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CllE: Anrclr

Diagnosing BipolarDisorder and

theEffect A Naturalistic ofAntidepressants: Study

Ivl.D. K. Goodwin, S. Nassir Ghaemi, M.D.;EricaE. Boiman, B.A.;andFrederick
he relative sadetyof antidepressarrts in thc trcatrnernt of bipolar disordercontinuesto be a matterof Sorne have suggestedthat antidepressants c:ontroversy. of the courseol'bican producea long-termlvclrsening polar illnessthroughthe inductionof treatment resistancc Othcrs har,ereportedno and rapid-cvclingepisocles.r-s Curin bipolar Il disorder.*" long-termrisks,particularly limit in texts and jclrrrnals rent standardrecotnmenclations Horvcvcr. cliniusein bipolarclisorcler.l'\rr antideprcssant on the side clf frequent cians have come dorvn strc'rngly use.Currentpractice: data basedon the Naantidepressant 'I'herapeutic that antiand lndcrrr irtdicate tional Disease depressant agents, as a classand indil'idutrlly,arc:morc frequently prescribedthan mood stabilizersfor patients 'l'herefore, rt'hile it is n<lt nerv ttr rvith bipolar disorder. rathertlranantidcrecommend the useof mood stabiliz-ers pressants, clinical practice patterns do trot indicate that are heeding suchrecommendations. clinicians poserisks in I)o antidcpressants Wh1"is this the case'? bipolar clisoruler? 'l'he purposeof this study was to systcmaticall!'' assess outparatesof bipolar illnessin an unsc:lccted diagn<lstic of tient ps,vchiatric sampleand to exalninethc clutcome treatmcnts. antidepressant METHOD rvith affccpatientsdiagnosccl Clharts of all cclnsecutive seenby I treatingclinician(S.N.(i.)during tive disorders hospital*erc revieu'ed. in an urbanacaclemic l2 rnonths Formal Structured Clinical Itrtervierv 1or l)SM-lV of (SCID)irdiaguoses wcrc'lnade usingthe mood modules by a lveremadc prclspcctivell thc SCID.'lhesediagnoses (S.N.(;.). in a{'ltcti't,c disorders psychiatrist with expertise in this assessment calnefrom clinical interDataincluded vierv rvith the patient artd outside report from farnill' or that thc diagnosis It shouldbc emphasized sources. clther clf alfective disorderin thesepatientswas nol rnaderctrospectively at the tinle of chart lsvisrv, but prospectil'c11.' u'ith duringthe clinical intervieu'altdu'asthen cornparecl fron.rpast mental hctllth tre.atnlent. Ieferral diagnoses October 2{10{) 61:10, J Clin Psychiatry

Obj ectives:' ['o dcterrni ne i {' bi polar di sor.der is accuratcly diagnosed in clinicalpractice and to :rssess the ellects ol antidepressants on the cour-se of bipolarillness. Lletltod: Charts of outpatientsrvith affective disordcr diagnosesseenin an outpatientclinic during | .vear(N = 8-5rvith bipolar tx unipolar disordcrs)rverereviclved. Pastdiagnosticand treatmentinformation x,asobtainedby patient psychiatrichistorl. Bipolar Ieport .rnd systernatic diagnosisrvasbasedon DSi\4-lV criteriztusing a SCID-based interview. Results: Bipolar disorder u,asI'oundto be rnisdiagnosed as unipolzir depression in31% of patientsrvho fir-stseea mental healthprofessional after their first maniclhypomanicepisode. Antidepressants rvere usedearlier and mole figrquently {han nrrnd stabilizcrs,an<I23c1, of this unselected samplc cxpcricnccrla nerv or rvorseningrirpidcycling courseattributable use. to arrtidepressant 'l that bipolar Conclusion: heseresults suggest as unipolar nrajor disorder tends be rnisdiagnosed seem depressivcdisolder and that antidepressants to bc assoc:iated w,itha w,orscncd courscof bipolar illness.I{cxvever, this naturalistic tdal rvas i"rncontrolled. is reand more controlledresearch quired to confirm or rel'utethesefindings. (J Cl i n P h iat y 2000:6 ) : 804-808 )

