l.i
Drug Therapyin the Preventionof Recurrencesin tJnipolarand BipolarAffeetive Disorders
Report of the NIMII CollaborativeStudy GroupComparir:rg Lithium Carbonate, Imipraririne,and a Lithiurii Carbonate-Imipi'amineCornbination
Robert F. Prien, PhD; David J. Iiupfer, MD; Petel A" l{ansky, MD; JoyceG. Small, l'{D; Vicente B. Ttrason,MD; Cai'lyleB. Voss,MD; l4rayneE. Johnson
c ln a double-blind, long-term follow-up study, 117bipolar f-\uring the pasttrvo decades, it h;,r becomeincreasingll patients received lithium carbonate, imipramine hydrochlo- LJ clear that niajor affective illness should be viewer ride, or both and 150 unipolar patients received lithium car- longitudinally rather than solely iir telms of the acutt bonate,imipramine, both lithiumcarbonate and imipramine, or episode.There is convincingeviden:e from studieson thr placebo. With bipolar patients, lithium carbonate and the courseof affective disorders that the majority of patientr combinationtreatment were superiorto imipraminein prevent- who havean initial episodeof major ciepressionor maniawil ing manic recurrencer and were as effectiveas imipramine in suffei' recurrences.L' Horvevef, maintenance pharmaco preventing manic recurrenees and were as elfective as im- therapy aimedat preventingthe occlli'renceofnew episodei ipramine in preventingdepressive episodes. The combination continuesto be studied far less adecluatelythan treatmen' treatment provided no advantage over lithium carbonate clirectedat the acuteepisode. As a result, there aremajor alone.With unipolar patients,imipramine and the combination gaps in knorvledgeregarding the long-term treatment anr treatment were more effective than lithiurn carbonate and managementof affectivedisolclers. placebo in preventingdepressive recurrences. The combina- The only conclusivefinding regarclinglong-tet'm preven tion treatment provided no advantageover imipraminealone. tive drug treatment is that lithium carbonateis effectiveit The lithium carbonale-treated group had fewer manic epi- preventingmanic lecurrencesin patients lvith bipolar clis sodes than the other groups. Treatmentoutcome, which was otder'.toThe effectivenessof lithium carbonale and anti evaluatedprimarily in terms ol the occurrenceol major depres- depressantdlugs in preventingdepressive reculrences it sion or manic episodes,was significantlyrelated lo character- bipolarand unipolardisorders is lessclear. istics of the index episode, ie, the episode that brought the A revien' of the six studies comparingIithium carbonatt patient into the study. against placeboin bipolar disordeCshowecl that lithiun (Arch Gen Psychiatry1984;41 :1096-1104) carbonate-trea.ledpatients had ferver deplessive tecui' lencesthan placebo-treatedpatients in eachof the trials Acceptedfor publicationApril 12, 1981. but that in only one study was tlie difference bet*'eei From the Pharniacologicancl Somatic t'eatments Rese:LrchBrarrch, treatments statistically significant at the \Vo level. Otrt Division of Extramural ResearchPrograms, National Institute of l\lenlal problemin interpleting the results for depressiverecur Health,Rochville, I'Id (Dr Prienand l{rJohnson); Department ofPsychia- rencesis that raost of the failui'esin placebo-tleatetlpa try, University of Piltsburgh Schoolof Medicine(Dr Kupfpr); Department of Psychiatry,Albanl, (NY) Medical College1Dr Mansky);Department of tients occurreclin those who had had a manic episocle llental Health, LaRue D. Carter MemorialHospital, Indianapolis (Dr leavinga relatively small clatabase from which to establisl Small); Department of Psychiatry, St Paul (Minn)-RamseyHospital and statisticalsignificince for ciepressiverecurrences. The onll Medical Center (Dr Tuason);and the Department of Psychiatry, iVlaine controlieclevaluation of an antidepressantin bipolardisor lledical Center,Portland (Dr \toss). ar Reprint requeststo l.lationalInstitute of Mental Health, Room 10C-06, cle15indicated that imipramineh;'drochloride was equally. ParklarvnBuilding, 5600 Fishers Lane, Rockville, MD 20857(Dr Prien). effective as iithium carbouate in preventing depresstvt
1096 Arch Gen Psvchiatrv-Vol41, Nov 1984 Unipolarand Bipolarlllness-Prien et a episoclesbut v;assiguiiiceirtly less effective in prevetiting invoh'eda two-yeardouble-blind coinpalison of the study treat- manlcr"ec!rrl.enceS. lnents. Studiescomparing lithium carbonateagainst placebo in PreliminaryPhase the mainteuancetreatrnent of unipolarillness suggest an advantageI'or lithium ,:arbonaie.""Horvever, the smalltotal During the index episodethe patient receivedthe treatment of numbefofplacebo-treated patients evaluated in thesetlials choiceof the psychiatrist lesponsiblefor preliminary phasecare. (92 in seven siudies) arrd diagnostit-allyheterogeneous Aftel the acute syrnptomswere controlled, the patient received populaticnspose diffici,rlties for interpreling findingsancl the ccmbinationof lilhium carbonateand imipranine at mainte- nance levels. Imipramine h,ydlochloridewas lhe r€asorrswhy lithiurncirlbonate has nct dose maintained at are 1;i'ilnai'/ been 150 mg/day. Patients rn-howere unable to tolerate 150 mg/day approvedby LheFood and Drug Administration for the long- becauseof adversereactions or medicalcomplications could