O A P L OXFORD AMERICAN PSYCHIATRY LIBRARY
Bipolar Disorder
O A P L OXFORD AMERICAN PSYCHIATRY LIBRARY
Bipolar Disorder
Stephen M. Strakowski, MD Senior Vice President for Strategic Planning & Business Development, UC Health The Dr. Stanley and Mickey Kaplan Professor and Chairman Department of Psychiatry & Behavioral Neuroscience University of Cincinnati College of Medicine Cincinnati, OH
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Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Oxford is a registered trademark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 98 Madison Avenue, New York, NY 006 © Oxford University Press 204 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. Library of Congress Cataloging-in-Publication Data Strakowski, Stephen M., author. Bipolar disorder / Stephen M. Strakowski. p. ; cm.—(Oxford American psychiatry library) Includes bibliographical references. ISBN 978–0–9–999568–4 (alk. paper) I. Title. II. Series: Oxford American psychiatry library. [DNLM: . Bipolar Disorder. WM 207] RC56 66.89′5—dc23 20400687
This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. The publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material. Without limiting the foregoing, the publisher and the authors make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publisher do not accept, and expressly disclaim, any responsibility for any liability, loss, or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material.
9 8 7 6 5 4 3 2 Printed in the United States of America on acid-free paper I would like to dedicate this book to my wife Stacy, my best friend since we were 6 and whose love and encouragement has supported me since we were kids!
Contents
Acknowledgments ix
. Introduction
2. Making a Diagnosis of Bipolar Disorder 5
3. Epidemiology of Bipolar Disorder 7 4. Illness Comorbidity and Co-occurrence in Bipolar Disorders 23
5. Neurophysiology of Bipolar Disorder 33
6. Genetics of Bipolar Disorder 47 7. Psychopharmacologic Management of Bipolar Disorder 55
8. Psychotherapy and Complementary Treatments 75
9. A Programmatic Approach to Treatment 85
0. Managing Special Populations 95
Appendix Example Mood Chart 07 Index 09
Keller Vasudevan. and Divya the outstandinghelpprovided D’Addona, by hisOUPteam:David Meredith tions. Healso thanks Dr. hisinput. Finally, CalAdler for heis indebted to providing onthepediatricpor criticalandcomments, feedback particularly thisbookand The authorthanksDr. reading MelissaDelBellofor mostof Acknowledgments - ix
O A P L OXFORD AMERICAN PSYCHIATRY LIBRARY
Bipolar Disorder
comprised of bipolar patients. Bipolar disorders (type I and II) affect upto II)affect bipolarpatients. Bipolardisorders I and (type comprised of their clinical practices healthcare providers experience 0–30% ormore of and misconceptions stillpersist),butmentalhealthpractitioners andother bipolar disorder (anddespitetheincreased untilrecently press, both stigma others (Table .).by a number of earlier. Moreover, asheisjoined inhistory bipolarking Saulwasnot theonly not history, if bipolar disorder hasaccompanied of since humanity thedawn with mania and depression, tell us that identify individuals moreeven clearly harp playing, whichfor long: was, unfortunately, not effective treatedepisodes, spirits” withDavid’s referredtoas“evil andwasinitially now thatIsrael’s believe king, Saul,suffered firstfrommanicanddepressive years ago. For example,somescholars mania anddepression, thousandsof bipolardisorder,writers described thekey clinical components of namely from thetruth.BiblicalandGreek Nothing could befurther fashionable. ply themisleadingimpression thatbipolardisordergives orsim issomehow new However, theseannouncements theapparent suddenincreasing frequencyof were reluctant pushedtobecome participants press. publicby anintrusive ditions helpstodestigmatize bipolardisorder, thoughoftentimesthey even publicfigures thesepopularandsuccessful todiscuss their con courage of surroundingthismentalillness. The mystery conversation totheshroud of withbipolardisorder, discussedFisher have theirstruggles helpingtobring ing fromPauley comedianJane BenStillertonewscaster toactress Carrie Othercelebrities known rang tothegeneralpublic. ments, was not typically disorder afterbeinghospitalized; bipolarIIdisorder, priortotheseannounce Jr.Jackson both announced thatthey were treatmentbipolarII receiving for actressited. Successful Jesse CatherineZeta-Jones andIllinoisCongressman problems publicbehavioral thatthey exhib theunfortunately tion becauseof Margot Kidderexperienced withbipolarillness received considerable atten order. Thedifficulties popularsingerBritney Spearsand actor, orpublicfigure—announces thatthey arewithbipolardis struggling years,another celebrity— In thepastfew itseemsthatalmostmonthly Introduction Chapter Stigma and misconception limited public awareness about historically This 3,000-year-old text,pluswritingsfrom other ancient sources that wall.” ( Sam. 8:0–) to the he thought “I will pin David hand. Saul hurled the spear for was playing theharpwithhishand,asusual;andaspearwasinSaul’s thehousewhileDavid inthemidstof uponSaulandheraved mightily Now itcameaboutonthenextdayspiritfrom thatanevil Godcame 2,3 Superman actress athlete, ------
1 2 Bipolar Disorder HIV infection. RecentHIV infection. studies demonstrate that bipolar disorder is the sixth other well-recognized conditions like diabetes, type rheumatoidarthritis,or itmore making common thegeneralpopulation worldwide, than 2–3% of and succinct descriptions of bipolardisorder anditsmanagement inorder to and succinct descriptions of modifications, and general lifestyle good health practices. incorporating sophisticatedpsychopharmacology, therapies, evidence-based bipolar disorder treatment isachallenge. Indeed, successful isprogrammatic, andmetabolicsyndromes.migraine, Consequently, treatment of effective disorder (ADHD), disorders,hyperactivity abuse, anxiety attentiondeficit themselves can bedifficult to treat. These conditionsinclude drugandalcohol other medicalandpsychiatric conditions that anumberof mon occurrence of complicated by illness is further the com ness management. The course of ill symptom of chasing, ratherthanadeliberateprogram on awildrideof nature inexperiencedits dynamic oftenleadsclinicians, clinicians, particularly that itcanbedifficult todiagnosetheillness. Even aftertheillnessisdiagnosed, complicate symptom patterns clinicalchanging, assessment,so multifaceted symptoms thatcomprise thesemoodstates. These complex combinations of with changes among bipolar mood disorderstates and is dynamic, course of challenges. psychiatry’s greatest The aging bipolardisorder may beoneof dipitous approaches to more targeted treatment development. able tomove from thecurrent empiricalandoften seren reliance onstrictly bipolardisorder isbetterdefined,treatment willbe advances of robiology management. inmitochondrialmolecular energy abnormalities prefrontal-limbic moodnetworks andmay reflect underlying regulation of precipitate theillness. Bipolardisorder therefore appearstoarisefrom dys interacts withenvironmentaleffects,such asstress orsubstance abuse,to it appearsprobablebipolardisorder thatgenesconferariskfor then genes thatcausebipolardisorder not have yet beenidentified.Moreover, disorders.including andanxiety majordepressive Unfortunately, thespecific abipolarproband, butsoare other conditions, members of mon infamily 85%. riskof a heritability bipolardisorder,play asignificant role intheonsetof as recent studiessuggest causes remain understood. It is now incompletely clear that genetic factors people with bipolar disorder. example,deathby upto5%of suicide for affects andmortality; morbidity both andisassociated worldwide withhighratesof disability leading causeof Table . Kaiser Wilhelm King George III King Charles XII King Charles IV King Saul Leader This Oxford American Psychiatry Library (OAPL)This OxfordAmerican Psychiatry Library practical volume reviews man Although bipolardisorder iscommon inclinical settings, effectively Although bipolardisorder represents amajorpublichealthproblem, its
Selected RulerswithBipolarDisorder 5 Moreover, isbipolardisorder more not only com Germany England Sweden France Israel Country 2,4 888–98 AD 760–80 AD 697–78 AD 322–328 AD 049–007 BC When Ruled – 3 6 Astheneu ------
useful for some patients and their families, aswell asmedicalorpsychology somepatientsandtheirfamilies, for useful provide aquick reference thebusy practitioner. for Thisvolume may alsobe 6. 5. 4. 3. 2. . References areorrelevant,I usedistinctions amongsubtypes important theplural form.] ismore common however,because thesingularform invernacular; when would I made becalled“bipolardisorders”correctly form). (plural thischoice conditions thatperhapsmore torepresentof agroup form) whatisprobably disorder. from peoplesuffering bipolar thisvolume istoimprove of thelives goal of cation changes, excessive polypharmacy, andpooroutcome. Ultimately, the “symptom-chasing” approach that often leads to frequent medi unnecessary matic approach tobipolardisorder managementinorder toeliminate the thisvolume istoprovide aprogram of focus mystifying condition. A major tobetterunderstandthiscomplexstudents whoare andsometimes trying
Neuroimaging andGenetics. bipolar disorder.cal modelof In: SM Strakowski, ed., and consolidation: A neurophysiologi Strakowski SM. Chapter 3: Integration New York: Oxford Press, 202. University Strakowski, ed., bipolardisorder. geneticsof In: SM JIJr.Nurnberger Chapter 9: General reconcile two survey’s estimates. Arch Gen Psychiatry 2002; 59:5–23. aclinical significance criterion to mental disorders inthe UnitedStates: using Robins LN,Regier DS, DA.Narrow WE,Rae prevalence Revised estimatesof KR. Jamison Recurrent Depression. KR. FK,Jamison Goodwin Stud Ben-Noun L.WhatwasthementaldiseasethatafflictedKingSaul?ClinCase [ Author’s Note 2003; 2(4): 270–282. Touched withFire. : In this book I use the term “bipolar thedisorder” term (singular this book I use : In h ioa ri: Integrating Neuroimaging and Genetics. The Bipolar Brain: 2nd ed. New York: Oxford Press, 2007. University New York: Oxford Press, 202. University New York: Free Press, 993. ai-ersieIles Bipolar Disorders and Illness: Manic-Depressive The Bipolar Brain: Integrating - - -
3 Chapter Introduction
one poleor“unipolar” depression). recurrenttwo poles)asdistinctfrom majordepression thosewith only (i.e., whoexperienced maniaanddepression“bipolar” todescribe (i.e., individuals by many psychiatrists, however, leadingLeonhard in957tocoin theterm manic-depressive insanity. Thisconceptualization astoobroad wasviewed now callbipolardisorder plusrecurrent major depression intheconcept of recovery, butdementiapraecox wasnot. Kraepelinincluded whatwe would based onoutcome, inwhich wasassociated manic-depressive with insanity phrenia, and“manic-depressive insanity.” Kraepelin’s distinctionwas largely “dementia praecox,” corresponds which roughly towhatwe now callschizo French concept withhislandmarkdescriptions andseparation in899of how we think about bipolardisorder today.of this EmilKraepelinadvanced cyclic illnessremains thebasis anunderlying ent expressions orphasesof ( thesamethingattime concluded virtually Baillarger independently cycling condition single thathetermed French psychiatrist thetwo moodstatesintoa Falret, in854,integrated melancholia orthatone syndrome precipitated theother. of form The amore concluding severe thatmaniawassimply and melancholia, typically der. From thattimeforward,writersexplored connections between mania mania withmelancholia, hintingatthecondition we now callbipolardisor behavior. and aggressive sive, “day andnight,”euphoriairritability, grandiosity, andimpetuous, impul energy indeed: excessive but the symptoms modern defining it seem very maniawere lessclear totheancients, perhaps“yellow bile,” The causesof and agitation—symptoms we stillusetoday todiagnosemajordepression. appetite,insomnia, melancholia toinclude prolonged despondency, lossof “black400 bile.”Hippocrates (c. excess of an humeralconstituents, inparticularly toarisefrombelieved animbalance of sion (called“melancholia”) andmaniaasmedicalconditions. Melancholia was spirits.” “evil expressions of 3,000-year-old andmanic-like biblicalwritingsdepictdepressive- ragesas not millennia.Nearly centuries if for has beendescribed, invariousforms, bipolar disorder is anancient condition that As mentioned inChapter , of BipolarDisorder Making aDiagnosis Chapter 2 la adouble folie forme 2.. BriefHistorical Overview Aretaeus of Cappadocia (c. Cappadocia (c. Aretaeus of ). Thisnotion thatmelancholia and maniawere differ 2 Theancient Greeks recognized both depres AD 50) is credited 50) is with being the first to link 2 Independentlandmark studiesby Angst la circulaire folie BC ) described the symptoms of ) described thesymptoms of
; hiscontemporary - - - - -
5
6 Bipolar Disorder throughout much of human history. throughout much of thiscondition were recognizedover thecore thecenturies, featuresof infact, bipolardisorder beenrefined have ter). Althoughthesymptoms andsigns of unipolardepression (orschizophrenia, thatmat for inthetreatment of tive bipolardisorder,therapeutic for effec mania, butnot especially particularly since lithium supported, is further relatively mood disorders was sification of lithiumincreased inthe960sand970s, thisclas illnesses. Astheuseof affective of thebipolar-unipolardivision datasupporting history and family (966), of depression. The excessive energy of mania may be purposefully directed mania may be purposefully depression. of The excessive energy of andcaninclude periods moment thatcanrangefrom euphoriatoirritability exhibit mood lability, demonstrating rapid shifts in mood from moment to individuals affected commonly anepisode;infact, day of every hourof every frequent, are listed in relatively Box 2.2. nia, thatare required not necessarily tomake adiagnosis, butnonethelessare Othersymptoms occurring duringmaniaorhypoma impairment. functional significant change from theindividual’stypical behavior, butdonot produce isdiagnosedwhensymptoms representdiagnosed. Incontrast, hypomania a someonerequires hospitalization duetothesesymptoms, then maniais if function; ininterpersonal,social,by definition, or nificant impairment work However,hypomania. maniaisdiagnosedwhenthesesymptoms causesig thecorner”andsimilar). ICD- “around DSM-5andICD-0(with usedcriteria sets, thetwo namely mostwidely for three ormore. Thesedefining symptoms, listedinBox asthebasis 2.,serve which variesaccording tothediagnosticcriteria setbut istypically number of mania,thespecific defining symptoms mustbepresent to make adiagnosisof several days (e.g., at least one week in DSM-5). atleast persistentfor andmustberelatively behavior in thepatient’stypical nied by amarked increase inenergy. Thesymptoms mustrepresent achange moodthatisaccompa orirritable expansive, Mania isdefined by aeuphoric, Bipolar disorder,hypomania. maniaor then,isdefined by theoccurrence of Distractibility • Impulsive • Grandiosity • Rapid speech • Racing • Decreased • Excessive energy • Euphoric, • Box 2. 2.2. ManiaandHypomania The extreme mood state of mania or hypomania is not necessarily fixed isnot necessarily maniaorhypomania The extreme moodstateof 3 Perris (968), thoughts/flight Defining Symptoms of Mania pleasure expansive, need for sleep seeking 4 andWinokurClayton (967) or of ideas irritable mood 6,7 Thesesamesymptoms define 6 Additionally, several other 5 provided clinical ------mania, and depression is often the more disabling mood state. spendmore timeindepressionviduals withbipolar disorder than typically indi illness. Infact, most casesdepression alsooccurs duringthecourse of bipolar disorder, defines thediagnosisof in Although maniaorhypomania medical condition other than to bipolar an disorder.underlying ondary mania,”thatis, referredtoas“secondary sec the manicepisodeiscommonly thesemore common conditions are listedinBox 2.3.Inthesecases, Some of from bipolardisorder duetoother medicalcausesthatimpactbrainfunction. Nonetheless, maniaisstillanonspecific syndrome thatcanoccur separately illness. episodesconsistentmanic anddepressive withabipolarcourse of recurrent hasan80%riskof individual manicepisode,theaffected a single requiring rapid intervention. and dehydration exhaustion. In the extreme, mania is a medical emergency deaththrougheral monthsandcanescalateintodelirium,catatonia,even sev maniamightpersistfor leftuntreated, anepisodeof If table individuals. may alsooccur, violentimpulsivity andeven aggressive withirri particularly isdirected toward mania,impulsivity pleasurable,butrisky, activities, cases of connected. Althoughinclassictheir conversation isoftenjumbledandloosely although nosleep. andthinkfast, hoursoreven talkfast few Manicindividuals a may days several go for with only sleep; manic individuals need for in lack of expressed and agitation.Thisexcessive istypically psychomotor level energy beexpressedband withnomusicalexperience), ormayasrestlessness simply (e.g., arock which mightbequitegrandiose starting toward projects, someof Box 2.2 Catatonia • Extravagance • Hyperreligiosity • Confusion • Aggressive • Severe • Delusions • Hallucinations • Brief • Hypersexuality • Mood • 2.3. BipolarDepression Mania is one of the most predictive syndromes themostpredictive inpsychiatric. Following Mania isoneof lar life course in over 80% of individuals. courselar life in over 80% of mania.Maniapredicts abipo of impairment functional by thegreater Key Point
periods lability thought Other CommonSymptoms of Mania : Mania and hypomania : Mania andhypomania impulsivity of disorder
depressed mood are symptomatically similar,are symptomatically butdiffer 8 The diagnosis - - - - -
7 Chapter 2 Making a Diagnosis of Bipolar Disorder 8 Bipolar Disorder rendous permanent solution for a temporary (and almost always treatable) (andalmostalways atemporary rendous solutionfor permanent during a severe episode, as with mania. depressive and weight. Psychosis (hallucinations anddelusions)catatoniacanoccur Neurovegetative signs include eitherincreased ordecreased sleep, appetite, mania. of as straightforwardinattention,ratherthanthedistractibility difficulties occur, althoughindepression these are moretobeexpressed likely more seesection2.4,“BipolarMixed onthistopic, States”). Concentration distinguishing anagitateddepression from(for amixed difficult statevery (psychomotor common retardation); andcanmake agitationisalsorelatively to mania), which may be accompanied by moving moreand thinking slowly episode.Typically,sive (incontrast low energy depressed patientscomplain of amajor depres mood arepresent alsocommonly andadefining symptom of course, persistentdespondency, sadness, interest and depressed insex. Of of down orsad,butwillacknowledgefeeling anhedonia,oftenexpressed asaloss some cultures, willnot complain andofteninmen,depressed about individuals pursue.In thatapersonwould normally disinterest inpleasurableactivities toexperience theability pleasure ora thelossof sode isanhedonia,namely symptoms, listed in Box 2.4. relies on the same set of isnodifferentfrom depression thatinanyone inbipolarindividuals elseand of Adapted from SaxandStrakowski Dementia Huntington’s disease Epilepsy CNS infections Hyperthyroidism Drug intoxication/withdrawal Brain tumors Cerebrovascular disease Traumatic brain injury Box 2.3 Suicidal • Impaired • Fatigue • Change • Psychomotor • Change • Feelings • Anhedonia • Depressed mood • Box 2.4 The most concerning symptom of depression suicide issuicidality; isahor The mostconcerning symptom of epi amajordepressive Despite itsname,themostdefining symptom of Defining Symptoms ofDepression Possible Medical CausesofSecondary Mania thoughts in in of concentration sleep appetite
worthlessness agitation pattern or and weight behavior or 3 or retardation excessive guilt - - -
disorder has among the highest lifetime rates of suicide attempts (up to half suicide attempts (uptohalf disorder ratesof hasamongthehighestlifetime treatment. Sadly, bipolar whichof isamajorfocus problem, theprevention of is mania;conversely, duringantidepressant treatment mixed states may be tions. Specifically, mixed tolithium than statesappeartobeless responsive lenging torecognize and may tosometreatment belessresponsive interven condition. Thesemixed chal manic-depressive episodesare diagnostically that of themoodlability can occur during“pure” even of maniaas part sleepversus insomnia).Moreover,need for moods anddysphoric depressive hence overlapping (e.g., poor concentration versus distractibility, decreased maniaanddepression are similarand the symptoms of episodes, asmany of bipolar mood tion. Thesedifferentapproaches arisefrom the of complexity episodes, allowingsive theclinician morethisdetermina leewayinmaking eithermanicordepres beenreplacedstates have by a“mixed”modifierof symptoms persistintoICD-).InDSM-5, (which willprobably sive In ICD-0, both criteriaepisodes. for both symptoms themanicanddepressive metfull how tobestdefinethem.InDSM-IV, being common, there hasbeenongoing controversy since Kraepelinabout andmanicsymptomsdepressive occur concurrently. Despitemixed states episodes, of one-half inroughly and thatthesetwo meet.Infact, polesnever exist on two individuals distinct depressionaffected poles, namely The “bipolar”nomenclature misleadingbecauseitimpliesthat issomewhat mania or hypomania. be made with the occurrencedisorder can only of bipolar tinguish bipolarfrom unipolardepression; asnoted, adiagnosisof symptoms,However, thesedepressive aloneorincombination, dis noneof catatonia may bemore common inbipolarthanunipolardepression aswell. episode.Psychosis withinadepressive than agitation,andmoodlability and weight loss, psychomotor retardation rather insomnia, weight gaininsteadof depression.atypical instead of depressionAtypical includes hypersomnia arethe same,depressedmoretoexpress bipolarindividuals likely so-called depressionsecondary is much more common than secondary mania. other psychiatric every diagnosis. Thisso-called including virtually function, any medicalcondition thatimpacts brain common consequencerelatively of is not diagnosedunlessitimpairspsychosocial Depression isalsoa function. majordepression. a diagnosisof concurrent and hopelessness. with dysphoria high energy nation of commonthey in mixed are particularly states with the potential lethal combi illness, although These attempts oftenoccur duringthedepressed phaseof any medicalcondition. patients)of patients)andsuicides (upto5%of of 2.4. BipolarMixed States Although the diagnostic criteria for bipolarandunipolardepressionAlthough thediagnosticcriteria for are Traditionally, symptoms depressive are required to make two weeks of the occurrence of mania or hypomania in bipolar disorder. mania or hypomania the occurrence of Key Point 7 they are identified by various combinations of manicanddepres they are identified by various combinations of : Bipolar and unipolar depression can only bedifferentiated by and unipolardepression canonly 6,7 As with mania, an episode of depression Aswithmania,anepisodeof 9 amixed diagnosedwhen statewasonly or 6 mixed mania ------
9 Chapter 2 Making a Diagnosis of Bipolar Disorder
10 Bipolar Disorder Given the symptom complexity of both maniaanddepression, itisnot sur thesymptom complexity of Given combinations manic and depressive on treatment planning. of considering thepotential impact symptoms andsigns, whilecarefully affective theentiremood statesinbipolarpatients,toreview rangeof itisimportant moodandcognition. dysphoric severely and highenergy thecombination of becauseof suicide, likely highest riskfor noted earlier, mixed phasewiththe statesappeartorepresent theaffective tomanicswitchesmore thanare sensitive “pure” episodes. depressive As can impart significant disability.can impart In children up cyclothymia, who demonstrate chronic and illness.typically Ineither case,itis ratherthananaffective style) asatemperament (i.e., ismore viewed apersonality accurately cyclothymia episodes.manic ordepressive andclinicians Someinvestigators that believe contain both features, full manicanddepressive meetcriteria butnever for replicate this observation. thiscategorical separation,althoughnot beenableto allstudies have porting Bipolar IIdisorder distinctfrom may bipolarI disorder, begenetically sup sants thanbipolarI disorder, althoughthisdifference isnot well established. withbipolarIIdisorder mayIndividuals bemore toantidepres responsive by more having frequent mood changes with less time spent in euthymia. thedisability. BipolarIIdisorder mayfrom alsodiffer bipolarI disorder of types, itis themore themajority symptoms persistentdepressive thatimpart order beinglessimpairingthanbipolarI disorder. Indeed,inboth bipolarsub symptoms, although this difference should not be interpreted as bipolar II dis the manic of impairment functional by of the level primarily lar I disorder Dunnerandcolleagues inthe970s. of beingdefined untiltheseminal notwork really modern, disorder isrelatively bipolar episode aswell asoneormore episodes. depressive of Thissubtype experience both mania and depression, so they are classified together. who individuals from thoseof substantially donot differ thislattergroup of mania. However, thetreatment, patterns symptom expression, andfamilial experience recurrent only individuals bipolarI disorder, perhaps0%of of occurs mania. during Although the depressioncourse typically occurrence of severe conditionsymptomatically called cyclothymia. bipolar I and bipolar II disorders, relatednamely as wellbut less as a possibly suggeststwodebate, althoughthebestevidence distinctbipolarconditions, classifiedare intocategories. not easily this To date,there is no resolution of symptoms manicordepressive inpeoplethat whether there isaspectrumof debateover existatallor anactive whetherthesesubtypes is currently differenttreatmentmight have requirements andprognoses. Indeed,there bipolardisorder that not centuries, aboutwhetherthere are of subtypes if prising thatclinicians andpsychiatric decades, debatedfor have investigators 2.5. BipolarDisorder Subtypes Cyclothymia is defined by the occurrence of significantmood changesthat Cyclothymia isdefined by theoccurrence of hypomanic atleastone Bipolar IIdisorder isdefined by theoccurrence of bipolar disorder, isthe classic version of defined Bipolar I disorder by the BipolarIIdisorderfrom differs bipo 0 Practically, then,whenassessing 6,7 ------
in adults is unlikely toprogress. isrelatedin adultsisunlikely Itappears, then,thatcyclothymia to two-thirds bipolardisorder, appeartolaterdevelop whereas cyclothymia essentially thesame inthepre- andpostpharmacologic eras,essentially raisingquestions illnessappearstobe Figure 2. of isthatthispattern of caveat An important not treated orotherwise disrupted. if recurrences, annually typically of tern until the condition shortens stable pat tends toward a relatively progressively perioduntilthenextepisode episode,theeuthymic ing each majoraffective bipolardisorder isprogressive. course of that theearly psychiatricAs illustratedinFigure 2., decades known have investigators for illness across span. the life bipolar aspecttosymptomagain suggestingadevelopmental expression of dromes inchildren represent progressiontobipolarI or IIdisorder, ariskfor thesenonspecific Thatsaid,like bipolar criteriasyn cyclothymia, inthefuture. treatmentfor decisions, but may heuristic have refining value for diagnostic then, the spectrum approach guidance does not provide useful particularly conditions IIdisorders. andthebetterrecognized At thistime, bipolarI and and genetic data providefor specific relationships support among these Disorder Not ElsewhereClassified(NEC). Bipolar Disorder, andinICD-0they are classified underBipolarAffective manic symptoms. InDSM-5thesepatientsare classified underUnspecified illnessisaccompanied by subclinical andwhosecoursement unresponsive of withrecurrent episodes, major depressive on individuals who are often treat hasbeen Considerablefocus lar IIdisorder) andmania(bipolarI disorder). increasing (bipo manicsymptoms (e.g.,hypomania through full cyclothymia) progresstotheadditionof recurrent episodesthatgradually depressive (chronic depression) through low-grade symptomsdepressive ordysthymia abipolarspectrum.Thisspectrummightextendfrom minor the notion of psychiatric investigatorsand theoristsadvocated for have A number of relatedare in adults remains genetically unclear. theconditionlife occurs. IIdisorders andbipolarI and Whethercyclothymia II disorders depending on when in an individual’s to bipolar I and differently 2.6. BipolarSpectrum and Patterns of Illness 2.7. BipolarDisorder CourseProgression ciently developed to guide clinicalat this time.developed decision-making ciently symptoms manicanddepressive isinsuffi of binations andseverity Key Point: toms in the former. associated withmanicsymp impairment functional the presence of Key Point . Bipolar The concept of abipolarspectrumdefined by various com concept of I disorder isdifferentiatedfrom bipolarIIdisorder by 2 6,7 Unfortunately, few treatment Unfortunately, few 3 Specifically,follow
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11 Chapter 2 Making a Diagnosis of Bipolar Disorder 12 Bipolar Disorder disruptive todisruptive people’s weeks or short-lived, a few lives, but it is relatively bipolardisorder. of Indeed,maniacan bequite impairment the functional time withmixed symptoms. the thetimewithmanicsymptoms and6%of toms, compared with9%of symp thetimewithdepressive viduals withbipolardisorder spent 32%of indi 3 years, thatover found Health (NIMH),investigators aperiod of Mental by theNationalInstituteof bipolarpatientssupported of large study bipolarillness. Inalong-term, symptomsdepressive dominatethecourse of tively, more dramatic than and depression,are nonetheless relatively about this condition. intorealistic expectations andtheirfamilies tant toguideyoung individuals bipolardisorder becomes impor naturecoupled of withtheprogressive mania relapse. power Understanding the predictive these individuals of of the time, so that the vast majority episodes,depressive more than 80% of illness, thatis, recurrent manicand bipolarcoursedicts along-term of maniapre againexperiencenever mania.Unfortunately, anepisodeof assumption thatthey will treatment basedonafalse viduals drop outof theseindi sothatmostof that theirmanicepisodewasaone-timeevent, andtheircare providers individuals often misleadsaffected intothinking long interval up to long, 3-4 years.on average This relatively be relatively afterafirstmanicepisodecan shortens,thewell interval vals progressively illness. thatleadsfrommanicepisodetoarecurring affective asingle ropathology neu inbipolardisorderprogressive intervals reflects anunderlying euthymic of shortening thatthisprogressive itislikely will bediscussed inChapter 5, impactthisprogression.As ourtreatments ultimately about how effectively Strakowski 202). light bar = data from Roy-Byrne et al. 985 cited in Strakowski 202. Adapted from episodes. (Source: Darktive bar = data from Kraepelin 92 cited in Strakowski 202; Figure 2.