Received April l l, l99q: o.t;epteLlr\Ior.h 23. 2000. t"rom the Psvt'hop l n r ma<'o l ogl l'ro gra nt, Canbrid ge H ospi tal. Cr,nsolitla ted f)epartnrcnl (Dr. Ghaemi): ol Psv:ltiatn. Hanunt llfedktrl S<:lnol, Catnbrillge, Afiuss. utLl thc l)epdrlnent of F'.9),<hiatrJ,, I'hc George WashirtrtlottUniversitt'. lktslinglcttt.D.C. (tls. Boinan untl I)r. O<totlwil). Supportetl hy a,m Abbott l.nboralorie,s,Alilntt Park, Ill. l:'itnn<i.ol dis. htsure: I)rr. (]huemi antl ()oodwin lutc rzt:<'it'cd ?rutts at weLlas lecture honanrria from Abbott l.ttfutalories. (jhaetni, ivl.D,, Hanord lliptilar Rescux'lt llcprint requcslsto: S. N<tssir (i<utentlHo.tpital, I5 Pirrknuut51.. I,'AC.112. Progntm,fulas.rttthu.sells Bttstttn, Ll.\O2ll4.


CME: Anncle

(N = 29) Disorder }{ajor Depressive Previously Diagnosed lVith Llnipolar Figure1. Subsarnple of BipolarPatients
Mean Age in Years

Firsl depressron

First mania

First professional visrt

First mood stabilizer


First brpolar dragnosis

Other clinical and demographicdata gathcredat clinical intcrviervn'erethe lollorving:age;sex;family histclt'y tnania. illness;age at ulset of deprcssion, of ps1-chiatric of episodesc'rfeach type; perand hypomania; nr.rmbers of illness;age at first centage of time spentin eachphase and u'ith consultation rvith a mental heaith prclfessional alld mentalhcalth numberol psychiatrists a psvchiatrist; professionals seen prior to correct diagntlsis;previotts diagnosis.lnlormation diagnclses; and age at first correcrt and Inood rvasalso gathered regardingpastantidepressant including rvhethertnania,hypostabiliz-er useand elTects, mania. or rapid cy'cling occurred subseqttent[o antideprrrssant use. Where possible,attempts w'ere made t<l verify thesehistoricaldata rvith outsidereportsfrom lamil1,'or clthersources,including hospital charts and previrecords. ous physician Statistical analysescotrsistedof nonparametrictests icated nolr-nclrmaldisrvherc f requenc.vdi stributions i ncl testsotherrvise.'l'he tributions of rau' data.and pararnetris signed tests used rvere the unpairedt test, the Wilcc'rxon rank test. the Mann-Whitne.vLI tcst, the Kruskal-Wallis test. and the chi-squaretest. Means and standarddeviations rvere computed frx' parametricdata. All statistical usittg the Statvielv statistical anal;,sesrvere perfr.rrmed Calif.) lbr the program (Abacus Concepts.lnc., Berkelel", personalc0rnputer. RESULTS diagnostic breakdol,n of the sample (N = 90, 49 disnren.-{l rvomen) was 34'/cuttipolar ntajor depressive o r d c r ( N = 3 1 ) , 3 0 % b i p o l a rI ( N = 2 7 ) . 1 2 7 , b i p o l a rI l (N = ll), t8% bipolar not otherwisespecified (NOS) (sec(N = 16), and67o(N = -5)rvith other mood disorclers and dysthymia).Figure I shorvsa time ondary depression and treatmentof the subgroupof bipolar line tor cliagnosis rvith unipolar patients beendiagnclsed n,hohad previously major depressive disorder (N = 29: 56%). Of this subgroup,38% (lll29) had a family historl"of bipolardisorOctober 2000 61:10, J Clin I'svchiatrv 'l'he

From First Seeking to CorrectDiagnosis Figure2. Years Professional Helpu



o c .QU o


0 Unipolar MDD All Bipolar Patients BipolarI Disorder Bipolar ll Disorder Bipolar Disorder NOS

Diagnoses oAbbreviations: VIDD = rnajor depressivedisorder,NOS = not otherwisespccificd. Diftcrences betrveendiagnoseswere s1:ttisticalll se s t ) ' . =.04' N = 82' Kruskal-\4'allit significant 1 f l = 6 . 3 - 1p