have term naintenancetreatment of unipolar disorder.DFive theil dosagereduced to a minimurnof 75mg/day. The serumlevel of stucliescorrrparing litj:iurn calbonateagainst a.nlidepres- lithiurnivas targel.ecl at 0.6to 0.9mEq/L. Thepatient was assigned santsfoirncl litliium cat'bonateto be equallyas effectiveas to double-blindmerlication (ie, enteredthe maintenancephase) imiprart'rinetand arniti'iptylinehydrochloride'n ancl ntore after trvoconditions ivere satisfied: (1) the patient had remainedon effectivelhari imipra-ntine,"maprotiline hydrochloride,'3 stable maintenancecloses (at least 75 mg/day of imipramine andmianserirr l.ivdrocirloride.'" Ttwo of t-hesesluclies'r" did hydrochloride and a serum lithium level of 0.6 mEq/L) for trvo (2) not use a placeboconirol ancltwo others'nuusetl placebo consecutivemonths, and the patient had a scoleof more than 60 the an li and gl'oupsconsisting of onl;7six atrdseven patients. on GASand SDX{total depressionscore a total mania scoreof lessthan ?. The fact that neithel lithiunrcalbonate nol anticleoi'es- santssrrch as imiplam,ne and amitliptylir.reale conipletely MaintenancePhase satisfactoi'yrnainteneitce tleahments foi' bipolai' and Bipolar and unipolar patients r,vererandomized separately to unipolar tlisoi'clershas led lo a search for albeirrat,ive maintenancetreatment regimens.Bipolar patientsli'ere randomly treatments.One altelniitiveis the combinationof lithiurn assignedto receiveone of three treatments:lithium carbonate, carbonateancl an antidepressant.The rabionalefor the imipramine, or the combination of ljthiuur cai'bonatearrd im- combinationis that litl,iurn carbonatewill ltrevent manic ipramine. Unipolar patients ruele raritlomly assignedto leceive recuri'encesanrl that t,he antideplessantr"rill prevent oneof four treatnrents:lithiurn carbonate, imipramine, the combi- depressiverecurl'ence:s. Although a recent cornllarisorr nation of lithium calhoirateand inriplanline,or placebo.Dosage betweenlithium carl.rolreteand the cornbinationof lithium was maintainedat tlie level establishedduling the preliminary phase. assigning carbonateand i:riilti'amine in with bipolarclisorcler In mairrtenancemi-.digrlbn, a "double-substitu- liatients tion" techniquewas usedto ensurepatient and ratel blindness. showecino significantdit'ference betu'een the two tleat- Patientsassigned to the combinationtleatrnent group continueclto ntettts,'"iirr: i-tr-,rnLiinatlr'ti len-rains a pci;ula.i'ti.catirlr:nt. lecei',,etlre rnaintenanceregimen establishe,l during the prelimi- To pro..,idernole clefinilive data regaldingthe lorrg-term nary phase.Patients assigned to the lithiurr carbonatetreatment prever-rtivetreatment cf recnli'ent affective illness, the group continuedon their lithium calbonateregimen and had an Pharmacologicancl Scrnatic Tlealn.rents Resear"ch Branch iraipramine placebo substituted for active inripramine. Those ofthe NationalInstitute of MentalHealth sponsorc,d a five- assignedlo the imiplaminetreatment gi'oup contiuued to receive hospitalcollaborillive pr'oject evaluating several long-telm imipraminervith a lithiurnplacebo substituted fr,)r active lithium maintenatr,:edrtrg trealments. The airrr of the cai'bonate.P:rtients assigned to receiveplacebo hatl an imiplamine lrlirnary placebo lithiurnplacebo rneclications. studyu,as to determine1,he compa.rative efficacies lithium and substitutedfor active of I\'ealments lr,ereadministered years. Patients carbonat,e, for t,r'o were seen imipramine, and the cornbinationof lithium at fcur- to six-weekintervals, u-ith inore frequent visits if there carbonateancl imipramirLe in lecurrentbipolar and unipolar rvasiircreased affective disturbance or adversereactiotrs to rnedi- disordei'.This article is the initial report of the study cation. Blood for determining sel'uinlithium levelswas drawn at findings. eachi'i-.it. Patients wele evaluatedat eachvisit by a psychiatrist ''blind" u'horvas to the iclentityof tire patie;rt'streatment. Neces- SUBJHCTSAND METHODS sary closageadjustments were made by :, nonblind psychiatlist who was rot involvedin the psychiatrice','aluation of the patient. Patierrts the stL:,'ivduring an epi-ocde enleled ol major unipolai' Outcome Measuresfor MaintenancePhase depression,rnajor bipolal ilepression,or mania (hereafter leferred to as the inder episode).To be eligible, a patient had to satisfv the Ti'eatment outcome lr,as evaluated prlmarily in telnrs of the follorvingcritelia: (l) a cr,rlrentepisoCe satisfying Resealch Diag- occltrrenceof affective episodes.Pai,ients rvho becanresympto, nostic Criteria (RDC)'o for' lrimary major depressive disorr.ler or matic were seenwithin 48 hout's. lf the patients conditionu'ors- manicdisorder; (2) a total depressionol mania scoreof 7 or more on ened,the patient was seenin five to sevenclays. A recurrencewas the Raskin Severity of Depr"essicnand }[ania Scale(RSDM)1? and a declared if the clinical condition satisfied the RDC for definite scoreof 60 or less on Lhe tliol,ralAssessment Scale (GAS)tr';(3) at majordepressive disolder or maniaand yielded a GASrating of 60 Ieastone episodeof nrajor C.'pressii'eor manic r'lisorderduring the or less. The recurrerrcewas treated ad lib by a psl'chiatrist not lll: yeais preceding the c:rrio,t