Medical Management of Bipolar Disorder A Pharmacologic Perspective

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2011
Differential Diagnosis anD eviDence-BaseD treatment strategies
This supplement was submitted by Albert Einstein College of Medicine, Montefiore Medical Center, CPNP, and Asante Communications, LLC, and supported by educational grants from Eli Lilly and Company and Janssen, Division of Ortho-McNeilJanssen Pharmaceuticals, Inc., administered by Ortho-McNeil Janssen Scientific Affairs. It was peer reviewed by Annals of Clinical Psychiatry.
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Date of Release: November 8, 2010 Date of Credit Expiration: November 7, 2011
This CME/CPE activity is jointly sponsored by Albert Einstein College of Medicine, Montefiore Medical Center, the College of Psychiatric and Neurologic Pharmacists (CPNP), and Asante Communications, LLC. This supplement was submitted by Albert Einstein College of Medicine, Montefiore Medical Center, CPNP, and Asante Communications, LLC, and supported by educational grants from Eli Lilly and Company and Janssen, Division of Ortho-McNeilJanssen Pharmaceuticals, Inc., administered by Ortho-McNeil Janssen Scientific Affairs. It was peer reviewed by Annals of Clinical Psychiatry.
Table of Contents
Faculty and Reviewers ................................................iv Preamble . ......................................................................v Faculty Biographies .....................................................ix Introduction .................................................................. 1 Chapter 1: Differential Diagnosis of Bipolar Disorder.....................................3
Roger S. McIntyre, MD, FRCPC
Chapter 2: Medical Management of Bipolar Disorder: A Pharmacologic Perspective. ...............23

Matthew A. Fuller, PharmD, BCPS, BCPP , FASHP
Chapter 3: Individualizing Treatment for Patients With Bipolar Disorder: Optimizing Efficacy, Safety, and Tolerability.............49
Christoph U. Correll, MD
Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies
iv
Faculty and Reviewers

Course Director and Reviewer, Albert Einstein College of Medicine
Associate Professor of Psychiatry and Behavioral Sciences Department of Psychiatry, Albert Einstein College of Medicine Bronx, New York Medical Director, Recognition and Prevention (RAP) Program Director, Adverse Events Assessment and Prevention Unit Advanced Center for Intervention and Services Research The Zucker Hillside Hospital, Center for Translational Psychiatry Glen Oaks, New York The Feinstein Institute for Medical Research North ShoreLong Island Jewish Health System Manhasset, New York
Course Director and Reviewer, CPNP
Matthew A. Fuller, PharmD, BCPS, BCPP, FASHP

Clinical Pharmacy Specialist, Psychiatry Louis Stokes Cleveland Department of Veterans Affairs Medical Center Brecksville, Ohio Clinical Associate Professor of Psychiatry Clinical Instructor of Psychology Case Western Reserve University Cleveland, Ohio Adjunct Associate Professor of Clinical Pharmacy The University of Toledo Toledo, Ohio

Associate Professor of Psychiatry and Pharmacology University of Toronto Head, Mood Disorders Psychopharmacology Unit University Health Network Toronto, Ontario, Canada
Preamble
Activity Goal
DateofRelease:November 8, 2010 DateofCredit Expiration:November 7, 2011
The goal of this knowledge-based activity is to update healthcare professionals on current strategies for the accurate differential diagnosis, evidence-based treatment, and management of patients with bipolar disorder (BD).
Intended Audiences
This activity is intended for physicians, pharmacists, and other healthcare professionals who diagnose and treat patients with BD. There are no prerequisites for this educational activity.
Statement of Need
BD is a chronic illness requiring long-term treatment to avoid relapse of symptoms and to improve quality of life. The assessment and diagnosis of BD present distinct challenges to psychiatrists. It is estimated that 69% of people with BD have been misdiagnosed; most notably, patients with BD have received a mean of 3.5 other diagnoses and have consulted 4 physicians before being accurately diagnosed.1 Adequate assessment and diagnosis of BD is a pressing area of educational need. Overdiagnosis, or unnecessary diagnosis of BD in patients who do not actually have the disorder, is also a problem. In one survey of patients with BD, more than one-third of patients reported waiting for 10 years or more before receiving a correct diagnosis.1 An oversight of diagnostic criteria may also contribute to the inaccurate diagnoses and thus inappropriate treatment of affected individuals. Indeed, these gaps represent a clear need for further education. BD is a common and serious condition that can be managed with appropriate multimodal treatment; however, patients often receive inadequate treatment. Several guidelines have been published, but a recent survey suggests that 34% of psychiatrists do not use treatment guidelines when managing this patient population and that 24% misinterpret the results of clinical trials.2 Healthcare professionals could thus benefit from clinical education on the importance of appropriate diagnosis, early intervention, evidence-based strategies for nonpharmacologic and pharmacologic treatment, and long-term multidisciplinary management of patients. Accordingly, this multimedia educational activity was designed to place clinicians, pharmacists, and related healthcare providers in a better position to improve outcomes for patients with BD.
References
1. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64:161-174. 2. Perlis RH. Use of treatment guidelines in clinical decision making in bipolar disorder: a pilot survey of clinicians. Curr Med Res Opin. 2007;23:467-475.
This and additional activities are available at
vi
Learners Gap
Growing evidence suggests that early, accurate diagnosis of BD and appropriate pharmacologic intervention can improve patient outcomes and provide neuroprotective benefits. Clinicians can benefit from a review of current and emerging nonpharmacologic and pharmacologic treatment options for BD, with an emphasis on use of guidelines and evidence-based recommendations. Further, knowledge of pharmacokinetic and pharmacodynamic profiles of different agents will help clinicians individualize patient therapy. Information on monitoring for efficacy, safety, adherence, function, and comorbidities is also critical to effective long-term management. Focused educational efforts in diagnosis and therapeutic treatment can help optimize healthcare provider performance and improve patient function and quality of life.
Learning Objectives
At the completion of this initiative, participants should be better prepared to: Conduct a differential diagnosis of BD based on a comprehensive and ongoing patient assessment Discuss the importance of early diagnosis and pharmacologic intervention Design and implement individualized, multimodal, patient-centered treatment plans that draw from available guidelines and evidence, as well as the pharmacokinetic and pharmacodynamic characteristics of available medications Monitor and adjust patient-based treatment plans over time to optimize treatment adherence and response Identify, monitor, and manage adverse effects
Accreditation Statement and Credit Designation

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Albert Einstein College of Medicine, Montefiore Medical Center, the College of Psychiatric and Neurologic Pharmacists (CPNP), and Asante Communications, LLC. Albert Einstein College of Medicine is accredited by the ACCME to provide continuing medical education (CME) for physicians.
Physicians
Albert Einstein College of Medicine designates this educational activity for a maximum of 1.25 American Medical Association (AMA) Physicians Recognition Award (PRA) Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Pharmacists
The College of Psychiatric and Neurologic Pharmacists (CPNP) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education (CPE). This activity has been assigned ACPE No. 0284-0999-10-034-H01-P and will award 1.0 contact hours (0.1 CEUs) of CPE credit. CPNP complies with the Criteria for Quality for Continuing Educational Programming.
Preamble
Method of Participation
There are no fees for participating in and receiving credit for this activity.
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Physicians
Online Certificate Fulfillment Instructions: Physicians who participate in this CME activity and wish to receive a certificate of credit can visit www.PSYCHClinician.com/ CEBDCompendium and complete the activity evaluation, pre- and post-activity questionnaires, and self-report credit form. You may print a certificate of credit upon successful completion of the activity. Mail or Fax Certificate Fulfillment Instructions: After completion of this activity, you may also download and print the activity evaluation, pre- and post-activity questionnaires, and self-report credit form instantly from www.PSYCHClinician. com/CEBDCompendium. Physicians must mail the completed forms to CCME, 3301 Bainbridge Avenue, Bronx, NY 10467, or fax them to (718) 798-2336. Please allow approximately 4 to 6 weeks for certificate processing. This activity is also available online at www.PSYCHClinician.com/CEBDCompendium, where a certificate of credit can be generated electronically upon successful completion.
Pharmacists
Online Statement Fulfillment Instructions: Pharmacists who participate in this CPE activity and wish to receive a statement of credit can visit www.PSYCHClinician. com/CEBDCompendium and complete the posttest, activity evaluation, and selfreport credit form. Pharmacists must answer at least 70% of the posttest questions correctly to receive credit; participants receiving a grade of less than 70% will be allowed one opportunity to retake the posttest. Mail or Fax Statement Fulfillment Instructions: After completion of this activity, you may also download and print the posttest, activity evaluation, and self-report credit form instantly from www.PSYCHClinician.com/CEBDCompendium. Pharmacists must mail the completed forms to Asante Communications, Attn: S. Montgomery, 800 Third Avenue, 23rd Floor, New York, NY 10022, or fax them to (646) 253-0889, Attn: S. Montgomery. A statement of credit will be mailed within 3 to 6 weeks to pharmacists who correctly answer at least 70% of the posttest questions. Pharmacists receiving a grade of less than 70% will be allowed one opportunity to retake the exam. This activity is also available online at www.PSYCHClinician.com/CEBDCompendium, where a statement of credit can be generated upon successful completion of the posttest.
Conflict of Interest Statement

The Conflict of Interest Disclosure Policies of Albert Einstein College of Medicine and CPNP require that faculty participating in any CME/CPE activity disclose to the audience any relationship(s) with a pharmaceutical, product, or device company. Faculty whose disclosed relationships prove to create a conflict of interest with regard to their contribution to the activity will not be permitted to participate. Albert Einstein College of Medicine and CPNP also require that faculty participating in any CME/CPE activity disclose to the audience when discussing any unlabeled or investigational use of any commercial product or device not yet approved for use in the United States.
Bipolar DisorDer Differential Diagnosis and Evidence-Based Treatment Strategies
viii
Faculty and reviewers of this program have indicated the following disclosure information: Christoph U. Correll, MD Has provided consultant services for Actelion Pharmaceuticals US, Inc., AstraZeneca, Boeheringer Ingelheim, Bristol-Myers Squibb, Cephalon, Inc., Eli Lilly and Company, GlaxoSmithKline plc, Hoffmann La-Roche Ltd., Intra-Cellular Therapies Inc., Janssen Pharmaceutica LP, Johnson & Johnson, Lundbeck A/S, Medicure Inc., Otsuka America Pharmaceutical Inc., Pfizer Inc, Schering-Plough Corporation, Sepracor/Sunovion Pharmaceuticals Inc., Supernus Pharmaceuticals Inc., Takeda Pharmaceutical Company Limited, and Vanda Pharmaceuticals. Matthew A. Fuller, PharmD, BCPS, BCPP, FASHP Has no conflict of interest(s) to report. Roger S. McIntyre, MD, FRCPC Has provided consultant and/or advisory board services for AstraZeneca, Biovail Corporation, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline plc, Janssen-Ortho Inc., Lundbeck A/S, Organon International, Pfizer Inc, Schering-Plough Corporation, Shire, and Solvay/Wyeth. He has received research grant support from Eli Lilly and Company, Janssen-Ortho Inc., and Shire. He has participated in the speakers bureaus for AstraZeneca, Biovail Corporation, Eli Lilly and Company, Janssen-Ortho Inc., Lundbeck A/S, and Wyeth. The staff of Albert Einstein College of Medicine and Montefiore Medical Center, Center for Continuing Medical Education (CCME), the staff of CPNP, and the staff of Asante Communications, LLC, have no conflicts of interest with commercial interests related directly or indirectly to this educational activity. Adrienne Drinkwater, PhD, scientific consultant for Asante Communications, LLC, has no conflicts of interest with commercial interests related directly or indirectly to this educational activity. Steven Jay Feld of Albert Einstein College of Medicine, or a member of his household, owns securities in Bioheart, Inc., Chelsea Therapeutics, Inc., and Pharmacopeia, Inc.
Copyright Information
2010 Albert Einstein College of Medicine, Montefiore Medical Center, the College of Psychiatric and Neurologic Pharmacists, and Asante Communications, LLC. All rights reserved. No part of this syllabus may be used or reproduced in any manner without written permission except in the case of brief quotations embedded in articles or reviews.
Online participation is available via
/CEBDCompendium
Faculty Biographies
Dr. Correll is a research psychiatrist at The Zucker Hillside Hospital in Glen Oaks, New York, and Associate Professor of Psychiatry and Behavioral Sciences at the Albert Einstein College of Medicine in Bronx, New York. He also is the Medical Director at The Zucker Hillside Hospitals Recognition and Prevention (RAP) Program, and the Director of the Adverse Events Unit and the Core Laboratory Unit, at The Zucker Hillside Hospitals Advanced Center for Intervention and Services Research. Dr. Correll completed his medical studies at the Free University of Berlin, Germany, and Dundee University Medical School in Scotland, United Kingdom. After finishing a general psychiatry residency at The Zucker Hillside Hospital, he trained in child and adolescent psychiatry at Schneider Childrens Hospital in New Hyde Park, New York. Dr. Corrells research and clinical work focus on the identification and psychopharmacologic management of severe psychotic and mood disorders in adults and youths. His areas of expertise include psychotic and bipolar prodrome, the treatment of mood disorders and schizophrenia, and the risk-benefit evaluation of psychotropic medications at all illness stages of disruptive behavior spectrum disorders, mood disorders, and psychotic spectrum disorders. He has authored numerous articles in major scientific journals on these topics. Dr. Correll has served as a member of several expert consensus panels on the use of antipsychotics across a range of psychiatric disorders. He is a reviewer for more than 50 journals and a member of the editorial board of the Journal of Child and Adolescent Psychopharmacology, The Open Psychiatry Journal, Mind and Brain the Psychiatric Journal, European Neuropsychopharmacology, and Schizophrenia Research and Treatment. Dr. Correll is the principal and co-principal investigator of a number of federally funded grants and has received numerous national and international research awards and fellowships for his work.
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Dr. Fuller is currently a Clinical Pharmacy Specialist in Psychiatry at the Louis Stokes Cleveland Department of Veterans Affairs Medical Center in Brecksville, Ohio. He is also an Associate Clinical Professor of Psychiatry and a Clinical Instructor of Psychology at Case Western Reserve University in Cleveland, Ohio, and an Adjunct Associate Professor of Clinical Pharmacy at The University of Toledo in Ohio. His additional responsibilities include his work as Director of an American Society of Health-System Pharmacists (ASHP)accredited PGY2 Psychiatric Pharmacy Residency Program. Dr. Fuller received his bachelor of science in pharmacy from Ohio Northern University and received his doctor of pharmacy degree from the University of Cincinnati. He completed a residency in hospital pharmacy at Bethesda Hospital in Zanesville, Ohio. Following the completion of his training, he joined the Louis Stokes Cleveland Department of Veterans Affairs Medical Center in Cleveland, Ohio. Dr. Fuller has more than 25 years of experience as a pharmacist. His main practice site is acute inpatient psychiatry. Dr. Fuller has received several awards, including the Upjohn Excellence in Research Award (1994), the Ohio Society of Health-System Pharmacists (OSHP) Hospital Pharmacist of the Year Award (1994), the Cleveland Society of Health-System Pharmacists Evelyn Gray Scott Award (Pharmacist of the Year in 1996), the OSHP Pharmacy Practice Research Award (2001), an Outstanding Contribution Award from the VA Healthcare System of Ohio (2003), a Certificate of Appreciation from the Japanese Society of Hospital Pharmacists, an Outstanding Leadership award from CPNP (2007), and a performance award from the Louis Stokes Cleveland Department of Veterans Affairs Medical Center (2009). Dr. Fuller is board certified in pharmacotherapy and psychiatric pharmacy and is an ASHP fellow. He is a past president of CPNP, for which he has also chaired and served as a member of the recertification committee and task force, residency and postgraduate training committee, business development committee, foundation committee, nominations committee, and the VA task force. He has also chaired and has been a planning committee member for the Midwest Neuropsychopharmacology Meeting. In addition, he is a member of local, state, and national pharmacy organizations. A recognized educator, he has presented at local, state, national, and international venues. He serves as a reviewer for Archives of General Psychiatry, Acta Psychiatrica Scandinavica, Journal of Clinical Psychiatry, American Journal of Health-System Pharmacy, Progress in
Faculty Biographies
Neuro-Psychopharmacology & Biological Psychiatry, Savvy Psychopharmacology, and Current Psychiatry. He also is a member of the Editorial Board, Panel on Psychiatry, for Annals of Pharmacotherapy. In 1998, Dr. Fuller joined Lexi-Comps editorial advisory panel and is the author of 2 psychotropic drug information handbooks and a co-author of a drug interactions handbook. He currently remains involved with Lexi-Comp as an independent contractor.
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Dr. McIntyre is Associate Professor of Psychiatry and Pharmacology at the University of Toronto and Head of the Mood Disorders Psychopharmacology Unit at the University Health Network, both in Toronto, Ontario, Canada. He completed his medical training at Dalhousie University in Halifax, Nova Scotia, Canada. Thereafter, he received his psychiatry residency training and fellowship in psychiatric pharmacology from the University of Toronto. Dr. McIntyre is involved in multiple research endeavors that primarily aim to characterize the association between mood disorders and medical comorbidity. This research involves elucidating metabolic adverse events associated with the use of psychotropic medications, the impact of medical comorbidity on the course of mood disorders, and the effect of glucose homeostasis on neurocognition. Dr. McIntyre is extensively involved in medical education. He is a highly sought-after speaker at national and international meetings. A renowned educator, he has received several teaching awards from the University of Toronto, Department of Psychiatry. He is also a recipient of the joint Canadian Psychiatric Association (CPA)/Council of Psychiatric Continuing Education Award for the Most Outstanding Continuing Education Activity in Psychiatry in Canada. Dr. McIntyre is a contributor to the CPA guidelines for the treatment of depressive disorders and the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of BD. He has published extensively in leading peer-reviewed journals and textbooks. Dr. McIntyre is also a reviewer for many journals, including the American Journal of Psychiatry, Biological Psychiatry, Journal of Clinical Psychiatry, and New England Journal of Medicine, and serves as a grant reviewer for the National Institute of Mental Health.
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Introduction
Christoph U. Correll, MD Matthew A. Fuller, PharmD, BCPS, BCPP, FASHP Roger S. McIntyre, MD, FRCPC
ipolar Disorder (BD) ranks high among the most prevalent and frequently underdiagnosed and undertreated affective disorders in the United States. Characterized by recurrent episodes of mania, depression, and mixed states, the annual economic burden of BDincluding healthcare costs and lost productivity of patients and their caregiverswas estimated at $24 billion in the United States in 1998.1-4 Despite the growth in research in recent years, an estimated 69% of people with BD have been misdiagnosed; most notably, patients with BD had received a mean of 3.5 other diagnoses and have consulted 4 physicians before being accurately diagnosed.5 BD increases the risk for suicide and is associated with several psychiatric and medical comorbidities, including substance misuse, anxiety disorders, cardiovascular disease, metabolic syndrome, and hypertension.1,6-8 An increasing body of evidence suggests that when appropriate pharmacotherapeutic interventions are initiated early in the course of the disorder, the ultimate prognosis is substantially improved.5,9 Longitudinal data on the management of patients with BD, including monitoring for efficacy, safety, adherence, and comorbidities, are available to provide practical, clinically applicable information. While knowledge about the diagnosis and treatment of BD has grown in recent years, it is not yet fully integrated within clinical practice. Several guidelines have been published on the treatment of BD; however, a pilot survey suggests that 34% of psychiatrists do not use treatment guidelines and that 24% misinterpret the results of clinical trials.10 We designed this multimedia resource compendium to educate healthcare professionals about recent developments in the differential diagnosis and medical management of BD, with focus on a patient-centered, individualized approach to treatment. Psychiatrists and neurologists, as well as pharmacists, primary care physicians, and other multidisciplinary team members, may find this compendium of particular value as a clinical reference tool to help improve care and outcomes of their patients with BD. In addition to
this print compendium, this multimedia continuing education activity will be available online via the PSYCHClinician.com Web site. In Chapter 1, Dr. Roger McIntyre reviews current strategies for distinguishing BD from other disorders such as major depressive disorder (MDD) or attention deficit hyperactivity disorder (ADHD) that have similar clinical presentations. In Chapter 2, Dr. Matthew Fuller focuses on some of the major classes of medications (eg, antipsychotics and mood stabilizers) used to treat BD and their mechanisms of action. Of signal importance to good practice parameters and ultimately to effective patient-centered treatment of BD is Dr. Fullers review of drug-metabolizing pathways, drug-drug interactions, and dose adjustment strategies deemed essential for personalized care. In Chapter 3, Dr. Christoph Correll discusses important elements of longitudinal treatment effectiveness, such as re-evaluating depressive and manic symptoms and assessing remission and residual symptoms. Key information is provided on potential complications associated with the use of antipsychotics and mood stabilizers, with a discussion on strategies for managing treatmentrelated side effects and optimizing treatment for an individual patient.
References
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text Revision, DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000. 2. Cousins DA, Young AH. The armamentarium of treatments for bipolar disorder: a review of the literature. Int J Neuropsychopharmacol. 2007;10:411-431. 3. Berns GS, Nemeroff CB. The neurobiology of bipolar disorder. Am J Med Genet C Semin Med Genet. 2003;123C:76-84. 4. Begley CE, Annegers JF, Swann AC, et al. The lifetime cost of bipolar disorder in the US: an estimate for new cases in 1998. Pharmacoeconomics. 2001;19:483-495. 5. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64:161-174. 6. Slama F, Bellivier F, Henry C, et al. Bipolar patients with suicidal behaviour: toward the identification of a clinical subgroup. J Clin Psychiatry. 2004;65:1035-1039. 7. Berk M, Berk L, Moss K, Dodd S, Malhi GS. Diagnosing bipolar disorder: how can we do it better? Med J Aust. 2006;184:459-462. 8. McIntyre RS, Konarski JZ, Soczynska JK, et al. Medical comorbidity in bipolar disorder: implications for functional outcomes and health service utilization. Psychiatr Serv. 2006;57:1140-1144. 9. Berk M, Hallam K, Lucas N, et al. Early intervention in bipolar disorders; opportunities and pitfalls. Med J Aust. 2007;187(suppl):S11-S14. 10. Perlis RH. Use of treatment guidelines in clinical decision making in bipolar disorder: a pilot survey of clinicians. Curr Med Res Opin. 2007;23:467-475.
Differential Diagnosis of Bipolar Disorder

