Insights into the Diagnosis and Treatment of Bipolar Disorder

Insights into the Diagnosis and Treatment of Bipolar Disorder

HYPOMANIA

DYSTHYMIA

Sponsored by Neuroscience Education Institute This activity is supported by an educational grant from

Released: October, 2007

CME Credit Expires: September, 2010

CME INFORMATION

Overview This monograph is a summary of the bipolar disorder sessions previously presented at the 2007 NEI Psychopharmacology 2-Day Academies, with a discussion of the neurobiology, diagnosis, and treatment of bipolar spectrum disorders.

Target Audience This activity was designed for healthcare professionals, including psychiatrists, neurologists, primary care physicians, clinical psychologists, pharmacists, psychotherapists, nurses, nurse practitioners, addiction counselors, social workers and others, who treat patients with psychiatric conditions.

Statement of Need The content of this educational activity was determined by rigorous assessment, including activity feedback, expert faculty assessment, literature review, and new medical knowledge, which revealed the following unmet needs:

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Thirty percent of bipolar patients are misdiagnosed. Four key areas are important for discerning if a patient may have a bipolar spectrum disorder: sleep, treatment-response history, family history, talking to a relative. In addition, bipolar spectrum disorders are progressive illnesses making tracking of symptoms and treatment responses necessary.

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Because efficacy and tolerability of mood stabilizers, particularly atypical antipsychotic mood stabilizers, may vary depending on the phase of illness, treatment selection and dosing may need to be state-dependent in bipolar spectrum disorders.

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Evidence-based and/or rational polypharmacy techniques for treating bipolar spectrum disorders are lacking, since most of the studies focus on monotherapy.

Learning Objectives Upon completion of this activity, you should be able to:

• • •

Track history and progression of symptoms and treatment responses for patients with mood/behavioral symptoms Select mood stabilizers and their doses based on patient presentation Use neurobiologic and mechanistic rationale when combining medications to treat bipolar spectrum disorders

Accreditation and Credit Designation Statements The Neuroscience Education Institute is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Neuroscience Education Institute designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Activity Instructions This CME activity is in the form of a printed monograph and incorporates instructional design to enhance your retention of the information and pharmacological concepts that are being presented. You are advised to go through this activity from beginning to end and then complete the posttest and activity evaluation. The estimated time for completion of this activity is 2 hours.

Instructions for CME Credit To receive your certificate of CME credit or participation, please complete the posttest (you must score at least 70% to receive credit) and activity evaluation found at the end of the monograph and mail or fax them to the address/number provided. Once received, your posttest will be graded and a certificate sent if a score of 70% or more was attained. Alternatively, you may complete the posttest and activity evaluation online and immediately print your certificate. There is no fee for this activity.

NEI Disclosure Policy It is the policy of the Neuroscience Education Institute to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. The Neuroscience Education Institute takes responsibility for the content, quality, and scientific integrity of this CME activity. All faculty participating in any NEI-sponsored educational activity and all individuals in a position to influence or control content development are required by NEI to disclose to the activity audience any financial relationships or apparent conflicts of interest that may have a direct bearing on the subject matter of the activity. Although potential conflicts of interest are identified and resolved prior to the activity, it remains for the audience to determine whether outside interests reflect a possible bias in either the exposition or the conclusions presented.

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Individual Disclosure Statements Author/Developer Laurence Mignon, PhD Medical Writer Neuroscience Education Institute, Carlsbad, CA No other financial relationships to disclose.

Content Editors Meghan Grady Director, Content Development Neuroscience Education Institute, Carlsbad, CA No other financial relationships to disclose. Stephen M. Stahl, MD, PhD Adjunct Professor, Department of Psychiatry University of California, San Diego School of Medicine, San Diego, CA Board Member: Cypress Bioscience; NeuroMolecular; Pierre Fabre; Tetragenix Grant/Research: Alkermes; AstraZeneca; Bristol-Myers Squibb; Cephalon; Cyberonics; Eli Lilly; GlaxoSmithKline; Janssen; Jazz; Neurocrine Biosciences; Novartis; Organon; Pfizer; Sepracor; Shire; Somaxon; Takeda; Wyeth Consultant/Advisor: Acadia; Amylin; AstraZeneca; Avera; Azur; Biovail; Boehringer Ingelheim; Bristol-Myers Squibb; Cephalon; CSC; Cyberonics; Cypress Bioscience; Eli Lilly; Epix; Forest; GlaxoSmithKline; Janssen; Jazz; Labopharm; Neurocrine Biosciences; NeuroMolecular; Neuronetics; Novartis; Organon; Pamlab; Pfizer; Pierre Fabre; sanofi-aventis; Schering-Plough; Sepracor; Shire; Solvay; Somaxon; Tethys; Tetragenix; Vanda; Wyeth Speakers Bureau: AstraZeneca; Cephalon; CSC; Eli Lilly; Pfizer; Wyeth

Peer Reviewer Meera Narasimhan, MD Professor, Department of Psychiatry Director of Biological Research, Office of Biological Research Department of Neuropsychiatry and Behavioral Science University of South Carolina School of Medicine, Columbia, SC Grant/Research: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Forest Laboratories, Inc.; Janssen Pharmaceutica Inc. Consultant/Advisor: Bristol-Myers Squibb Company; Eli Lilly and Company Speakers Bureau: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Eli Lilly and Company; Janssen Pharmaceutica Inc.

Editorial & Design Staff Rory Daley, MPH Program Development Associate Neuroscience Education Institute, Carlsbad, CA No other financial relationships to disclose.

Jahon Jabali Interactive Designer Neuroscience Education Institute, Carlsbad, CA No other financial relationships to disclose.

Jaime Derringer Project Manager Neuroscience Education Institute, Carlsbad, CA No other financial relationships to disclose.

Nancy Muntner Director, Medical Illustrations Neuroscience Education Institute, Carlsbad, CA No other financial relationships to disclose.

Stacey L. Hughes Director, Program Development Neuroscience Education Institute, Carlsbad, CA No other financial relationships to disclose.

Steve Smith President and COO Neuroscience Education Institute, Carlsbad, CA No other financial relationships to disclose.

Disclosed financial relationships have been reviewed by the Neuroscience Education Institute CME Advisory Board to resolve any potential conflicts of interest. All faculty and planning committee members have attested that their financial relationships do not affect their ability to present well-balanced, evidence-based content for this activity.

Disclosure of Off-Label Use This educational activity may include discussion of unlabeled and/or investigational uses of agents that are not approved by the FDA. Please consult the product prescribing information for full disclosure of labeled uses.

Disclaimer Participants have an implied responsibility to use the newly acquired information from this activity to enhance patient outcomes and their own professional development. The information presented in this educational activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this educational activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. Primary references and full prescribing information should be consulted.

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Copyright © 2007, Neuroscience Education Insitute. All rights reserved. Visit us online at www.neiglobal.com. v20070915 -4-

1. Introduction The family history of patient X reveals a history of mental illnesses. His maternal grandfather had suffered from depression and died in a psychiatric hospital; his mother was once hospitalized for depression and was treated with amitriptyline for most of her life; and his fraternal twin brother suffered from situational depression. As a child, patient X experienced episodes where his “thoughts and reactions seemed magnified” and was plagued with behavioral problems such as impulsivity, distractibility and hyperactivity. He was intelligent but never excelled in school. Since he was a child, he thought that “things would grow bigger and become dangerous.” The current state of mind of patient X is that he wants to be “pleasing, accepted, loved, admired, and special,” and he suffers from self-esteem issues, which could uncover signs of narcissistic personality traits. When he preaches, patient X “transcends sickness and reaches a high”; at the same time he thinks that his role as a preacher has diminished in today’s society and he feels worthless.

Patients with bipolar disorder (BPD) will often be misdiagnosed for many years, resulting in an escalation of symptoms and leading to an increased burden on the patient, their family and society.1 In worst cases, treatment based on an erroneous diagnosis can actually exacerbate the state and symptoms of the patients. An early and correct diagnosis, on the other hand, can substantially increase quality of life and lead to a productive social life. This monograph aims to educate the reader about the intricacies of diagnosing BPD and about the preferred use of different medications. 2. What is Bipolar Disorder? In the Diagnostic and Statistical Manual of Mental Disorders Version IV, Text Revision (DSM-IV-TR), BPD encompasses four distinct disorders, i.e. bipolar I (BP-I), bipolar II (BP-II), cyclothymic disorder, and bipolar disorder not otherwise specified (BP-NOS). The lifetime prevalence of BPD is approximately 1%2 but if the definition of the disease is widened to include all illnesses within the spectrum, the prevalence can be as high as 2.6% to 6.5%.3 Almost a third (31%) of patients with BPD have been misdiagnosed with unipolar depression, and about 35% of BPD patients have waited 10 or more years to be accurately diagnosed.4 In general, BPD can be difficult to differentiate from other psychiatric conditions especially unipolar depression, and until recently it has been widely underdiagnosed.5

In the last 8 years, patient X has been given a lot of medications, including tricyclic antidepressants, selective serotonin reuptake inhibitors, dual serotonin and norepinephrine reuptake inhibitors, norepinephrine dopamine reuptake inhibitors, norepinephrine and specific serotonergic agents, various antipsychotics and anticonvulsants, with varying degrees of efficacy, and side effects. After many failed attempts and a relapse, patient X is finally diagnosed with BP-II, and started on

Almost a third (31%) of patients with BPD have been misdiagnosed with unipolar depression, and about 35% of BPD patients have waited 10 or more years to be accurately diagnosed. The following case study illustrates how complicated it can be to properly diagnose BPD and how important it is to obtain a full medical and family history as well as the complete pharmacotherapeutic treatment the patient received throughout his life. Knowing which symptoms have responded to which drug can reveal a lot about the disease.

duloxetine 60 mg/day and ziprasidone 60 mg twice a day, and he is taking clonazepam 4 mg/nightly for his sleep problems. Under this treatment plan patient X does not suffer from hypomanic symptoms anymore. “I can preach and still enjoy being out in front of people, but don’t feel out of control and need to have this feeling to gain any pleasure.” He also has more energy, but still experiences periods of fatigue and residual symptoms of depression. Nonetheless, patient X can socialize again with his wife, and lead a better life than before.

Patient X, a 67-year-old evangelist preacher married for 45 years, complains of persistent problems with depression especially in the morning, sense of dread in the stomach, lack of energy, and occasional anger. His minor complaints include word-finding difficulties and feeling distressed and tense. In his 30s the patient had periods during which he was unable to sleep and was prescribed amitriptyline, which he said “saved [his] life.” At age 44, patient X had a major breakdown and was diagnosed with manic-depressive symptoms and given lithium to no avail. Since then, he states that he has only had three months of wellness.