episode; (.1)no ps1'chiatricilhress involved.in the mairrtenance treatment or evaluaticnof the patient. other than primary depr':ssicn or inania duritrg the preceding tu,o After recoveringfrom the recurrence,patients lverereassigned to yeat's; (5) belrveen 21 arrrl d0 ;,ears of age; (6) no medicat illness their originaldouble-blind medication. Only the tilst recurrence precludinguse of lithiuni rarbor;ate ol imiprar.nine;and (7) u.illing- wasused in the statisticalanal-,vsis. nessand abilitv to give ::'rfot'medconseltt. Both iripatients and Patientswere evaluatedcn a r,alie'L:{oi scales.This report deals outpatieli; ..','ereeligiL.le lii the stuiiy. Diagnostic ai-idse',ei'it.v of primarilyrvith re:'ults from t.ovcigir'bal scale-i, the G,l,Sand RSI{D. ulnessct'itel';:t :'equit'r-d tl,.: ;gr'eenret-riof t.rroindependent ratei,s. The GAS is art iltelviery scale 1.-rrevajuating srnrptoms aitd To qualifi' as haviirg a bi1-,olardrsolder, the patient mu::t have had functionaliniparlrnent. Score-: range ffoln 0 (il'rernost sei,erely at least one nraniceiti-sod:. To quaiify as having a unipolar.disolder. incapacitateclstate) to 100 (no s.vnrplomsor irrtr2i1'1ng1.rt).The the patient must have hl,'1no i:riilic episode. RSMDprovides a lotal Cepr..rsicrrEcor"-. r'anging fronr 3 to 15and a The study had trr.o pr'r:ses; ;r preliniinary phase ancl a nt:.inte- total mania sccreranging from 3 to 15.The GAS and RSDI{ were nancephase. The purposr' of the pr"alirninar.l,phase 1r,asto !rrrtti'cl comLrletedhy a ps5ciiiatr.istat ea,chvisit. Patieirtsivei'e also the index episode. stabilize the patieirih clirical curtlitioii, artr,l evaluatedat eachvisit on the HantiltonPsychiatrir Rating Scale establishstable niainten..rtfe rlo'ie levels of lithiurn calbr,iiate and for Depri,ss.ion,the }Ianic Behalitl Raiing Scale, the Blief trniprarnine irr i,reparatioit ti,i the maintenatrce1;hase" The niainte- Ps1'q51"r.t.Rating Scale" the SocialALljustrnent Self-Fe,i,,i t Ques- nancephase ,,.;asthe majol e:tpei'imental phase of the study and tionnaire,;rnd the Life lvents Scale. patlenls\liel'e dropped becaus€,01.poor cllnlcal t,aaponSe. The five centersparticipating in the study wereas ibllows: (1) the the dropcutsshou'ing a paor clinicalrespoirbe ha4 been rvii,ir a variet)' ,ri di'i:.gsciuriug an extended perioO CapitalDistrict PsychiatricCenter, Albarry (i{Y) }IedicalCollege; ai (2) Larue D. Carter Memorial Hospital, Indiana Universiiy, terminated frc,rn tlie study becausethe treatinl decidedthat iir,: p.o.p".i'of .i"f.;iirine',t; indianapolis; (3) Maine Medical Center, Poltland; (1) lVestern ";ii.JJtj PsychiatricInstitute and Clinir:.Llniversiry of Pittsburgh; and (5) leasonablepeli,-.cl was remote. Foul peleeut of the px11s, unable tc, tolerate lithium carbonate St, Paul-RamseyMedical Center, St Paul, Minn. T'iie aforernen- or imipraminsa, tioned unlts will be referred to as ceritersA, B, C, D, and E. percentnere drcppredbecause of iutercurrentillness, pre reipectively,ir the repot'iof results. or"moving from the c'atchrrientarea. Early termirratorssp€nt a medianoi20 ri'eelisin theprel RESULTS phase, indicating effort: that substantial were madst( Bipolar Patlents patientsin ti:e stu:i1'. Rttptd.C gtlt r:. .- Resultsfor rapiclryclers were exapil1, E*ekground Clraracteristir:s.-There ri'ei'e 216 bipolar pa- rately by de:,igni-iecause of the pool proqnosisfor the rienis admitte'i tr: the preliminary phase.Background characteris- di.sr rapi.dcycltr v,,;..defined as a patierr*,,,r'ho hatl an average are in Table l. pelcent patienis 0f tics sumniarized Foriy-two of the fcur episodesa vear during the precedingtu,o years.lhe the study as inpatients entered and 47Vaentered ri'ith a manic ninesuch patients. Only three reachecl the mairrtenance mixed (manic ph episodeor and depressive)episode. The vast major- nonehad treatr:rentsuccesses. ity' of the depressiveepisodes (957o) wele classifiedas endogenous Cotrtpari-sotzof Cont.pletprsu Nontampl.etels.-I1 rs,* depressionon the basisof the RDC. The sarnplevras at extremely tc, determine ra'hat factors differentiated patients high risk for early recurreneesbecause ofthe large nutnberofprioi' wh droppedduring the preliminary phasefrom thosewh6 gsl episodes(median ofseven). Studies ofthe courseofmajor affective the preliminaryphase (ie, entered- thp rnaiirtenancephassl illness indicate that after one suffers four or five episodes,the rvise, the capacity to generalizefrour maintenancephase averageinterval betrveenepisodes shrinl:s to approximately six would be restricted. Preliniinary phaseoutcome was months.re ana terms of nine predesignatedvariables: stucly center; sex: Preliminary Phase.