der, conrparedtvitb l77o (5/31) of the samplcin the sttrdl' on based disorder as unipolarmajor depressive diagnosecl intcrview to a SCID-bascd criteria applied DSM-IV (X] = 6.087. p = .014, N = 74). Iligrlar patients prerihacla sornervhat rvith unipolarclepression ously diagnosed diagnoscdbipreviously mania than those later onset of (6.6 was not statisticall-v years), this difference polar but = = tl = Mann-Whitney 27, (LI N .22, 6-5.5, significant P manic rvhose first patients l9 test).Notably.of the bipolar occurred prior to thcir first visit to epis<lde or h1.'pomanic 7 (37c/o)were nonetheless prclfessional. a mental health disorder. rvith unipolal maior depressive diagnosed from tho diagnosis Figure2 depictsthe tirne to correct 'I'hc: cliflerprofessional help. time of first mental health isignif statisticalll arc diagnoses between obsert'ed ences = = Post = test). N 82' KrLrskal-Wal1is cant(H 6.34,P .0'1, that thesedifferences$'cro stalistiinclicated hoc analyses n'ith bipolar disordsr ll all patie:nts call-"significantbetwee 805

CME: Anrtclr

(t-v"pe l. type ll, and NOS) and unipolarmajor depressive * 9.8 years disorder (mean * SD years to diagnosis= 8.!.) for bipolar dis<:rder vs. 3.3 * 1.2 .vears lor unipolar rnajcrr {e:pressive disorder:U = 463.5,p = .003,N = 81, Mann'I'he Whitnel' Li test). type of nental health prot'essional 'Ihe \vas scen somervhat relevantto rapidity of diagnosis. diagnosisctf bipolar disorderoccurrecl abclut6.5 * 10.7 y'crars psychiatrist, first visit after the to a comparedrvith about 8.9 t 9.8 vears after the first visit to any mental (z = 4.2, p < .0001,N = 86, Wilcoxon lrealtlrprofessional previously signedrank test).The professionals seeing our patientsincluded trvice as man.v allied mental health pro(ntean * SD = 3.2 t -1.4 l's. lessionalsas ps1,'chiatrists 5 . 1 3 3 , = p < . 0 0 0 1 ,N = 8 6 ,W i l c o x o ns i g n e d 1 . 5t 2 . 1; z rank test) beiorc the diagnosis ol' bipolar disorder rvas made. (or rcdiagnosed) Among all the paticntsdiagnosed in crurclinic as bipolar (N = -54). 78Vo(N = 42) had received arrtidepressants at some time. rvhile only 567c (N = 30) (Xz= 6.087. af = l.l had ever receivedrnood stabiliz,ers ( 1 ) ad receir'eclrl p = . 0 1 4 , 5 1 = - 5 . 1 ) .a n d o n l y 3 3 % 8 / , 5 4 h rno<rcl stabilizers alone.Filt1,-tivepercent(21138) of thc bi- | pcllarpatientsrvho receivedantidepressants for lr,'hom data I *ere availabledevcrloped h,u.,pomania or maniawhile tak[ (8135)developednew or acceleratedI ing them, antl 23o/t' rapid cycling. Of the 8 patientsrvho had sufficienthistorical information to establishrapid cycling prior to antidepressant use, 3 erperiencedrvorsening of rapiclcycling rvith antidepressant treatments. Of 27 patientsl,hcl tlid not haverapid c.vclingprior to antidepressant use,-5developed rvith thesednrgs. rapid cl,clingon treatmcrrt Figr.rre 3 depictsthe efftct of antidepressants on the annual numberof rnoodepisodes and the proportionof time or depression. again. spent ill u'ith mania, hy'grmania, in patients tor whom sutTicient data u'ere available (N = 16). 'l'here lvas an absoluteincrease in numberof rvere['ning nrood episodesper year while antidepressants was not statistically significant used,but this ditTerence = -l .29, 1t= .20, N = 16. Wilcclxonsignedrank test). (2, 'l'here rvas alsci a decline in proportion of time ill in statisticalsignificancc the samegroup, which approachecl (z = *1.80, p - .07. N = 16, Wilcoxonsignedranktest). Patientsin the big:lar group rvho had ever received (78%', 421 significantly antidepressants 54) e-rperienced x,31.07o of their lives) nrcrretime depressed(53.27t, than the l2 bipolar patientsnever treatedrvith antideprest.26.9c/oof their lives, t =2.09, p=.0"4. sants (29.8-9i: trend 2-tailedunpaired t test).'fhere was alsoa statistical grclup experienced lcss that the antidepressanlt-treated t32.2% of their lives) than those time cuthymtc(35.2'/o 8t)6

on RapidCyclingand l'igure 3. EffectofAntidepressants Durationof Illness'