3. How is Bipolar Disorder Diagnosed? A. Diagnostic and Statistical Manual of Mental Disorders Version IV, Text Revision (DSM-IV-TR) and the World Health Organization International Classification of Diseases Version 10 (WHO ICD-10) The American Psychiatric Association DSM-IV-TR6 and

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the WHO ICD-107 have substantially different definitions of “bipolar disorder” leading to discrepancies in diagnosis and treatment between both systems.

activity or psychomotor agitation, grandiosity, inflated self-esteem, pressured speech, flight of ideas, and excessive involvement in pleasurable activities that could have painful consequences.

i. DSM-IV-TR criteria for the diagnosis of bipolar spectrum disorders (BSD).

ii. WHO ICD-10 criteria for the diagnosis of bipolar affective disorder (BAD).

To be diagnosed with − BP I, patients need to have experienced at least one episode of full mania with possibly intervening major depressive episodes − BP II, patients need to have experienced at least one episode of hypomania and at least one episode of major depression − Cyclothymic disorder, patients need to present with hypomania plus subthreshold major depressive symptoms for at least two years, and this may occur without the progression to major affective episodes − BP-NOS, patients need to present with symptoms of the above disorders but without meeting full criteria for any of them

BAD-I is characterized by two or more episodes of significantly disturbed mood in conjunction with altered activity levels; which can be either an elevation of mood with increased activity, i.e. hypomania or mania, or a lowering of mood with decreased activity, i.e. depression. The ICD-10 then subdivides BAD into 7 categories: 1) BAD with current episode hypomanic, 2) BAD with current episode manic without psychotic symptoms, 3) BAD with current episode manic with psychotic symptoms, 4) BAD with current episode mild or moderate depression, 5) BAD with current episode severe depression without psychotic symptoms, 6) BAD with current episode severe depression with psychotic symptoms or 7) BAD with current episode mixed. BAD-II on the other hand, is classified under “other bipolar affective disorders.” Thus it becomes obvious why accurate diagnosis of BP-I and especially BP-II disorders can be problematic. Neither system allows a diagnosis of BPD to be made without the occurrence of a full episode of mania or hypomania even though the disorder often starts with an episode of depression without the hypomanic state meeting the criteria of duration.4 Additionally, the DSM-IV-TR and the WHO ICD-10 systems allow for a broad diagnostic criteria for unipolar depression and a very narrow one for BPD, thus biasing towards an underdiagnosis of the latter.4

A major depressive episode is characterized by depressed mood and loss of interest/pleasure for most days for two weeks, plus four of the following symptoms: insomnia/hypersomnia, difficulty concentrating or thinking, indecisiveness, psychomotor agitation or retardation, change in appetite/weight, fatigue, and feelings of worthlessness or guilt. A manic episode is characterized by an abnormally or persistently elevated, expansive or irritable mood that lasts at least one week, plus three to four of the following symptoms: decreased need for sleep, distractibility, increase in goal-directed

B. Differences between BP-I and BP-II BPD is divided into different subtypes, the main two cat-

A

B

Figure 1: Graphic representation of the different stages seen in BP-I (A) and BP-II (B).

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egories being BP-I and BP-II. The prevalence is between 3 and 6% for the general population with a higher prevalence in the 18- to 24-year-olds.8 In general, BP-I patients have full blown manic episodes followed by full depression or mixed episodes of full mania combined with full depression (Figure 1A9), and BP-II patients present with one full blown depressive episode followed by a hypomanic episode (Figure 1B9). Using a longitudinal study, Judd et al. found that BP-I patients experience three times more depressive states than manic states.10 Additionally subsyndromal symptoms, whether depressive or manic, are much more frequent than symptoms at their threshold.10 BP-I patients also exhibit higher rates of reckless activity, distractibility, agitated activity, irritable mood and increased self-esteem, and these 5 symptoms can correctly classify 83% of patients as manic or BP-I and 81% of patients as hypomanic or BP-II.11 Furthermore, BP-II patients will spend 20% more time in a depressed state than BP-I patients (Table 110). In general BP-II patients show a higher lifetime prevalence of more depressive episodes, shorter interepisode intervals, a faster onset, and a more chronic

C. Mixed episodes and rapid cycling Around 40% of patients with BPD will experience mixed episodes, i.e. manic and depressive episodes occurring simultaneously. Often times, one of the two states is the primary one, with signs of the other in the background.4 Adding to the difficulty of proper diagnosis is the fact that anxiety, personality disorder, substance misuse, and the use of antidepressants have a high rate of comorbidity with mixed states.4 Hypomanic symptoms that are most often associated with major depressive episode include irritability, risky activities, racing/crowded thoughts, psychomotor agitation, distractibility and suicidality.17 Major depressive episode symptoms ranging from weight gain, overeating, hypersomnia, worthlessness, guilt, diminished concentration, indecisiveness, and thoughts of death/suicide, on the other hand, can be associated with hypomanic symptoms.17 Mixed depression or depressive mixed states have been suggested to indicate a continuum between hypomania as seen in BP-II and depression as seen in major

% Time (hypo)manic

% Time depressed

% Time cycling/mixed

%Time asymptomatic

BP- I

9.3%

31.9%

5.9%

52.7%

BP-II

1.3% Pure hypomanic

50.3% Pure depressed

2.3%

46.1%

Table 1: Percent time spent in Symptom Categories in BP-I versus BP-II.

In general BP-II patients show a higher lifetime prevalence of more depressive episodes, shorter inter-episode intervals, a faster onset, and a more chronic course of the disease. course of the disease.12 Additionally there is a higher comorbidity with anxiety disorders in BP-II patients.

depressive disorder, but the jury is still out.17, 18 It is important to note, however, that there is a greater risk of suicidality in a mixed episode than in a purely manic phase.19

A study by Serretti and Olgiati challenged the notion of the DSM-IV-TR which describes manic episode as being similar to hypomanic episode except more severe.11 Additionally it is common for manic patients to undertake reckless activities due to psychomotor agitation and poor judgment,13 and uncommon for hypomanic patients to do so.14 The major depressive episodes seen in BP-II are often mixed with hypomanic symptoms, such as irritability, mood liability, racing thoughts, increased sexuality and distractibility, leading to a misdiagnosis as depressive mixed states.14 When compared to BP-I, more than half of BP-II patients exhibit their first symptoms before the age of 19,8 and there is a much higher prevalence of family history, i.e. a first-degree relative suffering from the same illness, in BP-II compared to BP-I (6.1% versus 1.8% respectively).15, 16

In 1974, Dunner and Fieve defined rapid cycling as a mood disorder. To be characterized as rapid cycling, patients have to exhibit at least four episodes of mania, hypomania or depression in one calendar year,20 all of which need to meet set duration parameters.6, 21 A period of two months between a switch from a manic to a depressive episode, or full remission, is required; additionally, an episode of mania has to last one week, hypomania four days and depression two weeks. Anything short of that will not count as rapid cycling based on the DSM-IV-TR criteria. Clinicians, however, treat patients whose cycles are much shorter and have proposed the following rapid cycling definitions based on the frequency of the cycles: 1) classical cycling lasts from three days to twelve weeks, with at least four episodes per year; 2) ultra rapid

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cycling lasts at least three days with at least four cycles per month and 3) ultra ultra rapid or ultradian cycling lasts less than twenty-four hours.22, 23 About 10–30% of BP patients exhibit a rapid cycling pattern and 70–90% of rapid cycling patients are women.24 There is also a higher risk in women (29.6%) than in men (16.5%) to develop rapid cycling.25 In general, BP-II patients have a higher risk (30.3%) of developing rapid cycling compared to BP-I patients (6%), especially if a depressive episode presented first.26, 27 In some patients, the rapid cycling pattern can subside after a few years.28, 29 In summary, the usual clinical profile of BP-II patients with rapid cycling includes 1) being a woman, 2) presenting first with a depressive episode, 3) exhibiting a sequence of cycles such as depression-mania-euthymia, 4) having a premorbid cyclo- or hyperthymic temperament and 5) in

E.

Misdiagnosis and subsyndromal symptoms

Misdiagnosis of BP-I and especially BP-II disorder often results from a lack of clear diagnostic criteria and an overlap of symptoms within the BSD. Depending on the definition of a hypomanic episode, a key component of BP-II, a misdiagnosis can occur. As mentioned earlier, the DSM-IV-TR calls for a hypomanic episode to last at least 4 days, but for a BP-II diagnosis, hypomanic episodes as short as two days should be included.3, 34 Using structured interviews that do not allow for a gray area can lead to misdiagnosis as well. Patients often minimize their depressive symptoms, and do not consider their hypomanic episodes as cumbersome; the patients actually feel better during those episodes and seek for them to recur.4 Of all the symptoms of hypomania, overactiv-

Diagnosing BPD in adolescents can be especially difficult due to the high comorbidity rate (87%) with attention deficit disorder. men, having a comorbidity with anxiety disorder and substance use.24

ity or increased goal-directed activity could be one of the best predictors of BP-II disorder, especially when trying to differentiate it from major depressive disorder.35 The younger the age of onset of BPD, the more likely it is to be initiated with a depressive symptom, and thus more often than not these patients will be misdiagnosed with unipolar depression.36

D. Comorbidity with substance use disorder In the Epidemiology Catchment Area study the rate of alcohol abuse and dependence was shown to be 46% for BP-I and 39% for BP-II patients, exceeding all other mood disorders including schizophrenia, panic disorder and unipolar depression.30 Recently, a new study confirmed these results and showed a 54% lifetime prevalence of substance use disorder in patients with BPD, with patients using substances such as alcohol, marijuana, sedatives, hypnotics, and cocaine mainly to alleviate their mood/anxiety symptoms, to become euphoric or to boost energy.31 Additionally among all psychiatric disorders, mania and hypomania are significantly more associated with alcohol abuse than any other mood disorder.32 Feinman et al. investigated three groups of patients: 1) a primary BP group who presented only with BPD, 2) a complicated group who had primary BPD that was complicated by substance abuse and 3) a secondary BP group, whose BPD started after the onset of substance abuse.33 Interestingly, when primary BP was complicated with substance use, the patients presented with an earlier age of onset of symptoms (13.3 years) and a higher percentage of suicide attempts (54.3% in the complicated group versus 30.1% in the primary BP group).33 Additionally, the complicated and the secondary BP group were more anxious and depressed, as measured on the Hamilton and Beck rating scales, than the primary BP group.33 Thus, it appears that substance use worsens the course of BPD.