-E at"l Terr,tination s. -Forty-six percent : s- at onset of the first affective episode;number. of prior phase. e, of the sample failed to completethe preliminary Trventy level of functioningbetween prior episodes;sevefity percent andll rvere dropped becauseof noncompliancein keeping ap- the index episode;inpatient i, outpatient admission; pointments ar-, or in adhering to the medicationschedule. Half of the used to treat the index episode.Forl' factors significang, noncompliantpatients terminated while thev were still sympto- entiatedpatients vrho completed the preliminary phasefrt matic. The other half wele droppedduring the stabilizationperiod rvhodid not (P<.1by 1?analysis or f testfor correlatedmea: following control of acute symptoms, usually becausethel' n6 tras a critical factor.Those completing the preliminaryph: longer wished to participate in pelcent the sludy. Fifteen of the an averageof 5.2 years older than those not compler preliniinary phaseat admissionto the study and2.2 years the ouset of the first episode.However', the major factor: entiating thc.rewho corrrpletethe preliniinary phasefror rvho did not were study center and inpatient zroutpatieni sions (Table 2). I\{uch of the difference between innatitr outpatients and among study centers resulted fi'om tl Table1.-Denrographic and ClinicalCharacteristics outcorneat the inpatient units of ceuters A and B. Ce irrpatientswere predoniinantly Vei,eransAdministratiou I Blpolar Unipolar adn.rissionswith a history offrequent hospitalizationsfor a Chsracterlstic (N=215) (N=343) disorders. Center B is a statelvide referral sout'cefur Age, yr patients n-l::'fail to lespcnd at othel levelsof the treatnr: Mean*SD 38.1+ 12.4 38.8:i12.4 system. If the inpatient results from centersA andB are o Sex, % thele is no major difi-erencein outcome betweeninpatier 42.0 33.0 ____ outpatientsor alnongstudy centers, F 58.0 67.0 I nit i al Tl'eatnle nt of I lt de:t E p i so de. -Eighty-three pt r the patients rvih a manic or mixed episode receiveci Age at onsetof 1st episo,,e,yr '10.9 Mean* SD 24.9* 27.7 + 11.2 carbonatealone or in combinationu,ith anotherdrug. Nirt percent of the patients with a depressiveepisode re,r( 4.0 Priorepisodes, median No. 7.A tricyclic antidepressant,usually imipramine aloneol in co Index episodei' tion rvilh lithium carbonate. GAS (mean) 45.0 48.1 llaintenance Phase.-Dosage.-The mean daily ti rs RSMD(mean) 9.9 10.1 imipramine hydrochlorideat the start of the maintenat.ct Inoatients.o/o 42.0 24.0 uas 132mg/day (range, 75 to 150mg/day). The meanseru,,i lithiumwas 0.?5 mEq/L (range,0.45 to 1.10mEq/L). Thele M""i" "; 4n ", "'i*d. significant difference in dosage between patients rece,vi *GAS indicates Global Assessment Scale; RSMD, Raskin Severity ot drugs ir-rcombination and those receiving the drugs indi 'it Depressionand ManiaScale. Ouerall Outcome.-Table 3 summarizesthe overa.llou c(
Table2.-Bipolar Inpatientsand OutpatientsEnterinq Maintenance Phaset'
Patients Cenler A Center B Center C Center D Center E lnpatients No. admittedto preliminaryphase 51 10
% admittedto maintenanceohase 33 29 BO DJ ot Outpatients No. admittedto preliminaryphase 21 28 45 % admittedto maintenanceohase cc 67 61 64 *See "Subjectsand Methc,ds"section for namesand lorationsof cenlers
1098 A.rchGen Psychiatry-Vol 41, Nov 1984 Uninolarand Bipolar ,:,i0 ",n"tt*. ,,1Pi$;1i7|; 7
the li7 blpol:il patienfs i",'hoe niered the maintenancepha;e. Thi.ee analyze the cortr'.qeof iliuess fol the three ti'eatn)eni gi'oLrp-s.:t:l outcoile r:atagclir; rrc iiefined: treatrnent failures. treat!nerlt These Inethods :ife i(ieal fol L-rrrg-ternrtlinical tt'ials becausethe;r' '*'ere successri, and otlier'. l(tiltr'.s included (1) paiients .r,'ho take into accour.rtthe vai.ying lengths of tiiiie that rratients are in ulable to coniplei.eeighi t','tisecuti,,'eweeks in lhe sLudv r."'ithiLll. the study as well as the outconre ilf treatnlent. In the actuarial suffelinE-a. r€rrr.l'i rri",ce, (:l) patients t',,hocornpleted eight tveeks Lir.rt method, ihe maintenance periocl lias partitioned into a series of subserluently iraC :. rec,:i'rence, and (3) patients rvho had no lhi"ee-uonth inler',,als. The I{aplan-L{eiei'lii'e t able is continuous, tecLifi'encebut *'ere telnl'nated for adverse reactions or tvol'sel- ',";ith lo grouping of measures. There i,..ereno majoi' dilferences 'Ihe ilg clinical coirditicn. Si'ri'e;st',suere patierts',vho renrained r,r.ell f6li1'6e11results ii'orn the tv,'o methods. actualial cur\res are and complet,:cl ;rt leasl oi:e i,ienl il the slutly. The "oiftet"' crr-egory preseilte(i in Fig l. The statistical signifir:ance of lhe ovelail inclutiedpatients '.',ho rer:..:t:it'l'"vellbnt faiie,:l t,i cortp.lelet.he tilst i1ifl'eielte in the cr'*r-serif illness ai:irrrg t)'1tr;'1.nt.itts',lastested by 1'ear, irsuaily becaitse tlrey no longer saw the need fcl takitrg the {len,:r'alizedS:vage Test that yields an:rgglegate ;1:statrstic.':r medicatioii, experiencecl:1rl in'Lcrcuri:eiit ilhtess, or lel't the study Th+ rlit"felenceanorig tleatmenis is strtisiicrlll'si.qiiificant at the alea. In ill,62ao of t.heLraitetits were il!lLtt'es,25% ruet'esr-lrcess.!r, .05 level. Individi,al ileatnient curl'es i',,er"a.omprfecl v;ith the and 7.3Vclenra-rned i.:,-r1,feiled to {-onlpleie llle year of tleat- Genelalizeil Savage Tesi. cliirce type 1 ei'Loi' 1'Lheplo'l:al:ility of "7sll ment. rletecting a differ':rce betueerr groulis ,\her rr,) true diffelence One sut;griirp c,f ta.ilur;s l,/al I'alis ca;l'luielrt. Fifteen pelr:eitt of exists) increases ;,'iLh the r.irimber of cr-'r-rrparisonsconriucted jntelance the adinissic'i:sto the ma phase l'ere nnable t-oronrp,lete between individital ,qr'.rups,oiie requires a mcre sti'ingent P velue eight ':onseeLiti','er.",eek:r 'i,ithout a l'ecuti'e1)cL:.llaity ,rf lliese lbl del.ermining stalis,ticalsignrticairce between indivirlual gloups patients had tri'o rL molj: i'ecilrt'enceslvhile on their maintenance than the .05 level ris+Lifor the cr.errll coml)ari.clr. Borrferloni's t!'eatment i'egimen beiirr': beiiig dropped or leaving t-hestutly. It equatioli"ris cne nte:trs for coinpensaling fol the ilflaiicn in type 1 can be argued that r*culi'er.rcescccurr"ing during the irist eigLt error that-res'.rlls flotir inultiple compali-ror,s.The ettriat!onineli- r.,'eekr:r'i rnaintenatrreti'..attnent lepresenl a coniir-ruationof the cates ihat for individira.l coL"Urafisrns l-retrveenlhrer: gir,rups. atr index episoderrther th:u r new episodearrd ale rrota h r,ielneasLti'e c.