ipolar disorder (BD) is a common psychiatric condition with a lifetime prevalence of 1.0% for bipolar I disorder (BD I), 1.1% for bipolar II disorder (BD II), and 2.4% for subthreshold BD.1 In the primary care setting, results of several studies indicate that 20% to 30% of individuals who have clinically significant depressive symptoms and are receiving antidepressant treatment actually have a bipolar spectrum condition.2-5 Recent studies reported increased rates of BD diagnoses in adult and pediatric outpatient populations during the past decade.6,7
Several factors contribute to the rising rate of BD diagnosis across multiple healthcare settings, including broader conceptualization of the diagnostic criteria (eg, BD II/bipolar spectrum), high rate of misdiagnosis, overdiagnosis (notably in pediatric populations), increased attention by the lay public and media, and in some cases, reimbursement incentives for a diagnosis of BD.7,8 It has been speculated that the observed increase in rate (cohort effect) could be due to an anticipation effect (actual increase in rate or onset at a younger age, due to presence of unstable nucleotides).9 This phenomenon has been documented in other neurologic disorders such as Huntingtons chorea.10 A report on national trends (199495; 200203) in the diagnosis and treatment for BD has also shown an increase in youth visits (from 25 to 1003 per 100,000) and adult visits (from 905 to 1679 per 100,000).6 These data could be potentially misinterpreted, due to revisits by the same patient with increased symptoms. Further studies are needed for standardized data collection and accurate diagnosis of BD. There are several reports in which individuals received a diagnosis of BD when a more appropriate diagnosis may have been major depressive disorder (MDD), personality disorder, and externalizing behavioral disorders (in pediatric populations).8 Although overdiagnosis of BD may add to the rising rate, a more critical issue is the delay in diagnosis and its negative effect on outcomes. It has been amply documented that the delay in BD diagnosis and, consequently, its treatment is the rule rather than the exception. For example, several organizations, notably the Depression Bipolar Support Alliance (DBSA), have reported that, on average, approximately 10 years often will elapse from the onset of
symptoms to the correct establishment of the diagnosis.11 Moreover, investigators from the Stanley Foundation Network and the National Depressive and Manic Depressive Association reported that the interval between the onset of BD symptoms and the initiation of pharmacotherapy is approximately 10 years.12,13 Similarly, a recent study (N=115) found that one-third of first episode patients who fulfilled Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for BD I did not receive treatment during the 8-year study duration.14 This diagnostic delay unnecessarily contributes to increased relapse risk, chronicity, and suicidality in the bipolar population. Taken together, the epidemiologic and clinical data underscore the need to improve detection and diagnosis of patients with BD.
Diagnostic Criteria
n the United States, the most widely used source for diagnosing BD is the DSM-IV.15 Diagnostic criteria for major depressive, manic, hypomanic, and mixed episodes are described in Tables 14.15 The essential feature of BD I is the presence of one or more manic or mixed episodes (at a minimum of 1 week or any time if psychosis is present or hospitalization is required) with or without a history of depressive episodes.15 BD II is characterized by the presence of at least one hypomanic episode (at a minimum of 4 days) with recurrent episodes of depression.15 A diagnosis of cyclothymic disorder is made when a patient has repeated mood swings that are not severe enough to be diagnosed as mania or depressive episodes, but rather fulfill diagnostic criteria for hypomania and dysthymia (ie, subthreshold depression lasting for at least 2 years without a euthymic episode of at least 2 months).15 Another variation is bipolar disorder not otherwise specified (BD-NOS) (Table 5),15 when patients have manic and depressive symptoms that do not meet BD criteria.15,16 Patients with BD-NOS may experience impairing symptoms for long durations. For example, one study (N=263) showed that in children and adolescents with BD-NOS (n=92), the time to recovery was longer than in those with BD I and BD II (P0.05).17
Differentiating Between Unipolar and Bipolar Depression
epressive symptoms and episodes dominate the course of BD and frequently predate periods of mania or hypomania in most patients.18-21 These episodes are typically the reason individuals will seek healthcare
services for BD.22 Establishing whether a depressive episode is presenting in the context of MDD or BD is arguably the most challenging element of differential diagnosis. No specific sign or symptom of depression is unique to MDD or BD. There are, however, features that may help clinicians
Table 1.
Criteria for a Major Depressive Episode.15
A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either 1) depressed mood; or 2) loss of interest or pleasure
1) Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad or empty) or observation made by others (eg, appears tearful). Note: In children and adolescents, can be irritable mood. 2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) 3) Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains. 4) Insomnia or hypersomnia nearly every day 5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 6) Fatigue or loss of energy nearly every day 7) Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) 8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) 9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
B. The symptoms do not meet criteria for a mixed episode C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning The symptoms are not due to the direct physiologic effects of a substance D. (eg, a drug of abuse, a medication) or a general medical condition (eg, hypothyroidism) E. The symptoms are not better accounted for by bereavement (ie, after the loss of a loved one, the symptoms persist for more than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation)
Note: Do not include symptoms that are clearly due to a general medical condition or moodincongruent delusions or hallucinations.
6
Table 2. Criteria for a Manic Episode.15
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting more than 1 week (or any duration if hospitalization is necessary) B. During the period of mood disturbance, 3 (or more) of the following symptoms have persisted (4 if the mood is only irritable) and have been present to a significant degree:
1) Inflated self-esteem or grandiosity 2) Decreased need for sleep (eg, feels rested after only 3 hours of sleep) 3) More talkative than usual or pressure to keep talking 4) Flight of ideas or subjective experience that thoughts are racing 5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli) 6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7) Excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
C. The symptoms do not meet criteria for a mixed episode D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features E. The symptoms are not due to the direct physiologic effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism)
Note: Manic-like episodes clearly caused by somatic antidepressant treatment (eg, medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of BD I.
differentiate depressive episodes associated with BD from those associated with MDD (Table 6).5,15,21,23-31 For example, ruling out a history of hypomania initially can provide some direction for diagnosis. To minimize misdiagnosis of BD, perhaps all patients who show signs of depression should be evaluated for a history of previous hypomania (periods of increased energy and decreased need for sleep). Individuals with BD are more likely to have an earlier age of onset (typically before 25 years of age).5,23 An initial presentation of a major depressive episode at age 20 years has a higher likelihood of being associated with BD than one that begins after age 30 years. The longitudinal course of illness can occasionally be a helpful differentiating factor. Individuals with
7
Table 3. Criteria for a Hypomanic Episode.15
A. A distinct period of persistently elevated, expansive, or irritable mood, lasting more than 4 days, that is clearly different from the usual nondepressed mood B. During the period of mood disturbance, 3 (or more) of the following symptoms have persisted (4 if the mood is only irritable) and have been present to a significant degree:
1) Inflated self-esteem or grandiosity 2) Decreased need for sleep (eg, feels rested after only 3 hours of sleep) 3) More talkative than usual or pressure to keep talking 4) Flight of ideas or subjective experience that thoughts are racing 5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli) 6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7) Excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, the person engages in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic D. The disturbance in mood and the change in functioning are observable by others E. The episode is not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization, and there are no psychotic features F. The symptoms are not due to the direct physiologic effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism)
Note: Hypomanic-like episodes clearly caused by somatic antidepressant treatment (eg, medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of BD II.
BD exhibit a greater tendency to cyclicity, since they have a higher rate of recurrence and shorter symptom-free intervals compared with individuals with MDD.23 Individuals with BD may have a more abrupt onset of depressive symptoms, whereas symptoms in MDD have a more insidious onset.21,32 Although both BD and MDD are subject to seasonal variability, individuals with BD appear more likely to report seasonal variation and mood destabilization with sleep deprivation and/or transmeridian travel.21,23,26 Mood disorders frequently occur during reproductive life events in women. Females with BD frequently report index depression, mixed state, or mania at the time of menses and postpartum.27 Increasingly, reports are documenting premenstrual
8
Table 4. Criteria for a Mixed Episode.15
A. The criteria are met both for a manic episode and for a major depressive episode (except for duration) nearly every day during at least a 1-week period B. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features C. The symptoms are not due to the direct physiologic effects of a substance (eg, a drug of abuse, a medication, or other treatment), or a general medical condition (eg, hyperthyroidism)
Note: Mixed-like episodes clearly caused by somatic antidepressant treatment (eg, medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of BD I.
Table 5. Clinical Scenarios Suggestive of Bipolar Disorder Not Otherwise Specified.15

Rapid alteration between manic and depressive symptoms that meet the threshold criteria, but do not meet the minimal duration criteria for manic episodes Recurrent episodes of hypomania, without intercurrent depressive symptoms Residual schizophrenia, manic or mixed episode superimposed on delusional disorder, or a psychotic disorder not otherwise specified Hypomanic episodes together with chronic depressive symptoms, which are not frequent enough for a diagnosis of cyclothymic disorder When the clinician has concluded that a bipolar disorder is present but cannot determine if it is primary, due to general medical condition, or substance induced
worsening of bipolar symptoms that is often erroneously diagnosed as premenstrual dysphoric disorder. It is also not uncommon to see mood destabilization during the menopausal transition.28,33 Although there are no features of a depressive episode that are pathognomonic for bipolar depression (or unipolar depression), phenomenologic studies have documented symptomatic patterns that differentially affect the bipolar population. For example, patients with BD are more likely to report and/or present with reversed vegetative features commonly associated with atypical depression (eg, increased appetite, hypersomnia).23,26,29
9
Table 6. Clinical Features Suggestive of Bipolar Disorder.5,15,21,23-31
1. Family history of bipolar disorder 2. Earlier age at diagnosis (<25 years) 3. High rate of recurrence, with short intervals of well-being between episodes (ie, high vulnerability to cyclicity) 4. Abrupt onset of depressive episode 5. Seasonal vulnerability 6. Vulnerability around reproductive cycles for women of reproductive age 7. Reversed neurovegetative features (eg, hypersomnia, increased appetite) 8. Psychotic symptoms 9. Migraine 10. Subsyndromal hypomania (ie, agitated depression) 11. Antidepressant misadventures
Clinicians should be cognizant of other clinical presentations such as atypical depression and psychotic features also observed in patients with MDD.29 The numerous clinical features rarely peculiar to MDD or BD underscore the importance of a thorough and longitudinal examination.34 Careful patient monitoring may reveal, for example, subsyndromal hypomania, an integral component of depressive episodes in patients with BD, especially BD II. Hypomanic symptoms include irritability and increased distractibility, psychomotor agitation, crowding of thoughts, and talkativeness or pressured speech. Such features are often labeled as agitation or agitated depression, which were historically conceptualized as part of mixed states.35 One feature that distinguishes agitated depression from dysphoria is decreased energy and increased need for sleep.36,37 While agitated depression is present in MDD, some clinical experience suggests it is more common in patients with BD. In contrast, a prospective epidemiologic study with a 20-year follow-up period (Zurich study), found that agitated depression was as common in MDD as in BD II.30 Combined agitated and retarded depressive states were, however, found to be more commonly bipolar than unipolar depression.30 Currently, antidepressants are not approved for the treatment of BD, since there is inconsistent evidence to support their efficacy and safety. Several
10
reports suggest that adding an antidepressant to a mood stabilizer does not increase the treatment efficacy. For example, in a study involving patients with depression, 23.5% (42/179) patients who received a mood stabilizer plus an antidepressant had a durable recovery, compared with 27.3% (51/187) patients who received a mood stabilizer and placebo (P=0.40).38 In bipolar patients with depression and manic symptoms, antidepressants did not accelerate time to recovery compared with mood stabilizers alone, and increased severity of manic symptoms in some patients.39 The large European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study (N=2416) found that patients in maintenance phase who were taking antidepressants had significantly higher Clinical Global Impressions-Bipolar Disorder (CGI-BP) scale depression scores (P<0.001) and a significantly higher rate of depression relapse (P<0.001) at 12 weeks and 24 months. This indicated that they were more likely to have a higher risk of depression relapse during follow-up.40 Some evidence suggests that antidepressants may be beneficial and safe for a subpopulation of bipolar patients. For example, analysis of complex medication regimens of 4035 subjects before entering Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found that polypharmacy was most often associated with antidepressants or atypical antipsychotics. These data indicated that there was a potential need for including antidepressants in treatment for patients with complex and recurrent/nonresponsive depressive episodes.41 Most experts agree that for BD I, antidepressants should only be used in combination with mood stabilizers; however, there is no consensus about whether or not antidepressants should be prescribed as monotherapy in BD II.42
Differential Diagnosis Beyond Unipolar Depression

ifferential diagnosis of BD extends beyond MDD and addresses such potential confounds as underlying medical comorbidity, anxiety disorders, persistent externalizing behavioral conditions (eg, attention deficit hyperactivity disorder [ADHD]), personality disorders, and substance abuse disorders. In general, if an adult patient reports neither attentional or externalizing behavioral problems as a child, then ADHD (with a usual onset in childhood or adolescence) is unlikely to play a causative role.15 ADHD is a common differential diagnosis for pediatric presentations consistent with the symptomatology of BD.43 Adult ADHD phenotype is also commonly seen in individuals with BD or MDD. A large (N=1000, STEP-BD) systematic evaluation of adult patients with BD showed that ADHD was frequent and associated with a more severe course of BD.44
A more recent study (N=300) reported that the ADHD phenotype was commonly seen in bipolar (and MDD) patients and was associated with greater illness burden and complexity.45 Personality disorders are defined as an enduring or lifelong pattern of chaotic, stormy, unstable relationships and work history.15 For example, an estimated 40% of patients with BD have a concurrent personality disorder.46 In the differential diagnosis of psychiatric disorders, the importance of first ruling out comorbid medical conditions, iatrogenic side effects, medication-induced mood episodes (eg, anabolic steroids), and alcohol or substance abuse applies universally. Thyroid disturbances are common medical conditions that present with mood instability, depression, or anxiety, and are frequently misinterpreted as psychiatric disorders. Substance abuse disorders are particularly challenging, since their associated signs and symptoms overlap considerably and mimic those of BD. More precisely, the clinical presentation of patients with substance abuse disorders may mask an as yet undiagnosed and coexisting BD. In such cases, a careful patient history should be taken with particular attention given to phenomenology as well as to the temporal relationship between the substance abuse and the presenting psychopathologic condition. As substance use disorders often begin after the onset of BD, early identification of the illness provides an opportunity to initiate preventive measures.12 A recent analysis of published literature indicates that medical comorbidities are prevalent in patients with BD.5 Three or more comorbid medical conditions were present in 40% of patients. Moreover, patients may have different sensitivities to stress-related medical comorbidities such as neurologic, circulatory, and metabolic disorders, resulting in a higher prevalence of epilepsy, multiple sclerosis, migraine, and circulatory disorders. While these health matters are common, they are most often underrecognized and suboptimally treated.5
11
Differentiating Between Bipolar I and Bipolar II and BD-NOS Disorders