Diagnosing BPD in adolescents can be especially difficult due to the high comorbidity rate (87%) with attention deficit disorder.37 Additionally, children and adolescents often present with short and frequent episodes of mania and/or depression as well as subsyndromal symptoms.38 As children exhibit less discrete episodes of mania and depression,37 clinicians need to look for higher rates of mixed mania (55%) and rapid cycling (87%). Many studies have shown that even though recovery is quite high in this population of patients, there is also a high rate of recurrence, despite the presence of pharmacotherapy, including many suicide attempts or completed suicides.38 Compared to adults, children and adolescents with BP-I spend more time symptomatic, have more mixed episodes and cycling occurrences and present with more subsyndromal symptoms.38 There is also a higher rate of conversion between BP-I and BP-II in youth compared to adults.38 Children will often be wrongly characterized as temperamental and explosive with a high degree of irritability, and non-treatment or mistreatment can be devastating to their future clinical history. The clinical consequences resulting from misdiagnosing BPD include the risk of suicide, substance abuse and iatrogenic complications.15 It has been shown that of

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the people who are misdiagnosed as having unipolar depression and treated with an antidepressant, 50% will develop mania or hypomania and 25% will develop rapid-cycling.39 Finally, misdiagnosing BPD has an important economic impact on society, as BPD is the 6th leading cause of disability worldwide.15

have doubled the rate of patients diagnosed with BPD who were originally classified as suffering from unipolar depression (the percentage went from 22% to 40%).45, 46 Obtaining key information from a close relative or significant other as well as re-interviewing the patient during a different episode can further enhance the proper diagnosis of BP-II.47 Following the 1989 and 1994 National Institute of Mental Health Workshops on Bipolar Disorder, an outcome measure was developed that would quantify daily aspects of the clinical course of BPD, namely the National Institute of Mental Health daily prospective Life-Chart Method (NIMH-LCM-p).48 This daily report has two separate versions; one where the patient (or self) rates himself, and one where the clinician (or observer) rates the patient. This allows clinicians to track the manic and depressive variations of a patient, thus providing a measure to follow the course and severity of BPD. Additionally, a specific treatment response, or a lag in response, can be followed as well with this LCM-p,48 providing clinicians with a new way of determining the efficacy of a treatment plan.

A very important aspect in treating BPD is to ascertain that the patients recover functionally and not only syndromally. Functional recovery is the restoration of normal functioning at work, at home, and with family and friends.40 A recent study has found that compared to non-depressed patients, subsyndromally depressed BP patients are significantly more likely to be impaired at work and at home, both in relationships with family members and with respect to home duties.41 The degree of impairment is also significantly correlated with the intensity of the subsyndromal symptoms and close to that of syndromally depressed patients.41 In general, subsyndromal depression is more common than subsyndromal mania and there is an association between the first subsyndromal symptoms and the subsequent mood episode of the same polarity.16, 42 The global impact that impairment in functionality has on society16 in addition to the poor quality of life of the patients supports the need to assess functional recovery in patients who have subsyndromal symptoms and to consider long-term treatment of these patients. F.

ii.

Due to the large range of symptoms presented in the BSD and their overlap with other mood disorders, it has been difficult for physicians to accurately distinguish between various mood disorders, BP-I and BP-II. Dr. Hirschfeld helped fill this gap by introducing the Mood Disorder Questionnaire, a simple-to-use one-page questionnaire.49 A series of thirteen yes-or-no questions based on the DSM-IV criteria and on clinical experience set out to unravel a lifetime history of manic and hypomanic syndromes. A score of 7, i.e. “yes” to at least seven questions, is the cutoff, as it provides good sensitivity and good specificity. Thus, the use of the Mood Disorder Questionnaire in addition to an in-depth evaluation of the patient may allow for the proper diagnosis of BPD.49 Mood charts as well as life charts can also be very helpful for the physician to make a proper diagnosis, and for the patient to realize the different phases they are in, or whether a specific event induced a specific mood. They also allow the physician to obtain a picture of the patient’s symptomatic profile between visits.

How can we achieve a better diagnosis?

A thorough evaluation of the patient and a solid grasp on the subtleties between different mood disorders can aid in correctly diagnosing BPD. There are a few indicators for BPD, and these include a family history, an antidepressant-induced (hypo)mania, a hyperthymic personality prior to depression, an early age of onset and brief episodes of the illness.17, 43 Other symptoms that can predict BPD include hypersomnia, hyperphagia, fatigue and sensitivity to rejection during a depressive episode. Additionally, BPD may have psychotic features, show a seasonal pattern, exhibit severe premenstrual syndrome, and be unresponsive to antidepressants.4 An abrupt onset or end are common. Symptoms that precede the manic episodes often include increased energy, elevated mood, disinhibition, and racing thoughts. i.

Mood Disorder Questionnaire

Asking the right question to the right person

The diagnosis of BP-II is improved when semistructured interviews are given to patients by trained clinicians who focus on the symptoms of hypomania.44 A systematic evaluation of hypomanic symptoms and the use of more elaborate checklists and alternative rating scales

4. Current Treatments in BPD A. What is the underlying neurobiology of BPD? The main three monoamine neurotransmitter (NT) systems norepinephrine (NE), dopamine (DA) and sero-

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tonin (5-HT) are all involved in the regulation of mood, and deregulation in any of them can lead to depression or mania. NE, DA and 5-HT can regulate their own release as well as the release of the other two NTs, and they project to brain areas such as the prefrontal cortex, the basal forebrain, the hypothalamus, the thalamus, the striatum and the nucleus accumbens, areas regulating sleep/arousal, hyperactivity, apathy, fatigue, weight and executive function to name a few. All of these brain circuits are involved in one way or another in BPD,50 and are often referred to as being either hyper- or hypoactive in BPD. It might be more appropriate, however, to say that these systems are “out of tune” or chaotic, as they might be “up” in one area and “down” in the other.9 The cholinergic system, as well as stress and glucocorticoids, have also been implicated in mood disorders. While the metabolism of monoamines is altered in BPD patients,51 it might be the signaling pathways within the previously mentioned systems that are “defective” and lead to the pathophysiology of this mental disorder. Intracellular signaling cascades including but not limited to the Gprotein and protein kinase C signaling, calcium levels, glycogen synthase kinase and signaling through glutamate receptors all play a role in BPD, and most drugs do indeed act through these pathways.50 B. What is a mood stabilizer? Mood stabilizers have been defined by the American Psychiatric Association's Practice Guideline for Treatment of Patients With Bipolar Disorder (Revision)52 as drugs “with both antimanic and antidepressive actions,” and they are used to treat mood disorders with rapid and unstable mood swings. Different mood stabilizers are often used in combination with each other or with antidepressants to alleviate all the symptoms of

BPD. Lithium, lamotrigine and quetiapine are the most effective mood stabilizers at treating both mania and depression in BPD. C. Treatment guidelines and their differences. Depending on the geographical location of a patient the treatment guidelines will be different as can be shown by comparing the recommendations of the Canadian Network for Mood and Anxiety Treatments (CANMAT), the American Psychiatric Association (APA) and the British Association of Psychopharmacology (BAP). The clinical recommendations of these associations are based on different categories with varying degrees of clinical evidence, including but not limited to double-blind randomized controlled trials with a placebo arm, prospective non-controlled naturalistic trials and, expert opinion/anecdotal reports. Table 2 represents the treatment guidelines of the different agencies.52-54 The Food and Drug Administration (FDA) normally approves treatment options for specific diseases based on the results from at least 2 double blind placebo controlled randomized clinical trials, and this evidencebased medicine is used to determine a treatment’s safety and efficacy. The following drugs are FDA-approved for the treatment of acute mania in BPD: aripiprazole, carbamezapine ER, chlorpromazine, divalproex ER, lithium, olanzapine, quetiapine, risperidone, and ziprasidone. The only monotherapy approved by the FDA for depression in BPD is quetiapine; while olanzapine is approved in combination with fluoxetine. As maintenance therapy for BPD, FDA-approved drugs include aripiprazole, lithium, valproate, lamotrigine, and olanzapine. Table 3 (pages 12 and 13) gives an overview of the different drugs used in the treatment of BPD; their

Acute Mania or Mixed Episodes (ME)

Acute Depression

Maintenance Treatment

APA

Severe mania or ME: Li in combo with AP or Val in combo with AP Less severe: SGA better than FGA Alternatives: CBZ, ZIP or QUE; psychosocial therapy In refractory illness consider Cloz and ECT

Initiate with Li or La; consider Li with AD In severe cases use ECT; if unresponsive add another AD

Li, Val, La, CBZ or maintenance ECT

BAP

Severe mania or ME: AP or Val Mild mania: AP, Val, Li or CBZ; If unresponsive switch AP or consider ECT

Severe: SSRI, or other AD (not TCA), ECT, and AP if patient is psychotic Moderate: SSRI, other AD (not TCA), consider La Mild: La or Li, psychosocial therapy

If mania predominates: 1) Li, Val, OLZ; 2) CBZ; 3) combo If depression predominates: 1) La; 2) Li; 3) combo

CANMAT

Li; Val; AP or 2 drug-combo (Li or Val + AP) If unresponsive consider CBZ, Cloz or ECT

If patient on Val or OLZ, RIS, ARI or ZIP, add SSRI, Li or La or QUE If patient is drug nude, use La, Li, QUE, OLZ+SSRI, Li/Val+SSRI or Li+Val If unresponsive, use different AD or consider ECT

1) Li, La, Val, or OLZ 2) CBZ, Li+Val; Li+CBZ; Li/La+OLZ; ARI; RIS; QUE; ZIP; Li+RIS/QUE; Li+La/SSRI; 3) Cloz; ECT; topiramate; omega-3-fatty acids, gabapentin

Table 2: Treatment recommendations for BPD. AD=antidepressant; AP=antipsychotic; APA=American Psychiatric Association; ARI=aripiprazole; BAP= British Association of Psychopharmacology; CANMAT=Canadian Network for Mood and Anxiety Treatments; CBZ=carbamazepine; Cloz=clozapine; ECT=electroconvulsive therapy; FGA=1st generation AP; La=lamotrigine; Li=lithium; ME=mixed episodes; OLZ=olanzapine; QUE=quetiapine; RIS=risperidone; SGA=2nd generation AP; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant; Val=valproate; ZIP=ziprasidone.