-leiel of 0.016 is re,:lriiret'lto ar'hievea true llpe I tlior ol .05" of the ta1-racit;yrf stud.r treattlents to i;revent r-rewrttaclts.r" IJring ihis criterioil, ihe diilerenr:es b+trr-eenlillriuin calbonat: Con';elselS',manl,' of lhe..riu.ly palients rvere at high 'isk fc. air and irnipramine ard bei,1'een tlie cornbir',afi,,n tt"eatment rntl early r';:rLtrreucea-nd hail alleady been in a stable clinical stat.etl.;r'a inripramine l'ere statistically s:igniiicant.. The rliifei"ence betr.,.eer.r nurrrberc,f months pleceilir:g adniissioirto the Iuainterance pitase. liihiurrr c;u'bonate::nrl ihe clrniliratiirn lleattreiil *'zis nct "qignilj- It is not incclrceivableth:rt scrneof t-liesepatir:nis.,roulcl ex;:et'ience cart " a ne,,vepiscrle duiing t!,r iilst fe$'rlonths of ilie itraiittenance Relcttionsliipof the I itrle.t:E pisolt !o Ot.ttt'ttnre,--t{ainterrance phase. This issue may i;e of iriore theoretical ihan |r'actical pharreorrtccrme r,,'as analyz,:d in tei'nrs of the nature altd se.,"el'it!'c,f impolta:rce ibr ihe ;tud;'. ionipi:r'irrcns inluitg lreatrrteltts ,,r,'ere the irrtle: episode. Fol the pr-ltlloseof atraly.sis,the natrte of the -,r '1na}tic ''depi'es.r.{1.'' not-siglifica.ntllleffectecl i^Len+"his i'rhgioup *as crnitted fi.oli the episrr{l{)ir,as classiljed as a1'11ri';gcl"r'r Ser,erity 'sevele." analysis" rvas ri.".ssifieclas "mcderat.e"or" Seierity i.r,asilefineC or.r Oui,:cijtr.itt"!,ttii..t!tlu:.! L\'rct:tt.,tts.-^(lut,:cltes il.ri th,,.tlriea t he lr: sis ri GAS and R S DM srot'es.tv{ od e rat,:,< e t.'e rit tl,.. as rlelii,ed treatnrent gl'.ups are suirrmarized il Tabla 4. Lithiutn c::rbonate as a G,\S score of 5l to G0(th.: r'arge of "'mr,.tltlateirrrpait n:errr:'on and the corrrbinationt,reatment plcciuced a signifit'antly )righei' lhe GAS) and an RSDI'{ tcial deplession or menia scof€ ol7 tl i1. A percentagec,f tr"e irrent !i:trcess€s(;13-qr) th?"n dicl iniiitramine (8%) s='t'pi'er,,risode was defined bv l GAS !..(\ie of 50 or le:.sor" an jlSLilr{ jhe (P<.05 b;l 1' anal;isis). diifelence ein(lr1gtreatlrer.its g,as tot;rl de1;i"essionof rirariiasccr'e of 12 eri'ir,,tle. attributable to iire higli i;rcidence oi manic recurrei:ces in lhe MairlEnence phase or,,tr:c:rtelr,as signi{lc!1itl-il,'i elr:ted to rh* imiplatnine-tl'eEtedgroup |-ifty-thlee pet'cetltof the irrrif,r'an'.iue- ireaterl patients hicl a nrrri.icor rnixed l'ecui'leltce,conrl;aretl rvith 26Vscl the ttt::ie
Table5.-F*rcentage of UnipolarPatients Entering Maintenance Phase by Levelof Functioning Betleen Episodesanci by StudyCenter*
Level oJ Functioning z No impairment No. admittedto preliminaryphase & % admittedto maintenanceDhase
% admittedto maintenancephase *See "Subjectsand l,4ethods"section frJr names and locationsof centers *
Tahle6.-tilaintenance Plrase Outcome for UnipolarPatients bv TreatmentGrouo z;t lmipramine lmipranrineand Lithium Hydrochloride LlthiumCarbonate Carbonate Placebo o/" -- --q!t"g!T (H=39),% (N=38), $t=37'r 1b (H=3a),% F"il.,* F)anroccinn 33 26 57 65.: Manic-Mixed _3- 5 I 6 Adversereaction 3 3 0 0 Remainingwell '18 Terminatedwell during year 1 5 -13 I Remainedwell for studyduraticn or terminatedwell during year 2 f,l ?1. *Differences amongtreatment groups statistically significant (P<.05, x2 analysis).
1'100 Arch Gen Psychiatry-Vol 41, Nov 1984 Unipolarand Bipolarlllness-Prien et al nledianof 18weeks in the preliminaryphase. cornbinedin the table.There are three importantlir.rdings in the Raptl Cyclers.-*Ninei'apid cyclers rvele admitted to the ple- table. First, the group with no history of inrpailnrentbett,een limin:try phase.Only t"r-ocompleted the preliminaly phaseand episodeshad a muchhighel pelcentageofsubjects cc.rmpleting the both rveredlopped becau:e of treatmentfailures during the first preliminary phase (607a)than did the grcup ',r-itha history of six monthsof the maintenancephase. impairment (357s).Second, the difference betr.veenthe not im- Co mpati son oJ' Co ntpl eters v ltlon contpl elers. -Preliminar'.y pairedand impairedgroups was consistentacross centels. In no phaseoutcome *'as analyzedin terms of the samefactors used for center did evenhalf of the patientstith a history of irnpaired the bipolar sample. Four fhctors significantly differentiated pa- functioningcomplete the preliminary phase. Third, asrcas the case tientswho ccmpleted the pr'eliminary phase from those l'ho did not with the bipolarsainple, centers A and B hadthe lorvestpercent- (P<.i0 by 1: analysisor i test for correlateclmeasures): age at agesofsubjects co;npleting the preiinriirai'yphase. This charaitc.r- admissionto the study; 3ge at onsetof the first episode;study istic is attribu'ual:le,in large nreasure,to the e. Fig2.