and

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Gerald Goldstein et al.

individual approaches that incorporate behavioral interventions, skills-building, and/or supportive services yield the most consistent and promising evidence for a positive impact on medication adherence (Zygmunt et al., 2002). Also showing evidence for an impact on treatment adherence are family-based psychoeducational approaches of two general types: those that include a behavioral component and specifically focus on family support for treatment adherence (Falloon and Pederson, 1985; Razali and Najib, 2000), and supportive family-based psychoeducation as a component of mixed modality interventions that include either a behavioral component (Azrin & Teichner, 1998) or focus on anticipated stressors, coping skills and problem-solving techniques, as well as the rationale for selected treatments and for long-term adherence to a program of maintenance medication (Goldstein et al., 1978; Hogarty et al., 1979; Glick et al., 1990). Work with the patient and family around identification of early warning signs during the acute phase is a core component of those family interventions that are designed to prepare for transition to community-based care (Glick et al., 1990; Herz and Lamberti, 1995). Empirically supported, family-based psychoeducational interventions launched during the acute episode phase of treatment address such issues of daily living as drug use, stigma, treatment noncompliance, and family criticism or emotional over-involvement (Goldstein et al., 1978; Leff et al., 1982). Family intervention shows a relatively consistent effect of significantly reducing rates of relapse and rehospitalization (Pharoah, Mari, & Streiner, 2003; Pitschel-Walz et al., 2001). Transition to stabilization phase

For the period of symptom resolution, current clinical practice guidelines call for a combination of pharmacologic intervention and supportive psychotherapy or a program of continued case management (Lehman, 1999). A key feature of this early phase of transitional care is the effort to instill hope in order to minimize and/or counteract depression and suicidality. For this phase of treatment, cognitive interventions that aim to combat depressogenic cognitions and enhance everyday coping skills and problem-solving behaviors appear to have utility in forestalling or preventing relapse. Such interventions aim to reduce the emotional impact of the emergence of secondary symptoms (e.g., anxiety, depression, suicidality) that are common to the post-psychotic phase of recovery. During the outpatient stabilization phase, the introduction of focused cognitive techniques within a supportive intervention can be initiated for relief of acute positive symptoms. There is some support for introducing cognitivebehavioral interventions that involve identifying delusional beliefs and learning to question and consider alternative cognitions. Tarrier et al. (2004) showed a greater reduction in anxiety and delusions among patients treated with a brief

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Schizophrenia

cognitive-behavioral therapy than those who received usual care. Drury et al. (1996) reported that an application of traditional cognitive-behavioral therapy is effective in reducing positive symptoms when introduced in combination with family intervention and structured activity interventions during the initial phase of treatment for acute psychosis. One general conclusion from a review of the controlled clinical trials of cognitive-behavioral therapies is that cognitive-behavioral interventions can have a positive impact on positive symptoms for individuals in the early, acute phase of the illness (Drury et al., 1996; Tarrier et al., 2004) as well as during the early stage of relapse (Gumley et al., 2003). It has also been shown to enhance coping with the problems of treatment-refractory positive symptoms. Systematic reviews of the findings from random-assignment clinical trials of cognitive-behavioral therapeutic approaches are handicapped by the heterogeneity of study design, variation in the timing and duration of treatment, phase of illness, and outcome domains measured. Thus, general conclusions from these reviews are equivocal, showing some evidence for positive symptom reduction, particularly during treatment but with questionable durability beyond treatment termination; minimal or no impact on negative symptoms; and no impact on relapse rates (Pilling et al., 2002). Subsequent controlled clinical trials have offered additional support to the evidence base. Applications of cognitive-behavioral approaches for medication non-responsiveness during the maintenance phase of schizophrenia have demonstrated a positive impact on symptom remission. Finally, there is some evidence that a relatively brief (20-session) cognitivebehavioral therapy added to standard multimodal treatment may have an incremental impact on negative symptoms over the long term. In the study by Tarrier et al. (2004), the specific benefits of a cognitive-behavioral therapy were found to be the long-term maintenance of improvement in both positive and negative symptoms at a 12-month follow-up. Cognitive-behavioral interventions that aim to reduce positive symptoms and enhance and maintain compliance with pharmacotherapeutic regimens have some demonstrated efficacy for the stabilization phase of care. Maintenance phase

Continuation of regular contact with a care provider is indicated for the maintenance phase of treatment following recent recovery from an episode and during the inter-episode phase of partial symptom remission. Programmatic psychosocial interventions are generally introduced as part of an overall strategy that aims to promote effective adaptation to the impact of the illness and residual symptoms. Social skills training has been shown to be an effective approach to the problems of illness self-management (Eckman et al., 1992) and

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socialization, although generalization beyond the training setting appears to be limited. In controlled clinical trials of social role therapy and, subsequently, an individually tailored psychotherapy, Hogarty et al. (1997) found that individuals in these social skills interventions showed improvements in social functioning and personal adjustment superior to those of individuals who received a combination of a supportive psychotherapy and family psychoeducation. Components of this multimodal approach include long-term programs of social skill interventions, vocational rehabilitation, and cognitive remediation approaches to enhance social and work role functioning. Cognitive rehabilitation has become an important form of intervention, advancing to comprehensive programs targeted toward direct remediation of the cognitive deficits that characterize schizophrenia. Wykes et al. (2003) have shown success using such techniques as errorless learning to effect improvement in executive function and memory with secondary benefits to self-esteem. Hogarty et al. (2004) have targeted aspects of social cognition, while others have trained a variety of cognitive abilities including facial affect recognition, memory, attention, and the executive abilities associated with the card sorting training. Several programs have integrated cognitive training in vocational applications involving work therapy or supported employment.

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64.

3

Schizophrenia among children and adolescents Jason Schiffman Department of Psychology, University of Hawaii at Manoa

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B
A
B B
B C
B C B

Notes: Age of onset received an A
because this is the defining characteristic of childhood-onset schizophrenia relative to adulthood. It should be noted, however, that the age of onset varies among youth and can range from as early as 5 until 18. Treatment received a B, but the strength of the evidence is among psychopharmacological treatments. To date, psychosocial interventions have not been systematically examined to the degree psychopharmacological treatments have, and would therefore receive a C if rated independently.

Introduction Schizophrenia among young people is a devastating and costly mental illness. Considered a more severe variant of adult schizophrenia, childhood schizophrenia can be a terrifying and debilitating condition for youth and family. Although the disorder is rare, interest in schizophrenia among children and adolescents has 39

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Jason Schiffman

grown as researchers and clinicians recognize the benefits of understanding the disorder. Continued research promises to increase the ability to diagnose and treat early forms of schizophrenia. Additionally, the study of early-onset variants of disorders often enables the examination of a more genetically homogeneous and less environmentally influenced disease condition. As such, understanding earlyonset schizophrenia may possibly provide useful information about the etiology and course of adult-onset schizophrenia (Kumra et al., 2000). Despite growing interest, however, research on schizophrenia among children and adolescents is limited. Several research groups currently pursue studies of individuals with early schizophrenia to discern functional and structural deficits associated with the disorder (e.g., Asarnow & Asarnow, 2003). While ongoing research continues to increase our understanding of biological and environmental factors associated with and contributing to the disorder, the rarity of the condition has resulted in only modest gains in understanding. Factors associated with early-onset schizophrenia such as basic demographics (e.g., prevalence, gender distribution, comorbidity), presentation, course and outcome, neuropathology, genetic factors, and treatment remain areas of relative mystery. Increased knowledge of the general portrait presented by children and adolescents with schizophrenia may increase understanding and have implications for mental health care provision. Epidemiology Prevalence of schizophrenia among youth

Very few studies have tracked rates of schizophrenia among youth in the general population. Gillberg and Steffenburg (1987) estimated very early onset schizophrenia (10 years of age or younger) rates at 1.6 per 100,000 in western Sweden. Remschmidt et al. (1994) suggested that approximately one in 10,000 children develop schizophrenia before 18 years of age. Among slightly older (12 to 19 years) youth receiving psychiatric outpatient services, Evans and Acton (1972) reported that the rate of a more inclusive condition of psychosis was approximately one percent. A study by Thomsen (1996) looked at childhood and adolescent onset schizophrenia throughout Denmark from 1970 to 1993. Findings indicated that 32 children younger than 15 met criteria for schizophrenia between 1970 and 1993, comprising 86% of the psychiatric in-patient population in this age group. As would be expected, the occurrence of schizophrenia increased with age. Between ages 15 and 17, 284 adolescents with schizophrenia were hospitalized from 1970 to 1993. Although informative, this Danish study did not include youth

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served in non-hospital settings. Given a trend towards least restrictive care in the United States, many children and adolescents with schizophrenia in the USA probably receive treatment outside of the hospital. While prevalence estimates in the USA are rare, we recently completed a study of youth with schizophrenia spectrum disorders served by the state mental health system of Hawaii (Schiffman & Daleiden, 2006). Schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder, psychotic disorder NOS) may be of particular interest to researchers and clinicians because they are genetically linked to schizophrenia and are slightly more available for study. Among other findings assessing children and adolescents seeking services through both hospitalization and community clinics served by the state mental health system in Hawaii, we estimated an observed prevalence of 5% among all youth registered for mental health services. As might be expected, the Hawaii analysis, which included home and community services, yielded a slightly lower prevalence rate estimate than that reported in a psychiatric in-patient population (Thomsen, 1996). In general, most studies of the epidemiology of early-onset schizophrenia converge to suggest low rates of the disorder attesting to the rarity of this condition among youth. Additional epidemiological reports are needed to augment the current understanding of schizophrenia in children and adolescents. Overall, Asarnow and Asarnow (2003, p. 461) note that current ‘‘prevalence figures must be viewed as highly tentative until more representative data become available’’. Gender distribution

Previous research suggests a male-to-female ratio ranging from 2:1 to 5:1 (Beitchman, 1985; Evans & Acton, 1972; Green et al., 1992; Hollis, 1995; Thomsen, 1996; Werry, 1992). Findings from the Hawaii study suggest a maleto-female ratio of 1 to 2.38 among youth with schizophrenia spectrum disorders. This range of gender ratios conflicts with general prevalence estimates of adult schizophrenia that suggest approximately equal gender distribution, but is consistent with the notion that males typically have an earlier age of onset than females. Kolvin et al. (1971) suggested that the predominance of males among youth with schizophrenia is a distinguishing characteristic of early-onset schizophrenia. Comorbidity

Youth with schizophrenia typically have multiple diagnoses. A study by Russell, Bott, Sammons (1989) reported that 68% of children with schizophrenia in their sample met criteria for another mental illness. Reports from the literature indicate that externalizing disorders such as conduct or oppositional defiant disorders as

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well as internalizing disorders such as depression are commonly diagnosed along with a schizophrenia spectrum diagnosis (Eggers, 1989; Nicolson et al., 2001; Werry, McClellan, & Chard, 1991). Among youth with psychosis, a study by Biederman et al. (2004) indicated that 131 of 132 identified youth with psychosis had a comorbid disorder. In the Hawaii study, disruptive behaviors and attentional problems were the most frequently diagnosed comorbid conditions for both youth with and without spectrum disorders. The rate of comorbid disruptive behavior and attentional problems among the comparison group of all youth in the system without a schizophrenia spectrum disorder (‘‘non-spectrum youth’’), however, was significantly greater than among youth with spectrum disorders. This pattern of results suggests that youth with disruptive and attentional disorders are more likely to be registered with the Department of Health than youth with any other diagnosis, but this effect was not as pronounced for youth with schizophrenia spectrum disorders. Youth with schizophrenia are also more likely to have mental retardation (Aylward, Walker, & Bettes, 1984). Consistent with that finding, youth in the Hawaii study with spectrum disorders were more likely to have a diagnosis of mental retardation than non-spectrum youth. Aylward et al. (1984) suggested that mental retardation can serve as a premorbid feature of early-onset schizophrenia and may relate to the course of the illness. This link between mental retardation and early-onset schizophrenia, however, may be underrepresented as some research groups exclude youth with severe intellectual disabilities from their studies of childhood schizophrenia (Friedlander & Donnely, 2004). Ethnicity

Given the rarity of the condition, research does not provide a clear description of the ethnic breakdown of youth with schizophrenia. Studying youth in Hawaii offered the advantage of a large multi-ethnic sample. This is particularly beneficial with childhood-onset schizophrenia as demographics in general are poorly understood and under studied. In the Hawaii study, ethnic background did not significantly differ between the spectrum and non-spectrum groups, with the exception of Asian youth (Schiffman & Daleiden, 2006). Our findings indicated that Asian youth accounted for a larger proportion of the spectrum disorder group than the non-spectrum control group of all other registered youth. The proportion of Asian youth in the non-spectrum group (18.2%) was less than the proportion of Asian youth (29.9%) in the general Hawaii population (US Census Bureau, 2000). The proportion of Asian youth in the spectrum group (30.2%) resembled the general population of Asian youth in Hawaii. Studies have reported lower representation among Asian Americans in hospital-based and

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community mental health service populations than expected based on census estimates (Leong, 1994). The source of underutilization is unclear, however, cultural factors may partially account for this finding (Leong, 1994; Sue & Morishima, 1982). The closer approximation to census estimates in the group of youth with schizophrenia spectrum disorders may suggest that, among other possibilities, the severity of spectrum disorders may contribute to the increased likelihood that Asian youth with schizophrenia spectrum disorders receive mental health services.

Age of onset The modal age of onset of typical schizophrenia is in early adulthood, usually before 25 years of age. While specific age cutoffs for early onset vary in the literature, researchers generally consider schizophrenia diagnosed before age 18 as early onset. Diagnoses before age 13 are rare and often labeled as ‘‘very early onset.’’ Given the low base rate of the phenomenon and normal developmental processes (e.g., childhood imagination), diagnosing schizophrenia prior to age seven is extremely uncommon. As might be expected, the rate of schizophrenia among youth increases with age. Among youth in Hawaii, registered youth with a diagnosis of a schizophrenia spectrum disorder in the mental health system were significantly older in relation to all other registered youth (14.6 years versus 12.0 years; Schiffman & Daleiden, 2006).

Presentation First rank symptoms

Current DSM-IV-TR diagnostic criteria for childhood-onset schizophrenia are the same as those used for adult schizophrenia. As with adults, the hallmark symptoms include delusions and hallucinations. When sufficiently severe, only one of these symptoms is required for a diagnosis. Other symptoms include disorganized speech, disorganized or catatonic behavior, and negative symptoms. In addition to the characteristic symptoms, DSM-IV-TR (American Psychiatric Association, 2000) also requires social or occupational dysfunction (generally school performance for young people), symptoms for at least six months, and symptoms not better accounted for by mood disorders, schizoaffective disorder, substance use, a general medical condition, or a pervasive developmental disorder (for pervasive developmental disorders, schizophrenia is given if delusions or hallucinations are present for at least a month).

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Specific patterns of symptom presentation among youth with schizophrenia are not well studied. Russell et al. (1989) reported hallucinations in 80% of their sample of 35 children with schizophrenia, with auditory hallucinations the most common form, followed by visual. Delusions were reported in approximately 63% of cases from this sample. In a descriptive account of 33 youth with schizophrenia, Werry et al. (1994) indicated that 61% of their sample reported hallucinations (57% auditory), and 55% of their sample reported delusions. The authors also noted that delusions tended to be less well-formed relative to adults. Communication may be impaired in youth with schizophrenia, with Caplan (1994) noting three patterns of deficits among 31 children with schizophrenia, including impaired discourse skills, loose associations, and illogical thinking. In a relatively large study of 132 youth with psychosis, Biederman et al. (2004) reported that 44% of the sample suffered from delusions, and 85% hallucinations. Auditory hallucinations were most common (79%), followed by visual (54%), tactile (23%), and olfactory (13%). Within delusions, delusions of persecution and reference were most common (27% and 23% respectively). Approximately 20% of youth expressed other symptoms such as incoherence, loosening of associations, flat affect, and inappropriate affect. Diagnostic methods

Developmental considerations may influence diagnostic decisions when evaluating children for schizophrenia, as the presentation quality of symptoms may differ from those seen in adulthood. For instance, some researchers suggest that negative symptoms are less common among children with schizophrenia, and delusions and hallucinations may be less well developed and involve more childlike themes (monsters or toys versus religious or sexual themes) (Volkmar, 2001). Evidence suggests that when accounting for developmental considerations, schizophrenia in children can be reliably diagnosed (Werry, 1992). Diagnostic interviews, such as the Schedule for Affective Disorders and Schizophrenia for School-Age Children, are useful in increasing the reliability and validity of the diagnosis (Kaufman et al., 1997). This interview provides the assessor developmentally tailored questions assessing for symptoms associated with schizophrenia and other disorders as expressed in childhood. Neuropsychological deficits

In addition to symptom presentation, youth with schizophrenia demonstrate a host of neuropsychological deficits. Most of these deficits are similar to those seen in adult schizophrenia. Kumra et al. (2000) reported that children with schizophrenia (average age 14.4 years) consistently demonstrated one to two

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standard deviation impairment across a range of neuropsychological tests (general IQ, achievement, attention, executive functioning, memory, motor skills, etc.). Likewise, in a review, Asarnow and Asarnow (2003) reported a similar array of neurocognitive deficits among children with schizophrenia (attention, visualmotor coordination and fine motor speed, executive functioning, and various forms of memory). Several studies have looked at particular patterns of neurocognitive deficits among young people with schizophrenia. A study of 17 adolescents with schizophrenia supported the global cognitive dysfunction findings, and specifically noted larger differences between cases and controls on working memory and attention (Kenny et al., 1997). Oie and Rund (1999) also reported similar global impairment among 19 adolescents with schizophrenia compared to control groups with and without other psychiatric conditions (Attention-Deficit Hyperactivity Disorder). The authors indicated particular deficits in the areas of abstraction, visual memory, and motor functioning. Among never medicated, first episode adolescents with psychosis (most of whom either subsequently developed schizophrenia or were deemed to have the disorder after further review of history), Brickman et al. (2004) reported global neuropsychological deficits, with the greatest deficits observed in executive functioning, attention, and memory. The authors also reported relatively intact language functioning, a finding also reported by Kenny et al. (1997). The findings from Brickman et al. (2004) are of particular interest as subjects were free of the potentially confounding impacts of neuroleptic treatment and long duration of illness. Collectively, these findings strongly support global neurocognitive impairment among youth with schizophrenia, with specific areas of relative deficits seeming to fall in the domains of memory (of varying type), attention, executive functioning, and perhaps motor functioning. Psychosis not otherwise specified

Interestingly, studies of neurocognitive functioning reveal that youth with schizophrenia resemble a potentially related group of youth not meeting full criteria for the disorder. As with adults, youth with psychotic symptoms not reaching diagnostic threshold for full schizophrenia are often diagnosed with psychotic disorder NOS. Neurocognitive reports comparing youth with childhood-onset schizophrenia to a group of youth with psychotic disorder NOS suggest few meaningful differences in neurocognitive profiles (McClellan et al., 2004). Given similarities in neurocognitive performance and symptoms presentations, some researchers speculate that psychotic disorder NOS may be a less severe condition genetically related to childhood-onset schizophrenia (Kumra et al., 2000).

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Course and progression The premorbid course of childhood-onset schizophrenia appears associated with an array of functional deficits. Kolvin et al. (1971), as well as others (AlaghbandRad et al., 1995; Hollis, 1995; Nicolson et al., 2000; Russell et al., 1989), report high rates of developmental delays including speech and language and social peculiarities. A more recent study by Nicolson and colleagues (2000) reported that over half of the 49 children with schizophrenia in their sample had premorbid impairment in motor, social, and speech and language functioning. While there was no comparison group in this study, the rate of impairment seems strikingly high and suggests a developmentally deviant premorbid course. The course of childhood schizophrenia once diagnosed is under studied and varies by individual. As seen in adult schizophrenia, it is believed that the progression roughly follows a period of deterioration, followed by stabilization, and hopefully improvement (Merry & Werry, 2001, p. 280). Based on a review of several studies of varying methodology tracking outcome among youth with a schizophrenia diagnosis, reviews by Asarnow, Tompson, and McGrath (2004) and McClellan et al. (2001) indicate that about one-half of youth with schizophrenia remain severely impaired over time, with the other half showing a variable course with some improvement in psychotic symptoms. A longitudinal descriptive report of psychosocial outcome among adolescents with schizophrenia by Lay et al. (2000) indicated that, among those available for follow-up at ten or more years, 83% had at least one re-hospitalization, 57% showed at least moderately vocational impairment, and 75% were supported by either their parents or public means. Generally, most evidence suggests that the majority of youth with schizophrenia show a slower onset and chronic pattern as opposed to an acute psychotic break (Asarnow et al., 2004). While difficult to compare directly, Nicolson et al. (2000) suggest that the premorbid course for individuals with childhood-onset schizophrenia may be worse than the premorbid course for adult-onset schizophrenia. Additionally, it seems that the earlier the onset, the worse the prognosis (Merry & Werry, 2001, p. 294). Among youth with psychotic disorders, those with worse premorbid characteristics and earlier onset tend to have worse outcomes. McClellan and colleagues note that poor premorbid adjustment, negative symptoms, and low IQ predicted poor outcome among youth with psychotic disorders (McClellen et al., 1999; Werry & McClellan, 1992). Similarly, Nicolson et al. (2001) reported that high levels of psychopathology, cognitive deficits, and motor impairments predicted poor outcome among a sample of 26 youth with psychotic disorder NOS. Collectively, these findings suggest that schizophrenia spectrum disorders

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in childhood appear associated with poor long-term outcome, with the worst outcomes associated with earlier onset, poor premorbid functioning, and impairment at intake (Asarnow et al., 2004; Gillberg, Hellgren, & Gillberg, 1993; Werry et al., 1991).

Suspected neuropathology A series of studies from the Child Psychiatry Branch of the National Institute of Mental Health (NIMH) suggest reduction in cerebral volume and pervasive pattern of brain deterioration in childhood-onset schizophrenia. Similar to adult schizophrenia, individuals with childhood-onset schizophrenia tend to have ventricular enlargement and progressive loss of gray matter (4% reduction in cerebral volume) (Rapoport et al., 1997; Rapoport et al., 1999). Confirming initial findings, Sowell et al. (2000) identified a similar reduction in gray matter and enlarged ventricles in an independent sample. Although limited in number, a handful of imaging studies suggest various other brain abnormalities seen in childhood-onset schizophrenia. Findings include abnormalities in the corpus callosum (Jacobsen et al., 1997; Keller et al., 2003; Sowell et al., 2000), and subcortical structures such as the vermis (Jacobsen et al., 1997) and basal ganglia (Blanton et al., 1999). Several follow-up studies from the NIMH group identify brain deterioration over time among youth with schizophrenia. For instance, Giedd et al. (1999) reported progressive brain deterioration among youth with schizophrenia, noting decreases in cerebrum and hippocampus volume, and increases in the lateral ventricles. The rates of deterioration appeared to level off as youth entered adolescence. Thompson (2002), discussing data from this project, noted a relation between rate of temporal cortical loss and positive symptoms, as well as a relation between gray matter loss in the frontal cortices and negative symptoms. In a more detailed and recent analysis, including additional subjects from the NIH project, Sporn et al. (2003) identified progressive loss in the frontal and temporal cortices across multiple assessments, suggesting neural deterioration spreading from parietal regions towards the cortex. Similar to the earlier study, the authors also noted that gray matter loss appeared to level off with age. Gray matter loss was related to premorbid impairment but, in contrast to an earlier report by Thompson (2002), it was also related to greater clinical improvement as measured by the Brief Psychiatric Rating Scale and the Scale for the Assessment of Negative Symptoms scores. The authors speculate that perhaps ‘‘compensatory ‘pruning’ of malfunctioning neural circuits’’ might in part begin to explain the relation

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between clinical improvement and brain volume loss (Sporn et al., 2003, p. 2188). Future imaging work among youth with schizophrenia is needed to replicate these early studies, as well as provide additional findings with respect to brain structure, function, and change over time. Related to imaging studies of neuropathology is the study of neurological functioning. Using a subsample from the above-described NIH study, Karp et al. (2001) noted high rates of neurologic abnormalities, including elevated rates of primitive reflexes and other abnormalities relative to controls, that persisted with age among youth with childhood-onset schizophrenia. These deficits suggest hemispheric inhibition of the brainstem, and strongly support general deficiencies in normal maturation. According to the authors, results from the study highlight the role of genetically mediated early central nervous system insults in the etiology of childhood-onset schizophrenia. Suspected neurochemical abnormalities Little is known about specific neurochemical abnormalities underlying schizophrenia in childhood. Perceiving childhood-onset schizophrenia as a related and continuous disorder with adult schizophrenia allows speculation that neurochemical abnormalities present in adult schizophrenia are similar to those found in childhood schizophrenia (e.g., dopamine, glutamate, serotonin). Much of the evidence for the influence of dopamine in adult schizophrenia comes from the fact that patients respond favorably to anti-dopaminergic medications and that dopamine agonists can cause psychotic symptoms among non-psychiatric individuals. This same pattern is true in children. While enough evidence exists to suggest that dopamine plays a role in childhood schizophrenia, specifics of that role are not understood. The few studies conducted in this domain with children report similar patterns of results as those typically found in adult schizophrenia (Asarnow & Karatekin, 2001). Genetic factors Early onset of schizophrenia seems associated with high genetic loading for the disorder. Research has borne out this relation, noting an increased risk of schizophrenia among the relatives of children with schizophrenia (Asarnow et al., 2001; Sham, MacLean, & Kendler, 1994). Asarnow et al. (2001) reported that the relatives of children with schizophrenia in their study were 17 times more likely to have a schizophrenia spectrum disorder in relation to controls. This risk is obviously far greater than the risk in the general population, as well as greater than that found in similar studies of relatives of adults with schizophrenia

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(three to six times more likely among relatives of adults with schizophrenia). Findings from this report suggest an increased genetic component to schizophrenia in childhood over and above that found in adult schizophrenia. In a similar report, Nicolson et al. (2003) advanced this line of study by including relatives of patients with adult-onset schizophrenia as a control group. Findings confirmed speculations made by Asarnow et al. (2001) that youth with schizophrenia are more likely to have relatives with a schizophrenia spectrum disorder in relation to adults with typical-age-of-onset schizophrenia. Collectively, these findings support the strong role of genetic contributions to early-onset schizophrenia. Other risk factors Obstetrical complication

In two independent samples, Matsumoto et al. (1999; 2001) reported an increase in obstetrical complications (OCs) associated with early-onset schizophrenia (16 years old and younger) in relation to control subjects. In both studies, individuals with obstetrical complications were over three times more likely to develop childhood-onset schizophrenia relative to psychiatric controls. This finding is consistent with other reports suggesting a link between OCs and earlier age of onset in adult schizophrenia (Rosso & Cannon, 2003), and a wealth of literature suggesting increased OCs among individuals with schizophrenia in general. As seen with other correlates, Matsumoto and colleagues suggest that the similarity in the relation between childhood and adult schizophrenia and OCs indicate continuity between the two disorders. Contrary to the findings from Matsumoto et al. (1999, 2001), Nicolson and Rapoport (1999) did not find an elevation in OCs among individuals with childhood-onset schizophrenia. The comparison group employed by Nicolson and Rapoport, however, was composed of the siblings of the patients who may share genetic risk for OCs, rather than genetically independent controls. Interestingly, however, the percentage of individuals with childhood-onset schizophrenia who had OCs were similar in both studies (34.3% in the Matsumoto et al. (2001) sample, 27.7% in the Nicolson and Rapoport (1999) sample). Treatment Level and cost of care

Schizophrenia in adulthood is associated with high levels of care and high cost for services (Cuffel et al., 1996; King, Singh, & Shepherd, 2000). In our analysis

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of youth with schizophrenia spectrum disorders in Hawaii, we found aboveaverage use of more restrictive levels of care. More restrictive levels of care may reflect that youth with schizophrenia spectrum disorders struggle with more severe problems. Problems faced by these youth may require great environmental resources and possibly put these individuals in danger. It is important to note, however, that results from the service analyses in the Hawaii study suggest that approximately four out of five youth with services procured for schizophrenia spectrum problems were treated in home or community settings. Approximately one half received intensive home and community services and almost all received less intensive outpatient services. In addition to requiring more services, we found that youth with spectrum disorders are financially expensive relative to other youth in the system. The average annual cost per youth with a schizophrenia spectrum disorder in Hawaii was $16,420, a rate nearly twice as high as the average annual cost per youth of others in the system. Schizophrenia is an expensive illness to manage, especially among young people. The above-average use of more restrictive services would seem to highlight an opportunity for the development of evidence-based strategies that support management of schizophrenia spectrum disorders in home and community settings. Presently, intervention with neuroleptic medication is the only empirically supported treatment for early-onset schizophrenia. Although the benefits of psychopharmacology are well documented, the intervention is global and does not specifically target individual areas of concern. Mental health therapists are likely to benefit from structured psychosocial strategies effective in helping youth with schizophrenia spectrum disorders. The efficacy of structured psychosocial interventions for early-onset schizophrenia has not yet been systematically assessed. Evidence from a range of areas, however, suggests that a psychosocial intervention targeting specific symptoms might benefit youth with early-onset schizophrenia (discussed below), especially when used as an adjunct to psychopharmacological intervention. Psychopharmacological treatment

Atypical neuroleptics seem to be the most effective means of treating childhood schizophrenia. Most research has focused on clozapine, with more recent studies beginning to investigate other atypical neuroleptics (Zalsman et al., 2003). As in adults, clozapine seems to offer the advantages of effectively treating both positive and negative symptoms, with less extrapyramidal side effects relative to typical neuroleptics. Less side effects, particularly attenuated extrapyramidal symptoms, generally lead to increased tolerability and medication compliance. Potentially fatal risk, however, is associated with clozapine (e.g., agranulocytosis), and

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therefore clozapine is not recommended as the first option in treating early-onset schizophrenia. Rather, non-clozapine atypical neuroleptics, not associated with fatal risk, are generally recommended. Two open-label studies of other atypical neuroleptics (one of risperidone and the other of olanzapine) have been conducted with youth with schizophrenia, with promising results. While these medications are not associated with life-threatening side effects, most do have some significant side effects, including, among others, some extrapyramidal symptoms, and significant and sometimes distressing weight gain and sedation. Given the rarity of the disorder, medication trials pose formidable methodological barriers that have slowed research in this area. In a recent review of the existing literature, Cheng-Shannon et al. (2004) concluded that atypical antipsychotic medications are in fact useful in treating psychosis among youth. The American Academy of Child and Adolescent Psychiatry practice parameters for the treatment of childhood schizophrenia also express this sentiment. Despite these positive conclusions, Remschmidt et al. (2001) estimated that approximately 15% of childhood-onset patients do not respond to typical or atypical neuroleptics. Additionally, while it appears that pharmacological therapy is useful for youth struggling with psychotic symptoms, little is known about the long-term effects of these medications. Frequent and regular contact with the treating psychiatrist is recommended. Psychosocial treatments

Practice parameters for the treatment of childhood schizophrenia established by the American Academy of Child and Adolescent Psychiatry call for a two-pronged symptom-specific and general-functioning approach to treatment. Specific symptom targeting includes addressing positive and negative symptoms directly, while general functioning refers to more broad social, academic, and family needs. The practice parameters call for a ‘‘comprehensive multimodal approach’’ to treatment (McClellan et al., 2001, p. 145), taking into consideration comorbid conditions and developmental considerations. This position is consistent with one study that systematically investigated a comprehensive community treatment approach for a small group of adolescents with schizophrenia reporting positive effects of working with parents, problem solving skills, and re-integration efforts (Rund et al., 1994). University of Hawaii child and adolescent thought disorders program

The Child and Adolescent Thought Disorders Program at the University of Hawaii at Manoa was established in 2003 to provide comprehensive assessment and psychosocial interventions to youth with schizophrenia spectrum disorders in Hawaii. The program is also designed to increase the understanding of thought

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disorders in youth through systematic collection of information from this population. Funding for this program is provided by the Hawaii Department of Health Child and Adolescent Mental Health Division. The clinic was designed with the American Academy of Child and Adolescent Psychiatry practice parameters in mind and serves as an example of the assessment and psychosocial treatments available for youth with schizophrenia. Assessment

Youth with suspected thought disorders eligible for services in our program participate in a thorough mental health examination. The initial assessment battery provides a thorough diagnostic and neuropsychological evaluation to verify diagnosis and identify relative strengths and weaknesses in functioning. The clinic employs a semi-structured interview designed to assess an array of psychopathology in youth, including psychotic processes (Kaufman et al., 1997). To provide more accurate and complete information, we interview the child, parent, and relevant adults in the child’s life (e.g., teacher, treating therapist, psychiatrist, etc.). Self-report questionnaires from various informants supplement interview information. Assessments particularly focus on identifying behaviors of impairment through interview as well as direct observation to help determine specific treatment goals for subsequent intervention. In addition to the diagnostic and functional components, we also offer a screening of neurocognitive functioning. Domains of functioning assessed include areas identified in the literature as potential deficits for youth with schizophrenia. We employ tests of executive functioning, attention, various forms of memory, and an abridged test of intelligence. The neurocognitive examination allows for an assessment of relative strengths and weaknesses in cognitive functioning and provides information useful for recommendations and treatment planning. Treatment

As mentioned above, there are currently no identified evidence-based psychosocial interventions for schizophrenia among youth. We attempt to systematically study our on-going treatment cases to provide useful approaches to treating other youth with similar conditions. The heterogeneity of the disorder, however, makes generalization from one case to the next difficult. To address the issue of variability of individual presentation, we employ a modular approach to therapy containing specific sections for specific problem behaviors. This approach provides our clinicians with a range of strategies to address target behaviors. Our modules are derived from a range of areas, including: cognitive and behavioral treatment for adult schizophrenia; empirically supported therapies for childhood anxiety, depression, and disruptive behavior disorders; social skills training;

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behavioral treatment for autism; community involvement; and motivational interviewing. Even if symptoms directly associated with symptoms of schizophrenia (e.g., hallucinations and delusions) are resistant to treatment, a modular approach is often effective in treating comorbid and related conditions (e.g., specific phobia of water caused by the delusional fear that evil creatures will drown the client). Family services

Additionally, our clinic also offers family therapy and multifamily therapy (McFarlane et al., 1995). Collateral work with parents and close relatives is essential for the complete care of youth with schizophrenia spectrum disorders. Additionally, multifamily therapy has been demonstrated effective in the treatment of adult schizophrenia. These groups focus on problem-solving strategies and community building between families struggling with similar issues. Family work has an underlying goal of reducing critical or over-protective comments from family members, referred to as ‘‘expressed emotion’’. High levels of expressed emotion are associated with relapse among adults with schizophrenia living with their families (Leff & Vaughn, 1985). The role of families in the lives of youth with schizophrenia spectrum disorders is possibly even more powerful and relevant than among adults with schizophrenia, as young people may be even more dependent on family for support. Related to work with the family is the importance of interdisciplinary coordination of services. Youth with schizophrenia often have many health care providers as team members. In addition to the parent(s), psychiatrists, psychologists, teachers, nurses, social workers, individual skills trainers, occupational therapists, and others are often involved in cases. Working collaboratively with all treatment team members is crucial to the functioning and outcome of the child. For all of our cases, we provide ongoing structured single-case evaluation protocols involving multiple informants for therapists to track the effectiveness of specific interventions. Ongoing monitoring and assessment of progress throughout the course of treatment enhances the ability to determine the most effective techniques for specific symptoms in a particular client and enables the monitoring of overall progress.

Conclusions The field of early-onset schizophrenia holds far more questions than answers. While interest and understanding of the disorder continue to grow, many

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unanswered questions remain. By definition, schizophrenia in childhood is similar to adult-onset schizophrenia in terms of defining symptomatology. Certain correlates and expression of the disorder in youth, however, vary relative to typical-onset schizophrenia. Although rates increase with age, the prevalence of early-onset schizophrenia is rare. This fact, perhaps more than any other, contributes to the limitations in understanding the disorder. Despite the rarity of the condition, schizophrenia in young people can be reliably diagnosed and researched. Research has revealed a preponderance of males relative to females and high rates of comorbidity. Additionally, the course of childhood-onset schizophrenia typically appears worse relative to the adult-onset variant of the disorder, with estimates of nearly half of youth diagnosed having poor outcomes. In line with poor prognosis, in vivo neuroimaging studies tend to show progressive deterioration in the brains of youth with schizophrenia. While research has yet to uncover all causal factors, genetics seem to play a large role in the etiology of the disorder. Consistent with our lack of understanding of the disorder, the field has only begun to identify effective treatments for schizophrenia among youth. Psychopharmacological treatment is an essential component to managing the disorder, but is rarely a cure. Comprehensive wrap-around psychosocial services for the youth and family are also important in helping individuals with this condition. Further research investigating all factors associated with childhoodonset schizophrenia, including the etiology, demographic profile, neurological correlates, and course and progression, may provide hope for future treatment of, and recovery from, this devastating condition. REFERENCES Alaghband-Rad, J., McKenna, K., Gordon, C. T., et al. (1995). Childhood-onset schizophrenia: The severity of premorbid course. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 1273
83. American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders, (4th edn., text version). Washington, DC: American Psychiatric Association. Asarnow, J. R. & Asarnow, R. F. (2003). Childhood-onset schizophrenia. In Child Psychopathology, 2nd edn., ed. E. Mash and R. Barkley. New York: Guilford Press, pp. 486
519. Asarnow, R. F. & Karatekin, C. (2001). Neurobehavioral perspective. In Schizophrenia in Children and Adolescents, ed. H. Remschmidt. Cambridge: Cambridge University Press, pp. 135
67. Asarnow, R. F., Nuechterlein, K., Fogelson, D., et al. (2001). Schizophrenia and schizophreniaspectrum personality disorders in the first-degree relatives of children with schizophrenia: The UCLA family study. US Archives of General Psychiatry, 58(6), 581
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94. Aylward, E., Walker, E., & Bettes, B. (1984). Intelligence in schizophrenia: Meta-analysis of the research. Schizophrenia Bulletin, 10, 430
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22. Kaufman, J., Birmaher, B., Brent, D., et al. (1997). Schedule for affective disorders and schizophrenia for school-age children. Present and lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child and Adolescent Psychiatry, 36(7), 980
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27.

4

Late-life schizophrenia Katerine Osatuke1, John W. Kasckow2, and Somaia Mohamed3 1

VHA National Center for Organization Development Department of Psychiatry, University of Cincinnati 3 Division of Psychiatry, Cincinnati VA Medical Center 2

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B B B B B B C D B

Epidemiology Schizophrenia in the elderly is a special case requiring special management (Altamura & Elliott, 2003). Unlike the extensive research on schizophrenia in young adults, however, little is known about late-life schizophrenia. In a comprehensive review of schizophrenia research by Heaton and Drexler (1987), only 13 of 100 studies included patients of 50 and older. In 1996, only 6% of schizophrenia studies currently published in leading psychiatric journals focused on the elderly (Jeste, cited in Sajatovic et al., 2002). This knowledge gap represents a serious challenge to the field (Palmer, Heaton, & Jeste, 1999), given the current demographic increase in numbers of the elderly, expected to continue over the coming years. General prevalence of schizophrenia is 0.2
2.0%, the common estimate being 0.5
1.0% (DSM-IV). Due to its usually chronic nature, incidence rates are lower 59

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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(estimated 1 per 10,000 yearly). Prevalence is the same for both genders, but the onset is earlier in men. In the growing numbers of geriatric schizophrenia patients, more will be women, reflecting a general demographic trend (Schultz et al., 1997). Geriatric schizophrenia cases include those with early onset (EOS: prior to the age of 40), late onset (LOS: after 40), and very-late onset schizophrenia-like psychosis (first diagnosis at age 60þ) (Altamura & Elliott, 2003). Prevalence, diagnostic subtype, and gender distribution vary greatly for groups with different age of onset: e.g., the paranoid type is the most prevalent in LOS, while the disorganized and catatonic types seem very rare (Jeste & McClure, 1997). LOS is 2
10 times more frequent in women (Jeste & McClure, 1997); most studies report 2:1 to 4:1 female/male ratio (Lehmann, 2003), in sharp contrast to the greater prevalence of men in EOS. Many EOS patients survive into old age (Jeste & McClure, 1997), representing an estimated 85% of all individuals with schizophrenia in the older age groups (Harris & Jeste, 1988).

Age of onset While DSM-III disallowed diagnosing schizophrenia after the age of 45, DSM-III-R permitted it, specifying ‘‘late onset’’ schizophrenia after the age of 45. DSM-IV did not include the age of onset nor an upper age limit. An estimated 13% of all hospitalized schizophrenia patients are first diagnosed in their 40s; 7% in their 50s; and 3% after 60 (Lacro, Harris, & Jeste, 1993). The ECA study reported a one-year community prevalence rate of schizophrenia of 0.6% in the age range of 45
64, and 0.1
0.5% at 65 and older (Regier et al., 1988). Thus, approximately 23.5% of patients have the symptom onset after 40 years of age (Harris & Jeste, 1988). The LOS/EOS distinction is no longer made in the DSM-IV or ICD-10, due to a lack of qualitative differences in symptoms; nevertheless, it is reflected in much past and current research on later-life schizophrenia. LOS cutoff age has been inconsistent across studies (55
65 years in Europe, 45 years in the USA) (Levy & Almeida, 1994). To address the controversy about whether LOS was a legitimate subtype of schizophrenia (Crespo-Facorro et al., 1999; Howard et al., 2000; Jeste et al., 1998b), an international expert panel reviewed all the available MEDLINE articles on LOS in 2000 and concluded that the diagnosis had face and clinical validity, for patients with onset of illness between the ages of 40 and 60 (Howard et al., 2000). The panel recommended the term very late-onset schizophrenia-like psychosis (VLOSLP), for cases with onset after 60. European investigators have also used the terms paraphrenia and late paraphrenia to refer to LOS and VLOSLP, respectively (Palmer, McClure, & Jeste, 2001). Positive symptoms in EOS, LOS, and VLOSLP are similar, but LOS and

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VLOSLP are more likely to occur in women, manifesting predominantly as persecutory delusions, while EOS manifests as formal thought disorder or affective blunting (Howard et al., 2000). Schultz (2001) advocated adding a distinct subtype of ‘‘true LOS’’ patients, whose pathologic process is the same as in EOS but different from degenerative psychosis. Schizophrenia of middle-age onset (MAOS) may have distinctive characteristics as well. Palmer et al. (2001) described MAOS as a primarily neurodevelopmental but also a distinct neurobiological subtype, largely similar to EOS but less prevalent, and different from EOS in several important ways (predominantly paranoid presentation; less negative symptoms and disordered thinking; more stable cognitive functioning; at least partial improvement in a substantial minority of patients).

Presentation Diagnostic criteria for schizophrenia include positive and negative symptoms (hallucinations, delusions, thought disorder, disorganized or unresponsive behavior; affective flattening, avolition, alogia). Cognitive impairment is prevalent, representing a core characteristic of schizophrenia in all age groups and in particular in the elderly with schizophrenia (Arnold & Trojanowski, 1996). Extending across multiple domains, cognitive impairment is not readily accounted for by a single ability deficit or anatomical region, and is not caused by chronic illness, treatment, or institutionalization (Mohamed et al., 1999). Cognitive dysfunction stabilizes in chronic patients, after the initial deterioration (Jeste & McClure, 1997). Cognitive impairments in this group predict impairments in adaptive function, and constitute better predictors of overall outcome than positive or negative symptoms (Harvey et al., 1997b). Cognitive or neuropsychological performance of older patients with better outcomes consistently does not deteriorate with age; they outperform patients with poor outcomes, even in the absence of symptomatic differences (Harvey, 2001). In the elderly with schizophrenia, instrumental and social skills deficits were more strongly correlated with cognitive impairments than with lack of behavioral control (Harvey et al., 1997b). All schizophrenia groups present with more cognitive deficits than controls, on all tasks except memory retention. However, learning, abstraction, and cognitive flexibility are less impaired in LOS than in EOS (Heaton et al., 1994); impaired pre-morbid educational, occupational, or psychosocial functioning is also less likely in LOS (Lehmann, 2003). LOS is prototypical of chronic psychotic disorders; delusions, often bizarre and persecutory, are its most prominent

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symptom (Jeste & McClure, 1997). Auditory hallucinations, including Schneiderian first-rank symptoms (two voices conversing, thought broadcasting), constitute the second most prominent LOS symptom (Jeste & McClure, 1997). Negative symptoms, loose associations, and inappropriate affect are less severe in LOS than in EOS (Jeste & McClure, 1997). LOS patients are less likely to have formal thought disorder and affective blunting, but they may have more colorful hallucinations (Pearlson et al., 1989). Schizophrenia prodromes include social isolation; impaired role functioning; peculiar behavior; poor hygiene; blunted or inappropriate affect; digressive, vague, overelaborate, or circumstantial speech; odd beliefs or magical thinking, influencing behavior inconsistently with cultural norms; unusual perceptions; and marked lack of initiative. These should represent a clear decrease from prior functioning level
a criterion often difficult to evaluate in the elderly (Jeste & McClure, 1997). Psychotic symptoms in the elderly are more likely to reflect a secondary than a primary psychotic disorder, due to identifiable medical or neurological conditions (Jeste & McClure, 1997) necessitating thorough differential diagnostics. The elderly chronic schizophrenia inpatients (i.e. 65þ) may have more negative and less positive symptoms than the younger patients, but they appear similar on affective symptoms or thought disorder (Soni & Mallik, 1993). Cognitive impairment may be greater in patients with more severe negative symptoms (Davidson et al., 1995). Age-related decreases in positive symptoms, with concurrent increases in negative symptoms, may possibly lead to underdiagnosing and under-treating schizophrenia in the elderly (Sajatovic, Madhusoodanan, & Buckley, 2000). High ratings on the activation factor of the PANSS (hostility, poor impulse control, excitement, uncooperativeness, poor rapport, and tension) are inversely correlated with discharge rates into community in elderly schizophrenic inpatients, independently of other symptoms (White et al., 2004). Poverty of speech is more common and severe in geriatric schizophrenia (Harvey et al., 1997a). Disconnected speech was, however, less common and less severe in older schizophrenics (not due to the lower amount of speech that they produce)
an inconsistency possibly pointing to dissimilar cognitive and biological underpinnings of these two dimensions of communication disorder. Diagnosing geriatric schizophrenia may require additional symptom constructs. In factor analyses of the Scales for the Assessment of Positive and Negative Symptoms (SAPS and SANS) for 45
84-year-old schizophrenia outpatients (McAdams et al., 1997), the SAPS bizarre behavior subscale loaded the highest on the depressive symptom factor (not on positive symptoms). The SANS avolition
apathy subscale loaded both on the negative symptom

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and the depressive symptom factors. Bizarre behavior and apathy may thus represent a separate construct related to depression in older schizophrenic populations. Schizophrenic presentation includes three dimensions (Cohen, 1990): psychopathology (symptoms); organic factors; and social functioning. Psychopathology diminishes with age, except in some subgroups (Cohen, 1990), while cognition declines, and ventricle-to-brain ratio (VBR) increases. The size of social network declines but quality of relationships and coping may increase (Cohen, 1990; Cohen et al., 2000). Since these domains are not correlated, clinical measures and outcomes should be established for them separately (Scherrell et al., 1999); furthermore, they must be separately investigated for geriatric populations. Course and progression Long-term outcome studies (Angst, 1988; Ciompi, 1980; McGlashan, 1988; Moller et al., 1988) do not support the previous view of progressive deterioration in schizophrenia. Cognitive and functional decline characterizing an EOS subgroup is not an obligatory outcome even in EOS (Schultz, 2001). Most deficits develop in the first 4
5 years, and stabilize or improve thereafter (Brier et al., 1992). In LOS, initially prominent positive symptoms diminish significantly with age (Lindamer et al., 1999). New symptoms rarely appear (Cohen, 1995). Some investigators believe that negative symptoms dominate the geriatric clinical presentation, while others report negative symptom remission (Cohler & Ferrono, 1987; McGlashan & Fenton, 1992; Schultz et al., 1997). Schizophrenia tends to have a chronic course (Lacro et al., 1993), possibly stabilizing with age (Cohen, 1995; Palmer et al., 1999). One third of chronic patients undergo remission or are left with only mild symptoms (McGlashan, 1988). Some patients thus show complete remission, others exhibit stable dysfunction, and yet others deteriorate, reaching dementia (Carpenter & Kirkpatrick, 1988; Ciompi, 1980; Winokur, Pfohl, & Tsuang, 1987). Long-term follow-up studies over the last 20 years found notable psychiatric improvement in half to two-thirds of elderly patients, but long-term outcomes were still heterogeneous (Lehmann, 2003). One study (Jeste et al., 2003) found age-related symptomatic decrease, even after controlling for duration of illness
yet, the patients were more impaired than controls. These authors disputed that schizophrenia progressively worsens or improves in elderly outpatients, arguing a stable course. Schizophrenia is associated with shorter life span, largely due to preventable extrinsic factors (e.g., unhealthy lifestyle, poor health care, medication side effects) which underscores a need for integrated models of care, particularly for geriatric schizophrenia (Bartels, 2004). Suicide attempts and death by suicide

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are pronounced in schizophrenia; greater hopelessness and longer duration of illness are important risk factors (Tarrier et al., 2004). Among the 1066 elderly schizophrenics in the Barak, Knobler, and Aisenberg (2004) study, 4.6% have attempted suicide. Except an almost significant gender difference (more males in the suicidal group), no specific geriatric risk factors were identified. Heterogeneity in late-life schizophrenia course is of interest because it may imply different subtypes, with dissimilar biological substrates and/or etiology. This possibility was examined in neuropathological studies reviewed in the following section.

Suspected neuropathology Brain-imaging techniques and post-mortem exams (Weiss & Heckers, 2001; Lawrie et al., 1999) consistently demonstrate structural brain abnormalities in schizophrenia. The temporal and frontal lobes are two implicated regions: reduced hippocampal size and related memory deficits appear well documented. Sachdev et al. (2000) found similar patterns of the same magnitude in the elderly schizophrenics, suggesting a lack of progressive deterioration (since illness duration did not make any difference). Neuropathological studies seek to clarify the neurodegenerative versus neurodevelopmental etiology of schizophrenia (Crespo-Facorro et al., 1999), and particularly the controversy of whether functional psychosis without identifiable organicity can begin over the age of 45 (Krull et al., 1991; Lesser et al., 1993; Miller et al., 1991). If no, then LOS would have a different etiology from EOS. Structural brain imaging shows a lack of gross abnormalities in LOS (CoreyBloom et al., 1995; Symonds et al., 1997), documenting some similarities and some differences in structural abnormalities in LOS and EOS (Crespo-Facorro et al., 1999). Krull et al. (1991) reviewed studies of specific cerebral abnormalities possibly causing schizophrenia-like geriatric psychoses, and studies of etiological non-specific abnormalities. As an example of specific pathology, diffuse ventricular dilatation was discovered in 50% and minimal cortical atrophy in 30% of late-onset patients, age 45þ (Haug, 1962). To illustrate non-specific abnormalities, mean VBR is larger in LOS patients (age 60þ) than in normals (Rabins et al., 1987), whereas ventricular enlargement in LOS appears nonsignificantly greater than in normals (Krull et al., 1991; Rabins et al., 1987). Studies also consistently find age-related increases in abnormal white matter hyperintensities (Krull et al., 1991). Postmortem studies established decreases in volume of the hippocampus or parahippocampal gyrus, decreases in the number and size of

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hippocampal neurons, and abnormal neuron orientation (Trojanowski & Arnold, 1995). Apparently, primary schizophrenia can begin after age 45, while depression and organicity may more commonly cause late-onset psychoses in the elderly (Almeida et al., 1995; Harris & Jeste, 1988). Subgroups of patients with schizophrenia without diagnosable organicity confirm a possibility of functional LOS. Symonds and Jeste (1997), using the MRI, showed a similar frequency, type, and severity of tumors and strokes in LOS and EOS, thus demonstrating that LOS can occur in the absence of gross structural brain abnormalities. Howard et al. (2000) concluded that structural changes in MRI among the schizophrenic elderly were independent of age of onset. The few existing studies exploring abnormal brain connectivity in schizophrenia (Arnold, 2001) established specific abnormalities in synapses and synapserelated proteins and mRNAs. Processes explicating illness-related changes in synaptic density included impaired synapse formation, abnormal synaptic pruning (increased or decreased), increased sprouting of new synapses in response to neural injury, or synapse loss due to degenerative process. Arnold (2001) interpreted these findings as evidence of decreased cerebral reserves in schizophrenics, which create more vulnerability to the usual effects of neurodegenerative lesions accumulated with age. Similar to Arnold’s model of interaction between neurodevelopmental and neurodegenerative factors, Crespo-Facorro et al. (1999) described the schizophrenic brain as neurodevelopmentally vulnerable to the illness, but not necessarily symptomatic until a stressor precipitates the disease. Understanding the course has important implications about the neurobiology of schizophrenia: while deterioration may imply neurodegeneration or progressive neural injury, a stable dysfunction could point to neurodevelopmental etiology. However (Arnold, 2001), these constructs may coexist rather than being mutually exclusive. A lack of neuropathological evidence for degeneration or neural injury has been now established almost without controversy, even for the most severely ill, elderly, and deteriorated patients (Arnold, 2001). These results are compelling because neuropathological abnormalities would be most likely to be revealed in older, more severely affected patients, with a longer duration of illness. Examining late-life schizophrenia thus helps better understand the disorder itself (Cohen et al., 2000).

Suspected neurochemical abnormalities Neurochemical findings in the elderly with schizophrenia have been documented as follows. Studies of synaptic integrity have suggested abnormalities in molecular

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signaling pathways (Arnold, 2001). Talbot et al. (2004) found that presynaptic dysbindin-1 reductions are frequent in schizophrenia, and related to glutamatergic alterations in intrinsic hippocampal formation connections. Arnold et al. (1991) used monoclonal antibodies to study the distribution of a key group of developmentally regulated neuronal cytoskeletal proteins in the hippocampal region of postmortem schizophrenic brain samples of geriatric subjects. They found defects in the expression of MAP2 and MAP5, two microtubule-associated proteins anatomically selective for the subiculum and entorhinal cortex. Arnold et al. concluded that MAP2 and MAP5 could underlie some of the previously described cytoarchitectural abnormalities, impairing signal transduction in the affected dendrites of the schizophrenic brain and ultimately affecting higher cognitive functions. Akbarian et al. (1995) also documented a reduced expression of glutamate decarboxylase (GAD) mRNA containing neurons in the dorsolateral prefrontal cortex (DLPFC) in older patients with schizophrenia. They hypothesized that reduced expression of GAD could seriously affect GABAergic synaptic transmission by neurons (Akbarian et al., 1995). Nishioka & Arnold (2004) found oxidative DNA damage and coordinated cell-cycle activation in elderly patients with pooroutcome schizophrenia. Although several of these preliminary neurochemical findings are promising, more research is clearly needed. Establishing the neurochemical etiology of schizophrenia, and specifically of geriatric schizophrenia, remains an important priority.

Genetic factors An estimated 85% of the variance of risk in schizophrenia is accounted for genetically (Cannon et al., 1998; McGuffin et al., 1994; see also Tsuang, Stone, & Faraone, 2000, for discussion of genetic liabilities for psychosis). Prevalence of schizophrenia approximates 7% in siblings and 3% in parents of all probands with LOS; the family history of schizophrenia is similar for LOS and EOS patients (Jeste & McClure, 1997). Gestational and perinatal complications, minor physical abnormalities (e.g., reduced head circumference reflecting decreased brain growth), and delayed childhood development are common history in schizophrenia patients (Arnold, 2001). Premorbid paranoid or schizoid personality traits are frequent in LOS (Jeste & McClure, 1997). Finally, sensory deficits play a role, particularly in LOS, due to a lack of correction of sensory impairment in elderly patients (Prager & Jeste, 1993).

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Other risk factors Studies of life events and familial stresses have suggested that both environmental and interpersonal factors are important in schizophrenia. Several models (Dohrenwend & Dohrenwend, 1980) incorporate these factors. For example, Patterson et al. (1997) examined the relationship between life events, symptoms of psychosis, and their impact on the life quality in geriatric schizophrenia. Increased psychotic symptoms were related to disturbances of psychosocial environment (decreased support, increased life events, increased avoidant coping). Psychosocial factors were weaker predictors of social maladjustment than psychotic symptoms. Depressive symptoms had a central role in predicting social environment. Social maladjustment greatly mediated the relationship between psychotic symptoms and health-related life quality. Some studies claimed no gender differences in clinical presentation and course of schizophrenia (Lehmann, 2003; Soni & Mallik, 1993), while others (Hafner et al., 1993) reported a more favorable course for women, in particular older women. Possibly, gender differences are more pronounced initially, attenuating with age due to female estrogen decline (Hafner et al., 1998). The estrogen also tentatively explains the greater female ratio in LOS: anti-dopaminergic properties of estradiol protect women from puberty to menopause, but not thereafter (Riecher-Rossler et al., 1994). The female bimodal distribution of onset of schizophrenia, with a large peak in young adulthood and a smaller peak around the menopause (Hafner & an der Heiden, 1997), supports the estrogen hypothesis. Increased psychosocial stressors and longevity additionally explain a greater female ratio in LOS (Jeste & McClure, 1997). The respective contributions of genetic, developmental, and environmental factors have implications for treatment, in particular in the context of aging, as discussed in the next section. Treatment Treating geriatric schizophrenia involves numerous challenges (Chan, Parisier, & Neufeld, 1999; Tariot, 1999; Wynn Owen and Castle, 1999). Frequent comorbidity with chronic medical conditions necessitates multiple medications (Kasckow et al., 2003). Polypharmacy, increasingly common with age, heightens the importance of appropriate medication choice. Older patients are more sensitive to side effects, which affects compliance and tolerability of drugs. Their physiologic status ranges from ‘‘physically fit’’ to ‘‘frail’’, widely influencing their response to medications. As the upcoming increases in the elderly patient

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population forecast growing numbers of older schizophrenia patients, awareness of their unique treatment needs becomes extremely important. Pharmacotherapy is the most common approach to treatment of schizophrenia, general or geriatric. Neuroleptic antipsychotic medications, available since the 1950s, have a long-documented effectiveness with younger patients (Kane & Marder, 1993). Many geriatric schizophrenia patients therefore have a long history of taking neuroleptics. Using neuroleptics with the elderly has modest support, in reduced dosages (Jeste et al., 1993; Mulsant & Gershon, 1993). Side effects of neuroleptics are particularly problematic for the elderly. First, sedation may create extreme confusion or agitation (Salzman & Nevis-Olesen, 1992). Second, orthostatic hypotension may result in sharp blood-pressure decrease when standing up, heightening the risks of fall and traumatic injury. These side effects, caused especially by low potency neuroleptics (chlorpromazine, thioridazine, chlorprothixen), make them non-preferred agents for geriatric schizophrenia. Extrapyramidal side effects (EPS), created by high potency neuroleptics, are especially problematic, since they result from drug action on dopamine receptors, and dopamine availability decreases with age (Salzman & Nevis-Olesen, 1992). EPS include parkinsonism (rigidity, tremor, bradykinesia); akathisia (extreme motor restlessness); and tardive dyskinesia (TD; involuntary, repetitive movements, usually facial but occasionally involving the whole body). Parkinsonism and akathisia develop within the first days of treatment or dosage increase. They may pose treatment problems if mistakenly attributed to psychosis, and addressed through further increases in the medication that had created these effects in the first place (Gregory & McKenna, 1994). TD, 5
6 times more prevalent in geriatric than in younger patients (Jeste et al., 1998a), develops after a long period of neuroleptic treatment. It is a highly noticeable, socially stigmatizing side effect, often irreversible even after full medication withdrawal. Atypical antipsychotics available since the 1990s are the first line of treatment for geriatric patients. Five newer antipsychotic drugs are available for use in the United States. Three of these (risperidone, olanzapine, and quetiapine) are used most readily with late-life schizophrenia. The atypical antipsychotic medications are strong antagonists of serotonin receptors, also possessing central dopamine antagonism. These drugs alleviate the positive and negative symptoms, with lower than conventional rates of EPS and TD (Jeste & McClure, 1997). A slower medication response in the elderly requires much lower starting dosages and increase rates of atypical antipsychotics than used for younger patients (Jeste & McClure, 1997). Risperidone, of the benzisoxazole class of compounds, is the drug of choice for addressing geriatric psychoses and behavioral disturbances in dementia (Comaty & Advokat, 2001). Its efficacy and tolerability are superior to haloperidol

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(Marder & Meibach, 1994). Common side effects in the elderly are dose-related, and include postural hypotension, sedation, and EPS; caution has been raised about a possibly higher incidence of cerebrovascular adverse effects with risperidone use. Risperidone nevertheless currently appears the safest antipsychotic (Finkel, 2004), associated with continued symptom improvement, decreases in pre-existing EPS, and low increases in TD in geriatric patients (Davidson et al., 2000). Olanzapine, structurally related to clozapine, acts on multiple neurotransmitters (dopamine, norepinephrine, serotonin, acetylcholine, histamine). Olanzapine has a low rate of EPS (Beasley, Tollefson, & Tran, 1997; Tollefson et al., 1997). Side effects include sedation, orthostasis, and weight gain. Olanzapine has been found safe for geriatric populations, but patient-specific factors remain important given insufficient research on controlled exposure of elderly patients to olanzapine (Kennedy et al., 2001). Elderly patients switched from conventional antipsychotics to olanzapine (vs. risperidone) appear more likely to complete the switching process, and improve on a brief psychological measure of quality of life (Ritchie et al., 2003). In a randomized, double-blind study of the cognitive effects of newer antipsychotics in the elderly (Harvey et al., 2003), low doses of risperidone and olanzapine improved patients’ cognitive functioning in areas previously shown to be related to functional outcomes, while no such improvement has been documented for conventional antipsychotics, generally (Blyler & Gold, 2002; Harvey et al., 2000) or specifically for the elderly (Harvey et al., 2002). Quetiapine is a dibenzothiazepine derivative active at histaminic and adrenergic receptors (Saller and Salama, 1993), with relatively low activity at dopamine and serotonin receptors (Allen, Cooney, & Lawlor, 1994). Quetiapine has minimal effects on EPS. Clozapine is not recommended for the elderly, both because of its side effects that increase with age (Alvir & Lieberman, 1994), and because too little information on ziprasidone and aripiprazole is available for geriatric populations. Medication compliance is complicated by the single most important factor of taking multiple prescriptions several times per day (Lamy, Salzman, & NevisOlesen, 1992). Geriatric non-compliance manifests in overuse, abuse, forgetting, schedule and dosage alterations
versus deliberate underuse due to side effects and cost considerations, typical of younger adults (Lacro & Jeste, 1997). This requires clear instructions and compliance monitoring in the elderly. Psycho-educational and psychosocial approaches have been reported successful with schizophrenia; however, no known studies have focused on older adults. The fragmentary nature of medical, psychiatric, and psychosocial services for the elderly with schizophrenia is a recognized concern (Cohen et al., 2000; Lehmann, 2003; Scherrell et al., 1999). Their medical vulnerabilities, same as for general

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geriatric populations, are frequently not addressed by their health care, due to inadequate coverage, transportation problems, and lack of awareness of medical needs (Roca et al., 1987). Also, the elderly with schizophrenia under-report medical symptoms, pain, or discomfort (Andreasen, 1987), often manifesting their illness through behavioral and cognitive changes (Scherrell, et al. 1999). Older men and women with schizophrenia may have areas of different treatment needs, caused by gender-related vulnerabilities and typical ages of onset. While women may need more focus on coping with relatively recent onset of psychiatric illness (stress, illness acceptance, or basic illness management), men may require attention to comorbid substance abuse, more prevalent in older men (54%) than in older women (10%) with schizophrenia and schizoaffective disorder (Sajatovic et al., 2002). Based on the estrogen hypothesis (protective effects of estradiol on premenopausal women), several studies examined estrogen replacement therapy as a supplement to antipsychotic medications, in elderly postmenopausal women with schizophrenia (Lindamer et al., 1999).

Conclusions The last decade has witnessed a surge of interest in geriatric schizophrenia, although the topic remains acutely under-researched, with many diagnostic, prognostic, etiological, and treatment questions still unanswered. The upcoming increases in the numbers of the elderly heighten the importance of understanding geriatric schizophrenia. Elderly and younger patients differ in nontrivial ways, possibly requiring additional symptom constructs and different explanatory models. Prevalence, gender distribution, presentation, and course of illness (e.g., deterioration versus stable dysfunction) also vary considerably for geriatric populations with different age of onset. The heterogeneity may reflect different underlying subtypes, with dissimilar biological substrates and etiology. Neuropathological studies examining this possibility have found no evidence of neurodegeneration, but increasingly suggested pathology in brain development and connectivity in geriatric schizophrenia. The constructs of neurodegeneration versus neurodevelopmental etiology may coexist, however, rather than being mutually exclusive. As much as 85% of the risk variance for schizophrenia is attributed to genetic factors. Both environmental and interpersonal factors contribute to precipitating and maintaining schizophrenia in the elderly; e.g., social maladjustment mediates the relationship between psychotic symptoms and health-related life quality. Depressive symptoms are the main predictor of social environment for older schizophrenic patients.

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Genetic, developmental, and environmental factors have important implications for treatment. Atypical antipsychotics are currently the first treatment line for schizophrenia. Risperidone, olanzapine, and quetiapine are the newer drugs most readily used with geriatric patients. Medical comorbidity and polypharmacy are common in the elderly, and age-related changes in drug metabolism and receptor sensitivity underscore the importance of optimal medication choices. The many medical, psychiatric, and psychosocial problems faced by older schizophrenic patients require a holistic treatment approach, accounting for patient factors and special needs and challenges in their age group. REFERENCES Akbarian, S., Kim, J. J., Potkin, S. G., et al. (1995). Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Archives of General Psychiatry, 52, 258
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9.

5

Schizoaffective disorder Daniel J. Abrams1 and David B. Arciniegas2 1 2

University of Colorado School of Medicine University of Colorado School of Medicine, Denver, CO

Summary of findings Grade of evidence Epidemiology Age of onset Clinical presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B Bþ B
C C C C C A


Introduction Schizoaffective disorder is characterized by persistent psychotic symptoms and episodic mood disturbances of the depressive, manic, and/or mixed type. However, there remains a lack of consensus regarding the most parsimonious diagnostic framework within which to consider this condition. Some experts assert that schizoaffective disorder reflects the co-occurrence of schizophrenia and a mood disorder, others argue that it is a variant of schizophrenia in which mood symptoms are prominent, and others view it as a mood disorder in which episoderelated psychotic symptoms persist to varying degrees between mood episodes (Dell’Osso et al., 1993; Marneros, Deister, & Rohde, 1990a, 1991). Others avoid categorical approaches to the description of schizoaffective disorder, and instead regard psychosis and emotional dysregulation as dimensional variables that are expressed to greater or lesser degrees among persons with neuropsychiatric symptoms (Liddle, 2001). In this view, schizophrenia in its ‘‘pure’’ form represents 78

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a condition at the severely disordered end of the psychosis continuum and at the normal end of the emotional regulation continuum, bipolar disorder represents the converse of schizophrenia in these regards, and schizoaffective disorder represents a condition in which patients experience symptoms towards the disordered ends of both continua. Such differences in theoretical orientation pervade the clinical and research literature regarding schizoaffective disorder, making difficult the development of a clear clinical and neurobiological framework within which to consider this condition. Historical background

The controversy regarding the optimal formulation of schizoaffective disorder is a longstanding one. Jacob Kasanin is credited with the first description of this condition in 1933 (in reprint as Kasanin, 1994). His formulation of this condition emphasized the combination of symptoms of schizophrenia and also mood (or, in the nosology of his era, ‘‘affective’’) disturbances. Over the following six decades, more than 24 (ostensibly) different definitions of schizoaffective disorder were developed (Winokur, Black, & Nasrallah, 1990), each ascribing greater or lesser weight to either the schizophrenia-like or mood-disorder-like features of this condition. In the first of several efforts to distinguish schizoaffective disorder as a unique clinical condition, the Research Diagnostic Criteria (RDC) (Spitzer, Endicott, & Robins, 1978) described schizoaffective disorder as a condition in which psychotic and mood symptoms sometimes occurred concurrently but in which psychotic symptoms also persisted for at least 1 week in the (relative) absence of mood symptoms. Two diagnostic sub-groups were described on the basis of the quality of the most prominent types of mood symptoms: cyclical, or bipolar, and depressive. The occurrence of at least some degree of depressive symptoms or psychotic ‘‘excitement’’ experienced by persons with schizophrenia presented a substantial diagnostic challenge for clinicians: at what point are mood symptoms among persons with schizophrenia of sufficient prominence to merit a schizoaffective disorder diagnosis? Conversely, how ‘‘absent’’ do those symptoms need to be in order to describe the patient as schizophrenic rather than schizoaffective? Further, to what degree must mood symptoms remit in order to regard inter-episodic persistence of psychotic symptoms as evidence of schizoaffective disorder rather than an incompletely resolved psychotic mood disorder? As Berner and Simhandl (1983) note, leaving poorly defined the severity of mood symptoms required for the diagnosis of schizoaffective disorder results in a more liberal assignment of this diagnosis than does the application of more restrictive diagnostic criteria.

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The DSM-III-R (1987) attempted to refine the diagnosis of schizoaffective disorder by requiring the persistence of psychotic symptoms for at least two weeks beyond the resolution of mood symptoms. Clarifying this further, Marneros et al. (1989) suggest that the diagnosis of schizoaffective disorder be made only when the mood symptoms, when present, are of an overt melancholic or manic quality, and that clinicians should not infer the need to assign a schizoaffective disorder diagnosis to a patient with schizophrenia simply because of the development of relatively minor depressive symptoms or euphoria alone. Beyond these refinements, however, little additional change has been made to this formulation of schizoaffective disorder in subsequent editions of the DSM or in American psychiatric research endeavors. Epidemiology Incidence and prevalence

The DSM-IV-TR cites, without reference, prevalence for schizoaffective disorder less than schizophrenia. Consistent with that estimate, published reports suggest a prevalence of 0.2
1.1% among adults (Marneros, 2003; Scully et al., 2004). However, the frequency of schizoaffective disorder among psychiatrically hospitalized adults is considerably higher (9%) (Zarate et al., 1997). Most studies suggest that schizoaffective disorder occurs less often than either schizophrenia or bipolar disorder. For example, Marneros, Deister, and Rohde (1990b) and Scully et al. (2004) observed schizoaffective disorder to be less common in the population by half when compared to schizophrenia and by two-thirds when compared to type I bipolar disorder. By contrast, Benabarre et al. (2001), in a study of 138 outpatients, report nearly identical rates of schizoaffective disorder and schizophrenia, each of which was slightly half as common as type I bipolar disorder. This wide range of prevalence estimates appears to reflect differences in ascertainment methods, including those arising from population-based vs. hospital-based subject recruitment, the periods over which such assessments are made (i.e., cross-sectional vs. longitudinal), and whether such assessments are made prospectively using clinical interview or retrospectively by chart review (Marneros et al., 1989; Marneros et al., 1991). Among children with psychotic disorders, schizoaffective disorder appears to be a relatively rare occurrence (Werry, McClellan, & Chard, 1991). However, estimating the frequency of schizoaffective disorder among children and adolescents is complicated by a relatively lower symptom/diagnosis stability over time than among adults (Hollis, 2000; McClellan & McCurry, 1999), the relatively high co-morbidity of intellectual disabilities (Friedlander &

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Donnelly, 2004), and as-yet uncertain effects of both substances of abuse and/or medications on clinical presentation among persons in this age range (Malla, Norman, & Scholten, 2000). Although firm estimates of the incidence and prevalence of schizoaffective disorder remain elusive, the literature suggests that it probably occurs no more often than either schizophrenia or bipolar disorder, is most likely less common than both of these conditions, and in all likelihood occurs less often than the frequency with which it is diagnosed in common clinical practice would suggest. The epidemiologic data is insufficiently developed for the purpose of drawing conclusions regarding the conceptualization of schizoaffective disorder as a unique clinical condition, a condition in which schizophrenia and bipolar disorder are comorbid, or instead as a variant of one or the other of these two other major mental illnesses.

Age of onset Schizoaffective disorder exhibits a relatively broad age of onset among adults (del Rio Vega & Ayuso-Gutierrez, 1990; Stieglitz & Helmchen, 1990). For example, Marneros et al. (1990b) prospectively studied by interview and record review approximately 300 subjects divided nearly equally into three groups (schizophrenia, mood disorders, and schizoaffective disorder). Approximately one third of people with schizoaffective disorder developed this condition prior to age 25, one third did so after age 35, and one third became ill in the intervening decade of life. Accordingly, the median age of onset among people with schizoaffective disorder was 29.5 years, while the median ages of onset for schizophrenia and bipolar disorder were 25 and 35 years, respectively. The observation of both later onset in comparison to schizophrenia and earlier onset in comparison to bipolar disorder is a relatively common one in studies that separate adults with schizoaffective disorder from these other diagnostic groups (Angst & Preisig, 1995; Dell’Osso et al., 1993). Although pediatric onset of schizoaffective disorder is uncommon, the age at which this illness first occurs does not appear to differ from that of pediatric-onset schizophrenia or bipolar disorder. When these illnesses develop among children and adolescents, the mean age of onset is approximately 14 years (Werry et al., 1991). The available evidence suggests that schizoaffective disorder differs from schizophrenia and bipolar disorder with respect to age of onset in its adultonset forms, but the interpretation of that evidence is complicated. If schizoaffective disorder represents simply a co-occurrence of schizophrenia and bipolar

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disorder, its age of onset should be nearly identical to schizophrenia (i.e., relatively young). Similarly, if schizoaffective disorder is a psychotic mood disorder with incomplete inter-episodic resolution of psychotic symptoms, then its age of onset should be most similar to that of the primary mood disorders (i.e., relatively older). It appears that each of these scenarios reflects age of onset in about one third of persons with schizoaffective disorder, but fails to describe adequately the age of onset in the remaining third. That the age of onset of schizoaffective disorder both overlaps in many cases with those of schizophrenia and mood disorders and also distinguishes schizoaffective disorder from these other disorders in others cases suggests the possibility that schizoaffective disorder may sometimes represent a schizophrenic illness in which prominent mood disturbances develop, a unique illness in some cases, and a psychotic mood disorder with incomplete inter-episodic resolution of psychotic symptoms in others. Gender

Marneros et al. (1990b) report that two thirds of people with schizoaffective disorder are female, a finding that is consistent with other reports examining this issue (Angst, Felder, & Lohmeyer, 1980; Lenz et al., 1991). There is, however, insufficient data from which to draw firm conclusions regarding gender differences and the role of gender in the development of schizoaffective disorder. Clinical presentation The clinical presentation of schizoaffective disorder varies considerably between and within individuals, and may include nearly ‘‘pure’’ psychotic presentations, similarly ‘‘pure’’ mood symptom presentations, and presentations in which there is an admixture of psychotic and mood symptoms. This variability is reflected in the complexity of the DSM-IV-TR criteria for this diagnosis. First, a disturbance of thought that includes two (or more) of the ‘‘positive’’ symptoms of schizophrenia (i.e., delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior) for a significant portion of time during a one-month period (or less if successfully treated) is required. Mood episodes meeting diagnostic criteria for major depressive episodes (in which depressed mood is a required feature), manic episodes, and/or mixed episodes also must be present for a substantial portion of the total duration of the active and residual periods of the illness. Finally, the diagnosis of schizoaffective disorder requires the presence of delusions or hallucinations for at least two weeks in the absence of prominent mood symptoms (i.e., symptoms meeting DSM diagnostic criteria). As these criteria suggest, patients may present with some or all of these symptoms

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at various times during the course of their illness. The clinical features of schizoaffective disorder will, when viewed only in cross-section, overlap considerably with schizophrenia and other psychotic disorders, major and minor mood disorders, and other neuropsychiatric syndromes (Fabisch et al., 2001; Taylor & Amir, 1994; Whaley, 2002). Accordingly, the diagnosis of schizoaffective disorder entails not only a careful evaluation of the clinical features at the time of any single presentation but also over the entire period of the illness. Course and progression Accordingly, a discussion of the clinical presentation of schizoaffective disorder cannot be divorced from one of the natural history of this condition. Since the clinical features of schizoaffective disorder vary considerably over time in any given patient, establishing a diagnosis of schizoaffective disorder entails accurate characterization of presenting features across multiple points in time. While it may be difficult to conduct this sort of extended evaluation in an era of medical care that imposes limits on clinician time for this purpose, failing to do so will in many cases result in inaccurate diagnosis (Benabarre et al., 2001; Fogelson et al., 1991; Schwartz et al., 2000; Taylor & Amir, 1994; Werry et al., 1991; Whaley, 2002). Assuming that the diagnosis has been made with certainty, the literature regarding natural history and functional outcomes in this population is at times contradictory. Some studies describe the symptomatic and long-term functioning of people with schizoaffective disorder as more like (or worse than) that associated with schizophrenia (Benabarre et al., 2001; Harrow et al., 2000). Others suggest that the long-term symptomatic and functional prognosis associated with schizoaffective disorder is better than that of schizophrenia (Marneros et al., 1989; Tohen et al., 2000) but worse than that of the mood disorders (Benabarre et al., 2001; del Rio Vega & Ayuso-Gutierrez, 1990; del Rio Vega & Ayuso-Gutierrez, 1992). The variability of these observations prompts concerns regarding the accuracy of diagnostic group assignments at the time of entry into the studies of the natural history of schizoaffective disorder. Moreover, other factors such as substance abuse, rapid cycling, family history, and pre- and post-morbid occupational functioning (Nolen et al., 2004), among others, may interact with diagnosis in the determination of the long-term outcome (i.e., natural history) of persons with schizoaffective disorder and are not routinely incorporated into studies of this issue. These cautionary notes notwithstanding, the present review suggests that schizoaffective disorder is associated with more frequent episodes of illness (including both psychotic and mood recurrences), less persistence of delusions,

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and better social adjustment than schizophrenia, and is on balance more similar with respect to natural history to mood disorders than to schizophrenia. Suspected neuropathology The heterogeneity of epidemiological findings regarding schizoaffective disorder is paralleled by a similar degree of heterogeneity in neurobiological findings, regardless of the specific neurobiological aspect under investigation of such studies. Not surprisingly, persons with schizoaffective disorder demonstrate neurobiological abnormalities that distinguish them consistently from healthy comparison subjects. However, these studies only occasionally offer evidence that distinguishes schizoaffective disorder from schizophrenia and/or mood disorders, and particularly bipolar disorder. Whether this reflects a true lack of neurobiological distinction between schizoaffective disorder and these other conditions remains a matter of uncertainty, as very few of these studies attempt to make such distinctions. However, readers should be aware of these issues in study design prior to formulating their own conclusions regarding the neurobiology of schizoaffective disorder in its own right and neurobiological differences, if any, between schizoaffective disorder, schizophrenia, and/or bipolar disorder. Neuropsychological findings

Schizoaffective disorder is associated with impairment in frontally mediated cognition including working memory, alternating attention, information recall, category generation and shifting, abstraction, and motor planning (Brenner et al., 2003; Bryson, Bell, & Lysaker, 1997; Bryson et al., 2002; Gooding and Tallent, 2002; Manschreck et al., 1997; Mitrushina, Abara, & Blumenfeld, 1996). Only rarely was schizoaffective disorder associated with better performance on such tests than schizophrenia (Goldstein, Shemansky, & Allen, 2005; Stip et al., 2005), and data with which to compare the neuropsychological performance of people with schizoaffective disorder to those with bipolar disorder is lacking. Neuroimaging

The neuroimaging literature regarding schizoaffective disorder has, for the most part, employed volumetric magnetic resonance imaging structural techniques, with a few others extending observations to include diffusion tensor imaging and magnetic resonance spectroscopy (Ardekani et al., 2003; Buchanan et al., 2004; Cannon et al., 2002; Keshavan et al., 2003; Prasad, Rohm, & Keshavan, 2004; Stone et al., 2005; Szeszko et al., 2005; Van Erp et al., 2002). Collectively, these studies suggest that schizoaffective disorder is associated with reductions in cerebral

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volumes, particularly in temporal (including medial temporal) and frontal regions, including both gray and white matter. The most consistent area of abnormality across these studies is the medial temporal lobe (i.e., hippocampus and parahippocampal gyri). The pairing of bipolar disorder and schizoaffective disorder in some of these studies and schizophrenia and schizoaffective disorder in others leaves uncertain the distinction between these disorders on the basis of neuroimaging. Electrophysiology

Schizoaffective disorder is associated with abnormal event-related potentials (P50, N100, N400, CNV, and others), auditory M100 localization, somatosensory M20 localization, middle ear muscle activity, and eye movements (Benson et al., 1996; Borenstein et al., 1988; Brenner et al., 2003; Bruder et al., 1998; Kathmann et al., 2003; Kayser et al., 1999; Kayser et al., 2001; Kumar & Debruille, 2004; Lieberman et al., 1993a, b; Olincy & Martin, 2005; Reite et al., 1999; Teale et al., 2000). As with the other categories of neurobiological investigation described in this chapter, subjects with schizoaffective disorder were only rarely studied independently and instead were most often included among groups of subjects with other psychoses (i.e., schizophrenia or bipolar disorder with psychotic features). Two studies (Boutros et al., 1997; Inui et al., 1998) suggest findings of greater similarity between subjects with schizoaffective disorder and bipolar disorder with psychotic features than schizophrenia. Conversely, Olincy & Martin (2005) observed P50 nonsuppression among persons with bipolar disorder with psychotic features and those with schizoaffective disorder, but not among those with bipolar disorder without psychotic features. When viewed in the context of prior studies demonstrating P50 nonsuppression among persons with schizophrenia, this observation would suggest that this electrophysiologic abnormality is associated with psychosis across conventional diagnostic boundaries. Collectively, these observations argue against conceptualizing schizoaffective disorder as a unique entity, at least as viewed from the perspective of electrophysiology, and instead suggest that the presence of psychosis is associated with electrophysiologic abnormalities regardless of whether that psychosis is persistent or episodic. Suspected neurochemical abnormalities Neuroendocrinology

The neuroendocrinology of schizoaffective disorder is the least developed area of neurobiological inquiry, consisting of only three studies to date, all of which

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focused on growth hormone abnormalities in this condition. Among these, Mokrani et al. (2000) observed a difference between subjects with schizoaffective disorder and schizophrenia with respect to growth hormone response to stimulation with clonidine, with the former group more closely resembling subjects with major depressive disorder and the latter demonstrating a response most like that of healthy comparison subjects. However, the studies of Kumar et al. (1993) and Lieberman et al. (1993b) demonstrated similar patterns of growth hormone response to pharmacologic challenge among persons with schizoaffective disorder and schizophrenia. Whether neuroendocrinological abnormalities are functionally significant and/or a means by which to distinguish schizoaffective disorder from other major mental illnesses requires further investigation. Neurochemistry

Meltzer, Arora, & Metz (1984) reviewed studies of the neurochemistry of schizoaffective disorder performed prior to 1984 and concluded that this condition bore similarities to both schizophrenia and bipolar disorder. Specifically, studies of CSF NE levels, PGE1 adenyl cyclase levels, and platelet 5HT content of schizophrenia and schizoaffective disorder suggested similarities between these conditions, whereas platelet 5HT shows similarities between bipolar disorder and schizoaffective disorder but not schizophrenia. Since that time, schizoaffective disorder has been associated with a variety of functionally significant neurochemical abnormalities (Faustman et al., 1999; Laruelle et al., 1993; Sharma et al., 1998). However, none of these studies offer data with which to separate schizoaffective disorder from schizophrenia or bipolar disorder. This remains an understudied aspect of all of these conditions and additional investigation is needed prior to reaching any conclusion regarding the nature of neurochemical abnormalities specific to schizoaffective disorder. Genetic factors Studies of the genetics of schizoaffective disorder have only in rare circumstances been performed in a manner that permits identification of features unique to this condition; instead, subjects with this condition have been included in studies of schizophrenia or bipolar disorder in such a way that the genetic features of this condition, if any, are opaque to explanation with the available data (Dick et al., 2003; Giouzeli et al., 2004; Kirov et al., 2004; Liu et al., 2005; Segurado et al., 2003; Skol et al., 2003; Staddon et al., 2005; Ujike et al., 2001; Wijsman et al., 2003). Among these studies, only Hodgkinson et al. (2004) demonstrate a finding unique

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to schizoaffective disorder, namely a decreased frequency of the common haplotype of intron 1/exon 2 and increase in exon 9 of DISC1. Additional studies of the genetics of schizoaffective disorder are needed in which this condition is considered separate from (or in comparison to) schizophrenia and bipolar disorder. Treatment Given the substantial overlap in clinical and neurobiological features between schizoaffective disorder and both schizophrenia and bipolar disorder, it is not surprising that the treatment of this condition overlaps considerably with these other conditions. Unfortunately, studies describing the treatment of schizoaffective disorder alone are few (Tohen et al., 2001; Vieta et al., 2001). The available data suggests that atypical antipsychotic medications are useful for the treatment of both psychotic and mood symptoms in this population, regardless of whether mood symptoms are manic or depressed (Baethge et al., 2004; Davis & Chen, 2004). Lithium and carbamazepine are also useful agents for treatment of the mood symptoms of people with schizoaffective disorder, although the concept of polypharmacy in the treatment of people with this condition may require reconsideration. For example, Keck, McElroy, and Strakowski (1996) suggest that among agitated schizoaffective patients, antipsychotic medications were more effective than lithium, and among depressed schizoaffective patients combined treatment with antipsychotic medications and antidepressants was no more effective than treatment with antipsychotic medications alone. Although other studies suggest that agents specific to the mood symptoms (i.e., lithium, carbamazepine, antidepressants) and psychotic symptoms (typical or atypical antipsychotics) are required for optimal treatment, it is possible that atypical antipsychotic medications with mood-stabilizing properties such as risperidone, olanzapine, and quetiapine may be sufficient to permit monotherapy with these agents in at least some people with schizoaffective disorder (Baethge et al., 2004; Levinson, Umapathy, & Musthaq, 1999). Additionally, emerging evidence suggests that some atypical antipsychotic agents (i.e., olanzapine, risperidone, and ziprasidone) may also afford improvements in cognition among persons with schizoaffective disorder (Bilder et al., 2002; Harvey, Siu, & Romano, 2004). Additional studies are needed to determine whether such improvements are functionally significant and also whether there are diagnosis-specific differences in the degree of cognitive improvement, if any, afforded by these agents.

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Conclusions The concept of schizoaffective disorder is anchored firmly in its historical conceptualization as a disorder in which both psychotic and mood symptoms manifest in a manner that bears some resemblance to schizophrenia and to bipolar disorder but that is nonetheless distinct from both of these conditions. This assumption has been questioned repeatedly in modern psychiatric discourse, and the available data leaves unanswered the matter of whether schizoaffective disorder is a unique clinical condition. In a psychiatric nosology that requires categorical distinction between conditions, schizoaffective disorder fits reasonably well
more often than not
into either the psychotic or mood disorder categories when attempting to distinguish patients in these categories from healthy comparators and those with non-psychotic mood disorders. When psychosis is the focus of an investigation, schizoaffective disorder is generally found to be similar to schizophrenia with respect to epidemiology, neurobiology, and treatment. By contrast, when studies focus on mood symptoms, schizoaffective disorder is often found to be similar to bipolar disorder with psychotic features. When a categorical approach to diagnosis is used to classify schizoaffective disorder apart from schizophrenia and bipolar mood disorders, only rarely do published findings support such a distinction. We suggest that it is this categorical approach to the diagnosis and study of schizoaffective disorder that limits the quality of the evidence regarding this condition (See Summary of Findings table). While the studies described in this chapter are, in general, of high quality with respect to the scientific question they attempt to address, the general tendency in them to include subjects with schizoaffective disorder among those with either psychosis (i.e., schizophrenia) or mood (i.e., bipolar) disorders limits severely our ability to draw conclusions regarding the nature of this condition both intrinsically and also with respect to the features, if any, that distinguish it reliably from these other conditions. A more productive approach to the study of schizoaffective disorder may be afforded by reconfiguring these studies so as to address a specific dimension of psychiatric illness
i.e., psychosis or mood disturbance
rather than to identify features that support categorical distinctions between the conditions in which such problems develop. Psychosis and emotional dysregulation are in all likelihood dimensional variables of neuropsychiatric function that are expressed clinically to greater or lesser degrees among persons with schizophrenia, bipolar disorder, and schizoaffective disorder (Liddle, 2001). The observation of schizoaffective disorder as a condition with epidemiologic, neurobiological, and treatment-response features that are very much like schizophrenia in some studies and rather more like bipolar disorder in others may reflect biases toward subject

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selection along the dimension of psychosis in the former and emotional dysregulation in the latter. Similarly, investigations of neurobiological features that are dimension-specific tend to demonstrate abnormalities specific to the dimension of neuropsychiatric function under study that cross conventional diagnostic boundaries. The clearest example of this approach to dimensional investigation among persons with psychiatric illnesses is provided by Olincy and Martin (2005), as described in the Electrophysiology section of this chapter. In reviewing the data presented in the preceding sections of this chapter, similar patterns of association between findings and the dimensions of illness and treatment response of subjects included in those studies emerge. It therefore seems reasonable to suggest a research agenda that seeks to characterize these conditions first in terms of their psychotic and emotional dimensions and second, if at all, with respect to categorical distinctions between them. So framing the study of schizophrenia, schizoaffective disorder, and bipolar disorder may facilitate a better understanding of the epidemiology, neurobiology, and treatment needs of patients based on their symptoms irrespective of their categorical (and perhaps largely arbitrary) clinical diagnosis. REFERENCES Angst, J., Felder, W., & Lohmeyer, B. (1980). Course of schizoaffective psychoses: Results of a followup study. Schizophrenia Bulletin, 6(4), 579
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84.

6

Schizophreniform disorder and brief psychotic disorder: the acute and transient psychoses Andreas Marneros and Frank Pillmann Department of Psychiatry and Psychotherapy, Martin Luther University Halle-Wittenberg, Germany

Summary of findings Grade of evidence Epidemiology: Incidence of brief and acute psychoses 1
2/100,000. Amount to 5
10% of inpatients with psychotic disorders. About twice as frequent in females as in males. Higher incidence in developing than in industrialized countries. Age at onset: From early adulthood to old age, median in the fourth decade, tentatively somewhat later than schizophrenia. Presentation: Acute onset of psychotic symptoms, often with characteristic ‘‘polymorphic symptoms’’, i.e. rapidly changing delusions and hallucinations and rapidly changing mood. Resolution of the acute episode is by definition complete, but the optimal duration criterion is still a matter of debate, suggestions ranging from 1
6 months. Course and progression: Relapse is frequent. So are other than brief and acute episodes during follow up, in particular affective and schizoaffective episodes, rarely schizophrenia. Outcome is usually favorable and evidence of long-term deterioration is absent. Suspected neuropathology: No consistent pathophysiological theory available. The clinical course implies the absence of progressive cerebral atrophy, but empirical data are scarce. Suspected neurochemical abnormalities: Despite isolated claims of thyroid or amino acid abnormalities, no consistent pattern has yet been found. Genetic factors: An increased prevalence of affective and psychotic disorders (not necessarily schizophrenia) in relatives indicates the importance of genetic factors. However, neither a phenotype ‘‘breeding true,’’ nor a specific ‘‘disease gene’’ have been identified. 96

B

C B

B

D

D C

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Grade of evidence Other risk factors: Mild or moderate life-events precede brief and acute psychoses more often than schizophrenic episodes. However, stressful life events are not characteristic for the majority of brief and acute psychoses, and the temporal and causal relation of these life events is not as close as suggested by the concept of psychogenic or reactive psychoses. Treatment: During the acute episode, treatment with antipsychotics is indicated in most cases, often supplemented with benzodiazepines, and should usually be continued for two years. Long-term therapy with antipsychotics is necessary in a substantial number of patients. The role of mood stabilizers and antidepressants in long-term therapy of brief and acute psychoses remains to be determined.

C

C

Introduction The criteria for brief psychotic disorder and schizophreniform disorder in the Diagnostic and Statistical Manual DSM-IV attempt to operationally define acute psychotic disorders of brief duration that can be differentiated from schizophrenia in their long-term course. As the optimal definition for these disorders is still under discussion, and to better delineate the subject of this chapter, the relevant diagnostic concepts and their nosological backgrounds need to be briefly reviewed (for a more comprehensive description see Marneros and Pillmann, 2004). The existence of acute psychoses of short duration, often presenting with intensive or even dramatic symptomatology, eventually resulting in full remission, has always been well known to clinicians. When Emil Kraepelin divided the so-called endogenous or functional psychoses into a group of dementia praecox (schizophrenia) and manic-depressive insanity (affective disorders), he conceded that there is a ‘‘not small group of disorders’’ which cannot be allocated
neither to schizophrenia, nor to affective disorders. Doubts about Emil Kraepelin’s dichotomic system, as well as Eugen Bleuler’s conception of schizophrenia, led to concepts such as ‘‘cycloid disorders’’ in Germany, ‘‘bouffe´e de´lirante’’ in France, ‘‘atypical psychoses’’ in Japan, ‘‘reactive or psychogenic psychoses’’ in Scandinavia, etc. (Marneros & Pillmann, 2004; Pillmann & Marneros, 2003; Table 6.1). The Norwegian psychiatrist, Langfeldt (1939), in an attempt to explain his observation that some cases of ‘‘schizophrenia’’ responded favorable to treatment while others failed to show a favorable response, differentiated between

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Andreas Marneros and Frank Pillmann Table 6.1. Some synonyms and partial synonyms of brief and acute psychoses

• • • • • • • • •

Bouffe´e de´lirante (Magnan, Ey) Cycloid psychoses (Kleist, Leonhard, Perris) Psychogenic (reactive) psychosis (Wimmer, Stro¨mgren) Atypical psychosis (Mitsuda) Brief reactive psychosis (DMS-III-R) Non-affective acute remitting psychoses (Susser) Brief psychotic disorder (DSM-IV) Schizophreniform psychosis (good prognostic features) (DSM-IV) Acute and transient psychotic disorders (ICD-10)

a nuclear group of schizophrenia with poor prognosis and a group of ‘‘schizophreniform psychoses’’ with a much better spontaneous prognosis. His criteria for schizophreniform disorder included an acute onset often in relation to a precipitating factor, the presence of confusion during the acute episode, and the absence of schizoid personality traits. The existence of brief good-prognosis psychotic disorders worldwide has been confirmed by several global epidemiological studies initiated by the WHO, showing that such psychoses are much more common in developing countries than in industrialized states (Marneros & Pillmann, 2004). The modern diagnostic systems, such as the Diagnostic and Statistical Manual (APA, 1994) and the International Classification of Diseases (WHO, 1992), tried to harmonize the various regional and national concepts concerning the abovementioned findings. DSM-IV provides the category of brief psychotic disorder (BPD). A diagnosis of BPD requires the presence of delusions, hallucinations, disorganized speech or grossly disorganized or catatonic behavior with a duration of at least one day, but less than one month and an eventual full return to premorbid functioning. In contrast to its predecessor in DSM-III-R, brief reactive psychosis, a severe antecedent stressor is not mandatory (Table 6.2). In DSM-IV, some psychotic disorders of brief duration may also be coded as schizophreniform disorder if they fulfill DSM-IV criteria for schizophrenia for one month (or less, if successfully treated), but remit within six months (Table 6.3). Thus, the main difference between DSM-IV schizophreniform disorder and DSM-IV schizophrenia concerns the six-month duration criterion. ‘‘Good prognostic features’’ are only included as specifiers, but are not obligatory for diagnosis. Some authors presented evidence that many patients with schizophreniform disorder meet the full criteria for schizophrenia at a later time (Strakowski, 1994). Others found evidence of a more favorable outcome in a subgroup of

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Schizophreniform and brief psychotic disorders Table 6.2. Diagnostic criteria for brief psychotic disorder according to DSM-IV

A. Presence of one (or more) of the following symptoms: • delusions • hallucinations • disorganized speech (e.g., frequent derailment or incoherence) • grossly disorganized or catatonic behavior Note: Do not include a symptom if it is a culturally-sanctioned response pattern. B. Duration of an episode of the disturbance is at least 1 day, but less than 1 month, with an eventual full return to premorbid level of functioning. C. The disturbance is not better accounted for by a Mood Disorder with Psychotic Features, Schizoaffective Disorder, or Schizophrenia and is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition. Specify if: With Marked Stressor(s) (brief reactive psychosis): if symptoms occur shortly after, and apparently in response to events that, singly or together, would be markedly stressful to almost anyone in similar circumstances in the person’s culture. Without Marked Stressor(s): if psychotic symptoms do not occur shortly after, or are not apparently in response to events that, singly or together, would be markedly stressful to almost anyone in similar circumstances in the person’s culture. With Postpartum Onset: if onset within 4 weeks postpartum. Source: APA, 1994

Table 6.3. Defining criteria of schizophreniform disorder according to DSM-IV

A. Criteria A, D, and E of schizophrenia are met.1 B. An episode of the disorder (including prodromal, active, and residual phases) lasts at least one month, but less than 6 months. (When the diagnosis must be made without waiting for recovery, it should be qualified as ‘‘Provisional.’’) Specify if: Without Good Prognostic Features With Good Prognostic Features: as evidenced by two (or more) of the following: 1. Acute onset of prominent psychotic symptoms 2. Confusion or perplexity at the height of the psychotic episode 3. Good premorbid social and occupational functioning 4. Absence of blunted or flat affect Source: APA, 1994 1 These criteria include the presence of the characteristic symptoms of schizophrenia, the exclusion of schizoaffective and mood disorders, and the exclusion of the effects of a substance or a general medical condition causing the disorder.

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Andreas Marneros and Frank Pillmann Table 6.4. Research criteria for acute and transient psychotic disorders according to ICD-10 (F23)

G1.

G2.

G3. G4.

G5.

There is acute onset of delusions, hallucinations, incomprehensible or incoherent speech, or any combination of these. The time interval between the first appearance of any psychotic symptoms and the presentation of the fully developed disorder should not exceed 2 weeks. If transient states of perplexity, misidentification, or impairment of attention and concentration are present, they do not fulfill the criteria for organically caused clouding of consciousness as specified for F05.-, criterion A. The disorder does not meet the symptomatic criteria for manic episode (F30.-), depressive episode (F32.-), or recurrent depressive disorder (F33.-). There is insufficient evidence of recent psychoactive substance use to fulfill the criteria for intoxication (F1x.0), harmful use (F1x.1), dependence (F1x.2), or withdrawal states (F1x.3) and (F1x.4). The continued moderate and largely unchanged use of alcohol or drugs in amounts or with the frequency to which the individual is accustomed does not necessarily rule out the use of F23; this must be decided by clinical judgement and requirements of the research project in question. Most commonly used exclusion clause. There must be no organic mental disorder (F00-F09) or serious metabolic disturbances affecting the central nervous system (this does not include childbirth). (The duration of the disorder must not exceed 3 months in subtypes F23.0, F23.3 and F23.8; it may not exceed 1 month in the subtypes F23.1 and F23.2, which include schizophrenic symptoms.)

Source: WHO, 1993

schizophreniform disorder (Zhang-Wong et al., 1995). In particular, the subtype with good prognostic features seems to be characterized by a benign long-term course (Benazzi, 1998; Iancu et al., 2002). Therefore, schizophreniform disorder, as presently defined by the DSM, is a heterogeneous category, which includes a small group of brief and acute psychoses with a benign long-term course (Naz, Bromet, & Mojtabai, 2003). In the tenth revision of the WHO International Classification of Diseases, ICD-10, the category of acute and transient psychotic disorders (ATPD) was created and operationally defined (WHO, 1992). The diagnostic criteria for the ICD-10 category F23 ‘‘acute and transient psychotic disorders’’ can be found in Table 6.4. The group is delineated into five subgroups: • acute polymorphic psychotic disorder with and without symptoms of schizophrenia, • acute schizophrenia-like psychotic disorder,

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• other acute predominantly delusional psychotic disorders, • other ATPD, • unspecified ATPD. But the main and essential group is the group of ‘‘acute polymorphic psychotic disorder’’. The BPD of DSM-IV is more narrowly defined than ATPD in ICD-10 so that every ‘‘brief psychosis’’ could be diagnosed as ‘‘acute and transient psychotic disorder’’, but not vice versa (Pillmann et al., 2002a). In this chapter, we focus on BPD and on those subforms of schizophreniform disorder that are characterized by acute onset and limited duration. To a large extent, this group of patients concurs with the ICD-10 definition of ATPD. As a comprehensive term, ‘‘brief and acute psychoses’’ will be used to denote this patient group. The empirical knowledge on brief and acute psychoses is still very limited. This is true for ICD-10 ATPD and even more for DSM-IV BPD. Studies on schizophreniform psychoses are hampered by an extremely heterogeneous composition of samples. The most comprehensive study on the topic so far is the Halle Study on Brief and Acute Psychoses (HASBAP) comparing a cohort of patients with ICD-10 ATPD with matched controls with schizophrenia and bipolar schizoaffective disorder, as well as with mentally healthy controls (Marneros & Pillmann, 2004). Results from this study will therefore be cited below. Additional knowledge mainly stems from Denmark (Jørgensen et al., 1997), Great Britain (Singh et al., 2004), India (Das, Malhotra, & Basu, 1999; Sajith et al., 2002), and the USA (Susser et al., 1998). Epidemiology Prevalence and incidence

There is little sound epidemiological evidence regarding the frequency of brief and acute psychoses. The interpretation of findings is further complicated by differences in definitions and probably by regional differences in incidence. Schizophreniform disorder has been estimated to have a lifetime prevalence of 0.2%, while BPD is reported as uncommon. Interesting data were reported by Susser and Wanderling (1994) in their re-analysis of data from the WHO Determinants of Outcome of Severe Mental Disorders. They determined the annual incidence per 10,000 people of non-affective acute remitting psychosis (NARP), representing a diagnostic entity roughly equivalent to the group of brief and acute psychoses covered in this chapter. They found the incidence to be 0.486 for males and 0.878 for females in developing countries

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and 0.040 for males and 0.104 for females in industrialized countries. The Nottingham study conducted by Singh et al. (2002) calculated incidence data for ATPD. Initially, an incidence of 3.9 per 100,000 was reported for ATPD, but after revision of the diagnoses at follow-up, this number dropped to 1.36 per 100,000. Compared with epidemiological incidence data, the frequency of brief and acute psychoses as a proportion of inpatients with broad definition psychotic disorders in a particular institution is much more commonly reported. These numbers, however, vary considerably dependent on the definitions used. BPD have been reported to represent 2% of non-organic psychoses, while the frequency of nonaffective acute psychoses in the definition of Susser and Wanderling (1994) has been reported at 3
6%. Acute and transient psychotic disorders have been found in the HASBAP to represent 8.5% of all inpatients treated for a non-organic psychotic disorder (ICD-10 F20), a number consistent with most other studies on ATPD (Marneros & Pillmann, 2004). In conclusion, the limited data available allow a cautious estimate of 1
2 per 100,000 for the yearly incidence of brief and acute psychoses. In clinical inpatient samples, brief and acute psychoses typically represent 5
10% of patients treated for a non-organic psychotic disorder. Developing countries

A considerable body of literature now points to a higher incidence of brief and acute psychoses in developing than in industrialized countries (Marneros & Pillmann, 2004; Susser & Wanderling, 1994; Thara, 2004). In the study mentioned above, Susser and Wanderling (1994) found a tenfold higher incidence of brief and acute psychoses in developing countries than in industrialized countries. Although the number still awaits replication, the phenomenon is consistent with the results of other WHO projects and with the impression of numerous researchers that brief and acute psychoses are particularly frequent in developing countries (Marneros & Pillmann, 2004; Thara, 2004). In fact, a considerable number of studies on brief and acute psychoses have been conducted in these countries, e.g. in India (Das et al., 1999; Sajith et al., 2002; Susser et al., 1998). Both organic and psychosocial factors have been deemed responsible for the difference in incidence, but the ultimate reason remains to be elucidated. Gender difference

A female preponderance can be observed in nearly all samples of brief and acute psychoses. In the HASBAP, the vast majority (78.6%) of patients diagnosed as having an ATPD was female. In other samples of ATPD or non-affective acute remitting psychoses, the proportion of female patients ranges from 60% to 86%

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(Marneros & Pillmann, 2004). This is in contrast to schizophrenia, which has been reported to be at least equally frequent in males as in females, with narrowly defined schizophrenia being probably somewhat more frequent in males. Samples with DSM-IV schizophreniform disorder typically do not show female preponderance, confirming the suggestion that DSM-IV schizophreniform disorder is a heterogeneous category comprising both cases of brief and acute psychoses and of schizophrenia. Age at onset Initially, onset of brief and acute psychoses was most frequently reported in young adults in their late 20s or early 30s. Recent investigations, including the HASBAP, have shown that the disorder may well present for the first time in later life. The patients in the Danish study conducted by Jørgensen et al. (1996) had a mean age at onset of 33 years (range 18
65 years). In the HASBAP, the mean age at onset for ATPD patients was 35.7 years, and more than half of the patients with ATPD became ill after the age of 33 years (Marneros & Pillmann, 2004). Studies from India reported a somewhat earlier mean age at onset of 25
27 years, but these differences may well represent differences in the age distribution of the general populations (Das et al., 1999; Sajith et al., 2002). Everything considered, the onset of brief and acute psychoses seems to occur somewhat later than that of schizophrenia, and definitely later than that of bipolar disorder. A somewhat later onset of brief and acute psychoses than schizophrenia would be compatible with the finding that early onset is a predictor of an unfavorable prognosis in mixed psychotic samples. Presentation In historical concepts of brief and acute psychoses, the sudden onset of rapidly changing psychotic symptoms was regarded as typical (Pillmann & Marneros, 2003). This turbulent symptomatological picture has been described as ‘‘polymorphic’’ or ‘‘cycloid.’’ In contrast to the historical descriptions, neither the criteria for BPD nor those for schizophreniform psychosis or ATPD require the presence of any particular symptom; just of psychotic symptoms in general. The investigation of unselected operationally diagnosed samples of ATPD and BPD, however, has corroborated polymorphic features as a frequent characteristic of brief and acute psychoses. In the HASBAP, rapidly changing delusions were present in 47.6% of the patients, while a rapidly changing mood was found in an even higher percentage, namely 69% (Table 6.5) (Marneros et al., 2005).