ifferentiating between BD I, BD II, and BD-NOS presents formidable challenges, particularly when evaluating an outpatient who has had mood instability and recurrent episodes of depression. The specific diagnosis has important implications for treatment and prognosis, and relatively clear-cut distinctions can be made upon presentation. For example, while bipolar mania is usually accompanied by severe impairment, BD II hypomania is associated with relatively minor impairment and behavioral
12
changes without psychotic features. As discussed previously, duration of illness may be longer in patients with BD-NOS compared with BD I and BD II.17 Hypomania, overall, is a milder presentation of shorter duration, with less severe symptomatology and less functional impairment. Hypomanias are, by definition, at least 4 days in duration, whereas manias last at least a week, although this duration requirement does not need to be met if the patient is psychotic or requires hospitalization.15 While hospital admission strongly implies a severe disorder, the current reimbursement and insurance landscape suggests that patients who do not have an admission record should also be carefully considered. There is a decidedly gray area for patients with moderate to severe impairment (ie, those presenting with problems at work or home who are still able to manage the activities of daily living and who do not have an obvious history of psychosis or hospitalization). Here, the evidence base supporting diagnostic and therapeutic decision making is limited, emphasizing the importance of good clinical judgment and collaborative discussion with clinicians, caregivers, family, and friends who know the patient well. A zone of delimitation has not been identified wherein BD I and BD II can be meaningfully disambiguated in many clinical circumstances. Depressive symptoms predominate in patients with both BD I and BD II. A seminal study by Judd and coworkers found that patients with BD I spent approximately 300% more time with depressive symptoms than with manic symptoms.18 In BD II, the proportion of weeks patients spent with symptoms of depression was almost 40-fold greater compared with hypomanic symptoms.19 More recently, Altshuler and coworkers showed that the possibility of having depressive symptoms was significantly higher for women than for men.47 The depressive symptoms of BD I may account for more workforce disability than observed in MDD. For example, results of a large study (N=20,747, based on Canadian Community Health Survey) showed that compared with MDD, individuals with BD had a significantly lower annual income (P<0.05), higher odds of reporting mental health disability days in the past 2 weeks (odds ratio [OR]=1.6; 95% confidence interval [CI]=1.02.6), and lower odds of good job security (OR=0.6, 95% CI=0.50.9).48 Patients with BD II, unlike those with BD I, frequently report 5 or more depressive episodes.49 Differences have also been observed in the psychosocial disability and working capacity. For example, a study that compared these domains in patients with BD I, BD II, or MDD via semistructured interviews across 15 years found that the inability to carry out work role functions was 30% in patients with BD I, compared with 20% and 21% in BD II and MDD,
respectively.50 Taken together, these data show that the symptomatology of depression constitutes a significantly greater part of the clinical picture in BD II than in BD I. Establishing an unambiguous distinction between the two requires a detailed patient history, with a clear focus on the clinical presentation and its evolving symptomatology.
13
Gender and Bipolar Disorder

ipolar I disorder affects men and women equally.1,15 However, BD II is more common in women than men.1,15 Gender-related differences have been noted in several studies. Compared with men, women with BD tend to have a greater disposition toward depression.15,47 Although men are likely to experience higher substance abuse than women in general, women with BD have a higher rate of alcohol abuse (7-fold) than women in the general population.51 Women may be more prone to rapid cycling and mixed states, which may present diagnostic challenges.52 Further, women are particularly susceptible to illness onset and/or destabilization during reproductive events, including menarche, pregnancy, postpartum, and menstrual transition.53 Also, patterns of comorbidity may differ between women and men; women have higher rates of lifetime comorbid eating disorder and drug and alcohol use. Besides, the relative risk of substance abuse is higher in women than in men.54 Migrane headaches and metabolic syndrome are other common comorbidities observed in patients with BD. Migraine is more common among patients with BD than in the general population and appears to be more common among women in both populations.28,31,55 Several factors that appear to contribute to the higher observed rates of metabolic syndrome in patients with BD include common physiologic etiologies (eg, abnormalities in cortisol regulation), unfavorable lifestyle and behavioral patterns (eg, cigarette smoking, physical inactivity, poor diet), and the metabolic effects of medications used to treat this illness, particularly atypical antipsychotics.56 Further, some evidence suggests that metabolic syndrome, a constellation of interrelated abnormalities comprising hypertension, insulin resistance, elevated body mass index, central adiposity, and dyslipidemia, may be more common in the bipolar population than in the general population.57 A comprehensive analysis of literature on metabolic syndrome and BD, mania, and manic-depression supports this observation and indicates that the increase in metabolic syndrome is due to the clustering of risk factors, negative health behaviors, and treatment-related weight gain.58
14
As discussed in a subsequent chapter, the co-occurrence of the metabolic syndrome in patients with BD is associated with a more complex presentation, an overall more serious illness with respect to course and outcome, and a less favorable response to treatment.58 For example, bipolar patients with metabolic syndrome also have an elevated risk of depressive symptoms/ episodes and suicidality. Comorbid metabolic syndrome may thus be a marker of greater disease burden. There is also the possibility that BD with comorbid metabolic syndrome may represent a phenotype that increases the risk of suicidality through direct and indirect factors.58
Age-Related Features of Bipolar Disorder
umerous studies suggest that the onset of BD typically occurs between the ages of 15 and 25 years.1,20,21,59 Pediatric BD may first appear much like an adult-onset presentation, with recurrent episodes of mania and depression. Compared with adults, pediatric-onset bipolar disorders tend to be more mixed, frequently presenting with both mania and depression.43,60 Rapid cycling is also more common in pediatric presentations. In contrast with the more stable, episodic course that often occurs in adults with BD, pediatric patients are more likely to report and/or manifest a chronic, nonremitting, rapid-cycling confluence of manic and depressive symptomatology. An estimated 10% of bipolar patients present with late-onset BD, with the first episode of mania occurring after the age of 60 or 65 years.61 The symptomatology of late-onset mania overlaps with younger-ageonset BD. Yet, there are some features that are more commonly seen in late-onset conditions. For example, there often is a behavioral component that dominates the clinical picture in older-onset BD, the disorder is more often mixed, and psychotic features are more prominent.15 Of interest, a retrospective study of 67 patients with late-onset BD reported that, on average, the first manic episode occurred 10 years after the first depressive episode.62 Almost one-half of the patients followed in one study had at least 3 depressive episodes before their first manic attack.62 Like the bipolar patient population in general, late-onset patients tend to have hypertension, dyslipidemia, and/ or other cardiometabolic abnormalities and the risk factors demand tight clinical management.63,64 Brain imaging studies also show a high rate of cerebrovascular disease in the late-onset patient population.65,66 Vascular-related changes in white matter may be causally related at least in part to late-onset BD. Notably, cerebrovascular disease mechanisms are thought to damage frontolimbic circuits involved in the pathophysiology of mania.65,66
Diagnosis of a Bipolar Prodrome and the Case for Early Intervention

imely diagnosis and individualized care are critical to treatment success. The earlier the illness is diagnosed and treated, the more likely it is that patients will achieve symptomatic remission and functional recovery.67-69 Longitudinal evaluation of patients provides the opportunity to clarify the diagnosis. For example, one study (N=413) that followed bipolar spectrum disorders in children and adolescents for 4 years found that 40% of the participants had syndromal or subsyndromal symptoms during 75% of the follow-up, and 38% patients with BD-NOS converted to BD I or BD II.16 Prognostic data prove persuasive for early and aggressive therapeutic interventions. For example, patients who experience frequent bipolar episodes are more likely to develop irreversible functional impairment.67-69 These and related data support ongoing efforts to investigate a putative prodromal state for BD.70,71 Descriptive studies have yielded important yet incomplete data. Adolescents and young adults with a family history of BD presenting with mood instability should arguably be conceptualized as at risk. A family history of BD has implications for a potential prodrome and may provide contextual insights for differential diagnosis. Although there are no biologic markers for BD, patients may have volumetric brain changes early in the course of their illness. A meta-analysis of magnetic resonance imaging (MRI) studies concluded that patients with first-episode bipolar disorders have significant reductions in total intracranial and white matter volumes compared with controls.72 Patients with BD are more likely to report histories of assaultive trauma than the general population.73 In this patient population, childhood abuse (sexual or physical) has been linked with changes in brain volume; however, MRI findings from various studies are somewhat inconsistent. In contrast with consistently seen small hippocampal volume in patients with MDD, brain morphometric data in bipolar disease are mixed, and show smaller, similar, or larger hippocampal volumes in women compared with controls.74-77 It is likely that clinical factors like childhood abuse influence such morphometric variability.77 Clinical research into states antecedent to bipolar presentation has targeted patient populations with externalizing behavioral disorders like ADHD and dysthymic, cyclothymic, or hyperthymic personalities.20,78 To date, these data are far from conclusive, and important clinical and scientific questions
15
16
remain unresolved. Presently, the DSM-IV provides critical guidance for the diagnosis of BD, although close attention to features as soft signs can certainly shape assessment and diagnosis (Table 6).
Screening Tools
he overarching aim of screening tools is to detect a phenotype consistent with BD. Validated screening tools balance sensitivity (the ability to unambiguously identify bipolar patients) with specificity, while appropriately addressing other key psychometric variables. Ideally, screening tools improve the signal-to-noise ratio during differential diagnosis, reducing false-positives and simultaneously reducing false-negatives or failure to recognize BD in a given patient. Nevertheless, the final assessment tool is the psychiatrists own judgment. Obtaining a longitudinal history, longitudinal self-rating by the patient, and monitoring by the psychiatrist may be helpful in accurate and timely diagnosis. Screening instruments available for BD are described in Table 779-83; the most commonly used is the Mood Disorder Questionnaire (MDQ).79 This is a self-report, paper-and-pencil, single-page questionnaire that consists of 13 yes-or-no items derived largely from the DSM-IV criteria. The questionnaire includes a yes-or-no item examining whether the reported symptoms occurred at the same time and an additional item assessing the level of functional impairment.79 A positive screen for BD on the MDQ includes answering yes for at least 7 of the yes-or-no symptom items; yes for co-occurrence of symptoms; and scoring moderate or serious for impairment.84 In one study assessing the clinical utility and reliability of the MDQ, Hirschfeld and colleagues screened 649 primary care patients receiving antidepressant treatment and reported that 138 (21.3%) were positive for BD.3 Overall, 86 of the 138 patients who screened positive on the MDQ and 94 of the 511 MDQ-negative patients completed the Structured Clinical
Table 7. Screening Tools for Bipolar Disorder.79-83
Mood Disorder Questionnaire (MDQ) My Mood Monitor (M-3) checklist Hypomania Checklist (HCL-16 and HCL-32) Hypomanic Personality Scale
Interview (SCID) for DSM confirming or rejecting a diagnosis of BD.3 While these psychometric data are beyond the scope of this review, the MDQ correctly identified 45 of 59 patients with SCID-diagnosed BD and 80 of 121 patients without BD, supporting its use as an initial screening instrument.3 In other studies, the MDQ has shown false-positives when screening for BD and borderline personality disorder and limited sensitivity as a screening tool for psychiatric outpatients.85,86 Taken together, the available evidence indicates that a screening tool like the MDQ may be a helpful adjunct but it does not supplant a thorough clinical evaluation with input from third parties who can provide meaningful observational information pertinent to the patient. The MDQ is a screening tool and does not diagnose BD, nor does it rule out BD. While in academic centers, more structured clinical interviews such as the Mini International Neuropsychiatric Interview (MINI) and the SCID may be used frequently, these instruments are not always practical in the clinical setting due to time constraints. In the absence of an ideal scale for measuring symptoms, many clinicians use the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Depression (HAM-D), the Inventory of Depressive Symptomology (IDS), and the Patient Health Questionnaire (PHQ-9), along with a mania scale, such as the Young Mania Rating Scale (YMRS), which can help to differentiate between BD I and BD II.87-91 Although the screening tools described above are useful in the diagnoses, careful assessment of the patients psychological history is important in making the diagnosis. Further information is available in Chapter 3.
17
Conclusions
ipolar disorder is a common psychiatric condition that often goes unrecognized or misdiagnosed for several years before patients receive appropriate treatment. The most common differential diagnosis of BD is MDD. Clinicians are encouraged to consider screening tools but are reminded that their positive and negative predictive values are suboptimal and do not replace a thorough clinical assessment. In addition, patient features (eg, young age, family history) and a precipitous onset of depression can provide clinical clues suggestive of a diagnosis of BD. Differential diagnosis of BD requires a careful patient history informed by results of assessment tools (eg, HAM-D, MADRS, YMRS), a detailed patient interview, and input from family and other individuals close with the patient.
18
References
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37. Maj M, Pirozzi R, Magliano L, Fiorillo A, Bartoli L. Agitated unipolar major depression: prevalence, phenomenology, and outcome. J Clin Psychiatry. 2006;67:712-719. 38. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722. 39. Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am J Psychiatry. 2007;164:1348-1355. 40. Rosa AR, Cruz N, Franco C, et al. Why do clinicians maintain antidepressants in some patients with acute mania? Hints from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM), a large naturalistic study. J Clin Psychiatry. 2010;71:1000-1006. 41. Goldberg JF, Brooks JO III, Kurita K, et al. Depressive illness burden associated with complex polypharmacy in patients with bipolar disorder: findings from the STEP-BD. J Clin Psychiatry. 2009;70:155-162. 42. Amsterdam JD, Shults J. Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study. Am J Psychiatry. 2010;167:792-800. 43. Sala R, Axelson D, Birmaher B. Phenomenology, longitudinal course, and outcome of children and adolescents with bipolar spectrum disorders. Child Adolesc Psychiatr Clin N Am. 2009;18:273-289, vii. 44. Nierenberg AA, Miyahara S, Spencer T, et al. Clinical and diagnostic implications of lifetime attention-deficit/hyperactivity disorder comorbidity in adults with bipolar disorder: data from the first 1000 STEP-BD participants. Biol Psychiatry. 2005;57:1467-1473. 45. McIntyre RS, Kennedy SH, Soczynska JK, et al. Attention-deficit/hyperactivity disorder in adults with bipolar disorder or major depressive disorder: results from the International Mood Disorders Collaborative Project. Prim Care Companion J Clin Psych. 2010;12:e1-e7. 46. Krishnan KR. Psychiatric and medical comorbidities of bipolar disorder. Psychosom Med. 2005;67:1-8. 47. Altshuler LL, Kupka RW, Hellemann G, et al. Gender and depressive symptoms in 711 patients with bipolar disorder evaluated prospectively in the Stanley Foundation bipolar treatment outcome network. Am J Psychiatry. 2010;167:708-715. 48. McIntyre RS, Wilkins K, Gilmour H, et al. The effect of bipolar I disorder and major depressive disorder on workforce function. Chronic Dis Can. 2008;28:84-91. 49. Mantere O. Recognition, Comorbidity, and Outcome of DSM-IV Bipolar I and II Disorders in Psychiatric Care. Helsinki, Finland: Department of Mental Health and Alcohol Research, National Public Health Institute, 2007. https://oa.doria.fi/dspace/ bitstream/10024/5640/1/recognit.pdf. Accessed September 7, 2010. 50. Judd LL, Schettler PJ, Solomon DA, et al. Psychosocial disability and work role function compared across the long-term course of bipolar I, bipolar II and unipolar major depressive disorders. J Affect Disord. 2008;108:49-58. 51. Frye MA, Altshuler LL, McElroy SL, et al. Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder. Am J Psychiatry. 2003;160:883-889. 52. McElroy SL. Bipolar disorders: special diagnostic and treatment considerations in women. CNS Spectr. 2004;9(8 suppl 7):5-18. 53. Freeman MP. Bipolar disorder and pregnancy: risks revealed. Am J Psychiatry. 2007;164:1771-1773.
54. McElroy SL, Frye MA, Hellemann G, et al. Prevalence and correlates of eating disorders in 875 patients with bipolar disorder. J Affect Disord. July 29, 2010 [Epub ahead of print]. 55. McIntyre RS, Konarski JZ, Soczynska JK, et al. Medical comorbidity in bipolar disorder: implications for functional outcomes and health service utilization. Psychiatr Serv. 2006;57:1140-1144. 56. Fagiolini A, Chengappa KN, Soreca I, Chang J. Bipolar disorder and the metabolic syndrome: causal factors, psychiatric outcomes and economic burden. CNS Drugs. 2008;22:655-669. 57. Fiedorowicz JG, Palagummi NM, Forman-Hoffman VL, Miller DD, Haynes WG. Elevated prevalence of obesity, metabolic syndrome, and cardiovascular risk factors in bipolar disorder. Ann Clin Psychiatry. 2008;20:131-137. 58. McIntyre RS, Danilewitz M, Liauw SS, et al. Bipolar disorder and metabolic syndrome: an international perspective. J Affect Disord. July 29, 2010 [Epub ahead of print]. 59. Kupfer DJ, Frank E, Grochocinski VJ, Cluss PA, Houck PR, Stapf DA. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. J Clin Psychiatry. 2002;63:120-125. 60. Geller B, Tillman R, Craney JL, Bolhofner K. Four-year prospective outcome and natural history of mania in children with a prepubertal and early adolescent bipolar disorder phenotype. Arch Gen Psychiatry. 2004;61:459-467. 61. Yassa R, Nair V, Nastase C, Camille Y, Belzile L. Prevalence of bipolar disorder in a psychogeriatric population. J Affect Disord. 1988;14:197-201. 62. Shulman K, Post F. Bipolar affective disorder in old age. Br J Psychiatry. 1980;136:26-32. 63. Cassidy F, Carroll BJ. Vascular risk factors in late onset mania. Psychol Med. 2002;32:359-362. 64. Subramaniam H, Dennis MS, Byrne EJ. The role of vascular risk factors in late onset bipolar disorder. Int J Geriatr Psychiatry. 2007;22:733-737. 65. Zanetti MV, Cordeiro Q, Busatto GF. Late onset bipolar disorder associated with white matter hyperintensities: a pathophysiological hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:551-556. 66. Tamashiro JH, Zung S, Zanetti MV, et al. Increased rates of white matter hyperintensities in late-onset bipolar disorder. Bipolar Disord. 2008;10:765-775. 67. Salvadore G, Drevets WC, Henter ID, Zarate CA, Manji HK. Early intervention in bipolar disorder, part I: clinical and imaging findings. Early Interv Psychiatry. 2008;2:122-135. 68. Salvadore G, Drevets WC, Henter ID, Zarate CA, Manji HK. Early intervention in bipolar disorder, part II: therapeutics. Early Interv Psychiatry. 2008;2:136-146. 69. Berk M, Hallam K, Malhi GS, et al. Evidence and implications for early intervention in bipolar disorder. J Ment Health. 2010;19:113-126. 70. Skjelstad DV, Malt UF, Holte A. Symptoms and signs of the initial prodrome of bipolar disorder: a systematic review. J Affect Disord. 2010;126:1-13. 71. Luby JL, Navsaria N. Pediatric bipolar disorder: evidence for prodromal states and early markers. J Child Psychol Psychiatry. 2010;51:459-471. 72. Vita A, De Peri L, Sacchetti E. Gray matter, white matter, brain, and intracranial volumes in first-episode bipolar disorder: a meta-analysis of magnetic resonance imaging studies. Bipolar Disord. 2009;11:807-814. 73. Neria Y, Olfson M, Gameroff MJ, et al. Trauma exposure and posttraumatic stress disorder among primary care patients with bipolar spectrum disorder. Bipolar Disord. 2008;10:503-510.
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74. Swayze VW II, Andreasen NC, Alliger RJ, Yuh WT, Ehrhardt JC. Subcortical and temporal structures in affective disorder and schizophrenia: a magnetic resonance imaging study. Biol Psychiatry. 1992;31:221-240. 75. Hauser P, Altshuler LL, Berrettini W, Dauphinais ID, Gelernter J, Post RM. Temporal lobe measurement in primary affective disorder by magnetic resonance imaging. J Neuropsychiatry Clin Neurosci. 1989;1:128-134. 76. Kemmerer M, Nasrallah H, Sharma S, Olson S, Martin R, Lynn M. Increased hippocampal volume in bipolar disorder (abstract). Biol Psychiatry. 1994;35:626. 77. Vythilingam M, Heim C, Newport J, et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. 2002;159: 2072-2080. 78. Henin A, Biederman J, Mick E, et al. Childhood antecedent disorders to bipolar disorder in adults: a controlled study. J Affect Disord. 2007;99:51-57. 79. Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 2000;157:1873-1875. 80. Gaynes BN, DeVeaugh-Geiss J, Weir S, et al. Feasibility and diagnostic validity of the M-3 checklist: a brief, self-rated screen for depressive, bipolar, anxiety, and posttraumatic stress disorders in primary care. Ann Fam Med. 2010;8:160-169. 81. Angst J, Adolfsson R, Benazzi F, et al. The HCL-32: towards a self-assessment tool for hypomanic symptoms in outpatients. J Affect Disord. 2005;88:217-233. 82. Forty L, Kelly M, Jones L, et al. Reducing the Hypomania Checklist (HCL-32) to a 16item version. J Affect Disord. 2010;124:351-356. 83. Meyer TD, Hautzinger M. Screening for bipolar disorders using the Hypomanic Personality Scale. J Affect Disord. 2003;75:149-154. 84. Hirschfeld RM. Screening for bipolar disorder. Am J Manag Care. 2007;13(7 suppl): S164-S169. 85. Zimmerman M, Galione JN, Ruggero CJ, et al. Screening for bipolar disorder and finding borderline personality disorder. J Clin Psychiatry. 2010;71:1212-1217. 86. Zimmerman M, Galione JN, Ruggero CJ, et al. Performance of the mood disorders questionnaire in a psychiatric outpatient setting. Bipolar Disord. 2009;11:759-765 87. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389. 88. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62. 89. Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med. 1996;26:477-486. 90. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-613. 91. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429-435.
Medical Management of Bipolar Disorder: A Pharmacologic Perspective