-Life"lable probabiliiyof remainingwell fcr eachtreatment Fig 3.-Maintenance phasetreatment successes tor unipolarpa- lor unipolarpatienls. tientsby severityof indexepisode. 1"0 lrl Fiacebo EE LithiumCarbonale o -^ andLithium Carbcnale i:j !mipramine 3 ue '. lmipramine s '- X LithiumCarbotrate E LithiumCarbonate e 08 - Placebo and lmiPramrne o E 491/" cE v., b 42% g 06 a c) E a a o UJ 0) I o o_ O l o 0..1 a d I P 03 f f L) a2 69 12 15 18 21 24 27 tu1onthat Risk lmipramineand No. L.iihi':mCarbonate 38 20 at Risk lmipramine 39 20 (n=17) (n=18) Liihiur*Carbonaie 37 12 (n= 1l) {n= i4) Flacebc 34 10 Moderaie iievere InderEpiscde incl*:re cisoda vvrrrYrcit I + hl,r-. i,laii a t"Lla;,iif€tic€t-'h;le rtrri,'rt'g ;1,:1i,1611jp.:inrl the ttlier BipolarStudy ,.:i: i i: rr:tei-, i:, ; t ir: c,:':i:cit ::ri i.ln t:'e:t r:rtl: 1.. €.:tuerial :..r.:iKaplen-iI,:ier l:fe-t:.ti,: nrethcds \r:,Ji'€ur:ar'l to The L,ipolar Irhase of the stuch' irroillt.ed ilifce mai irn.,li;r; i-ir. rijii.i"..,r:t: ili cr',;rs- ot ili,t.:i:: atri'ng th.. fr,ui'ri'eat i-irrdings First" lirhi':m r:elilo:iate lvar sigi.]ifi.F,rrl1rnr0' ]:reiti. Ti'.s :.iuriri"lj curve! ar€ L.l'eserileclin Fig i. The oi'erali eff€cti!3 tlian iir,ipraliiiir-: irr p:'oieclitig agaiilrl irtaitic r€ r.irfier.:r':e 'ri!'r"eir{jeS -'"i,zis a::i";iigt|eortt{eiits \,"'a.:statist,rc:rli.r,sigr,iir:;:lil al lhe "05 f and €:.1uail.ya,s effecti...e a"Sirr:iF:'amine i ., !':r'r1, :.: L'l=i.r"li.i!:r.:iib.\'th- L,aeneralizetlS;vage Te Bcnierruni's prolectillg agaihst clelrre-':r-e.IccLli'itrniea, .itr:,riril, 111 r,r':r:r aaiut:!rl': riir,.ilt,r r'i+terrnirt: the:pp|ogri'iatecr-1,-:,.1 tbi'contpat, coniliillaiicn oi'li'Lliiuii'c,{t'l-r.:}!tat€ anci iitiipi.r!liite pi,ovicle, t',1 ,,, i, ;,.i,1a;...'i11',: t-l ,'t,1ltl|;']iet,',tt rrD: its\i[ril'(Sil Ht'rUpS, no ad\-alttag,.o',-,iii. jithiu-tit carboitate :.lorie. Thii.cl. Iithiul l-' i,;iue ci.C0r. i.; achie'"ea llue lype I ellor of .05. \\'irh the use of cai'i,ioliat€ th!s string-,:nicrit-el'i'n for sia'iistic:l significance rhe differences \t,as ln0i'e ef'fective r,i'ith 1;aii:nts 1.,hose las (ie, ileiri,iet! itr,.ir:-,1';inil:r.lcl placeb,i att.:ii:,itrrl,:en ih: cunibinatrr,r: eliisorie lhe ii,iit: r.1.ri;,:de)r-as m:',1c iiieir r. ill, patient -riie|t 1!":.tri::rri- ;:;;1ql 1,j,,';1'-: !,tr,riistic:ili.v:r.lnific;r;rii)ornpil|i-r'rnl ,.,'1tcrelast epi's,,itl.. !i as i1:i.,i'issii,e. trei" '.:el ilirii,.tar,rli,.. :rnii liiiiLrt,. carLrtrlrateai',ii lretrveen the The fii'st finciir:g ':oliflt'iiis i'esitlti ii'oiri the r-rl'il.vothe ,:.!,T!lrr:!:i:rrni.ie aiir:,.iri :rld !!'tliiun carL.,;nateI'iei;i:r] P values sliici;.'ci;n:paring iiilriulr: .al'Lrr!lateaE:til.si inrii:,r':.,inine in I 3isl:i.+: ihai, .UiirJbiit les.. lh.:ri .l15 i'rrlrtp.l.r'iso',illetv,ree:i ini- bipoiai' poilrlat.iori.'lhe i,€rt lans Adni inisl-raiioir -Naliotra ipr"airrin: ,:nii th4 co:"nbi:rationtrealnrent and Iithium between Institrite of li.{enlalllealih (NlllIH) Cc'llaLrcrativeStudy o j.l llele carhlrnnte :il lilr.{'€bt trot sigt'rificant.In sr.im,the ana}vses I-,itlriuniThet'a1-rv'f i.l;orteri tl'r*t.it4ci:cf iniiplan.tiit:.ti'eate( ililicaf ec thar butlr iirript'arnirreancl th: coml:ination tr"eatntent p;rtients expet'ierrceila nlani.'episode t.omlla1"e(lii ith 117c '{?ru sigriiii altll superior'ro placebc',r'" hereas li'ihiLimcarbonate o receiving lithiurri riarllonate l..i;i: ftDt. Tlie imilrramine and combinatiort treatnients ri"ere also !)aiients The cui.i,ent studr sr-r1'...iartc the lithium carbonate treat.nient, but the differences foLr:rCthal 53% of tlie patients tre;rtecl x'ith irnipr.aniini iaii"il t,r lt'ech stltistic*l signiiicance:ar the .(l0tlievel. suflerecl a manic episode, coiiipalett r,ith ?€.,i receivini li..it,ii;rirshtpof tlre Ind.tt Dpisode to Outtor:te-Maintenance lithiurn cal'bollate. in boLh striclies,iil.hiutrr c:;i't,onate ani phase outcoiiie was aitalyzed iti terms of the severity of the index itniplamine were erlually eft'ecLiveagaillst clepr"essiverecui.. episodc alr.t in tefnrs of RDC-tlefined subt.i'pes of depression rerlces. Becailsethere r,vasno placeb{i-tleal-ecl gr"otip in thir ( charactr:riziirg thi: ep!sode ie, enclogetrous,agitated. r'eta.rcled, study. it is not possibleto deiermine il tlie high irrcidenceo :.iiu:rtiru;rl. sirrr;'le,arr.l psl'ch,rtir). Outcone i','irs not -signiiicantl',' manic recun'enees for irlipi'anrine.tleated patietrts re reiair.il to tl-resut,type of t,he index episode" Sevet'itr',houeve r'. sulted from iniipramine-induced lrlar.iiecr frout failui'e o l'r,,,.'e:ltc be a ci'itical factor. Figure 3 siroq'sihe percentage of iniiplamine to prelent nai.iila.ll.1clcct"ii'Lil1g nranic ..r:"':::s.s for eaqli ti'eatmeni group bi selerity of the index episodes ii-ri'.rcl+.Iror paii,,'nt"s'.,"ho had , mod!.i'ateintlex episocle(ie, a GAS Horvever', the fact that the VA-NI}IH stut11' shou'ecl nc !