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Andreas Marneros and Frank Pillmann Table 6.5. Symptomatology of the index episode in ATPD

n (%) Productive psychotic symptoms (hallucinations and delusions) Hallucinations Delusions Delusions of being influenced First-rank symptoms Rapidly changing delusions Affective disturbance Disturbance of drive and psychomotor disturbances Depressed mood Maniform symptoms Anxiety Rapidly changing mood Thought disorder Bipolar character of symptoms

42 (100) 32 (76.2) 41 (97.6) 21 (50.0) 30 (71.4) 20 (47.6) 42 (100) 36 (85.7) 31 (73.8) 32 (76.2) 32 (76.2) 29 (69.0) 36 (85.7) 12 (28.6)

Source: From Marneros & Pillmann, 2004

This polymorphous symptomatology has also proven to be the main characteristic distinguishing ATPD from schizophrenia and bipolar schizoaffective disorder (Marneros & Pillmann, 2004). An example of rapidly changing delusional topics and other productive psychotic phenomena follows: A 37-year-old physical therapist developed, literally overnight, a multitude of delusional and hallucinatory experiences in rapid succession: within a few hours she believed herself to be pregnant, believed that a certain book contained special references to her, felt persecuted by construction workers, and experienced optical, auditory and coenaesthetic hallucinations accompanied by disturbances of speech, affect and motor behaviour. (From Marneros & Pillmann, 2004)

A bipolarity of mood is found in some patients (28.6% of the HASBAP subjects). In the most typical instances, it manifested itself in the form of a coexistence of ecstatic feelings and feelings of anxiety, often accompanied by accordingly tainted productive symptoms: A 24-year-old cook experienced the onset of her psychotic episode immediately after a dental treatment. She described an ecstatic feeling of happiness combined with the anxiety that something dreadful would happen. The bipolar nature of the affect was mirrored by the contents of her delusions and hallucinations: she was at one time convinced that she was a princess of high birth, and shortly afterwards she was troubled by voices accusing her of having abused her son.

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One of the most frequent symptoms in brief and acute psychoses is anxiety. In the HASBAP, anxiety was significantly more frequent than in schizophrenia or in bipolar schizoaffective disorders. This corroborates the importance of anxiety suggested by historical concepts as the bouffe´e de´lirante (pananxiety) or the cycloid psychoses, especially the ‘‘anxiety-elation psychosis’’ of the Wernicke
Kleist
Leonhard school of thought. Schizophrenic first-rank symptoms are present at a high level in brief and acute psychoses. They do not reliably differentiate this disorder from schizophrenia. In accordance with this finding, there is little difference between the two subgroups of ICD-10 acute polymorphic psychosis with and without schizophrenic symptoms (Marneros & Pillmann, 2004).

Course and progression An acute onset with a rapid transition from a non-psychotic state to florid psychosis is characteristic of brief and acute psychosis. In some cases, ‘‘prepsychotic alterations’’ or ‘‘initial symptoms’’ of a non-psychotic character occur some time before the onset of psychotic symptoms. Initial symptoms of this kind include most frequently sleep disturbances, but also depressed mood and reduced drive. One third of patients show anxiety as an initial symptom. Despite the possibility of initially unspecific symptoms, the transition to a florid psychotic state takes place in a markedly acute manner, most often within two weeks at the longest (as incorporated in the ICD-10 diagnostic criteria for ATPD). Often this transition occurs within 48 hours. The acute onset seems to be an important element in the distinction of these disorders from schizophrenia. At present, acute onset is not formally requested by the DSM definitions of BPD and schizophreniform disorder, but empirical evidence supports the inclusion of an acute onset in future revisions of the classification. The duration of the psychotic episode is an important element of any operational definition of brief and acute psychoses. But there is no consensus on the optimal duration criterion. BPD must resolve within one month, ATPD within three months (or one month if schizophrenic symptoms are present), and schizophreniform disorder within six months. Mojtabai, Varma, & Susser (2000) have suggested generally extending the possible duration of brief and acute psychoses to six months. In the HASBAP, many patients showed very short psychotic periods (mean 17.5 days), but there was no clear evidence that the time criteria of the ATPD definition are more than arbitrary. It may well be that future diagnostic revisions will modify presently accepted duration criteria. Taken together, evidence suggests that reliable criteria for a full remission of the acute

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episode may be more important for the delineation of brief and acute psychoses than strict duration criteria. The typical course of brief and acute psychoses has been described as remitting and relapsing. Follow-up studies of ATPD have shown relapse rates of 33
80% within the first 1
3 years (Jørgensen et al., 1997; Marneros et al., 2003; Singh et al., 2004). Some studies conducted by the Susser group showed considerably lower relapse rates (e.g., 18% within 12 years, Susser et al., 1998), but these studies for inclusion demanded a relapse-free time after the initial episode for up to two years. Data from the HASBAP show that the risk of relapse during the first two years in ATPD is as high as in schizophrenia and may eventually approach 80% even in treated samples. Diagnostic stability is an issue addressed by most brief and acute psychoses follow-up studies. According to the results of the HASBAP, the proportion of patients showing only ATPD episodes in the long run is less than 50%. In those patients who relapse, the occurrence of other than brief and acute psychotic episodes is common. In particular, affective and schizoaffective episodes may occur (Marneros & Pillmann, 2004). However, the number of patients who eventually fulfill criteria of schizophrenia has been low in all studies on ATPD, NARP, or BPD. For example, in the HASBAP sample, after seven years 12.8% of the sample fulfilled the criteria for schizophrenia (Pillmann & Marneros, 2005). In DSM-IV schizophreniform disorder, a later diagnosis of schizophrenia is more frequent (Strakowski, 1994). In contrast, in patients showing the typical polymorphic symptom picture (e.g., the polymorphic subtypes of ATPD), a monosyndromal, diagnostically stable long-term course seems to be more frequent (Marneros & Pillmann, 2004). Historical concepts of brief and acute psychoses have generally stressed the lack of deterioration during long-term course, even though relapses may be frequent (Marneros & Pillmann, 2004; Pillmann & Marneros, 1998; 2003). Although a favorable prognosis (beyond remission of the acute episode) is not a diagnostic criterion of ATPD as defined by ICD-10, the diagnosis of ATPD carries the expectation of a favorable long-term course (WHO, 1992). A number of studies, including the HASBAP, have confirmed a favorable outcome of brief and acute psychoses in terms of global functioning, symptoms, and disability (Jørgensen et al., 1997; Marneros et al., 2003; Pillmann et al., 2002b; Sajith et al., 2002; Singh et al., 2004). In addition, the latest results of the HASBAP indicate that the presence or absence of continuing deterioration after the index episode may be a valid difference between brief and acute psychoses and schizophrenia. The findings in the control group confirm a modest degree of deterioration in the long-term course of schizophrenia, as evidenced by an increase in symptoms and social

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disability and a decrease in global functioning from the first to last follow-up. The same effect was not present in the index group of patients with ATPD, reinforcing the notion of long-term stability in this group (Pillmann & Marneros, 2005).

Suspected neuropathology For a long time, historical concepts of brief and acute psychoses as distinct from schizophrenia have been associated with speculations about different etiological factors acting in both groups of disorders. While in schizophrenia the assumption of a yet to be specified progressive brain disease initially dominated etiological theories, brief and acute psychoses were tentatively linked to the instability of brain stem circuits, humoral factors, epilepsy, psychogenesis and other factors (Pillmann & Marneros, 2003). When cerebral atrophy was described as a feature of schizophrenic psychoses and corroborated by several studies, it was hypothesized that brief and acute psychoses should fail to show this evidence of atrophy. For atypical psychoses and cycloid psychoses, a lower rate of cerebral atrophy, as determined by CCT, was found in comparison to schizophrenia (Hayashi et al., 1992; Ho¨ffler et al., 1997), but there are conflicting findings (Falkai et al., 1995). There is very little evidence from studies using modern definitions of brief and acute psychoses. In the HASBAP, there was an attempt to determine whether abnormalities of the brain scans differentiate between ATPD and the clinical control groups. As part of the standard diagnostic work-up, a computed tomography of the head was performed in most patients. However, a comparison of ATPD and control groups on standardized atrophy indices did not reveal any differences between the groups (Marneros & Pillmann, 2004). Scha¨r et al. (1995) assessed 26 patients with acute psychoses by means of Tc 99m HMPAO SPECT. They concluded that the prevalence of hypofrontality did not differentiate ATPD from schizophrenia, but the small number of patients investigated (only three ATPD patients) grossly limits their findings. Molina et al. (2005) investigated the occurrence of hypofrontality in 13 male patients with first-episode psychosis by means of FDG PET. Diagnoses were confirmed by a two-year follow-up. Six patients with DSM-IV schizophrenia demonstrated a significant hypofrontality in the dorsolateral prefrontal cortex in comparison with non-schizophrenic psychoses (six patients with schizophreniform disorder and one with BPD) and with mentally healthy controls. In conclusion, our pathophysiological understanding of brief and acute psychoses, as well as the data available at present, do not allow for definite conclusions with respect to neuropathological abnormalities in these disorders.

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Suspected neurochemical abnormalities Our state of knowledge regarding neurochemical abnormalities is similarly low. However, an ‘‘organic impression’’ of the symptomatology is not uncommon in ATPD, and may include features such as confusion or disorientation (Murai, Toichi, & Sengoku, 1996). Occasionally, therefore, metabolic or endocrinological mechanisms have been suggested to play a role in the pathogenesis of brief and acute psychoses (Pillmann & Marneros, 2003). Earlier speculations about the role of thyroid dysfunction were not corroborated by the results of the HASBAP, where no abnormalities of thyroid metabolism or vitamin B12 could be detected (Marneros & Pillmann, 2004). Pepplinkhuizen et al. (2003) studied the role of the amino acid serine in patients with acute transient polymorphic psychosis. Patients were loaded with serine and with the amino acids glycine and alanine as controls and subsequently evaluated for the development of psychopathological symptoms. In a subgroup of patients, this biochemical challenge resulted in the reappearance of ‘‘psychedelic’’ psychotic symptoms. Furthermore, significantly lower plasma concentrations of serine were found. For the authors, these results indicated that disturbances in amino acid metabolism may be involved in the emergence of brief and acute psychoses (Pepplinkhuizen et al., 2003). However, they need to be replicated by other groups. In conclusion, with the exception of the suspected cases of disturbed amino acid metabolism, which are awaiting independent replication, no specific neurochemical abnormalities have been found in brief and acute psychoses. Genetic factors There are very few family studies exclusively concerning modern definitions of brief and acute psychoses. Those family studies that used DSM or ICD criteria mostly focused on the ‘‘major’’ categories, namely schizophrenia and affective disorder. A notable exception is the Roscommon Family Study (Kendler et al., 1993). In this study, patients and relatives of patients were investigated according to DSM-III-R criteria. The categories ‘‘schizophreniform,’’ ‘‘delusional,’’ and ‘‘atypical psychotic disorders’’ were combined into the category ‘‘other nonaffective psychoses’’ (ONAP). This category could be partially equivalent to ATPD. Patients diagnosed as having ONAP more frequently (with significance) had schizophrenic relatives, and also (without significance) more relatives with schizoaffective disorders and ONAP. Thus, the Roscommon Family Study supports the idea of a spectrum concept, but not of a separate nosological entity of a ‘‘non-affective non-schizophrenic psychosis’’ (Kendler et al., 1993).

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The most comprehensive family study on patients with ICD-10 ATPD was conducted in Chandigarh, India by Das et al. (1999). The authors recruited 40 probands with ATPD and 40 schizophrenic control probands and personally interviewed 75% of all living first-degree relatives. They found a 3.35 times higher morbid risk for ATPD in relatives of ATPD probands than in relatives of probands with schizophrenia. A 4.5 times higher morbid risk for schizophrenia was found in relatives of probands with schizophrenia than in relatives of probands with ATPD. The overall morbid risk was 8.99 in relatives of probands with schizophrenia, and 4.60 in relatives of probands with ATPD (recalculated from Table 6.3 of Das et al., 1999). Benazzi (1998), conducting a family study on DSM-III-R schizophreniform disorder (good prognosis subtype), found no cases of schizophrenia in the first-degree relatives of his probands, but an elevated risk for affective disorders. In the HASBAP, a detailed family history of each subject was obtained using all available information, including the subjects’ own reports and information from the case records. The relatives themselves were not interviewed. In this study, the rate of psychotic and major affective disorders in first-degree relatives of ATPD patients was increased to a similar degree as in the relatives of patients with schizophrenia and bipolar schizoaffective disorder. There was some indication that in relatives of patients with ATPD, rates of both affective and psychotic disorders were elevated. In contrast, secondary cases in schizophrenia were mostly psychotic, and in bipolar schizoaffective disorder, secondary cases were mostly affective (Marneros & Pillmann, 2004). In conclusion, expectations that genetic epidemiology help define the nosological boundaries of brief and acute psychoses by finding entities ‘‘breeding true’’ have not been fulfilled. As far as the limited evidence goes, patients with brief and acute psychoses have fewer relatives with schizophrenia and more relatives with affective disorders than would be expected if brief and acute psychoses were just less severe forms of schizophrenia. The promising findings of recent years regarding the molecular genetics of schizophrenia (Shirts & Nimgaonkar, 2004) do not yet extend to brief and acute psychoses. Most samples underlying association studies and studies of susceptibility genes include patients with broadly defined schizophrenia. It remains for future research to compare the frequency of certain ‘‘disease genes’’ in schizophrenia and brief and acute psychoses. Other risk factors Further somatic, as well as psychosocial, risk factors have been asserted by some authors for brief and acute psychoses. Investigations carried out in India

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identified antecedent fever as a risk factor for the occurrence of brief and acute psychosis (Collins et al., 1999). In case reports, brief and acute psychoses have been reported in somatic conditions ranging from arachnoid cyst (Bahk et al., 2002) to mediastinal carcinoma metastasis (Scho¨nfeldt-Lecuona et al., 2004). However, this is not a general finding. In the HASBAP, no increased frequency of somatic disorders associated with ATPD could be found (Marneros & Pillmann, 2004). Some authors assumed that the so-called ‘‘atypical psychosis’’ of Japanese psychiatry has some relationship to epilepsy (Hatotani, 1996; Tucker et al., 1986). Inui et al. (1998) reported further evidence of this association, but no such association was found in the HASBAP (Ro¨ttig et al., 2005). There are no investigations with unselected samples of BPD, ATPD, or schizophreniform psychoses that confirm an increased prevalence of EEG abnormalities in these conditions. Another strong tradition views brief and acute psychoses mainly as ‘‘psychogenic’’ or ‘‘reactive’’ disorders (Pillmann & Marneros, 2003). Although the concept of reactive psychosis focuses on psychosocial triggers, in many cases a particular vulnerability of the personality is assumed, most often described as emotionally labile, easily impressed, and prone to disproportionate affective reactions (Stro¨mgren, 1986; Ungvari & Mullen, 2000). To date, empirical studies, however, have not been able to confirm specific personality features to be more prevalent in brief and acute psychoses than in other psychotic disorders. In fact, in the HASBAP, patients with ATPD had fewer abnormalities premorbidly than controls with schizophrenia (Pillmann et al., 2003b). Stressful life events occur more frequently within 6
12 months before an episode of brief and acute psychosis than before an episode of schizophrenia (Marneros & Pillmann, 2004). In contrast, a severe stressor as defined by the ICD-10 seems to be present in no more than 10% of ATPD episodes. This conforms to the obvious rarity of DSM-III-R brief reactive psychoses, for which such a severe and closely timed stressor was mandatory. In conclusion, mild or moderate life events precede ATPD more often than schizophrenic episodes. However, stressful life events are not characteristic of the majority of brief and acute psychoses, and the temporal and causal relation of these life events is not as close as suggested by the concept of psychogenic or reactive psychoses. Treatment The dramatic onset of brief and acute psychoses often calls for emergency treatment. Hospital admission is the rule, and pharmacotherapy is usually indicated. A small minority of patients with very short durations of psychotic symptoms go into remission before specific pharmacotherapy is started. With regard

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to historical concepts of brief and acute psychoses, treatment of the acute episode with electroconvulsive therapy has been advocated by several authors (Little, Ungvari, & McFarlane, 2000; Perris, 1974). However, the mainstay of therapy in brief and acute psychoses is antipsychotic medications. In the HASBAP, 95.2% of the sample were treated with an antipsychotic in the index episode. Some patients with ATPD also need antidepressant therapy or a mood stabilizer, but the vast majority of patients can be treated with only one antipsychotic. Tranquilizers are frequently needed, in particular to treat the prevalent anxiety. Protective measures are also often necessary, as suicide seems to be connected to the acute episode in ATPD (Pillmann et al., 2003a). Of great concern is the question as to how long pharmacotherapy of the acute episode should be continued given the
by definition
transient nature of the psychotic symptoms. Data from controlled studies are missing, therefore we have to refer to observational data. In Jørgensen et al. (1996), 82% of the 51 patients with ATPD were taking antipsychotic medication at the one-year follow-up, although most of them were no longer psychotic. Similarly, in the HASBAP, 71.1% of the patients with ATPD were taking psychotropic medication at follow-up, mainly antipsychotics (Marneros & Pillmann, 2004). Given the high relapse rates during the first two years after an episode of ATPD, a continuation of pharmacotherapy for at least two years appears advisable in the majority of cases. There is little empirical guidance for the long-term therapy of brief and acute psychoses. Evidence-based treatment recommendations and guidelines as in schizophrenia do not exist. While occasionally it is argued that the generally benign course of brief and acute psychoses obviates the necessity of long-term medication (Susser et al., 1998), the relapsing course speaks in favor of prophylactic medication. For the long-term prophylaxis of cycloid psychoses, lithium therapy has been described as effective (Mattsson & Perris, 1973; Perris & Smigan, 1985), but the effectiveness of mood stabilizers in brief and acute psychoses of modern operational definition has not been studied. Naturalistic follow-up data, as obtained with the HASBAP, show that presently most patients are treated with antipsychotics as long-term maintenance medication. In a small group of patients with brief and acute psychoses, it appears to be possible to stop medication during long-term course. In the HASBAP, after seven years approximately 30% of the ATPD patients were doing well without pharmacotherapy (Pillmann & Marneros, 2005). This number has to be taken with caution due to the purely observational character of the study. Evidence from this, as well as from other studies, however, indicates that the proportion of patients in which medication can be discontinued after two years is somewhat larger in brief and acute psychoses than in schizophrenia. Most of the remaining

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patients are currently treated with antipsychotics, with a number of them receiving antidepressants or mood stabilizers. Future research will have to show whether these treatments, in particular mood stabilizers, can substitute for treatment with antipsychotics in brief and acute psychoses. Conclusions Regardless of the diagnostic label used, the core group of acute and transient psychotic disorders can be characterized as a group of disorders which mainly concern females, with possible onset in all ages of adult life, but usually between the thirtieth and fiftieth year of life. Their onset is acute or even abrupt within 48 hours, but the onset is only rarely dependent on acute severe stress in spite of former assumptions. The psychotic period is very short, in some cases even only one day. Their response to antipsychotic drugs is very good and their outcome is usually favorable in spite of the fact that they are usually recurrent. They differ from schizophrenia regarding the gender distribution, age at onset and premorbid level of functioning and social interactions. The level of postepisodic functioning and out is more favorable in ATPD than in schizophrenia. Despite strong similarities, they have essential differences from schizoaffective disorders regarding gender, age at onset, mode of onset, and duration of symptomatology. Although syndromatic instability in long-term course prevents us to assume nosological independence of acute and transient psychotic disorders, their unique features make them a highly interesting group of disorders both from the clinical and the theoretical point of view. They are clinically important for the patients and their relatives
because of their favorable outcome. And they are theoretically important, because a better understanding of acute and transient psychoses may shed light on the relations between the major psychotic disorders and their actiology. REFERENCES APA (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Bahk, W. M., Pae, C. U., Chae, J. H., et al. (2002). A case of brief psychosis associated with an arachnoid cyst. Psychiatry and Clinical Neurosciences, 56(2), 203
5. Benazzi, F. (1998). Family history of DSM-III-R schizophreniform disorder with good prognostic features. Canadian Journal of Psychiatry, 43(5), 525
6. Collins, P. Y., Varma, V. K., Wig, N. N., et al. (1999). Fever and acute brief psychosis in urban and rural settings in north India. British Journal of Psychiatry, 174, 520
4.

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32. Falkai, P., Bogerts, B., Klieser, E., et al. (1995). Cranial computed tomography in schizophrenics, patients with cycloid psychoses and controls. In Leonhard’s Impact on Modern Psychiatry, ed. H. Beckmann, and K.-J. Neuma¨rker. Berlin, Wiesbaden: Ullstein Mosby, pp. 213
21. Hatotani, N. (1996). The concept of ‘atypical psychoses’: Special reference to its development in Japan. Psychiatry and Clinical Neurosciences, 50(1), 1
10. Hayashi, T., Watanabe, T., Kitoh, H., et al. (1992). Multivariate analyses of CT findings in typical schizophrenia and atypical psychosis. Japanese Journal of Psychiatric Neurology, 46, 699
709. Ho¨ffler, J., Bra¨unig, P., Kru¨ger, S., et al. (1997). Morphology according to cranial computed tomography of first-episode cycloid psychosis and its long-term-course: Differences compared to schizophrenia. Acta Psychiatrica Scandinavica, 96(3), 184
7. Iancu, I., Dannon, P. N., Ziv, R., et al. (2002). A follow-up study of patients with DSM-IV schizophreniform disorder. Canadian Journal of Psychiatry, 47(1), 56
60. Inui, K., Motomura, E., Okushima, R., et al. (1998). Electroencephalographic findings in patients with DSM-IV mood disorder, schizophrenia, and other psychotic disorders. Biological Psychiatry, 43(1), 69
75. Jørgensen, P., Bennedsen, B., Christensen, J., et al. (1996). Acute and transient psychotic disorder: Comorbidity with personality disorder. Acta Psychiatrica Scandinavica, 94, 460
64. Jørgensen, P., Bennedsen, B., Christensen, J., et al. (1997). Acute and transient psychotic disorder: A 1-year follow-up study. Acta Psychiatrica Scandinavica, 96(2), 150
54. Kendler, K. S., McGuire, M., Gruenberg, A. M., et al. (1993). The Roscommon Family Study. I. Methods, diagnosis of probands and risk of schizophrenia in relatives. Archives of General Psychiatry, 50, 527
40. Langfeldt, G. (1939). The Schizophreniform States. Kopenhagen: Munksgaard. Little, J. D., Ungvari, G. S., & McFarlane, J. (2000). Successful ECT in a case of Leonhard’s cycloid psychosis. Journal of ECT, 16(1), 62
7. Marneros, A. & Pillmann, F. (2004). Acute and Transient Psychoses. Cambridge: Cambridge University Press. Marneros, A., Pillmann, F., Haring, A., et al. (2003). What is schizophrenic in ATPD? Schizophrenia Bulletin, 29(2), 311
23. Marneros, A., Pillmann, F., Haring, A., et al. (2005). Is the psychopathology of acute and transient psychotic disorder different from schizophrenic and schizoaffective disorders? European Psychiatry (in press). Mattsson, B. & Perris, C. (1973). Cycloid psychoses: Aspects of therapy and possible prevention of relapses. Nordisk Psykiatrisk Tidsskrift, 27, 386
91. Mojtabai, R., Varma, V. K., & Susser, E. (2000). Duration of remitting psychoses with acute onset. Implications for ICD-10. British Journal of Psychiatry, 176, 576
80. Molina, V., Sanz, J., Reig, S., et al. (2005). Hypofrontality in men with first-episode psychosis. British Journal of Psychiatry, 186, 203
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60. Naz, B., Bromet, E. J., & Mojtabai, R. (2003). Distinguishing between first-admission schizophreniform disorder and schizophrenia. Schizophrenia Research, 62(1
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8. Pepplinkhuizen, L., van der Heijden, F., Tuinier, S., et al. (2003). The acute transient polymorphic psychosis: A biochemical subtype of the cycloid psychosis. Acta Neuropsychiatrica, 15(1), 38
43. Perris, C. (1974). A study of cycloid psychoses. Acta Psychiatrica Scandinavica, 253(Suppl.), 1
77. Perris, C. & Smigan, L. (1985). The use of lithium in the long-term morbidity suppressive treatment of cycloid and schizoaffective psychoses. In Psychiatry: The State of the Art. Vol. 3. Pharmacopsychiatry, ed., P. Pichot. New York: Plenum, pp. 375
80. Pillmann, F. & Marneros, A. (1998). Acute and transient psychotic disorders: Development of concepts. European Psychiatry, 14(suppl. 4), 321s. Pillmann, F. & Marneros, A. (2003). Brief and acute psychoses: The development of concepts. History of Psychiatry, 14(2), 161
77. Pillmann, F. & Marneros, A. (2005). Longitudinal follow-up in acute and transient psychotic disorders and schizophrenia. British Journal of Psychiatry, 187, 286
7. Pillmann, F., Haring, A., Balzuweit, S., et al. (2002a). The concordance of ICD-10 acute and transient psychosis and DSM-IV brief psychotic disorder. Psychological Medicine, 32, 525
33. Pillmann, F., Haring, A., Balzuweit, S., et al. (2002b). A comparison of DSM-IV brief psychotic disorder with ‘‘positive’’ schizophrenia and healthy controls. Comprehensive Psychiatry, 43(5), 385
92. Pillmann, F., Balzuweit, S., Haring, A., et al. (2003a). Suicidal behavior in acute and transient psychotic disorders. Psychiatry Research, 117, 199
209. Pillmann, F., Blo¨ink, R., Balzuweit, S., et al. (2003b). Personality and social interactions in patients with acute brief psychoses. Journal of Nervous and Mental Disease, 191(8), 503
8. Ro¨ttig, S., Pillmann, F., Blo¨ink, R., et al. (2005). Is there evidence in the EEG for a relationship between ICD-10 ‘‘acute and transient psychotic disorder’’ and epilepsy? Psychopathology, 38, 281
4. Sajith, S. G., Chandrasekaran, R., Sadanandan Unni, K. E., et al. (2002). Acute polymorphic psychotic disorder: Diagnostic stability over 3 years. Acta Psychiatrica Scandinavica, 105(2), 104
9. Scha¨r, V., Zeit, T., Heinemann, F., et al. (1995). Zur Hypofrontalita¨t im 99m-Tc-HMPOASPECT bei ‘‘akuten’’ Psychosen. Nervenheilkunde, 14, 379
84. Scho¨nfeldt-Lecuona, C., Freudenmann, R. W., Tumani, H., et al. (2004). Acute psychosis with a mediastinal carcinoma metastasis. Medical Science Monitor, 11(1), CS6
8. Shirts, B. H. & Nimgaonkar, V. (2004). The genes for schizophrenia: finally a breakthrough? Current Psychiatry Report, 6(4), 303
12. Singh, S. P., Croudace, T., Amin, S., et al. (2002). Incidence, course and outcome of ICD-10 acute and transient psychotic disorders. Acta Psychiatrica Scandinavica, 105(Suppl. 411), 20.

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9. Strakowski, S. M. (1994). Diagnostic validity of schizophreniform disorder. American Journal of Psychiatry, 151, 815
24. Stro¨mgren, E. (1986). Reactive (psychogenic) psychoses and their relations to schizoaffective psychoses. In Schizoaffective Psychoses, ed. A. Marneros and M. T. Tsuang. New York: Springer, pp. 260
71. Susser, E. & Wanderling, J. (1994). Epidemiology of nonaffective acute remitting psychosis vs schizophrenia: Sex and sociocultural setting. Archives of General Psychiatry, 51, 294
301. Susser, E., Varma, V. K., Mattoo, S. K., et al. (1998). Long-term course of acute brief psychosis in a developing country setting. British Journal of Psychiatry, 173, 226
30. Thara, R. (2004). Twenty-year course of schizophrenia: The Madras Longitudinal Study. Canadian Journal of Psychiatry, 49(8), 564
9. Tucker, G. J., Price, T. R., Johnson, V. B., et al. (1986). Phenomenology of temporal lobe dysfunction: A link to atypical psychosis
a series of cases. Journal of Nervous and Mental Disease, 174, 348
56. Ungvari, G. S. & Mullen, P. E. (2000). Reactive psychoses revisited. Australian and New Zealand Journal of Psychiatry, 34(3), 458
67. WHO (1992). The ICD-10 Classification of Mental and Behavioral Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: WHO. WHO (1993). The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: WHO. Zhang-Wong, J., Beiser, M., Bean, G., et al. (1995). Five-year course of schizophreniform disorder. Psychiatry Research, 59, 109
17.

7

Delusional disorder Theo Manschreck Harvard University

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B B
B B
C C Cþ Cþ C


Introduction Based on nineteenth-century descriptions of paranoia (particularly those of Karl Kahlbaum (1863) and Emil Kraepelin)(1919), delusional disorder is a recent addition to the classification of mental disorders. Indeed, the DSM IV and ICD-10 definitions (Tables 7.1 & 7.2) have revived the concept of paranoia, refined the criteria for this disorder, delineated better boundaries with other psychotic disorders, especially schizophrenia, and emphasized careful differential diagnosis including exclusion of diseases with known causes and idiopathic disorders (such as bipolar or schizophrenic disorders) (Manschreck, 2000). Despite this promising framework, progress in building knowledge of the features, natural history, neuropathology, and biology of delusional disorder has developed slowly (Table 7.3). The reasons are instructive. The untreated and unrecognized prevalence of this disorder is substantial. Individuals with this condition are frequently free of symptoms besides the delusion. In some cases their 116

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Delusional disorder Table 7.1. DSM IV diagnostic criteria for 297.1 delusional disorder

A. Non-bizarre delusion(s) of at least 1-month’s duration. B. Criterion A for schizophrenia not met. Tactile and olfactory hallucinations may be present, if they are related to the delusional theme. Auditory and visual hallucinations, if present, are not prominent. C. Behavior is not obviously odd nor bizarre, functioning not markedly impaired apart from impact of delusion(s) or its ramifications. D. If mood episodes have occurred concurrently with the delusions, their total duration has been brief relative to the duration of the delusional periods. E. Has never met criteria for schizophrenia, and it cannot be established that a general medical condition or the direct physiological effects of a substance initiated and maintained the disturbance. Types: Erotomanic, Grandiose, Jealous, Persecutory, Somatic, Mixed, Unspecified. Source: (American Psychiatric Association, 1994)

Table 7.2. ICD-10 delusional disorder

A delusion or a set of related delusions other than those listed as typically schizophrenic, (i.e., other than completely impossible or culturally inappropriate) must be present. The delusion(s) must be present for at least 3 months. The criteria for schizophrenia are not fulfilled. No persistent hallucinations in any modality (except transitory or occasional auditory hallucinations but not in the third person or giving a running commentary). Depressive symptoms or episodes may be present, provided the delusion(s) persist at times when there is no disturbance of mood. No organic mental disorder. Specified types: Persecutory, Litiginous, Self-referential, Grandiose, Hypochondriacal (somatic), Jealous, Erotomanic. Source: (World Health Organization, 1993)

Table 7.3. Main features of delusional disorder

Chief feature is a plausible delusion. Not a common disorder, nor rare. Minimal additional symptoms. Several subtypes based on predominant theme (erotic, persecutory, etc.). Difficult to treat and possibly treatment resistant. Distinct from schizophrenia and mood disorder. Etiology is unknown.

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Theo Manschreck Table 7.4. Epidemiological features of delusional disorder

Incidence Prevalence Inpatient psychiatric admissions Lifetime morbidity risk Age at onset Sex ratio

0.7
3.0/100,000 24
30/100,000 1
2% 0.05
0.1% 35
45 (range 18
80) Female 4 male

Source: (Kendler, 1982; Munro, 1999; Manschreck, 2000)

apparent normality may help them avoid drawing attention to their behavior and delusional preoccupations. They deny they are ill, and even the suggestion that they suffer from psychiatric disorder may provoke anger. Further, delusional disorder is a syndrome with an unknown etiology and associated with a number of delusion types. The latter include erotomanic, grandiose, jealous, persecutory, somatic, mixed, and unspecified. This fact has ramifications for diagnosis (there is no diagnostic test), and for its validation as a distinct entity (is it part of a spectrum of related psychotic conditions or one of many heterogeneous disorders with overlapping phenomenologies?) (Serretti et al., 1999). Moreover, the low prevalence of delusional disorder has limited the feasibility of carrying out large-scale studies. Further complicating its infrequent occurrence, delusional disorder patients often present to other medical specialists, judges, attorneys, the police, even pest exterminators, but seldom to psychiatrists. Also, clinical determination that a delusion is not bizarre (implausible and not understandable nor consistent with ordinary life experiences) may be difficult, especially across different cultures. Finally, the temporal stability of the diagnosis has been challenged in some reports (Fennig, Craig, & Bromet, 1996). Nevertheless, gains in understanding delusional disorder have occurred. The purpose of this chapter is to outline in greater detail evidence about this unusual and important psychotic disorder. Epidemiology Prevalence

Delusional disorder is not a common condition. Many have considered it rare. Unfortunately, reliable epidemiologic information is meager. Kendler (1982) assembled various data from 1912 through the 1970s to create estimates of incidence and prevalence (Table 7.4). The relevance of these numbers in relation to the disorder we currently call delusional disorder is questionable. As criteria are refined and applied in population studies, different numbers will probably develop

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(Copeland et al., 1998). Nevertheless, these are useful to guide our thinking. In summary, compared to schizophrenia and mood disorders, prevalence of delusional disorder is much less common. The persecutory type is the most common. Gender differences and other factors

Individuals with delusional disorder are somewhat more likely to be female and to be more socially and educationally disadvantaged compared to individuals with mood disorders where a substantial preponderance of patients are female. In contrast, there is a more equal distribution of gender in the incidence of schizophrenia. Women tend to be older than men when they are diagnosed. It is widely believed that jealous type delusional disorder occurs more often in men than women.

Age of onset The range is fairly wide (18
80 years) but most patients are middle aged at illness onset. Age of onset is later on average than in schizophrenia (by approximately two decades) yet, like schizophrenia, men tend to develop delusional disorder at earlier ages than women. Female cases may predominate in new cases among individuals of advanced age but do not approach the sex ratios characteristic of mood disorder. In one study (Yamada, Nakajima, & Noguchi, 1998), age of onset differed according to delusion type, the oldest age of onset being associated with the persecutory type and the youngest with the somatic type.

Presentation The cardinal feature of delusional disorder is a persistent, non-bizarre delusion not explained by other disorders according to DSM-IV. Onset can be acute or sudden following a precipitating event, or the condition may emerge gradually and become chronic. Insidious onset appears to be the more common pattern. The behavioral and emotional responses associated with delusional disorder are generally consistent with the content of the delusion (Table 7.5). The volitional, thinking, and emotional disturbances of schizophrenia are not present (including most hallucinations which are restricted in delusional disorder). Patients with delusional disorder show little impairment or disorganization in their general behavior or in the clarity and form of their thinking. Mood symptoms, even disorder, are associated with this condition, with onset usually after that of delusional disorder.

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Observed features Anger, irritability, quick annoyance Critical, accusatory behavior Defensiveness Grandiosity, narcissistic or excessive self-importance Hostility, sarcasm Humorlessness Hypersensitivity Litigiousness Obstinacy Seclusiveness Self-righteousness Suspiciousness Violence, aggressiveness Subjective features Overvalued, near delusional ideas Frank delusions (persecutory, jealousy, somatic, erotomanic, grandiose)

The delusions are indeed unusual yet they refer to experiences that can occur in real life, such as being cheated on, physically ill, in love, jealous, or persecuted. Winokur (1977) has suggested that these are possible rather than totally incredible and bizarre delusions, as are commonly found in schizophrenia. Delusions are categorized according to their content. The most common are characterized by persecution, disease (somatic), and jealousy. Delusions are persistent and unarguable. Individuals interpret facts to fit the delusion rather than modifying the delusion to fit the facts. Systemization is present: a single theme or series of connected themes is present which links to the predominant delusion. Normal life and functioning may gradually give way to the intensity of these delusional concerns. Herein lies the source of the dysfunction and impairment in social, occupational, and personal adjustment that accompany this illness. Some have suggested that there is a continuum of psychotic disorder into which delusional disorder falls, somewhere between paranoid personality and the paranoid subtype of schizophrenia, the continuum characterized in terms of behavioral disorganization and impairment of functioning. However, little evidence supports the concept that these disorders share more than overlapping psychopathology. Nevertheless, there have been proposals that a number of delusional conditions such as the Capgras and related syndromes, cycloid and

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reactive psychoses in the European literature, may be related to delusional disorder (Munro, 1999). Associated clinical features

A striking aspect in the clinical presentation of patients with delusional disorder is the absence of specific psychological or mental complaints or striking observable psychiatric features. In fact, there is active denial of the presence of symptoms. To the surprise of most clinicians is the discovery that appearance, thinking, orientation, mood and affect, attentional processes, memory capacity, perceptual processes, and often personality are intact. Thinking is coherent, yet may be abnormal (occasionally bordering on illogical) when delusional beliefs are expressed. In fact, evidence of delusional concerns and absence of insight may be the only observed characteristic features. There may be sarcasm, hostility, and even lack of cooperation because the patient’s agenda is not being addressed and the examiner appears to be on the trail of symptoms the individual denies having. Mental status examination can disclose level of impulsiveness and potential for violent or suicidal behavior. The deluded individual’s degree of self-righteousness and the intensity of the delusional experience, as well as its emotional impact, may be clues to the potential for violent behavior. Plans for harming other people, including homicide and suicidal thinking, are equally important possible features. As comorbidity with depression is high, impulses for self-harm that arise because of frustration, demoralization, and depressed mood or despair are common. Delusions of jealousy, persecution, and erotomania are especially important as they may be associated with possible aggression and violence. Stalking, history of abuse, and arrest records are occasionally encountered. Positive symptoms

First-rank symptoms of schizophrenia as described by Schneider (1959) are not characteristic of delusional disorder. Indeed, the occurrence of first-rank symptoms points to the differential diagnostic possibilities of schizophrenia or another medical condition with features of psychotic psychopathology. Indeed, positive symptoms other than the delusion are not typical. Negative symptoms

Similarly, negative symptoms, a critical dimension of the psychopathology of schizophrenia, are not typically found in delusional disorders. Comorbid mood disorder, such as depression, may result in episodes of reduced motivation and/or ambition and interest, and psychomotor slowing, but not the trait-like durability of negative symptoms typical of schizophrenia. Such ‘‘secondary’’ negative symptoms are also associated with antipsychotic treatment.

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Hallucinations

The presence of hallucinations in delusional disorder cases has been controversial, with some arguing that schizophrenia is a more likely diagnosis and others that delusional disorder is still diagnosable as long as hallucinations are not marked or persistent. There is no final resolution of this issue; DSM-IV (and ICD-10) considers infrequent, poorly organized, simple hallucinations that are not a prominent feature in the mental state to be consistent with delusional disorder. Such hallucinations may be auditory or visual; other types of hallucinations have also been reported. These include tactile or olfactory hallucinations which not only may be present but prominent if they are related to the delusional theme. They tend to be more common in acute cases. Emotional and behavioral symptoms

Patients with delusional disorder show emotional and behavioral response consistent with their experience of delusional concerns (Table 7.5). They may exhibit ideas of reference such that events, comments, looks from others, etc. have special significance for their delusional beliefs. Similarly, dysphoric or irritable mood may be present and understandable as a reaction to their beliefs. Overt anger and potential for violence may characterize individuals with jealousy or persecutory delusional beliefs. On the other hand, somatic delusional individuals may show largely normal moods. Litigious behavior, on the part of persecutory deluded individuals, can be pronounced: bringing suit, letter writing, hiring attorneys, and filing complaints can be common. There are comorbid conditions that can be somewhat difficult to distinguish and may add to the psychopathology. Among these, depression and other mood disorders frequently co-occur in the setting of delusional disorder (Maina et al., 2001; Manschreck, 2000; Munro, 1999). Individuals with comorbid disorders (72%) had an earlier age of onset and presentation of delusional disorder, with the comorbid disorder occurring usually subsequent to the delusional disorder illness. The most common subtype of delusional disorder with comorbid condition (usually mood disorder) is persecutory (54% in Maina et al., 2001). Neuropsychological findings

Psychological assessment may be helpful in revealing evidence of impaired intellectual functioning and may suggest brain abnormality. Differences in the verbal and performance spheres as well as scatter in the overall profile may provide clues indicating a different diagnosis. The limited data that we have on delusional disorder, especially among more chronic cases, suggests that the average patient shows normal or marginally low intelligence which is fairly characteristic of the condition. A comparison of 14 stable outpatients with late-onset delusional

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disorder matched to stable patients with late-onset schizophrenia indicated the presence of neuropsychological impairment in both groups of patients and is probably lower in delusional disorder than in schizophrenia (Evans et al., 1996). Yet the pattern of deficits was similar in both disorders and differences in deficits were not significant. This study, although small in sample size, is instructive. Careful diagnostic and neuropsychological assessments, covering verbal ability, psychomotor skills, abstraction/cognitive flexibility, attention, learning and incidental memory, motor skills, memory, and sensory abilities were administered. The extent to which age influences such results, although the author attempted to control for this, is unclear. Herlitz and Forsell (1996) reported a mild episodic (i.e., in recall tasks) deficit in the absence of other cognitive deficits in 33 elderly subjects with suspected delusional disorder compared to 66 matched controls. Other aspects of neuropsychological function, especially other components of memory, were intact. Course and progression Latency

The characteristics of delusional disorder before its initial presentation and diagnosis are largely unknown. Retrospective accounts of individual cases suggest that certain features are present. For example, there may be no evidence of psychosis in the period prior to presentation (Lewine, 1980). The average duration between onset of symptoms and hospitalization was estimated as 11.9 months in a small cohort of delusional disorder persons. Individual cases may be influenced by a variety of premorbid risk factors. These include isolation, certain personality traits, family history, sensory isolation, and recent immigration. For example, Munro (1999) asserts that many cases appear to arise in a markedly abnormal personality, characterized often by isolation and asocial features. Munro and Chmara (1982) found that 28 percent of a sample of 50 cases had personality disorders, most often schizoid personality disorder. Opjordsmoen and Retterstol (1991) in a study of 72 delusional disorder individuals found evidence of premorbid paranoid personality traits in 43%, avoidant traits in 18%, and schizoid traits in 3%. And Thewissen et al. (2005) have found a relationship between hearing impairment and the onset of psychotic features in a progressive study of a nonclinical population. Initial presentation

The typical case presents after considerable delay and by the most circuitous of routes. There are some cases in which initial presentation is acute, meaning that the development of the delusional thinking has occurred over a relatively short

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period of time. Such patients experience intense preoccupation with the content of the delusional thinking. There is also a tendency early on to experience rather marked mood changes, including irritability and depressive mood, but certainly frustration, disappointment, and demoralization are often present. Many individuals are not seen clinically; as in persecutory and jealousy cases, they voice their concerns to attorneys, the police, and others. Somatic cases bring their concerns to physicians. Psychiatrists and other mental health clinicians are seen last, usually the result of referral or court order. Presentation of psychotic symptoms

Given the limited array of psychopathologic features in delusional disorder, it is not unreasonable to consider that onset begins with the psychotic symptoms, specifically the delusion and its related behaviors. As occupational functioning and intellectual abilities appear to be relatively well maintained, the presence of a delusion and the behaviors associated with the delusion, namely suspiciousness, generally the source of impairment for the patient, are crucial in understanding the nature of this disorder. Prodrome

The prodrome of the illness is therefore not well charted. A number of features may be present. The delusion does not usually occur as a sudden insight, but rather as a culmination of brooding, preoccupations, and possibly odd behaviors on the part of the patient focused on the content of what becomes the delusion. As many cases have a gradual onset, it is likely that the thinking and the concerns associated with that thinking develop over extended periods, perhaps reaching delusional intensity only in the latter stages prior to the development of the illness. Opjordsmoen and Retterstol (1991) found a relationship between duration of symptoms prior to treatment (and diagnosis) and outcome. The longer the duration the poorer the outcome. Much of the evidence on course has come from Nils Retterstol’s personal follow-up and investigation of a large series of cases (Retterstol, 1970; 1991). It has been noted that the onset may begin in adolescence but that most cases occur during middle to late adulthood. There are variable courses including lifelong disorder in many cases. As most studies indicate that delusional disorder is not associated with severe impairment or abrupt changes in personality but rather a gradual or progressive involvement with delusional concerns, this characteristic is also noteworthy. Most patients live a normal life span despite a suicide rate that is considered to be modestly higher than normal. Spontaneous recovery is considered to be low but difficult to ascertain.

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Chronic forms of the illness, that is, patients who present with features of the illness that have been present for more than six months, tend to have an onset early in the fifth decade. Onset is generally acute in two-thirds of cases, and more gradual in the remainder. In Retterstol’s studies, in 53% of the cases the delusion had disappeared at follow-up, was improved in 10%, and was unchanged in 31%. For acute forms of the illness the age of onset is in the fourth decade and recovery occurs in over half the patients. Chronicity develops in nearly 10%, and a relapsing course is seen in 37%. In short, an acute and earlier onset of illness predicts a more favorable outcome. The presence of precipitating factors is often associated with a positive outcome, as is being female and married. Patients with persecutory delusions had the most favorable course and were was a somewhat less favorable course for delusions involving grandeur and jealousy. Patients with delusions of jealousy had fewer hospitalizations and were less likely to show severe psychotic deteriorations. Work status at follow-up has indicated that the majority of patients are employed. Although these observations are limited to a few cases, they provide some basis for being optimistic about this disorder. Perhaps half of the cases may remit, but relapse and chronicity are at least as common. Suspected neuropathology There is no evidence of localized brain pathology to correlate with the psychopathology of patients who suffer from delusional disorder. Because these patients seldom die early and show no consistent abnormalities in neurological examination, the prospect of finding a specific lesion to account for the features of this condition remains distant. Indeed, delusions similar to those of delusional disorders arise in many different disorders, some metabolic in nature and others associated with structural pathology such as degenerative dementias, epilepsy, cerebrovascular disease, extrapyramidal disorder, and traumatic brain injury. Hence, the term ‘‘organic delusional disorder’’ sees frequent use. In fact, there are at least 150 medical conditions in which delusional features have been identified (Manschreck, 2000), a fact that underlines the importance of differential diagnosis, especially because many of these are far more prevalent than delusional disorder. The occurrence of delusions in a variety of disorders with well described neuropathology has led to the proposal that the type of delusional experience that is characteristic of delusional disorders could be associated with subcortical pathology. That is, the elaborate, systematic delusions, tending to be chronic and involving intensely held beliefs and associated with limited if any intellectual impairments, but rather marked affective components, are similar to delusional experiences in patients who suffer from neurologic lesions involving the limbic

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system or subcortical nuclei (McAllister, 1992). This feature, coupled with the observation of the responsiveness of some patients to antipsychotic drug treatment, provides a basis on which to hypothesize the presence of a subcortical pathology, possibly involving temporal and limbic areas (Cummings, 1992). However, the available evidence suggests that, if there is a localizable lesion, it is subtle (Manschreck, 1995; 2000). Imaging studies have yielded subtle findings about delusional disorder. In one study, 16 patients with delusional disorder showed lateral ventricular enlargement greater than in subjects with schizophrenia (n ¼ 31) and almost twice that of age-matched controls (n ¼ 35) (Howard et al., 1994). These same 16 delusional disorder subjects also showed right
left asymmetry significantly greater in the temporal lobes. Delusional disorder patients showed greater dysfunction in saccadic eye movements than normal controls (Gambini et al., 1993). Wada and colleagues (1998) reported reduced regional blood flow in temporal and parietal areas using SPECT probes. Suspected neurochemical abnormalities In efforts to identify the neuropathology of delusional disorder, no specific lesions have been identified, but the search for neurochemical mechanisms underlying the symptomatology has been an area of interest. For example, Morimoto et al. (2002) found that patients with delusional disorder, compared to schizophrenic patients and healthy controls, had higher pretreatment plasma homovanillic levels. They also detected differences in dopamine receptor genetic polymorphisms. When the delusional disorder patients received the antipsychotic haloperidol, they achieved a clinical response with smaller doses compared to acutely psychotic schizophrenic controls. This prompted the researchers to suggest that delusional disorder, because of its focused psychopathology, may in fact be a pure dopamine psychosis. What is interesting about this proposal is that it had been suggested in earlier writings by Munro (1982), who had found that low doses of pimozide, a highly specific dopamine blocking agent, were effective particularly in the somatic form of delusional disorder in his series. These findings create a foundation for hypothesis testing, but much needs to be learned about the neurochemistry of delusional disorder. Genetic factors One of the risk factors for the development of delusional disorder is familial history, suggesting that genetic transmission may have a fundamental role in the production of these disorders. Genetic and family studies indicate possible specific family transmission of delusional disorder. For example, a study of genetic

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Delusional disorder Table 7.6. Prevalence of psychiatric disorders in relatives

Schizophrenia Unipolar depression Bipolar disorder Inferiority feelings Antisocial personality

Delusional disorder n ¼ 58

Schizophrenia n ¼ 585

2 3 0 12 12

7 4 1 4 6

Source: Kendler & Hays (1981) Table 7.7. Other risk factors possibly relevant to etiology

Age Subtle brain abnormality (e.g., head trauma) Social isolation Personality (sensitivity; narcissistic traits) Sensory impairment Immigration Lower socioeconomic status

variation and DNA sequence coding for dopamine D4 receptor protein strongly suggested the involvement of the relevant gene in conferring susceptibility to delusional disorder (Catalano et al., 1993). Comparison subjects either had schizophrenia or were normal controls. Delusional disorder does not appear to be genetically related to schizophrenia (Farmer, McGuffin, & Gottesman, 1984; Howard et al., 1997; Kendler & Hays, 1981; Watt et al., 1980). Findings from family or genetic studies also support the theory that delusional disorder is a distinct entity (Kendler, 1980). There is limited evidence that paranoid and avoidant personality disorder may be common among first-degree relatives of individuals with delusional disorders. If delusional disorder is simply an unusual form of schizophrenia or mood disorder, then the incidence of these latter conditions in the family studies of delusional disorder patient probands should be higher than that of the general population. However, this has not been a consistent finding. For example, a study by Winokur (1985) concluded that patients with delusional disorder are more likely to have family members who show suspiciousness, jealousy, secretiveness, even paranoid illness, than families of controls. Kendler and Hays (1981) found a threefold greater clustering of inferiority feelings among relatives of delusional disorder probands and no evidence of increased schizophrenic prevalence among their relatives (Table 7.6). There is also evidence of increased risk of alcoholism among relatives

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of patients with delusional disorders as compared to probands of schizophrenia, as well as probands with psychotic disorder, NOS, and probands with schizophreniform disorder (Kendler and Walsh, 1995). While it would be premature to suggest that a genetic transmission pattern of substantial influence has been found for this disorder, it is clear that some familial influence is operative. We await the results of additional studies. Other risk factors A number of risk factors in addition to genetic or familial risk have been described as associated with delusional disorder (Table 7.7). Munro (1999) reports in his series that individuals with delusional disorder frequently have a history of ‘‘cerebral insult’’, for example, traumatic brain injury, stroke, and diabetic neuropathy, and a history of psychoactive substance abuse. He argues that subtle brain abnormality may be a predisposing factor for delusional disorder. Others have suggested that aging contributes to risk, also perhaps related to a matrix of changes captured by the term ‘‘subtle brain impairment.’’ Immigration status appears to be an associated finding in many studies of delusional disorder. Kendler (1982) asserted that this association was greater than that for mood disorders or schizophrenia (McGrath, 2005). For example, the rate for delusional disorder in one Norwegian study among immigrants was forty fold that of the indigenous population (Eitinger, 1960), while the rate for schizophrenia was one and a half that of the indigenous population. Sensory deficits, common among older adults, may also be a predisposing factor to psychosis, although there is controversy concerning the specificity of the relationship (Manschreck, 2000; Thewissen et al., 2005). Factors that appear to be unrelated or not particularly relevant to delusional disorder include alcohol use and place of residence (rural or urban) (Kendler, 1982). In sum, the risk factors of lower socioeconomic and educational status, sensory isolation, immigration status, and cerebral insult may be important because of the comparatively low rates of mental disorder found in families of delusional disorder patients. These observations are consistent with Kraepelin’s proposal that environmental factors may be more critical than genetic in the pathogenesis of delusional disorder (paranoia). Treatment Sometimes delusional disorders are actually treated despite the tendency to avoid psychiatric intervention. Patients with the disorder have generally been regarded as difficult to treat, if not treatment resistant, and interventions have often focused

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on managing the morbidity of the disorder by reducing the impact of the delusion on the patient’s and the family’s life (Manschreck, 2000; 2005). Recent evidence has suggested that the outlook can be much less pessimistic. However, treatment is a delicate enterprise with many obstacles. Its goals are first to establish the diagnosis, to decide on appropriate interventions, and to manage complications. Fundamental to success in reaching these goals is an effective and therapeutic relationship, not easy to establish but critical to maintain. The psychiatric clinician in fact may be brought into the net of the delusional thinking. Psychosocial treatments

Limited evidence exists to substantiate the proposition that any particular approach to talking therapy is preferable. Insight oriented therapy is generally contraindicated, but most clinicians view supportive psychotherapeutic approaches possibly augmented by cognitive behavioral interventions as a sensible strategy. The key to treatment is recognition that this is a psychiatric condition that requires openness and reliability from the therapist at a level greater than is usually necessary in other conditions. Considerable skill is essential to deal with the profound and intense feelings that accompany these disorders. Patients appear to have fragile self-esteem and unusual sensitivity. This of course affects their general management and the course of any form of treatment. The strategy is to forge an alliance, avoiding direct questioning of the veracity of the delusion and responding to the sense of distress rather than to the content or characteristics of the delusion itself. As fear and anxiety may stimulate hostility in those with this disorder, it is useful to adopt a flexible approach that enhances empathy but maintains emotional distance with the patient. These individuals are suffering. They feel demoralized, miserable, isolated, abandoned, and unbelieved. Consequently, they may face rejection at home, from police or medical specialists, or on the job. The goals of such therapy are to allay anxiety and to encourage discussion of troubling experiences and consequences of the delusion, hoping thereby to develop an empathic collaboration with the patient. In some cases this strategy may suggest means of coping more successfully with the delusional thinking. Occasionally, intervention may also assist the individual to understand how features such as sensory impairment, social and physical isolation, and even stress contribute to making their condition worse. Cognitive approaches have attempted to reduce delusional thinking in this and other psychotic disorders through modification of the belief itself, a very different strategy focusing on the associated reasoning or the reality testing of the deluded individuals, unlike non-cognitive approaches that center attention on reduction of verbal behavior, that is, talking about the delusion. This strategy seeks a more lasting and meaningful intervention through multiple techniques that keep the

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relationship with the patient collaborative. These techniques include, amongst others, distancing, homework, and examination of emotions associated with the various delusions. The effectiveness of cognitive behavioral therapy has not been studied enough to warrant a strong recommendation, and it is important to understand the value of long-term follow-up as well as short-term impact of these treatments before making a final judgment. Nevertheless, the techniques are promising and suggest the value not only of further research but of thoughtful application of these treatments. Somatic treatment

As delusional disorder is in fact a psychotic disorder, understandably many have thought that it might respond to antipsychotic medication. However, control studies are few and the disorder is uncommon. Hence, evidence to support antipsychotic intervention is limited. Riding and Munro (1975) reported on the treatment of several cases of what was termed monosymptomatic hypochondriacal psychosis with the antipsychotic agent pimozide. This work was replicated in additional publications and indicated that a form of delusional disorder (i.e., the somatic subtype) is a treatable condition with this medication. They further found that in unimproved cases, noncompliance with medication was an important factor affecting outcome. Later, Munro and Mok (1995) reviewed experience with antipsychotic treatment of delusional disorder from the 1960s to 1994, critically analyzing approximately 1,000 articles dating from 1961. They only selected cases where clinical presentations conformed to DSM-IV criteria, and identified 257 cases, of which 209 were sufficiently detailed to report meaningfully about treatment. Only the broadest conclusions could be drawn from their review. Nevertheless, they concluded that delusional disorder was an illness with a reasonably good prognosis when adequately treated. They also observed that treatment response was positive regardless of the specific delusional content (subtype) of the disorder. Interestingly they also noted that pimozide had the strongest evidence of good results in these clinical reports. This writer has reviewed the literature published since 1994 (Manschreck & Khan, 2006). A similar selection process extracted some 221 usable cases. However, of these, only 131 had sufficient treatment information for analysis. A major innovation since Munro and Mok’s review (Munro & Mok, 1995) was the introduction of second generation (atypical) antipsychotic medications that some had predicted might successfully treat delusional disorder. New trends in medication therapy had also emerged during this interval. Among these were polypharmacy regimens including both multiple antipsychotics as well as antipsychotics and other psychotropic agents. The main results were that in the

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best documented cases a positive response was noted in nearly 50%. This observation contrasts with widespread pessimism about treatment in delusional disorder. As the literature seldom provides a forum for negative results and clinicians are reluctant to report such results, the reliance on case study rather than controlled trials and the lack of double blind randomized control studies raise concern about the evidence for this positive response. Despite the introduction of second generation agents over a decade ago, the number of reports is limited and experience thus far, though it parallels those of the older agents, limits major conclusions. Conclusions Delusional disorder remains an enigmatic and largely uncharted subject. Current knowledge, although rudimentary, frames a disorder with devastating psychopathology. Establishing a greater grasp of this condition will depend fundamentally on large-scale studies or more modest scale, systematic research on its many dimensions. A related obstacle is the limited understanding we have of delusions per se.

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4.

Part III

Mood Disorders

8

Psychosis in bipolar disorder Deborah Yurgelun-Todd Harvard Medical School and McLean Hospital

Summary of findings Grade of evidence Epidemiology: Psychotic symptoms occur in about half of bipolar patients, with inconsistencies in sex differences for psychotic symptoms. Age of onset: Psychotic symptoms are more common in early-onset bipolar disorder. Presentation: Delusions (grandiose, influence, or persecution) are the most common psychotic symptoms, with mood incongruent features in about 50% of patients; age of onset may predict the type of psychotic symptoms experienced. Course and progression: Psychotic symptoms predict further psychotic episodes, and are associated with poorer functional outcome. Suspected neuropathology: Shared volumetric reductions in first episode psychotic bipolar and schizophrenia, but reductions in psychotic bipolar are less widespread; psychosis is associated with white matter changes common to bipolar and schizophrenia; a number of neurophysiological changes in psychotic bipolar are more similar to schizophrenia than non-psychotic bipolar. Suspected neurochemical abnormalities: Reduced temporal lobe NAA in psychotic bipolar; post-mortem neurochemical abnormalities show commonalities with schizophrenia; dopaminergic changes in psychotic bipolar. Genetic factors: Shared susceptibility genes for psychotic bipolar with schizophrenia and within families with psychotic bipolar probands; familial aggregation of psychotic features in bipolar families. Other risk factors: Post-partum psychosis; Multiple sclerosis. Treatment: Mood-stabilizers, including lithium and anti-convulsants for acute and maintenance therapy, with adjunctive antipsychotics for 137

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Grade of evidence acute mania and antidepressants for depressive symptoms; integration of psychotherapy has additional benefits; mood-stabilizers and antipsychotics have similar efficacy on psychotic symptoms, with some evidence of an additive effect.

Introduction Bipolar disorder is a prevalent and often debilitating developmental neuropsychiatric illness, which is among the leading causes of disability worldwide. A recent investigation reported bipolar disorders affect approximately 2.3 million individuals in the United States or 1.2 percent of the population in a given year (Narrow et al., 2002). Characterized by severe alterations in mood (i.e. mania, depression) which are generally episodic and recurrent, bipolar disorder is currently considered to have several possible subtypes: bipolar I disorder (with mania, major depression, or mixed dysphoric-excited states), bipolar II disorder (major depression with hypomania), cyclothymic disorder, and bipolar disorder not otherwise specified, as well as the course-specifier rapid cycling (at least four recurrent episodes within one year of assessment) (APA, 1994). Psychotic symptoms are a common feature of bipolar disorder (Benazzi, 1999), most frequently manifesting as grandiose delusions, delusions of persecution, and delusions of influence, with formal thought disorder, hallucinations, and Schneider’s first-rank symptoms also observed but relatively less common. Bipolar patients with prominent psychotic features may even characterize a distinct subgroup (Swann et al., 2001). Moreover, researchers have recently challenged the Kraepelinean view of the dichotomous classification of bipolar disorder and schizophrenia (Kendler, Karkowski, & Walsh, 1998; Ketter et al., 2004). Epidemiology A recent eight-year study of first-episode psychosis observed an annual incidence of bipolar disorder with or without psychosis of 5.2 per 100,000 population aged over 15 years, with no difference in the incidence between males and females (Baldwin et al., 2005). In a 35-year epidemiological study, psychotic symptoms were experienced by 74% of 246 first-episode mania patients diagnosed with bipolar I disorder (Kennedy et al., 2005). An Australian prevalence study of

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112 bipolar I and II patients reported that 86% had experienced delusions, with only 21% ever experiencing hallucinations. More males had a life-time history of delusions than females (88% versus 83%) (Morgan, Mitchell, & Jablensky, 2005). In this study, manic or mixed episodes were present in 18.8% of the patients within the four weeks preceding interview, with 47.6% of these patients exhibiting grandiose delusions at this time. The authors did not report the number of patients presenting with hallucinations, but of those interviewed men were more likely to experience hallucinations and delusions than women (39% versus 21%) (Morgan et al., 2005). This study included only patients in contact with treatment services, therefore it was likely to select far more severe bipolar patients and possibly overestimate the prevalence of psychotic symptoms. In contrast, Yildiz and colleagues observed that only 42% of bipolar patients were positive for a history of psychotic symptoms, with 95% of these psychotic symptoms diagnosed in bipolar I patients. In this retrospective study, life-time history of psychotic symptoms was higher in women than men (48% versus 35%) (Yildiz & Sachs, 2003), in contrast to the aforementioned study. A recent review reported psychotic symptoms in 16
88% of pediatric and adolescent bipolar studies (Pavuluri, Herbener, & Sweeney, 2004), with higher prevalence rate (61
88%) reported in studies that used the Structured Clinical Interview for DSM III-R (SCID) rather than the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS) for diagnosis (Carlson, Bromet, & Sievers, 2000; McClellan et al., 1999; McElroy et al., 1997), indicating that methodological issues need to be considered. Overall, these studies and others (Coryell et al., 2001; Potash et al., 2001; Schulze et al., 2002; Schurhoff et al., 2000) indicate that at least half of patients with bipolar I disorder experience psychotic features at some time and less with bipolar II disorder (Benazzi, 1999; Yildiz & Sachs, 2003), however, further research is required to determined whether differences exist in the occurrence of psychotic symptoms in men and women.

Age of onset The median age of onset of bipolar disorder appears to be in the late teens to early twenties, although both early-onset (pediatric and adolescent) as well as late-onset bipolar disorder are being recognized with increasing frequency (Leboyer et al., 2005). Most studies agree that psychotic symptoms are more common in patients with early-onset than late-onset bipolar disorder; however, methodological differences prevent direct comparison between studies. In a 35-year study of first-episode mania, Kennedy and colleagues reported a significant age of onset effect with 77% of patients experiencing psychotic symptoms with onset earlier

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than 40 years old compared with 61% of patients 40 years old or over (Kennedy et al., 2005). A study of 210 consecutive admissions to psychiatric hospitals reported that 47% of adolescent bipolar patients (under 18 years old) had a history of psychotic symptoms compared with 26% of late-onset patients (over 40 years old) (Schurhoff et al., 2000). Similarly, Schulze and colleagues reported a greater number of patients with a history of delusions and hallucinations with early onset (20 years old or less) compared to late onset (30 years old or more) (Schulze et al., 2002). However, Yildez and colleagues reported that the mean age of onset was significantly younger for patients with a history of psychotic symptoms versus those without in males only in a retrospective study of 328 bipolar patients (Yildiz & Sachs, 2003), in concordance with a study reporting that males were over-represented in the early-onset group (under 21 years old) compared with the late-onset group (over 30 years old) in patients with psychotic features (Carlson et al., 2000). Earlier studies have generally supported the increased prevalence of psychotic symptoms in early-onset bipolar disorder (Ballenger, Reus, & Post, 1982; McGlashan, 1988; Rosen et al., 1983b), although no difference between groups was observed in a small study (Coryell & Norten, 1980), and lower prevalence of psychotic symptoms was reported in adolescents in one prospective study (McElroy et al., 1997). This latter study was methodologically different to previous studies as it compared current psychotic symptoms in hospitalized groups, and the demarcation of age groups (adolescent 12
18 years versus adult 19
45 years) precluded detecting any differences between early- and late-onset bipolar disorder.

Presentation Psychotic symptoms usually manifest during the manic phase as delusions and hallucinations, and these can be mood-congruent or mood-incongruent, with negative symptoms observed in some patients. The presence of these symptoms is associated with poorer functioning and increased hospitalization at the time of illness (Swann et al., 2004). For first-episode early-onset mania in patients seeking treatment, the most common psychotic features in bipolar disorder were grandiose delusions (62%), delusions of persecution (60%), and delusions of influence (38%) (Kennedy et al., 2005), with hallucinations less common (21%) (Morgan et al., 2005). Additionally, 50% of patients had experienced moodincongruent psychotic features and 41% positive formal thought disorder, but for a majority of these patients these psychotic episodes lasted less than one week. The type of psychotic symptoms experienced are associated with the age of onset, with mood-incongruent psychotic features, delusions of persecution and

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influence, and auditory hallucinations more evident in the early-onset group, while visual, somatic, and olfactory hallucinations, although relatively rare in bipolar disorder, are more common in the late-onset group (Kennedy et al., 2005). Similarly, Carlson and colleagues observed more grandiose and paranoid delusions in adolescents compared with late-onset patients, although rates of mood-incongruent delusions and hallucinations in this study were independent of age of onset (Carlson et al., 2000). Neuropsychological and emotional symptoms are dependent on the phase of illness, with depressive and manic episodes involving a complex mix and interplay of mood, motivational, cognitive, somatic, and behavioral symptoms, and residual cognitive impairments are often evident in the euthymic state (Coffman et al., 1990; Joseph, 1999). Bipolar depressed individuals show a decrease in focused attention and goal-directed or motivated behavior across multiple areas of functioning. In contrast, a manic episode is characterized by elevated, expansive, or irritable mood, and is usually accompanied by altered cognitive processing, heightened energy levels, higher sex drive, increased activity levels, pressured thought and speech, and distractibility (Altshuler, 1993; Sapin et al., 1987). Unlike depressed individuals, manic patients show an increased interest in pleasurable activities and a resultant increase in reward-directed behavior.

Course and progression Bipolar disorder is usually recurrent and multiple episodes or prolonged periods of impaired functioning are the rule rather than the exception. Initial symptoms may be manic or depressive with similar frequency at first presentation; there is often a delay between the onset of symptoms and treatment seeking. A survey of 500 patients reported that only 23% of patients consulted a medical professional within six months of initial symptom onset (Lish et al., 1994) and many do not for 5
10 years (APA, 1994). Bipolar has high rates of recurrence, with approximately 90% of individuals who have a single manic episode going on to have a future episode (Gitlin et al., 1995). Recurrent psychosis is predicted by the presence of psychotic symptoms during hospitalization (Goldberg & Harrow, 2004), particularly during the depressive phase (Coryell et al., 2001), and psychotic symptoms in major depression are associated with increased risk for later diagnosis of bipolar I disorder (Akiskal et al., 1995). The average cycle length between the first and second episodes varies between 2
4 years in different studies, with episodes occurring with increasing frequency subsequently (Goodwin & Jamison, 1990). Rapid cycling of at least four affective states per year occurs in 10
15% of patients. Manic episodes begin more abruptly than the relatively slower onset of

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bipolar depression, with symptoms lasting from a few days to several months (Lish et al., 1994). Psychosocial functioning can be affected severely in bipolar disorder, with up to 60% of patients unable to return to a premorbid level of functioning both socially and vocationally (MacQueen, Young, & Joffe, 2001). Comparing outcome for psychotic and nonpsychotic bipolar patients, poorer outcome has been reported in psychotic patients, including higher relapse rates (Tohen, Waternaux, & Tsuang, 1990), greater number of weeks ill (Coryell et al., 2001), and poorer social functioning (Cannon et al., 1997; Rosen et al., 1983a); however, not all studies have observed differences between these groups at outcome (Goldberg & Harrow, 2004; MacQueen et al., 1997). Poorer outcome may be associated with specific psychotic symptoms, for example, mood-incongruent psychosis at first manic episode were associated with shorter remission times (Tohen, Tsuang, & Goodwin, 1992), and poorer overall functioning (Strakowski et al., 2000), and Schneiderian first-rank symptoms predicted poor residential status (Tohen et al., 1992). Seriously impaired bipolar patients are more likely to be male, single, less educated, and more likely to experience hallucinations (31% versus 17%), but not delusions (Morgan et al., 2005).

Suspected neuropathology Bipolar studies have reported that brain abnormalities are mainly regional, particularly in the prefrontal cortical areas, amygdala, and striatum, with whole brain white and gray matter and ventricular volumes relatively less affected (reviewed by Haldane & Frangou, 2004; Strakowski, Delbello, & Adler, 2005). Most research examining brain abnormalities associated with psychosis has compared first-episode psychoses in bipolar patients and schizophrenics. Compared with healthy controls, both first-episode psychotic bipolar and schizophrenic patients have demonstrated a reduction in the volume of the left hippocampus (Velakoulis et al., 1999), anterior cingulate (Hirayasu et al., 1999), left temporal pole gray matter, and a reduction in hemispheric asymmetry (Kasai et al., 2003), with similar decreases in white matter reported in both groups (Farrow et al., 2005). Additionally, a greater proportion of psychotic bipolar and schizophrenic patients exhibit abnormal cavum septi pellucidi than controls, suggesting shared neurodevelopmental abnormalities and associated psychopathological outcome (Kasai et al., 2004). Some studies have identified volumetric changes specific to first-episode schizophrenia that were not apparent in psychotic bipolar disorder. These changes include a reduction in the volume of the superior temporal lobe gyrus (Hirayasu et al., 1998; 2000), insular cortex (Kasai et al.,

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2003), fusiform gyrus (Lee et al., 2002), the left prefrontal gray matter (Hirayasu et al., 2001; Wiegand et al., 2004). Findings specific to first-episode affective psychosis include asymmetry of the posterior amygdala-hippocampal complex (Hirayasu et al., 1998), and changes in the structure of the corpus callosum (Frumin et al., 2002). A recent longitudinal study of first-episode psychosis observed that psychotic bipolar patients exhibited reduced inferior temporal gyri volumes at initial presentation with decline in the anterior cingulate over two years, while schizophrenic patients demonstrated more widespread reductions in fronto-temporal gray matter at initial presentation, with additional losses in the lateral fronto-temporal regions and left anterior cingulate over time (Farrow et al., 2005). In studies that have looked beyond first-episode psychosis, disruptions of white matter connectivity appear to be important in the pathogenesis of psychosis. A computational morphometry study of bipolar patients with a history of psychosis and schizophrenics observed that these patients shared longitudinal and inter-hemispheric white matter abnormalities indicative of disconnectivity between frontal and temporoparietal cortex. However, patients with schizophrenia also exhibited more widespread cortical volume reductions of the fronto-temporal neocortex, medial temporal lobe, insula, thalamus, and cerebellum (McDonald et al., 2005). Interestingly, relatives of psychotic bipolar probands exhibit reduced volumes of the right anterior cingulate and ventral striatum, with familial risk of both schizophrenia and psychotic bipolar disorder associated with reduced white matter in the left frontal and temporoparietal regions (McDonald et al., 2004). These reported white matter changes associated with psychosis are consistent with downregulation of genes related to myelination and oligodendrocyte function observed in both bipolar and schizophrenia brains (Tkachev et al., 2003) and the higher prevalence of white matter hyperintensities in bipolar patients (Ahn et al., 2004). Only a few brain studies have compared bipolar patients with and without psychotic features. Strasser and colleagues demonstrated that psychotic bipolar disorder and schizophrenia were associated with enlarged lateral ventricles compared with nonpsychotic bipolar disorder and controls (Strasser et al., 2005), suggesting that psychotic bipolar disorder is a more homogeneous subgroup, with more similarities to schizophrenia than nonpsychotic bipolar disorder. However, in this study left hippocampal volume was reduced in schizophrenics, but there were no significant differences in hippocampal volume between psychotic and nonpsychotic bipolar patients and controls. Additionally, bipolar patients with a history of psychotic symptoms demonstrated a reversal of the cerebral asymmetry anterior-posterior equivalent current dipole locations compared with both controls and nonpsychotic bipolar patients (Reite et al., 1999). These findings are

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indicative of anatomical displacement of the precentral gyrus, and are similar to that seen in schizophreniform disorders. In a study of psychotic and nonpsychotic depressive patients including some diagnosed with bipolar disorder, shortened REM latency was related to psychotic symptoms independent of illness severity (Stefos et al., 1998).

Suspected neurochemical abnormalities A recent review has comprehensively reported neurochemical alterations in bipolar disorder in studies using proton (1H) and phosphorous (31P) magnetic resonance spectroscopy (MRS) in bipolar disorder (Stork & Renshaw, 2005). This review hypothesized that bipolar disorder was associated with mitochondrial dysfunction, indicated by reports of reduced N-acetylaspartate (NAA), a marker of neuronal dysfunction, as well as increased amino acids (glutamine and glutamate), lactate, and reduced intracellular pH, suggestive of a shift toward glycolysis. Additionally, altered phospholipid metabolism has been observed in bipolar patients, marked by an increase in choline and myo-Inositol, and altered phosphomonoester levels in these studies. There is a relative paucity of data examining the link between psychotic bipolar disorder and neurochemical changes: reduced NAA was observed in the temporal lobe of first-episode psychosis patients with either schizophreniform or bipolar disorder in one study (Renshaw et al., 1995), and NAA/creatine was reduced in the bilateral hippocampus in first-episode bipolar patients with psychosis compared with controls in another (Blasi et al., 2004). These results suggest that the neuronal integrity of the temporal lobes is impaired in bipolar patients with psychotic symptoms, and that these abnormalities are not related to the chronicity of symptoms. Reduced NAA in the hippocampus has also been observed in bipolar patients with and without psychotic symptoms (Bertolino et al., 2003; Deicken et al., 2003), therefore further investigation is required to determine if this finding is specific to psychotic symptoms. In postmortem bipolar disorder and schizophrenia brains, an overlap in the reduced expression of a number of neurochemical markers was suggestive of shared abnormalities in the GABA and developmental/synaptic neurochemical systems in these disorders (Torrey et al., 2005). There is also evidence to support the disruption of serotoninergic (Drevets et al., 1999; Vawter, Freed, & Kleinman, 2000) and dopaminergic (Strakowski et al., 2005) neurotransmitter systems in bipolar disorder. One study has reported that D2 receptor binding is increased in patients with psychotic symptoms only, with a relationship between psychotic symptoms and D2 receptor density (Pearlson et al., 1995), providing support that the dopaminergic system is important for the expression of psychoses.

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Genetic factors Findings from family, twin, adoption, and other genetic studies consistently report a strong genetic component to bipolar disorder that has been comprehensively reviewed (Craddock & Jones, 1999; 2001; Craddock, Dave, & Greening, 2001; Craddock, O’Donovan, & Owen, 2005; Smoller & Finn, 2003). Risk for the disorder increases as the amount of shared genetic material increases, with concordance rates between monozygotic twins approximately 40
70%, and for first-degree relatives 5
10%, compared to a lifetime risk of about 1% in the general population. Heritability is generally more specific for bipolar disorder (McGuffin et al., 2003), but the risks for schizophrenia and psychotic symptoms are also increased in first-degree relatives of bipolar patients (Gershon et al., 1988; Ketter et al., 2004; Maier et al., 1993; Rende et al., 2005). Additionally, bipolar disorder and schizophrenia are both associated with increased familial risk for schizoaffective disorder and there is overlap of the susceptibility genes 10p12
13, 13q32, 18p11.2, and 22q11
13 between these disorders (Berrettini, 2000), suggesting shared genetic risk that may be partially responsible for the expression of psychotic symptoms. Susceptibility genes for psychotic bipolar disorder have also been identified in bipolar families on chromosomal regions 13q31 and 22q12 (Potash et al., 2003b). A genetic role for the expression of psychotic symptoms in schizophrenia and affective disorders has been demonstrated in a number of familial studies. Increased risk for bipolar disorder with psychotic features was observed in relatives of schizophrenia probands, but the increased risk for schizophrenia in relatives of psychotic affective disorder probands did not reach significance (Kendler et al., 1993). Potash and colleagues have identified the familial aggregation of psychotic symptoms (delusions and hallucinations) in two independent samples of bipolar I patients (Potash et al., 2001; 2003a), and another study identified increased susceptibility to delusions amongst families of schizophrenic and bipolar probands (Schurhoff et al., 2003). Additionally, affected siblings with bipolar disorder show a correlation between dimension scores for psychosis (O’Mahony et al., 2002). In contrast, an earlier study reported family linkage of psychotic symptoms in schizophrenia and schizoaffective disorder, but not in unipolar and bipolar disorder; however, the number of subjects was significantly lower in the affective disorder groups (Winokur, Scharfetter, & Angst, 1985). Other risk factors The investigation of non-genetic antecedents to bipolar disorder is at an early and largely inconclusive stage (Goodwin & Jamison, 1990; Tsuchiya,

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Byrne, & Mortensen, 2003). Tsuchiya and colleagues reviewed the literature to identify seven putative socio-environmental risk factors showing evidence of an association with bipolar disorder, including recent stressful life events, socioeconomic status, birth seasonality, obstetric complications, post-partum psychosis, traumatic brain injury, and multiple sclerosis (Tsuchiya et al., 2003). Of these, evidence to indicate a relationship with psychotic symptoms has been reported for post-partum psychosis and multiple sclerosis only. There is convincing evidence to support a link between post-partum psychosis and bipolar disorder based on similar symptomatology, diagnosis and outcome, and family history (Chaudron & Pies, 2003). Women who are diagnosed with post-partum psychosis have a 60
75% risk of recurrence or further affective episodes and approximately 30% are diagnosed with bipolar disorder (Robling et al., 2000; Schopf & Rust, 1994; Videbech & Gouliaev, 1995). There is a higher risk for post-partum psychosis in women with bipolar disorder, with about 30% of women with bipolar disorder meeting the criteria for post-partum psychosis (Chaudron & Pies, 2003; Jones & Craddock, 2001), compared to one in 1000 women experiencing post-partum psychosis in the general population (Videbech & Gouliaev, 1995). In multiple sclerosis, a clinical study reported that 13% of patients with multiple sclerosis have a diagnosis of bipolar disorder (Joffe et al., 1987) and a history of mania or manic psychosis was more common in the ten patients with multiple sclerosis than the 2710 other consecutive admissions to a psychiatric unit (Pine et al., 1995). Additionally, the emergence of psychotic symptoms was associated with first neurological symptoms of multiple sclerosis or relapse in three case reports (Heila, Turpeinen, & Erkinjuntti, 1995; Salmaggi et al., 1995; Young et al., 1997), suggesting that psychotic symptoms were associated with the lesion site. However, a possible shared susceptibility gene locus has also been identified (Bozikas et al., 2003), indicating that there may be a more complex shared etiology. Treatment Bipolar disorder is a complicated and debilitating illness that is best managed by combining treatments of psychopharmacology and psychotherapy. Because there is a large neurobiological and neurochemical component, medication is the first line of defense to stabilize symptoms during treatment; however, there is usually a latency from illness onset to diagnosis and appropriate treatment (APA, 1994). Bipolar disorder carries a threefold increase in medical mortality and increased fatality risk secondary to commonly comorbid substance abuse. Despite these facts, as few as 20% of individuals with bipolar illness are evaluated medically and

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correctly diagnosed, and many are considered to have a unipolar major depressive disorder or schizophrenia. A very important medication in the treatment of bipolar disorder is the mood stabilizer, including lithium and the newer anticonvulsants: divalproex, carbamazepine, and lamotrigine. Other common treatments include typical antipsychotics (haloperidol, perphenazine, and chlorpromazine) and atypical antipsychotics (olazapine, risperidone, ziprasidone, and clozapine). Lithium and anticonvulsants reduce the manic/depressive episode, decrease the occurrence of episodes as well as prevent the worsening of episodes; therefore they are used for the acute and maintenance treatment of bipolar disorder. Lithium is not effective in all patients, particularly in rapid cycling and mixed symptoms, which show better response to anticonvulsants (Mensink & Slooff, 2004). Adjunctive antipsychotics, which are antimanic, sedative, and faster acting, are generally given for treatment of acute mania, particularly when symptoms are more severe, and some antipsychotics have been used as a monotherapy or adjunctive therapy for prophylactic care (Mensink & Slooff, 2004). Depressive symptoms are often treated with antidepressants (SSRIs); however, antidepressants should be used in conjunction with mood stabilizers, particularly lamotrigine, to prevent inducing hypomania and/or mania (Moller & Nasrallah, 2003). Integrating psychopharmacology with psychotherapy has been found to result in fewer and less severe episodes and fewer hospitalizations while also increasing social functioning (Lam et al., 2003). The addition of psychotherapy is generally recommended only for bipolar patients that are not experiencing a manic or psychotic episode. Earlier studies investigating a differential response to lithium by patients with psychotic and nonpsychotic symptoms did not observe consistent differences (Goodwin & Jamison, 1990). More recently, Kafantaris and colleagues reported that adolescent bipolar patients with psychotic symptoms respond less well to lithium monotherapy than adolescent nonpsychotic bipolar patients (Kafantaris et al., 1998), but this difference in response was not observed in adults with and without psychotic symptoms (Coryell et al., 2001). Response rate is better when a mood stabilizer is combined with antipsychotic medication, particularly in cases where psychotic symptoms are present (Delbello et al., 2002). In general, mood stabilizers and antipsychotics have similar efficacy, particularly in the treatment of psychotic symptoms (McElroy et al., 1996; Swann et al., 2001; 2002; Tohen et al., 2002). In treatment-resistant bipolar disorder, adjunctive clozapine was equally effective at treating psychotic and nonpsychotic bipolar disorder (Suppes et al., 1999). Consistent with this, Swann and colleagues have hypothesized that psychotic symptoms represent a more severe form of mania, suggesting that

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treatment of manic symptoms automatically ameliorates psychotic symptoms (Swann et al., 2004).

Conclusions In summary, psychotic symptoms are a common feature of bipolar disorder, and occur in approximately half of patients diagnosed with the illness. Most studies agree that psychotic symptoms are more common in patients with early-onset rather than late-onset bipolar disorder. The types of psychotic symptoms experienced have been associated with age of onset, with auditory hallucinations more prevalent in early-onset groups, while late-onset groups are more prone to experience visual, somatic and olfactory hallucinations. Psychotic symptoms predict further psychotic episodes, and are associated with poorer functional outcome, particularly within the social domain. Brain imaging studies have shown that psychosis is associated with white matter changes common in patients with schizophrenia or bipolar disorder, and several neurophysiological changes associated with psychotic bipolar disorder are more common in schizophrenia than nonpsychotic bipolar disorder. Recent evidence suggests there is an overlap of susceptibility genes for bipolar disorder and schizophrenia, and the risk of developing schizophrenia and psychotic symptoms is increased in first-degree relatives of bipolar patients. Patients with bipolar disorder or schizophrenia both demonstrate increased familial risk for schizoaffective disorder. Therefore, it is not surprising that researchers have recently challenged the Kraepelinean view of the dichotomous classification of bipolar disorder and schizophrenia. Additional research is necessary to clarify the role of psychosis in the diagnosis and treatment of bipolar disorder.

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Psychosis in major depression Eric G. Smith, Philip R. Burke, Jessica E. Grogan, Susan E. Fratoni, Chelsea S. Wogsland, and Anthony J. Rothschild Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B
C B
B C B
C D B


Introduction Major depression with psychotic features (MDpsy) is an under-recognized and understudied disorder despite being a common clinical problem. This difficulty in clinically recognizing the illness, often coupled with fear or a lack of insight on the part of patients, has slowed research advances. This chapter will review the state of knowledge of the epidemiology, age of onset, clinical presentation, course and progression, suspected neuropathology, suspected neurochemical abnormalities, genetic and other risk factors, and treatment of this serious illness.

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Epidemiology The prevalence of unipolar major depression with psychotic features (MDpsy)1 is often underappreciated, both in the general population and in clinical settings. The most recent large-scale epidemiological survey (Ohayon & Schatzberg, 2002) used a novel computer-based diagnostic program on a sizeable European sample (19,000 persons) and found 18.5% of all individuals meeting criteria for major depression met criteria for MDpsy (delusions, hallucinations, or both). While the computerized diagnostic approach had only moderate reliability when compared to psychiatrist interviews (kappa statistics of 0.44
0.78), this estimate is remarkably similar to results obtained in a previous lay interview study, the Epidemiologic Catchment Area study (ECA). The ECA study of a general population sample of 18,000 found that almost 15% of individuals who met criteria for lifetime major depression had a history of psychotic features (Johnson et al., 1991). Because the ECA study did not inquire about delusions of guilt, disease, poverty, or nihilism (common ‘‘mood congruent’’ delusions; see ‘‘Presentation’’ section below), and because of the difficulty obtaining a history of psychotic symptoms in a telephone interview by anonymous lay interviewers, this estimate may represent an underestimate of the community prevalence of MDpsy. (However, the failure of the ECA study to differentiate between psychotic depression and schizoaffective disorder may somewhat counterbalance this bias.) Nevertheless, the close agreement between the ECA estimate and the European study (Ohayon & Schatzberg, 2002) strengthens confidence that MDpsy constitutes between 15
20% of depression that is observed in the community. Both studies suggest that MDpsy is somewhat over-represented in clinical samples relative to its prevalence in the general population. The 2002 study found that individuals with psychotic depression were twice as likely to have a history of past psychiatric consultation, while the ECA study found that those with a history of MDpsy accounted for 20% of the individuals with major depression who received any psychiatric treatment, and 21% of individuals previously hospitalized for depression. In clinical samples, the prevalence of psychotic depression varies from approximately 18
45% of the patients seen with major depression, based on setting and demographics. One survey using DSM-III criteria found that 25% of patients consecutively admitted as inpatients for major 1

Throughout this chapter a distinction has been made when possible: MDpsy refers to the diagnosis of unipolar major depression with psychotic features, ‘‘psychotic depression’’ refers to mixed samples of patients with bipolar and unipolar depression, and ‘‘psychotic affective illness’’ refers to mixed samples that contain patients with unipolar major depression, bipolar depression, or bipolar mania with psychotic features. ‘‘Nonpsychotic depression’’ refers to the portion of any of those samples that did not exhibit psychosis (and so usually, but not always, refers to unipolar major depression without psychotic features).

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depression exhibited psychotic features (Coryell et al., 1984). In a more recent survey, approximately 18% of Danish inpatients with depression admitted for their first inpatient hospitalization were coded as having severe depression with psychotic features by ICD-10 criteria (representing 44% of the patients specified as having severe depression) (Kessing, 2003). A large sample of over 650 inpatients and outpatients given the Diagnostic Interview Schedule for depression found 28% of the sample had MDpsy (Thakur et al., 1999). The prevalence of psychotic depression in clinical samples increases with age (Brodaty et al., 1997), with one study finding psychotic features in 45% of elderly inpatients with depression (Meyers & Greenberg, 1986). In two separate elderly samples that comprised a mix of inpatients and outpatients presenting at a mood disorders clinic, approximately 33% of elderly patients with depression were found to have psychotic features (Brodaty et al., 1991; 1997). In the general population, the overall prevalence of psychotic depression among the elderly (age 60 or older) in Finland has been estimated to be one in 100 (Kivela & Pahkala, 1989). However, the 2002 European study (Ohayon & Schatzberg, 2002) found little difference in prevalence for MDpsy across age groups, with only 0.3% of individuals over 65 reporting depression with psychotic features, compared to 0.4
0.5% of younger individuals. In contrast, a study of 65 inpatients found a bimodal age distribution for MDpsy with the fewest patients having an age between 40 and 50 (Coryell et al., 1986a). Depression is more common in women than men, and this gender distribution is generally replicated for psychotic depression (Brodaty, et al., 1997; Kivela & Pahkala 1989). Both the ECA study and the 2002 European study found women might have a small additional increased risk for psychotic depression. The ECA study found 83% of the MDpsy sample were women compared to 73% of the major depression without psychotic features sample (Johnson, Horwath et al., 1991), while the 2002 study found that 67% of the MDpsy sample were women compared to 59% of the nonpsychotic depression sample (Ohayon & Schatzberg, 2002). Age of onset The ECA study found no statistically significant difference in average age of onset for the MDpsy and nonpsychotic depression samples (Johnson et al., 1991). Risk of onset of major depression overall has been observed to be fairly low until the early teens, and after that, risk of onset is roughly equivalent, regardless of age (i.e. prevalence increases roughly linearly by age) (Kessler et al., 2003). Some maintain that early-onset MDpsy should be considered initial episodes of bipolar disorder until proven otherwise, but this appears to be an

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oversimplification: several studies have demonstrated early-onset MDpsy patients who subsequently go on to develop bipolar disorder while others simply experience unipolar depression (Akiskal et al., 1983; Strober & Carlson, 1982). One study of adolescents hospitalized with unipolar major depression reported that 20% of patients later converted to a bipolar diagnosis over 3
4 years of follow-up. Most of these patients (75%) had a symptom cluster of moodcongruent psychotic features, psychomotor retardation, and rapid symptom onset, compared to only 6% of the ‘‘non-converters’’ (Strober & Carlson, 1982). Another study of 206 unipolar depressed outpatients found a similar 20% conversion rate to bipolar disorder during follow-up for as long as 25 years, with 42% of those converting having psychotic features compared to only 15% of ‘‘non-converters’’ (Akiskal et al., 1983). However, given the preponderance of patients who do not change diagnosis (‘‘non-converters’’), any given depressed patient with psychotic features in either study was more likely to remain with a diagnosis of unipolar depression than convert to a diagnosis of bipolar disorder (Akiskal et al., 1983; Strober & Carlson, 1982). Another recent study with briefer follow-up found only a 13% likelihood of patients with MDpsy suffering a mania or hypomania after 1
2 years (DelBello et al., 2003). These results strongly suggest that no definitive conclusions can be made regarding eventual diagnosis of a young adult with MDpsy. A related issue concerns the diagnostic stability of early-onset MDpsy versus schizophrenia. No studies exist examining MDpsy specifically, but one study of 81 adolescents followed for 10.5 years that classified both initial and subsequent episodes by DSM-IV criteria found that relatively few subjects (16%) with early-onset (diagnosed before 19 years) affective psychosis (40% major depression, 60% bipolar disorder) were later diagnosed with schizophrenia, and that only 5% of the cases originally diagnosed with schizophrenic disorders were later diagnosed with affective psychoses (Jarbin et al., 2003). One important predictor of patients whose diagnoses were changed from affective to schizophrenic disorders was a family history of non-affective psychoses in first- or second-degree relatives (Jarbin & von Knorring, 2003). In contrast, an extremely small study of early-onset patients with psychosis in which initial diagnosis was not necessarily made by DSM criteria in structured interviews found misdiagnosis common, with 55% of patients initially diagnosed with affective psychosis later being diagnosed under DSM-III-R as having schizophrenia, and 17% of patients diagnosed with schizophrenia later being diagnosed as having affective psychosis (McClellan et al., 1993). In sum, a sizeable proportion of patients with early-onset affective psychosis appear either initially or eventually to be bipolar, and a small proportion will later be diagnosed among the schizophrenic illnesses, but bona fide unipolar major depression can present at an early age.

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Late-onset depression with psychotic features may commonly represent MDpsy or a prodromal stage of Alzheimer’s disease or other dementing illness, just as late-onset depression without psychotic features can also be a marker for increased dementia risk (Alexopoulos et al., 1993). One study found that approximately 30% of late-onset MDpsy patients had greater treatment refractoriness and a ‘‘dementia-like presentation’’ (Aronson et al., 1988). In a sample with known Alzheimer’s Disease, depression raised the risk of delusions almost seven fold (Bassiony et al., 2002). Another study found 30
40% of patients with Alzheimer’s disease had depressive and psychotic symptoms, but complete mood or psychotic syndromes were less common (Wragg & Jeste, 1989). In addition, other neurological causes such as intracranial mass lesions can give rise to psychosis in the elderly and the young alike. Some authors (Galasko et al., 1988) recommend that patients with late-onset psychosis, focal neurological signs associated with psychosis, or unusual histories of depression undergo neuroimaging to exclude intracranial lesions. Presentation While the presence of either delusions or hallucinations in the context of a mood episode is required to establish the diagnosis of MDpsy, delusions are more common than hallucinations. One study found only 20% of 137 patients with MDpsy exhibited hallucinations (Parker et al., 1991). A much smaller study found that 50% of patients with MDpsy had hallucinations, but in every case these patients also expressed delusions, and usually the hallucinations and delusions had the same content (Lykouras et al., 1986). For these reasons, psychotic depression is alternatively referred to as ‘‘delusional depression.’’ Children are an exception: one study observed that 48% of children with depression had experienced hallucinations, while fewer than 10% experienced delusions (Chambers et al., 1982). A review of six studies of adults found the most common types of delusions observed in MDpsy were delusions of guilt, punishment, or persecution (44
69%), which were roughly twice as common as delusions of hypochondriasis (11
36%) (Kuhs, 1991). Delusions of poverty or nihilism (typically defined as delusional conviction of the nonexistence of one’s own person, living relatives, or even the whole world) were relatively rare (11.4% or less), except for one study that found a very high prevalence of nihilistic delusions (Frangos et al., 1983). An accompanying survey of 160 consecutively admitted inpatients found a particularly high prevalence of delusions of guilt (82.5%), while delusions of poverty (52%) were more common than delusions of hypochondriasis (39%) or punishment/persecution (30%), and nihilistic ideation was found to be relatively rare (13%) (Kuhs, 1991). Another study

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reported that hypochondriacal and nihilistic ideation were seen more frequently in patients with an age of onset of unipolar psychotic depression greater than 60 years old (Gournellis et al., 2001). The detection of delusions and hallucinations is often difficult in patients with MDpsy because MDpsy patients are often more able to keep their unusual thoughts and feelings to themselves than patients with schizophrenia or mania, and may be embarrassed or recognize that their thinking processes are not quite right (Rothschild and Schatzberg, 1994). As a result, a number of research groups have explored whether other characteristics might help distinguish patients with MDpsy from nonpsychotic depression (Parker et al., 1995). Identified characteristics have included psychomotor disturbance (either retardation or agitation) (Brodaty et al., 1997; Charney & Nelson, 1981), cognitive impairment (Basso & Bornstein, 1999; Belanoff et al., 2001; Jeste et al., 1996; Nelson et al., 1998; Rothschild et al., 1989; Schatzberg et al., 2000; Simpson et al., 1999), paranoid symptoms (Frances et al., 1981; Lykouras et al., 1986), hypochondriasis (Coryell et al., 1984), hopelessness (Frances et al., 1981), anxiety (Charney & Nelson, 1981; Glassman & Roose, 1981; Kuhs, 1991), sleep difficulties (early (Frances et al., 1981; Lykouras et al., 1986), middle (Lykouras et al., 1986), or terminal insomnia (Parker et al., 1995)), appetite or weight loss (Parker et al., 1995), and constipation (Parker et al., 1991; 1995). Patients with MDpsy have also been reported to lack the diurnal variation in mood that endogeneously depressed patients with nonpsychotic depression exhibit (Parker et al., 1991). The most consistent findings appear to be psychomotor disturbance (either agitation or retardation) and guilt (Schatzberg & Rothschild, 1996). An analysis of 21-item HAM-D rating scales for a large sample of patients with psychotic depression found the largest statistically significant differences in severity of guilt and psychomotor retardation, as well as paranoia, poor insight, loss of interest in work and activities, and depressed mood (Lattuada et al., 1999). Negative symptoms have become of increasing interest in schizophrenia research; a single study of 164 inpatients and outpatients (35 with MDpsy) found that negative symptoms were uncommon among subjects with MDpsy (20% of these subjects showed poor rapport, 16% blunted affect, and 16% communication difficulties such as delayed responses to questions), and almost always limited to the acute episode (Husted et al., 1995). A much smaller study of early-onset psychotic patients observed no difference in prevalence of negative symptoms between the unipolar psychotic depression and schizophrenia samples (Hill et al., 2004). A small literature exists on the distinctions between MDpsy and dissociative conditions such as borderline personality disorder. Patients with borderline personality disorder rarely endorse obvious delusions or hallucinations, but

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frequently endorse derealization or depersonalization (Nishizono-Maher, 1993). Another study found a very high prevalence of comorbid PTSD in a clinical sample with MDpsy (almost 60%, 4-fold the prevalence in the nonpsychotic depression sample) (Zimmerman and Mattia, 1999). An extensive debate exists about whether MDpsy should be viewed as a distinct subtype of depression, or merely a particularly severe variant (Cubells et al., 2002; Schatzberg & Rothschild, 1996). The basic arguments supporting its existence as a subtype are: 1) the fact that the illness appears to moderately ‘‘breed true’’ in families, with heritabilities similar to what is observed in schizophrenia; 2) the observation that MDpsy is the most consistent subtype of depression in longitudinal studies (for instance, generally only patients with MDpsy will be prone to psychosis in future episodes of depression); 3) the somewhat distinctive neurochemistry observed in MDpsy, especially the high rate of glucocorticoid dysregulation; 4) the evidence for a distinct treatment response; and 5) the observation that in some studies these differences are observed between MDpsy and nonpsychotic depression samples even when no differences in depression severity exist. Countering these arguments are the observations that in other studies MDpsy has been shown with rating scales to have more severe depressive symptomatology than nonpsychotic depression (Lattuada et al., 1999; Lykouras et al., 1986), the neurochemical differences are not absolute (e.g. severe nonpsychotic depression can often have glucocorticoid regulation abnormalities), and psychosis may only appear in MDpsy patients during their more severe episodes (Coryell et al., 1996). In DSM-III and DSM-III-R a distinction was made between ‘‘mood-congruent’’ psychotic symptoms (delusions of sin, guilt, punishment, inadequacy, illness, nihilism, and related auditory hallucinations such as self-deprecatory voices) and ‘‘mood-incongruent’’ (delusions of persecution, reference, jealousy, control; thought insertion or withdrawal; and auditory hallucinations such as command, persecutory, or commentatory). In a small study of 40 inpatients, no compelling evidence was found justifying the mood-congruent versus mood-incongruent distinction (58% of inpatients show signs of both) (Burch et al., 1994). Other studies offer mixed results on the importance of this distinction. Coryell found in a retrospective chart review that mood congruence versus incongruence appeared to have little prognostic significance; however, when follow-up interviews with patients or relatives were conducted, patients with mood-incongruent symptoms were more likely to have poorer occupational, marital, and mental status functioning (Coryell & Tsuang, 1985). Likewise, another prospective and retrospective study by the same group found trends towards worsened recovery and insight in patients with mood-incongruent symptoms, but these findings did not usually achieve statistical significance (Coryell et al., 1986;

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Tsuang & Coryell, 1993). Another study found mood incongruence predicted worse overall functioning (as indexed by the Global Assessment of Functioning Scale) at 24 months (Fennig et al., 1996a); a review by the same authors concluded that the concept of mood-congruent versus mood-incongruent symptoms in affective psychoses is of limited conceptual value, and primarily helps to predict eventual change to a nonaffective diagnosis (Fennig et al., 1996b). A more recent study found mood-incongruent symptoms to have negative prognostic symptoms for a mixed sample composed of schizophrenic, schizoaffective, and depressed patients (Harrow et al., 2000). Because psychotic symptoms in MDpsy only last as long as the depressive episode, patients with MDpsy have the potential to provide unique information about the consistency of episodic delusions over time, but very limited data exists. One study with limited follow-up information concluded that 80
90% of the patients with recurrent psychotic depression (n ¼ 12) had a similar delusion in their next episode (Lykouras et al., 1985). A second study concluded that delusions tended to be ‘‘of similar form and content from episode to episode’’ without giving specific statistics (Charney & Nelson, 1981). A third study found that only 17% of patients with recurrent psychotic depression exhibited delusions entirely different from those presented at the index episode (Kuhs, 1991). However, only 50% showed thematically identical delusions, with the remainder varying in presentation from episode to episode. The author speculates that these fluctuations are probably due to variations in depressive severity across episodes (Kuhs, 1991). Another study which classified delusions into three broad categories (persecution; bodily disease or damage; or guilt, worthlessness, punishment, and death) found either changes in delusions or multiple delusions to be the norm rather than the exception, with 70% of patients already having a history of delusions from more than one category by their index hospitalization (Miller & Chabrier, 1987). A recent meta-analysis of neuropsychological findings in patients with psychotic depression concluded that psychomotor speed and executive function domains were the most impaired, followed by verbal memory (z scores of
0.6 or worse). Smaller deficits were noted in visual memory, attention, and visual spatial tasks (Fleming et al., 2004). Several authors have noted that the pattern of neuropsychological deficits resembles that observed in schizophrenia, with either similar (Jeste et al., 1996) or lesser (Hill et al., 2004) levels of impairment observed in the psychotically depressed patients. Course and progression MDpsy tends to be a more recurrent illness than nonpsychotic depression, with increased risk for both nonpsychotic and psychotic episodes. In the most

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extensively studied cohort to date, Coryell and coworkers found that individuals with MDpsy relapsed approximately three times faster regardless of whether time to recurrence of any episode was considered or just nonpsychotic episodes (Coryell et al., 1996). A limitation of this cohort is that approximately 28% of the sample have a history of mania, although simultaneously controlling for psychotic features and bipolarity indicated that only psychotic features significantly explained the increased recurrence risk (Black et al., 1988; Coryell et al., 1996). A study examining rehospitalization after first admission found that patients with MDpsy were readmitted 45% sooner than patients with nonpsychotic depression (Kessing, 2003). A number of other studies have also observed that patients with MDpsy exhibit more frequent recurrences (Aronson et al., 1988a, b; Helms & Smith, 1983; Lykouras et al., 1986; Murphy, 1983; Nelson & Bowers, 1978; Robinson & Spiker, 1985; Spiker et al., 1985), although a couple of studies failed to observe increased recurrence risk (Coryell et al., 1987; Lykouras et al., 1994). Once a patient has had an episode of MDpsy, the risk of having psychotic features during future episodes of depression is substantial. Recurrence of psychotic features has been most extensively examined in an eight-year follow-up study of 424 patients with major depression (Coryell et al., 1994). The psychotic subtype was more consistent across episodes than the endogenous or psychomotorically disturbed subtypes, and risk of a new episode with psychotic features was 15-fold higher for patients with MDpsy during their first episode after the index episode compared to patients with nonpsychotic depression during their index episode. Even after four intervening episodes without psychotic features, the risk of developing psychotic features during the next episode of depression was four-fold higher than among patients with only a history of nonpsychotic depression. However, following any specific episode with psychotic features, patients with MDpsy had only a 28
60% chance that their next episode would include psychotic features (Coryell et al., 1994). This is a lower rate than observed in some other studies: one cohort found a striking 83% relapse rate into depression over 34 months, with almost all the relapses including psychotic features (Aronson et al., 1988), while another study found that recurrence of psychosis (judged either retrospectively or prospectively) had occurred or did eventually occur in 92% of patients (Helms & Smith, 1983). However, when compared to patients with schizophrenia, patients with MDpsy were less likely to have delusional symptoms on three separate follow-ups (Harrow et al., 1995). It is not fully known what proportion of the population has recurrent psychotic depression versus single episodes. A study of 42 patients with MDpsy found that 35% of early-onset patients had only a single episode over 34 months of follow-up

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compared to none of the 15 patients with late-onset MDpsy (Aronson et al., 1988b). Another study found patients with late-life MDpsy were more likely to relapse, especially if maintained only on antidepressant monotherapy (Flint & Rifat, 1998b). In addition to the recurrence risk, psychotic depression is associated with greater overall impairment and severity of depressive symptoms, resistance to conventional pharmacotherapies (Schatzberg & Rothschild, 1996), and possibly an increased risk of suicide. Estimates of the degree to which MDpsy increases risk for suicide, suicide attempts, or suicidal ideation vary widely (Table 9.1). Estimates of suicide risk range from a five-fold increase in risk for inpatient suicides (Roose et al., 1983) to no increase in risk in long-term cohort studies of outpatients (Black et al., 1988; Coryell & Tsuang, 1982). Risk of suicide attempts also varies considerably from study to study, from increases of 2.6-fold (Hori et al., 1993) to no increase in risk (Lykouras et al., 2002). Similarly, some studies (Isometsa et al., 1994) but not others (Lykouras et al., 2002) have found MDpsy patients to have an increased risk of using violent methods. Patients with MDpsy have increased use of services, greater disability, and poorer clinical course compared with patients with nonpsychotic depression at both short-term (Coryell et al., 1986b; Rothschild et al., 1993) and longer-term follow-up (Coryell et al., 1996). Several studies have demonstrated residual social and occupational impairment in MDpsy patients despite improvement in psychotic and depressive symptoms at one-year (Rothschild et al., 1993), five-year (Coryell et al., 1990), and ten-year follow-up (Coryell et al., 1996), but a 40-year follow-up study found no consistent trends distinguishing MDpsy from nonpsychotic depression on marital, occupational, residential, or symptomatic outcome ratings (Coryell & Tsuang, 1982). One other study found that patients with MDpsy had greater psychosocial impairment in the five years prior to study entry, but after the first six months of treatment were as likely to recover as patients with nonpsychotic depression over the next 18 months (Coryell et al., 1987). This study also observed that early response to treatment was more predictive of later course for MDpsy patients than nonpsychotic depression patients (Coryell et al., 1987). The social and occupational impairment may be due to subtle cognitive deficits associated with the higher cortisol levels frequently observed in MDpsy patients (Rothschild et al., 1993; Schatzberg & Rothschild, 1988) or other reasons. One recent study found patients with MDpsy had a two-fold greater risk of overall mortality than patients with nonpsychotic depression, and this mortality resulted from medical causes (rather than suicide) in 88% of the deaths (Vythilingam et al., 2003). While MDpsy is more disabling and refractory than nonpsychotic depression, first-episode patients with MDpsy are more likely to recover symptomatically

Patients

Inpatient sample followed prospectively for 34þ years

Inpatient sample followed prospectively for 2
13 years

Inpatient sample followed prospectively for 0
3 years

Coryell & Tsuang (1982)

Black et al. (1988)

Wolfersdorf et al. (1987)

COMPLETED SUICIDE

Study

perceived quality)

OR¼2.1 (not statistically significant)

Completed suicide

MDpsy: 46 pts/52 yo/ 30%M

Nonpsychotic depression:

No difference in suicide rate (MDpsy 3.3%, Nonpsychotic depression 3.4%)

(Both groups had a 7% suicide risk after 34
39 years of F/U)

No difference

Finding (risk in MDpsy versus MDnon-psy)

Completed suicide

Completed suicide

Suicidality measure

Not given

MDnonpsy: 102 pts/ 44yo/42%M

MDpsy: 122 pts/ 44/47%M

Demographics (size of sample/mean age(+SD)/% male)

Very few suicides (4 in MDpsy sample vs 2 in nonpsychotic depression sample) MDpsy sample 1.85 fold as

Longest follow-up available

Comments

Table 9.1. Summary of studies of suicide risk in psychotic major depression (studies in each section are ordered in descending order of approximate

Roose et al. (1983)

Inpatients

Control group: 28 pts/ 58/21%M

Suicide group: 14 pts/56/ 50% M

46 pts/53 yo/ 30%M (Matched)

Pts with MDpsy Completed suicide are 5 as likely to while in commit suicide as hospital, eloped, or pts with MDnon-psy on pass

Suicide would be expected to be 2 more likely in MDpsy group just based on prevalence of men, who have higher completed suicide risk.