Although mania and hypomania define bipolar I and IIdisorders respec definebipolarI and Although maniaandhypomania inter euthymic becausethelengthof Also asillustratedinFigure 2., Years 0 2 3 4 5
Chart illustrating decreasing length of intervals between successive intervals affec illustrating decreasingChart length of 3 234 8 Depression is also associated with most of Depression is also associated withmostof Interv al numbe r 5 ------
for months or for even years become and crippling.truly Moreover, bipolar withouttreatment.months atmosteven Incontrast, depression canpersist Dysthymia Recurrent major depression with bipolar disorder include: fused thediagnosis.ruled outwhenmaking Commonconditions thatmay becon conditions share symptoms withbipolardisorder,A numberof somustbe Chapter 8). until they are episode(see oldenoughtoexpress aclear manicorhypomanic IIdisorder mayfor many bipolarI or not bepossible years, cific diagnosisof bipolardisorder. of However, history family intheseyoungaspe individuals, instability coupled witha thisaffective suggestedby thepresencetypically of episodes. Intheseyoungadiagnosiscanbechallenging andis people,making distinct manic ordepressive few with expressed instability as chronic affective dren andadolescents withbipolar disorder, moodsymptoms are commonly periods.between Inchil maniaanddepression, achieve euthymic butnever Chapter 8). cycling, which isalso more common inbipolarIIthanI disorder (see medications.to new Women appear to be rapidmore to develop likely stressors,life disease thyroid or other medical illness, new and exposure Common precipitants rapidcycling include drug or alcoholfor abuse, major initiatedby aspecificand isprobably psychosocial orbiologicaltrigger. betimelimited difficult to be very treat, althoughitappearstogenerally episodeswithinasingle year.or more distinctaffective cyclingRapid can However,four defined as rapid develop cycling, typically some individuals mania followed or preceded bysettle into andepression. annual cycle of bipolar depression in Chapter 7. sion; we will discuss the management of to standard antidepressant pharmacotherapy thanunipolarmajordepres depression lessresponsive canbequiteachallenge totreat, asitisrelatively 2.8. Differential Diagnosis ofBipolarDisorder mal symptoms of mania. depression; however, also exhibitsubsyndro withcyclothymia individuals canalsobedifficult todistinguish,as both experience subsyndromalthymia andcyclo Dysthymia maniaorhypomania. made untiltheoccurrence of bipolardisorder cannot be episodes. Again,adiagnosisof major affective depression between subsyndromal symptoms of of exhibit thesetypes withbipolardisorder to(episode). Itisnot uncommon individuals for syndrome amajordepressive symptoms thatdonot of achieve thelevel episodes. identifying manic or hypomanic rent majordepression dependentupon canbedifficult andis completely experience recur from thosewhoonly Distinguishing bipolarindividuals rare.syndromes, episodesare relatively such thatthemanicorhypomanic symptoms illnesswithdepressive and theircourse of der spendmuch of Some individuals may also develop chronic affective maysymptoms thatswitch chronic alsodevelop Some individuals affective bipolar disorder,unmanaged,willoften courseAs noted, thetypical of if : Dysthymia isacondition characterized by chronic depressive : Dysthymia : As noted, individuals suffering from suffering bipolardisor noted,: As individuals ------
13 Chapter 2 Making a Diagnosis of Bipolar Disorder 14 Bipolar Disorder Schizoaffective disorder,Schizoaffective bipolar type Schizophrenia Drug/alcohol use disorders Attention Deficit Disorder Hyperactivity (ADHD) Borderline personality disorder ated with mood instability and behavioral dyscontrol and behavioral that mightresembleated withmoodinstability ness at a later age. bipolarill disorder, ADHDmay predict theemergence of theonsetof bipolar in younger patients. Moreover, of history inyouth withafamily and bipolardisorder exclusive co-occur are andcommonly not mutually ADHD bipolar in disorder the teens. is typically Diagnoses of onset of whereas thesodes. By definition, ADHD beginspriorto age7 years, epi affective distinguishedfrom ADHDby theoccurrenceis further of Bipolardisorder mania orhypomania. they present withinepisodesof persistentandchronic, whereas inbipolardisorder,tend toberelatively However, mania or hypomania. in ADHD these symptomssymptoms of distractibility, behavior, impulsive similartothe andexcessive energy disorder. andsexualabusethanbipolar childhood physical of ated withahistory is more common inwomen. Italsoappearstobemoreassoci commonly commonorder between sexes, isequally borderline disorder personality exclusive,ditions are so may not mutually co-occur. Whereas bipolar dis inadolescents.to differentiateattimes, Moreover, particularly these con distinct ageatonset.However, thesetwo difficult conditions canbevery andoftenarelatively euthymia, mania),periodsof episodes (particularly distinct,affective borderline disorder personality by theoccurrence of bance ininterpersonalrelationships. Bipolardisorder isdistinguishedfrom emergingfromdistur alifelong impulsivity. gradual, Theonsetistypically relationships, andoftenchronic self-destructive suicidal behavior, and disorderity exhibitchronic moodinstability, tempestuousinterpersonal bipolar I disorder. the same as for is virtually thiscondition bipolarI disorder. Indeed,treatment of of an extreme form author) consider disorder, schizoaffective represent tosimply bipolar-type controversial,somewhat andmany psychiatric (including investigators the symptoms. is Thisdiagnosticcategory affective psychosis independent of illness, yet also experience periodsof prominent throughout thecourse of disorder, exhibitboth maniaanddepression bipolartype, thatisrelatively symptoms. affective persistent independent of episodes, whereas restricted inschizophrenia, toaffective marily psychosis is the co-occurring psychosis. Additionally, psychosis inbipolardisorder ispri symptoms thatare moreidentifying affective prominent and common than disorder with psychotic features can be differentiated from schizophrenia by betweencontributes theseconditions. totheconfusion However, bipolar bipolar disorder,also occur with depression during the course of which depression. Psychosis occurs commonly duringmanicepisodesandcan of Mostpeoplewithschizophreniational impairment. alsoexperience episodes psychotic profoundfunc symptoms, deterioration,andtypically personality : Schizophrenia isacomplex condition: Schizophrenia characterized by chronic : Chronic drugoralcohol associ use iscommonly : Chronic : Individuals suffering from suffering borderline personal : Individuals : Individuals suffering from suffering schizoaffective : Individuals : ADHD ischaracterized by : ADHD ------Other neurological andmedical illnesses Adapted from Sax&Strakowski 999 Other • CNS • Metabolic • Neurological • Head trauma • Box 2.5 detail in Chapter 3. aswell, which willbediscussed inmore individuals bipolar thaninhealthy theseconditions are more common in as thoselistedinBox 2.5.Someof toruleoutconditions medicalevaluation such acareful warrants 50 always ated withmaniaandare listedinBox 2.5. beenassoci have medicalconditions thatimpactbrainfunction number of bipolardisorder. rare outsideof Nonetheless, event a mania isarelatively function, any nonspecific condition thatimpactsbrain response tonearly following acute detoxification. symptoms affective substance abuse,orrapidresolution of to theonsetof symptoms prior affective sobriety, onsetof symptoms duringperiodsof affective tosubstance illnesssecondary abuse by occurrenceaffective of Bipolardisorderder atsomepointintheirlives. canbedifferentiatedfrom withbipolardisor individuals of alcohol abuseoccurs inmore thanhalf that look like mania.complicating Further this differential is that drug and produce cifically symptoms. depressive Stimulantscanproduce symptoms bipolardisorder. abuse(e.g., alcohol) spe the symptoms of Many drugsof bipolar disorder. of history afamily episodesandanabsence of manic orhypomanic bipolar disorder, clear be distinguished bybut can typically a lack of Key Point Klinefelter’s • CNS lupus • HIV/AIDS • Neurosyphilis • Wilson’s • Cushing’s • Hyperthyroidism • Huntington’s • Temporal • Tuberous • Cerebral • Brain • Multiple • Stroke • infection illnesses Examples ofMedical Causesof Mania : A number : A number diseases cancer abnormalities or sclerosis disease sarcoidosis disease brain sclerosis lobe syndrome or tumors disease of medicalandpsychiatric conditions resemble of epilepsy hemorrhage 4 : Although depression isacommon, : Although 4 A first onset of maniaafterage onsetof A first - - -
15 Chapter 2 Making a Diagnosis of Bipolar Disorder
16 Bipolar Disorder References 4. 3. 2. . 0. 9. 8. 7. 6. 5. 4. 3. 2. .
New York: Marcel Dekker, 999. der withmedicalillness. In: Tohen M,ed. bipolardisor Co-occurrence of Sax KW, Strakowski SM.Chapter 8: The Press, 202. NeuroimagingBrain: Integrating and Genetics SMStrakowski, ed., bipolardisorder.ological modelof In: neurophysi andconsolidation: a Strakowski SM.Chapter 3: Integration der: benefits vs. risks. World Psychiatry 20; 0:8–86. bipolardisor Strakowski SM,Fleck DE,MajM.Broadening thediagnosisof illness. Biol Psychiatry 976; :3–42. affective of intheseverity FK.Heritablefactors Goodwin Dunner DL,GershonES, with mixed and manic bipolar disorder. Am J Psychiatry 996; 53:674–676. Strakowski SM,McElroy SL, Keck PEJr., West among SA.Suicidality patients Press, 994. PsychiatricMental HealthDisorders (4thed.).Washington DC: American American Psychiatric Association. DiagnosticandStatisticalManualof bipolar I disorder.status of Arch Gen Psychiatry 2002; 59:530–537. symptomatic theweekly Rice JA,Keller of MB.naturalhistory Thelong-term Schettler PJ,Endicott HS, Judd LL,Akiskal J,MaserSolomonDA, LeonAC, Health Organization, 992. Descriptions andDiagnosticGuidelines. Geneva: World Disorder: Clinical Mental andBehavioural World HealthOrganization.ICD-0Classificationsof Press, 202. AmericanPsychiatric Health Disorders (5thedition).Washington, DC: Mental American Psychiatry Association. DiagnosticandStatisticalManualof Press, 976. Recent Advances inBiological Psychiatry orders separatedaccording J,ed., In: Worris togeneticandclinical factors. dis affective Winokur G,Clayton P. of types studies: I. Two history Family 44(3):238–248. psychoses. depressive ActaPsychiatrPerris Scand968; Thecourse C. of Berlin: Springer-Verlag, 966. J. Angst Disord 200; 67:3–9. and rebirth. J Aff birth from times: conception, Angst J,MarnerosA.Bipolarity ancient tomodern Stud 2003; 2(4): 270–282. Ben-Noun L. What was the mental disease that afflicted King Saul? ClinCase Zur Atiologie undNosologie Psychnose endogener depressiver (Vol 0),pp. 35–50.New York: Plenum Comorbidity in Affective Disorders Comorbidity inAffective . New York: Oxford University University . New York: Oxford The Bipolar - - - - . .
bipolar spectrum remains tobeestablished,butthese studiessuggestthat the population. noted to occur inapproximately 6%of Europeangested inseveral studies, asbipolarspectrumconditions were IIdisorders.diagnoses, ratherthanbipolarI or thesubjectsexpressing subthreshold orspectrum of three-fourths nearly bipolarspectrumwas4.8%,with therateof Mental Healthsurvey initiative, thoserepresenting subthreshold cases. of 4.5%, withover half bipolardisorder spectrumof Nonetheless, theNCS-Rreported arateof peoplewiththeseconditions arecontroversial somewhat andvariable. of therates for thesesubthresholdupon definition“bipolar”cases, studiesof IIdisorders. Becausethere isnoagreed bipolarI or meetcriterianever for people who exhibit depression and manic symptoms who the prevalence of attempts beenmadetoidentify Several have to mania(bipolarI disorder). increasing symptoms progresswiththeadditionof episodes thatgradually extends from symptoms minor depressive through recurrent depressive illness that a bipolar spectrum, that is, a spectrum of est inthe concept of to conclude that bipolar disorders prevalent worldwide. are similarly differences isnot inmethodsandcaseascertainment clear, butitis reasonable these cross-national differences reflect “true” differences inratesorinstead bipolarIIdisorder similar, lower.rates of althoughperhapsslightly .3–.8%with intherangeof were typically bipolarI disorder ies, ratesof 6 around 2.0%. around 0.2%tohighsintheNetherlandsof Iceland andAsiaof tries andcultures withcross-national studiessuggestingarangefrom lows in bipolar I disorder. consistent across Theseratesappeartoberelatively coun .%. Survey-Revised (NCS-R)ittobesimilarbipolarI disorder, found namely bipolar II disorderfor are more variable,although the National Comorbidity –.5%(Table 3.). converge aroundprevalence rateof alifetime recent,several large-scale epidemiologicstudies that, despite some variability, bipolarI disorderincluded. Nonetheless, beenidentifiedthrough have ratesof disorders are differentiated, and whetherbipolar“spectrum” conditions are II disorder onthedefinitionapplied,whetherbipolarI and dependsinpart bipolar common; Bipolar the disorderspecific prevalence is relatively of Disorder Epidemiology ofBipolar Chapter 3 Consistent with this observation, in a review of a number of European stud anumberof of inareview Consistentwiththisobservation, 3.. Population Prevalence andIncidence As described in Chapter 2, in recent years there has been increasing inter 3 Other studies find bipolar II disorder to be slightly less OtherstudiesfindbipolarIIdisordercommonthan tobeslightly 6 Even higherrates were sug 5 The validity of the of The validity 3 IntheWorld 5 Whether – 4 Rates Rates 4 - - - - –
1717
18 Bipolar Disorder bipolar-like conditions may be more common thought than using currently particular, episodes are oftennot recognized hypomanic inbipolarII disorder, In bipolar disorder 7–0 years. are for diagnosedonaverage not correctly symptoms inadolescence younger. oreven with Unfortunately, individuals bipolardisorder whodevelop beginexperiencingknow thatmostindividuals begin inadolescence.der alsoappearstocommonly Consequently, we now tries, andethnic/racial groups. survey methods, coun 8–22 years across of avariety onset intherangeof converged toward largely have amedian ageat bipolarI disorder Studies of Bipolar disorderduringyouth starts andthenpersistsacross span. thelife 3.2.2. Age Effects spectrum also appears to demonstrate similar rates across the sexes. .3% respectively. 0.9%and ratesof NCS-R, menandwomen demonstratedsimilarlifetime rates appeartobesimilarbetween menandwomen. For example,inthe this equal risk extends across nations and cultures. sex distributions were noted in cross-national studies, suggesting that of types intheNCS-R, these rates were 0.8% and.%. .7% respectively; bipolarI disorder inmenandwomen wereSurvey, .6%and ratesof lifetime distributed between the sexes. For example, in the National Comorbidity tobediagnosedthanmen,bipolardisorderlikely appearstobesimilarly Unlike depressive disorders in which women are two to three times more 3.2.. Gender existing criteria sets. Group. Survey-Revised; NCS-R = National Comorbidity ECA = Epidemiologic Catchment Area study; Table 3. CNCG, 996 NCS-R, 2005 990 NCS, ECA, 980 Study 3.2. Subgroups andOtherFactors The sex distribution of bipolarIIdisorder islessclear, The sexdistributionof butagainlifetime disorder. Key Point tions may increase that rate to 6%. lesswell thepopulationworldwide; definedspectrum condi –3% of Key Point 4
: Bipolar : Bipolar Rates ofBipolarI Disorder inEpidemiological Studies : Men : Men 3 Although data are sparse, the less well defined bipolar and women are equally likely to develop bipolar todevelop likely and women are equally disorder is common, with types I and II affecting II affecting disorder iscommon, I and withtypes Althoughlesswell studied,bipolarIIdisor NCS = National Comorbidity Survey; NCS = NationalComorbidity 3 CNCG = Cross-National Collaborative 0.5-.5 .0 .7 0.9 Prevalence (%) 4 – 6 2
2,3 Similar - - -
years of multiple ineffective antidepressant multiple ineffective trials. Mania with psychosisyears (i.e., of recurrent majordepression andthen leading tofrequent misdiagnosesof on rates of bipolar disorder, on contrasts focus between white on ratesof withaprimary ethnic orracial designation examined theimpactof studies have number of countries and cultures. Within the Unitedacross States, a a wide range of bipolardisorder are approximately thesameAs noted previously, ratesof 3.3.3. Race/Ethnicity and progresses prior to the first manic episode. about how bipolar disorder presents inyoung patients, and how it evolves cohorteffects.Clearly, birth much remains tobelearned in theabsence of order in adolescents to be much less than adult rates, as would be predicted bipolardis ratesof lifetime tion ingeneral.Indeed,other found studieshave of the condi bipolar disorder isidentifiedand reflects anincreased awareness duringthepast reflect changesin century thattheseageeffects howlikely the controversygiven around diagnosis in younger people, it seems more producedhave Moreover, observe. amuch higherratethanwe currently there hasbeenasubstantialincrease witheach generation,since thatwould described andrecognized that ascommonmillennia,itseemsunlikely for However, cohorteffect. so-called birth thatbipolardisorder hasbeen given more prevalentover time;thatis, increasing rateswitheach generation,the whetherbipolardisorder isbecoming These findingsraisethequestionof inthe930s.lar disorder born across generationsbeginningwithindividuals bipo into0-year cohorts, increasedivided there wasaprogressive inratesof that in adults. In the ECA study, when respondents were of be less than half since, basedonthatmedian,theprevalence intheyounger agerangeshould to that in adults. was.4%,similar in5-to7-year-old individuals bipolarI disorder rate of lenges attempts to identify the specific prevalence rates. In the NCS study, the inthemannerwhich bipolardisorderUncertainty presents inyouth chal receive spectrumdiagnoses(e.g., Unspecified BipolarDisorder inDSM-5). may bemore chronic andcontinuous, sothatthey often ratherthanepisodic, bipolar disorder suggestthat,priortomid-to-lateadolescence, thecondition children atriskfor standard adultcriteria (e.g., DSM-5,ICD-0). Studiesof episodesthatmeet topresent withmanicorhypomanic these individuals uncommontroversial for it is relatively since, as mentioned in Chapter 2, correct. is actually theseconditions than alaterageatonsetof impression by many clinicians of bipolar illness often does not occur until the 20s, leading to a false nition of tion). Africandescent (discussed inthenextsec of individuals highfor particularly misdiagnosedasschizophrenia; isfrequently thisriskis bipolar I disorder) Diagnosing bipolar disorder in the early teensorinpreadolescentsDiagnosing bipolardisorder iscon intheearly recurring episodes. manic and depressive bipolarillness, thatis, course willexperience alife-long of individuals episodehasoccurred,adulthood. Once most amanicorhypomanic Key Point 7,8 Consequently, occurs inadolescence, althoughonsettypically recog : Bipolar 2 This finding is inconsistent with a median onset of 8 years, This finding is inconsistent with a median onset of disorder typically begins in mid-adolescence to early beginsinmid-adolescencedisorder toearly typically ------
19 Chapter 3 Epidemiology of Bipolar Disorder
20 Bipolar Disorder be diagnosedwithschizophrenia in thanotherwise similarwhiteindividuals African Americanswithmooddisorders are two toninetimesmore likely disorders. bipolarandother Inparticular, affective phrenia withlower ratesof schizo Europewestern appeared toreceive excessive clinical diagnosesof Africandescent intheUnited Statesand of that darker-skinnedindividuals in the NCS-R. uals; however, thisracial difference inbipolardisorder rateswasnot observed inAfricanAmerican comparedgeneral andmaniaspecifically towhiteindivid disorders in affective wasthattheNCSreportedlowerobservation ratesof bipolardisorder between thesetwo groups.Oneexception tothat rates of are controlled, racial not differences epidemiologicalstudieshave found in and AfricanAmericansubjects. Typically, differences once other demographic of the time with symptoms is spent in depression. Recovery from symptoms of Asdescribed inChapter 2, euthymia. thebulk age toachieve someperiodsof withbipolar disorderwithrecurrent struggle symptoms,individuals butman symptoms, whereas another 6%are ill;therefore, chronically two-thirds of recover essentially individuals minimal with relatively observed that 6% of episodes.depressive Inthe40-year Zurich outcome study, AngstandPreiseg bipolarillness; namely, and progress toalife-long recurrent hypomanic, manic, will individuals duration. Once afirstmanicepisodeoccurs, more than90%of withbipolardisorder;these studiesrangedfrom to40 yearsin individuals in symptomscognitive throughout their lives. and Consequently, withbipolardisorder withaffective struggle individuals episodes, there isnoknown episodes. thatprevents intervention allnew treatments decrease thefrequencyanddurationof Although anumberof which there illnessfor isnoknown alifelong cure.Bipolar disorder istypically 3.3.. MorbidityandDisability a diagnosis. ferences insymptom expression whenassigning amongmulticultural groups symptoms. Regardless, thisliterature reminds todif clinicians tobesensitive from describehow different ethnic backgrounds theirbehavioral individuals of distress,” that is, the difficulty maydifferences reflect cultural in“idioms of seems toimprove thisproblem, althoughdoesnot correct itentirely. Some structured interviews, example,through diagnosticcriteria, for theuseof of mooddisorders asschizophrenia. application More careful identification of phasize psychotic symptoms, symptoms leadingtomis andminimize affective clinicians overem studiessuggestthatintheseindividuals, in theUK.Several clinical settings. Similardiagnosticdifferences are inAfro-Caribbeans observed 3.3. Burden ofDisease A number of longer-term outcome studies examined the course of illness outcome longer-term studiesexaminedthecourse of A numberof In contrast observed toepidemiologicstudies,decadesinvestigators for being clinically misdiagnosed with schizophrenia.being clinically Key Point 7,8 : African : African 2,3 Americans withbipolardisorder are athighriskfor ------9
symptoms are episodes. after several typical illness, and subsyndromal inthecourse of early appears to bemost likely predict the behavior of groups, they to aspecific are often difficult toapply predict of the behavior suicide attempts. previous of suicide isahistory Thestrongestmany individuals. predictor of year in from depression tomaniaormixed statesoccurring atthat timeof spring, perhapsreflecting seasonal variationinmoodstate,withswitches suicide. Suicide may bemore inthe likely disordersety increase theriskof states, drugandalcohol abuse,inadequate treatment, andco-occurring anxi which menare moretocomplete likely suicide thanwomen). Mixed mood rates are similarbetween thesexes (incontrast tothegeneralpopulation,in attempt, withwomen moretodosothanmen,althoughcompletion likely willmake asuicide bipolar individuals of illness. Up tohalf of 5–0 years viduals withbipolardisorder commit suicide, withtheriskhighestinfirst counterparts in the general population. bipolar disorder diefrom medicalillnessesatyounger agesthantheir unaffected be cardiovascular risksinherent tobipolarillness. Consequently, with individuals and alcohol usedisorders) thatoccur in bipolardisorder, althoughthere may also 80% insomestudies),obesity, (e.g., lifestyles drug IIdiabetes, type andunhealthy (upto smoking highratesof reflectsgeneral population.Thisrisklikely the very the from cardiovascular diseasethatistwo tothree timeshigherthanthatof premature mortality In particular, withbipolardisorder ariskof have individuals medicalillnessescontributing tothisincreased risk(seeChapter 4). of a variety with bipolar disorder this increased also exhibit higher rates of risk,individuals of age.Althoughsuicide isamajorcomponent every general populationatvirtually premature deaththanthe withbipolardisorder higherratesof have Individuals andSuicide 3.3.2. Mortality often worldwide, among the top 0 most disabling conditions. medical disability the leading causeslar disorderof is recognized as one of worsen outcome.drug andalcohol Indeed,bipo usedisorders thatfurther other are medicalillnesses, oftencomplicated andtheirlives by co-occurring a wide range of with bipolar disorder from suffer higher rates of individuals to thosefrom other several studies. Moreover, asdiscussed inChapter 4, occurred after the first even manic episode, and these findings were similar orrelationships; employment, theseimpairments social function, of ous levels with struggled psychosocialindividuals unable to return to function, previ during the first followingyear an acute manic episode, more than 75% of Cincinnati outcome studies of many months.for TheUniversity persists functional impairment episode, resolve anacute following affective Preventing suicide remains difficult. Although risk factors may be useful to Preventing factors suicide remainsmay beuseful difficult. Althoughrisk bipolardisorder. indi Suicide isacommon consequence of Upto5% thepicture, as, assymptoms even Symptom of recoveryapart isonly resolved. from bipolardisordermonthsaftersymptoms have oftenpersistsfor Functional impairment worldwide. disability leading medicalcauses of Key Point : Bipolar : Bipolar disorder isarecurrent condition thatisamongthe 2 0 found that found - - - -
21 Chapter 3 Epidemiology of Bipolar Disorder
22 Bipolar Disorder References order is discussed in more detail in Chapter 8. withbipolardis suicidal individuals ataspecific time. individual Treatment of . 0. 9. 8. 7. 6. 5. 4. 3. 2. .
contributor to this increased risk. than theirpeers from the general population, and suicide isa major Key Point and RecurrentDepression. KR,eds., FK,Jamison In: Goodwin suicide risk. managementof KR.Chapter 25: Clinical FK,Jamison Goodwin 55:646–652. amanicormixed hospitalizationfor following episode. ML,HaggardBourne P. patientswithbipolardisorder 2-monthoutcome of Keck PE Jr., McElroy SL, Strakowski SM, West SA, SaxKW, JM, Hawkins Arch Neurol Psychiatr 995;46:5–23. from study 959to985.Schweiz aprospective of patients: results fective unipolar, bipolarandschizoaf aclinical cohortof Angst J,Preisig M.Courseof Arch Gen Psychiatry 202; 69:593–600. disorders.race onclinical andethnicity assessmentinpatientswithaffective patient Neighbors HW, LM,Strakowski SM.Influence WilsonDR,Arnold of Gara MA,Vega WB, WA, EscamillaM,Fleck DE,Lawson LesserI, S, Arndt psychoses. KB, Amicone anddiagnosisinpatientswithaffective J,Adebimpe VR.Ethnicity Strakowski SM,Keck PEJr., LM,CollinsJ,Wilson R,Fleck DE,Corey Arnold Psychiatry 20;68:24–25. lar spectrumdisorder Arch intheworld mentalhealthsurvey initiative. Gen Posada-Villa bipo J,Sagar R,Wells JE,Zarkov Z.Prevalence andcorrelates of KaramAndrade LH,HuC, EG,LadeaM,Medina-MoraME,Ono Y, Merikangas KR,JinR,HeJP, Kessler RC, SampsonNA,VianaMC, LeeS, Neuropsychopharm 2005; 5:425–434. bipolardisorder inEuropean countries.H-U. Euro Prevalence andburden of deQueirozPini S, V, Pagnin D, Pezawas L,AngstJ,CassanoGV, Wittchen major depression and bipolar disorder. of JAMA 996; 276:293–299. miology M, Wells E, Wickramaratne PJ, Wittchen H-U, Yeh E-K. Cross-national epide Joyce PR,Karam EG,LeeC-K,Lellouch J,LepineJ-P, Rubio-Stipec SC, Newman Weissman HwuH-G, GreenwaldS, MM,BlandRC, C, CaninoGJ,Faravelli 2007; 64(5): 543–552. order Survey replication. intheNationalComorbidity Arch GenPsychiatry. bipolarspectrumdis M, Kessler RC. and2-monthprevalence of Lifetime AngstJ,Greenberg RM,Petukhova HS, PE,Hirschfeld Merikangas KR,Akiskal Survey.Comorbidity Arch Gen Psychiatry 994; 5:8–9. psychiatric disorders in the United States. Results from the National DSM-III-R Wittchen HU, Kendler and2-monthprevalence of Lifetime KS. Kessler NelsonCB, RC, KA,ZhaoS, Hughes M, EshlemanS, McGonagle Epidemiologic CatchmentAreaStudy LN,Regier DA, eds. ders. In: Robins PJ, Florio LP,Weissman MM, Bruce disor ML, Leaf Affective Holzer C. : Individuals : Individuals J ClinPsychiatry with bipolar disorder have higher mortality rates with bipolardisorder highermortality have New York: Oxford Press, 2007. University 2003; 64:747–754. , pp. 53–80. New York: Free Press, 99. Manic-Depressive Illness: Bipolar Disorders Illness: Bipolar Manic-Depressive Psychiatric Disorders in America: The Psychiatric Disorders in America: The Am JPsychiatry 998; ------
conditions are listed in Table 4.. can confoundillness managementand,typically, worsen illness course. These relevantasthey higher thaninthegeneralpopulation andare particularly psychiatric conditions occur inbipolardisorder atratesmuch A numberof or risk factors. conditions rates that suggest common at elevated etiologies number of thegeneralpopulation.However,that affect exhibit a bipolarindividuals withbipolardisorder aretion. Individuals not protected from illnesses system (e.g., again, streptococcal meet the strict defini likely pharyngitis) at populationbaseratesandthatare unrelated tothecentral nervous illnesses difficult, althoughsecondary occurring comorbidity isrelatively accurate. Consequently, theterm. “co-occurrence” theterm is often moremisuse of Although thislattersituationisoftencalledcomorbidity, thatisa technically illness. withtheprimary population baseratesbecauseitshares riskfactors lar etiology. Inthis case, the second condition occurs ata rate higher than ease experiences a stroke, then these conditions vascu share anunderlying dis withcoronary artery anindividual base populationrate.Incontrast, if secondthewith any oneillnesswilldevelop unrelated illnessesatessentially unrelated,are so etiologically comorbid. Itisexpectedthataperson streptococcal diseasedevelops thenthesetwoartery pharyngitis, illnesses someonewithcoronary these conditions beindependent.For example,if medical conditions concurrently. defined, comorbidity requires Strictly that two ormore referstotheoccurrenceIn medicalparlance, of “comorbidity” Disorders Co-occurrence inBipolar Illness Comorbidityand Chapter 4 4.. WhatIsComorbidity? 4.2. Co-occurring Psychiatric Illnesses Because the specific etiology of bipolar disorder isunknown, defining of Because thespecific etiology co-occurring medical and psychiatric conditions. Key Point : The course of bipolardisordercomplicated iscommonly by of - - -
2323
24 Bipolar Disorder Hypothesis 4. Hypothesis 3. Hypothesis 2. Hypothesis . common co-occurrence. higher thaninthegeneralpopulation.We this for proposedhypotheses four Thisrateis three times peopleatsomepointintheirlife. tofour of up tohalf alcohol abuse,affecting withbipolardisorder exhibithighratesof Individuals 4.2.. AlcoholUseDisorders Disorder Table 4. 2 ADHD Personality disorders disordersAnxiety Drug use disorders Nicotine use disorders Alcohol use disorders Condition Higher in younger individuals withbipolardisorder Higherinyounger individuals HigherinbipolarI thanIIdisorder such a factor. Unfortunately data to identify these risk factors aresuch lacking. a factor. data to identify these risk factors Unfortunately episodesinbipolardisorder and relapsestive inalcohol abuse,so it could be and genetics. Stress, example,hasbeenassociated withprecipitating for affec environmentalfactors tributing totheriskaswell orperhapsaninteractionof con sothere isgenetic, may beenvironmentalfactors this shared riskfactor both conditions.studiesare inconclusivethat Family increase thelikelihood of For toward might decision-making example,agenetictendency impulsive suggeststhatalcohol use andbipolardisordershypothesis share riskfactors. might precipitate bipolar illness is not known. withanotherwiserisk.How lower alcohol abuse in theseindividuals familial order. Consequently, alcoholism may toinitiate bipolar illness be necessary bipolardis bipolar illnessbeginslater,of history lessfamily andwhohave ies suggestthatpremorbid alcoholism may whose bepresent inindividuals Moreover, maniainmany individuals. precedes theonsetof somestud lar disorder. Ageatonsetfindingssuggest thatalcohol abuse commonly in general, although, again, this association may occur in some individuals. not demonstrate strong temporallinks, thisassumption so do not support both conditions illness data for do insomnia or anxiety. Asnoted, course of toself-medicatesymptoms,attempt example, by for bipolar individuals some individuals. be true for incorrect isprobably ingeneral,althoughitmay suggesting thishypothesis close temporalassociationsymptoms, between alcohol useandaffective lead toincreased alcohol use.However, a donot support studiestypically
Psychiatric ConditionsCo-occurring withBipolar The symptoms of bipolar disorder (e.g., impulsivity of mania) bipolar disorder (e.g.,of impulsivity symptoms of The Some investigators proposed investigators thatalcohol abusecausesbipo Some Historically, clinicians assumedthatalcohol abusewasan Historically, Rather thanalcoholcausingbipolardisorder, directly Rather thefinal – 3 28–90% 38–48% 42–77% 2–4% 46–80% 38–48% Disorder Prevalence Bipolar Lifetime 2 5–0% 9–3% 5–25% 6–8% 2% 4–8% General Population Lifetime Prevalence - - - - -