{i)i:- t'f5l tc 6[i). the sutcess t'irtelbl the three acti\c nte(iication nlajoi' diff'erer0e bei$,;eeri iri.rilii'irrriri:ancl placel,,oin th,; gi'r,i.t;.:in:as signifrrantl"i,. gre ater-tliait that fu| placeb'_r(P<.05 b1' itrcicleirceof riiairia pl"ovides suppcrt fo;" the latter in- 'lliei'e 1: ;1i!;,i.vrii). r,,,astro majoi'tlitfei'ence ir.rsuccess rate aniong the terpretation. Regai'dlessof horv one interpi'ets the finding, tit:'::: fli'ilE gfoul-rr. For trra-lier,isu,ho had a sevei'eincle;< episocle (ie, the use of irnipraurirrr foi' tire iong-telrn pi'eventive treat- ir Gli.S s,-'ri'ecf 50 ,,rrk'ss), the:iuccesslates ibr imipt'amine arrdtlie merii of bipolai' disor' 1lti? /*.reh Gen Psychiatry--Vol 41, Nov 1984 Unipolarand Bipoler lilness-Prien et al The finding that imipramine was more effective over"all the superiority of lithium carbonateover an antidepres- thanlithium carbonatein preventingdepressive episocles is santu'"" used relatively stable samplesthat had been at variance rvith results from two other multihospital euthymic or episode free for periods of at least seven collaborativestudies. The VA-l.lIMFI study founcllitliium months to a yeai'. The trvo studies reporting equal effec- carbonateto be equally as elfective as imipraminet ancla tivenessoflithium carbonateand an antidepressant5,'0initi- BritishiVledical Research Council (MRC) study reported no ated treatments within a relatively shoit period after. significantdiffetence in effectivenessbetrveen lithium car- recoveryfiom an acute episodein patients rvith less stable bonate and amitriptyline.'0Both studies used designs histories.The current,study also found lithium carbonate similarto that usedin the current study. andan antidepressantto be equallyeffective, but only rvith One possibleexpianation for the differenceirr results patier.rtswhose index episodervas of moclerateseveril'7. The betrveenthe current study and the MRC and Vr\-NIMH antidepressantploved superior l.rhen severe episodes wele studiesis that lhere may havebeen differences among the involved. patientpopulations. Unfortunately, the i'eportof the [,IRC The provocativefincling that the respotrseto pt'eventive study cloesnot pro'ride information on samplechar.acteris- lithium carbonatetherapy was related to the severityofthe tics other thar.rage and sex. Thus, it is not possibleto last (index)episode must be interpretedwith caution.This compalestuclies in terms of the severityof iilnessarrd other is a preliminaryfinding anclrequir.es further exploration. pertinentcharacteristics of the studysamples. Compalison For example,it is importantto determinewhether patients ofthe VA-NIMH study io the currentstudy is alsodifficult with a moderately severe index episode differed flom becausethe two studiesused diffelent measures ofusvcho- palientswith a severeinclex episode in v,'aysothel than the pathologyand impairnient. Horvever,the VA-NiMfi pa- sevet'ityof depressivesymptoms or degree of fur.rctional tient sanrple*'as coll-ciclerablyless ill in telms of ihe impairment.Factors such as the frequencyand severityof frequencyof prior episodes.The mea.nnumbel of nrior prior episodes,nature ofthe depressivesymptoms, and age episoclesfor LheVA-NtlIH samplervas 1.5, compai'eclivith should be examinecl.However, for the presetit, if one four lbl the culrenb siriily (unpublisheclfindings, R.F.p., assumesthat the findingis not a functionof confounditrgby January1984). Another ilifferencebetrveen the trvo studies other variablesand that the severityofthe iast episocleis a is that the VA-I.IIMH sLlidyattracted a far gr.eaterpropor- goodestimate ofthe sevelityofthe next episocle,the results tiotr of patients irith classicrecurrelit affective illness strongly suggestthat lithiurl carbonateis relativelyinei'- characterizedby clear-eulonset and t"ecoveryof episodes. fectivein preventingsevere unipolar depression. andeuthymia betr.reenattacks. The VA-NIi\.iH study was There is a possibleexplanation for the relationshipbe- initiated in 1967, rvhen lithium carbonateivas stili an lween lithium carbonate'spi'eventive efficacy and severity investigationaldrug ancllong-term preventive drug therapy of the index episode.llany clinicianssuggest that niainte- wasnot a widely prescribedpr.actice. The study centers nance lithium car"bonatetherapy may not prevent the \lrereamong the few placeswhele liihium carbonatewas appearanceof episodes,but rather mav act by darnpening available.In this culr.enteLa, rrrauy ofthe patientsleferrecl emergirigl'ecurrences sufficiently to preventa fuil-blown to the VA-NIMH stuclyqtrobably x'ould have been treated attack. If attenuationlather than pre.;entionis the mairi satisfactorilyin the co:iimunity and would not har,ebeerl action of long-term lithium carbonatetheralty, litiiirrnr t'eferredto or soughttr:atment at the meclicalcenters that carbonate could have the capacill to clampenrnilder participatecl in the currttrt study.Thus, there were some- depressiverecullences but be relabivelyineffective againsl what differentpopulations in the two stndies,rvhich might the more severerecurlences. This explanationrvill be havecontributed to the differencein results. exploredin future analysesthat r'..illexarnine the severity r-'f ,. ?he only controlleclstudy showing an aclvantageof recurrencesfol eachtreatment qrolip as well as the pres- lithium carbonaieover a tricyclic anticlepr.essant"aclm"ittecl ence of symptomsthat did nol reach the severity of a only