bipolar psychopharmacotherapy...bipolar psychopharmacotherapy caring for the patient editors hagop...

BipolarPsychopharmacotherapy

Caring for the Patient

Editors

Hagop S. AkiskalInternational Mood Center,

University of California at San Diego, La Jolla, CA, USA

and

Mauricio TohenLilly Research Laboratories, Indianapolis, IN and McLean Hospital,

Harvard Medical School, Belmont, MA, USA

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Innodata0470032308.jpg

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Bipolar Psychopharmacotherapy

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BipolarPsychopharmacotherapy

Caring for the Patient

Editors

Hagop S. AkiskalInternational Mood Center,

University of California at San Diego, La Jolla, CA, USA

and

Mauricio TohenLilly Research Laboratories, Indianapolis, IN and McLean Hospital,

Harvard Medical School, Belmont, MA, USA

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Library of Congress Cataloging in Publication Data

Bipolar psychopharmacotherapy : caring for the patient / editors, Hagop S. Akiskal and Mauricio Tohen. p. cm.

Includes bibliographical references and index. ISBN-13 978-0-470-85607-9 (cloth : alk. paper)ISBN-10 0-470-85607-6 (cloth : alk. paper) 1. Manic-depressive illness—Chemotherapy. 2. Lithium—Therapeutic use. 3. Antipsychotic drugs. 4. Psychopharmacology. [DNLM: 1. Bipolar Disorder—drug therapy. 2. Anticonvulsants—therapeutic use. 3. Antimanic Agents—therapeutic use. 4. Antipsychotic Agents—therapeutic use. 5. Bipolar Disorder—prevention & control. WM 207 B6176 2006] I. Akiskal, Hagop S. II. Tohen, Mauricio. RC516.B529 2006 616.89′5061—dc22

2005013978

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

ISBN-13 978-0-470-85607-9 (HB)ISBN-10 0-470-85607-6 (HB)

Typeset in 11/13pt Times by Integra Software Services Pvt. Ltd, Pondicherry, India Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, WiltshireThis book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production.

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http://www.wiley.com

Dedication

This book is dedicated to bipolar patients and their families, for the privilege ofcaring for them.

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Contents

List of Contributors ix

Preface xiii

Chapter 1 The Scope of Bipolar Disorders 1 Hagop S. Akiskal

Chapter 2 Lithium Treatment: Focus on Long-Term Prophylaxis 9 Mogens Schou and Paul Grof

Chapter 3 Valproate: Clinical Pharmacological Profile 27 Charles L. Bowden and Vivek Singh

Chapter 4 Pharmacological Profile and Clinical Utility of Lamotrigine in Bipolar Disorders 43 David J. Muzina, Joseph R. Calabrese

Chapter 5 Carbamazepine, Other Anticonvulsants and Augmenting Agents 63 Heinz Grunze

Chapter 6 Olanzapine in Treatment for Bipolar Disorder 85 Mauricio Tohen, Giedra Campbell, and Daniel Lin

Chapter 7 Haloperidol and Risperidone in Mania 105 John Cookson

Chapter 8 A Comparison of “Second Generation Antipsychotics” in the Treatment for Bipolar Disorder: Focus on Clozapine, Quetiapine, Ziprasidone and Aripiprazole 125 Paul E. Keck, Jr. and Susan L. McElroy

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viii Contents

Chapter 9 Complex Combination Therapy: The Evolution Toward Rational Polypharmacy in Lithium-Resistant Bipolar Illness 135 Robert M. Post, Andrew M. Speer and Gabriele S. Leverich

Chapter 10 The Primacy of Mania 169 Athanasios Koukopoulos

Chapter 11 Diagnostic and Clinical Management Approaches to Bipolar Depression, Bipolar II and Their Comorbidities 193 Giulio Perugi, S. Nassir Ghaemi and Hagop S. Akiskal

Chapter 12 Bipolarity in Women: Therapeutic Issues 235 Susan L. McElroy, Lesley M. Arnold and Lori L. Altshuler

Chapter 13 Pediatric Bipolar Disorder: The Promise of Psychopharmacotherapy 279 Joseph Biederman

Chapter 14 Treatment for Bipolar Disorder in Older Adults 301 Kenneth I. Shulman

Chapter 15 Psychosocial Interventions in Bipolar Disorders: Rationale and Effectiveness 313 David J. Miklowitz

Chapter 16 The Pivotal Role of Psychoeducation in the Long-Term Treatment of Bipolar Disorder 333 Francesc Colom and Eduard Vieta

Chapter 17 The Role of Treatment Setting in the Pharmacotherapy of Bipolar Disorder 347 Jean-Michel Azorin

Chapter 18 Suicide Prevention 353 Zoltán Rihmer

Chapter 19 Principles of Caring for Bipolar Patients 367 Hagop S. Akiskal and Kareen K. Akiskal