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A

Atypical Antipsychotic Actions in Psychotic and Nonpsychotic Mania

5HT2A

D2

Atypical Antipsychotic Actions in Bipolar Depression

B

5H

M1

A T1

M3

H 1

1 2

5HT1D

SRI

atypical antipsychotic

NRI

5HT2C

D1

3 5HT

5HT 7

D2 D4

D3

clinical actions

pharmacologic actions

NE and DA disinhibition

mood and cognition

antihistamine NE and DA disinhibition

H1

5HT2A 5HT disinhibition

H1

5HT2A

mood

2 SRI NRI

SERT inhibition

2C

mood 2

1D

SRI NRI

mood

2C

NET inhibition

mood

7

6

mood and cognition

7

6

NE and DA disinhibition

trophic factors

insomnia 1A

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X

5HT2A

1D

Atypical antipsychotics have been shown to be effective at treating mania and depression in BPD, and some are also used as maintenance therapy. There are different feasible mechanisms of action that can explain the efficacy of atypical antipsychotics. Their DA D2 receptor blocking activity is mainly responsible for reducing psychotic events, while the blocking ac-

blocks DA hyperactivity

reduces glutamate hyperactivity

1A

Despite its age, lithium remains the gold standard in the treatment of BPD and is effective at relieving manic and possibly depressive symptoms. Importantly, it is the only drug known to reduce suicidality in BP patients.56 Lithium is a very effective drug, even if it can induce significant side effects. When lithium is given towards the bottom of its therapeutic window in combination with other mood stabilizers however, the occurrences of side effects can be limited while achieving the same therapeutic value due to synergistic effects with the other drugs. This might be the new way to use this old drug. An anticonvulsant and mood stabilizer, valproate is efficacious at treating acute mania, and possibly depression in BPD and is used for maintenance therapy.57 Valproate also has unacceptable side effects at the doses needed for monotherapy, but similarly to lithium when given in addition to other mood stabilizers at the low end of its therapeutic range, it can be really efficacious and improve tolerability and compliance. Thus for both lithium and valproate, combination therapy might be preferred as it will reduce side effects while optimizing therapeutic value. The anticonvulsant lamotrigine, whether as monotherapy or as adjunct, has been shown to be very effective in preventing depressive relapses in BPD, most likely due to its mechanism of action profile.58, 59 At doses between 50–200 mg/ day lamotrigine is well tolerated and, unlike antidepressants, does not lead to increased rates of switching to manic or hypomanic states.59 Monotherapy with lamotrigine is also efficacious at stabilizing mood swings and helping rapid cycling BP patients achieve euthymia, as shown by a recent study using the NIMH-LCM-p over a 6-month period.60 Anticonvulsants are not necessarily the most efficacious monotherapy for BP mania, however, these are useful drugs as add-ons. Some side effects of concern need to be mentioned though: there is a risk of developing polycystic ovarian syndrome with valproate, and carbamazepine is known to have teratogenic effects and to lead to drug-drug interactions which can render any form of contraception ineffective.

tions at the 5-HT2A receptors, which leads to the reduction of glutamate within various different circuits, is probably responsible for both anti-manic and anti-depressive actions (Figure 2A).9 Additional mechanisms of action include increasing the neurotransmitters DA, NE and 5-HT, which can be valuable in relieving depressive symptoms (Figure 2B)9. All atypical antipsychotics however have slightly different binding properties giving them a variable portfolio of actions. Understanding the pharmacological and clinical action of a specific drug by knowing which receptors it interacts with, can aid the physician in determining which drugs to combine in practice, which side effects might result from a specific drug combination and which can be eliminated.61

5H T6

mechanism of action; the FDA-approved doses and other issues to be aware of.55 Additionally, for each drug the non FDA-approved usage has been added, and is based on what is effective in practice.

neurogenesis? circadian rhythms

sleep, mood?

Figure 2: Actions of atypical antipsychotics in mania (A) and depression (B)

Drug Name, Class and Mechanism of Action (MOA)

FDA-Approval * (Non FDA-Approval)

Dosing

Lithium (Li) -- Original mood stabilizer

Tx of manic episodes; maintenance Tx for manic depressive patients with a history of mania

- acute: 1800 mg in 3 doses - maintenance: 900-1200 mg/day in divided doses or at night - start dosing at 300 mg 2-3X/day, then increase dose while monitoring plasma levels

Maintenance Tx of BP-I

- monotherapy for BPD: 100-200 mg/day - adjunctive Tx for BPD: 100 mg/day in combo with Val, or 400 mg/day in combo with CBZ - titrate VERY slowly up to 200 mg/day (25 mg/day for 2 wks; 50 mg/ day wk 3; 100 mg/day wk 5; 200 mg/day wk 6)

Mania; migraine prophylaxis; maintenance Tx of BPD

- dosage to achieve therapeutic plasma level vary widely (750-3000 mg/ day) - for acute mania start at 1000 mg/day and increase rapidly - for less acute mania, begin with 250-500 mg/day and titrate upward as tolerated, can go up to 1200-1500 mg/day

Tx of mania in BPD (as controlled release formulation)

- 400 mg/day increased slowly up to 1200 mg/day to enhance tolerability of sedating SE - can require upward dosage adjustment as it induces its own metabolism, thus lowering plasma levels during the 1st several wks/months of Tx

Schizophrenia; manic type of manicdepressive illness; combativeness and/or explosive hyperexcitable behavior in children; hyperactive children; psychosis; acute mania

- 200-800 mg/day - low dose may have more sedative effects - ampuls and vials contain sulfites that could cause allergic reactions; one of the few AP available as suppository

Different applications in schizophrenia; acute mania and mixed episodes associated with BPD

- 80-160 mg/day in divided doses, or 10-20 mg IM - start oral dose of 40 mg 2X/day; on day 2 increase to 60 or 80 mg 2X/day - too low a dose might block 5-HT2C receptors; best efficacy seen at doses higher than 120 mg/day; best if taken with food, as food can double bioavailability by increasing absorption and increasing plasma drug levels

Schizophrenia and maintaining stability in schizophrenia; acute Tx of BP mania/mixed states

- 15-30 mg/day - lower doses may be needed to avoid akathisia/activation and for max tolerability - if patient is switched from another AP to ARI, consider adding a full dose of ARI to the maintenance dose of 1st AP for several days prior to a slow down-titration of the 1st drug

Schizophrenia and maintaining response; acute agitation associated with schizophrenia; acute mania; BP maintenance; acute agitation associated with BP-I mania; BP depression

- 10-20 mg/day (oral or IM) - start with 5-10 mg 1X/day, then increase by 5 mg/day 1X/week until desired efficacy is reached - raising the usual dose to 15 mg/day can be efficacious for agitated or Tx- resistant patients with little SE - for IM dosing: start with 10 mg, followed by 2nd injection of 5-10 mg given 2 hrs later; do not take more than 20 mg/day and no more than 3 injections/24 hrs - for non-responding patients dose can be increased to 30 mg/day (which is above approved limit of 20 mg/day)

Schizophrenia; acute mania; BP depression

- for acute BP mania: 400-800 mg/day in divided doses - on 1st day, start dosing with 2X/day with max of 100 mg/day total, then increase in increments of 100 mg/day to 400 mg/day on day 4, adjust dosage up to 800 mg/day by day 6 - is often underdosed; initial doses of 400-800 mg/day might optimize chances of success in acute mania; higher doses generally achieve greater response, some patients may need more than 800-1000 mg/day

Schizophrenia and delaying relapses in schizophrenia; other psychotic disorders; acute mania

- 2-8 mg/day orally for acute psychosis and BPD - 0.5-2.0 mg/day for children/elderly - 25-50 mg depot IM every 2 wks - start with 1 mg/day in 2 doses, increase each day by 1 mg/day until desired efficacy is reached; max effect seen at 4-8 mg/day; max oral dose is 16 mg/day - can decrease dose in patients with SE without loosing efficacy; best efficacy seen around 2-6 mg/day orally - only use long-acting risperidone if patients tolerate 2mg/day oral risperidone

MOA: complex; alters sodium transport across cell membranes in nerve and muscle cells; inhibits NT via phosphatidyl inositol 2nd messenger system

Lamotrigine (La) – Anticonvulsant Ca++ Na+

K+

Na+ channel unit

MOA: blocks VSSCs; interacts with open channel conformation of VSSCs at the alpha pore-forming subunit; inhibits Glu release

(BP depression, adjunctive Tx in major depressive disorder, vascular headache, neutropenia)

(BD depression; BP mania (adjunctive and 2nd line); psychosis; adjunctive Tx in schizophrenia)

glu

Valproate (Val) – Anticonvulsant; mood stabilizer Na+ Ca++

MOA: increases brain concentrations of GABA by blocking VSSCs

(BP depression; psychosis; adjunctive Tx in schizophrenia)

glu GABA

Carbamazepine (CBZ) -- Anticonvulsant Ca++ Na+ K+

GABA

MOA: blocks VSSC; interacts with open channel conformation of VSSCs at the alpha pore-forming subunit; inhibits Glu release

(BPD; psychosis; adjunctive Tx in schizophrenia)

Na+ channel unit

Chlorpromazine (Chlor) -- Conventional AP M1

MOA: blocks D2 receptors; combo of D2, H1 and cholinergic M1 blockade in vomiting center may reduce nausea/vomitin

H1 1

D2

Ziprasidone (ZIP) -- AAP; mood stabilizer A T1 5H PA

5HT2A

1

5HT1D

SRI

NRI

5HT2C

D2 5HT

7

D3

MOA: blocks D2 and 5-HT2A receptors; interactions at 5-HT2C; 5-HT1A and 1D receptors may contribute to efficacy in cognitive and affective symptoms

Aripiprazole (ARI) -- Partial DA agonist; mood stabilizer A T1 5H PA

5HT2A

D2 D3

PA

MOA: D2 partial agonist; D3 agonist, 5-HT1A partial agonist; 5-HT2A antagonist which could lead to enhanced DA release in certain brain regions

Olanzapine (OLZ) -- AAP; mood stabilizer X

M1

M3

H

5HT2A

1

1

5HT2C

3

D2

5H

T6

5HT

D1

D4

D3

MOA: blocks D2 and 5-HT2A receptors, causing site-specific enhancement of DA release; has antagonist actions at 5-HT2C receptor

Quetiapine (QUE) -- AAP; mood stabilizer T1 5H

MOA: blocks D2 and 5-HT2A receptors, causing site-specific enhancement of DA release; also acts at 5-HT1A receptors, which could improve cognitive and affective symptoms

A X?

PA

M1

M3? H

5HT2A

1

1 2

5H

5HT 7

T6

D2

Risperidone (RIS) -- AAP; mood stabilizer X?