23
Mechanisms of Action of Major Classes of Medications Used to Treat Bipolar Disorder
umerous medications are available to treat bipolar disorder (BD) I and II. These include mood stabilizers, antipsychotic agents, and antidepressants (Table 1).1-21 Understanding their respective pharmacologic and clinical profiles is critical to improved patient care. Here, we will explore select features of mood stabilizers and antipsychotics, while the next chapter will provide perspectives on use of antidepressants. Mood Stabilizers
The pathophysiology of mood disorders is complex, and a focus on the correction of neurochemical deficits alone has proven simplistic.22,23 Recently, researchers have focused on how pharmacotherapeutic agents influence neuroplasticity.1,24,25 Conventional medications used for BD mediate their effects through complex biochemical cascades, as illustrated in the figure.1 The various mood stabilizers available to cliniciansincluding lithium and anticonvulsants such as carbamazepine, valproic acid, and lamotrigine operate through neural signaling pathways, the clinical implications of which are as yet unknown. Translational research efforts are underway to delineate precisely how mood stabilizing agents influence neurotransmitter receptors and their respective intracellular signaling pathways that affect gene expression, cell differentiation, proliferation and death, and the structure and function of nerve cell activity. Select agents have been linked directly with changes in gene expression and neuroplasticity.1 For example, lithium and valproic acid enhance expression of brain-derived neurotrophic factor (BDNF), activation of which inhibits programmed cell death, or apoptosis, and promotes cellular proliferation.1 These agents also inhibit glycogen synthase kinase-3 (GSK-3), a pro-apoptotic enzyme highly expressed in the hippocampal neurons and involved in synaptic plasticity.26 Inhibition of GSK-3, therefore, is thought to protect neurons from apoptosis.27-29 Mood stabilizers also increase expression
24
Table 1. Approved Medications for Bipolar Disorder.1-5
Acute mania Acute depression Maintenance/ prophylaxis X X X X X X X X X X
Agent
Mood stabilizers
FDA approved indication(s)

Monotherapy acute manic episodes acute mixed episodes associated with BD Ia Monotherapy acute manic episodes associated with BDb Monotherapy maintenance treatment of BD I Monotherapy acute manic episodes maintenance treatment of manic-depressive illness
Carbamazepine ER6,7 Divalproex/ valproic acid8 Lamotrigine9 Lithium10,11
Typical antipsychotics
Chlorpromazine12 Monotherapy
acute manic episodes associated with manic-depressive illness
Atypical antipsychotics
Aripiprazole13
Monotherapy X acute manic episodes mixed manic episodes maintenance treatment associated with BD I Combination therapy adjunctive therapy to lithium or valproate for acute treatment of BD I Monotherapy acute manic episodes acute mixed episodes associated with BD I in adults Monotherapy acute manic episodes acute mixed episodes maintenance treatment agitation associated with BD I mania in adults
Asenapine14
Olanzapine15
25
Acute mania Acute depression Maintenance/ prophylaxis X X X X
(as adjunct)
Agent Olanzapinefluoxetine combination16 Quetiapine17,18
FDA approved indication(s)

Monotherapy acute treatment of depressive episodes associated with BD I in adults Monotherapy acute manic episodes acute treatment of depressive episodes Combination therapy approved for maintenance therapy as adjunct with lithium or valproate for acute treatment of BD I
Risperidone19
Monotherapy X acute manic episodes acute mixed episodes associated with BD I in adults and in children and adolescents aged 10-17 years Combination therapy as adjunctive therapy with lithium or valproate for short-term treatment of acute manic or mixed episodes associated with BD I Monotherapy maintenance treatment of BD I Combination therapy as adjunctive therapy with lithium or valproate for maintenance treatment of BD I Monotherapy acute manic episodes acute mixed episodes associated with BD I Combination therapy approved for maintenance therapy as adjunct with lithium or valproate for acute treatment of BD I
Risperidone long-acting injection20
Ziprasidone21
X
(as adjunct)
BD I = bipolar I disorder; ER = extended release; FDA = Food and Drug Administration.

a b
Only Equetro ER capsules approved for BD. Only Depakote DR capsule, DR and ER tablets approved for manic episodes associated with BD. Equetro is a registered trademark of Validus Pharmaceuticals. Depakote is a registered trademark of Abbott Laboratories.
26
of a critical antiapoptotic protein, Bcl-2.1 Precisely how these molecular and cellular events modulate mood, emotion, affect, and other clinical features we see in our patients remains only partly understood. Table 2 summarizes the mechanisms of action (MOA) of medications used for BD.1,3-5,30-38 Antipsychotics Antipsychotics include the typical agents (eg, haloperidol, chlorpromazine, fluphenazine, and perphenazine) and the following atypical agents approved for BD in the United States: aripiprazole, asenapine, olanzapine, quetiapine,
2 3 5 AC Signal transduction P cAMP ATP cascades 6 P 4
BclP P
2 Ca
GSK-3
6
GSK-3
Transcription factors Gene expression
1) Glutamatergic neurotransmitter system, ionotropic and metabotropic receptors 2) Corticosteroid receptors reflecting the function of the HPA axis 3) Monoaminergic receptors 4) Signal transduction cascades 5) Neurotrophic factor receptors 6) Bcl-2 and GSK-3, representing regulators of cellular resilience and death 7) Chromatin remodeling and changes in transcription factor expression
AC = adenylate cyclase; ATP = adenosine triphosphate; Ca2+ = intracellular calcium; cAMP = cyclic adenosine monophosphate; GSK-3 = glycogen synthase kinase-3 beta; HPA = hypothalamic-pituitary-adrenal; P = phosphorylation.
Figure. Signal transduction cascades involved in the mechanism of action of bipolar disorder medications.1
27
Table 2. Mechanism of Action of Medications Used to Treat Bipolar Disorder.
Drug
Mood stabilizers
Mechanism Decreases stimulation of neural discharge related to the influx of sodium ions across cellular membranes5,38; depresses neuronal activity in the nucleus ventralis of the thalamus4
Carbamazepine
Divalproex/valproic Increases GABA activity and mimics the action of acid/valproate GABA at the postsynaptic receptor; enhances BDNF expression3,37; inhibits GSK-3; increases the antiapoptotic protein Bcl-236 Lamotrigine Increases glutamate clearance and decreases glutamate release, protecting against damage to neurons and glia1; inhibits voltage-sensitive sodium channels that are thought to stabilize neuronal membranes35 Increases glutamate clearance and decreases glutamate release, protecting against damage to neurons and glia34; enhances BDNF expression33; inhibits GSK-331,32; increases the antiapoptotic protein Bcl-236 Act at serotonin, norepinephrine, and dopamine receptors on the cell surface to produce variable effects on signal transduction cascades, resulting in downstream changes in metabolism, energetics, and gene expression1,30
Lithium
Antipsychotics
BDNF = brain-derived neurotrophic factor; GABA = gamma-aminobutyric acid; GSK-3 = glycogen synthase kinase-3.
risperidone, and ziprasidone. The atypical antipsychotic clozapine is not approved for BD, but this agent may be used for treatment-resistant individuals with BD.39-42 While the mechanisms underlying the efficacy of these agents in BD are not well understood, modulation of dopamine and serotonin levels is thought to be important in acute mania and maintenance treatment (Tables 1, 2). More specifically, some antipsychotics may affect the GSK-3 signaling pathway and regulate central responses to environmental stressors by inhibiting corticotropin-releasing hormone (CRH) secretion from the hypothalamus and the hippocampus.2,43 The selection of an antipsychotic agent for the management of BD should be determined after a thorough assessment of bipolar subtype (BD I vs BD II) and associated features (eg, psychosis, rapid cycling), prior treatment response, patient side effect experience, medication side effect profile, patient preference, adherence history, risk for drug-drug interaction, and cost.44
28
Table 3. Receptor Binding Profiles of Antipsychotics.45,46,a
Acetylcholine muscarinic M1 Adrenergic 1 Adrenergic 2 750 600 500 2400 74d 1.2b 158 3 280 80 80 8 154 Histaminic H1 0.2b 260 8 5 30b 1.0b 3.1 12.3 0.08 3.4 19 5.2 4.6 Dopamine D2
Serotonin 5-HT2A
Agent
Chlorpromazine Haloperidol Perphenazine Loxapine Aripiprazole Asenapine Clozapine Iloperidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone
a
2.0b 2.6 1.4

b c
8.0b 61 5
b
25.0b >10,000b 1500 62.5 6780b 8128b 1.4b 4898b 2.5

b b
2.6 17 10 27.8 26b 1.2b 6.8 0.31 44 10 8.1

b
71.4
1.7 8.7b 0.06b 2.59 0.2 1.5 1.2 31 0.15 0.12
0.66b,d 1.3b 210 3.3 20 2.8 770 3.8 2.6
>10,000 120b >10,000 300b
2.7 2.6
Data represented as the equilibrium constant (Ki) (nM), ie, nanomolar amount of the antipsychotic needed to block 50% of the receptors in vitro. Therefore, a lower number denotes stronger receptor affinity and binding; bData from cloned human brain receptors; cDopamine D2L; dPartial agonism.
Typical and atypical antipsychotics vary widely in their affinity for dopaminergic, serotonergic, and other receptors (Table 3).45,46 In some cases, adverse event profiles are influenced positively (Table 4).47 For example, aripiprazole (currently indicated for schizophrenia and for acute and maintenance treatment of manic/mixed episodes associated with BD I) has no muscarinic activity and, thus, few anticholinergic side effects.13 Further, it does show partial agonist activity at dopamine D2 and 5-HT1A receptors, suggesting that it may be beneficial in the depressed phase of a mood disorder.48 Some evidence indicates that olanzapine has weak activity at gamma aminobutyric acid (GABA) and benzodiazepine receptors, implying that it may have a calming effect similar to that of an anxiolytic, and is also approved for acute
29
Table 4. Relationship Between Receptor Activity and Adverse Effects.47
Receptor activity 1 (adrenergic) antagonism 2 (adrenergic) antagonism D2 (dopamine) antagonism Adverse effects Postural hypotension; dizziness; reflex tachycardia; potentiation of antihypertensive effects of prazosin, terazosin, doxazosin, and labetalol Blockade of antihypertensive effects of clonidine, hydrochloride, guanabenz acetate, and methyldopa EPS (Parkinsonism, dystonia, akathisia), tardive dyskinesia, endocrine effects due to hyperprolactinemia (eg, galactorrhea, gynecomastia, menstrual changes, sexual dysfunction in males) Sedation, drowsiness, weight gain, potentiation of central depressant drugs Blurred vision, attack/exacerbation of narrowangle glaucoma, dry mouth, sinus tachycardia, constipation, urinary retention, memory impairment Decreased risk of EPS
H1 (histamine) antagonism Muscarinic antagonism 5-HT2A (serotonin) antagonism
EPS = extrapyramidal symptoms.
and maintenance treatment of BD.49 Ziprasidone, a serotonin-dopamine antagonist, is also a partial 5-HT1A agonist, with putative anxiolytic actions.50 This agent also inhibits serotonin and norepinephrine reuptake and may show some efficacy as an antidepressant.51 An olanzapine-fluoxetine combination translates to a greater serotonergic effect and for this reason has been found useful in individuals with BD I depression.52 In addition, the olanzapinefluoxetine combination may be particularly beneficial in bipolar depression due to its synergistically therapeutic impact on serotonin, norepinephrine, and dopamine levels in the central nervous system (CNS). Other approved antipsychotics, such as chlorpromazine, asenapine, quetiapine, and risperidone, are effective for the treatment of mania.53-56 Quetiapine may also be used to treat acute depression in both BD I and BD II.57,58 Further, quetiapine and risperidone long-acting injection are useful for maintenance therapy and monotherapy/adjunctive therapy, respectively.59,60 Most patients with BD require a combination therapy, as indicated by studies listed in Table 5.61-73 According to these and related data, combination therapies are more effective than monotherapy.72 The new emphasis is now on treating acute and maintenance phases to remission and attempting
30
to maintain this in long-term prophylaxis because of the potentially devastating psychosocial, cognitive, and medical consequences of inadequately treated illness and repeated relapses. Minor symptom breakthroughs are also precursors of more major episode recurrence. Long-term careful monitoring is essential. Such a shift in emphasis to the long-term has important implications for the choice of agents not only regarding efficacy but especially long-term tolerability.
Table 5.
Clinical Studies With Combination Regimens.