Curiously, patients with nonpsychotic depressions were 1.5-fold as likely to be judged suicidal at admission, perhaps because suicidality is an important criteria for hospitalization among the nondelusional population.

likely to endorse past suicide attempts.

Patients

Psychological autopsy

Mixed sample from all MDD suicides over 1 yr.

Study

Robins (1959)

Isometsa et al. (1994)

approximate perceived quality)

MDpsy group MDpsy group also more likely more likely to use violent means (88% vs 59%, to be receiving psych tx (54 to p¼0.03) 39%), and to be hospitalized at time of suicide (21 to 11% but only 4% vs 2% on premises). Completed suicide

MDpsy: 24 pts/50 +13/ 67% M Nonpsychotic depression: 46 pts/50 + 18yo; 61% M

15.9% of the suicide victims with affective disorder had psychosis.

No discrimination between unipolar and bipolar disorder

Fact that these are inpatient suicides may limit generalizability

Comments

Completed suicide

Suicidality measure

Finding (risk in MDpsy versus MDnon-psy)

134 suicides in St. Louis in 1950s

Demographics (size of sample/mean age(+SD)/% male)

Table 9.1. (Cont.) Summary of studies of suicide risk in psychotic major depression (studies in each section are ordered in descending order of

Johnson et al. (1991)

Community, retrospective (ECA study)

SUICIDE ATTEMPTS

Nonpsychotic depression: 662 pts/41 + 16/27%M

MDpsy: 114 pts/42+ 16yo/17%M,

History of suicide attempts

Pts with MDpsy reported a 42-fold risk for past suicide attempts, even after control for sociodemographics, site, other

Little difference between groups was noted in the frequency of suicidal ideation/attempts during worst episodes

None of MDpsy group receiving combination treatment at time of suicide. Since this sample represents all suicides in 1 year, if 15
18% is used as the prevalence of MDpsy among all patients in the community with major depression, the 34% rate of MDpsy in completed suicides represents approximately a 2-fold increased risk.

Patients

Inpatient

Elderly Inpatient

Study

Lee et al. (2003)

Lykouras et al. (2002)

approximate perceived quality)

Nonpsychotic depression:

MDpsy: 40 pts/70 + 6/30%M

105 Total pts

Demographics (size of sample/mean age(+SD)/% male)

Pts with MDpsy had higher risk of suicide attempt

No significant difference (OR ) in risk for current or current þ past suicide attempts

Suicide attempt

psychiatric disorders, or when patients rediagnosed over the next year as having bipolar D/O or schizophrenia were excluded. Suicide attempts

Suicidality measure

Finding (risk in MDpsy versus MDnon-psy)

No difference in risk for violent attempts

Pts with MDPSY also had higher HAM-D scores and lower MMSE scores

Very few differences noted between number or types of symptoms observed during worst episode.

Comments

Table 9.1. (Cont.) Summary of studies of suicide risk in psychotic major depression (studies in each section are ordered in descending order of

Inpatient retrospective

MDnonpsy: 55 pts/47+ 13/47% M

MDpsy: 38 pts/51+ 15yo/44%M

Thakur et al. (1999) Mixed inpatient
MDpsy: 189 pts/ outpatient sample 67% < 60yo/ 33%M

Hori et al. (1993)

64 Pts/70+ 5/23%M

Suicidal attempt, intent, or ideation

Suicide attempt or suicide ideation

Univariate OR of 1.71 but ‘‘suicide potential’’ not significant in

(47% vs 18%) and a 1.25-fold increase of suicidal ideation

MDPSY had 2.6fold risk of suicide attempt

Delusional group had significantly less psychomotor retardation (71% vs 93%). Also had a more intermittent or chronic course versus remitting (only 13% experienced remission while 71% of nonpsychotic depression patients did). Also more likely to use violent methods (56% vs 47%).

Patients

Miller and Chabrier Inpatients, (1987) retrospective

Study

approximate perceived quality)

Extensively matched sample of 45 delusional patients

Nonpsychotic depression: 485 pts/51%< 60yo/37%M

Demographics (size of sample/mean age(+SD)/% male)

Suicide attempts in last 6 mos and over lifetime

Suicidality measure

Pts with somatic symptoms had lower rate of lifetime medically serious attempts than pts with guilt, worthlessness, deserved punishment, and persecution (29% vs 64%)

multiple logistic regression (OR 1.27, CI 0.75
2.15 by clinician rating scale; OR 0.98, CI 0.55
1.75 by self-rated rating scale)

Finding (risk in MDpsy versus MDnon-psy)

Pts with somatic delusions also had statistically significant lower risk of serious suicide attempt in last 6 months, and mean number of lifetime suicide attempts. MDpsy Pts had a nonsignificant 1.5-fold risk of suicide attempts compared to

Comments

Table 9.1. (Cont.) Summary of studies of suicide risk in psychotic major depression (studies in each section are ordered in descending order of

Sax et al. (1997)

Inpatients at first hospitalization

SUICIDAL IDEATION

Typical-onset: 38 pts/ 23yo+2 yo/ 39.5% F Late-onset: 23 pts/49+ 12/56.5%F

Early-onset 27 pts/16 yo/ 48% F

HAM-D Suicide scale

Early-onset group suicidality score4typical onset or late onset group

Study of affective psychosis
MDpsy comprised only 19% of early-onset group, 6% of typical-onset group, and 30% of late-onset group

extensively matched nonpsychotic depressed sample

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and functionally (81% recovered) at six months than patients with other psychotic disorders (36
70%) (Tohen et al., 2000). Suspected neuropathology Neuropathological findings reported as associated with MDpsy include enlarged brain ventricle size, cerebral vascular changes, and P300 and EEG abnormalities. Multiple groups have reported enlarged cerebral ventricles in MDpsy (Jones et al., 1994; Luchins & Meltzer, 1983; Rothschild et al., 1989; Schlegel & Kretzschmar, 1987; Targum et al., 1983). The first study to observe enlarged ventricles in melancholic patients with psychotic depression failed to find statistically significant differences overall, but one quarter of that MDpsy sample had ventricles (ventricle-to-brain ratio, or VBR) that were at least two standard deviations larger than the control group (versus none of the nonpsychotic depression sample) (Targum et al., 1983). Luchins and Meltzer (1983) found mean VBR to be 44% larger in patients with bipolar or unipolar psychotic depression compared to a slightly younger sample with nonpsychotic depression. Fifty-six percent (5/9) of patients with psychotic depression had VBRs greater than one standard deviation larger than the control group versus only 11% (1/9) of the nonpsychotically depressed patients. The authors contrast their findings to reports at the time that VBR was smaller in patients with schizophrenia. A larger study found increased VBRs in patients with psychotic affective illness as well as older patients and male patients and did not find an association between VBR and Dexamethasone Suppression Test (DST) results or unipolar patients versus bipolar patients (Schlegel & Kretzschmar, 1987). Another study found that differences in VBR were more pronounced between patients with psychotic depression than nonpsychotic depression in a group including bipolar patients (Rothschild et al., 1989). One hundred percent of the MDpsy patients had cella media VBR ¸ 0.61 compared to 58% of nonpsychotic depressed patients (p ¼ 0.03). Similar proportions were observed for DST-nonsuppressors versus suppressors, although these results only reached borderline statistical significance (p ¼ 0.067). Sulcal size, a possible indicator of ‘‘atrophy’’, was also judged to be larger in the left and right inferior parietal areas (Brodmann’s areas 39 and 40) of patients with psychotic depression (Rothschild et al., 1989). A study of 54 patients with affective psychosis similarly found larger third ventricle size among patients with psychotic affective illness, but observed that no clear threshold existed between ‘‘normal’’ and ‘‘enlarged’’ ventricles (Jones et al., 1994). A study of older patients found no abnormalities in temporal lobe atrophy, periventricular white matter lesions, DST, or cognitive testing results between the MDpsy and nonpsychotic depression samples, but did find a greater number

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of vascular risk factors and a nonsignificant trend to greater number of deep white matter lesions in the MDpsy sample (O’Brien et al., 1997). Another study of MDpsy patients over 55 years of age found that the absolute volume of prefrontal cortex was smaller in the group with MDpsy than with nonpsychotic depression, and that this decreased volume correlated with Wisconsin Card Sorting performance (Kim et al., 1999). A study of psychiatric symptoms in patients with vascular or Alzheimer’s dementia found delusions or hallucinations common, but these symptoms appear to be more correlated with dementia than depression (Ballard et al., 2000). For instance, among patients with mild dementia (MMSE 4 20), less than 10% of patients with psychotic symptoms had depression (Ballard et al., 2000). Another study found that among individuals with dementia, psychotic symptoms were more likely among individuals with a psychiatric history (Berrios & Brook, 1985). Decreased amplitude and increased latency in P300 event-related potentials have been reported in schizophrenia, but comparatively little data exists for MDpsy. Melancholic patients with MDpsy were found to have decreased P300 amplitude compared to melancholic patients with nonpsychotic depression (Santosh et al., 1994). A study of 22 unipolar depressed patients (82% with major depression, 18% with dysthymia) found that scores on the psychotism subscale of a 90-item symptom checklist correlated with an overall reduction in P300 amplitude, especially over the left temporocentral electrode chain. However, the sample was selected for depression, not psychosis, and none of these subjects had particularly high psychotism scores (Kaustio et al., 2002). In contrast, Salisbury et al. (1998) observed no differences in left temporal amplitude between patients with affective psychosis and healthy controls, but only 14% of those with psychosis had unipolar major depression. EEG studies of MDpsy are also rare. One study found abnormal EEG findings in 17% of a medicated sample of patients with mood-incongruent MDpsy and 10% of patients with mood-congruent MDpsy compared to 3.2% of healthy controls (Inui et al., 1998). Furthermore, 33% of patients with mood-incongruent MDpsy were found to have ‘‘epileptiform’’ EEG variants, compared to 0% of MDpsy patients with mood-congruent psychosis. The authors argue for a possible similar biological substrate for ‘‘atypical psychoses’’ (mood-incongruent MDpsy, schizoaffective disorder, or schizophreniform disorder, all of which had similar proportions of epileptiform variants) (Inui et al., 1998). However, studies of outcome have observed that mood-incongruent MDpsy has outcomes much more similar to mood-congruent MDpsy than schizoaffective disorder or schizophrenia (Coryell and Tsuang 1982). An EEG sleep study found that patients with MDpsy exhibited increased wakefulness, decreased REM sleep, and decreased REM activity compared to patients with nonpsychotic depression after controlling

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for age, severity, and agitation. REM latency appeared to be a marker for duration of illness as well; patients with recent-onset MDpsy had marked initial insomnia and long REM latency, whereas patients with illnesses of longer duration had extremely short REM latencies (Thase et al., 1986). Suspected neurochemical abnormalities Patients with MDpsy frequently exhibit high rates of nonsuppression on the DST with markedly elevated post-dexamethasone cortisol levels and high levels of 24-hour urinary free cortisol. This finding is one of the most reliable alterations of the hypothalamic-pituitary axis in psychiatric patients (American Psychiatric Association, 1987; Rothschild, 2003). While a meta-analysis found the postdexamethasone cortisol nonsuppression rate to be substantially higher in patients with psychotic depression (64%) than nonpsychotic patients (41%) (Nelson & Davis, 1997), this yields a sensitivity of only 64% and specificity of 59%. Studies have observed that using a cutoff value higher than the traditional ¸5 mg/dL of cortisol post-dexamethasone produces greater specificity for MDpsy at the cost of sensitivity. One study found 50% of the MDpsy patients had cortisol values ¸15 mg/dL, compared to only 7% of nonpsychotic depression patients (a sensitivity of 50% and specificity of 93%), and 43% of patients with MDpsy had cortisol values of ¸17 mg/dL, while none of the nonpsychotic depression patients did (sensitivity of 43%, specificity of 100%) (Schatzberg et al., 1983). The DST may also discriminate well between patients with MDpsy and other psychoses such as schizophrenia (American Psychiatric Association, 1987). In one study, 57% of patients with MDpsy had postdexamethasone cortisol values greater then 14 mg/dL, whereas none of the psychotic schizophrenic patients had values that high, and the mean postdexamethasone cortisol level for MDpsy patients (13.0+8.1 mg/dL) was significantly higher than that for the psychotic schizophrenic patients (2.4+2.8 mg/dL; p < 0.05) (Rothschild et al., 1982). The mechanism by which cortisol is associated with psychosis is not exactly clear, but both endogenous (e.g. Cushing disease) and exogenous steroids have been associated with psychosis. Our group has hypothesized that elevated cortisol induces a hyperdopaminergic state (Schatzberg & Rothschild, 1988; Schatzberg et al., 1985); however, one study failed to find evidence of hyperdopaminergic activity in MDpsy (Duval et al., 2000). These authors instead reported a blunted growth hormone response to clonidine that they concluded implies the occurrence of a hyposensitivity of noradrenergic alpha-2 receptors in affective psychosis, rather than dopamine system dysregulation (Mokrani et al., 2000). However, several older studies observed elevated dopamine levels in plasma

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(Rothschild et al., 1987) or homovallinic acid, a dopamine metabolite, in either CSF or plasma of patients with MDpsy (Schatzberg et al., 1995), and MDpsy shows a strong clinical response to combined treatment of antidepressants and dopamine blockers (either typical or atypical antipsychotics) (see ‘‘Treatment’’ section below). A rather consistent neurochemical finding in MDpsy is the reduction of dopamine b-hydroxylase (DBH) activity among patients with MDpsy but not bipolar psychotic depression (Schatzberg & Rothschild, 1996). Five (Cubells et al., 2002; Meltzer et al., 1976; Meyers et al., 1999; Mod et al., 1986; Sapru et al., 1989) of six (Lykouras et al., 1988) studies showed that plasma DBH was significantly reduced in MDpsy versus nonpsychotic depression or normal controls, with a seventh small study showing reductions in DBH that did not reach statistical significance (Eisemann et al., 1983). Because serum DBH did not increase for most patients immediately following successful treatment, one group has suggested DBH may be a trait-dependent rather than state-dependent finding in MDpsy (Meltzer et al., 1976). Low CSF DBH activity has also been associated with psychosis induced by disulfarim (Major et al., 1979) and cocaine (Cubells et al., 2000). However, one study (Hamner & Gold, 1998), but not another (Meltzer et al., 1976), has observed elevated, rather than reduced, DBH activity in psychotic patients with bipolar disorder compared with normal controls and higher DBH levels in patients with schizophrenia than in patients with MDpsy (Meltzer et al., 1976). These authors suggest low DBH may be a trait-specific, rather than state-specific, vulnerability factor. The possibility that 5HT2 receptors may be involved in psychotic depression is weakly hinted at from clinical responses observed with amoxapine (which has both serotonin agonist and dopamine antagonist effects) (Anton & Sexauer, 1983), but this has not been supported by genetic studies (see ‘‘Genetic Factors’’ section below). A few studies have also found lower CSF 5-HIAA (Mendels et al., 1972) or urinary MPHG (Sweeney et al., 1978) in patients with MDpsy compared with nonpsychotic depression. One study examined the relationship between exogenous 5HT (a serotonin precursor) and serum cortisol and found patients with MDpsy to have less of a 5HT-induced increase in cortisol, but it is unclear whether this may be due to higher cortisol at baseline (Meltzer et al., 1984). It has been hypothesized that abnormal cortisol levels in patients with MDpsy might contribute to the profile of neuropsychological deficits observed (Rothschild et al., 1993) (see ‘‘Presentation’’ section above). One study (Belanoff et al., 2001) found that those MDpsy patients who had higher mean afternoon cortisol levels on day of testing compared with the nonpsychotic depression or nondepressed patients had more errors of commission (falsely believing they had been previously presented with words they had not seen)

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and omission (forgetting words that were presented) on a verbal (Wallach Memory) recognition test. This pattern is similar to that observed in healthy comparison subjects given corticosteroids (Belanoff et al., 2001). Genetic factors Family history studies have supported the tendency for MDpsy to ‘‘breed true’’
heritability estimates for MDpsy fall between that of nonpsychotic depression and bipolar disorder. A review of family history studies found that heritability estimates for MDpsy (if a multifactorial model is assumed) ranged from 62
78%, compared to 46
50% for families of patients with nonpsychotic depression (Lykouras et al., 1988). However, one family study found a nonsignificant increased risk of affective illness overall in families of patients with nonpsychotic depression (17% of relatives) compared to MDpsy (12% for probands with mood-congruent depressive psychosis, 6% for mood-incongruent). Families of probands with MDpsy had a higher risk of schizophrenia (2
4% depending on mood congruence, versus 0% for probands with nonpsychotic depression). One study found a significantly higher rate of bipolar I disorder in the families of patients with MDpsy (Prusoff et al., 1984), while another study from the same group found that the children of patients with MDpsy had a three-fold increased risk of cyclothymia (Weissman et al., 1988). Two studies by a second group found that first-degree relatives of patients with MDpsy had increased risk for any affective disorder and a trend towards increased risk for bipolar disorders (bipolar I, II, and cyclothymia) (Goldstein et al., 1998). A finding by this group that first-degree relatives had an increased risk of MDpsy was not replicated in the second study, and another group found no increase in risk of psychosis in relatives of patients with MDpsy compared with nonpsychotic depression (Winokur et al., 1985). A study in Ireland found that the presence of psychotic affective illness (especially mood-incongruent affective illness) in the parents of a child with schizophrenia predicted a four-fold increased risk of schizophrenia in that child’s siblings (Kendler et al., 1996), with the authors speculating that parents with affective psychosis are less severely impaired and thus have a greater chance of passing on psychosis risk to their offspring. One study found that probands with MDpsy and abnormal DST results had both an increased risk of delusions and an increased familial prevalence of depression, but not alcoholism (Bond et al., 1986). The preponderance of studies examining the involvement of specific genes in MDpsy has yielded negative results. One group has reported that none of the serotonin system candidate genes they examined (polymorphisms in the 5HT transporter protein, 5-HT1A, 5-HT2A, and 5-HT2C receptors) appeared to be involved in MDpsy (Serretti et al., 1999a; 1999c; 2000). However, long variants

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of the dopamine D4 gene (allele 7, which is associated with reduced cAMP formation) were found to be statistically significantly associated with the delusional subscale of the HAM-D in a combined sample with bipolar and unipolar depression, as well as for unipolar and bipolar depressed patients analyzed separately (Serretti et al., 1998). This same group found DRD4 variants (specifically, the exon 37 allele variant versus the 2 allele) to be associated with delusional symptoms among a mixed group of 461 patients with major psychoses (Serretti et al., 1999d), but also subsequently reported that in a larger group, DRD4 variants did not appear to play a major role in risk for psychosis (Serretti et al., 1999b). As discussed in the ‘‘Suspected neurochemical abnormalities’’ Section reduced dopamine b-hydroxylase (DBH) activity is a consistent finding in MDpsy, but genetics studies of the DBH gene have yielded mixed results. One study of patients with diagnosed MDpsy found that the most common DBH genotype associated with reduced activity (C-1021T) was not associated with MDpsy, nor were other major dopamine b-hydroxylase variants (Cubells et al., 2002). The study had insufficient power to determine if differences in a minor candidate allele, C1603T, which was more prevalent in MDpsy (14%) than nonpsychotic depression (5%), were statistically significant. The authors speculate that the elevated glucocorticoid levels also consistently seen in MDpsy may reduce DBH gene expression in a non-genetic fashion (such as through binding to a glucocorticoid response element in front of the DBH gene). This remains speculative, however, since acutely administered glucocorticoids increase, rather than decrease, DBH expression in cultured cell models (Cubells et al., 2002). Another study of patients with major depression found a G to A polymorphism at DBH gene nucleotide 444 (which lowers activity of the gene) was not associated with psychotism scores on the Hopkins Symptom Checklist, but was associated with increased interpersonal sensitivity and paranoia subscale scores (Wood et al., 2002). Other risk factors Although premorbid risk factors have been extensively delineated for other psychotic disorders, little evidence exists for MDpsy. Uterine atony and late winter births were associated with increased risk for early onset of affective psychosis in one study (Hultman et al., 1999), though the number of patients with MDpsy was not indicated. In contrast, exposure to influenza five months before birth was shown to be related to decreased rates of affective psychosis (and corresponding increased rates of schizophrenia) in females, but not males (Takei et al., 1993). Premorbid hysterical symptoms and eating disturbances

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during adolescence were associated with later affective psychotic disorder, but of the 28 cases reviewed, only eight had MDpsy (Cannon et al., 2001). Assessments of functioning including the Zigler-Phillips Social Competence Scale and the Social Adjustment Scale (SADS) showed significantly lower levels of premorbid functioning in 22 patients with MDpsy compared to 70 patients with nonpsychotic depression (Sands & Harrow, 1995). Urbanization has been linked to increased rates of both depression and psychosis, although there is no data directly addressing the effect of urbanization on the incidence of MDpsy (Sundquist et al., 2004). Treatment The treatment of MDpsy poses unique challenges. Given the potential for an increased risk of suicidality with MDpsy, the first priority for treatment is to take appropriate steps to assess and ensure safety, including hospitalization if necessary. Once safety issues have been addressed, the American Psychiatric Association practice guidelines recommend treatment with either electroconvulsive therapy (ECT) or an antidepressant plus an antipsychotic (APA, 2000). Several clinical algorithms for the treatment of MDpsy have also been published (Bell & Rothschild, 2004; DeBattista et al., 2002; Iwanami et al., 1999; Wheeler Vega et al., 2000) which incorporate new treatments that have been better studied since the publication of the APA guidelines. A key initial decision in the treatment of MDpsy is whether to pursue pharmacotherapy or move immediately to ECT. ECT has a strong literature documenting its efficacy in MDpsy (Avery & Lubrano, 1979; Avery & Winokur, 1977; Parker et al., 1992; Petrides et al., 2001). A meta-analysis of 44 published studies of treatments of MDpsy compared ECT with medication treatment, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, and typical antipsychotics, alone or in combinations. It found a mean effect size for ECT of 2.3 compared to 1.6 for the combination of TCA and typical antipsychotic therapy (Parker et al., 1992). There is also evidence suggesting ECT may be at least slightly more efficacious in MDpsy than nonpsychotic depression. One of the largest studies of ECT showed a 95% response rate (completers only) for patients with MDpsy versus 83% for major depression without psychosis (Petrides et al., 2001). In addition, response rates in elderly patients with MDpsy in one study were more than three-fold greater for ECT than for pharmacotherapy (Flint & Rifat, 1998a), although this comparison is limited by the study’s brief (six-week) duration. The question of whether response rates to medication treatment differ by age has not been addressed either in meta-analyses (Parker et al., 1992) or recent reviews (Wheeler Vega et al., 2000), but it is a focus of the

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NIMH Study of the Pharmacotherapy of Psychotic Depression (STOP-PD) study, currently ongoing and scheduled for completion in 2007. Current guidelines recommend consideration of immediate ECT if the patient is pregnant, has suicidal intent, is medically unstable (such as patients who are refusing oral intake), or is unable to take oral medications, and some consider it the treatment of choice for elderly patients with MDpsy. One potential disadvantage to ECT is a high rate of early relapse. In one study of 84 patients with major depression, 60% of those assigned nortriptyline and 39% assigned nortriptyline plus lithium maintenance treatment relapsed in the first 24 weeks after ECT completion, with relapse being especially likely in the first month after ECT completion (Sackeim et al., 2001). Other disadvantages of ECT include its limited availability (Bell & Rothschild, 2004) and that some patients find the treatment or associated cognitive effects distressing (Parker et al., 1992). Patients with major depression and comorbid PTSD or major depression plus psychotic symptoms secondary to drug use may be less likely to respond to ECT (DeBattista et al., 2002), so potential ECT candidates should be screened for these conditions. Many experts feel ECT is underutilized as a treatment for MDpsy, possibly due to a negative image perpetuated by film and the media (Fink, 2003). Most studies indicate combination pharmacotherapy with an antidepressant and antipsychotic is more efficacious than either as monotherapy. The largest randomized, placebo-controlled trials of pharmacotherapy for MDpsy showed a statistically significant advantage to combination treatment in one 124-subject trial (with a 64% response rate for olanzapine plus fluoxetine versus a 35% response rate for olanzapine alone and 28% placebo response rate), but only nonsignificant differences between olanzapine plus fluoxetine, olanzapine alone, and placebo in a second 125-subject trial (response rates of 48%, 36%, and 32%, respectively) (Rothschild et al., 2004). In comparison, a smaller (n ¼ 16
18 patients per group) double-blind study of high-dose perphenazine (average dose 49 mg/day) in combination with amitriptyline showed the combination had superior efficacy over either agent as monotherapy (Spiker et al., 1985). This study, which did not include a placebo control, showed response rates (17-item HAM-D rating scale of six or less in combination with an elimination of delusions) of 78% for the combination vs. 41% and 19% for amitriptyline and high-dose perphenazine monotherapy, respectively. However, these results were for completers only: 12% of the sample dropped out and when these are added to the sample in a post hoc estimate of an intent-to-treat approach, the response rates become 64%, 37%, and 18% respectively. These authors also reported that when nonresponders to monotherapy were converted to combination therapy, 71
85% responded, and the response was rapid (usually within one week) (Spiker et al., 1985). A follow-up report noted that levels of amitriptyline and nortriptyline were

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significantly higher in the group receiving combination treatment than those receiving amitriptyline alone (Spiker et al., 1986). Meta-analyses of medication treatment for MDpsy all predate the serotonin reuptake inhibitor (SRI) era (Chan et al., 1987; Parker et al., 1992). One metaanalysis suggested that combination therapy ‘‘is not so distinctly superior’’ to tricyclic (TCA) monotherapy (effect size for 28 studies of TCA alone, 1.16 versus 1.56 for 12 studies of TCA plus typical antipsychotics), and both this meta-analysis and an earlier one (Kroessler, 1985) find typical antipsychotic monotherapy to be as efficacious or slightly more efficacious than TCA monotherapy, in contrast to the Spiker et al. (1985) study. One group (Zanardi et al., 1996) has reported response rates as high as 75% for MDpsy treated with the selective SRI sertraline as monotherapy, although the comparison group of a different SRI, paroxetine, had a high dropout rate and lower efficacy (46%). This study should be interpreted with caution due to its lack of a placebo control and a standardized instrument to diagnose MDpsy in all subjects (Rothschild & Phillips, 1999). Naturalistic studies indicate a low rate of antipsychotic prescribing for patients with MDpsy in the community (Mulsant et al., 1997). This may represent the failure of treaters to diagnose psychotic features in depressed patients. With no head-to-head trials, it is difficult to compare the efficacy of tricyclic antidepressants versus SRIs, or typical antipsychotics versus atypicals. Because of a desire to lower the side-effect burdens, most treatment algorithms recommend initiating combination treatment with an SSRI or venlafaxine plus an atypical antipsychotic. If the patient has responded well to a particular class of antidepressant or antipsychotic in the past, that is often a good starting point for further treatment. When there is no treatment history, beginning treatment with an SRI may have the added advantage of treating post-traumatic stress disorder, an illness shown to be four times more common in MDpsy than nonpsychotic depression (Zimmerman & Mattia, 1999). The antidepressant amoxapine, which is chemically related to the antipsychotic loxapine, was shown to have similar efficacy to amitriptyline plus perphenazine for MDpsy in a single double-blind, randomized study, although there was a tendency towards lower global response rates with amoxapine (Anton & Burch, 1990). However, amoxapine is one of the least prescribed antidepressants and has risks of seizures at higher doses (Wheeler Vega et al., 2000). The trial of an SRI and atypical antipsychotic must include both adequate dosages and duration, typically 8 to 12 weeks, before a determination of effectiveness can be made. For non-responding patients, treatment strategies include the use of a different SRI (or SNRIs, such as venlafaxine or duloxetine) in combination with an atypical antipsychotic, use of TCAs or typical antipsychotics, or commencement of ECT.

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If a patient shows a partial response to an antidepressant/antipsychotic combination, augmentation with lithium may be of benefit. In a retrospective study, lithium augmentation of antidepressant plus antipsychotic combinations was shown to be effective for bipolar depression with psychotic features (89% response rate), but much less effective for MDpsy (25% response rate) (Nelson & Mazure, 1986). Lithium augmentation of an antidepressant/antipsychotic combination doubled response rates in one very small and brief (six-week) study (Flint & Rifat, 1998a). Effective serum levels for lithium augmentation are generally in the 0.5 to 0.8 mEq/L range (Bell & Rothschild, 2004). As usual with lithium treatment, renal function, thyroid function, and electrolytes should be monitored on a regular basis. The effectiveness of lithium augmentation is being evaluated in the NIMH STOP-PD trial. Minimizing exposure to antipsychotics is desirable because of concerns that risks of tardive dyskinesia may be higher in affective psychosis (Rush et al., 1982). Other potential adverse effects include neuroleptic malignant syndrome and metabolic syndromes, such as obesity, diabetes, and dyslipidemia. One study examining duration of antipsychotic treatment found that 73% of 30 patients responding to fluoxetine plus perphenazine, who had perphenazine tapered to discontinuation after four months, did not show any return of their psychotic symptoms in the next 11 months. The remaining 23% of patients were able to be successfully tapered off perphenazine after eight months of combined treatment (Rothschild & Duval, 2003). Although most patients can be tapered off of antipsychotics in this time frame, antidepressant treatment is usually more longterm. One study found that the presence of psychotic features was one of the predictors of a group of patients requiring lengthy antidepressant treatment (36 months on average) to prevent relapse (Aronson & Shukla, 1989). Antidepressants may need to be continued indefinitely, especially if the patient has had more than one major depressive episode in his or her lifetime. As patients with MDpsy often have elevated glucocorticoid levels, the glucocorticoid antagonist, mifepristone, has been investigated as a treatment for MDpsy. The only double-blind, randomized placebo-controlled study of 208 patients with MDpsy failed to find a significant difference between a one-week course of mifepristone or placebo added onto treatment as usual regarding their primary endpoint, improvement in psychosis at day 7 that was sustained to day 28 (DeBattista, 2003). Another randomized, double-blind trial in bipolar patients was largely negative, finding significant decreases in HAM-D and MADRS scores, but only at day 14, not day 7 or day 21 of the trial (Young et al., 2004), and only if a correction for multiple comparisons was not done (Rubin & Carroll, 2004). A small, randomized, open-label inpatient trial (Belanoff et al., 2002) had previously found that 68% of patients receiving mifepristone had a 30% reduction

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in psychosis scores (BPRS positive symptoms scale) and 40% had a 50% reduction in the Hamilton Depression score (21-item) after a week of treatment. The efficacy of mifepristone is currently a topic of intense debate, with some maintaining that the treatment lacks robust findings or a consistent rationale, since in some trials participants have not had demonstrated abnormalities in glucocorticoid levels (Rubin & Carroll, 2004). In addition to medication, the treatment of MDpsy should include a comprehensive psychosocial assessment and treatment plan. Although no studies to date have looked specifically at psychotic depression, the benefit of individual psychotherapy in the treatment of major depression without psychosis is well documented (APA, 2000). In addition, substance abuse can complicate the treatment of depression and should be treated if present. As with all psychiatric disorders, patient and family education is important, as are adequate social supports for patients with MDpsy.

Conclusions Major depression with psychotic features, a disorder with considerable morbidity and mortality, is often not recognized or accurately diagnosed. As a result, patients frequently receive less than optimal treatment and have poorer outcomes. Biological studies have identified distinct characteristics of major depression with psychotic features, including marked dysregulation of the hypothalamicpituitary-adrenal axis and decreased dopamine-beta-hydroxylase activity, although studies of genetic or other risk factors are still inconclusive. The treatments with the best evidence basis continue to be antidepressants plus antipsychotic medications in combination, or electroconvulsive therapy. Further research on this important and common psychotic disorder continues to be acutely needed.

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14.

Part IV

Neurodevelopmental and Genetic Disorders

10

Psychosis with intellectual disabilities Colin P. Hemmings1 and Nick Bouras2 1 2

South London and Maudsley NHS Trust, MHiLD, Guy’s Hospital, London, UK King’s College London, Institute of Psychiatry, Estia Centre, London, UK

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B C C C C D C C C

Introduction People with intellectual disabilities (ID) have higher rates of mental disorders compared to people of more typical intelligence (Smiley, 2005). They can experience the full range of psychotic disorders seen in the wider population (Reid, 1972). However, the evidence base regarding the epidemiology, etiology, assessment, and management of psychotic disorders in people with ID remains limited. Probably the best known and most studied of the psychotic disorders in people with ID as well as in the wider population are the schizophrenias and schizophrenia-associated spectrum disorders. This chapter will focus on these specific psychotic disorders in people with ID. It has long been thought that the relationship between psychoses and intellectual impairment may provide important clues to the etiology of psychoses (Offord & Cross, 1971). Kraepelin (1919) described pfropfschizophrenie as being psychosis literally ‘engrafted’ onto ‘idiocy’ and accounting for 197

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up to 7% of cases of ‘‘dementia praecox.’’ He believed that pfropfschizophrenie was an early-onset and severe form of psychosis in pre-existing ID. Kraepelin also believed that schizophreniform psychosis beginning in the first decade could itself cause ‘‘mental defect’’ (Heaton-Ward, 1977). However for a long time after Kraepelin, most researchers believed that the joint occurrence of both conditions in the same individual was merely a chance combination (Heaton-Ward, 1977). There was accordingly a lack of research interest in the study of co-morbid ID and schizophrenia (Turner, 1989). Recently interest has been renewed, as part of the wider increased research into mental disorders in people with ID. Opinion has also been growing once again that the study of schizophrenia and the schizophrenia-associated spectrum disorders in people with ID may lead to important clues in the understanding of these disorders in the wider population.

Epidemiology For several reasons there have been longstanding difficulties with establishing true incidence and prevalence rates of psychosis in people with ID. Psychosis in people with ID is generally more difficult to detect and diagnose than in the general population. The research in this field has also been hampered by inconsistencies in diagnostic criteria and rating instruments used (Sturmey, 1999). A major reason for the inconsistency of approaches has been the continued doubts about the usefulness of standard diagnostic classification systems in diagnosing psychosis in those with more severe ID. Specific problems of diagnosis

There are many possible pitfalls in the diagnosis of psychosis in people with ID. Sometimes a specific diagnosis of schizophrenia in people with ID is impossible. ‘‘First rank’’ (Schneider, 1959) positive symptoms of schizophrenia are conceptually complex and thus often difficult to reliably assess in people with ID (Hucker et al., 1979). There may be difficulties distinguishing true delusional beliefs and hallucinations from self-talk, fantasies, and talking to imaginary friends, which can be developmentally appropriate for a person with ID (Heaton-Ward, 1977; Hurley, 1996). People with ID often ‘‘remember’’ conversations and think out loud about them. They often do not readily recognise that this is socially inappropriate. Under stress all of these developmentally appropriate features may become more prominent and exaggerated (Hellendoorn & Hoekman, 1992). Formal thought disorder may also be difficult to elicit in people with ID, for it can often be difficult anyway to follow the thread of their speech. People with ID are

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also often hypersensitive to how they are perceived by others, often grounded in real-life experiences of being mocked and rejected (Hurley, 1996). This may be mistaken for delusional persecutory thinking. It has also been suggested that people with ID are more likely to be able to be persuaded of the falseness of the delusional beliefs. Hence it may be more important to observe their readiness to restate their beliefs when not so subject to suggestibility (Hurley, 1996). Apparent ‘‘negative’’ symptoms can also be misattributed to a psychotic disorder when they may be due to many other factors such as institutionalisation, over-sedation, lack of environmental stimulation, and severe cognitive impairment (James & Mukhergee, 1996). Moss, Prosser, and Goldberg (1996) showed negative symptoms to have low specificity for schizophrenia in adults with ID. They found that auditory hallucinations seemed easiest to elicit in people with ID and psychosis, followed by thought disorder, and then by delusions relating to replacement of will. It may be difficult to discriminate psychotic symptoms from baseline features of ID, a diagnostic problem which Sovner and Hurley (1986) termed ‘‘baseline exaggeration.’’ However, the difficulty of differentiating psychotic symptoms and features related to a person’s ID may also lead to the problem of ‘‘diagnostic overshadowing’’ (Reiss, Levitan, & Zyszko, 1982) and psychosis therefore being under-diagnosed in this patient group. Another problem with diagnosing schizophrenia in people with ID is the difficulty of differentiating it from autism. The term ‘‘autism’’ itself was actually coined by Bleuler (1911) to describe social withdrawal in schizophrenia. He included autism as one of the four core characteristics of schizophrenia. Kolvin (1971), though clearly later, showed that the pervasive developmental disorder of childhood autism was distinct from schizophrenia and other psychoses. The risk of schizophrenia in people with autism is also probably no more frequent than that of schizophrenia in the general population, suggesting that autistic spectrum disorders and schizophrenia are not inter-related (Volkmaar & Cohen, 1991). However, it may still be impossible to decide whether a person has autism or the negative symptoms of chronic schizophrenia unless a good developmental history is available (James & Mukhergee, 1996). Unusual preoccupations held rigidly by people with autism may be particularly difficult to differentiate from delusions. Flattened and incongruent affect, poor non-verbal communication, and poverty of speech are commonly seen in autism as well as schizophrenia and so also lead to diagnostic difficulties. Problems with inconsistent criteria

The study of mental disorders in people with ID has been hampered by the use of inconsistent criteria. The major difference in the various approaches used has been whether researchers have used standardised criteria or criteria modified for

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people with ID. For example, Hucker et al. (1979) modified the Research Diagnostic Criteria of Feighner et al. (1972) in their study of schizophrenia in people with ID and thus included features such as ‘‘behaves as if hallucinated’’ as evidence of the disorder. Nor have definitions of the term ‘‘Intellectual Disabilities’’ itself been consistent. However, recent improvement in consistency of criteria used in studies of mental disorders in people with ID has allowed greater comparison between them. The specific problems of diagnosis of schizophrenia in people with ID have improved in recent years with the development of standardised assessment instruments for this patient group. For example, the schizophrenia sections of the PAS-ADD instruments are now available to increase the reliability of the identification of schizophrenia in the ID population (Moss et al., 1996). Limitations of standard classification systems

One of the major reasons why inconsistent criteria have been applied in ID research is that the validity of the standard diagnostic classification systems for use in this patient group is questionable to some degree. In people with mild ID and good verbal skills it seems that the standard classification systems can be used with reliability and validity (Dosen & Day, 2001). By analogy, ICD and DSM criteria for schizophrenia have been shown to be reliable when used with children with typical IQ as young as seven years old (Green et al., 1992). The linguistic competence of a normal seven-year old is similar to an adult with moderate ID (Melville, 2003). The developmental perspective can be illuminative, as complex delusions and hallucinations are unusual in young children but become more frequent in older children and children with a higher IQ (Watkins et al., 1988). Most of the research literature on psychosis in ID has focused on people with mild ID (IQ 50
70). Reid (1972) influentially argued that it is impossible to diagnose schizophrenia in people with limited verbal communication. In practice, this means below an IQ level of around 45. A person with more severe ID has limited verbal expression and ability to employ abstract reasoning, which are essential for the manifestation of the complex, subjective experiences of the language-based symptoms of schizophrenia. Sovner (1986) has described this phenomenon as ‘‘intellectual distortion.’’ Sovner and Hurley (1986) also argued that ‘‘cognitive disintegration,’’ or psychotic-type reactions to stress, occurred in people with ID because of their limited coping abilities. Higher incidence of schizophrenia and related schizophrenia spectrum disorders have been found in those with mild ID compared with more severe ID (Bouras & Drummond, 1992; Cowley et al., 2004). However it remains unclear whether this reflects reality or whether it merely reflects the problems in detection of psychosis in people with more severe ID. The generally accepted criterion for psychosis is the absence of

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insight and loss of sense of reality (Heaton-Ward, 1977). Hence it could be argued that those with severe ID could be all considered psychotic. However, most researchers probably share the view of Heaton-Ward (1977) that a person’s degree of insight and touch with reality cannot be reliably assessed if they do not have a reasonable level of intelligible communication. Prevalence and incidence

Turner (1989) has reviewed the epidemiological studies of prevalence rates of schizophrenia in ID. The studies have converged around point prevalence rates of about 3% and this figure has become widely accepted (Deb, Thomas, & Bright, 2001; Fraser & Nolan, 1994; Turner, 1989). This prevalence rate is around three times higher than in the general population although this is still thought to be an underestimate of the true figure (Turner, 1989). There are no studies published specifically of incidence rates of schizophrenia in people with ID. Reasons for increased prevalence rates

There are three major possibilities for the increased prevalence of schizophrenia in people with ID. First, a lowered IQ could be a premorbid sign of schizophrenia (Gunnell et al., 2002). Second, cerebral abnormalities caused by genetic factors or in utero may cause both ID and SSP. This has been described as the ‘‘common etiology’’ hypothesis (David et al., 1997). Third, low IQ could lead to incorrect social assumptions and thus increased risk of symptoms such as delusions and hallucinations. David et al. (1997) showed that low intellectual ability in itself is a risk factor for schizophrenia and other psychoses, although their study, like the vast majority in schizophrenia research, excluded those with premorbid ID. Other epidemiological factors

Doody et al. (2000) reported that women with ID generally developed schizophrenia later than men with ID, who were also less likely to have a family history of the disorder. They suggested that gender differences in schizophrenia might be more pronounced amongst the co-morbid population, where early cognitive impairment can herald the onset of a more severe form of onset. Cowley et al. (2004) found higher prevalence of schizophrenia and related schizophrenia spectrum disorders with older age, whereas Cooper (1997) found no differences in the prevalence of schizophrenia between younger and older adults with ID. Ethnicity has also been associated with schizophrenia and schizophrenia spectrum disorders in the ID population, with a higher incidence in those of South Asian origin (Chaplin et al., 1996). Cowley et al. (2004) also found lower prevalence rates of schizophrenia and schizophrenia spectrum disorders in white participants compared to non-whites.

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Age of onset Meadows et al. (1991) suggested that schizophrenia might have a significantly earlier age of presentation in people with ID. Fraser and Nolan (1994) believed that the age of onset of psychosis does seem to be earlier in ID but thought that the reasons for this remained unclear. One possibility is that the existence of schizophrenia in the context of ID is more likely to produce a more severe illness with earlier appearance of psychotic symptoms (Meadows et al., 1991). However, there is also the possibility that the presence of schizophrenia increases the likelihood of an individual being diagnosed as having ID, and vice versa (Sanderson et al., 2001). There can sometimes also be a delay in presentation of schizophrenia in people with ID due to the difficulties of detection, including the finding that the onset of psychosis may sometimes be less noticeable in people with ID because florid symptomatology is less common (James & Mukhergee, 1996). However, Doody et al. (1998b) found no significant differences in the ages of first symptoms of schizophrenia, consultation, admission, or diagnosis between subjects with both mild ID and schizophrenia, and matched controls with schizophrenia alone. This was despite the fact that co-morbid subjects had more psychopathology and duration of admissions than the controls. Presentation Turner (1989) described the symptoms of schizophrenia in people with ID as ‘‘often shallow or banal.’’ Because of their reduced opportunity to engage in normal life experiences and social opportunities, the delusions of people with ID, when they occur, may be unremarkable. For example, there is little attempt to interpret strange subjective phenomena and secondary elaboration either of abnormal perceptions or odd beliefs producing complex delusional systems rarely occurs (Reid, 1989). Complex hallucinations such as voices giving as running commentary in the third person or discussing the person between himself or herself are also uncommon. Sovner (1986) described this phenomenon as an example of ‘‘psychosocial masking’’ of symptoms in people with ID. James and Mukhergee (1996) found that the presenting complaints of schizophrenia in people with ID were very often a decline in functioning, deterioration of skills, and social withdrawal, rather than hallucinations and delusions. Reid (1993) suggested that hebephrenic, paranoid, and catatonic subtypes of schizophrenia could all be seen in people with ID. Many clinicians believe though that it is less often possible to sub-classify schizophrenia in people with ID than in those with more typical IQ.

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Positive and negative symptoms

Although researchers in the field of psychosis in ID have used the categorisation of psychotic symptoms into ‘‘positive’’ and ‘‘negative’’ (Andreasen, 1982), the validity of these in the ID population remains unclear (Melville, 2003). There have been conflicting findings; for example, Bannerjee et al. (2001) and Cherry et al. (2000) emphasised positive symptoms in the presentation of schizophrenia in people with ID whilst Doody et al. (1998b) found ‘‘negative’’ symptoms to be more common. Disagreement remains whether or not the presentation of schizophrenia is significantly different in people with and without ID. Most of the literature suggests that there are no substantial differences in the symptoms of schizophrenia between people with ID and people of normal intelligence (Hucker et al., 1979; Meadows et al., 1991; Moss et al., 1996; Reid, 1972). Meadows et al. (1991) suggested that there was no difference whatsoever in the presentations of symptoms of schizophrenia between those with and without ID. Their subjects formed a small, highly selected group of those in hospital. It is possible that those with florid symptomatology would have been more likely to been included within their study. But even with this sample, there was still a trend for less overt psychopathology in thirteen of the sixteen symptoms. Bassett et al. (2003) also found no significant differences in the schizophrenia phenotype between patients with and without ID. However, other studies have found differences in presentation, especially a tendency for less florid positive symptoms of schizophrenia in those with ID. For example, Linnaker and Helle (1994) found that those diagnosed with schizophrenia with the Psychopathology Instrument for Mentally Retarded Adults (PIMRA) had fewer delusions, flatter affect, and more incoherent speech than people with schizophrenia of normal intelligence, especially persecutory delusions and formal thought disorder. Doody et al. (1998b) and Bouras et al. (2004) also found differences between presentations of schizophrenia in the ID and non-ID populations. Emotional and behavioral symptoms

Some researchers have argued that there are possible behavioral manifestations or ‘‘behavioral equivalents’’ of mental disorders such as psychosis in people with ID (Dosen, 2005). However, the association between problem behaviors and schizophrenia is unclear. Certainly some behavioral problems respond to antipsychotic medication suggesting that they may be caused or exacerbated by underlying psychosis that is difficult if not impossible to diagnose clearly using standard diagnostic criteria. It has been argued that people with ID and psychosis may present with other atypical features. For example, hysterical type symptoms

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such as over-breathing, pseudo-fits, gait disturbance, and Ganser states may be more frequent in people with ID and psychosis (Dosen & Day, 2001; Hucker et al., 1979; Reid, 1972). Some schizophreniform psychoses also present acutely with apparent changes in consciousness (Reid, 1993). Turner (1989) reported that disturbed and aggressive behavior, bizarre rituals, and ‘‘hysterical’’ behaviors are relatively more common in ID and may complicate the presentation of psychosis in ID. People with ID and schizophrenia may also present with social withdrawal, fearfulness and sleep disturbance (Eaton & Menolascino, 1982; Myers, 1999). The ‘‘DC-LD’’ guide (Royal College of Psychiatrists, 2001) suggests that early signs of a psychotic illness could be new problem behaviors (especially when odd or bizarre or uncharacteristic for the person), or an increase in frequency or severity of preexisting behaviors. A presumptive diagnosis of schizophrenia in ID may sometimes thus be made on the basis of observations. For example, behavior that might suggest auditory hallucinations could be the person with ID shouting back apparently at people not present when this has not been their previous behavior. Similarly, suspiciousness, blunted or incongruent affect, and social withdrawal not previously part of the person’s personality and behavior could also be suggestive of a schizophreniformtype psychosis. Non-verbal evidence for possible psychosis by necessity becomes of greater diagnostic significance in the more severely intellectually disabled. Earl (1934) suggested that abnormal movement disorders, mannerisms, and stereotypies seen in more severe ID were a ‘‘form of schizophrenia played out upon the psychomotor level rather than the symbolic.’’ It has been claimed that it is possible using observations and non-verbal communication to diagnose schizophrenia in people with more severe ID (Eaton & Menolascino, 1982). The authors believed that three of their patients with severe ID showed evidence of schizophrenia by the presence of bizarre behavior, persistent withdrawal, echolalia, and blunted affect. Cherry et al. (2000) also described characteristics of schizophrenia in a study sample of people with severe or profound ID. Heaton-Ward (1977) argued that for some people with more severe ID, their emotional lability, noisy outbursts, disorganised, purposeless activity, including aggression, destructiveness, and selfmutilation could be considered ‘‘psychotic’’. However, as previously noted he recognised that it would be impossible to determine whether such individuals were demonstrating lack of insight and loss of sense of reality, which is characteristic of true psychosis. This appears to be the mainstream view of researchers in the field. Turner (1989) noted the persistent comment on catatonia in the literature. Hucker et al. (1979), Eaton and Menolascino (1982), and Heaton-Ward (1977) all remarked upon the high proportion of their study samples of subjects with ID and schizophrenia who showed catatonic features. The relationships between

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catatonia, movement disorders, and schizophrenia in ID are complex and as yet under-researched and need further clarification. Neuropsychological findings

Kay (1989) pointed out the overlap in performance on tests of intellect, adaptive behavior, and cognition between people with ID without schizophrenia and people with chronic schizophrenia. An episodic psychotic illness may be associated with a reduction in transient functioning to the mild or even moderate level of ID (Russell & Tanguay, 1981). A chronic psychosis may, however, lead to a prolonged or even permanent reduction in intellectual and social functioning. Sometimes those with chronic schizophrenia are thus mistakenly diagnosed as also having ID, because of deterioration in intellectual functioning. Heaton-Ward (1977) found a 20 percent fall in IQ in some of his patients with ID and schizophrenia over time. There is little specifically published in the literature of neuropsychological findings in people with ID and schizophrenia. Doody et al. (1998b) found that their co-morbid subjects were more likely to have impairment of episodic memory, which may affect their compliance with treatment. They also had greater impairment of theory of mind on second order tests than subjects with schizophrenia and normal pre-morbid IQ (Doody et al., 1998a). Rowe, Rudkin, and Crawford (2000) found that there was an increased rate of mixed handedness among people with co-morbid ID and schizophrenia compared to controls. Mixed handedness is taken as an index of diminished cerebral dominance or laterality and thus these findings also supported the idea of a neurodevelopmental hypothesis of schizophrenia. Weinberger (1987) has suggested that people with ID and schizophrenia form a subgroup of schizophrenia with a neurodevelopmental etiology. Doody et al. (1998b) found evidence consistent with the neurodevelopmental hypothesis in their study of co-morbid ID and schizophrenia. For example, they found that their co-morbid subjects had more ‘‘soft’’ neurological signs than controls. They suggested that there is a form of schizophrenia that manifests in childhood with cognitive impairment prior to the onset of psychotic symptoms.

Course and progression It has long been established that in patients with schizophrenia there is a relationship between pre-psychotic IQ and disease prognosis (Offord & Cross, 1971). There has been very little published, however, into the long-term prognosis in people with ID and schizophrenia. There have not been either any published studies of the latency period or prodrome before presentation of psychotic

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symptoms in this patient group. Most clinicians believe that the course of schizophrenia in people with ID will tend to be more severe than in people with normal IQ. However, again the literature is scant and findings so far are contradictory. For example, Reid (1972) found in his study that the psychoses ran a more benign course in people with ID, especially in those with more severe ID. Bouras et al. (2004) showed that in a group of people with schizophrenia spectrum disorders and ID, matched for duration of illness, there was higher observable psychopathology, more negative symptoms, and greater functional disabilities compared to a group with schizophrenia spectrum disorders attending a general mental health outpatient clinic. The authors suggested that the increased prevalence of observable psychopathology might lead to increased risk of stigma and social isolation for those with schizophrenia who also had ID. The higher rate of negative symptoms seen also might contribute to social withdrawal and isolation and raised the question of whether those with ID as well as schizophrenia might have progressed more rapidly to the chronic deficit state of schizophrenia. The findings of this study suggested that people with ID are more debilitated by schizophrenia than those without ID and may thus need additional input. Doody et al. (1998b) found that patients with dual diagnosis of schizophrenia and ID had fewer psychiatric admissions but for longer periods of time, and that at point of discharge they needed more support than patients with schizophrenia alone. With some outcome parameters, such as total time in hospital and offending behavior, there was no evidence that the co-morbid group were more impaired than the schizophrenia control group. However they also found that those with both conditions received more community supports than control subjects with schizophrenia alone. Doody et al. (2000) showed that in people with co-morbid ID and schizophrenia, males with an early age of onset and no known family history of either ID or schizophrenia were more likely to require care and treatment in a high security hospital.

Suspected neuropathology In the classification systems of DSM-IV (American Psychiatric Association, 1994) and ICD-10 (World Health Organisation, 1992) it is stipulated that schizophrenia should not be diagnosed in the presence of ‘‘overt’’ brain disease, which is more common in people with ID (Hagberg & Kyllerman, 1983). This complicates the study of neuropathology in individuals with both schizophrenia and ID. A recent case-controlled study of volumetric cerebral magnetic resonance reported that, in terms of brain structure, people with ID and schizophrenia resemble those with schizophrenia more closely than those with ID (Sanderson et al., 1999).

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These findings were confirmed by further studies (Moorhead et al., 2004; Sanderson et al., 2001). Sanderson et al. (1999) suggested that the higher frequency of schizophrenia in ID was due to the greater tendency of people with schizophrenia to develop cognitive deficits and that within the ID population there may be people whose deficits result from undiagnosed schizophrenia. These authors support the view that co-morbid schizophrenia and ID may represent an early onset and severe form of schizophrenia, rather than ID complicated by psychosis (Moorhead et al., 2004) Rare congenital syndromes associated with ID can also provide some clues for the study of psychosis in ID. For example, the Andermann syndrome is a variable familial syndrome combining ID, congenital corpus callosum agenesis, peripheral neuropathy, dysmorphic features, and psychosis (Andermann et al., 1972). It thus provides an opportunity to examine the relationship between psychotic symptoms and neuropathology. Filteau et al. (1991) found no significant relationship between corpus callosum agenesis and psychosis. However, there was a relationship between atrophy of the structures in the posterior fossa, including the cerebellum, and psychosis in this syndrome, suggesting that such defects could be associated with psychosis.

Suspected neurochemical abnormalities There have been no reports in the literature of neurochemical abnormalities specific to people with ID and schizophrenia.

Genetic factors Kallman (1938) found no increase in ID in the relatives of people with schizophrenia and vice versa. This study suggested that the co-morbid state was a chance occurrence of two unrelated conditions and contributed to a period of subsequent decreased research interest into co-morbid ID and schizophrenia (Turner, 1989). However Kallman’s study did not consider the co-morbid probands and, when Doody et al. (1998b) considered these, both the prevalence of ID and schizophrenia were increased in the relatives of the co-morbid probands. This suggested that the occurrence of both conditions only by chance was unlikely and supported the idea that a highly familial form of schizophrenia might occur in the ID population. Doody et al. (1998b) also showed that there was a high rate of chromosomal variants in karyotype testing in the co-morbid group. Cytogenetic anomalies, which are often associated with intellectual impairment, may be associated with

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an earlier age of onset of schizophrenia (Bassett et al., 1998). High rates of schizophrenia have been reported in adults with velo-cardio-facial syndrome (VCFS), which is associated with a deletion on chromosome 22 and often, but not invariably, associated with ID. (Scambler, 2000). In a large study of 50 adults with VCFS Murphy, Jones, and Owen (1999) found that fifteen (30%) had psychotic disorder, with twelve (24%) fulfilling DSM-IV criteria for schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion including 6% of the early-onset cases (Usiskin et al., 1999). Higher rates of 22qds may be present in subsets of schizophrenia with ID (Bassett, Chow, & Weksberg, 2000). Increased rates of dysmorphic features, cognitive impairment, and structural brain abnormalities have led to the proposal of 22q11 as a model for a neurodevelopmental subtype of schizophrenia. However, VCFS is not an entirely suitable model for ID and psychosis as it is not invariably associated with ID. Many studies of VCFS and psychosis have also excluded people with ID. Other genetic syndromes and abnormalities have been associated with ID and psychosis. For example, atypical psychotic symptoms also seem associated with Prader-Willi syndrome, particularly the maternal disomy form of the syndrome (Boer et al., 2002; Verhoeven, Curfs, & Tuinier, 1998). Associations have also been reported between schizophrenia and sex chromosome anomalies (De Lisi et al., 1994), which are in turn associated with an increased likelihood of ID as well as XXYY (Lee, 1996). Schizophrenia and ID in association have also been reported with a wide variety of autosomal chromosomal abnormalities, for example on chromosome 9 (Park et al., 1991) and chromosome 5 (Bennett et al., 1997). Other risk factors Epilepsy

Deb et al. (2001) and Doody et al. (1998b) found that those with schizophrenia and ID were more likely to have epilepsy compared to those with schizophrenia of typical intelligence. Epilepsy can lead to problems with diagnosis, for example differentiating temporal lobe epilepsy from schizophrenia, as well as treatment, as antipsychotics typically lower the seizure threshold. In contrast, Cowley et al. (2004) found that in their study people with epilepsy and ID had a lower incidence of schizophrenia. In this study, level of ID may have been a confounding factor, as epilepsy increases in prevalence in more severe ID (Bowley & Kerr, 2000). The phenomenon of ‘‘forced normalisation’’ has been described in relation to the schizophreniform psychoses of epilepsy (Trimble, 1996) whereby a reduction in seizure activity following the introduction of anticonvulsant agents is associated with an exacerbation of psychosis. It is possible that this mechanism may be of

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etiological importance in a proportion of the co-morbid population (Doody et al., 1998b). Obstetric complications

O’Dwyer (1997) found that, in people who develop ID and psychosis, the number of obstetric complications increases, compared to those matched for age, sex, severity of ID, and epilepsy. These complications included abnormally long labour, dysmaturity, pre-eclamptic toxemia, and maternal episiotomies, all of which may give rise to anoxic cerebral trauma, which the authors concluded was the major etiological factor predisposing people with ID to develop psychoses. Hucker et al. (1979) studied 24 people with ID and schizophrenia, and 40 control subjects. They found higher proportions of people with impaired hearing, gestation below 36 weeks, and low birth weight in the group with schizophrenia. Sensory impairments

Sensory impairments are more common among people with ID (Carvill, 2001). It is not known whether there is a general association between sensory impairments and predisposition to psychosis in people with ID, although many clinicians believe this to be the case. There is a specific association with psychosis in some cases of Usher’s syndrome, which is associated with schizophrenia in about 15% of cases (Hallgren, 1959).

Treatment The principles of treatment of schizophrenia in people with ID are essentially similar to those when the patient is of normal intelligence. The few existing studies have suggested that treatment with antipsychotics in ID is broadly similar in efficacy with no significant risk in side effects (Craft & Schiff, 1980; Reid, 1972). Shedlack et al. (2005) found that in those with schizophrenia spectrum disorders there was substantial improvement in social withdrawal following treatment with both typical and atypical antipsychotic medication. Some studies have reported good effects and fewer side effects with atypical antipsychotics (Advokat, Mayville, & Matson, 2000; Williams et al., 2000). Clozapine also appears to be safe, efficacious, and well tolerated in people with ID and co-morbid mental illness, including schizophrenia (Antonacci & de Groot, 2000). Many clinicians have reported that the optimal dosage levels of antipsychotic medications appear to be lower in ID patients than in patients with normal IQ (Menolascino et al., 1985). The exacerbation of cognitive impairment and the lowering of seizure thresholds can be particular problems in the prescribing of

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antipsychotics for people with ID. There is a consensus that antipsychotic prescribing often needs to be instigated and increased more cautiously than in patients without ID. Overall, there are still too few studies that have been published of people with ID-prescribed antipsychotics for treatment of psychosis rather than for behavioral problems. Duggan and Brylewski (1999) have thus argued that there is insufficient evidence to judge the efficacy of antipsychotics in people with ID. The use of antipsychotics to treat schizophrenia in this patient group therefore is still largely based on extrapolation from the evidence base of general adult psychiatry. There remains an urgent need for randomised controlled trials of the efficacy of antipsychotic medication in people with ID and schizophrenia. Clarke (2001) argued that people with brain pathology are more likely to develop tardive dyskinesia than the general population. In a study of people with ID in a long stay institution (Sachdev, 1992), 34% of those receiving antipsychotic medication had tardive dyskinesia. Accordingly, it has been suggested that clozapine may be a particularly useful antipsychotic for people with ID given a possible propensity towards tardive dyskinesia (Cohen et al., 1991; Rao, Cowie, & Matthew, 1987). However, the evidence for increased risk of tardive dyskinesia due to antipsychotic medication in people with ID and schizophrenia is not conclusive. For example, Gualtieri et al. (1986) found no evidence that ID increased the risk. One possible reason for this discrepancy in findings is that differentiating between movement disorders and medication side-effects is more difficult in patients with ID. Rogers et al. (1991) showed that people with more severe ID also have high rates of motor disorders not attributable to antipsychotic medication. The presence of muscle tone abnormalities and stereotypies including tics, mannerism, and self-stimulatory behaviors can all mask the presence of antipsychotic-induced movement disorders (Shedlack et al., 2005). As well as tardive dyskinesia, neuroleptic malignant syndrome may also be possibly increased in people with ID on antipsychotic medication (Boyd, 1992). Electro-convulsive therapy (ECT) has been used in the treatment of mental disorders in people with ID, but there has been little published regarding its use as treatment of schizophrenia in ID (Chanpattana, 1999). There is also little evidence regarding the use of psychosocial (including family) interventions for people with intellectual disabilities. Behavioral techniques have been used to improve the social skills of individuals with psychosis and ID (Hatton, 2002). The application of either individual or family CBT approaches has not been systematically evaluated adequately as yet in people with ID who have psychosis. A case series of cognitive-behavior therapy for five patients with psychosis and mild ID has been reported (Haddock et al., 2004). This included two cases in which family interventions were also integrated into the individual CBT.

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There are no treatments for schizophrenia therefore which are specific to people with ID. The underlying intellectual impairment does influence the outcome of level of independence and functioning (Reid, 1993). In general, there is evidence to suggest that people with ID and schizophrenia may have even more complex needs than patients with schizophrenia of typical intelligence and thus may be harder to treat. There is some evidence that outcomes may be better when people with both ID and psychosis are treated by specialist rather than generic services (Raitasuo, Taiminen, & Salokangas, 1999).

Conclusions The relationships between ID and schizophrenia remain unclear. We are not likely to see any clear-cut relationships between them when ID is itself on a spectrum with the general population. The relationship between IQ itself and schizophrenia is complex, as lower IQ may cause vulnerability to the development of schizophrenia or be an early manifestation of the disorder (Offord & Cross, 1971). Although in some individuals with ID the development of schizophrenia may be by chance, it seems that for others there may be direct and indirect links. Many believe that co-morbid ID and schizophrenia may often represent a severe form of schizophrenia with poorer outcomes (Doody et al., 1998b) and both arising from the same genetic etiology. The majority of studies of schizophrenia have excluded people with premorbid intellectual disabilities. It is important that further research occurs with those who are co-morbid with schizophrenia and intellectual disabilities. Studying schizophrenia in this particular subpopulation might not only improve diagnosis and treatment but also help to identify those with ID who go on to develop schizophrenia. It may also provide one important way forward in the understanding of schizophrenias in general.

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427.

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Velo-cardio-facial syndrome Wendy R. Kates1,2 and Wanda Fremont1 1 2

Department of Psychiatry and Behavioral Sciences Program in Neuroscience, State University of New York at Upstate Medical University, Syracuse, New York

Summary of findings Grade of evidence Epidemiology: Incidence of psychosis in VCFS is between 10% and 30%; no association between age, gender, IQ, or congenital anomalies and incidence of psychosis. Age of onset: Findings inconsistent. Mean age of onset ranges from 21 years (SD, 5 years) to 26 years (SD, 9 years). Presentation: Findings inconsistent. Some evidence that individuals with VCFS and psychosis have fewer negative symptoms than non-VCFS individuals with psychosis. Course and progression: Unknown. Suspected neuropathology: Enlarged ventricles, and volumetric reductions in posterior regions of the brain, particularly the parietal lobe and cerebellum. Alterations also noted in striatum and thalamus. Although findings are consistent with non-VCFS individuals with psychosis, direct comparisons between VCFS and non-VCFS individuals with psychosis are needed. Suspected neurochemical abnormalities: Unknown. Dopaminergic abnormalities are suspected. Genetic factors: Unknown; however, several genes in the 22q11.2 deleted region are expressed in brain tissue and implicated in psychosis, such as COMT and PRODH. Other risk factors: Unknown; hypothesized risk factors outlined in text. Treatment: Unknown.

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Introduction Velocardiofacial syndrome (VCFS) is a relatively common disorder that affects one in 4000 individuals (Ryan et al., 1997). Caused by a microdeletion on 218

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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chromosome 22q11.2, VCFS, also known as 22q11.2 Deletion Syndrome, is associated with a highly variable phenotype that can include palatal anomalies, conotruncal heart defects, hypocalcemia, velopharyngeal insufficiency, neurocognitive deficits, and behavioral disorders. Up to 30% of adolescents and adults with VCFS eventually develop a psychosis (Bassett et al., 1998; Murphy, Jones, & Owen, 1999), leading several investigators to characterize VCFS as a genetic-based subtype of schizophrenia (Bassett and Chow, 1999). Since the publication in 1992 of the initial report of an association between VCFS and psychosis (Shprintzen et al., 1992), the incidence, clinical phenotype, and molecular basis of psychosis in individuals who harbor this microdeletion has been the subject of increasingly intensive study. Epidemiology Although the behavioral phenotype of children with VCFS is well described (see below), relatively few studies have used structured psychiatric interviews from which specific psychiatric diagnoses can be derived. The few extant studies indicate that up to 45% of children with VCFS are diagnosed with attention deficit disorder, 28% with generalized anxiety disorder, 61% with phobias, between 11% and 33% with obsessive compulsive disorder, and between 18% and 30% with mood disorders (including ultrarapid cycling bipolar disorder with hallucinations) (Arnold et al., 2001; Feinstein et al., 2002; Goldberg et al., 1993; Gothelf et al., 2004; Papolos et al., 1996). There is some evidence, however, to suggest that the psychiatric prevalence rates of several of these disorders in children with VCFS do not differ significantly from cognitively matched samples (Feinstein et al., 2002). As children with VCFS have been followed into adolescence and adulthood, more evidence has emerged that indicates that these children are at increased risk of developing major psychiatric disorders. Higher rates of psychopathology have been reported in published studies; however, the rates differ with respect to the specific diagnosis reported. Several studies have reported an increased incidence of psychosis (10
30%) (Papolos et al., 1996; Pulver et al., 1994; Schwab and Widanhaner, 1999; Shprintzen et al., 1992). Murphy et al. (1999) reported a rate of 30% of psychotic disorders in adults with VCFS. The most common psychotic disorder was schizophrenia (24%) but high rates of schizotypy, a trait marker for schizophrenia were also noted. Additional studies of individuals with VCFS have reported an association between VCFS and schizophrenia (Bassett et al., 1998; Gothelf et al., 1997; Karayiorgou et al., 1995; Usiskin et al., 1999). Bassett and Chow (1999) report that the risk of schizophrenia for an individual with VCFS approaches 25 times the risk in the general population. No differences in age, sex,

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or IQ of individuals with VCFS with or without psychosis have been reported (Murphy et al., 1999). Moreover, no association has been found between occurrence of schizophrenia in VCFS and occurrence of congenital anomalies such as cardiac defects or cleft palate (Bassett et al., 2003; Murphy et al., 1999). Research studies have also been conducted to determine if there is an increased prevalence of chromosome 22q11 deletions in adult schizophrenic patients. Although the true prevalence of VCFS in schizophrenia is difficult to ascertain, the results of the literature indicate that the minimum prevalence rate is between 0.3
2% (Arinami et al., 2001; Bassett et al., 1998; Gothelf et al., 1997; Karayiorgou et al., 1995) as compared to a rate of 1% in the general population. A higher rate of chromosome 22q11 deletion (6%) has been reported in patients with early-onset schizophrenia (before the age of 13 years) (Usiskin et al., 1999). Karayiorgou and Gogos (2004) have suggested that ethnic differences may underlie the 22q11 schizophrenia susceptibility risk. They note that among adult patients, the lowest rate (0.3%) has been reported in a case sample from Japan (Arinami et al., 2001) and the highest rate of a sixfold to sevenfold increase was reported in two independent Caucasian samples (Karayiorgou et al., 1995; Wiehahn et al., 2004). A high prevalence of bipolar spectrum disorders, including bipolar I, bipolar II, and cyclothymia have been noted in adolescents and adults with VCFS. (Papolos et al., 1996). Increased rates of attention deficit disorder (36%), anxiety disorders including simple and social phobia (29%), and obsessive-compulsive disorder (14%) have also been reported in adults (Pulver et al., 1994). Age of onset and presentation The presentation and severity of behavioral, psychological, and cognitive difficulties in children and adults with VCFS varies considerably (Ryan et al., 1997). Although behavioral difficulties have been noted in most children with VCFS, problems may first present during early childhood (3
5), latency age (6
11), or adolescence (12
18). Learning difficulties have been reported in 82
100% of children (Swillen et al., 1999b). Studies using behavioral rating scales noted elevated scores on social problems, attentional problems, withdrawn, and thought problems scales (Heineman-De Boer et al., 1999; Swillen et al., 1999a). Children with VCFS have been described as overactive, impulsive, perseverative, emotionally labile, shy/withdrawn, or disinhibited (Gerdes et al., 1999; GoldingKushner, Weller, & Shprintzen, 1985; Swillen et al., 1999a). It is our experience that children with VCFS also have difficulties with time perception; however, empirical data is needed to substantiate this observation. Social problems are also common, most often involving peer difficulties (Swillen et al., 1997; 1999a).

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A cross-sectional study of children with VCFS (Swillen et al., 1999a) reported a trend that increased with age of more internalizing problem behaviors (withdrawn, somatic complaints, and anxious/depressed) than externalizing behavior (delinquent and aggressive). However, social problems, withdrawal, attention problems, and thought problems were consistently reported across the different age groups. As noted above, some of the behaviors observed in children with VCFS are not uncommon in children with developmental delays. Like patients with VCFS, children with developmental delays and learning disabilities have been reported to exhibit a higher rate of specific psychiatric disorders as well as overreactivity, attentional problems, impulsivity, low frustration tolerance, and perseveration (Beitchman et al., 1986; Beitchman and Young, 1997; Einfeld and Tonge, 1996; Feinstein and Reiss, 1996). Studies are needed, therefore, to differentiate behaviors that are primary psychiatric conditions from behaviors that are due to other risk factors associated with developmental and cognitive delays. Results of studies comparing the clinical phenotype of adults with VCFS and schizophrenia to that of schizophrenic adults without VCFS are not consistent (Bassett et al., 2003; Murphy et al., 1999). Murphy et al. (1999) found that the mean onset age of 26 years (SD, 9 years) for individuals with VCFS was older than individuals without VCFS (mean age: 19 years, SD: 4 years), and that patients with VCFS displayed fewer negative symptoms. In contrast, Bassett et al. (2003) found no differences in age of onset, occurrence of positive and negative symptoms, or severity of anxiety and depression. The discrepancy in these findings may be due to differences in ascertainment: whereas the sample of individuals with VCFS for the former study were recruited from genetics clinics, the sample for the latter study was drawn from individuals initially diagnosed with schizophrenia and later found to carry the 22q11.2 deletion. However, Bassett and coworkers also reported that individuals with VCFS and schizophrenia displayed higher levels of poor impulse control, uncooperativeness, and hostility than non-VCFS individuals with schizophrenia (Bassett et al., 2003), which is consistent with the emotional lability reported in a subset of children with VCFS.

Course and progression It is possible that some of the behaviors observed in childhood are prodromal features of more severe psychiatric illnesses. Research studies suggest that lateronset conditions may be causally connected with VCFS, including schizophrenia (Carlson et al., 1997; Pulver et al., 1994; Shprintzen et al., 1992), bipolar disorder (Papolos et al., 1996), and major depressive disorder (Murphy et al., 1999).

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Descriptions of psychosocial dysfunction that characterize children and adolescents at high risk for developing schizophrenia are consistent with descriptions of children with VCFS and include prominent anxiety and social withdrawal (Hans et al., 1999). Taken as a whole, the literature suggests that VCFS may be a genetic cause of schizophrenia. Further research is needed to determine the validity of an association between chromosome 22q11 deletions and schizophrenia and other psychiatric conditions. Moreover, longitudinal studies of children with VCFS are needed to identify prodromal symptoms and areas of dysfunction that precede the development of psychiatric disorders. Suspected neuropathology The increasingly widespread availability of non-invasive, high resolution MRI has led to an upsurge during the past decade of information about the developing and adult brain in VCFS. Several initial qualitative MRI studies (Chow et al., 1999; Mitnick, Bello, & Shprintzen, 1994) reported the presence of white matter hyperintensities, periventricular cysts, and reduced cerebellar vermi in the brains of individuals with VCFS. More recently, quantitative imaging studies have identified volumetric alterations in brain regions of children and adults with this disorder. Most of these studies are limited by small sample sizes, and vary in the composition of control groups, thus diluting the generalizability of anatomic imaging results. However, several consistent findings have emerged. Relative to typically developing children, patients with VCFS exhibit reductions of approximately 11% in total brain volume (Eliez et al., 2000; Kates et al., 2001). Volumetric studies have indicated that patients with VCFS exhibit alterations in both cortical and subcortical regions of interest. Subcortical regions that appear to be altered in patients with VCFS include the thalamus (Bish et al., 2004), posterior fossa (Eliez et al., 2002b), cerebellum (Eliez et al., 2000), and caudate nucleus (Eliez et al., 2002a; Kates et al., 2004). Volumetric studies of the morphology of the cerebral cortex in children with VCFS have consistently revealed reductions in parietal gray matter volumes (Eliez et al., 2000) and parietal and temporal white matter volumes (Kates et al., 2001). In contrast to posterior regions of the brain, generalized frontal lobe gray and white matter volumes do not appear to be reduced disproportionately to whole brain volume in children with VCFS relative to controls (Eliez et al., 2000; Kates et al., 2001; 2004). However, a recent diffusion tensor imaging study has demonstrated white matter alterations in axonal connections between the frontal and temporal lobes (Barnea-Goraly et al., 2003). In addition, the corpus callosum, comprised of white matter axonal processes that transmit information between cerebral

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hemispheres, appears to be increased in area (Antshel et al., 2005; Shashi et al., 2004; Simon et al., 2005) and displaced posteriorly in children with VCFS. Despite the absence of overall alterations in frontal cortex relative to whole brain volume, frontal
posterior, and inter-hemispheric connections may be disrupted. Due to the increased incidence of schizophrenia in adults with VCFS, the venues from which samples have been ascertained, and the relative unavailability of non-schizophrenic adults with VCFS, imaging studies of adults with VCFS vary in sample composition, limiting our ability to tease out which neuroanatomic alterations are due to VCFS, and which are specific to individuals comorbid for schizophrenia. Extant studies suggest that relative to healthy controls, individuals with VCFS with or without psychosis exhibit increases in ventricular cerebrospinal fluid (Chow et al., 2002; Van Amelsvoort et al., 2004a) and reductions in frontal white matter (Chow et al., 2002), frontal, parietal, and temporal gray matter (Chow et al., 2002; Van Amelsvoort et al., 2001; 2004a), and cerebellar tissue (Van Amelsvoort et al., 2004a). These findings are in agreement with results of imaging studies of children with VCFS without psychosis (Eliez et al., 2000; Kates et al., 2001), and to some extent to non-VCFS adults with psychosis. However, relative to individuals with VCFS without psychosis, individuals with VCFS and psychosis exhibit a generalized reduction in total tissue volume and total white matter volume coupled with selective increases in frontal gray matter volume (Van Amelsvoort et al., 2004a). This may suggest that whereas a generalized disturbance in brain development may increase vulnerability to psychosis in VCFS, alterations in the frontal lobe specifically may be a necessary precursor to the onset of schizophrenia (Van Amelsvoort et al., 2004a). One major caveat is that we do not have a comprehensive understanding of the trajectory of brain development in VCFS. Insofar as the psychiatric phenotype is developmental, we would expect the neuroanatomic underpinnings of that phenotype to be developmental as well. There is preliminary evidence that temporal lobe gray volume decreases with age during adolescence (Eliez et al., 2001). This is consistent with the findings of absolute reductions of temporal gray matter volumes in adults with VCFS (Chow et al., 2002; Van Amelsvoort et al., 2001) but not children with VCFS (although, as noted above, the sample composition of adult and child studies were different). Comprehensive longitudinal studies of children with VCFS, as well as direct comparisons between VCFS adults with psychosis and non-VCFS adults with psychosis, are essential to our understanding of the effect of brain development on neuropsychological function and risk for psychiatric disorder in individuals with this developmental disorder.

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Suspected neurochemical abnormalities The neurochemical abnormalities that increase vulnerability to psychosis in VCFS are not known. Due to the presence of the catechol-O-methyltransferase (COMT) gene at the q11.2 locus of chromosome 22, however, it is strongly suspected that dopaminergic pathways are altered in VCFS. The COMT gene encodes for an enzyme that regulates the degradation of synaptic dopamine levels and which mouse models suggest is expressed throughout brain development (Maynard et al., 2003). Since all individuals with VCFS are missing a single copy of the COMT gene, and therefore will be heterozygous for either the Met or Val allele at this locus, the availability of synaptic dopamine (or other catecholamine neurotransmitters) will most likely be altered (Lachman et al., 1996). We discuss the potential effect of this alteration in more detail below. Genetic factors Although the genetic mechanism that increases vulnerability to psychosis in VCFS is not known, several of the thirty genes that reside within the deleted region are expressed in brain tissue, and have been implicated in schizophrenia in the nonVCFS population (Bilder et al., 2002; Egan et al., 2001; Glatt, Faraone, & Tsuang, 2003; Jacquet et al., 2002; Karayiorgou & Gogos, 2004; Liu et al., 2002a; Matsumoto et al., 2003; Noal et al., 2004; Saito et al., 2003; Sanders et al., 2004; Shifman et al., 2002; Tunbridge et al., 2003; Wonodi et al., 2003). The genes at the 22q locus that are expressed in brain tissue vary according to effects on neurogenesis, migration, and synaptic stabilization (Maynard et al., 2003). Accordingly, the presence of only one copy of each of these genes most likely disrupts both development and function of neuronal circuits (Maynard et al., 2003). To the extent that schizophrenia is associated with alterations in both neural development and function, it seems likely that the alterations of multiple genes within this region converge and interact to produce susceptibility to schizophrenia (Maynard et al., 2003). As noted above, the catechol-O-methyltransferase (COMT) gene has been the subject of extensive investigation. Several functional polymorphisms of this gene, and their combined haplotypes (Bray et al., 2003; Shifman et al., 2002) have been investigated in relation to schizophrenia (Bilder et al., 2002; Egan et al., 2001; Glatt et al., 2003; Liu et al., 2002a; 2002b; 2004; Matsumoto et al., 2003; Shifman et al., 2002; Wonodi et al., 2003). The Val108/158Met polymorphism has been linked to risk for psychiatric disorder, performance on neuropsychological tasks of working memory and executive function, and prefrontal physiology (Akil et al., 2003; Egan et al., 2001; Matsumoto et al., 2003). However, the results of the studies

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investigating this polymorphism have been conflicting, as have the few investigations of the effect of this polymorphism on psychiatric and neurocognitive function in VCFS. Whereas one study found an association between the presence of the Met allele and psychiatric disorder in VCFS (Lachman et al., 1996), a second study found an association between presence of the Val allele and diminished performance on tasks of executive function (Bearden et al., 2004). This ambiguity could be due to the possibility that both alleles contribute to susceptibility to psychosis, depending on interaction with other allelic variants both within and beyond the deleted region (Karayiorgou & Gogos, 2004). It has been hypothesized that one mechanism by which the COMT gene confers susceptibility to schizophrenia is through its interaction with PRODH, a gene in the deleted region that encodes for proline dehydrogenase (Karayiorgou & Gogos, 2004). PRODH is expressed primarily in the adolescent mouse brain, during the stabilization of synaptic connections (Maynard et al., 2003), which appear to be compromised in schizophrenia (Freedman et al., 2001; Mirnics et al., 2001). The role of PRODH in schizophrenia susceptibility is supported by studies of linkage disequilibrium (Liu et al., 2002b; 2004) and genomic rearrangement (Jacquet et al., 2002). Support for the association between PRODH, which appears to modulate glutamatergic activity (Hoogendoorn et al., 2004; Karayiorgou & Gogos, 2004), and schizophrenia is strengthened by evidence that PRODH deficiency in mice is predictive of deficits in prepulse inhibition (Gogos et al., 1999), a deficit that has been described in individuals with schizophrenia (Light and Braff, 1999) and, recently, in non-schizophrenic children with VCFS (Sobin et al., 2005). To date, no investigations of allelic variation in the PRODH gene in VCFS have been reported. Several other genes within the 22q11.2 locus, including ZDHHC8 (Karayiorgou & Gogos, 2004; Liu et al., 2002a) and ARVCF (Sanders et al., 2004), are expressed in either developing or mature brain tissue and have also been implicated in schizophrenia independently of VCFS. Accordingly, it is likely that the heterozygous deletion of multiple genes at this locus is contributing, in complex and interacting patterns, to schizophrenia susceptibility in VCFS. The challenge of identifying the relative contribution of each of these genes to schizophrenia susceptibility has generated enormous interest among both VCFS and schizophrenia investigators, and we can expect significant progress during the next decade. Other risk factors Psychophysiological markers for psychosis have been explored to some extent in VCFS, but the data are sparse. As noted above, deficits in prepulse inhibition,

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which have been widely described in individuals with schizophrenia, have been identified in children with VCFS (Sobin et al., 2005). In addition, smooth pursuit eye tracking deficits, which consititute a fairly robust marker for schizophrenia, are found in a subset of children with VCFS (Kates, unpublished manuscript). Finally, the neurocognitive phenotype of children and adults with VCFS also overlaps with individuals with schizophrenia. Individuals with VCFS display deficits in executive function (Van Amelsvoort et al., 2004b; Woodin et al., 2000) and attention (Sobin et al., 2004; Van Amelsvoort et al., 2004b). The specificity and predictive validity of these markers, however, have not been established. Only longitudinal studies, currently in progress at several research sites, will elucidate the extent to which these are truly risk factors for psychosis in VCFS. Treatment No controlled treatment studies of psychosis in VCFS have been reported. However, the effects of pharmacologic interventions targeted at the COMT enzyme on neuropsychiatric symptoms in VCFS have recently been reported. In one report (Graf et al., 2001), open-label trials of metyrosine, which decreases catecholamine production, were conducted with five individuals with the 22q11.2 deletion and severe neuropsychiatric disorder. All of the individuals in this study were found to have the low-activity, Met allele, presumably resulting in higher levels of synaptic dopamine. Therapeutic levels of metyrosine were associated with moderate improvements in symptomatology in four of the five individuals. This study, coupled with a single-case report of similar findings (O’Hanlon et al., 2003), suggests that controlled studies of pharmacological agents that reduce catecholamine production are warranted with individuals who are comorbid for VCFS and psychosis. Conclusions Although investigations of the association between VCFS and psychosis have yielded much information, it is critical that we implement longitudinal studies that identify the risk factors for severe psychiatric disorder in individuals with this genetic disorder. Although the neuroanatomic, neurophysiological, and neuropsychological phenotype of individuals with VCFS overlap with those with schizophrenia, we do not know which aspects of that phenotype might serve as specific markers or risk factors for the onset of psychosis. Moreover, we do not have a good understanding of whether the behavioral phenotype during childhood increases the risk for the development of severe psychiatric disorder

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in adulthood. Longitudinal studies using structured psychiatric interviews will clarify the extent to which the psychiatric disorders in childhood constitute a prodrome for psychosis in adulthood. Moreover, comprehensive studies of genotype
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12

Psychosis in autism Angelina Kakooza-Mwesige1, Laura Stoppelbein2, and Dirk M. Dhossche2 1 2

Department of Pediatrics & Child Health, Makerere University Medical School, Kampala, Uganda Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi

Summary of findings Grade of Evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

C C C D D D D D D

Introduction Psychosis has carried different meanings since its introduction more than 150 years ago (Beer, 1996). Others have described the social and intellectual contexts that have shaped the concept of psychosis at different times and places (Berrios, 1987; Beer, 1995). Modern classification systems incorporate psychosis in various disorders as a serious disturbance in ‘‘reality testing’’ expressed as hallucinations, delusions, thought disturbance, disorganized behavior, or catatonia. Recent advances in neuroscience hold the promise of elucidating the brain mechanisms of psychosis and finding improved antipsychotic treatments. Fujii & Ahmed (2004) have recently proposed conceptualizing psychosis as a neurobiological syndrome with its own pathophysiology and treatment algorithm regardless of etiological factors and underlying diagnoses. This view has heuristic value 233

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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for refining current classification systems, focusing research, and tailoring treatments on an individual basis. In this chapter, we report on the characteristics of psychosis superimposed on autism. First, some definitions of autism are presented. In DSM-IV classification, autism covers the group of the Pervasive Developmental Disorders (PDDs) (American Psychiatric Association, 1994), i.e., Autistic Disorder, Asperger Disorder, Childhood Disintegrative Disorder, Rett’s Disorder, and Pervasive Developmental Disorder Not Otherwise Specified (PDD NOS). The PDDs are behavioral syndromes with a broad range of severity and characterized by lifelong impaired communication, impaired social interactions, and repetitive interests and behavior (Wing & Attwood, 1987; Rapin, 1997). DSM-IV diagnostic criteria of AD, AsD, and CDD, are shown in Table 12.1. PDD NOS is a residual category that is used to classify cases that do not satisfy full criteria of AD, AsD, or CDD. Rett’s Disorder is also listed among the PDDs. However, a causal genetic defect on the X chromosome has been identified

Table 12.1. DSM-IV criteria of selected Pervasive Developmental Disorders (PDDs).

Unique features Age of onset Development

Regression Abnormal communication* Shared features

Autistic Disorder (AD)

Asperger Disorder (AsD)

Onset before age 3 Clinically significant delay in language, cognitive development, self-help skills, adaptive behavior, or curiosity about the environment

No clinically significant delay in language, cognitive development, self-help skills, adaptive behavior, or curiosity about the environment No regression -

Regression in 30% þ

Childhood Disintegrative Disorder (CDD)

Onset before age 10 At least two years of apparently normal development

Massive regression þ

Qualitative impairment in social interaction (e.g. impairment in nonverbal behaviors, failure to develop peer relationships, impaired expression of pleasure in other people’s happiness, lack of social or emotional reciprocity) Restricted, repetitive, and stereotyped patterns of behavior, interests, and activities, including motor stereotypies and mannerisms

*qualitative impairments in communication (e.g. delay or lack of spoken language, inability to initiate or sustain a conversation, stereotyped and repetitive use of language, lack of varied make-believe play)

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(Amir et al., 1999). In this report, the PDDs, with the exclusion of Rett’s Disorder, are collectively referred to as autism. The prevalence of autism is 0.1
0.2% (Fombonne, 2003) for narrow diagnosis of autistic disorder and 0.6% for less restrictive diagnoses. Males predominate with approximately a four times higher rate than in females. Prevalence rates have been said to increase, but changes in diagnostic methodology and ascertainment strategy complicate comparisons across time (Fombonne, 2003). The diagnosis of autism is made clinically on the basis of behavioral symptoms that are not apparent until the ages of two to three, at least in classic autism (AD). Although medications can relieve symptoms in some autistic people, there is presently no known cure. The possibility that various metabolic and genetic factors may play a role in the occurrence of autism is a subject of intense research. About one third of autistic people develop some type of epilepsy (Gillberg, 1991b). Increased rates of seizure disorders (Deykin & MacMahon, 1979; Gillberg, 1991b) and worsening of autistic symptoms or overall behavioral deterioration (Gillberg & Schaumann, 1981; Gillberg, 1991a) have been reported around puberty. Cognitive deficits are present in more than half of autistic people (Rutter, 1983).

Epidemiology Reviewing psychosis in autism may appear a daunting task at first sight, or an easy one, depending on one’s perspective, because of the following issues. Leo Kanner separated autism from early-onset psychosis or childhood schizophrenia in 1943 by stating that the condition he described ‘‘differed markedly and uniquely from anything reported so far (Kanner, 1943).’’ Subsequent studies on childhood psychoses have highlighted differences in cardinal symptoms (e.g. absence of hallucinations in autistic children), course of illness, intellectual functioning, sex distribution, social class, brain abnormalities, age of onset, and family history of schizophrenia (Rutter, 1972). Studies support that autism and schizophrenia cannot often be diagnosed in the same patient (Volkmar & Cohen, 1991). Overall, the evidence seems overwhelming that psychosis does not occur often in people with autism justifying the separate classification of autism since DSM-III. However, there continues to be a provision in DSM-IV (American Psychiatric Association, 1994) that schizophrenia can be diagnosed in individuals with autism who develop characteristic features of schizophrenia with prominent delusions or hallucinations for one month. In the next paragraphs, those few studies that have assessed psychotic symptoms in autism will be reviewed. Modern criteria of psychosis and schizophrenia have been applied in a few reports of people with autism, especially of the high-functioning type, who

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develop chronic psychotic disorders similar to schizophrenia (Petty et al., 1984; Clarke et al., 1989; Kurita, 1999). Petty et al. (1984) described the development, by school age or early adolescence, of psychotic symptoms including hallucinations, delusions, and thought disorder satisfying formal criteria of schizophrenia in three children who had been diagnosed with autism during the first years of life. All three cases developed communicative speech and had borderline or normal IQ. The authors note that most autistic children do not develop communicative speech and have IQs in the mentally retarded range, precluding the assessment of hallucinatory experiences, paranoia, and thought disorder, and thus a formal diagnosis of schizophrenia or other psychotic disorder. Clarke et al. (1989) reported two adult cases with Asperger Disorder, one case with atypical autism (PDD NOS) and one case with classic autism, all developing superimposed affective and non-affective psychotic conditions. A fifth case was previously diagnosed with schizophrenia based on enduring obsessional behavior and withdrawal but was rather thought to have Asperger Disorder given the absence of hallucinations or delusions. The authors warn that PDDs may be complicated by psychotic illnesses presenting in adulthood. Conversely, PDDs may be mistaken for psychosis. Volkmar & Cohen (1991) conducted a chart review on 163 adolescents and adults with well documented histories of autism. About half of the patients were largely or entirely mute. DSM-III-R criteria for a lifetime diagnosis of schizophrenia were applied. Only one patient satisfied unequivocal criteria for schizophrenia, according to their assessments. Around 15 years of age, this male patient started complaining of auditory and occasional visual hallucinations. His speech became difficult to follow and he exhibited catatonia on at least one occasion. The patient had a strong family history of schizophrenia. Other patients had fluctuating bizarre interests and preoccupations that were considered part of autism. No other patients presented with hallucinatory experiences. The authors admit that hallucinations and delusions could not be assessed in the non-verbal patients. It was concluded that within the limitations of a chart review and inadequacy of DSM-III-R criteria of schizophrenia in nonverbal autistic populations, schizophrenia was not more common in autism than in the general population. There is also evidence that catatonia may be common in adolescents and young adults with autism (Dhossche et al., 2006b). Only two systematic studies of catatonia in autism have been reported (Wing & Shah, 2000; Billstedt, Gilberg & Gilberg, 2005). They suggest that catatonia-like features are present in about one of seven (12
17%) adolescents and young adults with autism and constitute an important source of impairment in this population. In a recent study, 17% of a large referred sample of adolescents and young adults with autism satisfied

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modern criteria for catatonia (Wing & Shah, 2000). Thirty persons with autism aged 15 or older met criteria for catatonia. Classic autistic disorder was diagnosed in 11 (37%), atypical autism in 5 (17%), and Asperger disorder in 14 (47%). None of those under the age of 15 had the full catatonic syndrome, although isolated catatonic symptoms were often observed. In the majority of cases, catatonic symptoms started between the ages of 10 and 19. Five individuals had brief episodes of slowness and freezing during childhood, before age 10. Schizophrenia was not diagnosed in any of these patients. In a report based on a population study (Billstedt et al., 2005), 13 (11%) of 120 autistic individuals between the ages of 17 and 40 (mean age 25.5 years) had clinically diagnosed catatonia with severe motor initiation problems. Another 4 had several catatonic symptoms but not the full syndrome. Autistic disorder was diagnosed in 8 of the 13 people with catatonia; atypical autism was diagnosed in the remaining 5. The proportion of those with autistic disorder in whom catatonia was diagnosed was 11% (8/73); 14% of those with atypical autism (5/35) had catatonia. An increasing number of case reports and case series of catatonia in autism that satisfy DSM criteria for catatonia have been published over the last 15 years (Realmuto & August, 1991; Dhossche, 1998; Ghaziuddin, Quinlan & Ghaziuddin, 2005; Dhossche et al., 2006b).There is considerable overlap of psychomotor symptoms between the two disorders, e.g. muteness, echolalia, stereotypical movements, and other psychomotor peculiarities (Stoppelbein, Greening & Kakooza, 2006). The progression of autistic symptoms into full-blown catatonia has been described in adolescent cases (Dhossche, 1998). Age of onset Hallucinations, delusions, and catatonia have only been described in post-pubertal patients with autism (Petty et al., 1984; Clarke et al., 1989; Realmuto & August, 1991; Dhossche, 1998; Kurita, 1999; Ghaziuddin et al., 2005). In the catatonia study of Wing & Shah (2000), all of those with catatonia were aged 15 or older. None of those under age 15 had the full syndrome although isolated catatonic symptoms were often observed. In the majority of cases, catatonic symptoms started between 10 and 19 years of age. Five individuals had brief episodes of slowness and freezing during childhood, before age 10. Presentation Autistic people can develop typical symptoms of psychosis, including hallucinations, delusions, thought disorder, and catatonia. Reliance on self-report is

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problematic given the cognitive and verbal deficits in this population. A comprehensive clinical psychiatric evaluation should be conducted to diagnose any type of psychosis in people with developmental disorder. There are no widely accepted standardized diagnostic interviews for psychotic disorders in autism or mental retardation, to our knowledge. It is unknown if current catatonia rating scales are applicable in people with autism. Modified criteria for catatonia in autism allowing for baseline levels of stereotypies, echolalia, and other catatonic symptoms have recently been published (Dhossche, Shah & Wing, 2006a), but these need further testing. High rates of atypical symptoms of psychosis or negative symptoms in autistic people have been reported, but their significance is often unclear. It is unknown if such individuals are prone to develop psychosis or if those symptoms are more related to autism or the frequently associated cognitive deficits. Next, we will review three studies that have directly compared individuals with autism and schizophrenia. Future studies are warranted to show the significance of these findings. Rumsey, Andreasen, & Rapoport (1986) examined 14 adults with DSM-III diagnoses of autism (mostly high-functioning) and used comparison groups diagnosed with schizophrenia and mania. Autistic individuals had a high incidence and severity of poverty of speech, poverty of speech content, perseveration, and affective flattening. They showed significantly less derailment, illogicality, and ‘‘positive thought disorder’’ than schizophrenic or manic patients did. Deficit symptoms, such as negative thought disorder and affective flattening, were similar between autistic and schizophrenic patients. In another study (Dykens, Volkmar & Glick, 1991), thought disorder was assessed in 11 high-functioning autistic young adults utilizing objective ratings and projective tests. Autistic adults showed more poverty of speech than schizophrenic individuals did. No illogicality was manifest in any of the autistic subjects. On the Rorschach’s Schizophrenia Index, no differences were found between autistic and schizophrenic groups suggesting a high incidence of poor reality testing, compromised perceptual accuracy, perceptual distortions, and cognitive slippage in both groups, at least during tests of freeassociation to stimuli. The authors interpret their findings as evidence of shared features of thought disorder between autism and schizophrenia, but confirm that the presence of similar features does not imply continuity of the disorders. Finally, symptoms of 14 males with DSM-III-R autism and 14 males with DSMIII-R paranoid schizophrenia were compared in a recent study (Konstantareas & Hewitt, 2001). Instruments for diagnosis and assessment included a structured clinical interview, a schedule for positive symptoms, and a schedule for

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negative symptoms. None of the men with paranoid schizophrenia met criteria for autism. Seven of those with autism met criteria for schizophrenia, disorganized type, with mainly negative symptoms (affect flattening, alogia, attentional difficulties). Although many subjects with autism made statements that could be interpreted as delusional (‘‘people pick on me’’) or grandiose (‘‘I am the smartest guy around’’), these were not seen as psychotic since they could be explained reasonably by living environment and/or cognitive/emotional immaturity. Course and progression Longitudinal studies of psychosis or catatonia in autism providing information on clinical risk factors and prodromal signs are not available in the literature. In the case reports that were discussed earlier, the psychotic disorder seemed stable and chronic. Larger studies are needed to confirm this. In the study of Wing & Shah (2000), obsessive-compulsive and aggressive behavior preceded catatonia in some. Visual hallucinations or paranoid ideas were occasionally reported, but no diagnosis of schizophrenia could be made. Referred patients with catatonia were significantly more likely than patients without catatonia to have had impaired language and passivity in social interaction before the onset of catatonia. Suspected neuropathology The biological basis of autism and psychosis remains unknown. There are no published accounts of neuropathological findings of psychosis in autism. Developmental processes have been recognized as key to understanding autism (Belmonte et al., 2004). Involvement of different brain areas is widespread and includes the cerebellum, brain stem, frontal lobes, parietal lobes, hippocampus, and amygdale (Palmen et al., 2004). There have been a few attempts to describe a coherent anatomical or pathophysiological theory of autism. There is some variability between those hypotheses depending on whether the authors considered social, cognitive, or affective abnormalities as the primary deficit in autism. For example, Maurer and Damasio (1982) using anatomical and etiological inferences based on a wide range of autistic symptoms concluded that dysfunction of phylogenetically older parts of the frontal and temporal lobes best accounted for the clinical manifestations of autism. Gualtieri (1991) on the other hand noted similarities between autism and the Klu¨ver-Bucy syndrome, a syndrome described in rhesus monkeys after bilateral temporal lobectomies. This suggested to him that deep temporal and frontal lobes may be involved.