10 9 I -7
! ai 6

6096 50% tr_

ao.z" E 6 q 9 R, R -^ :.
ano/: ZU"/o

o Ua

a e6 -ix

9al O a

2 1 0
Before Antidepressants After Antidepressants



'Mood episodesper year increasedmore than ?-fold u'ith antidepressant use.but this was not stalisticalll-significant (z= -1.29, p =.20, N = [6. Eilcoxon signod lank test). T'herewas a statistical i n p e r c e n to f t i r n c i l l ( z = - l . 8 0 , p = . 0 7 , t r e n dt o w a r da d e c r e a s e N = 16, Wilcoxon signedlank test).

of never treirteclrvith antideplessants(56.0% x. 30.8c/r, t test). t h e i r l i v e s ,t = - 1 . 7 - 5 ,p = . 0 9 , 2 - t a i l e d u n p a i r c d Further, rvhile there rvere absolute increasesin tnitnic (-1.,5 episodcs t 9.7 r,s.1.1* 1.9episodes) and depressivc (13.9t 23.6 vs. -tr. in the anfidepressantI r 3.8 episodes) treated bipolar groLrp versus the non-antideprerssanttreated bipolar group, these cliffercnces werc not statisticalll' significant due to the small samplesize. As seenin Figure4. therervasa statisticaltrend foward an earlier onset 01 illness among bipolar patielrts than a m c ) n gu u i p c l l a rp a t i e n t s( t I = 6 i 2 . - 5 . p = . 1 0 . N = 8 3 , Mann-Whitney LI test). In bipolar patients,major depression occurredsignificantly earlier than mania or hypomania (mean difference for mania=-5.7 years. z='2.8. p = .006. N = 27, Wilcoxon signcclrank tcst: meandiffer= 6.2 ycars.z = -2.3,P = .02.N = 3 l. encefbr hypomania periods Wilcoxonsignedrank test).ln the bipolarsample, lastedlonger than periodsof maniaor hypoof deprcssion mania, rvith patients spending nearly half their adult (mean= 19(/<, * 3l%), versvs I2(h * 9%, lives depressed of their lives manic r:r hypomanic(2.= *5.6, p < .0001, N = 46. Wilcoxon signedrank test). Patients rvith unipolar depression 'were also more readill, diagnosedand treatedappropriately than patients rvith bipolar disorder(seeFigure 4). DISCUSSION the Clonclusions basedon thesefindings are limited b,u.uncontrolled nature and the limited satnple size of tltis 2000 6l:10,October J Clin Ps-v-chiatry

CME: Anrrclp

Irigure4. Time Linesfor Disorder, Diafnosis, and'lreatment Unipolar (N= 31) Major Depressive Disorder sample

patient Aqe inyears


Frrst depressron

Firsl First prolessional antivisrt depressanl use

First correcl d,agnosis

Bipolar Disorder Sample(N = 54)

Firsl depressron

Firsl prolessional vrsll

Frfst Fifst anlidepressanl mania use

Frrstmood stabilizer use

Firstbipolar dragnosrs

'l'he stucly. main specific results rvere that 37% ol the sarnplervas misdiagnosed as having unipolarmajor depressivedisorderby a mental healthprofessional a1'ter the onset of the first manic or hypomanic episode and that 2-3%cleveloped a nerv or rvorseningrapid-cyclingcourse rvith antidepressant associated usc. It mi.rht be arguedthat this samplcis unrepresentativc duc to the high ratio of bipolar to r.rnipolar illness.Yet this study included patientsrvith type Il and NOS diagnoses, s'ho are sometimesexcludecl in other reports.'"Oftcn. much is madeof the academictertiary-care settingand the. lack of generalizability of the more refractory patients seenthcre.'Ihat u,asnot the caseu,iththis sample. Almost all cif the patients belonged to a university-rr"rn hcalth (HMO). psychiatric maintcnance organiz-ation and thc:ir care ciccurrcdin rvhat rvasessentialll, a primary care setpatients ting. F'erv haclrefractoryillness,and most did not come to the universityseekingspecialized care,but rather bccauseit reprcsented sourceof care as part of their onl_v 'I'his quite generalizthe HMO. is, iamentablyperhaps, able to the tl,pical patient today. l'his sample is thus unsclected and minimally altectedby samplingbiasof the kinclmentionecl. In fact. these findings are consistent \vith previt'rus restuciiesin clthcr settings. Hgelanciand colleaguesrs ported that about l0 years elapsedliom onset of illness before Amish individuals rvith bipolar disorder receir,ed treatrnentthorvever,sclmeof that delal' may have been due tcl a reluctanceto seek treatmenton the part of the patie:nts rather than misdiagnclsis by or undertreatrnent J Clin Psychiatry 6l:10,October 2{-100