Study focus Mania
Combination used Aripiprazole + lithium or valproic acid/valproate (VPA)/divalproex
Lamotrigine + lithium or VPA
Depression, mania
Lamotrigine + VPA or lithium
Depression
Lamotrigine added to VPA, lithium, atypical antipsychotic (ie, clozapine, olanzapine, quetiapine, risperidone), SSRI (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) Lithium + VPA
Changes in psychiatric rating scales
Maintenance
Olanzapine + lithium, VPA, or carbamazepine
Maintenance treatment for treatment-resistant disease
Metabolic Pathways, Drug-Drug Interactions, and Importance of Dose Adjustment

nderstanding the metabolic pathways involved in a given disease state is critical for rational treatment selection. A thorough assessment of hepatic or renal health informs dosage adjustments and the need for concomitant medications. Table 6 summarizes metabolic pathways and clinically important drug-drug interactions for medications used in BD. 7,10-12,14-16,21,74-89
31
Study details
Results
46-week, open-label adjunctive study; patients Addition of aripiprazole to either lithium or VPA was safe and with mania who completed a 6-week doubleeffective71 blind study comparing adjunctive aripiprazole vs placebo were eligible (N=283) Retrospective analysis of patients after 3 months of treatment Combinations were effective in reducing depression and mania, with a greater reduction in mania than depression70 Improvement in depression was observed69
In this naturalistic study, patients who had not responded to mood stabilizers received lamotrigine and were monitored up to 52 weeks (N=109)
Addition of lamotrigine resulted in Lamotrigine was added to existing clinical improvement68 psychotropic regimen of patients with bipolar I disorder during the 8- to 16-week, open-label, preliminary phase of 2 clinical trials (N=1305) Addition of VPA to lithium did 6-month, double-blind, parallel-group not provide greater prophylactic maintenance trial; patients enrolled in an acute benefit vs lithium alone67 stabilization phase were eligible (N=31) Multinational open-label study with a follow-up A combination of lithium and of up to 24 months (N=330) VPA and lithium monotherapy could prevent relapse; the study could not reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy, but both lithium and lithium-VPA cotreatment were superior to VPA monotherapy66 Patients received olanzapine while maintaining Olanzapine may be useful for longother drugs, and were followed up to 43 weeks term adjunctive treatment73 (N=23)
Continued on page 32
32
Combination used Olanzapine + other antipsychotics, anticonvulsants, and/or lithium Quetiapine + lithium or VPA Study focus Mania
Maintenance
Risperidone + lithium or VPA Risperidone or haloperidol + lithium or VPA
Mania (pediatric) Mania
Ziprasidone + lithium or VPA
Mania, maintenance
SSRI = selective serotonin reuptake inhibitor.
Mood Stabilizers Lithium is removed from the body by the kidney and eliminated unchanged in the urine.90 Thus, an individual with renal dysfunction is not an ideal candidate for lithium treatment; however, lithium does not undergo hepatic metabolism and may be suitable for patients with compromised hepatic function. Carbamazepine is infrequently used for the management of BD primarily because it induces cytochrome P450 (CYP) enzymes and is therefore associated with drug-drug interactions.6,7 Carbamazepine reduces its own levels and is also a heteroinducer, influencing other medications that patients with BD may be receiving.7,91 Further, carbamazepine has several Black Box warnings (eg, hematologic abnormalities and dermatologic reactions) that limit its use.6,7 Lamotrigine is approved for the maintenance phase of BD and appears most beneficial in preventing depressive episode recurrence.9,92 It is
33
Study details
Evaluated at 12 weeks, from a 24-month, prospective observational study of patients with acute mania/mixed mania (N=2004)
Results
Combinations were effective65
Naturalistic study followed bipolar patients for Combination of quetiapine plus lithium or VPA was more effective 4 years (N=232) than lithium or VPA monotherapy A double-blind, placebo-controlled 12-week in maintaining euthymia; efficacy study; evaluated effiicacy of quetiapine as of quetiapine monotherapy, lithium adjunct therapy with lithium or VPA in reducing monotherapy, and combination alcohol consumption in bipolar I patients with of lithium or VPA was similar coexisting alcohol dependence (N=363) in preventing the recurrence of major depressive episodes64 Adding quetiapine to lithium or VPA did not improve measures of alcohol use and dependence compared with placebo63 Prospective, 6-month, open-label trial of Both combinations were patients with manic or mixed episodes (N=37) effective62 3-week, randomized, double-blind, placebocontrolled study involving patients with bipolar disorder and a current manic or mixed episode (N=156) 6-month maintenance study; subjects who achieved stability for at least 8 weeks with ziprasidone and lithium or VPA were eligible (N=240) Combination of risperidone and mood stabilizer was more efficacious than a mood stabilizer alone61 Adding ziprasidone to a mood stabilizer was more effective than adding placebo72
frequently used in combination with other mood stabilizers or antipsychotic agents for the management of BD. Exceptionally careful upward titration is key to lamotrigine use due to the risk of occasionally fatal Stevens-Johnson syndrome that is dose- and titration-ratedependent. The Black Box warning came about in part from adverse events related to coadministration of lamotrigine with valproic acid, which elevates lamotrigine levels by as much as 100%, especially at higher than recommended starting doses.92 Antipsychotics When a patient is using a hepatic CYP enzyme inducer like carbamazepine, the dose of aripiprazoleas with all hepatically metabolized antipsychoticsshould be appropriately increased.13 Conversely, if an individual is taking a CYP3A4 inhibitor such as ketoconazole, or a CYP2D6 inhibitor
34
Table 6. Metabolic Profiles of Bipolar Medications and Potential Drug Interactions.
Agent
Mood stabilizers
Metabolic pathways Oxidation, hydroxylation, conjugation
Carbamazepine
Divalproex/valproic acid
-oxidation, CYP450 system, glucurodination
Lamotrigine Lithium
Glucurodination, CYP450 system 95% renal excretion
Chlorpromazine
CYP1A2, CYP2D6, CYP3A4, CYP2C1987,88
Aripiprazole
CYP2D6 > CYP3A489
Asenapine Fluoxetine (used in combination with olanzapine)
Primarily glucurodination (UGT1A4), secondarily CYP1A214 CYP2D616
Olanzapine
CYP1A2, CYP2D6
35
Potential drug-drug interactions of clinical relevance Potent inducer of CYP3A4 , CYP 1A2, 2B6, 2C8, 2C9, 2C19, 3A4 enzymes.7,86 It may plasma concentrations of medications primarily metabolized through CYP3A4 (eg, acetaminophen, bupropion, olanzapine, oral contraceptives, valproate); CYP3A4 inhibitors carbamazepine levels7 Inhibits lamotrigine metabolism, increasing lamotrigine concentrations, which may result in serious toxic reactions84; coadministration with warfarin or aspirin can interfere with blood clotting83,84 Clearance with carbamazepine, phenytoin, phenobarbital, and primidone but with valproic acid82; plasma levels by oral contraceptives79-82 Diuretic-induced sodium loss may renal clearance of lithium, increasing levels and leading to lithium toxicity10,11; in addition, lithium toxicity can result from interactions with NSAIDs, indomethacin, piroxicam, metronidazole, angiotensinconverting enzyme inhibitors, and calcium channel blockers; acetazolamide, urea, xanthine preparations, and alkalinizing agents may lower lithium concentrations10,11 Coadministration may phenytoin concentrations; concomitant administration with propranolol results in concentrations of drugs; thiazide diuretics may potentiate phenothiazine-related hypotension12 Need to dose when a CYP2D6 inhibitor is given (eg, fluoxetine or paroxetine) Need to dose when a CYP3A4 inducer (eg, carbamazepine) is given and dose when a CYP3A4 inhibitor is given or a CYP3A4 inducer is discontinued78 Coadministration with fluvoxamine fluvoxamine concentrations; may enhance effects of certain antihypertensive agents14 Coadministration with other drugs that are tightly bound to protein may cause displacement of fluoxetine; coadministration with other drugs metabolized by CYP2D6 (eg, alprazolam, haloperidol, clozapine) may concentrations of these drugs; may concentrations of carbamazepine and phenytoin; coadministration with lithium may or lithium levels; potential pharmacodynamic interactions when coadministered with other centrally acting drugs or serotonergic drugs; should not be used along with an MAOI or for less than14 days after discontinuing an MAOI due to risk of serious interaction; concomitant administration with pimozide or thioridazine contraindicated due to QTc prolongation74 Coadministration with carbamazepine olanzapine levels85; and fluvoxamine olanzapine levels77,84; pharmacodynamic interactions should be considered when coadministered with other centrally acting drugs or alcohol; may potentiate effects of certain antihypertensive agents84; smoking decreases blood levels15
36
Agent Quetiapine Metabolic pathways CYP3A4, sulfoxidation, and oxidation
Risperidone
Hydroxylation, CYP2D6, CYP3A4
Ziprasidone
Aldehyde oxidase > CYP3A4
CYP = cytochrome P450; MAOI = monoamine oxidase inhibitor; NSAIDs = nonsteroidal anti-inflammatory drugs; QTc = corrected QT.
such as fluoxetine or paroxetine, the aripiprazole dose should be appropriately reduced.13 Asenapine is unique because it is a substrate for UDP glycosyltransferase 1 family, polypeptide A4 (UGT-1A4), and CYP1A2 and is, therefore, likely to be influenced by CYP1A2 inhibitor antidepressants such as fluvoxamine.14 Further, because cigarette smoking induces CYP1A2, smokers on average may require a higher dose of olanzapine and clozapine than nonsmokers to compensate for the lower medication levels.93 Asenapine levels are not influenced by smoking.14 For individuals on multiple medications that are metabolized by CYP3A4, drug-drug interactions with quetiapine may pose a problem. Interactions between risperidone and agents that inhibit CYP2D6 (eg, fluoxetine, paroxetine) are clinically important since higher levels of risperidone may produce extrapyramidal side effects.94 Drug-drug interactions are generally less likely with ziprasidone, given its alternative metabolic pathway involving aldehyde oxidase.90 Selecting from among the atypical antipsychotics will depend to some extent on idiosyncratic metabolic factors and concomitant medications that increase the risk of drug-drug interactions (Table 6).
Available Formulations of Medications for Bipolar Disorder

nderstanding available formulations (Table 7)6-8,10-18,20,21,92,95-97 and dosages (Table8)84 can help guide the selection of medications. The controlled-release (CR) form of lithium will prove useful in patients who
37
Potential drug-drug interactions of clinical relevance CYP3A4 inhibitors (eg, fluvoxamine, clozapine) may quetiapine levels76; CYP3A4 inducers (eg, carbamazepine) may quetiapine levels; quetiapine can levels of the main active metabolite of carbamazepine; although study results conflict, valproic acid may quetiapine levels75,76 Potent CYP2D6 inhibitors (eg, fluvoxamine, fluoxetine, paroxetine) can risperidone plasma levels in poor and extensive metabolizers77; coadministration with carbamazepine risperidone and active moiety levels and carbamazepine levels84 Carbamazepine coadministration may ziprasidone levels21; potent CYP3A4 inhibitors (eg, ketoconazole) may ziprasidone levels21; should not be used with other drugs that cause QT prolongation; may enhance effects of certain antihypertensive agents21
will benefit from up to a 4-hour delay in maximum concentration (Cmax).98 Lithium syrup with 1 hour to Cmax is also available.99 The CR dosage is recommended for patients who cannot tolerate the gastrointestinal side effects of lithium. With valproic acid, the extended-release (ER) formulation has a delayed time to peak and a lower bioavailability versus the delayed-release (DR) formulation, and the ER formulation can be given once daily.100 Finally, the 10% to 20% reduction in bioavailability with the ER formulation will require patients switching from DR to have a dosage increase.101 In addition to their unique drug-drug interaction profiles, antipsychotics vary by available formulations as well. Short-acting injectable formulations are available for chlorpromazine, haloperidol, aripiprazole, olanzapine, and ziprasidone, and are appropriate for patients with acute mania. While injectable haloperidol and ziprasidone are not indicated for BD, they may be used with or without lorazepam for the management of acute mania. For individuals who require a long-acting injectable agent due to preference or adherence issues, the only Food and Drug Administration (FDA)-approved agent is long-acting risperidone.20 Other nonapproved long-acting injectable formulations are available and may be used in the clinical setting. These include haloperidol decanoate, fluphenazine decanoate, paliperidone longacting injection, and olanzapine pamoate. The extent to which these nonapproved agents are beneficial is currently unclear, as at present there are few data on efficacy from clinical studies. Recommendations for switching from an oral antipsychotic regimen to a long-acting antipsychotic differ. With haloperidol or fluphenazine, a loading
38
Table 7. Available Formulations of Agents Approved for Bipolar Disorder.
Shortacting injectable Xc X Xd Xd Xc Longacting injectable Xc X
Agent Carbamazepine ER/XR6,7 Divalproex/ valproic acid8,96 Lamotrigine92
Forms Tablet, chewable tablet, ER or XR capsule, ER or XR tablet, suspension
Mood stabilizers
Capsule, DR capsule, sprinkle capsule, Xb DR and ER tablet, oral solution, syrup, short-acting injectable Tablet, chewable dispersible tablet, orally disintegrating tablet, ER tablet Tablet, CR tablet, capsule, syrup X
Lithium10,11
Chlorpromazine12 Tablet, short-acting injectable

Aripiprazole13 Asenapine14 Olanzapine

15,97
Tablet, orally disintegrating tablet, solution, short-acting injectable Sublingual tablet Tablet, orally disintegrating tablet, short-acting injectable, long-acting injectable Capsule
Olanzapinefluoxetine combination16 Quetiapine17,18 Risperidone

20,95
Tablet, XR tablet Tablet, orally disintegrating tablet, solution, long-acting injectable Capsule, short-acting injectable
Ziprasidone21
CR = controlled release; DR = delayed release; ER = extended release. a Only Equetro ER capsules approved for BD. b Only Depakote DR capsule, DR and ER tablets approved for manic episodes associated with BD. c Not currently approved for BD. d Approved for acute agitation associated with BD. Equetro is a registered trademark of Validus Pharmaceuticals. Depakote is a registered trademark of Abbott Laboratories.
Oral Xa X X X X X X X X X
dose of depot medication is usually given and the amount of overlap with oral administration should be minimal.102,103 However, when using the longacting dosage form of risperidone, oral administration and injection should overlap for at least the first 3 weeks.20 In clinical practice, a 4- to 6-week overlap with oral administration may be needed for individuals to derive maximum benefit and to avoid the risk of relapse. With long-acting risperidone, only 1% of drug is released during the first 3 weeks of treatment. Additional drug is then released slowly until a peak is reached during the next week and a half. Risperidone concentrations peak about 4.5 weeks after the initial injection.20 In contrast, the long-acting dosage forms of paliperidone and olanzapine do not require overlap and provide an option that achieves therapeutic drug levels quickly without a need for oral administration.97,104 However, with the long-acting injectable paliperidone, a second injection at Week 1 is required once to achieve therapeutic blood levels.104 It is important to remember that these two agents are not approved for BD, but rather for schizophrenia.
39
Patient-Specific Factors Influencing Therapeutic Selection Strategies

n addition to drug-specific factors, patient-specific factors must be considered when selecting treatment. For example, lithium should be used with caution in patients with a history of cardiovascular disease or patients who are dehydrated due to an effect on the atrioventricular node and the adverse impact on lithium concentration in the dehydrated state.11,105 In addition, lithium may influence thyroid function, potentially leading to hypothyroidism, so longitudinal monitoring of thyroid function and levels of concomitant thyroid medications is necessary.11 Because carbamazepine and valproic acid are sedating agents, concomitant use with other drugs that have sedative properties increases the risk of additive or synergistic effects and should therefore be managed with caution.6-8 Valproic acid has been associated with hepatic failure and pancreatitis; as such, lithium may be a preferable substitute for patients with hepatic impairment.8 Olanzapine, quetiapine, and chlorpromazine are all relatively sedating compounds. Other antipsychotics, such as aripiprazole, risperidone, and ziprasidone are less sedating and should be considered when sedation is an issue.106,107 Teratogenicity has been associated with the anticonvulsants and lithium, despite the relatively minimal risk of lithium. The labeling for valproic acid
40
Table 8. Dosing and Therapeutic Drug Monitoring for Drug Use in Bipolar Disorder.84
Drug
Mood stabilizers
Daily dose range (mg/d) 3002400 6002400
Therapeutic plasma level range 0.51.5 mEq/L Not reported
Lithium Carbamazepine (oxycarbamazepine)
5003000
50125 g/mL
Lamotrigine
25400 200600 530 1020 520 6/2512/50 400800 16 80160
Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported
Chlorpromazine
Aripiprazole Asenapine Olanzapine Olanzapine-fluoxetine combination Quetiapine Risperidone Ziprasidone
BMI = body mass index; CSF = cerebrospinal fluid; DR = delayed release; ECG = electrocardiogram; ER = extended release; HgbA1c = glycosylated hemoglobin.
41
Additional notes on therapeutic drug monitoring
Serum levels should be monitored 12 hours after a dose Steady-state usually achieved in 45 days; 78 days in the elderly Serum levels of carbamazepine should be measured 12 hours after a dose but do not correlate with clinical response CSF levels of the 10-, 11-epoxide metabolite are associated with clinical response Obtaining serum levels may provide guidance related to adherence or to whether an individual may be a poor or rapid metabolizer Initial levels may decrease with time, as autoinduction of its own metabolism develops across time Serum concentrations are best obtained at trough, 12 hours after valproic acid 2x/d ER formulation serum concentrations are some 25% greater than DR formulation equivalents per unit time ER serum levels of 100 g/mL, translate to 75 g/mL with the DR formulation When using the ER formulation, check serum level at 1820 hours. Loading with 2030 mg/kg is possible Maintenance dose usually at 20 mg/kg Monitor for hypersensitivity reaction (especially rash)
Monitor metabolic profile (weight/BMI, lipids, glucose/HgbA1c)
Monitor metabolic profile (weight/BMI, lipids, glucose/HgbA1c) Monitor metabolic profile (weight/BMI, lipids, glucose/HgbA1c) Monitor metabolic profile (weight/BMI, lipids, glucose/HgbA1c) Monitor metabolic profile (weight/BMI, lipids, glucose/HgbA1c) Monitor metabolic profile (weight/BMI, lipids, glucose/HgbA1c) Monitor metabolic profile (weight/BMI, lipids, glucose/HgbA1c) Obtain baseline ECG; monitor metabolic profile (weight/BMI, lipids, glucose/HgbA1c)
42
contains a Black Box warning related to neural tube defects in the offspring of pregnant women who received this agent.8 This warning may prompt selection of alternative therapies, such as antipsychotic agents, for the management of BD in young female populations of childbearing age and those who are pregnant or desire to become pregnant, although the safety of antipsychotics during pregnancy has not been conclusively established. A recent report indicates that prenatal exposure to valproic acid may affect the long-term developmental outcome of children. In this study, the mean full-scale IQ (FSIQ) of children who were exposed to valproic acid in utero was 83.9 (95% confidence interval [CI], 64.2-103.6), compared with 102 (95% CI, 90-116) in the control group.108
Concluding Remarks and Future Directions