sive co-occurrence of bipolarandalcohol usedisorders. Itappearsmostlikely co-occurrencesive of tion to all of them concurrently. tion to all of drug abuse,including cigarette oftenoccur smoking, togetherrequiring atten with suddencourse changes. drugabuse,particularly Alcoholmonitor for and suicide. Consequently, clinicians mustclosely cial recovery andhigherratesof bipolardisorder,course episodes, of withincreased poorpsychoso affective the reasons, worsens the drugabusesignificantly alcohol abuse. Regardless of drugabuse are unknown, butaresimilartothosefor likely increased ratesof abuse. Again, the for reasons drugs of of selective are differentially individuals cannabis beingmostcommon; there isnoconvincing thatbipolar evidence drugusewith abusedreflectof most commonly generalpopulationpatterns drugs of three thaninthegeneralpopulation.Thetypes tosixtimesgreater noted inTable 4., drugabuseinbipolardisorder is prevalence of thelifetime illicit andprescription drugusein bipolardisorder.is alsoanexcess of “legal” drugs (nicotine and alcohol), thereIn addition abuse to elevated of 4.2.3. OtherDrugUseDisorders bipolar disorder.management of address thisco-occurrence inthe cigarette toaggressively use,itisimperative of healtheffects the negative associations alcohol discussed for abuse.Given thehypothesized not occurs known, althoughitlikely from accumulation of atquitting.less successful Thereasonsthiscommon for co-occurrence are iscigarette usemoreonly common inbipolardisorder, are bipolarindividuals bipolardisorder. would belessened effects by thepresence of Moreover, not stroke, diseaseandthere andheart isnoreason tothink rette use is associated with increased and suicide anxiety in addition to cancer, bipolar disorder isnot well studied,althoughinthegeneralpopulationciga individuals. unfortunately, iscommon smoking inbipolardisorder, upto80%of affecting cigarette are smoking well known, and, healthconsequencesThe negative of 4.2.2. NicotineUseDisorders both conditions produces likely the best outcomes (Chapter 8). recent studiessuggestthat concurrent managementusingbestpractices for fied, both alcohol useandbipolardisorders mustbemanagedaggressively; whentreatment responseworsens.ticularly orcourse Once suddenly identi withbipolardisorder, alcohol abuseinindividuals par of evidence diligent for suicide, andoutcome. worse functional Consequently, cliniciansof must be with impaired treatment response, increased timeindepression, increased risk bipolarillness. Alcohol abuseisassociated worsens thecourseabuse clearly of bipolarandalcohol usedisorders, alcoholthe common co-occurrence of the specificand perhaps othersfor reasons not yet identified. Regardless of theseproposed associations that thisco-occurrence accumulates from allof At this point, then, none of these hypotheses singularly explainstheexces singularly thesehypotheses At thispoint,then,noneof to optimize illness outcome. each withbestpractices ditions shouldbe managedconcurrently for bipolarillness. Thesecon commonare andworsen very thecourse of Key Point 4 Despite being common, the impact of smoking on the course of onthecourse smoking of Despitebeingcommon, theimpactof : Co-occurring substance usedisorders, including smoking, a priori thatthese – - 3 As ------
25 Chapter 4 Illness Comorbidity and Co-occurrence
26 Bipolar Disorder but anxiety disorders typically require disorders additionaltreatment.but anxiety typically Moreover, treat symptoms, bipolarconditionanxiety willoftenalleviate theprimary ment of manage bipolarillness. Aggressive disordersanxiety worsens thecourse of panic disorder, andpost-traumatic stress disorder (PTSD).Thepresence of disorder (OCD), obsessive-compulsive report excessive co-occurrence of bipolar disorder beenreported.However, have mostconsistently, studies (Table 4.2). timesmorefour common inbipolardisorder thaninthegeneralpopulation anxiety Reflecting thishighrateof euthymia. relative als, across allmoodstates, duringperiodsof andeven illness in mostbipolar individu occursAnxiety throughout thecourse of 4.2.4. AnxietyDisorders been proposed for the high rates of ADHD in bipolar disorder.been proposed the high rates of for symptoms astheillnessesprogress. Consequently, have hypotheses several bipolardisorder, geneticrisksfor development, andvariableexpression of rates withagemay represent acomplex interplay between andbrain cognitive be duetoADHDsymptoms resolving over time.Alternatively, thisdecline in co-occurring ADHDmay and adolescents. Thedecrease withaginginratesof bipolarchildren adultswithbipolardisorder andupto80%of one-third of disorder (ADHD) affects hyperactivity Co-occurring attentiondeficit 4.2.5. Attention DeficitHyperactivityDisorder monitored after traumatic events. so should be carefully susceptible toPTSD,viduals withbipolardisorder appeartobeparticularly viduals were PTSD. todevelop amongthemostlikely note, the9/attacks particular following onNew York, bipolarindi Of ioral therapy) (seeChapter 8). may needtoberelied onmore extensively Consequently, therapies(e.g.,bipolar individuals. behav cognitive alternative managed withantidepressant medicationsthatare toleratedby not always ing theseconditions canbecomplicated, since disorders anxiety are typically Source: Adapted from Merikangaset al., 20. PTSD = post-traumatic stress disorder disorder;GAD = generalized anxiety WHO = World disorder; HealthOrganization;OCD = obsessive-compulsive Table 4.2 Social Phobia GAD PTSD OCD Panic disorder Condition ever possible. ever second conditions, withaneye treatment toward when integrated bipolardisorder, ment of butanxiety Key Point
3,5 : Anxiety WHO Rates ofAnxietyDisorders inBipolarDisorder Increased rates across the spectrum of anxiety disorders anxiety in Increased ratesacross thespectrumof
symptoms Bipolar I Disorder may resolve as part of thestandard treat may resolve of aspart symptoms 35% 27% 26% 8% 8% 5
disorders , anxiety , anxiety needtobemanagedas Bipolar IIDisorder disorders 6 Consequently, indi 36% 33% 25% 2% 7% 7 are three to ------risk, there are medical illnessesthatare several more common inbipolar managing bipolardisorder. of Inadditionto this generalincreasedtial part Attending toco-occurring medical illnesses, ingeneral,istherefore anessen premature duetotheseillnesses thanthegeneralpopulation. mortality medicalillnessesand withbipolardisorder higherratesof have Individuals bipolar disorder. therapy)behavioral togainimprovement, inadditiontotreating theprimary require psychotherapies andfocused long-term ders typically (e.g., dialectical suicide. Personality disor illness), and increases the risk of plicating course of com recovery, drugandalcohol abuse(further rates of increases theriskof disorder apersonality decreases treatment adherence, leadstolower ence of Thepres bipolarindividuals. of common andoccur inuptohalf particularly disorders personality andavoidant are obsessive-compulsive, histrionic, tic, co-occurring disorders. personality that controlled moodstateinbipolardisorder for stillreporthigh ratesof Recentacteristics thatpersistbeyond studies moodstatesintoeuthymia. aco-occurring disorder char personality demandsongoing behavioral of ornarcissistic disorders).histrionic, personality Consequently, adiagnosis DSM-5 cluster Bdisorders (e.g., borderline, those of orders, particularly personality dis instability fromand symptomscognitive the affective of bipolardisorder canbedifficult todistinguish symptoms of The dynamic 4.2.6. Personality Disorders in Chapter 8. cussed further symptoms are emergingintheseat-risk theseconsiderations kids; are dis mood a mood stabilizer if treatments ADHDor concurrent for prescribing of at-risk children. Consequently, alternative for consideration shouldbegiven mania. Indeed,stimulantexposure may precipitate moodsymptoms inthese depression and gence theemergence duringtreatment of for and follow-up bipolar disorder risk for suggests increasedADHD in a child with dili familial this co-occurrence over time.Regardless,leading todecreases in the rates of episodes, affective ADHD symptoms become components more of clearly lar illnessinchildren beforethey mania.Asillnessprogresses, develop these bipo anevolving expression of suggeststhatADHD isanearly best evidence 4.3. Co-occurring Medical Illnesses 3. 2. . Research supports these hypotheses tosomeextent,althoughperhapsthe Research thesehypotheses supports der are dependent in part on the developmental stage of theindividual. stage of der areonthedevelopmental dependentinpart Key Point
lead to overdiagnosis of ADHD in bipolar individuals, particularly in ADHD in particularly bipolar individuals, lead to overdiagnosis of Symptoms common toboth conditions (e.g., inattention,impulsivity) ADHD is a prodromal expression of bipolar disorder.ADHD is a prodromal expression of ADHD and bipolar disorder share risk factors; or children; : Clinical : implications of co-occurring ADHDinbipolardisor implications of 8 Elevated rates of borderline, narcissis ratesof Elevated ------9
27 Chapter 4 Illness Comorbidity and Co-occurrence
28 Bipolar Disorder These are listed in Table 4.3 and discussed subsequently. disorder thanwould beexpectedfrom generalpopulationprevalence rates. risk factor for other medicalconditions for IIdiabetesmellitusand including type risk factor etal demographics. generalsoci in AmericanthanEuropean samples, emphasizingtheimpactof inbipolardisorder obesity are higher inherent intheillness. Notably, ratesof obesity associated episodes, withdepressive suggestingariskof is typically in treatment-naïve Inthislattergroup, bipolarindividuals. increased weight overweight isacontributing are even factor, observed tainly highratesof Although oftenattributedtopsychotropic medicationexposure, which cer andoverweightbe atincreased obesity riskfor beginningatayounger age. may well itappearsthatbipolarindividuals asageandother demographics, reportsas weight generalpopulation.Nonetheless,datesof adjusting for interpretation, however, an over is a background in the United States of withbipolardisorder. individuals Complicating reported inmultiplestudiesof II diabetes mellitus. and type sity common variable).Particularly are(although reportedratesare obe widely order, which is approximately increase a two-fold over the general population with bipolar dis individuals The metabolic syndrome is present in 30–50% of are disease,stroke, listedinBox heart anddiabetes;theseriskfactors 4.. of thatincrease thelikelihood riskfactors The metabolicsyndrome of isagroup 4.3.. MetabolicDisorders/Diabetes/Overweight Table 4.3 Elevated • Hypertension • Low • Elevated • Increased • Least Three oftheFollowing Box 4. Migraine Cardiovascular disease II) Diabetes (type Obesity Condition Widely variabledependingonsampledemographics Widely Symptoms-and -Diagnosis-of-Metabolic-Syndrome_UCM_ 30925_Article.jsp Source: Obesity is problematic for bipolar individuals as it represents is problematic bipolar individuals Obesity a significant for High HDL rates http://www.heart.org/HEARTORG/Conditions/ More/MetabolicSyndrome/ American Heart AssociationMetabolicSyndrome—At American Heart
serum serum abdominal Common Medical ConditionsinBipolarDisorder < of 40 mg/dL in men or 50 mg/dL in women
overweight > 30 mm Hgsystolic or85 mm Hgdiastolic bloodpressure glucose triglycerides girth > 00 mg/dL (BMI > 02 cm in men or 88 cm in women > 0, 25–40% –50% 8–7% 2–35% Bipolar Disorder 50 mg/dL > 25) and obesity 7–6% 7–20% 6–8% 20–36% General Population (BMI > 30) have been - - - - -
mon in bipolar disorder than the general population, despite high rates of mon inbipolardisorder thanthegeneralpopulation,despitehighratesof the metabolicsyndrome. Type IIdiabetesisuptothree timesmore com mal serotonergic neurotransmission processes. or inflammatory this co-occurrence isunknown, althoughit may berelated toabnor cause of seeaneurologist never or other headache specialist.migraine The specific withbipolardisorder oftennot addressed; and many individuals unfortunately bipolarillnessandis worsens thecoursewith themenstrualcycle. of Migraine general population.Inwomen, may both vary moodsymptoms andmigraine women, which is three tosixtimesmore common thaninthe two-thirds of andas many as migraines, develop bipolarindividuals of Table 4.3, half nearly Asnoted in migraine. from bipolardisorder alsoexperience highratesof not suffering centuries, thatindividuals decades, for if It hasbeenobserved 4.3.3. Migraine cardiovascular events. health strategies (e.g.,preventative weight loss, to prevent stopping smoking) the risks, clinicians areindeveloping encouraged toassistbipolarindividuals regulation processes or inflammatory associated with bipolar illness. Given cardiovascular disease,perhapsrelateddys tohormonal increased riskof withbipolardisorder may aninherent individuals have multiple riskfactors, Additionally, aftercontrolling somestudiessuggestedthateven these for bipolardisorder may addadditionalcardiac effects. used inthetreatment of suddendeath,andother medicationscommonly also addanadditionalriskof II diabetes,anddrugalcohol antipsychotics smoking, abuse.Conventional obesity, cardiovascular type for diseasethatinclude highratesof risk factors inthischapter,previously withbipolardisorder anumberof have individuals two tothree timeshigherthaninthegeneralpopulation(Table 4.3). Asnoted is theseillnessesinbipolarindividuals therateof Consistent withthisstatistic, die prematurelyfromdiseasecompared heart withthegeneralpopulation. are(the othertwo issuicide); tothree bipolarindividuals timesmoreto likely in bipolardisorder thatare increased compared withthegeneral population premature death thetwo majorcausesof Cardiovascular diseaseisoneof 4.3.2. Cardiovascular Disease II diabetes.to type overweight processes plustheinteractionwithdevelopmental leading tion of samples may beshiftedtoyounger agegroups,thereby increasing thedura those responsibleglucosemanagement.Asnoted, weight for gaininbipolar multiplesystems thatinclude may dysregulation of involve generalhormonal lar disorder, antipsychotics. atypical especially Additionally, bipolardisorder diabetes hasbeenassociated medicationsusedtotreat withseveral bipo IIdiabetes. type Specifically,type II may contributerateof totheelevated inboth groups.Consequently,obesity inthebipolarpopulation other factors ture death in these individuals. prema cardiovascular as it is a leading cause of disease is warranted problematic inbipolardisorder.particularly Specific attentiontoward Key Point : Medical : Medical conditions related tothemetabolicsyndrome are ------9
29 Chapter 4 Illness Comorbidity and Co-occurrence
30 Bipolar Disorder detail in Chapter 8. minimize excessive medicationprescribing. Treatment isdiscussed inmore bothto usebestpractices conditions for whenthey co-occur to whiletrying and theseco-occurring illnesses;therefore, therecommended approach is treatments beenidentifiedthatimprovesingle have both bipolar symptoms somepsychiatric andmedicalconditions. Tomay increase theriskof date,no other illnessescommon inthegeneralpopulation.Moreover, bipolardisorder bipolardisorder doesnotfrom protect individuals As noted, thepresence of References 9. 8. 7. 6. 5. 4. 3. 2. . Co-occurring Conditions 4.4. General Principles for Managing
practices for eachpractices condition. for best clinical requires of concurrent administration and integration Key Point 2009; 60:47–56. review. Psychiatrcal illnesses among persons withbipolardisorder: a Serv Roshanaei-Moghaddam B, Katon W. Premature from generalmedi mortality disorders.personality J Clin Psychiatry 2000; 6:34–39. Strakowski SM.Twelve-month outcome inbipolarpatientswithandwithout Dunayevich E,SaxKW, Keck PEJr., McElroy MT, SL,Sorter BJ, McConville 2006; 8:70–720. disorders in children. BipolarDisordhyperactivity lar andattention-deficit Singh MK,DelBelloMP, Kowatch bipo RA,Strakowski SM.Co-occurrence of disorder. J Clin Psychiatry 2006; 67:394–399. posttraumatic stress disorder September following inpatientswithbipolar Perlman Sachs GS, Miyahara S, GhaemiSN,ThaseME,OttoMW. C, Persistent Pollack RJ, Nierenberg MH, Simon NM, Fagiolini A, Pitman R, AA, McNally Psychiatry 20; 68:24–25. lar spectrumdisorder intheWorld Arch MentalHealthSurvey Initiative. Gen Posada-Villa bipo J,Sagar R,Wells JE,Zarkov Z.Prevalence andcorrelates of DaramEG,LadeaM,Medina-MoraME,OnoY,Andrade LH,HuC, Merikangas KR,JinR,HeJ-P, Kessler RC, SampsonNA,VianaMC, LeeS, and treatment considerations. Bipolar Disord 20; 3:439–453. cigarette andbipolardisorder: phenomenology smoking co-occurrence of JR,DelBelloMP,Heffner JL,Strawn Strakowski SM,AnthenelliRM.The Survey.Comorbidity Arch Gen Psychiatry 994; 5:8–9. psychiatric disorders in the United States. Results from the National DSM-III-R Wittchen HU, Kendler and2-monthprevalence of Lifetime KS. Kessler NelsonCB, RC, KA,ZhaoS, Hughes M, EshlemanS, McGonagle 264:25–258. Results from theEpidemiologicCatchment Area (ECA)Study. JAMA990; mentaldisorders withalcohol andother drugabuse. of FK. Comorbidity Locke DS, Regier BZ,Keith DA, ME,Rae Farmer SJ,JuddLL,Goodwin disorders. 2000; 20:9–206. Rev Clin Psychology Strakowski SM, DelBello MP. bipolar and substance use The co-occurrence of : Managing co-occurring illnesses in bipolar disorder typically co-occurring illnessesinbipolardisorder typically - - - 0. . disorder and type 2 diabetes: more thanjustcomorbid disorders.disorder 2diabetes: more AnnMed andtype CV,Calkin T, Gardner DM, Ransom Alda M. The relationship between bipolar Psychiatry 203; 70:265–274. prevalence ratesandmoderators. AmJ of bipolar disorder: A meta-analysis P, ProbstM.Metabolicsyndrome in M,DeHert andmetabolicabnormalities Vancampfort D, Vansteelandt K,CorrellCU, Mitchell AJ,DeHerdt A,Sienaert 203; 45:7–8.
31 Chapter 4 Illness Comorbidity and Co-occurrence
modulate human emotional function, originatingintheventromedialmodulate human emotional and function, iors thatcharacterize human interactions. Two prefrontal networks specifically opment thatunderlies themore subtleandcomplex emotional-social behav amygdala and ventral striatum, respectively. bythe driven behaviors andreward-seekingbehaviors; “fight/flight” primitive of increases,ity more animalspecies nuanced demonstrateincreasingly variations as prefrontal anatomy comparative perspective, cortical complexevolutionary andother from processed throughoutsensory information thebrain.From an thesenetworks receive and5.2).Thevariouscomponentscuits (Figures 5. of cir and feedforward feedback the originating prefrontal iterative cortex to form thestriatumthenthalamuspallidumbeforeconnecting back to regions of mon architecture. Namely, each prefrontal area maps to specific corresponding regions. Despite this complexity, each prefrontal region demonstrates a com heterogeneous structure distinct functional comprising multiple histologically and5.2). cortex (seeFigures 5. iors, emotional states are modulated by networks originating in the prefrontal result frominmoodregulation. abnormalities Like mostcomplex human behav clinical considerations, bipolardisorder appears to of review Based onthisbrief symptoms. behavioral diverse conditionlife-long of beginning inadolescence thatprogressesover timetobecome arecurrent, brainsystems moodandcognitive of dysfunction must describe adynamic bipolardisorder cal considerations modelsof suggestthatneurophysiological episodes. These frequentclini affective periodswithincreasingly euthymic of begins duringadolescence shortening andthenexhibitsprogressive symptoms.and other behavioral Moreover, bipolardisorder commonly recurrent depression neurovegetative, withitsadditionalmood,cognitive, alsoexperience behaviors.Mostbipolarindividuals and signs, andimpulsive extreme moodstates, impaired cognition, neurovegetative symptomsof are depression. syndromes Both maniaandhypomania least oneepisodeof mania,whereas bipolarIIdisorder plusat ischaracterized by hypomania of isdefined by theoccurrence bipolarI disorder As discussed inChapter 2, Disorder Neurophysiology ofBipolar Chapter 5 5.. ClinicalConsiderations 5.2. Emotional BrainNetworks andBipolarDisorder 5.2. Humans are distinguishedfrom other animalsby extreme prefrontal devel The prefrontal cortex is a relatively complex, complex, Theprefrontal cortexisarelatively ------
3333
34 Bipolar Disorder to threats. Inhumans, ventral prefrontal networks nuance thisresponse to behavioralresponses As noted, theamygdala isresponsible “fightorflight” for 5.3.. Amygdala bipolar disorder. neuroanatomy of the functional thismodelprovidescorresponding impairments; cognitive for aframework emotional systems produces occurs. of Consequently, dysfunction primary networksdorsal moreover, (cognitive) are deactivated; theconverse also Consequently, whenventral (emotional) prefrontal systems are activated, connected toemotional (ventral) networks withintheanterior cingulate. networks originateindorsalprefrontalCognitive areas, butare reciprocally each other throughinform connections atvariouspointsalongthese circuits. expressions interpreting in others. example, correctly facial for “feels.” Theventrolateral prefrontal emotional network cues, managesexternal referencednetwork processes emotional states, internally thatis, how aperson organizationasillustratedinFigure 5.2. Theventromedial prefrontal of patterns ventrolateral prefrontal cortices, respectively, thesesamegeneral andfollow Figure 5. in EmotionalNetworks from5.3. BipolarDisorder Abnormalities Results prefrontal cortex Dorsolateral Although prefrontal independent,they networks influence are and largely cingulate Anterior works likely underlies the symptoms of bipolar disorder. worksunderlies the symptoms likely of networks.dorsal (cognitive) Together, within thesenet dysfunction networksfrontal thatare corticaliterative reciprocally connected to Key Point cortex (ventral) prefrontal Orbitofrontal
Schematic of key areas involved in the expression of bipolar disorder. key areas involved in the expression of Schematic of : Human : Human Amygdala emotional behavior ismanagedbyemotional two behavior ventral pre Nucleus Accumbens Globus pallidus Thalamus Striatum - - networks underlying human emotional brain networksnetworks (adapted underlying from Strakowski Figure 5.2 Amygdala overactivation has also been observed in healthy relatives of Amygdala overactivation relatives has of also been observed in healthy adolescents reportamygdala affect. inresponse overactivation tofacial lies. Perhaps most commonly, multiple studies across manic adults and reflects anatomic anoma thatlikely thesedevelopmental dysfunction Chapter 2). illness (see inthecourse of early clinically episode frequencythatisobserved appeartocorrespond withtheprogressionof dala structure andfunction other medicationexposure, however. Regardless, changes inamyg dynamic structure inadults. Thissubsequentenlargementmay bedueto lithium or the underdevelopment in adolescence, there is a subsequent overgrowth of intheformer.ment isobserved suggeststhatafteramygdala Thisobservation adults, althoughperhapsmostcommonly,lar andhealthy amygdala enlarge differences inamygdala between beenobserved bipo volumes have range of youth andteenswithADHD(Figure 5.4). both healthy appeared toexperience amygdalaand, infact volume losscompared with amygdala growth, toexhibithealthy manic episode,bipolaradolescents failed (Figure 5.3). in youth with bipolar disorder is decreased compared teens with healthy in bipolar disorder. central role inemotional behavior, theamygdala studied hasbeenfrequently inbipolardisorder.species gone andthathave awry Consequently, its given humanemotional statesthatcharacterize our contribute tothewiderangeof External EmotionalControl Neuroimaging studies also consistently observe evidence of amygdala of evidence Neuroimaging observe studiesalsoconsistently the more replicable findings in psychiatry is that amygdalaOne of size Ventromedial Ventrolateral (BA 0,47) G. Pallidus Thalamus striatum
PFC Schematic of the proposed ventrolateral and ventromedial prefrontalSchematic of 2 Moreover, we demonstratedthatduringthefirst year after a Cognition (DorsalPFC) Anterior cingulate temporal cortex (BA 24,32) (BA 38,20) Anterior Amygdala Subgenual cingulate (BA 25) Rostral insula Internal EmotionalControl 3 Incontrast, awide Ventromedial Accumbens PFC/OFC G. Pallidus Thalamus Nucleus (BA ) ). - - - -
35 Chapter 5 Neurophysiology of Bipolar Disorder 36 Bipolar Disorder meta-analysis (Pfeiffer et al. (Pfeiffer meta-analysis Figure 5.3 compared teens and teens with ADHD (Bitter et al. with healthy Figure 5.4 reported. are amygdala commonly function and depression,of similarabnormalities of cues. cognitive Duringeuthymia types tovarying and flexibility ficity amygdala response healthy speci suggestingalossof vation isobserved, tasks, cognitive amygdala underacti structural changes. of Inother types may abnormalities precede suggestingthatfunctional bipolar individuals, (a)
Volume (cm3) emotional extremes. modulation of healthy in a loss of in andflexibility response to cues, cognitive function reflected clinically Key Point –2.5 2. 3. 3. 4. 5 0 5 0 CHILD STUDIES ADULT STUDIES p =0.0
Left Amygdal Studies of amygdala volumes in adolescents and adults—results of a amygdala volumes in adolescents and adults—results of Studies of Trajectory of amygdala in adolescents development with bipolar disorder Trajectory of : Bipolar –2.0 Baselin Health ADHD Bipola Standar r e – .5 y aR disorder is characterized by loss of healthy amygdala healthy disorder ischaracterized by loss of Time dized MeanDi 2 – .0 ). –0.5 2 months ** e re 0.0 nc e of 3. 3. 3. 4. (b) 0 4 8 2 0.5 Amy ight Amygdala Baselin gdalar Health ADHD Bipola .0 ADUL CHILD POOLEDESTIMAT e Vo r y lumes T POOLEDESTIMAT .5 Time 3 Chang, 2005 Blumberg, 2005 DelBello Frazie Brambrilla, 2003 Chen, 2004 R Ve Blumberg, 2003 Altshuler, Strako ). osso lak oulis 2.0 r, , 2007 wski 2005 , 2004 2000 , 2008 , 999 2 month 2.5 E E s - -
5.3.2. Ventral Prefrontal Cortex putamen andcaudatethatmaptoventral prefrontal regions thatcomprise the the The ventral striatumincludes thenucleus accumbens of andventral portions 5.3.3. Ventral Striatum disconnections occur during depression. reverses Similar, withrecovery (Figure 5.6). butmore complex, functional is decreased between amygdala andlateralventral prefrontal cortexthat tex andamygdala inbipolardisorder. connectivity Duringmania,functional connections between ventral in functional prefrontalabnormalities cor bipolar disorder. at risk for in individuals appears to go awry significant changes in prefrontal functionstructure cortical that period of and sodes andduringthelateteensyoung adulthood.Indeed,adolescence isa prefrontal volume appearstooccur epi Finally, withrecurrent affective lossof abnormalities, prefrontal inbipolardisorder over abnormalities develop time. suggest that,like Theseobservations amygdala observed. vation iscommonly findings inadults, inadolescents withbipolardisorder increased prefrontal acti to stress may orother thenleadtomoodepisodes. factors, Incontrast tothese thiscompensation,pensated by inresponse increased prefrontal control. Lossof amygdala illness, may overactivation underlying becom this remitted phaseof amygdala (Figure 5.5). overactivation presence of (remission), increased ventral inthe prefrontalhasbeenobserved activation tasks. Incontrast, duringeuthymia depression,degree across of awidevariety prefrontal corticalregions hasbeenreportedduringmania,andtoalesser Not surprisingly, inboth then,decreasedlateralandmedialventral activation As noted, humanemotion ismanagedby ventral prefrontal corticalnetworks. with permission fromwith permission Nature Publishing Group). in bipolar disorder colors (Strakowski are activation et al. greater (gray) in bipolar disorder; lighter cortex labeled with “2.” Dark colors indicate less activation bipolar disorder.tion in euthymic Amygdala labeled with “,” ventrolateral prefrontal Figure 5.5 Supporting theseconsiderations,Supporting neuroimagingreport studiescommonly structures. theamygdala andother limbicbrain ventral prefrontal modulationof Key Point
Ventrolateral in response to increased amygdala hyperactivation activa : Mood : Mood episodes in bipolar disorder appear to reflect loss of episodes inbipolardisorder appeartoreflect lossof 1 4 This finding suggests that in Thisfindingsuggeststhatin 2 4 Reprinted 2 - - - - -
37 Chapter 5 Neurophysiology of Bipolar Disorder
38 Bipolar Disorder white mattertracts. Usingthesemethods, white matter studies observed Recent inMRI(e.g., tensorimaging)provide advances diffusion measures of Connections 5.3.4. White Matter Findings: Abnormalities in bipolarillness. developing structures for mayrepresent consequently ariskfactor integrative these important der, of duringmania.Disruption infunction especially and amygdala. Additionally, occurs excessive inbipolardisor striatalactivation predatestriatal abnormalities illness onset, priortochanges inprefrontal cortex bipolarprobands. These findingssuggest andunaffected co-twins of individuals infirst-episodebipolar comparedsubjectsisobserved bipolar withhealthy may tomedication exposure, besecondary striatalandpallidalenlargementin tum arereportedinbipolardisorder.these changes commonly Althoughsomeof thesenetworks, inthestria abnormalities works. Aswithother components of well asother brainareas, thereby role inemotion providing net anintegrative pallidus.globus Thesebrainregions inputfrom receive theamygdala extensive as linked tothesestructures discussed. Closely isthe emotional networks previously Strakowski SM, unpublished data). right amygdala (labeled “”) (Cerullo M, Fleck DE, Eliassen J, Adler CM, DelBello MP, in prefrontalcolors connectivity indicate increasing cortex (labeled “2”) with functional gray during mania and after recovery Increasing brightness and extent of (euthymia). Figure 5.6 Euthymia Mania
Changes in connectivity between right amygdalaChanges in connectivity and prefrontal cortex 22 11 1 1 - - -
der, connections amongtheprefrontal cortex,striatum consistent withlossof inventral prefrontalabnormalities regions andperiventricular inbipolardisor mood episodes), a decrease in total energy production and substrate availability productionmood episodes),a decrease andsubstrate availability intotal energy lar brain;thisshift isreflected inincreased (during glutamate levels lactate and inthebipo shiftstoward phosphorylation) anaerobic processestive (glycolysis) Specifically, theneuron’stypical reliance onaerobic processes (namely, oxida in bipolar disorder converge to suggest that mitochondrial is impaired. function subjects (Table 5.).between bipolar and healthy these molecules exhibit differences in concentrations ters (PME). Most of membrane metabolites, example, phosphomonoes for and high-energy lular energetics, such asadenosinetriphosphate(ATP), creatine phosphate, phosphorusandmeasures molecules relevanttocel the concentration of isbasedon MRSmethod,P3-MRS, Analternate glutamate. predominantly althoughinprefrontal GABA, andglutamine, includes glutamate, cortex,itis (NAA), choline, creatine, n-acetyl-aspartate neurochemicals studiedinbipolardisorder include: hydrogen concentrations invariousmolecules. Usingthistechnique (H-MRS) bipolardisorder. usedMRStechnique measures of Themostwidely the study the brain molecular substrateof Magnetic resonance spectroscopy (MRS)provides the studying techniques for bipolar illness.defines a lifelong moodepisodesthat followed recurrence by aprogressive or hypomania of duringadolescence, andasthey evolvedevelopmentally they leadtomania malities inthesesamebrainareas. appeartooccur Theseabnormalities isreflected instructuralabnor function modulate emotion. Thisabnormal humanbrainnetworks that components of responses cues tocognitive of and other isreflected emotional brainregions. inabnormal Thisdysfunction amygdala prefrontal modulationof bipolardisorder arisefrom alossof of When considered together, neuroimaging studiessuggestthatthesymptoms Summary 5.3.5. Functional Neuroanatomy ofBipolarDisorder: illness. to the first manic episode and a bipolar gresses course of prefrontal networks andtheamygdala, thereby settingasubstratethat pro connections developmental may amongventral abnormalities disrupt healthy predatethese abnormalities illness onset. These premorbid white matter bipolar disorder (i.e., aparent thathave withbipolardisorder) suggestthat whitematterinsubjectsatriskfor noted earlier.abnormalities Studiesof and amygdala;functional connectivity thesefindingsare likely related tothe 5.4. BrainMetabolismandBipolarDisorder In their extensive review,In theirextensive Stork and Renshaw networks that modulate human emotional behaviors. withinprefrontal and structuralabnormalities corticalbrain functional Key Point : Bipolar : Bipolar disorder illnesscharacterized isadevelopmental by myo -inositol, andGlx.Glxisamixed measure that in vivo inhumans and so has been applied to 6 concluded that MRS findings 5 ------
39 Chapter 5 Neurophysiology of Bipolar Disorder
40 Bipolar Disorder distributed widely throughout the networksdistributed widely illustrated in Figures 5.2 and 5.7. Althoughmonoamines originateincircumscribedfunction. brain nuclei, they are thatinclude changes inbrainserotonin effects andnorepinephrine has amyriad of block dopamineneurotransmission antimanicagents. Lithium andare effective Additionally, with bipolar disorderindividuals (see Chapter 7). antipsychotics aswitch into mania whenusedin Antidepressants may alsoincrease theriskof serotonin or norepinephrine (or both) in the synapse. increase of the availability lithiumandantipsychotics.a lesserdegree, Specifically, mostantidepressants antidepressants and,to arose fromeses largely theneurochemical of effects disorders. Thesehypoth dopamine, andnorepinephrine, caused affective monoamine neurotransmitters, namely, serotonin (5-hydroxytryptomine; 5-HT), For decades, of investigators that hypothesized in abnormalities the function Dopamine 5.5.. Monoamines: Serotonin, and Norepinephrine, This model is illustrated observed. in Figure 5.7. abnormalities and functional prefrontal cortical volumes, thereby unitingthestructural,chemical, or lossesof white mattertracts tensor imagingmeasures of in diffusion example, abnormalities ordeath,contributing andwhitematter, tostructuralchanges ingray nal injury for order, asdiscussed previously. Additionally, excessive may glutamate causeneuro inemotional brainnetworks inbipolardis reflecthyperactivation simply regional drial genes all come from a person’s mother). Moreover, these shifts may some of transmitted(N.B., mitochon bipolardisorder ismaternally that, insomefamilies, and decreased PME).Thespecific lesionisunclear, althoughgeneticstudiessuggest (decreased PCr and NAA), and altered Cho phospholipid metabolism (elevated Up arrow isincreased; down arrow isdecreased. (Adapted from Kimet al. PME PCr mI Cho Cr Glx NAA Metabolite Healthy Subjects Metabolite ConcentrationsinDifferent MoodStates with Table 5. Disorder 5.5. Neurotransmitter HypothesesofBipolar function. consistent inbrainenergeticsandmitochondrial withabnormalities Key Point