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Of some interest is the role of the cerebellum in autism and psychosis. One of the most consistent findings in autism is the selective vulnerability of the cerebellar Purkinje cell (Ritvo et al., 1986; Kemper & Bauman, 1993). Nine brains from patients with well documented autism (six children and three young adult males) have been studied systematically (Bauman, Filipek & Kemper, 1997). All brains showed a marked reduction of Purkinje cells and a variable decrease in granular cells throughout the cerebellar hemispheres. There was no significant gliosis and no retrograde of inferior olivary neurons, suggesting that the abnormalities were acquired early in development at or before the 30th week of gestation. The cerebellum remains an understudied yet important area in both disorders. Evidence for cerebellar involvement in psychosis is limited to imaging studies given the limited number of neuro-anatomical studies. Reductions in cerebellar volume have been reported in chronic schizophrenia (Okugawa, Sedvall & Agartz, 2003), catatonic schizophrenia (Joseph, Anderson & O’ Leary, 1985; Wilcox, 1991), and autism (Courchesne et al., 1988).

Suspected neurochemical abnormalities Neurochemical studies have not been done in people with comorbid autism and psychosis (or catatonia). It is possible that some abnormalities in metabolism of serotonin, dopamine, GABA, and other transmitter molecules are shared between autism and psychosis (and catatonia). However, further speculations are futile at this stage.

Genetic factors Although a medical or neurological disorder is found in a small proportion of cases with autism, most cases are idiopathic. In those cases, a strong genetic component is likely but the pattern of inheritance is complex. Twin studies show a 60
91% concordance rate in monozygotic twins, depending on whether a narrow or broad phenotype is considered. There are no observations of concordance in dizygotic twins under narrow phenotypic definition and a low concordance (10%) under broader phenotypic definition (Bailey et al., 1995). Sibling recurrence rate has been estimated to be 4.5%. This pattern of sharply increasing risk for first-degree relatives and monozygotic twins relative to the population prevalence does not fit a simple dominant or recessive model, but indicates the involvement of multiple genes interacting with one another to lead to disease susceptibility. No definite susceptibility genes for autism have been discovered, despite the encouraging possibility of candidate regions on chromosomes. Molecular genetic

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studies have narrowed down certain candidate regions, with two regions being identified in several (but not all) studies. These are 15q11-13, near the GABAAb3 receptor subunit gene (GABRB3) and a second one on 17q11.2, near the serotonin transporter gene (SLC6A4) (Veenstra-Vanderweele, Christian & Cook, 2004). There are also a few studies that suggest that there are shared genetic risk factors between autism and certain types of psychosis. First, DeLong (1994) found increased rates of affective disorder, particularly bipolar disorder, in family members of autistic probands. In a sample of 40 autistic children and adolescents, without neurological disease, from 37 families, he reported a family history for bipolar disorder in 29 (78%) families. In another family study (Piven et al., 1991), the rate of major depressive disorders was higher in parents of autistic probands than in parents of non-autistic probands. Second, parental schizophrenia-like psychosis and affective disorder were significant risk factors for autism in offspring in a nationwide Danish case-control study of 698 children diagnosed with autism between 1972
1999 (Larsson et al., 2005). Relative risks were 3.44, 95% CI 1.48
7.95 and 2.91, 95% CI 1.65
5.14, for parental schizophrenia-like disorder and affective disorder respectively. Other significant variables were breech presentation (RR ¼ 1.63), low Apgar score at 5 minutes (RR ¼ 1.89), and gestational age at birth less than 35 weeks (RR ¼ 2.45). Weight for gestational age, parity, number of antenatal visits, parental age, or socioeconomic status were not significant risk factors. These findings support that perinatal factors and parental psychopathology are associated with risk of autism. It remains an open question whether perinatal adversity was due to environmental factors, factors associated with autism in the fetus, or a combination of these and possibly other (unmeasured) variables. Finally, it has also been noted that about 40% of children with onset of schizophrenia before age 10 had symptoms of autism during infancy and early childhood (Watkins, Asarnow & Tanguay, 1988). In a sample of children with childhood-onset schizophrenia (COS) (before their 13th birthday), 19 of 75 (25%) of children with COS had a lifetime diagnosis of PDD (Sporn et al., 2004). Two siblings of children with COS were diagnosed with classic autism (AD). This suggests a familial link between certain types of autism and childhood-onset schizophrenia. Future family psychiatric studies assessing psychotic disorders, including catatonic subtypes, as risk factors for autism are warranted. Previous studies have typically not separated out catatonic subtypes of schizophrenia, affective disorder, or other psychotic disorders. The only genome scan reporting on catatonic schizophrenia gave a linkage signal in the region 15q11.2-q21.1

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(Sto¨ber et al., 2000). This region has also been linked with autism (Cook et al., 1998; Menold et al., 2001; Nurmi et al., 2003) and bipolar disorder (Papadimitriou et al., 1998; Otani et al., 2005). Finding shared genes for autism, catatonia, and bipolar disorder would support the hypothesis of common biological pathways between these disorders. GABA receptor subunit genes located on 15q11-13 warrant special attention as candidate shared genes (Dhossche, 2004).

Other risk factors It is conceivable that other risk factors such as adverse life events or medical/ neurological illnesses may precipitate psychosis in some individuals with autism as in individuals without autism or any other developmental disorder. However, there are no systematic studies in this area. The clinician evaluating a possible psychotic episode should inquire about sudden psychosocial changes or adverse events, and rule out medical/neurological illnesses associated with psychosis. Treatment There are no controlled trials of psychosis or catatonia in autism in the literature. However, it is reasonable to treat the autistic patient with current antipsychotic treatment once a diagnosis of psychosis is made. This reflects the practice of using the primary treatments for hyperactivity, aggression, anxiety, and obsessive features in people with autism and other developmental disorders. Atypical antipsychotics, especially risperidone (Hardan et al., 1996; Shea et al., 2004), also seem useful in decreasing the overall level of behavioral and emotional disturbance in autism. There are a handful of case reports of autistic patients diagnosed with a catatonia with a positive response to benzodiazepines (Dhossche & Bouman, 1997; Dhossche, 1998) and ECT (Zaw et al., 1999; Ghaziuddin et al., 2005; Fink, Taylor & Ghaziuddin, 2006). These treatments have shown efficacy in catatonic patients without autism (Fink & Taylor, 2003). Firm conclusions about the efficacy of these treatments in autistic patients with catatonia must await future controlled trials (Dhossche et al., 2006a). Acknowledgements Research support from the Thrasher Research Fund, Salt Lake City, Utah, is gratefully acknowledged.

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5.

Part V

Central Nervous System Disorders

13

Psychotic disorder due to traumatic brain injury Daryl E. Fujii1, Nikki Panasci Armstrong2, and Iqbal Ahmed3 1 2 3

Department of Neuropsychology, Hawaii State Hospital Department of Psychology, University of Hawaii at Manoa Department of Psychiatry, John A. Burns School of Medicine, University of Hawaii at Manoa

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B B B B B C C B C

Introduction Psychotic disorder due to traumatic brain injury (PDDTBI) is a relatively rare disorder that is in the nascent stage of being understood. Despite the paucity of empirical investigations on PDDTBI in the literature, this disorder has the potential to provide clues for understanding schizophrenia and psychosis in general. The purpose of this chapter is to outline existing knowledge on PDDTBI and to examine a possible link between traumatic brain injury (TBI) and psychosis. The literature on PDDTBI is summarized, with the goal of elucidating different aspects of the syndrome, including epidemiological issues, clinical presentation, course and latency of onset, suspected neuropathology, genetic and environmental risk factors, and treatment. The chapter concludes with a proposed model describing the relationship between TBI and psychosis, as well as potential 249

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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mechanisms accounting for latency between sustaining TBI and the onset of psychosis. Epidemiology Recent data estimate that the annual incidence rate of TBI ranges from 100 to 444 per year (Jager et al., 2000; National Institute of Health, 1999), while psychiatric disorders, in general, have been reported to develop in approximately half the people sustaining moderate to severe traumatic brain injury (Fann et al., 2004; Koponen et al., 2002). The most common psychiatric sequelae of TBI are depression (44.3%), post-traumatic stress disorder (14.1%), substance abuse (13%), panic disorder (9.2%), generalized anxiety disorder (9.1%), and obsessive compulsive disorder (6.4%) (Van Reckum, Cohen, & Wong, 2000). Incidence rates of psychotic disorder due to traumatic brain injury (PDDTBI) have ranged from 0.7
8.9% among individuals who sustain TBI (Davison & Bagley, 1969; Fann et al., 2004; Koponen et al., 2002), making it a relatively uncommon, but fascinating psychiatric condition related to TBI. Severity of injury, as measured by duration of loss of consciousness (LOC) and post-traumatic amnesia, varied from mild to severe (Achte, Hillbom, & Aalberg, 1969; Achte et al., 1991; Fujii & Ahmed, 2001; 2002a; Fujii, Ahmed, & Hishinuma, 2004; Sachdev, Smith, & Cathcart, 2001). Although some studies reported the majority of patients who develop PDDTBI sustained a moderate to severe head injury (Achte et al., 1969; Davison & Bagley, 1969; Fujii & Ahmed, 1996; Sabhesan, Arumughan, & Natarajan, 1990), PDDTBI has occurred in patients with mild TBI, including those without loss of consciousness (Fujii & Ahmed, 2002a). Thus, studies examining which severity is most highly associated with PDDTBI remain inconsistent, with one study reporting no relationship (Violin & De Mol, 1987). Despite the seemingly rare occurrence of PDDTBI, it has been suggested that diagnostic issues related to conceptualization of the disorder may contribute to an underestimation of PDDTBI prevalence (Ahmed & Fujii, 1998; Fujii & Ahmed, 2002a). Specifically, Ahmed and Fujii (1998) argue that establishing psychosis as a direct physiological consequence of TBI and determining that the psychosis is not due to another medical condition are both aspects of PDDTBI criteria that can lead to diagnostic difficulties for clinicians. Evidence for the failure to consider TBI as contributory to psychiatric illness supports this assertion. For instance, many patients with psychotic disorders, such as schizophrenia, have sustained TBI (Davison & Bagley, 1969), with one study reporting that 67% of patients sustained TBI within one year of admission to an acute psychiatric hospital, yet TBI documentation was absent in

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the patients’ charts (Burg et al., 1996). Additional studies report that patients who meet DSM-IV (American Psychiatric Association, 1994) criteria for Psychotic Disorder Due to a General Medical Condition, including TBI, typically receive diagnoses of schizophrenia spectrum disorders (Feinstein & Ron, 1990; Fujii & Ahmed, 1996; 2002a). Age of onset A high level of variability exists in the age of onset for PDDTBI. The mean onset reported in most studies is between the mid-20s and mid-30s, with standard deviations as large as 10.2 to 15.4 years (Achte et al., 1969; 1991; Fujii & Ahmed, 2001; 2002a; Sachdev et al., 2001). Although one study that examined war veterans with head injury reported a high percentage of schizophrenic psychosis (56.5%) occurring prior to age 20, such early-onset cases appear to be relatively uncommon and may be associated with a more severe presentation of psychosis (Davison & Bagley, 1969). Presentation Among PDDTBI patients, persecutory delusions are reportedly present in up to 22
80% of all patients (Achte et al., 1969; 1991; Davison & Bagley, 1969; Fujii & Ahmed, 2001; 2002a; Sachdev et al., 2001; Violin & De Mol, 1987) and are ranked first in the majority of studies (Fujii & Ahmed, 2002b), making this delusional subtype the most common psychotic symptom of PDDTBI. Auditory hallucinations are highly prevalent, as well, occurring in 60
93% of all PDDTBI patients (Achte et al., 1969; 1991; Fujii & Ahmed, 2001; 2002b; Sachdev et al., 2001). Although much less common, visual hallucinations (8
32%), negative symptoms (15
22.2%), grandiose delusions (15
20%), somatic delusions (15%), and formal thought disorder (4.4%) have also been reported (Fujii & Ahmed, 2002a; Sachdev et al., 2001). Additionally, intriguing results of one study indicated that experiential factors of substance abuse and sexual disorders were associated with delusions of jealousy and infidelity (Achte et al., 1991). The percentages of seizure disorders among non-psychotic TBI patients is much lower than those observed in PDDTBI patients, suggesting that seizure disorder, particularly temporal lobe epilepsy, is another common sequela of PDDTBI (Lishman, 1997). One study of World War II Finnish soldiers reported that post-traumatic epilepsy occurred more frequently in patients with psychosis than in those without (57.7% vs. 31.8%) (Achte et al., 1969). More recent studies indicate the percentage of seizure-related psychosis in PDDTBI patients ranges

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from 9
34% (Fujii & Ahmed, 2002a; Sachdev et al., 2001); although rates of co-occurrence have reached as high as 67
70% when PDDTBI patients with positive temporal lobe EEG findings, but without a documented history of seizure disorder, have been included in estimation procedures (Achte et al., 1969; Fujii & Ahmed, 1996; 2001; 2002a). Neuropsychological impairments have also been documented in the literature. Specifically, memory and executive functioning deficiencies have been the most consistent finding among PDDTBI patients (Fujii & Ahmed, 2002a; Fujii et al., 2004; Sachdev et al., 2001). Functional deficits in visuospatial and vocabulary domains have been less frequently reported in PDDTBI studies (Fujii & Ahmed, 2002; Fujii et al., 2004).

Course and progression The high variability in latency between TBI and onset of psychotic symptoms is an issue that has continued to challenge researchers when determining the etiological significance of TBI to the development of psychosis. Although the mean latency is four to five years (Achte et al., 1991), the range of documented latencies has spanned as wide as two days to 48 years (Achte et al., 1969); hence, the emergence of psychosis can often be unexpected and bewildering, and can raise doubts about the contributory factor of TBI to the emergence of psychosis. Despite this broad range of latencies, evidence suggests that the modal onset of psychosis lies within the initial two years post-TBI (Fujii & Ahmed, 2002a). For example, one exploration of case studies in the literature reported a highly skewed distribution of latencies that extended up to 34 years, with 38% of patients demonstrating psychotic symptoms within one year of TBI, approximately half of the patients exhibiting symptoms before the second year, and 72% within four years (Fujii & Ahmed, 2002a). Similarly, other researchers reported that roughly 73% of TBI patients experienced psychotic symptoms within five years post-injury (Davison & Bagley, 1969). Further, a study of HMO patients sustaining TBI suggested an increased prevalence of psychotic symptoms from the first to second years post-injury for those with moderate to severe brain injuries (Fann et al., 2004). Although most studies indicate the majority of PDDTBI patients demonstrate symptoms within two years of sustaining injury, one longitudinal study following TBI patients for 30 years suggested a bimodal distribution of onset may exist. Specifically, half of the patients developed psychosis within one year of sustaining a TBI, while the other half developed psychotic symptoms no earlier than 10 years post-injury (Koponen et al., 2002).

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There is some evidence suggesting that differences in onset of psychosis following TBI may be related to type of head injury (e.g., mild vs. moderate/severe; open vs. closed). For example, Fujii and Ahmed (2002a) found that patients experiencing a brief delay between TBI and onset of psychosis (i.e., one year and less) had more mild brain injury as opposed to moderate/severe TBI. Additionally, a previous meta-analysis of the literature reported that most closed head injury patients (52%) demonstrated psychotic symptoms within one year post-injury, and 85% of closed head injury patients exhibited symptoms within five years of TBI (Davison & Bagley, 1969). Similarly, another study with predominantly closed head injury patients reported a mean onset of 5.9 years (Fujii & Ahmed, 1996). By contrast, two studies consisting of World War II veterans with 98.9% sustaining splinter or gunshot wounds report longer latencies. More specifically, one of the studies reported that 60% of patients had latencies of more than five years, while the other indicated a majority of delusional psychoses occurred between 15 and 19 years post-TBI (Achte et al., 1969; 1991). Some evidence indicates that duration of latencies may be associated with different characteristics of TBI or psychosis and therefore may have clinical significance. In particular, people with shorter latencies (i.e., within one year of initial insult) are more likely to have sustained diffuse brain injuries (Davison & Bagley, 1969) and experience visual hallucinations (Fujii & Ahmed, 2002). Additionally, a longitudinal study of Finnish soldiers sustaining missile wounds found that paranoid schizophrenia was common (23%) in cases with short latencies, while delusional disorder was quite rare (4%) in the early-onset cases (Achte et al., 1969; 1991). Conversely, longer latencies have been related to localized temporal lobe damage (Davison & Bagley, 1969), the presence of epilepsy (Davison & Bagley, 1969), and the development of delusional disorder (Achte et al., 1969; 1991). To date, only one study has described prodromal symptoms of PDDTBI (Sachdev et al., 2001). In this study, about half of the patients demonstrated bizarre behaviors, while roughly a third displayed antisocial behaviors, affective instability, and academic or vocational deterioration, and approximately a fifth of the patients exhibited social withdrawal after TBI but before the onset of PDDTBI (Sachdev et al., 2001). The course of illness for PDDTBI patients appears to be highly variable, with both relatively brief and chronic courses reported in the literature. Fujii & Ahmed (2002a) described the course of illness for 25 cases in the existing literature, of which 64% were reported to be improved, 28% reported no improvement, and 8% experienced a progressive worsening of symptoms. Other investigators have associated chronicity with premorbid schizoid personality (Davison & Bagley, 1969). Moreover, individuals who acquire schizophrenic-like psychosis following

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TBI are more likely to demonstrate a chronic course of illness (63%) than those who develop delusional disorder (40%) (Achte et al., 1969; 1991). Suspected neuropathology Despite differences in populations and data collection methods, which have included EEG, lesion location, and imaging techniques, studies have consistently implicated the temporal regions of the brain in the neuropathology of PDDTBI. Although with less consistency, structural damage to the frontal lobes has been reported as well. Specifically, four of five studies with localization data reported predominantly temporal lobe damage on CT or MRI scans, with rates of positive findings ranging from 20.4
39% (Achte et al., 1969; Davison & Bagley, 1969; Sachdev et al., 2001; Violin & De Mol, 1987). The fifth study reported a preponderance of temporal lobe abnormalities (70%) on EEG (Fujii & Ahmed, 2002a). Frontal lobes abnormalities were observed in two of the five studies, with rates ranging from 23.8
42% (Achte et al., 1969; Fujii & Ahmed, 2002a). Findings for hemispheric laterality of lesions remain inconsistent (Fujii & Ahmed, 2002a).

Suspected neurochemical abnormalities There have been no studies directly evaluating neurochemical abnormalities in PDDTBI. Abnormalities in the dopaminergic system have been indirectly implicated as a descriptive study of case studies in the literature reported that neuroleptics were the most efficacious treatment for PDDTBI (Fujii & Ahmed, 2002a).

Genetic factors Research on possible genetic determinants of PDDTBI has been quite limited; however, some biological risk factors have been reported. Male gender is the most commonly cited risk factor for developing PDDTBI (Fujii & Ahmed, 2001). Although there was a definite selection bias in earlier war veteran studies (Achte et al., 1969; 1991), males have been overwhelmingly represented in studies procuring samples from general clinical populations as well, with numbers ranging from 78
100% (Fujii & Ahmed, 2001; 2002a; 2000b; Fujii et al., 2004; Sachdev et al., 2001). Some evidence suggests that a family history of psychotic illness may be a risk factor for PDDTBI. In particular, a family history of schizophrenia was reported

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in 2.9
18% of patients with PDDTBI, which appears to be intermediate between higher incidence rates among patients with schizophrenia and lower rates documented in normal controls (Davison & Bagley, 1969). Mental retardation has also been reported as a potential risk factor for PDDTBI development (Achte et al., 1969). Other risk factors Environmental risk factors for PDDTBI have been noted in the literature. In one study (Fujii & Ahmed, 2001), investigators found that an early TBI, neurological, neurodevelopmental, or learning disorder was a significant risk factor for persons developing PDDTBI after a second TBI, most often occurring in late adolescence or early adulthood. Other risk factors include substance abuse (Nasrallah, 1992) and previous psychological disturbances (Violin & De Mol, 1987). These environmental factors, taken together with genetic risk factors, would suggest that persons developing psychosis post-TBI may have had a previously abnormal or vulnerable brain (Fujii & Ahmed, 2001). Treatment The treatment responsiveness of patients with PDDTBI appears to be highly variable (Fujii, 2002). The most widely used and most efficacious treatments, to date, have been neuroleptics, followed by anticonvulsants and lithium (Fujii & Ahmed, 2002a). Proposed considerations for selection of anti-psychotic medication include the increased sensitivity of the brain-injured patient to the sedating, anti-cholinergic, and seizure threshold-lowering side effects (Ahmed & Fujii, 1998). For example, chlorpromazine has been reported to produce a delusional state, along with cognitive decline (Sandel, Olive, & Rader, 1993). We recommend several pharmacological strategies to treat PDDTBI. Atypical anti-psychotics, such as risperidone, olanzapine, or quetiapine, are recommended for acute or chronic psychotic symptoms associated with TBI, starting at low doses to reduce the risk of side effects. Psychotic agitation may also be acutely managed with parental haloperidol. Benzodiazepines, such as lorazepam or diazepam, should be considered for acute management if seizure activity is thought to be a risk. For acutely psychotic patients who are suspected of having seizure activity, anti-convulsants, such as valproic acid with or without benzodiazepines, are recommended. Anti-convulsants are also recommended for treating symptoms like mood lability, irritability, impulsivity, or affective aggression, and for patients with chronic psychosis who demonstrate EEG abnormalities, such as temporal dysrhythmias.

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Conclusions In summary, PDDTBI is a disorder that has not received much attention from researchers until recently. The sparse and generally descriptive nature of the literature demands large-scale, prospective, longitudinal studies to better illuminate our understanding of the relationship between TBI and psychosis. Thus far, results from studies using diverse populations and methodologies suggest that PDDTBI can result from brain injuries of varying severity, including mild TBI. The clinical presentation of most PDDTBI patients includes persecutory delusions and auditory hallucinations, although negative symptoms, visual hallucinations, thought disorder, and other forms of delusions have been reported in some patients. Studies have consistently implicated lesions to the temporal and frontal lobes in PDDTBI, with deficits to memory and executive functions being the most common neuropsychological impairments. The course and progression of PDDTBI appears to be highly variable. The latency between sustaining TBI and the onset of psychosis has ranged from a few days to 48 years, with the modal onset falling within two years post-injury. Although the distribution seems to be positively skewed, a bi-modal distribution may exist. Some evidence suggests that the duration of latencies may be of clinical importance. Specifically, longer latencies have been associated with temporal lobe pathology, presence of epilepsy, and delusional disorders, while shorter latencies have been associated with diffuse damage, schizophrenia-like psychosis, and visual hallucinations. In terms of treatment, neuroleptics appear to be the most efficacious medications, followed by anti-convulsants and lithium. We conclude with a classification scheme for PDDTBI (Fujii & Ahmed, 2002b) that was adapted from Lishman’s (1997) description of the possible relationships between TBI and psychotic disorder. This conceptual framework is based on the assumption that psychosis is a neurocognitive behavioral syndrome that results from sufficient damage to frontal and temporal structures and the dysregulation of the dopamine system (Fujii & Ahmed, 2002b). Tenets of this framework are presented in Table 13.1. The model of PDDTBI is followed by a discussion on potential explanations for long latencies between TBI and the onset of psychosis. TBI can be the primary cause of psychosis

In this category, psychosis development is directly caused by the TBI. In these cases, there is no family history of schizophrenia and low or no genetic risk for psychosis. TBI sustained in early life appears to be a risk factor for this type of patient (Fujii & Ahmed, 2001).

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1. TBI can be the primary cause of psychosis. 2. TBI can contribute to the development of psychosis through: a. inducing secondary epilepsy which results in a psychosis b. increasing biological vulnerability so that future damage or changes to frontal or temporal structures or the dopamine system will trigger a psychosis c. inducing physiological and psychological changes that render the individual more vulnerable to stress d. triggering a psychotic episode in those who are biologically predisposed. 3. TBI may be unrelated to the development of a psychosis.

TBI can contribute to the development of a psychosis

In the second category, TBI can contribute to the development of psychosis in four ways. One way this can occur is the development of a seizure disorder that in turn generates the development of a psychosis. As mentioned previously, the relationship between seizure disorder and psychotic disorder is well established and seizure disorder is a common sequela of TBI. In addition, while there may not be frank seizure activity seen clinically or on EEG, mechanisms that can lead to seizures, such as kindling, may still be ongoing and eventually can result in the development of psychosis (Kraus, 2000). The second manner that TBI may contribute to the development of a psychosis is to increase biological vulnerability or risk. Vulnerability can be increased by damage to frontal and temporal structures, and subsequent dysregulation of the dopamine system. These structures have been implicated in schizophrenia and other disorders associated with secondary psychosis. Damage to these structures from TBI will render the person vulnerable to develop a psychosis with additional damage or changes to these areas. Psychosis results when a threshold of damage to temporal/frontal structures is reached. In addition to direct structural damage, the sequelae of TBI, such as cognitive deficits, behavioral dyscontrol, and emotional distress (Gualteri & Cox, 1991), can contribute to risk by increasing the individual’s psychological vulnerability to stress. A reduction in coping skills would render one vulnerable to stress that is associated with increases in dopamine release (Roth et al., 1988). Reduced coping abilities may also foster behaviors that would increase the risk for psychosis, such as substance abuse and damage from further TBI. Traumatic brain injury can also contribute to the development of a psychosis by triggering a psychotic episode in patients who have biological risk. In such cases, an individual would already have significant vulnerability to develop

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a psychosis due to frontal and temporal lobe abnormalities. The TBI would raise the person above the threshold for psychosis. For these patients, the development of psychosis may have been inevitable with additional damage or changes, and even mild TBI could trigger a psychosis. Conversely, it is also possible that they may never develop a psychosis if good health is maintained. These four proposed subcategories for how TBI contributes to the development of a psychosis are not mutually exclusive. Hence, these subcategories should be conceptualized as illustrations of different ways that TBI can contribute to meeting the threshold for psychosis. TBI may be unrelated to the development of a psychosis

In the final category, the episode of TBI and the onset of psychosis are unrelated. Simply, the TBI does not cause or contribute to psychosis development. However, the TBI may exacerbate cognitive deficits or the severity and treatability of the psychotic condition. In such cases, there is probably a high genetic loading for schizophrenia, the TBI is very mild without loss of consciousness, or the TBI is sustained after the onset of psychotic symptoms. Explanations for latencies in onset of PDDTBI

As previously discussed, psychosis results when a threshold of damage to temporal and frontal regions is reached. These structural changes cause a dysregulation of neurochemical systems, such as dopamine, glutamate, and GABA, which in turn impairs a person’s ability to perceive and respond to internal and external stimuli (Benson & Stuss, 1990; Cummings, 1992; Selemon & Goldman-Rakic, 1999). In cases of PDDTBI, we agree with Gualteri and Cox (1991) that TBI instigates a pathophysiological process that results in neurochemical dysregulation and ultimately psychosis. It is plausible that TBI can trigger multiple processes that can contribute to the development of psychosis. Given the reported latencies between TBI and the onset of psychosis, it is likely that these processes generally take between one to five years. Several possible contributory mechanisms to developing a psychosis include kindling or sensitization, and to a lesser extent, apoptosis or excitotoxic damage. For instance, kindling in the mesial temporal areas, similar to epilepsy, may contribute to latencies. There is some indirect support that a kindling-type mechanism can cause a delayed onset of psychosis (Sachdev, 1998). In epileptic patients who later develop schizophrenia-like psychosis, there are similar long latencies between onset of seizures and psychosis, reported to be roughly 10
14 years (Slater, Beard, & Glithero et al., 1963). These delays are similar to

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Davison & Bagley’s findings (Davison & Bagley, 1969) of a long delay in onset associated with temporal localization and epilepsy. Kindling and sensitization have been implicated in the progression of symptom severity in schizophrenia as well (Duncan, Sheitman, & Lieberman, 1999). In such cases, a developmental insult has been implicated in reduction of NMDA receptor functioning, and this in turn facilitates sensitization in dopamine systems, resulting in formal illness onset. Slow, progressive changes in the neural networks of the mesial temporal areas triggered by TBI may be another mechanism involved in latencies. Potential changes include Wallerian degeneration, apoptosis, or damage from free radicals or glutamate neurotoxicity, which are abnormally perpetuated beyond the acute and post-acute phases of injury. Latency between TBI and onset of psychosis is believed to vary based upon an interaction between the amount, type, and location of damage, the pathophysiological processes involved, and characteristics of the premorbid brain (Fujii, 1996). Type of damage may be associated with different mechanisms of psychotic development, while amount of damage would contribute to threshold levels. Location of damage would dictate where subsequent pathophysiological processes would occur. For persons with earlier onset PDDTBI, the threshold of damage has been reached, so the pathophysiological processes can occur, or the patient may be biologically predisposed so the pathophysiological processes occur rapidly. This proposal is consistent with reports suggesting that early-onset PDDTBI is associated with a genetic predisposition to schizophrenia (Achte et al., 1991) or more diffuse damage (Davison & Bagley, 1969). Visual hallucinations, which have been associated with earlier onset psychosis, may reflect a more severe or generalized TBI. Several possible explanations for why some PDDTBI patients demonstrate long latencies exist. For some, the threshold of damage has not been attained for the proposed pathophysiological processes to occur. Thus, additional damage or neuronal changes (e.g., normal developmental pruning) may be necessary before a threshold of damage is met to trigger a psychosis. In other patients, a slower process or combination of processes may be involved, such as kindling or sensitization, with or without seizure disorder development, or other processes like degenerative changes described above are required. Development of a seizure disorder may take between one and five years (Annegars et al., 1980), which then triggers the pathophysiological process resulting in psychosis. Therefore, in cases in which latency is longer than five years, it is likely that TBI is a contributor rather than the primary cause of psychosis.

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102.

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Schizophrenia-like psychosis and epilepsy Perminder Sachdev Neuropsychiatric Institute, The Prince of Wales Hospital and School of Psychiatry, University of New South Wales, Sydney, Australia

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B C B C B C D C D

The association between epilepsy and schizophrenia has attracted the attention of psychiatrists since the nineteenth century (Trimble, 1991). This clinically observed association was seen as a basis for exploration of the pathogenesis of mental illness, with epilepsy-related psychosis as a possible model of schizophrenia. It was this relationship that prompted the exploration of convulsive therapy in the treatment of psychiatric disorders. The pro-convulsant nature of neuroleptic drugs and the occurrence of psychosis with anticonvulsants have further fuelled the interest. We have come a considerable distance since the first efforts of understanding this association, but many aspects of this relationship still remain controversial (Mace, 1993; Mendez et al., 1993; Stevens, 1995; Taylor, 2003; Trimble, 1991; Trimble, Ring, & Schmitz, 1996). This chapter will review the current evidence for the relationship, and attempt to synthesize the understanding that emerges from its examination.

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1. Ictal psychosis: a. Partial complex or psychomotor status b. Simple partial status c. Petit mal status 2. Postictal psychosis: a. Single episode b. Recurrent 3. Brief interictal psychosis a. Alternating psychosis b. Non-periodic 4. Bimodal psychosis 5. Chronic interictal psychosis 6. Anticonvulsant drug-induced psychosis 7. Neuroleptic-induced epilepsy in a schizophrenic patient

Classification A consensus on the classification of schizophrenia-like psychosis associated with epilepsy (SLPE) is lacking, and neither DSM-IV nor ICD-10 has addressed this issue specifically. Application of DSM-IV criteria results in an ambiguous situation in which one can make the diagnosis of a primary psychotic syndrome or secondary syndrome (due to a general medical condition) depending on whether the nature of the evidence prompts one to deduce that the psychotic disturbance is etiologically related to the epilepsy ‘‘through a physiological mechanism’’ (DSM-IV, p. 307). Most often, separate diagnoses of epilepsy and the particular psychotic syndrome are appropriate. In such circumstances, note should be made of the relationship of the psychosis with the onset of epilepsy, seizure frequency, recent seizure episodes, current anticonvulsant medication, EEG abnormalities, and the underlying neurological lesion, if known. Since clinical seizures are the outstanding feature of epilepsy, psychotic syndromes have traditionally been classified according to their temporal relationship to these events, as ictal, postictal (or peri-ictal), and interictal, with the last type being either brief or chronic. For this review, I will retain this classification without implying that these categories are distinct in their pathophysiology or clinical manifestations (Table 14.1).

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Ictal psychosis A non-convulsive status epilepticus can result in symptoms resembling psychosis. The psychosis is necessarily brief, usually minutes to hours. When prolonged into days, it is likely to be ictal behavior that extends postictally. Epidemiology

The true prevalence of ictal psychosis has not been documented, as these patients are generally characterized as suffering nonconvulsive status epilepticus (NCSE). In population-based studies, the annual incidence of status epilepticus (SE) has been estimated as approximately 50 per 100,000 individuals (Shorvon, 1994) of which 4% to 20% (Krumholz, 1999) are NCSE. Of all patients with NCSE, the relative proportion of patients with petit mal SE (PMSE) compared to complex partial SE (CPSE) varies among studies. One found a 3:1 ratio of absence status epilepticus (ASE) compared to CPSE, whereas another population-based study of NCSE found the ratio was reversed (Krumholz, 1999). What proportion of these has psychotic symptoms deserves investigation. Age of onset

Absence seizures usually begin in childhood or early adolescence. Complex partial epilepsy also generally begins in childhood or adolescence, and later onset often suggests secondary epileptogenesis. The duration between onset and the occurrence of NCSE is extremely variable. Presentation

The most common association is with partial complex (or psychomotor) status, and patients may present a wide range of perceptual, behavioral, cognitive, and affective symptoms, often in association with automatisms involving oral activity, picking at clothes, and paucity of speech or mutism (Lee, 1985; Scholtes, Renier, & Meinardi, 1996). These episodes of automatisms may be recurrent, with behavior not being normal in the intervening periods although the patient may respond to simple instructions. Hallucinations may be prominent, and paranoid delusions or overvalued ideas may be present. Consciousness is altered during the episode but may be difficult to test, and patients are amnesic for the episode. Therefore, the appropriate DSM-IV diagnosis would be delirium. Simple partial status may produce affective, autonomic, and psychic symptoms that may include hallucinations and thought disorder in clear consciousness. Insight is usually maintained, and the manifestation is not that of a true psychosis, but the symptoms may be misinterpreted or embellished by the patient, and behavioral disturbance may result (Engel et al., 1991).

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Petit mal status (absence or spike-wave status) results in altered consciousness and such motor symptoms as eyelid fluttering and myoclonic jerks, and it may superficially resemble psychosis with disorganized behavior, but delusions and hallucinations are lacking (Scholtes et al., 1996). Patients almost always have a history of absence seizures or rarely generalized tonic-clonic seizures, and the onset is usually before the age of 20. If it has a later onset, there is frequently an underlying metabolic disturbance (Fenton, 1972). The onset and offset is abrupt, and the episode may last from minutes to several hours or even days. The alteration of consciousness is variable, ranging from slowing of thinking and behavior to marked disorientation to stupor. Neurophysiological disturbance

By definition, ictal psychosis is concurrently associated with epileptic discharges in the brain and, except in some patients with simple partial status (Devinsky et al., 1988), scalp EEG abnormalities are detectable. The majority of discharges in psychomotor status have a focus in the limbic and isocortical components of the temporal lobe, but the focus is extratemporal in about 30% of patients (Williamson & Spencer, 1986), usually in the frontal or cingulate cortex. Since the scalp EEG may be normal in simple partial seizures, the behavioral disturbance may be mistaken to be interictal, and a high index of suspicion is necessary. In such cases, if the patient is on anticonvulsant medication, the dose may have to be reduced, especially if EEG telemetry is planned. Activating techniques such as light sleep or sleep deprivation may be useful, and special recordings (sphenoidal, esophageal, or foramen ovale) may be necessary. Resolution of the disturbance with intravenous diazepam is not diagnostically foolproof as many nonepileptic behaviors may so resolve (Engel et al., 1991, pp. 97
111). Some assistance in diagnosis may come from the examination of serum prolactin levels, which rise after epileptic seizures, peaking at about 20 minutes and returning to baseline around one hour (Trimble, 1978). With partial complex seizures, the rise is less than that after generalized convulsions, but rises above 500 mU/L should be considered as suggestive (Dana-Haeri, Trimble, & Oxley, 1983). A rise may be insignificant or absent after a simple partial seizure. Symptoms may reflect one of two mechanisms (Gloor, 1991): 1. A positive effect of the seizure discharge, i.e. the epileptic discharge activates a behavioral mechanism represented in the area subjected to the discharge. This may result in a myriad of symptoms in the behavioral, cognitive, affective, perceptual, or autonomic domains. 2. A negative effect, i.e. either: a. the individual is unable to engage in a certain behavior owing to the temporary paralysis of the anatomical substrate of that behavior; or

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b. some behaviors are released by the inactivation of structures that normally suppress them. Behavioral disturbance due to a negative effect may occur in other situations, e.g. when the whole cerebral cortex is subjected to a relatively mild form of seizure activity represented by generalized spike and wave discharges. This negative effect may continue postictally, or it may initiate then. Experiential phenomena in ictal psychosis are likely to be due to positive effects, whereas automatisms may be caused by positive or negative effects. Genetics

Genetic factors are known to play a role in many epileptic syndromes. The idiopathic mendelian epilepsies have largely emerged as channelopathies, with mutations identified in a number of genes: nicotinic acetylcholine receptors (CHRNA4, CHRNB2), potassium channels (KCNQ2, KCNQ3), sodium channels (SCN1A, SCN2A, SCN1B), chloride channels (CLCN2), and GABAA receptors (GABRG2, GABRA1) (Steinlein, 2004). These are associated with generalized seizures, often with febrile onset. Nicotinic receptor mutations have been associated with lateral temporal lobe epilepsy. Non-ion channel genes related to idiopathic epilepsy include LGl1 and G-protein coupled receptors (MASS1, VLGR1). In mendelian symptomatic epilepsies, a number of genes have been identified. These include the progressive myoclonic epilepsies: Lafora disease (EPM2A, EPM2B), Unverricht-Lundborg disease (CSTB), neuronal ceroid lipofuscinosis (PPT, CLN2, CLN3, CLN5, CLN6, CLN8), Sialidosis (NEU1), and myoclonic epilepsy with ragged red fibers (MTTK, MTTL1). Neuronal migration disorders with epilepsy and a genetic basis include: Miller-Cieker/ isolated lissencephaly (LIS1), subcortical band heterotopia (DCX), and periventricular nodular heterotopia (FLN1) (Gardiner & Lehesjoki, 2000). The majority of familial epilepsy has a complex non-mendelian pattern of inheritance, and progress in the genetics of these disorders is just beginning to occur. Familial patterns have not been described in SLPE, and the genetics of these syndromes are unknown. Treatment

The treatment of ictal psychosis involves treatment of NCSE and the optimal management of epilepsy thereafter to prevent its recurrence. Postictal psychosis (PIP) The behavioral disturbances that may follow a seizure, or a bout of seizures, have received increased attention in the last two decades (Akanuma et al., 2005;

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Baumgartner et al., 1995; Fisher & Schachter, 2000; Kanemoto et al., 1996a; 1996b; Kanner et al., 1996; Ketter et al., 1994; Krishnamoorthy, 2000; Logsdail & Toone, 1988; Savard et al., 1991; So et al., 1990). Since PIPs are brief and occur in close proximity with seizures, they are ideal for the investigation of some pathogenetic mechanisms of psychosis. They usually follow seizure clusters or a recent exacerbation in seizure frequency (Logsdail & Toone, 1988) that may be related to withdrawal of anticonvulsants, often as a part of the video-EEG monitoring of patients (Kanner et al., 1996; Savard et al., 1991). Epidemiology

Postictal psychoses (PIP) are common in epilepsy-monitoring facilities; 6.4% of the patients in one study developed this syndrome (Kanner et al., 1996), and nearly 10% did so in another study (Kanemoto et al., 1996b). A confounding factor in the evaluation of PIP in video-EEG monitoring facilities is that these patients have often had a withdrawal of their anticonvulsants, and it has been suggested that this itself may result in psychopathology (Ketter et al., 1994) even though psychosis is not usual in the absence of seizures. Presentation

Between the last seizure and the psychosis there is usually a nonpsychotic period, which ranges from a few hours to a few days. In the Kanner et al. (1996) study, it was 12
72 hours and up to one week according to Logsdail and Toone (1988). Some clouding of consciousness is often present in this period, and it may extend to the initial period of psychosis or even the whole episode. The psychotic symptoms are pleomorphic (persecutory, grandiose, referential, somatic, and religious delusions, catatonia, hallucinations, etc.), and affective symptoms (manic or depressive) are often prominent (Kanemoto et al., 1996a; Logsdail & Toone, 1988). First-rank symptoms of Schneider can occur but are rare (Kanner et al., 1996). Postictal psychoses resolve within a few days, with the mean duration in the study by Kanner et al. (1996) being about 70 hours (range ¼ 24
144), and all resolving within one month in the study by Savard et al. (1991). The predisposing factors of PIP are poorly understood. The majority of reported patients suffer from partial complex seizures that are secondarily generalized. Epilepsy has often been present for more than 10 years before the onset of psychosis (Kanemoto et al., 1996b; Kanner et al., 1996; Logsdail & Toone, 1988). EEG abnormalities persist during the psychosis in the majority of cases (Logsdail & Toone, 1988). While Kanner et al. (1996) found no specific predisposing factors that differentiated their psychotic group from a comparable nonpsychotic epilepsy group, Savard et al. (1991) were impressed

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with a high rate of ictal fear, bilateral independent discharges, and gross structural lesions (six out of nine patients), including the presence of alien tissue tumors. Kanemoto et al. (1996a) also noted frequent psychic auras, and Umbricht et al. (1995) noted frequent bitemporal foci in their subjects. In contrast with the other literature, Devinsky et al. (1995) found similar rates of PIP in partial and primary generalized epilepsies, although they did note bilateral independent interictal discharges in those with partial seizures. PIP has also been associated with frontal lobe epilepsy, accounting for three out of eleven cases in one series (Adachi et al., 2000). Five of the 14 patients studied by Logsdail and Toone (1988) had abnormalities on brain computerized tomography (CT). In a magnetic resonance imaging (MRI) study (Kanemoto et al., 1996b), postictal psychosis was most likely to occur in patients with resistant temporal lobe epilepsy stemming from mesial temporal sclerosis, especially on the left side. In summary, the weight of the evidence supports a stronger association with complex partial

Table 14.2. Possible pathogenetic mechanisms of the postictal state with relevance to postictal psychosis

1. Electrophysiological: a. Continuous ictal discharges leading to psychomotor change b. Neuronal ‘‘exhaustion’’ from a seizure cluster 2. Neurotransmitter changes: a. Catecholamine depletion b. Increased postsynaptic dopamine sensitivity c. Increased endogenous opiates d. Increased adenosine e. Increased nitric oxide 3. Postictal inhibitory mechanisms: a. Fast inhibitory postsynaptic potential (GABAA mediated) b. Later hyperpolarizing potential (GABAB mediated) c. After hyperpolarization due to calcium-activated potassium currents d. Na-K hyperpolarizing pumps e. Increased extracellular Kþ f. Hþ induced attenuation of NMDA receptors g. Increased opiates, adenosine and NO 4. Cerebral blood flow alterations due to poor autoregulation 5. Other: a. Low folic acid b. Hyponatremia

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epilepsy, especially of temporal lobe origin, in which there is bilateral pathology, although this relationship is not exclusive. Neurophysiology and neurochemistry

The finding of chronic frequent subictal discharges suggests that ictal activity in the temporal lobe may be directly related to this kind of psychosis. Changes in monoamines, particularly postsynaptic dopamine receptor sensitivity, have been suggested as the mediating mechanism (So et al., 1990). Some support for the dopamine mechanism came from a single photon emission computed tomography (SPECT) study using [(123) I]iodobenzamide that demonstrated low levels of striatal dopamine D2 receptors in patients with peri-ictal psychosis (Ring et al., 1994). Low folic acid levels have been suggested to have a role (Reynolds, 1991), but firm evidence is lacking. More importantly, it would be fruitful to examine PIP in the context of the homeostatic mechanisms that are brought about in the brain to control seizures, which have been divided into electrophysiological mechanisms, cerebral blood flow (CBF) changes, and neurotransmitter and receptor changes (Fisher & Schachter, 2000). Postictal psychosis in this context has been conceptualized as a phenomenon akin to Todd’s paralysis, indicating the postictal inactivation of cortical regions involved in the ictal event, which usually include bilateral medial temporal structures (Engel, 1991, pp. 97
111). An important aspect of seizure termination is active inhibition, in which a number of mechanisms are involved. A hierarchy of inhibition is produced by fast inhibitory postsynaptic potential (IPSP) mediated by GABAA receptors, a later hyperpolarizing potential mediated by GABAB receptors (Fisher & Schachter, 2000) and after hyperpolarization produced by calcium-activated potassium currents. While these inhibitory mechanisms are brief, prolonged inhibition of neuronal activity can be produced by hyperpolarizing pumps, whose object is to restore the steady-state ionic balance after neuronal activity (Table 14.2). Treatment and prognosis

While the resolution of PIP is generally spontaneous, it is aided by neuroleptic medication, usually in small doses. A further seizure may exacerbate the psychosis, and anticonvulsant treatment should be carefully monitored, which includes dealing with non-compliance. The brief psychosis may recur, at a frequency of two to three episodes per year in two studies (Kanner et al., 1996; Lancman et al., 1994), and in some patients
15% in one study (Logsdail & Toone, 1988)
these episodes may become chronic. More longitudinal studies of patients with PIP are needed to examine its course, its likelihood of recurrence, and factors that predispose a transition into chronic interictal psychosis.

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Brief interictal psychosis (BIP) Brief psychotic episodes can also develop when seizures are infrequent or fully controlled. These psychoses last from days to weeks, they are usually self-limiting, and their separation from postictal psychoses may be difficult. Presentation

The phenomenology is characterized by paranoid delusions and auditory hallucinations, but multiple other features, including affective symptoms, may occur (Pakalnis et al., 1987; Ramani and Gumnit, 1982; Tellenbach, 1965; Wolf, 1984). Tellenbach (1965) pointed out the presence of premonitory symptoms such as insomnia, anxiety, feelings of oppression, and withdrawal as heralding the psychosis. The relationship of BIP to seizures and EEG abnormality has received much attention. Inter-ictal implies that these psychoses occur in between seizures rather than in close proximity with them. The favored description is of an alternating psychosis (Tellenbach, 1965), i.e. a brief psychosis alternating with periods of increased seizure activity such that the seizures and psychosis appear antagonistic. Unlike postictal psychosis, this psychosis can be ameliorated by the occurrence of one or more seizures (Wolf, 1991). Neurophysiology and the concept of ‘‘forced normalization’’

The concept of forced normalization (forcierte Normalisierung) (FN) was introduced by Landolt (1953) for the puzzling observation that the EEGs of epilepsy patients often looked less pathological when their behavior had deteriorated. This phenomenon, also called ‘‘paradoxical’’ or ‘‘spurious’’ normalization (Wolf, 1991, pp. 127
42), has been documented by a number of authors (Kristensen & Sindrup, 1987; Pakalnis et al., 1987; Wolf, 1991) with the additional observations that: (1) the EEG may become more, rather than entirely, normal; (2) the manifestation is not always of psychosis, and other disturbances, such as affective symptoms, an anxiety or dissociative state, and behavioral disturbance, may be present; and (3) not all brief interictal psychoses manifest this phenomenon (Ramani & Gumnit, 1982). Forced normalization is not exclusive to inter-ictal psychosis and has been occasionally described with post-ictal psychosis, suggesting a complexity of the relationship of seizure activity with psychosis. Interestingly, Landolt (1953, 1958) described this phenomenon in relation to childhood absence seizures, and some authors have suggested that it is more likely to occur with primary generalized epilepsy (Schmitz, 1998). The neurophysiological basis of forced normalization is not definitely known. One suggestion is that it reflects ongoing subcortical or mesial temporal epileptic activity with enhanced cortical inhibition (Schmitz, 1998; Wolf, 1984). This has

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been referred to as an ‘‘inhibitory surround’’ in response to ongoing seizures. This explanation argues that ongoing epileptic activity is necessary for the maintenance of inhibition as well as the development of psychosis. While the role of inhibition in response to seizure activity, as a homeostatic mechanism against ictal activity, is an appealing hypothesis to explain forced normalization, it is possible that it does not represent ongoing epileptiform activity, but is a prolonged response to preceding epileptiform activity. It is known that occasionally patients may develop prolonged unconsciousness after a seizure or a series of seizures, especially in elderly or ill patients (Willmore, 1976). Todd’s paralysis has been reported to last for up to 36 hours (Rolak et al., 1992). Therefore, it is possible that inhibition after a seizure or a series of seizures may be fairly prolonged. The inhibitory events described above are most likely to occur in close proximity to the seizure focus, thereby reducing the electrical current generated from the focus, and this may be the basis for the normalization. Even a reduction in the frequency of epileptic events will produce a relative normalization. Epidemiology

Alternating psychoses are uncommon, and Schmitz and Wolf (1995) reported three cases of alternating psychosis in 697 epilepsy patients. Ramani and Gumnit (1982) observed forced normalization in only one of nine epilepsy patients who became psychotic while being treated in the hospital for their epilepsy. Treatment

Systematic investigations into treatment are lacking. The disorder is usually selflimiting. Chronic interictal psychosis The investigation of the relationship between epilepsy and chronic SLPE was brought into the modern era by Slater, Beard, and Glithero (1963). For some time, there was high expectation that this would become a model psychosis that would reveal the pathogenesis of schizophrenia. Despite a great deal of further work, many aspects of this relationship remain controversial, and the promised insights have been slow to arrive. Epidemiology

The evidence that there is indeed an affinity between schizophrenia and epilepsy must come from epidemiological data. The epidemiological evidence for this association is summarized in Table 14.3. The rates must be interpreted in light

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Table 14.3. Epidemiological evidence for the association between epilepsy and schizophrenia-like psychosis (SLP)

Measure and Authors

N

%

Prevalence of SLP in epilepsy clinic groups: Gibbs & Gibbs (1952) 11,612

2.8

Currie et al. (1971)

666

1.8

37

8.0

1,611

9.25

697

4.0

1,285

9.1

Standage & Fenton (1975) Mendez et al. (1993)

Schmitz & Wolf (1995) Onuma et al. (1995)

Prevalence of SLP in epileptic patients in community
based studies: Krohn (1961)
2.0 Gudmundsson (1966) Qin et al. (2005)

987

8.1

2.27106

RR2.93 (2.69
2.20)

Prevalence of epilepsy in psychotic patients: Kat (1937) 50,000 Davison & Bagley (1969) Betts (1981, pp. 175
84) 1,950

0.33 1
10 2.1

Annual incidence of psychosis in epileptic patients: Lindsay, Ounsted, & Richards (1979) 87

10

Onuma et al. (1995)

0.3

1,285

Comment

Reliability of psychiatric diagnosis uncertain; majority of subjects young No criteria described; only patients with temporal lobe epilepsy included Temporal lobe epilepsy not different from other epilepsies 1.06% of migraine (comparison) subjects had schizophrenia-like psychosis; comprehensive assessment used DSM-III-R criteria Both generalized and focal epilepsies represented Point prevalence, 4.0% Additional 9% had incapacitating behavioral disorder Entire epileptic population of Iceland studied Danish longitudinal register Risk increased with age and family history of schizophrenia and epilepsy

Estimates from published data Hospitalized patients Temporal lobe epilepsy subjects followed up for 39 years

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of the general prevalences of psychosis, schizophrenia, and epilepsy in the general population. Methodological difficulties in the studies should also be taken into account in the interpretation of the prevalence data. For example, the classic study by Slater et al. (1963) drew its subjects from tertiary centers in two major London hospitals. The overall evidence suggests that SLPE is many times higher in epileptic patients than in the general population. A recent study based on the Danish longitudinal registers is particularly noteworthy for its comprehensive coverage of a population of 2.7 million (Qin et al., 2005). The relative risk of schizophrenia in patients with epilepsy was 2.48 (95% CI 2.20
2.8) and of SLPE 2.93 (2.69
3.20). The risk was the same in men and women, increased with age, and with family history of schizophrenia or epilepsy. Clinical features

Slater et al. (1963) reported that they had found a mean age at onset of about 30 years and that the symptoms were largely paranoid-hallucinatory, commonly associated with catatonia, affective blunting, and volitional symptoms. Phenomenologically, the disorder was indistinguishable from schizophrenia, although the authors reported a better preservation of affect, mood swings, mystical experiences, and visual hallucinations. Investigators in two controlled studies from London (Perez & Trimble, 1980; Toone, Garralda, & Ron, 1982) also noted the largely paranoid-hallucinatory characteristics of the disorder, but they stressed the greater frequency of ‘‘organicity.’’ One report commented on the rarity of negative symptoms, formal thought disorder, and catatonic symptoms (Kraft, Price, & Peltierm, 1984), while another reported that visual hallucinations were more prominent than auditory ones (McKenna, Kane, & Parrish, 1985). In the study by Mendez et al. (1993), the epilepsy-with-schizophrenia group did not differ from the nonepileptic schizophrenic comparison subjects on any psychosis item except increased suicidal behavior. In conclusion, except for minor reported differences, which may be accounted for by selection biases in the comparison group, the chronic psychoses of epilepsy are similar to schizophrenia. Many authors have commented on the relative lack of negative symptoms and a more benign course for epileptic schizophrenia (Perez et al., 1985; Slater et al., 1963) but supportive controlled studies are lacking. Nearly half (45%) of the patients of Slater et al. (1963) had a chronic course. In a 10-year followup study in Japan (Onuma et al., 1991), 64% of the patients had a chronic course. In the absence of an appropriate comparison group, it is difficult to know if this outcome is different from that in schizophrenia with a relatively later age at onset.

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Perminder Sachdev Table 14.4. Putative risk factors for chronic schizophrenia-like psychosis of epilepsy

1. 2. 3. 4.

Age: Early age of onset, but evidence conflicting Sex: A female bias reported by one group but not others Family history: F/H of psychosis or epilepsy Characteristics of epilepsy: a. Many years (usually 10
14) between onset of epilepsy and onset of psychosis b. Severe epilepsy: multiple seizure types, history of status epilepticus, multiple hospital admissions, resistance to drugs c. Partial complex epilepsy, especially of mediobasal temporal lobe origin d. History of secondary generalization e. Left sided focus 5. Neuropathology: a. Presence of neuroembryodysplastic lesions, e.g. gangliogliomas, hamartomas. b. Bilateral pathology 6. Neurological examination: sinistrality

Risk factors of chronic SLP with epilepsy

While a number of studies have examined the risk factors, the literature remains contentious, without a clear consensus emerging on many variables. The putative risk factors are summarized in Table 14.4. Is greater risk of psychosis particular to temporal lobe epilepsy?

Suggestions that psychosis in epilepsy might be exclusively or preferentially associated with temporal lobe epilepsy are supported by a majority of case series (Bruens, 1971; Gibbs, 1951; Perez & Trimble, 1980; Slater et al., 1963; Toone et al., 1982). Mendez et al. (1993) reported a higher rate of partial complex seizures, but not temporal lobe foci, in their group with SLP plus epilepsy. In the large Danish study, the relative risk associated with complex partial epilepsy was slightly but non-significantly higher than other types of epilepsy (Qin et al., 2005) (relative risk after adjustment for complex partial epilepsy 3.38, for other partial epilepsy 3.18, for generalized epilepsy 2.81). Another argument (Stevens, 1991, pp. 79
96) has been that the proportion of temporal lobe epilepsy in epilepsypsychosis patients is no different from that in the adult epileptic population in general, the latter being estimated to be about 60% (Hauser, Amegess, & Rocca, 1996; Shorvon, 1990). This debate, therefore, has not resolved but continues to be in favor of a special, but not exclusive, relationship between SLPE and temporal lobe epilepsy. Additionally, there are neuroimaging and neuropathological data linking the temporal lobe with psychosis.

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There is also a suggestion that the phenomenology of the psychosis associated with TLE is somewhat different from that associated with generalized epilepsy. The latter are reportedly relatively mild, shorter in duration, often associated with confusion in the early stages, and lacking in Schneiderian first-rank symptoms (Small, Milstein, & Stevens, 1962). Laterality of epileptic focus?

Since the suggestion by Flor-Henry (1969) of a preponderance of left-sided pathology in patients with SLPE, many studies have examined this issue. In the EEG studies, the majority opinion favors an excess of left temporal foci in the patients with temporal lobe epilepsy and schizophreniform psychosis (Perez & Trimble, 1980; Sherwin, 1981) although there have been some negative laterality studies (Jensen & Larsen, 1979; Kristensen & Sindrup, 1987; Shukla et al., 1979). There are many problems with the available data. First, the rigour with which laterality was established differs across studies, and the use of surface EEG recordings to establish laterality is open to question. Second, the presence of an epileptic focus on one side does not mean that pathology is restricted to that side. Third, left-sided preponderance of temporal lobe foci may not be restricted to psychotic individuals, as the evidence supports a left-sided bias for temporal lobe epilepsy in general (Currie et al., 1971). Fourth, there is emerging evidence that epilepsy patients with schizophrenia have generalized seizures even when they have a temporal focus (Mendez et al., 1993; Wolf, 1991). Fifth, the instruments and diagnostic criteria used for psychosis are language dependent, thus introducing a left-side bias (Stevens, 1991). The neuroimaging studies that examined laterality were inconclusive (Conlon, Trimble, & Rogers, 1990; Gallhofer et al., 1985; Marshall et al., 1993; Perez et al., 1985; Toone et al., 1982). Neuropathological studies have not supported lateralization of pathology (Bruton, Stevens, & Frith, 1994; Roberts et al., 1990). Therefore, the laterality issue remains undecided, but the importance of a leftsided focus is not striking. It is possible that the structural abnormality in epileptic psychosis is not lateralized and is possibly bilateral, but that the functional abnormality is predominantly left-sided. However, right-sided abnormality seems to be sufficient, and generalization of the epileptic disturbance is commonly present. Genetics

Patients who have SLPE generally have been reported not to have a greater than normal familial aggregation of schizophreniform disorders (Perez et al., 1985; Slater et al., 1963; Toone et al., 1982). In the Danish longitudinal registers study, (Qin et al., 2005) family history of psychosis was associated with a relative risk

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of 3.12 (2.83
3.43) of SLPE. Interestingly, a family history of epilepsy also increased the risk of schizophrenia or SLP, even after adjusting for the effects of personal history of epilepsy and other confounding factors. This familiar aggregation of epilepsy and SLP suggests shared genetic and/or environmental factors. Neuroimaging studies

A few neuroimaging studies must be highlighted in relation to chronic SLPE. An MRI study already referred to (Conlon et al., 1990) did not show any difference in T1 relaxation times between epilepsy-psychosis patients and schizophrenic comparison subjects. There is extensive literature on MRI brain morphometry of schizophrenia and temporal lobe epilepsy, and some of the morphological abnormalities described (large ventricles, small hippocampus) are common to the disorders (Barr et al., 1997). A positron emission tomography (PET) study using 15 O-H2O demonstrated lower oxygen extraction ratios in the frontal, temporal, and basal ganglia regions of psychotic patients with epilepsy than in nonpsychotic epileptic patients (Gallhofer et al., 1985), and a small study using SPECT showed lower left medial temporal blood flow in psychotic than nonpsychotic epileptic patients (Marshall et al., 1993). The left temporal lobe abnormality was supported by another study (Mellers et al., 1998), but a more recent SPECT study of interictal psychosis in patients with TLE failed to find a significant difference from controls, with a trend for increased blood flow in the posterior cingulated region (Guarnieri et al., 2005). The PET study of patients with psychosis by Reith et al. (1994), which included two patients with chronic and two with postictal SLPE, showed higher than normal levels of dopa decarboxylase activity in SLPE and schizophrenia, and it was suggested to be due to suppressed tonic release of dopamine in the striatum because of low corticostriatal glutamatergic input. Neuropathological studies

Neuropathological studies of SLPE have been limited. A large series from London, drawing on subjects with histories of temporal lobectomies, has been reported (Roberts et al., 1990; Taylor, 1975). Taylor (1975) commented that epilepsy patients with SLPE were less likely to have mesial temporal sclerosis and more likely to have alien tissue lesions (small tumors, hamartomas, and focal dysplasias). In the report by Roberts et al. (1990), 40% of patients with SLPE had mesial temporal sclerosis, 20% had alien tissue gangliomas, and 20% had no lesions (49%, 4%, and 15% of the total epileptic group, respectively). Histories of birth injury, head injury, and febrile convulsions were not overrepresented in the group with SLPE, but the frequency of alien tissue tumors and early onset of seizures suggested a developmental lesion in the medial temporal structures that

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Schizophrenia-like psychosis and epilepsy

had been physiologically active from an early age. On the other hand, Stevens (1986, pp. 117
46) reported widespread pathology in six cases of epilepsy and psychosis; the pathology included the hippocampus, hypothalamus, thalamus, pallidum, and cerebellum. In a study by Bruton et al. (1994) epileptic patients with SLPE had larger ventricles, more periventricular gliosis, more focal damage, and more periventricular white matter softenings than nonpsychotic epileptic comparison subjects, but similar rates of mesial sclerosis, suggesting greater nonspecific neuropathology. Possible pathophysiological mechanisms for psychosis in epilepsy

Discussion has centered broadly on two mechanisms: (1) the psychosis is due to the repeated electrical discharges, either directly or through the development of neurophysiological or neurochemical abnormalities; or (2) the epilepsy and psychosis share a common neuropathology that may be localized (emphasis on temporal lobe but also frontal lobe and the cerebellum) or widespread in the brain. Both mechanisms may be operative, the latter being primary and the former modifying the presentation, determining exacerbations and remissions, or being the proximate cause. The possible roles of psychological factors, neurotoxicity of anticonvulsant drugs, deficiencies (e.g. folic acid), and abnormal experiences seem to be of secondary importance. Composite model

An attempt at a synthesis of the pathophysiological hypotheses is presented in Figure 14.1. According to this view, epilepsy patients who develop chronic SLPE have a brain lesion that makes them vulnerable to psychosis. This lesion may be neurodevelopmental, leading to cortical dysgenesis, or be acquired through trauma, hypoxia, infection, etc. The abnormality may be widespread but is particularly likely to involve the limbic structures, leading to abnormalities of connectivity of these structures to their afferent and efferent projection regions. Since the development of medial temporal structures is asymmetric, it may explain some of the laterality data. The abnormality is likely to cause electrical storms in the limbic cortex, with seizures occurring at an early age. The occurrence of frank seizures or microseizures exacerbates the abnormality owing to kindling mechanisms or the regenerative and neuroplastic changes involving axonal sprouting, synaptic reorganization, dendritic changes, glial changes, etc. In due course, these result in disruption of anatomically distributed functional systems and lead to SLPE, accounting for the ‘‘affinity’’ between epilepsy and SLPE. Seizures, either by the presence of continuous subictal activity or by their modulation of catecholamine and pre- and post-synaptic glutamatergic and GABAergic activity, modulate the expression of the psychosis or act as brakes,

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Figure 14.1. Possible pathophysiological mechanisms for the association between epilepsy and schizophrenia-like psychosis

sometimes leading to the impression of antagonism. There may be long-term changes in the balance between excitation and inhibition. The picture is further complicated by drug therapy, with its potential for neurotoxicity, and psychosocial factors related to epilepsy, a chronically disabling and stigmatizing illness. Treatment

Patients chronically affected by SLPE must be treated as for schizophrenia in general. In using antipsychotic drugs, one must be mindful of the potential of these drugs to worsen seizure control. Drugs differ in their potential to worsen seizures (Table 14.5), with atypical neuroleptics in general being worse than the classical drugs. Of atypical antipsychotics, risperidone is the safest and clozapine most epileptogenic, with the effects being dose-related. However, with good monitoring of seizures, all antipsychotics can be used in epileptic patients. Compliance with anticonvulsant drugs should be carefully monitored in psychotic patients. Hospitalization may be necessary to observe more complex cases. Benzodiazepines can be used to control agitation or insomnia, but their abrupt cessation may precipitate seizures. Lithium does worsen seizure control. In a patient with marked abnormality of mood or florid delusion and hallucinations, electroconvulsive therapy can be used if drug treatment is ineffective or slow in producing a response. A patient with SLPE needs intensive rehabilitation, much like one with schizophrenia. The presence of SLPE is not a contraindication to surgical treatment of epilepsy. However, it is important to distinguish the psychiatric disturbance from the seizures, and inform the patient that the psychosis will most

279

Schizophrenia-like psychosis and epilepsy Table 14.5. The relative risk of seizures with antipsychotic drug used

High risk

Intermediate risk

Low risk

Clozapine (HD to MD) Chlorpromazine (HD)

Clozapine (LD) Chlorpromazine (MD to LD) Olanzapine Quetiapine Thioridazine

Haloperidol Trifluoperazine Fluphenazine Flupenthixol Pimozide Molindone Risperidone

Note: HD high dose; MD moderate dose; LD low dose Source: Adapted from: Alldredge (1999)

likely not improve with the surgery. There are cases in which SLPE worsens after surgery, but this is not the usual case. It is also important that the psychotic patient is able to give informed consent for the procedure. Acknowledgements Angie Russell helped with manuscript preparation. The work was supported by a Progam Grant (ID350833) from the National Health and Medical Research Council of Australia. REFERENCES Adachi, N., Onuma, T., Nishiwaki, S., et al. (2000). Inter-ictal and post-ictal psychoses in frontal lobe epilepsy: A retrospective comparison with psychoses in temporal lobe epilepsy. Seizure, 9, 328
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Psychosis following cerebrovascular accident James A. Bourgeois University of California, Davis Medical Center, Sacramento CA, USA

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

C C C C C D None reported C C

Introduction Psychosis is a term for a series of psychiatric symptoms that have in common clinical evidence of impairment in reality testing. Specific symptoms characteristic of psychotic disorders include hallucinations (sensory experience without sensory input, an impairment between internal sensory experience and external stimuli), illusions (distortions of sensory input at the level of perception), and delusions (fixed, false beliefs in the context of intact sensory processing, thus a disorder of attribution). In addition, ‘‘psychosis’’ also applies to deficits in cognitive organization (not just impairment in memory). Examples of cognitive disorganization include the inability to initiate and persevere on mental tasks, impaired language use (e.g., inappropriate rhyming or use of bizarre sentence constructions), and deficient affective modulation or control (e.g., affect that is discordant to the ongoing emotional status, or silly, labile, or odd).

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It is important to distinguish between isolated symptoms of psychosis (which can be classified among the symptom types above) that reflect a ‘‘primary’’ psychotic disorder versus those psychotic symptoms that may be best attributed to another psychiatric illness. Other psychiatric illnesses that may also feature psychotic symptoms include mood disorders (e.g., major depression with psychotic features and bipolar I disorder, manic episode with psychotic features), substance use disorders, delirium, and dementia. While the psychotic symptoms seen in these other psychiatric conditions may substantially overlap with the psychotic symptoms of ‘‘primary’’ psychotic disorder, the context will be different. Mood disorder episodes with psychotic features include profound depression, mania, or a ‘‘mixed state’’ of alternating mania and depression. Substance userelated psychosis is seen in the context of substance intoxication or withdrawal, or, less frequently, persistent psychosis after withdrawal. Psychosis in delirium features other symptoms of delirium, e.g., acute or subacute onset, fluctuating level of consciousness and clinical course, alterations of circadian rhythm, and variable decrements of cognitive performance. Finally, psychosis in dementia is typically associated with cognitive impairment and a gradually declining clinical course. It is customary to classify a ‘‘psychotic disorder’’ when psychosis is the predominant area of mental functioning affected by a psychiatric illness, whether ‘‘primary’’ or ‘‘secondary’’ to a focal CNS lesion. Psychosis referable to a stroke (which is also called ‘‘post-CVA psychosis’’), therefore, will phenomenologically resemble a ‘‘primary’’ psychotic disorder (e.g., schizophrenia or delusional disorder) but will occur in a time frame suggesting proximity and thus a causal or at least inferential relationship to the cerebrovascular accident. As such, an inferential connection must be drawn from a presumed sequence of: pre-morbid negative psychiatric history 4 documented cerebrovascular accident 4 new onset of psychotic symptoms to declare a case as one of ‘‘post-CVA psychotic disorder’’ with reasonable clinical certitude. This chapter will review existing literature on this subject, almost all of which is derived from clinical reviews, case reports or small case series, in an attempt to derive characteristic clinical patterns for this clearly relatively rare phenomenon. Epidemiology The prevalence of psychotic disorder specifically caused by cerebrovascular accident appears to be low (Richardson, 1992). Most of the literature on this phenomenon is based on case reports and case series, data sources not lending themselves readily to epidemiological inference. The prevalence of mania (technically a mood disorder but included here since patients may often present with psychotic symptoms) has been estimated at 1% following CVA

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(Robinson, 1998; cited in Carota et al., 2002). The true prevalence of psychosis following stroke is unknown but is probably less than the 1% risk for mania (Carota et al., 2002). Systemic studies of the incidence and prevalence of psychosis following CVA are lacking (Dupont, Cullum, & Jeste, 1988). As overall incidence and prevalence rates are indeterminate, it is not possible to definitively speculate about gender differences in post-CVA psychosis, due to the small number of cases described in detail in the literature. The cases discussed and referenced later in this chapter reflect an equal sex distribution. In addition to the apparently rare occurrence of psychosis attributable to cerebrovascular accident, there is the critical issue of phenomenology. ‘‘Psychosis’’ as usually understood in the bulk of the psychiatric literature usually refers to ‘‘positive’’ symptoms (e.g., delusions and hallucinations) and ‘‘negative’’ symptoms (e.g., disorganized thought processes, idiosyncratic use of language, and regressed emotional and motor behavior). In the post-CVA psychosis patient, there is a risk of other cortical abnormalities: e.g., amnesia, visual-spatial orientation deficits, and other cognitive deficits that may collude to create a picture of ‘‘psychosis’’ that is qualitatively different from the psychosis seen in schizophrenia and other solely ‘‘psychiatric’’ disorders. As such, the literature on post-stroke psychosis must be read with due caution as to the phenomenological and neuropsychiatric co-morbidities contained in patients’ clinical presentations. As such, the association of stroke with psychosis remains an elusive construct. Battaglia and Spector (1988) completed CT scans of 45 patients presenting with their first psychotic episode. Two had CT evidence suggesting cerebrovascular disease relating to the psychotic illness. One was a 35-year-old female with bizarre behavior, labile affect, hallucinations, and disorganized thought processes. CT revealed ‘‘decreased attenuation near the right frontal horn, cortical and mild central atrophy . . . possibly consistent with a frontal white matter infarct.’’ The other was a 21-year-old male with violent behavior, paranoid ideation, and somatic delusions. He had a seizure disorder since the age of six. CT revealed a ‘‘lucency though the left caudate nucleus, possibly indicating a basal ganglia infarct.’’ Inferring causality of psychosis from cerebrovascular lesions in this particular cohort would imply a risk of 4% for stroke in an unselected group of psychotic patients, but does not address the inverse construct, which is the risk of psychosis in CVA patients. Since there are few cases in the literature, it is not possible to definitively comment on the age of onset for post-CVA psychosis. All of the cases included here occurred in adults, with a broad age range from the 20s to over 80. Of note is that the age of onset of ‘‘pure’’ psychotic illness in schizophrenia-spectrum patients is usually before age 30, while the onset of psychosis in old age is much more likely to be attributable to structural and/or metabolic factors.

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Presentation The presentation of psychosis following stroke defies ‘‘clean’’ demarcation along habitual lines of psychiatric diagnostic classification. Thus, the clinician may expect to encounter the much more common post-CVA depression and vascular dementia (which can both antedate and follow the CVA) in the post-CVA patient manifesting psychotic symptoms. Indeed, the post-CVA psychosis is often a complex phenomenon that effectively ‘‘bridges’’ the border between psychiatry and neurology. Some symptoms, such as the denial of ‘‘ownership’’ of a paretic extremity (somatophrenia) and the sense of ‘‘reduplication’’ of body parts (pseudopolymelia) can be logically classified as ‘‘somatic delusions’’ by psychiatric terminology as well as ‘‘anosognosia’’ in neurologic terminology (Carota et al., 2002). Carota et al. (2002) described four specific ‘‘symptom clusters’’ for postCVA psychosis: 1. affective (which would include mania and psychotic depression); 2. paranoid delusions; 3. confusional state (which may overlap with delirium and vascular dementia); and 4. changes in mood with behavioral disturbances. According to a review by Dupont et al. (1988), the possibility of CVA as a cause of late-life new onset delusions should be actively considered. This is especially important if such a patient appears on clinical examination to be disoriented and exhibiting other cognitive impairments. A review of poststroke psychotic syndromes by Starkstein, Robinson, and Berthier (1992) distinguished between hallucinations (disturbed perceptions with impaired insight) and hallucinosis (similar perceptions but with preserved insight) in post-CVA psychosis. Regarding the usual classification of psychotic symptoms into the familiar categories of positive symptoms, negative symptoms, and cognitive/emotional/ behavioral symptoms, many cases of post-CVA psychosis are ‘‘mixed.’’ In addition, neuropsychological findings reflecting cognitive impairment have been seen in post-CVA psychosis. Unfortunately, formal neuropsychological testing has not always been obtained in case reports of post-CVA psychosis, so a connection between post-CVA psychosis and dementia (either pre-existing or as a consequence of CVA) remains speculative. There are too few cases in the literature to develop a ‘‘characteristic’’ description of post-CVA psychosis based on phenomenology alone, although the several cases of post-CVA ‘‘delusional misidentification’’ syndromes are striking and may represent psychotic symptoms somewhat more specific to the post-CVA psychotic condition. These phenomena include reduplicative paramnesia, Capgras’ syndrome and Fregoli’s syndrome (Carota et al., 2002; Hudson & Grace, 2000). In reduplicative paramnesia (also called ‘‘environmental reduplication’’), the patient cannot

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acknowledge the place and delusionally believes him/herself to be in different place. On mental status testing, this technically is ‘‘disorientation’’ and could be initially attributed to a cognitive disorder, such as dementia or delirium. Within reduplicative paramnesia, three subtypes have been described. ‘‘Place reduplication’’ involves the existence of two identical places, which are named the same, but are physically distant from each other (Carota et al., 2002). ‘‘Chimeric assimilation’’ means that two place identities are ‘‘combined,’’ e.g., the patient believes him or herself to be in the ‘‘home’’ that has somehow been ‘‘transformed’’ into a hospital (Carota et al., 2002). Finally, ‘‘extravagant spatial localization’’ infers that the patient believes him or herself to be in another place, often a familiar one (Carota et al., 2002). Simultaneous presence of spatial neglect and visualspatial defects cannot completely account for these delusions. Post-CVA psychosis with disorientation for place and/or reduplicative paramnesia

Fisher (1982) reported seven cases of disorientation for place following nondominant cerebral hemisphere CVA. Case 1 was a 72-year-old man with occlusion of the right internal carotid artery and a lesion in the inferior right parietooccipital region. He had variable disorientation for place (onset one week later), thinking himself to be in various cities on different dates. He spontaneously improved after 33 days. Case 2 was a 66-year-old man with thrombosis of the right internal carotid artery who was also variably disoriented for place (onset immediately post-stroke), with several erroneous cities stated sequentially as his location. He improved within five weeks. Case 3 was a 44-year-old man who had a stroke following clipping of a ruptured internal carotid-posterior communicating aneurysm. This patient also exhibited disorientation (onset three days later), believing himself to be in various different places. He improved by day 22. Case 4 was a 71-year-old man with onset one week after neurological signs of disorientation. He later suffered a progressive course consistent with Alzheimer’s disease. Case 5 was an 80-year-old man with a thrombosis of the right internal carotid artery. He also believed himself to be in various different cities. Case 6 was a 64-year-old woman with a rupture of a right middle saccular aneurysm. She believed that her kitchen was located in the hospital, near her room. This improved within five weeks. Case 7 was a 62-year-old woman with a right thalamic hemorrhage. She experienced disorientation for place (with misidentification of the city) that persisted for one year. Berthier and Starkstein (1987) described a 63-year-old male with visual, tactile, and auditory hallucinations and delusions (including somatic delusions). He exhibited confabulation and confused the identities of others. EEG revealed right paroxysmal slowing without seizure activity. He would ‘‘misplace’’ the hospital in different cities. He also displayed apathy, elation, and irritability.

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Residual neurologic deficits that may have contributed to his psychiatric state were hemispatial neglect, motor impersistence, constructional apraxia, acalculia, and spatial dysgraphia. CT revealed extensive right fronto-temporo-parietal infarction and mild ventricular dilatation. Formal cognitive testing included Wechsler Adult Intelligence Scale-Revised (WAIS-R) verbal IQ 97, performance IQ 77, and a 91 on the Wechsler Memory Scale. He was unable to complete any categories on the Wisconsin Card Sorting Test (WCST). Six months later he was significantly improved, having cleared the hallucinations, reduplication, and somatic delusions. He was then able to complete three WCST categories. Leiguarda (1983) described a 74-year-old man with an acute hemiparetic stroke with right thalamic hemorrhage with extension into the posterior limb of the internal capsule and to the ventricular system. Moderate cortical atrophy and ventricular dilatation were also noted. Five days after onset, he was disoriented to place, stating he was in another nation. He subsequently reported disorientation to several other cities. This symptom continued until his death two months later. Ruff and Volpe (1981) reported a 23-year-old woman with right fronto-parietal hematoma and arterio-venous malformation (AVM) of the right middle cerebral artery with environmental reduplication. After neurosurgical intervention, she claimed to be in her home, not the hospital. Psychological testing showed impaired spatial perception and visual memory. Within ten days, her psychosis and visual-spatial difficulties resolved. Post-CVA psychosis with capgras’ syndrome

Capgras’ syndrome is the patient’s belief that a familiar individual (which may include the patient) has been replaced by an identical-appearing ‘‘imposter’’ (Carota et al., 2002; Dupont et al., 1988). Collins et al. (1990) reported Capgras’ syndrome associated with CVA of the right internal capsule. A 69-year-old female presented with irritable and suspicious behavior. She had refused to allow firefighters to enter her home to extinguish a house fire, claiming that they were not ‘‘real firemen.’’ She also assaulted a group of neighbors by pouring water on them, claiming that the women were not ‘‘real neighbors.’’ She also claimed that her sister had been replaced by a double. She had paranoid delusions about objects in her apartment being moved and her having been victimized by a laser beam. She was treated first with droperidol and then trifluoperazine, and her symptoms resolved in three weeks. Post-CVA psychosis with fregoli’s syndrome

Fregoli’s syndrome is the attribution of a psychological characteristic from one person to another or the delusional misidentification of familiar persons disguised as others (Carota et al., 2002). De Paw, Szulecka, and Poltock (1987) described

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a case following a CVA. A 66-year-old female presented with a four-month history of new onset psychosis. She had become convinced that her cousin had moved into her neighborhood, and that the cousin and a companion were in disguise and following her in a threatening manner. Formal testing revealed WAIS between 80 and 90 (verbal IQ 85, performance IQ 78) and a 27 on the Mini Mental State Examination (MMSE). CT revealed low attenuation of the right posterior temporal area, suggesting infarct of the posterior temporal branch of the right middle cerebral artery, and a moderate degree of cortical atrophy. She was treated with trifluoperazine 15 mg po qhs for three months, during which time her delusions initially cleared. Two months later, her symptoms recurred. She was then treated with carbamazepine 800 mg qd for six weeks, without improvement. Subsequent treatment with pimozide 10 mg qd resulted in improvement, but only re-start of trifluoperazine completely relieved her delusional symptoms. Hudson and Grace (2000) reported a 71-year-old woman who misidentified her spouse as her (deceased) sister while also claiming that her home was now a ‘‘duplicate’’ of her real home. These symptoms began within days of the onset of neurological symptoms. The patient had an area of likely ischemic damage to the anterior portion of the right fusiform gyrus and middle and anterior temporal gyri, with associated hippocampal and parahippocampal atrophy. These symptoms were unchanged two years later. Neuropsychological assessment revealed average to above average verbal IQ, but a performance IQ 25 points lower than verbal IQ. She also had impaired visual attention, visual memory, and executive functions. The authors postulated that the delusions were due to disruption of connections between the fusiform gyrus and inferior and medial aspects of the right temporal lobe, interrupting continuity between areas responsible for facial and scene recognition. Cases of post-CVA psychosis with various psychotic, mood, and cognitive symptoms

Bogousslavsky et al. (1988) described a 73-year-old female with excessive speech, delirium, inappropriate humor, disinhibited and inappropriate comments, delusions, and confabulations present acutely with a new CVA. She completed no WCST categories. CT revealed a recent right thalamic infarct in the posterior thalamo-subthalamic paramedian artery territory and an old lacunar lesion in the head of the left caudate nucleus. EEG revealed slowing on the anterior regions, predominating on the right. SPECT showed hypoperfusion in the right thalamic region with associated hypoperfusion on the right cortex, mainly in the frontal area. Within two months, her behavior had improved. At six months, she showed further behavioral improvement and was then able to compete three WCST categories.

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Levine and Finklestein (1982) presented a series of eight cases of psychosis following vascular lesions of the posterior portion of the right cerebral hemisphere. Seven had new onset seizures post-CVA, and there was a temporal relationship between seizures and psychosis. The cases ranged in age from 23
85; five were female. Specific lesions included parieto-occipital hemorrhage and temporo-parieto-occipital infarction each in two cases, with temporo-parietal infarction, temporoparietal contusion, temporoparietal hemorrhage, and posterior embolic infarction in one case each. Psychotic symptoms included hallucinations in all cases, delusions in seven, and agitation in five. Onset of psychotic symptoms ranged from one month to 11 years after CVA. Case 1 was a 47-year-old woman with CVA and right posterior intracerebral hematoma and EEG with right temporal slowing, with onset of seizures six days after presentation. Nearly four months after CVA she was readmitted, with psychosis consisting of delusional misidentification, disorientation for place, disorganization, and paranoid delusions. She received with phenytoin up to 1200 mg qd, carbamazepine 800 mg qd, and trifluoperazine 80 mg qd, but continued to be psychotic for three weeks until she died of a pulmonary embolus. Case 2 was a 58-year-old woman with right parieto-temporal hemorrhage. Eight months later, she developed hallucinations and paranoid delusions. EEG revealed right temporal slowing without paroxysmal activity. She was treated with phenytoin, and the hallucinations resolved two days later. Nineteen months later, after stopping anticonvulsant treatment, she developed motor seizures. She improved with IV phenytoin, but developed hallucinations yet again. Repeat EEG now showed slowing over the right hemisphere and frontal sharp waves. Case 3 was a 34-year-old woman who 11 years previously had had an episode of hand weakness followed by personality changes including distancing from friends and irritable, spiteful behavior. At age 45, she developed paranoid delusions, hallucinations, and visual misidentification. A WAIS revealed verbal IQ 71 and performance IQ 51. EEG revealed bursts of generalized sharp waves while awake and fronto-temporal slowing during sleep. CT showed an old infarction in the temporo-parietal region. She was treated with phenothiazines and haloperidol, and her psychotic symptoms improved within two months. The presentation of post-CVA psychosis can also contain symptoms suggestive of mania as seen in classic bipolar disorder. McGilchrist et al. (1993) reported a 43-year-old man with intermittent apathy, inappropriate affect, disinhibited social behavior and disturbed cognitive function. CT revealed an infarct in the right thalamus. His psychiatric symptoms were treated with tricyclic antidepressant and electro-convulsive therapy, with minimal improvement. Six months later, with continued and worsening psychiatric symptoms, a repeated CT revealed bilateral thalamic infarcts. SPECT showed hypoperfusion of the frontal lobes and thalami bilaterally. Full scale IQ was 107, and he performed poorly on the Rey-Osterrieth

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figure, Trial Making Test, and Cognitive Estimates Test. He later experienced mania, including pressured speech, flight of ideas, increased sleep, delusions of self-reference and visual hallucinations. He responded to lithium carbonate and remained stable for six months. Mesulam et al. (1976) reported three cases of acute confusion following right middle cerebral artery infarctions. Case 1 was a 61-year-old man with acute onset of incoherence, agitation, diminished attention, and grossly impaired cognition. He had auditory hallucinations, disorientation, paraphasias, and circumlocutions. Technetium scanning revealed abnormality in the right parieto-occipital region. Case 2 was a 65-year-old man with confusion and incoherent speech. He was disoriented and agitated with significant cognitive impairment. Technetium scanning revealed abnormality in the right parieto-temporal region. Case 3 was a 74-year-old man with confusion, disorientation, and agitation. Paraphasic errors were present. CT revealed an abnormality in the right inferior frontal gyrus. These cases had the common symptoms of inattentiveness, distractibility, inability to ‘‘grasp’’ the current situation, incoherent stream of thought, disorganized behavior, disorientation, anomia, dysgraphia, and lack of insight. Pakalnis, Drake, and Kellum (1987) presented a 52-year-old woman with abrupt onset of agitation, delusions of ‘‘demonic possession,’’ visual hallucinations, and depression. These symptoms followed a cranial ‘‘pressure’’ sensation. She also showed mild disorientation to time. CT revealed a lacunar infarct in the right parieto-occipital region. Her agitation responded to haloperidol 15 mg qd. The authors believed that her lesion’s involvement of the geniculocalcarine tract might have accounted for the prominence of the visual hallucinations. Peroutka et al. (1982) reported a 72-year-old woman with acute onset of psychosis following a right temporo-parieto-occipital infarction. She presented acutely with auditory and visual hallucinations following a sudden, severe headache. Two days later, she heard a loud buzzing noise and believed that a ‘‘bee’’ was in her home. She later hallucinated various ‘‘people’’ and ‘‘a fire.’’ These hallucinations were accompanied by paranoid delusions. She also had tactile hallucinations of having her hair ‘‘pulled.’’ EEGs revealed slowing over the right hemisphere on day 5, which was significantly improved by day 20. WAIS full scale IQ was 98, verbal IQ was 104, and performance IQ was 90. She had abnormal visual-spatial performance on psychological testing. Her hallucinations resolved on haloperidol 15 mg qd. Price and Mesulam (1985) presented five patients aged 45
78 with psychosis following right hemisphere infarctions. All showed agitation, inattention, suspiciousness, paranoia, hallucinations, and lack of insight. Case 1 was a 66-yearold man with delusions, numerical obsessions and a belief that he would win the lottery. EEG was normal, while CT revealed right parietal infarction.

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Treatment with imipramine, haloperidol, and benztropine was ineffective. Three months later, he had episodes of left upper extremity weakness, along with inattentiveness and impaired visual-spatial skills. Repeated CT showed a small lacunar infarct in the right anterior internal capsule in addition to the previous lesion. His behavioral symptoms gradually resolved. Case 2 was a 45-year-old woman with a resolved episode of left hemiparesis ten years earlier. At age 45, she had four psychotic episodes (duration between one day and one week) in a period of eight months. These included visual and auditory hallucinations, delusions of poisoning and being killed, associated with panic and depression. CT revealed an old infarct in the white matter of the right frontal region. EEG showed bitemporal epileptiform activity during drowsiness and sleep. She responded to phenobarbital. Case 3 was a 61-year-old woman with agitation, anorexia, and suicidality, who threatened to kill her husband and attempted to set her home afire. She was inattentive and disoriented, unconcerned, perseverative, and had visual-spatial impairment. CT was unremarkable, and EEG showed mildly slowed background activity. She was treated with haloperidol. Five months later, a repeat EEG showed paroxysms of right posterior temporal sharp theta waves. Her behavior later spontaneously improved. Case 4 was a 78-year-old woman with abrupt onset of confusion, fears of being poisoned, and delusions of being ‘‘Hitler.’’ EEG showed intermittent rhythmic sharp theta waves with phase reversal in the right parietal region. Diphenylhydantoin was ineffectual. Haloperidol decreased her agitation but she continued to have episodic exacerbation of her psychotic behavior. Case 5 was a 76-year-old man with acute onset confusion, irritability, indifference, perseveration, and visual-spatial impairment accompanied by left-sided motor deficits. He was delusional about a ‘‘plot’’ against him, and repeatedly attempted to flee. He was also convinced that he was in a ‘‘prison’’ or a ‘‘hotel.’’ EEG showed background slowing; CT showed no focal lesions. Richardson (1992) described a 64-year-old man who developed hallucinations, delusions, and agitation after a right hemisphere cerebrovascular accident in the temporo-parieto-occipital region. He presented acutely with left-sided weakness and confusion with agitation. He was noted to gesture about his hospital room at ‘‘bugs’’ and ‘‘animals.’’ He was noted to be talking to himself, but stated that his ‘‘grandson’’ was present; he later claimed that a ‘‘baby was in bed’’ with him. He responded to haloperidol, which improved his symptoms within one week. Serra Catafau, Rubio, and Peres Serra (1992) reported a 68-year-old male with left hemiparesis and paresthesias who experienced vivid visual hallucinations of people, animals, and houses limited to the left visual field. He retained insight (recognizing that these were hallucinations) and intact cognition. CT revealed atrophy, while MRI showed ischemia of the right posterior thalamocapsular region. EEG showed low voltage waves with diffuse fast rhythms and theta waves

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on the right temporal region. His visual hallucinations resolved. The authors speculated that lesions of the nucleus reticularis might have been implicated. Feinberg and Rapcsak (1989) reported a similar case. An 83-year-old man experienced vivid visual hallucinations of people and animals. The hallucinations were very frightening to the patient and he needed restraint for subsequent agitation. MRI revealed increased signal intensity of the right dorsomedial thalamus. These visual hallucinations resolved within three days. Course and progression The latency from initial cerebrovascular lesion to the presentation of psychotic symptoms is variable. Post-stroke psychotic symptoms can present simultaneously with the acute neurological findings of CVA or can manifest much later (Berthier & Starkstein, 1987; Bogousslavsky et al., 1988). Duration is usually brief (hours to weeks or months), but can persist indefinitely (Berthier & Starkstein, 1987; Bogousslavsky et al., 1988; Carota et al., 2002; Fisher, 1982). Among their eight cases reported by Levine and Finklestein (1982), post-CVA psychosis developed acutely, within hours to days, and had variable duration, from days to months. Two patients had clear recurrences; two others were suspected to have had recurrences as well. Similarly, the influence of psychopharmacologic treatment on course and prognosis suffers from insufficient cases in the literature to offer clarity. Suspected neuropathology A specific and detailed anatomic basis for post-CVA psychosis has not been identified (Dupont et al., 1988). However, the bulk of cases suggest localization to the right side of the brain, suggesting a mixed model of diffuse cortical injury combined with more focal lesions in many cases (Dupont et al., 1988). There have also been reports of psychosis following brainstem stroke (Dupont et al., 1988). Delusional misidentification symptoms in acute stroke have been associated with ‘‘disconnection’’ of cortical areas representing face (the fusiform gyrus) and place (parahippocampal gyrus) perception from areas of the right temporal lobe, where functions of long-term memory, memory retrieval, and visual recognition are localized (Carota et al., 2002). According to Hudson and Grace (2000), the misidentification syndromes may be related to right temporal lobe lesions. The areas of the temporo-parietal-occipital junction and the thalamus appear most commonly in post-CVA psychosis (Carota et al., 2002; Fisher, 1982; Starkstein et al., 1992). Pre-existing cortical atrophy may increase risk for post-CVA psychosis (Carota et al., 2002; Starkstein et al., 1992). Right-sided thalamic infarct has

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been associated with ‘‘manic delirium’’ and visual hallucinations (Carota et al., 2002; Serra Catafau et al., 1992). It has been postulated that the hallucinations experienced by post-CVA psychotic patients may follow activation of regions near the occipital cortex, triggering the experience of visual stimuli (Carota et al., 2002). Levine and Grek (1984) addressed the anatomic basis of post-CVA delusions. They compared nine cases with right-sided CVA and delusions to 16 similar CVA patients without delusions. Symptomatically, the nine delusional patients had symptoms including ‘‘confabulation, disorientation, false identities, and unreasonable beliefs about the future.’’ The patients with delusions did not have lesions in a specific area of the right hemisphere that distinguished them from the nondelusional patients. However, patients with delusions had larger ventricles and wider sulci (consistent with pre-CVA brain atrophy) than non-delusional comparison subjects. There was a trend for delusions to be more common in older patients. Levine and Grek (1984) hypothesized that, due to the apparent importance of pre-CVA atrophy in their study, the condition of the brain unaffected by the acute CVA (particularly the left cortex) may determine whether a right-sided CVA patient develops post-stroke psychosis. A presumed model offered is that delusions following stroke depend on an interaction between the focal right-sided lesion and diffuse pre-existing brain atrophy. This may be due to combined impairments in memory and thought that results in delusional confusion. Rabins, Starkstein, and Robinson (1991) reported five patients with atypical schizophreniform psychosis following right hemisphere stroke, which were compared to matched controls with similar lesion size and location but no psychosis. The psychotic patients had a larger frontal horn ratio and larger third ventricle ratio than controls. The authors suggested that pre-existing subcortical atrophy and right hemisphere lesion were risk factors for post-CVA psychosis. A cautionary note is struck by Howard et al. (1995), who compared a group of 38 patients with late-onset (after age 60) psychosis and normal volunteers. They found that periventricular and deep white matter and subcortical hyperintensities on MRI were not more common in the group with psychosis than controls. The relationship between seizures and post-CVA psychosis may be of importance. In the eight cases of Levine and Finklestein (1982), seizures preceded the onset of psychosis in five patients and followed the onset of psychosis in two others. Despite this coincidence, the specific relationship of seizure and psychosis in these patients remains unclear. As all of their patients had lesions in the temporo-parieto-occipital region, Levine and Finklestein (1982) surmised that spatial disabilities in right hemisphere stroke patients might contribute to psychosis. An epileptic discharge in the right hemisphere (some with minimal motor

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manifestations) could precede psychosis, which represents an unstable pathophysiological state in the course of recovery from seizure activity in this region. A review by Starkstein et al. (1992), focusing primarily on hallucinatory symptoms post-CVA, also associated seizures and subcortical atrophy with these symptoms. Richardson (1992) described two models for post-stroke psychosis. One presentation is in patients without chronic disease who develop post-CVA psychosis at a time distant from CVA; these patients often have epileptic activity on EEG and clinically respond to anticonvulsants. The other type has chronic illnesses antedating stroke and develop psychosis soon after CVA; presumably, atrophy from the antecedent conditions predispose to the post-CVA psychosis. This group responds with some variability to antipsychotic agents. Staton, Brumback, and Wilson (1982), in an in-depth presentation of a head injury (not stroke) patient with reduplicative paramnesia, considered this symptom to be a ‘‘disconnection syndrome of memory.’’ The neuropsychological battery of their patient localized deficits to the right hemisphere, primarily the posterior association cortex. Because of the prominence of disorientation with reduplicative paramnesia, Staton et al. (1982) considered reduplicative paramnesia to be consistent with a primary ‘‘amnesia,’’ similar to Korsakoff syndrome. Since there is a disorientation component, this symptom cluster (and similar ones, such as Capgras’ syndrome) blurs the distinction between ‘‘purely cognitive’’ symptoms and ‘‘purely psychotic’’ ones. They speculated that the deep white temporo-parieto-occipital junction was a location where ‘‘disconnection’’ of the memory system could plausibly produce disorientation. In a similar, albeit non-CVA case, Wilcox and Waziri (1983) reported a case of a woman with Capgras’ syndrome who had neuropsychological testing and evoked potential evidence of right hemisphere dysfunction, despite an unremarkable CT scan. Her Capgras’ delusion consisted of a belief that her parents had been killed and replaced by doubles. She responded to a trial of haloperidol 20 mg qhs, but did not achieve full remission. While not addressing post-stroke psychosis, per se, Joseph et al. (1999) studied 10 psychiatric inpatients (nine with paranoid schizophrenia and one with bipolar disorder), all of whom experienced reduplicative paramnesia (RP), one of the delusional misidentification syndromes anecdotally reported in post-stroke psychosis. Compared to controls with similar psychiatric illness but without RP, the RP subjects had more cortical (frontal, temporal, and occipital lobes) atrophy, cortical fissure enlargement, and deep brain atrophy. The authors concluded that bilateral anterior cortical, brain stem, and cerebellar vermis atrophy may be implicated in the genesis of RP and other delusional misidentification syndromes. An intriguing model for CVA and psychosis is presented by Iizuka et al. (2003). They studied stroke-like lesions in the MELAS syndrome, which is a constellation

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of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Their study included MRI, EEG, and SPECT within one month of onset. They examined four stroke-like episodes in three patients. Two presented with psychosis. In three of the stroke-like episodes, seizure developed in association with the stroke-like lesion. The MRI findings progressed from the temporal cortex to parietal or occipital cortex. However, of the two patients with psychosis, one had a right-sided lesion on MRI, while the other had a left-sided lesion. Suspected neurochemical abnormalities The literature to date offers little guidance as to neurochemical abnormalities in post-CVA psychosis. Response of at least some cases to trials of antipsychotic medication leads to the suggestion that dopamine blockade by the typical antipsychotic agents described reverses a relative hyper-dopaminergic condition, but this is speculative at best.

Genetic factors There are no reported genetic factors in post-CVA psychosis. Other risk factors The only additional risk factor for post-CVA psychosis is old age (Carota et al., 2002; Levine and Grek, 1984), which is difficult to separate from the general increased risk of CVA in the elderly.

Treatment Prospective treatment-response studies for post-CVA psychosis are unavailable (Dupont et al., 1988). For antipsychotic treatment of post-stroke psychosis, atypical antipsychotic medications are preferred (Chemerinski & Robinson, 2000). As most stroke patients are older and many have pre-existing cortical atrophy and/or vascular dementia, lower starting doses of antipsychotic medications (e.g., risperidone 0.5 mg po bid) are recommended, with cautious dose escalations as necessary to control symptoms. In cases that are refractory to treatment with atypical antipsychotics, especially if there is clinical suspicion of a seizure disorder and/or an abnormal EEG, a trial of anticonvulsants may decrease psychotic symptoms (Chemerinski & Robinson, 2000). Certainly, it would appear to be prudent to consider anticonvulsants earlier

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if the patient has a documented abnormal EEG. In some cases, especially with incomplete response to antipsychotic or anticonvulsant medication, combined therapy with atypical antipsychotics and anticonvulsants may be considered. Duration of treatment should be individualized. As duration of symptoms appears quite variable, with some reports of apparent spontaneous recovery accompanied by other cases with persistent symptoms, a reasonable course of action would be to offer antipsychotic (and/or anticonvulsant) medication for several months with close monitoring, followed by a cautious tapering of medication and close surveillance for recurrence of symptoms. Patients who experience a prompt re-emergence of psychotic symptoms after medication is stopped should be re-treated. In any patient with a documented history of CVA, vigilance for the later emergence (even years later) of psychotic symptoms is warranted. It is reasonable to obtain new neuroimaging and EEG in the case of onset of psychotic symptoms that occur well after the initial stroke. Further episodes of psychotic symptoms should lead to a trial of antipsychotic and/or anticonvulsant therapy. Consideration of cholinesterase inhibitors for concurrent cognitive symptoms, as is increasingly routine for vascular and Alzheimer’s dementia, appears prudent as well. Antidepressants for mood and anxiety symptoms should also be integrated into the treatment model, targeting specific mood symptoms. Psychiatric referral should be considered at a low clinical threshold in the post-CVA psychosis patient. Due diligence in monitoring for suicidality, homicidality, and psychotic disorganization is needed, with hospitalization for the dangerous and unstable patient. Conclusions Psychosis following cerebrovascular accident is an infrequently reported neuropsychiatric illness. While the clinical phenomenology of post-stroke psychosis may resemble that of more common psychotic disorders (e.g., schizophrenia), there may be associated cognitive, mood, or anxiety symptoms in the post-stroke presentation. The cases in the literature suggest that post-stroke psychosis may be preferentially associated with right-sided vascular lesions, via an unknown mechanism. Clinical intervention with conventional psychopharmacologic agents may be associated with symptomatic improvement. REFERENCES Battaglia, J. & Spector, I. C. (1988). Utility of the CAT scan in a first psychotic episode. General Hospital Psychiatry, 10, 398
401.