of bipolardisconl'usion Othershavereported clinicians. order with other conditions in special populations,such or schizodisorclerin adolcscenlsr" as attention-deficit patients.rr phreniain ps1,'chotic but thc generalizabilitl' of these results to adult paticnts. most of rvhom havc 'l'he Epidcmiononps-"-chr:rtic bipolar illness,is uncertain. Area rcported thal only 32% ot study'rr logic Catchment patientsrvith bip<llardisorder receivemcntal healthtreatment, but, again, hcln, much of this undr'rtrcatlllcnti5 due to patients' lack of insight or compliancc is nol knorvn.A self-reportsurvey of membersclf the National found Associationrs Depressiveand Manic-Depressive afler an averagcof 8 that bipolar disorder rvasdiagnosecl years had elapsedfrom patients' first metltal health prtr fessionalvisit. Also. 48%,of patientsreceiveda bipolar diagnosisonly after seeing 3 or more metrtalhealth prt> received another majclr psl,chiatric fessionals,and 57o/t, common diagnosisrvas unipolar mathe most diagnosis: jor depressive (147c), follorvedby schizophrcnia disorder (31o/(,). misdiagnosisratcr We previously reported a 4014, of bipolar disorderas unipolar depressionin hospitaliz-ed patients.'" 'l'he finding that long-termrapid cy'clingis associatcd use also agrees u'ith a number of w'ith antidepressant an associalicrn Kukopuloset al.r" first described studies. worsening rapidnew or antidepressant useand a betlveen patients. Altshuler and of illnessin bipolar c;-clingcourse rv patients pecti i th vely fo und that 35% ol' retros associates3 to the Nareferred bipolar disorcler treatrnent-resistant to havedeveltional Institr.rte of Mental Healthappeared


Anrrcla CME:

opcd a tleatment-resistant cctursein relation to chronic antidepressant use.'I'heyalso reported a possiblygrcrlter risk for antidepressant-induced rapid cycling in bipolar disordert1'peIl than in bipolar disordertype I. ln another retrospective studl' of patientsrvith rapid-cy'cling bipolar disorder, Wehr and Goodrvin2identified about 506/r, of patients as having a history,,consistent rvith antidepressilntrelated rapid c-vcling.Although these studies are retrospcctiveand arc lirnited to rapid-cyclingor treatrnentresistant samples, with possibly lirnitedgeneralizability tcr most p;rtients rvith bipolar dis<lrder,our sample rvas unselected and nonretiactory. Naturalistic, retrrtspective suchas this one,are studics, subjectto rc:callbias and type Il crror ou,ing to limitc:d samplesize.Yet they arestill usefulin providingevidc'nce rvith real-rr,t'lrld samplesthat are often excludedfrom controlled research studies.Nonetheless, more controlled rescarchon this topic is needed. CONCLUSION naturalisLic study, uncontrolledand limited in sample size. found that bipolar disorder rvas misdiagnosedin 37Voof the sampleand that antidepressants lvere associateil r.vitha rapid-cycling coursetf illness in abclut ?3I/oof patients.Given the importanceof the clift'erential cliagnosis of bipolarversus unipolardisorder, thescresults suggestthat further controlled research is imperativeand that greatclinical cliligence needs to be exercised in diagnosingand treatingthesepopulati<lns. usoge:T'heauthorshave deterrnined that, to thc besl of their kncxvledge. no investigationalinformation aboul pharmaceutical agents has been presentedin this article that is oulside U.S. l:ood zrndl)ru g Ad mini stration-approvecllabeling.