: Bipolar : Bipolar Summary ofFindings inBipolarDisorderSummary Comparing disorder ischaracterized by neurochemical findings Mania ↑ ↓ ↑ ↑ ↓ ↑ Depression ↑ ↓ ↑ ↑ ↑ ↑ 5 ) Euthymia ↓ ↓ ↓↑ ↓ ↓ ↑ ↑ ↑ ↑ ,7 - - - - mine transporter (DAT)mine transporter (COMT) transferase genes, andcatechol-O-methyl ciations between bipolardisorder andD2-D3-receptor alleles, dopa function, including asso dopaminemetabolism and findings in components of antipsychotic following administration. Moreover,tivity genestudies reported dopaminereceptor supersensi that lithiummay prevent of thedevelopment receptors, ratherthanexcessive dopamine maniamay D2-dopamine for berelatedsuggest thatliability tosupersensitive disorder hasbeeninconsistent. to This inconsistencyledsomeinvestigators increased dopamineconcentrations inbipolar subjects, of sothatevidence produce manic-like syndromes. Braindopamineisdifficult toassay inhuman Correspondingly, dopamineagonists such asamphetamineorL-dopa may antimanictreatments. effective (i.e., antipsychotics) universally are nearly byevidenced theconsistent findingthatD2-receptor dopamineagonists ied, despiteexcess dopaminergicneurotransmission occurring inmania,as understud inbipolardisorder beenrelatively Dopamine abnormalities have 5.5... Dopamine using diffusion tensor using diffusion dashed arrows = potential identified in bipolar disorder abnormalities connectivity black boxes = regional that may structural abnormalities predate illness onset; that appear to occurabnormalities after illness onset (i.e., first manic episode); gray boxes = regional subjects; differences between bipolar and healthy structural follows: dashed the figurefunctional imaging are from as structural and Other characteristics of phosphocreatine (PCr) areand phospholipid (PME) levels also decreased. bipolarparents. Finally,prior to illness onset, in at-risk prefrontal offspring of increasedin basal ganglia; mI (dotted arrow) in orbitofrontal is observed cortex myo- in mania and (Glu) depressionobserved throughout these networks. Increased neuroimaging. Neurochemical are abnormalities noted with increased glutamate disorder using magnetic resonance spectroscopy and structural and functional Figure 5.7 Glu inositol (mI) and choline across(Cho) are observed commonly mood states External EmotionalControl
Ventromedial Ventrolateral Abnormalities identified within emotional networksAbnormalities in bipolar G. Pallidus PME PCr Prefrontal striatum Thalamus border = brain consistent functional regions exhibiting relatively Cognition (DorsalPFC) imaging (adapted from Strakowski Anterior cingulate temporal cortex (BA 38,20) mI Cho (BA 24,32) Anterior Glu Amygdala Subgenual cingulate per se Rostral (BA 25) insula Glu ; several studies suggested ; several ). Internal EmotionalControl mI Cho Accumbens Ventromedial G. Pallidus Thalamus Prefrontal Nucleus PME PCr mI Glu - - - -
41 Chapter 5 Neurophysiology of Bipolar Disorder
42 Bipolar Disorder increased noradrenergic neurotransmission and turnover may occur during suggestingthat todepressionmetabolites inmaniarelative andeuthymia, bipolar. Additionally, increases relative somestudiesfound innorepinephrine whetheritisunipolaror transmission inmajordepression, independentof decreased noradrenergic neuro establishedtheoccurrence largely of have However, many antidepressants impactnoradrenergic systems, andstudies inhumans. study isdifficult todirectly Like dopamine,norepinephrine itself 5.5..2. Norepinephrine treatment. withthetiminganddurationof regions, seemstovary althoughthiseffect withinsomebrain rine metabolism.Lithiummay alterdopaminergicactivity variants. COMT plays role animportant inboth dopamineandnorepineph mits” the release of dopaminergicandnoradrenergic modulationleadingto mits” therelease of other environmental andneuralevents, thislow “per serotonergic function the dopaminergic andnoradrenergic systems. Consequently, dependingon both lesionproducing lowmary serotonergic toneresults indysregulation of hypothesis.” the “serotonin permissive with changes duringmaniaintheother observed two monoaminesledto low serotonin inmooddisorders levels ingeneral coupled The findingsof inboth noradrenergic anddopaminergicpathways.tion islinked toactivity to lead to clinical improvement.stabilizes monoamine function interpretedtosuggestthatlithium and dopamine.Investigators theseeffects lithiumtreatment, similartonorepinephrine and thedurationtimingof dependonthebrain theseeffects regionbeingstudied serotonergic activity; per se mood disturbances, rather than a direct relationship with bipolar disorder be reduced in both mania and depression, suggesting nonspecific changes with been difficult to replicate. However,levels in 5-HIAA cerebrospinal fluid may serotonin genesinbipolardisorder, transporter althoughthesefindingshave in abnormalities geneticstudiesobserved eral. More recently, anumberof inconsistently,instead, andsomewhat are associated withdepression ingen 5-HT serotonin receptors inmooddisordersincreased (mainly concentrations of serotonin); and isaprecursor depression (tryptophan of with historiesof depletioninindividuals depression withtryptophan viduals; precipitation of suicidal indi 5-hydroxyindoleacetic acid; 5-HIAA)inthecerebrospinal fluidof lar depression. Findingsinclude reduced serotonin metabolites(namely, disorders generally,tive insubjectswithunipo althoughpredominantly affec Serotonergic instudies of been observed have abnormalities 5.5..3. Serotonin Serotonin and the Permissive Hypothesis treatment. brain regions and with the timing and duration of across that,like dopamine,appearstovary tions withnoradrenergic activity lithiumandother moodstabilizers suggestcomplex associa ants. Studiesof with COMT (noted intheprevioussection)andtyrosine hydroxylase vari noradrenergic neurotransmission ormetabolismincluding links aspects of mania. Genestudiesreportedassociations between bipolardisorder and The actions of monoaminesare not independent.Serotonergic func The actionsof 2 . Consistentwiththissuggestion,lithiumboth increases anddecreases ). However, forbipolardisorder, nospecificity thesefindingshave but 7 7 This hypothesis statesthatapri Thishypothesis 7 ------
This hypothesis hasnot withstoodtestingnortime,however, This hypothesis andmany of increasesabnormal thatproduce maniaanddecreases thatcausedepression. tors might underlie bipolar disorder. Several small studies found evidence of tors mightunderlie bipolardisorder. of evidence smallstudiesfound Several the day, or winter. mania in the spring and depression in the fall namely consistent of strate aseasonalpattern withthelengtheningandshortening during bipolar than unipolar depression. Bipolar disorder may also demon Moreover, increased sleep, need for may be more or hypersomnia, common bipolar disorder. atreatmentfor program protecting of sleepisacritical part episodesinbipolardisorder.that triggersaffective Asdiscussed inChapter 7, it isthesleepdisturbance resulting from stress, ratherthan stress directly, that hypothesized somehave infact, inbipolarindividuals; sleep deprivation Moreover, studies may suggest that mania and be hypomania triggered by be difficult andthese two experiences mutually exclusive. are not necessarily distinguishing between tosleepcan decreased andinability clinically needfor decreased der, accompanied by maniaistypically disturbedsleepand,inparticular, a Sleep disturbances occur inmooddisorders. commonly Inbipolar disor lesions elsewhere. ings from primary reflect find may secondary with monoamines,observed simply abnormalities bipolardisorder remains unclear,rotransmitters intheexpression of and,as neu thesetwo important therole of Consequently successful. particularly glutamate on receptorshave drugswithspecific effects not been studies of associations withgenesrelatedactivity. toGABAorglutamate Unfortunately, increases inbipolarmoodstates.few inglutamate Genestudiesidentified a tems. Moreover, observed consistently asnoted, relatively MRSstudieshave these neurotransmitter sys inboth of and other moodstabilizers alter activity the communication pathways in networks that modulate emotion. Lithium of excitatory neurotransmitter,the primary so both are significant components neurotransmitterations. GABAisthebrain’s andglutamate inhibitory primary bipolardisorder arose from consider several of tamate intheneurobiology acid (GABA)andglu gammaaminobutyric Interest inthepotential roles of 5.5.2. Glutamate andGammaAminobutyric Acid and mitochondrial function. inemotion networks, incell aswell dysfunction signaling asabnormalities of these monoaminergicfindingsare now thoughtto represent epiphenomena 5.6. Sleep andCircadian Rhythm Abnormalities Together, regula circadian rhythm dysfunctional these findings suggest that demonstrate. bipolardisorder hasbeendifficult to causesof malities are primary serotonin, andGABA.Direct thattheseabnor glutamate, evidence eral major neurotransmitters, including dopamine,norepinephrine, sev function of aswell astreatmentinthe abnormalities effects Key Point need : Bipolar : Bipolar for sleep. for This latter symptom is unique to mania, although disorder isassociated withmetabolicandgenetic 7 More research is needed. 8 ------
43 Chapter 5 Neurophysiology of Bipolar Disorder
44 Bipolar Disorder nonetheless appears to provide clinical benefit. bances inbipolardisorder remain however, sleep unclear; management of been difficult to replicate. clock geneswere again,thesefindingshave observed; of which abnormalities cadian clock ingeneticstudiesbipolardisorder dysregulation wasfound in of cir evidence these findingsinlargerstudieshasbeendifficult. Additional toenvironmentalcues (zeitgebers). Unfortunately, replicating sensitivity sive response orexces orlossof “clock,” orunstablerhythms, phase-advanced thatincluded afree-running inbipolarindividuals disrupted circadian rhythms as a major component of cellular epigenetic andmitochondrial control. as amajorcomponent of naling system alsomodulatesprotein C(PKC) kinase activity, which serves of glutamate. Thisphosphoinositidesig excessive dria, offsettingeffects IP3 decrease thecalcium burdenstores, onmitochon lowered of levels calcium release(IP3). Since from IP3facilitates endoplasmicreticulum inositol-,4,5,-triphosphate4,5-biphosphate (PIP2)andconsequently thereby decreasing cellular inositol,which depletesphophatidylinositol- disorder, mania.Lithiuminhibitsinositolmonophosphatase, especially bipolar for thetreatment of namely specific, therapeutically is relatively cium metabolism.Lithiumisuniqueamongpsychotropic drugsinthatit in bipolar disorder. observed imaging abnormalities hence functional ventral prefrontal networks may therefore underliethebioenergeticand regulation combined withincreased neurotransmission glutamatergic within metabolic processes are alreadyinefficient. Impaired mitochondrial calcium mitochondrial ATP, if thecell, particularly energeticmolecule of theprimary Too calcium intomitochondria candisrupt production of rapidaninfluxof leading torapidcalcium intomitochondria. influxinto cells and consequently (NMDA) opensneuronal receptorsand glutamate N-methyl-D-aspartate during maniaanddepression,neurotransmission glutamatergic isincreased, bipolardisorder.developing Moreover, asnoted, MRSstudiessuggestedthat gene associated withcellular processes, calcium regulatory may conferriskof der, and recent gene studies allelesof suggested that certain themostreproducible findingsinbipolardisor cium metabolismisoneof explain thesefindingsisimpaired cellular calcium modulation.Impaired cal incellular metabolism andsignaling.abnormalities Onemechanism thatmight in bipolar disordersuggesting are mitochondrial dysfunction consistent with naling andepigeneticcontrol. Moreover, asnoted previously, MRSstudies bipolardisorder liesbelow tocell simplereceptor sig activity of pathology direct cell few receptor suggest that the neuro effects. These observations delayed by days orweeks. Moreover, moodstabilizers such aslithiumhave receptor onmonoamine systems, bindingandeffects but clinical response is drugs(e.g.,problem thatmany thymoleptic antidepressants) immediate have treatment response inmooddisordersraisedthe consistently Studies of Bipolar Disorder 5.7. CellSignaling andCalciumMetabolismin Additionally, several of lithium’s mechanisms of actionimpactcal lithium’sAdditionally, mechanisms of of several 8 Consequently, the specific causes of sleepdistur Consequently, thespecific causesof CACNAC , a , ------
initiate a cascade of events leadingtoclinical events improvement. Indeed, lith initiate acascadeof Consequently, mediatedthrough lithiumeffects inositolpathways might . References this complex, condition. dynamic bipolardisorder,lie emotional dysregulation andother symptoms of creating these emotional networks appear to under bioenergetics, and modulation of these areunknown. Regardless, remains essentially development, abnormal leadingtosymptoms, toinitiateepigeneticevents necessary althoughwhat emotional networks.events Specific may environmental be of to dysfunction combinations,in several ratherthanalllesionsoccurring inallpeople,leading disorder heterogeneous, islikely interact thesegeneticvariationsprobably bipolar emotional brainnetworks. of Since thegeneticetiology of function regulation thatdisruptcircadian theneurochemistry, rhythm structure, and cellregulation, and/or signaling, brain development, mitochondrial function, order arisesfrom genetic variations inmonoaminergic or glutamatergic was developed. thischapter,From the considerations themodelillustratedinFigure 5.7 of Jamison lesioninbipolardisorder (seeSchloesser et al.the primary lular signaling pathways that modulate neuronal energetics and plasticity as perhaps other moodstabilizers andantidepressants correct adeficit in cel Together and survival. function theseconsiderations suggestthatlithiumand critical intracellular pathways. Itiscentral toneuronaland impactsdozens of monoamine neurotransmission, GSK-3 processes regulates circadian rhythm protectlular signalingpathways againapoptosis. Modulatedby thatfurther intracel (GSK-3),synthase kinase-3 aprotein thatsitswithinanumberof that protect againstcell death(i.e., apoptosis). Lithiumalsoinhibitsglycogen lithium issomehow neuroprotective. Indeed,bcl-2 modulatesprocesses increases matterassociated withlithiumadministration;namely, ingray that drial calcium capacity. increases protein), bcl-2 (B-cell which lymphoma-2 increases mitochon calcium modulatingglutamate-induced influx.Italsounit, thereby further theNMDA receptor NR2Bsub of ium alsosuppresses phosphorylation 5.8. Summary ofBipolarNeurophysiology5.8. Summary Neuroimaging and Genetics. New York: Oxford Press 202. University bipolardisorder.model of In: Strakowski SM,ed., TheBipolar Brain: Integrating Strakowski SM. Chapter 3: Integration andconsolidation: a neurophysiological discussed thepreviously hintsatamechanism for This latterobservation handling may be central to these processes. intracellular signalingthatimpactneuralplasticity. Neuronal calcium disorder may arisefrom deficits in key cell metabolicprocesses and Key Point 7 for review). Additionalwork isneededtoextendtheseobservations. review). for : Guided This integrated neurophysiological model of bipolardis modelof neurophysiological Thisintegrated by the effects of lithium,studiessuggestthatbipolar of by theeffects 9 or Goodwin and orGoodwin ------
45 Chapter 5 Neurophysiology of Bipolar Disorder 46 Bipolar Disorder 6. 5. 4. 3. 2. 9. 8. 7. PF. Renshaw Stork C, inbipolardisorder: evi Mitochondrial dysfunction Reviews bipolardisorder. andtreatment of Neuropsychopharmacology pathophysiology cascadesinthe ManjiHK.Cellularplasticity Schloesser RJ,HuangJ,KleinPS, Illness.Manic-Depressive Sleepandcircadian rhythms. 6: KR.Chapter FK,Jamison Goodwin New York: Oxford Press 2007. University KR.Chapter 4: Neurobiology. FK,Jamison Goodwin 0:900–99. dence from magneticresonance spectroscopy research. MolPsychiatry 2005; Neuroimaging andGenetics. ing in bipolar disorder. SM, ed., In: Strakowski Kim JE, Lyoo PF. IK,Renshaw and metabolic imag Chapter 4: Neurochemical Neuropsychopharmacology 2004; 29:734–740. unmedicated bipolar disorder. sustained attention in euthymic, of FMRI study Strakowski SM,AdlerCM,HollandSK,MillsN,DelBelloMP. Apreliminary sode. amygdala volumetric in adolescents abnormalities after their first manic epi Bitter SM,MillsNP, AdlerCM,Strakowski SM,DelBelloMP. Progressionof Child Adolesc Psychiatry 2008; 47:289–298. amygdala volumes inchildren andadolescents withbipolardisorder. JAmAcad Welge JC, Pfeifer J,Strakowski SM,AdlerCM,DelBelloMP. of Meta-analysis J Am Acad Child Adolesc Psychiatry 20; 50:07–026. 2008; 33:0–33. New York: Oxford Press 2007. University New York: Oxford Press 202. University The Bipolar Brain: Integrating The Bipolar Brain: Integrating Manic-Depressive Illness.Manic-Depressive - - -
genes as discussed in section 6.2.2. (as mentionedinChapter 5). reflects that this variability multiplerisk It is likely inheritancestrict Mendelian tomaternal dominant orrecessive patterns families from transmissionthat unclearresembles asitvariesamongdifferent mood disorder is increased based on the proband’s subtype. unipolarmajordepression; of each however, type as of riskof therelative theother aswell disorder “breeds true” inthatboth increased have ratesof results are summarized bipolar inTable 6.. of Asillustrated,neithersubtype bipolardisorder, II.These types I and of namely specific subtypes of families since approximately 980attempted risksin tobetterdelineatetherelative depression thanbipolardisorder. ismore common inbipolarfamilies Studies duetoitshighprevalence, unipolarmajor unipolar majordepression; infact, increased membersalsoexhibitatwo-fold riskof lation. First-degree family bipolardisorder, increase a0-fold overrate of essentially thegeneralpopu a2% membershave family first-degree that,onaverage, in generalfound der by addressing three questions: Nurnberger, members. Asdescribed by illnessamongfamily ratesof then identifyrelative (theproband) and individual withanaffected start studiestypically Family 6... Family StudiesofBipolarDisorders familial risks. bipolar disorder and to define relative of heritability studies, twinstudies, andadoption studies—helpedtoestablishthe family investigations—namely thecentury. of Thesetypes of toward the latterhalf andaccumulated twentieth century particularly risksbegan intheearly familial illness. Studiesto clarify specific affective of history withnofamily individual not longer.500 years, Itisunusualinclinical practice if toencounter abipolar hasbeenrecognized atleast Thisfact Bipolar disorder for runsinfamilies. Genetics ofBipolarDisorder Chapter 6 6.. BipolarDisorder IsFamilial 3. 2. . Unfortunately, the specific mode of inheritance of bipolardisorder remains inheritance of Unfortunately, thespecific modeof andJamison, byAs reviewed Goodwin
Can a specific mode of inheritance be identified? Can a specific mode of do other related as well? conditions occur rates in families at elevated Do other riskwithbipolardisorder;thatis, disorders share afamilial disorder? peoplewithoutbipolar theconditionfor compared of withrelatives withbipolardisorder atincreased anindividual risk Are of relatives these studies clarify the manner of inheritance of bipolardisor inheritance of thesestudiesclarify themannerof 2 family studies of bipolardisorder studiesof family ,2 - -
4747
48 Bipolar Disorder While bipolar disorder runs in families, this does not necessarily mean that meanthat thisdoesnotWhile bipolardisorder necessarily runsinfamilies, 6..2. Twin Studies and environmental factors in the development of bipolardisorder istouse of in the development and environmental factors genetic approach contributions therelative of todisentangle An alternative 6..3. Adoption Studies trauma or substance abuse. not yet definedbut could include significantneurobiological stresses such as are therisk(5–20%)remains environmental.Environmentalfactors some of condition andmostmedicalconditions. Nonetheless, since itisnot 00%, disorder is80–85%. bipolar in the5–25%range.Basedonthesedifferences, of theheritability bipolardisorder. developing Fora 70–80%riskof dizygotic twins, thisriskis onetwinhasbipolar disorder,types. For monozygotic twins, if theother has monozygotic IIdisorder sub thanindizygotic both bipolarI and twinsfor bipolardisorder concordancesistent. Namely, are much higherin ratesof diagnosticcriteria, theresults are con of withawidevariety than acentury index (H the Holzinger heritability thecondition. riskiscalled used tocalculate geneticriskfor Thisrelative arelative twins, i.e., rates inwhich both twinsinasetarecanthenbe affected) two of types bipolardisorder (between twins. the ternal) Differences in concordance ratesof both monozygoticmore affect commonly (identical)twinsthanboth dizygotic(fra bipolardisorder isgeneticit would beexpectedto environment. Specifically, if geneticsand provide oneapproach toward clarifyingcontribution therelative of their genes likewith any dizygotic other siblings, twins, who 50% share of only theirgenesincommon, Studies comparing monozygotic twins, 00%of who have this condition. Consequently, thecause environment of could be the primary share both since genes and a common families it is genetic, environment. Source: Adapted fromandJamison Goodwin Unipolar MajorDepression from Family Studies Table 6. Healthy PopulationHealthy Major Depression Bipolar II Bipolar I Disorder Proband Although twin studies of bipolar disorder have been performed for more for bipolardisorder beenperformed have Although twinstudiesof likely reflects environmental factors. reflectslikely environmental this illness duetogenetics.developing Nonetheless, theremaining risk Key Point H
2 = (monozygotic concordance : Bipolar : Bipolar Rates (Percentages) ofBipolarDisorders and – 4 This genetic risk is higher than for any other This genetic risk is higher than for psychiatric disorder runs in families with 85% of the risk for theriskfor with85%of disorder runsinfamilies (00-dizygotic concordance). BPI 0. 0.8 2. 5.2 2 ), and is calculated as: 2 - dizygotic concordance)/ BPII 0.9 2.4 6.5 3.8 MDD 20.5 2.6 6.6 7.3
- - -
order is primarily genetic, rather than environmental, then rates of bipolar ratherthanenvironmental,thenratesof genetic, order isprimarily bipolardis theriskfor adoption studies. thatif Adoption studieshypothesize ers associated with bipolardisorder chromosomes, onseveral with perhaps theillness. Nonetheless, linkagestudiesidentifiedmark the geneticbasis of with bipolardisorder, understandingof advanced linkage studiesminimally thechromosome nearagenethatmay be associated of part but issimply difficult to replicate.Additionally, since amarker agene, is not necessarily bipolar disorder,tial genetic markers of but these findings proved to be 3 are considered meaningful. example.LOD0 times more thannonlinkage, for likely scores than greater LOD .0meansthatlinkage is score. aLOD Becauseitislogarithmic, score of linkageor theoddsof linked tobipolardisorder iscalculated asalogarithmof bipolar disorder The probability that a marker within families. is rence of chromosomes to identify whether specific loci are associated with the occur linkage studies. the basis of between genes that forms inherited together. inrecombination Itisthisvariability basedondistances ter, allelesare typically thenare considered sothatthesecopies of “linked” tocrosslikely over (recombine) than genesthatare close together. Thelat ents. This thegrandpar genesfromthereby each of providing mixed combinations of separated (meiosis),genes“cross over” from onechromosome toanother, asthechromosomes are gameteformation is inherited.Intheprocess of genes complement of afull ent sothat,whencombined duringfertilization, chromosomes separate in order to provide one allele from each par only of pairs andovumthese genepairsiscalledanallele.Duringsperm formation, each of Consequently, each geneisrepresented induplicate; onememberof genes, inheritedfrom each parent. thetotal complement of of that is, half chromosomes,In humans, chromosomes existinpairs, withonesetof 6.2.. Linkage Studies these studies. has been a consistent of focus itshighheritability, humandisease.Given bipolardisorder of development genes that contribute to thegenome, leading to increasing identification of thehuman anexplosioninmethodstostudy The lasttwo decades saw genetic. bipolar disorder developing that the risk is for primarily support family. originratherthantheadoptive Theseresults further of family bipolardisorder inthebiological exhibithigherratesof families in adoptive ficult, thatbipolarprobands but beenraised results have consistent—namely becausethey are dif beenperformed thesestudieshave combination. Fewof each bipolardisorder of inrelatives cal parents andthenexaminingratesof probands raisedbyorbiologi eitheradoptive identifying bipolarandhealthy parents.than adoptive In bipolar disorder, involved typically these studies have thebiologicalrather children whoare adopted willreflect thatof disorder of 6.2. Genetics ofBipolarDisorder Early linkagestudiesraisedconsiderable excitementEarly by identifyingpoten Linkage studiesmeasure differences inDNAmarkers (loci) locatedalong recombination of genes is not random; genes farther apart are apart more genesisnot random;genes farther of – 3 ------
49 Chapter 6 Genetics of Bipolar Disorder
50 Bipolar Disorder putative marker,putative whetherthegeneisassociated withbipo andthen evaluate der or on linkage studies in which a promising gene is known to be close to a bipolardisor of relevantgenesbasedeitherontheneurobiology potentially disorder, butnot specific genes. Associationby firstidentifying studiesstart As noted, linkagestudiesdefinepotential markers associated withbipolar 6.2.2. AssociationStudies multiple genes. that is, occurspolygenetic, from combined risks of from multiplechromosomes wasalsoaninitialhintthatbipolardisorder is significantmarkers specific genesthatmay beTheoccurrencerelevant. of bipolardisorder, not thegeneticbasisof buthave identified for evidence chromosome 6. of and thelong(p) arm chromosomes 6, 8, 3, and 22, of (q) arms the short the for best evidence Disrupted inSchizophrenia (DISC): DISC NeurotrophicBrain-Derived Factor(BDNF) D-Amino Acid Oxidase Activator (DAOA) promising findings are here and listed inreviewed Table 6.2. of bipolardisorder,has identifiedaspecificof themore cause however. A few theseresults beenreplicated thesehave oneormore times. Noneof some of bipolardisorder beenidentifiedusingthesemethods, have and expression of reported by Nurnberger, psychiatric disorders ingeneralandbipolardisorder specifically. of As study thousands. beenappliedtothe Thesemethodshave example, inthetensof for large, points. samplesmustbe Consequently,very study tobeeffective, data thousandsof limitationbeingthestatisticalinterpretation of the primary geneinthegenome,with every virtually examinationof ciation studiespermit conserved DNA.Genome-wideasso highly subjects inanotherwise relatively DNAthatshow across variability human are smallareastide polymorphisms of nucleo inlargesamplesallatonce. Single morphisms (SNP)canbeevaluated nucleotide poly single inwhich millionsof inDNAchipadvances technology studies (GWAS), were introduced inthepastdecade,becoming possiblewith interest. disorder with the gene of bipolar a trio, theassociation of multipletriostodetermine andthenstudy lar disorder. Oftenthesestudiesuseaproband andthetwo parents, called development. control microtubule inneurons, development thereby contributing to brain other psychiatric conditions, including bipolardisorder. that Subsequent studiesfound schizophrenia. withagenetictranslocationandmultiple cases of family psychiatric and neurological diseases, including bipolar disorder.of esis.found inanumber Associations been withdifferent BDNF alleleshave thatplays acritical role factor growth and neurogen inbraindevelopment arborization, so may play a role in brain development. disorder, withinconsistent results. The geneisalsoassociated withdendrite inbipolar receptor. beenperformed serine have clinical Several trialsof (NMDA) glutamate theN-methyl-D-aspartate ter serine.Serineactivates acting genes(called A more comprehensive set of methods, calledgenome-wideassociation A more comprehensive setof G30 several candidate genes potentially underlying the the underlying candidategenespotentially several and G72 DISC ) thatoxidize neurotransmit theputative : DAOA arisesfrom two inter function allelicvariantswere associated with : BDNF is a widely studiedneuronal isawidely : BDNF was originally isolated ina Scottish was originally Thesedataprovide additional DISC appearsto ------methods. advances, we willbebetter positionedtounderstandresults from older bipolardisorder,the geneticbasis of butastherelated basicneuroscience impactedunderstanding of thesemethodshasyet significantly Neither of andchromatinied mechanisms todateare remodeling. DNA methylation stud genome.The most commonly the underlying timing and expression of research acknowledges thatcells modifyDNAtranscription toimpactthe theentire genome.Epigenetic of more detailedanalyses promiseoffer of studies using“nextgeneration” methods(so-callednext-gen sequencing) theseandother promising geneswillarise.For example,sequencing of CACNAC Ankyrin 3 (ANK3) Tryptophan Hydroxylase (TPHand2) Monoamine Oxidase A (MAOA) TransferaseCatechol-O-Methyl (COMT) Serotonin Transporter (5HTT) Table 6.2 Source: Adapted from Nurnberger Potentially Involved intheExpression ofBipolarDisorder CACNAC ANK3 TPH&2 MAOA COMT 5HTT DISC BDNF DAOA Gene mechanism of action for lithium. action for mechanism of most common findingsinbipolardisorder andalso represent a potential incalcium metabolismare abnormalities amongthe noted inChapter 5, neuronal action potential and, hence, neuronal communication. mation of sodiumchannels. iscentral tothefor Sodiumtransport of in theformation as a rate-limiting step in serotonin tryptophan synthesis. metabolism of order as noted. bipolardis norepinephrine, which allmay play arole intheexpression of psychiatric diagnoses,for bipolar disorder. suggesting little specificity processes cognitive andacross different been associated withanumberof COMT allelicvariantshave inbipolardisorderabnormalities (Chapter 5). which shown have dopamineand norepinephrine, both of metabolism of and, to a lesser extent, bipolar disorder.depression generally tonergic neurotransmission beenassociated have frequently with major As genetic technologies advance, it is likely thatbetterunderstandingAs genetictechnologies itislikely advance, : This calcium As channel gene is associated withcalcium: This function.
Candidate Genes from AssociationStudies : This genecodesastructuralmembraneprotein for involved : As discussed inChapter 5, insero abnormalities : MAOA metabolizes serotonin, dopamine,and calcium channel function impacts sodium channel structure serotonin synthesis monoamine metabolism monoamine metabolism serotonergic neurotransmission neuron microtubule formation neurogenesis and brain development neurotransmissionglutamate Possible Function : These two enzymescontrol theinitial : These : COMT plays asignificant role inthe: COMT - - - -
51 Chapter 6 Genetics of Bipolar Disorder
52 Bipolar Disorder times studies have risen and fallen depending on the diagnoses of only a few afew only dependingonthediagnosesof risenandfallen times studieshave condition. Consequently, identifyingbipolar“cases” canbedifficult, so at complex anddynamic order nature, isthat,by itisabehaviorally itsvery bipolardis themajorcomplexities associated withgeneticstudiesof One of disorder. developing AsillustratedinTable 6.3, of therisktoanindividual withbipolar individuals membersof studies provide family guidance for families, groups.tions interact in different complicating studies across precipitate illness. Moreover, thatdifferentgene likely combina itissimilarly differentgenesthattheninteract withenvironmentalstressors to of variety suggeststhatbipolardisorderevidence arisesfrom theinteractionsamonga gene” will nothas not be, isolated. been, Instead, and accumulatingprobably that bipolardisorder isageneticillness. Unfortunately, aspecific “bipolar Family, twin,adoption, andgeneticstudiesprovide overwhelming evidence ciation methods to extend these findings. be linked to chromosome large studies are5q. Several underway using asso mania. Additionally, andmay there thatlithiumresponse isevidence isfamilial specific tobipolardisorderparticularly, and, istherapeutic efficacy relatively islithiumresponse, endophenotype since lithium’s useful one potentially been difficultendophenotypes have todefine in bipolar disorder. However, measurable and,ideally, reflect known neurobiological processes. To date, as biologicalcharacteristics thatare stable,associated withanillness, directly tify endophenotypes toguide genetic studies. Endophenotypes are defined Toindividuals. address thisdifficulty, have attempted toiden efforts recent Table 6.3 Identical twin with BD Both parents with BPD Parent with BPD Sibling with BPD with BPD relative 2nd-degree General population Situation Counseling inBipolarDisorder andRelevance6.4. Summary for Genetic 6.3. BipolarEndophenotypes Even in the absence of specific genetic tests for bipolar disorder, specific genetic tests Even in the absence of these been identified nonetheless. that causethedisorder. promising candidategeneshave A number of bipolardisorder, notof buthave yet identifiedaspecific geneorgenes Key Point
: Genetic : Genetic Relative Familial Risksfor BipolarDisorder methods have further establishedthegeneticbasis further methods have 70–80% 50%+ 5–25% 5–25% 3–4% –2% Risk - - - -
the family. However, the risk for onset is largely within the age range of 5 the family. However, withintheagerangeof onsetislargely theriskfor bipolar disorder increases withincreasing geneticcloseness andloadwithin 5. 4. 3. 2. . References illness. sion of treatment, diseaseprediction and,ideally, preventing theonsetandprogres inpersonalized developments understood,leadingtomeaningful increasingly thatthese combinations itislikely willbe powerful ods become increasingly bipolardisorder. natureabout thepolygenetic of However, asgeneticmeth there reflecting isconsiderable previous amongfamilies, variability comments in middle adulthood. soAdditionally,risk decreasesto 35 years, significantly
Neuroimaging andGenetics. bipolardisorder. SM,ed., model of In: Strakowski Strakowski SM.Chapter 3: Integration andconsolidation: a neurophysiological ders. Br J Psychiat 977; 30:330–35. disor majoraffective B, A,Harvald Hauge B.of Bertelsen ADanishtwinstudy genetic influence. Psychol Med 20; 4:33–40. ioral disorders of and degree Kendler OJ,DavydowBienvenu DS, Psychiatric KS. “diseases” versus behav New York: Oxford Press, 2007. University Genetics. In: KR.Chapter 3. FK,Jamison Goodwin New York: Oxford Press, 202. University Strakowski SM,ed., bipolardisorder. Generalgeneticsof In: 9: JIJr.Nurnberger Chapter genetic risk within an individual. order, provides tocounsel history someinformation althoughfamily Key Point : Specific : Specific 5 genetic testsare bipolardis not yetfor available The Bipolar Brain: Integrating NeuroimagingThe Bipolar Brain: Integrating andGenetics. New York: Oxford Press 202. University The Bipolar Brain: Integrating Manic-Depressive Illness Manic-Depressive - - - - - .