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31. Bogousslavsky, J., Ferrazzini, M., Regli, F., et al. (1988). Manic delirium and frontal-like syndrome with paramedian infarction of the right thalamus. Journal of Neurology, Neurosurgery, and Psychiatry, 51, 116
19. Carota, A., Staub, F., & Bogousslavsky, J. (2002). Emotions, behaviors, and mood changes in stroke. Current Opinion in Neurology, 15, 57
69. Chemerinski, E. & Robinson, R. G. (2000). The neuropsychiatry of stroke. Psychosomatics, 41, 5
14. Collins, M. N., Hawthorne, M. E., Gribbin, N., & Jacobson, R. (1990). Postgraduate Medical Journal, 66, 1064
7. De Paw, K. W., Szulecka, T. K., & Poltock, T. L. (1987). Fregoli syndrome after cerebral infarction. Journal of Nervous and Mental Disease, 175, 433
8. Dupont, R. M., Cullum, C. M., & Jeste, D. V. (1988). Poststroke depression and psychosis. Psychiatric Clinics of North America, 11, 133
49. Feinberg, W. M. & Rapcsak, S. Z. (1989). ‘‘Peduncular hallucinosis’’ following thalamic infarction. Neurology, 39, 1535
6. Fisher, C. M. (1982). Disorientation for place. Archives of Neurology, 39, 33
6. Howard, R., Cox, T., Almeida, O., et al. (1995). Biological Psychiatry, 38, 86
91. Hudson, A. J. & Grace, G. M. (2000). Misidentification syndromes related to face specific area in the fusiform gyrus. Journal of Neurology, Neurosurgery, and Psychiatry, 69, 645
8. Iizuka, T., Sakai, F., Kan, S., & Suzuki, N. (2003). Slowly progressive spread of the stroke-like lesions in MELAS. Neurology, 61, 1238
44. Joseph, A. B., O’Leary, D. H., Kurland, R., & Ellis, H. D. (1999). Bilateral anterior cortical atrophy and subcortical atrophy on reduplicative paramnesia: A case-control study of computed tomography in 10 patients. Canadian Journal of Psychiatry, 44, 685
9. Leiguarda, R. C. (1983). Environmental reduplication associated with a right thalamic haemorrhage. Journal of Neurology, Neurosurgery, and Psychiatry, 46, 1154. Levine, D. N. & Finklestein, S. (1982). Delayed psychosis after right temporoparietal stroke or trauma: Relation to epilepsy. Neurology, 32, 267
73. Levine, D. N. & Grek, A. (1984). The anatomic basis of delusions after right cerebral infarction. Neurology, 34, 577
82. McGilchrist, I., Goldstein, L. H., Jadresic, D., & Fenwick, P. (1993). Thalamo-frontal psychosis. British Journal of Psychiatry, 164, 113
15. Mesulam, M.-M., Waxman, S. G., Geschwind, N., & Sabin, T. (1976). Acute confusional states with right middle cerebral artery infarctions. Journal of Neurology, Neurosurgery, and Psychiatry, 39, 84
9. Pakalnis, A., Drake, M. E., & Kellum, J. B. (1987). Right parieto-occipital lacunar infarction with agitation, hallucinations, and delusions. Psychosomatics, 28, 95
6. Peroutka, S. J., Sohmer, B. H., Kumer, A. J., et al. (1982). Hallucinations and delusions following a right temporoparietooccipital infarction. Johns Hopkins Medical Journal, 15, 181
5. Price, B. H. & Mesulam, M. (1985). Psychiatric manifestations of right hemisphere infarctions. Journal of Nervous and Mental Disease, 173, 610
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9. Richardson, J. K. (1992). Psychotic behavior after right hemispheric cerebrovascular accident: A case report. Archives of Physical Medicine and Rehabilitation, 73, 381
4. Robinson, R. G. (1998). Poststroke mania: Prevalence and clinical symptoms. In The Clinical Neuropsychiatry of Stroke. Cambridge, UK: Cambridge University Press, pp. 297
302. Ruff, R. L. & Volpe, B. T. (1981). Environmental reduplication associated with right frontal and parietal lobe injury. Journal of Neurology, Neurosurgery, and Psychiatry, 44, 382
6. Serra Catafau, J., Rubio, F., & Peres Serra, J. (1992). Peduncular hallucinosis associated with posterior thalamic infarction. Journal of Neurology, 239, 89
90. Starkstein, S. E., Robinson, R. G., & Berthier, M. L. (1992). Post-stroke hallucinatory delusional syndromes. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 5, 114
18. Staton, R. D., Brumback, R. A., & Wilson, H. (1982). Reduplicative paramnesia: A disconnection syndrome of memory. Cortex, 18, 23
6. Wilcox, J. & Waziri, R. (1983). The Capgras symptom and nondominant cerebral dysfunction. Journal of Clinical Psychiatry, 44, 70
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Psychosis in patients with brain tumors Tamara Dolenc and Teresa Rummans Mayo Clinic

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

C C C C C D D D D

Introduction Primary brain tumors are a diverse group of neoplasms arising from the brain parenchyma (primarily from astrocytes, oligodendrocytes, and less frequently ependymal cells), meninges, pituitary region, pineal region, and skull base. To this date, over 120 types of brain tumors have been identified. The incidence of primary brain tumors varies by gender and geographic location, and has risen over the past decades. The most common histologic tumor types are meningiomas (27%), glioblastomas (21%), other astrocytomas (11%), neuromas (8%), and oligodendrogliomas (4%). Histologic tumor types affecting children are different from those in adults. For gliomas and meningiomas, the incidence increases with age, reaching a peak in late adulthood. Primary CNS lymphoma is rare, representing about 1% of all primary brain tumors; its incidence has dramatically increased in the past decades, in part due to the AIDS epidemic (Batchelor, Dorfman, & Hunter, 2005; DeAngelis, 2001). 302

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Most brain tumors in adults are supratentorial. Primary brain tumors are most commonly located in the posterior fossa (30%), frontal and temporal area (22%), and less commonly in the parietal area (12%), pituitary (10%), and the occipital lobes (4%). In children, primary brain tumors are primarily infratentorial. Brain metastases typically arise in mid-to-late adulthood, are common, and affect up to 25% of cancer patients. They most commonly originate from primary cancers of lung, breast, gastrointestinal tract, kidney, and skin. Testicular and thyroid cancer, though uncommon, also frequently metastasize to the brain (Batchelor et al., 2005; DeAngelis, 2001). Although the overall prevalence of occult tumors in psychiatric patients is unknown, brain tumors have been found in only a small percentage of institutionalized psychiatric patients, and have been associated with diverse psychopathology, including psychosis. While psychosis can occur with tumor in any part of the brain and with any histologic tumor type, psychotic symptomatology most commonly occurs with tumors located in the frontal and temporal lobes and with bilateral involvement (Lisanby et al., 1998; Price, Goetz, & Lovell, 2002; Roy-Byrne & Upadhyaya, 2002). Tumor treatments, such as surgery, chemotherapeutic agents, interferon, corticosteroids, and antiepileptic levetiracetam can also produce psychosis (Gilbert, 2004; Holland, Fasanello, & Ohnuma, 1974; Kerschner & Wang-Cheng, 1989; Lisanby et al., 1998; Ron et al., 1992). Epidemiology About 40,000 Americans per year are diagnosed with a primary brain tumor (17,000 are malignant) and about 170,000 with brain metastases. Although brain tumors account for only 2% of all cancers, they result in a disproportionate share of cancer morbidity and mortality. In 2002, malignant brain tumors claimed 13,000 deaths (Central Brain Tumor Registry, 2002; DeAngelis, 2001). Brain tumors in psychiatric patients

The epidemiological studies of psychiatric symptomatology in brain tumor patients are limited and often flawed as a result of small sample sizes, inconsistent diagnostic criteria, and methodological and reporting flaws, which makes it difficult to estimate how common psychiatric symptoms in brain tumor patients really are. It has been reported that primary brain neoplasms are more common in psychiatric patients than in psychiatrically healthy controls (Lisanby et al., 1998; Price et al., 2002). The review of 19 autopsy studies spanning over 80 years (from 1884 to 1964) found the prevalence of brain tumors in psychiatrically hospitalized patients at about 2
3%. A general hospital series yielded a lower rate

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of around 2%. Five chart review and hospital census studies in psychiatric hospitals, involving over 250,000 patients, found an even lower brain tumor rate of 0.1% (Lisanby et al., 1998). In contrast with psychiatric patients in general, the prevalence of brain tumors in patients with psychosis is unknown. Psychiatric symptoms in brain tumor patients

Our present understanding of psychiatric phenomenology in brain tumor patients is based on the findings of retrospective case reports and uncontrolled case series, many of which were published decades ago. Due to the inconsistent criteria for diagnosing psychiatric disorders in the studies predating the implementation of the Diagnostic and Statistical Manual of Mental Disorders (DSM) (American Psychiatric Association, 2000), there are significant difficulties with interpreting and comparing results of different studies (Price et al., 2002; Rogers & Mendoza, 2005). Nonetheless, it is generally believed that the prevalence of psychopathology in this population is higher than in the general population. The two largest studies found the prevalence rates of psychiatric symptoms in brain tumor patients at 51% and 78%. There is a divergent opinion in the literature on the prevalence of psychotic symptoms in patients with brain tumors, with prevalence rates varying from 2% to 50% (Filley & Kleinschmidt-DeMasters, 1995; Price et al., 2002; Rogers & Mendoza, 2005).

Age of onset and presentation The development of psychosis in patients with brain tumors can occur at any age and obviously follows the age distribution of the specific tumor types. Intracranial neoplasms generally produce progressive symptoms. Brain tumor-related psychiatric symptoms typically develop over a period of weeks to months. The initial symptoms are often vague and nonspecific. In some cases, the onset of psychopathology may be abrupt (i.e., the acute apoplectic onset is associated with hemorrhage or development of hydrocephalus). Occasionally, psychiatric symptoms may be present for years prior to neurologic signs, and in some cases brain tumor may only be diagnosed post mortem. However, there is no uniform presentation of psychotic symptoms in patients with brain tumors (Filley & Kleinschmidt-DeMasters, 1995; Keschner et al., 1938; Lisanby et al., 1998). Most commonly, psychotic symptoms due to a brain tumor may mimic primary psychotic disorders, like schizophrenia and delusional disorder, major depressive or bipolar disorder. Psychotic symptoms may follow seizures, which are common with brain tumors, especially if located in the temporal lobes (Davies & Clarke, 2004).

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The few retrospective reports that exist on psychotic symptoms in brain tumor patients primarily describe perceptual disturbance and delusional thinking. Hallucinations in brain tumor patients tend to be less complex than in patients with schizophrenia. Visual hallucinations seem to be more common than auditory hallucinations, and are generally short lasting and rarely well formed. Nonetheless, there are reports of brain tumor patients with auditory hallucinations, ranging from simple sounds, like ringing, humming, or buzzing, to more complex perceptual disturbance. In addition, delusions secondary to brain tumors are commonly of paranoid or persecutory type and less complex than those occurring in primary chronic psychotic disorders. Nevertheless, establishing the diagnosis of a brain tumor solely on the psychotic symptom pattern is not possible (Filley & Kleinschmidt-DeMasters, 1995; Keschner et al., 1938).

Course and progression Determining the diagnosis always requires an integration of diverse information from the history of present illness, past medical and psychiatric history, family history, the mental status and neurologic examination, as well as pertinent diagnostic tests. In the presence of soft neurologic signs or new-onset seizures, an underlying neurologic condition such as a brain tumor should be strongly considered. Psychiatric symptoms are often the earliest and sometimes the only symptom of an intracranial tumor, and the diagnostic possibility of a brain tumor should always be considered in patients with new-onset psychosis (Fogel & Stoudemire, 2000). The wide variety of psychiatric symptoms that occur with brain tumors, however, makes diagnosing and localizing lesions on the sole basis of psychiatric phenomenology difficult (Lisanby et al., 1998). When this is possible, the most appropriate DSM-IV TR diagnosis is psychosis due to a general medical condition (i.e., brain tumor) or psychosis secondary to tumor-related treatments (i.e., surgery, chemotherapy, corticosteroids, interferon, levetiracetam). Also, the brain tumor and associated edema, elevated intracranial blood pressure, brain radiation, chemotherapeutic agents, and interferon have all been associated with delirium. Other physical symptoms indicating possibility of underlying brain tumor include: – headaches of new onset or changed in characteristics, as well as nocturnal, positional, or if present immediately after waking up – nausea and vomiting – visual, auditory changes, and vertigo – other focal neurologic signs, like weakness, sensory loss, and ataxia

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– acute or slow changes in one’s cognition, behavior, or personality, especially when coupled with neurologic symptoms (Batchelor et al., 2005; Lisanby et al., 1998; Maity et al., 2004; Price et al., 2002). Additional information that can help differentiate primary from secondary psychotic disorder includes an elevated prolactin level, EEG (especially if showing focal abnormalities), and most importantly a gadolinium-enhanced magnetic resonance imaging (MRI) which has replaced computerized tomography (CT). The sensitivity of MRI to pathologic alterations in the brain tissue, its superior anatomic resolution, and its ability to differentiate varying tissue types within tumors favors its use in patients with a suspected brain tumor. However, CT remains superior for visualizing intratumor calcifications and bone erosions. Patients with medical contraindication to MRI, like implanted cardiac pacemaker or ferromagnetic foreign body, should be imaged with CT. The definitive diagnosis of a brain tumor, though, usually requires histopathological assessment, which is the gold standard for diagnosis (Batchelor et al., 2005). The course of psychosis in brain tumor patients is poorly understood. In untreated tumors, the symptomatology, including psychosis, tends to be progressive. Appropriate tumor treatment may alleviate or remove psychotic symptoms, but also can exacerbate or worsen psychosis. Prognosis is variable: while glioblastoma multiforme, a high-grade glioma, continues to have extremely poor prognosis, meningioma or pituitary adenoma may be completely cured or their growth stopped with appropriate treatment. Suspected neuropathology Parenchymal brain tumors are thought to produce symptoms by three main mechanisms: (1) infiltration along nerve fiber tracts typical of low-grade astrocytomas and oligodendrogliomas, (2) displacement of brain tissue and production of vasogenic edema typical of cerebral metastases, and (3) mass growth and destruction of surrounding neuropil that occurs with rapidly growing aggressive tumors, such as high-grade astrocytomas (Maity et al., 2004). The tumor size and rate of growth, associated cerebral edema, mass effect, increased intracranial pressure, hydrocephalus, secondary cerebral ischemia, and tumor secretions may contribute to development of psychosis. Genetic, developmental, and environmental factors are also believed to impact the symptom occurrence. Pre-existing psychiatric problems may predispose someone to developing psychiatric symptoms, such as psychosis, when brain tumor develops (Lisanby et al., 1998; Price et al., 2002; Weitzner, 1999). Tumor-related psychosis tends to be more common in the elderly but also occurs in younger adults and children (Lisanby et al., 1998). Psychotic symptoms

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have been associated with a variety of tumor types, yet to this date no histologic tumor type has been particularly associated with psychosis. While the findings of reports addressing the impact of tumor laterality on the development of psychotic symptoms are inconsistent, patients with bilateral involvement seem to be at a higher risk for psychosis (Price et al., 2002). Certain tumor locations have been associated with specific psychotic symptoms. For example, frontal lobe tumors have been associated with auditory and olfactory hallucinations (Azuonye, 1997; Takeuchi et al., 1993), ideas of reference, frank olfactory and paranoid delusions, and Capgras syndrome (Avery, 1971; Durani, Ford, & Sajjad, 1991; Keschner et al., 1938; Kim, 1991; Rogers & Mendoza, 2005; Sato et al., 1993; Takeuchi et al., 1993). Temporal lobe tumors have produced non-specific hallucinations and delusions, along with mood changes but typically preserved affect. In some cases, but not all, these features help distinguish psychosis due to temporal lobe tumors from schizophrenia (Binder, 1983; Filley & Kleinschmidt-Demasters, 1995; Kan et al., 1989; Keschner et al., 1938; Malamud, 1967; Okada, Aida, & Abe, 1992; Roberts, Williams, & Stack, 1987). Parietal and occipital tumors are less often associated with psychotic symptoms than tumors in the frontal and temporal lobes, and have been associated with paranoid delusions and delusional misidentification syndromes, like Capgras syndrome, as well as schizophrenia (Roberts et al., 1987). With occipital tumors, visual hallucinations, paranoid ideation, and frank delusions have been described (Binder, 1983; Nagaratnam, Virk, & Brdarevic, 1996; Rogers & Mendoza, 2005). Tumors below tentorium tend to have lower incidence of psychiatric symptoms than supratentorial lesions. Nonetheless, psychiatric symptomatology noted in these patients is as diverse as with supratentorial lesions, and auditory and visual hallucinations, and delusions have been described (Cairns, 1950; Maiuri et al., 2002; Pollak et al., 1996; Sandyk, 1993; Wilson, 1946). Cerebellar and cerebellopontine tumors and aqueductal stenosis have been associated with hallucinations and paranoid delusions (Nadvi & Ramdial, 1998; Parisis et al., 2003; Sadamoto et al., 1993). Peduncular hallucinosis with vivid life-like complex visual hallucinations has been described with tumors compressing the midbrain (Miyazawa et al., 2001; Nadvi & Ramdial, 1998; Parisis et al., 2003; Sadamoto et al., 1993). Psychosis has also been reported in patients with subcortical tumors in the diencephalic and periventricular area (Buchanan & Abram, 1975; Carson et al., 1997; Coppola et al., 2002; Craven, 2001; Izci et al., 2003; Kugaya et al., 1996; Lobosky, Vangilder, & Damasio, 1984; Mahendran, 1998; Upadhyaya & Sud 1988). Corpus callosum tumors have been associated with paranoid thinking and koro, an otherwise typically culture-bound syndrome (Durst & Rosca-Rebaudengo, 1988).

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Psychiatric presentation of pituitary tumors is diverse and reflects not only tumor location and growth into other structures but also the impact of the altered hormonal levels. Pituitary adenomas are commonly associated with hyperprolactinemia and Cushing’s syndrome, which have both been associated with auditory and visual hallucinations, ideas of reference, paranoid and other delusional thinking, and psychosis (Gerson & Miclat, 1985; Saad et al., 1984; Sandyk, Bergsneider, & Iacono, 1987; Tran & Elias, 2003).

Suspected neurochemical abnormalities The specific pathophysiology of psychosis in brain tumor patients has not been thoroughly studied. In contrast with schizophrenia, in which neuroanatomic, cytoarchitectural, neurochemical, and neural circuitry disturbances have been extensively researched, little is known about suspected neurochemical correlates of psychosis in the presence of a brain tumor. No dopaminergic, glutamatergic, or cholinergic neurochemical abnormalities have been reported in tumor-associated psychosis. Our present understanding of the pathophysiology of schizophrenia can therefore inform, yet not fully explain, the appearance and characteristics of psychotic symptoms in brain tumor patients; the pathophysiology of psychotic symptomatology with brain tumors remains to be fully elucidated. Disruption of the neural circuits connecting the nearby and distant brain areas probably plays a major role, and may help conceptualize the astonishingly similar symptomatology with tumors in grossly different locations.

Genetic and other risk factors Genetic factors are thought to contribute to development of rare hereditary tumors occurring in neurofibromatosis type 1 and 2, tuberous sclerosis, von Hippel-Lindau disease, and Sturge-Weber syndrome. The occurrence of psychosis in those populations is unknown. These risk factors, however, account for only a small amount of cases, and in the majority of patients the combined effects of genetic and environmental factors are probably responsible for brain tumor development. The most commonly identified risk factors for brain tumors are brain radiation and immunosuppression. Risk factors for tumor-related psychosis are unknown. While some brain tumors have gender predilection (i.e., meningioma is more common in women, prostate cancer brain metastases occur only in men, and breast cancer metastases primarily in women), no overt gender differences in the incidence of tumor-related psychosis have been established.

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A number of tumor treatments may exacerbate psychotic symptoms. Surgery, chemotherapeutic agents (L-asparaginase, tamoxifen), corticosteroids, interferon, and levetiracetam all can induce psychosis (Kershner & Wang-Cheng, 1989; Rogers & Mendoza, 2005). Dopamine agonists (i.e., bromocriptine and lisuride) produced psychotic symptoms, including hallucinations and delusions, in eight out of 600 treated for a pituitary tumor (Turner et al., 1984). Individual cases of new-onset psychosis with bromocriptine-treated prolactinomas have also been described (Peter, Autz, & Jean-Simon, 1993). Little is known about psychosocial risk factors for psychosis in this patient population. Patient’s premorbid personality and coping style, personal and family psychiatric history, the availability of social support, presence of physical or psychological impairment, and the effects of brain tumor treatments are all believed to impact the emergence, nature, and severity of psychotic and other psychiatric symptoms (Price et al., 2002; Weitzner, 1999). Treatment Treatment of psychosis in patients with brain tumors is complicated. Clearly the elimination of the tumor and its related conditions may greatly improve psychotic symptoms; however, these tumor treatments may also produce psychotic symptoms. Surgical treatment may resolve or alleviate tumor-related psychopathology but also result in worsening of psychosis. The increase in psychotic symptoms is most frequently associated with post-operative delirium, which may result from the intraoperative injury, brain edema, and high-dose corticosteroid treatment. This is often temporary but may require use of antipsychotic medication (Andermann et al., 1999; Keshavan, Kahn, & Brar, 1988; Kumar et al., 1999; Scott, 1970). While the exact incidence of brain radiation-related neurotoxicity is unknown, it is estimated that diffuse radiation injury occurs in up to half of treated patients (Maity et al., 2004). Somnolence, nausea, and irritability are common in the first post-radiation months, and brain necrosis with cognitive impairment may occur. Brain radiation alone has, however, not been associated with psychosis (Maity et al., 2004). Chemotherapeutic agents can be neurotoxic (Gilbert, 2004). L-asparaginase has been associated with hallucinations, delusions, and delirium (Holland et al., 1974) and tamoxifen with reversible encephalopathy and delusions (Ron et al., 1992). Psychosis also occurs with corticosteroid treatment and interferon use (Gilbert, 2004; Kerschner & Wang-Cheng, 1989). Brain tumor patients often have difficulties with executive functioning and cognitive flexibility, which may interfere with successful treatment intervention.

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Since psychosis can have a major detrimental impact on a patient’s ability to make decisions and compliance with medical and surgical treatment, rapid and appropriate treatment is important. Only a few retrospective case reports exist to guide us in the treatment of tumor-related psychosis. In these cases, antipsychotic agents have been found to successfully treat brain-tumor-related psychosis in some but not all patients (Price et al., 2002; Rogers & Mendoza, 2005). In the absence of prospective randomized control trials, the treatment of brain-tumor-related psychotic symptoms is modeled on the established treatments of primary psychotic disorders. Prior to starting an antipsychotic agent, patients should have a thorough medical evaluation. This begins with a history of all the medications including complementary or over-the-counter treatments that the person is taking. Most antipsychotics are metabolized in the liver and have the potential to interact with other medications being metabolized through the cytochrome P-450 system. Examples of this potential interaction include antipsychotic and antiepileptic medications. Carbamazepine induces this system and can lead to lower blood levels of other medications metabolized through the same system. On the other hand, valproic acid can inhibit the system, leading to toxic levels of medications metabolized through the cytochrome P-450 system. Physical exam and laboratory assessment can help determine whether someone may develop some of the potential side effects associated with antipsychotics. For example, antipsychotics can aggravate existing obesity or orthostatic hypotension. Assessing cardiac and liver function is essential, as all antipsychotics have the potential to impact these areas. QTc interval found on an ECG should be established prior to initiating any antipsychotic medication. A prolonged QTc interval of greater than 450 milliseconds predisposes an individual to potential cardiac toxicity with antipsychotics. It is always clinically wise to use as few medications as possible to achieve the desired therapeutic effect. As with patients with other brain pathology, patients with brain tumors are more susceptible to psychotropic side effects, such as extrapyramidal, anticholinergic, epileptogenic effects, and sedation. It is thus recommended to ‘‘start low and go slow,’’ keeping in mind that brain tumor patients may require equivalent doses of psychotropics to those used in patients without brain lesions (Price et al., 2002; Roy-Byrne & Upadhyaya, 2002). For short-term treatment, haloperidol may be the agent of choice although it has a high potential for extrapyramidal side effects; its intravenous administration may be particularly useful for rapid onset of action and has been associated with a lower risk of extrapyramidal effects. If, however, a patient has had tumorassociated seizures, an agent like risperidone, that may even raise seizure threshold, is preferred. For patients who are overweight, the antipsychotic

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agents associated with significant weight gain (i.e., olanzapine) should be avoided. All antipsychotics can cause hyperprolactinemia and therefore should be avoided, if possible, in patients with pituitary prolactinomas (Melkersson & Hulting, 2000; Pal & Sarino, 2000). Psychosis developing in patients taking antiepileptic levetiracetam is best treated by changing the antiepileptic medication. To this date, evidence is limited on the recommended duration of antipsychotic therapy, therefore once the medication has been started, the need for ongoing treatment should be repeatedly reassessed. The decision has to be made on a caseby-case basis, carefully assessing the patient’s psychiatric symptomatology, the status of a brain tumor, its treatment, medical and psychiatric comorbidities, as well as the medication’s effectiveness and tolerability (Price et al., 2002; RoyByrne & Upadhyaya, 2002). Electroconvulsive therapy (ECT), though primarily used to treat depression and less frequently mania, can also be used to treat medication-resistant psychosis. The presence of an intracranial mass alone without elevated intracranial pressure is a relative contraindication for the use of ECT. Case reports have documented the successful use of ECT in these patients. However, rapid demise can occur in those with both brain tumor and increased intracranial pressure. Consequently, caution should be used if ECT is being considered for one with a known brain tumor, and evaluation immediately prior to ECT for presence of increased intracranial pressure should occur (Greenberg et al., 1988; Kohler & Burock, 2001; Maltbie et al., 1980; McKinney, Beale, & Kellner, 1998; Patkar et al., 2000; Starkstein & Migliorelli, 1993). Conclusions Brain tumors, although relatively rare, are often disabling and fatal. Though uncommon in psychiatric patients, they are often misdiagnosed, especially if neurological findings are absent or minimal. Psychotic symptoms may be harbingers of a brain tumor, in many cases occurring months before the emergence of hard neurologic signs. Psychosis is most frequent with temporal and frontal lobe tumors, and tends to be more common with bilateral involvement and in the elderly. Due to their nonspecific nature, tumor-related psychotic symptoms are not pathognomic for a brain tumor and may mimic psychosis in other primary psychiatric illnesses, like schizophrenia, delusional disorder, major depression, mania, or dementia. Therefore, in any patient with a new onset of psychosis, brain tumor should be entertained, especially if psychotic presentation is atypical or coupled with neurologic symptoms. Tumor treatment can resolve symptoms, but may also further brain injury and aggravate psychosis. Surgery, radiation therapy, certain chemotherapeutic agents, corticosteroids, interferon, and levetiracetam

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can all exacerbate or propagate psychosis. When treating psychosis directly, a careful selection of an antipsychotic agent or treatment such as ECT is necessary to account for the anticipated drug
drug interactions and adverse effects. When these guidelines are followed, safe and effective treatments can be used to minimize the impact of psychosis in brain tumor patients.

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17

Psychosis secondary to infections Sarah Reading and John T. Little Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD

Introduction This section focuses on selected infectious diseases that have been directly associated with neuropsychiatric syndromes, specifically those resulting in secondary psychosis. Secondary psychosis is a severe abnormality of thought content or form due to an identifiable medical or neurological condition that can have many manifestations (Cummings, 1985; 1988). Although there is no single area where brain injury will reproducibly induce psychosis, temporo-parietal regions, caudate nuclei, and cholinergic and dopaminergic tracts appear to be important substrates in many cases of psychosis (Gaudreau & Gagnon, 2005; Iyo, Sekine, & Mori, 2004; Seeman et al., 2005; Shaw et al., 2004). Definition and diagnostic criteria Using the nomenclature of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV; American Psychiatric Association, 1994), secondary psychosis may be classified as Delirium Due to a General Medical Condition, Psychotic Disorder Due to a General Medical Condition, or Mood Disorder Due to a General Medical Condition, with Psychotic Features. Psychosis in delirium occurs only during the episode of delirium. Delirium is an acute syndrome secondary to a medical condition with disturbance in consciousness, attention, and cognition, and which may fluctuate over hours (American Psychiatric Association, 1994). The latter two diagnoses refer to psychosis due to a general medical or neurological condition in which either the psychosis or the mood symptoms predominate. In this chapter we shall focus on psychosis secondary to infectious causes. While most infectious causes of psychosis have viral etiologies resulting in encephalitis, other infectious agents such as bacteria, fungi, and parasites may also invade the nervous system and

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cause the syndrome. Due to the legion types of CNS infections which may cause secondary psychoses, we shall only consider selected conditions in detail. These conditions were chosen based on their prevalence, the availability of literature on their psychiatric manifestations, and their importance in neuropsychiatry. Viral infections Viruses are intracellular parasites of living cells. These replicating biologically active particles carry genetic information in either DNA or RNA molecules, but not both. Viruses replicate by using their genetically active nucleic acids to subvert the metabolic activities of the cell that they infect to bring about the synthesis and reassembly of their component parts (Sherris, 1990). Human immunodeficiency virus (HIV) Summary of findings Grade of evidence Epidemiology: 0.5
15% in individuals with HIV-1. Age of onset: No data. Presentation: Persecutory delusions, auditory hallucinations. Course and progression: Highly variable. Suspected neuropathology: Subcortical neurodegeneration. Suspected neurochemical abnormalities: High levels of intracellular free calcium. Genetic factors: No data. Other risk factors: No data. Treatment: Atypical antipsychotic agents.

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Epidemiology

Acquired immune deficiency (AIDS) results from infection with human immunodeficiency viruses, of which two are currently known, HIV-1 and HIV-2. Globally, the vast majority of AIDS cases result from HIV-1 infection, whereas AIDS secondary to HIV-2 appears to be confined primarily to a region in West Africa (Lishman, 1997, pp. 317
21). An estimated 36 million people worldwide are infected with HIV (Piot et al., 2004). Whereas psychotic symptoms may occur in delirium secondary to HIV infection, HIV may also cause a new-onset psychosis in the absence of delirium. Large-scale surveys have found the

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prevalence of new-onset psychosis to be less than 0.5% among individuals infected with HIV-1 while chart review studies have found the prevalence ranging from 3
15%. Thus secondary psychotic symptoms are uncommon but not rare in HIV-infected populations (Alciati et al., 2001; Koutsilieri et al., 2002; Sewell et al., 1994). Age of onset

There is little or no published data on the age of onset associated with HIV psychosis. Presentation

The clinical presentation of new-onset psychosis due to HIV infection is extremely variable. Delusions are the most common psychotic symptom in HIV infection. In some series, delusions with persecutory, grandiose, or somatic components, account for almost 90% of the cases of psychosis in individuals infected with HIV. Persecutory themes can be quite elaborate. Somatic delusions as well as delusions of thought insertion, thought broadcasting, and of passivity and control are also described. When hallucinations occur, auditory hallucinations are slightly more common than visual hallucinations. A majority of studies also report disorders of thought process, including loosening of associations or frankly disorganized thinking. Disturbances of affect commonly coexist with the psychosis, with anxiety being the most prevalent symptom, followed by depressed mood, euphoria, or irritability. Bizarre behavior is also commonplace in these settings (Atkinson et al., 1988; Harris et al., 1991; Sewell et al., 1994). Course and prognosis

The course and prognosis are highly variable in psychosis secondary to HIV and depend on whether specific complicating conditions coexist. For example, concurrent dementia due to HIV disease indicates a poor prognosis. There is some evidence that death occurs earlier in patients with psychosis compared to nonpsychotic patients with similarly advanced HIV disease. In the short term, prognosis with regard to symptom control is quite favorable, with most patients responding to low-dosage regimens of antipsychotic medications (Dolder, Patterson, & Jeste, 2004). Suspected neuropathology

A number of hypotheses have been proposed in an attempt to explain the pathogenesis of new-onset psychosis in HIV infection: (1) brain damage from some other opportunistic infection; (2) an inferior immune response in

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the CNS that allows for more damage from infectious pathogens (Sewell et al., 1994); (3) subcortical neurodegeneration caused by HIV itself or in the presence of other viral infections (Hinkin et al., 2001); (4) psychosis secondary to HIV encephalopathy (Halstead et al., 1988); or (5) the psychosis is due to an underlying dementia (El Mallakh, 1992). Despite the fact that none of these hypotheses fully explain the pathogenesis of new-onset psychosis in HIV disease, continued examination of these hypotheses may provide valuable insight into the prevention and treatment of new-onset psychosis in HIV infection (Dolder et al., 2004). Suspected neurochemical abnormalities

It has been suggested that high levels of intracellular free calcium can lead to inappropriate neurotransmitter release that may contribute to psychosis in HIV (El Mallakh, 1991). Genetic factors

There is little or no published data on genetic factors associated with HIV psychosis. Other risk factors

There is little or no published data on other risk factors associated with HIV psychosis. Treatment

Treatment for new-onset psychosis associated with HIV infection or existing psychosis in concomitant HIV infection requires a combination of pharmacotherapy and psychosocial interventions. Results from published reports (Harris et al., 1991; Sewell et al., 1994) suggest that HIV infected patients with psychosis generally respond well to antipsychotic medications, but that these individuals are especially sensitive to their side-effects (Hinkin et al., 2001; Sewell, 1996; Shedlack et al., 2005). HIV-infected patients are particularly susceptible to extra-pyramidal symptoms (EPS) and tardive dyskinesia (TD) induced by conventional antipsychotic agents (Ayuso, 1994). The likelihood of patients with AIDS developing EPS or TD from typical antipsychotic agents was reported to be more than twice that in non-AIDS patients after controlling for the mean dose and body weight (Hriso et al., 1991). Atypical antipsychotic agents, therefore, are the treatment of choice for HIV-related psychosis.

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Herpes simplex encephalitis (HSE) Summary of findings Grade of evidence Epidemiology: 0.001% in individuals with HSV-1. Age of onset: Peak ages between 60
64 years. Presentation: Auditory, olfactory, and gustatory hallucinations. Course and progression: Both acute and chronic presentations; often rapid onset of acute symptoms, the chronic course can develop over time with slow progression to psychosis. Suspected neuropathology: Gray matter lesions in medial temporal cortex and other limbic areas; hemorrhagic necrosis. Suspected neurochemical abnormalities: No data. Genetic factors: No data. Other risk factors: No data. Treatment: Antiviral agents, antipsychotic agents, carbamazepine.

B C B B

B

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Epidemiology

Herpes simplex encephalitis results from infection from Herpes Simplex Virus, type 1 (HSV-1) and accounts for approximately 10% of all cases of viral encephalitis in the United States (Tyler, 2004). Only about one in 100,000 persons affected with HSV-1, however, will actually develop HSV encephalitis (Corey, 1990). Age of onset

There is a bimodal distribution of HSE with only a third of cases occurring in those less than 20 years old and a half in those aged 50 years or more. In a recent polymerase chain reaction (PCR) study of 516 patients with clinical evidence of encephalitis, 7.4% of cases were due to HSV infection and most HSE cases were in those 40 years of age or older (Koskiniemi et al., 1996). The peak incidence of HSE occurred in subjects aged between 60 and 64 years, for whom HSV accounted for 37.5% of all cases of encephalitis (Tyler, 2004).

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Presentation

Typically there is rapid onset with severe illness in the acute stage. Pyrexia and seizures are frequent in all age groups, meningeal irritation is common, and drowsiness or global confusion is prominent. In some cases the psychological symptoms can predominate (Drachman & Adams, 1962). Hallucinations can resemble those of delirium tremens in being vivid and colorful, and in provoking a marked emotional reaction. Other symptoms can include anosmia, olfactory and gustatory hallucinations, or marked memory impairment out of proportion to the impairment of intellect (Steadman, 1992). Finally, there have been isolated cases of chronic HSV infections leading to temporal lobe seizures, disorders that have been associated with personality change and olfactory hallucinations (Cornford & McCormick, 1997). Course and prognosis

Treatment is often a matter of urgency and the outcome depends on the speed with which treatment is initiated. Before the advent of acyclovir, mortality exceeded 70% and prognosis was poor as only a minority of individuals could return to normal function (Illis & Merry, 1972). With acyclovir the prognosis has improved considerably, but when the temporal lobes have been damaged the consequences can still be grave. Seizures, dysphasia, personality change, and severe amnestic states have been described (Oxbury & MacCallum, 1973). Even with patients who make apparently excellent recoveries, neuropsychological testing may reveal evidence of cognitive deficits (Gordon et al., 1990). Suspected neuropathology

Pathologic changes characteristic of other forms of encephalitis are seen with perivascular infiltration of lymphocytes and histocytes in the cortex and adjacent white matter, proliferation of microglia, and the formation of glial nodules. Microscopically, Cowdry type A inclusion bodies are often detected in affected neuronal cells. The cerebral cortex is mainly affected in adults (Lishman, 1997, p. 356). MRI evaluation reveals the characteristic findings of medial temporal lobe and insular involvement. The lesions usually begin in the medial temporal cortex, with bilateral spread along limbic pathways to the orbital frontal lobe and insular cortex. Parietal, occipital, brain stem, internal capsule, and cingulate gyrus involvement often occurs with further spread, but the basal ganglia and lobar white matter are relatively spared (Wasaya et al., 2005). There have been EEG abnormalities reported with HSV encephalitis and have included frontotemporal delta slowing, periodic lateralized epileptiform discharge, and runs of spike activity. EEG can normalize after treatment but has a poor correlation with overall outcome (Misra & Kalita, 1998).

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Suspected neurochemical abnormalities

There is little or no published data on neurochemical abnormalities associated with HSV psychosis. Genetic factors

There is little or no published data on genetic factors associated with HSV psychosis. Other risk factors

There is little or no published data on other risk factors associated with HSV psychosis. Treatment

The management of the patient with suspected HSV-1 encephalitis parallels the diagnostic tests, immediate antiviral chemotherapy being mandatory. Given the appropriate clinical setting, acyclovir is promptly administered (Johnson, 1996; Vernassiere et al., 2003). Toxicity is usually mild and not treatment-limiting; it may include thrombocytopenia, increased transaminases, creatinine, and BUN. In rare cases of significant treatment-limiting acyclovir side effects or of acyclovir resistance, vidarabine or foscarnet are alternative antiviral agents that can be given (Vernassiere et al., 2003). Supportive measures in the management of a patient with suspected HSV-1 encephalitis are extremely important and psychotic symptoms should be treated with antipsychotic agents. Further, a number of case reports have suggested that the addition of carbamazepine can result in marked reduction in EEG-detected seizure activity and in the frequency of emotional outbursts, extending to as much as one year after treatment (Gaber & Eshiett, 2003; Vallini & Burns, 1987).

Bacterial infections Bacteria are small micro-organisms without mitochondria whose nuclear material consists of a single large, double-stranded DNA molecule without a surrounding nuclear membrane (Sherris, 1990). Bacterial infections that have a predilection for the central nervous system can first present with psychiatric symptoms, particularly hallucinations and delusions. We will focus here on two prototypical spirochetal infections that may specifically present with psychotic symptoms. Spirochetes differ from other bacteria in that they have a flexible cell wall around which several fibrils (small filamentous structures) are wound (Neidhardt, 1990).

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Lyme disease Summary of findings Grade of evidence Epidemiology: 0.008% in general US population. Age of onset: No data. Presentation: Persecutory delusions; auditory olfactory, and visual hallucinations. Course and progression: Widely variable. Suspected neuropathology: Frontal lobe white matter hyperintensities, frontal hypoperfusion. Suspected neurochemical abnormalities: No data. Genetic factors: No data. Other risk factors: No data. Treatment: Antimicrobial therapy, antipsychotic agents.

B N/A C C D N/A N/A N/A B

Epidemiology

Erythema migrans, the early skin lesion now recognized as pathognomonic for Lyme disease, was first reported in 1970 (Scrimenti, 1970) and Lyme arthritis was first identified in 1977 (Steere et al., 1977). In 1982 Burgdorfer identified a new bacterium, the Borrelia spirochete, in the midgut of a tick that had caused an erythema migrans rash (Burgdorfer et al., 1982). This spirochete, similar in several respects to the agents of syphilis, was named Borrelio burgdorferi in honor of its founder. The disorder is now referred to as either Lyme disease or Lyme borreliosis. The infection is now endemic in Europe, Asia, and in more than 15 states in the USA. Since surveillance was begun in the USA in 1982, the number of reported cases has increased dramatically. In 2002, a total of 23,763 cases of Lyme disease were reported to the United States Centers for Disease Control and Prevention (CDC), yielding a national incidence in the United States of 8.2 cases per 100,000 population. Most cases occur in northeastern, mid-Atlantic, and north central states (Centers for Disease Control, 2004b). In Europe, Lyme borrreliosis is widely established in forested areas. The highest reported frequencies of the disease are in middle Europe and Scandinavia, particularly in Germany, Austria, Slovenia, and Sweden (Stanek, 1999). The infection is also found in Russia (Korenberg, 1994), China, and Japan (Masuzawa, 2004). Lyme borreliosis in all locations is transmitted by ticks of the Ixodes ricinus complex (Lane, Piesman, & Burgdorfer, 1991; Spielman, 1994). These ticks have

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larval, nymphal, and adult stages and require a blood meal at each stage. The risk of infection in a given area depends largely on the density of these ticks as well as their feeding habits and animal hosts, which have evolved differently in different locations. The most common carriers of the tick are deer and the white-footed mouse. However, these ticks have been found on at least 30 types of wild animals and 49 species of birds (Anderson, Magnarelli, & McAninch, 1988). Age of onset

There is little or no published data on the age of onset of psychosis associated with Lyme disease. Presentation

Lyme borreliosis is often classified into three stages: early localized, early disseminated, and late. Early infection consists of a localized erythema migrans, followed within days or weeks by disseminated infection that affects the nervous system, heart, or joints, followed within weeks or months, by late persistent infection (Steere, 2001). Approximately a third of patients do not recall any rash and the flu-like symptoms may be mild (Fallon et al., 1992), so they may not realize that they have been infected and later neurological or neuropsychiatric symptoms may be the presenting complaint (Fallon et al., 1993). The psychiatric symptoms associated with Lyme disease can include depression (Barr et al., 1999; Fallon & Nields, 1994; Logigian, Kaplan, & Steere, 1990), obsessive compulsive disorder (Leonard & Swedo, 2001), anxiety, and panic disorder. There is only a sparse world literature on the psychotic manifestations of Lyme disease consisting mostly of case reports of paranoid delusions (Diringer, Halperin, & Dattwyler, 1987; Fallon et al., 1995; Hess et al., 1999; Omasits, Sieser, & Brainin, 1990; Pfister et al., 1993; Roelcke et al., 1992; Stein et al., 1996), auditory hallucinations (Diringer et al., 1987; Fallon et al., 1995; Hess et al., 1999; Omasits et al., 1990; Pfister et al., 1993; Roelcke et al., 1992), olfactory (Reik et al., 1985), and visual hallucinations (Hess et al., 1999) associated with infection. These reports are provocative and suggest that more systematic and standardized studies could lead to a better understanding of the burden of psychosis with this infectious process. Course and prognosis

Acute disseminated disease occurs during the first month, with the most common symptoms being fatigue, myalgia or arthralgia, headache, fever or chill, and stiff neck. In 20% of persons infected with B. Burgdorferi who do not receive antibiotic treatment, no other symptoms beyond erythema migrans develop. The description of Lyme disease as flu-like is misleading because Lyme disease does not include any cough, sore throat, or other symptoms of upper respiratory

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tract infections. If untreated, Lyme disease may disseminate to other organs and produce subacute or chronic disease. Subacute symptoms can develop over months. Signs and symptoms of CNS infection develop in about 15% of untreated patients. Typically these present as fluctuating meningitis accompanied by facial palsy and a peripheral neuropathy (Steere, 1989). The course and prognosis of the psychiatric manifestations vary widely and depend on the early identification of the underlying infectious process. Suspected neuropathology

Specific neuropathology associated with Lyme disease has not been determined. There have been reports of frontal lobe white matter hyperintensities by MRI in subjects with CNS involvement of Lyme disease (Belman et al., 1992) and in one case report of a patient with a psychotic manifestation of Lyme disease a SPECT scan showed hypoperfusion in deep frontal lobe regions (Stein et al., 1996). Suspected neurochemical abnormalities

There is little or no published data on neurochemical abnormalities associated with psychosis secondary to Lyme disease. Genetic factors

There is little or no published data on genetic factors associated with psychosis secondary to Lyme disease. Other risk factors

There is little or no published data on other risk factors associated with psychosis secondary to Lyme disease. Treatment

Lyme disease is usually treated successfully with antimicrobial therapy (Reik et al., 1985). However, some treated individuals have persistent subjective complaints, and a few patients fail to respond to antibiotic therapy, as evidenced by signs of persistent infection (Belman et al., 1992; Steere, 1989). For patients with late disease presenting chiefly as arthritis, neurological and neuropsychiatric symptoms, response to treatment is typically slower and prolonged administration of parenteral penicillin is usually necessary (Belman et al., 1992). Some cases are treatment refractory and progress to post-treatment Lyme disease syndrome, or chronic Lyme disease (Klempner et al., 2001). When psychotic symptoms are present, antipsychotic agents are given concomitantly with appropriate antimicrobial therapy.

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Syphilis Summary of findings Grade of evidence Epidemiology: 0.002
8% worldwide with significant geographic differences. Age of onset: No data. Presentation: Insidious personality change, cognitive impairment, dysphoric or elevated mood, hallucinations, delusions, or delirium. Course and progression: Widely variable; can move from progressive disorientation, convulsions, tremors, incontinence, euphoria, and depression, to delusions, hallucinations with impaired memory and judgment. Mild or early case has a greater chance of spontaneous resolution. Suspected neuropathology: Widely variable; diffuse cortical degeneration and infarcts, frontal and parietal white matter hyperintensities, frontal hypoperfusion. Suspected neurochemical abnormalities: No data. Genetic factors: No data. Other risk factors: No data. Treatment: Low concentrations of Penicillin G, antipsychotic agents.

B N/A B B

C

N/A N/A N/A B

Epidemiology

In 2001 the number of reported cases of syphilis in the United States was 2.2 cases per 100,000 population (Centers for Disease Control, 2004a). In Western Europe, syphilis prevalence has declined substantially since the peak after the Second World War, with incidence rates below 5 per 100,000 in the majority of countries (Costello et al., 1998; Garcia-Lechuz et al., 1999; Paget & Zimmermann, 1997). In contrast with the decline in rates observed in Western Europe, since 1989 there has been an alarming increase in infection rates of syphilis in the newly independent states of the former Soviet Union. The incidence of syphilis has increased from 5
15 per 100,000 observed in 1990 to as high as 120
170 per 100,000 of population in 1996 in the newly independent states of the former Soviet Union (Renton et al., 1998). In the Western Pacific, relatively high prevalence rates of syphilis have been found in Cambodia (4%), Papua New Guinea (3.5%), and the South Pacific Islands (8%) (World Health Organization, 1999). Age of onset

There is little or no published data on the age of onset associated with neurosyphilis.

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Presentation

Syphilis passes through a series of frequently overlapping stages. The spirochete, Treponema pallidum, causes syphilis and is spread through contact with infectious lesions or body fluids. Patients typically develop a skin lesion (chancre) at the site of inoculation approximately 21 days after exposure. Signs and symptoms of secondary syphilis typically begin four to ten weeks after the appearance of the chancre. Rash is the presenting complaint in more than 70% of patients. Secondary syphilis can resolve without treatment, although approximately one quarter of untreated patients develop recurrences during the four years following infection, most frequently in the first year (Clark, 1954). The CDC differentiates early and late latent syphilis as asymptomatic infection during the first year following infection and during the period thereafter, respectively. Approximately a third of patients with untreated secondary syphilis develop late tertiary disease (Clark, 1954; Golden, Marra, & Holmes, 2003). Tertiary syphilis may present as a central nervous system disease, neurosyphilis. Early neurosyphilis occurs within weeks to a few years after primary infection and may be asymptomatic. Symptomatic forms of early neurosyphilis include meningitis, with or without cranial nerve or eye involvement. Late neurosyphilis affects the meninges and brain or spinal cord parenchyma, is extremely rare in the antibiotic era, and usually occurs decades after primary infection. Manifestations of late neurosyphilis include general paresis with psychotic features, and tabes dorsalis, a spinal cord disorder with sensory ataxia and bowel and bladder dysfunction (Golden et al., 2003). General paresis involves the general deterioration of mental and physical capabilities. Symptoms typically begin ten to fifteen years after the initial infection and include subtle cognitive and emotional changes, such as problems with concentration and irritability; if untreated, it can lead to memory loss, confabulation, anomia, apraxia, or pseudobulbar palsy. Neurosyphilis may present with virtually any psychiatric symptom, including insidious personality change, cognitive impairment, dysphoric or elevated mood, hallucinations, delusions, or delirium (Dawson-Butterworth & Heathcote, 1970; Emsley et al., 1988; Rundell & Wise, 1985). Late psychiatric manifestations of neurosyphilis consist predominantly of dementia that is indistinguishable from other forms of dementia, and includes impaired judgment, confusion, and lack of insight (Dawson-Butterworth & Heathcote, 1970). Course and prognosis

Approximately a third of patients with untreated infection develop late sequelae (Clark, 1954; Golden et al., 2003). Untreated paretic neurosyphilis is characterized by progressive decline of the intellect and general deterioration

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of motor function to ultimate paralysis and death. Convulsions are frequent in later stages of the disease. Spontaneous remissions and improvement may occur without specific treatment. In a five-year follow-up of patients with neurosyphilis, 50% of patients showed resolution of disorientation, convulsions, tremors, incontinence, euphoria, and depression, while only 25% of patients showed resolution in delusions, hallucinations, and impaired memory, judgment, speech, and calculations. Mild or early cases predictably have a greater chance in showing resolution of symptoms. Patients with active disease, as evidenced by CSF pleocytosis, were more likely to respond to treatment than were patients with static pathology without CSF pleocytosis (Graman, Trupei, & Reichman, 1987). Men are more likely to have confusion after ten to fifteen years, while women are more often dysarthric and depressed (Dawson-Butterworth & Heathcote, 1970). Suspected neuropathology

In neurosyphilis, or general paresis, there is extensive cortical degeneration of the brain and large numbers of T. pallidum are found in the affected areas. There are high rates of white matter hyperintensities in the frontal and parietal lobes, as well as generalized atrophy. Patients present with focal neurological findings secondary to multiple small infarcts due to an endarteritis that produces hypertrophy of the intimal layer of the vasculature and fibroblastic proliferation (Gabay, Hallinan, & Lovett, 1983; Russouw et al., 1997). Neuroimaging with CAT scanning or SPECT show multiple diffuse cortical infarcts (Ortego et al., 1995). Suspected neurochemical abnormalities

There is little or no published data on neurochemical abnormalities associated with neurosyphilis. Genetic factors

There is little or no published data on genetic factors associated with neurosyphilis. Other risk factors

There is little or no published data on other risk factors associated with neurosyphilis. Treatment

Treponema pallidum is killed by low concentrations of penicillin G. Long exposure to penicillin is required in established disease, probably because of

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the long generation time of the organism and its inaccessibility in some lesions. Alternative regimens of Amoxicillin and Ceftriaxone have been used successfully but their efficacy has not been documented in large-scale studies (Mohr et al., 1976; Tramont, 1976). Spontaneous remissions and improvement may occur without specific treatment. Treatment effectively arrests the course of the disease. Functional return depends upon the stage of the disease at which treatment was begun and upon the acuteness of the disorder. In severely demented patients, a complete cure cannot be expected (Bordon et al., 1995). Psychiatric symptoms due to neurosyphilis should be addressed therapeutically in the same manner as the psychiatric illnesses that they mimic. Other infections Parasitic

Despite the relative infrequency of parasitic infections in the temperate, highly sanitized societies of the industrialized world, parasitic diseases remain among the major causes of death worldwide. Two parasitic infections with specific predilection for the CNS are briefly reviewed. Malaria is responsible worldwide for 273 million clinical cases and 1.12 million deaths annually. More than 40% of the global population (42.1 billion people) is estimated to be at risk for malaria. Malaria occurs in approximately 100 countries, but is mainly confined to the developing tropical areas of Africa, Asia, and Latin America (Toure & Oduola, 2004). Cerebral malaria is the most potentially life threatening neurological complication. Varied psychiatric manifestations have been described as a part of cerebral malaria including psychosis, manifested as paranoid delusions, often accompanied by manic syndromes in the acute stage and depression as a late sequelae. These psychiatric manifestations may be the first presenting feature in patients with acute uncomplicated malaria, especially in association with hyperpyrexia. Of note, neuropsychiatric complications have also been associated as side effects from certain antimalarial drugs (Daroff et al., 1967; Kochar & Shudhakaran, 1998; Prakash & Stein, 1990; Weinke et al., 1991). Worldwide, neurocysticercosis is another common parasitic infection of the human central nervous system, and its epidemiology is changing with increased migration of human tapeworm carriers from endemic regions. Neurocysticercosis is caused by neuronal infection by the larval form of the pork tapeworm Taenia solium (Garcia et al., 2003). Clinical signs vary depending upon the size and stage of the parasites and location of lesions. Various psychiatric symptoms are known to occur in neurocysticercosis; however, depression, rather than psychosis, seems

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to be the most common presentation (Forlenza et al., 1997; Shriqui & Milette, 1992; Tavares, 1993). Neurocysticercosis should be considered in the differential diagnosis of psychiatric disease in the context of endemic T solium, or a history of exposure to human carriers (Schantz et al., 1992). Fungal

Fungi are a distinct class of micro-organisms, a few of which can produce diseases in humans, and even fewer may cause CNS manifestations (Johnson & Naraqi, 1993; Ryan, 1990). An exception to this rule is in immunocompromised patients, where fungal infections may lead to CNS complications that can include major depression, adjustment disorder with depressed mood, and delirium with affective, delusional, or cognitive dysfunction (Detmer & Lu, 1986). Prion

The transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders of humans and animals that share a common feature, i.e., the conversion of the cellular prion protein into disease-specific species. The altered isoforms are believed to be responsible for neuropathologic changes and disease transmissibility (Puoti et al., 1999). Human Creutzfeldt-Jakob disease (CJD) is the most notable neurodegenerative disorder caused by prions. Creutzfeldt-Jakob disease (CJD) is a rare dementia characterized by a rapidly progressive course (Will & Ward, 2004). Psychiatric symptoms, including depression and personality change, occur early in the clinical course in about a third of cases (Brown et al., 1979) and in one series, 10% of patients were first admitted to psychiatric wards (Puoti et al., 1999). Psychiatric symptoms associated with CJD have led to erroneous initial diagnoses of functional psychosis (Keshavan, Lishman, & Hughes, 1987), depressive pseudodementia (Azorin et al., 1993), or hysteria (Stevens & Lament, 1979). Conclusions Hallucinations and delusions may become manifest by central nervous system infiltration of specific infectious agents. The medical literature suggesting infectious causes of psychotic phenomena consists primarily of case reports or anecdotal observations and so there is a need for more systematic study of these conditions. While direct and rapid antimicrobial management of the underlying infection is the mainstay of treatment, appropriate psychiatric treatment can provide substantial relief to the patient and greatly facilitate medical management of the underlying infectious process.

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18

Psychosis secondary to inflammatory and demyelinating disease Katherine H. Taber and Robin A. Hurley VISN 6 MIRECC, Hefner VAMC, WFGSM, BCM, Salisbury, North Carolina

Multiple sclerosis Grade of evidence Epidemiology: 430/100,000 in northern Europe, southern Australia, middle North America, less elsewhere; Relapsing-remitting form 2
3 female: 1 male. Age of onset: Most 20s
40s. Presentation: Psychosis can be presenting symptom. Course and progression: Psychosis commonly episodic. Suspected neuropathology: Demyelination and axonal destruction, brain atrophy, inflammation; Myelin-directed inflammatory autoimmune process; Psychosis correlated with frontal and/or temporal abnormalities. Suspected neurochemical abnormalities: Inflammatory cytokines, autoantibodies, matrix metalloproteinases, and reactive oxygen species may participate in disease; Glutamate excitotoxicity may cause oliogodendrocyte injury/death. Genetic factors: Multiple genes contribute to susceptibility; Major histocompatibility complex
chromosome 6p21. Other risk factors: Environmental; Viral exposure. Treatment: Multiple agents in limited patients: some successes, haloperidol; increased side effect vulnerability.

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B B B C
C
B D C
D

D B
B B C D

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating illness that can affect any aspect of the central nervous system. Neuropsychiatric (NP) symptoms may be the presenting complaints or may arise during the course of illness (Asghar-Ali et al., 2004; Feinstein, 2004). Epidemiology

Prevalence of MS varies considerably by geographic region (Noseworthy et al., 2000). Prevalence is highest (greater than 30 per 100,000) in northern Europe, southern Australia, and middle North America. MS is uncommon in India, the Orient, the Arabian peninsula, and continental South America (Compston, 1999). Prevalence in the United States (USA) ranges from 85
190 per 100,000 (Mayr et al., 2003; Noonan, Kathman, & White, 2002). A geographic gradient has been suggested, with lower rates in the southern USA (Herna´n, Olek, & Ascherio, 1999; Noonan et al., 2002). Incidence varies from approximately 4
8 per 100,000 (Mayr et al., 2003). While there is evidence for an increase in incidence during the last 100 years, a recent study suggests that prevalence and incidence have been stable over the past 20 years (Mayr et al., 2003). The relapsing
remitting form of MS is more common in females (about two or three to one) (Compston, 1999; Keegan & Noseworthy, 2002). Primary progressive MS affects men and women equally (Keegan & Noseworthy, 2002). Age of onset

Initial presentation for the relapsing
remitting form is commonly in the second to fourth decades (Herna´n et al., 1999; Noseworthy et al., 2000). Childhood onset does occur. MS may be under-diagnosed in this age group (Ghezzi, 2004; Ruggieri et al., 2004). Presentation

This disorder is traditionally viewed as a solely neurological condition. However, a meta-analysis concluded that 40.4% had neuropsychiatric (NP) symptoms (Davids, Hartwig, & Gastpar, 2004). Reports indicate a 50% lifetime risk of depression with a 7
14 times risk of suicide over the general population (Feinstein, 2004; Schapiro, 2002). In one study, 17 of 23 MS patients had affective disorders (74%) (Lyoo et al., 1996). In their literature review, those authors found a range from 6
54% of depression in MS. Bipolar symptoms can be twice as common in MS as the general population (Feinstein, 2004; Modrego & Ferra´ndez, 2000). A prospective study found 95% of patients with measurable NP symptoms: depression (79%), hallucinations (10%), and delusions (7%) (Diaz-Olavarrieta et al., 1999). All were in remission. None were receiving steroids or psychotropic medication. Reported NP symptoms include slowed cognition,

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Inflammatory and demyelinating disease

executive dysfunction, depression, pathological crying, personality changes, mania, and psychosis. Delusions and/or hallucinations are generally found as part of an affective illness (e.g. mania with psychosis). There are rare care reports in the literature with pure psychosis and no affect component. (Asghar-Ali et al., 2004; Carson & Searle-White, 1996; Clarke, Wadhwa, & Leroi, 1998; Heila¨, Turpeinen, & Erkinjuntti, 1995; Hurley et al., 1999; Mendhekar, Mehta, & Puri, 2004; Modrego & Ferra´ndez, 2000; Zarei et al., 2003). Course and progression

The most common pattern (about 85%) is relapsing
remitting, with full recovery after an episode (Keegan & Noseworthy, 2002). Most will eventually develop secondary-progressive MS in which full recovery no longer occurs. Less common (about 15%) is primary-progressive in which symptoms do not remit (Keegan & Noseworthy, 2002). Prognosis varies widely. By 15 years, 10
15% of patients are wheelchair bound while 20
25% are still ambulatory (Keegan & Noseworthy, 2002). Females generally have a better prognosis than males (Keegan & Noseworthy, 2002). With an early onset (before age 16) progression may be slower (Ghezzi, 2004). Psychosis can occur at all stages of the illness. Case reports indicate that psychosis is commonly episodic (Carson & Searle-White, 1996; Felgenhauer, 1990; Modrego & Ferra´ndez, 2000). Neuropathology

The classic histopathology is characterized by demyelination and inflammation surrounding venules and extending into the myelin sheath (Noseworthy et al., 2000). Infiltrating cells include T lymphocytes (CD4 and CD8 phenotypes), activated macroglia, and plasma cells (Owens, 2003). Infiltration of these cells and inflammatory cytokines produced in situ are directly associated with demyelination and plaque formation. The current interpretation is of a myelin-directed inflammatory autoimmune process. T lymphocyte response to an infectious agent (e.g. Epstein-Barr virus) is a popular hypothesis (Owens, 2003). The structural and immunological characteristics of plaques are relatively uniform within each individual, but vary considerably between individuals, suggesting MS may be a constellation of syndromes with different pathogenic mechanisms (De Groot et al., 2001; Lucchinetti et al., 2000). A recent study has questioned the autoimmune hypothesis, presenting data supporting apoptotic oligodendrocyte death as the initiating event, with inflammatory responses secondary to myelin phagocytosis (Barnett & Prineas, 2004). Common supratentorial lesion locations are periventricular white matter, inner surface of the corpus callosum, and cortical gray/white junction (Bakshi et al., 2004). Most are bright on T2 weighted (T2W) magnetic resonance

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images (MRI) and best visualized with fluid-attenuated inversion-recovery (FLAIR) technique (Figure 18.1). T2W MRI is nonspecific, as inflammation, edema, demyelination, axonal loss, and repair processes will appear similar (De Groot et al., 2001; Meier et al., 2004). These MRI-visible lesions are frequently neurologically silent. Areas of active inflammation can be detected by contrastenhanced MRI. Some lesions are dark on T1W MRI. Lesions that remain dark, rather than resolving, may represent permanent axonal loss (Meier et al., 2004). Correlation between lesion load and clinical disability is better for lesions that are dark on T1W than are bright on T2W MRI (Bakshi et al., 2004). Patients with NP symptoms or psychosis had a heavier lesion burden in the temporal lobes than those without (Feinstein, Du Boulay, & Ron, 1992; Honer et al., 1987). Both euphoria and hallucinations may correlate with moderately severe frontotemporal abnormalities (Diaz-Olavarrieta et al., 1999). Frontal lobe abnormalities (lesions in two, hypometabolism in one) have been reported in patients with manic psychosis (Heila¨ et al., 1995; Modrego & Ferra´ndez, 2000).

Figure 18.1. Magnetic resonance image of a young female patient with multiple sclerosis (MS). (Axial FLAIR MRI of a female who was hospitalized on two occassions previously
once for mania and once for depression. Note the generalized atrophy and the periventricular oval-shaped lesions that are characteristic of MS. She presented with intractable insomnia, anxiety, depressed mood, suicidal ideation, bradykinesia and bradyphrenia. Although she had none of the classical clinical signs of MS, subsequent testing confirmed the diagnosis.)

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Suspected neurochemical abnormalities

Various proposed mechanisms have been suggested to explain relapsing
remitting symptoms in MS including axonal demyelination/remyelination and inhibition of axonal function by inflammatory cytokines (Neumann, 2003; Noseworthy et al., 2000). Autoantibodies, matrix metalloproteinases, and reactive oxygen species may also participate (Neumann, 2003). Glutamate excitotoxicity has been implicated. Activated macrophages and microglia increase synthesis of glutamate in and around MS lesions (Neumann, 2003; Werner, Pitt, & Raine, 2001). Axonal injury correlates with presence of glutamate-producing macrophages and microglia (Werner et al., 2001). A recent study found increased glutamate in cerebrospinal fluid of MS patients. Higher levels are correlated with active disease (e.g. clinical symptoms and contrast-enhancing lesions) (Sarchielli et al., 2003). Oligodendrocytes may be central to white matter glutamate homeostasis, which is impaired in MS lesions and surrounding normal appearing white matter (Pitt et al., 2003; Werner et al., 2001). Proton magnetic resonance spectroscopy (MRS) studies have shown neuronal dysfunction in white matter areas that appear normal on MRI, supporting the hypothesis of more widespread axonal pathology (Filippi et al., 2003; He et al., 2005). A recent whole-brain MRS study of early MS supported the presence of permanent axonal injury, in contrast to reversible inflammation-related dysfunction (Filippi et al., 2003). There are conflicting studies, so this is controversial (Vrenken et al., 2005). Genetic factors

The familial recurrence rate for MS is 15% (Compston, 1999). Concordance rate is 25
30% for monozygotic and 3
5% for dizygotic twins (Compston, 1999; Keegan & Noseworthy, 2002). Ethnicity appears to be a risk factor, with people of European ancestry at higher risk than those of African or Asian ancestry (Compston, 1999). Evidence suggests that more than one gene contributes to susceptibility. The major histocompatibility complex (MHC) is associated with susceptibility to MS (Herrera & Ebers, 2003). The apolipoprotein E epsilon4 allele has been implicated in a more rapidly progressing form (Herrera & Ebers, 2003; Keegan & Noseworthy, 2002). There is increasing evidence of genetic heterogeneity (Sotgui et al., 2004). Other risk factors

There are clear environmental influences. High MS rates in northern Europeans are not found in their children following migration to southern Africa; prevalence of MS in children of immigrants from Africa to the United Kingdom increases

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Katherine H. Taber and Robin A. Hurley

(Compston, 1999). Viral exposure has been linked to relapse. Early viral exposure increases the risk of MS (Compston, 1999; Keegan & Noseworthy, 2002). Treatment

There are MS treatments for acute exacerbations and those that affect the longterm course (disease-modifying therapy). Interventions should include immunotherapeutic and symptom-based pharmacotherapies and rehabilitation, psychosocial interventions, and patient/family education (Schapiro, 2002). Current research focuses on therapeutics that interrupt the inflammatory cascade (Adorini, 2004; Fox & Ransohoff, 2004). Corticosteroids are the mainstay for acute exacerbations, intravenous methylprednisolone, followed by oral prednisone. Plasmapheresis is used for patients unresponsive to corticosteroids. Side effects are a concern as corticosteroids can induce psychiatric conditions (mania, depression, psychosis, and rarely cognitive decline) (Brown & Chandler, 2001; Sirois, 2003; Wada et al., 2001). Steroid-induced psychosis can include hallucinations, delusions, agitation, disorganized behaviors, or thought processing abnormalities. Generally these symptoms improve with dose tapering and/or administration of neuroleptics (haloperidol, less commonly olanzapine or risperidone). Occasionally, carefully titrated lithium or other mood stabilizers are prescribed (Sirois, 2003). With lithium or carbamazepine, the clinician must watch carefully for renal compromise (corticosteroid-induced) or carbamazepineinduced decreases in prednisolone levels (Sirois, 2003). Lithium-induced delirium is a high risk in neurologically compromised patients. A recent retrospective study found recurrent episodes in seven out of 15 patients with corticosteroid-induced mood disorder, and two out of three patients with corticosteroid-induced psychosis (Wada et al., 2001). All patients with psychosis were responsive to haloperidol (3 mg/day). Disease-modifying therapies for MS include interferon (IFN) ß, glatiramer acetate, or mitoxantrone (Goodin, 2004). General concensus is that these agents, although costly (over $10,000 annually), are partially effective in decreasing relapses and/or delaying progression (Noseworthy et al., 2000). Given the risk of depression with IFN-ß, patients with a history of depression should be prescribed a selective serotonin reuptake inhibitor (SSRI) and monitored closely. The evidence-based treatment for psychosis in MS is very limited (no FDA approved medicines), with only case reports, letters to the editor, expert opinion, and community standard to guide the practitioner (Feinstein & Ron, 1998; Goodin, 2004). A PubMed search found one case review and eight other published letters to the editor or case reports that specifically address the treatment of psychosis due to MS in the last ten years. The case review study included 44 patients with psychosis due to eight different neurological conditions

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Inflammatory and demyelinating disease

(five with MS) (Feinstein & Ron, 1998). All patients were treated successfully with low doses of haloperidol (<10 mg/day) or equivalent doses of other typical neuroleptics over a short period of time. The psychoses were intermittent and resolved very quickly with medications. The remaining case reports noted a variety of both typical and atypical antipsychotic treatments (Asghar-Ali et al., 2004; Chong & Ko, 1997; Clarke et al., 1998; Davids et al., 2004; Heila¨ et al., 1995; Mendhekar et al., 2004; Modrego & Ferra´ndez, 2000; Young et al., 1997). The cases demonstrated mixed results with one patient failing antipsychotics, but the psychosis resolved with steroids (Mendhekar et al., 2004). Some had concomitant treatments with lithium, carbamazepine, sodium valproate, or other mood stabilizers (oxcarbazepine, lamotrigine). Haloperidol was the most commonly reported successful agent in low doses, with other antipsychotics (chlorpromazine, methotrimeprazine, levopromazine, trifluperazine, risperidone, olanzapine, ziprasidone, perphenazine, fluphenazine, thioridizine, quetiapine, clozapine) having mixed successes. The salient features to remember include potential for higher vulnerabilities to side effects, the need to ‘‘start low and go slow’’ with medications, likelihood of psychosis resolution with rapid, time-limited treatments, consideration of drug side-effect profiles in relation to symptoms, and potential for drug
drug interactions with steroids (Chong & Ko, 1997; Davids et al., 2004; Sirois, 2003). Vulnerabilities include lithium-induced or anticholinergic-induced delirium, higher than normal rates of extrapyramidal symptoms, sedation, orthostasis, ataxia, and more sexual dysfunction. A cautious conservative approach is key. Balance the risk of side effects with the need to treat a potentially dangerous psychosis. System lupus erythematosus Grade of evidence Epidemiology: 3
6/100,000 in US; 5
10 female: 1 male;
B B B B C C C

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Grade of evidence Suspected neurochemical abnormalities: Autoantibodies; Glutamate excitotoxicity. Genetic factors: Genetic diversity. Other risk factors: Poorer socio-economic conditions. Treatment: Rule out delirium; immunosuppressive agents; haloperidol and risperidone.

C D B C C

Table 18.1. Neuropsychiatric systemic lupus erythematosus syndromes (NPSLE)

Diffuse psychiatric and neuropsychological syndromes

Neurologic syndromes of the central nervous system

Neurologic syndromes of the peripheral nervous system

• • • • •

• • • • • • •

• • • • • • •

Anxiety disorder Acute confusional state Cognitive dysfunction Mood disorder Psychosis

Cerebrovascular disease Demyelinating syndrome Headache Aseptic meningitis Movement disorder (chorea) Seizure disorder Myelopathy

Guillain-Barre Syndrome Mononeuropathy Autonomic disorder Plexopathy Polyneuropathy Myasthenia gravis Cranial neuropathy

Systemic lupus erythematosus (SLE) is a complex autoimmune rheumatic disease affecting multiple organ systems including skin, joints, kidneys, and nervous system. The considerable diversity in the nervous-system-related symptoms has made the study of lupus difficult. In order to standardize descriptions, the American College of Rheumatology (ACR) has developed case definitions and diagnostic criteria for 19 neuropsychiatric (NP) SLE syndromes (ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature, 1999) (Table 18.1). This replaces terms such as ‘‘lupus cerebritis’’ and ‘‘CNS lupus’’ (Hermosillo-Romo & Brey, 2002). Psychosis is one manifestation of NPSLE. The ACR guidelines emphasize excluding other conditions, including central nervous system infection and corticosteroid administration (Hermosillo-Romo & Brey, 2002). Epidemiology

Current incidence estimates are three to six per 100,000 (range 1
63.7) in the USA (Jime´nez et al., 2003; Petri, 2002). Prevalence has been increasing,

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Inflammatory and demyelinating disease

most likely due to improved treatment (Petri, 2002). Estimates vary, but ratios of five to ten females to one male are frequently found. Males suffer more morbidity (Mikdashi & Handwerger, 2004; Petri, 2002). SLE is more common in those of Hispanic, African, or Asian descent, although the interaction of genetics and socio-economic variables is not yet clear (Jime´nez et al., 2003; Petri, 2002). Recently, at least one NP syndrome was identified in 60
95% of patients with SLE (Ainiala et al., 2001; Brey et al., 2002; Costallat, Bertolo, & Appenzeller, 2001; Sanna et al., 2003a; Sibbitt et al., 2002). Of these, between 0
12% had manifested symptoms of psychosis. With standardized criteria, cerebral vascular disease has a prevalence of 2
24%; headaches 21
61%; mood disturbances 27
74%; psychosis 5%; and cognitive impairment 52
80% in the lupus population (Brey & Petri, 2003). The occurrence may be higher with pediatric onset (95% had occurrence of NP symptoms, 12% psychosis) (Sibbitt et al., 2002). Age of onset

The majority are diagnosed between 20 and 40 years of age with a peak at 30 (Jime´nez et al., 2003; Petri, 2002). Onset may be later in males, with a peak after age 50 (Jime´nez et al., 2003). A recent review concluded that onset of psychosis occurs earlier than the other NP syndromes (Mack, Fricchione, & Rogers, 2002). Presentation

Common presenting symptoms include photosensitivity, butterfly facial rash, fever, and fatigue (Dall’Era & Davis, 2003). Uncommonly SLE may present with psychosis (e.g. paranoia, hallucinations, mania) (Jennekens & Kater, 2002b; Khan et al., 2000). The ACR has four required criteria for lupus-induced psychosis: hallucinations or delusions; clearance from delirium; no other known cause; and significant functional impairment (Bodani & Kopelman, 2003). Course and progression

A remitting
relapsing pattern is most common although both chronically active disease and long quiescence are also seen (Petri, 2002). NPSLE symptoms can occur at any time, including periods when no disease activity is apparent (Hermosillo-Romo & Brey, 2002; Karassa et al., 2000; Mikdashi & Handwerger, 2004; Shimojima et al., 2005). Psychosis may be intermittent, with clear remissions of long duration (Turkel, Miller, & Reiff, 2001). Each occurrence of NP symptoms triples the NP recurrence risk (Karassa et al., 2000). Symptoms vary across episodes (Shimojima et al., 2005). Improved treatment has increased the survival rate (93
95% after five years, 85% after ten years) (Jime´nez et al., 2003).

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NP symptoms were not associated with a poorer outcome in a recent prospective study (Jo¨nsen, Bengtsson, Nived et al., 2002). However, in another study psychosis was associated with greater disease activity (Mikdashi & Handwerger, 2004). Suspected neuropathology

The pathology underlying NPSLE is not well understood. Proposed mechanisms include ischemia, hemorrhage, white matter disease, neuronal dysfunction due to presence of autoantibodies, and deficit psychological reaction (Jennekens & Kater, 2002a). Psychosis can be present on an intermittent basis, accompanied by no obvious brain pathology (Turkel et al., 2001). There can also be clear atrophy and focal changes in absence of NP symptoms. Transient opening of the blood
brain barrier has been proposed as one mechanism for intermittent NP symptoms (Abbott, Mendonc¸a, & Dolman, 2003). Hyperintense focal lesions in the periventricular and subcortical white matter on T2W or FLAIR MRI are common (Govoni et al., 2004; Graham & Jan, 2003). Cortical atrophy, hemorrhage, and large infarctions may be present. Studies suggest that MRI abnormalities and cerebral perfusion deficits may be more common in patients with NP symptoms (Chen et al., 2002; Handa et al., 2003; Huang et al., 2002; Kikukawa et al., 2000; Oku et al., 2003; Sanna et al., 2000). Little neuroimaging has been done in patients exhibiting psychosis. In one study of pediatric NPSLE, seven out of ten were psychotic while only two out of ten had any MRI abnormality (Turkel et al., 2001). Focal perfusion deficits were present in multiple regions (frontal, parietal, and/or temporal lobes) regardless of specific NP symptoms. Similarly, the pattern of perfusion deficits did not differ with specific NP symptoms in an adult study (Chen et al., 2002). Suspected neurochemical abnormalities

Autoantibodies may participate in the pathologic changes (Arbuckle et al., 2003). The presence of particular autoantibodies has been associated with NP symptoms in some studies (Conti et al., 2004; Lai & Lan, 2000; Mikdashi & Handwerger, 2004; Sabbadini et al., 1999; Sanna et al., 2000; 2003a; Turkel et al., 2001; Williams, Sugiura, & Tan, 2004). Anti-ribosomal P protein antibodies are present in a high percentage of patients with psychosis, and levels may vary with symptoms (Reichlin, 2003). However, a recent study found that onset laboratory test results were similar between patients with and without NP symptoms (Shimojima et al., 2005). In addition, during relapse patients with NP symptoms often had better laboratory values than at onset (Shimojima et al., 2005).

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Glutamate excitotoxicity, which has also been implicated in the pathophysiology of schizophrenia, may be one mechanism for neuronal injury in SLE (Benes, 2000; DeGiorgio et al., 2001; Omdal, 2002). Given the known psychotomimetic effects of agents that act as glutamate receptor antagonists, other subsets of autoantibodies may mediate the induction of psychosis (DeGiorgio et al., 2001; Omdal, 2002). In a recent study, autoantibodies to a glutamate receptor subunit were more prevalent in SLE patients than either clinical controls or healthy subjects (Husebye et al., 2005). In one patient, changes in the levels of this autoantibody correlated with changes in neurological symptoms. Genetic factors

Although the incidence of SLE in homozygous twins is greater than expected (25
58% vs. 2
5%), supporting the importance of genetic factors, the frequency in relatives is relatively low (Jime´nez et al., 2003; Manson & Isenberg, 2003; Tsao, 2003). SLE is more common in those of Hispanic, African, or Asian descent (Jime´nez et al., 2003; Petri, 2002; Tsao, 2003). Results of genetic screening suggest considerable genetic diversity in susceptibility, some perhaps related to ethnicity (Manson & Isenberg, 2003; Tsao, 2003). In a recent study, symptoms (seizure and psychosis) were used to select for a more genetically homogeneous population (Nath et al., 2002). A putative gene for SLE showed linkage for families of European-American descent, but not African-American descent. Other risk factors

Poorer socio-economic conditions may be associated with a more aggressive course and greater mortality (Jime´nez et al., 2003). Treatment

Before beginning treatment, determine the etiology of the mental status changes. A key question is whether the psychosis is unrelated (e.g. cocaine, alcohol, or schizophrenia), due to secondary effects, concurrent treatment, metabolic abnormality, or immunosuppression (i.e. CNS opportunistic infection) (Hermosillo-Romo & Brey, 2002). ‘‘Acute confusional state’’ (delirium) must be ruled-out. Impaired consciousness, increased anti-ribosomal P antibodies, or elevated CSF IgM, IgA, or IgG supports that the psychosis is related to the lupus-disease process and not to steroid treatment (Hermosillo-Romo & Brey, 2002). There is a growing body of case reports and retrospective chart review studies that note considerable success when cyclophosphamide and/or azathioprine

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is combined with pulsed methylprednisolone for the NP symptoms in lupus (Bodani & Kopelman, 2003; Mok, Lau, & Wong, 2003; Sanna et al., 2003b). In one study of 13 psychotic patients treated with the azathioprine following cyclophosphamide, only one out of 13 had a psychotic relapse (Bodani & Kopelman, 2003). Antipsychotic agents were used in nine out of 13 patients and anticonvulsants in three (specific agents not listed). Steroids and immunosupressives can induce mania and/or psychosis (Brey & Petri, 2003). Steroid-induced mania or psychosis may be worse with initial dosing or with dosage increases (Brey & Petri, 2003). It may also be worsened by low serum albumin and is more likely with higher-dose steroids (Chau & Mok, 2003; Lo´pez-Medrano et al., 2002). This psychosis generally remits with dosage decreases. Studied treatments focus on suppression of the lupus activation. In some cases the psychosis will improve. In others, or in patients where lethality or severely disabling symptoms are occurring, antipsychotics are added. There are no double-blind placebo-controlled studies of antipsychotics for this condition, only retrospective chart reviews, case reports, and open-labeled series. One author notes the ‘‘current therapeutic approach’’ for psychosis (‘‘mild CNS disease’’) to be haloperidol, chlorpromazine, or risperidone. Cases of psychosis non-responsive to antipsychotics may respond to the corticosteroids (Sanna et al., 2003b). One author noted success in combining risperidone at low dose (2 mg bid) to clonazepam and steroid reduction (Lo´pez-Medrano et al., 2002). Another reported remission with an eight-week course of a phenothiazine (Chau & Mok, 2003). One case report noted partial improvement with electroconvulsive therapy for catatonia after failure of prednisone and cyclophosphamide (Malur, Pasol, & Francis, 2001). The evidence for successful treatments of psychosis in children with lupus is very limited. One retrospective review series had ten patients with CNS-lupus (seven with psychosis). Five were treated with haloperidol, trifluoperazine, or risperidone in addition to the intravenous methylprednisolone and pulse cyclophosphamide. All psychoses resolved; one had return of psychosis two years later (Turkel et al., 2001). Treatments under investigation include plasmapheresis, stem cell transplantation, and new immunosuppresive therapies (Goldblatt & Isenberg, 2005; Milstone, Meyers, & Elia, 2005; Traynor et al., 2002). In summary, practitioners are treating the lupus exacerbations with immunosuppressive agents. If the psychotic markers are disabling enough, then antipsychotic agents are used. Most common agents in the last five years were either haloperidol or risperidone. As with any psychosis due to a general medical condition, the practitioner should start low and go slow with

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medication titrations. Patients with concomitant brain pathologies are often much more sensitive to drug
drug interactions and to medication side effects. Leukodystrophies

Metachromatic leukodystrophy

X-linked leukodystrophy

Summary of findings

Grade of Summary of evidence findings

Grade of evidence

Epidemiology

1/40,000

C

1/21,000 males 50% of heterozygous females

C

Age of onset

Juvenile 4
10 years Adult 4 16 years

C

Childhood: 3
10 years Adolescent: 11
21 years Adult: by middle age

C

Presentation

Conduct disorder, depression, psychosis

C

Childhood: attention deficit disorder, neurologic, psychiatric Adolescent: neurologic, psychiatric Adult: motor, psychiatric

C

Course and progression

Progressive: may take decades

C

C Cerebral form progresses quickly, disability in 2
3 years, death in 3
10

D Suspected Accumulation of neuropathology cerebroside sulfate, abnormal myelin formation, myelin degeneration

Accumulation of very long chain fatty acids, altered membrane structure and stability

D

Suspected neurochemical abnormalities

Arylsulphatase A deficiency

C

Adrenocortical insufficiency

B

Genetic factors

Autosomal recessive chromosome 22q

C

X-linked recessive chromosome Xp28

C

Other risk factors

Environmental and D emotional stressors

Environmental, head injury

D

Treatment

None in literature

Bone marrow transplantation Dietary (‘‘Lorenzo’s oil’’)

C

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The leukodystrophies are white matter diseases characterized by failed development or progressive degeneration of myelin. Psychosis has been associated with both metachromatic leukodystrophy (MLD) and X-linked adrenoleukodystrophy (X-ALD). Metachromatic leukodystrophy (MLD) MLD is a lysosomal storage disorder that has infantile, juvenile, and adult forms (Schestag et al., 2002). The infantile form is the most common (about 80% of cases). There is rapid progression with loss of developmental milestones. Death usually occurs before age five in a rigid, vegetative state. Neuropsychiatric abnormalities, including psychotic features similar to those present in schizophrenia, are found in the juvenile and adult forms (Fluharty, 1990; Hyde, Ziegler, & Weinberger, 1992; Kim et al., 1997). Epidemiology

MLD occurs worldwide with a frequency of one in 40,000
100,000, although higher frequency clusters have been identified (Holve, Hu, & McCandless, 2001; Maria et al., 2003; McKusick, 2003). Age of onset

Juvenile MLD commonly presents between four and ten years. Adult MLD arbitrarily begins at age 16 (McKusick, 2003). Psychosis is mostly associated with juvenile and early adult onset (Hyde et al., 1992). A review found that 53% of cases with onset between 10 and 30 years evidenced symptoms such as hallucinations, delusions, and/or diagnosis of psychosis or schizophrenia (Hyde et al., 1992). Age of onset may be related to the degree of enzyme deficiency (Hyde et al., 1992). Presentation

The juvenile and adult forms are distinguished from infantile MLD by a preponderance of neuropsychiatric abnormalities, including behavioral problems, decline in school performance, nonverbal learning disability, alcohol or substance abuse, dementia, depression, and schizophrenia-like psychosis (Baumann et al., 2002; Fluharty, 1990; McKusick, 2003). Two distinct clinical patterns of adult MLD have been described (Baumann et al., 2002). One presents with predominantly sensorimotor manifestations similar to infantile cases. The other presents with a psychosis sufficiently similar to schizophrenia that patients have been frequently misdiagnosed

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Inflammatory and demyelinating disease

early in the disease course (Hyde et al., 1992). Symptoms may include disinhibition, complex delusions, bizarre behaviors or posturing, catatonia, and classic mood-incongruent auditory hallucinations (Baumann et al., 2002; Hyde et al., 1992; Salmon et al., 1999). Prominent negative signs include psychomotor slowing, apathy, apragmatism, and poor judgment/insight. Dementing symptoms may also be present. Extrapyramidal symptoms including choreoathetosis and dystonia, seizures, and peripheral neuropathy occur rarely. Course and progression

Whatever the age of onset, progression is the rule (Baumann et al., 2002). As demyelination progresses, psychosis may be overshadowed by a florid dementia resembling a subcortical dementia, including impaired verbal fluency, impaired memory retrieval, and executive dysfunction. Motor signs (choreoathetosis and dystonia) can be absent until decades into the illness despite the characteristic white matter appearance on neuroimaging (Finelli, 1985). The prominent behavioral disturbance and more subtle initial cognitive dysfunction combined with the lack of motor signs can make recognition of this degenerative dementia challenging. All cases eventually manifest dementia and spasticity. Seizures can occur in later stages of adult-onset illness (Bostantjopoulou et al., 2000). Suspected neuropathology

It is not clear at this time whether the neuropsychiatric profile of adult MLD is a direct manifestation of low arylsulphatase A (ARS-A) activity, or whether neuropsychiatric abnormalities, particularly psychosis, reflect disruption of brain white matter tracts. Adult MLD and schizophrenia have similar psychotic and cognitive features, and both are characterized by widespread anatomic dysconnectivity and secondary functional disruption (Black, Taber, & Hurley, 2003). In favor of the low-ARS-A-activity-neuropsychiatric-phenotype model is the observation of increased psychopathology in some first-degree relatives of MLD patients. These individuals are presumably heterozygote carriers of one defective allele of the ARS-A gene (Fluharty, 1990). However, it has not been definitively established that ARS-A deficiency or pseudodeficiency is higher in the psychiatric than in the general population (Fluharty, 1990; Lejoyeux et al., 1989; Propping et al., 1986; Shah, 1990). Symmetrical confluent areas of increased signal intensity, indicating myelin disruption, are present in the cerebral white matter on T2W or FLAIR MRI (Figure 18.2) (Black et al., 2003). Progressive demyelination most commonly

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Katherine H. Taber and Robin A. Hurley

Figure 18.2. Magnetic resonance image of a middle aged male patient with adult onset metachromatic leukodystrophy (MLD). (Axial FLAIR MRI of a male who initially presented with difficulty with walking and co-ordination and later developed psychiatric symptoms, including disinhibition, agression, and depression. After a full neurological work-up and brain biopsy, the patient was determined to have adult-onset MLD. Note the ventricular enlargement, cerebral atrophy, and hyperintense signal around the ventricles, characteristic of white matter disease.)

begins within the frontal lobes, and psychosis may be particularly associated with this stage of the illness (Hyde et al., 1992). Exceptions to this pattern of early frontal lobe involvement occur (Kim et al., 1997). Initial sparing of the subcortical U fibers is common. Thin, radially oriented dark stripes are often present (Kim et al., 1997). A recent histopathological study found that stripes correlate with perivascular regions containing spared myelin, macrophages, and lipid-laden glial cells (van der Voorn et al., 2005). Results from the few studies using diffusion weighted MRI are mixed, with both restricted and increased diffusion reported, perhaps reflecting differences in disease stage (Engelbrecht et al., 2002; Oguz et al., 2004; Sener, 2002; 2003). The few case reports in which functional imaging techniques were included have shown areas of cortical decrease, particularly in the frontal poles and medial frontal cortex (Fukutani et al., 1999; Johannsen, Ehlers, & Hansen, 2001; Salmon et al., 1999; Tamagaki et al., 2000).

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Suspected neurochemical abnormalities

The enzyme affected in MLD, arylsulphatase A, is critical for the degradation of sulphatide. The assay for this enzyme is important for confirming the diagnosis. Metachromatic material (cerebroside sulfate) accumulates in brain oligodendrocytes and microglia, in peripheral nerve Schwann cells, and in kidneys, and is excreted in urine. The accumulation of this material leads to abnormal myelin formation and to myelin degeneration by as-yet-unknown pathophysiological mechanisms. Microglial activation may contribute (Gieselmann et al., 2003). Nerve conduction studies and biopsies are also important for diagnostics. Genetic factors

MLD is caused by an autosomal recessive mutation on chromosome 22q. Multiple mutations have been identified (Berger et al., 1997; Gieselmann et al., 2003; McKusick, 2003). Variability in clinical symptoms may relate to the effect of different mutations on residual enzyme activity (Schestag et al., 2002). There is evidence that the primarily psychiatric form may be associated with the I179S mutation, while the primarily motor form may be associated with the P426L mutation (Baumann et al., 2002). Strict genotype
phenotype correlations may not apply in all cases. Genetic background probably modifies the clinical profile (Berger et al., 1997). Other risk factors

It has been suggested that low-enzyme activity individuals may be at increased risk for neuropsychiatric disability. An influence from environmental and/or endogenous stressors is possible (Fluharty, 1990; Kohn et al., 1988). Treatment

Although MLD has been reasonably well described in the medical literature, references to any treatment of MLD-induced psychosis could not be found. In the absence of any evidence-based treatments for this psychosis, the authors suggest that clinicians follow guidelines for the treatment of psychosis due to a general medical condition (i.e. symptom-targeted medications with attention to side effects, conservative dosing, and drug
drug interactions). X-linked adrenoleukodystrophy (X-ALD) There are many different clinical expressions of X-linked adrenoleukodystrophy (X-ALD). Some have a very young onset and are so rapidly progressing that

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Katherine H. Taber and Robin A. Hurley

total disability and/or death occur within three or four years. Others progress over decades. They do not all have psychiatric involvement (Moser et al., 2004b). Only the cerebral form will be discussed in detail here. Epidemiology

X-ALD is estimated to affect one in 21,000 males, with cerebral involvement in 50
60% (Moser et al., 2004b). Half of females that are heterozygous for X-ALD will develop symptoms, but only 2
3% will have cerebral involvement (Moser et al., 2004a; 2004b; Rosebush et al., 1999). More than half of adult onset cases of X-ALD had psychiatric symptoms (Rosebush et al., 1999). Approximately 15% were psychotic (Rosebush et al., 1999). Age of onset

A third of males will have onset between three and ten years, 4
7% between 11 and 21 years, and 50% will have an adult onset (usually by middle age) (Moser, 1997; Moser et al., 2004b). The mean age for presentation of psychiatric symptoms is 32 years (Rosebush et al., 1999). However, actual age of onset may be difficult to determine. Mild symptoms, such as behavior or personality changes, may not be identified as X-ALD-related until after development of more severe disease (Rosebush et al., 1999). Childhood onset is rare in females, who commonly develop symptoms in middle or old age (Moser et al., 2004b). Presentation

Childhood-onset cerebral X-ALD may present with attention deficit disorder, followed by development of cognitive, behavioral, and neurological deficits (Moser et al., 2004b; Rosebush et al., 1999). When onset is during adolescence, the presenting symptoms may be neurological or psychiatric (Moser et al., 2004; Rosebush et al., 1999). In adult onset the most common presenting symptoms are motor. X-ALD can present with psychosis, dementia, mania, or behavioral disturbance (Moser et al., 2004b; Rosebush et al., 1999). A review indicated that 56% of adult-onset cases had psychiatric symptoms, with 15% manifesting psychosis (Rosebush et al., 1999). Misdiagnosis may be common when the initial symptoms are purely psychiatric (Garside et al., 1999). Females have milder neurological signs and symptoms and may be misdiagnosed as having multiple sclerosis (Rosebush et al., 1999). Course and progression

There are two principal phenotypes (Moser, 1997; Moser et al., 2004b). The cerebral form of X-ALD progresses quickly, has widespread effects in the brain,

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Inflammatory and demyelinating disease

and usually includes presence of an inflammatory myelinopathy. With childhood onset progression is rapid, with total disability in two to three years and death in three to ten years. Progression may be slower with onset in adolescence or adulthood. In one case, for example, initial symptoms began at nine years of age, with development of increasingly bizarre behavior until hospitalization for evaluation of a schizophrenia-like psychosis at age 13 (Kopala et al., 2000). In another, the development of memory deficits and changes in personality including impulsivity and perseveration commenced in the early thirties and worsened gradually over a period of four to five years prior to psychiatric evaluation (Luda & Barisone, 2001). Adrenomyeloneuropathy (AMN) progresses slowly (commonly over decades) and principally affects the dorsal columns and corticospinal tracts. However, 30
40% of male patients and 2% of female patients with AMN will develop the rapidly progressing cerebral form (Moser, 1997; Moser et al., 2004b). The actual age of onset (and therefore latency to presentation of psychotic symptoms) can be difficult to determine (Rosebush et al., 1999). Disease progression in patients with psychosis may be more aggressive (Rosebush et al., 1999). Suspected neuropathology

Defective oxidation of saturated very long chain fatty acids (VLCFA) leads to their accumulation in all tissues, but principally in the adrenal cortex, testes, and white matter of the brain. Presence of high concentrations of VLCFA may interfere with membrane stability in myelin, oligodendrocytes, axons, and adrenal cortical cells. However, the actual pathological process in X-ALD is not well understood, and alternative mechanisms have been proposed, including involvement of mitochondrial abnormalities (Moser et al., 2004b). A rapidly progressing inflammatory myelinopathy that may be immune-mediated develops in about 50% (Moser et al., 2004b). Accumulation of VLCFA may trigger the inflammatory process by activating microglia and astrocytes (Paintlia et al., 2003). Most patients with psychiatric presentations will have areas of increased signal intensity on T2W MRI, suggestive of myelin disruption (Rosebush et al., 1999). These are commonly symmetric and first seen in the parieto-occipital regions, with progression into the frontal lobes (Rosebush et al., 1999). Frontal lobe involvement occurs first in 15% (Loes et al., 2003; Rosebush et al., 1999). Other presentations occur, including early involvement of the cerebellum and asymmetrical mass lesion that could be mistaken for a brain tumor (Loes et al., 2003; Rosebush et al., 1999). Progression may be more rapid when lesions are contrast-enhancing (Loes et al., 2003). A prognostic scoring system has

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Katherine H. Taber and Robin A. Hurley

been established that reliably incorporates imaging findings (Loes et al., 2003; Moser et al., 2004a). Diffusion tensor MRI may be more sensitive than T2W MRI (Eichler et al., 2002b; Ito et al., 2001; Schneider et al., 2003). Proton MR spectroscopy has potential in identifying areas of abnormality that are normal on T2W and even diffusion tensor MRI (Dubey et al., 2005; Eichler et al., 2002a; 2002b). Suspected neurochemical abnormalities

Two-thirds of males with X-ALD have primary adrenocortical insufficiency (Moser et al., 2004b; Rosebush et al., 1999). However, adrenal function may be normal in the presence of clear psychiatric or neurologic symptoms (Rosebush et al., 1999). Genetic factors

This is an X-linked recessive disease. The genetic defect has been mapped to the Xq28 gene, which codes for the ALD protein, a peroxisomal membrane protein. Although there are a variety of identified mutations (more than 500 to date), there is no correlation between genotype and phenotype (Moser et al., 2004b; Rosebush et al., 1999). At present there is no way to predict whether a male with X-ALD will develop the severe or the mild form (Moser et al., 2004b). Body fluid and plasma assays for VLCFAs are now available (Moser et al., 2004a). Although heterozygotes may have a false negative rate of up to 20%, early diagnosis is vital to intervention strategies. Prenatal and extended familial genetic testing is recommended for family planning. Other risk factors

Environmental factors are presumed to have a role, as identical twin pairs often differ (Moser, 1997). A few cases have been reported in which a head injury may have triggered onset of the degenerative process (Rosebush et al., 1999). Treatment

Treatment of adrenocortical insufficiency (if present) with adrenal cortical hormone therapy is essential and life saving, but does not alter the neurological disease progression (Moser et al., 2004b). Bone marrow transplantation has been helpful for extending a period of stabilization and, in rare cases, disease reversal in young patients with early evidence of the inflammatory cerebral myelinopathy (Moser et al., 2004a; 2004b; Peters et al., 2004). Circulating levels of VLCFA can be decreased, but this may not affect disease progression (Moser, 1997; Moser et al., 2004b). The most widely studied dietary intervention is oral administration of ‘‘Lorenzo’s Oil’’ (a 4:1 mixture of glyceryl

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Inflammatory and demyelinating disease

trioleate and glyceryl trierucate) coupled with dietary fat restriction. This can normalize serum VLCFA levels within one month, but consistent clinical efficacy is still uncertain (Moser et al., 2004a; 2004b). It may reduce neurological involvement if begun prior to the onset of neurological symptoms in males under six years of age (Moser et al., 2004a; 2004b). Other potential therapies include lovastatin, phenylbutyrate, coenzyme Q10, stem cell transplant, and gene therapy (Moser et al., 2004a; 2004b). Treatment of the psychiatric symptoms is challenging, with limited evidencebased published guidance. Medication choices are then symptom and side-effect based. Patients with X-ALD may not have a typical response to medication, and may also be more likely to develop side effects, especially extrapyramidal side effects (Rosebush et al., 1999). It is therefore critical for the clinician treating this psychosis to be mindful of the increased risk of medication-induced complications. Start any medication at very low doses and titrate very slowly. Lithium is probably contraindicated due to the potential for electrolyte imbalance in ALD (Rosebush et al., 1999). Psychotic or manic symptoms may be treatable with olanzapine or clozapine, but in the presence of adrenal insufficiency and medical compromise, anticholinergic side effects may be worsened. A case report noted effective treatment with valproic acid of affective lability in an adult onset ALD patient (Leo, 1998). Another case report noted control of mania and psychosis with haloperidol and carbamazepine followed by fluvoxamine when the patient progressed to depression (Gothelf, Levite, & Gadoth, 2000). Up to 20% of patients with X-ALD develop seizures, and clozapine may increase that risk (Rosebush et al., 1999). Patients with psychosis may be more treatment-resistant (Rosebush et al., 1999). REFERENCES Abbott, N., Mendonc¸a, L., & Dolman, D. (2003). The blood
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7.

Part VI

Substance Abuse and Medications

19

Cannabis-induced psychosis Luis Alfonso Nu´n˜ez Domı´nguez Centro Me´ dico, Navarra, Spain

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B C B B C C B D D

Introduction Over the last five years a series of research works have been published, relating cannabis use with psychiatric disorders such as schizophrenia and depression. These studies have described the role that cannabis use could play in the etiology and pathology of schizophrenia, the increased risk of developing depression in adulthood if cannabis use was started during adolescence, and the development of problems with social integration. By contrast, the number of research reports examining the controversy about the existence of a true cannabis psychosis have been rather scarce. These papers have been limited to bibliographic reviews and have been rather inconclusive (Poole & Brabbins, 1996; Thomas, 1993; Thornicroft, 1992; 1990). The present chapter is an updated review of the literature on psychosis associated with cannabis use. 369

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Epidemiology Cannabis psychosis is generally considered to be an infrequent disorder (Hall & Degenhardt, 2004), although McBride and Thomas (1995) have found that around 15% of cannabis users report experiencing psychotic symptoms during consumption. Benabud (1957) had elicited a psychosis prevalence of 5% among users; Chopra and Smith (1974) found higher rates of cannabis-induced psychosis, up to 15% of the general population, in areas where consumption is high, such as in India. In the majority of studies, a greater proportion of psychotic symptoms have been observed in male subjects, partly because males habitually consume more cannabis, and do so more frequently. In addition, partly because female hormones related to the luteal cycle might protect women from the effects of cannabinoids, as observed in laboratory animals (Gonza´lez et al., 2000). Rolfe et al. (1993) describe a higher frequency of psychosis among persons using high doses of cannabis (4.4 times greater than users of usual doses). Nevertheless, the real incidence of the disorder remains unknown, partly due to an absence of large epidemiological studies. However, a greater prevalence of this disorder has been observed at least in Italy (between 1984 and 1994) (Preti & Miotto, 2000), as well as in a number of other areas of the world (Cantwell et al., 1999). Presentation Cannabis psychosis is usually observed in young subjects (around 20
22 years old), after several years of use with a pattern of increased consumption during the six months prior to the emergence of the psychotic manifestations (Miller et al., 2001). In subjects with cannabis addiction, who started consuming at age 16 years or younger, a higher incidence of psychotic symptoms is observed at ages 18 to 21 years (Fergusson, Horwood, & Swain-Campbell, 2003). The onset of symptoms is usually sudden, within one week of use, and in some cases even in less than 24 hours after an episode of use (Basu et al., 1999). Chaudry et al. (1991) provide a clear description of the main features: manic symptoms and paranoid symptoms. They also observed the existence of grandiosity, excitement, hostility, confusion, hallucinations, as well as unusual thought content. Rottanburg et al. (1982) found manic symptoms among users; Pa¨lsson, Thulin, and Tunving (1982) described affective and schizophrenia-like symptoms, aggressive behaviour, confusion, and visual hallucinations; Thacore and Shukla (1976) mentioned disturbances in thought process, with flight of ideas, and violent behaviour among users; Keup (1970), Tennant and

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Groesbeck (1972), Talbott and Teague (1969), and Negrete (1983) described a greater number of disturbances within the cognitive sphere. Patients recognize the relationship between cannabis use and disturbances in perception (color, brightness, time, etc.). Another commonly described symptom in psychoses induced by cannabis is a state of depersonalization
derealization (Nu´n˜ez Domı´nguez & Gurpegui, 2002). There appears to be a link between cannabis use and psychosis. Verdoux et al. (2002) found a connection between the use of cannabis and the positive and negative dimensions of psychosis. Similarly, Stefanis et al. (2004) in their study of early cannabis exposure and psychotic symptoms in adolescence, reported proportion of individuals with at least one positive score on one of the psychosis items
paranoia 65%, first-rank symptoms 36%, grandiosity 24%, and hallucinations 3%, bearing a low average grading in the Schneiderian first rank symptoms (FRS). First use of cannabis below age 16 years was associated with a much stronger effect than first use after age 15 years, independent of life-time frequency of use. There are a few studies which have used structured clinical scales such as the Present State Examination (PSE). Cannabis users were found to experience positive symptoms, perception disorders, depersonalization
derealization, delusions of reference, manic symptoms, disorder of thinking, and visual hallucinations, the latter two symptoms being less frequent than in schizophrenia (McGuire et al., 1994; Nu´n˜ez Domı´nguez & Gurpegui, 2002; Rottanburg et al., 1982). Murray et al. (1992) claim that Schneider’s first rank symptoms are quite frequent in psychoses induced by drugs; yet, the data contributed by McGuire et al. (1994) and Nu´n˜ez Domı´nguez and Gurpegui (2002) do not support this hypothesis. As for the negative symptoms, Thacore and Shukla (1976) describe the presence of emotional dullness, although to a lesser degree than in schizophrenia. At the same time, negative symptoms have been observed after acute cannabis use (D’Souza et al., 2004).

Course and progression The onset of cannabis psychosis is usually very sudden, with a brief period of latency from the initial manifestations till the full emergence of symptoms. Symptoms are expected to subside in conditions of sustained abstinence (Murray et al., 1992), although Chaudry et al. (1991) describe residual symptoms in a small proportion of subjects. The vast majority of authors report that psychotic symptoms respond well to treatment if the person maintains abstinence.