1. KukopulosA, Caliari B, TundoA. et al. Ilapid cyclers,tempcrament. and antidepressants, Compr Ps1,'chiatry 1983',14:249-258

2. WehrTA, GoodrvinFK. Can antidepressants causemania and )vdrsen thr courseof atTeclive illnessJ Arn J Psychratly1987;1 44: l 4O-l-1 4J I 3. Altshuler LL, I'ostRJr4, t-everich CS. et al.Anticiepressanl-induced mania andcycleacceleratiou: a controversv revisited. Am J Psychiatry I 995;I 52: il 30-1138 4. Quitkin FN{.Kane.l,Rifkin A, et irl. Prophylactic with lithium carbonate andwithoutimipramine for bipolal I patients. Arch Oen Psychiatr] 1981 ; 38:902-907 5. SachsGS. BipolLirmood disolder:practicalstrategres for acute and maintenance phasc treatrnent. J Clin I'sychopharmacol 1996:16(suppl I t: ,12S--l7S 6. Ams[erdam J. IJfficacy and safel-r" of venlnftr,rinein the treahent of bipoliLr 1998:18: II major depressive episode. J Clin Psvchopharmacol 4t14ti ?. AmsterdamJ. Garcra-Espana F, haw'cett.l, ct al. EiTicacyand safetv of lluoxetine iu trcatingb'iprdar II major-depressive episode. J Clin PsychopharmacolI $8;*l-10 in prc8. Kuptbr D.l, Cirrpenter Ll-. Fiank E. Possiblcrolc of antidepressirnts cipiL?ting in recufient depression. Am.l f'sychiatlv maniaandhypomania iJ(M--ti08 I 98tt: l -15: 9. I-elvis.11,, Winokur G. The inductionof mania;a naturrl historvstlrd!'with controls.Arch (ien PsychiatryI 982:-39:-103-306 10. Goodlin FK. JamisonKR. Ivlamcl)epressii,e lllness.New York. NY: Oxford LlniversityItess: 1990 componentof bipolar drsorder. I l. Kalin N. N{anirgement of the depressivrr f)eprcss Anxictv I 996-1997:4: I 9G-198 '[ lnder. New Jerse"r": 12. lMS. National Disease and herapeutic IMS America: l99tt l.l. FirstlvlB. Spitzer RL,,GibbonM. et al. Structured Clinical lntciliew lbr DSlvt-lV.New Ybrk, NY: Biometric Rcscarch, New \bfk StatePsychiatnc lnsttute; l!)95 prevalnca 14. Regiel D, tsoydJ. BurLe.TD of mental Jr, et al. One-nronth disorders in the lJnitedStates: basedon five Epidemiologic Ciatchment Area sites. Arch Gen Psl"chiatry1988;45:97-r-986 of 15. Egeland RL. Nee-1, et ai. Reliabilitl and relationship JA. tslurnenthal variousagesof onsetcdteria lit major at'fective distrrder J Aflbct I)isord 19E7:1 2:I 59-l 65 I 6. BiedeLrnan Faraone .1, S, lvlick E. et al. Attcntion deficit disorderandjui'csc Ps5"chtnile mania: an overlooked comorbiditl. J Am Acad ChildAdole atr), 1996;35:99-1ft18 17. PopeHGJr.l.,ipinskiJFDi.rgnosisinschizophreniirandnrirnic-depressivc 1-828 1978;35:81 illness. Arch (ien Psychiatry and 1,3.Lish l, Dime-Meeuan S, \fu'h1 bro*' P et d-'l'he NationalDepressive (DMDA) survey r.lfbipolarnrembers. .l AiAssociatron l!{anic-Depressive fect Disord I 99.1:-1 I :281-294 (iS. ChiouAIr4,t't al. ls bipoLirdisordelslill undcr19. Ghaiemi SN. Sachs ovenrtilizedlJ Affect Disord l9!)i);-52: diagnoscdlare antidepressamts I 35-l 44 P. et al. (burse of the manic20. KukopulosA, ReginaldiD, L;tddomada Phtrrmakops.v-chiatr depressive cycle and changescausedb)- treatments. 1980;13:1,s6-167


2tlOti 6l:10,October J Clin Psychiatry