Index 389

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List of Contributors

Hagop S. Akiskal, International Mood Center, Department of Psychiatry at theUniversity of San Diego and Veterans Administration Medical Center, 3350 La JollaVillage Dr. (116-A), San Diego, CA 92161, USA

Kareen K. Akiskal, International Mood Center, University of California at SanDiego, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA

Lori L. Altshuler, UCLA Mood Disorders Research Program, UCLA, USA

Lesley M. Arnold, Women’s Health Research Program, University of CincinnatiCollege of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA

Jean-Michel Azorin, Department of Psychiatry, Ste Marguerite Hospital, 13274Marseille Cedex 9, France

Joseph Biederman, Pediatric Psychopharmacology Unit (ACC 725), MassachusettsGeneral Hospital, 15 Parkman Street, Boston, MA 02114-3139, USA

Charles L. Bowden, Department of Psychiatry, Mail Code 7792, Universityof Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio TX78229-3900, USA

Joseph R. Calabrese, Case Western Reserve University, School of Medicine,Cleveland, Ohio 44106, USA

Giedra Campbell Lilly, Research Laboratories, Eli Lilly & Co, 525 S. MeridianStreet, Indianapolis, IN 46225, USA

Francesc Colom, Bipolar Disorders Program, Stanley Research Center, IDIBAPS,Hospital Clínic, University of Barcelona, 08036 Barcelona, Spain

John Cookson, Royal London Hospital, St Clement’s, 2A Bow Road, London E34LL, UK

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x List of Contributors

S. Nassir Ghaemi, Bipolar Disorder Research Program, Cambridge Hospital,Department of Psychiatry and Harvard University, Cambridge, MA 02139, USA

Paul Grof, Deparmtent of Psychiatry, University of Ottawa, Royal Ottawa Hospital,1145 Carling Avenue, Ottawa, Ontario K2E 7L2, Canada

Heinz Grunze, Psychiatrische Klinik und Poliklinik LMU München, LudwigMaximilians Universität München, Nussbaumstrasse 7, D-80336 Munich,Germany

Paul E. Keck, University of Cincinnati College of Medicine, Department ofPsychiatry, 231 Albert Sabin Way, ML 559, Cincinnati, OH 45267-0559, USA

Athanasios Koukopoulos, Centro Lucio Bini, Via Crescenzio 42, 00193 Rome, Italy

Gabriele S. Leverich, Biological Psychiatry Branch, National Institute of MentalHealth, Bldg. 10, 10 Center Drive MSC 1272, Bethesda, MD 20892-1272, USA

Daniel Lin Lilly, Research Laboratories, Eli Lilly & Co, 525 S. Meridian Street,Indianapolis, IN 46225, USA

Susan L. McElroy, Psychopharmacology Research Program, Department ofPsychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way,Cincinnati, OH 45267, USA

David J. Miklowitz, Department of Psychology, Davie Hall CB#3270, Universityof North Carolina, Chapel Hill, NC 27599-3270, USA

David Muzina, Department of Psychiatry and Psychology, Desk P-57, 9500Euclid Avenue, Cleveland, Ohio 44195, USA

Giulio Perugi, Institute of Psychiatry, Via Roma 67, 56100 Pisa, Italy

Robert M. Post, Biological Psychiatry Branch, National Institute of MentalHealth, Bldg. 10, Rm. 3s239, 10 Center Drive MSC 1272, Bethesda, MD20892-1272, USA

Zoltán Rihmer, National Institute for Psychiatry and Neurology, Budapest 27,POB 1, 1281 Hungary

Mogens Schou, The Psychiatric Hospital, Skovagervej 2, DK-8240 Risskov,Denmark

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List of Contributors xi

Kenneth I. Shulman, Department of Psychiatry, Sunnybrook & Women’s CollegeHealth Sciences Center, University of Toronto, 2075 Bayview Avenue, Toronto,ON M4N 3M5, Canada

Vivek Singh, Department of Psychiatry, University of Texas Health Science Center,7703 Floyd Curl Drive, San Antonio TX 78229-3900, USA

Andrew Speer, Biological Psychiatry Branch, National Institute of MentalHealth, Bldg. 10, 10 Center Drive MSC 1272, Bethesda, MD 20892-1272, USA

Mauricio Tohen, McLean Hospital, Harvard Medical School, Belmont, MA andLilly Research Laboratories, Eli Lilly & Co, 525 S. Meridian Street, Indianapolis,IN 46225, USA

Eduardo Vieta, Clinical Institute of Psychiatry and Psychology, Hospital Clinic,University of Barcelona, Villarroel 170, 08036 Barcelona, Spain

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Preface

Bipolar disorder has emerged as a major public health problem. Its prevalence,phenomenology, subtypes, treatment and outcome are all under reevaluation.A burgeoning research-based literature has appeared and continues to grow.New therapeutic modalities, both psychopharmacologic and psychosocial, havebeen introduced. The clinical and scientific challenges presented by this conditionhave created the psychiatric subspecialty for bipolar disorders. One of the major chal-lenges for this subspecialty is to integrate the emerging clinical science of bipolartreatments.