ur understanding of the mechanisms by which mood stabilizers and antipsychotics achieve their effects in patients with BD has expanded, which may help identify novel therapeutic targets. Despite such advances, treatment remains inadequate for many patients with BD. Most patients require a combination of medications. Therefore, considering drug-drug interactions and metabolic effects of individual agents is critical when selecting therapy. To improve prognosis and outcomes and to minimize the burden of disease symptomatology, a focus on early and long-term treatment is needed.
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34. Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7:426-437. 35. Prica C, Hascoet M, Bourin M. Antidepressant-like effect of lamotrigine is reversed by veratrine: a possible role of sodium channels in bipolar depression. Behav Brain Res. 2008;191:49-54. 36. Chen G, Zeng WZ, Yuan PX, et al. The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS. J Neurochem. 1999;72:879-882. 37. Yasuda S, Liang MH, Marinova Z, Yahyavi A, Chuang DM. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry. 2009;14:51-59. 38. McLean MJ, Macdonald RL. Carbamazepine and 10,11-epoxycarbamazepine produce use- and voltage-dependent limitation of rapidly firing action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther. 1986;238:727-738. 39. Ciapparelli A, DellOsso L, Bandettini di Poggio A, et al. Clozapine in treatment-resistant patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: a naturalistic 48-month follow-up study. J Clin Psychiatry. 2003;64:451-458. 40. Chang JS, Ha KS, Young Lee K, Sik Kim Y, Min Ahn Y. The effects of long-term clozapine add-on therapy on the rehospitalization rate and the mood polarity patterns in bipolar disorders. J Clin Psychiatry. 2006;67:461-467. 41. Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatmentresistant illness and a history of mania. Am J Psychiatry. 1999;156:1164-1169. 42. Green AI, Tohen M, Patel JK, et al. Clozapine in the treatment of refractory psychotic mania. Am J Psychiatry. 2000;157:982-986. 43. Tringali G, Lisi L, De Simone ML, et al. Effects of olanzapine and quetiapine on corticotropin-releasing hormone release in the rat brain. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1017-1021. 44. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text Revision, DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000. 45. Correll CU. From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics. Eur Psychiatry. 2010;25(suppl 2):S12-S21. 46. Gardner DM, Baldessarini RJ, Waraich P. Modern antipsychotic drugs: a critical overview. CMAJ. 2005;172:1703-1711. 47. Richelson E. Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry. 1999;60(suppl 10):5-14. 48. Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol. 2002;441:137-140. 49. Marx CE, VanDoren MJ, Duncan GE, Lieberman JA, Morrow AL. Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents. Neuropsychopharmacology. 2003;28:1-13. 50. Buckley PF, Harvey PD, Bowie CR, Loebel A. The relationship between symptomatic remission and neuropsychological improvement in schizophrenia patients switched to treatment with ziprasidone. Schizophr Res. 2007;94:99-106.
51. Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. J Clin Psychiatry. 2003;64(suppl 19):6-12. 52. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapinefluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1088. 53. McIntyre RS, Konarski JZ, Jones M, Paulsson B. Quetiapine in the treatment of acute bipolar mania: efficacy across a broad range of symptoms. J Affect Disord. 2007;100(suppl 1):S5-S14. 54. McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Asenapine for longterm treatment of bipolar disorder: A double-blind 40-week extension study. J Affect Disord. 2010;126:358-365. 55. Yatham LN. Efficacy of atypical antipsychotics in mood disorders. J Clin Psychopharmacol. 2003;23(3 suppl 1):S9-S14. 56. Perlis RH, Welge JA, Vornik LA, Hirschfeld RM, Keck PE Jr. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry. 2006;67:509-516. 57. McElroy SL, Weisler RH, Chang W, et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010;71:163-174. 58. Young AH, McElroy SL, Bauer M, et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010;71:150-162. 59. Fagiolini A, Casamassima F, Mostacciuolo W, Forgione R, Goracci A, Goldstein BI. Risperidone long-acting injection as monotherapy and adjunctive therapy in the maintenance treatment of bipolar I disorder. Expert Opin Pharmacother. 2010;11:1727-1740. 60. Ketter TA, Brooks JO, 3rd, Hoblyn JC, et al. Long-term effectiveness of quetiapine in bipolar disorder in a clinical setting. J Psychiatr Res. April 6, 2010 [Epub ahead of print]. 61. Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Bowden CL. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry. 2002;159:1146-1154. 62. Pavuluri MN, Henry DB, Carbray JA, Sampson G, Naylor MW, Janicak PG. Open-label prospective trial of risperidone in combination with lithium or divalproex sodium in pediatric mania. J Affect Disord. 2004;82(suppl 1):S103-S111. 63. Stedman M, Pettinati HM, Brown ES, Kotz M, Calabrese JR, Raines S. A double-blind, placebo-controlled study with quetiapine as adjunct therapy with lithium or divalproex in bipolar I patients with coexisting alcohol dependence. Alcohol Clin Exp Res. 2010;34:1822-1831. 64. Altamura AC, Mundo E, DellOsso B, Tacchini G, Buoli M, Calabrese JR. Quetiapine and classical mood stabilizers in the long-term treatment of bipolar disorder: a 4-year follow-up naturalistic study. J Affect Disord. 2008;110:135-141. 65. Vieta E, Panicali F, Goetz I, Reed C, Comes M, Tohen M; EMBLEM Advisory Board. Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania: 12-week results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study. J Affect Disord. 2008;106:63-72. 66. The BALANCE investigators and collaborators, Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination therapy versus monotherapy for relapse
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prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375:385-395. 67. Kemp DE, Gao K, Ganocy SJ, et al. A 6-month, double-blind, maintenance trial of lithium monotherapy versus the combination of lithium and divalproex for rapid-cycling bipolar disorder and co-occurring substance abuse or dependence. J Clin Psychiatry. 2009;70:113-121. 68. Bowden CL, Edwards S, Evoniuk G. Open-label, concomitant use of lamotrigine and other medications for bipolar disorder. CNS Spectr. 2008;13:75-83. 69. Chang JS, Moon E, Cha B, Ha K. Adjunctive lamotrigine therapy for patients with bipolar II depression partially responsive to mood stabilizers. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1322-1326. 70. Redmond JR, Jamison KL, Bowden CL. Lamotrigine combined with divalproex or lithium for bipolar disorder: a case series. CNS Spectr. 2006;11:915-918. 71. Vieta E, Owen R, Baudelet C, McQuade RD, Sanchez R, Marcus RN. Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week, open-label extension following a 6-week double-blind study. Curr Med Res Opin. 2010;26:1485-1496. 72. Bowden CL, Vieta E, Ice KS, Schwartz JH, Wang PP, Versavel M. Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebocontrolled, double-blind trial. J Clin Psychiatry. 2010;71:130-137. 73. Vieta E, Reinares M, Corbella B, Benabarre A, Olanzapine as long-term adjunctive therapy in treatment-resistant bipolar disorder. J Clin Psychopharmacol. 2001;21:469-473. 74. Prozac [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009. 75. Aichhorn W, Marksteiner J, Walch T, Zernig G, Saria A, Kemmler G. Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol. 2006;21:81-85. 76. Castberg I, Skogvoll E, Spigset O. Quetiapine and drug interactions: evidence from a routine therapeutic drug monitoring service. J Clin Psychiatry. 2007;68:1540-1545. 77. Raggi MA, Mandrioli R, Sabbioni C, Pucci V. Atypical antipsychotics: pharmacokinetics, therapeutic drug monitoring and pharmacological interactions. Curr Med Chem. 2004;11:279-296. 78. Citrome L, Macher JP, Salazar DE, Mallikaarjun S, Boulton DW. Pharmacokinetics of aripiprazole and concomitant carbamazepine. J Clin Psychopharmacol. 2007;27:279-283. 79. Pennell PB, Newport DJ, Stowe ZN, Helmers SL, Montgomery JQ, Henry TR. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology. 2004;62:292-295. 80. Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia. 2000;41:709-713. 81. Sidhu J, Job S, Singh S, Philipson R. The pharmacokinetic and pharmacodynamic consequences of the co-administration of lamotrigine and a combined oral contraceptive in healthy female subjects. Br J Clin Pharmacol. 2006;61:191-199. 82. Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurology. 2003;61:570-571. 83. Sweetman SC. Martindale: The Complete Drug Reference. London: Pharmaceutical Press; 2005:380.
84. Musenga A, Saracino MA, Sani G, Raggi MA. Antipsychotic and antiepileptic drugs in bipolar disorder: the importance of therapeutic drug monitoring. Curr Med Chem. 2009;16:1463-1481. 85. Besag FM, Berry D. Interactions between antiepileptic and antipsychotic drugs. Drug Saf. 2006;29:95-118. 86. Agency for Healthcare Research and Quality (AHRQ). Evidence-Based Practice Center Systematic Review Protocol. Project Title: Evaluation of Effectiveness and Safety of Antiepileptic Medications in Patients With Epilepsy. http://www.effectivehealthcare. ahrq.gov/ehc/products/159/463/EpilepsyCERProtocol6%2024%2010%20docx-1%20 cmw%20Posting.pdf. Accessed September 13, 2010. 87. Yoshii K, Kobayashi K, Tsumuji M, Tani M, Shimada N, Chiba K. Identification of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human liver microsomes. Life Sci. 2000;67:175-184. 88. Wojcikowski J, Boksa J, Daniel WA. Main contribution of the cytochrome P450 isoenzyme 1A2 (CYP1A2) to N-demethylation and 5-sulfoxidation of the phenothiazine neuroleptic chlorpromazine in human liver-A comparison with other phenothiazines. Biochem Pharmacol. 2010;80:1252-1259. 89. Swainston HT, Perry CM. Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. Drugs. 2004;64:1715-1736. 90. Keck PE Jr, McElroy SL. Clinical pharmacodynamics and pharmacokinetics of antimanic and mood-stabilizing medications. J Clin Psychiatry. 2002;63(suppl 4):3-11. 91. Baldessarini R, Henk H, Sklar A, Chang J, Leahy L. Psychotropic medications for patients with bipolar disorder in the United States: polytherapy and adherence. Psychiatr Serv. 2008;59:1175-1183. 92. Lamictal [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009. 93. Carrillo JA, Herraiz AG, Ramos SI, Gervasini G, Vizcaino S, Benitez J. Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol. 2003;23:119-127. 94. Simpson GM, Lindenmayer JP. Extrapyramidal symptoms in patients treated with risperidone. J Clin Psychopharmacol. 1997;17:194-201. 95. Risperdal M-Tab [package insert]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc.; 2010. 96. Depakene [package insert]. North Chicago, IL: Abbott Laboratories; 2009. 97. Zyprexa Relprevv [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009. 98. Kirkwood CK, Wilson SK, Hayes PE, Barr WH, Sarkar MA, Ettigi PG. Single-dose bioavailability of two extended-release lithium carbonate products. Am J Hosp Pharm. 1994;51:486-489. 99. Guelen PJ, Janssen TJ, De Witte TC, Vree TB, Benson K. Bioavailability of lithium from lithium citrate syrup versus conventional lithium carbonate tablets. Biopharm Drug Dispos. 1992;13:503-511. 100. Dutta S, Reed RC. Distinct absorption characteristics of oral formulations of valproic acid/divalproex available in the United States. Epilepsy Res. 2007;73:275-283. 101. Davis LL, Li X, Bartolucci AA, Williford RB, Lowe JS. A pharmacokinetic and clinical evaluation of switching patients with bipolar I disorder from delayed-release to extended-release divalproex. J Clin Psychiatry. 2007;68:1546-1551. 102. Prolixin Decanoate [package insert]. Weston, FL: Apotex Corp.; 2001.
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103. Haldol decanoate prescribing information. Drugs.com Web site. http://www.drugs.com/ pro/haldol-decanoate.html. Accessed July 11, 2010. 104. Invega Sustenna [package insert]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2009. 105. Shiraki T, Kohno K, Saito D, Takayama H, Fujimoto A. Complete atrioventricular block secondary to lithium therapy. Circ J. 2008;72:847-849. 106. Tandon R. Safety and tolerability: how do newer generation atypical antipsychotics compare? Psychiatr Q. 2002;73:297-311. 107. Komossa K, Rummel-Kluge C, Schmid F, et al. Aripiprazole versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2009:CD006569. 108. Banach R, Boskovic R, Einarson T, Koren G. Long-term developmental outcome of children of women with epilepsy, unexposed or exposed prenatally to antiepileptic drugs: a meta-analysis of cohort studies. Drug Saf. 2010;33:73-79.
Individualizing Treatment for Patients With Bipolar Disorder:

General Treatment Considerations
49
Optimizing Efficacy, Safety, and Tolerability
he principal goals of bipolar disorder (BD) treatment are symptomatic remission (prolonged euthymia) and functional recovery.1 Attaining them requires acute treatment followed by long-term maintenance. Symptom resolution to a level that does not fulfill criteria for the diagnosis of mania or bipolar depression should be regarded as partial success only. Guidelines for patient assessment and evidence-based treatment may provide direction to the clinician, but individualized care requires careful consideration of patient and disease-related variables.2,3 For example, when formulating a treatment plan for an individual patient, different treatment phases and their associated goals should be clearly defined (Figure 1).4 From the outset, the clinician should determine the level of support the patient will need and whether or not hospitalization will be required. In general, the selection and sequence of medications is dictated by the following considerations: the patients symptoms, illness phase and polarity, comorbidities, preferences, previous treatment response, and tolerability; the medications efficacy and safety profile and the availability of different formulations/regimens; the clinicians familiarity with the available medications; and cost considerations. While a relatively large number of medications are approved for the treatment of an acute manic or mixed episode, the only currently approved medications to treat bipolar depression are quetiapine and an olanzapine-fluoxetine combination.5,6 Medications approved for maintenance therapy are also limited. Combination treatment is not uncommon because one agent is often insufficient to address all aspects of the psychopathology and related morbidity.3,7 Treatment is predicated on longitudinal monitoring for symptom and illness response, for medication side effects, and, in the important maintenance phase, for emerging signs of relapse. When a patient relapses, it is important to rule out partial or full nonadherence as the cause before changing the medication. In addition, unusual life eventsincluding a change in living
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Comorbidities Residual SXS Nonadherence
Exacerbation Illness severity

Psychosis, agitation, aggression
Relapse
Response Resolution Remission Recovery Treatment phase Stabilization Maintenance Relapse prevention
Acute
SXS = symptoms.
Figure 1. Treatment phases and goals in bipolar disorder.4
situation, divorce, rape, or some other traumatic incidentcan precipitate relapse and should be considered and addressed. In such cases, helping the patient achieve a more stable environment and/or receive targeted psychosocial interventions is likely to be more successful than changing medication(s). Additional causal factors for relapse should be evaluated. Comorbid psychiatric and medical conditions, for example, may complicate and adversely affect the presentation, course, and response to treatment.8-11 Complications such as substance abuse or comorbid anxiety disorder may also contribute to relapse and should be addressed in addition to maintenance therapy for the mood disorder.
Measuring Treatment Effectiveness Over Time

o maximize treatment outcomes and individualize treatment decisions, it is critical to obtain a clear picture of the patients symptoms, illness, comorbidities, and past as well as present therapeutic and side effect response. This is best achieved by utilizing evidence- and measurementbased clinical practice tools. Using simple rating scales for assessing depressive and manic symptoms (Table 1)12-19 in clinical practice can help to identify treatment targets and needs in a systematic and scalable way.
Individualizing Treatment for Patients With Bipolar Disorder: Optimizing Efficacy, Safety, and Tolerability
Time constraints may influence the selection of screening strategies and instruments. Clinicians may use, for example, a 10-point numeric scale indicating patient-perceived and/or clinician-assessed severity of symptoms. The scale may be administered verbally or as a visual-analog scale. Patients can use these scales to rate their symptoms of depression and mania (scale of 010, with 0 being normal). Another approach, the Clinical Global Impression (CGI) severity and improvement scale (severity scale of 17), has been widely used in both clinical trials and in clinical practice.20 Functional Assessment Select scales can provide perspectives into the functional status of patients; among the more clinically useful are the Global Assessment of Functioning (GAF) scale and the Sheehan Disability Scale (SDS).21 The GAF is a bidimensional measure of the patients level of overall functioning, which considers the severity of psychopathology and impairment of psychosocial and occupational functioning, whereby the area with the greatest severity determines the ultimate score (inverse severity scale 0100; higher scores indicate greater level of functioning).22 In the SDS, a 11-point visual-analog scale (0, no disruption; 10, maximum disruption) is used to assess the degree to which the patients symptoms impair work/school, social life, home life, or family responsibilities.21 Daily Symptom Measurements Life-chart methodology is a validated technique that provides continuous daily measurements of symptom fluctuations.23 A version of a mood chart can be obtained freely from the internet.24 Patient involvement in the lifechart enhances the therapeutic relationship, fosters treatment adherence, helps to destigmatize bipolar disorder, and enables patients to be active and informed participants in their disease management.25 Further, this method allows documentation and anticipation of treatment resistance, cycle acceleration, discontinuation-induced treatment refractoriness, and possible switches in polarity. Measuring Remission and Managing Residual Symptoms Validated tools are available to evaluate symptom remissionthat is, sustained euthymia. Although remission of mania is generally defined as a score of less than 12 on the Young Mania Rating Scale (YMRS), recent reports suggest the qualifying YMRS score should be lowered to no more than 8.26,27 Patients should also present without relevant levels of
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Table 1. Scales for Measuring Depressive and Manic Symptoms.
Assessment Type MADRS12 Number of items included in the questionnaire What is measured 10 items Core symptoms of depression
Measurement of depressive symptoms
HAM-D14
21 or 17 items
The 17 items measure symptoms of depression. In addition, 4 items assess factors such as diurnal variation of depressive symptoms and the presence of additional features (ie, depersonalization, paranoid symptoms, and obsessional symptoms). Additional items assess melancholic and atypical symptom features.
IDS30 and QIDS1615-17
IDS30: 30 items QIDS16: 16 items Uses DSM-IV criteria for major depressive disorder Uses 9 DSM-IV criteria
PHQ-918
Depression severity
Measurement of mania
YMRS19
11 items
Core symptoms of manic phase, addresses full range of possible severity. For each item, severity ratings are based on the patients report during the past 48 hours and the clinicians observations during the interview.
HAM-D: Hamilton Rating Scale for Depression; IDS30: Inventory of Depressive Symptomology (30-item); MADRS: Montgomery-Asberg Depression Rating Scale; PHQ-9: Patient Health Questionnaire; QIDS16: Quick Inventory of Depressive Symptomology (30-item); YMRS: Young Mania Rating Scale.
depression, for example, characterized by a score of no more than 10 on the Montgomery-Asberg Depression Rating Scale (MADRS), although cut off scores of 12 and 5 (for complete remission) have been reported as well.28-30 Functional recovery requires significant progress across educational, vocational, and psychosocial domains. In this context, management of residual symptoms is critical to the achievement of long-term goals. Residual symptoms are present if, after treatment, the patient
53
Method for completion Completed by clinician, based on patient interview and evaluation Completed by clinician, based on patient interview and evaluation Approximate time required 15 minutes13
Intensity scale 0-6
0-4 or 0-2
15-20 minutes15
0-3, measures severity and frequency of specific symptoms over last 7 days 0-27 for total scores from the 9 criteria, 0-3 of daily frequency
Both IDS30 and QIDS16 are available in the patient- and clinicianrated versions Reported by patient, scored by clinician
IDS-C30: 10-15 minutes QIDS-C16: 5-7 minutes15,16 (IDS-C30 and QIDS-C16 represent the clinician-rated version) <2 minutes for clinician scoring15
0-4 for 7 items, 0-8 for Completed by clinician 4 items
15-30 minutes15
retains a mild to moderate depression, mania, or psychosis. Data from one prospective cohort study suggest that residual threshold or subthreshold symptoms of mood elevation predispose patients to relapse into mania and depression.1 Similar results were observed in a 2- to 4-year follow-up study of patients who were hospitalized for first manic/mixed episodes. Predictors of recurrent mania included initial psychosis and initial manic presentation, whereas initial mixed presentation and comorbidity were
54
associated with recurrent depression.31 Further, functional recovery is most likely when medication treatment is combined with psychosocial management approaches.32
Monitoring Treatment-Emergent Adverse Events