5HT2A

1 2

5HT7

D2

MOA: blocks D2 and 5-HT2A receptors, causing site-specific enhancement of DA release; alpha2 antagonist properties may lead to AD action

(BPD)

(BP maintenance; BP depression; behavioral disturbances in children and adolescents; disorders associated with impulse control, and other psychotic disorders

(BP depression; various behavioral disturbances; disorders associated with problems with impulse control; BP maintenance)

(other psychotic disorders; AD-resistant unipolar depression; various behavioral disturbances; disorders associated with problems with impulse control)

(other psychotic disorders; BP maintenance; various behavioral disturbances including in Parkinson’s disease; disorders associated with problems with impulse control)

(BP maintenance and BP depression; various behavioral disturbances; disorders associated with problems with impulse control)

Table 3: Drugs used in the treatment of BPD, their mechanism of action, FDA-approved doses, and side effects and special considerations. *these drugs have additional FDA-approved uses not mentioned in the table. For additional information please refer to Stahl SM (2005) Essential Psychopharmacolgy. The Prescriber's Guide. Cambridge: Cambridge University Press. (1) Risk categories in Pregnancy -- Risk Category C: some animal studies show adverse effect, no controlled studies available in humans; Risk Category D: positive evidence of risk to human fetus, during 1st trimester may increase risk of neural tube defects or congenital anomalies

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Side Effects and Special Considerations (SC) Most common: ataxia, dysarthria, delirium, tremor, memory problems, polyuria and polydipsia (nephrogenic diabetes insipidus), diarrhea, nausea, and weight gain Life-threatening: lithium toxicity, renal impairment, cardiovascular changes SC: closely monitor patients as therapeutic window is very narrow; not recommended in patients with renal and cardiac impairments; elderly will most likely require lower dose and may be more sensitive to SE; no safety and efficacy assessment in children under 12; risk category D in pregnancy(1); discontinue drug or bottle feed BUT lithium is very effective at decreasing suicide attempts in unipolar, BP-I and BP-II patients and often under-prescribed as it is an old drug Most common: benign rash (+/- 10%), sedation, blurred vision, dizziness, ataxia, headache, tremor, insomnia, poor coordination, fatigue, nausea, vomiting, abdominal pain Life-threatening: serious rash with greater risk in pediatric patients SC: use caution when giving to patients with renal, hepatic or cardiac impairment; elderly will most likely require lower dose and may be more sensitive to SE; risk category C in pregnancy(1); discontinue drug or bottle feed; may be best first line Tx for BP depression, appears effective at preventing both manic and depressive relapses; may be best tolerated mood stabilizer with little weight gain or sedation; use lamotrigine at ½ dose when given with valproate as valproate can double lamotrigine levels Most common: sedation, tremor, dizziness, ataxia, asthenia, headache, abdominal pain, nausea, vomiting, diarrhea, constipation, alopecia (unusual) Life-threatening: rare hepatotoxicity with liver failure (especially in children under 2), rare and sometimes fatal pancreatitis SC: be alert to symptoms of hepatotoxicity and pancreatitis; contraindicated in patients with hepatic impairment; elderly will most likely require lower dose; look for sedation in elderly and monitor fluid intake and nutritional intake; not generally indicated for children under 10; risk category D in pregnancy(1); drug found in breast milk, but generally safe to continue breastfeeding if infant is monitored for adverse effects; 1st line of Tx and best for patients with mixed states of BPD or with rapid cycling BPD; more effective in Tx of manic versus depressive episodes of BPD; may be more effective in preventing manic versus depressive relapses; also used to treat aggression, agitation and impulsivity in BPD and schizophrenia. When valproate is given in combination with lamotrigine, reduce lamotrigine to ½ the dose, as valproate can double lamotrigine levels Most common: sedation, dizziness, confusion, unsteadiness, headache, nausea, vomiting, diarrhea, benign leucopenia (up to 10%), rash Life-threatening: rare aplastic anemia, agranulocytosis, rare but severe dermatologic reactions, SIADH SC: monitor patients for signs of unusual bleeding and bruising; use with caution in patients with renal, hepatic and cardiac impairment; elderly patients may tolerate lower doses better; approved to be used in children for epilepsy with the same therapeutic plasma levels as in adults; risk category D in pregnancy(1); discontinue drug or bottle feed; 1st anticonvulsant widely used for Tx of BPD, but use is declining; may be effective in people who fail to respond to lithium or other mood stabilizer; preferred as 2nd or 3rd line treatment for mania; not clearly effective for depressed phase of BPD Most common: neuroleptic-induced deficit syndrome, akathisia, priapism, EPS, parkinsonism, TD, galactorrhea, amenorrhea, dizziness, sedation, impaired memory, dry mouth, constipation, decreased sweating, sexual dysfunction, hypotension, tachycardia, syncope, weight gain Life-threatening: rare neuroleptic malignant syndrome, rare jaundice, agranulocytosis, rare seizures SC: use with caution in patients with renal and hepatic impairment; cardiovascular toxicity or orthostatic hypotension may occur; use lower doses in elderly patients and monitor them; use cautiously in children and adolescents; risk category C in pregnancy(1); discontinue drug or bottle feed; dystonia, TD and sedation have been observed in breastfed infants Most common: dizziness, EPS, sedation, dystonia, nausea, dry mouth, asthenia, skin rash, rare TD, orthostatic hypotension Life-threatening: rare neuroleptic malignant syndrome and rare seizures SC: no dose adjustment needed in patients with renal or hepatic impairment; contraindicated in patients with cardiac impairment, especially with a history of QTc prolongation; not officially recommended for patients under the age of 18, but may be safe and effective for behavioral disturbances in children and adolescents if monitored closely; risk category C in pregnancy(1); unknown if ZIP found in breast milk, best to discontinue drug or bottle feed; well-accepted in clinical practice, especially if weight gain is an issue, causes less weight gain than other AAP; monitor patient even though less risk of diabetes and dyslipidemia; more activating that other AP at low doses, and 1 of only 2 AP with a short-acting IM formulation

Most common: dizziness, insomnia, akathisia, activation, nausea, vomiting, occasional orthostatic hypotension, theoretical risk of TD Life-threatening: rare neuroleptic malignant syndrome, rare seizures SC: dose adjustment not necessary in patients with renal and hepatic impairment; use in patients with cardiac impairment not studied; not officially recommended for patients under 18, but clinical experiences suggest it is safe and effective; risk category C in pregnancy(1), probably found in breast milk, best to discontinue drug or bottle feed; well accepted in clinical practice especially as it results in less weight gain, and leads to less sedation as most AP; may not have diabetes or dyslipidemia risk; favorable tolerability profile Most common: risk for diabetes mellitus and dyslipidemia, dizziness, sedation, dry mouth , constipation, weight gain, joint, back and chest pain, abnormal gait, peripheral edema, tachycardia, rare orthostatic hypotension, rare TD, rare rash due to sunlight exposure Life-threatening: hyperglycemia, rare cases associated with ketoacidosis or hyperosmolar coma and death, increased incidence of cerebrovascular event, increased incidence of mortality in elderly patients with dementia-related psychosis, rare neuroleptic malignant syndrome, rare seizures SC: women have decreased clearance of OLZ; lower dose for patients with hepatic impairment and monitor liver function tests; no adjustment for patients with renal impairment; use with caution in patients with cardiac impairment due to orthostatic hypotension; lower dose in elderly; increased risk of stroke in elderly; not officially recommended for children under 18, but clinical experience suggests it is safe for Tx of behavioral disturbances in children and adolescents, if monitored closely; risk category C in pregnancy(1); may be preferable to anticonvulsants during pregnancy; best to discontinue drug or bottle feed, monitor infants closely if breast-fed; useful in Tx-resistant cases, efficacious as augmenting agent to SSRI (fluoxetine) in BP depression; causes more weight gain than other AP; less sedation; cigarette smoking decreases OLZ levels; 1 of only 2 AP with a short-acting IM formulation Most common: may increase risk of diabetes and dyslipidemia, dizziness, sedation, dry mouth, constipation, dyspepsia, abdominal pain, weight gain, tachycardia, orthostatic hypotension Life-threatening: hyperglycemia, in some case with associated ketoacidosis or hyperosmolar coma and death, rare neuroleptic malignant syndrome, rare seizures SC: no dose adjustment in patients with renal impairment; downward dose adjustment in patients with hepatic impairment; use with caution in patients with cardiac impairment due to orthostatic hypotension; lower doses used in elderly; not officially recommended in children under 18; but safe for Tx of behavioral disturbances in children and adolescents, if monitored closely; risk category C in pregnancy(1); may be preferable to anticonvulsants during pregnancy; best to discontinue drug or bottle feed, monitor infants closely if breast fed; preferred AP for psychosis in Parkinson’s disease and Lewy Body dementia; efficacious in Tx-resistant patients, efficacy often underestimated as it is often underdosed; induces more sedation than other APs, no motor SE or prolactin elevation Most common: may increase risk for diabetes and dyslipidemia, dose-dependent EPS, dose-related hyperprolactinemia, rare TD, dizziness, insomnia, headache, anxiety, sedation, nausea, constipation, weight gain, rare orthostatic hypotension, tachycardia, sexual dysfunction Life-threatening: hyperglycemia, sometimes associated with ketoacidosis or hyperosmolar coma and death, increased incidence of cerebrovascular event, increased incidence of mortality in elderly patients with dementia-related psychosis, rare neuroleptic malignant syndrome, rare seizures SC: oral solution not compatible with cola/tea; in patients with renal or hepatic impairment and in elderly start drug at 0.5 mg/day 2X/day for 1 wk, increase to 1 mg/day 2X/day during 2nd wk; look for orthostatic hypotension in patients with cardiac impairment; most frequent AP used in children/adolescents; safe for Tx of behavioral disturbances in children and adolescents, if monitored closely; risk category C in pregnancy(1); may be preferable to anticonvulsants during pregnancy; best to discontinue drug or bottle feed, monitor infants closely if breast-fed; well accepted for Tx of agitation and aggression in elderly demented patients and for behavioral symptoms in children/adolescents; useful in Tx-resistant patients; only AAP to raise prolactin levels; hyperprolactinemia in women with low estrogen could accelerate osteoporosis; monitor sedation and weight gain in pediatric patients; problematic in Parkinson’s disease or Lewy Body dementia; the only AAP with longacting depot formulation Abbreviations: 5-HT=serotonin; 5-HT(1A, 2A, 2C, 1D)=specific serotonin receptors; AAP=atypical antipsychotics; AP=antipsychotic; ARI=aripiprazole; CBZ=carbamazepine; Chlor=chlorpromazine; DA=dopamine; D(2,3)=specific dopamine receptors; EPS=extrapyramidal side effects; GABA=gamma-aminobutyric acid; Glu=glutamate; H1=histamine receptor; hrs=hours; IM=intramuscular; La=lamotrigine; Li=lithium; M1=muscarinic receptor; MOA=mechanism of action; NT=neurotransmitter; OLZ= olanzapine; QUE=quetiapine; RIS=risperidone; SC=special consideration; SE=side effects; SIADH=syndrome of inappropriate antidiuretic hormone secretion; TD=tardive dyskinesia; Tx=treatment; Val=valproate; VSSCs=voltage-sensitive sodium channels; Wk(s)=week(s); ZIP=ziprasidone.