The idea for this book was born in October 1998 at the ECNP Congress in Paris.One of the topics discussed at that meeting was the fact that clinicians in bothEurope and the United States used antipsychotics in bipolar disorder, yet USguidelines gave priority to lithium or anticonvulsants. The two editors decided tohold an international conference in Paris, France, on bipolar disorder at the 50thanniversary of the introduction of chlorpromazine in the same city in 1952. Itwould be recalled that the first patients treated with this agent suffered frombipolar mania.

For a variety of logistic reasons, the conference was held in Monte Carloinstead of Paris in February 2002. Presided by the present editors and supportedby an unrestricted educational grant from Eli Lilly, the conference covered theclinical psychopharmacology and related topics dealing with all agents availableat that time for the treatment of bipolar disorder. With a roster of 24 of the topexperts in the field and over 500 opinion leaders and researchers from all over theworld in attendance, to the best of our knowledge, it was the largest freestandingconference on bipolar disorder.

As we were editing the book on the material presented at the Monte Carlo con-ference, the field of bipolar psychopharmacology virtually exploded into a revolu-tion. With so many new agents approved for bipolar disorder between 2002 and2005, we had to revise the plans for this book in a radical way. The 19 chapters ofthe present book now overlap no more than 20% with the original conference inMonte Carlo. All chapters have been independently peer reviewed and updatedthrough April 2005. We have endeavored – and we believe we have succeeded –in recruiting contributors who are the pioneers in bipolar psychopharmacotherapyand its clinical applications in children, the elderly and women. Special attention

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xiv Preface

is also given to bipolar depression, which has emerged as a major clinical andtherapeutic challenge.

The book goes beyond pharmacotherapy to cover innovative psychoeducationaland psychosocial interventions, managing the patients in the hospital and subse-quent long-term care in the community. Questions about the health care climate,advocacy organizations for bipolar disorder and social parameters impacting it arealso addressed. Finally, suicide prevention is given special consideration. Thisbook, then, provides a broad integrative philosophy of caring for bipolar patientsand their families.

Hagop S. Akiskal and Mauricio Tohen

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Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen © 2006 John Wiley & Sons, Ltd

CHAPTER

1The Scope of Bipolar Disorders

Hagop S. Akiskal International Mood Center

University of California at San Diego, USA

DIAGNOSTIC AND PUBLIC HEALTH ASPECTS

Recent advances in the epidemiology, psychopathology and pharmacotherapy ofbipolar disorders have led to a greater recognition of this illness in all of its varieties(Akiskal et al., 2000). The lifetime risk for bipolar conditions is about 1% for thecore (bipolar I) phenotype, making it at least equal in prevalence to schizophrenia.A higher percentage of acute psychiatric hospital admissions is now beingassigned to the category of mania, and the recognition of clinically attenuatedoutpatient forms of the illness (soft bipolar spectrum) is increasing. The latter(bipolar II and beyond) is now estimated to be at least 4–5 times more prevalentthan bipolar I (Angst et al., 2003; Hirschfeld et al., 2003; Judd and Akiskal, 2003).

Reasons for the current focus on the entire diagnosable range of bipolar conditionsare several. Predominant among these is the tendency of diagnostic practice tofollow the availability of effective treatment modalities (Lehmann, 1969). Afterthe discovery of chlorpromazine, North American psychiatrists were tacitlyencouraged to elicit subtle degrees of formal thought disorder from their patientsso as to bring them the benefits of this new class of drugs. By the early 1970s,schizophrenia had become more or less synonymous with psychosis. With theadvent of lithium carbonate treatment and its well-documented efficacy for bipolardisorders, this trend became reversed in favor of bipolar disorders. Beginning withDSM-III (American Psychiatric Association, 1980), the concept of schizophreniahas been largely restricted to a core group of deteriorating psychotic disorders, whilemood disorders have been broadened to include even those with mood-incongruentpsychotic features that may or may not coincide with affective episodes. Thisdiagnostic approach reflects more than just therapeutic fashion; it is supportedby familial aggregation, course and outcome (Akiskal, 2002). Available evidenceindicates that mood disorders are often recurrent and, especially in bipolar conditions,

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2 Bipolar Psychopharmacotherapy

can lead to considerable impairment in developmental, conjugal and social spheres.The public health significance of bipolar disorder is summarized in Table 1.1. Themost important of these is suicide, seen in as many as 20% of those who receiveinadequate or no treatment, and must be considered a preventable complication(Khuri and Akiskal, 1983). It now appears that bipolar II may account for adisproportionately large portion of suicidal morbidity and mortality among all theaffectively ill (Rihmer and Pestality, 1999), emphasizing the importance of earlyand accurate diagnosis.