53 Chapter 6 Genetics of Bipolar Disorder
cessfully managed with one or more of thesechoices (Table 7.). managedwithone ormore of cessfully ment options areand, ingeneral,mostmanicepisodes canbesuc available USFDA-approved treat studied, so that a number of has been extensively II disorders, respectively. maniabipolar I and Fortunately, the treatment of areAs noted thedefining syndromesfor inChapter 2, maniaandhypomania 7.2.. Treating Mania illness. treatment each options phase of for dosing rangeslistedinTable 7.2. Asillustrated,there are potential several usedtotreatcommonly bipolardisorder islistedinTable 7., withtypical treatment across drugs thatarephases. basefor The evidence connection of illness, althoughthisorganizationshouldnot beinterpreted tosuggestdis of plicity, pharmacologicaltreatments are organized according phase toaffective is psychopharmacology nonmedical components,required. effective For sim Although thebesttreatmentbipolardisorder for involves both medical and conditions (e.g., diabetes). medical order similartootheranddynamic chronic, asaprogram, lifelong, bipolardis togethertoconceptualizewill pulleverything thetreatment of treatments thatcomplement psychopharmacology. Finally, we in Chapter 9, we willdiscuss psychotherapies InChapter 8, andother individuals. in given tomanagebeyond oftenhaving strictevidence placed withinthecontext of Inthischapter, lives. tive pharmacologictreatments, for evidence we review peoplewithbipolardisorder andproduc lead successful of vast majority approach toward maximizingpsychosocial clinicians canhelpthe function, ing treatment options coupled andmedicalevidence, withaprogrammatic disorder canbechallenging andattimesperplexing. However, by understand condition.behavioral Itshouldnot besurprising,then,thattreating bipolar As discussed inpreviouschapters, bipolardisorder isacomplex, dynamic, Disorder Management ofBipolar Psychopharmacologic Chapter 7 7.. Introduction andOverview of BipolarDisorder 7.2. Psychopharmacology ofPhases
– 3 When ------
5555 56 Bipolar Disorder include effective antimanic treatmentsinclude effective USFDA that aretypically approved bipolar disorder aslistedinTable 7.. First-line “A”aspects of treatments in other efficacy in mania,butalsohave effective drugs thatare not only exhibits response ratesashigh80%. Therefore, first-line treatments include course, euphoric is thatin so-called classic mania—early uals willrespond in3–6weeks onany one. One possibleexception to thisrule Table 7.3of manicindivid efficacious, are inthatapproximately similarly 50% third-line treatment options. management. plify long-term as maintenancecan also serve and antidepressant therapies, in order to sim Moreover, possibleitispreferabletouseantimanictreatments whenever that profiles aswell asside-effect anddrug-druginteractions cacy are considered. deciding where toplace a drug inatreatment effi algorithm, for evidence Bipolar Disorder, by PhaseofIllness Table 7. 5 4 3 2 failedtrials. or efficacy clinical for use/opinion;D = minimal evidence expert least onedouble-blindplacebo controlled C = uncontrolled trialdemonstratingefficacy; trialsor double-blind placebo-controlled B = at demonstrating efficacy; clinical trialormeta-analysis Key: X = USFDA not USFDA approved then: A = replicated approved thisphase;if for Olanzapine Risperidone antipsychotics Atypical Haloperidol Chlorpromazine antipsychotics Conventional Lithium Medication Oxcarbazepine Lamotrigine Carbamazepine Divalproex Antiepileptics Clozapine Paliperidone Asenapine Lurisadone Aripiprazole Quetiapine Ziprasidone USFDA approved augmentationtherapy disorder, for inmajordepressive not bipolardepression. USFDA approved for augmentation of lithiumanddivalproex. USFDA approved augmentationof for As monotherapy. USFDA incombination withfluoxetine. USFDA approved inslow-release injectable form. Table 7.3 classifies potential antimanicmedicationsintofirst-, second- and
Commonly Used Pharmacologic Treatments in Mania D X X X X X X X X X X C C C A A – 3 In general, all of themedicationslistedin Ingeneral,allof Depression X D 2 D D D D D X X C C C C A A B /B 5 3 individuals—lithium individuals—lithium Maintenance X X X D D D D X X X C C A B B B 4 4 - - - alone in the treatment of mania.Not allcombinations beenshown have to alone inthetreatment of antipsychoticatypical maydivalproex bemore efficacious than lithiumor used, it is a reasonable choice. Nonetheless, circumstances in certain in which other treatments cannot be illness. littlestudiedinthisphaseof mania, althoughithasbeenrelatively option inthetreatment therapy of Electroconvulsive (ECT)isaneffective inducing depression. Oxcarbazepine lacks sufficient datato move ithigher. illness by midal sideeffects,andthey may worsen thelong-term course of ment. Theconventional antipsychotics are lessdesirableduetoextrapyra profileillness andacomplex thatplaces adverse-effect itasathird-line treat antimanicbuthaslimiteddatain other phasesof Clozapine isaneffective agent; itisalsolesswell toleratedingeneralthanother medications. carbamazepine lowers it to asecond-linedrug-drug interaction profile of chiatrists would move olanzapine to “A” or second line. “A” as well. Similarly, category profile, due to its side-effect some child psy lithium’s isless intothis wellestablished,soit efficacy may be downgraded note, inchildren, relapse prevention. illness, Of particularly other phasesof in efficacy for inadequateevidence becauseof slightly but are downgraded Table 7.2 Pharmacologic Treatments inBipolarDisorder Oxcarbazepine Lamotrigine Carbamazepine Divalproex Antiepileptics Clozapine Asenapine Paliperidone Lurisadone Aripiprazole Quetiapine Ziprasidone Olanzapine Risperidone Atypical antipsychotics Haloperidol Chlorpromazine antipsychoticsConventional Lithium Medication A number of studies suggest that lithium or divalproex combined studiessuggestthatlithiumordivalproex withan A numberof mania, the complex Despite its USFDA approval thetreatment for of
Typical Dosage Range for Commonly Used 600-2400 00-300 200-600 500-2500 300-900 0-20 3-2 20-60 5-20 200-800 40-60 5-30 2-6 5-5 300-900 600-2400 mg)dose, Range (daily limited data not antimanic; slow titration required. Therapeutic range: 4-2 mcg/ml Therapeutic range: 50-50 mcg/ml must monitor WBC levels sublingual administration IM dosing 39-234 mg monthly not approved in mania available antagonist dopamine partial only mania not antidepressant Fluoxetine combination available 2 weeks slow-release injectable 2.5-50 mg q not recommended not recommended Therapeutic range: 0.6-.2 meq/L Comments dose higher (>500 mg) - - -
57 Chapter 7 Psychopharmacologic Management 58 Bipolar Disorder ing the current relapse prevention therapy (discussed in section 7.2.4.). bettermaximiz ormayreported by bipolarindividuals, bemanagedby simply treatment approach. not However, illness iscommonly thismilderphaseof tions are provided later in this chapter. these medica respond within the first week. Additional details about each of occurs over willbeginto a3-to6-week period,althoughmany individuals pointa starting as well. Treatment these compounds response from any of toaspecific treatment, thenthat choice as mightserve responded favorably member withbipolar disorder who afamily of there isahistory chosen. If thesedrugsinthepast,thenitshouldbeagain vidual hasresponded tooneof ment response, and,whenindicated,serumdruglevels. Typically, anindi if the dosingrange(Table 7.2) thentitratingupward basedontolerability, treat antipsychotics), theatypical atthelower starting endof proex plusoneof lithiumordival selecting amedicationfrom Table 7.3 (oracombination of medication. from events adverse adding asecond riskfor balanced againstthegreater amoreor likely rapid response mustbe thebenefitof individual, thanmonotherapy. work faster binations simply Regardless, inany given response, com ies suggestthat,ratherthanincreasing theoverall rateof response toperhaps60–70%. increase therateof be betterthanmonotherapy, but ingeneral,thesecombinations appearto Table 7.3 *USFDA approved Paliperidone Asenapine* Ziprasidone* Divalproex* First-line “A” treatments Risperidone* Aripiprazole* Olanzapine* Quetiapine* Lithium* First-line treatments ECT Haloperidol Chlorpromazine* Oxcarbazepine Clozapine Third-line treatments Carbamazepine* Second-line treatments Hypomania, asitoccurs inboth IIdisorders, bipolarI and asimilar follows The generalpharmacologicalapproach toward treating maniainvolves
Medications for Bipolar Mania 3 However, somestud ------be useful in some depressed bipolar individuals, although the evidence base insomedepressed althoughtheevidence bipolarindividuals, be useful Similarly, ordextroamphetamine may stimulantssuch as methylphenidate relapse prevention therapy. effective alreadyreceiving best usedinindividuals fore, not recommended. When antidepressants are considered, they are theoldertricyclic antidepressants,appears tobehighestfor which are, there thisrisk moodcycling insomebipolarindividuals; or increasing therateof role intreating anxiety. Moreover, precipitating mania there may beariskof for bipolardepression, in generalalthoughthey mayare play ineffective a used,recentdrugs are large-scale,multisitestudiessuggest thatthey widely polar) antidepressants inbipolardepression iscontroversial. Althoughthese standard (uni Therole of auniquerolehave inpregnancy(seeChapter 8). compromised therapy Electroconvulsive mayor medically individuals. also able choice anditmay beconsidered psychotic, suicidal, firstlineinacutely lar andbipolardepression. Foritmay someindividuals, bethebest avail comment. rated thanthemorecompoundsin highly effective Table 7.4. deserve Several treatments include compounds thateitherlackor sufficient study areless in bipolar disorder, leading to their second-line classification. The third-line haps tolerated), although both have antidepressant and efficacy other uses sion instudies, andolanzapinemonotherapy islesswell studied(andper as monotherapy. not established.Again,thesecompoundstolerated are, ingeneral,similarly forbipolardepressionwhom timemay in becritical. Lithiumefficacy youth is in depressed individuals severely for itlessuseful slow dosetitration,making symptoms preventing relapse depressive be betterfor thantreating acute depressive which may both been reportedlithiumhave and for lamotrigine, both of note, however,viduals will improve in 6–8 weeks. clinical Of trials negative bipolardepressed indi such thatapproximately 50%of effective similarly plus lithiumandlamotrigine (Table 7.4). bipolardepressionments for include thethree USFDA-approved treatments instudies demonstratedefficacy tions thathave First-line (Table 7.). treat medica requires bipolardepression “off-label”useof typically treatment of bination drugcontaining fluoxetine andolanzapine (Table 7.). Consequently, quetiapine,lurisadone,andacomtreatments bipolardepression, for namely antidepressants. three compounds At thistime,only are USFDA-approved bipolar identifiedeffective studieshave few in contrast tomania,relatively much morewithdepression. struggle commonly Unfortunately,individuals althoughmaniadefinesbipolardisorder,As noted inChapter 2, bipolar 7.2.2. Treating Depression Electroconvulsive therapy is an effective antidepressantforboth unipo therapyElectroconvulsive isaneffective monotherapy for bipolar depres efficacious Divalproex is less consistently Key Point prior history of response profiles. and tolerability of prior history efficaciousinvolve inmania.Choices amongthesedrugs balancing any USFDA-approved treatmentsthere thatare are similarly anumberof per se : The . Lamotrigine treatment is further complicated by. Lamotrigine avery treatment isfurther treatment of bipolarmaniahasbeenwell studiedsothat treatment of ,2,4 All of thesedrugsappearto be Allof ------
59 Chapter 7 Psychopharmacologic Management 60 Bipolar Disorder then, involves selecting a medication from Table 7.4 or one of thecombina then, involves selectingamedicationfrom Table 7.4 oroneof or lamotrigine. pion), divalproex, binations includeantidepressants lithiumplusthenewer (e.g., SSRIs, bupro for treating bipolardepression than monotherapy.more effective These com depression in adults. prescribe bipolar this approachstimulantsfor canalsobeappliedtosafely relapse prevention therapy isinplace. Althoughnot well studied,presumably usedaslongeffective a stimulant;inthesecases, stimulantscanbesafely youth withbipolardisorder experience co-occurring ADHDthatmay require mania.However, of increase theriskof as noted inChapter 4, more thanhalf this approachfor is underdeveloped. Like antidepressants, stimulants may type. Unliketype. bipolarI disorder, antidepressant therapy in may bemore useful lar IIdisorder, clinical studiesinthissub few althoughthere are relatively vided later in this chapter. thesemedicationsare pro mid-range doses. Additionaldetailsabouteach of the range,depression may respond atlower or dosing atthehigherendof may take aslong8–2weeks. Moreover, whereas maniaoftenrequires mania, oftenwithlittlechangefull duringthefirst–2 response weeks, anda these compounds tends to occur more thanwith slowly response from any of thesemedicationsinthepast, thenitshouldagainbechosen. Treatment of responded toone anindividual whenindicated.Again,if and serumdruglevels (Table 7.2) thentitratingupward basedontolerability, treatment response, thedosingrange atthelower andstarting endof tions discussed previously *USFDA approved Table 7.4 ECT Stimulants (with established maintenance) Antidepressants (not tricyclics) Risperidone Asenapine Oxcarbazepine Carbamazepine Third-line treatments Olanzapine (monotherapy) Divalproex Second-line treatments Lamotrigine Lithium Olanzapine/fluoxetine combination* Lurisadone* Quetiapine* First-line treatments This sameapproach isalsoreasonablemanagingdepression for inbipo The generalpharmacologicalapproach toward treating bipolardepression, As with mania, there is some evidence that certain combinations may be
Medications for BipolarDepression ,2,4 ------
depressive symptoms;depressive however, more clinical research withthispopulationis bipolar IIdisorder, asmonotherapy perhapseven inthosewithpredominantly combine medications involves arisk-versus-benefit balancing the analysis eithermedication.Again,thedecision to compared with monotherapy of may improve similarly lithiumplusdivalproex relapse risk combination of decrease recurrence ratescompared alone.The withlithiumordivalproex lamotrigine andthesefirst- andsecond-line antipsychoticsfurther atypical note, whencombined withlithiumor divalproex, to thehighercategory. Of listed are promising, butlack tofirst-line data relative choices tomove them could beconsidered firstline by reasonable clinicians. The other medications maintenance therapy may sothereforeuse suggest divalproex be an effective nonetheless, clinical prevention other trialwasnegative; trialsandextensive illness, and lurasidone, which in mania. has not established efficacy of for preventing both acute phases quetiapine,which may beeffective tions of in preventing maniathandepression, more with the excep effective typically venting depression antipsychotics ratherthanmania.Theatypical listedare decreases suicidality.for pre effective Lamotrigine appearstobeprimarily Lithium prevents both episodesand,perhapsuniquely, manicanddepressive European lithiumclinics. studiesof from follow-up largescale,long-term prevention from not double-blind only placebo controlled trials, but also Lithium has, by far, relapse themostrobustitsuse for databasesupporting and 7.5. received USFDA approval thisindication;theseare for listedinTables 7. as well and have been shown medications have newer to be effective ber of episodes inbipolardisorder. Fortunately, duringthepastdecadeorso, anum medicationdemonstratedtoprevent50 years, affective lithiumwastheonly thepast onoutcomes. effects sodes, dramaticpositive canhave For mostof tions thatprevent recurrences, namely, by increasing between epi intervals recurrences good outcomes. long-term iscritical for Consequently, medica lution by weeks or episode, months following preventing a major affective recurrences.depressive recovery Since oftentrailssymptom functional reso disorderbehavioral defined by mania,but characterized mixed, by manic, and As noted throughout this book, bipolar disorder complex is a dynamic, 7.2.4. Preventing Relapse: Maintenance Therapy aging mixed states, therefore, mania recommendations should be followed. inmixedsome are than“pure” lesseffective mania(e.g., lithium).Whenman in mixed maniaare states,In general,medicationsusedfor effective although 7.2.3. Treating Mixed States needed approaches.to identify more definitive Divalproex is listed assecondDivalproex line because the one large-scale relapse First-line maintenancebipolar disorder therapies for are listedin Table 7.5. treatment needed. options are desperately treatmentsare and50%response oftenused.Withfew rates, more treatments bipolardepression. for Consequently, off-labeltreatments Key Point : In contrast tobipolarmania,thereUSFDA-approved are few ,2,5 ------
61 Chapter 7 Psychopharmacologic Management 62 Bipolar Disorder two concurrent medicationsinbipolar disorder. Thisnumberincludes other more thansitate such achoice. Indeed,there are no controlled studiesof more than three psychotropic medicationsunless clear circumstances neces maximalrelapsecation for prevention, itisnot recommended toprescribe erability. willrequire Althoughmost bipolarindividuals more thanonemedi to get the maximal relapse medications necessary prevention andtol fewest monitorandrecord symptomsto carefully over time inorder toidentifythe time. Aswillbediscussed laterin this chapter, treatment along-term goal is maintenance therapysible), andthenmonitorthechoice asaneffective over been tions demonstrated that to also preventhave relapses pos (whenever episodes, withmedica when treating itisbestpractice tostart acute affective moodmonitoring. careful Consequently,vention therapy oftentakes years of episodes may occur thebestpre at2-to8-month intervals,sodetermining yearsseveral between episodes. Even afterprogressionstabilizes, affective may illness, untreatedhave even bipolarindividuals inthecourse of that early as other subtypes. Asnoted so inChapter 2, bipolardisorder isprogressive, process, andthisapproach both bipolarI and issimilarfor IIdisorders aswell relapsesdepressive is not established. antidepressant long-term orstimulantusetoprevent Similarly, thebenefitof illness, soare not recommended asmaintenance therapies.the course of for preventing depressive relapses andmayeven worsento beineffective relapse prevention. Asnoted previously, conventional antipsychotics appear events. adverse against the increased likelihood of size) in modesteffect recurrence rates of potential decreases (typically Table 7.5 *USFDA approved Lurasidone Carbamazepine Divalproex Second-line treatments Quetiapine Olanzapine Risperidone (long-acting injectable)* Aripiprazole* Lamotrigine* Lithium* First-line treatments Oxcarbazepine Clozapine Asenapine Third-line treatments Ziprasidone Paliperidone Identifying the best maintenance medication is a long-term, trial-and-error Identifying thebestmaintenance medicationisalong-term, Third-line options lack sufficient datatofor recommend themmore highly
Medications for Relapse Prevention (Maintenance) ------
in the management of anxiety, soclinicians aretomake advised wisemedica in themanagementof treatments, tohelpwithsleeporbenzodiazepinesancillary such ashypnotics relapses, and this improvement may accumulate over time. manicanddepressive schizophrenia. decreases the risk of Lithium significantly antipsychotics,in noefficacy despite having to“primary” lar mania,equivalent approved inthisagegroup. Notably, antipsychotic inbipo lithiumisaneffective episodes, in children anditsefficacy is unclear despitebeingUSFDAaffective than 8–0previous fewer with in individuals Lithium isalsomore effective and response ratesinacute bipolar depression tendtobeinthe40–50%range. higher,is even inmixed asmuch as80%.Incontrast, states, itislesseffective lithium characterized by euphoriaandminimalpsychosis, theresponse rateof treatedInso-called classic mania, individuals. occureffects inmore than50%of than inadequateefficacy, failure. Side oftenbeingthe for reason treatment with tolerability, manic individuals, rather within 3–6 weeks in 50–60% of tive vention treatment inbipolardisorder. shown Studieshave lithiumtobeeffec treatmentfor bipolar disorder. specific, relatively lithiumidentifieditasthefirstefficacious, and of useandstudy extensive approval mania),butinEurope, Australia, andelsewhere, until970(for become toxic.window Thetoxicity andcanquickly delayed effects USFDA hasanarrow treatmentforbipolardisorder;and(2) it therapeutic effective it an lithium: () is coincidental events highlight two features important of deaths. These was being used asa saltsubstitute andcaused a number of for treating mania.Concurrently,revealed thatlithiumwaseffective lithium into rats, lithiumproduced Subsequentstudiesinhumans acalmingeffect. discoveredIn 946, Australian John Cade inadvertently that, when injected 7.3.. Lithium maintenance therapy is discontinued. 6–2 months if mood stability, will most relapse bipolar even decades individuals of within ments “cures” shownbipolar disorder; studies have after years that even or these treat decreasesity with each medication added.Importantly, noneof therapy, guidingtreatment, andtolerabil becomes tolerability amajorfactor medication withlong-term befaced willtherefore typically bipolar individuals medications. over Because andstart withtrialanderroralternative tive, thechoices, pick theoneortwo beenmosteffec thathave reconsider allof psychotropic medicationsandcontinues thenitisbestto tobesymptomatic, withbipolardisorderdifferent isonfour anindividual treatment response. If and tolerability documentation of tion choices long-term basedoncareful 7.3. Specific Medications As noted, lithium is an effective antimanic, antidepressant, antimanic, and relapse preAs noted, lithiumisaneffective recommended. to maximize outcome, butmore thanthree medicationsisnot treatment options. Oftenmore thanonemedicationisrequired cation inbipolardisorder, althoughrecent increased have advances Key Point : Lithium : Lithium remains thebest-studied relapse prevention medi ------
63 Chapter 7 Psychopharmacologic Management 64 Bipolar Disorder In acute mania, lithium is typically started at900–,200mgperday started withdose In acute mania,lithiumistypically once daily, at night. schedule. Lithium can be administered usually effectively 3–5 days,achieved for madeonthat sothat dosageadjustmentsare typically 8–24 hours, are serum levels steady-state not of lithium has a serum half-life ered asmaniaresolves inorder tomaintaina constant Because serumlevel. ordepression;thedosemay consequently needtobelow during euthymia kidneys, andstudiessuggestthatitisexcreted duringmaniathan more rapidly Lithiumismetabolizedby the almostentirely than 0.8meq/Lare effective. therange,andthere isstillsomecontroversy less whetherserumlevels of psychotic, maniaoftenrequiresSevere, particularly dosingatthehigherend 0.6–.2meq/L. day. lithiumisatrough of Thetherapeuticrangefor level and tolerability, dosagesrangefrom althoughtypical 600mgto2,400per divalproex. antipsychotics theatypical (e.g., olanzapine) or not assignificant assomeof common, although waterretention, isrelatively 2–3poundsof increase of inyounger Weight individuals. acne, particularly gain,including aninitial Lithium may aserum blood level). cause intheabsenceing lithiumeven of someone istak on therapeuticdoses(andsometimes awayif todetermine latter may improve onlower tremor serumlevels. iscommon A mild even does sometimes produce cognitive dulling that may not be tolerated; the sedatingbut tions are Lithiumisnot typically moretocausediarrhea. likely tions are moretocausenausea,whereas likely delayed-release prepara are mostcommon, butwilloftenresolve over time;short-release formula symptoms resolve once returns to the serum therapeutic range.level always, these care. Nearly supportive treatment, andaggressive hydration, requiringemergency immediateattentionthatincludes discontinuing lithium ress tocoma death.Any significantacute andeven lithiumtoxicity isamedical tremors, muscle andnystagmus twitches, thatcanprog cardiac arrhythmias, toxicity include slurredspeech, disorientation,ataxia, effects. Symptoms of lithium. starting lenges of inpatientstays short withtheinitialchal tobalance thepressurescan learn of toxicity concerns. Nonetheless, with experience, clinicians used becauseof topredictfor lithium,thesearebeen developed thebest“final”doserarely Althoughthere intervention. are loadingdosestrategiesthathave effective itis author believes aslithiumremains afirst-lineunfortunate, treatmentforbipolardisorder (the often disregarded acute inshort-term, inpatient settings;thisdisregard is ment compared antipsychotics), withother treatments (namely itisnow requires andperhapsabitmore serumlevels diligence initsinitialmanage Because lithium 6–2 months. els can be checked at every as infrequently concentrations isstable,lev withinthetherapeutic range;once theindividual necessary, to improvewith bipolar depression, if tolerance. ability, and serum levels. Titration lower can start and go abit more slowly dependingonsymptom response, 3–5 days increases toler occurring every Common side effects areCommon sideeffects listedin Table 7.6. toxicity andside Perhaps usinglithiumistheriskof for thelimitingfactor Initially, toensure serum 5–7 days shouldbechecked serumlevels every efficacy ratherthanonly Lithium isdosedtoatherapeuticserumlevel, the first-line treatment);for many people,it isthe most Gastrointestinal sideeffects ------chronic thatrequires usemay leadtoclinical or subclinical hypothyroidism release, renal hormone and other risksfor disease.Lithiuminhibitsthyroid inpeoplewith probably changesmight leadtoirreversible inrenal function, go tothebathroom. diabetesinsipidus Somestudiessuggestthatlong-term hoursbeforebedtimemighthelpwithnighttime awakeningto the couple of at night.Restricting water intake although canbe for bothersome particularly isreversible, dangerouscentrate andusually urine;thisproblem isnot typically renal tubules to con and urination)thatresults from of changes intheability Table 7.6 sedation and cognitive effects. sedation andcognitive a +++ = severe orcommon. Key: 0 = placebo + = minimalorrare; ++ = moderateoroccasional; rateornever; Treatments inBipolarDisorder Oxcarbazepine Lamotrigine Carbamazepine Divalproex Antiepileptics Clozapine Paliperidone Asenapine Lurisadone Aripiprazole Quetiapine Ziprasidone Olanzapine Risperidone antipsychotics Atypical Haloperidol Chlorpromazine antipsychoticsConventional Lithium Medication Also considers metabolicsyndrome riskthatoftencorrelates withweight gain; Long-term use of lithiumproduces diabetesinsipidus(i.e., increased thirst useof Long-term
Adverse EffectsofCommonly Used Pharmacologic Weight gain +++ +++ +++ +++ ++ ++ ++ ++ ++ + + + + + + + a CNS +++ +++ +++ +++ +++ +++ ++ ++ ++ ++ + + + + + + b +++ EPS ++ ++ ++ ++ ++ ++ + + 0 0 0 0 0 0 0 Derm +++ +++ ++ ++ + + + + + + + + + + + + +++ ++ ++ ++ ++ ++ GI + + + + + + + + + + aplastic anemia, syndrome ovarian polycystic agranulocytosis typically) significant not (clinically QTc prolongation hyperprolactinemia hyperprolactinemia dyskinesia, tardive antihistaminic anticholinergic, therapeutic index tremor; narrow renal,thyroid, Comments syndrome Stevens-Johnson interactions drug-drug b CNS includes -
65 Chapter 7 Psychopharmacologic Management
66 Bipolar Disorder to extensive testing in schizophrenia, thereby providing the first glimmer of hope hope testinginschizophrenia,to extensive thereby providingglimmer of thefirst of chlorpromazine led suffered from psychotic mania,theantipsychotic effects thesepatientsprobably improved.dramatically Althoughinretrospect, many of agitatedpsychotic patients, who tated patients.of Itwasthentriedinagroup using chlorpromazine asapre-anesthetic andnoted thatitseemedtocalmagi mania,FrenchAt were aboutthetimelithiumwasbeingstudiedfor physicians 7.3.2. Conventional Antipsychotics work-up, respectively, is indicated. thyroid suggestsaof abnormalities renalor insufficiency.or thyroid Evidence renal unlessindicatedearlierduetosymptomswith checkingserumlevels of canbeobtainedconcurrentmonitoring (creatinine, thattypically TSHlevels) replacement. hormone These renaleffects require andthyroid laboratory cal course of epilepsy (e.g., episodes, intermittent progression insymptoms) cal course of bamazepine, similaritiesinthe clini inbipolardisorder basedonhypothesized as well European asseveral centers car began testingantiepileptics, primarily MentalHealth(NIMH) attheNationalInstituteof In the970sinvestigators 7.3.3. Antiepileptics these drugs. across most of and sexual dysfunction effects. antidopaminergicversus anticholinergic andantihistaminic of potency tive in Table 7.6, althoughthere isconsiderable dependingontherela variability earlier in treatment. nounced andmay therefore provide moreforagitatedpatients rapidbenefit low-potency antipsychotics are more pro of particularly the sedatingeffects treatment response issimilartolithium, Although therateandtimecourse of treating the sameas used for acute psychosis in is typically schizophrenia. mania or not these tolerated.compounds Dosing the for treatment for of antipsychoticswhich lithium,atypical orantiepileptics are eitherineffective Nonetheless, these drugs remain third-line acute mania in cases in agents for they donot appeartoprevent, andmay recurrences. hasten,depressive even maintenance agentsinbipolardisorder;particular, tobeeffective found ics like chlorpromazine). Second, conventional antipsychotics not have been may thelow-potency antipsychot belesswell toleratedingeneral(especially antipsychotics andextrapyramidal (EPS)thannewer kinesia sideeffects and dys tardive reasons. of thedevelopment ahigherriskfor First,they impart bipolardisordertwo primary for ventional antipsychotics intodisfavor fell standard treatments mania. However, for as other drugs were identified, con For decades, several conventional antipsychotics, alongwithlithium,were the not all,conventional antipsychotics antimanictreatments. are effective all, if received USFDA approval mania, there for is convincing that nearly evidence in its treatment.effective Although no other conventional antipsychotic has neurotransmission, so that dopamine antagonists areuniversally essentially and was USFDAeffective, approvedfor this use in 973. mania, in which it is also chlorpromazine its way found back to the treatment of humankind’smostdisablingillnesses. Eventually, oneof thetreatmentfor of The side effects of representative antipsychoticsconventional are listed of The sideeffects excessive dopaminergic mania is a state of As discussed in Chapter 5, The primary concerns are with EPS, tardive dyskinesia, weight gain, concerns dyskinesia, are tardive Theprimary withEPS, ------
anisms. Although since that bipolar and epileptic then it dis seems less likely that were represent diseasemech thoughttopotentially common underlying by the USFDA for the treatment of mania until2004.Thestudiesleadingto by theUSFDA thetreatment for of itwas not approvedAlthough carbamazepine was studiedpriortodivalproex, 7.3.3.2. Carbamazepine nificant abdominal symptoms. orwithsymptoms; amylase shouldbecheckedperhaps annually withany sig topenia. Consequently, hepaticprofiles andblood counts are recommended include hepatotoxicity,side effects pancreatitis, hemorrhagic andthrombocy be monitored (e.g., menstrual cycle). Finally, rare dangerous but potentially should and,whenitisused,reproductive history intheseindividuals carefully consequently, fertility; divalproex shouldbeused can besignificantandaffect ovarian syndrome polycystic that has beenassociated withincreased ratesof be nonspecific pain complaints, and weight gain. canWeight gaininparticular include gastrointestinal divalproex (GI)disturbances, sedation,tremor,of divalproex (Table 7.6). The of common side-effects potential effects adverse routine canbecheckedserum levels of follow-up performing whenever inbipolardisorder.can bedosedonce daily isstabilized, Once theindividual has some relapsedivalproex prevention qualities. nance study, clinical experience althoughother suggest studiesandextensive lished. Asnoted, itdidnot separatefrom mainte placebo ontheprimary episodes.inbipolardepression Itsefficacy is not wellestab prior affective mixed states or multiple the presence of response is similar independent of demonstrates lessspecificity, butbroaderthanlithium,inthat efficacy its guidedby clinical responsethese canbelargely andtolerability. Divalproex days duringinitialtitrations, few butonce responseevery isestablished, should viduals be respond checkedSerum levels toandtoleratedivalproex. manic indi dose.Aswithlithium,within3–4weeks,divalproex 50–60%of an effective provide a good 20–25mg/kg typically initial estimate of then, of in thetherapeuticrangewere doses, andwell developed tolerated.Starting Second, pseudoloadingdosestrategiesthatpredict dose afinalsteady-state improvement ascompared thanserumlevels andtolerability withlithium. this wide therapeutic range, dosing is much more dependent on symptom some investigators prefer at least 80 mcg/mL or greater. Practically, given 50–50 mcg/mL provides antimanic efficacy, although, again,of serum level order were done,extrapolationfrom never existingstudiessuggestedthata studiesinbipolardis serum-level-finding therange.Althoughformal end of a much widertherapeuticrangethanlithiumandismuch lesstoxic atthehigh reasons.treatment bipolardisordertwo has primary for First,divalproex prescribed becamethemostwidely proex sodiumin995,anditquickly dival itwasUSFDA of approvedbe effective; form for thisindicationinthe Consequently, inthe980svalproic to acid wasstudiedinmaniaandfound 7.3.3.. Valproic Acid approaches totreatingcarbamazepine suggestedalternative bipolardisorder. orders share common etiopathologicalmechanisms, success preliminary with Although divalproex has a serum half-life of 9–6hours, like lithium,it of hasaserumhalf-life Although divalproex quite significant (e.g., >25 pounds). In girls and young women, divalproex ------
67 Chapter 7 Psychopharmacologic Management
68 Bipolar Disorder in bipolar disorders, although few, if any, of thesestudieswould meetcur any,in bipolardisorders, althoughfew, of if episodes affective antidepressant andmaytive perhapsprevent relapse of Olderstudiessuggestcarbamazepine maybecome beaneffec ineffective. oralcontraceptives sothatthey time. Itcanalsodecrease of serumlevels plex drug-drug interactions, but also to changes in its own over serum levels tocomerties. Itinduces theenzymesthatmetabolize it,leadingnot only 4–2 mcg/mL. Third, carbamazepine has complex pharmacological prop of lithium, ithasanarrow therapeuticindexwithaserumconcentration range difficult to Second,was developed. prescribe. carbamazepine Like isrelatively little financialtoseekUSFDA method incentive approval delivery until anew reasons.occurred several for sothere First,carbamazepine wasgeneric, response Thelongdelay tolithiumanddivalproex. inFDA approval ing of this approval thatissimilarinrates andtim demonstratedantimanicefficacy an increase in the dose of thelatterwhenthis combination isused.Oral an increase inthe doseof added. Carbamazepine decreases lamotrigine serumlevels, oftenrequiring ine, requiring slower titrationandalower targetdosewhen lamotrigine is lamotrig 00–300 mgperday). increases Divalproex of theserumlevels 200mgperday (range by 50mgor00perweek tothetargetdoseof mg perdaytwo weeks, for then 50mgperdaytwo weeks, for thenincreased at25 antipsychotics, started Lamotrigine istypically lithium,ordivalproex). bipolardisorder withmedicationstheoppositeprofile (e.g., atypical of antimanic efficacy. Consequently, itiscombined inthe commonly treatment any,episodes andtreating acute bipolardepression, althoughithaslittle,if andUSFDALamotrigine approved iseffective for preventing depressive 7.3.3.3. Lamotrigine initially, should be followed along with the CBCs. particularly sothatserumelectrolytes, individuals, in5–40%of hyponatremia leukopenia occur. (e.g.,infection) fatigue, of Carbamazepine alsocauses tive treatment symptoms andthenwhenever sugges of ing thefirst2–3 months counts (CBC)including other plateletsshouldbechecked week dur every aplastic anemia. Consequently, complete0,000 to 25,000 blood risk of with a in individuals carbamazepine produces leukopenias in 7–0% of carbamazepine. Additionally, requires discontinuationrash, then, typically of a syndrome,Stevens-Johnson threatening. which canbelife Occurrence of which asmallpercent progressto als oncarbamazepine arash,of develop individu Upto0%of may alsoproduce adose-dependentbradyarrhythmia. improve withlowering theserumconcentration (Table 7.6). theseare dosedependentso dizziness, many of anddysphoria; fatigue, values are checkedratory effects. adverse to monitor for autoinduces itsown canbefollowed metabolism.Serumlevels asother labo andwillneedtobeforseveral weeks ascarbamazepine side effects) repeated aresponse toadjustdosingwhileawaiting (andavoiding toring canbeuseful doserangeis400–,600mgperday.The typical Asnoted, moni serum-level day thenincreased basedontolerability, clinical response, andserum levels. at200mgtwice per started mania,carbamazepine istypically treatment of rent double-blind,placebo-controlled designstandards. Nonetheless,the for The common side effects of carbamazepine include GI effects, sedation, The commonof sideeffects Carbamazepine ------