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Still, one study reported that symptoms were treatment refractory with brief treatment and supervised abstinence (Rolfe et al., 1993). Nu´n˜ez and Gurpegui (1997) have closely monitored 23 patients diagnosed with cannabis-induced psychosis over a five-year period, and reported that half of them evolved to a functional psychotic disorder (schizophrenia or schizoaffective disorder). The authors related continued use to pre-morbid features of an anti-social personality. Cantwell et al. (1999) found that the diagnosis of cannabis-induced psychosis remains stable after three years. Pa¨lsson et al. (1982) support the existence of acute, sub-acute, and chronic toxic psychoses in their interpretation of the different clinical courses of psychotic symptoms reported in the literature. Yet other studies raise the possibility of an evolution towards a chronic psychotic disorder, bearing similar characteristics to those of schizophrenia (Longhurst & Boutros, 1997; Rolfe et al., 1993) that persists in some cases after the consumption of cannabis has ceased (Ghodse, 1986). For several authors (Hart, 1976) the fact that cannabis psychosis may lead to schizophrenia indicates that cannabis psychosis is an initial step towards schizophrenia and not a distinct disorder. There are other data regarding the possible evolution of this disorder. In a study by McGuire et al. (1995), two out of three of the patients with cannabis psychosis had previously demonstrated psychotic symptoms. Addington and Addington (1998) found in their sample of schizophrenics that almost 50% of subjects had been diagnosed with toxic psychosis at some time in the past. Suspected neuropathology Relatively limited research appears to have been conducted in connection with the pathophysiology of cannabis psychosis. Chronic users show changes at the level of dopamine receptors, an overall alteration of the dopaminergic system, and a global reduction of the metabolism of the brain, especially in the frontal lobe and the cerebellum. These changes can be reversed after acute exposure to cannabis (Loeber & Yurgelun-Todd, 1999). In addition, alterations in the EEG (Struve, Straumanis, & Patrick, 1994) have been observed in alpha and beta frequencies. As for brain morphology, Campbell et al. (1972) and Hart (1976) find certain changes in the brain of users similar to those found in persons with schizophrenia (modifications in the ventricular size) which, in their opinion, would lead to the appearance of a disorder they have called ‘‘propfschizophrenia’’ and which would be the basis on which the worsening of the symptoms after cannabis consumption would take place. Maykut (1985) found modifications

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in the limbic structures of subjects who are cannabis users and suggests that the intake during adolescence would lead to alterations in brain development. He argues that these alterations can increase the person’s vulnerability to psychosis, and that schizophrenic symptoms can emerge with continued use. A study by Wilson and Mathews (2002) reported that subjects who began using cannabis before age 15 years demonstrated a greater reduction of cerebral blood flow than those who began after 17. Moreover, they have less brain weight and height, less gray matter on the cortex and more global white matter, but there are no differences in the size either of the brain or the ventricular volumes. Likewise, a decrease in the cerebral blood flow (CBF) in the frontal lobe has been detected in chronic users of cannabis (Lundqvist, Jo¨nsson, & Warkentin, 2001), while increase of CBF has been reported after new cannabis use. Suspected neurochemical abnormalities The endocannabinoid system has been proved to modulate several systems and neurotransmitters, including the dopaminergic, glutamatergic, GABAergic, and cholinergic, with the first three involved in the patho-physiology of psychotic disorders (Rodrı´guez de Fonseca et al., 2001). The consumption of cannabinoids causes an increase in the dopaminergic mesolimbic activity (increase in the synthesis of dopamine and inhibition of the reuptake of dopamine). Treatment with D2 antagonists can cause a remission of the psychotic symptoms induced by cannabis consumption (D’Souza et al., 2004). The acquired sensitization of the dopaminergic mesolimbic system caused by repeated consumption of cannabis could be the underlying mechanism in the development of psychosis (also observed in other drug psychoses). Effects of dopaminergic sensitization depend on the developmental stage of the person using the cannabis, beginning in the teenage years. The results obtained by Stefanis et al. (2004) support that grandiosity is the symptom that can be considered the clearest example of sensitization induced by cannabis, while hallucinations would be the least sensitive. Such dopaminergic sensitization would be the common basis of schizophrenia and cannabis use, it being possible that the glutamatergic system and the dopaminergic receptors D3 have an influence on it (Tsapakis, Guillin, & Murray, 2003). There are theories about the sensitization hypothesis, specifically in relation to psychotic disorders induced by stimulants, with Sato’s (1992) hypothesis standing out. This hypothesis supports that prolonged intake of toxins causes a permanent alteration of the cerebral homeostasis that clinically assumes the

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form of a psychotic disorder. After each new use the psychotic symptoms reappear. The so-called ‘‘autonomous psychosis’’ (Bowers et al., 1995) is quite similar: prolonged consumption causes sensitization. However, in these authors’ opinion just an episode of psycho-social stress is enough to trigger off the reappearance of psychosis. Finally, Kalivas and colleagues (2000) describe the characteristics of what he calls ‘‘psychosis through sensitization.’’ Progressive development, with peaks of worsening following new intakes occurs, even after prolonged abstinence. On a biochemical basis this implies the existence of long lasting modifications in the neuronal response. All these hypotheses have been considered by Ujike (2002) in his model, which considers two possible patterns of evolution after psychosis through sensitization. One pattern is towards a state of sensitization, with peaks of intensification of the psychotic symptoms after cannabis use and remission after treatment and abstinence of toxic substances. The other pattern is towards an irreversible development of schizophrenia. As far as the biological basis of personality changes are concerned, a decrease in frontal dopaminergic activity has been described in schizophrenic individuals, while anti-social personality disorder subjects show serotoninergic hypoactivity together with subcortical dopaminergic hyperactivity and frontal hypodopaminergic activity (Siever & Davis, 1991). Individuals using cannabis could show a reward-deficiency syndrome similar to the manifestations typical of schizophrenic subjects, which would lead them to the consumption of substances to try to palliate the deficits that such a syndrome causes in them (Green et al., 1999). It has also been suggested that the endogenous cannabinoid system works as an ‘‘endogenous neuroleptic’’ (Emrich, Leweke, & Schneider, 1997), a hypothesis that has been reinforced after the finding of increases of endocannabinoids in the cerebrospinal fluid of schizophrenic individuals (Leweke et al., 1999) and the appearance of schizophrenic-like behaviour in knock-out rats for the CB1 receptor. However, the consumption of THC in humans causes an increase of dopamine (Vorugatti et al., 2001). Likewise, Bowers and Hoffman (1986) have found that high doses of cannabis raise the homovanillic acid (HVA) in the caudate, prefrontal cortex, and olfactory tubercle of rats, and that chronic consumption of THC causes a decrease of CB1 receptors, as well as hypersensitivity to them. Could it be that chronic consumption, especially in adolescents, should cause a permanent alteration in the homeostasis of the endocannabinoid system (Pistis et al., 2004)? As a result, intake following the appearance of the sensitization could trigger not only a new alteration, but also the total failure of the system’s balance leading to schizophrenia-like manifestations. Could these cases be explained by the ‘‘primary addiction’’ hypothesis

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(Chambers, Krystal, & Self, 2001), which claims that both schizophrenia and drug addiction share a common pathophysiology that would, in turn, explain the high prevalence of drug consumption among the schizophrenic population? In such cases it would be possible to consider the appearance of predisposed psychotic symptoms as a logical consequence of consumption, because of the co-existing neuropathology of the brain. In this case, the use of THC would be considered to be prompted by the common predisposition to schizophrenia and substance abuse, with resultant neurobiological alterations, and as a result the drug consumption which itself may not be psychotogenic, may lead to a greater neurobiological disturbance leading to the appearance of schizophrenia-like symptoms and/or schizophrenic manifestations. Nevertheless, in subjects lacking such a neurobiological predisposition, it could be considered that chronic consumption of cannabis causes downregulation in the endocannabinoid system, together with an increase of sensitivity to dopamine (there is an increased incidence of psychotic symptoms at follow-up in cannabis users who did not present cannabis-induced psychosis at baseline, according to the prospective study of Van Os et al. (2002). It has been observed that in subjects with psychotic disorders due to cannabis consumption, the appearance of such disorders comes after a recent increase in consumption, either because of more frequent intake or through the use of preparations with higher THC yield. This increase would cause a new rise in the release of dopamine in the mesocorticolimbic circuit, which would lead to the appearance of the psychotic manifestations. In reference to this, Bowers et al. (1995) suggest that drug users who show psychotic symptoms could bear a greater vulnerability due to the existence of a higher number of dopaminergic receptors; cannabis consumption would increase the concentration of dopamine in the synaptic space; both facts together, would lead to the appearance of psychotic symptoms. When consumption is maintained (abstinence is a necessary circumstance for the remission of the symptoms) (Murray et al., 1992), this mechanism will persist over time, causing the subject to develop either a chronic cannabis psychosis or schizophrenia. Genetic factors Genetic variants of the CB1 receptor might be associated with a specific sensitivity to cannabinoids (Krebs et al., 2002), as well as the development of hebephrenic schizophrenia (Ujike et al., 2002). On the other hand, genetic factors in women might be associated with a greater tendency for both abuse of and dependence on cannabis, with the subsequent risk of developing a psychotic disorder (Kendler & Prescott, 1998).

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Tsuang, Simpson, and Kronfold (1982) described a greater prevalence of schizophrenia in the families of users with long-lasting cannabis-induced psychosis, and suggest that psychoses caused by cannabis should fall in the schizophrenia spectrum. The same opinion is held by Chaudry et al. (1991), Mathers and Ghodse (1992), and McGuire et al. (1995). Other researchers, however, have not found family history of schizophrenia to be a risk factor in cannabis-induced psychosis (Miller et al., 2001; Phillips et al., 2002; Rolfe et al., 1993). Other risk factors The existence of certain personality traits have been found to be risk factors for developing a psychosis secondary to cannabis use. Cuesta, Peralta, and Caro (1999) reported subjects with cannabis-induced psychosis were high in sociopathic and schizoid traits (Williams et al., 1996). Studies using the MMPI reported high scores in SC (Negrete, 1984), and neuroticism (Mendhiratta, Wing, & Verma, 1978) in such patients. Nu´n˜ez Domı´nguez and Gurpegui’s (2002) found a high frequency of anti-social personality. Yet another risk factor would be the beginning of cannabis use during adolescence (Stefanis et al., 2004). More recently Caspi et al. (2005) have reported that a functional polymorphism in the catecholO-methyltransferase (COMT) gene moderated the influence of adolescent cannabis use on developing adult psychosis. Carriers of the COMT valine158 allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis. Cannabis use had no such adverse influence on individuals with two copies of the methionine allele. It was concluded that these findings provide evidence of a gene-environment interaction, and suggest that a role of some susceptibility genes is to influence vulnerability to environmental pathogens. Treatment In general, neuroleptics have been used as the primary treatment of cannabisinduced psychotic symptoms (Chaudry et al., 1991), and remission is usually achieved within a few days (Rottanburg et al., 1982). More recent treatment has been the use of atypical antipsychotics. These drugs have proved to have fewer extrapyramidal side effects than the typical antipsychotics. Olanzapine and haloperidol appear to be equally effective in the treatment of cannabisinduced psychosis, but the former causes fewer extrapyramidal side effects (Berk, Brook, & Trandafir, 1999). Carbamazepine has also been utilized as an adjunct to neuroleptics (Leweke & Emrich, 1999). Nu´n˜ez Domı´nguez (unpublished findings,

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2004) has used ziprasidone in the treatment of a group of patients (25 individuals) with cannabis-induced psychosis, and observed good tolerance, efficacy, scarce adverse effects, and a slight antidepressant effect. Conclusions Taking into account the facts described in this chapter, we could conclude that the main characteristic of cannabis psychosis is a rapid onset of psychotic symptoms with prolonged cannabis use. Cannabis use generally begins during adolescence, with a recent increase either in frequency or in the concentration of THC. The main symptoms are affective disturbances of the manic type, perceptual disorders, delusional ideas of reference, and aggressiveness. In addition, there are disturbances in thought processes, visual hallucinations, and Schneiderian first rank symptoms, the latter being less frequent than in schizophrenia. These disorders have a brief course and remit with abstinence or treatment with neuroleptics. Its progression may be influenced by the existence of risk factors for schizophrenia. If these risk factors exist, these psychotic symptoms could represent the first step towards schizophrenia if use is maintained. On the other hand, if the risk of schizophrenia does not exist, the progression would be towards a new psychotic episode if cannabis use persists, due to the phenomenon of brain sensitisation. Other risk factors include family history of psychosis, and premorbid anti-social and schizoid personality features. One of the most frequent criticisms in papers related to the existence of this disorder is the poor quality of research methodology. It is recommended that future studies adopt a sounder scientific approach while examining the existence of risk factors and the mid- and long-term progression of the disorder. REFERENCES Addington, J. & Addington, D. (1998). Effect of substance misuse in early psychosis. British Journal of Psychiatry, 172(Suppl.), 134
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53. Caspi, A., Moffit, T. E., Cannon, M., et al. (2005). Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-omethyltransferase gene: Longitudinal evidence of a gene X environment interaction. Biological Psychiatry, 57(10), 1117
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65. Emrich, H. M., Leweke, F. M., & Schneider, U. (1997). Towards a cannabinoid hypothesis of schizophrenia: Cognitive impairments due to dysregulation of the endogenous cannabinoid system. Pharmacology, Biochemistery and Behavior, 56, 803
7. Fergusson, D. M., Horwood, L. J., & Swain-Campbell, N. R. (2003). Cannabis dependence and psychotic symptoms in young people. Psychological Medicine, 33, 15
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9. Loeber, R. T. & Yurgelun-Todd, D. A. (1999). Human neuroimaging of acute and chronic marijuana use: Implications for frontocerebellar dysfunction. Human Psychopharmacology Clinical and Experimental, 14, 291
301. Longhurst, J. G. & Boutros, N. N. (1997). Cannabis-induced chronic psychosis: An underacknowledged disorder? Australian and New Zealand Journal of Psychiatry, 31(2), 304
5. Lundqvist, T., Jo¨nsson, S., & Warkentin, S. (2001). Frontal lobe dysfunction in long-term cannabis users. Neurotoxicology and Teratology, 23, 437
443. Mathers, D. C. & Ghodse, A. H. (1992). Cannabis and psychotic illness. British Journal of Psychiatry, 161, 648
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38. McBride, A. J. & Thomas, H. (1995). Psychosis is also common in users of ‘‘normal’’ cannabis. British Medical Journal, 311, 875. McGuire, P. K., Jones, P., Harvey, I., et al. (1994). Cannabis and acute schizophrenia. Schizophrenia Research, 13, 161
8. McGuire, P. K., Jones, P., Harvey, I. et al. (1995). Morbid risk of schizophrenia for relatives of patients with cannabis-associated psychosis. Schizophrenia Research, 15, 277
81. Mendhiratta, S. S., Wing, N. N., & Verma, S. K. (1978). Some psychological correlates of long-term, heavy cannabis users. British Journal of Psychiatry, 132, 482
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6. Thacore, V. R. & Shukla, S. R. P. (1976). Cannabis psychosis and paranoid schizophrenia. Archives of General Psychiatry, 33, 383
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Cocaine Daryl E. Fujii1 and Erin Y. Sakai2 1 2

Hawaii State Hospital Beth Israel Deaconess Medical Center

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

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Introduction Cocaine is a drug that was developed in the mid nineteenth century. It gained notoriety towards the end of that century due to Sigmund Freud’s addiction as well as its inclusion as an ingredient in Coca-Cola (Baker, 1987). Despite its long history of abuse, the first papers on cocaine-induced psychosis began appearing much later in the 1960s (Goodman and Gilman, 1965). Since then, there have been very few studies on cocaine-induced psychotic disorder. The current chapter attempts to elucidate the relationship between cocaine and psychosis by systematically reviewing the human literature on this topic. Epidemiology Cocaine use has been associated with both transient psychosis occurring within the context of use as well as a more persistent psychosis. A transient psychosis 382

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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has been estimated to occur in 44
68% of patients who seek treatment for cocaine use and related psychiatric disorders (Brady et al., 1991; Manschreck et al., 1988; Satel, Southwick, & Gawin, 1991), but only in 18% of recreational cocaine users (Siegel, 1978). Brady et al. (1991) reported that 48% of cocaine abusers seeking treatment indicated that they were not able to use cocaine without experiencing paranoia. In a study on individuals who were admitted for cocaine dependence treatment, 29% reported a gradual onset of psychosis (Manschreck et al., 1988). No significant differences in age or duration of cocaine use were found between psychotic cocaine users and nonpsychotic cocaine users seeking treatment (Brady et al., 1991), however, individuals in the psychosis-positive group seemed to use significantly more cocaine than the psychosis-negative group in the year before attending an inpatient treatment facility (p < 0.02), as well as during their lifetime (p < 0.01) (Brady et al., 1991). Similarly, Manschreck et al. (1988) found that psychotic cocaine abusers used twice as much cocaine as nonpsychotic cocaine users. There is evidence that men are significantly more likely than women to develop cocaine-induced psychosis (p  0.05) (Brady et al., 1991). Age of onset The age of psychosis onset in cocaine abusers varies and appears to be related to the duration of cocaine use prior to psychosis. Satel et al. (1991) found that 50% (17 out of 34) of psychosis-positive, cocaine abusers reported psychosis onset within 25 months of regular cocaine use, 35% (12 out of 34) reported psychosis between 25
57 months following regular cocaine use, while the remaining 15% (5 out of 34) experienced psychotic symptoms after 57 months. In general, the onset of psychosis occurred after an average of 34.7 months of cocaine use (Satel et al., 1991). The mode of cocaine intake also appeared to affect the onset of psychosis. Forty-eight percent of the individuals with cocaine-induced psychosis reported first experiencing psychosis within a week of changing from intranasal administration to intravenous or inhalation (Brady et al., 1991). Presentation The psychotic presentation of cocaine abusers includes delusions and hallucinations. Grandiosity and paranoia are the most common delusions and occur in 93% of psychotic patients (Manschreck et al., 1988; Post, 1975). About 90% of paranoid delusions are associated with drug use (Brady et al., 1991).

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Cocaine abusers often believe that the police or drug dealers are searching for them or that other people want to steal their drugs (Satel et al., 1991). Brady et al. (1991) reported that 96% of cocaine abusers with psychosis experience hallucinations. Auditory hallucinations are the most common type and are experienced by about 50
83% of those with psychosis (Brady et al., 1991; Mitchell & Vierkant, 1991). About 35
56% reported visual hallucinations, while tactile hallucinations such as formication, which is the feeling of bugs under the skin, occur in about 21
23% of psychotic cocaine abusers (Brady et al., 1991; Manschreck et al., 1988; Mitchell & Vierkant, 1991). Auditory hallucinations can be well-formed such as Schneiderian first-rank symptoms of voices arguing or commenting on a person’s actions, such as telling them to buy more drugs or seek help. This type of symptom was experienced in 32% of psychotic cocainedependent patients seeking treatment (Manschreck et al., 1988; Mitchell & Vierkant, 1991). Individuals with visual hallucinations claim to see people following or looking through windows at them. Not all of cocaine-associated hallucinations are well-formed. Auditory hallucinations can also be noises that are interpreted by the individual as a sign that they are being followed or watched, while visual hallucinations resulting from cocaine use can also include geometric shapes and movement in the peripheral areas of the visual field. Regardless of the type of auditory or visual hallucination, they are generally integrated into paranoid delusions associated with cocaine use. This integration of symptoms is supported by a study reporting a strong correlation between scores for delusions and hallucinations of psychotic cocaine users on a newly developed Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP) (Cubells et al., in press). Other common symptoms include behavioral stereotypies occurring in 27% of cocaine-dependent psychotic patients (Brady et al., 1991), insomnia (52%), proneness to violence (42%), low impulse control (39%), uncooperativeness (36%), and blunted affect (36%) (Manschreck et al., 1988). A majority of patients demonstrated poor insight into their symptoms (81%). Cocaine psychosis is often indistinguishable from paranoid schizophrenia, particularly in the acute phases (Serper et al., 1999). However, unlike psychosis associated with schizophrenia, cocaine psychosis does not typically involve bizarre delusions and there is an absence of a formal thought disorder as abstract reasoning and linear thought processes are generally preserved (Mendoza & Miller, 1992; Mitchell & Vierkant, 1991; Rosenthal & Miner, 1997). Conversely, individuals suffering from paranoid schizophrenia rarely experience tactile hallucinations. Although there are no studies specifically examining neurocognition in psychotic cocaine users, in general individuals who abuse cocaine demonstrate

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impairments in learning, memory ability, visuospatial skills, calculations, abstraction ability, and judgement (Nambudiri & Young, 1991; Strickland et al., 1993). They also appear to have deficits in mental processing speed, attention, memory, and mental flexibility (Meek, Clark, & Solana, 1989; Miller, 1985). Course and progression Paranoia associated with cocaine use has been reported to develop after an average of using the drug for three years (Satel et al., 1991), whereas simpler visual and tactile hallucinations may begin to occur after six months of recreational use (Siegel, 1978). A majority will experience symptoms after a ‘‘binge’’ or continual use in a short period of time (Satel et al., 1991; Siegel, 1978). Although the vast majority of cocaine-induced psychosis resolves within 24 hours after the last use (Brady et al., 1991), psychosis can persist for longer periods of time. Manschreck et al. (1988) reported that the mean duration of psychosis for patients hospitalized for these symptoms was 16 days (standard deviation ¼ 18), with one patient remaining psychotic for 60 days. Still, very few cocaine abusers seeking substance abuse treatment are actually diagnosed with a schizophrenia spectrum disorder with numbers resembling the incident rate in the general population (1.3%) (Rounsaville et al., 1991). Taken together, these data would suggest that cocaine psychosis is of relatively short duration and amenable to treatment. Several researchers report that the onset of cocaine-induced psychosis follows an orderly progression. According to Siegel (1978), there is a progression of visual sensations he called ‘‘snow lights,’’ to seeing geometric shapes, and then to tactile sensations that felt like insects crawling on the skin. Post (1975) reported that increasing doses and chronicity of cocaine use results in increasingly severe affective and cognitive changes that progress from depression to mania, and then to schizophrenia. Brady et al. (1991) found that 72% of psychotic individuals reported their cocaine-induced psychosis increased in frequency over time and required less of the drug for psychosis to occur. Suspected neuropathology There have been no studies specifically examining the neuropathology of cocaine psychosis, thus we will report findings on the neuropathology of cocaine dependence. Magnetic resonance imaging (MRI) studies suggest that abnormalities in cerebral white matter might be associated with cocaine dependence. T2 signal hyperintensities and metabolite abnormalities have been found in the white matter of cocaine abusers (Lim et al., 2002). Damaged white matter

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microstructure, mainly in the inferior frontal brain region, appears related to cocaine use (Lim et al., 2002). In addition, proton spectroscopy studies reported that cocaine users who had stopped using the drug for several months had lower N-acetyl aspartate, which suggests possible neuronal and axonal damage (Chang et al., 1999; Meyerhoff et al., 1999). Increased putamen volume, which is linked to cocaine abuse, has also been reported on MRI (Jacobsen et al., 2001). Functional neuroimaging and neuropsychological studies suggest that cocaine also affects the anterior part of the brain. Functional neuroimaging indicated that cocaine users showed decreased relative cerebral blood flow (Volkow et al., 1988) and brain glucose metabolism levels (Volkow et al., 1992) in the frontal cortex. Even after six months without cocaine use, individuals showed significant deficiencies in cerebral blood flow (Strickland et al., 1993). Meanwhile, neuropsychological studies indicated abstracting and problem-solving deficiencies in cocaine abusers (Beatty et al., 1995; O’Malley et al., 1992) that are believed to be connected to the prefrontal cortex (Hartley & Speer, 2000). Suspected neurochemical abnormalities Cocaine exerts a strong effect on the dopamine system by increasing synthesis and blocking reuptake, thereby facilitating its release from the synapse (Post, 1975). This action results in an increase in the number of cocaine receptors and increases the availability of dopamine in mesolimbic neuronal circuits, including the nucleus accumbens (Broderick et al., 2004). The stimulant model of psychosis hypothesizes that psychosis is associated with the increase in availability of dopamine in these structures (Ellison, 1994; Lieberman, Kinon, & Loebel, 1990). Cocaine also affects other neurotransmitter systems such as serotonergic projections to the nucleus accumbens, as well as increasing norepinephrine and acetylcholine (Broderick et al., 2004). Although more speculative, Broderick et al. (2004) argue an increase in serotonin may also contribute to cocaine-induced psychosis. Genetic factors Since patients with cocaine-induced paranoia do not seem significantly different from non-paranoid patients with respect to their length of drug use, total drug exposure, use of other drugs, or means of drug administration, some suggest that genetic factors are involved in cocaine-induced psychosis. Studies have found that polymorphisms in the catecholamine-related genes that encode the dopamine transporter (Gelernter et al., 1994) and dopamine b-hydroxylase (Cubells et al., 2000) are related to cocaine-induced paranoia. These studies suggest that the

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susceptibility to cocaine-induced paranoia may vary among individuals because of the brain’s sensitivity to cocaine (Boutros et al., 2002). Boutros et al. (2002) identified a connection between P50 sensory gating deficiencies and paranoia experienced following cocaine use. Sensory gating deficiencies occur when inhibition of incoming stimuli fails and can lead to psychosis. P50 gating deficiencies associated with psychosis are hereditary and could have a locus on chromosome 15q (Boutros et al., 2002). However, deficient P50 gating is only found in some cocaine abusers, suggesting that this deficiency predetermines cocaine-induced paranoia in chronic cocaine users rather than resulting from it. Other risk factors Prior history of major mental disorder predestines more severe, longer-lasting psychotic symptoms. This predisposition is evidenced by the fact that patients with previous mental illness had used freebase cocaine less frequently and for a shorter period of time than their counterparts with no previous mental illness (Manschreck et al., 1988). Paranoid individuals were more likely to have had previous substance abuse, other than cocaine, before they had become dependent on cocaine (Satel et al., 1991), experienced transient paranoid symptoms while using cocaine (Satel & Edell, 1991), and experienced more intense effects with smaller doses of cocaine over time (Bartlett et al., 1997). Factors related to the patient’s acute clinical status that can impact response to cocaine include the type of psychiatric illness, the degree of recent stress or loss, a vulnerable phase of a circadian or ultradian rhythm (Post, 1975), and aging as reduced hepatic blood flow and enzymes results in a slower metabolism of the drug (Nambudiri & Young, 1991). Attention Deficit Hyperactivity Disorder (ADHD) has been reported to be a risk factor for using cocaine, as 12
35% of adult cocaine users had a history of the disorder (Boutros et al., 2002), which may also increase risk for prolonged psychosis (Gomez, Janowsky, & Zetin, 1981). Treatment Neuroleptics have generally been used to curb the acute psychotic reactions, hallucinations, paranoia, and hyperactivity caused by cocaine abuse (Baker, 1987; Flemenbaum, 1977; Nambudiri & Young, 1991). A more recent study reported that the atypical antipsychotic clozapine was effective in blocking cocaine’s effect on both the dopaminergic and serotonergic neurotransmitter systems (Broderick et al., 2004). Lithium has also been studied as an alternate form of treatment for cocaineinduced psychosis. Lithium treatment appears to control cocaine-induced

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euphoria and treats affective disorders resulting from cocaine use and does not have the side effects of neuroleptics (Flemenbaum, 1977). In one study, a patient reported having a ‘‘high’’ of lesser degree when he used cocaine while on lithium treatment as opposed to without treatment (Scott & Mullaly, 1981). Conclusions Cocaine can induce a psychosis that can mimic paranoid schizophrenia, with symptoms including paranoid and grandiose delusions as well as Schneiderian first-rank symptoms. The onset of psychosis appears to be dose- and durationrelated, with simple visual hallucinations of ‘‘snow lights’’ and geometric shapes and tactile hallucinations occurring after about six months of use and the onset of paranoia after about three years. Delusions and hallucinations are strongly related to drug use, for example, police are looking for the individual, and increase in frequency with longer duration of cocaine use. Formication, or the delusion that bugs are crawling on one’s skin, is another common symptom. The psychotic person generally has little insight into his symptoms, but maintains linear thought processes. Psychosis experienced while using cocaine can occur in 18
68% of patients seeking treatment for cocaine abuse. Over time, about 29% of those seeking treatment can develop a persisting psychosis that lasts for about an average of two weeks after last use of the drug, but can last up to two months. It is generally believed that cocaine-induced psychosis results from an increase in dopamine in the mesolimbic areas. Psychotic symptoms are treatable with antipsychotics, and lithium has also been found to be a useful medication. There appears to be a genetic predisposition for psychosis as persons with a history of psychiatric illness require less drug to trigger a psychotic episode that appears to be longer lasting than persons without a psychiatric history. Other risk factors include a premorbid drug use history, and those who experience transient psychosis are more likely to develop a persistent psychosis. Thus far, there have been no reports of the effects of multiple episodes of persisting psychosis, thus it is not known whether the episodes of persistent cocaine psychosis increase in duration over time. REFERENCES Baker, F. M. (1987). Cocaine psychosis. Journal of the National Medical Association, 81, 987, 990, 994, 996, 999
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82. Beatty, W., Katzung, V., Moreland, V., & Nixon, S. (1995). Neuropsychological performance of recently abstinent alcoholics and cocaine abusers. Drug and Alcohol Dependence, 37, 247
53. Boutros, N., Gelernter, J., Gooding, D., Cubells, J., et al. (2002). Sensory gating and psychosis vulnerability in cocaine-dependent individuals: Preliminary data. Society of Biological Psychiatry, 51, 683
6. Brady, K., Lydiard, R., Malcolm, R., & Ballenger, J. (1991). Cocaine-induced psychosis. Journal of Clinical Psychiatry, 52, 509
12. Broderick, P., Hope, O., Okonji, C., Rahni, D., & Zhou, Y. (2004). Clozapine and cocaine effects on dopamine and serotonin release in nucleus accumbens during psychostimulant behavior and withdrawal. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 28, 157
71. Chang, L., Ernst, T., Strickland, T., & Mehringer, C. (1999). Gender effects on persistent cerebral metabolite changes in the frontal lobes of abstinent cocaine users. American Journal of Psychiatry, 156, 716
22. Cubells, J., Kranzler, H., McCance-Katz, E., et al. (2000). A haplotype at the DBH locus, associated with low plasma dopamine b-hydroxylase activity, also associates with cocaineinduced paranoia. Molecular Psychiatry, 5, 56
63. Cubells, J., Feinn, R., Pearson, D., et al. (in press). Rating the severity and character of transient cocaine-induced delusions and hallucinations with a new instrument, the Scale of Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SPAS-CIP). Drug and Alcohol Dependence. Ellison, G. (1994). Stimulant-induced psychosis, the dopamine theory of schizophrenia and the habenula. Brain Research Reviews, 19, 223
39. Flemenbaum, A. (1977). Antagonism of behavioral effects of cocaine by lithium. Pharmacology, Biochemistry, and Behavior, 7, 83
5. Gelernter, J., Kranzler, H., Satel, S., & Rao, P. (1994). Genetic association between dopamine transporter protein alleles and cocaine-induced paranoia. Neuropsychopharmacology, 11, 195
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53. Jacobsen, L., Giedd, J., Gottschalk, C., Kosten, T., & Krystal, J. (2001). Quantitative morphology of the caudate and putamen in patients with cocaine dependence. American Journal of Psychiatry, 158, 486
9. Lieberman, J. A., Kinon, B. J., & Loebel, A. D. (1990). Dopaminergic mechanisms in idiopathic and drug-induced psychoses. Schizophrenia Bulletin, 16, 97
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19. Miller, L. (1985). Neuropsychological assessment of substance abusers: Review and recommendations. Journal of Substance Abuse Treatment, 2, 5
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5. O’Malley, S., Adamse, M., Heaton, R., & Gawin, F. (1992). Neuropsychological impairment in chronic cocaine abusers. American Journal of Drug and Alcohol Abuse, 18, 131
44. Post, R. (1975). Cocaine psychoses: A continuum model. American Journal of Psychiatry, 132, 225
31. Rosenthal, R. N. & Miner, C. R. (1997). Differential diagnosis of substance-induced psychosis and schizophrenia in patients with substance use disorders. Schizophrenia Bulletin, 23, 187
93. Rounsaville, B., Anton, S., Carroll, K., et al. (1991). Psychiatric. Diagnoses of treatment-seeking cocaine abusers. Archives of General Psychiatry, 48, 43
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11. Satel, S., Southwick, S., & Gawin, F. (1991). Clinical features of cocaine-induced paranoia. American Journal of Psychiatry, 148, 495
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Methamphetamine Liz Jacobs and William Haning III University of Hawaii

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B C B C B B C C C

Introduction Methamphetamine (MA) use is rising in the United States (Community Epidemiology Work Group, 2003). While historically its use has been concentrated among young men in urban centers on the West Coast, recent emergency room statistics show increased use in other areas of the country and among women, children, and middle-aged adults (Community Epidemiology Work Group, 2003; Drug Abuse Warning Network, 2004). Recent maps of methamphetamine laboratory seizures confirm widespread use in the United States (National Drug Intelligence Center, 2005). Hawaii, as a state, is believed to have the highest prevalence of methamphetamine users, with the drug most commonly available in a smokable form called ‘‘ice.’’ It is considered by authorities to be the state’s most significant drug threat (United States Drug Enforcement Agency, 2005).

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Methamphetamine use affects an individual in ways that tend to vary with the duration of use (National Institute on Drug Abuse, 2002). Short-term use is often described as pleasurable and is associated with increased wakefulness, attention, increased motor activity, and decreased appetite. Chronic use is associated with tolerance, withdrawal, violent behavior, anxiety, confusion, mood disturbances, and suicidal or homicidal ideation. Psychotic symptoms are also common during chronic use and withdrawal and include paranoid delusions and auditory, visual, and tactile hallucinations. According to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, Text Revision (DSM-IV-TR; American Psychiatric Association, 2000), a diagnosis of methamphetamine-induced psychotic disorder (MA psychosis) may be given when psychotic symptoms are believed to be uniquely attributable to current or past methamphetamine use. Some researchers have noted difficulties in the use of this diagnostic category, however, because the disorder can present very similarly to the paranoid subtype of schizophrenia (Flaum & Schultz, 1996; Shaner et al., 1998). In the past, MA psychosis was studied as a drug model of schizophrenia in animals, and this model contributed to the formation of the dopamine hypothesis of schizophrenia (Baumeister & Francis, 2002). Some researchers have concluded that the disorders are indistinguishable (Flaum & Schultz, 1996; Sato et al., 1992) or closely related (Boutros & Bowers, 1996) while others maintain that they are distinct entities which may require different approaches to assessment and treatment (Caton et al., 2005). The clinical management problem is complicated by the issue of co-morbidity, in which the ‘‘functional’’ psychosis, such as schizophrenia, is compounded by use of methamphetamine. As the respective courses of methamphetamine-induced psychosis and schizophrenia do certainly differ at least in etiology, if ultimately not so much in neuro-pathophysiology, the distinction is an important one bearing on prognosis and on intensity and duration of treatment. With the impact of methamphetamine use increasing, research is needed to better understand MA psychosis and its relationship to other psychotic disorders. Epidemiology Due to the secrecy associated with drug use, it is difficult to estimate the prevalence of MA psychosis in the population. As noted above, available indicators from law enforcement and emergency room statistics suggest that methamphetamine use is increasing across the United States (Drug Abuse Warning Network, 2004; National Drug Intelligence Center, 2005). Kalechstein et al. (2000) found that among a prison sample of 1580 arrestees, 10.7% reported methamphetamine dependence.

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Chen et al. (2003) interviewed 445 methamphetamine users and found that 39% reported methamphetamine psychosis, and 7% reported psychosis that lasted more than a month. In a large study (n ¼ 1016) of methamphetamine-dependent individuals, average scores on the psychoticism scale of the Brief Symptom Interview were high despite exclusion of those with Axis I disorders (Zweben et al., 2004), suggesting that symptoms of MA psychosis may be quite prevalent among users who meet criteria for dependence.

Age of onset While it is less meaningful to discuss age of onset in this disorder than in those more idiopathic in origin, it should be noted that MA psychosis is more a disorder of the young adult (M. Toles, L. Lettich, & D. Goebert, unpublished data, 2004). The relative lack of a late-onset syndrome suggests more than simply an epidemiological bias, as MA psychosis is not reliably associated with duration or quantity of use.

Presentation The DSM-IV-TR provides criteria for diagnosis of substance-induced psychotic disorder, with specific references to the amphetamine category of substances. An individual must develop psychotic symptoms within one month of intoxication or withdrawal of methamphetamine and the symptoms should not be attributable to another psychotic disorder. The guidelines suggest that factors such as duration of drug use, age of onset, and persistence of symptoms be used to distinguish substance-induced psychotic disorder from other psychotic disorders. The DSM-IV-TR also states, however, that symptoms can persist for weeks or longer after the individual has consumed amphetamines, which complicates differential diagnosis based on these criteria. Several researchers have studied symptom patterns in individuals with MA psychosis. Iwanami et al. (1994) recorded the symptoms of 104 individuals with MA psychosis in Japan, and found that most exhibited ideas of reference, delusions of persecution, and auditory hallucinations. They also observed that individuals whose symptoms persisted for more than three months reported higher levels of other types of hallucinations. Two studies have assessed negative symptoms of schizophrenia in small groups of individuals with MA psychosis relative to those with schizophrenia using the Scale for Assessment of Negative Symptoms (SANS) (Tomiyama, 1990; Yeh et al., 2001). One study reported that the negative symptoms in the MA psychosis group were lower than the moderate

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levels obtained for the schizophrenia group (Yeh et al., 2001). The second study also detected lower scores on the SANS, while noting that the scores tended to increase with age of onset in the MA psychosis group but not in the schizophrenia group (Tomiyama, 1990). Age of onset did not correlate with duration of drug use, which varied considerably in the sample. While no known studies to date have focused on neurocognitive functioning in individuals with methamphetamine-induced psychosis, several studies have documented neurocognitive deficits in methamphetamine-dependent individuals. Kalechstein, Newton, and Green (2003) compared a group of individuals with methamphetamine dependence with nonuser controls using performances on a neurocognitive battery, and found that the methamphetamine-dependent group demonstrated significantly poorer performances in domains of memory and attention/psychomotor speed. Simon et al. (2000) compared 65 individuals with methamphetamine dependence with 65 nonuser controls on a neurocognitive battery, and found that the methamphetamine-dependent individuals exhibited deficits on two out of three tests involving the manipulation of information and on a cognitive inhibition task. Salo et al. (2002) administered a single trial, computerized version of the Stroop test of selective attention and priming to men with methamphetamine dependence and controls, and the methamphetamine-dependent group exhibited deficits in interference (longer reaction times) but not priming, suggesting that cognitive processes are affected differentially by methamphetamine use. Trites et al. (1976) compared 50 individuals who abused ‘‘speed’’ (amphetamine) with both sibling and peer controls on a number of variables including a neurocognitive test battery. Preliminary findings suggested that lower attention was found in user and sibling groups compared with peers. The group that abused speed also exhibited impairments compared to both control groups on memory and rapid letter
number sequencing tasks. Slight impairments were noted in adaptive tests and motor skills tasks. Three studies used multiple comparison groups to better understand cognitive performance in methamphetamine-dependent individuals with comorbid ADHD (Sim et al., 2002), HIV (Rippeth et al., 2004), and marijuana use (Gonzalez et al., 2004). Both HIV and ADHD are associated with cognitive deficits, and results of the first two studies suggested that when individuals with either condition also are dependent on methamphetamine, their cognitive performance appears to be lower than that of either condition alone. Researchers from both studies concluded that this is an additive effect, with methamphetamine use further contributing to cognitive decline in these individuals; however, due to the cross-sectional design of both studies and inability to randomize participants to condition, it is possible that individuals

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with HIV or ADHD who also use methamphetamine may be different from those who do not (e.g., they may have greater cognitive deficits prior to methamphetamine use). The effects of marijuana use on neurocognitive performance has not been well studied, and results of the third study do not suggest an additive effect. The effects of marijuana use on neurocognitive functioning are not well understood (Grant et al., 2003). While evidence is mixed across studies as to the specific domains of neurocognitive functioning affected, current cross-sectional evidence suggests that methamphetamine-dependent individuals may exhibit deficits in several domains, similar to those with schizophrenia. Course and progression Mixed findings have been reported on the course of MA psychosis. Yeh et al. (2001) followed participants for six months and reported that positive symptoms tended to improve over time, while negative symptoms remained relatively constant. Other researchers have suggested that the symptoms can be chronic or recurrent (Sato et al., 1992; Tomiyama, 1990). Sato and colleagues (1992) reviewed Japanese studies on the course of MA psychosis and suggested that the course of MA psychosis could be divided into three types: transient, prolonged, and persistent. The transient type occurred only upon reuse of methamphetamine, the prolonged type persisted for up to one month after the direct pharmacological effects of the drug had subsided, and the persistent type continued for more than one month despite abstinence from methamphetamine use. While all three types were described as difficult to distinguish from schizophrenia at the cross-sectional level, the third type also resembled schizophrenia in course. Suspected neuropathology Several studies have used brain scanning techniques and neurocognitive testing to examine brain irregularities and functional consequences in methamphetaminedependent individuals. Chang et al. (2002) used Magnetic Resonance Imaging (MRI) and perfusion MRI scans to compare 10 men and 10 women with methamphetamine dependence who were abstinent from the drug at the time of the study with 20 gender-matched, nonuser controls. A neurocognitive battery was also administered to both groups. While no differences were found between methamphetamine-dependent subjects and normative data for verbal memory, fine motor speed, gross motor functioning, psychomotor speed, or executive functioning, differences were seen on tests of focused sustained attention,

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particularly on tasks that involved working memory. Several measures of attention were linked to differences in relative regional cerebral blood flow (rCBF) on the perfusion MRI. The methamphetamine-dependent group had significant reductions in rCBF bilaterally in the putamen/insular cortices and the right lateral parietal region. Relative rCBF was increased in the methamphetamine-dependent group in the left temporoparietal white matter, the left occipital brain region, and the right posterior parietal region. A gender interaction effect was found in which females with past methamphetamine dependence showed increased relative rCBF in both the right occipital cortex and midline structure and males showed decreased relative rCBF compared to controls. The findings suggest that attentional deficits in MA psychosis may be related to alterations in certain structures in the brain, and that these effects may differ somewhat between males and females. Volkow et al. (2001b) conducted Positron Emission Tomography (PET) scans using a dopamine transporter ligand on 15 individuals with a history of methamphetamine dependence and 18 nonuser controls. A neurocognitive battery was also administered. On the PET scan, dopamine transporter availability was lower in the methamphetamine-dependent group in the caudate and putamen but not in the cerebellum. A significant correlation was found between years of methamphetamine use and dopamine transporter level in the caudate. Dopamine transporter levels were not correlated with days since last methamphetamine use. A striatal dopamine transporter level was averaged for the caudate and putamen, and this score was correlated with apparent neurocognitive deficits in motor and verbal memory tasks. These results suggest that disruption to striatal dopamine transmission may be related to neurocognitive deficits on motor and verbal memory tasks. In a second study by Volkow et al. (2001a) using a subset of five individuals from the same participant group, researchers conducted PET scans when the participants initially stopped using methamphetamine and again after nine months of abstinence. Results showed a significant increase in dopamine transporters in the striatum. The degree of increase was negatively correlated with years of drug use. Performances on the motor and verbal memory tasks on which the participants initially exhibited deficits did not significantly improve after the abstinence period. These results suggest that some recovery of dopaminergic neurotransmission occurs after drug cessation, but did not suggest that recovery is associated with increased performance on neurocognitive measures. Paulus et al. (2003) compared the performances of 14 individuals with methamphetamine dependence and 14 nonuser controls on a two-choice prediction task. Functional MRIs were conducted during the task. No differences were found on the impact of success and failure, switching rate, or predictability

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of outcome on behavioral responses; however, the degree of success or failure did affect outcome-related strategies. Regardless of error rate, methamphetaminedependent subjects exhibited more win-stay/lose-shift consistent responses. Results of the MRI showed methamphetamine-dependent subjects had less taskrelated activation in the bilateral inferior prefrontal cortex and dorsolateral prefrontal cortex independent of error rate. They also showed less task-related activation in the bilateral parietal cortex, left postcentral gyrus, and left superior temporal gyrus. The comparison group showed more task-related activation when the error rate was low, while the methamphetamine-dependent group showed more task-related activation when the error rate was most unpredictable (50%). The methamphetamine-dependent group appeared to process the prediction task differently and used different behavioral response strategies indicative of a more rigid stimulus
response relationship. Results from brain imaging studies provide evidence that methamphetamine use affects certain regions of the brain, including the striatum, prefrontal cortex, and parietal cortex, and that such changes persist in spite of abstinence (Ernst et al., 2000). Performances on several tasks of attention/working memory, verbal memory, and motor abilities appear to be somewhat related to these disruptions in brain functioning. Interestingly, however, the one study that looked at dopamine transporter recovery after protracted abstinence found that neurocognitive deficits persisted despite partial recovery of brain function. Future research is needed to better elucidate the effects of abstinence on recovery of brain function in methamphetamine-dependent individuals.

Suspected neurochemical abnormalities Evidence from rat studies suggests that long-term methamphetamine use damages the nerve terminals of dopaminergic neurons (Seiden & Sabol, 1996). As a result of this damage, it is believed that the vesicles continuously release dopamine into the synapse. This damage is evidenced in humans by a reduction in dopamine transporters (Sekine et al., 2001; Volkow et al., 2001). In both human and animal trials, a partial recovery of dopamine transporters has been shown after protracted abstinence (Cass & Manning, 1999; Harvey et al., 2000; Volkow et al., 2001a). Reductions in dopamine transporters are documented in individuals with Parkinson’s disease and have been associated with neurocognitive deficits in methamphetamine-dependent individuals (Volkow et al., 2001b). In MA psychosis, increased dopaminergic neurotransmission in the mesolimbic pathway is associated with positive symptoms (Baumeister and Francis, 2002).

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The subsequent reduction of dopamine receptors and transporters may result in reduced dopamine transmission in certain parts of the brain which may be associated with negative symptoms, cognitive impairment, and depression (Abi-Dargham, 2004). Other neurotransmitters have been implicated in MA psychosis. According to a review by Nordahl, Sab, and Leamon (2003), methamphetamine use may affect serotonergic and glutamatergic systems. Dopamine interacts with both of these neurotransmitters, and the mechanism by which they are affected probably involves other neurotransmitter systems as well. Nordahl et al. (2003) suggest that a complex interaction of many neurotransmitters may be involved in the development of MA psychosis. In a subset of individuals with MA psychosis, symptoms tend to remit and recur over time despite abstinence from the drug (Sato et al., 1992; Tomiyama, 1990). Stress appears to play a role in the recurrence of psychotic symptoms. Yui et al. (1999) studied 45 female prisoners with a previous history of MA psychosis, 29 of whom experienced recurrences. Blood plasma levels were assayed for norepinephrine, epinephrine, dopamine, and markers of norepinephrine and dopamine. The investigators found that individuals with recurrences of psychotic symptoms had been exposed to extreme (e.g., physical and sexual abuse) and severe (e.g., divorce, unwanted pregnancy) stress more often than those who did not experience recurrences. Frightening psychotic content (e.g., voices threatening to kill them, being chased by the police or an imagined gangster) was also more common in individuals who experienced recurrences. Mild stressors which often preceded recurrences included conflicts with other inmates and fear of prison staff. Norepinephrine levels were higher in the recurrent MA psychosis group than in the comparison group. One marker of increased dopaminergic activity, 3-methoxytiramine, was elevated among individuals experiencing recurrences. To explain the results of this study, Yui et al. (1999) suggested that high stress may precipitate or occur in conjunction with stimulant use in individuals who experience recurrences of psychotic symptoms. Exposure to high stress in individuals who use stimulants may sensitize the noradrenergic system to subsequent stressors, as occurs in nonusers, as well as the dopaminergic system, which has been disrupted by stimulant use. As a result, individuals with stimulantinduced psychosis may experience not only typical manifestations of stress sensitization (e.g., memories of trauma, exaggerated stress response) but also psychotic symptoms. According to Yui and colleagues, concurrent sensitization of both systems may explain why participants in the study experienced recurrences of psychotic symptoms with frightening content following mild interpersonal stressors.

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Genetic factors Genetic factors have not yet been defined, although recent work within NIDA’s Methamphetamine Clinical Trials Group (MCTG) (Haning et al., unpublished data) suggests strongly that methamphetamine-dependent patients may be speciated on the bases both of medication response and patterns of usage. Other risk factors Not all individuals who are dependent on methamphetamine develop MA psychosis, indicating that other contributing factors must be present. Chen et al. (2003) interviewed 445 methamphetamine users and compared those with MA psychosis (174) to those who had not experienced psychotic symptoms. Those with MA psychosis had significantly higher prevalence of major depression, alcohol dependence, and antisocial personality disorder, although the direction of the relationship was unclear. They reported first use at a younger age and reported using larger amounts of the drug. They also had higher levels of premorbid schizoid or schizotypal personality traits. Another archival study of 29 inpatients with treatment-resistant MA psychosis found that 23 had premorbid indicators of neurological conditions including: head injury, placement in special education, attention deficit hyperactivity disorder, birth complications, and pathological lefthandedness (Fujii, 2002). Thus, environmental contributors and vulnerability in the user may both contribute to the development of this disorder. Mikami et al. (2003) used exploratory eye movements as a vulnerability marker for schizophrenia to compare individuals with Sato’s three types of MA psychosis (see Course and Progression section) to a group of individuals with schizophrenia and a group of non-psychiatric controls. No differences were found between those with persistent MA psychosis or schizophrenia nor between those with the transient or persistent types of MA psychosis and the non-psychiatric controls. The authors hypothesized that individuals with the persistent type of MA psychosis may have had a pre-existing vulnerability to schizophrenia, although longitudinal research would be needed to clarify this relationship. Treatment Effective pharmacotherapy for methamphetamine dependence, as for other stimulants of abuse, has still not been demonstrated (Ling & Shoptaw, 1997). Pharmacological strategies are being explored in clinical trials in a number of sites, notably the NIDA Methamphetamine Clinical Trials Group, with emphasis on agents such as bupropion, ondansetron, selegiline, and topiramate. The few

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allusions in the literature to treatment of methamphetamine psychosis emphasize a need to address this problem at its origin, that is in attempting to arrest the methamphetamine use. It is noteworthy that twelve-step facilitation (TSF), cognitive-behavioral therapies (CBT), and contingency contracting methodologies all have efficacy, but length of treatment continues to be the best predictor of positive outcome (Rawson, Gonzales, & Brethren, 2002). Successful management of MA psychosis presently relies upon the schizophrenia metaphor. Management addresses three areas, (1) behavior, (2) thought, and (3) drug usage. It entails interpersonal therapy (IPT), pharmacotherapy, and management of the social and family milieu. Therapeutic emphases rely on the context and timing of presentation. In the circumstance of MA psychosis in the emergency department, for example, the context demands emphasis upon controlling injurious behavior, calling for rapid and effective sedation in conjunction with confinement, reassurance, and direction. A literature-based discussion of the employment of different antipsychotic medications has yet to be written, and present clinical practice is empiric, favoring high-potency neuroleptics with the capability for parenteral administration (Graham et al., 2003; Lowinson et al., 2005). The presence of negative symptoms to a level of 21% or higher in the MA psychosis population (Srisurapanont et al., 2003) would appear to argue for greater employment of atypical antipsychotic agents such as aripiprazole, olanzapine, or risperidone. But these agents appear to hold little advantage over older agents such as haloperidol for short-term management, while being considerably more expensive. As amphetamines bear the risk of hyperthermia, altered atrioventricular cardiac conduction patterns, and lowered seizure threshold, it is generally held that antipsychotic medications with strong anticholinergic properties (e.g., chlorpromazine) are inappropriate. Because reduction in the source phenomena (hallucinations and delusions) that are driving paranoia may not occur immediately with antipsychotic pharmacotherapy, rapid-onset benzodiazepenes are commonly and safely used. With regard to timing, continued methamphetamine use in conjunction with psychosis invariably reflects methamphetamine dependence. Thus, the additional dimension of MA use in this psychosis as distinct from schizophrenia requires exceptional emphasis upon gaining abstinence as a goal. Two representative vignettes follow, to demonstrate several of the confounds encountered in correctly identifying and dealing with MA psychosis. CASE 1 A 22-year-old cosmopolitan male was arrested by the police for arson. An intermittent user of MA by inhalation since age 17, he went to the home of his two aunts, bearing sharpened sticks, and wounded them both before setting the home on fire. The conflagration was rapid,

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Liz Jacobs and William Haning III but the aunts survived for several days and were able to identify their nephew, and to report his behavior as having been progressively ‘‘paranoid’’ during the preceding year. He acknowledged that he had become convinced that both were vampires. Independent examiners for the court made findings of schizophrenia, bipolar disorder Type I, and schizoaffective disorder. He was therapeutically committed to a state hospital, having shown some response to initial sedative
hypnotic (alprazolam) management followed by antipsychotic medication (olanzapine). [The case suggests both the diagnostic obscurity caused by MA use, and the complexity of differentiation predicated on phenomenology and history alone.]

CASE 2 A 25-year-old Asian female delivers a healthy but underweight full-term daughter, who at first is restless and feeds poorly. By the end of the third day postpartum, the infant is doing well, but the mother refuses to breast feed and spends lengthy periods staring at the infant. Agitated and distressed, the mother confesses that she cannot rid herself of the belief that the child is a satanic imp. The mother’s urine contained MA prenatally; the meconium was also positive for MA. The infant was placed in temporary foster care. [Postpartum depression is sufficiently common that an astute obstetrician or pediatrician may recognize its signs, particularly as psychotic symptoms arise. However, the correct impression may be derailed by the intact if agitated affect of the mother, and denial of any depressive symptoms, when in fact the syndrome is one of persistent MA psychosis. The multigenerational nature of methamphetamine use in some locations accounts for the placement difficulties that may be encountered in caring for the newborn. Although some delusional content and fearfulness persisted for three months, this case had a good outcome with antipsychotic medication (risperidone) and residential substance dependence treatment with a cognitivebehavioral focus.]

Conclusions The natural history of methamphetamine psychosis remains poorly defined, accounting in turn for the difficulty in reaching conclusions about successful treatment. Relying for diagnosis on phenomenology, history, and demonstration of MA use, the syndrome is complicated by a high coincidence of MA use among those with other psychotic disorders. Studies describing the course of MA psychosis against serial imaging studies hold promise of characterizing both the anatomical and the biochemical messenger lesions, as well as demonstrating the course of recovery. Development of cohering pathological models will most likely aid in directing therapy more effectively; one investigator (L. Chang, private communication) has noted the possibility of inflammatory changes being linked to the structural brain changes witnessed on imaging studies. Treatment remains symptom-directed for the psychotic syndrome, and

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multi-dimensional (milieu, group, and individual psychotherapies; social constraint and support) for the dependence syndrome. Psychopharmacological treatment options for dependence have not been conclusively demonstrated, yet examination of extant clinical trials suggest that they are probably imminent.

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4210). Washington, DC: Government Printing Office. Nordahl, T. E., Salo, R., & Leamon, M. (2003). Neurocognitive effects of chronic methamphetamine use on neurotransmitters and cognition: A review. Journal of Neuropsychiatry and Clinical Neurosciences, 15, 317
25. Paulus, M., Hozack, N., Frank, L., Brown, G. G., & Schuckit, M. A. (2003). Decision by methamphetamine-dependent subjects is associated with error-rate independent decrease in prefrontal and parietal activation. Biological Psychiatry, 53, 65
74. Rawson, R. A., Gonzales, R., & Brethren, P. (2002). Treatment of methamphetamine use disorders: An update. Journal of Substance Abuse Treatment, 23, 145
50. Rippeth, J. D., Heaton, R. K., Carey, C. L., et al. (2004). Methamphetamine dependence increases risk of neurocognitive impairment in HIV infected persons. Journal of International Neurocognitive Society, 10, 1
14. Salo, R., Nordahl, T. E., Possin, K., et al. (2002). Preliminary evidence of reduced cognitive inhibition in methamphetamine-dependent individuals. Psychiatric Research, 111, 65
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22. Seiden, L. S. & Sabol, K. E. (1996). Methamphetamine and methylenedioxymethamphetamine neurotoxicity: Possible mechanisms of cell destruction. Abstract. NIDA Research Monographs, 163, 251
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90.

22

Medication-induced psychosis Junji Takeshita1, Diane Thompson2, and Stephen E. Nicolson3 1

University of Hawaii Queen’s Medical Center 3 Massachusetts General Hospital 2

Medication-induced psychosis is a common occurrence. Both in and out of the hospital, patients with multiple health problems are at an increased risk of developing both psychosis and delirium with the addition of prescription and over-the-counter medications. This chapter will define medication-induced psychosis, differentiate this disorder from delirium, and discuss the drug classes most often associated with psychosis. Unlike many forms of psychosis, medication-induced psychosis does not have specific long-term psychiatric symptoms, prodromes, positive versus negative symptoms, common brain neuropathology, or genetic factors. It is neither gender specific nor age specific. The sole risk of medication-induced psychosis lies in a patient’s general risk of developing a medical problem that requires the use of drug therapy. Many medications when taken at therapeutic doses are associated with the development of psychotic symptoms (Anonymous, 2002). There are few large studies to substantiate these relationships; instead we must rely on case studies. Because many of these same medicines can also cause delirium (Trzepacz & Meagher, 2005), it is necessary to differentiate ‘‘delirium’’ from ‘‘psychosis’’ as there is obvious overlap between the disorders. Differentiating between drug-induced psychosis and delirium can be difficult. This distinction appears to be at least historically ambiguous if not controversial. Some texts group delirium in with ‘‘secondary psychoses’’ whose characteristic features of ‘‘clouding of consciousness’’ and ‘‘fluctuating course’’ differentiate them from primary psychoses. Charlton and Kavanau argue that most psychiatric conditions, including primary mental illness as well as intoxications have a delirious component to the disease (Charlton & Kavanau, 2002). This makes the discrimination between delirium and psychosis a particular challenge. For example both delirium and psychotic mania may entail emotional lability, anxiety, paranoia, decreased ability to concentrate, hallucinations, and delusions. In this text we will be using the distinction between the terms ‘‘psychosis’’ and ‘‘delirium’’ in the manner defined by the DSM IV-TR. Delirium is 406

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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characterized by ‘‘a disturbance of consciousness’’ and ‘‘a change in cognition’’ while psychosis is defined by ‘‘prominent hallucinations or delusions’’ in the absence of delirium (American Psychiatric Association, 2000). Thus the diagnosis of delirium trumps that of psychosis. Many broad categories of medications are known to cause psychotic symptoms. The data are difficult to interpret as case reports are common. Studies frequently involve patients with illnesses that predispose them to psychiatric disorders. Nonetheless the level of the evidence varies widely among categories of medications. However, we have found an undeniable association between medications approved by the Federal Drug Administration for various conditions and psychosis. The following review will focus on classes of medications where the level of evidence is strongest. Antidepressants Summary of findings Grade of evidence Epidemiology: 8%. Age of onset: No consistent relationship. Presentation: Development of psychosis associated with starting of medications. Course and progression: Worsening of symptoms with medication usage. Suspected neuropathology: Possibly related to interference with neurotransmitters. Suspected neurochemical abnormalities: Serotonin, dopamine. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Cessation of antidepressant medication, adjuvant antipsychotics.

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Introduction

Because of their ability to alter the synaptic concentrations of neurotransmitters, antidepressants have been hypothesized to potentially cause psychosis (Iqbal & van Praag, 1995). Specific classes are briefly described below: Bupropion

Bupropion is believed to affect dopaminergic systems (Muley, Joshi, & Manekar, 1984). Due to its structural relationship to amphetamines and inhibition of neuronal uptake of dopamine and noradrenaline, the link to psychosis may be

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clearer than with other classes of antidepressants. Bupropion has been noted to cause paranoia and auditory hallucinations in various case reports (Golden et al., 1985; Howard & Warnock, 1999; Shepherd, Velez, & Keyes, 2004). Selective serotonergic re-uptake inhibitors (SSRIs)

SSRIs have been associated with complex visual hallucinations (Cancelli, Marcon, & Balestrieri, 2004). Citalopram (Lamps, 2002), fluoxetine (Webb & Cranswick, 2003), fluvoxamine (Ueda et al., 2003), paroxetine (Kumagai et al., 2003), and sertraline (Marcon et al., 2004) have all been linked to hallucinations or paranoia. Combination serotonin and norepinephrine antidepressants

Venlafaxine in combination with propafenone (an antiarrhythmic thought to increase venlafaxine concentrations) produced an ‘‘organic’’ psychosis in a case report (Pfeffer & Grube, 2001). Another case report details an 85-year-old man who developed paranoia three days after starting venlafaxine (Iraqi, 2003). Tricyclic antidepressants (TCAs)

Tricyclic antidepressants have also been associated with psychotic symptoms (Nelson, Bowers, & Sweeney, 1979), drug-induced mania, withdrawal mania (Mirin, Schatzberg, & Creasey, 1981), and hypnopompic and hypnogogic visual hallucinations (Hemmingsen & Rafaelsen, 1980). Tricyclic antidepressants have been linked to musical hallucinations (Gordon, 1994; Terao, 1995). There are several reports of TCA-induced visual hallucinations (Hudgens et al., 1966). Amitriptyline has been connected to paranoia (Baldessarini & Willmuth, 1968; O’Connel, Campbell, & Anath, 1972) and with non-sleep related visual hallucinations even at low doses (Rundell & Murray, 1988). Herbal supplements

St. John’s wort, a herb that has been thought to have antidepressant properties, has also been associated with psychosis (Stevinson & Ernst, 2004). Epidemiology

In one inpatient study, 43 (8.1%) of 533 psychiatric patients were diagnosed with antidepressant related mania or psychosis (Preda et al., 2001). Another study indicated that three of 200 patients taking fluvoxamine developed psychosis (Sim & Massabki, 2000). In another study, one of 20 adolescents on a trial of fluvoxamine for obsessive compulsive disorder (OCD) or major depressive disorder (MDD) had to discontinue treatment because of development of psychosis (Apter et al., 1994). In an article documenting reported side effects of SSRIs, 10 of 1861

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reports involved psychosis and 30 involved hallucinations (Spigset, 1999). Mirtazapine was associated with a 1.3% incidence of hallucinations in one large study in England (Biswas, Wilton, & Shakir, 2003). Age of onset

There is no consistent relationship. Presentation

Development of psychosis associated with starting of medications. Course and progression

There is worsening of symptoms with medication usage. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

Suspected neurochemical abnormalities is possibly related to interference with neurotransmitters. All drug classes have cases associated with psychosis. Due to the known relationship between dopamine and psychosis, the inciting neurochemical abnormality with bupropion is probably related to dopamine. Dopamine reuptake inhibition and sigma receptor binding are also proposed hypotheses for serotonin reuptake inhibitor related psychosis (Schuld, Archelos, & Friess, 2000). Fluoxetine has been associated with psychosis in case reports both with and without serotonin syndrome. (Hersh, Sokol, & Pfeffer, 1991; Narayan, Meckler, & Nelson, 1995). These reports again stress the unpredictable effects of neurochemical abnormalities in medication-induced psychosis. Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown although probable increased risk in medically compromised individuals. Prior psychiatric illness may be contributory. In a fourpatient case series, sertraline administration was documented to coincide with the emergence of psychotic symptoms, although three of the four patients had a history of psychotic symptoms that had been well controlled (Popli, Fuller, & Jaskiw, 1997). There have been postulated risk factors for bupropion-induced psychosis that probably apply to other antidepressants as well: past history of psychosis, bipolar disorder or psychostimulant abuse, rapid titration, high doses,

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older age, hepatic impairment, and drug interactions with other dopaminergic medications (Wang et al., 2005). Interactions with other medications are also common with antidepressants and may contribute to psychotic reactions. The combination of tramadol and paroxetine has been associated with hallucinations that did not cease until the medications were stopped (Devulder et al., 1996). Furazolidone, an antibiotic with monoamine-oxidase inhibiting properties has been reported as causing an acute psychosis in a woman with no previous psychotic symptoms who had been taking amitriptyline for depression. The psychosis cleared within a day of stopping the antibiotic (Aderhold & Muniz, 1970). A series of four patients who were started on a tricyclic antidepressant for mood symptoms that occurred during steroid treatment developed psychosis after the antidepressant was started. In each case, stopping the antidepressant and starting an antipsychotic relieved the symptoms (Hall, Popkin, & Kirkpatrick, 1978). In another case report, a patient developed paranoia, auditory and visual hallucinations three days after sertraline was added to his regimen, which included amitriptyline (50 mg/day). The symptoms resolved after sertraline was stopped (Marcon et al., 2004). Drug
drug interaction of elevated blood levels through Cytochrome P450 isoenzyme IID6 as well as anticholinergic effects may have contributed to this case report. The combination of SSRIs and zolpidem has been reported to cause visual hallucinations in several case reports (Coleman & Ota, 2004). In one study, five reports of hallucinations were reported in patients on antidepressants soon after zolpidem was added to their regimen. The hallucinations that occurred in these patients were of longer duration (lasting hours instead of minutes) than in previously reported cases of zolpidem-induced hallucinations (Elko, Burgess, & Robertson, 1998). Thus an interaction between the medicines is suspected. Treatment

Treatment involves discontinuation of medication, adjunctive use of antipsychotics. Discontinuation is especially important where the psychosis is felt to be related to a drug interaction as noted previously. Three days after initiating fluoxetine, a 16-year-old developed ego-dystonic command auditory hallucinations that subsided three days after the medicine was stopped (Webb & Cranswick, 2003). Another patient being treated for obsessive compulsive disorder (OCD) developed psychotic mania that resolved when his paroxetine treatment was halted (Christensen, 1995). Fluvoxamine treatment has been associated with symptoms of thought broadcasting, thought insertion, paranoia, and hallucinations (Ueda et al., 2003). These symptoms resolved upon discontinuation of the drug. However, there is a case where one man developed psychosis after discontinuing nortriptyline (Patterson, 1984).

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Cardiovascular medications Summary of findings Grade of evidence Epidemiology: 0.6%. Age of onset: No relationship. Presentation: Positive symptoms. Course and progression: Related to use of medication. Suspected neuropathology: Enkephalins, cortisol, and electrolytes have been implicated. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Discontinuation of offending medication.

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Introduction

The relationship of cardiovascular medications and their psychiatric effects is historical. Reserpine, a centrally acting antihypertensive, played a role in the development of the biogenic amine hypothesis of depression (Flores et al., 2004). The drug was also used as an antipsychotic for a short period of time (Wilkaitis, Mulvihill, & Nasrallah, 2004). Conversely, reserpine has been associated with psychosis in case reports (Keller & Frishman, 2003). Hydralazine has been reported to cause psychosis and hypomania (Keller & Frishman, 2003). Angiotensin-converting enzyme (ACE) inhibitors (Tarlow et al., 2000) and angiotensin receptor blockers (Ahmad, 1996) have been linked to psychotic reactions with and without associated delirium. Case reports have implicated lisinopril in mania as well (Keller & Frishman, 2003). There are also case reports linking beta-blockers to psychosis (Prakash, Campbell, & Petrie, 1983; Steinhert & Pugh, 1979). Hallucinations have been linked to the alpha antagonists doxazosin and prazosin (Evans, Perera, & Donoghue, 1997), although one series of three case reports of prazosin-induced psychosis revealed delirium, not psychosis (verified by EEG), as the cause (Chin, Cho, & Tse, 1986). Brimonidine tartrate (Alphagan), an alpha-agonist used to treat glaucoma, has been implicated in a case report of a man who developed acute paranoid psychosis after starting the eye drops (Kim, 2000). The anti-arrhythmics procainamide, quinidine, lidocaine, and tocainide have been linked in case reports to psychosis and delirium, thus it is difficult to differentiate the syndromes due to

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lack of data (Keller & Frishman, 2003). Digoxin has been linked to delirium since 1785. Unlike other cardiac medications, calcium-channel blockers have been used in the treatment of bipolar disorder, depression, and schizophrenia and are unlikely to induce psychosis. Symptoms of psychosis have only been reported anecdotally. Epidemiology

In a review of 31 studies, the incidence of ‘‘hallucinations and illusions’’ was reported as 0.6% in patients taking beta-blockers (Keller & Frishman, 2003). Health and Welfare Canada has been tracking adverse drug reactions since 1965 and reported 213 cases of encephalopathy secondary to digitalis and nine cases of psychosis (Keller & Frishman, 2003). Unfortunately, there are no specific studies concentrating on psychiatric effects and most large-scale studies do not include the necessary details for psychiatric diagnoses. Thus most data comes from case reports that link cardiovascular medications to psychosis (Keller & Frishman, 2003). Gender or other differences are unknown. Age of onset

There is no relationship in age of onset. Presentation

Presentation includes positive symptoms. Course and progression

Course and progression are related to use of medication. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

One proposed mechanism suggests that ACE inhibitors inhibit the peptidase responsible for hydrolysis of enkephalin, an endogenous opioid (Rabinowitz & Reis, 2001). Another potential mechanism is through the ability of angiotensin II to stimulate release of cortisol (Keller & Frishman, 2003). Lisinopril has been implicated in hyponatremia with transient psychosis (Giupponi & Erfurth, 1998). The mechanism of psychosis in this case is through electrolyte imbalance. Similar reports have been made regarding the link of thiazide diuretics (which only enter the brain in low concentrations) to psychosis (Keller & Frishman, 2003).

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Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown but probably related to other risk factors for delirium such as older age, dementia, hepatic impairment, visual impairment, sleep deprivation, and hospital setting. Treatment

Treatment involves discontinuation of offending medication. Nonsteroidal anti-inflammatory medications Summary of findings Grade of evidence Epidemiology: Unknown. Age of onset: Unknown. Presentation: Hallucinations with temporal relationship to medications. Course and progression: Associated with medication usage. Suspected neuropathology: Unknown. Suspected neurochemical abnormalities: Structure similar to serotonin. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Discontinuation of the NSAID.

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Introduction

There are multiple case reports in the literature referring to indomethacin-induced psychosis (Bessa, 1994). One series of case reports describes five patients with previous psychiatric diagnoses ranging from depression and anxiety to schizophrenia and bipolar disorder (Jiang & Chang, 1999). Each of the patients, in nine separate incidents, had worsening of their condition when a nonsteroidal anti-inflammatory drug (including diclofenac, piroxicam, naproxen, ibuprofen, and sulindac) was added to their medications; three of the patients became psychotic.

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Epidemiology

Epidemiology is unknown. Age of onset

Age of onset is unknown. Presentation

Presentation involves hallucinations with temporal relationship to medications. Course and progression

Course and progression are associated with medication usage. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

The commonly prescribed nonsteroidal anti-inflammatory drugs have been hypothesized to potentially cause psychosis due to their indolic molecular structure which resembles serotonin or by their role in prostaglandin inhibition (Defromont, Portenart, & Couvez, 1999). The presence of cyclooxygenase in the brain is hypothesized as a mechanism for the psychiatric effects of celecoxib (Hawkey, 1999). Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown. Treatment

Treatment involved discontinuation of the medication. In each of the cases referenced above, the symptoms resolved upon discontinuing the antiinflammatory medication. In a case report, a 78-year-old woman who reported auditory hallucinations within ten days of starting celecoxib experienced relief within four days after discontinuation (Lantz & Giambanco, 2000). She experienced a recurrence of the hallucinations upon resumption of a lower dose of the drug. The authors report that the patient’s cognition remained intact and her sensorium was clear throughout the incident (Hawkey, 1999).

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Retinoids Summary of findings Grade of evidence Epidemiology: Unknown. Age of onset: Unknown. Presentation: Hallucinations. Course and progression: Associated with medication usage. Suspected neuropathology: Unknown. Suspected neurochemical abnormalities: Possible relationship to Vitamin A. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Discontinue medication.

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Introduction

Retinoids have been hypothesized to play a role in schizophrenia (Goodman, 1998). Isotretinoin (Accutane) has a chemical structure related to that of Vitamin A, which has been linked to psychosis. The Canadian Medical Association issued a drug alert involving ‘‘psychiatric adverse effects’’ of the drug. A military study showed five cases of psychosis developed in 500 soldiers given the medication (Barak et al., 2005). Four of the five responded well to atypical antipsychotics, but the report does not indicate how long the patients remained on this treatment regimen. The age of the patients (19
20 years) leaves open the question of whether an underlying psychotic disorder was triggered or started coincidentally during treatment with the acne-fighting medication. The rate of five in 500 is similar to the rate of schizophrenia in the general population. Another large-scale study revealed no association between isotretinoin and psychosis (Jick, Kremers, & Vasilakis-Scaramozza, 2000). Epidemiology

Epidemiology is unknown. Age of onset

Age of onset is unknown.

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Presentation

Presentation involves hallucinations with temporal relationship to medications. Course and progression

Course and progression are associated with medication usage. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

Retinoids have a possible relationship to Vitamin A. If the abnormality can be modeled after Vitamin A induced disorders, excess retinol may bind to lipoproteins with resultant toxic effects (O’Donnell, 2003). Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown. Treatment

Treatment involves discontinuation of medication, adjunctive use of antipsychotics. Disulfiram Summary of findings Grade of evidence Epidemiology: More often used in males. Age of onset: Adult use. Presentation: Unclear ‘‘psychotic symptoms’’ noted in case reports. Course and progression: Associated with medication usage. Suspected neuropathology. Suspected neurochemical abnormalities. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Discontinuation of medication, adjunctive use of antipsychotics, one report of lithium therapy.

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Introduction

Disulfiram has been related to psychosis in case reports including Capgras syndrome (Daniel, Swallows, & Wolff, 1987). One study of 52 patients in India revealed six patients who had prior histories of mood disorders; psychosis occurred during treatment with disulfiram 250 mg twice a day (Murthy, 1997). A review of over 50 cases in the literature found nine cases of psychotic reactions, differentiating them from encephalopathies (delirium) which were more common (Quail & Karelse, 1980). The authors also suggested that psychosis was more common at the higher doses previously used in alcohol cessation (Antabuse) treatment. Epidemiology

Based on overall demographics of disulfiram use; it is prescribed more often to males with alcohol dependence. Age of onset

Based on overall demographics of disulfiram use; it is prescribed more often to males over age 40 (Nielsen et al., 2000). Presentation

Presentation is unclear as ‘‘psychotic symptoms’’ are noted in case reports. Course and progression

Course and progression are associated with medication usage. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

Suspected neurochemical abnormalities involve a possible relationship to low levels of DBH. A study of CSF dopamine-beta-hydroxylase (DBH) measurements indicated that men with lower pretreatment levels of DBH had a higher incidence of psychosis (Major et al., 1979). Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown.

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Treatment

Treatment involves discontinuation of medication, adjunctive use of antipsychotics, one report of lithium therapy (Murthy, 1997). Steroid medications Summary of findings Grade of evidence Epidemiology: Up to 18.4%. Age of onset: No relationship. Presentation: Positive symptoms. Course and progression: Associated with medication usage. Suspected neuropathology: Unknown. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: Higher dose. Treatment: Reduction in corticosteroids and treatment with antipsychotic medications.

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Introduction

Steroids have long been associated with psychotic symptoms (Brown & Suppes, 1998; Sirois, 2003). Psychiatric disturbance have been noted from the time of introduction in the 1950s, and the relationship has been extensively reviewed. Anabolic steroids have also been noted to have varying psychiatric symptoms (Uzych, 1992), including psychosis. Unfortunately, the methodology of studies involved self reports from athletes recruited from gyms. Furthermore, many such participants used large doses of anabolic steroids as well as other medications in combination, making it difficult to specifically categorize the psychosis as ‘‘steroid-induced’’ psychosis. Epidemiology

Severe psychiatric symptoms were noted in 18.4% of individuals treated with doses greater than 80 mg daily. Unfortunately, many studies involve subjects treated with either low doses of steroids chronically or a high dose of steroids over a brief period of time (Yi Chau & Chiu Mok, 2003). Age of onset

Age is not a factor.

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Medication-induced psychosis

Presentation

Later reports detailed the temporal course of steroid-induced psychosis. The clinical course includes both an early onset (four days) as well as a late onset (three weeks) of symptoms. Positive symptoms do not appear to be dose dependent and recovery occurs within several weeks. Course and progression

Course and progression are related to use of medication. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

Suspected neurochemical abnormalities are unknown. Genetic factors

Genetic factors are unknown. Other risk factors

Although cases of steroid-induced psychosis are more common in women, illnesses such as a systemic lupus erythematosis and rheumatoid arthritis that require corticosteroids are also more common in women. Excluding such cases, there were still greater numbers of women with psychosis. Few studies have identified other risk factors for steroid-induced psychiatric symptoms. As a result, specific risk factors are unknown. The presence or absence of psychiatric illness had little bearing on the likelihood of developing steroid-induced psychosis. Despite the risk of psychosis at any dose, dexamethasone doses greater than 40 mg/day appear to be associated with a greater incidence of symptoms. Treatment

Reduction in corticosteroids and treatment with antipsychotic medications is the usual treatment. Although there are some reports of the use of atypical antipsychotic medications, haloperidol remains widely used with the advantage of various routes of administration. The use of mood stabilizers such as lithium and anticonvulsants have been used to prevent the emergence of steroid-induced psychosis, but such strategies by themselves pose a number of potential problems such as worsening of a pre-existing medical condition and cardiac toxicities. Efforts to minimize steroid-induced psychiatric illness, including alternate day dosing of corticosteroids, have not been definitive.

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Anti-epileptic medication Summary of findings Grade of evidence Epidemiology: 1
3.4%. Age of onset: No relationship. Presentation: Positive symptoms. Course and progression: Related to use of seizure medications. Suspected neuropathology: Unknown, possible GABA dysregulation or epoxide formation. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: No clear treatments.

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Introduction

Anticonvulsants have been associated with psychiatric disorders (Trimble, 1996). Indeed many anticonvulsants are specifically used for treating psychiatric disorder, particularly mood disorders. The relationship between psychosis and seizure disorders has long been studied with the early observation of the low association of seizure disorder in patients with psychosis. This ultimately led to the development of electroconvulsive treatment for psychiatric disorders, including psychosis in the early twentieth century. At the same time psychosis has been noted to be more frequent in some patients with epilepsy, particularly partial complex seizures. Psychosis has been associated with the use of many anticonvulsants, including carbamazepine, valproic acid, phenobarbital, and phenytoin (Gatzonis et al., 2003). This aspect is particularly interesting as many of these medications such as carbamazepine and valproate are often specifically used for their psychotropic effects. New drugs such as gabapentin (Jablonowski, Margolese, & Chouinard, 2002), felbamate, lamotrigine, tiagabine, topiramate (Duggal and Singh, 2004), vigabatrin, and zonisamide have been associated with psychosis. Epidemiology

Levetiracetam, an adjunctive medication for partial epilepsy, has been associated with psychosis in 1.2% of patients (Mula et al., 2003). In fact with vigabatrin, the rate of psychosis is 0.7% with clear psychosis and 3.4% if other severe abnormal behaviors are included (Ferrie, Robinson, & Panayiotopoulos, 1996).

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The high rates of psychosis noted may be misleading as much of this data comes from clinical trials of anticonvulsants which involved relatively high doses, fast titration with the potential for drug toxicity, and participants who had histories of refractory seizures and partial complex seizures. The issue with vigabatrin is not whether there is an association with psychosis but rather if vigabatrin has a higher association with psychosis than other anticonvulsants. Age of onset

Age of onset is unknown. Presentation

Presentation involves positive symptoms related to medications. Course and progression

Course and progression are related to use of seizure medications. Suspected neuropathology

The concept of ‘‘forced normalization’’ or an increase in psychosis with treatment of seizures was also theorized. In this situation, a reduction of anticonvulsants resulted in worsening of epilepsy but an improvement in psychosis. This concept is important in that all reports of psychosis related to anticonvulsant use may be due to the phenomenon of forced normalization. There is no definitive evidence for this concept, nor has the pathophysiology been elucidated. If forced normalization is the case, then reduction of anticonvulsant medication should always result in worsening of seizures but improvement of psychosis. Such cases are not evident in the literature. Suspected neurochemical abnormalities

Vigabatrin is believed to inhibit GABA-transaminase which breaks down GABA. This is felt to result in enhanced GABA activity, which in turn results in inhibition in the substantia nigra. A similar mechanism may be at work with other anticonvulsants and may be the etiology of paradoxical worsening of psychosis with this class of medications and other GABA-related medications such as the benzodiazepines. Of course, such agents frequently also result in improvement of psychosis. In patients with schizophrenia and epilepsy, valproate has been used as an adjunctive agent in treating psychotic symptoms (Citrome, Levine, & Allingham, 2000). Such cases of psychosis may be more related to delirium. Genetic factors

Genetic factors are unknown.

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Other risk factors

Polypharmacy and the potential of drug
drug interactions further cloud the direct relationship of a specific anticonvulsant and psychosis. Thus the specific relationship between anticonvulsants and psychosis remains unclear and it is difficult to state a direct effect of the anticonvulsant itself versus a reflection of the underlying seizure disorder. An ideal study would evaluate the rate of psychosis in a large number of patients with specific epilepsy related to a generally accepted dose of a specific anticonvulsant. Unfortunately, such a study is not available. In fact the relationship of psychiatric illness to anticonvulsantrelated epilepsy is unclear, as such patients are excluded from clinical trials of medications. Obviously it is difficult to categorize worsening of psychosis as related to anticonvulsants versus other factors, such as worsening of underlying psychotic illness. Nonetheless, there may be some increased risk of psychosis in patients with a psychiatric disorder. Treatment

There is no clear treatments as in some cases discontinuation of anticonvulsants have worsened psychosis and in other cases, improved psychosis. Parkinsonian medication Summary of findings Grade of evidence Epidemiology: 20
30% of patients with hallucinations or delusions. Age of onset: Unknown. Presentation: Positive symptoms. Course and progression: Related to use of medication. Suspected neuropathology: Dopamine. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Reduction or ‘‘drug holiday’’.

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Introduction

Parkinson’s disease is another neurological illness with a strong association with psychosis. Like seizure disorders, the psychosis may be related to the treatment of Parkinson’s disease (PD) versus the underlying disorder itself. Furthermore, psychosis may be related to an exacerbation of an underlying psychiatric disorder rather than related to PD or the treatment of PD. This situation is particularly

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a problem in older patients with schizophrenia as they are at increased risk for PD from both their antipsychotic therapy and advancing age. Epidemiology

Psychosis is present in 20
30% of patients with typical symptoms of visual hallucinations, delirium and paranoid delusions (Friedman, 1991; Kuzuhara, 2001). Age of onset

Age of onset is unknown. Presentation

Hallucinations, particularly visual hallucinations, and delirium are problematic for all of the treatments, including levodopa and dopamine agonists such as bromocriptine and amantadine. Course and progression

Course and progression are related to use of medication. Suspected neuropathology

Patients who may decrease in cholinergic neurons such as the elderly, and especially patients with dementia, may be more vulnerable to psychotogenic effects of anticholinergics (Cummings and Kaufer, 1996). Suspected neurochemical abnormalities

The mechanism is believed to be excess dopamine either through direct dopamine agonists or through the use of levodopa. The risk of psychosis appears to increase with the duration of treatment (Young, Camicioli, & Ganzini, 1997). Visual hallucinations may also be due to Lewy Body dementia rather an effect of medications. Selegiline, a non-anticholinergic medication, is commonly used in PD and has been associated with a number of behavioral symptoms including psychosis and mania (Boyson, 1991; Kurlan & Dimitsopulos, 1992). Possible mechanisms include the L-amphetamine and L-methamphetamine metabolites of selegiline. Genetic factors

Genetic factors are unknown. Other risk factors

Anticholinergic medications are often used in conjunction with other PD medications and are helpful in reducing tremors. Examples include

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trihexyphenidyl, benztropine, biperiden, procyclidine, and ethopropazine. Unfortunately, anticholinergic medications can cause psychosis in a healthy individual, let alone someone who is medically compromised. Parkinson’s patients are likely to be more susceptible to psychotic symptoms due to concomitant risk factors such as dementia, advanced age, and polypharmacy. Treatment

Reduction in PD medications is the first treatment, although this may be accompanied by a subsequent worsening of PD. Another strategy is the use of ‘‘drug holidays,’’ discontinuation of levodopa for one to two weeks, then resumption at a lower dose, although there is much controversy regarding this regimen. The use of ‘‘drug holidays’’ is basically a more severe form of a dose reduction and the potential worsening of PD is higher. If psychosis persists or the worsening of PD is intolerable, then treatment with antipsychotic medications is employed. Atypical antipsychotics are preferred over the older antipsychotics which are more prone to exacerbate PD by blocking dopamine D2 receptors. Clozapine (The Parkinson Study Group, 1999) and quetiapine (Fernandez et al., 2003) are probably the least likely to worsen Parkinsonian symptoms, while treating the psychotic symptoms. Anti-viral medication Summary of findings Grade of evidence Epidemiology: 0.5%
15% in HIV patients. Age of onset: Not related. Presentation: Positive symptoms. Course and progression: Related to use of medication. Suspected neuropathology: Unknown. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: HIV-associated encephalopathy. Treatment: Withdrawal of medication; use of antipsychotics.

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Introduction

Many of the antiviral treatments, including abacavir, combivir, and gancicylovir, for HIV have been associated with psychosis although it is difficult to determine whether psychosis is related to delirium due to HIV versus a medication effect (Foster clajide & Everall, 2003). HIV and AIDS have long been associated with

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psychotic symptoms perhaps due to a direct effect of the infection or co-morbid substance abuse. Nonetheless it has been difficult to associate a direct causal relationship between HIV and psychosis. Nevirapine, a reverse transcriptase inhibitor used to reduce viral load, has been reported to result in psychosis (Jan Wise, Mistry, & Reid, 2002). These case reports involve patients with no history of mental illness, onset of psychosis with nevirapine, and resolution after nevirapine was discontinued. Efavirenz, another reverse transcriptase inhibitor, has also been associated with similar psychotic symptoms (Poulsen & Lublin, 2003). Epidemiology

New-onset psychosis in patients with HIV range from 0.5%
15% (Kendler et al., 1996; Sewell et al., 1994). Age of onset

Age is not a factor. Presentation

Presentation involves positive symptoms. Course and progression

Course and progression are related to use of medication. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

Suspected neurochemical abnormalities are unknown. Genetic factors

Genetic factors are unknown. Other risk factors

HIV-associated encephalopathy may also contribute to psychosis. Treatment

Treatment involves withdrawal of medication; use of antipsychotics. Patients with AIDS are at higher risk for developing neuroleptic malignant syndrome (NMS) (Breitbart, Marotta & Call, 1988; Kieburtz et al., l991), extrapyramidal side effects (EPS), and tardive dyskinesia (TD). Therefore, titration of antipsychotic

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medication should be gradual, with a goal of low dose and brief duration (Khouzam, Donnelly, & Ibrahim, 1998). Antibiotic medication Summary of findings Grade of evidence Epidemiology: Case reports. Age of onset: Unrelated. Presentation: Positive symptoms. Course and progression: Related to use of medication. Suspected neuropathology: Unknown. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: History of psychiatric illness. Treatment: Withdrawal of medication.

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Introduction

Infectious disease medications have also been associated with the onset of psychosis, although rates are generally low. Ciprofloxacin, a commonly used fluoroquinolone antibiotic, was noted to cause psychosis in a patient treated for resistant tuberculosis. Psychotic symptoms resolved after antitubercular medications were changed (Norra et al., 2003). Topical ciprofloxacin was also noted to cause psychotic symptoms (Tripathi, Chen, & O-Sullivan, 2002). The mechanism and incidence of psychosis is unknown. Other antibiotics that may have induced psychosis include aminoglycosides, cycloserine, ethionamide, rifampin, cephalosporins, penicillin, metronidazole, and sulfonamides. Symptoms tend to resolve quickly with discontinuation of the offending medication. Epidemiology

Epidemiology is difficult to determine as case reports involving antibiotics are common but difficult to evaluate as comorbid medical factors, drug interaction, and prior psychiatric illness may be causative; this has been reviewed in detail (Sternbach & State, 1997). Age of onset

Age is not a noted factor.

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Medication-induced psychosis

Presentation

Presentation involves positive symptoms for case reports. Course and progression

Course and progression are related to use of medication. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

Suspected neurochemical abnormalities are unknown. Genetic factors

Genetic factors are unknown. Other risk factors

Pre-existing psychiatric illness or a strong family history of mental illness complicates the direct cause and effect of the psychosis due to medications. Treatment

Treatment involves discontinuation of medication. Antimalarial medication Summary of findings Grade of evidence Epidemiology: Unknown, case reports. Age of onset: Pediatric and adult cases. Presentation: Positive symptoms. Course and progression: Related to use of medication. Suspected neuropathology: Possible effect as a noncompetitive inhibitor of acetylcholinesterase and butyrylcholinesterase. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Withdrawal of medication.

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Introduction

Mefloquine, a medication used for antimalarial prophylaxis, was noted to induce psychosis (Fuller, Naraqi, & Gilessi, 2002; Kukoyi & Carney, 2003).

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The development of psychosis is relatively uncommon. Risk factors for predicting the onset of psychosis are not known, although previous psychiatric illness may be a problem and hepatoxins such as alcohol should be avoided. Unfortunately, cases of mefloquine-induced psychosis typically occur in remote regions where psychiatric care is often not readily available. Since the data primarily involves case reports, information is limited. Epidemiology

Epidemiology is unknown. Age of onset

There are both pediatric and adult case reports (Havaldar & Mogale, 2000; Sowunmi et al., 1995). Presentation

Presentation involves positive symptoms. Course and progression

Course and progression are related to use of medication. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

Suspected neurochemical abnormalities possibly involve an anticholinergic mechanism (Speich & Haller, 1994) or transient hepatocellular damage. Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown. Treatment

Treatment involves discontinuation of the offending agent and the use of antipsychotics.

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Medication-induced psychosis

Antimycobacterial medication Summary of findings Grade of evidence Epidemiology: Case reports. Age of onset: Age over 50. Presentation: Positive symptoms. Course and progression: 1 month after beginning treatment. Suspected neuropathology: Unknown, possible excess catecholamines. Suspected neurochemical abnormalities Genetic factors: Unknown. Other risk factors: Higher dose. Treatment: Discontinuation of the medication and the use of antipsychotics.

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Introduction

Isoniazid (INH), the first line treatment for tuberculosis, was also noted to cause psychosis (Pallone, Goldman, & Fuller, 1993). Epidemiology

Epidemiology is unknown. Age of onset

Age of onset is unknown. Presentation

Presentation involves positive symptoms. Course and progression

Onset of psychosis was noted on average four weeks after starting INH and was related to doses greater than 5 mg/kg. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

Two possible mechanisms include excess catecholamines and serotonin through irreversible monoamine oxidase inhibition and interference of vitamin B6 activity which indirectly results in decreased dopamine, serotonin, and norepinephrine. In other words, psychosis is caused paradoxically by excessively high or low dopamine levels.

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Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors include age greater than 50 years of age, medical comorbidities including diabetes, hepatic disease, alcoholism, hyperthyroidism, and past psychiatric illness. Treatment

Treatment involves discontinuation of the medication and the use of antipsychotics. Anticholinergic medication Summary of findings Grade of evidence Epidemiology: Frequent in elderly patients and medically ill patients. Age of onset: Older age. Presentation: Similar to delirium. Course and progression: Prodrome of confusion that rapidly develops into full blown delirium over days. Suspected neuropathology: Cholinergic neurotransmission. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: Polypharmacy. Treatment: Discontinuation of the medication.

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Introduction

Anticholinergic medications have long been noted to cause psychosis. Typical offenders include medications such as diphenhydramine, benztropin, and tricyclic antidepressants such as amitriptyline and imipramine. Many medications commonly used in hospitalized patients such as furosemide and digoxin also have significant anticholinergic effects. Transdermal scopolamine used for motion sickness has also been noted to cause delirium (Rozzini, Inzoli, & Trabucchi, 1988) Epidemiology

Epidemiology is unknown although the additive effect of multiple medications is often responsible for causing an anticholinergic delirium with resultant psychotic symptoms. Elderly patients and medically ill patients for whom polypharmacy is common are particularly susceptible to an anticholinergic delirium.

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Medication-induced psychosis

Age of onset

Anticholinergic delirium can occur at any age but elderly are more susceptible. Delirium in younger patients is typically as a result of drug of abuse. Angel’s trumpet has been used primarily by adolescent substance abusers (Gopel, Laufer, & Marcus, 2002). Angel’s trumpet has hallucinogenic as well as anticholinergic effects. Ingestion, typically in the form of a tea made from the trumpet-shaped flowers, results in hallucinations and severe agitation. Anticholinergics are not evident upon the usual toxicological screens. Presentation

Presentation typically involves a delirium with waxing and waning sensorium, fluctuations in attention and concentration, hallucinations, illusions and delusions. Course and progression

Typically there is a prodrome of confusion that rapidly develops into full-blown delirium over days. Suspected neuropathology

Patients with a decline in cholinergic neurons in the brain, such as the elderly and patients with dementia, may be more prone to psychotic symptoms (Cummings & Back, 1998). Suspected neurochemical abnormalities

Cholinergic neurotransmission is involved in memory and cognition and has been implicated in Alzheimer’s disease. The psychotic symptoms are typically related to delirium and may be due to relative deficiency of acetylcholine and/or excess of dopamine. There may also be an interaction between cholinergic and dopaminergic neurons (Trepacz, 2000). Genetic factors

Genetic factors are unknown. Other risk factors

Advanced age and polypharmacy are risk factors. Treatment

Treatment involves discontinuation of the anticholinergic medications along with supportive care. Cholinergic medications may be of benefit although infrequently used. Antipsychotics both typical and atypical and anxiolytics may be needed to manage the severe agitation which typically remits quickly.

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Cholinergic rebound causing psychosis Summary of findings Grade of evidence Epidemiology: Unknown. Age of onset: Not related. Presentation: Unpredictable. Course and progression: Not predictable. Suspected neuropathology: Dopamine dysregulation. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Supportive care, slower tapering of anticholinergic medication.

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Introduction

Abrupt discontinuation of anticholinergic medication frequently results in a cholinergic rebound. Epidemiology

Epidemiology is unknown. Age of onset

Age of onset is unknown but is not believed to be contributory. Presentation

Presentation involves nausea, diarrhea, headache, restlessness, agitation, hypersalivation, and sweating, which can result in significant behavioral problems including confusion and agitation. Such symptoms are also noted with anticholinergic psychotropics upon discontinuation. Clozapine is an atypical antipsychotic medication with effects on dopamine and serotonin. In addition there are a number of side effects through anti-muscarinic, histaminergic, and adrenergic pathways. Rebound psychosis from abrupt discontinuation of clozapine has been noted (Shiovitz et al., 1996). Course and progression

Course and progression are not predictable. Suspected neuropathology

Suspected neuropathology is unknown.

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Medication-induced psychosis

Suspected neurochemical abnormalities

Weak dopamine binding and mesolimbic dopamine supersensivity are possible mechanisms for the psychosis. Metoclopramide, a dopamine D2 antagonist typically used for gastrointestinal disorders, has also been associated with a supersensitivity psychosis (Lu et al., 2002). In these cases, patients became psychotic upon discontinuation of metoclopramide. Of course, it is entirely possible that psychosis is due to an exacerbation of the underlying illness rather than an effect of the medication. Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown. Treatment

Treatment involves supportive care, slower tapering of anticholinergic medication and/or use of antipsychotics. Stimulants and herbal supplemental medications Summary of findings Grade of evidence Epidemiology: Unknown. Age of onset: Affects all ages. Presentation: Paranoia and hallucinations. Course and progression: Related to use. Suspected neuropathology: Dopamine dysregulation Suspected neurochemical abnormalities Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Discontinue medication.

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Introduction

Herbal supplements containing ephedra can cause psychosis (Walton & Manos, 2003). Ephedrine is found in the ephedra plant known as ma huang. Qualitative

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toxicology screens can result in a false positive test for amphetamines. These preparations are used for multiple uses including weight loss and body building. Stimulants approved for attention deficit disorder may also cause psychosis. Dextroamphetamine, methylphenidate, pemoline, and other psychostimulants such as caffeine and ephedrine are used in the hospitalized patient to target depression and over-sedation and can contribute to psychosis. Epidemiology

Epidemiology is unknown. Age of onset

Age of onset is not contributory as it affects all ages. Presentation

Paranoia and hallucinations are common presenting symptoms and frequently associated with overdose and abuse (Klein-Schwartz, 2002). Course and progression

Course and progression are related to use of medication and supplements; most have short half lives; for example, methylphenidate has a half life of approximately two to three hours. Neuropathology

Neuropathology is unknown. Suspected neurochemical abnormalities

Mechanism is probably related to dopamine activation. Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown. Treatment

Typically symptoms abate with discontinuation of the offending agent, although emergence of a primary psychotic disorder is possible.

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Medication-induced psychosis

H2 blockers Summary of findings Grade of evidence Epidemiology: Rare in outpatient settings, more common in hospitalized patients. Age of onset: Unclear. Presentation: Positive symptoms. Course and progression: Occur at the start of treatment and resolve shortly after withdrawal of medication. Suspected neuropathology: anticholinergic dysfunction. Suspected neurochemical abnormalities Genetic factors: Unknown. Other risk factors: Older age may be a risk factor. Treatment: Discontinuation of medication.

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Introduction

All of the histamine H2 antagonists, cimetidine, ranitidine, nizatidine, and famotidine, have been associated with psychosis, especially cimetidine (Catalano, Catalano, & Alberts, 1996). Distinctions between psychosis and delirium are not clear and changes in sensorium could be from other contributing factors. Epidemiology

The estimated incidence of central nervous system reactions is 0.2% or less in outpatients and 1.6
80% in hospitalized patients (Cantu & Korek, 1991). Age of onset

The risk in elderly is possibly higher but this association may be due to polypharmacy. Presentation

Presentation involves positive symptoms. Course and progression

According to a review of case reports, the reactions typically occur at the start of treatment and resolve within three days of drug withdrawal (Cantu & Korek, 1991). Suspected neuropathology

Suspected neuropathology is unknown.

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Suspected neurochemical abnormalities

Possible mechanisms include the effect on the anticholinergic system which raises the possibility of using a cholinesterase inhibitor for treatment. Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown. Treatment

Treatment involved discontinuation of the medication.

H1 blockers Summary of findings Grade of evidence Epidemiology: Unclear, case reports. Age of onset: Pediatrics and adults. Presentation: Visual hallucinations. Course and progression: Related to use of these medications Suspected neuropathology Suspected neurochemical abnormalities: Possible anticholinergic dysfunction. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Discontinuation of medication.

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Introduction

Histamine type 1 receptor blockers have been associated with central nervous system effects, especially in the earlier generation of medicine which have a greater lipophilicity and cross the blood
brain barrier more easily than newer drugs (Milgrom & Bender, 1997). Dimenhydrinate is an antiemetic that has been abused for its euphoric and hallucinogenic effects (Halpert, Olmstead, & Beninger, 2002).

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Medication-induced psychosis

Pheniramine has also been abused as a hallucinogen (Jones et al., 1973). Cyproheptadine is a histamine and serotonin antagonist. It also has anticholinergic and calcium channel blocking properties (Watemberg et al., 1999). It has also been associated with a central anticholinergic syndrome at therapeutic doses (Watemberg et al., 1999). Case reports have also cited psychosis as a side effect (Berger et al., 1977; von Muhlendahl & Krienke, 1978). An anticholinergic delirium may be a significant causative factor in H1 blocker-related psychosis. Epidemiology

Epidemiology is unknown as data are based on case reports. Age of onset

Age of onset is not a factor as all ages are affected. Presentation

Promethazine, a phenothiazide derivative, is mentioned in several case reports of visual hallucinations and psychosis involving children, although the distinction from delirium is unclear in these cases (Timnak & Gleason, 2004). Course and progression

Course and progression are related to use of these medications. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

Suspected neurochemical abnormalities may be related to anticholinergic effects although exact etiology is unknown. Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown. Treatment

Treatment involves supportive care and discontinuation of the H1 blockers.

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Junji Takeshita, Diane Thompson, and Stephen E. Nicolson

Muscle relaxants Summary of findings Grade of evidence Epidemiology: Unclear, case reports. Age of onset: Unclear. Presentation: Delusions and hallucinations. Course and progression: Usually associated with toxic dose. Suspected neuropathology: GABA/dopamine dysfunction. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Discontinuation of medication.

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Introduction

Baclofen is an analog of gamma-aminobutyric acid used frequently to treat spasticity and has been associated with a variety of psychiatric disorders. Cyclobenzaprine is a centrally acting agent structured similarly to the tricyclic antidepressants. In case reports, it has been associated with hallucinations and delirium in the elderly (Douglass & Levine, 2000). Other case reports have described recurrences of mania with paranoia in bipolar patients treated with cyclobenzaprine (Beeber and Manring, 1983; Harsch, 1984). Epidemiology

Epidemiology is unknown as data involve primarily case reports. In a series of 18 patients admitted with baclofen overdose, toxic psychoses were observed in six cases (Chodorowski, Sein Anand, & Wisniewski, 2004). Age of onset

Age of onset is unknown. Presentation

Presentation involves persecutory and paranoid delusions along with auditory hallucinations. Course and progression

Onset of symptoms occur a month after starting cyclobenzaprine. Suspected neuropathology

Suspected neuropathology is unknown.

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Medication-induced psychosis

Suspected neurochemical abnormalities

Suspected neurochemical abnormalities are possibly due to disturbance in the GABA/dopamine system in the basal ganglia (Yassa & Iskandar, 1988). Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown. Treatment

Symptoms are typically self-limited and disappear with discontinuation of the medication. The symptoms of cyclobenzaprine-induced psychosis resolved within 72 hours of stopping the medication. (Beeber & Manring, 1983). Hypnotics Summary of findings Grade of evidence Epidemiology: Unclear, case reports. Age of onset: Primarily adult use. Presentation: Hallucinations. Course and progression: Variable. Suspected neuropathology: GABA dysfunction. Suspected neurochemical abnormalities: Unknown. Genetic factors: Unknown. Other risk factors: Possible dose or patient weight risks. Treatment: Discontinuation of medication.

D D D D D D D D D

Introduction

Non-sleep related hallucinations have been reported with zolpidem taken at therapeutic doses, both with (Markowitz & Brewerton, 1996; Markowitz et al., 1997) and without (Elko et al., 1998) delirium. Zaleplon, another hypnotic with activity at the GABA receptor complex, was also associated with acute onset of visual hallucinations in a single case report (Bhatia, Arora, & Bhatia, 2001). Benzodiazepines are also used as hypnotics. While there are not specific reports of psychosis, it is well known that this class of medication can worsen delirium and promote confusion in medically compromised patients. Age of onset

Age of onset is unknown.

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Presentation

Presentation involves hallucinations. Course and progression

In one study, 10 reports of hallucinations were investigated. In each case, hallucinations were reported soon after taking zolpidem. The hallucinations were of longer duration (lasting hours instead of minutes) in patients concurrently taking antidepressant medicine (Elko et al., 1998). Other symptoms such as paranoia and delusions have also been reported (Markowitz & Brewerton, 1996). Authors have reported that these side effects may be dose dependent or related to a patient’s weight. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

The mechanism of both zolpidem and zalepion includes binding to GABA receptors which may heighten susceptibility to psychosis. Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown. Treatment

Treatment involves discontinuation of the hypnotic. Chemotherapeutic medications/adjuvant therapy Summary of findings Grade of evidence Epidemiology: Unclear, case reports. Age of onset Presentation: Delusions, agitation, and hallucinations. Course and progression: Usually progresses with treatments (additive). Suspected neuropathology: Dopamine dysfunction. Suspected neurochemical abnormalities: Unknown possible role of inflammation/cytokines. Genetic factors: Unknown. Other risk factors: Unknown. Treatment: Discontinuation of medication, antipsychotic treatment.