At the “softest” end of the spectrum, milder degrees of bipolar disorder – subsumedunder the rubrics of cyclothymic disorder (Akiskal etal., 1977) and bipolar disordernot otherwise specified (bipolar NOS) – are now categorized as mood disordersrather than being grouped with neurotic or personality disorders. Although theseseemingly attenuated and “atypical” variants may not be easily distinguishablefrom nonaffective personality disorders, the clinician is advised to err on the sideof affective diagnosis because of treatment implications.

External validating strategies – such as family history, course and inter-episodictemperamental features – are often necessary to confirm the diagnosis of thebipolar spectrum (Akiskal, 2003). The most established of bipolarity beyond classicmania and bipolar I is the bipolar II type, so-named originally by Dunner, Gershonand Goodwin (1976). Like diabetes type II, its onset is often insidious, but itsravages no less devastating than that of the psychotic forms of the illness. This isparticularly true for cyclothymic depression, a variant of bipolar II we have termed“bipolar II-½” (Akiskal and Pinto, 1999). Arising from a cyclothymic temperament,it pursues an unstable course and is likely to be misdiagnosed as axis II cluster B.These patients represent the “dark side” of bipolarity (Akiskal, Hantouche andAllilaire, 2003; Hantouche, Angst and Akiskal, 2003).

The American Psychiatric Association (2000) Diagnostic Manual of MentalDisorders, even in its last edition (DSM-IV), does not recognize hypomanic or

Table 1.1: Public health aspects of bipolar disorder

• Lifelong cyclical illness • 1–5% of population • Peak onset 15–30 years • 5–10-year delay in correct diagnosis • Frequent hospitalization • Repeated hospitalization • Repeated conjugal disruption: promiscuity • Repeated job change/loss • Financial disasters • Alcohol/substance abuse • 50% nonadherence to medication • Increased cardiovascular mortality • Suicide (highest within 10 years of illness onset)


The Scope of Bipolar Disorders 3

manic switches occurring during pharmacotherapy, electroconvulsive therapy,phototherapy and sleep deprivation as indicators of bipolar disorder. These patientsare obviously not unipolar major depressive disorder (MDD), nor are they classifiedunder bipolar not-otherwise specified (NOS). Therefore, this common clinicalphenomenon is voted by the DSM Committee out of existence! Since at least 1983,there has been good evidence that such switching on antidepressants requires bipolarfamily history (Akiskal et al., 1983, 2000, 2003). They are best regarded as lesspenetrant forms of bipolar disorder (bipolar III). Diagnostic status of depressivestates with mood swings in the setting of multiple drug abuse, particularly that ofstimulants, is controversial, but we contend that many of these individuals belongto a provisional bipolar type III-½ (Akiskal and Pinto, 1999; Maremmani et al.,2003; Camacho and Akiskal, 2005). This is relevant in a book on advances in bipolardisorder, because many of these patients respond favorably to anticonvulsant moodstabilizers. Finally, I would like to mention bipolar type IV, which refers toindividuals who develop depression later in life from a lifelong background ofhyperthymic temperament (hypomanic traits without clear-cut episodes); theirbipolar status might be inferred from familial bipolarity (Cassano et al., 1992).

In a French national study (Table 1.2), 65% of all major depressions belonged tothe bipolar spectrum, of which the most prevalent were the bipolar II and II-½phenotypes (Akiskal et al., 2005b). These considerations are important becausenearly all pharmacologic treatments covered in this book – certainly thoseapproved by regulatory bodies – pertain to bipolar I. Thus, there is a wide gapbetween the psychopharmacology of bipolar disorder and the public healthsignificance of the phenotypes observed in the community and the clinic.

Lithium was the first specific agent for bipolar disorder approved for clinical use.This was 35 years ago. Many other agents have been approved since then, almost allof them in the last decade. They are all covered in this book. Lithium medicalizedpsychiatry in bringing significant attention to the course of bipolar disorder. Itsimportance should not be overshadowed by these new developments. Many patients,

Table 1.2: Bipolar spectrum subtypes (n=316)in the French EPIDEP study of major depression(n=493): validation by bipolar family history*

* Akiskal et al. (2005b)

N %

Bipolar I 41 8.4Bipolar II 61 12.4Bipolar II-½ 164 33.5Bipolar III 28 5.7Bipolar IV 22 4.5

Total 316 64.5



especially those in the “core” classic form of the illness, do respond to lithium. Itsjudicious use, often in combination with other agents in rational polypharmacy,requires intimate knowledge of its physiological and medical characteristics.Regrettably, young psychiatrists are not having adequate experience with thisagent. A summary of the medical workup of patients in preparation of lithium use(Akiskal, 1999) is given in this chapter’s appendix.