slow titration is believed to decrease the risk of Stevens-Johnson syndrome, Stevens-Johnson slow todecrease titrationisbelieved theriskof decreasecontraceptives lamotrigine canalsosignificantly serumlevels. This aripiprazole). As aclass, then,these drugsallbindD2receptors, which likely D2 receptors atany dose(e.g., quetiapine) orareD2agonists (e.g., partial dosing (e.g., “targeted” risperidone), do not bind much more than 65% of possess alargerdoserangebetween theseoccupancy ratesallowing more row anddifficult totarget clinically. Inatypical antipsychotics contrast, either is such thatthedoserangebetween thesetwonar occupancy ratesisvery occurring at85%occupancy. antipsychotic Conventional D2-receptor binding about 65% withextrapyramidal symptoms (EPS) at D2occupancy ratesof of thesemedications are thought to occurSpecifically, antipsychotic effects definitionis related tobindingatthedopamineD2 receptor.functional from “conventional” thebest antipsychotics elusive, hasbeensomewhat antipsychoticof an“atypical” separating them Although aspecific definition 7.3.4. AtypicalAntipsychotics pressants some individuals. for der, to benzodiazepines or antide anxiolytic although it may be an alternative episodesor relapse prevention inbipolardisor acute affective treatment of bipolarmania.Ithasnorole inthe worse) thanplacebo inthetreatment of in the990s, untilstudiesdemonstrateditwasnobetter(andperhaps even enzymatic autoinduction are absent. (e.g.,hyponatremia)the severe effects and adverse aplasticanemia,rash, similartocarbamazepine, althoughit tendstobe bettertoleratedand effects mg perday andresponse. basedontolerability Oxcarbazepine produces side epilepsy,for with600mgperday starting andincreasing upto2,400 namely bipolardisorder that used for areSerum levels not known. Dosingistypically butdataare antimanic, limited. clinical trialssuggestedthatitisaneffective with weight loss rather than weight gain. It may cause nephrolithiasis. to itsadministration.Unlike mostbipolartreatments, topiramate is associated ticular, topiramateisassociated withword-findingunique difficulties relatively word-finding difficulties. particularly thesias, Inpar impairment, andcognitive fatigue, pares includemade basedonweight.sedation, Commonsideeffects response. For children lessthan0 years old,downward adjustmentsmustbe and 00–400mgbasedontolerability week untilreaching atargetdoseof lepsy, at50mgperday starting andincreasing by namely 50mgperday each epi thetitrationusedfor topiramatefollows size wasmodest.Dosingfor group, antimanicinthis younger age may beaneffective althoughtheeffect ies inadults. Inadolescents, onedouble-blindtrialsuggestedthattopiramate inlargeplacebo-controlledin smallmaniaclinical trials, butthenfailed stud not USFDA approved. Topiramate promising results demonstratedinitially otherSeveral antiepileptics areusedinbipolar disorder, commonly butare Antiepileptics 7.3.3.4. Other a rash. tolerated in the absence of include headaches, GIeffects,ormildsedation.Ingeneral,lamotrigine is well withlamotrigine.the majorside-effect concern Other common sideeffects Gabapentin was widely prescribed years bipolardisorderseveral for Gabapentin waswidely Oxcarbazepine similar to iscarbamazepine, chemically and several small ------
69 Chapter 7 Psychopharmacologic Management
70 Bipolar Disorder advantage of “useful” side-effects, such as sedation in an agitated individual. side-effects,such assedationinanagitatedindividual. “useful” of advantage can bedosedonce daily, althoughsometimesmultipledosingisusedtotake rangesare typical providedbility; inTable 7.2. all Despitevariablehalf-lives, require serumlevels, butare dosedbasedon clinical response andtolera tion islurisadone,which hasnot beenstudiedinmania.Thesedrugsdonot (months);theexcep not (weeks), inthelongterm althoughprobably term like better lithium, than lithium and tolerability perhapsin the short slightly antimanicagents, with response rates effective demonstrated tobesimilarly treatingand even bipolar depression. atpreventing thesecompounds appeartobeeffective psychotics, someof thanconventional antipsychotics.kinesia Moreover, unlike conventional anti dys of EPSand tardive accounts antimanic efficacy, for have but lower rates density. functions andbone on effects reproductive negative that may long-term have Finally, dyskinesia. tardive risperidonecauses adramaticincrease inprolactin patients. EPSandakathisiaitcancause Ithasadose-dependent riskfor inyoungerdizziness. Risperidoneisassociated withweight gain,particularly hypotension, and more commoninclude sedation,orthostatic sideeffects decreases); inchildren, dosing above 3mgperdayindicated. The israrely dosed upto6mgperday (higher dosescanbeused,althoughtolerability at –2 mg per day started and manic relapse). Risperidone is typically of ily antimanicandmaintenance treatment(primar Risperidone isaneffective disorder in2003;italsoisapproved useinchildren for andadolescents. Risperidone wasUSFDA approved schizophrenia for in993andbipolar 7.3.4.2. Risperidone and response.tolerability Higher doses may be used during acute mania. 300–450mg,basedon increased by 25–50mgperday toatargetdoseof at25mgperday started and from thatpointforward.Clozapine istypically checks followed by monthly 6 months, 2 weeks for then every 6 months, registered whitebloodcell andrequires counts program (WBCs) weekly for threatening; consequently, beprescribed clozapine within aspecific canonly andcanbecome life individuals occurs inperhaps%of gain. Agranulocytosis tachycardia,andweight dizziness, hypotension, sedation, hypersalivation, interventions.of It has a complex profile side-effect that includes high rates with markedindividuals treatment resistance to other first- and second-line usedinbipolardisorder.monly Primarily, useinbipolar itisreserved for antischizophrenia uncom treatments, itisrelatively the nextgenerationof managing treatment-resistant schizophrenia, thesearch anditspawned for dopamine-binding properties. Althoughitrepresented in amajoradvance Clozapine antipsychotic istheoriginalatypical basedonitsD2 7.3.4.. Clozapine mine receptor occupancy. profiles Side effects are listed in Table 7.6. onD2dopa syndrome, basedlargely althoughspecific risksappeartovary andneuroleptic malignant dyskinesia tardive EPS, potential risksfor labels for diabetes. andtype-2 They alsocarry hyperlipidemia abnormalities, namely beenassociatedIn general,thesedrugshave withweight gainandmetabolic As listedinTable 7., antipsychotics theatypical ingeneral,allbeen have, ------
7.3.4.3. Olanzapine per day lower (although itmayeven bestarted inchildren andindividuals pressant inbipolardisorder. efficacy at 5 mg started Aripiprazole typically is augmentation therapy inmajordepression, ithasnot demonstratedantide ment inthisyounger population.Although ithasbeenUSFDA approved for drugUSFDAadolescents andistheonly approved maintenance treat for manicrelapse)for inbipolardisorder. Itisapproved useinchildren for and as an antimanic and maintenance(primarily Aripiprazole agent is effective 7.3.4.6. Aripiprazole its D2 dopamine receptor binding profile. risk,consistent with dyskinesia tardive perhaps asimilarlow orabsentriskfor in children. noEPSliability, minimal or even Quetiapine appears tohave and The areThe majorsideeffects sedation,which isoftenpersistent,and weight gain. (e.g., 300 mg on average) than antimanic doses (e.g., 500 mg on average). to 800mgperday. Antidepressant andmaintenance dosesmay belower at 50–00mgperday toup andincreased andtolerability basedonefficacy approved useinchildren, started for teens, andadults. Quetiapineistypically bipolardisorder andisUSFDA in all phases of Quetiapine is effective 7.3.4.5. Quetiapine is not known. dyskinesia tardive It may causeakathisiaorEPSathigherdoses. Theriskof is not associated with significant weight gain. It typically cardiac arrhythmias. historiesof inpeoplewithpersonalorfamily should beprescribed cautiously widespread use.Nonetheless,much clinicaleven significance it with relatively ciated withQTc prolongation ontheEKG, althoughthischange hasnot had well tolerated, although it may cause generally dizziness oragitation. It is asso and titratedastoleratedby response upto60mgperday. Ziprasidoneis initiatedat80mgperday (40mgbid) illness. Inmania,ziprasidoneistypically the thisphaseof sion studies, soisnot recommended thetreatment for of inbipolardepres whenusedincombination.lithium anddivalproex Itfailed antimanicthatmay improveZiprasidone isaneffective relapse prevention of 7.3.4.4. Ziprasidone prolactin in children. testsand function liver associated withakathisiaingeneralandelevated inbipolardisorder isunknown. dyskinesia However,ine causestardive itis placebo, low,EPS appearstobevery andwhetherolanzap of atthelevel mended treatments. mouth and dizziness. It may The risk for also cause dry theserecom any of ine isassociated withthehighestweight-gain of liability persist throughout itstreatment course, andweight gain.Indeed,olanzap associated witholanzapineare effects adverse sedation,which appearsto per day; lower dosesareusedinchildren. commonly Themostproblematic at0mgperday started andcanbeincreased to30mg adults, itistypically mania. In is USFDA approved use inadolescentsthe treatment for for of weak antidepressant (which improves whencombined withfluoxetine). It antimanicandmaintenance agentandmay be Olanzapine isaneffective a
latter
can
be
significant
(e.g.,
>25
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and
is
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71 Chapter 7 Psychopharmacologic Management
72 Bipolar Disorder schizophrenia, however, antimanic consistent with aneffective itislikely in yet itsefficacy beenstudied as amaintenance mania. Given agent or for treatmentforbipolar depression, buthasnotLurisadone isaneffective 7.3.4.7. Lurisadone with dementia. ciated with an increased stroke individuals risk for in elderly appearsto be low. dyskinesia EPS andtardive risk for Its use has been asso gain in younger It individuals. can cause agitation or akathisia, although its littleweight-gain inadults, liability althoughisassociated withweighttively initially. appearstodiminish Thissideeffect over time.Aripiprazole has rela for aripiprazole problematic isnauseaand vomiting, particularly sideeffect may0 mg. require Someindividuals higherdoses. Themostcommon and daysfew toatargetdoseof andtitratedwithina tosideeffects) sensitive under study so that additional trials mayunder study impact designations in Table 7.. medicationsare thenewer stillrelapse prevention) andtolerability. Someof in across (particularly basedonefficacy differentphases them isgenerally bipolardepression and maintenance therapy.treatment of Choosing among mania but more for bipolar the disorder recently for also for particularly EPS and akathisia, insomnia, and weight gain. tolerability. Thecommoninclude sedation,dizziness, sideeffects dose-related at5mgbid,thentitratedtoclinical response started and and inmaniatypically bipolardisorder. inother phasesof Itisadministered sublingually to beuseful antimanicagent,althoughithasnot beenestablished Asenapine isaneffective 7.3.4.9. Asenapine dose is 7 mg. monthly then the typical later; oneweek 56mggiven at234mg,withaseconddone thatisstarted doseof paliperi response andtolerability. of There isalong-actinginjectable form risperidone)andtitratedtoclinical per day (corresponds to3mgperday of at6mg started risperidone).Paliperidone istypically metaboliteof is anactive risperidone,which istheparent(paliperidone drug profile issimilartothatof phrenia). inbipolardepression Itsside-effect Itsefficacy is not determined. relapse. ItisUSFDA approved useinchildren schizo for andadolescents (for mania for prevention of asanantimanicagentand Paliperidone iseffective 7.3.4.8. Paliperidone weight gain. not well definedinbipolardisorder. littleassociation with Ithas relatively thatis dyskinesia tardive and akathisia,GIdisturbances, riskfor andalikely 60 mg per day. include sedation,dose-related Lurisadone side effects EPS and increased basedonclinical response andtolerability, perhapsashigh initiatedat20mgperdayother dopamineantagonists. Lurisadoneistypically Atypical antipsychotics increased significantly have treatment options within different clinical circumstances. these options, useful asthey are allpotentially themselves withallof possibilities and combinations.new Clinicians are to familiarize advised expanded duringthepast20 years, significantly have for many allowing Key Point : Psychopharmacologic treatment options inbipolardisorder - - - -
5. 4. 3. 2. . References necessary, as discussed in Chapter 8 and 9. not forbest clinicaloutcomes, sufficient however, soadditionaltherapies are mize bipolardisorder outcomes. Medicationsare but critical andnecessary researchthen, future onpersonalizingmedicationchoices willfocus tomaxi drugdevelopment, Inadditiontonew individual. drug combinationagiven for andtrialerrorremains toidentifythebestdrugor is curative, necessary did theirpredecessors 20 years thesemedications ago. Nonetheless, noneof bipolar illness. Consequently, clinicians today many more have options than has been a dramatic increase medications to manage all phases of in new lithium andconventional antipsychotics), duringthelasttwo decadesthere limitedpsychopharmacologic treatment options (namely After decadesof 7.4. Conclusions
Manic-Depressive Illness.Manic-Depressive Maintenance medicaltreatment. 20: KR.Chapter FK,Jamison Goodwin Illness.Manic-Depressive depression. treatment of KR. Chapter 9: Medical FK, Jamison Goodwin Press, 2007. mania andmixed states. hypomania, treatment of KR.Chapter 8: Medical FK,Jamison Goodwin der: update 203. Bipolar Disord 203; 5:–44. patientswithbipolardisor CANMAT themanagementof guidelinesfor of BipolarDisorder update for (ISBD)collaborative Society and International Treatment MoodandAnxiety Berk M.CanadianNetwork for (CANMAT) R, BondDJ,Frey B, BN,GoldsteinBI,Lafer Birmaher HaK,NolenWA, V, Sharma MacQueenG,McIntyre RS, C, A,Young Ravindran LT, Milev Yatham LN,Kennedy SH,Parikh SV,S, AldaM, A,Beaulieu O’Donovan Schaffer drug treatments bipolar disorder. for of CNS Drugs 200; 5:70–78. Strakowski SM,DelBelloMP, andtolerability efficacy AdlerCM.Comparative New York: Oxford Press 2007. University New York: Oxford Press, 2007. University Manic-Depressive Illness.Manic-Depressive New York: Oxford University - -
73 Chapter 7 Psychopharmacologic Management
emotional responses. therapy behavioral Cognitive has been shown to be this basic premisefor that cognitive interventions can be used to modify providesfrontal neurobiological cortex,as discussed inChapter 5, support thepre of betweennections observed theemotional parts andcognitive break this cycle. Thereciprocal arebehavior implementedtofurther con componentcognitive inwhich modificationsbasedon correcting negative this thoughtsto break therapy thecycle.tive Behavioral isanextensionof therapy attemptsCognitive to identify and modifytheseautomaticnega symptoms (Figure 8.). andbehavioral result inimpairedultimately function thoughtsthat andexpectationsleadingtoadditionalnegative behavior tive thoughtsfollowed by negative corresponding nega avicious cycle of for matic thoughtsthatareresponse, anindividual’ssetting them up default premise thatdepression (andother conditions) auto arisesfrom negative by developed Aaron Beck, therapyOriginally cognitive works from the health care. As suggested by the name, CBT is based on two components. psychotherapeuticlished evidence-based treatments practiced inmental therapies(CBT)are behavioral perhapsthemostwell estab Cognitive 8... Cognitive Behavioral Therapy psychotherapeutic evidenced-based interventions. of Consequently, bipolar disorder requires a comprehensive use treatment of relapse. symptoms diminishingdepressive aswellfor asdecreasing riskof address these issues.psychotherapies useful Certain may alsobeparticularly recreation. Medicationscannot finances,evenformance, enjoyment and of psychosocial consequences, damaginginterpersonalrelationships, jobper depression, oftencreate significant the hopelessnessanddesperationof inmaniaor episodes,forexample,impulsivity affective The symptoms of improvement requiresfunctional psychotherapeutic typically interventions. symptoms, anding perhaps affective by improving cognition, additional recoverylution. Althoughmedicationscontribute by tofunctional decreas correlated with symptomFunctional improvementreso partially is also only tional improvement oftenlagssymptom resolution by weeks ormonths. ficient to maximize outcomes. In particular, researchfunc has shown that bipolar disorder,critical to improve not suf the course of it alone is typically psychopharmacologic and managementisboth necessary Although effective TreatmentsComplementary Psychotherapy and Chapter 8 8.. Introduction ------
7575 76 Bipolar Disorder superior to other psychotherapeutic interventions is not fully established. superior toother psychotherapeutic isnot interventions fully relapses,episodes andprevent althoughwhetherCBTisspecifically affective beenshown CBThave toimprove recovery from acute depressive studies of thanin other cifically related majordepression.conditions, Ingeneral, namely and problems. approachesfunction and cognitive tolife’s stressesimprove specific areas of acute symptom exacerbations andover to thelonger term management of therapy theshort-term behavioral canbeusedbothtreatment. for Cognitive andvalidatedinclinical beendeveloped trials todirectals have thecourse of theseconditions, specific manu psychiatric conditions. Inmany of of variety depression, disorders, anxiety addictions, and a inthetreatment of effective Figure 8. 6. Comorbidities 5. 4. 3. 2. . Box 8. Hopelessness Cognitive behavioral therapy behavioral hasbeenless studiedinbipolardisorder spe Cognitive – Smoking – Eating disorders – ADHD – OCD – PTSD – Alcohol and drug abuse disorders and anxiety – Anxiety Medication adherence Interpersonal interactions Stress reduction Relapse prevention Managing acute depression Helplessness
Example UsesofCBT inBipolarDisorder The vicious cycle of automatic negative thoughts. automatic negative The vicious cycle of NEGATIVE THINKING Self-defeating behavior STRESS Insomnia Anxiety - -
the role of CBT in the management of bipolar disorder to expand. is likely CBT in the management of the role of Regardless, in many the efficacy other related andgiven relevant conditions, fied, thetherapy moves toward social rhythms reestablishing both healthy thatthese cause. Once identi and the disruptions in socialbehaviors rhythms therapy (IPSRT), interpersonal onfirstidentifyingmaladaptive then,focuses bipolardisorder. of Interpersonal andsocial rhythm ile circadian rhythmicity (e.g., thefrag thatinterrupt is disruptions insocialsleeppatterns) rhythms from relapse interpersonalstress theriskfor derived that acomponent of stress episodes. precipitate affective from previousfindingsthatinterpersonal disruptions andtheaccompanying symptoms, precede therebydisruptions affective thatimmediately working interpersonaltherapy Pittsburghadvanced by onsocial focusing of University ordirectionality areabout causality made.EllenFrank andcolleagues atthe tionships andsymptoms, experiences. ratherthanpastlife Noassumptions current rela onimprovingso focuses these interactions withinthecontext of social interactionsaremaladaptive connected symptoms with depressive and depression. Itoperatesfrom thepremise that inthemanagementof ticularly application inpsychiatry andpar of Interpersonal therapy hasalonghistory 8..2. Interpersonal andSocialRhythm Therapy balance, with bipolar disorder. then, CBT is recommended individuals for treatments management(e.g., medicationsandhospitalizations).On fewer in CBTappearstobeoffset other aspectsof by savings additional cost of patterns.Moreover,thought andbehavior administered, the wheneffectively more internalize accumulate adaptive over asindividuals time,presumably improvement. functional long-term Indeed, improvement from CBT may problematic (e.g., antidepressants). Combined, these effects contribute to whenstandard approaches particularly totheseconditions may berelatively therapy, choice managingcomorbidity, for therefore, may bethetreatment of orders, PTSD, andOCD, aswell asother conditions. behavioral Cognitive lar disorder including drugandalcohol disorders, abuse,anxiety eatingdis thecommon comorbidities thatoccur inbipo approaches many of existfor interpersonal and other behaviors.tive Additionally, evidence-based CBT symptoms,interepisode anddecrease affective stress by modifyingmaladap Specifically, CBTcanbeappliedtoimprove medicationadherence, manage prevention whenaddedtoanexistingmaintenance medicationregimen. psychosis in any affective state. or in the presence of therapy behavioral hasnodemonstratedrolemens. inacute Cognitive mania anddoesnot interactwithexistingpharmacological effects adverse regi few CBTover other isthatithas interventions of isinitiated. Theadvantage ogy although itmay inasecond-line serve role afteradditionalpsychopharmacol ioral therapy adjunct in nonpsychotic may also be a useful severe depression, behav adding another medication. Cognitive (e.g.,cology lithium) instead of In thisrole, CBTisusedasanadjuncttoexistingmaintenance psychopharma represents afirst-linefor mildtomoderatebipolardepression. intervention bipolar disorder (Box 8.).Asawell-established antidepressant therapy, CBT In additiontoitsrole inacute depression, CBTappearstoimprove relapse Currently, applicationsinthetreatment important of CBThasseveral 2 As part of thistherapy, itis postulated of Aspart ------
77 Chapter 8 Psychotherapy and Complementary
78 Bipolar Disorder Family-focused therapy (FFT)works fromFamily-focused theinterpersonalmodelwith 8..3. Family-Focused Therapy remains unclear, however. tion asanadjuncttomedication.Whetheritissuperiorother therapies shown maintained.Studieshave thatIPSRTdently enhances relapse preven thatcanbeindepen behaviors each individual’s adaptive todevelop ability can beusedboth dependingontreatment short- andlong-term goals and gies. Techniques fromintoIPSRT. CBTare oftenintegrated Like CBT, IPSRT ous social andbiologicalcomponents, strate more life developing adaptive toidentifylinksamongvari thetherapistby learning become independentof personal problem areas. Over time, the to goal the bipolar is for individual (e.g., sleep, exercise, inconjunction andeating patterns) withmanaginginter developed an educational approach that brings together parents of children aneducationalapproachdeveloped thatbringstogetherparents of any treatment plan and interaction throughout itscourse. of venture alifelong part Education andwillneedtoremain isreally anactive avoidevidence onmedicalandscientific misinformation. to to sitesthatrely withbipolardisordertreating andtheirfamilies clinicians guideindividuals inanelectronic materialnow available world, itisrecommended that of Alliance (DBSA),from thevariability publishers, orfromGiven theInternet. MentalHealth(NIMH)ortheDepression andBipolar Support Institute of ture onbipolardisorder from nationalorganizationssuch astheNational expandtoexistinglitera toclinicians,begins withtalking butcanrapidly reacting tosymptoms. simply Education the illnessby anticipating insteadof improvesorder andtheirfamilies outcomes by helpingtobettermanage withbipolardis individuals lar disorder cannot beoverstated. Education of bipo course, expectedoutcomes, treatment options, andother aspectsof understandingthe of andtheirfamilies The valuetobipolarindividuals 8..4. EducationandEducationalTherapy than other psychotherapies. evidence-based tive pharmacology, althoughithasnot yet beendemonstratedtobemore effec therapy, psychoout.” Family-focused adjunctto effective then,isauseful therapy appearstoincrease “burn medicationadherence anddecrease family during acute episodesandover timetoprevent relapse. Family-focused disorder. other psychiatric illnesses, which, asnoted inChapter 6, iscommon in bipolar from memberssuffer bipolarand plex interactionsinwhich multiplefamily therapyloved isalso well positionedtomanagethecom one.Family-focused membersasthey helpmanagebipolardisorder intheir den onthefamily therapy acknowledges dynamics. Family-focused thestress andbur family bipolardisorder anditsimpacton theparticipants’ understandingof all of improve stress, communication, decrease and advance and family individual to in order interactionstyles toidentifyandmodifymaladaptive and thefamily therapies, however, individual FFTworks withboth concurrently theaffected withbipolardisorder. individuals of in thelives membersrepresent relationships themostimportant assumption thatfamily Additionally, Fristad recently and colleagues attheOhioStateUniversity thatFFTimproves found Studies have outcomes term both intheshort 3 Unlike other interpersonal ------
for education. for with bipolarandother mooddisorders toprovide context agroup andsupport interventions. modeltoprovide morefeatures intothesupportive consistent therapeutic duetotimeor resourcecifically toadapt constraints,key nonethelesstry unable to follow them spe with structured psychotherapies if and even Consequently, itisrecommended themselves thatclinicians familiarize therapy becomes thedefault. sothat supportive are available not always psychotherapies aresuperior, probably these althoughclinicians todeliver similarly.pies andattimesitperforms Onbalance, however, structured therapyive is often used as a comparison treatment to structured thera medicationvisits.even short In research, support within theconfines of structured. pragmaticandrarely Itcanbe(andis)delivered is inherently therapy.that isreferredtoincombination assupportive therapy Supportive thepreviousdiscussed therapies tion management,andpieces from allof education,encouragement, acute problem solving,medica hodgepodge of Perhaps a appliedtherapy themostcommonly inclinical practice istypically 8..5. Supportive Therapy psychopharmacology.ily isprimar whenthefocus theirpractice even style, withinthecontext of apply is recommended thatclinicians astandard develop educationalapproach to intreatment. sources It individuals thatcanbeadapted useful for potentially book. Indeed,thisbookprovides pointtoguideclinicians toward astarting those symptoms. managing mood symptoms and the impact of in thesechildren; itassistsboth parents in children andaffected skills develop therapy improve (MFPEP)hasbeenshown instudiestosignificantly outcomes 8. 7. 6. 5. 4. Neurobiology 3. Epidemiology 2. . Box 8.2 Box 8.2 lists common areas of education based largely on the outline of this ontheoutlineof educationbasedlargely Box 8.2 lists common areas of Treatment options risk patterns Genetics and family Common Comorbidities Clinical presentation Educational resources Finding a support group – – – – – – – – Symptoms Treatment adherence management Lifestyle Psychotherapy options Medications—risks versus benefits illness and prognosis Course of relapse identification of Early Diagnostic criteria Common EducationalTopics inBipolarDisorder 4 This method, called multifamily psychoeducational psycho Thismethod,calledmultifamily ------
79 Chapter 8 Psychotherapy and Complementary
80 Bipolar Disorder illness, DBT may some individuals. be indicated for borderline traitsinbipolar personality order, highrateof therelatively given inbipolardis demonstratedtobeeffective tion. Althoughnot specifically inborderline disorderutility personality inwhich itisthefirst-line interven therapy its Dialectical behavioral hasamassedalargedatabasesupporting toward whilemovingfeelings more individuals responses adaptive tothem. therapy by validatingtheassociated managesthesebehaviors thoughts and with borderline disorder. personality individuals Dialectical behavioral of behavior designed to manage the suicidalityand self-destructive specifically disorder. therapy Dialecticalbehavioral (DBT)isamanualized, modifiedCBT bipolar otherSeveral psychotherapies may beconsidered inthetreatment of 8..6. OtherPsychotherapies Nonetheless, a few approachesNonetheless, show a few promise. bipolargeneral disorder, for lacking. so that the evidence base is typically Unfortunately, in investigated CAMapproaches not have been adequately Consequently, withbipolardisorder. tomany individuals CAMisattractive improve intervention. individuals withasingle of abouthalf only typically and bipolardisorder significantsideeffects for arethese oftenhave available, noted earlierinthischapter,evidence-based treatments althougheffective management,andnon-Westernplements, lifestyle traditionalremedies. As medical practice are clear, not always sup CAMincludes dietary generally (or both).ability Although the boundaries between CAM and conventional which conventional medicaltreatments lack ortoler eithersufficient efficacy medical practicewith chronicin modern as society struggles illnesses for medicine (CAM)hasbecome acatchphrase andalternative Complementary consequently, at this recommended.time these therapies are not generally bipolardisorder (orother majormentalillnesses); the course orsymptoms of interpretation, andother not methodshave been demonstratedtoimprove Similarly, psychotherapies classic psychoanalytic usingfree association, dream thistreatment basefor approachthe evidence isminimalinbipolardisorder. for depression. However,mats, beendemonstratedtobe effective have psychodynamic psychotherapy,versions of including strict,time-limitedfor upbringing.conscious andthoughts, Some oftenbasedonunhealthy drives sub areof from behaviors manifestations anassumption thatmaladaptive fromevolving roots. psychoanalytic Psychodynamic psychotherapy works Bipolar Disorder andAlternative8.2. Complementary Medicine in Psychodynamic psychotherapy inpsychiatry, hasalonghistory originally recover psychosocial function. comes. Psychotherapies neededto maximally are almostcertainly improveapproaches significantly overall treatment response andout psychopharmacology in bipolar disorder, evidence-based several Key Point : Although : Although psychotherapy usedasanadjunctto isalways 5 – 7 ------
8.2.. Dietary Supplements 8.2.. Dietary iors, that is, social rhythms, to improve course of illness. Workiors, that is, to improve social withrhythms, IPSRT course of IPSRT behav As noted involves previously, modulating lifestyle akey of part 8.2.2. Lifestyle Management strated efficacy. vitamin supplements, butnoneyet demon have of avariety peutic dosesof studiesexaminedsuprathera preliminary. preliminary Finally, anumberof agomelatine) may alsoimprove moodsymptoms, although studiesare still compounds (e.g.,to helpmanageinsomnia.Melatonin andmelatonin-active (e.g., tohypnotics might provide zolpidem) orbenzodiazepines analternative inbipolardisorder.shown tobeeffective However, it for someindividuals, but,todate,hasnotit could been beusedtomodulatecircadian rhythms treatment bipolardisorder. for interest in that Melatonin hashypothetical antidepressant properties, butithasnot proven orsafe tobeaneffective serotonin. St.John’s Wort weak aprecursorappearstohave tryptophan, of its useinbipolardisorder. dietary beennoted have for Similarobservations in depression withmixed results; not todate,thesestudies have supported ledtostudies pathways Thisactivity thatmay altercatecholamine function. these treatments. both of is needed for investigation further bipolardisorder.been proposed tobeinvolved intheexpression of However is abrainantioxidant andsomay improve processes inflammatory thathave treatment.as athird-line NAC adjunctive which isaprecursor glutathione, for symptoms inbipolardisordersive inonerecent study, leadingtoitsinclusion option. Similarly, well tolerated,itisrecommended by someguidelinesasathird-line adjunctive beenmixed. Findingshave metabolism (asnoted inChapter 5). Becauseitis lithium’s istoalterphosphoinositol effects primary treatment, becauseoneof the oil (e.g., fish). with allergies to the source of also increase bleedingtimesathigherdosesandshouldnot beusedinpeople acids may to bedoserelatedgastrointestinal. andareOmega-3fatty primarily note, research further. studies raised the dose considerably tend Side effects then titratingupward perhapsto3g/day; based ontolerability however, of acids) and omega-3fatty hexaenoic acid of (DHA)(i.e., thetwo subforms eicosapentanoic acid (EPA) anddocosa amix of withg/daystarting of acids alsoremains undefined,but recentfatty recommendations suggest and whetherthey prevent relapse omega-3 isstillunclear. Specific dosingof To antimanicagents, acids donot appeartobeeffective date,omega-3fatty for decreasing symptoms depressive inboth adultsandadolescents.effective acids beenstudiedinbipolardisorder have andappeartobe omega-3 fatty supplementation provided improvement. inmind, Withtheseobservations acid studiesin majordepression inwhich omega-3fatty led toanumberof acids; thesedatainpart higher incountries omega-3fatty withlower dietary depression may be our diets. suggeststhatratesof Epidemiologicalevidence by humans,thesized sowe intrinsically are dependentonobtainingthemin Omega-3 fattyacids S-adenosylmethionine (SAM-e) is a cofactor in a number of biochemical inanumberof S-adenosylmethionine (SAM-e) isacofactor Inositol has been examined in a number of studies primarily as an adjunctive as an adjunctive studies primarily hasbeenexamined in a number of N-acetyl cysteine serve a variety of biological functions andcannot besyn biologicalfunctions of avariety serve (NAC) wasreportedtoimprove depres ------
81 Chapter 8 Psychotherapy and Complementary
82 Bipolar Disorder so belong in the management of bipolar illness. so belong in the management of diet,exercise,healthy substantialhealthbenefitsand have andsleeppatterns direct findings, improve almostcertainly outcome.behaviors Regardless of changes toeliminatethese bipolarillness, solifestyle worsen thecourse of and alcohol abuse,including cigarette beendemonstrated to have smoking, regular,eral healthbenefitsof moderateexercise are well established.Drug beendifficultings have todemonstrateinlargerstudies. Nonetheless, thegen beenexaminedindepressionhave withmixed promising results;find initially exercise regular, illness. Direct of benefitsof moderatelevels all course of relapse inbipolardisorder andimprove affective over to decrease theriskof terns. Inparticular, techniques thatmanageandprotect lifestyle sleepappear that interventions help to stabilize sleep,supports eating, and exercise pat 2. . References to maximizepsychopharmacology treatment benefit and outcome. psychotherapy withsophisticated disorder therefore requires of the integration bipolar approach programmatic tothemanagementof tion. A state-of-the-art complement outcomes tomaximize psychopharmacology behavioral andfunc bipolardisorder. akeyhave role inthetreatment of Namely, psychotherapies Psychotherapies, CBT, particularly FFT, educational approaches, and IPSRT, for bipolar disorderbenefits are not established. is considerablethesetreatments enthusiasmfor andrisksappeartobelow, bipolarsymptoms. yogamanagingprimary Again,althoughthereporting for withbipolardisorder;however,individuals there aresup nostudiesdirectly andstressanxiety management.Inthisrole, then,they may for utility have ined inpsychiatric disorders, andyoga techniques are common mainstays for yoga beenexam therapieshave treatment bipolardisorder. for of A variety therapy.adjunctive To date,there torecommend isinadequateevidence this indepressionefficacy and, byextension,bipolardisorder, as an primarily Consequently, itspotential there todetermine beenrecent have efforts non-Western medicine millennia.Acupuncture for has been a staple of 8.2.3. Traditional Therapies 8.3. Conclusions
Rhythm Therapy.Rhythm Frank E. New York: Oxford Press, 2007. University KR. Chapter 22: Psychotherapy. FK,Jamison Goodwin recommended as part of bipolar disorder management. recommended of as part managementhasmultiplebenefitstobe lifestyle Nonetheless, healthy acids, theseapproaches supporting evidence isminimal. omega-3 fatty lar disorder, therapy with adjunctive with the possible exception of Key Point Treating Bipolar Disorder: A Clinician’s Guide to Interpersonal andSocial Guide toInterpersonal Treating Bipolar Disorder: A Clinician’s : Although New York: Guilford Press, 2005. there isconsiderableCAMinbipo enthusiasmfor 5 – 7 Manic-Depressive Illness.Manic-Depressive ------
3. 7. 6. 5. 4.