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Medication-induced psychosis

Introduction

Oncology patients undergoing adjuvant therapy are at increased risk for developing psychiatric disorders. The most common disorders include depression, anxiety, and adjustment disorders. There are, however, several reports of psychosis with interleukin-2 and interferon alpha. Interferon alpha is an antiviral medication most commonly used to treat chronic hepatitis and various malignancies, including ovarian cancer and melanomas. The target of the therapy is to affect the inflammatory process. Mood disorders are typically more common than psychosis although there have been a number of case reports of the latter (Garcia-Pares, Domenech, & Gil, 2002; Smith & Khayat, 1992; Tamam, Yerdelen, & Ozpoyraz, 2003). Several other chemotherapeutic agents have also been associated with an agitated mental status. Ifosfamide, an alkylating agent, has been noted to cause delirium with electroencephalogram patterns consistent with diffuse cortical slowing (Merimsky et al., 1992). There is one report of psychosis in which the authors specifically delineate the case from a reduction in consciousness (delirium). After six cycles of chemotherapy, a patient experienced delusions, hallucinations, and disorganized behavior. His symptoms improved with risperidone therapy (Hernandez, Juan, & Alberola, 2004). There is otherwise a paucity of data in the oncology literature. This may be due to a lack of chemotherapy-induced psychosis; however, the possibility that patients are under-diagnosed or diagnosed with delirium certainly exists as well. Other oncologic-related medications have also been implicated in perceptual abnormalities. Recombinant human erythropoietin (rhu-EPO) is frequently used in anemia associated with chemotherapy. Case reports of visual hallucinations appear to coincide with a rhu-EPO leukoencephalopathy. Interestingly, an electroencephalogram reported specified occipital (versus diffuse) slowing in a bone marrow transplant recipient. The report suggests that the hallucinations may be more closely categorized as a medication-induced psychotic symptom versus a delirium (Bent et al., 1999). Epidemiology

Epidemiology is unknown as data are based on case reports. Age of onset

Age of onset is unknown. Presentation

The most common symptoms appear to be agitation, hallucinations, and delusions (Denicoff et al., 1987). In some cases psychosis has persisted

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even after discontinuation of the interferon alpha, although it is unclear whether interferon may have triggered an underlying illness. A series of HIV-positive patients with hepatitis C were followed during treatment with interferon alpha. Six patients were screened prior to subcutaneous treatment and neither had a history of psychosis nor met the criteria for a psychotic disorder. During treatment, four of the six patients developed psychosis. Three of the four patients received antipsychotic medication with alleviation of symptoms. Of note, the fourth patient did not reveal his symptoms of psychosis (paranoid delusions, auditory and visual hallucinations) until several months after therapy was completed. The author goes on to hypothesize that documented high rates of depression and suicidal ideation in the interleukin-2/alpha-interferon patient may, at times, be due to an underlying first episode of psychosis (Hoffman et al., 2003). Course and progression

Symptoms appear to worsen with additive treatments. Suspected neuropathology

Suspected neuropathology is unknown. Suspected neurochemical abnormalities

The mechanism is unknown but may be related to neurotoxicity or effect on dopamine (Capuron et al., 2002; Dunn, Wang, & Ando, 1999). New developments in psychiatric oncology suggest that common symptoms of fatigue and cognitive slowing may be due to alterations in dopaminergic pathways (Capuron, Ravaud, & Dantzer, 2001; Zifko et al., 2002). As dopamine is known to play a major role in psychotic behavior, this merits further exploration. There is some evidence that the neoplastic disease itself, through neurochemical alterations, is responsible for alterations in the dopaminergic pathways leading to anhedonia. The possibility of psychosis has not been explored (Lissoni et al., 2003; Messina et al., 2003). Genetic factors

Genetic factors are unknown. Other risk factors

Other risk factors are unknown. Treatment

Treatment involves discontinuation of medications and antipsychotic treatment.

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Conclusions In conclusion, the literature is rife with case reports of medication-induced psychosis. Frequently, it is not clear whether there is a direct correlation between the medication and the resulting psychosis (i.e. a medication effect) or a mere association. For example, the medications may have coincidentally been used with the emergence of a psychotic disorder. In other instances, the medications or underlying medical disorder caused a delirium which resulted in psychosis. Despite these serious shortcomings, various classes of medications have been fairly consistently associated with the onset of psychotic symptoms. Since the medications represent heterogeneous classes of medications, the pathophysiology of psychosis is probably multifactorial and related to dysregulation of neurotransmitters. Fortunately, in most cases psychosis improved with a combination of discontinuation of the possibly offending agent and/or antipsychotic treatment. The actual incidence of psychosis related to medications is probably much higher, as there is considerable under-reporting of adverse effects, thus creating greater urgency to study medication-related psychosis. REFERENCES Aderhold, R. M. & Muniz, C. E. (1970). Acute psychosis with amitriptyline and furazolidone. Journal of the American Medical Association, 213, 2080. Ahmad, S. (1996). Losartan and reversible psychosis. Cardiology, 87, 569
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62. Apter, A., Ratzoni, G., King, R. A., et al. (1994). Fluvoxamine open-label treatment of adolescent inpatients with obsessive-compulsive disorder or depression. Journal of the American Academy of Child and Adolescent Psychiatry, 33, 342
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3. Barak, Y., Wohl, Y., Greenberg, Y., et al. (2005). Affective psychosis following accutane (isotretinoin) treatment. International Clinical Psychopharmacology, 20, 39
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7.

Part VII

Neurodegenerative Disorders

23

Psychosis secondary to Alzheimer’s disease Robert A. Sweet1 and James E. Emanuel2 1 2

University of Pittsburgh Medical Center University of Pittsburgh Medical Center, From the Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

A A A B B C B N/A A

Introduction Psychosis in Alzheimer’s Disease (AD with psychosis, ADþP) is defined by the occurrence of either delusions or hallucinations. When present, psychotic symptoms can cause significant distress for the patient experiencing them. ADþP is similarly associated with significant distress to family members providing care to these patients (Kaufer et al., 1998). Recent work has begun to define the epidemiology of psychosis in AD, and in individuals at risk for AD due to being diagnosed with mild cognitive impairment. A large body of data has shown that when ADþP is present, it is associated with both greater cognitive impairment, and more rapid cognitive decline, than seen in AD subjects without psychosis. Current treatments for ADþP, derived from treatments

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developed for psychosis in schizophrenia, are inadequate for many subjects (Schneider & Dagerman, 2004), and there is no clearly effective preventative treatment. Finally, recent studies of the familial aggregation of ADþP have indicated that the risk for psychosis in AD is heritable, and influenced by genetic variation. These findings suggest that specific biologic pathways contributing to ADþP may be identified, offering ultimate promise for the development of more efficacious therapies and/or for effective prevention. Epidemiology Historically, numerous studies of the frequency of psychotic symptoms in AD have been reported, with estimates widely varying between 10% and 73%, presumably resulting from non-systematic sampling in clinic populations (Wragg & Jeste, 1989). Recently, several studies have examined the rates of psychotic symptoms occurring in individuals diagnosed with AD or mild cognitive impairment (MCI) in elderly community samples (Lyketsos et al., 2000; 2002). In these studies, delusions were present during the past month in 19.4
22.4%, and hallucinations in 10.8
13.1% of individuals with AD. The corresponding rates in individuals with MCI were 3.1% and 1.3%, and were 2.4% and 0.6% in individuals without dementia. Cumulative prevalences of delusions and hallucinations (i.e., symptoms that were ever present since onset of cognitive impairment) were higher. Delusions had a cumulative prevalence of 30.1% in AD subjects, and 4.7% in MCI subjects. For hallucinations the cumulative prevalences were 16.3% in AD subjects and 2.5% in MCI subjects. Because not all subjects examined would have completed their course of AD, ultimate cumulative prevalences of these symptoms may be still higher. For example, a recent report in a clinic population identified a three-year cumulative incidence of ADþP of 51% (Paulsen et al., 2000b). Data from our center is similar, with an annual incidence of psychosis in AD subjects of 0.19/person-year (Figure 23.1; Wilkosz et al., 2004). Post-mortem studies, which have the potential advantage of recording a complete cumulative incidence of ADþP, have similarly reported rates of approximately 40
60% (Sweet et al., 2000). Age of onset With the exception of a minority of early-onset familial AD cases, AD is a disorder of the elderly, with rates that rise throughout late life. For example, Kukull et al. (2002) reported an increase in AD incidence from 2.8 per 1000 person-years for individuals age 65
69 years to 56.1 per 1000 person-years in the older than

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Figure 23.1. Time to onset of psychosis in 288 subjects diagnosed with AD or MCI and without psychosis at initial presentation

90-year age group. Though not extensively studied, the majority of psychosis incidence in AD subjects has been reported to occur within the first four years after initial clinical presentation (Paulsen et al., 2000b). Thus, the age of onset of ADþP will closely resemble that of AD itself, with a several year lag. Presentation Psychotic symptoms

The definition of psychotic symptoms in AD has generally been limited to the presence of delusions and hallucinations. In the absence of delusions and hallucinations, disorganized thought processes are attributed to the cognitive impairments of AD, and not taken to represent a ‘‘thought disorder’’ indicating a superimposed psychotic syndrome. A wide variety of delusions have been reported in AD, including delusions of persecution, delusions of infidelity, delusions of abandonment, or delusions that deceased individuals (e.g., parents) are still living. In addition, a set of misidentification delusions are frequent in AD patients: belief that one’s home is not one’s home; belief that a family member is someone else, has been reduplicated, or is an imposter; belief in the presence of phantom boarders; and the belief that images on the television are actually people present in the house. Hallucinations in AD can occur in any sensory modality, but visual and auditory hallucinations are most common (Tariot et al., 1995).

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Determining the presence of delusions in AD can be clinically challenging. Delusions must be distinguished from simple forgetting by further evaluation. Was the information ever encoded in memory? Additional characteristics, such as whether the individual refuses to accept reality testing and whether the false idea is persistent over time are useful in distinguishing delusions (Devanand et al., 1992). Though no absolute standard definition of persistence over time exists, the criteria used have generally required presence of at least two to three episodes a week (Devanand et al., 1992; Jeste & Finkel, 2000; Sweet et al., 1998). Hallucinations and delusions limited to a period of acute delirium or a transient medication-induced state are generally excluded. Associated symptoms

Individuals presenting with ADþP demonstrate more severe cognitive impairments than AD subjects without psychosis. ADþP has been associated with more severe cognitive and functional deficits in AD subjects matched on other clinical characteristics such as age, age of onset, gender, education, and duration of AD, or controlling for these variables in the analysis (Jeste et al., 1992; Lopez et al., 1997; Rockwell et al., 1994; Stern et al., 1987). When specific cognitive domains have been examined, reduced verbal fluency has often been reported (Jeste et al., 1992; Paulsen et al., 2000b; Perez-Madrinan et al., 2004). In addition to cognitive symptoms, most studies have found an association between ADþP and the presence or severity of depressive symptoms, or history of depressive disorders (Bassiony et al., 2002; Lyketsos et al., 2001; Tractenberg et al., 2003; Wilkosz et al., 2004). Similarly, there is strong evidence for a significant association between ADþP and the development of aggressive behaviors (Aarsland et al., 1996; Deutsch et al., 1991; Sweet et al., 2001b). Course and progression Emergence and persistence of psychosis in AD

Once psychotic symptoms emerge during AD, their presence and/or severity is at least moderately persistent over time. Thus, Devanand et al. (1997) found the six-month probability of persistence of delusions and hallucinations to be 0.59 and 0.52, respectively. Steinberg et al. (2004) found an 18-month persistence rate for delusions of 65.5%, and for hallucinations of 25.0%. Cognitive and functional course

Most studies have found that individuals with ADþP experience more rapid cognitive deterioration than individuals with AD without psychosis

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(Ballard et al., 1997b; Drevets & Rubin, 1989; Levy et al., 1996; Lopez et al., 1999; Paulsen et al., 2000b). The accelerated rate of decline appears to precede the onset of psychosis (Paulsen et al., 2000a). Psychotic symptoms also predict more rapid functional decline (Drevets & Rubin, 1989; Lopez et al., 1999), and premature institutionalization (Magni et al., 1996).

Suspected neuropathology The clinical observation that ADþP was associated with more severe cognitive pathology, in combination with evidence from functional imaging studies that have found ADþP subjects to demonstrate excess impairment of frontal, temporal, and parietal cerebral blood flow and glucose metabolism in comparison to AD subjects without psychosis (Starkstein et al., 1994; Sultzer et al., 1995), indicate that ADþP subjects experience increased impairments within at least selected cortical regions. A number of investigators have therefore examined whether ADþP was correlated with evidence of regionally more severe AD neuropathology. Earlier studies were limited as a group by not controlling for the presence of Lewy Body pathology and not correcting for multiple comparisons and/or accounting for within-subject correlations of severity of neuropathology across brain regions. Results from these studies were variable, without consistent associations of regional severity of neuritic plaque or neurofibrillary tangle pathology with ADþP (Forstl et al., 1994; Mukaetova-Ladinska et al., 1995; Zubenko et al., 1991). Two studies recently addressed these limitations. Sweet et al. (2000) examined 24 ADþP subjects and 25 AD subjects without psychosis. The groups were matched on clinical characteristics and on the presence of Lewy Body pathology. There were no significant associations between neuritic plaque and neurofibrillary tangle severity and ADþP, and no significant associations with any individual psychotic symptom. Farber et al. (2000) examined 69 ADþP and 40 AD subjects without psychosis. A significant association between ADþP and increased neurofibrillary tangle area density was found, but limited to select heteromodal neocortical regions (middle frontal, superior temporal, and inferior parietal). In contrast, in the medial temporal lobe structures examined, no increase in neurofibrillary tangle area density was found. The associations were not altered after accounting for comorbid Lewy Body pathology. No association of ADþP with neuritic plaques was found. The discrepancy between these results is not readily explained, though it remains possible that some cases of ADþP do demonstrate excess neurofibrillary pathology in neocortical regions.

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Suspected neurochemical abnormalities In schizophrenic psychosis (Chapter 2) there is substantial evidence for reduced neuronal size and loss of synaptic elements in select neocortical regions. Though no direct anatomical studies of these features have been conducted in ADþP, indirect neurochemical assessments of these gray matter constituents are possible postmortem via magnetic resonance spectroscopy. We used this approach to examine ADþP subjects in comparison to AD subjects without psychosis in six brain regions: medial temporal lobe (amygdala); dorsolateral prefrontal cortex; superior temporal gyrus; inferior parietal cortex; occipital cortex; and cerebellum (Sweet et al., 2002c). In neocortical regions in the ADþP group in comparison to AD subjects without psychosis, significant reductions were found in concentrations of N-acetyl-L-aspartate (NAA), reflecting loss of total neuronal volume. There were also significant elevations in concentrations of the phosphodiester membrane breakdown product, glycerophosphoethanolamine (GPE), most readily interpreted as due to degeneration of synaptic elements. It is noteworthy that similar observations have been reported in vivo in subjects with schizophrenia (Keshavan, Stanley, & Pettegrew, 2000). These congruent findings raise the hypothesis that factors effecting neocortical neuronal and synaptic integrity and number may contribute to psychosis in both disorders, though the obvious differences in the neuropathology of AD and schizophrenia suggest that the specific pathologic mechanisms may not overlap. A limited number of other neurochemical abnormalities have been reported in AD. We examined whether striatal dopamine receptor-3 (DRD3) density was altered in association with psychotic symptoms in subjects with AD and in subjects with AD plus Lewy bodies (Sweet et al., 2001a). There was a significant increase in DRD3 density in those subjects with a history of psychosis, which did not appear to be an artifact of neuroleptic exposure. The increase in DRD3 density in psychosis was present in subjects with AD alone and with AD plus Lewy bodies. Overall, subjects with psychosis had a 72% elevation of mean DRD3 density in comparison to nonpsychotic subjects, a magnitude consistent with that reported in subjects with schizophrenia (Gurevich et al., 1997). Recently, motivated by the finding in some studies that cholinesterase treatment can mitigate behavioral symptoms in AD subjects, including psychotic symptoms, Lai et al. (2001) examined muscarinic cholinergic receptor M1 (CHRM1) and CHRM2 density in prefrontal and lateral temporal cortex in AD subjects characterized for psychotic symptoms. Elevated densities of CHRM2 in both regions were associated with delusions and hallucinations. CHRM1 density was not associated with either psychotic symptom.

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Genetic factors Familiality and heritability

Before discussing the results of genetic studies of ADþP, it is useful to consider the evidence that this clinically identified phenotype may be genetically determined. First and foremost is evidence that it is transmitted in families. We recently analyzed the publicly available data from the NIMH AD Genetics Initiative (Sweet et al., 2002b). ADþP frequency was determined in 461 siblings of 371 probands diagnosed with AD. Both a broad definition of ADþP (presence of either delusions or hallucinations at any time point during initial or follow-up examination), and a narrow definition of ADþP requiring multiple symptoms (presence of either more than one psychotic symptom at an assessment, or psychotic symptoms during more than one assessment) were examined. Using the broad definition, the risk of ADþP in family members of ADþP probands (versus family members of nonpsychotic AD probands) was significantly increased (O.R. 2.41; 95% C.I. 1.46, 4.0; p ¼ 0.0006). Requiring multiple psychotic symptoms strengthened the association (O.R. 3.18; CI: 2.17
4.66; p < 0.0001). Similar results were obtained for various supplementary analyses that included sibling age and age of onset, or presence of extrapyramidal symptoms in the model. The only other study to address this question also found moderate evidence of familiality (Tunstall et al., 2000). Our analysis of familiality of ADþP in the NIMH AD Genetics Initiative families suggested the hypothesis that heritability of ADþP is increased in subjects with multiple psychotic symptoms. The estimated heritability of ADþP, defined as at least one psychotic symptom, was 29.5% (p ¼ 0.04). For multiple psychotic symptoms the estimated heritability was 60.8% (p ¼ 0.004). Similar estimates of heritability were using an alternative analytic approach, i.e. 32.3% (p ¼ 0.003) and 69.6% (p < 10
5) for one or more and multiple psychotic symptoms, respectively (Bacanu, et al., 2005). Linkage analysis of ADþP

Genome-wide linkage analysis using short tandem repeat polymorphisms at average intervals of 16.3 cM was recently reported among 292 affected sibling pairs from the NIMH AD Genetics Initiative (Kehoe et al., 1999). We re-analyzed the marker data for these sibling pairs, restricting our analysis to families having two or more siblings with multiple psychotic symptoms as described above (n ¼ 65 families; Bacanu, et al., 2002 ). Even in this relatively small sample, evidence for linkage was detected in three novel regions on chromosomes 2p, 6q, and 21q. The evidence for linkage was strengthened when the ADþP sample was restricted to families with two or more APOE4 carriers (42 families), with the linkage on

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2p now reaching genome-wide significance. Recently, the linkage of ADþP to 6q has been replicated in a partially overlapping cohort (J. Williams and M. J. Owen, personal communication). There was also evidence of elevated linkage on 8p, though this did not reach the thresholds for significant or suggestive linkage. The elevated linkage on 8p is in the same region as NRG1, which shows linkage and allelic association in schizophrenia (Stefansson et al., 2002). Association of ADþP with putative psychosis genes

Recent findings that are highly likely to advance our understanding of psychoses have been the identification of several genes demonstrating linkage and association with schizophrenia (see Chapter 2). The association of two of these genes with ADþP, Catechol-O-Methyltransferase (COMT) and Neuregulin-1 (NRG1), has been reported. Catechol-O-Methyltransferase and ADþP

COMT has long been known for its role in enzymatically inactivating dopamine. It has more recently been appreciated as a positional candidate gene in schizophrenia, as it is located on chromosome 22q11.2, within the site of microdeletions found in patients with velocardiofacial syndrome, a disorder in which up to 30% of sufferers have schizophrenia. The most frequently examined COMT polymorphism in subjects with schizophrenia has been RS4680, a G ! A substitution at codon 108/158 of COMT resulting in a Val ! Met substitution. A recent meta-analysis reviewed 14 case-control and five family studies of RS4680 in schizophrenia, concluding that there was evidence to indicate a minor increase in risk for schizophrenia associated with the Val(G) allele in caucasian populations (Glatt, Faraone, & Tsuang, 2003). The heterogeneity of findings may have resulted in part, however, from the failure of most studies to consider other variation within COMT or haplotype effects, or to consider sex-specific associations (Shifman et al., 2002). Recently an association of ADþP with RS4680 was reported (Borroni et al., 2004). They examined 181 AD subjects characterized for the presence or absence of psychosis. The Odds Ratio (OR) for risk of psychosis in RS4680 G allele carriers was 2.66 (CI: 1.6
6.62), taking into account possible confounding factors. We further evaluated RS4680 for association with risk of psychosis in 373 AD subjects, in conjunction with the other markers of the schizophrenia risk haplotype, RS737865 and RS165599, and a C/T polymorphism adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region (Sweet et al., 2004). There was a highly significant association of haplotype with ADþP in females (w2 ¼ 25.7; DF ¼ 6; p < 0.0005) and in males (w2 ¼ 30.1; DF ¼ 6; p < 0.0005). The best summary of psychosis risk for females for these loci was

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the additive impact of risk alleles at RS4680 and ERE6 (or RS737865 as ERE6 and RS737865 were in nearly absolute linkage disequilibrium). There was a strong linear relationship between number of ERE6 C and RS4680 G alleles and the risk for ADþP in females (r2 ¼ 0.94, p ¼ 0.007). In males, alleles at all four loci, or more likely three loci due to the confounding of ERE6 and RS737865, interacted to confer risk. In a logit model specifying a three-way interaction of loci RS4680, ERE6, and RS165599, the three-way interaction was close to significant (p ¼ 0.08), though a model containing the three-way interaction, main effects of RS4680 and ERE6, their interaction, and the interaction of RS4680 and RS165599 fit the data similarly well. Neuregulin-1 and ADþP

Steffanson et al. (2002) first identified a region of suggestive linkage on 8p12
21 in a cohort of Icelandic families, ultimately finding a core haplotype in the 5’ region of NRG1 that was strongly associated with schizophrenia risk. Replications in other populations followed, with identification of additional associated SNPs, including a non-synonymous SNP in exon 2, RS392499 (Yang et al., 2003). Go et al. (2004) examined linkage of short-tandem repeat polymorphic markers typed in the complete NIMH AD Genetics Initiative families, and linkage/ association of three SNPs from the NRG1 Icelandic core haplotype and RS392499 in the same 65 ADþP families included in our linkage analysis. Multipoint linkage results were significant on 8p12, encompassing the NRG1 region (Entire Family Cohort ZLR score ¼ 2.0; 65 ADþP families ZLR score ¼ 4.2; both p < 0.05). For the individual SNPs, one, RS392499, demonstrated linkage and allelic association with ADþP. None of the other SNPs showed any significant associations. The three SNPs that were part of the Icelandic core haplotype were examined next. These analyses revealed a trend for the A-C-G genotype to be transmitted more often to siblings with ADþP, z ¼ 1.73, p ¼ 0.076. The association of RS392499 with ADþP, because obtained in a family sample, cannot result from population stratification. Clearly further examination in case-control cohorts as well as evaluations of SNPs tagging all haplotype blocks within NRG1 are needed. Other genetic associations and ADþP

The one identified genetic determinant of sporadic, late onset AD is the apolipoprotein E4 allele, which encodes the E4 isoform (APOE4). While one large and two smaller studies have found an association of APOE4 and ADþP (Ballard et al., 1997a; Harwood et al., 1999; Ramachandran et al., 1996), most reports have found no association of APOE4 with ADþP (Sweet et al., 2002a). Furthermore, though the major effect of APOE4 on AD phenotype is to reduce

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age of onset of AD (Corder et al., 1993), APOE4 genotype is not associated with reduced time to onset of ADþP (Sweet et al., 2002a). Both the DRD3 and the serotonin receptor 2A (HTR2A) may confer a small increase in risk for schizophrenia psychosis (Lohmueller et al., 2003), and have therefore been examined for association with ADþP. For DRD3, studies have reported both positive and negative findings (Craig et al., 2004; Holmes et al., 2001; Sweet et al., 1998). For HTR2A, all published studies to date have found evidence of association of a C102T polymorphism with ADþP (Assal et al., 2004; Holmes et al., 1998; Nacmias et al., 2001; Rocchi et al., 2003). The associations of ADþP with variation in other dopamine and serotonin system genes have also been investigated. For DRD1, two studies have shown an association with a noncoding polymorphism (Holmes et al., 2001; Sweet et al., 1998). For HTR2C and the serotonin transporter gene (HTT) both positive and negative associations have been reported (Assal et al., 2004; Holmes et al., 1998; Sukonick et al., 2001; Sweet et al., 2001b).

Other risk factors We are not aware of studies consistently identifying other risk factors for psychosis secondary to AD.

Treatment A number of recent reviews have examined the treatment of psychosis in Alzheimer’s disease. Both nonpharmacological and pharmacological interventions can be used. Though there is little controlled evidence for the effectiveness of behavioral interventions, when considering side-effect profiles of pharmacological interventions in the elderly, it is sensible to use nonpharmacological approaches as a first-line therapy (Richards & Sweet, 1999), or in conjunction with pharmacotherapy. With regard to studies of pharmacotherapy for ADþP, several caveats apply. Though placebo-controlled studies exist, because psychotic symptoms are associated with aggression and other behavioral symptoms, most studies have evaluated outcomes for combined symptom measures, rather than for psychosis per se. It should also be noted that no medication has an FDA-labeled indication for the treatment of psychosis in Alzheimer’s disease. Despite these limitations, however, there is evidence for the efficacy of conventional and second-generation antipsychotic medications in ADþP. Conventional antipsychotics, of which haloperidol has been the most studied, appear to be effective in about one third of patients, but carry significant motor

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side effects, such as tardive dyskinesia, akathisia, and parkinsonism (Tariot et al., 2004b). There is growing evidence that low doses of second-generation, or atypical, antipsychotics show at least equivalent efficacy for psychotic symptoms, but cause lower incidences of tardive dyskinesia and extrapyramidal symptoms (Schneider & Dagerman, 2004). The greatest body of evidence exists in support of risperidone (Bhana & Spencer, 2000). Olanzapine has also been shown to be more effective than a placebo in treating psychosis (De Deyn et al., 2004) and psychosis with agitation (Street et al., 2000). Aripiprazole has shown efficacy on psychosis measures in randomized, controlled trials (Jeste, et al., 2003; Streim, et al., 2004; De Deyn et al., 2005). Despite promising preliminary evidence, a recently published controlled trial on quetiapine failed to demonstrate efficacy (Tariot et al., 2006). We are not aware of any controlled studies of ziprasidone in AD + P. A recent meta-analysis of controlled trials determined that only risperidone and aripiprazole were significantly more effective than placebo for behavioral symptoms, but none were more effective on psychosis subscales; olanzapine’s effects on behavioral symptoms were positive, but non-significant (Schneider, Dagerman & Insel, 2006). Although atypicals may have lower rates of some side effects than conventional antipsychotics, there is some doubt to their efficacy compared to placebo. Unfortunately, atypical antipsychotics also may be associated with an increased risk of cerebrovascular adverse events such as stroke (Herrmann, Mamdani, & Lanctot, 2004; Smith & Beier, 2004; Wooltorton, 2002; 2004). More recently the FDA has issued a warning applying to all atypical antipsychotics that these agents have led to increased rates of all-cause mortality during short-term (ten-week) use in elderly patients with dementia (FDA Public Health Advisory, 2005). There is more limited data for the use of other pharmacological treatments, including selective serotonin reuptake inhibitors and cholinesterase inhibitors. Pollock et al. (2002) compared the efficacy of the selective serotonin reuptake inhibitor citalopram and the neuroleptic perphenazine with a placebo, for the treatment of psychosis and behavioral disturbances in non-depressed patients with dementia. They showed that patients treated with citalopram or perphenazine, compared to the placebo, had statistically significant improvement in psychosis symptoms. Several controlled studies, but not all such studies, suggest that cholinesterase inhibitors reduce the total burden of, or prevent the emergence of, behavioral symptoms relative to placebo treatment in AD (Wynn & Cummings, 2004). Similar evidence is present for treatment with memantine (Tariot et al., 2004a), indicating that the benefits of cognitive enhancers for behavioral symptoms may not be specific to cholinergic mechanisms. Despite evidence of global effects on behavior, findings with regard to a specific effect

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of cognitive enhancers on reduction in severity, or prevention of emergence, of psychosis, are inconsistent (Wynn & Cummings, 2004). Conclusions Psychosis in Alzheimer’s disease is often a disturbing symptom for both patients and caregivers. It occurs in approximately 50% of individuals with AD at some point in the disease course. Pharmacological treatment can carry significant side effects such as Tardive Dyskinesia with conventional antipsychotics and cerebrovascular events with atypical antipsychotics. More importntly, there is some doubt that these treatments are effective for the psychotic components of the disease, although some may be effective for psychosis in the global context of behavioral and psychological symptoms of dementia. Emerging evidence suggests that AD+P is both heritable and may be associated with genes which have previously shown linkage and association with other psychotic disorders. Further examination and confirmation of these results may be necessary, but they may imply common or overlapping endophenotypes which result in multiple final outcomes, conferring risk for other psychotic disorders and AD+P. Further pursuit of these findings may help lead to the discovery of biological mechanisms that explain why some individuals develop AD+P but not others, leading to improved treatment strategies. REFERENCES Aarsland, D., Cummings, J. L., Yenner, G., & Miller, B. (1996). Relationship of aggressive behavior to other neuropsychiatric symptoms in patients with Alzheimer’s disease. American Journal of Psychiatry, 153(2), 243
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24

Dementia with lewy bodies Sasha Ericksen1 and Debby Tsuang1,2 1

Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington 2 Mental Illness Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, Seattle, Washington

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

C Bþ Bþ B A B C D C

Introduction Dementia with Lewy bodies (DLB) probably accounts for 15
25% of all irreversible dementia cases and is the second most common form of dementia after Alzheimer’s disease (AD) (McKeith et al., 1996). The disorder is named after Lewy bodies, the pathological finding in the central nervous system, first described by F. H. Lewy in 1913 (Lewy, 1913) and later described in conjunction with clinical dementia by Okazaki and colleagues in 1961 (Okazaki et al., 1961). DLB shares many clinical and pathological features with other diseases of the elderly, including AD, Parkinson’s disease (PD) and Parkinson’s disease with dementia (PDD) (Aarsland et al., 2004a; Cummings, 2004). For instance, patients with DLB suffer from an irreversible dementia and progressive cognitive decline as in AD, but may also have motor symptoms such as muscle rigidity, bradykinesia, and masked 472

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Dementia with lewy bodies Table 24.1. Consensus clinical diagnostic criteria of DLB

Central feature

Core features: two required for ‘‘probable DLB’’ and one for ‘‘possible DLB’’ Suggestive features

Supportive features

Features making DLB less likely

• Progressive cognitive decline with compromised social and occupational function • Prominent attention, executive dysfunction and visuospatial deficits. • Fluctuating cognition with variable attention and alertness • Recurrent visual hallucinations • Spontaneous features of parkinsonism • REM sleep behavioral disorder • Severe neuroleptic sensitivity • Low dopamine transporter uptake in basal ganglia (by PET and SPECT) • Repeated falls and syncope • Transient, unexplained loss of consciousness • Systematized delusions • Other hallucinations • Severe autonomic dysfunction • Depression • Stroke, focal neurologic signs or imaging findings • Physical or brain illness that could account for clinical findings • If parkinsonism only appears for the first time at a stage of severe dementia

Source: McKeith et al. (2005)

facies, which are typical of PD. As with most dementias, clinical diagnosis can be challenging, and diagnosis can only be confirmed by neuropathological studies. In 1996, the First International Workshop of the Consortium on Dementia with Lewy Bodies published consensus guidelines to aid clinical and pathological diagnosis of DLB (Table 24.1). These guidelines state that DLB requires first and foremost a progressive cognitive decline that causes functional impairment in social and/or occupational spheres. Additional ‘‘core features’’ include spontaneous parkinsonism, recurrent visual hallucinations, and fluctuating cognition or alertness; patients who have one of these core features are clinically diagnosed with ‘‘possible’’ DLB, while patients who have two core features receive a diagnosis of ‘‘probable’’ DLB (McKeith et al., 1996; 1999). Using the consensus diagnostic criteria, sensitivity (correct diagnosis of DLB) is low and ranges from 22
83%, meanwhile specificity (correct diagnosis of not DLB) is high, 90
100%

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(Hohl et al., 2000; Litvan et al., 1998; Lopez et al., 1999; 2002; Luis et al., 1999; McKeith, 2002; Merdes et al., 2003; Verghese et al., 1999). Therefore, the criteria make it easier to rule out DLB than diagnose it, leading to the underdiagnosis of this disorder. Psychiatric symptoms play a prominent role in DLB. For example, while psychotic symptoms are common in many dementias, the frequency and severity of visual hallucinations in DLB is considered key to diagnosis and potential treatment. Research investigating the neuropathology, neurochemistry, and treatment of DLB has found evidence that cholinergic and dopaminergic dysfunction may be associated with psychosis in DLB. Further studies will help illuminate the underlying pathophysiology in DLB, thereby providing clues to develop more specific treatments for this increasingly recognized, common disease. For the remainder of this chapter, we will refer to the clinical entity as ‘‘DLB’’ and the pathological findings that confirm this diagnosis as Lewy body pathology (LBP). Epidemiology Autopsy findings based on hospital and specialty center samples show a prevalence of LBP in 10
36% of patients with dementia (Ala et al., 1997; Barker et al., 2002; Hansen, et al., 1990; Perry et al., 1990; Weiner et al., 1996). Findings from community-based samples of dementia report prevalence estimates of 5
23% (Holmes et al., 1999; Rahkonen et al., 2003; Wakisaka et al., 2003). Researchers have estimated that by the year 2020, three million Europeans will have DLB (Graeber & Muller, 2003). However, all studies to date have included primarily Caucasian and Japanese subjects. No prevalence estimates of DLB in other ethnic groups or developing countries exist. In general, men appear to be slightly more likely to be affected with DLB than women, with a ratio of 1.5:1 (Del Ser et al., 2000; McKeith, 2002). No environmental risk factors have yet been associated with DLB, although there are mixed reports about the protective effects of cigarette smoking for both AD and PD (Allam et al., 2004; Almeida et al., 2002). Age of onset Like any other dementia, subtle symptoms often appear years prior to clinical diagnosis. Age of onset for DLB generally ranges from 50 to 83 years of age, similar to that observed in other dementias (McKeith, 2002). Like other familial forms of AD and PD, age of onset in familial cases can be earlier than that observed in sporadic cases (those without clear family history), with age of onset as early as

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45 years old for dementia symptoms and 34 years old for parkinsonian signs and symptoms (Tsuang et al., 2004). Age of death typically ranges from 68 to 92 years (Papka et al., 1998) and is usually from bronchopneumonia, similar to terminal events in other dementias (Fu et al., 2004). Presentation Presenting symptoms vary widely in DLB. The consensus criteria for the clinical diagnosis of DLB describe symptoms of dementia, fluctuating cognition and attention, parkinsonism, and psychosis which may be present at initial evaluation (McKeith et al., 1996). Dementia symptoms include progressive decline in cognition characterized by deficits in attention and concentration, verbal fluency, psychomotor speed, and visuospatial and executive functions (Ala et al., 1997; McKeith et al., 1996; Mori et al., 2000). Unlike AD, memory is often spared early on. Baseline Mini-Mental State Exam (MMSE) scores at presentation for DLB patients vary from 16 to 23 (out of 30) (Del Ser et al., 2000; Salmon et al., 1996; Weiner et al., 1996), which is consistent with mild to moderate dementia. A recent meta-analysis of 28 studies that included neuropsychological data found that DLB has significantly more visual-perceptual, semantic, attention, and executive impairments than AD (Collerton et al., 2003). Fluctuations in cognition and attention occur in 80
90% of DLB patients at presentation (McKeith et al., 1996). Patients with DLB may experience fluctuations over seconds, minutes, hours, and weeks as measured by serial attention tests and EEG monitoring (Walker et al., 2000). In addition, transient loss of consciousness and syncope have been described in patients with DLB, indicating further profound deficits in alertness. Fluctuations may accurately predict DLB versus AD or normal controls, with EEG verification (Walker et al., 2000). However, more recent studies showed that reaction time, vigilance, and fluctuating attention were comparable in patients with DLB and PDD (Ballard et al., 2002). Prospective validation of these assessment instruments in a larger sample of patients is necessary. Parkinsonian symptoms in DLB include posture and gait abnormalities, bradykinesia, difficulty arising from a chair, masked facies, rigidity, and action tremor (Aarsland et al., 2001b). Repeated falls have also been reported in patients with DLB (McKeith et al., 1996). Fifty to ninety percent of DLB patients develop these symptoms which, as in PD, often occur spontaneously without neuroleptic exposure (Aarsland et al., 2001b; Del Ser et al., 2000; McKeith, 2002; Merdes et al., 2003). In DLB, parkinsonism is less responsive to L-dopa therapy than in PD (Bonelli et al., 2004). One explanation for this difference may be that DLB patients

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Sasha Ericksen and Debby Tsuang Table 24.2. Neuropsychiatric symptoms in DLB

Symptom

Frequency Comments

Fluctuating cognition and 80
90% attention Visual hallucinations 42
84% Delusions Auditory hallucinations Delusional misidentification Depression

Include transient confusion, mutism; may be mistaken for transient ischemic attack or delirium Usually well-formed, often auditory component 50
70% Often paranoid component up to 50% Usually accompany visual hallucinations up to 50% Misidentification of common objects, such as mirror images and television images 20
50% Similar to frequency of depression in AD

are less likely than PD patients to develop essential tremor, which is the most likely PD symptom to respond to L-dopa treatment (Louis et al., 1997). Differences in the nigrostriatal dopaminergic systems in DLB and PD may also be important (Piggott et al., 1999). Psychiatric symptoms in DLB include both psychotic and affective symptoms (Table 24.2). The focus of this chapter is on psychotic symptoms. Numerous studies show that visual hallucinations and other psychotic features tend to develop within the first four years of clinical dementia and strongly predict DLB (Aarsland et al., 2001; Ballard et al., 1999; Del Ser et al., 2000; Harding et al., 2002). Psychotic features in DLB range widely. One large study showed that of 98 patients who hallucinated, 71 had visual hallucinations, 37 had auditory hallucinations, eight had olfactory hallucinations, and three had tactile hallucinations (Aarsland et al., 2001a). More than half (56%) of DLB patients concurrently experience two or more types of hallucinations (Ballard et al., 1996), with visual hallucinations occurring in 42
84% of DLB patients. The quality of visual hallucinations in DLB differs from that in AD. For instance, visual hallucinations in AD tend to be mute, while more than half of visual hallucinations in DLB have an auditory component. DLB patients with visual hallucinations typically describe well-formed images of common objects. Aarsland and colleagues report detailed visual hallucinations in a group of DLB patients, in which 80% saw well-formed adults, 48% animals, 17% children, 15% inanimate objects, and 11% fire (Aarsland et al., 2001a; Del Ser et al., 2000; McKeith et al., 1996). These hallucinations can be black and white or in color. They may be frightening or benign to the patient, who may ignore or attempt to interact with the hallucinations. One study found that 76% of patients saw their hallucinations move and 51% heard them speak or make noises (Ballard et al., 1996). In 84% of patients the hallucinations may have been life-size, and in

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89% of patients the hallucinations may have been detailed; these hallucinations were not necessarily associated with sleep
wake transitions (Ballard, Harrison & Mckeith, 1996). Interestingly, in a one-year follow-up study of DLB and AD patients, visual hallucinations were more likely to be persistent in DLB compared to AD patients (Ballard et al., 2001). Other common psychotic symptoms include auditory hallucinations, delusions, and delusional misidentification (considered by most to be a perceptual disturbance rather than a delusional process). Up to 50% of DLB patients report auditory hallucinations (Aarsland et al., 2001a; Ballard et al., 1999), with the majority associated with visual hallucinations talking or making noises (Ballard et al., 1996). Fifty to seventy percent of all DLB patients report delusions (Barber et al., 2001), which often involve paranoia. Frequently, DLB patients have delusions of theft and of phantom boarders, in which someone has moved into the home unbidden. Capgras syndrome, a belief that imposters have taken over the identity of well known acquaintances, has been described in DLB (Aarsland et al., 2001a; Marantz & Verghese, 2002). Up to 50% of DLB patients exhibit evidence of delusional misidentification, in which the patient misidentifies common items and talks to mirror images or sees television characters in the room (Aarsland et al., 2001a; Ballard et al., 1999). Again, these symptoms may be accounted for by perceptual disturbances common in dementia rather than by delusions. For example, visual agnosia is the inability to recognize familiar objects and/or persons despite intact vision. The patient’s interpretation of the misidentified objects is therefore essential in distinguishing these processes. However, DLB patients also frequently report delusions of spousal infidelity and abandonment (Aarsland et al., 2001a). Insight into delusions and other psychotic symptoms is variable (McKeith, 2002). Finally, Schneiderian first-rank symptoms are rare in all dementias, including DLB (Ballard et al. 1996; Flint, 1991). Sleep dysfunction has been closely associated with DLB. Often REM sleep behavior disorder (RBD) precedes DLB by many years. Patients with RBD lose normal atonia during sleep, resulting in prominent motor activity related to dreams including vocalization and movement (Boeve et al., 2004). One study found that 12 of 15 patients with RBD had LBP on autopsy about 10 years later (Boeve et al., 2003). Therefore, the association between RBD and DLB has prompted the consideration of inclusion of RBD in the clinical diagnosis of DLB (personal communications, Fourth Consensus Conference on DLB). Course and progression Like other progressive dementias, the course in DLB is variable. Most studies find that the average duration of illness ranges from months to many years (McKeith,

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2002; McKeith et al., 1996) and does not differ significantly from AD (Forstl et al., 1993). In a retrospective study, Klatka and colleagues found that duration of illness was similar for AD and DLB, but longer for PD (Klatka et al., 1996). Meanwhile, others report that the duration is shorter than that found in AD or PD (Del Ser et al., 2000; Klatka et al., 1996; Weiner et al., 1996). Neuropathology Long identified with disease in the substantia nigra (SN) in PD, Lewy bodies (LBs) are spherical intracellular entities composed of ubiquitin and a-synuclein aggregated proteins. LBs are also the classic neuropathological finding of DLB, where they may appear in various areas of the brain, including the brainstem, limbic system, and neocortex. On standard hematoxylin and eosin (H&E) histological staining, substantia LBs are pink (eosinophilic) and may have concentric rings of different color intensity, and a surrounding uncolored ‘‘halo’’ (Figure 24.1) (Pollanen et al., 1993). Outside of the pigmented nuclei (SN and locus coeruleus), LBs may appear amorphous with lighter and more uniform color and without the characteristic concentric rings or halo (Figure 24.2)

Figure 24.1. Alpha-synuclein Lewy bodies and neurites in the neocortex. Courtesy of Dr. James Leverenz.

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Dementia with lewy bodies Table 24.3. Neuropathology of DLB

Finding

Description

Distribution

Lewy body

Brain stem nuclei, paralimbic and neocortical areas

Lewy neurite

Neuronal inclusion composed of aggregated proteins including ubiquitin and a-synuclein Aggregated neurofilament

Neuronal loss

Regional patterns of loss

Spongiform change Plaques

Microvacuolation Neuritic and diffuse types

Brainstem nuclei, hippocampal region CA2/3, dorsal vagal nucleus, basal nucleus of Meynert, transentorhinal cortex Brainstem (substantia nigra and locus coeruleus), basal nucleus of Meynert and basal forebrain Temporal cortex Similar to AD

Source: McKeith et al. (1996).

Figure 24.2. H & E Lewy bodies in the substantia nigra. Courtesy of Dr. James Leverenz.

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(Pollanen et al., 1993). LBs may be multilocular or fusiform and even extracellular, particularly in DLB. Lewy neurites, diffusely aggregated neurofilament proteins, are also often present in DLB, especially in the hippocampal CA2
3 region. Other associated lesions include neuritic plaques, neurofibrillary tangles, regional neuronal loss (particularly in the brainstem and nucleus basalis of Meynert), microvacuolation (spongiform change), and synaptic loss (Table 24.3) (McKeith et al., 1996). Currently, a-synuclein immunostaining provides the most sensitive method for the detection of LBP in the brain (Gomez-Tortosa et al., 2000; McKeith et al., 1996; Schneider et al., 2002). Investigations of cases with ‘‘pure’’ LBP without substantial AD pathology suggest that LBP alone may be associated with dementia (Duda, 2004). However, ‘‘pure’’ LBP cases are rare and as many as 65% of patients with LBP have concomitant AD pathology (Barker et al., 2002; Hamilton, 2000; Leverenz & Sumi, 1986). In these latter cases, it is not possible to determine the individual effects of AD and LBP on cognitive impairment, and some studies suggest that these pathophysiologies may interrelate. For instance, AD may exacerbate LBP (Jellinger, 2004; Marui et al., 2002; Wakisaka et al., 2003). On the other hand, AD pathology may exhibit a threshold effect, with neurofibrillary tangles masking clinical symptoms of DLB (Ballard et al., 2004; Merdes et al., 2003). Interestingly, one clinical-pathological study found that hallucinations were associated with greater LB density in the medial temporal lobe (amygdala and parahippocampal gyrus) (Harding et al., 2002). However, more studies are necessary to confirm these findings. In general, few studies look at the correlation between specific symptoms in DLB and the distribution of LBP. Finally, imaging studies demonstrate that regional brain atrophy that is commonly observed in AD appears less marked in DLB (Barber et al., 2001). One study found that DLB patients typically do not have medial temporal lobe atrophy or severe hippocampal atrophy on MRI (Barber et al., 1999). Typically, hippocampal atrophy is marked in AD, moderate in DLB, and mild or absent in PDD (Aarsland et al., 2004a). However, recent SPECT studies showed metabolic reductions in the occipital cortex of DLB patients, with a sensitivity and specificity of 90% and 80% respectively. Therefore, occipital hypoperfusion is a potential antemortem marker for DLB (Minoshima et al., 2001).

Suspected neurochemical abnormalities Multiple neurochemical systems in the brain have been implicated in DLB. The majority of DLB neurochemical studies focus on dopamine and cholinergic systems, and may lead to insights into potential pharmacologic therapy.

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Like PD, DLB shows substantial dopaminergic loss. However, unlike PD, remaining neurons in DLB do not compensate for this loss nor respond with the same efficacy to L-dopa treatment. For instance, in-situ studies using tissue from DLB patients demonstrate a 17% decrease in dopamine D2 receptor expression levels in the caudate and putamen compared to both PD and normal controls. Furthermore, while L-dopa treated PD patients demonstrated an increase in D2 receptors density (Piggott et al., 1999), DLB patients did not. These findings may account for the observations that DLB patients have only a partial response to Ldopa treatment. Cholinergic deficits are also prominent in DLB. The nucleus basalis of Meynert (a major source of cholinergic input) has consistent and severe LBP in DLB patients, and its degeneration correlates with cognitive decline. The deficits in choline acetyltransferase (ChAT) activity in DLB are markedly worse and occur earlier in the course of illness than in AD, especially in the neocortex (Tiraboschi et al., 2002). In cases with mild to moderate dementia, ChAT activity correlates with MMSE scores in DLB (Tiraboschi et al., 2000; 2002). ChAT has also been implicated in the development of psychotic symptoms, with decreased ChAT activity in patients with hallucinations compared to those without (Perry et al., 1990). Acetylcholine receptor system deficits are also prominent in DLB. Muscarinic receptors responsible for G-protein coupled signal transduction are differentially distributed in AD, DLB, and control subjects (Duda, 2004). M1 muscarinic receptor upregulation in the temporal cortex may account for higher response rates to cholinergic agents in DLB, compared to AD (Shiozaki et al., 2001). Other studies have shown reduced nicotine binding in DLB without the neuronal loss that accompanies such changes in PD. And the loss of nicotinic receptors in AD appears to be greater than in DLB, despite equal cholinergic dysfunction in these brain regions (Perry, 1995). These studies suggest that neurochemical systems have changed chemically, but not structurally, and may be amenable to medications. Genetic factors While causative mutations and genetic risk factors have been discovered in AD and PD (Bird, 2005; Forman et al., 2004; Huang et al., 2004), the genetics of DLB remain much less clear. Families have been described with multiple generations probably affected by DLB, some with autopsy confirmation. A recent literature review of potential DLB families revealed at least 12 families that fulfilled criteria for parkinsonism, with dementia and autopsy-confirmed LBP in at least one member (Tsuang et al., 2004). However, significant clinical and pathological

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heterogeneity exists, and changing diagnostic criteria and techniques for LB identification hampers comparisons across studies. Most of the molecular genetic studies in DLB are limited to candidate gene analysis. Polymeropoulos and colleagues identified a mutation in the a-synuclein gene that was causative in early-onset PD (Polymeropoulos et al., 1997), and this gene was hypothesized to link DLB with PD (Singleton et al., 2003). However, screening for missense and triplication mutations in the a-synuclein in DLB have been negative (El-Agnaf et al., 1998; Higuchi et al., 1998; Johnson et al., 2004). Therefore, a-synuclein mutations are probably not associated with DLB. On the other hand, the apolipoprotein 4 (APOE 4) allele is a well-established genetic risk factor for AD. Some studies have found a genetic association between APOE 4 and DLB, especially in cases with concomitant AD (Singleton et al., 2002; Tsuang et al., 2005). Meanwhile, similar to PD, this association does not exist in cases with LBs alone. Therefore, different genetic susceptibility factors probably exist in LBP with and without concomitant AD pathology. Genetic linkage analysis has identified several chromosomal regions linked to both AD and PD (Li et al., 2002). Families with AD and concomitant LBP may be a distinct genetic subtype (Scott et al., 2000). One of these shared linkage regions is on chromosome 12. Recent identification of the leucine-rich repeat kinase 2 (LRRK2) gene on this chromosome as the PARK8 locus may be critical to DLB (Paisan-Ruiz et al., 2004; Zimprich et al., 2004). Affected mutation-positive cases in one family exhibit strikingly heterogeneous neuropathology despite clinical features of typical PD; one autopsied case had diffuse LBP (Wszolek et al., 2004; Zimprich et al., 2004). More studies are necessary to determine if mutations in this and other genes exist specifically in DLB. Other risk factors Research on other risk factors is very sparse. Other than age, being male, and having a family history of DLB, studies to date have identified no additional clear risk factors. Treatment Current therapy for DLB is symptomatic since no disease modifying treatment is available. In DLB patients, severe hypersensitivity reactions may occur with antipsychotic therapy, which may be fatal (McKeith et al., 1996). This response usually occurs within the first two weeks of treatment and typically consists of cognitive decline, increased parkinsonism, drowsiness, and features of neuroleptic malignant syndrome, which may be related to dopaminergic dysfunction. There is

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no clear association with dose, sex, age, severity of illness, or clinical profile (Ballard et al., 1998). Similar neuroleptic hypersensitivity may occur with both typical and atypical antipsychotics (Ballard et al., 1998). Nevertheless, open label clinical trials using atypical antipsychotics show mild to moderate effectiveness in low doses. Olanzapine and risperidone, both of which have subsequently been linked to cerebrovascular accidents in the elderly, have been moderately effective in reducing hallucinations, delusions, and agitation in DLB (Aarsland et al., 1999; Cummings et al., 2002). Recent clinical trials in DLB and PD suggest that cholinesterase inhibitor treatment may delay progression of disease (Emre, 2004; McKeith, 2000). In DLB, only one randomized, controlled, multi-center trial exists, while the majority of studies are open label. Seven out of nine studies in efficacy reported improvement in cognitive and behavioral symptoms, mostly in apathy and hallucinations (Aarsland et al., 2004b). Two found no changes during treatment. In the one randomized trial, McKeith and colleagues found that after 20 weeks of rivastigmine treatment, patients had less apathy and anxiety and fewer delusions and hallucinations than those on placebo. In addition, cognition improved, particularly attention, memory, executive function, and planning. After three weeks of washout, DLB symptoms returned to baseline (McKeith et al., 2000). The authors reported no changes in parkinsonism. Predominant side effects in these studies include nausea, vomiting, and diarrhea (Aarsland et al., 2004b). Conclusions In summary, DLB is now recognized as a frequent cause of dementia in the elderly, and shares symptoms and neuropathological findings with AD and PDD. Epidemiologic studies estimate DLB prevalence at 5
36%, with a male predominance. Age of onset is generally after 50 years and may vary depending on risk factors not yet recognized. Presenting symptoms of DLB include cognitive, motor, and neuropsychiatric symptoms such as psychosis. The variability in symptoms has led to consensus criteria for ‘‘possible’’ and ‘‘probable’’ clinical diagnosis of DLB. Most patients will present with a history of progressive cognitive decline with prominent attention and executive function deficits, motor symptoms such as rigidity or bradykinesia, and neuropsychiatric findings such as visual hallucinations or dramatic fluctuations in attention and cognition. The insidious development and fluctuation of symptoms makes diagnosis difficult, and sensitivity of diagnostic criteria are low, while specificity is fairly high, suggesting underdiagnosis of DLB. Research into the pathophysiology of DLB has focused on neuropathologic findings, including the presence of LBs, Lewy neurites, and neuronal loss.

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The primary component of LBP appears to be a-synuclein, which is also found in PD. Neurochemical studies show a deficit of acetylcholine, and dopamine abnormalities may also be involved. Genetic risk factors remain unclear, although some studies show an increased risk with the APOE 4 allele, and families with this allele have been described with autopsy-confirmed DLB. Treatment for DLB, as with other dementias, involves cholinesterase inhibitors, which appear to help with cognitive and psychiatric symptoms but do not substantially modify the disease process. One unique aspect of treatment involves the careful use of neuroleptics, given severe hypersensitivity reactions in this population. Future challenges in DLB research and management include refining clinically valid guidelines for diagnosis with improved sensitivity and specificity, investigating antemortem biomarkers or imaging techniques that may help with early diagnosis, and developing further treatment options. Ultimately, research in DLB, AD, and PDD may uncover information about neurodegenerative disorders which can lead to better understanding and definitive treatment of these diseases, which may be closer related than previously thought. REFERENCES Aarsland, D., Larsen, J. P., Lim, N. G., & Tandberg, E. (1999). Olanzapine for psychosis in patients with Parkinson’s disease with and without dementia. Journal of Neuropsychiatry and Clinical Neurosciences, 11(3), 392
4. Aarsland, D., Ballard, C., Larsen, J. P., & Mckeith, I. (2001a). A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson’s disease with and without dementia. International Journal of Geriatric Psychiatry, 16(5), 528
36. Aarsland, D., Ballard, C., Mckeith, I., Perry, R. H., & Larsen, J. P. (2001b). Comparison of extrapyramidal signs in dementia with Lewy bodies and Parkinson’s disease. Journal of Neuropsychiatry and Clinical Neurosciences, 13(3), 374
9. Aarsland, D., Ballard, C. G., & Halliday, G. (2004a). Are Parkinson’s disease with dementia and dementia with Lewy bodies the same entity? Journal of Geriatric Psychiatry and Neurology, 17(3), 137
45. Aarsland, D., Mosimann, U. P., & Mckeith, I. G. (2004b). Role of cholinesterase inhibitors in Parkinson’s disease and dementia with Lewy bodies. Journal of Geriatric Psychiatry and Neurology, 17(3), 164
71. Ala, T. A., Yang, K. H., Sung, J. H., & Frey, W. H. (1997). Hallucinations and signs of parkinsonism help distinguish patients with dementia and cortical Lewy bodies from patients with Alzheimer’s disease at presentation: A clinicopathological study. Journal of Neurology, Neurosurgery and Psychiatry, 62(1), 16
21. Allam, M. F., Campbell, M. J., Hofman, A., Del Castillo, A. S., & Fernandez-Crehuet Navajas, R. (2004). Smoking and Parkinson’s disease: Systematic review of prospective studies. Movement Disorders, 19(6), 614
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3. Ballard, C., Holmes, C., McKeith, I., et al. (1999). Psychiatric morbidity in dementia with Lewy bodies: A prospective clinical and neuropathological comparative study with Alzheimer’s disease. American Journal of Psychiatry, 156(7), 1039
45. Ballard, C. G., O’Brien, J. T., Swann, A. G., et al. (2001). The natural history of psychosis and depression in dementia with Lewy bodies and Alzheimer’s disease: Persistence and new cases over 1 year of follow-up. Journal of Clinical Psychiatry, 62(1), 46
9. Ballard, C. G., Aarsland, D., McKeith, I., et al. (2002). Fluctuations in attention: PD dementia vs DLB with parkinsonism. Neurology, 59(11), 1714
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205. Barker, W. W., Luis, C. A., Kashuba, A., et al. (2002). Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer’s Disease and Associated Disorders, 16(4), 203
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Parkinson’s disease David L. Sultzer1 and George Webster Ross2 1 2

University of California at Los Angeles and VA Greater Los Angeles Healthcare System VA Pacific Islands Healthcare System

Summary of findings Grade of evidence Epidemiology: The prevalence of hallucinations in patients with PD is 16% in a community based study and approaches 50% in clinic based populations. Age of onset: Age at onset of PD is not associated with occurrence of hallucinations. PD patients with hallucinations are older than those without. Presentation: Visual hallucinations are typically vivid, colorful, well formed images of people or animals. Auditory, tactile, and olfactory hallucinations are less common. Insight is usually intact early while paranoid delusions regarding the hallucinations tend to occur later and in the setting of dementia. Course and progression: a. Left untreated, hallucinations in PD patients tend to persist. b. Presence of hallucinations in PD patients are a significant predictor of nursing home placement. Suspected neuropathology: a. In patients with PD or DLB, greater density of Lewy bodies in medial and inferior temporal cortex at autopsy are associated with visual hallucinations during life. Density of Lewy bodies in primary visual cortex is not associated with visual hallucinations. b. In patients with DLB, those with Lewy bodies more widely spread throughout the neocortex are more likely to have had persistent delusions and visual hallucinations compared to those with Lewy bodies restricted to the brainstem. Lower density of neocortical neurofibrillary tangles is associated with visual hallucinations.

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Grade of evidence Suspected neurochemical abnormalities: a. Dopaminergic medication treatment is associated with development of visual hallucinations in patients with PD. Nearly all PD patients with psychosis are taking dopaminergic or anticholinergic medication. b. In autopsy samples of patients with DLB, presynaptic cholinergic activity in the temporal cortex is lower in patients who had visual hallucinations. c. In autopsy samples of patients with DLB, cholinergic receptor density in temporal cortex is abnormal in patients who had delusions. Genetic factors: Visual hallucinations in PD may be associated with specific dopamine receptor polymorphisms. Cortical activity associated with psychosis: Metabolic rate or blood flow is lower in temporal cortex or higher in frontal cortex in PD patients with visual hallucinations compared to those without visual hallucinations. In patients with PD or DLB, hypometabolism or hypoperfusion in occipital cortex is common, but is not associated with the presence of visual hallucinations. Treatment: a. Patient and caregiver education, environmental adjustments, and behavioral interventions are effective for treatment of psychosis in PD. b. Reducing antiparkinsonian medications can improve psychosis in PD, but reducing L-dopa often exacerbates the motor signs of PD and is not generally recommended. c. Low-dose clozapine is often effective for treatment of psychosis in PD. Worsening of motor symptoms is rare; tremor may improve. Adverse effects may include sedation, hypotension, sialorrhea, or neutropenia. Regular monitoring of white blood cell count is required. d. Low-dose quetiapine is often effective for treatment of psychosis in PD. Motor worsening may occur in some patients at higher dosages or in patients with dementia. Adverse effects include sedation and dizziness. e. Low-dose risperidone may be effective for patients with psychosis and PD, although dose-related worsening of motor signs occurs in about 30% of treated patients. Olanzapine is not recommended for patients with PD, due to frequent motor worsening. f. Cholinesterase inhibitor treatment may improve or reduce the emergence of psychosis in PD, although most studies have focused on the cognitive effects in PD patients with dementia. g. Low doses and slow titration of all medications used in the treatment of psychosis in PD are recommended. Medication adverse effect profiles in PD are not well understood.

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This chapter provides a brief overview of Parkinson’s disease (PD), then describes the clinical features, underlying neurobiological mechanisms, and management options for psychosis in PD. The discussion focuses primarily on hallucinations and delusions that occur in nondemented PD patients and often occur coincident with dopaminergic or anticholinergic therapy. Psychoses associated with dementia with Lewy bodies (DLB) and with Alzheimer’s disease (AD) are reviewed in chapters 24 and 23, respectively, of this book.

Overview of parkinson’s disease PD, the second most common neurodegenerative disorder, is characterized by the gradual onset and slow progression of bradykinesia or slowness of movement, rest tremor, and muscle rigidity. Postural reflex impairment tends to occur later in the disease course. There are many causes of the parkinsonian syndrome, but the prominence of rest tremor, asymmetry of clinical signs, and robust response to dopaminergic therapy help to distinguish PD from other parkinsonian syndromes related to dopamine blocking drugs, cerebrovascular disease, and other neurodegenerative conditions. While movement abnormalities represent the core features of the disease, there are non-motor features that contribute equally to impaired quality of life and disability, including olfactory impairment, autonomic dysfunction, cognitive deficits and dementia, mood disturbances, and psychosis. Mean onset age for PD is around the sixth decade and incidence increases with increasing age. The overall prevalence for PD is one per 1000; however, this figure increases to 1% for the population over the age of 65 years. Onset before age 50 is rare. The mean duration of illness is approximately 13 years and survival rates are close to or modestly higher than the general population (Fall et al., 2003; Marras et al., 2005). Most studies indicate that PD is slightly more common in men than women. The neuropathologic hallmark of PD is loss of melanin-pigmented, dopamineproducing neurons in the pars compacta region of the substantia nigra, associated with target-shaped inclusions called Lewy bodies within the degenerating neurons. The loss of these neurons over time leads to profound dopamine deficits in the striatum (caudate nucleus and putamen) and the motor abnormalities of PD. However, it is well known that PD pathology occurs throughout the pigmented nuclei of the brainstem and even extends into the cerebral cortex and autonomic nervous system (Del Tredici et al., 2002). Extra-nigral pathology may explain the non-motor features of the disease. Symptomatic treatment exists in the form of dopamine replacement therapy, which is very effective for the motor signs of the disease to the point that lack

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of a good response is reason to question the diagnosis. Levodopa, administered orally, is absorbed through the blood
brain barrier, taken up by the dopaminergic neuron and converted to dopamine. However, over time, complications develop that eventually lead to worsening disability. These complications include dramatic fluctuations in motor function, other abnormal movements (dyskinesias) related to dopamine therapy, and psychosis. Dopamine agonists (bromocriptine, pergolide, pramipexole, and ropinirole) are medications that imitate dopamine by stimulating the dopamine receptors in the caudate nucleus and putamen. These are often the initial agents to be used in patients with PD owing to the lower likelihood of future motor complications compared to levodopa. However, confusion and psychosis are a major complication related to the use of these medications, especially in the elderly. Anticholinergic medications such as trihexyphenidyl and benztropine mesylate are useful adjunctive medications. Potent side effects, including impaired memory and hallucinations, limit the use of these medications in the elderly. Amantadine has weak dopaminergic properties that make it useful for the treatment of PD. Monoamine oxidase B inhibitors such as selegiline and rasagiline inhibit the metabolism of dopamine in the brain, potentiating the effect of dopamine. These agents have shown promise in the treatment of PD with motor fluctuations (Parkinson Study Group, 2005). Historical perspective of psychosis in PD and the role of dopaminergic meds Psychosis in PD has been recognized as a possible complication of dopaminergic and anticholinergic therapy since treatment of the disease began. There has been debate regarding whether psychosis may exist independent of therapeutic complications. In his original description of the disease, James Parkinson did not mention psychosis as a disease characteristic and none of the six cases he described were reported to have hallucinations or delusions. In fact, it was his observation that the intellect remains intact (Parkinson, [1817] 2002). Case reports published long before the levodopa era mention suspiciousness and hallucinations occurring in PD patients that could precede the classic motor signs of the disease by months to years (Jackson, Free, & Pike, 1923; Schwab, Fabing, & Prichand, 1950). These early reports are difficult to interpret based on today’s understanding of PD and changes in psychiatric nomenclature. For example, several of the cases described probably had post-encephalitic parkinsonism rather than idiopathic PD. Post-encephalitic parkinsonism occurring as a consequence of an early twentieth century worldwide flu epidemic was common during the first half of the century (Nisipeanu, Paleacu, & Korczyn, 1997). Paroxysmal behavioral symptoms and atypical motor disturbances such as oculogyric crisis were common in these patients. Adding to the challenge of understanding psychosis in PD,

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some symptoms interpreted as tactile hallucinations in these early descriptions, such as feelings of electricity passing through the body, are now recognized pain syndromes that occur in PD patients. In fact, psychosis is probably uncommon in untreated usual PD. It has long been known that hallucinations may be caused by biogenic amines such as dopamine and anticholinergic medications. Psychosis may occur occasionally in patients treated with dopamine agonists used to block prolactin secretion in functioning pituitary tumors (Turner et al., 1984). Hallucinations occur following an increase in dose of these medications in PD patients and the phenomenology of hallucinations is the same regardless of drug class (Goetz, Tanner, & Klawans, 1982). The frequency of hallucinations in PD increases with years of drug exposure. In fact, it has been shown that PD patients who develop hallucinations soon after initiation of levodopa therapy (three months or less), in contrast to those who develop them only after prolonged therapy, are more likely to have had a pre-existing psychiatric disease or an atypical parkinsonian syndrome such as dementia with Lewy bodies (Goetz et al., 1998b). Furthermore, psychosis associated with PD may diminish or resolve once dopaminergic or anticholinergic therapy is reduced or discontinued (Goetz et al., 1982; Kuzuhara, 2001; Saint-Cyr, Taylor, & Lang, 1993). The weight of the evidence, therefore, indicates that most hallucinations in nondemented PD patients are triggered by antiparkinsonian therapy. However, hallucinations do not occur in all PD patients on dopaminergic agents. There is a lack of association between total levodopa equivalent dose and occurrence of psychosis (Barnes & David, 2001; Fenelon et al., 2000; Sanchez-Ramos, Ortoll, & Paulson, 1996). Even high-dose levodopa intravenous infusions in PD patients with daily hallucinations do not necessarily provoke hallucinations (Goetz et al., 1998a). Hallucinations may subside with decrease in dopaminergic medications in individual patients. However, when groups of PD patients with hallucinations are followed longitudinally, the hallucinations are more likely than not to persist (Goetz et al., 2001). This suggests that in most cases antiparkinsonian medications, while usually necessary, may not be sufficient to cause hallucinations. Other disease-related factors probably play a role. Epidemiology of PD-related psychosis The reported frequency of psychotic symptoms in PD varies widely owing to population characteristics and psychosis ascertainment methods. One community-based study attempted to find all cases of PD within a defined region of western Norway. The assessment of psychosis was based on a single question from the Unified Parkinson’s Disease Rating Scale thought disorder

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subscale that rates disturbances of perception and thought on a scale ranging from vivid dreams to hallucinations with preserved insight to disabling hallucinations accompanied by delusions. Approximately 10% of PD patients had hallucinations with insight preserved while another 6% had hallucinations with loss of insight or with delusions (Aarsland et al., 1999a). On the other hand, the lifetime prevalence of all hallucinations in a clinic-based population has been reported to be nearly 50% (de Maindreville, Fenelon, & Mahieux, 2005; Fenelon et al., 2000). Characteristics of PD-related psychosis Age

While the age at onset of PD is not associated with presence of psychosis, most studies report that hallucinations in PD occur more frequently with older age (Barnes & David, 2001; Fenelon et al., 2000). Symptom description

Hallucinations are the most common manifestation of psychosis in PD. These may be as simple as sensing the presence of a person or animal in the room or seeing a person or animal passing sideways (Fenelon et al., 2000). Visual hallucinations are commonly vivid, colorful, well-formed, and non-threatening images of people or animals, and less often of objects (Fenelon et al., 2000; Goetz, 1999; Goetz et al., 1982). Insight is spared in most patients; secondary delusions tend to occur later and are commonly associated with dementia (Fenelon et al., 2000). Auditory hallucinations occur much less commonly, are usually verbal or musical, and may occur alone or with visual hallucinations. Tactile or olfactory hallucinations are rare (de Maindreville et al., 2005; Fenelon et al., 2000; Goetz et al., 2005). Hallucinations tend to last very briefly, but occur at least weekly in most patients who have them (de Maindreville et al., 2005; Diederich, Goetz, & Stebbins, 2005; Fenelon et al., 2000). Delusions nearly always occur in the presence of hallucinations and are most often characterized as paranoid (Aarsland et al., 2001b; Marsh et al., 2004). Risk factors and PD characteristics

The presence of cognitive impairment is one of the strongest risk factors for psychosis in PD. Both hallucinations and delusions occur more frequently in PD patients with dementia (hallucinations 54%; delusions 29%) compared to those without dementia (hallucinations 14%; delusions 7%) (Aarsland et al., 2001a). PD patients with visual hallucinations also tend to have a longer duration of disease, higher stage of disease, and poorer motor score on a PD rating scale than those without hallucinations (Barnes & David, 2001; Fenelon et al., 2000).

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Risk factors and co-morbid conditions

Ocular disorders including cataract, retinal disease, and glaucoma were found to be predictors of hallucinations in one prospective study of PD patients free of hallucinations at baseline (de Maindreville et al., 2005). Poor visual discrimination as measured by contrast sensitivity and color sensitivity is also more common in PD patients with hallucinations compared to non-hallucinating controls, even among those with normal visual acuity (Diederich et al., 1998). The association of ocular pathology with hallucinations in PD is reminiscent of the Charles Bonnet syndrome where diminished visual sensory input leads to hallucinations through a release phenomenon (Menon et al., 2003). In addition, abnormal eye movements and altered visuospatial attention occur in cognitively intact PD patients (BodisWollner, 2003) and those with visual hallucinations have impaired object perception and facial recognition and enhanced mental images with word stimuli (Barnes et al., 2003). These visual attention and processing alterations may also provide a substrate for visual hallucinations. Sleep abnormalities are present in nearly all hallucinating PD patients, suggesting that a continuum exists that begins with sleep fragmentation, progresses to vivid dreams, and ends with hallucinations (Kulisevsky & Roldan, 2004; Pappert et al., 1999). Vivid dreams and nightmares, in particular, are highly associated with presence of hallucinations. However, data from a longitudinal study indicate that altered dreams do not necessarily predict the future occurrence of hallucinations (Goetz et al., 2005). PD patients with hallucinations have more daytime somnolence (Fenelon et al., 2000), less total rapid eye movement (REM) sleep time, and less percent REM sleep time than non-hallucinators (Comella, Tanner, & Ristanovic, 1993). Moreover, cognitively intact PD patients with daily visual hallucinations have reported daytime hallucinations coincident with REM sleep intrusion observed on polysomnogram (Arnulf et al., 2000). Thus, structural degeneration in cholinergic pedunculopontine neurons in the brainstem, or dopaminergic changes that result from the disease process or replacement therapy, may contribute to disordered REM sleep and circadian rhythms, along with visual hallucinations and vivid dreams in at least some patients with PD. Sequelae of psychosis in PD

The presence of hallucinations in PD is a significant predictor of nursing home placement, and mortality in these individuals is very high (Aarsland et al., 2000; Goetz & Stebbins, 1993). However, mortality is not greater for PD patients with hallucinations living at home relative to non-hallucinators (Factor et al., 2003; Goetz & Stebbins, 1993; 1995). While the presence of hallucinations is associated with lower cognitive function in cross-sectional studies, it remains uncertain whether cognitively intact PD patients with hallucinations are at higher risk for

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future dementia (Factor et al., 2003; Goetz et al., 2001; Sanchez-Ramos et al., 1996). Caregiver burden is greater in PD patients with psychosis compared to patients without psychosis (Aarsland et al., 1999b; Marsh et al., 2004). Neurobiological mechanisms for psychosis in PD Several lines of evidence indicate that psychosis in PD reflects specific neurobiological changes and is neither a random symptom nor entirely due to diffuse neurodegeneration, global cognitive impairment, visual misperceptions, or dopaminergic medications. Regional neuropathology

In an autopsy study, Harding and colleagues measured the density of cortical Lewy bodies (LB) in patients meeting criteria for PD without dementia, PD with dementia, or DLB (Harding, Broe, & Halliday, 2002). All patients had clinical parkinsonism and brainstem LB. Across the three disorders, those patients who had experienced well-formed visual hallucinations early in their course of illness had greater density of LB in the inferolateral temporal cortex and parahippocampal gyrus, but not in cortical regions outside the temporal lobe, compared to those with no or late-occurring hallucinations. Of note, LB in the primary visual cortex were rare in all groups, whether or not visual hallucinations were present. Another autopsy study of 112 patients meeting neuropathological criteria for DLB found that those patients with more widespread LB involving neocortical regions were more likely to have had visual hallucinations or delusions that persisted for at least six months during life (Ballard et al., 2004). Thus, LB in the neocortex, particularly in inferior and medial temporal regions, may play a prominent role in the expression of visual hallucinations in patients with PD or DLB synucleinopathies. Regional neurochemistry

The increased risk for visual hallucinations among PD patients treated with dopamine precursors or receptor agonists indicates that increased dopaminergic activity contributes to psychosis. Elevated dopamine sensitivity in mesolimbic circuits may mediate this effect. Alterations in regional cholinergic activity are also likely important. In autopsy assays, level of cortical choline acetyltransferase (ChAT), a marker for presynaptic cholinergic activity, was lowest in DLB patients with visual hallucinations (Perry et al., 1990; 1991). Regional specificity was suggested in an autopsy study by Ballard et al. DLB patients who had experienced visual hallucinations had lower ChAT level in temporal visual association cortex

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than those who did not have hallucinations, but no differences were apparent in other parietal or temporal regions (Ballard et al., 2000). DLB patients with delusions had similar levels of cortical ChAT compared to those without delusions, but had a 50% increase in M1 receptor binding in the posterior temporal cortex. Finally, another autopsy study of DLB patients demonstrated that reduced binding of specific cholinergic receptor subtypes in the temporal cortex is associated with either visual hallucinations or delusional misidentification (Court et al., 2001). These results suggest that alterations of cholinergic tone, particularly in the temporal cortex and involving individual receptor subtypes, are associated with visual hallucinations and perhaps delusions in DLB. Treatment with cholinesterase inhibitor medication may relieve the cognitive deficits or psychotic symptoms in patients with either PD and dementia or DLB by increasing cholinergic tone in critical neuronal circuits. Regional cortical activity

The neuropathological and neurochemical findings at autopsy demonstrate trait markers for psychotic symptoms that occurred in patients during life. In contrast, functional neuroimaging techniques can measure neurophysiological processes in vivo and reveal ongoing state markers for psychosis in neurodegenerative disorders (Sultzer et al., 2003). In functional neuroimaging studies, metabolic rate or blood flow has been shown to be altered in the frontal or temporal cortex of those PD patients with visual hallucinations (Nagano-Saito et al., 2004; Okada et al., 1999). Interestingly, a single photon emission computed tomography study found that occipital perfusion was similar in DLB patients with and without visual hallucinations (Lobotesis et al., 2001). Thus, while PD and DLB are characterized by hypoperfusion and hypometabolism in the occipital visual cortex, this reduced functional activity does not appear to be associated with visual hallucinations. Finally, neuronal activity in subcortical limbic regions may mediate visual hallucinations: a patient with PD and electrodes placed in the subthalamic nucleus to allow deep brain stimulation for relief of motor symptoms experienced vivid, well-formed, and reproducible visual hallucinations during periods of electrode stimulation (Diederich, Alesch, & Goetz, 2000). Genetics

Genetic factors may predispose to psychosis in PD or DLB. Visual hallucinations and delusions occurred in only one of two families with familial DLB (Tsuang et al., 2002). In other studies, an association between a dopamine receptor polymorphism and medication-induced hallucinations was demonstrated (Makoff et al., 2000).

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A neurobiological model for psychosis in PD

While the current data do not provide a complete view of the mechanisms, research results reveal a tentative model that describes conceptually the etiology of medication-triggered psychosis in PD (Figure 25.1). In this model, neuronal loss and synuclein-containing LB in the brainstem are fundamental characteristics. Disease modifiers, including the extent of cortical LBs and reduced cholinergic tone in the temporal cortex, appear to drive the visual hallucinations that often occur. The disorder is influenced additionally by specific changes in perception and cognition that may also be related to regional neuropathology. Finally, preliminary evidence suggests that modulatory effects related to psychosis can be measured as ongoing cortical activity using functional neuroimaging. In this model, multiple factors and interactions among factors are probably most important. For example, cholinergic alterations may lead to visual hallucinations most frequently when LBs densely affect the temporal cortex. Impaired vision or sleep may further reduce the threshold for hallucinations. Understanding better the neurobiological factors involved in the expression of hallucinations and

Figure 25.1. A conceptual model for the development of psychosis in PD.

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David L. Sultzer and George Webster Ross Table 25.1. Approach to clinical management of psychosis in PD

1. Assessment Identify specific clinical symptoms and circumstances Hallucinations (sensory modality) Visual illusions Delusional thoughts Behavior disturbance Anxiety or mood symptoms Consider underlying psychiatric disorder, e.g. primary psychotic or mood disorder Review medical status and new medications Evaluate cognition and determine whether dementia or delirium is present Assess visual acuity 2. Review anti-parkinsonian medications If a recent med adjustment has promoted psychosis or if delirium occurs, consider med discontinuation or substantial dose reduction Reduce medications that have not been particularly effective Maintain regimen that promotes optimal motor function 3. Treatment Define target symptoms Environmental adjustments, behavioral interventions, and education Pharmacotherapy Cholinesterase inhibitor, if dementia Atypical antipsychotic medication Monitor symptoms and adjust treatment as needed

delusions in PD can help clarify basic mechanisms involved in the development of these symptoms, identify shared mechanisms for psychosis across neuropsychiatric disorders, provide a biomarker to help refine clinical syndromes and phenotypes in PD, and define specific neurophysiological targets for treatment interventions. Managing psychosis in parkinson’s disease Patient management principles

An overview of the clinical approach to psychosis in PD is shown in Table 25.1. Management begins with an evaluation to define the specific symptoms that are present, elucidate contributing factors, and identify target symptoms for interventions. Cognitive skills are assessed, as psychosis in PD is up to seven

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Parkinson’s disease Table 25.2. Behavioral management strategies for patients with PD and psychosis

Education Define psychosis for patient and family Distinguish psychosis in PD from psychosis due to other psychiatric syndromes Alert to possible adverse effects of dopaminergic medications, including psychosis Education and support organizations National Parkinson Foundation www.parkinson.org Parkinson’s Disease Foundation www.pdf.org Environmental Adjustments Increase daytime light, increase or decrease nighttime light Improve sleep conditions If dementia: Promote safety
stove, electricity, door latches, driving Maintain activities and reasonable level of stimulation Provide appropriate level of care and support Accommodation and Behavioral Interventions Patient strategies Direct attention away from hallucination Focus specifically on hallucination If dementia, assist with distraction or provide reassurance

times more common in those with dementia (Fenelon et al., 2000) and cognitive impairment needs to be addressed in the treatment plan. Since parkinsonism with visual hallucinations and dementia can reflect DLB, the primary diagnosis should be reconsidered if cognitive impairment has been prominent over the entire course of illness. Psychosis accompanied by clouded sensorium or inattention probably reflects a delirium or acute confusional state. In delirium, visual hallucinations are usually more persistent and less well formed than in cognitively intact PD (Goetz et al., 1982). If delirium is suspected, causative factors must be considered and treated. Finally, the severity of psychosis and patient distress, the extent of associated behavioral disturbances, and the impact of psychosis on patient safety and caregiver well-being helps define the need for treatment and appropriate strategies. Patient and caregiver education, environmental adjustments, and behavioral interventions are essential elements of treatment for psychosis in PD (Table 25.2). Patients often use a variety of coping strategies such as conscious self-reassurance or reassurance through discussions with others that the hallucinations are not real and will go away (Diederich, Poeri, & Goetz, 2003).

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Adjusting anti-parkinson’s medications

Reducing or discontinuing antiparkinsonian therapy can improve or eliminate psychotic symptoms (Friedman, 1991; Goetz et al., 1982; Koller et al., 1981). Discontinuing medication is most appropriate when psychosis occurs soon after a new medication is added or when a delirium due to antiparkinsonian therapy is suspected. In other circumstances, most clinicians do not aggressively reduce dopamine agonists or L-dopa treatment, because motor exacerbations usually occur and alternative treatments are often effective. Anticholinergic agents, selegiline, and amantadine are often discontinued due to their less favorable risk/ benefit ratio. If further med discontinuation is necessary, dopamine agonists, COMT-inhibitors, controlled-release L-dopa, and finally L-dopa are reduced, but not beyond the level at which significant motor worsening occurs. Treatments for psychosis

Recent studies have examined the efficacy and adverse effects of medication treatments for psychosis in PD, although most are open treatments or retrospective reviews, sample sizes are generally small, and target symptoms and assessment strategies vary widely. There are few med comparison trials. Nonetheless, emerging research results and clinical experience have helped to inform practice. Typical antipsychotic medications

Traditional antipsychotics such as haloperidol, thioridazine, and perphenazine were used in the past to treat psychosis in patients with PD. The potent dopamine receptor antagonism of these medications usually worsens the bradykinesia and rigidity of PD and they are no longer routinely prescribed in this population. Atypical antipsychotic medications

Atypical antipsychotic medications (clozapine, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone) have more prominent serotonergic effects and less propensity to exacerbate parkinsonism than typical antipsychotics, although specific neuroreceptor binding and motor effects of meds in this class vary. Treatment trials and clinical experience currently support the use of quetiapine or clozapine for psychosis in PD. Risperidone treatment may be a second-line choice for some patients, although motor symptoms may worsen. The initial dose of atypical antipsychotic medication is very low in patients with PD, and the dose is increased slowly if psychosis persists. Most medications are effective at low dosage. A few patients may ultimately benefit from higher doses, although PD patients are particularly susceptible to motor and cognitive adverse effects.

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Atypical antipsychotic medication treatment was associated recently with increased risk for cerebrovascular events (Herrmann & Lanctot, 2005) and mortality (Food and Drug Administration, 2005) in patients with dementia. Whether these risks also apply to patients with PD and psychosis is not clear. The optimal length of antipsychotic treatment for psychosis in PD is unknown. Hallucinations generally persist in patients with PD, and most patients continue on effective medication treatment for at least several months and are observed carefully when medication is discontinued. Two studies showed that psychosis recurred in about 80% of patients after successful treatment with either clozapine or quetiapine for 20 months (Fernandez, Trieschmann, & Okun, 2005) or 16 weeks (Pollak et al., 2004), although a third study found that many patients did not experience recurrence after clozapine withdrawal (Klein et al., 2003). Clozapine

Two placebo-controlled, four-week, flexible-dose trials support the efficacy of clozapine for psychosis in PD (n ¼ 60 in each study). In both studies, the initial dose in the clozapine group was 6.25 mg/day and dose increases were in increments of 12.5 mg or less. Mean dose was 24.7 mg/day (range 6.25
50 mg/ day) (Parkinson Study Group, 1999) or 35.8 mg/day (range 12.5
50 mg/day) (Pollak et al., 2004). There was no significant change on global motor rating scale scores, but tremor improved with treatment (Parkinson Study Group, 1999). Mean MMSE scores did not decline. Across the two studies, three patients developed transient leukopenia. An earlier placebo-controlled study showed that sedation, confusion, and motor worsening occurred with higher clozapine doses (mean dose 171 mg/day) (Wolters et al., 1990). Two open studies of clozapine treatment for five years demonstrated persistent efficacy and few side effects for most patients (Fernandez et al., 2004a; Klein et al., 2003). Controlled trials thus support the use of low-dose clozapine for psychosis in PD. However, the need for regular monitoring of white blood cell count is a practical barrier to its routine use. Quetiapine

Several open trials or chart reviews suggest that quetiapine is effective for psychosis in PD. A review of 106 patients treated with quetiapine (mean dose 60 mg/d; range 12.5
600 mg/d) for an average of 15 months showed that 82% were improved (Fernandez et al., 2003a). Motor worsening was noted in 32%, but led to med discontinuation in only 9%. Lower response rate and greater motor decline occurred in patients with dementia. Another review of 43 patients treated with

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quetiapine (mean dose 54 mg/d) for an average of 10 months found improved psychosis in 81% (Reddy et al., 2002). Motor worsening occurred in 12.5%, exclusively in those with dementia. An open treatment study with randomization to either clozapine (mean dose 26 mg/d; range 12.5
50 mg/d) or quetiapine (mean dose 91 mg/d; range 25
200 mg/d) for 12 weeks showed no efficacy difference between the two treatments (Morgante et al., 2002). Mild motor worsening occurred in three patients with quetiapine dose over 100 mg/d. In summary, although controlled trials are lacking, quetiapine appears to be effective and generally well-tolerated, with mild dose-related motor worsening in some patients. There is no risk for agranulocytosis and quetiapine is often selected currently as first-line treatment for psychosis in PD. Risperidone

One open trial and several case series have shown notable improvement in PD-related psychosis with risperidone treatment, but parkinsonism worsened in about 30% of patients. Increased parkinsonism is generally dose-related but can occur at very low dose in individual patients (Friedman & Fernandez, 2002; Leopold, 2000). Thus, risperidone is not generally recommended for first-line treatment. Olanzapine

Two double-blind, placebo-controlled trials of olanzapine (mean dose 4.2 mg/d or 4.1 mg/d) for four weeks in patients with PD and psychosis found no significant efficacy over placebo, but significant worsening of motor symptoms in the olanzapine group (Breier et al., 2002). Other studies have shown beneficial effects of olanzapine treatment on psychosis, but motor worsening is frequent and sometimes severe (Friedman & Fernandez, 2002). Thus, olanzapine is not usually recommended for patients with PD. Aripiprazole

Aripiprazole is an antipsychotic medication with partial dopamine agonist activity, which could benefit patients with PD. However, very preliminary experience indicates that efficacy may be modest and motor worsening may occur in some patients (Fernandez et al., 2004b; Schonfeldt-Lecuona & Connemann, 2004). Cholinesterase inhibitors

The prominent cholinergic deficit in patients with Lewy body disorders and its association with psychosis suggest that cholinesterase inhibitor treatment may be efficacious. Donepezil, galantamine, and rivastigmine are FDA approved for

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treatment of mild to moderate AD and large clinical trials indicate that there may be beneficial effects on psychosis in AD. In patients with PD and dementia, treatment with donepezil (Aarsland et al., 2002), galantamine (Aarsland, Hutchinson, & Larsen, 2003), or rivastigmine (Emre et al., 2004) resulted in modest cognitive improvement, and beneficial effects on hallucinations or delusions were also observed. In the largest controlled trial, 50% fewer PD patients developed hallucinations with rivastigmine treatment compared to a placebo over the six-month treatment trial (Emre et al., 2004). In open studies of cholinesterase inhibitor treatment where at least some patients had clinically significant psychosis at study entry, hallucinations and delusions improved in the majority of PD patients either with (Aarsland et al., 2003; Reading, Luce, & McKeith, 2001) or without (Fabbrini et al., 2002) dementia. Across the studies, doses were similar to those for usual treatment of patients with AD or modestly lower in some patients. Up to about 50% of the PD patients developed doserelated adverse gastrointestinal symptoms, which appeared to be more common than seen in AD trials. Increased rigidity or bradykinesia was uncommon, although at least mild increased tremor occurred in up to 20% of patients. These results indicate that cholinesterase inhibitor medication may be a reasonable treatment choice for psychosis in PD patients with dementia, although additional data are needed. Dose should be titrated cautiously, with attention to possible adverse gastrointestinal effects or worsening tremor. Other treatments

A few reports have described inconsistent antipsychotic effects of ondansetron (a 5-HT3 receptor antagonist) (Eichhorn, Brunt, & Oertel, 1996; Zoldan et al., 1995), electroconvulsive therapy (Fernandez et al., 2003b), or deep brain stimulation (Lozano & Mahant, 2004; Diederich et al., 2000). Antipsychotic efficacy is uncertain with these treatments and clinical experience is limited. Overall, although there are few large-scale controlled trials, the treatment data and clinical experience indicate that quetiapine or clozapine are optimal initial choices for treating psychosis in PD. Cholinesterase inhibitor treatment may be a first-line choice when dementia is present and the clinical circumstances allow titration over one to two months.

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Part VIII

Sensory Impairments

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Psychosis associated with sensory impairment Suzanne Holroyd University of Virginia, Department of Psychiatric Medicine, Charlottesville VA

Summary of findings Grade of evidence Epidemiology: 11
77% visual hallucinations in visual impairment, 50
80% phantom limb phenomena. Age of onset: Older age for visual hallucinations in visual impairment and musical hallucinations/paranoia in auditory impairment, all ages for phantom limb phenomena. Presentation: Visual hallucinations in visual impairment: sudden onset often with change in vision, no associated hallucinations, can be simple or complex. Phantom Limb: sudden onset usually right after amputation, can be variety of sensations or pain. Auditory hallucinations in auditory impairment: musical hallucinations, sudden onset. Course and progression: Visual hallucinations in visual impairment: usually resolves over time or with treatment of visual problem. Phantom Limb: resolves or becomes chronic. Musical hallucinations: chronic unless hearing deficit resolves. Suspected neuropathology: Sensory deprivation causes release hallucinations vs. irritative lesion sending abnormal signals. Also, cortical reassignment hypothesis. Suspected neurochemical abnormalities: Sympathetic activity in phantom limb. Genetic factors: Chromosome 15 in rat studies for phantom pain. Other risk factors: Visual hallucinations in visual disorders: sudden change in vision, older age, worse cognition, living alone. Phantom limb: pain prior to amputation, current stump pain, bilateral or lower limb amputation. Treatment: Visual hallucinations in visual disorders: reassurance, improving vision, anticonvulsants. Phantom limb: memantine to prevent phantom limb, TENS, opioids, ketamine, calcitonin improves compared to placebo.

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Introduction The relationship of sensory deprivation to psychosis is complex and includes: (1) visual impairment and visual hallucinations; (2) sensory impairment and tactile hallucinations (phantom limb sensations and phantom pain); (3) auditory impairment and auditory hallucinations/paranoia. This chapter will review the current knowledge of sensory impairment and psychosis. For the purpose of this chapter a hallucination is a perception without an external stimulus, and does not include lack of insight in the criteria. Epidemiology Visual hallucinations

Visual hallucinations are reported in 11
21% of patients with visual system lesions or visual impairment (Kolmel, 1985; Lepore, 1990; McNamara, Heros, & Boller, 1982; Teunisse et al., 2000; Weinberger & Grant, 1940). However, these studies did not exclude other psychiatric disorder that may have caused visual hallucinations. In studies that excluded psychiatric disorders including delirium and dementia, a prevalence of 6.3
13% is reported (Holroyd et al., 1992; 1994). An interesting study revealed that approximately 19% of normals undergoing sensory deprivation developed visual hallucinations (Zuckerman & Cohen, 1984). Similarly, thirteen normals who underwent sudden and complete visual deprivation for five days, revealed that ten (77%) reported simple hallucinations (spots of lights) and complex hallucinations (faces, landscapes) during the first day of blindfolding (Merabet et al., 2004). These studies highlight the role of sensory deprivation in the development of visual hallucinations. In Alzheimer’s and Parkinson’s disease, visual hallucinations are associated with sensory deprivation and eye disease, with a prevalence of 11
50% (Chapman et al., 1999; Holroyd, 2004; Holroyd & Sheldon-Keller, 1995; Holroyd, Currie, & Wooten, 2001). Sensory impairment with tactile hallucinations

Phantom limb occurs when amputation is followed by the sensation that the body part is still present. The syndrome presents in 50
80% of all amputees (Davis et al., 1998; Jensen & Nikolajsen, 1999) and 80% of lower limb and 41% of upper limb amputees (Dijkstra et al., 2002). Among children, 69.7% with amputations report phantom sensations while 49.5% report phantom pain (Wilkins et al., 1998). Others report that 100% of children with traumatic amputations (accidents) report phantom sensations while 83
100% report phantom pain (Krane & Heller, 1995; Ritchie, 1980).

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‘‘Telescoping,’’ the sensation of retraction of the phantom limb toward the residual limb or shrinking of the phantom limb, occurs in approximately 30% (Cronholm, 1951; Katz, 1992b). Auditory impairment with auditory hallucinations or paranoia

Prevalence of auditory hallucinations or paranoia with auditory impairment is unknown. The association of paranoia to hearing loss was examined in inpatients comparing 54 ‘‘paranoid’’ elderly to 57 elderly with affective non-paranoid psychosis. Audiometric assessment revealed 46.3% of paranoid elderly had deafness compared to 3.5% of affective psychotic elderly (Cooper et al., 1974). Age of onset Visual hallucinations

When elderly with eye disease experience visual hallucinations, it is sometimes termed Charles Bonnet Syndrome (Alroe & McIntyre, 1983; Berrios & Brook, 1982; Gold & Rabins, 1989; Hosty, 1990; McNamara et al., 1982; Rosenbaum et al., 1987; Schultz & Melzack, 1991). The syndrome has a variety of definitions but generally links visual hallucinations in the elderly with eye disease (Damas-Mora, Skelton-Robinson, & Jenner, 1982; Patel, Keshavon, & Martin, 1987; Ribeiro, Oliveira-Souza, & Alvarenga, 1989). Unfortunately, much of the literature does not screen for or rule out other causes of visual hallucinations in the elderly, such as delirium or dementia (Cole, 1992; Olbrich et al., 1987; Teunisse et al., 2000), For example, a study of so-called Charles Bonnet patients revealed nine of the thirteen had marked cognitive impairment (Cole, 1992), making the diagnoses of dementia or delirium with visual hallucinations likely. In another study, post-operative elderly patients with visual hallucinations were labeled Charles Bonnet without considering post-op delirium (Olbrich et al., 1987). A follow-up study of six Charles Bonnet patients revealed that two developed dementia, raising the possibility that such patients may have early dementia (Gold & Rabins, 1989). In summary, the eponym Charles Bonnet Syndrome has become a convenient term to label elderly patients with eye disease who happen to develop visual hallucinations, as if the label itself is an explanation, instead of critically examining individual patients for the causes of visual hallucinations. Thus much of the Charles Bonnet literature is largely unhelpful in the study of visual impairment and hallucinations. It is most helpful to study patients with visual hallucinations in terms of their clinical state, including cognition and other psychiatric disorder to better understand this phenomenon (Berrios & Brook, 1982; Holroyd, 2002).

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Otherwise, older age has been postulated as the time of onset of this phenomenon. However, because many diseases of the eye are age related, it is not clear that age is a factor. A study of macular degeneration patients with visual hallucinations found no differences on age (Holroyd et al., 1992). A study of 104 patients with visual hallucinations and visual disorders revealed older age was not associated with hallucinations (Lepore, 1990). However, a study of ophthalmology patients of ages 14 to 95 revealed no patient under age 60 reported visual hallucinations and found older age to be associated with the presence of visual hallucinations (Holroyd et al., 1994). The sensory deprivation study of normals that experienced visual hallucinations had a mean age of 25, suggesting that rapid and complete visual deprivation is sufficient to induce visual hallucinations independent of age (Merabet et al., 2004). In summary, patients with visual impairment and visual hallucinations are typically elderly, but this is probably due to the increased rates of eye disease in the elderly rather than the effect of age itself. Sensory impairment with tactile hallucinations

Phantom limb occurs across the life span, from children to the elderly (Flor, 2002). There is controversy about whether older children have a higher frequency of phantom pain (Krane & Heller, 1995; Ritchie, 1980; Wilkins et al., 1998) than younger children (Dijkstra et al., 2002). Auditory impairment with auditory hallucinations or paranoia

Musical hallucinations are reported in the hearing impaired elderly (Hammeke, McQuillen, & Cohen, 1983; Murata, Naritomi, & Sawada, 1994; Ross et al., 1975). Seven patients with musical hallucinations and hearing loss all had onset of hallucinations after age 60 (Wengel, Burke, & Holemon, 1989). The literature of paranoia and hearing loss has focused on the elderly (Cooper, 1976; Garside & Kay, 1976; Moore, 1981; Todd, 1974). However, since hearing loss is age related, the role of age versus hearing loss is unclear. In those with prelingual deafness, no tendency towards paranoia is found, suggesting that acquired hearing loss rather than deafness may predispose to paranoia (Lebuffe & Lebuffe, 1979; Sanchez et al., 2000). Presentation Visual hallucinations

Patients with visual hallucinations may not report them due to fears of being labeled as crazy (Damas-Mora et al., 1982, Hosty, 1990; Holroyd et al., 1992; Menon et al., 2003; Rosenbaum et al., 1987; Teunisse et al., 2000). Interestingly,

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patients often report curiosity or amusement regarding the hallucinations, unlike visual hallucinations in other psychiatric disorders (Cole, 1992; Damas-Mora et al., 1982; Holroyd & Rabins, 1996; Hosty, 1990; Rosenbaum et al., 1987; Schultz & Melzack, 1991; Teunisse et al., 2000). The visual hallucinations share characteristics that may differentiate them from other disorders. First, there are no other hallucinations of other modalities, i.e. the visual hallucinations are silent (Holroyd et al., 1992; 1994; Lance, 1976; Merabet et al., 2004; Rosenbaum et al., 1987; Teunisse et al., 2000; Weinberger & Grant, 1940). Visual hallucinations may start as geometric patterns (brick grid or spider web) and develop into more complex figures such as animals or people. (Damas-Mora et al., 1982; Gold & Rabins, 1989; Holroyd et al., 1992; 1994; Lance, 1976; Roth & Cooper, 1992, p. 35; Schultz & Melzack, 1991). They typically present in the area of visual loss (Kolmel, 1985; Lance, 1976); however, hallucinations can occur in areas without documented visual impairment (Holroyd et al., 1992; Lance, 1976). Visual hallucinations usually begin suddenly, often with a change in vision (see Course and Progression). They are usually short in duration
seconds to minutes, although a minority report hours to days (Holroyd et al., 1992; Roth & Cooper, 1992, p. 35; Schultz & Melzack, 1991). Hallucinations occur more commonly in poorly lit areas or at night-time (Holroyd et al., 1992; Rosenbaum et al., 1987; Roth & Cooper, 1992, p. 35). Content of the hallucination may be familiar or unfamiliar to the patient (Holroyd et al., 1992; Teunisse et al., 2000). Interestingly, patients may be able to modify the hallucinations by closing or moving eyes, or attempting to touch the hallucination (Holroyd et al., 1992; Kolmel, 1985; Rosenbaum et al., 1987; Roth & Cooper, 1992, p. 35; Schultz & Melzack, 1991). Sensory impairment with tactile hallucinations

Phantom sensations or pain may occur with any body part including surgical removal of breast, rectum, penis, testicles, eye, tongue, or teeth (Flor, 2002). Nonpainful phantom sensations include changes in position or shape of the phantom part, other movement of the phantom, feelings of warmth or cold, electric sensations, tingling, numbness, ‘‘feels asleep,’’ itchiness or tickling (Flor, 2002; Wilkins et al., 1998). In children, tingling was reported in 60%, numbness 52%, itchy 40%, ‘‘feels asleep’’ 40%, and tickling 32% (Wilkins et al., 1998). The most common position in upper limb amputees is fist clenched (50%) and in lower limb amputees, toes flexed (47%) (Wilkins et al., 1998). The phantom is reported as shorter (36%) or same length (60%) than the corresponding limb (Wilkins et al., 1998). Telescoping, where the phantom limb

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recedes and may disappear in the residual, is associated with other sensations and pain (Flor, 2002; Gru¨sser et al., 2001; Montoya et al., 1997). Sensations may last from seconds to minutes in 76%, hours in 12%, and days in 12% (Flor, 2002; Wilkins et al., 1998). Triggers include anxiety, anything approaching the stump area, not wearing a prosthesis, or physical illness (Wilkins et al., 1998). Phantom pain is most intense distally (Flor, 2002). Pain is triggered with sensations of the phantom moving, temperature or weather changes, touching the residual limb, or exercise (Flor, 2002; Wilkins et al., 1998). Pain can be throbbing, pins and needles, burning, cramping, tingling, or stabbing (Flor, 2002; Sherman, 1994; Wilkins et al., 1998). Pain usually begins within days of the amputation (Flor, 2002; Grouios, 1999; Jensen et al., 1983; 1985), but a study of adolescents revealed the phantom pain began immediately in 35.5%, days 17.6%, weeks 5.8%, months 23.5%, and years 5.8% (Wilkins et al., 1998). Interestingly, there are individuals with congenital missing limbs who also report phantom sensations and pain (Brugger et al., 2000; Poeck, 1964; Saadah & Melzack, 1994; Sohn, 1914; Weinstein, Sersen, & Vetter, 1964; Wilkins et al., 1998). However, triggers for these individuals include positive feelings such as feeling happy or cheerful (Wilkins et al., 1998). Auditory impairment with auditory hallucinations or paranoia

Musical hallucinations are reported in hearing loss (Murata, Naritomi, & Sawada, 1994; Ross et al., 1975; Wengel et al., 1989), although one report noted voices in addition to the music (Hammeke et al., 1983). The music may be singing or instrumental, usually familiar to the patient and not threatening (Roth & Cooper, 1992, p. 36). Less commonly reported is unformed hallucinations including tinnitus or irregular sounds of pitch or tone (Hammeke et al., 1983). Unlike visual hallucinations or phantom sensation, musical hallucinations are continuous, not episodic or intermittent (Roth & Cooper, p. 36) and appear in the setting of chronic and progressive deafness (Hammeke et al., 1983). Patients frequently report worsening hallucinations when ambient noise levels are low or when they are mentally nonactive (Hammeke et al., 1989). No study has examined the specific presenting symptoms of paranoia in association with hearing loss. Course and progression Visual hallucinations

Visual hallucinations occurred within hours to days of visual loss due to hemianopia and disappeared when the hemianopia resolved (Kolmel, 1985).