PSYCHOLOGICAL AND SOCIAL ASPECTS

The long-term, essentially life-long, nature of bipolar disorder and its vicissitudesdictate continuity of treatment and long-term caring. To solve practical problems inthe patients’ lives requires caring that goes beyond medications and psychotherapy, toinclude the family, significant others and the community.

Bipolar disorder continues to be poorly understood by both the public anddoctors. More often than not, a bipolar child is classified as having conduct disorderor Attention Deficit Hyperactivity Disorder (ADHD) (Dilsaver, Henderson-Fullerand Akiskal, 2003). A teenager’s suicide attempt is misattributed to problems ofthe heart, adolescent crisis or substance abuse; promiscuous behavior is blamed onchildhood “sexual abuse.” Bipolar patients from time to time describe their parents as“monsters” or “emotionally abusive,” which some psychotherapists accept on blindfaith without ever talking to the parents. Bipolar II patients are often diagnosed asunipolar and/or borderline personality (Akiskal, 2004), treated with antidepressantswithout mood stabilizers, resulting in tragic aggravation of the course of theillness (Akiskal and Mallya, 1987; Akiskal et al., 2005a). Excessive spending,squandering, of one’s economic resources and pathological generosity may leadto financial ruin before bipolarity is considered.

Polls of members of the Depressive and Manic-Depressive Association in theU.S. have shown a latency of 10 years from the onset of symptoms until thecorrect diagnosis of bipolar disorder (Hirschfeld et al., 2003). Early diagnosis iscritical because suicide in bipolar patients often occurs within this early period.The comfort, support, destigmatization, information and advocacy provided bysuch a conglomeration of patients, families and community leaders (many ofwhom are themselves bipolar) represents a novel approach in the rehabilitation ofthe bipolar patient into society. This is a humane and just cause.

Given that about 10% of patients with bipolar illness have creative and leadershipachievements (Akiskal and Akiskal, 1988), sophisticated clinical management ofbipolar illness can potentially safeguard the adaptive capacity and contributions thatgifted bipolar people provide to society. Although psychotically ill (bipolar) patientsare represented in the media as being creative, this is a destigmatization campaignat best and glamorizing madness at worst. Achievement and creativity are largelyattributes of the softer spectrum represented in the attenuated temperamentalexpressions of bipolarity involving bipolar II (Akiskal and Akiskal, 1988, 2005).



Spanning from temperament to psychosis, bipolarity is a fascinating yet tragichuman condition. Mental health professionals who treat these individuals must usepharmacotherapy and psychosocial interventions compassionately, judiciouslyand rigorously – only rarely “aggressively.” Severe bipolar illness is not just anordinary illness to be medicated to “mediocrity.” The temperament of theseindividuals deserves all our consideration and respect. While most psychotic bipolarpatients are neither leaders nor creators, they are the reservoir of the genes, whichin dilute form, might serve as the seeds of genius (Akiskal, 2000).

APPENDIX: LABORATORY CONSIDERATIONS IN THE CLINICAL USE OF LITHIUM

More than any other development, the introduction of lithium has emphasized therole of physicianship in psychiatry. The scientific literature and clinical wisdomon the therapeutic aspects of this salt have been well summarized in a monographby Jefferson et al. (1983). The success of lithium treatment is dependent on thethoroughness of the initial workup, on dosage titration procedures and on appropriatemonitoring throughout therapy.

The type of workup depends on the age of the patient and concurrent medicalconditions (Table 1.3). In young (less than 40 years), physically healthy subjects,preparation for lithium therapy should include medical history (especially focusedon neurologic, renal, cardiac, gastrointestinal, endocrine and cutaneous systems),physical examination and laboratory evaluation focusing on electrolytes andthyroid. In older patients or those with a history of cardiac disease, a baselineelectrocardiogram (EKG) should be obtained, and an electroencephalogram(EEG) performed if epilepsy is suspected; if there is a history of renal disease,thorough evaluation of baseline kidney function is mandatory. Given rigor-ous indications for lithium, major medical illness and abnormalities in laboratoryindices do not necessarily contraindicate its use; they do dictate, however, greatermedical vigilance, including frequent determination of blood levels and use oflower doses.

Table 1.3: Recommended laboratory workup of patientsconsidered for lithium therapy

Healthy


A short-term lithium trial in the controlled environment of a hospital is relativelyeasy to administer and is recommended for acutely manic, medically ill or elderlysubjects. In outpatient practice, the physician must make sure that the patient andsignificant others understand the importance of adherence with periodic laboratoryprocedures and monitoring of side effects.

Lithium is rapidly and completely absorbed from the gastrointestinal tract andpeaks in the serum in about 1.5–2.0 (standard preparation) or 4.0–4.5 hours (slowrelease preparation), depending on age. Its half-life varies from 24–36 hours; steadystate is reached in about four days. Lithium is not protein bound and is excretedunchanged almost entirely through the kidneys. It can be safely combined withmost classes of drugs except diuretics and nonsteroidal anti-inflammatory agents(other than aspirin), which tend to increase the serum lithium level.