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When following FDA guidelines does not lead to improvements in patients, clinicians often adopt alternatives depending on the patient’s symptoms, and use drugs off label.62, 63 Because some patients do not readily respond to one treatment or another, physicians have to make educated guesses as to which treatment plan to adopt next. Physicians are even more inclined to use drugs off label when treating BP depression as there are fewer FDA-approved drugs for the treatment of BP depression when compared to BP mania, but the patients

example start with 4–6 mg and not 12–16 mg as per drug insert. Risperidone is advantageous due to its very rapid onset of action, despite the need to watch for extrapyramidal side effects. Low doses (25 mg) of long-acting injections of risperidone are useful in the maintenance treatment of patients, as seen in a recent 12-month follow-up study.65 Both oral and IM formulations of olanzapine are very effective in the treatment of acute mania; however the recommended 10 mg per day is often too low, and needs to be raised to 20 or 30 mg to be efficacious. Olanzap-

When following FDA guidelines does not lead to improvements in patients, clinicians often adopt alternatives depending on the patient’s symptoms, and use drugs off label. spend more time in the depressed state. Additionally, while FDA-approved drugs do show positive results in clinical trials, the doses used in these trials, and thus the doses appearing on the labels, might not always be the most effective ones. Often times the best dosing strategies are determined after the drug has hit the market. Clinical know-how and years of experience has led to off-label use of the drugs mentioned in Table 3 in the treatment of mania or depression in BPD. Intramuscular (IM) injections (10–60 mg) of ziprasidone have robust antimanic effects without the sedative actions of other atypicals, and they allow for easy transitions to oral formulations. After two to three days of 20–40 mg IM ziprasidone, a patient can be switched to 160 mg oral at bed time, and if need be the dose can be titrated up to 240 mg. These doses have been shown to be beneficial in the clinic even if they are much higher than what the drug inserts specify (i.e.160 mg). With drugs such as ziprasidone, it can be tricky to find the correct dose, as both too low and too high of a dose can induce side effects. For oral dosages, it might be best to start with 80 mg at bedtime, and if patients have trouble with insomnia or show side effects such as akathisia, then the drug should be switched to the morning or the dose lowered, respectively. Starting with 80 mg allows the physician to dial up or down depending on the patient’s response. Either way, ziprasidone needs to be taken with food, as this will aid in its absorption and ascertain that the entire dose is actually metabolized. When compared to other atypical antipsychotics, the most clinically significant advantage of ziprasidone is its tendency to induce less or no weight gain.64 If risperidone is chosen in the treatment of acute mania, it is preferable to “start low and go slow;” for

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ine, though, can be problematic due to its metabolic side effects and weight gain. Olanzapine in combination with the SSRI fluoxetine, is one of two drugs that has been FDA-approved for BP depression. The other drug approved for the treatment of BP depression is quetiapine. On label, quetiapine, can be used as first line monotherapy at a dose of 300 mg/day, however, this dose can induce sedation and weight gain. The weight gain with quetiapine is linear, thus lowering the dose can reduce weight issues. Off label, quetiapine can be used at lower doses and in combination with other mood stabilizers or atypical antipsychotics for the treatment of disorders along the bipolar spectrum. It can be advantageous to use atypicals as monotherapy in BP depression as there is no risk of switching patients into mania. The doses of quetiapine needed to treat acute mania are quite high (400–800 mg), can be sedating and may have effects on the metabolic system. The slow release formulation of quetiapine has been approved for the treatment of schizophrenia and might be advantageous in BPD as well. Finally, aripiprazole is an interesting drug and has often been termed the “atypical atypical” because it has the unique pharmacology of being a partial DA agonist or “DA system stabilizer.” Aripiprazole is available in tablets, oral solution and as an IM formulation. While the oral formulation is normally used for acute and maintenance treatment of schizophrenia and BPD, the IM formulation lends itself well for the treatment of agitation in both disorders.66 While aripiprazole is effective and exhibits fewer side effects than some of the other atypicals, it can be hard to dose properly due to its non-linear dose response curve. To treat mania the strategy for in-patients is to use a loading dose of 30 mg at bedtime; however, this treatment regimen can be tricky for out patients especially if they are hypomanic. Additionally, the doses should be lowered for mixed states. When it comes to dosages for the treatment of

BP depression, the off label use with aripiprazole is only 5 mg, which is much lower than the dose recommended by the manufacturer. D. Antidepressants, combination therapies and treatment-resistant cases The fact that manic patients like their manic state and do not want them to fade away pharmacologically, as they spend most of their time depressed, is a reason why noncompliance is an issue in BPD. At the same time, BP patients rarely respond to only one drug, and thus need a combination of drugs for alleviation of all symptoms. Unfortunately a treatment regimen that requires taking multiple doses at different intervals, might further lead to noncompliance. However, it has been shown that even with complicated treatment regimens, combination therapies can actually increase compliance.67 For the treatment of acute mania in a hospital setting, polypharmacy combining an atypical antipsychotic, a mood stabilizer and possibly a high potency benzodiazepine, is often recommended. The rationale for using combination therapies versus monotherapy in BPD relies on the “symptom-based treatment algorithm,” where a diagnosis is broken into the differ-

sant treatment might be warranted no matter what. Interestingly though, antidepressants, without the addition of mood stabilizers, are the most commonly prescribed drugs in the treatment of BP,69 especially since BP is often initially misdiagnosed as unipolar depression. Gijsman and colleagues performed a systematic review of randomized, controlled trials to get to the point of the “antidepressant issue”.70 Similar to what Goodwin and Jamison had noticed in the ‘90s,71 Gijsman and colleagues showed that different classes of antidepressants appear to have a higher propensity of inducing switches to mania, with tricyclic antidepressants having the highest rates (rate of switching of 10% versus 3.2%, respectively); monoamine oxidase inhibitors inducing less mania than tricyclic antidepressants, and SSRI being most efficacious in treating depression in BPD.70 On the other hand, Ghaemi et al. found that antidepressant treatment in BP versus unipolar depression resulted in more switches to mania and cycle accelerations, and that co-treatment with mood stabilizers only partly prevented the manic switches.72 Recently, the effectiveness of short-term treatment of major depressive episodes in BP patients was evaluated by the National Institute of Mental Health with the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

BP patients rarely respond to only one drug, and thus need a combination of drugs for alleviation of all symptoms. ent symptoms the patient is suffering from, with each symptom being then matched to a certain brain and neurotransmitter pathway causing these symptoms. Pharmacotherapies targeting these different mechanisms can then be used to alleviate each symptom one at a time.9 Thus by looking at the different mechanisms of action of various drugs, it might be useful to use a mood stabilizer in combination with an atypical antipsychotic, or a mood stabilizer, an antipsychotic and an antidepressant or different mood stabilizers. In general, atypical antipsychotics have shown superiority compared to placebo in reducing manic symptoms when given as add-on medication to mood stabilizers with risperidone, olanzapine and quetiapine having the best results.68 Additionally, when using combination therapies it is sometimes possible to reduce the doses of all agents and still get a good response due to the synergy between the drugs,9 which can also lead to fewer and less serious side effects. The use of antidepressants in BP patients is greeted with mixed reviews, with some believing that it might cause the patients to enter hypomania or lead to more cycling. This notion is debated, and depending on the severity of the patient’s symptoms antidepres-

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The study showed that the use of bupropion or paroxetine in conjunction with a mood stabilizer was as efficacious as a mood stabilizer alone when treating BP depression, and that neither treatment option led to an increase in switches to mania. Unfortunately, though, the study did not look at the use of antidepressants without mood stabilizer.73 In general, patients on an antidepressant in addition to a mood stabilizer or an atypical antipsychotic were more likely to respond and reach remission, supporting a positive efficacy for antidepressants in BPD.70 Finally the selegiline transdermal system might be an interesting choice in the treatment of BP depression, as it does not lead to manic switches at low doses. There are however various drug-drug interactions to be aware of with the patch formulation.74 Thus it has become accepted that when an antidepressant is to be used, it is best to first start patients on a mood stabilizer and then add the antidepressant as this might reduce the risk, if any, of a manic switch, and because the mood stabilizer itself can prove to have antidepressive action.75 Additionally the switch rate is much lower in BP-II than in BP-I patients, suggesting that antidepressant treatment in BP-II patients may be accepted, especially in light of the fact that BP-II patients spend more time in the depressed state.75 Figure 3 exemplifies the most common, but certainly not

the only, combinations of drugs used by clinicians that have both evidence- and practicebased rationales, and that have been the most efficacious.9 Rationale differences between various drug combinations might also exist depending on the geographical location of physicians and patients (Boston Bipolar Brew; California Careful cocktail or Tennessee mood shine).9 Finally, various other agents need to be mentioned, as studies are currently underway to determine their efficacy in the treatment of BPD. These include memantine and amantadine, both NMDA glutamate receptor antagonists, with amantadine having the additional property of releasing DA. Consistent data however are still required to ascertain their efficacy in BPD. The anesthetic ketamine might be an interesting drug for treatment-resistant depression in BPD, as it shares the NMDA receptor antagonism of the two previous drugs, and has also proven beneficial in treatmentresistant unipolar depression.76 By blocking phosphokinase C activity, omega-3 fatty acids share their mechanism of action with valproate. Despite a high heterogeneity in results, omega-3 fatty acids have shown to be efficacious in unipolar and BP depression and they have additional health benefits important for psychiatric patients.77 Inositol might be useful as an augmenting agent to an antidepressant, especially as this product is also linked to the signal transduction cascade of 5-HT2A receptors; one of the main receptors of atypical antipsychotics. L-methylfolate, the active form of the folate vitamin, can increase levels of 5-HT, DA and NE and has shown to enhance the therapeutic efficacy of antidepressants.78 Additionally some patients may lack folate vitamin, as anticonvulsants can interfere with both the absorption and the metabolism of folate, thus adding it to anticonvulsants might be a good idea. Finally the T3 thyroid hormone has shown mood stabilizing properties in some patients but should be studied in more detail. The DA D2/D3 agonist pramipexole, currently FDA-approved for the treatment of Parkinson’s disease and Restless Leg Syndrome, has been tested in the treatment of BPD, because its mechanism of action of enhancing DA release and having neurotrophic effects could potentially be very useful in BPD. When added to mood stabilizers, such as lithium and valproate, pramipexole (at a dose between 0.375–4.5 mg/day) significantly reduces depressive symptoms

Evidence Based Bipolar Combos

+ atypical-lithium combo

atypical

lithium

DPA

+ atypical-valproate combo

atypical

valproate divalproex

DPA

Practice Based Bipolar Combos

+ Li-Do

divalproex

lithium

+ La-Do

lamotrigine

caution

divalproex

+ La-Li

lamotrigine

lithium

+

+ La-Li-Do

lamotrigine

divalproex

lithium

Boston bipolar brew (any combo but antidepressant)

caution

antidepressant

+

California careful cocktail (any combo with antidepressant)

antidepressant

caution

+ Tennessee mood shine (atypical + antidepressant)

atypical

antidepressant

Buckeye Bipolar Bullets

lamotrigine monotherapy

stealth treatment

+ lami-quel

Lamictal/ lamotrigine

Seroquel/ quetiapine

+

quel kit (any combo containing quetiapine)

quetiapine

+ modafinil lamotrigine

+ modafinil

+

modafinil combo

+ lamotrigine/Quetiapine

antidepressant

reluctant combo

Figure 3: Different drug combinations used in the treatment of bipolar disorder.