urrent guidelines address several dimensions of evidence for medication efficacy, which usually constitutes 2 positive placebo-controlled trials (level A evidence).22 However, since numerous medications are available that fulfill these criteria, recent guidelines incorporate differences in side effect profiles or other issues that may potentially interfere with overall effectiveness into the level of recommendation.33,34 During acute treatment, side effects that can cause therapy discontinuation (eg, marked extrapyramidal symptoms [EPS] or akathisia, dystonic reaction, fainting/syncope, marked sedation, or severe gastrointestinal [GI] side effects) should be avoided and the long-term consequences of treatment thoroughly assessed. Longer-term side effects can include endocrine problems such as thyroid dysfunction, polycystic ovary syndrome like symptoms (PCOS) and prolactin abnormalities, metabolic complications (eg, dyslipidemia, diabetes), weight gain, sexual dysfunction, and tardive dyskinesia (TD). Antidepressants Patients on antidepressants may experience nonspecific symptoms such as agitation, anxiety, insomnia, GI disorders, or sexual dysfunction.35 In addition, in adolescents and young adults, suicidal behaviors can possibly emerge, prompting an FDA warning. Importantly, these agents can sometimes precipitate mania and induce or accelerate rapid cycling.36 A recent meta-analysis, for example, showed that adding an antidepressant to a mood stabilizer reduced overall risk of depression recurrence by approximately 27%, but also conferred a 72% increase in the risk of new episodes of mania (including hypomania and mixed states).36 An antidepressant-induced mood switch into hypomania or mania is an increasingly well-characterized phenomenon. For instance, in a double-blind study in which patients were evaluated after 8 weeks of acute treatment and during maintenance treatment for up to 1 year, bupropion was less likely to induce mood elevation (1 of every 9 patients) than desipramine (5 of every 10 patients).37 In other studies, risk of switches into hypomania or mania was significantly higher in patients treated with venlafaxine compared with bupropion, or sertraline, or paroxetine.38,39 Risk factors for antidepressant-induced mania include BD I, a history of antidepressant-induced mania or hypomania, a manic phase preceding the
current depressive episode, and mild or subthreshold mania symptoms during a depressive episode.40-45 Alcohol or substance abuse, use of tricyclic antidepressants (TCAs) or serotonin and norepinephrine reuptake inhibitors (SNRIs), and hyperthymic traits also appear to increase this risk.46-48 While these data suggest an unfavorable risk/benefit profile for long-term antidepressant therapy in BD, especially BD I, some patients with resistant depression or others receiving concomitant mood stabilizing agents, especially those with BD II, may benefit from adjunctive antidepressant therapy.36 Further studies are needed to guide individualized treatment approaches for these patient subpopulations and decisions need to be made on a case-by-case basis.35 Table 2 provides select data for assessing antidepressant candidacy.35,40,42,43,45,49-53 Mood Stabilizers and Antipsychotics Although side effects remain a concern with all mood stabilizers and antipsychotics, the focus has shifted in recent years from awareness of GI and neuromotor side effects to suicidality and cardiovascular and metabolic risk factors, such as coronary artery disease, hyperlipidemia, weight gain, insulin resistance, and diabetes. Common side effects and Black Box warnings for mood stabilizers and antipsychotics are summarized in Table 3.3,5,6,54-66 Risk factors for suicide should be assessed proactively, not only as a side
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Table 2. Assessing Antidepressant Candidacy in Bipolar Depression.35

Favors antidepressant use Bipolar II disorder Depressed (nonmixed) states Absence of rapid cycling Discourages antidepressant use Bipolar I disorder40 Mixed manic and depressive features42,49 Presence of rapid cycling50,51
Absence of recent mania or Mania or hypomania in past 2 to 3 hypomania (preceding 2 to 3 months) months43 Absence of comorbid alcohol or substance use disorder Prior favorable antidepressant response No history of antidepressant-induced mania or hypomania Presence of comorbid alcohol or substance use disorder52,53 Suboptimal responses to prior antidepressants History of antidepressant-induced mania or hypomania45
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Table 3. Side Effects, Black Box Warnings, and Special Monitoring Recommendations.
Agent
Mood stabilizers
Common side effects Dizziness, drowsiness, unsteadiness, nausea, and vomiting; lowering of its own level in the blood and of other hepatically metabolized medication levels55,56
Carbamazepine
Gastrointestinal symptoms (nausea, vomiting, heartburn); less frequently, dermatologic effects (rash, alopecia), neurologic effects (drowsiness, irritability, ataxia), low platelet count, and hair loss59
Lamotrigine
Dizziness, ataxia, somnolence, headache, double vision, blurred vision, nausea, rash59
Lithium
Fine hand tremor, mild thirst, polyuria, nausea; early signs of lithium intoxication include diarrhea, vomiting, drowsiness, muscular weakness, dysarthria, and lack of coordination60,62
Antipsychotics
Aripiprazole
Nausea, vomiting, light-headedness, somnolence, constipation, postural dizziness, restlessness, akathisia59
57
Black Box warnings Serious and potentially fatal dermatologic reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome; aplastic anemia and agranulocytosis55,56
Special monitoring recommendations Signs and symptoms of hepatic, hematologic, or dermatologic side effects; CBC and platelet measurements during the first 2 months, liver function tests every 2 weeks; thereafter, blood counts and liver function tests at least every 3 months, with more frequent monitoring in patients with signs of hematologic or hepatic abnormalities3 PCOS may develop with VPA treatment; for stable patients taking VPA, monitor hematologic and hepatic function at least every 6 months; patients who are unable to reliably report signs and symptoms of VPA toxicity should be monitored more frequently3 Instruction to patient and family to report each rash and routine inquiry about this
Hepatotoxicity, teratogenicity, pancreatitis61
Life-threatening serious rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death; additional factors that may increase risk of rash may include coadministration with valproate and exceeding recommended initial dose or dose escalation of lamotrigine57 Lithium toxicity60,62
Before starting lithium, review patients general medical history, physical exam report, BUN, creatinine level, pregnancy test, thyroid function. For patients older than 40 years, review ECG with rhythm strip and CBC findings; monitor for neurologic toxicity3,60,62 Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter54
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs; increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders54
58
Agent Asenapine Common side effects Somnolence, dizziness, EPS other than akathisia, weight gain58
Chlorpromazine
Drowsiness, postural hypotension, EPS63
Olanzapine
Dry mouth, edema, postural hypotension, weight gain, elevated plasma glucose and triglycerides59
Olanzapine-fluoxetine combination
Disturbance in attention, dry mouth, fatigue, hypersomnia, increased appetite, peripheral edema, sedation, somnolence, tremor, blurred vision, weight gain5
Quetiapine
Dry mouth, sedation, dizziness, somnolence, postural hypotension, weight gain59
Risperidone
EPS at high doses, weight gain, tachycardia, hyperprolactinemia, headache, dizziness, abdominal pain59
59
Black Box warnings Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs58 Special monitoring recommendations Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter58 Frequent CBC during first few months of treatment for patients with pre-existing low WBC count or a history of drug-induced leukopenia/neutropenia63 Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter64 Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter5
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs63 Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs64
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs; increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders5 Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs; increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders6
Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter. Initial lens examination (for cataracts, based on animal data only) when starting treatment and every 6 months thereafter; blood pressure measurement at initiation of, and potentially during treatment in children and adolescents6 Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter. Orthostatic vital signs in patients for whom orthostatic hypotension is of concern65
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs65
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Agent Ziprasidone Common side effects Somnolence, EPS including akathisia, dizziness, abnormal vision, asthenia, vomiting66
BMI = body mass index; BUN = blood urea nitrogen; CBC = complete blood cell; ECG = electrocardiogram; EPS = extrapyramidal symptoms; MDD = major depressive disorder; PCOS = polycystic ovary syndrome; VPA = valproic acid; WBC = white blood cell.
effect precaution but as part of general management. These risk factors include clinical deterioration, agitation, comorbid personality disorders and substance misuse, mixed episodes, and a personal or family history of suicide.5,6,54,55,57,61,67 Interestingly, patients with BD and schizophrenia, at least when each patient population is treated with second-generation antipsychotics, have similarly elevated rates of metabolic syndrome.68 This suggests that patients with BD and schizophrenia share a susceptibility to antipsychoticassociated metabolic effects, which is unrelated to psychiatric diagnosis or concomitant mood stabilizer therapy.68 At least during antipsychotic monotherapy and in patients who received prior antipsychotic treatment, olanzapine and clozapine have been associated with the largest weight gain, risperidone and quetiapine appear to be associated with intermediate weight gain, and aripiprazole and ziprasidone have the least weight gain potential.69-71 Some evidence suggests that both first-episode and antipsychotic-nave patients are at highest risk for antipsychotic-induced weight gain and metabolic side effects, and that none of the antipsychotics is fully weight neutral.72-75 Although risperidone and quetiapine seem to have a similar weight gain potential, quetiapine appears to be associated with a greater liability to cause metabolic abnormalities, especially dyslipidemia.72,73 The only head-to-head comparison study of aripiprazole and ziprasidone showed no difference in weight gain and metabolic risk potential between the two medications.76
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Black Box warnings Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs66 Special monitoring recommendations Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter. Baseline serum potassium and magnesium measurements for patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances; patients with low serum potassium and/ or magnesium should be repleated prior to treatment to avoid ECG/cardiac conduction abnormalities66
Assessing the risk for cardiometabolic side effects involves weight gain measurement at each clinical visit plus encouragement of patient selfmonitoring, as well as assessment of blood pressure, fasting blood glucose, and lipids.69 Further discussion follows. Although EPS and TD are generally of less concern with secondgeneration antipsychotics than with older agents, clinicians should assess motor function at baseline and monitor motor side effects during titration of the antipsychotic dose and at 3-month intervals once the target dose has been reached. The Simpson-Angus Scale (SAS) and the Abnormal Involuntary Movement Scale (AIMS) should ideally be administered at baseline (or during titration for the SAS) and every 3 months thereafter to monitor for EPS and TD.20,77,78 When it is not possible to complete a full SAS, moving the patients elbow or shoulder to test for stiffness/resistance and observing the patients gait can provide a useful general assessment of EPS. Similarly, when it is not possible to perform a full AIMS, observing the patients face and tongue with the mouth open allows the clinician to detect the most frequently occurring orofacial movement abnormalities. The Barnes Akathisia Scale, which involves assessment of movement as well as awareness of restlessness and global clinical assessment of akathisia, is also recommended for monitoring akathisia at baseline during dose titration and 3 months thereafter.79
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As with the antipsychotics, the side effect profiles of mood stabilizing agents warrant ongoing monitoring. Several studies have demonstrated endocrine-related side effects for mood stabilizing agents. Lithium may induce hypothyroidism, while females of childbearing age treated with valproate may present with PCOS.80-82 Reproductive system features of PCOS include amenorrhea or oligomenorrhea and hyperandrogenism, which may cause acne, hirsutism, and male pattern balding.83 Blood tests should be obtained during titration and maintenance treatment to rule out these and other side effects (further discussion below). Medical Issues Any medical issues that may affect treatment and response to treatment should be considered and monitored. Further, when the white blood cell (WBC) count is low or there is a history of drug-induced leukopenia/neutropenia, complete blood cell (CBC) count should be frequently evaluated during the first few months of treatment.5,6,54,58,63-66,84 Current guidelines recommend measuring prolactin levels when signs and symptoms suggest the presence of clinically important hyperprolactinemia (ie, sexual dysfunction with impairment of libido, arousal, orgasm, or performance, or associated problems such as gynecomastia or galactorrhea in males, or amenorrhea, oligomenorrhea, galactorrhea, or breast tenderness in females).2,77 If prolactin levels are elevated, a dose reduction or switch to a prolactin-sparing medication should be considered. Only in cases where these measures do not reduce markedly elevated prolactin levels (>200 ng/dL) or where temporal visual field defects are noted, an MRI of the sella turcica should be performed to rule out a possible secreting prolactinoma.85 Response to antipsychotic therapy varies considerably between patients. While the patient-specific genetic, neurochemical, and psychosocial factors underlying this differential responsiveness to individual agents are not firmly established, evidence-based recommendations support thorough baseline assessment and tight clinical management. Certainly, clinicians should address efficacy, metabolic risk, patient preference, and other factors that can contribute to improved adherence and treatment success.3 Table 4 describes recommendations for monitoring weight, blood pressure, and metabolic parameters in patients receiving second-generation antipsychotics.69 Physical assessment and blood analysis for full blood count, electrolytes, thyroid function, fasting glucose, and lipid profile should be performed at baseline. For patients on mood stabilizers, blood tests should be obtained during
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Table 4. Monitoring Protocol for Patients Taking SecondGeneration Antipsychotics.69
Quarterly Annually X X X X X X X X X X X X X* Baseline Every 5 years 4 weeks 8 weeks 12 weeks
Personal/family history Weight (BMI) Waist circumference Blood pressure Fasting plasma glucose Fasting lipid profile
X X X X X X
*All subsequent guidelines endorse annual (instead of 5-yearly) lipid monitoring, coinciding with glucose monitoring.
titration and maintenance treatment, including thyroid function for lithium and complete blood count for valproate (to rule out thrombocytopenia) and for carbamazepine (to rule out leukopenia). In addition, therapeutic blood levels of lithium, valproate, and carbamazepine should be monitored. Longitudinal examination is critical, providing the basis for therapeutic adjustments, sideeffect management, and switching medications, as needed.
Monitoring Treatment Adherence

oor adherence to medications is common in patients with BD.86,87 For example, a large study (N=1500) demonstrated that the mean duration of continuous lithium adherence was as short as 76 days.88 Poor adherence is a multifactorial problem that varies on a patient-by-patient basis, and can be attributed in part to intolerable side effects, breakthrough symptoms, ineffective treatment, stigma of taking medications, a negative attitude towards medications in the close environment, concerns about the long-term side effects of medications, a dislike of having ones mind or mood altered by medications, complex medication regimens, disorganization or forgetfulness, lack of awareness about the consequences of nonadherence, and practical issues, such as cost.89-92 Patients will normally show worse adherence in some phases of illness than others.91 The manic phase of BD, for example, may be associated with an elevated risk of nonadherence, possibly due to limited insight or cognitive dysfunction.91,93
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Concurrent conditions such as substance abuse and cognitive deficits may also adversely affect adherence.92,94 Nonadherence is associated with severe consequences, including lowered response during acute episodes, more relapse rates in general, higher relapse rates during euthymic periods, reduced quality of life, and ultimately, loss of remission, increased hospitalization, and suicide attempts.95 Tracking Adherence Several methods can be used to track patient adherence (Figure 2).96 Most studies of nonadherence have been confounded by self-report or providerreport methods, which are often indirect and unreliable.96 Objective methods, such as pill counts and electronic refill data, provide a more direct assessment but also have important limitations. For example, an electronic monitoring system using a microchip in the bottle cap indicates when the bottle was opened, but not whether the medication was actually ingested.96 Biological markers of adherence, such as blood and urine levels, can provide a snapshot at the time of measurement and may work best with home visits.96 In their expert consensus meeting, Velligan and coworkers agreed that a medication gap of at least 1 week without medication satisfied the minimal threshold for nonadherence.97 The second largest group of clinicians
120 100
107
Number of studies
80 60 40 20 0
51 35 25 16
1 = Self-report 2 = Provider report 3 = Significant other report 4 = Chart review 5 = Pill count 6 = Electronic refill 7 = Electronic monitoring (MEMS) 8 = Blood level 9 = Urine 10 = Tracer
8
6
6
7
5
8
4
9
1
10
Assessment type
MEMS = Medication Event Monitoring System.
Figure 2. Methodologies for assessment of adherence.96
participating in this survey defined 4 consecutive days with no medication intake as nonadherence. Additional data underline the importance of monitoring adherence. First, among patients with schizophrenia, a 110-day medication gap doubled the odds for rehospitalization.98 Although similar data are not available for patients with BD, a medication possession ratio (MPR) below 0.75 has been associated with an increased risk of rehospitalization following hospital discharge.99 Clearly, well-designed studies are required to evaluate a working definition of nonadherence, the effects of nonadherence on patient outcomes, and strategies designed to overcome barriers to improved adherence. Improving Adherence: Communicating With the Patient Numerous studies and expert opinion support the need for routine monitoring of past and present patient adherence. Insights into patient attitudes towards and problems with their medicationsincluding treatmentrelated side effectscan help clinicians identify factors that complicate adherence to the prescribed regimen.97 If there is a noticeable worsening in symptoms, nonadherence should always be suspected and ruled out as one of the possible reasons. Patients are not always the best informants, since they may conceal their nonadherence to avoid embarrassment to self or the doctor. In such cases, interviewing family members or significant others about adherence may be useful. If a patient is relatively new to the clinician and has a history of adherence, assessments made monthly or during each visit are recommended.97 If a patient has a history of nonadherence, weekly updates are recommended, particularly when a worsening of symptoms occurs, to avoid relapse and rehospitalization.97 Improving communication with the patient through psychosocial interventions and family involvement can significantly improve adherence. Table 5 lists psychoeducational strategies for patients and their families that can be helpful in achieving this goal.97 Useful Information for a familys understanding of the disease and potentially helpful interventions for dealing with a patients depressive symptoms and mania are listed in Table 6.100
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Strategies to Optimize Efficacy and Manage Side Effects