Acutely manic and possibly bipolar depressive patients have a high tolerancefor lithium and preferentially retain it during the first 10 days while excretingsodium; a regular diet is recommended. Postpubertal bipolar patients, who typicallyhave excellent glomerular function, require higher doses to achieve the same levelof equilibrium in the serum. The reverse is true in the geriatric age group. Elderlysubjects with adequate glomerular function can benefit considerably from judiciouslithium use. However, greater medical vigilance is required for this group; initialdoses should be low (150–300 mg/day), with frequent clinical and laboratorymonitoring to maintain blood levels in the lower range (0.3–0.8 mEq/L). Specialattention must be paid to signs of sinus node dysfunction (bradycardia) or neuro-toxicity; the latter is particularly likely in patients with concurrent neurologicdisease or sedative and alcohol abuse.

In healthy subjects who achieve good episode prevention, quarterly serum levels(12 hours after the last dose) and serum creatinine are generally sufficient; thyroidindices must be obtained at least once a year. For elderly or medically compromisedpatients, laboratory tests should be repeated as dictated by the medical condition,with frequent serum lithium levels; the dosage should be kept at the lowest possiblelevel compatible with prophylaxis.

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Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen © 2006 John Wiley & Sons, Ltd

CHAPTER

2Lithium Treatment: Focus on

Long-Term ProphylaxisMogens Schou1 and Paul Grof2

1 Syrenvej 4, Risskov, DK-8240, Denmark2 Mood Disorders Center of Ottawa, Suite 301, 1929 Russell RD,

Ottawa, Ontario, Canada.

INTRODUCTION

It is difficult to tell the exact age of lithium treatment for mood disorders. In the1880s lithium was used for the treatment and prevention of recurrent depressions(Lange, 1886; Schioldann, 2001), but statistics and controlled trials were not knownat that time, and the observations remained clinical impressions. In the 1950s lithiumtreatment for mania became evidence based (Schou etal., 1954), and in 1967–1970,prophylactic lithium treatment did the same (Baastrup and Schou, 1967; Baastrupetal., 1970). There is nevertheless good reason to count the age of lithium treatmentfrom 1949, when Cade (1949) published his paper “Lithium salts in the treatmentof psychotic excitement”, for lithium has remained in psychiatric use since then.

Why is lithium treatment still being used after half a century? This chapter doesnot aim at giving a systematic chronological exposition of the history of lithiumtreatment in psychiatry. This has been done in other publications to which thereader is referred, e.g. Johnson (1984), Schou (1992), and Healy (1997). An attemptwill be made to answer the question by recounting briefly and commenting in detailon selected events. Methodological problems are given more attention than pres-entation of data. There have been many misunderstandings about lithium. Some ofthem will be addressed in this chapter, but it has not been possible to deal withthem all.

The original version of this paper was published in the Journal of Affective, Disorders in 2001: Mogens Schou:Lithium treatment at 52. J Affect Disord 2001; 67: 21–32. The journal kindly permitted an updating by Schouand Grof in 2003. This chapter has not been updated since 2003. The authors.



Since lithium is used primarily for the prevention of recurrences, this review –based on previous work by Schou (1993b, 1998c, 2001) – deals primarily withprophylactic treatment and disregards treatment for individual episodes. In collab-oration with Grof (2003), this chapter has been thoroughly updated from previouscontributions to address contemporaneous challenges in the long-term treatmentfor what the authors term “typical” bipolar disorders.

CADE’S PIONEERING STUDY

It has often been claimed that the so-called “psychopharmacological era” startedwith the introduction of chlorpromazine in 1952. The era actually started whenCade introduced lithium as an antimanic drug in 1949.

When the word “serendipity” was used about Cade’s discovery, he becameannoyed and pointed out that it was based on a specific hypothesis and experimentalobservations. The hypothesis was that mental illnesses are caused by intoxicationwith an unknown compound, and that this toxic agent can be found in the patients’urine. His hypothesis led him to inject lithium urate, the only soluble salt of uric acid,into guinea pigs, and when he saw that they became docile and lethargic, he startedtreating psychiatric patients with lithium carbonate after having tried it on himselfwithout ill effects. Whereas schizophrenic and depressed patients did not show essen-tial changes, all ten manic patients showed abatement or cessation of their symptoms.Later attempts to induce lethargy in guinea pigs with lithium showed, however, thatthis was possible only with high doses. Cade’s animals were presumably intoxicatedrather than merely lethargic. To make therapeutic discoveries on the basis ofmisinterpreted experiments requires curiosity, daring, luck and compassion for patients!