Guilford Press, 2008. DJ. Miklowitz J Affect Disord 203; 50:707–79. systematic review. to pharmacotherapydisorders: a moodandanxiety for AV,Ravindran therapies as add-on and alternative da Silva TL. Complementary Med 20; 7:88–890. issues,rent andclinical considerations. safety evidence, Complement JAltern J,LakeSarris J,HoendersR.Bipolardisorder medicine: cur andcomplementary Treatment, andNeurobiology. Adler, MPDelBello, eds., medicinetive in child and adolescent bipolar disorder. Strakowski, CM In: SM Cottle A, McCabe T. S, Gracious BL, Gurumurthy and alterna Complementary 4:254–262. children with bipolar disorder. of Bipolar Disordfamilies for 2002;groups psychoeducation SM.Multifamily Gavazzi JS, Fristad MA,Goldberg-Arnold Bipolar Disorder: A Family-Focused Treatment Approach. rgeso fBipolar Disorder inYouth: Presentation, Progression of New York: Oxford Press, 204. University New York: - -
83 Chapter 8 Psychotherapy and Complementary
individual. Although it is not necessary to use one of these interviews to these interviews Although it is not to use one of necessary individual. manuals provide from aprocess obtaining consistent each for information (K-SADS), Disorders andSchizophrenia Affective for SchoolSchedule AgeChildren for DSM-5(SCID), for such astheStructuredavailable, ClinicalInterview based onpreconceptions orcultural biases. There are manualized approaches obtained andtoguard againstprematurely jumpingtodiagnosticconclusions toward psychiatric initialpsychiatric tobesure picture evaluations thatafull is step. To thisend,each clinician asemistructured needstodevelop approach condition. Consequently, acomprehensive diagnosticassessmentisthefirst a clinical diagnosis. There isnobloodtestorMRIscanthatidentifiesthe Bipolar disorder (like all psychiatric and many other medical conditions) is 9.2.. Comprehensive ClinicalAssessments will now put together (Box 9.). which thatwe we alreadyreviewed, have components, several have most of withtherighttreatment Theseprograms program. particularly lives, healthy Despite thesechallenges, mostpeoplewithbipolardisorder leadrelatively recurrence.recovery affective isoftenslow withevery andisinterrupted ing and,by definition,causemarked psychosocial Functional impairment. themselves. for Symptomssending peopleouttofend are multipleandchang optimal management requires prescribing more amedicationand thansimply Like other complex medical illnesses courses with dynamic (e.g., diabetes), to guide treatment people with bipolar disorder. planning for associated program withbipolarillness. Thischapter anintegrated develops andimpairments behaviors matic treatment approach tomanagetherangeof these must be built into a program interventions, but to be most effective pharmacologicandtherapy and8provide of overviews viduals. Chapters 7 affected indi benefit differentmodalitiestomaximally ment thatintegrates andsophisticatedtreat considered,complexity requires thoughtful, carefully spheres. andlife behaviors This acrosscognition, awiderangeof andfunction As noted, bipolardisorder isacomplexillnessthatimpacts mood, dynamic to Treatment A Programmatic Approach Chapter 9 9.. Introduction 9.2. Pulling ItAllTogether: The Program 2 or the Diagnostic Interview for GeneticsStudies(DIGS). for ortheDiagnostic Interview
3 These - - - -
8585 86 Bipolar Disorder new information will become available during the course of treatment and will becomeduringthecourse available of information new treatment. goals later in recreationalment, and even to guide functional activities relationships, toform employmentprior ability history, educationalachieve However, goals, toidentifyrealistic assessmentsare of functional necessary even when managingmild astomoderate possible, symptoms. as effectively some time. hasbeenintreatmenttion doesnot comefor tolightuntilafteranindividual informa history mation canbeunreliable inmany orspotty; cases, family However, oftendonot discuss mentalillnesses, thisinfor because families canoftenguideboth diagnosisandtreatment decisions.so thisinformation mood disorders, of history whodoesnot afamily have bipolar individual der, in Chapter 4. as reviewed include conditions for evaluations thatco-occur commonly in bipolar disor psy-world.com/madrs.htm psychology-tools.com/young-mania-rating-scale/ online (e.g.,and other available rating scales are YMRS widely at: as measures over tofollow timeinorder tointerpret treatment effects.These Scales Depression (MADRS)Rating tom ratingscalessuch astheYoung Mania(YMRS) toinclude specificassessment. Withthisapproach, symp itisoftenhelpful acomprehensive process timeisacritical component of each andevery aspecific following theapproach acomprehensive evaluation, of perform 6. 5. 4. 3. 2. . Box 9. Consequently, donot endafterthefirst meeting; diagnosticevaluations function treatment istohelpbipolarindividuals Ultimately, a majorgoal of itisanunusual theevaluation; of isacritical part history Additionally, family appointment that: Integrate all aspects of care for long-term managementintoasystematic care long-term for allaspectsof Integrate Set treatment goals—emphasize adherence networkBuilding a support episodes symptoms and affective management of Aggressive evaluation Ongoing safety assessments Comprehensive k. j. i. h. g. f. e. d. c. b. a. Makes and systematically. treatment changes deliberately Provides CBT or other therapy Answers questions and provides education. and plans functional goals. Reviews drug and alcohol use, includingReviews smoking. medical issues.Identifies new Performs assessments. safety general health measures. and supports Reviews adherenceReviews to treatment. the mood chart. Reviews (comorbid) and secondary symptoms.Evaluates primary Components ofaProgrammaticComponents Treatment Plan ). Importantly, these clinical assessments must 5 to assess the severity of symptoms and of toassesstheseverity ; MADRSat: 4 or Montgomery-Asberg orMontgomery-Asberg http://www. http:// - - - - -
(and family members).Moreover,(and family medicalandpsychiatric new conditions with increasing collaboration between theclinician andthebipolarindividual first step is to reevaluate the current treatment (if any) toidentifywhether it first stepisto the current treatmentreevaluate (if appointment.Once an episodeoccurs, every the of episode, mustbe part affective common thosethatpredict symptoms, an ensuing full particularly step toward of managingacute review episodesisto prevent them.Careful in such amannerthatcantake weeks monthstorepair. oreven Thefirst life-threateningbehaviors,acute episodesdisrupt psychosocial function of altering. episodes canbelife InadditiontoincreasingAcute therisk affective Interepisode Symptoms 9.2.3. Aggressively Manage Acute Episodesand der. Managing these comorbidities is discussed in more detail in Chapter 0. thatoccur andsmoking inbipolardisor obesity associated withhighratesof a recurrent illness, aging, and risks medical illnesses occur as a consequence of may priortosignificantdestabilization. New intervention leadtoasuccessful thesecomorbidities suspicion for ahighindexof failing, regimen issuddenly symptoms to provide successful treatment thisWhen support. a previously must remember toinquire aboutknown medicalconditions ornew medical illnesses, the treating psychiatrist and other mental health providers to better medical care. Consequently,individuals with inbipolar individuals by necessity, needtoassume ageneralmedicalrole orhelpguidebipolar complaints withmentalillness, fromsothatpsychiatrists individuals willoften, ening. shown Studieshave thatgeneralpractitionersoftendiscount physical and medicaldisorders (e.g., cardiovascular disease) may becomethreat life management). more care restrictive (e.g., hospitalizationversus outpatient on thesideof care. Asageneralrule,whenindoubt,err the mostappropriate of level others. todetermine riskassessmentisnecessary Aswithsuicide, acareful and states, andmay to self leadtolife-threateningpoordecisions orharm ening. Similarly, and are aggression common impulsivity in mania and mixed can lead to impaired self-care that may or decision-making become threat life severe, sufficiently Chapter 0. Psychosis canoccur inany moodstateand,if is discussed suicidal in individuals more detail in Managementvidual safe. of more care, restrictive including hospitalization,isrequired tokeep theindi whether consideration of athoughtful at aspecific timeandthenmaking individual potential risksinagiven requiressuicidality assessmentof acareful are suicidality, behaviors.Managing psychosis, andaggressive andimpulsive acute life-threateningrisksinbipolardisorder Theprimary alive. individuals At timesthemajorchallenge inmanagingbipolardisorder iskeeping affected 9.2.2. Ongoing Safety Evaluation (and mental health care more generally). was complete, sothatongoing reevaluationistheruleinbipolardisorder care expected, the firstassumption to challenge is that thediagnostic assessment treatment is not as working in younger If individuals. particularly alternatives, illnessthatrequire treatment changes or may duringthecourse develop of In additiontotheseacute risks,co-occurring commonly substance use
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87 Chapter 9 A Programmatic Approach to Treatment 88 Bipolar Disorder that donot meetepisodecriteria alsocreate significantmorbidity. These treatment needs to occur. each thevalueof instances, once of thepatientisstabilized, critical review ever, thisapproach illindividuals, may inseverely not bepossible.Inthese thatchange; how treatment change atatimeinorder togaugetheimpactof tomake one possible,itisbesttotry initiated.Whenever systematically both medications and other therapies, are and identified and deliberately managementoptions, evidence-based possible. Then,appropriate alternative (e.g., again,antidepressants duringmania)andeliminateormodifythemif interventions. Thenextstepistoidentifyany possibletriggersorprecipitants pressant therapy manicepisode),andtoeliminateunnecessary duringanew contributing to theadding benefit or potentially is really relapse (e.g., antide want to prescribe as much medication as needed but as little as possible.” thatisthebest approach.tematic intervention A mantra I keep inmindis“We bipolar disorder condition, isalifetime sothere adeliberate,sys is timefor treatment atatimeispreferred,remembering that changing oneaspectof benefitandso not offering requireprobably reassessmentand change.Again, significant symptomshave onthree medications, then themedicationsare someonecontinues to ing two drugs, there are nonewiththree ormore. If combination therapy involv (Chapter 7). Although therestudiesof are afew three psychotropic or fewer medications at any time, as noted previously management. short-term for improve necessary sothatmedicationsare sleephygiene only additions toward thisgoal. When usingtheseagents, agoal istoconcurrently zodone (e.g., antipsychotics 50–00mg)orsedatingatypical may beuseful (e.g.,sleep aidssuch ashypnotics zolpidem), benzodiazepines, low-dose tra preparing behaviors themtosleep. Whennecessary, of tern pharmacologic apredictable develop pat Clinicians aretohelpbipolarindividuals advised Developing approaches sleepis central hygiene to healthy to this process. managing thisillnessistoprotect regular sleeppatterns. critical component of episodes, a affective new inbipolardisorder andtheonsetof dian rhythms polypharmacy. intolerable and ineffective butalsooftenleadsto tendstofail notsymptoms. only Thelatterstrategy “chasing” recurrence, ratherthanreactively indicatorsof early monitoring for managesymptoms by maximizingrelapsebest toproactively prevention and prescribemedications andtherapiestoappropriately them.Related, itis these problems canbemanagedby understandingthe clinicians sufficiently tience, thatis, thetreatment not waitinglongenoughfor towork. Both of inadequatedosingorimpa becauseof simply indicated. Many treatments fail but once thesesymptoms occur, deliberate,systematic treatment trials are adjuncts. Again,preventionmay isthebetterpath whenpossible, beuseful orserotonin-reuptaketerm) inhibitingantidepressants (inthelongerterm) age anxiety, preferred,butbenzodiazepines CBTisprobably (intheshort episode recurrenceis associated andpooroutcomes. withaffective To man symptoms but also anxiety, affective include typical symptoms not only which In terms of providing medications, I recommend a treatment goal of atreatment goal of providing medications, I recommend of In terms the potential modulated circarelationship between poorly Because of Although acute episodesare themostdestabilizing,significant symptoms ------
9.2.4. Build a Support Network9.2.4. BuildaSupport evident for three for weeks,evident andmaximal benefittakeseven longer. Asnoted treatment benefits trail by several weeks; initialimprovement may not be produce immediately, example, side mood effects stabilizers typically but goals, clinicians musttake thetimetounderstandhow treatments work. For agement, understated outcomes produce apathy. In order to set treatment realisticto develop treatment goals; overstated outcomes leadtodiscour treatment success istowork withbipolarindividuals A majorcomponent of 9.2.5. SetTreatment Goals: Emphasize Adherence participation. group support of andtheirloved ones.individuals Itishard tooveremphasize theimportance is otherwise difficult to create, but that can provide real benefit to bipolar provide Thesegroups disorder network that andtheirfamilies. asupport withbipolarthese and other organizations in theirarea to guideindividuals theirmembers. Clinicians with are encouraged tobefamiliar treatment of communityprovide awarenesstoimprove anddrive educationalprograms They toeducationalpamphletsandpoliticalactionactivities. groups port localsup resources helpful ranging from listsof anumberof have groups members. Basedontheirnationalstructure andsize, thesetwo their family from peoplesuffering bipolarand and alliesfor relateddisordersfor and over thathave, two nationalgroups time, proven tobestrong advocates Ill (NAMI) mentalhealth care.ance theMentally withmodern TheNationalAlliance for are linked to large national organizations that developedhave a strong alli these most communities have existing groups. support Often the best of bipolardisorder. of Becausebipolardisorderage thedisability iscommon, and mentalhealthservices, bestpersonalpractices anddevelop toman psychiatric order each other, consumers tosupport of buildanetwork of withcommon experiences relateding togetherindividuals totheillnessin helplost, to andcombat groups alone. Support by these feelings bring feel isolated, families to andtheir individuals tion thatcausesmany affected this process. assistwith therapiescansignificantly family-focused inChapter 8, reviewed disorder inorder tohelpsetexpectationsandguidedecision-making. As bipolar structureing thissupport isregular educationaboutthecourse of coordinated the entire to best support family. A central component to build withtheirown mentalhealthconcernsto bestruggling thatmay needtobe members heritable,itisnot uncommonfamily bipolar disorder for isstrongly Moreover, inyoungertreatment individuals). adherence (particularly since episodesand symptoms, andaidwith affective psychosocial consequences of symptoms toprevent warning episodes, managethe identifyearly individuals members can be enlisted to help bipolar system. Friendssupport and family als intheperson’s care assoonpossiblemightcreate amore effective relationships,can devastate however, individu soenlistingtheseimportant andfriends. Bipolardisorder family with somepsychosocial namely support, attreatmentthefirsttime for withbipolardisorder arrive Most individuals Bipolar disorder isacomplex andattimesmystifying and disablingcondi 6 and the Depression Alliance and Bipolar(DBSA) Support 7 are are ------
89 Chapter 9 A Programmatic Approach to Treatment 90 Bipolar Disorder ing. Goalsettingwillevolve ageandbecome over more timeasindividuals liv daily of bipolar disorder intoactivities managementof how tointegrate choices (e.g.,functional whetherornot totake anight-shift job),andlearn bipolar illness has on symptoms, understand the impact management of moods from to distinguish normal affective learn tant as bipolar individuals improvement.chosocial functional impor Thelatterbecomes increasingly symptom management,butalsopsy include not only These goals willideally response aretobe. likely risks,relative benefits, andratestimingof therapiesandwhatthe evidence-based anunderstandingof that integrate withbipolardisordermended thatclinicians setspecific goals withindividuals theeducationalprocess, itisrecom altering.life Consequently, of aspart psychotherapy tobe isunlikely not years, sessionof example.A single for if earlier, there thatlithiumbenefitsaccumulate issomeevidence over months of mood states and symptoms. of specific to develop habitsthatinclude regular monitoring bipolar individuals requires approach along-term tothisillnessthat requires both clinicians and periods.recurrences This goalto minimize andextendeuthymic affective cause to stop treatment. asked a not directly aboutbutis commonly reportedif tion, which israrely and addressed. For example,medications may contribute tosexualdysfunc inquire tobesureto regularly aboutsideeffects they are identified, reported, enhance treatment adherence.significantly requires clinicians Thissensitivity inorderConsequently, to side effects tocan maximize tolerability sensitivity antibiotics?). course of completed every actually example,have book, for you reading this immediate,benefits(how many of outweigh the,essentially thesideeffects Finally, living. medicationsif healthy mostpeoplestoptaking restructuring cognitive leadingtosuccessful, ence intothelargercontext of how toplace thetraining,teaching treatment individuals adher apy of aspart medicationandther treatment adherencewell-designed CBTintegrates of days, several gence example.Third, medication for afternot for a taking here,Again, to demonstrate mood can charting be useful symptom emer repeated over toward time,may betteradherence. bringsomeindividuals not following treatment, educational demonstrating program the impact of andadmit it.Second, someonedirectly awell-developed toface than having recorded impersonally in whichrather itcanbesomewhat ontoachart, (see section 9.2.6.) provides one method to monitor treatment adherence adherence willbereported andaddressed nonjudgmentally. Moodcharting toward managing treatment nonadherence sothatnon rapport istodevelop A first step needingmedicationtodifferentindividuals). (e.g., themeaningof cultural factors ithard of making tomanage,andavariety polypharmacy) help adhere totreatment plans, complex overly treatment (e.g., excessive education regarding treatment, theneedtofollow insufficientto support to nonadherence are multiple and include poor insight into illness, lack of treatment Factors contributing failure. Nonadherence is a leading cause of care, goal-setting is an ongoing process, not a one-time event. bipolardisorder atmanagingtheirillness, so,effective like other aspectsof Ultimately, by virtue of itscyclicity,Ultimately, bipolardisorder amajorgoal for is of by virtue theplan. follow any treatmentA majorgoal for planistoactually ------
aged ratherthan cured. To strategy achieve thismanagement,along-term Bipolar disorder, like other chronic recurrent, conditions, lifelong isman Management 9.2.7. Integrate AllAspectsofCare: Long-Term clinicians a specific to best manage mood cycling individual. for that iseasy tocomplete, used,andcanbeshared will beconsistently with mood charting be more “userfriendly.” Thekey featureistofindameansof health-slideshow/top-iphone-android-apps-bipolar-disorder thissamepurpose(e.g.,cations thatcanserve phone) explosionhasproduced computerandappli andphoneprograms provided Additionally, intheAppendix. cell thetechnological (andespecially varioustreatment interventions. A sample is mood chart of effects long-term recordings tobetteridentifythe canbereviewed weeks monthsof andeven events.medication adherence, Then,duringappointments, life orstressful sleep, alcoholized toinclude use, potential mood triggers, such ashoursof and interpretation. Moreover, canbeextendedandindividual thecharting time. Ideally, toallow easy shouldrecord viewing themoodchart graphically aprocess develop clinician tomonitortreatment andbipolar individual over alcohol)ment success helpboth the (e.g., hoursworked, decreased useof treat measures moodsymptoms of orother individualized simple record of cess. recommended. For ishighly Even thesereasons,moodcharting a daily thatmay orsuc term bemisattributedtotreatmenttion intheshort failure can alterpresenta treatment andnegative) (both positive near thetimeof thisapproach events previous appointmentinterval; canbemisleadingaslife illnessover the appointments, course ratherthanreviewing of at thetimeof feels onhow thebipolarindividual willrely clinicians andbipolar individuals specific approaches toward thesemeasurements, making both the absence of symptoms inresponse tochanges intreatment over time.Unfortunately, in episodes ischallenging; therefore, itbecomes critical tomonitorchanges in for decreasing thenumbersof tifying thetreatment thatismosteffective trialanderror, treatmentevidence-based iden relies amountof onacertain treatment, symptom recurrences canandwilloccur. Moreover, since even may variableandextendedinterepisode have intervals. Even witheffective symptoms andsyndromes andbehavioral and waningmood,cognitive, that As noted, bipolar disorder condition is adynamic characterized by waxing 9.2.6. MoodCharting Key Point critical to determine the effectiveness of treatment interventions. of the effectiveness critical to determine trial-and-error treatment assignment; consequently, is moodcharting Key Point collaboration. improve cansignificantly treatment adherencetions successfully and tial toguidetreatment decisions andexpectations. Managingexpecta : Thoughtful, : Thoughtful, Bipolar : is a dynamic, cycling illness managedis a dynamic, through realistic, and hopeful treatment goals arerealistic, andhopeful essen http://www.healthline.com/ ) andthatmay ------
91 Chapter 9 A Programmatic Approach to Treatment 92 Bipolar Disorder appointment that can be operationalized as follows: involves a multistep systematic standardizedintegration approach at each From thedimensionsreviewed. theclinician side,this across allof integrated “chasing” illnessmanagement.To toproactive dothis, clinical care mustbe is required; asnoted, care needstomove awayfrom symptom reactive doing so will lead to best outcomes. bipolarillness; direct contrast sometimeschaotic to thedynamic course of adopt corresponding deliberate habitsincians canhelpbipolar individuals goals. Byprovidingand settingfunctional systematic predictable care, clini withatherapistwhoprovidesagement andassessmentsinpartnership CBT make example, a psychiatrist bedistributed;for mightprovide medicalman . 0. Depending on the clinician’s professional discipline, some of these steps Depending ontheclinician’s professional discipline, someof 9. 8. 7. 6. 5. 4. 3. 2. .
charting. changes with mood and monitorthe impact of andsystematically ately oneatatime.MakePlan treatment changes changesdeliber ideally (i.e., events stress). life behaviors, and decreasing the impact of managing interepisode symptoms (e.g., and interpersonal anxiety) Provide CBTorother therapy on treatment withafocus adherence, Answer questions and provide education. being met. goals are psychosocial andwhetherfunctional Review function cessation plans. drugandalcohol use,including smoking.Review Develop the individual’s mental illness. of part complaints as dismissphysical and other specialists whodonot simply findinternists (e.g., studies).Helpbipolarindividuals weight, laboratory medicalissuesandmakeIdentify new medicalassessmentsasindicated managing dangerousness. strategies for tem to develop insomeinstances.safe Work witheach individual’s sys support closely thoughts asindicated.Hospitalizationmay tokeep benecessary people suicidaland andother behaviors Perform assessmentsof safety and regular,hygiene predictable rhythms. life sleep lar sleepandexercise. healthy develop Helpbipolarindividuals generalhealthmeasures—forexample,regu andsupport Review improve adherence. the problem educationalorCBT-based anddevelop to interventions adherencereview (e.g., recording helps to identify on the mood chart) tononjudgmentally Buildingrapport treatment failure. causeof mary adherenceReview totreatment. Nonadherence totreatment isapri and the long term. how symptoms respond totreatment interventions, inboth theshort over toidentifysymptom themoodchart patterns timeandReview episode recurrences. prevention soon of as possible for ensuingepisodes, inorder as tointervene symptoms of and behavioral symptom todefineearly Over time,work withthebipolarindividual manage anxiety and sleep disturbances.attention to and aggressively (comorbid) and secondary symptoms.Evaluate primary Pay particular ------
7. 6. Group Links Support 5. 4. Symptom Rating Scales 3. 2. . Semi-Structured DiagnosticInterviews References
Depression Alliance and Bipolar (DBSA): Support National Alliance on Mental Illness (NAMI): change. Br J Psychiatry 979; 34:382–389. to depression SA,AsbergM.Anew scaledesignedtobesensitive Montgomery and sensitivity.validity Br J Psychiatry 978; 33:429–435. Young RC, BiggsJT, VE,Meyer Ziegler DA. mania: reliability, Arating scalefor Mental Health, 2004. Diagnostic Genetic for Interview Studies KSADS). Kiddie Disorders andYoung andSchizophrenia (WASH-U- Affective for AdultSchedule Geller B, Zimerman WilliamsM,Frazier J. York,New NY 0032, 995. New YorkState PsychiatricDepartment. Institute,722West 68thStreet, Patient DSM-IVfor Edition Axis (SCID-I/P). I Disorders- First MB, Spitzer RL,GibbonM,WilliamsJBW. Key Point of its expression. of erate systematic treatmentthataddresses program thebroad nature St. Louis, MO: Washington University School of Medicine, 996. St. Louis, MO: Washington School of University : Due to itscomplex nature, bipolardisorder requires adelib v. 4.0. Rockville, MD: National Institute of www.nami.org Washington University inSt.Washington Louis University www.dbsalliance.org Structured Clinical Interview BiometricsResearch -
93 Chapter 9 A Programmatic Approach to Treatment
psychological perhaps thebestapproach functions, inyouth istomaintain a emotional, cognitive, andsocial developing neuro nosis withinthecontext of diag thecomplexitiesand anincreased of onset.Given geneticriskthantypical monitoring treatment response maysuspicion while carefully be informative. datamightclarify diagnosis. AswithADHD, history with family ahighindex of mania(e.g., grandiosity, decreased distinguishing featuresof itdifficult todistinguish making from bipolarmixed states.onthe Again, relying bipolar disorder. example,worsening symptomsfor withstimulantprescription mightsuggest bymay treatment monthsandmay not beclear response; for beinformed abipolardisorder for diagnosis.adds support Inmany instances, thediagnosis bipolardisorder of history bipolardisorder, ADHD. A family of butnot of thecourse episodicity, asthesefeaturesareof part of euphoria, andevidence moodsymptoms, approach onprimary especially istofocus the mostuseful atric depression. occur inother common childhood conditions, example,ADHDandpedi for more chronic orirritability. moodlability Unfortunately, thesesymptoms bipolardisorder inchildren; namely, childrenexpression of may present with maniausedinadultsmay not represent the the strictepisodicdefinitionof bipolardisorder inyouth suggestthat Attempts toclarify thepresentation of more in symptomsthese children. “typical” in the future predict the onset of who may beexpressing bipolardisorder;thesesymptoms “atypical” may also anddistractible children irritable, activated, research identifiesanumberof meetingadultmaniacriteria areIn theseyounger rare, groups,individuals yet difficult mania(e.g.,tointerpret. grandiosity) symptoms of can make “adult” diagnoses inyounger children, andemotional inwhomcognitive development well manic episodes. Thisrequirement applies isthesameinyouth andgenerally manicorhypo bipolardisorder hingesontheoccurrence of The diagnosisof 0... Diagnosis ofPediatric BipolarDisorder specific differences are highlighted here. bipolar disorder inadultsandyouth are noted throughout thisbook,afew lescents withbipolardisorder iscommon. Althoughdifferences between bipolardisorder somanagingado beginbeforeage2 years, Most casesof Managing SpecialPopulations Chapter 0 0.. Pediatric BipolarDisorder Earlier onsetbipolar disorder isassociated withpoorer outcome long-term Pediatric andagitation, depression expressed isfrequently withirritability Distinguishing ADHD from bipolar disorder in children is difficult. Perhaps to older adolescents (e.g., >5 years). However, debate need for sleep) along sleep)along for exists around - - - - -
9595
96 Bipolar Disorder involvement, and good mood charting, general health measures. pharmacology, appropriate targetedpsychotherapies, educationandfamily including systematic psycho matic approach asdescribed in Chapter 9, youth withbipolardisorder,treatment of aswithadults, requires aprogram prevention, althoughcontentthechild’s mustbeadjustedfor age.Successful approaches bipolardepression for and relapse are promising, particularly therapy (CBT) andcognitive-behavioral to medications. Both family-focused bipolar disorder, decreased risks relative althoughthe option they of offer ring with some antipsychotics are more pronounced in children. dren age,doseadjustmentswillbeexpected.Finally, prolactin increases occur weight) may importantly, body benecessary; doses (afteradjustingfor aschil higher thanadults, sothatrelatively metabolize drugsfaster people typically excessivedoses toavoid impairments.Conversely, sedationorcognitive young andsomay sideeffects benefit tocognitive also bemorefrom sensitive lower curvesvidual growth mustbefollowed carefully. Children andadolescents may adults. Consequently, height and attention weightto relative percentiles in indi problematic, with drugseven considered “weight neutral” in to be relatively thesemedications. Inparticular, of weight gainismuch more thesideeffects of approved below age 0 years. treating bipolardepression inchildren oradolescents, andnomedicationis Notably, the fluoxetine-olanzapine only combination isUSFDA approvedfor USFDA-approved few bipolaryouthrelatively medicationsfor (Table 0.). adults, itcannot beassumedtothesame.Moreover,to thatof there are pediatricbipolardisorder issimilarinapproach Although thetreatment of 0..2. Treatment ofPediatric BipolarDisorder history, symptomas family and evolution, treatment response. any initialdiagnosiswhilegatheringadditionalclinical datasuch skeptical of view Bipolar Disorder in Youth Table 0. Aripiprazole For Maintenance Risperidone Aripiprazole Olanzapine Quetiapine Lithium For Mania Psychotherapies have been relatively infrequently studiedinyouth infrequently withPsychotherapies beenrelatively have Children andadolescents thanadultstomany appear tobemore sensitive maximal outcomes. treatment require differentstrategies inorder somewhat toachieve the same as bipolar disorder in adults. Differences in diagnosis and Key Point : Pediatric
Medications USFDA Approved for Treatment of bipolar disorder cannot simply beassumed tobe bipolar disorder cannot simply - - - - -
cations that are being prescribed, even if they beentaken years. have for For cations thatare beingprescribed, if even delirium (e.g., reevaluate all medi confusion), of those suggestive particularly symptoms, new isachieved. Atuntil astabletherapeuticlevel thefirstsignof ing efficacy.levels, Fordrugswithserum relevant check thesemore frequently and then titrate more while assess slowly, tolerability for monitoring carefully thestandard adultdose toone-third of medication,beginatone-half a new that arebecome tolerableinmidlife toxic withaging. Therefore, whenstarting older adults. guidelines can be Nonetheless followed.several of attentiontotheneedsandconcerns beenstudiedwithparticular rarely have thatmaybidity alterdrugdispositionandmetabolism.Finally, psychotherapies medical comor bipolar disorder higherratesof iscomplicated by significantly of standard therapiesis welldefined. Second, late-life nortolerability efficacy First,thereclinical studiesinthisagegroup, arefactors. few sothatneither uncommon. are listed in Boxin older individuals 0., although, again, they are relatively proven otherwise. medical condition until an underlying should be considered a consequence of is quiteuncommon Inthislattergroup, afterage50 years. mania new-onset and mania,becomesdefined by new-onset less common afterage35 years bipolar disorder, New-onset 5–25 years. from onset ages of the typical suicide increases behavior, with age as well. during impulsive falls and risk of from medical illness must be considered, example, injury for higher rates of similar across theadultagespan.Risksfrom depression andmania related to younger ages;otherwise, diagnosticandcourse-of-illness considerations are pronounced, symptoms so that depressive predominate more even than in manicandpsychoticIn olderbipolarindividuals, symptoms tendtobeless mooddisorders inthisagegroup. casesof 0.4%, comprising 0–25%of isupto bipolardisorder inpeopleover age60 years the prevalence of Nonetheless, associated withtheillness (seeChapter 4). mortality age of Bipolar disorder to the younger is lesscommon due in large part in late life, Stroke Box 0. 0.2. Late-Life BipolarDisorder With aging,drugmetabolismdecreases. Consequently, medicationdoses bipolardisorder inolderadultsiscomplicated byTreatment several of illness acontinuationIn mostcases,bipolardisorderof late-life issimply Vitamin B2 deficiency pressureNormal hydrocephalus after surgery Brain injury Hemodialysis CNS infection Epilepsy Dementia Brain tumor Head trauma 4 Medical CausesofManiainLate Life 2 – 4 The more frequent medical causes of new-onset mania new-onset The more frequent medical causes of 2,3 2,3 - - -
97 Chapter 0 Managing Special Populations
98 Bipolar Disorder focus on minimizing the number of medications prescribed. on minimizing the number of focus morethaninyoungerwitha Chapter 9 isperhapseven important individuals, deliberateapproach asystematic, following older individuals, asdescribed in spouse, partners, and friends.sleep, In health, declining and loss of physical including decreased laterlife to ability pies mustincorporate thestresses of by thesamedecision processes asinyounger adults. Finally, psychothera better tolerated and safer. Otherwise, medication choices guided are largely asitmightbe choice thaninyoungerhigher level inthisagegroup individuals ated with sudden death in older adults. therapy Electroconvulsive may be a Moreover,decline afterage65 years. someantipsychotics beenassoci have toxicity develop withrenal suddenly function 0.6meq/Lcanrelatively of level 20 yearsexample, apersononlithium,200mgfor withalong-standingserum miscarriage, prematuremiscarriage, delivery, underdevelopment. Consequently, andfetal tions. However, untreated maniaanddepressionincreased impart risksof mental risksthatmightresult from neurodevelop thelong-term littleisknownundefined. Inallcases, of very USFDAcally class C aswell. Risksfrom other standard treatments are largely diazepines are contraindicated inpregnancy, andantidepressants are typi occur withfirst-trimestermalformations exposure. Moreover, many benzo These malformations. neural tubeandcraniofacial increased20-fold riskof areleptic medicationscarbamazepine anddivalproex associated withuptoa leading to cardiac conductionformation and ejection problems. The antiepi tricuspid valve Ebstein’s namely anomaly, of malformation, amalformation cardiac Lithium is associated with a three- to eight-fold increased risk of Unfortunately, many bipolardisorder treatments are teratogenic(Table 0.2). childbirth, is arelapse high-risk periodespecially for in bipolar women. Managing bipolardisorder duringpregnancyiscomplex. Pregnancy, and evidence of risk. evidence riskinhumans;C = riskcannot beruledout;D = positive show of norisk; B = noevidence followingThe FDA categories: A = controlled inpregnancy usingthe classifies drugsafety studies Table 0.2 Oxcarbazepine Lamotrigine Carbamazepine Divalproex antipsychoticsAtypical Lithium Medication 0.3. BipolarDisorder andPregnancy distribution and metabolism. attention toco-occurring medicalproblems aswell aschanges indrug Key Point : Managing : Managing
Bipolar Disorder Medications inPregnancy bipolar disorderrequires inlatelife increased in utero exposure topsychotropic medica USFDA Rating D D D C C C ------
not be appropriate. stoppingalltreatment inapregnantsimply woman withbipolardisorder may mixed states, symptoms fluctuationsamongmanic anddepressive occur, but called.During isnot “ultrarapidcycling”lability asitissometimes mistakenly day thatcaninclude depressed Consequently, mood (seeChapter 2). mood lability, the namely, rapidmoodchanges andfluctuationsduringthe course of episode.Additionally,rather thananew maniaisoftencharacterized by mood thecurrent episode, ment butbefore8weeks isconsidered acontinuation of sion. A relapse,episode, occurring aftersymptom improve thatis, full anew remis episode recurrencedepression) afteratleast8 oranaffective weeks of Typically, thiscriterion isdefined switch (e.g.,by apolarity from maniato this definition is that the episodesyear. aresingle aspect of A critical episodeswithin a four or more cycling isdefinedas distinctaffective Rapid stopping or remaining on treatment. risksof therelative psychiatrist withongoing assessmentsanddiscussion of must becoordinated amongthepregnant woman, herobstetrician, andher pregnancy. Inallcases, bereinitiatedcare duringthefinalmonthof generally relapse at delivery,mester. standard treatment should the high risk of Given acute episodesduringthefirsttri treatment for of particular alternative, an duringpregnancyandoffers safe therapyElectroconvulsive isgenerally acid therapyshould beincreased mightbeconsidered. andomega-3fatty medications are discontinued, psychotherapy andgeneralhealthmeasures help guidethesedecisions. Inboth unplannedandplannedpregnancy, when tinuing treatment may no longerbethebestchoice. Fetal ultrasoundsmay thepregnancyisnot brought toattentionuntilafterthatperiod,discon if However,safe. theriskoccurs inthefirsttrimester, asnoted, since mostof tions, sowhen possible,as deemed they should bediscontinued as rapidly dangerous exposuregoal medica isstilltominimize fetal topotentially relapse. in case of developed priortoattemptsbe tapered atpregnancyandcontingencyplans slowly during that time. Regardless,only with either approach, medications should occurs inthefirsttrimester, itmay bepreferredtodiscontinue medications theentire theteratogenicriskfor pregnancy. Alternatively, since mostof tions withoutrapidrelapse, itmightbepossibletodiscontinue medications abletostopmedica mildbipolarillnessorwaspreviously relatively of history to minimize the woman medication exposure has baby.a tothe developing If 0.4. Rapid Cycling In many cases, however, pregnancyisunplanned;intheseinstances, the a planned pregnancy, attempt should be made every ideally In the case of among the pregnant woman, her obstetrician, and her psychiatrist. The decisions require well-coordinated assessments anddiscussions thepregnancy. or not toremain onmedicationsatvariousstagesof whether complex, risk-versus-benefit requiring careful calculations of Key Point : Managing : Managing pregnancy inwomen withbipolardisorder is distinct ------.