harmacologic strategies to optimize efficacy and minimize side effects include dose adjustment, addition of adjuvant medications, and switching of medications. Nonpharmacologic strategies such as healthy lifestyle counseling and intervention and various forms of psychotherapy
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Table 5. Psychoeducational Strategies for Patients and Their Families.97
Patient-focused education
Cognitive behavioral therapy
Identifies negative thoughts about medications and reinforces patient beliefs that taking the medication will help in achieving their goals Bipolar patients may benefit from a model based on concordance Focuses on psychoeducation and motivational interviews to improve patients understanding about nonadherence and relapse, and increases motivation to take the medication
Compliance therapy
Interpersonal and social Helps stabilize daily routines and solve interpersonal problems and reduce relapses rhythm therapy Psychoeducation
Individual and group counseling with written/ audiovisual materials teaches patients about the illness, medication side effects, and relapse prevention. Techniques for changing behavior, attitudes, and skills can improve adherence Psychoeducation, alone or as a component of a complex intervention plan, may potentially improve the course of bipolar disorder Involving partners and families may be effective in improving adherence and reducing the risk of manic episodes Although this approach does not specifically target medication adherence directly, it reduces family stress and conflicts, enhances problem-solving skills, and may improve mood symptoms
Family-focused education
Psychoeducation
may also be helpful and deserve additional study. For generally stable patients on a new therapeutic regimen, it is advisable to wait 2 to 4 weeks to determine if the change(s) resulted in improved efficacy.2 For an acutely ill patient who requires more rapid symptom improvement, it may be prudent to try a different strategy sooner, possibly within 7 to 10 days, although well-designed studies are needed to further research this issue. Patients with medical comorbidies or those who develop treatment-related medical complications such as diabetes, hyerlipidemia, or hypertension may benefit from a specialist consult and, possibly, further management.
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Table 6. Understanding Bipolar Disorder: Advice for Family Members.100
Symptom
Depression
Advice
Keep up good levels of communication even when not reciprocated
Depressed mood, loss of interest or pleasure in nearly all activities, social withdrawal Inability to concentrate, difficulty in constructing sentences Suicidal ideation
Attend to safety issues that poor concentration can cause Have realistic expectations Be aware of suicide risk; ask the appropriate questions Communicate with treating team about this issue; suicidal thoughts may be a reason for hospitalization
Avoid placing unrealistic demands on the person Decreased energy, tiredness, and fatigue, even without physical exertion
Sense of worthlessness or guilt Reduced appetite and weight loss Changes in sleep patterns, most commonly insomnia
Mania
Connect with the emotion of the experience rather than try to change someones mind (eg, It must be very hard to feel so low) Be aware of hydration and nutrition issues; again, patient may need hospitalization Encourage exercise like walking around the block Medications can certainly assist Do not participate in the escalation of excitement, avoid conflicting situations When the person is able to take feedback, provide something like You are a little high at the moment, what about listening to some music, in a gentle way Do not make too many demands Reduce stimulation and loud noises Avoid conflict Remember that this is the illness speaking
Elevation in affect (mood)
Thoughts racing Inflated self-esteem
Manic speech, usually loud Try to manage your emotional state as the patient will pick up on your distress and you may have to and difficult to interrupt
defend yourself
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Symptom Advice Increased physical mobility, Encourage short walks energy, and restlessness Be conscious of the safety factor
Avoid dehydration; encourage the patient to drink small amounts regularly
Decreased need for sleep, most active at night Expansiveness and recklessness such as extensive conversations with strangers, spending sprees, driving fast
Encourage the person to have a bath or a shower, or a warm drink Reduce access to dangerous situations (eg, put car keys in a safe spot)
Do not argue about the reality Delusions and hallucinations, especially of Connect with the emotion of the delusion or a grandiose nature hallucination
Dose Adjustment To ensure that the patient has achieved maximal treatment efficacy, and if the patient has achieved at least a partial response, the dose should be optimized before another medication is added or a switch is performed. Medications should be titrated to efficacy or to maximum-tolerated dose. If there are no dose-limiting side effects that significantly influence patient function, dose may be titrated upward to the therapeutic limit, as long as a thorough monitoring plan is in place. Adding Medications The American Psychiatric Association (APA) guidelines recommend combination therapy for patients who have severe mania or who do not respond adequately to monotherapy.2,3 If a patient has dose-limiting side effects and/or an insufficient treatment response, switching medications or adding an adjuvant medication should be considered. Switching medications is preferable, since it avoids the drug-drug interactions, side effects, and adherence-limiting complexity associated with adding medication. However, for patients whose psychiatric stability is either tenuous or very good, switching medications can be destabilizing. In fragile patients and in those who have shown clinically relevant (though perhaps insufficient) improvement on the first agent, it may be more appropriate to add another pharmacologic agent. When adding medication, potentially additive side
effects should be monitored and drug-drug interactions should be anticipated and minimized as much as possible. For patients with acute bipolar mania, numerous studies have demonstrated that combination therapy with an antipsychotic plus a mood stabilizer is superior to mood stabilizer monotherapy.101 For acute treatment of mania/mixed episodes, aripiprazole, asenapine, olanzapine, quetiapine, risperidone, or ziprasidone can be used with lithium or valproate, while longacting risperidone is currently indicated for maintenance therapy.6,54,64-66,84 (see Table 1 in Chapter 2, Medical Management of BD) As a general approach to BD management, adding another agent to an existing treatment regimen (augmentation/combination therapy) is often appropriate, particularly when medications with complementary mechanisms of action and target symptoms can be used together. Exceptions to this general rule are notable. For instance, if a patient is not tolerating the current medication, or has gained no benefit at all or, even, showed worsening of symptoms or functioning, then switching is more appropriate. Adding a medication can accelerate a therapeutic response, as has been reported for example when combining an atypical antipsychotic with a conventional mood stabilizer, such as lithium or valproic acid.102,103 Further, if the addition of an antipsychotic to a mood stabilizer is ineffective, then a trial with the same antipsychotic as monotherapy can be avoided. Numerous studies have shown that combination therapy is likely to achieve better response and remission rates and may be associated with increased adherence.96,101 Side effects can be minimized by careful titration, consideration of potential drug-drug interactions, and using sub-maximal doses of each medication. As part of a combination regimen, it is reasonable to continue lithium due to its neuroprotective and anti-suicidal benefits.104 Switching Medications Switching may be considered when a patient has been responsive to other medications in the past. Further, the clinician should consider switching a medication for patients who experience residual symptoms that cause distress or impair functioningthat is, partial, inadequate, or nonresponsivenessor side effects that are severe or impairing. Switching antipsychotics can be associated with destabilization and is sometimes complicated by potential withdrawal or rebound effects.105 These rebound effects can make it difficult to interpret the efficacy of a new agent, since any insufficient efficacy can be due to either discontinuation-related
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exacerbations or continuation/exacerbation of illness-related symptoms. Table 7 lists corrective strategies during the initial switch period.105 It is important to utilize switching practices that accommodate differences in pharmacodynamic side effects (Table 8).106 For example, a slower, overlapping switch may be required to avoid rebound side effect phenomena (eg, rebound anxiety, insomnia, or agitation) from histaminergic or cholinergic blockade (Figure 3).105-107 Rebound can also occur if the dose of a new medication is not sufficiently high, as observed when switching from a high-affinity dopamine receptor antagonist (eg, high or medium potency first-generation antipsychotics, paliperidone, risperidone, iloperidone)to a lower affinity dopamine receptor antagonist (eg, quetiapine, clozapine) or to a partial dopamine agonist (aripiprazole). Switching to an agent with a strong 5-HT2A blockade relative to a dopamine blockade (eg, ziprasidone, especially when underdosed or not taken with food) can cause a similar effect.105 This can manifest as transient intraswitch restlessness or worsening of psychosis, mania, or
Table 7. Managing Undesirable/Rebound Effects at Antipsychotic Treatment Initiation and During the Initial Switch Period.105
Side effect Akathisia Corrective approach or (transient) adjuvant medications
Lower dose, slow down switch Add benzodiazepine, antihistamine, beta-blocker, mirtazapine, gabapentin, low dose low potency first-generation antipsychotic Reverse/slow down titration of prior antipsychotic, increase new antipsychotic; add benzodiazepine, valproate Slow switch, increase new antipsychotic; add benzodiazepine, valproate Use lower starting dose, slow switch, restrict excessive caffeine use Add benzodiazepine, antihistamine, antidepressant, gabapentin Slow switch, restrict excessive caffeine use, add benzodiazepine, hypnotic, antihistamine, trazodone Less likely with lower starting dose, slow switch Consider dosing twice daily until side effect abates, give with fatty food (to slow absorption); add antihistamines or antiemetics if needed
Mania, psychosis Agitation Anxiety
Insomnia Nausea/vomiting
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Table 8. Side Effects During Switching.106
Rebound/withdrawal Psychosis, mania, agitation, akathisia, withdrawal, dyskinesia
Receptor Blockade D2 Antipsychotic, antimanic, antiaggressive, EPS/akathisia, tardive dyskinesia, increased prolactin Anxiolytic, sedation, weight gain, anti-EPS/akathisia
H1 M1 (central)
Anxiety, agitation, insomnia, EPS/ akathisia
Memory, cognition, dry mouth, Agitation, confusion, psychosis, anti-EPS/akathisia anxiety, insomnia, sialorrhea, EPS/akathisia Diarrhea, diaphoresis, nausea, vomiting, bradycardia, hypotension, syncope EPS/akathisia, ?psychosis
M2-4 Blurry vision, constipation, (peripheral) urinary retention, tachycardia, hypertension 5-HT2A Anti-EPS/akathisia, ?antipsychotic
agitation, and should be monitored and possibly be treated by increasing the dose of the postswitch antipsychotic or by adding sedating medications until the switch has been completed successfully.105 Differences in half-life or absorption can result in pharmacokinetic rebound phenomena, for example, when the switch is abrupt, from a drug with a shorter half-life to a drug with a longer half-life.105,106 Half-lifes for secondgeneration antipsychotics and selected first-generation antipsychotics are shown in Table 9.58,107 When worsening symptoms necessitate an expedited switch or when a rebound phenomena complicates a switch, coprescription of a benzodiazepine, valproic acid, or antihistamine may reduce these symptoms and facilitate the process.105 As reviewed in Chapter 2, Medical Management of BD, including steps for the switch process, changing from an oral to a long-acting injectable antipsychotic can be an effective option for patients, particularly for those who are nonadherent to oral antipsychotic therapy.108 Managing Side Effects Both conventional and second-generation antipsychotics are associated with side effects that differ in type and/or degree. Sedation is a common side effect for low-potency conventional agents, especially, when taken
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A. Abrupt switch
Dose level, %
Days
B. Cross-titration
Dose level, %
Days
C. Plateau cross-titration*
Dose level, %
Days
DARK GREY closed line: Initial antipsychotic dose. LIGHT GREY closed line: New antipsychotic dose. Dashed line: Antipsychotic plasma concentration. *Use stepwise approach: start with partial D2 agonist; lower starting dose recommended.
Figure 3. Plateau switch strategy to minimize rebound when switching to an agent with little histaminic or cholinergic blockade and/or a long half-life.106
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Table 9. Half-Life of Second-Generation Antipsychotics and Select First-Generation Antipsychotics.58,107
Antipsychotic Asenapine Aripiprazole Clozapine Haloperidol Molindone Olanzapine Paliperidone Perphenazine Quetiapine Risperidone Ziprasidone Half-life (h) 24 72 16 20 1.53 30 20 812 7 3 7
in high doses, whereas it is less frequent with high-potency conventional agents and second-generation agents, except for clozapine, quetiapine, and, possibly, olanzapine. The sedative effects of quetiapine and clozapine are attributed to its very strong binding to sedating histamine H1 receptors, starting at very low doses.109 Patients with bipolar disorder may require interventions to manage endocrine or cardiometabolic issues, such as weight gain and obesity, hyperlipidemia, hyperglycemia, and arterial hypertension. Table 7 lists strategies that can be used to acutely manage the undesirable side effects of antipsychotics, particularly those likely to occur early in treatment.105 For example, evidence suggests that adding a dopamine agonist or partial agonist such as aripiprazole reduces prolactin levels and alleviates related symptoms in patients with risperidone- or haloperidolinduced hyperprolactinemia.110,111 Likewise, metformin or topiramate may benefit patients with antipsychotic-induced weight gain.112 Patients who develop diabetes, clinically relevant dyslipidemia, or hypertension should be referred to a primary care practitioner or an endocrinologist. Bipolar Disorder Medical Care Model Serious mental illness is associated with a lifespan that is shortened by 20 to 30 years.113 A 2006 study of the persistently mentally ill showed a
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significantly elevated rate of premature mortality mainly due to cardiovascular disorders.113 Other mortality studies have produced similar results.114 The higher rate of mortality in patients with BD is likely due to a higher prevalence of dyslipidemia, metabolic syndrome, obesity, diabetes, hypertension, and smoking than in the general population.115 Patients with both BD and metabolic syndrome often present with complex conditions, the course, outcome, and treatment responsiveness of which are far more serious when compared to age-matched controls.116 These comorbidities also adversely affect health-related quality of life across time.117 Importantly, implementation of a BD medical-care model, a manual-based psychoeducational intervention that incorporates content on cardiovascular disease-related risk factors, has demonstrated significant health benefits in this vulnerable patient population.118 Selecting appropriate medications to achieve symptomatic control in patients with BD is critically important for therapeutic success. Equally important is the role of long-term monitoring, particularly of cardiometabolic risk factors, suicidality, and nonadherence, owing to, among several common reasons, negative attitudes towards medications and/or problematic treatment-related side effects, Based on these findings, clinicians can tailor psychoeducation strategies accordingly, emphasizing healthy lifestyle behaviors, improved diet and exercise, and the importance of the mutually reinforcing relationship between improved somatic and mental health.
Conclusions
ipolar disorder is a severe and often chronic disorder associated with significant functional impairment, increased disability, and a high incidence of relapse. Careful monitoring, the use of measurement tools and scales, and adequate management of available treatments can enhance the effectiveness of overall disease management. Residual symptoms, comorbidities, side effects, and nonadherence may interfere with treatment success. Measurement-based evaluation and monitoring of treatment efficacy and side effects via multimodal individualized treatment has the greatest chance of maximizing treatment outcomes in patients with BD. Functional and subjective domains such as subjective well-being, quality of life, and functional capacity are important in this patient population. Adverse drug reactions, along with weight gain and obesity, may impair mental wellbeing, quality of life, and medication adherence.98 Weight gain and obesity are also closely related to life-shortening medical comorbidities.98,113 Treatment guidelines are useful for clinicians seeking a sequenced treatment approach that takes into account level A evidence from at least
2 randomized, controlled positive trials for a given medication. Treatment guidelines also help the clinician select treatments with the best efficacy/ safety balance tailored in a shared decision-making process to the individual patient and illness phase. A personalized treatment approach may improve the psychiatric prognosis, while enhancing treatment alliance and the adherence status of the patient. A holistic psychosocial approach that considers the physical and mental health, as well as the social, educational and vocational functioning of the patient with BD is essential for optimizing treatment outcomes.
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Medical Management of Bipolar Disorder A Pharmacologic Perspective

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Differential Diagnosis anD eviDence-BaseD treatment strategies

P 3 ov o 4 10 D e rd . C is h I n o s m p eve 0 ig h t le t l e ly P 1 tr re s 2 P o e a tm e n t; 3 a s e A d s n A d m ib ly t m it s 4 d e d m it s b ill illn e D e n ie it s p e h a n s os v i e s a illn e s ib l io r c ny ss e c han ha g be n e g e i , bu nb t eh av

Date of Release: November 8, 2010 Date of Credit Expiration: November 7, 2011

Chapter 2:  Medical Management of Bipolar Disorder: A Pharmacologic Perspective. ...............23

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Faculty and Reviewers

Course Director and Reviewer, CPNP

Matthew A. Fuller, PharmD, BCPS, BCPP, FASHP

Roger S. McIntyre, MD, FRCPC

DateofRelease:November 8, 2010 DateofCredit Expiration:November 7, 2011

This and additional activities are available at

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Accreditation Statement and Credit Designation

Conflict of Interest Statement

Bipolar DisorDer Differential Diagnosis and Evidence-Based Treatment Strategies

Online participation is available via

This and additional activities are available at

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Matthew A. Fuller, PharmD, BCPS, BCPP, FASHP

Roger S. McIntyre, MD, FRCPC

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

This and additional activities are available at

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Differential Diagnosis of Bipolar Disorder

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Differentiating Between Unipolar and Bipolar Depression

Differential Diagnosis of Bipolar Disorder

Criteria for a Major Depressive Episode.15

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Differential Diagnosis of Bipolar Disorder

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Table 5.  Clinical Scenarios Suggestive of Bipolar Disorder Not Otherwise Specified.15

Differential Diagnosis of Bipolar Disorder

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Differential Diagnosis Beyond Unipolar Depression

Differential Diagnosis of Bipolar Disorder

Differentiating Between Bipolar I and Bipolar II and BD-NOS Disorders

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Differential Diagnosis of Bipolar Disorder

Gender and Bipolar Disorder

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Age-Related Features of Bipolar Disorder

Differential Diagnosis of Bipolar Disorder

Diagnosis of a Bipolar Prodrome and the Case for Early Intervention

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Differential Diagnosis of Bipolar Disorder

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Differential Diagnosis of Bipolar Disorder

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Differential Diagnosis of Bipolar Disorder

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Medical Management of Bipolar Disorder: A Pharmacologic Perspective

Mechanisms of Action of Major Classes of Medications Used to Treat Bipolar Disorder

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

FDA approved indication(s)

Carbamazepine ER6,7 Divalproex/ valproic acid8 Lamotrigine9 Lithium10,11

acute manic episodes associated with manic-depressive illness

Medical Management of Bipolar Disorder: A Pharmacologic Perspective

Agent Olanzapinefluoxetine combination16 Quetiapine17,18

FDA approved indication(s)

Risperidone long-acting injection20

BD I = bipolar I disorder; ER = extended release; FDA = Food and Drug Administration.

Bipolar Disorder Differential Diagnosis and Evidence-Based Treatment Strategies

Chapter 2: Medical Management of Bipolar Disorder: A Pharmacologic Perspective. ...............23

Table 5. Clinical Scenarios Suggestive of Bipolar Disorder Not Otherwise Specified.15