DISCOVERY OF THE PROPHYLACTIC ACTION OF LITHIUM

By 1964 Schou (1956), Hartigan (1963) and Baastrup (1964) had independentlymade observations on small groups of patients that seemed to indicate that pro-longed treatment with lithium might ameliorate or prevent not only manic but alsodepressive recurrences. This was a new and unexpected observation, and it calledfor closer examination.

NON-BLIND MIRROR TRIAL

A confirmation of the original observations came from a large, open study. A non-blindtrial lasting six years and involving eighty-eight bipolar and unipolar patients whohad suffered at least two episodes within two years provided the first systemati-cally collected evidence of a prophylactic action of lithium against both manic anddepressive episodes of manic-depressive illness (Baastrup and Schou, 1967). Theaverage number of episodes per year decreased by 87% from the time before lithium


Lithium Treatment 11

treatment to the time during lithium treatment (p < 0.001). The decreases wereequally large in the two groups. A Swiss–Czech–Danish collaborative trial confirmedthe findings (Angst et al., 1970).

Psychiatrists in other countries then initiated lithium treatment. They alsoobserved depressive as well as manic recurrences diminish in intensity and frequency,and they were gratified by lithium’s prophylactic action. However, Blackwell andShepherd (1968) expressed sharp skepticism. This was not based on a failure toconfirm the Danish findings for they never tried treating patients with lithium;their skepticism was purely speculative.

Blackwell and Shepherd contested the validity of the evidence. They felt thatbias and the suggestive power of the psychiatrists accounted for the observations,and that patients selected because they had suffered frequent episodes duringrecent years could be expected to have fewer episodes during the following years. Intheir reply Baastrup and Schou (1968) pointed out that most of the patients weredischarged soon after starting lithium treatment. General practitioners, who were una-ware of the ongoing trial and therefore unbiased, determined when a recurrencehad taken place. Moreover, rather than decrease, the frequency of episodes mustbe expected to increase in the way that is characteristic of recurrent affectivedisorders (Angst and Weis, 1969; Grof etal., 1970a). Blackwell and Shepherd wereapparently not familiar with these findings, or they chose to overlook them.

The discussions between Blackwell and Shepherd, and Baastrup and Schou wenton for some time and created uncertainty among British and American psychiatrists,who hesitated to start prophylactic lithium treatment. Baastrup and Schou felt thatno useful purpose was served by continuing a potentially interminable discussionand that double-blind observations were required.

DOUBLE-BLIND DISCONTINUATION TRIAL

Baastrup, Schou and their associates therefore carried out a double-blind discon-tinuation trial (1970). Bipolar and unipolar patients who had been given lithium forat least a year were allocated randomly to either placebo or continued lithiumtreatment. Within six months the difference between the groups had reached apre-determined significance level (p


OBSERVER BIAS, DISEASE COURSE

Schou, Thomson and Baastrup (1970) tested the assumptions on which Blackwell andShepherd had based their criticism. The effect of observer bias and psychologicalfactors on the recording of recurrences was investigated by comparing the diseasecourse of a group of patients in whom lithium treatment was switched double-blindto placebo, and another group who stopped taking lithium on their own initiative.When lithium is discontinued during a double-blind study, observer bias andsuggestion continue to work at full force; when lithium is discontinued openly,their psychological effect ends. The percentage of patients who suffered relapseeach month was the same in the two groups. The trial showed that in manic-depressivepatients neither observer bias nor placebo effects were strong enough to exertsignificant influence on the recorded recurrence rate.

In the same study a survival analysis revealed that before lithium treatment 14%of the patients relapsed each month. While the patients were in lithium treatment, theproportion of patients who relapsed was 1.5%. When lithium was discontinued,16% of the patients relapsed each month. The low frequency of episodes duringlithium treatment was accordingly not a result of ‘regression toward the mean’ asBlackwell and Shepherd had suggested.

FURTHER DOUBTS ABOUT THE EFFICACY OF LITHIUM TREATMENT

Lithium prophylaxis became widely used during the following years, but occasionallydoubts about its efficacy were still expressed.

Dickson and Kendell (1986) found that even though long-term lithium treatmentwas being increasingly administered in Edinburgh during the period 1970–1981,admission rates for mania and depression were on the rise; the authors felt that thiscast doubts on the efficacy of lithium treatment. Schou (1986) pointed out thatdrawing conclusions about the efficacy of a treatment administered to a limitednumber of patients from the admission rates of a much larger number is a dubiousprocedure. Prophylactic lithium treatment is given only to manic-depressivepatients with frequent recurrences, so even if lithium treatment were 100% effective,it could only be expected to prevent a small fraction of re-admissions. Grof (1987)drew attention to the many other factors that could have led to a rise in the numberof admissions, for example a shift in diagnostic practice. In other hospitals rises inadmissions for comparable reasons were observed.

In 1995 Moncrieff claimed that a prophylactic action of lithium treatment wasnever satisfactorily demonstrated. She found it likely that development of sideeffects had compromised the blindness of the prophylactic lithium trials, but shepresented no evidence in support of that notion. The evidence available shows thatthe blindness had not been invalidated (Schou, 1998a).