99 Chapter 0 Managing Special Populations
100 Bipolar Disorder clinicians can assist family members so that they,clinicians can assist family too, are with comfortable moveclinician may forward tobettersolutions. helptheindividual Similarly, aboutthesethoughts withanempathic aboutsuicide, sotalking ambivalent are diminishestherisk.Many individuals likely thissimpleintervention fact, suicide andin highrisk.Discussing suicide doesnot increase theriskof of during periods appointments, particularly assessment aroutineof part suicide inpeoplewithbipolardisorder. stepistomake suicide A critical bipolar disorder.the management of may now bedecreasing; nonetheless, suicide remains asignificant in concern Fortunately, withincreasing and awareness, treatment thisrate availability themselves.kill Thisrateis30timeshigherthaninthegeneralpopulation. peoplewithbipolardisorder attempt suicide, andabout5% Up to50%of bipolardisorder.Suicide isatragicandalltoocommon consequence of cycling in rapid than other choices.less effective therapy thatprevents possible.Ingeneral,maintenance psychotropicthree orfewer medicationsif systematic drugchanges whileprescribing the core treatment principles of drug. Whileaddressingor switch toanalternative rapidcycling, remember is, increase moodstabilizer dosesastolerated,addasecond moodstabilizer, and address maximizingrelapse-prevention itwhileconcurrently therapy; that precipitantgoal inmanagingrapidcycling, then,is to identifytheunderlying cycling rapid arecific trigger. listedinBox 0.2.Thefirst Commoncausesof treatment algorithms. episodes, are including thosewithmoodlability managedaccording tomania represent mixed asingle episoderatherthan“rapidcycling.” Mixed andmanic Life events (stress) events Life Box 0.2 Disorder 0.5. Managing Suicidal IndividualswithBipolar There are several steps clinicians can take to help decrease the risk of There are stepsclinicians several cantake tohelpdecrease theriskof When itoccurs,atime-limitedresponse toaspe rapidcycling istypically cipitant; the first response, then, is to manage the precipitant. Key Point Treatment nonadherence Stimulant use Antidepressant use Other medical illness disease Thyroid Alcohol abuse Drug abuse Sleep disruption : Rapid cycling Precipitants ofRapid Cycling both maniaanddepression ispreferred;lithiummay be is typically atime-limited statecausedby apre is typically 5 - - problem-solving manner. and these discussionsinanonjudgmentalsupportive andcanparticipate vidual and their family members manage these impulses. Over the long term, vidual and their family outpatient careincreasing for suicidal thoughtswillhelpboth thebipolarindi hospitalization isnot clear needed,thendeveloping contingencyplansduring whetherhospitalizationisnecessary. isusedtodetermine factors If tective pro acute andchronic inflectionpoints, andthepresence riskfactors, of that aid assessment and can be enhanced (Table 0.3).protective factors risk by energizingdepressedFinally, andhopelessindividuals. there are also suicidal behavior. Inparticular, mixed suicide statesandrapidcycling elevate stress (e.g., increased divorce orloss),thatindicateaneedfor vigilance for another majorlife majormedicalillness,oping anew ortheoccurrence of drugoralcohol abuse,devel talization, switch intoamixed state,relapse of Withintheserisksaretreatment inflectionpoints, orlifestyle. such ashospi context riskassessment.Otherscanbeaddressed for through changes in (Table 0.3). Source: Goodwin andJamison Table 0.3 Limited access to highly lethal methods of suicide (e.g., guns) lethal methods of Limited access to highly Ongoing mental health care Good coping skills Future orientation Strong social support Strong religious beliefs at home family/children Supportive Factors Protective Chronic medical illness stressorMajor life Recent loss onset illness Early Personality disorder Psychosis Anxiety/Panic attacks Drug/Alcohol abuse cycling Rapid Hopelessness Depression Mixed state Suicidal ideation suicide of history Family Prior suicide attempts Risk Factors When an individual expresses suicidal thoughts, a careful assessment of expresses suicidal assessmentof thoughts,When anindividual acareful managing suicide istorecognize riskfactors A second component of
5 Suicide RiskandProtective Factors inBipolarDisorder Some of these cannot be modified, but nonetheless provide Some of 5 - - - -
101 Chapter 0 Managing Special Populations
102 Bipolar Disorder hoped that the risk of this tragic outcome can be ameliorated. hoped that the risk of asdescribed bipolardisorder inthisbook,itis comprehensively treatment of and difficult that is often impulsive tobehavior predict. By approaching the frequent safety. butsmallamountsfor Regardless, suicide remains acomplex therisksassociated withoverdose, itmay needtobeprescribed in because of choice although insuicidal individuals, quently, lithiummay bethetreatment of lithiumdecreases suicide riskunlike otherin Chapter 7, treatments; conse behaviors.Finally, adaptive by asnoted alternative developing ing riskfactors risks; therapy canbetargetedtomanagesuicidal impulsesandtheunderly whileminimizing inbuildingmore protective factors the bipolarindividual with chronic suicidal ideationinparticular, treatment mustbetailored toassist ders integrated therapy manuals(seeWeissders integrated andConnery eral research are specific groups developing bipolarandsubstance usedisor both conditionsstrategies for thatmightprovide approach; sev anintegrated drug-drug interactions. Incontrast, there isoverlap incognitive/behavioral and effects adverse negative and9monitoringfor Chapters 7 rule of men, again, keeping in mind the “three psychotropic or fewer medications” mood-stabilizing regi willneedtobeaddedanexistingeffective typically drugsarethelatter, usedfor bipolar andsubstance usedisorders, these if co-occur. lar andsubstance usedisorders whenthey mustbemanagedconcurrently bipolarillness. Consequently, bothrelapse bipo andworsening course of addiction for episodes andtheassociated stresses setuptheseindividuals abuse hasremitted. Thispositionisalsountenable,asrecurrent mood not treating for advocate thebipolardisorder untilco-occurring substance mood stabilizers are wellness. critical for Conversely, somepsychiatrists stance not with reasonable bipolaris clearly disorder, individuals for since other conditions; this ering from drugoralcohol addictionsregardless of againstany advocated medication useinpeoplerecovsome self-helpgroups bipolardisorder. theoverall treatment of Historically, addressed of aspart illness, somustbedisorder. impactcourse of Theseconditions negatively with bipolar individuals of Drug andalcohol abuseoccur in more than half 0.6.. SubstanceUseDisorders general guidelines are provided here.only thisbook,so potential combinations exceeds thescope of vast numberof willrequiremost bipolarindividuals treatmenttheseother conditions. for The co-occurring psychiatric, medical,andsubstance usedisorders. Consequently, bipolar disorder complicated is commonly by As discussed in Chapter 4, 0.6. Managing Comorbidities Because there is currently minimal overlap in effective medications for medications minimal overlapBecause there is currently in effective risk factors and acute stressors.risk factors whilecompensating for protective factors requires of ongoing support Key Point : Suicide isasignificantriskinbipolardisorder;management 6 asanexample). ------
ated as soon as possible in bipolar individuals withtheseconditions.ated assoonpossibleinbipolarindividuals Research Regardless, standard approaches todrugandalcohol abuseshouldbeiniti second condition. matic treatment described inChapter 9 apply, withexpansiontoinclude the program critical inthesecomplex situations. Again,thegeneralprinciples of becomes interventions both identifyeffective conditions tosystematically of co-occurring OCD. symptomsand provide treatment Charting of primary example,awell-designed CBTcanassistwithbipolardepression for tive; psychotherapies. crafted psychotherapy Carefully is often a good alterna competing andeliminatingmultiplepotentially mizing polypharmacy mini for both conditions,pies thatare toward effective thegeneral goal of the second condition ensues. Ideally, when possible, it is best to use thera in order to improve control behavioral and treatment adherence. disorder, therapy thepersonality without initiatingdialecticalbehavioral for orders mightnotintreatmentbipolar disorder beabletoparticipate for withboth bipolarandborderline dis personality example, anindividual thatdonotusing interventions disrupt treatmentbipolar disorder. for For managedwith obtainingmoodstabilization,thenitshouldbeconcurrently thesecond condition isinterfering illness. Theexception tothisruleisif symptoms)anxiety may resolve withimprovement bipolar intheprimary managedfirst.Moreover,appropriately someapparent (e.g.,comorbidity itisnot ments (e.g., antidepressants) thatcandestabilize bipolardisorder if other psychiatric for interventions illnesses(e.g., OCD)may require treat themoresince disablingcondition. bipolardisorder Additionally, istypically aging these situations proceeds as follows. present uniquechallenges,and individual thegeneralapproach toward man co-occurmonly inbipolardisorder Althougheach combination (Chapter 4). In additiontosubstance usedisorders, other psychiatric conditions com 0.6.2. Co-occurring Psychiatric Conditions tion during this period is warranted. drugandalcohol interven use,sothatpreventative theonsetof risk timefor high also suggeststhatthe yearfor maniaisa very afterafirst hospitalization Once mood stabilization is established, then aggressive management of managementof Once moodstabilizationisestablished,thenaggressive thebipolarillness, istomaximize moodstabilizationfor The toppriority treatments when possible. condition,then managethe secondary withan eye toward integrated and other psychiatric disorder is to first stabilize the bipolarillness and Key Point treatment both conditions for is preferable. integrated thesubstance usedisorder. therapiesfor aggressive When possible, ment regimeninitiating bipolar illness while concurrently possible for identifythebesttreat and substance usedisorders istoaggressively Key Point : The best : The best overall approach managingco-occurring for bipolar overall approach managingco-occurring for bipolar ------
103 Chapter 0 Managing Special Populations
104 Bipolar Disorder medications, somay eitherbereluctantstandard tostart medicaltherapiesor care providerswithpsychotropicmary oruncomfortable are oftenunfamiliar chiatric condition, thereby challenge discounting is that pri them. A second medicalillnesstothepsy specialist medicalproviders attributesymptoms of the specific forthisbiasarereasons not clear, and that primary itislikely in the community as compared with people without mental illness. Although shownhave that people with mental illness receive substandard medical care lenges whenmanagingmedicalcomorbidities inbipolardisorder. First,studies and cardiovasculardiabetes, migraine, disease. many medical conditions such as higher rates than the general population of withbipolardisorderfrom suffer individuals Also asdescribed inChapter 4, 0.6.3. Co-occurring Medical Illnesses 3. 2. . References mental illnesses. andspecialist care providersthe bestprimary whowork withpeople symptoms andby withinthelocalbipolarcommunity working toidentify theircare treatmentmedical bycan facilitate beingdiligentinseeking for bipolar disorder toreceive optimal medicaltreatment. Bipolarindividuals for peoplewith thebestopportunity with mentalhealthclinicians offers medicalproviders andspecialty fying primary whowork collaboratively complaintsillness andtake seriously. theirphysical Inboth cases, identi ships withmedicalproviders whodonot stigmatize peoplewithmental help theirbipolarclients relation by identifyingandestablishingreferral dangerous drugcombinations.against potentially Nonpsychiatrists can andguard tominimize polypharmacy withother physicians work closely treatmentmedical illnessesinorder referrals.They canalso tofacilitate Psychiatrists oftenprovide medicalcare by someprimary screening for within the medical community. individuals affected as for advocates serve the latter.renal clearance of over-the-counter ibuprofencanlead tolithiumtoxicityinhibits astheformer bipolardisorder. using ment of For example,asimplerecommendation of impacttreat potential drug-druginteractionsthatnegatively are unawareof
Hopkins University Press, 2007. University Hopkins Sajatovic M,Blow FC. Geriatric Pharmacotherapy 2006; 4:347–364. Aziz R,LorbergB, Tampi RR.Treatments bipolardisorder. late-life for AmJ Adolescents. Geller B, DelBello MP, eds. To address theseproblems, clinicians managingbipolardisorder must individuals. bipolar of by mental health advocacy providersactive on behalf Key Point : Managing New York: Guilford Press, 2008. medical illness in bipolar disorder typically requiresmedical illness in bipolar disorder typically Bipolar Disorder inLater Life. ramn fBipolar Disorder inChildren and Treatment of 4 There are chal two primary Baltimore, MD: Johns Baltimore, MD: Johns ------4. 6. 5.
eia lns.I: Tohen M, ed., medical illness. In: Sax KW, bipolardisorder with Strakowski SM.Theco-occurrence of Substance Abuse. Weiss RD, HS. Connery New York: Oxford Press, 2007. University risk. suicide Clinicalmanagementof 25: KR.Chapter FK,Jamison Goodwin New York: Dekker, 999. ai-ersieIles Bipolar Disorders andRecurrentDepression. Illness: Manic-Depressive New York: Guilford Press, 20. Integrated GroupTherapy Bipolar Disorder for and Comorbidity in Affective Disorders. Comorbidity in Affective
105 Chapter 0 Managing Special Populations
Appendix Example Mood Chart
107107 108 APPENDIX
Day Measurement 2 3 4 5 6 7 8 9 0 2 3 4 5 6 7 8 9 20 2 22 23 24 25 26 27 28 29 30 3 Medications: Lithium 900 mg X X X X X X X X X X X X X X X X X X X X X X X X X X Lamotrigine 300 mg X X X X X X X X X Alcohol use, glasses 0 2 5 3 6 4 6 4 3 5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Sleep, hours 7 8 7 8 7 4 5 4 3 5 2 2 6 9 9 2 2 2 2 0 0 9 8 8 7 6 7 7 7 7 Mood: Severe mania Moderate mania X X Mild mania X X X X X X Feeling well X X X X X X X X Mild depression X X X X X X Moderate depression X X X X X X X X X Severe depression Example of a mood chart identifying possible items to be measured. In this example individual, discontinuing lithium (day 7) is associated with increased manic symptoms and increased alcohol use, followed by cycling into depression (day 6). Lamotrigine is added on day 23 to address these symptoms. Note changes in sleep associated with mood switches. The changes here are exaggerated for illustration purposes only and should not be viewed necessarily as a typical course or treatment response. This design is loosely based on the “Personal Calendar” available from the Depression and Bipolar Support Alliance (DBSA). The DBSA sells at a nominal cost a more detailed, 6-month calendar/ mood chart that is strongly recommended for any practice in which people with mood disorders receive care. DBSA can be contacted on their web site—www.DBSAlliance.org—or at DBSA, 730 N. Franklin Street, Suite 50, Chicago, IL 6060-7224. (800) 826-3632. Month: July
Adherence toplan, ADHD. SeeAttention deficit Acupuncture, indicateboxes, ”,and“t” figures, andtables. Page numbersfollowed by “b”,“f Antipsychotics Antiepileptics, Antidepressants, Anterior cingulate, Ankyrin 3(ANK3), Anhedonia, Anatomy Amygdala, Amphetamines, D-Amino Acid Oxidase medicine, Alternative Alcohol abuse, Agomelatine, Age effects, Aged populations, African Americans, effects, Adverse Adoption studies, Adolescence, overview of conventional, of overview atypical, of overview olanzapine, neurotransmitter lurisadone, clozapine, asenapine, aripiprazole, white matterabnormalities ventral striatum of, overview neurotransmitter amygdala abnormalities importance of, of, importance disorder hyperactivity Inhibitor (DAOA), 24 56t 69 7 58t and, hypotheses 60t 58t 60t 65t and, 37 and, abnormalities 35f 40 and, hypotheses and, – 25 Index – , – – , , , , , , 96 72 38 43 , 66 59 65t 62t 62t 7 38 34 24t 33 , , 8 8 , – 56t – – 38f 4f 56t , , , , 60t 72 56t 8 39 56t 9 36 , 82 72 65t 65t 56t 34 – 56t 33 02 4 , 9 4 , , , 65t , , 57 – 40 , 95 57t , , 36f – 97 – , 62t 57t 48 , 36 57t 89 70 72 34 – 5 34 66 9 5 57t , , , – – 03 – 57t 44 , , – 96 98 , 96 , , , – , 50 80 49 , , 36f 40 58t 90 65t 59 34f , 69 20 5t 56t , , , 58t , , – , 97b 98 96t , 5t , 82 , 4 , , , B-cell lymphoma-2 proteinB-cell lymphoma-2 Awareness, depression,Atypical Attention deficit Association studies, Assessments, clinical, Asenapine, Aripiprazole, Cappadocia, Aretaeus of Apiprazole, disorders,Anxiety Cardiovascular disease, Carbamazepine, CAM. SeeComplementary Calcium metabolism, Cade, John, CACNAC Brain networks. See neurotrophicBrain-derived Borderline personality mass index(BMI), Body Black bile, cohort effect, Birth Bipolar spectrum, Bipolar IIdisorder, Bipolar I disorder, Disorder,Bipolar Affective BDNF. SeeBrain-derived ziprasidone, risperidone, quetiapine, paliperidone, (bcl-2), 60 (ADHD), disorder hyperactivity 5t 60t 65t 26 66 57t medicine and alternative 5 Emotional brainnetworks (BDNF), factor disorder, neurotrophic factor 62t 60t 65t 58t 62t , , , , , , 95 26t 67 62t 7 58t , , , , , – gene, 65t 62t 7 59 65t – 5 68 , , 45 72 56t 62t 9 62 65t 60t , 4 , , , , 4 56t 60t 56t 7 65t 72 98t 56t 56t , , , , 56t , 57t 27 44 , 72 62t 56t , , 24t , 57t , , 6 57t 0 24t 0 70 , 50 , 57t 57t , 9 , , 5 50 57t , 58t , 9 , , 65t 57 , 44 , , 28 85 62t 7 , 58t , , 7 , – 5t , 58t 58t 29 , 5t , 5 – , – 28 , 58t , 45 87 5 , , , , , , Comorbidity and Comorbidity networks,Cognitive therapy behavioral Cognitive Clozapine, Clinical assessments, disorders,Circadian rhythm Cigarettes, Chromosomes, Chromatin remodeling, Choline, Chlorpromazine, Children, Cell signaling, CBT. SeeCognitive Caudate, Catechol-O-methyl Catatonia, alcohol usedisorders, ADHD and, psychiatric conditions, disorderspersonality and, of, overview evaluation ongoing safety nicotine usedisorders and, and, migraine metabolic disorders, management of management of, drug usedisorders and, drug usedisorders, cardiovascular disease disordersanxiety and, alcohol usedisorders and, co-occurrence 76f (CBT), 62t comprehensive, 43 58t therapybehavioral 4 (COMT),transferase 24t and, 24t and, diabetes, overweight conditions, 24t 02 and, 26 24 02 – – , , , 44 42 96 65t 65t , – , , , 39 26t – 25 – , 37 9 27 25 25 87 28 29 03 03 5 75 9 , , 56t 24t , , 70 66 , – 40t 24t , – 95 44 29 , 5t 77 , 24t 2 57 25 – , 29 49 – , , 30 , 4f 96 56t 23 45 28b , , 76b – 02 28 57t 85 , 50 , 34 , 96t 24t , 57t – – , 87 5 04 58t 03 24t , , ,
109 110 INDEX DBT. SeeDialectical DBSA. SeeDepression and Day length, DAT. SeeDopamine D-Amino Acid Oxidase Cyclothymia, Cycling, Creatine, COMT. See and Complementary Dopamine, L-Dopa, Docosahexaenoic acid DNA methylation, DNA markers, DNA. SeeGenetics Divalproex, Disrupted inschizophrenia Disability, See Diagnostic DIGS. Differential diagnosis, supplements, Dietary Dialectical behavioral for Diagnostic Interview Diagnosis Diabetes, DHA. SeeDocosahexaenoic Dextroamphetamine, Depression andBipolar Depression Dementia praecox, subtypes and, subtypes of progression andpattern mixed statesand, and, mania, hypomania of, history differential, depression and, bipolar spectrumand, pharmacologic treatment pediatric, diagnosis and, atypical, (DHA), 60t (DISC), Studies Genetics for Interview 3 therapy, 85 Genetics Studies(DIGS), acid 78 Alliance (DBSA), Support therapybehavioral Alliance Bipolar Support genes transporter Inhibitor (DAOA), transferase Catechol-O-methyl (CAM), medicine alternative illness and, 6 of, – , , – 89 5 6 7 59 4 , , 39 28 20 , 6b 5b – 9 – 62t 8 80 40 80 43 95 3 57t , 6 – – 50 , 5 0 40t 29 2 3 – 7b – , , , , , 82 6 49 4 , 2f 65t – 60t , – 0 5t , 7 58t , 28b 5 8b – – – 4f 7 – – 9 5 50 42 , 5 – , 9 , , 3 , 67 9 3 – , 59 5b 8b 50 8 59 , 65 0 , , 8b , 2f , , 98t – 3 5t 60 Emotional brainnetworks therapyElectroconvulsive Elderly. bipolar SeeLate-life Eicosapentanoic acid (EPA), Education andeducational ECT. SeeElectroconvulsive Ebstein’s anomaly, Dysthymia, DSM-V cluster Bdisorder, DSM-IV criteria set, DSM-5 criteria set, Drugs. SeeMedications; Drug abuse Dosage ranges, typical, Dopamine transporter Families, Falret, Jean-Pierre, interval, Euthymic Europeans, Ethnicity, Epigenetics, Epidemiology EPA. SeeEicosapentanoic Environmental influences, Energy, low, Endophenotypes, ventral striatum of, overview amygdala abnormalities and, evaluation safety nicotine, differential diagnosisand, comorbidity and alcohol, race/ethnicity and, population prevalence and andsuicide and, mortality anddisability morbidity gender and, age and, white matterabnormalities 98 (ECT), disorder 8 therapy, therapy Psychopharmacology 57t genes (DAT), 2f acid 48 37 and, abnormalities 34f and, 4 24t co-occurrence and, 24t incidence, 2 and, and, , – , , 99 50 37 97 – – – , , , 47 38 5 22 9 35f 25 02 , 38 34 20 4 57 8 24t 38f – , 7 3 78 – 5 , 8 – – – 49 38f – , 20 – 02 – 39 36 2 5 58t – , 8 9 03 33 , 79 25 7 , 48t , 4 – , 36f – 50 24 , – 03 98 59 34 5 79b 6 8 9 – – – – , , 9 5 25 , 3 0 60t 8t – 87 , , , 20 , 27 H GWAS. SeeGenome-wide Glycogen synthase kinase-3 Glx, Glutamine, Glutamate, Glucose management, Globus pallidus, Genome-wide association Genetic screening, Genetics Genetic counseling, Gender, acid Gamma aminobutyric Gabapentin, Frank, Ellen, Fluoxetine, Fisher, Carrie, FFT. SeeFamily-focused Fetal development, histories, Family therapy Family-focused Inositol Inositol, Inheritance, distress, Idioms of ICD-0 criteria set, Hypomania, Hypersomnia, 5-Hydroxytryptomine 5-Hydroxyindoleacetic acid index Holzinger heritability Histrionic personality bipolardisorder, of History Hippocrates, 5-HIAA. See Heritability, Haloperidol, 2 overview of, of, overview linkage studies, bipolar of heritability endophenotypes, counseling and, association studies, index.SeeHolzinger heritability index heritability association studies (GSK-3), 43 studies (GWAS), (GABA), therapy (FFT), (IP3), 9 (5-HT). SeeSerotonin (5-HIAA), (H disorder, acid 5-Hydroxyindoleacetic – – 39 52t disorder, 5t , 0 2 2 ), 44 , , - 2t , 40t 44 8 49 44 , 78 4 , , , , 59 5 39 39 , 5 47 47 8 2 , 56t 45 27 77 39 6 – 69 4f ,-triphosphate 5 96 – 42 , 6 , – – 9 47 – , 7 60t 2 40t 40 , 49 49 38 40t , 86 57t – 49 58 52 , , 52 49 , , 20 85 40t 48t 98 , 48t 4f , 6 50 – , – 50 – 4f 58t , , 50 65 53 50 53 – 48t , – 29 99 4f 5 , , , – , 52t 65t 43 52t 5 , , , Medications. See MAOA. SeeMonoamine Manic-depressive insanity, Mania Maintenance therapy, Magnetic resonance See MADRS. Lurisadone, Lithium Linkage studies, management, Lifestyle Leonhard, Karl, L-Dopa, bipolardisorder,Late-life Lamotrigine, Lability, K-SADS. SeeSchedule for Kraepelin, Emil, Kidder, Margot, JesseJr.,Jackson, IPSRT. SeeInterpersonaland Interpersonal andsocial antipsychotics antipsychotics (atypical), antiepileptics, of, effects adverse pharmacologic treatment medical causesof, diagnosis and, and, suicidality pregnancy and, of, overview neurotransmitter mixed statesand, mania and, maintenance therapy and, and, endophenotypes and, divalproex depression and, cell signalingandcalcium of, effects adverse Psychopharmacology also Lithium; oxidase A spectroscopy (MRS), Scale Depression Rating Montgomery-Asberg 60t 97 6 Age Children Schizophrenia School for Disorders and Affective therapy social rhythm 77 therapy (IPSRT),rhythm (conventional), 56t of, 7b and, hypotheses 6 metabolism and, , – – , 62t 98 78 62t , , 99 55 , 4 8b 62t , , 69 , 97b 8 , – 65t 56t 65t 58 – 56t – 57 72 , 82 , 56t 68 , , , 5 – 5 56t 49 56t 6 57t 72 57t 02 58 98t – – 57 59 , – 6 7 69 , , 63 , 50 , 9 , , 58t 66 5 65t 65t 56t , 58t – 59 59 – , 6b 40 60t – 63 44 8 0 98t – b 66 , , , , 52 69 , 39 , 60t – – 66 62t 42 45 82 5 , Montgomery-Asberg Montgomery-Asberg Monoamines, Monoamine oxidase Mixed states, Mitochondrial energy Migraine, MFPEP. SeeMultifamily Methylphenidate, N-Methyl-D-aspartate N-Methyl-D-aspartate Metabolism, Metabolic disorder, Menstrual cycle, Melatonin, Melancholia, Meiosis, ziprasidone, valproic acid, topiramate, stimulants, sleep aids, risperidone, quetiapine, pregnancy and, paliperidone, oxcarbazepine, olanzapine, methylphenidate, lurisadone, lamotrigine, haloperidol, gabapentin, fluoxetine, divalproex, dextroamphetamine, clozapine, chlorpromazine, carbamazepine, asenapine, aripiprazole, (MADRS), Scale Depression Rating A (MAOA), 44 management, psychotherapy psychoeducational receptor, (NMDA) glutamate (NMDA), 62t 60t 59 58t 60t 59 60t 68 59 58t 60t 58t 58t 67 57t 60t 62t – 45 , , – , – , 49 , , , , , , , , , , , 60t 60t 60t 69 68 62t 29 65t 62t 62t 62t 65t 6 62t 65t 58t 62t 65t 8 , , , , , , 56t , 39 98t 98t 50 88 5 59 56t , , , , , , , , , 59 6 62t 44 56t 6 62t 9 56t 56t 57t 65t 40 69 86 69 7 65t 65t 65t 65t 66 60t 65t 7 56t 56t 56t 56t – 56t – , , 5 56t 56t – , , – , 0 , – 40 5t 29 , , 60t , – 57 , , , 60 , 57 62t 2 45 62t 57t , , , , , , , 98 43 59 , 65t 57t , , 28 65t 72 , 69 57t 57t 56t , 58t , , 70 72 72 70 62t 72 56t 57t , , , 57t 57t 57t , 5t 57t , , 39 6 59 , 67 57t – 44 , – – , 57t , , 60t 57t , , , 96 , , , 99 29 44 , 65t , 60 98t 65t 58t , – , , 7 59 58t , – , , 98t 58t 59 57 , – 59 65t 40 57t , , 58t 58t 60 , 58t , 45 , 58t – , , 28b , , 98t , , , , , 60 , 7 96 , , , , , , Neurotransmitters Neurophysiology. See Neuroanatomy. See Networks. SeeEmotional SeeNot Elsewhere NEC. NCS-R. SeeNational Mental National Instituteof National Comorbidity the National Alliance for Narcissistic personality NAMI. SeeNationalAlliance (NAC),N-Acetyl cysteine (NAA), N-Acetyl-aspartate Myo psychoeducational Multifamily SeeMagnetic MRS. Mortality, Morbidity, Mood lability, Mood charting, Obsessive-compulsive Obsessive-compulsive Obesity, Nucleus accumbens, Not ElsewhereClassified Norepinephrine, N-Methyl-D-aspartate N-Methyl-D-aspartate NIMH. SeeNational Nicotine use, Next-generation sequencing, glutamate, glutamate, acid, gamma aminobutyric dopamine, serotonin, norepinephrine, monoamines, Physiology Anatomy brain networks Classified Survey-Revised Comorbidity Health (NIMH), 7 Survey-Revised (NCS-R), Ill(NAMI), Mentally disorder, Ill theMentally for 39 78 psychotherapy (MFPEP), resonance spectroscopy 26t disorder (OCD), (NEC), receptor, (NMDA) glutamate (NMDA), Health Mental Institute of 5 -Inositol, 39 dopamine, norepinephrine, and 4f , , , 8 40t 03 , , 28 40t , 43 2 , 8t 20 – 4f , , 27 – 29 50 39 – 40 39 44 44 4f 24t 22 99 2 , , – 90 , , – 40 28b 40 5t , 40 4 , 40t 40 45 43 , 25 40 – , , 9 – , 78 43 42 , 40t 42 26 42 37 , 4f , 42 , – 08 , 89 44 , 43 8
111 INDEX 112 INDEX Pharmacology. See Personality disorders, Pediatric bipolardisorder, PCr. SeePrefrontal Pauley, Jane, Paliperidone, Oxcarbazepine, Overweight, acids, Omega-3 fatty Olanzapine, Protein C(PKC), kinase bipolar Progression of treatmentProgrammatic Pregnancy, Prefrontal phosphocreatine Prefrontal cortex, Post-traumatic stress PME. See PKC. SeeProtein C kinase PIP2. See Physiology. Seealso Phosphomonoesters (PME), Phosphatidylinositol treatment goals and networks,support evaluation safety of, overview mood charting, long-term for integration comprehensive clinical management aggressive sleep andcircadian clinical considerations, cell signalingandcalcium 44 disorder, approach (PCr), 35f disorder (PTSD), Phosphomonoesters 4,5-biphosphate Phosphatidylinositol- Anatomy; Metabolism 39 5-biphosphate (PIP2), Psychopharmacology Medications; 27 95 phosphocreatine 62t 60t 59 adherence, emphasis on (ongoing), 08 management, assessments, symptoms, and interepisode acute episodes of and, abnormalities rhythm metabolism and, – , , – , , , , 40t 03 60t 45 96 38f 65t 62t , 4f 43 , , 96t , , 98 4f 62t 72 69 56t – 28 56t – 44 , , 99 – 85 – , 98t 65t 87 57 3 29 87 , 57t 89 , , 90 57t 33 85 98t , , 86b , , – 9 – -4 57t 2f , , 7 28b 88 90 , 26 89 8 – , 58t 9 – , 24t 34f 44 87 58t 92 , , , , 58t 26t , 33 – 99 , , 44 , 45 , Rapid cycling, Rapid Race, Quetiapine, Putamen, PTSD. SeePost-traumatic Psychotherapy Psychosis, Psychopharmacology. See Psychodynamic Serotonin Seasonality, SCID. SeeStructured Clinical Schizophrenia, disorder,Schizoaffective Affective Schedule for Israel), Saul (Kingof Safety, ongoing, S-Adenosylmethionine Risperidone, Remission, Relapse prevention, Recovery, epidemiology Recombination, supportive therapy,supportive psychodynamic of, overview multifamily interpersonal andsocial therapy,family-focused education andeducational dialectical behavioral behavioral cognitive of, overview mixed statestreatment, mania treatment, maintenance therapy, depression treatment, 59 stress disorder also Medications psychotherapy, 5-HT), (5-hydroxytryptomine; DSM-5 for Interview bipolar type, Age Children (K-SADS), Schizophrenia School for Disorders and (SAM-3), 60t and, 00b psychotherapy, psychotherapy, psychoeducational 77 therapy,rhythm 78 therapy, therapy, 76f therapy, 56t 59 , 9 , 60t 62t – , – 20 , – , 96 78 6 96 58t 20 37 , 9 – 40 , 6 , , 2 43 65t 56t 8 60t 8 – 56t , 78 80 75 , 3 3 42 5 62t 75 55 – , , 87 , 49 4 , – – , , 82 70 57t – 4 57t 2f 79 77 99 43 , 6 80 65t 55 , , , , – , 80 78 – , 20 58t 79b 76b 00 37 79 63 58t – 6 , 58 , 7 , , – , 38f , 62t , 6 , 63 85 Suicidality Structured Clinical St. John’s wort, Stimulants, Stiller, Ben, Spectrum, bipolar, Special populations Spears, Britney, therapy,Social rhythm SNP. SeeSingle-nucleotide Smoking, Sleep disturbances, Sleep aids, needfor,Sleep, lack of Single-nucleotide Side effects, interest in, Sex, lossof Serotonin genes, transporter Serotonin permissive Ultrasonography, Ultrarapid cycling, Twin studies, Tryptophan hydroxylases Tryptophan, Treatments. See TPH and2.See Topiramate, drugs, Thymoleptic Teratogens, networks,Support therapy,Supportive Supplements, dietary, patient managementand, mixed statesand, and, epidemiology diagnosis and, suicidal individuals, rapid cycling and, pregnancy, people over age60 years, comorbidities, children, safety evaluation and, evaluation safety (SCID), DSM-5 for Interview 77 polymorphisms 77 50 (SNP), polymorphisms 42 hypothesis, (TPH and2), Psychotherapy Psychopharmacology; treatment approach; Programmatic medicine; Medications; and alternative Complementary Tryptophan hydroxylases 00 99 97 00 – – , 5 78 78 – – – – 00 98 , , , 24t 02 02 5t 8 8 88 95 59 85 , 98 65t 69 97b , 42 , – – 98 48 – – 00b , , 25 82 82 – 96 42 60 0t 0t , 8 – 99 8 , 02 96 99 , – , – 99 5 88 99 96t 43 60t
9 89 , 43 , 44 3 0 79 , 98 – 98t 2
5t 8 04 – , 8 7 44 – 87 22 , Ventromedial prefrontal Ventrolateral prefrontal Ventral striatum,37–38,38f Valproic acid, 56t,67.See Unspecified Bipolar Cincinnati of University networks, 34,35f networks, 34,35f also Divalproex Disorder, outcome studies, 2 Uploaded by[StormRG] , 37 YMRS. SeeYoungYMRS. Mania Yellow bile,5 World MentalHealthsurvey Women, 3,29 White matterabnormalities, Weight, 28–29,28b Vitamin supplements, 8 Rating Scale Rating 7 initiative, 38–39 Zurich outcome study, Ziprasidone, 56t,57t58t Zeta Jones, Catherine, Zeitgebers, 44 Young patients, 95–96, Young Scale ManiaRating Yoga, 82 20 62t, 65t7 96t (YMRS), 86
113 INDEX