patients rvho were able to remain euthyrnic for six recurrence. monthsfollowing recovery from a depressiveindex episode. The t'indingsprovide no evidencetha- the combination i'lrther, patients had to r.emaineuthyn.ric for an aclditional treatment has any advantageover imiplarnine fol uiripolar six weeks duling a dosage-stabilizationperiod rvith im- patients or lithium carbonatefor bipolar patients. The tpramine. The severity of the priot episodewas not re- relativelyhigh percentage ofunipolar patients in the eombi- ported. Ho*'ever, the fact that patients had to r.emain nation group who experiencedaclverse reactions of more euthynic for at least7/: monthsinclicates that patientswith than mild severity(367o) is further reasollfor cautionin use re.lativelyshort intervals betweenepisodes arrd patients of the combination. who wet'enot euthymicbetrveen episodes il'ere excluded In sum, it would seemthat an antidepressantsuch as trom the study. The report for the study dicl not inclicate imipramineis the preferablechoice for. long-term pl"eveii- what proportion of patietrts who recoveleclfrom the incler tive tleatment followingrecovet'y from an acuteepisode, if episode were ableto satisfythe stringentadmission crile- for no other reasonthan the fact that the VA-NIMH and ria. In the cui'reittstud;g, these criteriiw,oultl have e: 1. N1'siromS: Depressions:Factors relateil to ten-yearplognosis. Acfo Nerrr"r, September l9'i6, p 3. Psyci iolr Scoridi979;60:225-238 13. CoppenA, Monlgomerl'SA, GuptaRK BaileyJE: A double-blind 2. Zis AP,Goodrvin FIi: Majorafiective disorder as a recunent.illness: A cornparisonof lithium carbonateand maprotilile in the prophylaxisof the criticallevier. ArcltGett Psgchiotrll 1979;36:835-839. affectivedisorders. Br J Psythiotrglg76;128:{79-485- 3. PrjenRF: Long termproph.t'1.'r':ir.r pha)'nracriogrc t) eatnriri o1'bipolar 14. CoppenA. Chr,reX, Rri,P:llianserin 21:1r ]iff rlmin theprophylaris illness,in GrinspoonL (ed ): Psycl irrfry Lrprlate:The Att ie rittLtt Psycli ici lric of dept'ession.Br J Psychi.airy1978;133:?06-2111. AssociationAnttual Rerie u,. \Vashingtori DC, AmericanPs.yrhiatric Pless 15. Iiane Jlil, Quiikin FlJ, Rifliin A, Ral:os-LorenziJR, Saraf K. Inc, 1983,vol 2, pp 303-3lE. HorvartlA, FileinDF: Prophl'lacticlitiriun tviih and tr-ithoutimipramine for 4. DavisJM: Or,ervieiv:Maintenarice therapy in psychiatr-r':ll. Affeutive bipolarI patients:A double'blindsiud1.. Ps3lrlu opltai'ittecol Bir11 l9E1;17: disorclers.Ani J Psychiatt'y1976;133:1-13. 744-r45. 5. Prien RF, I{lett CJ, CaffeyEM; Lilhium carbonateancl imipranrine in 16. SpitzerR, EndicottJ, RobinsE: ResearchDiagnostlc Crtteria.fbr ti pt'eventionof affectiveepisodes: Repr-rrt from the VA-l"lIMH collaborative Selec{edGroup o;fFuncttonal Disorders, ed 2. Ne-r York, Bionetrics stud;r'of lithium therapy. Arch Gtt Psychiatry 1973;29:42A-425. Division, Neri,Yorli State PsychiatricInstilute, 1975. 6. BaaslrupPC, PoulsonJC, SchouI,I, Thomsen K, Anrdi;enA: Prophl'- 17- RaskinA, SchulterbrancltJ, ReatigN, IilcKeonJJ: Repiicationof lacliclithium: Double-blind discontinriation in manic-depressiveand recur' iactors of psychopathologfil inten'iel', t'artl behavior',and self-report rent disorders.Lancet I9i0;2:326-33D. ratingsof hospitalizedclepressives. J Nerz, Il[t;tt D[s 1969;148:87-98. 7. CoppenA, NoguetaR, BaileyJ, BurrrsBH, S..ranitr{S, Hare EH, i3. EndicottJ, SpitzerRL, FleissJL, CohenJ: The globalassessment GarclnerR. MaggsR: Ploph.ylacticlithium in affeci.ive(li:rorders. Ln,rc,rr scale:A lrtocedurefor nreasuringoverall severit.v of ps-vcliiatricdistur' l9iL:Z:275-279. bairce.Art'li GenPsychirLiry 1976;33:766 771. E. CundallRL, BrooksPW, [Iui'i'a.yLG: Controlleclevaluation of lithium 19. Angst J, Grof P: The courseof nronopolardepressions and bipolar prophylaris in affeciivedisorders. Psychol LIerl 1972;3:30S311. psyclrosis,iir VilleneuveA ( ed):LithitLnt in P sgchiatry:A.s3r rr ops is. Quebec 9. FieveRR, KurnbarachiI DunnerDL: Lithiumprophyla-ris of clepres- City, Les Pressesde l'University Laval,1976,pp 93-103. sior,in bipolar I, bipolar II ancl unipolar patients.Am J Psychiatry 20. Quitkin F, Rifkin A, I{lein DF: Prophylaxis of affeciive disorders. 19?ti;i33:925-929. Arch GenL'sycltiatry 1976;33:33?-341. 10. Glen A1[I, JohnsonAL, ShepardM: Continuationthellpy rvith 21. FleissJL,Dunner DL, StalloneF, FieveRP': The lil'e table: A method Lthiumand amitriplyline in unipolardepressire illness: A contrr-.lledclinical for analyzinglongitudinal studies. Arch GenPsgchiatry 1976;33:107-112. trial. P sa c h ol,4{ed 1981;11 :.109-416 22. Iiaplan EL, Meier P: Nonparametlicestimatjon frorn incomp)ete 11. Iiane JM, Quitkin FIvI,Fiiftin A, Flarnos-LorenziJR, Na-valiDD, observations.J Anr StatAssoc 1958;53:.157-1E]. Horvai'dA: Lithiumcarbon.,te anLl irniplaniine in theprophvlaris ofuiripolar 2;1.Lachin Jl{: Statisticalinference in cli,ri.:altrials, in'I\'silup N. anclbipolar II illrress,Arcli GettPsychiatrg 1982;39:1065-1069. LachinJM, Juhl E (eds):Th.e Ro.ttdonti:ed Cltnical Ttial in Therapeutic l2 A look insideFDA. A"tcri,:ot,Psllchiat.ric Associatian Psych.iair[c DecIsions.I.Iew Yolk, MarcelDekker Inc, 1982,pp 183-184" '1984 1104 A.r"chGen Psychiatry--Vol41, Nov Unipolaranci Bipolar lllness-Prien et al