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+

quetiapine modafinil lamotrigine

quetiapine

in BP-II patients.79 In 67% of patients, pramipexole when given in addition to lithium, valproate, carbamazepine, lamotrigine, and/or topiramate, leads to a 50% reduction in depressive symptoms with a median response time of four weeks.80 The use of pramipexole in the treatment of depression in treatmentresistant BP patients appears to be safe overall; however patients should be monitored for the occurrence of manic episodes.81 E.

Psychosocial therapies

It can be very tricky to impossible to treat manic patients with psychotherapy, as they might not be receptive to it. Psychotherapy is most efficacious when patients are euthymic or depressed. There are different types of psychosocial therapies available and the main goal is to educate the patients about how their lifestyle can impact their disorder. For some patients, psychotherapy can be a good alternative to polypharmacy as it does not have any side effects. It is important to note, though, that psychosocial therapy requires trained clinicians and can be expensive.

rate of relapses, of both manic and depressive episodes, and had fewer hospitalizations than patients in the control group.86 Interestingly, when PE is given to the family and caregivers, it not only allows the family to understand and support the patient, but this added support also translates into better outcomes for the patients, such as lower rate of relapse, longer inter-episodes intervals and better treatment adherence.87 Finally, suicide attempts are significantly reduced in patients on pharmacotherapy, especially lithium, when it is coupled with PE, as the patients can better recognize the beginning of a relapse and they feel supported by the environment providing this education.88 ii.

Cognitive-behavior therapy

Cognitive-behavior therapy (CBT) was originally developed and used in the treatment of unipolar depression, and focuses on changing the patient’s bad behaviors that could lead to further mood episodes. When adapted for BPD, CBT aims at

When PE is given to the family and caregivers, it not only allows the family to understand and support the patient, but this added support also translates into better outcomes for the patients, such as lower rate of relapse, longer inter-episodes intervals and better treatment adherence.

i.

Psychoeducation

The goal of psychoeducation (PE) is 1) to provide the patient with information about the illness and 2) to render the patient an active collaborator in the treatment of the illness.82, 83 Helping the patients understand the history of their disease will allow for better recognition of future symptoms. Additionally, enticing the family to participate in this education is very important as a broader understanding of the disease by all affected members leads to better treatment. It is best if PE is given to the patients during a euthymic phase, mainly as a prophylactic treatment, as this will increase information assimilation.82, 83 Different positive results have been obtained by combining PE with pharmacotherapy, such as better compliance to lithium therapy and less variable serum levels.84 While some studies show improvement only in the manic or only in the depressive state of BP following PE, a recent study favored PE as it improved mood stability in general and prevented relapses up to one year in 80% of the patients.85 Patients undergoing PE presented with a lower

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increasing awareness of mood, recognizing subsyndromal symptoms and signs of upcoming episodes, and preventing the escalation to full blown episodes.88, 89 Adding CBT to pharmacotherapy results in better adherence to medical treatment, fewer hospitalizations and relapses and less fluctuations in mood.90, 91 iii.

Family-focused treatment

The family-focused therapy (FFT) was developed by Miklowitz and colleagues and combines PE with communication skills training and problem solving along with an assessment of the family, as family emotions, which tend to be unsupportive, can induce relapses in patients.89, 92 FFT appears to be useful in addition to pharmacotherapy, and patients undergoing FFT show fewer relapses, longer time to relapse, improvement in depressive symptom and more medication adherence over a two-year period.87, 93

iv.

Interpersonal and social rhythm therapy

family and society, and therefore we need to improve our knowledge about the disease and its treatments.

An adaptation from the interpersonal therapy by Frank and colleagues94 led to the development of the Interpersonal and social rhythm therapy (IPSRT) for BPD, a specifically designed treatment therapy that includes PE, social rhythm therapy and interpersonal psychotherapy with a special emphasis on understanding the link between mood and life events and their impact on BPD.89 When offered in conjunction with lithium, IPSRT has been shown to significantly reduce suicidality over a two-year period.88 Thus psychosocial therapies in general, when given in addition to pharmacotherapy, are beneficial in reducing the number of relapses, increasing the interval between relapses and increasing treatment adherence, as well as educating the patient and the family about disease progression and the importance of treatment. F.

Reference List 1. 2. 3. 4. 5. 6.

7. 8. 9. 10. 11. 12. 13. 14. 15.

Treatment of the “at risk” population

16.

In patients with comorbid substance use, treatment can often be difficult, mainly because of noncompliance. In a recent pilot study on BP patients abusing cocaine, it was determined that valproate significantly improved the percentage of cocaine and alcohol abstinent days and significantly decreased the use of marijuana. Additionally, significant improvements were observed in manic, depressive and sleep symptoms.95 Valproate has also been shown to be beneficial in reducing the number of days drinking and the number of drinks per day in BP patients suffering from comorbid alcohol abuse.96 Thus in a population of patients suffering from BP as well as substance use, it is beneficial to treat both diseases at the same time, as improvement in one may facilitate remission in the other. Valproate and lithium are also beneficial in treating BPD in children and adolescents;97 and the use of antidepressants without a mood stabilizer should be limited in this patient population, as there is a higher risk of inducing switches, and of suicidality in these fragile patients. 5. Summary and Conclusion

17. 18. 19. 20. 21.

22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

BPD is difficult to diagnose and treat, but better diagnostic tools, more awareness and more studies investigating different treatment regimens, such as “real-life” combination therapies, in different patient populations (the young, the elderly) should enhance treatment outcomes. Systematic monitoring can also help in the treatment of patients, as the more often the patient is seen by a physician, the better picture the doctor will have to adequately adjust treatment plans. BPD has a devastating impact on the patient, their

36. 37. 38. 39. 40. 41. 42.

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Calabrese JR et al., J Clin Psychiatry 64, 425 (2003). Kessler RC et al., Arch Gen Psychiatry 51, 8 (1994). Angst J, Journal of Affective Disorders 50, 143 (1998). Berk M, Berk L, Moss K, Dodd S, Malhi GS, Med J Aust 184, 459 (2006). Kessler RC et al., Journal of Affective Disorders 96, 259 (2006). APA, Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, Washington, DC, ed. 4th edn; text revision, 2000). WHO. WHO ICD-10. 2007. Hirschfeld RMA et al., J Clin Psychiatry 64, 53 (2003). Stahl SM, Essential Psychopharmacology.3rd Edition, in press. Judd LL et al., Archives of General Psychiatry 59, 530 (2002). Serretti A, Olgiati P, Journal of Affective Disorders 84, 159 (2005). Judd LL et al., Journal of Affective Disorders 73, 19 (2003). Akiskal HS, Azorin JM, Hantouche EG, Journal of Affective Disorders 73, 7 (2003). Benazzi F, Akiskal HS, Journal of Affective Disorders 73, 59 (2003). Dunner DL, Bipolar Disorders 5, 456 (2003). Wyatt RJ, Henter I, Soc Psychiatry Psychiatr Epidemiol 30, 213 (1995). Benazzi F, Progress in Neuro-Psychopharmacology and Biological Psychiatry 31, 97 (2007). Benazzi F, Progress in Neuro-Psychopharmacology and Biological Psychiatry 30, 1043 (2006). Dilsaver SC, Chen YW, Swann AC, Shoaib AM, Krajewski KJ, Am J Psychiatry 151, 1312 (1994). Dunner DC, Fieve RR, Arch Gen Psychiatry 30, 229 (1974). APA, Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, Washington, DC, ed. 4th edn, 1994). Alarcon RD, Comprehensive Psychiatry 26, 522 (1985). Kramlinger KG, Post RM, British Journal of Psychiatry 168, 314 (1996). Papadimitriou GN, Calabrese JR, Dikeos DG, Christodoulou GN, Int J Neuropsychopharmacol 8, 281 (2005). Tondo L, Baldessarini RJ, Am J Psychiatry 155, 1434 (1998). Baldessarini RJ, Tondo L, Floris G, Hennen J, Journal of Affective Disorders 61, 13 (2000). Kupka RW, Luckenbauch DA, Post RM, Leverich GS, Nollen WA, J Clin Psychiatry 64, 1483 (2003). Koukopoulos A et al., Journal of Affective Disorders 73, 75 (2003). Coryell W et al., Archives of General Psychiatry 60, 914 (2003). Regier DA et al., JAMA 264, 2511 (1990). Bizzarri JV et al., Bipolar Disorders 9, 213 (2007). Grant BF et al., Archives of General Psychiatry 61, 807 (2004). Feinman JA, Dunner DL, Journal of Affective Disorders 37, 43 (1996). Judd LL et al., Archives of General Psychiatry 60, 261 (2003). Benazzi F, Psychopathology 40, 54 (2007). Bowden CL, Psychiatr Serv 52, 51 (2001). Geller B et al., Journal of Child and Adolescent Psychopharmacology 10, 157 (2000). Birmaher B, Axelson D, Development and Psychopathology 18, 1023 (2006). Ghaemi SN, Boiman EE, Goodwin FK, J Clin Psychiatry 61, 804 (2000). Mintz J, Mintz LI, Arruda MJ, Hwang SS, Arch Gen Psychiatry 49, 761 (1992). Altshuler LL et al., J Clin Psychiatry 67, 1551 (2006). Frye MA et al., J Clin Psychiatry 67, 1721 (2006).

43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62.

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67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86.