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A series of 66 patients revealed visual hallucinations began within one year of becoming blind (Fitzgerald, 1971). In macular degeneration, 84.6% had onset of hallucinations with an acute change in vision (Holroyd et al., 1992). A three-year follow-up of macular degeneration patients revealed 60% experienced cessation of hallucinations within 18 months (Holroyd & Rabins, 1996). Some reported a gradual decrease, while others reported cessation following laser treatment to the eye (Holroyd & Rabins, 1996). Other reports reveal the hallucinations resolve spontaneously in some (Alroe & McIntyre, 1983; Rosenbaum et al., 1987) or resolve secondary to treatment of the visual loss (cataract surgery) (Rosenbaum et al., 1987). In Alzheimer’s disease, visual hallucinations decrease as the patient passes into advanced stages of the disorder (Drevets & Rubin, 1989; Reisberg et al., 1982; 1988). Sensory impairment with tactile hallucinations

Phantom sensations and pain may improve over time (Jensen et al., 1983; 1985) or become chronic (Flor, 2002; Teunisse et al., 2000). However, no long-term follow-up studies have been reported. Auditory impairment with auditory hallucinations or paranoia

One report of a man who experienced sudden right-sided hearing loss due to hemorrhage, with ipsilateral musical hallucinations, had cessation of the hallucinations when the hearing returned two weeks later (Murata et al., 1994). In three cases, the hallucinations were chronic (Hammeke et al., 1983; Ross, 1978). Suspected neuropathology Visual hallucinations

Sensory deprivation is the presumed major factor in the development of visual hallucinations in those with visual impairment; however, the proposed mechanism must account for the fact that not all individuals with visual impairment develop visual hallucinations. Visual hallucinations are associated with disorders at every level of the visual system, from retina to occipital lobe, suggesting that there may be a final common pathway that leads to visual hallucinations (Holroyd, 2002). It has been proposed that sensory deprivation causes decreased input to cortical and subcortical areas, allowing previous visual perceptions into consciousness as ‘‘release hallucinations’’ (Asaad & Shapiro, 1986; Manford & Andermann, 1998; Merabet et al., 2004; Poeck, 1964; Schultz & Melzack, 1991; Zuckerman & Cohen, 1984). The thalamus has been proposed

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as another site of origination of visual hallucinations, theorizing the thalamus generates visual hallucinations in a feedback circuit to the visual cortex when it is not receiving visual input, causing idealized or ‘‘hyper-realistic’’ hallucinations (Pelaez, 2000). An additional hypothesis is that an irritative lesion sends abnormal input to visual processing areas, which are then misinterpreted as visual hallucinations (Holroyd & Rabins, 1996; Holroyd et al., 1992). This theory is consistent with macular degeneration patients who reported immediate cessation of visual hallucinations after laser treatment to the eye but without improvement of vision (Holroyd & Rabins, 1996), suggesting that afferent neurons can be involved in hallucinations. Retinal afferent neurons are hypothesized as damaged due to retinal hemorrhage and send abnormal signals, subsequently misinterpreted by the visual cortex as hallucinations. The laser surgery would have silenced these damaged neurons, ending the visual hallucinations (Holroyd & Rabins, 1996). Both a sensory deprivation or an irritative lesion hypothesis could occur in different eye disorders. It is also possible that both mechanisms could occur in the same patient (hemorrhage causing both deprivation and irritative lesions). It has been suggested in deafferation studies that the bursts of slow waves observed in the visual cortex and lateral geniculate nucleus represent release phenomena (Goodman, 1982). An fMRI study demonstrated activation of ventral extrastriate cortex in patients with visual impairment and visual hallucinations (Ffytche, Howard, & Brammer, 1998). Specific types of hallucinations were associated with specific regions of cortex. For example, hallucinations of faces were associated with increased activity in the cortex involved in facial recognition. The authors concluded that each visual cortical area has its own associated visual hallucination and that the pathophysiology of visual hallucinations was a localized increase in cerebral activity in those areas (Ffytche et al., 1998). A follow-up study, based on the theory that pathological increases in activity in one brain region may spread to neighboring regions, examined patients with visual hallucinations and visual impairment using fMRI and demonstrated that there were three segregated clusters of hallucinations that were felt due to interconnections of specific visual regions (Santhouse, Howard, & Ffytche, 2000). In patients with dementia, it has been observed that not all dementing illnesses have similar prevalence of visual hallucinations (Holroyd, 2002). For example, Huntington’s disease, a subcortical dementia, rarely produces visual hallucinations while Parkinson’s disease, another subcortical dementia, almost exclusively causes visual hallucinations when hallucinations are present (Holroyd, 2002; Holroyd et al., 2001). In Alzheimer’s disease, it is noted that

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visual hallucinations do not occur evenly throughout the disease, but are stage-specific phenomena, with the majority of hallucinations occurring in the middle stages of the disease (Berg, 1982; Drevets & Rubin, 1989; Hughes et al., 1984). This suggests that a certain amount of cortical degeneration is required for visual hallucinations to occur, but that severe degeneration can no longer ‘‘support’’ these symptoms (Holroyd, 1998). Similarly, greater brain pathology has been noted in Alzheimer patients with visual hallucinations than without visual hallucinations. A single photon emission study revealed greater hypoperfusion in bilateral parietal lobes in patients with visual hallucinations (Kotrla et al., 1995). A neuropathological study revealed Alzheimer patients with psychosis had more plaques and tangles in the prosubiculum and middle frontal cortex (Zubenko et al., 1991). A pilot study of Parkinson’s disease patients with visual hallucinations revealed that those with visual hallucinations had increased activation in the visual association cortex compared to those without visual hallucinations (Holroyd & Wooten, 2002). A model has been proposed for visual hallucinations in dementing or neurodegenerative disorders (Holroyd, 2002) that accounts for the differences in prevalence of visual hallucinations in different disorders and the stage specificity of hallucinations. Visual hallucinations are produced as increased activity in the visual association cortex. As the dementia progresses, neuronal networks that normally suppress or modulate visual association activity may become damaged or work in an abnormal way. This deafferation mimics sensory deprivation and allows release hallucinations into consciousness. This model can be expanded to visual hallucinations with visual impairment in non-dementia patients in that risk factors noted to be associated with visual hallucinations such as history of stroke or decreased cognition may be evidence of damaged or sub-optimally performing neuronal networks that are no longer able to suppress or modulate visual association cortex activity. Clearly, however, further research is needed to refine and test this model. Sensory impairment with tactile hallucinations

Peripheral, spinal, and central nervous system mechanisms have been studied (Flor, 2002; Florence & Kaas, 1995; Hill, 1999). Melzack proposed the ‘‘neuromatrix’’ where various brain regions form the anatomical substrate of the self, including the reticular formation, somatosensory cortex, thalamus, limbic system, and posterior parietal cortex (Melzack, 1990). Accordingly, amputation causes a lack of normal sensory input, or over-activity of damaged nerves, leading to the experience of a phantom. This theory is similar to the release hallucination and irritative lesion hypothesis considered with visual hallucinations.

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Another theory is cortical reassignment, where cortex adjacent to areas involved in the amputated limb make changes in their functional assignments. For example, owl monkeys have shown changes of primary somatosensory cortex, where cortex adjacent to cortex corresponding to the amputated digits became involved or ‘‘invade’’ the area corresponding to the amputated digits (Merzenich et al., 1984). Studies of humans with arm/hand amputations may have the phantom elicited by stimulating the ipsilateral face areas, consistent with the theory that the somatosensory cortex has reorganized (Ramachandran, Rogers-Ramachandran, & Stewart, 1992). Similarly, imaging studies show that humans with arm/hand amputation demonstrate a shift of the mouth into the hand representation of the primary somatosensory cortex (Birbaumer et al., 1997; Flor et al., 1995; Ramachandran et al., 1992). Interestingly, the larger the shift of the mouth representation into the area of the amputated limb, the greater the phantom pain (Flor et al., 1995). Similarly, lip movements have led to activation of the cortical area involved with the area of the hand/arm amputation, causing phantom pain (Chen et al., 1998). An interesting study showed reversal of these cortical changes (and pain) by eliminating peripheral input from the amputation stump by brachial plexus anesthesia in three of six amputees. The other three had no changes in reorganization or pain, demonstrating that for some but not all, peripheral input may maintain cortical reorganization and phantom pain (Birbaumer et al., 1997). A study presenting visual stimuli to amputees with phantom pain, amputees without phantom pain, and normals, demonstrated EMG responses were larger in patients with phantom pain on the ipsilateral side (Larbig et al., 1996) and visual evoked potentials demonstrated late positivity. The data suggest that both peripheral and central processes are altered in phantom pain. In addition to the cortex, reorganization has been noted in the thalamus and is associated with phantom perceptions (Florence, Taub, & Kaas, 1998). Controversy exists whether these changes are relayed from spinal regions or from the cortex (Ergenzinger et al., 1998; Florence & Kaas, 1995). Proposed spinal mechanisms involve increased activity of peripheral nociceptors, causing increased excitability of dorsal horn neurons by reduction of inhibitory signals (Doubell, Mannion, & Woolf, 1999). Peripheral nerve injury may cause degeneration of C-fibre nerve terminals in lamina II of the spinal cord, causing abnormal sprouting of A-fibre terminals that give input misinterpreted as pain (Woolf, Shortland, & Coggeshell, 1992). It is hypothesized that other abnormal sproutings and reorganization of representation of the amputated area also occur in the spinal cord (Cook et al., 1987; Flor, 2002). Ectopic signals from continued stump pain have been proposed (Flor, 2002; Wall & Gutnick, 1974). However, since local anesthesia of the stump

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does not eliminate phantom pain (Birbaumer et al., 1997), it is felt that peripheral factors cannot be the sole or primary factor in phantom pain (Flor, 2002). Auditory impairment with auditory hallucinations or paranoia

A study of tinnitus found cortical reorganization of the auditory cortex, suggesting that tinnitus may be an ‘‘auditory phantom phenomenon’’ and may involve similar mechanisms to those in phantom limb pain (Muhlnickel et al., 1998). Most suggest that the hallucinations are a combination of sensory deprivation or decreased afferent activity, causing ‘‘release’’ hallucinations (Hammeke et al., 1983). No specific neuropathology has been suggested for paranoia in hearing impairment. Suspected neurochemical abnormalities Visual hallucinations

None known. Sensory impairment with tactile hallucinations

Changes of sympathetic activity have been postulated (Katz, 1992a; 1992b) but research on the role of the sympathetic system in phantom pain is scarce (Flor, 2002). Although cases reducing phantom pain using beta adrenergic blockers or surgery blocking sympathetic activation have been reported, there were no controls (Flor, 2002). Interestingly, epinephrine injections have caused increased phantom pain in some (Torebjo¨rk et al., 1995). Glutamate has been proposed as involved in phantom pain (Sandku¨hler, 2000). Also proposed is a reduction of GABAergic activity in the spinal chord with a downregulation of opioid receptors, possibly due to the inhibitory effects of cholecystikinin which is upregulated in injured tissue (Woolf & Mannion, 1999). Auditory impairment with auditory hallucinations or paranoia

None known. Genetic factors Visual hallucinations

Although no genetic factors are known, it is interesting that both the grandfather of Charles Bonnet and Charles Bonnet himself suffered from visual hallucinations associated with eye disease (Damas-Mora et al., 1982; Hosty, 1990).

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Sensory impairment with tactile hallucinations

Genes on chromosome 15 have been suggested in an animal model for phantom pain in rats (Seltzer et al., 2001). A case report of a family of amputees with phantom symptoms suggested a genetic component (Schott, 1986). Auditory impairment with auditory hallucinations or paranoia

None known. Other risk factors Visual hallucinations

Sensory deprivation is the postulated risk factor for development of visual hallucinations in those with visual impairment. However, because not everyone with visual loss experiences hallucinations, there must be other predisposing factors. Sudden loss of vision may be an important factor as 84.5% of macular degeneration patients reported onset of hallucinations following a sudden worsening of vision (Holroyd et al., 1992). Other risk factors in macular degeneration patients include bilateral versus unilateral worse acuity, lower cognitive score, living alone, and history of stroke. Personal or family history of psychiatric illness was not associated with hallucinations (Holroyd et al., 1992; Zuckerman & Cohen, 1984). In patients with various visual disorders but predominantly macular degeneration, female gender, living alone, hearing problems, older age, and lower cognition were associated with visual hallucinations (Holroyd et al., 1994). In Alzheimer’s disease, age, visual acuity, and visual agnosia correctly classified 91% of patients as hallucinators vs. non-hallucinators (Holroyd & Sheldon-Keller, 1995). Visual hallucinations in Parkinson’s disease are associated with lower visual acuity, lower cognitive score, depression, and disease severity, but not psychiatric history, dose, or duration of antiparkinson medication (Barnes & David, 2001; Goetz et al., 2001; Holroyd et al., 2001). Sensory impairment with tactile hallucinations

Factors associated with the development of phantom sensations/pain include current stump pain, pain prior to amputation, traumatic amputation (vs. planned amputation), bilateral amputation, and lower limb amputation (Dijkstra et al., 2002; Flor, 2002). Depression has been postulated (Jensen et al., 2002), although in a group of amputees who were not specifically seeking help for their pain, depression only accounted for 4% of the variance in the presence of limb pain (Whyte & Niven, 2001). This suggests that depression is associated with seeking

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help for pain, rather than associated with the pain itself. Others have noted that psychological factors do not appear to be risk factors for phantom sensations or pain, but may affect the course and severity (Flor, 2002; Hill, 1999; Sherman, Sherman, & Bruno, 1987). Auditory impairment with auditory hallucinations or paranoia

Because most individuals do not develop hallucinations in the setting of hearing loss, risk factors other than auditory impairment must exist. Brain pathology has been postulated (Hammeke et al., 1983; Miller & Crosby, 1979; Ross et al., 1975). Treatment Visual hallucinations

Because visual hallucinations are often not distressing, simple reassurance to the patient that they are not ‘‘going crazy’’ is all that is needed for many patients (Holroyd et al., 1994; Menon et al., 2003; Teunisse et al., 2000). Patients tend to accept the explanation that the ‘‘visions’’ have to do with their visual problem (Fernandez, Lichtshein, & Vieweg, 1997; Holroyd et al., 1994; Menon et al., 2003; Teunisse et al., 2000). Decrease in the frequency of visual hallucinations in three Alzheimer’s disease patients occurred when optical aids were used, theoretically reducing visual sensory impairment (Needham & Taylor, 1992). Similarly, visual hallucinations are noted to have ended upon treatment of eye disorders such as laser surgery in macular degeneration (Holroyd & Rabins, 1996; Holroyd et al., 1994) or cataract surgery (Levine, 1980; Olbrich, Lodemann, & Engelmeier, 1987; Rosenbaum et al., 1987). Antipsychotics have not been reported as helpful (Holroyd & Rabins, 1996; Hosty, 1990; Paulig & Mentrup, 2001), nor have drugs such as benzodiazepines or antidepressants (Holroyd & Rabins, 1996; Hosty, 1990; Paulig & Mentrup, 2001). Successful case reports exist for anticonvulsant drugs, including neurontin (Paulig & Mentrup, 2001), carbamazepine, and valproate acid (Batra, Bartels, & Wormstall, 1997; Hori et al., 2000; Menon et al., 2003), with the theoretical mechanism of decreasing abnormal neuronal excitement (Paulig & Mentrup, 2001). Sensory impairment with tactile hallucinations

Treatments including local anesthesia, and surgery including cordotomy, rhizotomy, and sympathectomy have been shown to improve pain symptoms

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in about 30%, which is no better than a placebo (Fainsinger, de Gara, & Perez, 2000; Flor, 2002). Controlled studies exist for opioids, ketamine, and calcitonin, improving phantom pain compared to a placebo (Huse et al., 2001; Jaeger & Maier, 1992; Nikolajsen et al., 1996). Use of a transcutaneous nerve stimulation (TENS) unit improved pain in one controlled study (Katz & Melzack, 1991). Although antidepressants and anticonvulsants are used, no controlled study has been done of their efficacy (Flor, 2002; Sindrup & Jensen, 1999). Prevention of phantom limb phenomena using pre-emptive analgesia, both peripheral and central, has not been successful in controlled studies, despite case reporting success (Flor, 2002; Nikolajsen et al., 1997; Sherman, Sherman, & Gall, 1980). A study using memantine, a NMDA receptor antagonist, compared to a placebo, added to brachial plexus anesthesia in patients undergoing amputation of fingers or hand, revealed significant reduction in the development of phantom sensations/pain one year from surgery (Wiech et al., 2001). The theory is that NMDA antagonists prevent cortical reorganization (Flor, 2002; Wiech et al., 2001). Finally, patients report reassurance and education from physicians, nurses, and peer supports are important in the treatment (Mortimer et al., 2002). Auditory impairment with auditory hallucinations or paranoia

Antipsychotics were not successful in treating musical hallucinations in a case (Wengel et al., 1989). Improvement of hearing in two patients resulted in elimination of musical hallucinations (Murata et al., 1994). Although paranoia associated with hearing loss is presumably treated with antipsychotic drugs, there are no publications specific for paranoia associated with hearing loss. Improving the hearing is recommended, but no evidence exists that such treatment improves paranoid symptoms (Roth & Cooper, 1992, p. 33). REFERENCES Alroe, C. J. & McIntyre, J. N. (1983). Visual hallucinations: The Charles Bonnet syndrome and bereavement. The Medical Journal of Australia, 2, 674
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20.

Part IX

Conclusion

27

Conclusion Daryl E. Fujii1 and Iqbal Ahmed2 1 2

Hawaii State Hospital University of Hawaii

Introduction In this chapter we integrate the information on the spectrum of psychotic disorders. First, we summarize data from each of the nine sections. Second, we examine whether the collective data supports our neurobiological hypothesis of psychosis. Next, we utilize the collective data to update our conceptual framework for developing a psychosis. Fourth, implications for DSM-IV diagnostic criteria for psychosis are discussed. Fifth, we report limitations of the data as it relates to psychosis as a neurobiological syndrome. We conclude the chapter and the book by proposing future studies to further elucidate the phenomenon of psychosis. To promote clarity and avoid redundancy, material cited by chapter authors will not be referenced. Instead, readers are encouraged to refer to each chapter for specific citations.

Epidemiology The epidemiology of psychotic disorders associated with different etiologies is wide ranged, varying from less than 1% of the overall population for acute and transient psychosis, to up to 84% of patients with Lewy body dementia. Prevalence rates appear to be related to the type of disorder and its neurobiology, although variability exists within each group of disorders. The group with the smallest prevalence rate, around 1% of the general population, is comprised of ‘‘primary’’ psychotic disorders including schizophrenia, schizoaffective disorder (SAD), delusional disorder (DD), and brief psychotic disorder (BPD). Neurological disorders that are commonly associated with temporal lobe pathology or white matter lesions have estimated prevalence rates of psychosis ranging from 1
15%. Specific disorders in this group include traumatic brain injury (TBI) (1
9%) and epilepsy (6
10%), as well as subcortical white matter 535

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lesions such as cerebral vascular accident (CVA) (1
4%), multiple sclerosis (MS) (10%), human immunosuppressant virus (HIV) (3
15%), X-linked adrenoleukodystrophy (15%), and systemic lupus erythrematosus (SLE) (0
12%). Associated psychosis has also been observed in other neurological disorders, such as those resulting in infections and encephalitis as well as brain tumors. In the former, there are only a handful of case studies within the literature, thus prevalence rates are unknown, while the sparse literature on brain tumors report highly disparate rates of psychosis with one study reporting 2% and another indicating 50% prevalence. Pervasive developmental disorders (PDD) have generally been associated with a higher prevalence of secondary psychosis. Catatonia in autism has been reported in 17% of individuals with ‘‘high rates of atypical symptoms of psychosis or negative symptoms.’’ Although not a formal DSM-IV diagnosis, velo-cardio-facial syndrome (VCFS) is a disorder of childhood onset that is associated with learning and behavioral problems. Studies estimate that up to 30% of people with the disorder develop a psychosis by adulthood. About 3% of people with severe intellectual deficiencies (ID) meet criteria for schizophrenia, although this is probably a low estimate due to diagnostic difficulties particularly in the lower levels of mental retardation. Indeed, other estimates of psychosis not reported in our review chapter indicate lifetime prevalence rates for psychosis to range from 21
38% (Eaton & Menolascino, 1982; Philips & Williams, 1975). Abuse of substances increasing the availability of dopamine in the brain have also been associated with a high frequency of psychosis. It has been estimated that 15% of cannabis users experience psychotic symptoms during consumption, while the figures are higher for users of cocaine with estimates ranging from 44
48%. Methamphetamine, a substance that has been steadily rising in abuse in the United States, has also been known to cause a transient psychosis in 39% of long-term users, while 7% demonstrate a persistent psychosis for more than a month. Axis I psychiatric disorders are also associated with a relatively high prevalence rate of psychosis, although the ranges vary between specific disorders. For mood disorders, the prevalence rate for psychosis in bipolar affective disorder (BAD) ranges from 42
88%, whereas it is much lower for major depression (MD) with an estimate of 19%. Although not covered in our book, the literature also reports a wide range of prevalence rates for psychosis associated with certain anxiety disorders that is generally lower than for mood disorders. For example, comorbid psychosis in post traumatic stress disorders has been described in 20
40% of combat veterans (for a review see Seedat, Stein, Oosthuizen, Emsley, & Stein, 2003), whereas the occurrence rate is much lower in obsessive compulsive disorder (5
9%) (Eisen & Rasmussen, 1993; Wilner et al., 1976).

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Conclusion

The disorders that are associated with the highest prevalence of psychotic symptoms are the dementias. It is estimated that 16
50% of individuals with Parkinson’s disease (PD), 53% of those with metachromatic leukodystrophy (MLD), 40
60% of those with dementia of the Alzheimer’s type (DAT), and 42
84% of those suffering from Lewy body dementia (LBD) demonstrate psychotic symptoms. Hallucinations in people with sensory loss are qualitatively different from the symptoms in the aforementioned disorders, as they are purer sensory experiences, nonthreatening in nature, and are not associated with a thought disorder. Prevalence rates are wide-ranging but relatively high. Psychosis has been estimated to occur in 11
20% of people with visual loss, 50
80% in people with loss of a limb, and 46% of those with hearing loss. Finally, psychosis secondary to prescription medications also demonstrate considerable variability from about 1% for retinoids to 20
30% for antiParkinson’s medications. Other medications with relatively high prevalence rates of psychosis include antidepressants that increase dopamine (8.1%), disulfram (11
18%), and steroids, although figures for the latter have not been reported. The categories of neurological disorders and associated prevalence rates would indicate that for ‘‘secondary psychotic disorders,’’ prevalence appears to be related to degree of neuropathology, as the lowest rates are demonstrated in neurological disorders that are associated with less dysfunctional behaviors or more circumscribed cortical or subcortical lesions, while the highest rates are found in disorders that result in more profound functional impairment or more widespread involvement of frontal and temporal regions, or the underlying white matter connections such as pervasive developmental disorders and dementias. In addition, it is believed that intracategorical differences in prevalence rates can also be heavily attributed to differences in the severity of pathology. Age of onset Data from the secondary psychotic disorders indicate that psychosis can occur at virtually any age. The onset of psychosis for a specific etiology is strongly related to the general occurrence of the disorder in the lifespan. For example, psychosis associated with the dementias or visual and auditory sensory loss primarily occurs in senescence. The onset of more persistent psychosis in substance abuse generally occurs after years of heavy use. Whereas in disorders such as MD or loss of a limb, that can occur throughout the lifespan, associated psychosis is not commonly associated with a specific age.

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Although psychosis can occur in childhood, the frequency of occurrence is low, as the onset of psychosis for most childhood disorders generally occur post puberty. For example, in autistic children, although some catatonic symptoms can occur before age ten, chronic symptoms generally occur after puberty. In both VCFS and childhood-onset epilepsy, psychosis does not typically develop until adolescence or early adulthood. In mentally retarded children who develop a psychosis, 33% experience the onset from the ages of 11
20, while in 54% the onset is between the ages of 20
30 (Eaton, 1982). Similarly in childhood schizophrenia, an onset of symptoms before age 13 is reported to be ‘‘very rare.’’ Although somewhat controversial, the exception in early childhood psychosis appears to be mood-related psychosis such as grandiosity. In one study not reported in the book, the mean onset of BAD was 7.4 þ/
3.5 years, and 51% demonstrated grandiose delusions (Geller et al., 2004). Course and progression The course of psychosis secondary to different etiologies is highly variable. Psychotic symptoms can be short term as in delusions associated with CVA, cannabis, or cocaine; episodic as in MS, SLE, or BAD; or chronic as in mental retardation, DAT, LBD, or DD. The course of psychosis can also vary within etiology, as although the majority of medical and substance related etiologies are associated with transient psychotic symptoms, chronic psychosis can develop in a minority of individuals. It is believed that course of illness is related to the mode and severity of neuropathology. For most etiologies there is a latency between the onset of illness and onset of psychosis, particularly if the psychosis is chronic. For example, in TBI the mean latency before the onset of psychosis is 4
5 years, whereas for epilepsy and syphilis the latency is around 10
14 or 15 years. Even when psychosis is secondary to childhood disorders such as autism or mental retardation, the onset of symptoms is generally in adolescence or adulthood. The latency between the onset of illness and psychotic symptoms would suggest that changes in brain structures, connections, or neurochemistry that underlie psychosis occur gradually in these neurological conditions. As speculated in schizophrenic illness, it is possible that changes may be associated with normal development such as neuronal pruning in adolescence (Feinberg, 1983), or myelination of frontal areas (Benes, 1989). In cases of rapid-onset psychosis, it is assumed that neuropathological or neurochemical changes are more immediate. Etiologies associated with rapid onset psychosis include CVA, untreated infections due to lyme disease (LD)

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or malaria, sensory losses, or medication-induced psychosis. In cases of medication-induced psychosis and psychosis due to infections, psychotic symptoms are probably associated with a delirium. Interestingly, in general, the course in most rapid-onset psychotic disorders is relatively short with treatment of the illness or treatment with antipsychotics. This pattern is also seen in schizophrenia spectrum disorder, for example, in BPD the onset and duration of illness is very quick, whereas in DD, acute onset is associated with an earlier onset and better prognosis for recovery. In addition, there is some evidence that the more severe courses of schizophrenia are associated with a more insidious onset (Sartorius et al., 1986). Episodic courses of psychosis are generally associated with disorders characterized by intermittent remissions of illness such as MS, SLE, and HIV. For reasons unknown, it should be mentioned that other disorders associated with white matter pathology such as BAD and late life MD with psychotic features also demonstrate an episodic course. Similarly, abstinence from substances that increase the availability of dopamine will usually result in a dissipation of psychotic symptoms as the drug is eliminated from the brain. In general, disorders associated with chronic courses of psychosis tend to have more severe widespread neuropathology such as the dementias and PDD. Again, this pattern is also demonstrated in schizophrenia. Studies have reported greater neuropathology in schizophrenic patients with a more chronic and a progressively declining course (Davis et al., 1998). Similarly, the presence of psychosis appears to be associated with a more virulent form of a particular illness. For example, in people with DAT, those who also demonstrate a psychosis are reported to demonstrate a more rapid deterioration. In HIV, psychosis is associated with increased mortality. People who develop psychosis secondary to epilepsy generally tend to experience more severe and frequent seizures. In individuals with MD, psychosis is associated with a quicker relapse, while for individuals with BAD, psychotic symptoms are associated with higher relapse rates, poorer social functioning, and longer duration of episodes. Symptoms

The most common psychotic symptom is delusions that occurred in 100% of the neurological disorders that have been reviewed and reported specific symptoms with the exception of sensory impairments. The most common delusion was persecutory. The data on delusions support three findings in the neuropsychiatric literature. First, Schneiderian symptoms, such as ideas of reference, which were once hypothesized to be a clinical marker for schizophrenia,

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are not exclusive to that disorder, as these symptoms can also be present with psychosis associated with cannabis, HIV, ATP, and BAD. Second, delusions of misidentification are associated with frontal and right posterior parietal hemispheric abnormalities (Joseph, 1986). Examples include DAT (deficits in verbal and design fluency and visuospatial processing), tumors (frontal/parietal/ occipital), and CVA (right hemisphere). Third, delusional content is a function of cerebral integrity as delusions in people with more widespread neuropathology such as dementia and mental retardation appear to be more simplistic in nature (Cummings, 1985). Auditory hallucinations are the most common form of hallucination that also occurred in 100% of psychotic etiologies, followed by visual and tactile hallucinations. Auditory hallucinations have been associated with activation in the temporal areas, anterior cingulate, and inferior frontal/insular (Shergill et al., 2000). Temporal pathology has been reported in only 11 of the 22 disorders that are associated with auditory hallucinations (50%), although in four disorders neuropathological data was not available. This less than perfect correspondence would suggest that pathological processes other than temporal abnormalities may be present in auditory hallucinations. Visual hallucinations are the second most common hallucination across the spectrum of psychotic disorders and are particularly common in secondary psychotic disorders such as PD, LBD, DAT, tumors, LD, herpes, meningitis, sensory impairments, and anti-Parkinsonian medications. Cummings and Mega (2004) have proposed several potential mechanisms that can cause visual hallucinations, including anticholinergics toxicity (PD, LBD, DAT), disorders of the mid-brain, particularly the substantia nigra (LBD, PD, compressions from tumors), occipital abnormalities (LBD), delirium (herpes, LD, meningitis), and reduction of visual input (sensory abnormalities). Tactile hallucinations have been associated with drugs such as methamphetamine and cocaine psychosis, as well as in phantom limb pain from amputation. Formal thought disorder is less common or severe in psychotic disorders of other etiologies in comparison to schizophrenia. The exception is in psychosis associated with ID in which thought disorder is more common. Other etiologies associated with thought disorders include autism, TBI, HIV, cannabis, cocaine, LBD, and antidepressants. Negative symptoms such as flat affect, alogia, and amotivation, are also absent or attenuated in non-schizophrenic psychotic disorders, for example, DD, TBI, epilepsy, MD, and tumors. The lower prevalence and severity of negative symptoms in non-schizophrenic psychosis may suggest that this symptom may be associated with a more severe form of psychosis or relatively independent of positive psychotic symptoms. In schizophrenic illness, negative symptoms

541

Conclusion

are associated with increased chronicity and poorer prognosis (Fenton & McGlashan, 1991). Similarly, the only group in which negative symptoms, and possibly related catatonia, are more common in psychosis are associated with PDD such as autism and mental retardation, as well as MLD, the latter a progressive and particularly virulent form of demyelinating diseases. Dementias such as DAT, PD, and LBD may also present with apathy, which is phenomenologically similar to negative symptoms. Apathy and negative symptoms all may be a manifestation of underlying frontal subcortical dysfunction involving the dopamine pathways. Another common symptom of the spectrum of psychotic disorders is neurocognitive deficits. Although not all etiologies reported specific cognitive deficits, for example, autism, MLD, and MR are associated with global deficits, of the disorders in which specific cognitive domains were described, the most frequent impairments were found in executive functioning and memory. Memory impairments were reported in psychosis secondary to dementia (by definition), cocaine, MS, syphilis, herpes, epilepsy, TBI, VCFS, MD, BAD, HIV, PD, ID, methamphetamine, cannabis, and fungal infections. Deficits in executive functioning were reported in dementia, cocaine, MLD, TBI, MD, and MS. Impairments in memory and executive functioning are two of the most common neurocognitive problems associated with schizophrenia. Interestingly, people with DD demonstrate few cognitive deficits, however, their neurocognitive profile is also similar to schizophrenia.

Suspected neuropathology Imaging studies on the spectrum of psychotic disorders commonly report lesions in frontal and temporal lobes as well as white matter located in these areas. Frontal lobe and white matter lesions have been found in the following disorders: DAT, PD, LBD, MLD, epilepsy, CVA, tumors, syphilis, SLE, TBI, LD, and MD. Temporal lesions have been reported in DAT, LBD, PD, SLE, MS, tumors, TBI, and epilepsy, while VCFS, schizophrenia, and BAD has been associated with abnormalities in frontal and temporal connections. Similarly, functional imaging studies of people with psychosis have reported lower frontal hyperperfusion in cannabis, cocaine, and methamphetamine use, frontal hyperperfusion in PD, while those with DD have reported hypoperfusion in temporal-parietal areas. Although not specific to frontal and temporal lobes, other studies have reported more global atrophy such as in psychotic disorders secondary to herpes simplex (necrosis), HIV, and ATP. Psychosis has also been associated with cerebellar lesions in schizophrenia,

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Daryl E. Fujii and Iqbal Ahmed

and psychosis secondary to autism and mental retardation, whereas delusions of misidentification are commonly associated with right posterior lesions in people with CVA. Suspected neurochemical abnormalities The neurotransmitter system that appears most consistently involved in psychosis is the dopamine system. This is particularly notable in schizophrenia, and mood disorders associated with psychosis, as well as in some of the neurological disorders such as DAT, LBD and epilepsy, genetic disorders such as VCFS, or with substances or medications such as cocaine, methamphetamine, cannabis, and antiparkinsonian agents. The mechanisms for overactivity may involve abnormalities in dopamine receptors, altered breakdown by enzymes such as COMT, and increased release. In addition, dopamine activity may also be increased through the activity of other neurotransmitters such as decreased GABA or acetylcholine activity, or increased glutamate activity (Kalkman & Loetscher, 2003). Of course, effectiveness of antipsychotics in treating psychotic symptoms provides indirect evidence of increased dopaminergic activity in psychosis secondary to a number of other disorders. Dopamine involvement in secondary psychotic disorders is consistent with findings in primary psychotic disorders. Still, dopaminergic mechanisms have not been solely implicated in schizophrenia. Neuroactive steroids (NAS) have been implicated in schizophrenia, both in the pathogenesis, and also possibly from a therapeutic standpoint (Shulman, 2005). Alterations in electrolytes, endogenous opioids, prostaglandins, and lipoproteins have also been implicated in explanation of drug-induced psychosis such as in psychosis due to ACE inhibitors, non-steroidal antiinflammatories, and retinoids. These mechanisms may still involve effects on dopamine. Genetic factors While genetic risk in the development of the primary psychotic disorders such as schizophrenia has been described, there is little data on genetic risk in the development of secondary psychosis with the different disorders, even though there is data supporting genetic risk in the development of the particular disorders themselves. The exception may be VCFS, where the 22q11.2 locus may contribute to schizophrenia-like psychosis susceptibility in VCFS. The COMT gene polymorphism Val108/158Met has been linked to risk

543

Conclusion

for the psychotic symptoms. This type of polymorphism may indeed be involved in the development of psychosis in schizophrenia and in psychosis secondary to use of substances such as cannabis. For DAT with psychosis, the C102T polymorphism has been reported with the HTR2A gene. Most recently, and most convincingly, genes have been identified in which variation appears to confer risk for schizophrenia, schizoaffective and bipolar disorder such as the gene encoding D-amino acid oxidase activator on chromosome 13q, one of the regions implicated in genome scans of both disorders (Craddock, O’Donovan, & Owen, 2005). Another example is the gene Disrupted in Schizophrenia 1 (DISC1). It is quite likely that psychosis is a syndrome which probably has polygenic contribution much like schizophrenia. Current genetic findings suggest that rather than classifying psychosis as a dichotomy, a more useful formulation may be to conceptualize a spectrum of clinical phenotype with susceptibility conferred by overlapping sets of genes. Other risk factors While a number of other risk factors such as gestational, perinatal factors have been implicated in schizophrenia, only a handful of ‘‘secondary’’ psychotic disorders report other risk factors. For example, dementia may increase the risk of visual hallucinations in patients with decreased visual acuity. Premorbid psychiatric disorders, such as personality disorders, may be risk factors, particularly for substance-induced psychosis such as from cannabis. Other biological factors may also play a role in a number of the secondary psychoses, such as sensory impairment, prior neurodevelopmental problems, and organ system problems affecting drug disposition. At risk genes probably interact with other risk factors to lead to the development of psychosis in patients who experience environmental or biological stress from medical disorders or when the brain is injured secondary to trauma, tumors, infections, exogenous or endogenous toxins. Depending on the ‘‘dose’’ of at risk genes, the ‘‘dose’’ of the other risk factors could be low or high (this includes the total number of current and previous risk factors) to lead to the development of psychosis. Taken together, it appears that patients who develop secondary psychosis do not have a normal brain or psychological functioning or due genetic or acquired brain insults. This appears to interact with neurochemical alterations secondary to other factors such as medications or substances of abuse resulting in psychotic symptoms. This is very similar to the ‘‘two hit’’ hypothesis of schizophrenia.

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Treatment Treatments are driven by the conceptual framework we have described. The primary approach is to reduce the psychotic symptoms by altering dopaminergic functioning. However, since there are other factors and mechanisms which may contribute to the overall morbidity from these disorders, the treatment approach to the ‘‘secondary’’ psychotic disorders would include other approaches to symptomatic treatments
mood in bipolar disorder, antidepressants in psychotic depression and cholinesterase inhibitors in DAT. Other interventions include the use of ECT as in the case of psychotic depression and Parkinsonian psychosis. Non-pharmacologic treatment such as cognitive therapy may help with delusions. In addition, the primary etiology affecting the dopamine system or other mechanisms of psychosis such as the temporal and frontal systems, and sensory processing mechanisms have to be addressed. This etiologic approach would include removal of offending agents such as medication, abused substance, infective agent, or tumor as a critical intervention. In addition, specific treatments of underlying etio-pathogenic factors is necessary such as treating the infection, seizure disorder, or surgical, radiotherapy, or chemotherapy of brain tumors, etc. Where sensory impairments are present, such as visual impairment with visual hallucinations, vision correction with eye glasses, or removal of cataracts would be important. Conclusions Is psychosis a neurobiological syndrome?

An examination of the studies on the spectrum of psychotic disorders provides preliminary support for the hypothesis that psychosis is a neurobiological syndrome. We will describe individual criteria and cite support for each. 1. A constellation of symptoms is reliably associated with neuropathology in a circumscribed structural location or neural circuit. 2. Similar neurobiological disturbances (location or neural circuit) secondary to different etiologies would result in similar cognitive or behavioral symptoms. These criteria are supported by a modal constellation of symptoms characterized by auditory hallucinations and persecutory delusions. Neuropathologically, in essentially every etiology in which adequate information is provided, there is either evidence for structural or functional abnormalities in frontal systems, temporal areas, or the underlying dopaminergic

545

Conclusion

systems (FTD). In medications in which there is a relatively high rate of secondary psychotic symptoms (those reporting incidence rates similar to schizophrenia are not included), only disulfram and steroids do not directly affect dopamine. However, these two drugs, and other drugs such as anticholinergics causing delirium, may also affect dopamine indirectly. Although not present in every etiology of psychosis, the robustness of the data presented in this book would indicate that abnormalities to FTD systems are associated with psychosis. 3. Smaller amounts of similar neurobiologic disturbances are associated with milder symptoms. Evidence for this criterion comes from comparing etiologies within a given category. For example, among the primary psychotic disorder category, schizophrenia is associated with more severe symptoms and pronounced neuropathological findings as compared to disorders with more circumscribed or time limited symptoms such as DD or BPD. A similar comparison can be made among drugs affecting the dopaminergic system. Methamphetamine has a longer half-life and is associated with a higher level of neurotoxicity than cocaine and more severe symptoms, and is also more likely to result in a persistent psychosis. 4. Additional symptoms such as cognitive, mood, psychiatric, or other associated neurological symptoms are related to other networks simultaneously being affected by underlying neurochemical or neuropathologic processes. The primary support for this criterion comes from neurocognitive data. Of disorders that specify domains of cognitive deficits, impairments in executive functioning and memory are the most common. This pattern of deficits parallels modal findings of frontal and temporal pathology across the different etiologies of psychotic disorders. 5. Aside from treating the underlying disease process, treatment for the associated symptoms of a neurobiological disorder of different etiologies is similar. The most common pharmacological treatment for psychotic disorders of different etiologies is antipsychotic medications that typically target the dopamine system. Modified conceptual framework for psychosis

One implication of the data presented in this book is a modification of our conceptual framework for psychosis (Fujii & Ahmed, 2002). In addition to the data presented in this book, modifications are based heavily on ideas proposed by Weinberger (1986), Cummings and Mega (2005), and Kapur (2003).

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1. Psychosis is associated with imbalances in neurochemical systems, sensory systems, or structural changes that ultimately lead to overactivation of temporo-limbic and sensory areas of the brain with resultant disturbance in emotional experience, salience, and sensory phenomena along with underactivation of frontal subcortical monitoring, modulatory and memory context areas. Imbalances can occur through: a. structural lesions to frontal and temporal systems and the connectivity between the two systems. b. alterations to the dopamine system resulting in decreased dopaminergic projects to frontal areas and increased dopaminergic activity in the limbic and sensory systems. Alterations can occur: i. directly through drugs that increase or deplete dopamine; ii. indirectly through neurotransmitters, neurochemicals, or other mechanisms that can modulate the release of dopamine. c. external sensory input deprivation and with greater prominence of internally derived sensory neural area activation. This tenet indicates that imbalances in neural systems result in central cognitive processes which lead to psychosis. While the abnormality in dopamine function in the primary psychotic disorders may be due to increased dopamine function due to altered receptor mechanisms or increased overall levels of dopamine, or an imbalance between glutamate and GABA due to genetic factors, there may be other mechanisms for dysregulated dopamine function in the ‘‘secondary psychoses’’ such as: (a) increased dopaminergic activity from drugs such as antidopaminergic agents, and substances of abuse such as cannabis, cocaine, and methamphetamine; (b) an imbalance between DA and ACH as seen in anticholinergic psychosis, delirium, and dementias such as DAT, LBD, and PD; (c) focal damage to neurons producing GABA or glutamate, with secondary effects on dopamine in neurological disorders such as strokes, tumors, seizure disorders. The net effect from the different mechanisms involved is decreased dopaminergic activity in the frontal systems and increased dopaminergic activity in the limbic and sensory systems. The nature of the psychotic symptoms may be related to location of the dopamine overactivity, such as overactivity in the amygdala and nucleus accumbens leading to paranoid and grandiose delusions, and overactivity in the auditory or visual processing systems resulting in auditory and visual hallucinations. The nonneurochemical mechanism may involve a lack of input to the sensory systems of the brain, with resultant release of internally based sensory experiences, the so-called ‘‘release phenomena’’ leading to hallucinatory experiences.

547

Conclusion

In addition, structural damage to frontal systems would affect the selfmonitoring function of the brain reducing its ability to appreciate the ‘‘unreality’’ of the experience. It has been proposed that a central role of dopamine is to mediate the ‘‘salience’’ of environmental events and internal representations. It is proposed that a dysregulated, hyperdopaminergic state, at a ‘‘brain’’ level of description and analysis, leads to an aberrant assignment of salience to the elements of one’s experience, at a ‘‘mind’’ level. Delusions are a cognitive effort by the patient to make sense of these aberrantly salient experiences, whereas hallucinations reflect a direct experience of the aberrant salience of internal representations. Antipsychotics ‘‘dampen the salience’’ of these abnormal experiences and by doing so permit the resolution of symptoms. The antipsychotics do not erase the symptoms but provide the platform for a process of psychological resolution. However, if antipsychotic treatment is stopped, the dysregulated neurochemistry returns, the dormant ideas and experiences become reinvested with aberrant salience, and a relapse occurs (Kapur, 2003). 2. Psychosis will develop when a threshold of damage or changes to frontal and temporal systems, their connections, or alterations in dopaminergic projections is attained, resulting in the aforementioned imbalance in the system. The threshold for psychosis differs for each individual depending upon the integrity and quality of his or her brain. This tenet states that similar to dementia, once a threshold of damage or changes is reached, resulting in an imbalance, psychosis will result. Thresholds, however, differ for each individual based upon the ability of the brain to maintain the balance between frontal and temporal/limbic structures. Brain organization and integrity are important factors that contribute to neuronal adaptability of the individual. Anything resulting in neuronal loss or reducing the resiliency or integrity of the brain such as genetic predispositions, minor head injuries, prolonged alcohol abuse, normal aging, or previous transient psychosis, can lower the individuals’ threshold for developing a future psychosis. 3. All individuals are at risk for developing a psychosis if a threshold of structural damage or neurochemical imbalance is attained. Contributing factors include: a. genetic predisposition. b. environmental factors. i. damage sustained through trauma, disease, substance abuse. ii. effects of experience on neuronal structures and neurochemical release. c. neuronal and biochemical changes during normal human development.

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Although slightly reworded, this tenet generally remains unchanged and describes the different factors that can contribute to brain changes that contribute to a psychosis. 4. The presentation of psychosis is determined from the interaction of the characteristics of etiological contributors which include: (a) direct or indirect effects on neuronal networks and neurotransmitter systems; (b) progressive versus static nature of the etiology or the processes that it triggers; (c) location of neuropathology; and (d) severity of neuropathology, with existing brain structures and neuronal and neurochemical changes associated with normal development. This tenet indicates that the presentation of psychosis is not just determined by the type of neuropathology affecting FTD systems. Instead, the type and severity of pathology interacts with the existing brain and dynamic changes that occur throughout the person’s lifespan. There are several implications of this tenet. First, the exact same neuropathological mechanism, for example daily use of methamphetamine for five years, will affect individuals differently due to the properties of their pre-existing brain structures, neurochemical systems, or due to the genetic predisposition or presence of risk genes such as the COMT polymorphisms. In this regard, the individual with more existing damage to or dysfunction in FTD systems would be more likely to experience psychosis or develop a persistent psychosis as there is less resiliency or neuronal adaptability within the brain. Second, the presentation and course of psychosis would depend upon characteristics of the neuropathological etiology and how it affects the FTD system. In this manner, one would expect a more immediate onset of psychosis if the neuropathological etiology directly affected FTD systems (methamphetamine) versus one that is indirect (tumor). Temporary or brief psychosis would result if the neuropathological etiology is removed and did not cause permanent damage. Psychosis would be chronic if changes are nonreversible and severe enough to overcome normal neuronal resiliency and adaptability, and episodic if there is a waxing and waning of imbalances and equilibrium. Worsening psychotic symptoms would be due to neuropathology that is progressive (e.g. DAT) versus a static etiology (e.g. CVA, using and then discontinuing methamphetamine), or secondary to a progressively damaging process in the brain such as excitotoxicity or apoptosis that has been triggered by the neuropathological etiology (Fujii & Ahmed, 2002). The specific psychotic presentation would be determined by the FTD structures that are affected by the neuropathological etiology. It should be stressed that our model is a work in progress and will probably need to be modified as new information on psychotic disorders is generated as well as refinements in our understanding on how the brain works.

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Conclusion

Diagnostic implications

An important implication of the data is application to current DSM-IV diagnostic criteria for schizophrenia and psychotic disorders. Data indicate that there is much overlap in presentation across the spectrum of psychotic disorders with auditory hallucinations and paranoid delusions being the most common symptoms. Similarly, neurocognitive deficits in executive functioning and memory are demonstrated in a broad range of psychotic disorders. Almost all etiologies of psychotic disorders are associated with abnormalities to at least one of the following: frontal systems, temporal areas, and the dopaminergic system. The significant overlap in presentation and neuropathology would argue for a neurobiological relatedness of psychotic disorders which could render etiology less relevant to diagnosis. For example, if abnormalities to frontal and temporal areas and the dopamine system underlie most psychotic conditions, then in a given individual there may be multiple contributors to the onset of psychosis including genetic predisposition, TBI, cannabis or methamphetamine abuse, and neuronal pruning associated with normal aging. If this is the case, then for this individual it would be difficult to render a DSM-IV diagnosis as, aside from severity and chronicity of symptoms, the major differential between schizophrenia and psychotic disorder due to a general medical condition or substance-induced psychosis is determining or ruling out other etiologies. We argue that the requirement of etiological determination for diagnosis is an issue that would have to be addressed in DSM-V. Given the similarity in presentation and neuropathology across psychotic disorders of different etiologies, what role will etiology play in diagnosis? How will DSM-V address the issue of multiple risk factors found in many persons with schizophrenia? Should schizophrenia be a diagnosis based primarily on severity and chronicity? Despite these potential questions, it is argued that knowing etiological contributors would still be important clinically, as this knowledge could contribute to developing effective treatment and also have prognostic value. Treatment implications

It is argued that conceptualizing psychosis as a neurobiological syndrome as opposed to the current DSM-IV dichotomy of primary and secondary psychotic disorders could have important treatment implications. By examining the underlying neurobiology of psychosis instead of basing diagnosis on etiology, it is hoped that researchers would eventually be able to associate symptoms with localized neuropathology or neurochemical abnormalities. This knowledge could then be used for both developing medications that selectively target abnormalities

C

C U C

Epilepsy

Stroke Brain tumors HIV

U C C

C

U

C

none U

U U

U NR

none

none

U NR

NR

C

NR

U

C

C?

U C

C C

C C C

C

C

U NR

C?

C C

C

C

C

C C

less than schiz less than schiz NR U NR

C

C less than EOS less than EOS

NR C NR

NR

U

NR none C

NR

U

strong strong

strong some

NR

some

NR NR NR

NR

some

NR NR NR

NR

some

NR NR

strong

strong

some

some strong

NR

some some

some

none

some

strong some

NR NR none

none

NR

NR suspect

some possible indirect NR

suspect

none

strong

strong suspect

Temporal Dopamine

some some some some subcortical NR

some

some

some strong

NR

less than less than NR schiz schiz NR NR strong strong strong some

NR

less than less than NR EOS EOS

strong strong

Memory Executive deficits deficits Frontal

more than strong schiz U NR NR NR

NR NR none none

none none

C

C

C NR

more than U schiz C NR U NR

none U

U

C

C less than EOS less than EOS

Auditory Visual Negative hallucinations hallucinations Delusions Sx

Intellectual disabilities Autism Velo-cardio-facial syndrome Brain injury

Schizophrenia Childhood onset schizophrenia Late onset schizophrenia Schizoaffective Acute/transient psychosis Delusional disorder Bipolar disorder Major depression

Disorder

First rank Thought Sx disorder

Table 27.1. Psychotic symptoms, neuropsychological deficits, and neuropathology by etiology of psychotic disorder

Herpes Lyme disease Syphilis Multiple sclerosis Systemic lupus Metachromatic leukodystrophy X-linked adrenoleukodystrophy Cannabis Cocaine Methamphetamine Alzheimer’s disease Lewy body dementia Parkinson’s disease Sensory impairments Antidepressants Anti-Parkinonsian Steroids Cardiovascular Disulfram Retinoids Anti-inflammatory Anti-epiletic Anti-viral Anticholinergic

Disorder C C C NR NR none NR U C C C C C C NR C NR C NR NR C C C C

U C C C C C

NR

C C C C C U C C U NR C NR NR C C C C

C C C C C C none C C NR NR C NR NR C C C

NR

NR C C C C C

C C none U none none C NR NR NR NR NR NR NR NR NR

NR NR none none NR NR NR NR NR NR NR NR NR NR

NR

NR NR NR NR NR NR

none none none none NR NR NR NR NR NR NR NR NR NR

C none

NR

NR NR NR NR NR NR

First rank Thought Sx disorder

C C

NR

NR NR NR NR NR C

Auditory Visual Negative hallucinations hallucinations Delusions Sx

NR some some strong NR strong none NR NR NR NR NR NR NR NR NR NR

NR

some NR some some NR strong

NR some none strong strong strong none NR NR NR NR NR NR NR NR NR NR

NR

NR NR NR some NR strong

NR some some some none some none NR NR NR NR NR NR NR NR NR NR

some

none some some NR some some

Memory Executive deficits deficits Frontal

none none some strong some some none NR NR NR NR NR NR NR NR NR NR

none

some none none some some none

suspect strong strong some strong strong none strong strong none none none none none none none suspect

None

NR NR NR none none NR

Temporal Dopamine

C C C C C NR C C C

C C C C C C NR C C

C = common, U = uncommon, NR = not reported

Antibiotic Stimulants H2 blockers Anti-malarial Anti-mycobacterial H1 blockers Muscle relaxants Hypnotics Chemotherapeutic/ adjuvant

Disorder C C C C C NR C C C

NR NR NR NR NR NR NR NR NR

Auditory Visual Negative hallucinations hallucinations Delusions Sx NR NR NR NR NR NR NR NR NR

NR NR NR NR NR NR NR NR NR

First rank Thought Sx disorder NR NR NR NR NR NR NR NR NR

NR NR NR NR NR NR NR NR NR

NR NR NR NR NR NR NR NR NR

Memory Executive deficits deficits Frontal

Table 27.1. (Cont.) Psychotic symptoms, neuropsychological deficits, and neuropathology by etiology of psychotic disorder

NR NR NR NR NR NR NR NR NR

none suspect indirect none suspect indirect suspect none suspect

Temporal Dopamine

553

Conclusion

in specific neurotransmitter systems as well as prescribing the most effective medication for the symptoms of a given patient. Limitations

Our analysis of the data on psychotic disorders of different etiologies should be viewed as an initial step in examining psychosis as a neurobiological syndrome. Although we believe the data demonstrate that many consistencies in presentation and neuropathology exist between different etiologies, there are several limitations to our findings: (1) The data for many disorders are descriptive and frequently based on case studies or small sample sizes and not on large-scale, well designed epidemiological studies. (2) Descriptions of several disorders are incomplete as specific symptoms, localized neuropathology, and domain-specific cognitive deficits are not always reported. This missing data weakens our interpretation and support for our findings. (3) Despite general consistencies, many inconsistencies were also reported. However, this is not surprising as the brain is a highly complex organ that is yet to be fully understood. Thus knowledge of brain functioning has generally been based upon the preponderance of similar findings versus data that are entirely consistent. In addition, even if exceptions to our proposed neurobiological circuit of psychosis do exist, this would not rule against our hypothesis, but indicate that the brain is truly complex and psychosis can result from disturbances to other neurobiological systems. Future Studies

Given the limitations in the current literature and knowledge base of psychotic disorders of different etiologies, we propose several directions for future studies to facilitate our knowledge in this area: (1) Large-scale, prospective studies with stronger controls and measurements of symptoms are needed to improve the existing data for much of the etiologies. (2) Studies comparing psychotic disorders of different etiologies with schizophrenia on measures such as neuroimaging, positive and negative symptoms, and neuropsychological test data would assist in teasing out differences between primary and secondary psychotic disorders. (3) Studies correlating structural and functioning neuroimaging data, neuropsychological test data, and psychiatric symptomatology would assist in understanding relationships between neuropathology and presentation in psychosis. One manner this could be accomplished would be through functional MRI studies correlating functional changes with specific symptoms, as well as using other brain imaging studies such as PET and SPECT using radioactive receptor binding ligands to correlate neurotransmitter functioning with objective measures of symptomatology. (4) Studies examining the presence of schizophrenia-related genes in people with psychiatric disorders of different etiologies would assist in understanding

554

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why only a small percentage of people who contract high-risk neurological disorders become psychotic. (5) Similarly, studies can examine whether relatives of people with psychotic disorders of different etiologies possess proposed phenotypic markers for schizophrenia such as neurocognitive deficits, eye movement abnormalities, or abnormalities in P300 amplitudes.

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26.

Index

abacavir 424 absence seizures 264, 265 abstract attitude 20 acetylcholine receptor systems, dementia with Lewy bodies 481 acute and transient psychotic disorders (ATPD) age at onset 103 antipsychotic medication 111 course 105–7 duration of treatment 111 epidemiology 535 gender 102–3 genetics 108–9 neurochemical abnormalities 108 neuroimaging 107 neuropathology 107 outcome 106 presentation 103–4 progression 105–7 psychogenic 110 reactive 110 serine 108 treatment 110–2. See also brief psychotic disorder acyclovir, herpes simplex encephalitis 321, 322 addiction hypothesis, primary 374–5 adrenocortical insufficiency 356–7 adrenoleukodystrophy, X-linked 353–7 age of onset 354 brain changes 355–6 course 354–5 environmental risk factors 356 epidemiology 354 genetic factors 356 neurochemical abnormalities 356 neuroimaging 355–6 neuropathology 355–6 presentation 354 progression 354–5 temporal lobe pathology 535–6 treatment 356–7 very long chain fatty acids 355–6 adrenomyeloneuropathy 355 affective disorders

catatonia 234 human immunodeficiency virus 318 affective flattening, autism 238–9 aggression Alzheimer’s disease 458 delusional disorder 121 alcoholism, delusional disorder association 127–8 alprazolam 402 Alzheimer’s disease dementia with Lewy bodies linkage 482 prodromal stage 160 visual hallucinations 524, 525 Alzheimer’s disease-related psychosis 455–6 age of onset 456–7 associated symptoms 458 brain changes 459 course 458–9 epidemiology 456, 537 genetic factors 461–4 linkage analysis 461–2 neurochemical abnormalities 460 neuropathology 459 onset of psychosis presentation 457–8 progression 458–9 putative psychosis genes 462–3 symptoms 457–8 treatment 464–6 amantadine Parkinson’s disease 493, 502 psychosis risk 423 amino acids, brief and acute psychoses 108 amitriptyline 430 amphetamines 434 Andermann syndrome 207 angel’s trumpet 431 angiotensin converting enzyme (ACE) inhibitors 411 angiotensin receptor blockers 411 anosognosia 288 antibiotics Lyme disease treatment 325 psychosis induction 410, 426–7 syphilis treatment 328–9

557

558

Index anticholinergic medication 423–4 cholinergic rebound 432–3 Parkinson’s disease 493 psychosis induction 430–1 anticonvulsants bipolar disorder treatment 147 cerebrovascular accident 298–9 corticosteroid-induced psychosis 419 traumatic brain injury 255, 256 visual hallucinations 525 antidepressant-induced psychosis 407, 410 neurochemistry 409 presentation 409 treatment 410 antidepressants bipolar disorder 147 cerebrovascular accident 299 major depression 180–3 psychosis induction 407–10 serotonin and norepinephrine combination 408 anti-epileptic medication-induced psychosis 420–2 antimalarial medication, psychosis induction 427–8 antimycobacterial medication 429–30 antipsychotics Alzheimer’s disease 464–5 bipolar disorder treatment 147 brain tumor psychosis 310–1 brief and acute psychoses 111 cerebrovascular accident 298–9 delusional disorder 130–1 epilepsy with schizophrenia-like psychosis 278 human immunodeficiency virus 319 hyperprolactinemia 310–1 intellectual disabilities with psychosis 209 major depression 181–3 multiple sclerosis 343 Parkinson’s disease-induced psychosis 502 schizophrenia 68 seizure risk 279 systemic lupus erythematosus 348–9 tardive dyskinesia 210 traumatic brain injury 255 antipsychotics, atypical Alzheimer’s disease 465 bipolar disorder treatment 147 cannabis psychosis 376–7 cerebrovascular accident 298 corticosteroid-induced psychosis 419 delusional disorder 130–1 dementia with Lewy bodies 483 epilepsy with schizophrenia-like psychosis 278 intellectual disabilities with psychosis 209–10 methamphetamine-induced psychosis 401 multiple sclerosis 343 Parkinson’s disease-induced psychosis 502–4 schizoaffective disorder 87–8 schizophrenia 50–1, 68–9 traumatic brain injury 255 antisocial personality, cannabis psychosis 372, 376 antiviral medication, psychosis induction 424–6

anxiety brief psychotic disorder 105 epidemiology 536 human immunodeficiency virus 318 schizophreniform disorder 105 apathy 540–1 apolipoprotein E4 (APOE4) allele Alzheimer’s disease 463–4 dementia with Lewy bodies 482 aripiprazole Alzheimer’s disease 464–5 methamphetamine-induced psychosis 401 Parkinson’s disease-induced psychosis 504 arylsulphatase A 351, 353 asparaginase, psychosis risk 309 Asperger disorder 238 attention, dementia with Lewy bodies 475–6 autism 233–5 affective flattening 238–9 age of onset 538 atypical 238 catatonia 235, 238–42 catatonic variant 242 cognitive deficits 237 conceptualization 233–42 course 538–9 diagnosis 236–7 electroconvulsive therapy 241 epilepsy association 236–7 genetic factors 236 hallucinations 238–9 intellectual disabilities differential diagnosis 199 medical disorders 236 neurological disorders 236 prevalence 236 psychosis 234–5, 237 schizophrenia association 237–9 speech 239–40 symptom overlap with catatonia 241 terminology 235 thought disorders 238–9 autosomal chromosome anomalies, psychotic symptoms 208 avoidant personality disorder 127–8 axonal pathology in multiple sclerosis 341 azathioprine 347–8 baclofen 438 bacterial infections 322–9 behavioral disturbance cocaine-induced psychosis 384, 387 metachromatic leukodystrophy 351 X-linked adrenoleukodystrophy 354 benzodiazepines epilepsy with schizophrenia-like psychosis 278–9 methamphetamine-induced psychosis 401 psychosis induction 439 traumatic brain injury 255 benztropin 430 Parkinson’s disease 493

559

Index beta blockers 411 biogenic amines depression hypothesis 411 hallucinations 494 bipolar disorder 138 age of onset 139–40 brain abnormalities 142–4 course 141–2 depression treatment 147 epidemiology 138–9, 536 GABA abnormalities 144 gender differences 140 genetic factors 145, 543 major depression association 178 conversion 159 mania 147–8 multiple sclerosis association 146 neurochemistry 144 neuropathology 142–4 outcome 142 post-partum psychosis association 146 presentation 140–1 prevalence 138–9 progression 141–2 psychosocial functioning 142 psychotic/nonpsychotic brain differences 143–4 recurrence 141–2 schizoaffective disorder differential diagnosis 81 socio-environmental risk factors 146 subtypes 138 symptoms 139–41 treatment 146–8 velo-cardio-facial syndrome 220–2 white matter abnormalities 143 young people 140 bone marrow transplantation, X-linked adrenoleukodsytrophy 356–7 Borrelia burgdorferi 323 brain lesions in neurological syndromes 7–8 radiation effects 308–10 brain changes Alzheimer’s disease 459 auditory hallucinations 525 cocaine-induced psychosis 385–6 dementia with Lewy bodies 480 imbalances in systems 546–8 methamphetamine-induced psychosis 396–8 multiple sclerosis 339–41 neuropathological mechanisms 548 Parkinson’s disease-related psychosis 491, 498 psychosis 7–9 severity 548 systemic lupus erythematosus 346 temporal lobe pathology 535–6, 541–2 white matter 143, 222–3, 541–2 X-linked adrenoleukodystrophy 355–6 brain injury, traumatic 249–50 age of onset 251 classification 256

cognitive impairment 252 contribution to psychosis development 257–8 course 252–4, 256, 538–9 delusions 251 diagnosis 250–1 disconnection syndrome of memory 297 dopaminergic system 254 environmental risk factors 255 epidemiology 250–1 gender differences 254 genetic factors 254–5 hallucinations 251, 259 incidence 250 kindling 258–9 latency 252, 253, 256, 258–9 neural network changes 259 neurochemistry 254 neuroleptics 254–6 neuropathology 254 onset 252–3 pathophysiological processes 259 presentation 251–2 primary cause of psychosis 256 prodromal symptoms 253 progression 252–4, 256, 538–9 reduplicative amnesia 297 seizure disorders 251–2 sensitization 258–9 severity of injury 250 temporal lobe pathology 535–6 treatment 255, 256 unrelated to psychosis development 258 brain tumors 302–3 age of onset 304–5 antipsychotics 310–1 course 305–6 diagnosis 305–6 electroconvulsive therapy 311 epidemiology 303–4 genetic factors 308–9 hallucinations 305, 307 immunosuppression 308–9 incidence 302 location 303, 307 neurochemical abnormalities 308 neuroimaging 306 neuropathology 306–8 presentation 304–5 prevalence 303 prognosis 305–6 prolactin level 306 psychiatric patients 303–4 psychiatric symptoms 304 psychosocial risk factors 309 surgery 309 symptoms 304–6 mechanisms 306 treatment 303 of psychosis 309–11 psychosis risk 309 types 302

560

Index brief and acute psychoses antipsychotic medication 111 duration of treatment 111 treatment 110–2. See also acute and transient psychotic disorders (ATPD); brief psychotic disorder; schizophreniform disorder brief psychotic disorder age at onset 103 amino acids 108 antecedent fever 109–10 anxiety 105 course 105–7 criteria 97–101 developing countries 102 diagnostic stability 106 diagnostic systems 97–101 differential diagnosis 106–7 epidemiology 101–3, 535 gender 102–3 genetics 108–9 incidence 101–2 mood bipolarity 104 neurochemical abnormalities 108 neuroimaging 107 neuropathology 107 outcome 106 presentation 103–5 prevalence 101–2 progression 105–7 psychogenic 110 psychotic episode duration 105–6 rapid onset 538–9 reactive 110 symptoms 104 brimonidine tartrate 411 bromocriptine Parkinson’s disease 492–3 psychosis risk 309, 423 bupropion methamphetamine-induced psychosis 400–1 psychosis induction 407–9 caffeine 434 calcitonin 526 calcium, intracellular free 319 calcium channel blockers 412 cannabinoid system 374–5 cannabinoids 373 cannabis psychosis 369 brain changes 372–3 course 371–2 epidemiology 370 gender differences 370 genetic factors 375–6 mania 370–1 neurochemical abnormalities 373–5 neuropathology 372–3 paranoia 370–1 personality traits 376 presentation 370–1 progression 371–2

schizophrenia 372, 376 symptomatology 370–1 treatment 376–7 Capgras’ syndrome 288–90, 297 dementia with Lewy bodies 477 carbamazepine bipolar disorder treatment 147 brain tumor psychosis 310 cannabis psychosis 376–7 Fregoli’s syndrome 291 multiple sclerosis 342, 343 psychosis induction 420 schizoaffective disorder 87 visual hallucinations 525 X-linked adrenoleukodystrophy 357 cardiovascular medications epidemiology of psychosis 412 neurochemistry of psychosis 412 psychosis induction 411–13 catatonia affective disorders 234 autism 235, 238–42 childhood 234 electroconvulsive therapy 241 intellectual disabilities with psychosis 204–5 mania 234 symptom overlap with autism 241 catechol-O-methyltransferase (COMT) gene 27, 542 Alzheimer’s disease 462–3 cannabis psychosis 376 chromosome 22q 218–19 locus 224 schizophrenia association 225 velo-cardio-facial syndrome 224–5, 542–3 celecoxib 414 cerebellar atrophy 207 cerebral insult, delusional disorder association 128 cerebrospinal fluid, ventricular, velo-cardio-facial syndrome 223 cerebrovascular accident, psychosis after 285–6 age of onset 287 Capgras’ syndrome 288–90, 297 confusion 293 course 295 delusional misidentification 288–9, 295 delusions 292, 293, 295–6 with disorientation for place 289–90 dopamine system 298 epidemiology 286–7 Fregoli’s syndrome 288–91 hallucinations 292–6 latency 295 mania 292 MELAS syndrome 297–8 neurochemical abnormalities 298 neuroimaging 287 neuropathology 295–8 presentation 288–95

561

Index prognosis 295 rapid onset 538–9 reduplicative paramnesia 288–90 schizophreniform disorder 296 seizures 296–7 symptom clusters 288 symptoms 291–5 temporal lobe pathology 535–6 treatment 298–9 Charles Bonnet syndrome 515–16 chemotherapy, psychosis risk 309, 440–2 childhood disintegrative disorder 235 children/young people autism 234–5 catatonia 235 bipolar disorder 140 catatonia 234, 235 ictal psychosis onset 264 metachromatic leukodystrophy 350 psychosis onset 538 schizoaffective disorder 80–1 schizophrenia 39–40 age of onset 43, 538 autism symptoms 240 comorbidity 41–2 course 46–7 ethnicity 42–3 gender distribution 41 genetic factors 48–9 neurochemical abnormalities 48 neuropathology 47–8 obstetric complications 49 pervasive development disorders 235–7 presentation 43–5 prevalence 40–1 progression 46–7 treatment 49–53 University of Hawaii Child and Adolescent Thought Disorders Program 51–3 X-linked adrenoleukodystrophy 353–7. See also velo-cardio-facial syndrome chimeric assimilation 288–9 chlorpromazine bipolar disorder treatment 147 systemic lupus erythematosus 348–9 traumatic brain injury 255 choline acetyltransferase (ChAT) 497 dementia with Lewy bodies 481 cholinergic deficit, dementia with Lewy bodies 481 cholinergic rebound 432 cholinergic receptors, muscarinic 460 cholinesterase inhibitors Alzheimer’s disease 465–6 cerebrovascular accident 299 dementia with Lewy bodies 483 Parkinson’s disease-induced psychosis 504–5 chromosome 22 deletion in velo-cardio-facial syndrome 208 mutation in metachromatic leukodystrophy 353 chromosome 22q 218–19

COMT gene 224 microdeletion schizophrenia 220 velo-cardio-facial syndrome 218–19 cimetidine, psychosis induction 435–6 ciprofloxacin 426 clonazepam, systemic lupus erythematosus 348–9 clozapine 50 autism with catatonia 241–2 bipolar disorder treatment 147 cholinergic rebound 432–3 cocaine-induced psychosis 387–8 intellectual disabilities with psychosis 209, 210 Parkinson’s disease-induced psychosis 503 tardive dyskinesia 210 X-linked adrenoleukodystrophy 357 cocaine 382 cocaine-induced psychosis 382 age of onset 383 behavioral disturbance 384, 387 brain changes 385–6 course 385 epidemiology 382–3 genetic risk factors 386–7 mental disorder prior history 387 neurochemistry 386 neuroimaging 385–6 neuropathology 385–6 P50 sensory gating deficiencies 387 presentation 383–5 schizophrenia 384 treatment 387–8 cognitive disintegration, intellectual disabilities with psychosis 200–1 cognitive impairment 541 Alzheimer’s disease 458–9 autism 237 cocaine-induced psychosis 384–5 dementia with Lewy bodies 475–6 intellectual disabilities with psychosis 206–7 methamphetamine-induced psychosis 395–6 traumatic brain injury 252 cognitive rehabilitation, schizophrenia 32 cognitive
behavioral interventions delusional disorder 129–30 schizophrenia 30–1 combivir 424 compliance with medication, schizophrenia 69 confusion, cerebrovascular accident 293 congenital syndromes, intellectual disabilities with psychosis 207 cortical reassignment 521–2 corticosteroids multiple sclerosis 342 psychosis induction 418–19, 542 risk 309, 342, 348 systemic lupus erythematosus 348 cortisol, major depression 176–8 Creutzfeldt
Jakob disease (CJD) 330 cyclobenzaprine 438, 439

562

Index cyclophosphamide 347–8 cyclothymic disorder 138 velo-cardio-facial syndrome 220 cyproheptadine 436–7 deep brain stimulation, Parkinson’s disease 505 delirium anticholinergic medication 430–1 human immunodeficiency virus 317–18 infections 316–17 medication-induced psychosis 406–7 parkinsonian medication 423 delusional disorder 116–18 absence of psychiatric features 121 age of onset 119, 124 aggression 121 antipsychotic treatment 130–1 behavioral symptoms 122 chronic forms 125 clinical features 121 cognitive
behavioral therapy 129–30 comorbidity 122 course 123–5 emotional symptoms 122 epidemiology 118–19, 535 gender differences 119 genetic factors 126–8 hallucinations 122 imaging 126 incidence 118–19 jealous type 119 latency 123 misidentification 288–9, 295 negative 121 neurochemistry 126 neuropathology 125–6 neuropsychological findings 122–3 onset 119–20 organic 125 persecutory type 119 premorbid risk factors 123 presentation 119–23 initial 123–4 psychotic symptoms 124 prevalence 118–19 prodrome 124–5 progression 123–5 psychosocial treatment 129–30 psychotic disorder continuum 120–1 rapid onset 538–9 somatic treatment 130–1 somatic type 119 symptoms 122 positive 121 presentation 124 treatment 128–31 delusions 3, 285, 539 Alzheimer’s disease 456–8 autism with catatonia 240–1 bipolar disorder 138–41, 145 brief interictal psychosis 270 categorization 120–1

cerebrovascular accident 292, 293, 295–6 cocaine-induced psychosis 383–4 dementia with Lewy bodies 477 episodic 163 erotomania 121 grandiosity 383–4, 538 human immunodeficiency virus 318 intellectual disabilities with psychosis 198–9 jealous 119–21, 124, 125 major depression 160–1, 163 methamphetamine-induced psychosis 394–5 multiple sclerosis 338–9 neuropathology 125 paranoid 293 brief interictal psychosis 270 bupropion psychosis 407–8 cocaine-induced psychosis 383–4, 387 parkinsonian medication 423 Parkinson’s disease-related psychosis 495 persecution 119–21, 124 traumatic brain injury 251 preoccupation 123–4 schizophrenia 43–4 somatic 119–21, 124, 288 traumatic brain injury 251 dementia cognitive impairment 541 Creutzfeldt
Jakob disease 330 epidemiology 537 human immunodeficiency virus 318 major depression with psychosis 174–5 neurosyphilis 327 psychosis 286 dementia with Lewy bodies 472–4 age of onset 474–5 Alzheimer’s disease linkage 482 brain changes 480 course 477–8 diagnostic criteria 473 epidemiology 474, 535, 537 gender differences 474 genetic factors 481–2, 484 neurochemistry 480–1, 484, 497–8 neuropathology 478–80, 483–4 presentation 475–7, 483 progression 477–8 symptoms 475–7, 483 treatment 482–3 depersonalization
derealization state 371 depression Alzheimer’s disease 458 biogenic amine hypothesis 411 bipolar disorder 141 delusional disorder comorbidity 122 multiple sclerosis 338, 342 tactile hallucinations 524–5 velo-cardio-facial syndrome 221–2 depression, major with psychosis age 158 of onset 158–60 antidepressants 181–3 antipsychotics 181–3

563

Index bipolar disorder association 178 conversion to 159 borderline personality disorder 161–2 cortisol levels 176–8 course 163–74 delusions 160–1 episodic 163 dementia 174–5 depression subtype/variant 162 dexamethasone suppression test 176 disability level 165–74 dopamine b-hydroxylase 177, 179 dopamine D4 gene 178 duration of depressive symptoms 163 early-onset 158–9 electroconvulsive therapy 180–1 electroencephalography 175–6 epidemiology 157–8, 536 executive function 163 gender differences 158 genetic factors 178–9 glucocorticoids 183–4 hallucinations 160–1 5HT2 receptors 177 impairment level 165 late-onset 160 lithium 183 mifepristone 183–4 negative symptoms 161 neurochemistry 176–8 neuropathology 174–6 occupational impairment 165–74 P300 event-related potentials 175 presentation 160–3 prevalence 158 progression 163–74 psychomotor disturbance 161, 163 psychosocial assessment 184 recurrence risk 164–5 relapse rate 163–4 sleep studies 175–6 social impairment 165–74 suicide risk 165, 166 symptom severity 165 treatment 180–4 tricyclic antidepressants 180–2 vascular risk factors 174–5 ventricle-to-brain ratio 174 developing countries, brief psychotic disorder/ schizophreniform disorders 102 dexamethasone suppression test, major depression 176 diagnosis criteria 5–6 psychotic disorders 4–5 schizophrenia 5–7 diagnostic criteria 549 psychotic disorders 4 schizophrenia 4 substance-induced psychotic disorder 4–5 diathesis stress model of schizophrenia 8

diazepam, traumatic brain injury 255 digoxin 411–12, 430 dimenhydrinate 436–7 diphenhydramine 430 DISC1 gene 543 schizoaffective disorder 86–7 disorientation for place 289–90 disulfiram, psychosis induction 416–18 diuretics, thiazide 412 divalproex 147 donepezil 504–5 dopamine cannabinoid system 374 dementia with Lewy bodies 481 parkinsonian medication psychosis 423–4 dopamine agonists Parkinson’s disease 492–3 psychosis risk 309, 423 dopamine b-hydroxylase (DBH) disulfiram psychosis 417–18 major depression 177, 179 dopamine D4 gene 178 dopamine D4 receptor protein 126–7 dopamine hypothesis of schizophrenia 24, 26 dopamine receptors Alzheimer’s disease 460, 464 cannabis psychosis 375 polymorphisms in delusional disorder 126 dopaminergic system 542 bipolar disorder 144 cerebrovascular accident 298 cocaine-induced psychosis 386 imbalances in systems 546–7 methamphetamine-induced psychosis 397–9 sensitization in cannabis psychosis 373–4 traumatic brain injury 254 treatment of psychosis 544 velo-cardio-facial syndrome 224 doxazosin 411 droperidol 290 drug holidays 424 DSM-IV nomenclature for psychosis 5–7, 549 elderly people major depression 158. See also schizophrenia, late life electroconvulsive therapy autism with catatonia 241 brain tumors 311 brief and acute psychoses 110 epilepsy with schizophrenia-like psychosis 278–9 major depression 180–1 Parkinson’s disease-induced psychosis 505 systemic lupus erythematosus 348–9 electroencephalography (EEG) epileptic focus laterality 275 ictal psychosis 265 major depression with psychosis 175–6 encephalitis 316–17 endophenotypes 8–9 environmental factors 543

564

Index environmental reduplication 288–90 ephedrine 434 epilepsy autism association 236–7 brief and acute psychoses 110 complex partial 268–9 idiopathic mendelian 266 intellectual disabilities with psychosis 208–9 progression 538–9 schizophrenia association 208–9, 262 seizures 263 temporal lobe pathology 535–6 epilepsy with schizophrenia-like psychosis age of onset 538 antipsychotic drugs 278 brief interictal psychosis 270–1 chronic interictal psychosis 271–9 classification 263 clinical features 273 epidemiology 271–3 epileptic focus laterality 275 genetics 275–6 ictal psychosis 264–6 neuroimaging 276 neuropathology 276–7 pathophysiology 277–8 postictal psychosis 266–9 risk factors 274–5 surgery 278–9 treatment 278–9 erotomania delusions 121 erythema migrans 323, 324 erythropoietin, recombinant human 441–2 ethnicity in schizophrenia 42–3 chromosome 22q 218–19 microdeletion 220 event-related potentials, schizoaffective disorder 85 executive function, major depression 163 expressed emotion, schizophrenia 53 extra-pyramidal symptoms, HIV treatment 319 extravagant spatial localization 288–9 eye tracking deficit, smooth pursuit schizophrenia 226 velo-cardio-facial syndrome 226 family services, schizophrenia 53 Fergoli’s syndrome 288–9 fever in brief and acute psychoses 109–10 forced normalization 421 brief interictal psychosis 270–1 Fregoli’s syndrome 288–91 Fujii and Ahmed hypothesis for psychosis, neurobiological syndrome 9–10 fungal infections 330 furosemide 430 GABA 542 bipolar disorder abnormalities 144 glutamate imbalance 546 schizophrenia abnormalities 144 vigabatrin-induced psychosis 421–2

GABAA receptors 269 galantamine 504–5 ganciclovir 424 general deficit syndrome, schizophrenia 19, 20 genetic predisposition to psychosis 8, 542–3 environmental factors 543 glatiramer acetate in multiple sclerosis 342 glucocorticoids, major depression 183–4 glutamate GABA imbalance 546 multiple sclerosis 341 systemic lupus erythematosus 347 glutamate decarboxylase (GAD) 66 glycerphosphoethanolamine 460 grandiosity 383–4 age of onset 538 growth hormone in schizoaffective disorder 85–6 Halle Study on Brief and Acute Psychoses (HASBAP). See schizophreniform disorder hallucinations 3, 285, 540 Alzheimer’s disease 456–8, 524, 525 auditory 540 sensory impairment with psychosis 515, 516, 518, 519, 523, 525 autism 238–9 with catatonia 240–1 biogenic amines 494 bipolar disorder 138–41 brain tumors 305, 307 brief interictal psychosis 270 bupropion psychosis 407–8 cerebrovascular accident 292–6 cocaine-induced psychosis 383–4 delusional disorder 122 dementia with Lewy bodies 474, 476–7, 480 epidemiology 537 herbal medication 434 herpes simplex encephalitis 321 human immunodeficiency virus 318 intellectual disabilities with psychosis 202 major depression 160–1 methamphetamine-induced psychosis 394–5 multiple sclerosis 338–9 non-steroidal anti-inflammatory drugs 414 parkinsonian medication 423–4 Parkinson’s disease 493–5, 524 Parkinson’s disease-related psychosis 495–7 retinoids 416 schizophrenia 43–4 sensory impairment with psychosis 514 age of onset 515–16 course 518–19 epidemiology 514–15 genetic factors 523–4 neurochemical abnormalities 523 neuropathology 519–23 presentation 516–18 progression 518–19 treatment 525–6 SSRI psychosis 408 stimulants 434

565

Index tactile 540 sensory impairment with psychosis 514–19, 521–6 traumatic brain injury 251, 259 visual 540 sensory deprivation 524, 525 sensory impairment with psychosis 514–21, 523 haloperidol Alzheimer’s disease 464–5 bipolar disorder treatment 147 brain tumor psychosis 310–1 cannabis psychosis 376–7 corticosteroid-induced psychosis 419 multiple sclerosis 342, 343 Parkinson’s disease-induced psychosis 502 systemic lupus erythematosus 348–9 traumatic brain injury 255 X-linked adrenoleukodystrophy 357 herbal supplements, psychosis induction 433–4 herpes simplex encephalitis 320–2 age of onset 320 course 321 epidemiology 320 neuropathology 321 presentation 321 prognosis 321 symptoms 321 treatment 322 herpes simplex virus 320 histamine H1 blockers, psychosis induction 436–7 histamine H2 blockers 435 psychosis induction 435–6 homovanillic acid cannabinoid system 374 delusional disorder 126 5HT2 receptors, major depression 177 5HT2A receptor, Alzheimer’s disease 464 human immunodeficiency virus (HIV) 330 antiviral medication psychosis induction 424–6 temporal lobe pathology 535–6 human immunodeficiency virus (HIV), new-onset psychosis 317–19 course 318 epidemiology 317–18 neurochemical abnormalities 319 neuropathology 318–19 presentation of psychosis 318 prognosis 318 treatment 319 hydralazine 411 hypnotics, psychosis induction 439–40 ictal psychosis 264–6 age of onset 264 epidemiology 264 genetic factors 266 neurophysiological disturbance 265–6 presentation 264–5

symptoms 265–6 treatment 266 ifosfamide 441 illusions 285 imipramine 430 immigration status, delusional disorder association 128 immunosuppression brain tumors 308–9 psychosis risk 348 systemic lupus erythematosus 348 indomethacin 413 infections 316 definition 316–17 diagnostic criteria 316–17 fungal 330 parasitic 329–30 prion diseases 330. See also bacterial infections; viral infections intellectual disabilities with psychosis 197–8 age of onset 201–2 autism differential diagnosis 199 behavioral symptoms 203–5 catatonia 204–5 cognitive deficits 206–7 cognitive disintegration 200–1 congenital syndromes 207 course 205–6 diagnostic classification systems 200–1 diagnostic criteria inconsistency 199–200 diagnostic pitfalls 198–9 emotional symptoms 203–5 epidemiology 198–201 epilepsy 208–9 gender differences 201–2 genetic factors 207–8 genetic syndromes 208 hysterical symptoms 203–4 incidence 201 intellectual distortion 200–1 negative symptoms 199, 203, 206 neuropathology 206–7 neuropsychological findings 205 obstetric complications 209 positive symptoms 203 presentation 202–5 prevalence 201 progression 205–6 psychosocial interventions 210 schizophrenia diagnosis 204 symptoms 198–9 sensory impairment 209 severity 200–1 symptoms 202–5 tardive dyskinesia 210 thought disorders 198–9 treatment 209–11 interdisciplinary coordination of services, schizophrenia 53 interferon, psychosis risk 309 interferon a 441–2

566

Index interferon b 342 interictal psychosis, brief 270–1 epidemiology 271 forced normalization 270–1 neurophysiology 270–1 presentation 270 seizures 270–1 interictal psychosis, chronic 271–9 interleukin-2 441 isoniazid 429–30 isotretinoin 415 ketamine 526 kindling schizophrenia 259 traumatic brain injury 258–9 lamotrigine, bipolar disorder treatment 147 leucine-rich repeat kinase 2 (LRRK2) gene 482 leukodystrophies 349–57. See also adrenoleukodystrophy, X-linked leukodystrophy, metachromatic 350–3 age of onset 350 behavioral disturbance 351 clinical patterns 350–1 course 351 environmental factors 353 epidemiology 350, 537 genetic factors 353 neurochemical abnormalities 353 neuroimaging 351–2 neuropathology 351–2 presentation 350–1 progression 351 treatment 353 levetiracetam brain tumors 311 psychosis risk 309, 420–1 levodopa 423–4, 494 drug holidays 424 Parkinson’s disease 492–3, 502 Lewy bodies Lewy body pathology 459, 460 Parkinson’s disease 492–3 psychosis 497. See also dementia with Lewy bodies lidocaine 411–12 lisinopril 411, 412 lisuride, psychosis risk 309 lithium bipolar disorder treatment 146–8 brief and acute psychoses 111–12 cocaine-induced psychosis 387–8 corticosteroid-induced psychosis 419 major depression 183 multiple sclerosis 342, 343 schizoaffective disorder 87 traumatic brain injury 255, 256 lorazepam autism with catatonia 241–2 traumatic brain injury 255

Lorenzo’s oil, X-linked adrenoleukodsytrophy 356–7 Lyme disease 323–5 course 324–5 epidemiology 323–4 neuropathology 325 presentation 324 prognosis 324–5 rapid onset 538–9 treatment 325 malaria 329 rapid onset 538–9 mania bipolar disorder 141 cannabis psychosis 370–1 catatonia 234 cerebrovascular accident 292 psychotic symptoms 147–8 MAP2 and MAP5 expression in schizophrenia 65–6 medication-induced psychosis 406–7 epidemiology 537. See also named drugs mefloquine 427 MELAS syndrome, cerebrovascular accident 297–8 memantine Alzheimer’s disease 465–6 sensory impairment with tactile hallucinations 526 memory disconnection syndrome 297 impairment 541 mental retardation 538–9 schizophrenia 42 methamphetamine 392–3 methamphetamine-induced psychosis 5–6, 393 age of onset 394 brain changes 396–8 cognitive impairment 395–6 course 396 delusions 394–5 epidemiology 393–4, 536 hallucinations 394–5 neurochemical abnormalities 398–9 neuroimaging 396–8 neuropathology 396–8 presentation 394–6 progression 396 risk factors 400 schizophrenia 400 stress 399 symptoms 394–6 treatment 400–2 methylphenidate 434 methylprednisolone 347–9 metyrosine 226 mifepristone 183–4 mitoxantrone 342 mood congruence/incongruence with psychotic symptoms 162–3 mood disorders

567

Index bipolar disorder 140–1 bipolarity in brief psychotic disorder/ schizophreniform disorder 104 delusional disorder comorbidity 122 epidemiology 536 schizoaffective disorder 82–3, 88–9 mood stabilizers, bipolar disorder treatment 146–8 multiple sclerosis 338–43 age of onset 338 antipsychotics 343 axonal pathology 341 bipolar disorder association 146 brain changes 339–41 carbamazepine 343 corticosteroids 342 course 339 delusions 338–9 depression 338, 342 environmental factors 341–2 genetic factors 341 glutamate toxicity 341 hallucinations 338–9 haloperidol 343 interferon b 342 lithium 343 neurochemical abnormalities 341 neuroimaging 339–40 neuropathology 339–40 presentation 338–9 prevalence 338 progression 339 suicide risk 338 symptoms 338–9 T lymphocytes 339 temporal lobe pathology 535–6 treatment 342–3 viral infections 341–2 muscle relaxants, psychosis induction 438–9 N-acetylaspartate (NAA) 144, 460 negative affect 540–1 neural networks, traumatic brain injury 259 neuregulin 1 (NRG1) gene 27 Alzheimer’s disease 462, 463 neuritic plaques 459 dementia with Lewy bodies 480 neurobiological syndrome 7–10, 544–5 symptoms 544–5 neurochemical imbalance 547–8 neurocysticercosis 329–30 neurofibrillary tangles 459 dementia with Lewy bodies 480 neuroleptic malignant syndrome 241 intellectual disabilities with psychosis 210 risk with AIDS 425–6 neuroleptics cannabis psychosis 376–7 cocaine-induced psychosis 387–8 multiple sclerosis 342 schizophrenia 68

traumatic brain injury 254–6 neurological syndromes 7–8 neuronal networks 548 neuronal pruning 8 neurontin 525 neuropsychological deficits 550 neurosyphilis 327 neuropathology 328 paretic 327–8 neurotransmitter systems 542, 548 nevirapine 425 non-affective psychoses, other 108 non-steroidal anti-inflammatory drugs (NSAIDs), psychosis induction 413–14 obsessions, autism with catatonia 240–1 obsessive compulsive disorder 536 obstetric complications intellectual disabilities with psychosis 209 schizophrenia 49, 209 olanzapine 51 Alzheimer’s disease 464–5 bipolar disorder treatment 147 brain tumor psychosis 310–1 cannabis psychosis 376–7 methamphetamine-induced psychosis 401, 402 Parkinson’s disease-induced psychosis 504 schizoaffective disorder 87 schizophrenia 69 traumatic brain injury 255 X-linked adrenoleukodystrophy 357 oncology patients, adjuvant therapy 440–2 ondansetron methamphetamine-induced psychosis 400–1 Parkinson’s disease-induced psychosis 505 opioids 526 P50 sensory gating deficiencies, cocaine-induced psychosis 387 P300 event-related potentials, major depression with psychosis 175 paranoia bupropion psychosis 407–8 cannabis psychosis 370–1 cocaine-induced psychosis 387 herbal medication 434 stimulants 434 paranoid personality disorder, delusional disorder association 127–8 paraphrenia 60–1 parasitic infections 329–30 parkinsonian drugs adjustment 502 psychosis induction 422–4 parkinsonism 492 dementia with Lewy bodies 475–6 Parkinson’s disease 422–4 visual hallucinations 524 Parkinson’s disease-related psychosis 492–3 age of onset 490, 492, 495 Parkinson’s disease-elated psychosis (cont.)

568

Index behavioral management 501 brain changes 491, 498 characteristics 495–7 clinical management co-morbid conditions 496–7 cortical activity development model epidemiology 490, 494–5, 537 genetic factors 491, 498 management 500–5 medication adjustment 502 neurobiological model 499–500 neurochemistry 491, 497–8 neuropathology 490, 492–3, 497 presentation 490 progression 490 psychosis 493–4 regional cortical activity 498 risk factors 495–6 sequelae 496–7 symptoms 495 treatment 491–3 pemoline 434 pergolide 492–3 perphenazine bipolar disorder treatment 147 major depression therapy 183 Parkinson’s disease-induced psychosis 502 personality disorder, borderline 161–2 pervasive development disorders (PDDs) 235 categories 235–6 childhood-onset schizophrenia 235–7 epidemiology 536 petit mal 265 phantom pain, sensory impairment with psychosis 517–18, 521–4 treatments 525–6 pheniramine 436–7 phenobarbital, psychosis induction 420 phenothiazine 348–9 phenytoin 420 pimozide delusional disorder 126, 130 Fregoli’s syndrome 291 pituitary tumors 308, 310–1 polypharmacy, late life schizophrenia 67–8 post traumatic stress disorder 536 posterior fossa atrophy 207 postictal psychosis 266–9 active inhibition 269 dopamine mechanisms 269 epidemiology 267 neurochemistry 269 neurophysiology 269 pathogenesis 268 predisposing factors 267–9 presentation 267–9 prognosis 269 treatment 269

post-partum psychosis, bipolar disorder association 146 Prader
Willi syndrome, psychotic symptoms 208 pramipexole, Parkinson’s disease 492–3 prazosin 411 premorbidity 543 prepulse inhibition deficit schizophrenia 225–6 velo-cardio-facial syndrome 225–6 primary addiction hypothesis 374–5 prion diseases 330 procainamide 411–12 PRODH gene, schizophrenia 225 prolactin, brain tumors 306 promethazine 436–7 pseudopolymelia 288 psychiatric disorders brain tumors 303–4 premorbid 543 psychoeducational interventions, schizophrenia 29–30, 69–70 psychogenic psychoses, brief and acute psychoses 110 psychomotor disturbance, major depression 161, 163 psychosis chronic 539 conceptualization 7–9 disease virulence 539 episodic 539 etiology 3, 550 imbalances in systems 546–7 modified conceptual framework 545–9 not otherwise specified in schizophrenia 45 rapid onset 538–9 reactive in brief and acute psychoses 110 psychosocial interventions in schizophrenia 29, 31–2, 51, 69–70 psychotic disorders diagnostic criteria 4 primary 286 quetiapine Alzheimer’s disease 464–5 Parkinson’s disease-induced psychosis 503–4 schizoaffective disorder 87 schizophrenia 69 traumatic brain injury 255 quinidine 411–12 rasagiline 493 reactive psychoses in brief and acute psychoses 110 reduplicative amnesia, traumatic brain injury 297 reduplicative paramnesia 288–90 reserpine 411 retinoids, psychosis induction 415–16 Rett’s disorder 235–6 risperidone 51 Alzheimer’s disease 464–5 bipolar disorder treatment 147 cerebrovascular accident 298

569

Index epilepsy with schizophrenia-like psychosis 278 methamphetamine-induced psychosis 401 Parkinson’s disease-induced psychosis 504 schizoaffective disorder 87 schizophrenia 68–9 systemic lupus erythematosus 348–9 traumatic brain injury 255 rivastigmine dementia with Lewy bodies 483 Parkinson’s disease-induced psychosis 504–5 ropinirole 492–3 Rorschach Schizophrenia Index 240 St John’s wort 408 schizoaffective disorder 78–80 age of onset 81–2 atypical antipsychotics 87–8 cannabis psychosis 372 children 80–1 clinical presentation 82–3 diagnosis 88 early descriptions 79–80 differential diagnosis 81 early descriptions 79–80 electrophysiology 85 epidemiology 80–4, 535 event-related potentials 85 functional outcomes 83 gender 82 genetic factors 86–7, 145, 543 growth hormone 85–6 incidence 80–1 mood disorders 82–3, 88–9 natural history 83–4 neurobiology 84–6 neurochemistry 86 neuroendocrinology 85–6 neuroimaging 84–5 neuropsychological performance 84 prevalence 80–1 psychosis 88–9 thought disorders 82 treatment 87 schizoid traits, cannabis psychosis 376 schizophrenia age of onset 17–18, 43 late life 60–1 velo-cardio-facial syndrome 221 antipsychotic medication 68 atypical antipsychotics 50–1, 68–9 autism association 237–9 brain abnormalities 24–5, 47–8, 143–4 brief and acute psychosis differential diagnosis 106–7 cannabis psychosis 372, 376 care levels 49–50 children 39–40 age of onset 43, 538 autism symptoms 240 comorbidity 41–2 course 46–7 ethnicity 42–3

gender distribution 41 genetic factors 48–9 neurochemical abnormalities 48 neuropathology 47–8 obstetric complications 49 presentation 43–5 prevalence 40–1 progression 46–7 treatment 49–53 chromosome 22q 218–19 microdeletion 220 clinical trials 29 cocaine-induced psychosis 384 cognitive deficits 21, 44–5, 61–2 intellectual disabilities with psychosis 206–7 cognitive heterogeneity 21 cognitive rehabilitation 32 cognitive testing 19 cognitive
behavioral interventions 30–1 comorbidity children 41–2 conditions 16 young people 41–2 compliance with medication 69 comprehensive multimodal approach 51 COMT gene 225 cost of care 49–50 course 19, 21–4, 538–9 children 46–7 intellectual disabilities with psychosis 205–6 late life 63–4 young people 46–7 deficit 20 delusions 43–4 diagnosis 5–7, 15–16 intellectual disabilities with psychosis 204 late life 62–3 diagnostic criteria 4, 16, 43, 61 diagnostic methods 44 diathesis stress model 8 dopamine hypothesis 24, 26 drug therapies 28, 50–1 early phase 29–30 epidemiology 16–17, 535 epilepsy association 208–9, 262 ethnicity children 42–3 chromosome 22q microdeletion 218–20 young people 42–3 evidence-based treatments 29 expressed emotion 53 familial stress 67 family services 53 first break/episode 18 gender distribution children 41 late life 67, 70 young people 41 general deficit syndrome 19, 20 genetic factors 26–7, 145, 543 children 48–9

570

Index schizophrenia (cont.) intellectual disabilities with psychosis 207–8 late life 66 young people 48–9 geriatric 60 glutamate decarboxylase 66 incidence 16, 17, 201 intellectual functioning 22–3 interdisciplinary coordination of services 53 kindling 259 late life 59–60 age of onset 60–1 brain imaging 64–5 course 63–4 diagnosis 62–3 gender distribution 67, 70 genetic factors 66 heterogeneity 64 neurochemistry 65–6 neuropathology 64–5 PANSS scale 62 polypharmacy 67–8 presentation 61–3 progression 63–4 treatment 67–70 life events 67 life span 63–4 long-term course 23 maintenance phase 31–2 MAP2 and MAP5 expression 65–6 mental retardation 42 methamphetamine-induced psychosis 400 middle-age onset 61 molecular signaling pathway abnormalities 65–6 mortality 16, 63–4 neurochemical abnormalities 24–6, 144 children 48 late life 65–6 young people 48 neurocognitive phenotype 226 neurological functioning 48 neuropathology 24–6, 143–4 children 47–8 intellectual disabilities with psychosis 206–7 late life 64–5 young people 47–8 neuropsychological deficits 44–5 intellectual disabilities with psychosis 205 obstetric complications 209 children 49 young people 49 outcome 46–7 PANSS scale 62 premorbid period 21–3, 46 prepulse inhibition deficit 225–6 presentation 6–7, 18–21 children 43–5 late life 61–3 young people 43–5 prevalence 201 children 40–1

increase in intellectual disabilities with psychosis 201 young people 40–1 PRODH gene 225 progression 21–4, 538–9 children 46–7 intellectual disabilities with psychosis 205–6 late life 63–4 young people 46–7 psychoeducational interventions 29–30, 69–70 psychosis not otherwise specified 45 psychosocial functioning 22–3 psychosocial interventions 29, 31–2, 51, 69–70 psychotic bipolar similarities 143–4 schizoaffective disorder differential diagnosis 81 relationship 78–9 sensitization 259 smooth pursuit eye tracking deficit 226 social maladjustment 67 social skills training 31–2 somatic treatments 28 stabilization phase 30–1 subgroups 17 symptoms 18–19 first rank 43–4, 105, 198–9 intellectual impairment with psychosis 202–3 synapse abnormalities 65–6 treatment 27–32 children 49–53 early phase 29–30 intellectual disabilities with psychosis 209–11 late life 67–70 maintenance phase 31–2 stabilization phase 30–1 young people 49–53 University of Hawaii Child and Adolescent Thought Disorders Program 51–3 Usher syndrome association 209 velo-cardio-facial syndrome 219–22 vulnerability 8–9 white matter abnormalities 143 young people 39–40 age of onset 43 comorbidity 41–2 course 46–7 ethnicity 42–3 gender distribution 41 genetic factors 48–9 neurochemical abnormalities 48 neuropathology 47–8 obstetric complications 49 presentation 43–5 prevalence 40–1 progression 46–7 treatment 49–53 schizophrenia-like psychosis very late-onset 60–1. See also epilepsy with schizophrenia-like psychosis schizophreniform disorder age at onset 103 amino acids 108

571

Index antipsychotic medication 111 anxiety 105 cerebrovascular accident 296 course 105–7 criteria 97–101 diagnostic systems 97–101 differential diagnosis 106–7 duration of treatment 111 epidemiology 101–3 genetics 108–9 incidence 101–2 intellectual disabilities with psychosis 204 mood bipolarity 104 neurochemical abnormalities 108 neuroimaging 107 neuropathology 107 outcome 106 presentation 103–5 prevalence 101–2 progression 105–7 psychogenic 110 psychotic episode duration 105–6 reactive 110 symptoms 104 treatment 110–12 schizophreniform disorders developing countries 102 gender 102–3 schizotypy, velo-cardio-facial syndrome 219–20 scopolamine 430 seizure disorders traumatic brain injury 251–2. See also epilepsy seizures 263 absence 264, 265 behavioral disturbances 266–7 brief interictal psychosis 270–1 cerebrovascular accident 296–7 risk with antipsychotics 279 termination by active inhibition 269 selective serotonin reuptake inhibitors (SSRIs) Alzheimer’s disease 465 major depression 182–3 psychosis induction 408 selegiline methamphetamine-induced psychosis 400–1 Parkinson’s disease 493, 502 psychosis induction 423–4 sensitization schizophrenia 259 traumatic brain injury 258–9 sensory deprivation 546 visual hallucinations 524 sensory impairment with psychosis 514 age of onset 515–16 course 518–19 epidemiology 514–15 genetic factors 523–4 intellectual disabilities 209 neurochemical abnormalities 523 neuropathology 519–23 presentation 516–18 progression 518–19

treatment 525–6 serine, brief and acute psychoses 108 serotonergic system, bipolar disorder 144 serotonin and norepinephrine combined antidepressants 408 serotonin receptor 2A 464 sertraline, psychosis induction 409 sex chromosome anomalies, psychotic symptoms 208 sleep disorders dementia with Lewy bodies 477 Parkinson’s disease-related psychosis 496 sleep studies, major depression with psychosis 175–6 smooth pursuit eye tracking deficit schizophrenia 226 velo-cardio-facial syndrome 226 social maladjustment, schizophrenia 67 social skills training, schizophrenia 31–2 sodium valproate 343 somatophrenia 288 speech in autism 239–40 spirochetes 322 status epilepticus 264 nonconvulsive 264, 266 partial complex 264 petit mal 265 simple partial 264 steroids, psychosis induction 418–19, 542 stimulants, psychosis induction 433–4 stress, methamphetamine-induced psychosis 399 stroke. See cerebrovascular accident, psychosis after substance abuse 5–6 angel’s trumpet 431 epidemiology 536. See also cannabis psychosis; cocaine; methamphetamine substance-induced psychotic disorder, diagnostic criteria 4–5 suicide major depression with psychosis 165, 166 multiple sclerosis 338 synapses, schizophrenia 65 syphilis 326–9 course 327–8, 538–9 epidemiology 326 neuropathology 328 presentation 327 prognosis 327–8 tertiary 327 treatment 328–9 systemic lupus erythematosus 343–9 temporal lobe pathology 535–6 systemic lupus erythematosus, neuropsychiatric syndromes 344 age of onset 345 autoantibodies 346–7 brain changes 346 course 345–6 epidemiology 344–5 genetic factors 347 glutamate toxicity 347

572

Index systemic lupus erythematosus, neuropsychiatric syndromes (cont.) lupus activation suppression 348–9 neurochemistry 346–7 neuroimaging 346 neuropathology 346 presentation 345 progression 345–6 symptoms 345 treatment 347–9 T lymphocytes, multiple sclerosis 339 Taenia solium (tapeworm) 329–30 tardive dyskinesia human immunodeficiency virus treatment 319 intellectual disabilities with psychosis 210 major depression therapy 183 thiazide diuretics 412 thioridazine 502 thought disorders 19, 540 autism 238–9 bipolar disorder 140–1 intellectual disabilities with psychosis 198–9 schizoaffective disorder 82 tick-borne disease 323–4 tinnitus 523 tocainide 411–12 topiramate 400–1 transcutaneous electrical nerve stimulation (TENS) 526 transmissible spongiform encephalopathies 330 treatment of psychosis 544, 549–53 Treponema pallidum 327–9 tricyclic antidepressants major depression 180–2 psychosis induction 408, 410, 430 trifluoperazine 290, 291 Fregoli’s syndrome 291 systemic lupus erythematosus 348–9 trihexylphenidyl 493 tuberculosis medication 429–30 University of Hawaii Child and Adolescent Thought Disorders Program 51–3 Usher syndrome intellectual disabilities with psychosis 209 schizophrenia association 209 valproic acid brain tumor psychosis 310 psychosis induction 420 traumatic brain injury 255 visual hallucinations 525

vascular risk factors, major depression with psychosis 174–5 velo-cardio-facial syndrome 208, 218–19 age of onset 220–1, 538 behavioral phenotype 219–21 bipolar disorder 220–2 brain changes 222–3 development 223 chromosome 22q 218–19 microdeletion 218–19 COMT enzyme targeting 226 COMT gene 224–5, 542–3 course 221–2 depression 221–2 dopaminergic pathways 224 epidemiology 219–20, 536 genetic factors 224–5, 542–3 imaging 222 neuroanatomy 222–3 neurochemical abnormalities 224 neurocognitive phenotype 226 prepulse inhibition deficit 225–6 presentation 220–1 progression 221–2 psychiatric disorder risk 219–20 psychosocial dysfunction 221–2 schizophrenia risk 219–22 schizotypy risk 219–20 smooth pursuit eye tracking deficit 226 treatment 226 ventricular cerebrospinal fluid 223 white matter 222–3 ventricle-to-brain ratio, major depression with psychosis 174 very long chain fatty acids (VLCFA) 355–6 Lorenzo’s oil 356–7 vigabatrin 420–2 violence, delusional disorder 121 viral infections 316–22 multiple sclerosis 341–2 white matter brain changes 143, 223, 541–2 schizophrenia 143 velo-cardio-facial syndrome 222–3 zaleplon 439, 440 ziprasidone bipolar disorder treatment 147 cannabis psychosis 376–7 schizoaffective disorder 87 zolpidem 439, 440