Lithium Treatment 13

Basing her arguments purely on speculation Moncrieff claimed that discontinuationstudies are invalid because abrupt discontinuation of lithium treatment provokesmanic recurrences. This is strange logic. Even if a discontinuation design withrebound manias might inflate the size of lithium’s effect, this in itself shows thatlithium is not without effect (Goodwin, 1995).

Moncrieff insisted that the rise in frequency of recurrences after discontinuation oflithium was not caused by the removal of an active prophylactic drug. The cause wasinstead, she claimed, rebound recurrences precipitated by withdrawal of lithium. Shereferred to a study by Suppes etal. (1993) that reported rapid development of predom-inantly manic recurrences after abrupt discontinuation of lithium. These observationsare impressive, but they were made in patients who differed diagnostically from thosein whom lithium was originally shown prophylactically effective in 1967–1970.During the last decades the increasing use of standardized cross-sectional diagnoses(DSM) has led to a widening of the indications for lithium use (Grof, 1998). Patientswith, for example, excessive motor activity have been classified as bipolar manic andgiven lithium, and many of them benefitted somewhat from the anti-aggressive andanti-psychotic effects lithium also has in bipolar patients (Kingsbury and Garver,1988). In the early prophylactic trials the patients were diagnosed according to ICDcriteria and had classical manic-depressive illness, and in these patients discontinu-ation of lithium led to re-emergence of recurrences at a rate that did not exceed theirexperiences before they started lithium treatment (Grof, Cakuls and Dostal, 1970b;Schou, Thomsen and Baastrup, 1970; Rifkin, Quitkin and Howard, 1975; Fyrö andPetterson, 1977; Sashidharan and McGuire, 1983; Mendlewicz, 1984; Berghöfer,Kossman and Müller-Oerlinghausen, 1996).

Moncrieff had extrapolated from one group of patients to another group thatwas diagnosed differently. The principal argument in Moncrieff’s “case” againstprophylactic lithium treatment failed.

DEBATE

There are few psychiatric treatments that have been debated as hotly as pro-phylactic treatment with lithium. The reasons for this are difficult to understand.Perhaps the treatment was so effective that psychiatrists who had not themselvesused it for their patients found the observations utterly unlikely and refused tobelieve the evidence.

METHODOLOGICAL ISSUES

The debate raised by Blackwell and Shepherd revealed two different attitudes towardclinical trials. Shepherd himself had worked with randomized, placebo-controlledtrials and was convinced that valid evidence could be obtained only with this procedure;



any other evidence had to be rejected. The 1967 trial by Baastrup and Schou was notrandomized and placebo controlled, the reason being that it had started more or less onan exploratory basis and then had gradually grown. The authors felt, however, thatdata collected in an open prophylactic study of mirror-design need not necessarily bedisregarded. The marked and long-lasting change produced by lithium in the course ofthe disease of patients having had a median of nine episodes prior to lithium treatmentcoincided with the start of that treatment and was unlikely to be fortuitous.

PERSONAL ISSUES

Perhaps it may at this point be appropriate to correct an error that started withShepherd’s description of Schou as an “enthusiastic advocate”. This is anambiguous compliment. The term “enthusiast” might refer to someone who isstrongly engaged in their work, but in the given context the term “advocate” canhardly have been meant as a compliment. In British English an advocate issomeone who gathers evidence exclusively for or exclusively against a particularcase or person. A clinical scientist, on the other hand, is someone who gathersall relevant evidence and then weighs it carefully before drawing a conclusion.The latter is usually in the form of a hypothesis that may later be rejected, by thescientist himself or by others.

A conversation between Healy and Schou (Healy, 1997) revealed that Shepherdused his epithet with a more special meaning.

Healy: “I happen to know that there are people at the Maudsley who explainyour position by hinting that you yourself had manic-depression and are onlithium and that therefore you have a vested interest in seeing things oneway . . . Did you know that?”

Schou: “This is entirely new to me. Perhaps it explains why Shepherd alwaysreferred to me as an enthusiast, clearly meaning an uncritical person whoseopinions couldn’t be trusted. Well, I am not manic and never was in lithiumtreatment. But what difference does it make? Baastrup’s and my data, argu-ments and conclusions are there for anyone to assess. Should data, argumentsand conclusions presented by insane persons be disregarded rather thanjudged on their merits?”

This may appear to be a personal grudge without wider implications. It involves,however, an important question of principles. A reader may pay attention to theauthor’s assumed motives and his mental state. But should this, apart from perhapssharpening the reader’s critical sense, lead him to reject totally the data, argumentsand conclusions of a person whose motives the reader does not find sufficiently nobleor whose mental state he does not deem sufficiently sane? If that were so, science andthe patients might be deprived of potentially valuable information.


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