Akiskal HS, F. Benazzi, J Clin Psychiatry 66, 914 (2005). Dunner DL, Tay KL, Comprehensive Psychiatry 34, 303 (1993). Allilaire JF et al., Encephale 27, 149 (2001). Akiskal HS et al., Journal of Affective Disorders 96, 197 (2006). Hantouche EG et al., Journal of Affective Disorders 50, 163 (1998). Denicoff KD et al., Depression and Anxiety 15, 1 (2002). Hirschfeld RMA et al., Am J Psychiatry 157, 1873 (2000). Manji HK et al., World Psychiatry 2, 136 (2003). Berns GS, Nemeroff CB, American Journal of Medical Genetics Part C (Semin. Med. Genet. ) 123C, 76 (2003). American Psychiatric Association, Am J Psychiatry 159, 1 (2002). Goodwin GM, for the Consensus Group of the British Association for Psychopharmacology, J Psychopharmacology 17, 149 (2003). Yatham LN et al., Bipolar Disorders 8, 721 (2006). Stahl SM, Essential Psychopharmacolgy. The Prescriber's Guide (Cambridge University Press, Cambridge, 2005). Baldessarini RJ, Tondo L, Hennen J, J Clin Psychiatry 64, 44 (2003). Smith LA, Cornelius V, Warnock A, Bell A, Young AH, Bipolar Disorders 9, 394 (2007). Montes JM, Saiz-Ruiz J, Lahera G, Asiel A, Journal of Affective Disorders 86, 69 (2005). Muzina DJ, Elhaj O, Gajwani P, Gao K, Calabrese JR, Acta Psychiatrica Scandinavica 111, 21 (2005). Goldberg JF et al., Biological Psychiatry In Press, Corrected Proof, (2007). Shayegan DK, Stahl SM, CNS Spectrums 9, 6 (2004). Neuroscience Education Institute. Distinguishing the Diagnosis and Treatments for Bipolar Mania, Mixed Mania, and Difficult-to-Treat Depression within the Bipolar Spectrum. 2005. NEI Press. Neuroscience Education Institute. Bipolar Disorder: Differential Diagnosis Problems and Novel Treatment Choices in Adults and Children. 2006. NEI Press. Sages of Psychopharmacology. Greenberg WM, Citrome L, CNS Drug Reviews 13, 137 (2007). Han C et al., Progress in Neuro-Psychopharmacology and Biological Psychiatry 31, 1219 (2007). McIntyre RS, Soczynska JK, Woldeyohannes HO, Miranda A, Konarski JZ, Expert Opinion on Pharmacotherapy 8, 1001 (2007). Sajatovic M, Valenstein M, Blow F, Ganoczy D, Ignacio R, Psychiatr Serv 58, 855 (2007). Scherk H, Pajonk FG, Leucht S, Archives of General Psychiatry 64, 442 (2007). Ghaemi SN, Ko James y, Goodwin FK, Journal of Psychiatric Practice 7, 287 (2001). Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM, Am J Psychiatry 161, 1537 (2004). Goodwin FK, Jamison KR, Manic depressive illness (Oxford University Press, New York, 1990). Ghaemi SN et al., Am J Psychiatry 161, 163 (2004). Sachs GS et al., N Engl J Med 356, 1711 (2007). Rapaport MH, J Clin Psychiatry 68, 31 (2007). Goldberg JF, J Clin Psychol 63, 475 (2007). Zarate CA Jr. et al., Archives of General Psychiatry 63, 856 (2006). Freeman MP et al., J Clin Psychiatry 67, 1954 (2006). Abou-Saleh MT, Coppen A, Journal of Psychosomatic Research 61, 285 (2006). Zarate CA et al., Biological Psychiatry 56, 54 (2004). Goldberg JF, Burdick KE, Endick CJ, Am J Psychiatry 161, 564 (2004). Sharma V, Smith A, Am J Psychiatry 164, 351 (2007). Elger G, Hoppe C, Falkai P, Rush AJ, Elger CE, Epilepsy Research 42, 203 (2000). Rouget BW, Aubry JM, Journal of Affective Disorders 98, 11 (2007). Colom F et al., Bipolar Disorders 7, 32 (2007). de Andres RD et al., Journal of Affective Disorders 93, 253 (2006). Colom F et al., Archives of General Psychiatry 60, 402 (2003).

87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97.

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Abbreviations: 5-HT=serotonin; 5-HT(1A, 2A, 2C, 1D)=specific serotonin receptors; AAP=atypical antipsychotics; AD=antidepressants; AP=antipsychotic; APA=American Psychiatric Association; ARI=aripiprazole; BAD=Bipolar Affective Disorder; BAP=British Association of Psychopharmacology; BPD=Bipolar Disorder; BSP=Bipolar Spectrum Disorder; BP-I=Bipolar I disorder; BP-II=Bipolar II disorder; BP-NOS=Bipolar disorder not otherwise specified; CANMAT=Canadian Network for Mood and Anxiety Treatments; CBT=Cognitive-Behavior Therapy; CBZ=carbamazepine; Chlor=chlorpromazine; Cloz=clozapine; DA=dopamine; D(2,3)=specific dopamine receptors; DSM-IV (TR)=Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision; ECT=electroconvulsive therapy; EPS=extrapyramidal side effects; FDA=Food and Drug Administration; FFT=Family-Focused Treatment; FGA=first generation antipsychotic; GABA=gamma-aminobutyric acid; Glu=glutamate; H=histamine; H1=histamine receptor; IM=intramuscular; IPSRT=Interpersonal and Social Rhythm Therapy; La=lamotrigine; Li=lithium; M1=muscarinic receptor; ME=mixed episodes; MOA=mechanism of action; Na=sodium; NE=norepinephrine; NMDA=N-methyl-d-aspartate; NIMH-LCM-p=National Institute of Mental Health daily prospective Life-Chart Method; NT=neurotransmitter; OLZ=olanzapine; PE=Psychoeducation; QUE=quetiapine; RIS=risperidone; SC=special consideration; SE=side effects; SGA=second generation antipsychotics; SIADH=syndrome of inappropriate antidiuretic hormone secretion; SSRI=selective serotonin reuptake inhibitor; TD=tardive dyskinesia; Tx=treatment; Val=valproate; VSSCs=voltage sensitive sodium channels; Wk=week; WHO ICD-10=World Health Organization International Classification of Diseases Version 10; ZIP=ziprasidone.

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Posttest and Activity Evaluation To receive your certificate of CME credit or participation, please complete the posttest and activity evaluation answer sheet found on the back cover flap and return by postage-paid mail or fax it to 760-931-8713. Upon receipt, your posttest will be graded and, along with your certificate (if a score of 70% or more was attained), returned to you by mail. Alternatively, you may complete these items online and immediately print your certificate at www.neiglobal.com/pt/07bipolarmonograph. (Please circle the correct answer on the answer sheet provided.) 1. Compared to patients with BP-I, patients with BP-II A. B. C. D. E.

7. The usual clinical profile of a BP-II patient is:

Spend more time in the depressed state Spend less time cycling or in a mixed state Spend more time in the manic state A and B B and C

A. B. C. D. E.

2. Children and adolescents with bipolar disorder

Being a woman Having a manic episode at onset Hyperthymic temperament A and C A, B and C

8. Which statement is false?

A. Have shorter episodes, and are often misdiagnosed

A. Psychoeducation works best in depressed patients as

with attention deficit disorder B. Have longer episodes, and are often misdiagnosed with attention deficit disorder C. Are never misdiagnosed with attention deficit disorder D. Always adhere to their treatment

they are more willing to assimilate new information B. Psychoeducation combined with pharmacotherapy

shows positive results C. Psychoeducation is beneficial in decreasing treatment

adherence, the number of relapses and the relapse interval D. Involving the family through psychoeducation can be helpful to the patient

3. Which of the following drugs are normally started at a

lower dose than the package insert recommends? A. B. C. D.

9. When co-administering valproate and lamotrigine, one

Risperidone and olanzapine Aripiprazole and olanzapine Risperidone and aripiprazole Quetiapine and olanzapine

needs to be cautious, because: A. B. C. D.

4. The rate of suicide attempts is greatest in which

Lamotrigine can double the levels of valproate Both drugs act as agonists at the glutamate receptors Valproate can double the levels of lamotrigine Both drugs should be given at lunch time

disorder? 10. Which 2 antipsychotics have intramuscular

A. Unipolar depression B. Bipolar I C. Bipolar II

formulations? A. B. C. D.

5. According to the DSM-IV the parameters for rapid

cycling are as follows:

Ziprasidone and aripiprazole Quetiapine and risperidone Ziprasidone and risperidone Olanzapine and ziprasidone

A. Mania that lasts 3 days, hypomania that lasts 3 11. Which antipsychotic does not act at the 5-HT1A

days; depression that lasts 3 days; with at least four episodes in one month B. Mania that lasts 1 week, hypomania that lasts 4 days; depression that lasts 2 weeks; with at least four episodes in one year C. Mania that lasts 24 hours, hypomania that lasts 24 hours; depression that lasts 3 days; with many episodes in one month

receptor? A. B. C. D. E. F.

6. Ultradian cycling refers to: A. Circadian rhythm of the patient B. Ultra ultra rapid cycling that lasts less than 24 hours C. Switching between treatment therapies in BP patients

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Olanzapine Aripirazole Risperidone Ziprasidone A and C B and D

Insights into the Diagnosis and Treatment of Bipolar Disorder Posttest and Activity Evaluation To receive your certificate of CME credit or participation, please complete the posttest (you must score at least 70% to recieve credit) and activity evaluation answer sheet found on this page and return by postage-paid mail or fax it to 760-931-8713. Upon receipt, your posttest will be graded and, along with your certificate, returned to you by mail. Alternatively, you may complete these items online and immediately print your certificate at www.neiglobal.com/pt/07bipolarmonograph. (Circle the correct answers)

Posttest 1.

A

B

C

D

2.

A

B

C

3.

A

B

C

4.

A

B

5.

A

6.

A

E

7.

A

B

C

D

D

8.

A

B

C

D

D

9.

A

B

C

D

C

10.

A

B

C

D

B

C

11.

A

B

C

D

B

C

E

E

F

Activity Evaluation Please rate the following, using a scale of: 1-poor

2-fair

3-good

4-very good

5-excellent

1.

The overall quality of the content was…

1 2 3 4 5

2.

The relevance of the content to my professional needs was…

1 2 3 4 5

3.

The level at which the learning objective was met of teaching me to track history and progression of symptoms and treatment responses for patients with mood/behavioral symptoms

1 2 3 4 5

4.

The level at which the learning objective was met of teaching me to select mood stabilizers and their doses based on patient presentation

1 2 3 4 5

5.

The level at which the learning objective was met of teaching me to use neurobiologic and mechanistic rationale when combining medications to treat bipolar spectrum disorders

1 2 3 4 5

6.

The level at which this activity was objective, scientifically balanced, and free of commercial bias was…

1 2 3 4 5

7.

The overall quality of this activity was…

1 2 3 4 5

8.

Based on my experience and knowledge, the level of this activity was: Too Basic

9.

Basic

Appropriate

Complex

Too Complex

Based on the information presented in this activity, I will: A. B. C. D.

Change my practice Seek additional information on this topic Do nothing as current practice reflects activity’s recommendations Do nothing as the content was not convincing

10. What barriers might keep you from implementing changes in your practice you’d like to make as a result of participating in this activity?

11. The following additional information about this topic would help me in my practice:

12. How could this activity have been improved?

13. Additional comments:

Name:

Credentials:

Specialty: Address: City, State, Zip: Email:

Phone: