rgs

erapy and rd neurol'n, atticles urological re place in :al agcnts. {L'rncnl oI roPsych(} n5 Letlers to

Opttttol CURRENT
t{il

rjJsf)lrr roooc(t l. (.1)&7.256 | | rl. rrr?,rg?t$r G0?67rt6 @/0

frlar4rt{ry lfttrr, At rohlt tr'?.ytar

Potential Sensitising Effects of Antidepressant Drugs on Depression

Giounwti A. Fnan of Psychiatry, Universityof New York at Buffalo,Buf{alo, State Department NervYork,USA;and of Psychology, ltaly UniversityoI Bologna, Bologna, Department

Absfruct

malLim10,New i; Europe must be JS dotlar . given in ,nt Kont 12,Tokyo

;houl the roduced, anical or )rmation opyright rlication. le for the :s. ot {or product nesis for )pinions iditor or

Thepo"ssibility drugs. depression thatantidepressant whileeffectively treating prccess hasbeen in theshorttcrn. may wor.sen its course througha.sensitisation proposed. Although of this hypothesis exten.sivcly tcsted. a number hasnot been point towardthis possibility: the very unfavourable long tsrm clinicalfindings paradoxof majordcprcssion whentreated outcom means: by pharmacological with ical (dcpression-inducing) effcct.s of antidepres.sanr drugsin somepatients moodandanxiety antidepressant-induced andcycle acdisturbanccs: switching celeration in bipolardisorder;the occurrencc of tolcrance lo thc effectsof antidepres.sants duringlong term lreatmenti lhe onset of resisrance uponrechallenge with thenamc .syndromcs antidepressanf drug in somepatients: andwithdrawal following di-rcontinuation of mood-elcvating drugs. Theoccurrence maybe of a process of sensitisation in susceptible individuals drug Continued expluined on thebasisof the oppositional modclof tolerance. treatment may recruit processe.s of a drug. that oppose thc initial acuteeffcct.s Whendruglreatment at leastfor cnds,theseprocesses may operete unopposed, (ime.This hypothesis is, however. some untested andits rcientific subgantially exploration is likely to encounter considerable rncthodological and idcological difficultie.r, to be verifiedby epidemiological clinical It needs studies, controlled investigations. trials,follow-up studies andpsychobiological Theclinicalimplications of thcsensitisation hypothesis in dcpression areconwith antidcprcmant siderable. The reatmentof depression drugswould not be questioned, andapplicarions mayundergo changes. but its modalities important would needto bc rc-examined A numberof currcntpractices suchasthe (inappropriatc) useof antidepressant drugsin minor mooddisturbanccs, thetreatrnent with antidepressants, of anxietydisorderr dosages of antithe useof suboptimal theapplication dcpressant drugs, agents. and of antideprcssants asprophylactic vermodalitie* of discontinuation. Acost-benefit appraisal of psychothcrapeutic suspharmacological tratment would also needto be considered. Evcn thoughthe hypothcsis of scnsitising cffectsof antidcpressant drugs,0t prescnl,hasno cmpirical suppon,il is imponantenoughlo deserve exGnsive anddcbate. studies paradox';tll the most appropriate agentsfor trcating bactcrial infections are also the agentsmost effecresistant tivc in selectingand propagating strains, which persistin the environment evenwhen expo-

In clinical medicine,the likelihood rhat a specific treatmenr, while alleviatingthe symptoms of disease,may aggravateits course,has often been evaluated. lt is besr illustratcdby the 'anribiotic

248

Sensitir

.{
J

ID

ll D

IL c g
a J lr

: D ) n
j f

t 5'

:.
f

3
T D

) ) = D ) )
J

t v
5

: } *
c

)
t I

r ,
I
L

i
I

1 i L

: ) )
a

sure to the drug is stoppedThe needto minimise is thusemphrrinappropriate useof new antibiotics sised.lll exist in different branches of Other exarnples medicine.The issueof whetherearly reatment of wirh levodop*mayworsen disease disParkinson's progression preease has been discussed.lrl Both clinical (ncurotoxicityin tissuecultures) andclinical (gradual decrease of therapeuticresponse, refracand the onsetof dementie which was not toriness, seenbefore the i*troduction of levodopatherapy) findings promprcdthis hyporhesis.Fl Similar concerns havs been raised about the long term treatwhich ment of asthmawith inhaledp.3gsnl515Fl have beenassociated with tolerancetal because of the lossof bronchodilator effect with time. Obviously. these problems rrre rather difficult and complex to *tudy and definitiveanswers may questions not be available.Nonetheless. these are always worth asking. at least for a better understanding of the adverseeffecrc of therapy and of therapeutic ehoices. The possibility that antidepressant drugs might unfavourablyaffect the outcomeof depre.rsion was fonnulatedin a specifichypothesis in t994.tslI suggestedthat long term use of antidepressant drugs * the biochemical may increasc* in some cases vulnerabilityto depres.sion and worsenits long term outcomeand symptomatic expression, decreasing boththe likelihoodofsubsequent to pharresponse macological ustmentand thedurationof symptornfree pericds.This largely .speculative hyporhesis was subsequently extended to the rishsand implicationsof intenuptingmaintenance psychotropic drug therapylol and developedin neurobiological terrns.lTl The aim of this paperis to updure undcomplete theoriginal,tentative forrnulation,lsl by reviewing which maysuggerir theclinical literature rhepotenof sensitising phenomena tial occurrence relatedto drug useand discussing anlidepressant the neurobiologiculframeworkfor suchevent-ti" In secrions 3 and 4. sornesuggestions lbr f urtherresearch in areaand its clinical implications this neglected ure prcsented.

L CliniccrlPhenomenq Suggestiveof $ensitising Effeclsof AntidEpressonts

A number of clinical observationsseattsred throughoutthepsychiatric literaturcprovidea potcn- at lesstin somepatientsfor postulating tial basi.s drugs.Many of these sensitisation by antidepressmt dam arc derivedfrom uncontrslledclinical observa* tions andbearlimited implicationsif they areconsideredon theirown, butachievsrneaningandraiseimportanlquestions if they arc cxamincdin the light of a unifyinghypothesis. l.'l Long TermOutcome of Phcrmocologicclly Treofed Mojor Depression awareness of the bleak Therehasbeenincreasing long term outcomeof depression, in terms of relap.se and recurrence.ts"lttl 5u*1tan outcome is exfollow*up emplifiedby a recent 2-yearprospective with respectto study on the courseof depression remission and relapse.llrl Remission after treatrnent wa$ rcpid. with symptomsin with antidepre$$ants 707cof patients remitting within 6 monthsand those padents of failing to dCI in only 6% so by 15 monthsHowevel 40% of pailents relapsedover the subwith all relapses months. occurringduring sequent the first l0 months. The poor outcomefioundin follow-up studies may be explainedon the basisof severaldistinct yet ostensiblyrelatedphenornena. Firstly. it may rcflecl the inadequate treiltmentwhich piltinu may sonretimes receive.lsl Secondly.it miry reflect thc pailiul n:ltureof this treatment. even in specialised leavlnga substimtial amount of residua] cen[rc:i, symptomatology" which is probablythe n:ostpow| Thi rdly, reltpse.l|1'l'1 crlirl predictor of subsequent drivc it may derivefrom thechronicandincreasing illness.Fourthll,.it may be due to thc of dcpressive placeboell'ectsratherthan the loss of nonspecilic lrl loss of true drug efl'ects.l But, it muy ulso be u resultol' antidepressant prospective study,ll5f ln a nrtrrrulistic drug rreutnrent. low dosesof untidepressants lppsared to be lesl frenel'iciul lhiureitherhigherdoses or clirticul malt:

ageme 2 treat These Nation Depn:s there * red wir pared r Baldwi 259cot depress experie ery, rlnc about I main st apPear drugsbt drugsse oulcom{ 1,2Pi

ln lg, of imipri depressir procedur depressir tientswir A few follow-u1 who hadr lntidepre ils today,i tricyclic withan in whichart Potients.' increased be regurd, which.af thetricycl used'.l tYl Simitar
tltcnt of an

Cornmenti depressian

?50

5en:

{ 5

(D ol (D OJ

o :
D

iO (D
g,

6" or

C'

<) g.
TD

(a

(t

3
(D o o
(l

o o

o
(D

{u o
0, g
q

z
:

s1sl.lrs.:tl deserve credit lbr raisingthe issuethat maniamay not simply be a antidepressant-induced temporary and fully reversible phenomenon, but that it triggrrs complex biochemical mechanisms of illnessdeterioration. Despiteinitial denial,the view lhst usr of antidepressant drugsmay worsenthecoursof bipolar possiwide eurreney.lallThe disorder hasachieved bility, however,that antidepre$sant drugsmay induce episodsacceleration in unipolar depression hasnot beenadcquatety studied.Goodwinl:?I has illustrated how this could occur.If bothdepressive andmanicepisodes tendnaturallytoevolvetoward remission(eitherinto a euthyrnicphase or an epipolarity)andantidepres$ant .sode of opposite drugs acceleratc this naturaltendcncy, drug trcetment may acclerate the next seguence in the naturalcourse (i.e. the onsetof a manicepisode instead of euthymiai: 'lf the naturclsequencc unipolar of recurrent illness goes from depression to recoyery and then cventuallyto the next episode, treatmennthat accelerate recoveryof the index depression could also accelerale the onsetof the next episogg'.1:'rl

while ally responded fully to imipramine retrapsed reeeivingfull'dose imipramine.The return of depressi antidepreve $ymptoms during maintenance ssanttreatmcntwas found to occur in 9 ro 57% af patientsin publishedtrials, as examinedin detail in a recentrcview.l}3fThese rcsults brar strong rsemblances to the progrcssivelossof effects which and have been observedwith both antidepressant anti-anxiety drugsin anxiety6lstrdsrs.ll+lTheyhave 'fading'(a progressive decreaalsobeendefinedas se of therapeuticeffecls refractory to dosage insymptomatic improvecrease, after non-immediarc ment).1351 to Antidepresssnls I,5 Resistonce

I ! of ar after tomr pre.s!

o
choli unlit withr ning tionsi
TTENC,

Th verse
anddt tratn circul nessa for m< *n adc cal ma

n) ? o
(D ocl

= (D
l) :i'

cr

3 AJ
ll

:) e3 lt
T

o
D
! f-

:)
:r

) ] f :. )

thercfracIn 19S4, Lieb and Balterl-llldescribed in some patientsto antidetorine$sof .symptoms prFssanl drugswhich had beeneffective in previous depressive A changeto anotherantidecpisodes. pressant drugyieldedclinical benefits,but wasfoles well, l0 years later, I lowed by refractoriness describedsimilar phenomenaand related them to treatment.l5l long term lowdose antideprcssant as this refracroriness defined Lieb and Bshgd'trl 1.4Toleronce to Anfidepressonts 'tachyphylaxisn increasingtolerance to a drug tthe point to the exist' Scveralclinicatobservations rhat dcvelopsfollowing repeatedadministration). snce of lolerancephenomena during antidepressant In bipolar disorder.. it has repcatedly been obser' ysdl36'ltl patients who respondedwell to lithtreatrnnt.l6l that Somestudiesl:tl'lul *in, to disposirionnl (pharmacokinetic) tolerance theconium do not alwaysregain lhe samedegrceof initial , which reduces with lithium reinstitution. In a 6 centrationof a drug or its durationof sction. For responsiveness papatients who relapsed year outcomestudyof unipolar depression,lrel instance, whilereceiving flu* while drug-free were prescrioxetine(20 mg/day)responded tients who relapsed to an increased dosageof the .same that was effective in drug(40 mg/day).|:rl bed the sameantidepressant occurredin 4Voof the episode. Resistance Otherstudies. however, suggest initial the likelihood cases. processes of pharmacodynamic which change senis attract' sitir,ityto (hc drug-Mannlrtlldescribed the lossot' The problem of rcl'ructorydepre.*sion ysl lhe specificconef'lectwith long term monoumine ing increasingattention.l{{t'"rll lnlidepressant is in inducing refractoriness oxidase(MAO) inhibitor (MAOI) lrearmenl tributionof resistance withwith described 3 patienm out rhelossof MAO inhibition. Donaldsonlrrl Lieb andBalterlrrl unknown. phenwho relapsed whilereceiving the development of lolerance described to anride- majordeprcssion rvhich prcssilnt severe depres' was reffactory who developed u chronic et'lects to dosage elzineand incrcasc, sion that wss rctiactory ro other treatmcnts. rnay b! Probablythe bestexemplilicationof tolerance, The issuesof loleranceand resistance Maintentnce however. comestrom the Pittsburgh reluted.and point to a common underlyingmeche'
dJ lttl | |

2.I

Ina descrit necessi rement which i or prop, havea , theclin al mode ser,eral

Accc menlrni aculeef This ma patients pet rhe i unte.spo disorder. processie
lhe rrr^o

SensitisingEffectsof Antirleprr.ssantsl

251

whilc elapsed returnof detce antidePren9to5?%of inedin detail ,earstrong reeffectswhich gpressant and {'qlTheyhave :ssivedecreato dosageinraticimprove-

ts rcd the refracnts to anddeve in previous tother antidei. but was fol* years later, I lated them to eatmenll5l 'iness r: as lnL* ro a drug ministration). r been obserI well to lithgrce of initial rtion. In a 6-s5isn,l3el pawere prescris effective in red in 4Vaof .ion is attractspecific con'ractoriness is parientswirh reivingphenrronic deprtsmenls. lance may be lying mecha-

vulne creused rabilitytc r1; lilp.,ie. As Buldessarinil{'l remarks. the assumprion that such physiological Wi rhdrur.r,al syslplom$ tirllowing discont i rruation proce.sses will readust afler a wirhdrawalphaseis of rntidepres.{illll lrealnrent werg recogni.red soon nol $upported hy current{witrenersin the field ol' alterthc introduction af thcse drugs.f+tlThc synrp- drugdependg69g.ltll tenrshlve beendescrihed rvithall types al'anridcThe type of oppositionalprocesses thar can bc {'lt hut particu I i-rxt pressanls'l liul.r'M AOI s ancl SS RIs.t recruited and/arsen.tirised try antidepres.sant drugs Qneof the first poten{ial explarrarinns involved is open to que.$tiofi. Severalrncchnnisrr:s mai- he cholirrcrgic rebound: horvcver. this h-vporhesis is postulatcd, They nrayinclude: unlikely to explainthe seroronergieally nrcdiuted . interactions betweendifferent types of serotowithdrawal syndromes of SSRlc.lr'rl Theexnctnrea| ni n recePtor(l'r':"i{ ningof these syndromes is ulrclear. asis theirrela. thecornplex balance of differentneurotransmittion.ship with posr-rreatment discontinuation recuter sYstet71sls'rl rrencerisk. r interactionshetweenneurotransmitter balance Thereare .some datawhich may suggest an inand the hypothalamic-piruirary-adrenal (HpA) verserelationshipbetween durationof maintenance slisls$"5?l an{idepressanl treatrnent and time to recurrence nf . cross-.\ensitisttion betweenantidepressam drugs treatment.lst)l This raisesconcernabout potential and behavisural and cognitivephencmena,lssl circularity.in the propo.sirion thatrecune nceof illAnother potenrialneurobiologicalmechanism nessafter interruptingtreltment prores the need may involve direct sensitisarion. Neurophysiolofor rncretreatment, andsuggests thepossibilityof gists have usedlhe term .sensirisation, as opposed an *ddiction modeln whosemosl imnrediate clinito habituation,to refer lo rhe long-lastingincrecal manifestalions are withdrawal.symptoms. ment in response cccurring upon repea{edpresentationof a srinrulus thar reliably elicits a response 2. TheSensitirotion Flypothesis at its inirial presenluion.lsel Psychostimutants such as arnphetamine and cocaine have been fouad to In an arrernpt to view the clinical phenomena induce sensitisatiorr. Antidepressant therapymay described in secrionI undera unifying light, ir is inducetime*dependenr sensitisallos.l6ttl necsssflry to refer to the conceptof tolerance.Decrementalpharmacodynamic rnodelsof tolerance. 3. Tesfingthe Hypolhesis which focus on processes tharchangethe number or propenies of drug-sensitive receptor populations, Verifyingtheoccurcnce of potential sensitising havea vcry limited explanatory power in terrnsof effects of antideprc$sant drugs in depressionis astheclinical phenomena described. The oppasition- sociatedwith considerablemdhodological diffi culal model of tolerance.l5ll however, seems to entail ties. A basicproblem is that antidepressants have several imponant implications. been used so widely that ir is difficult ro recruil According to this model,continueddrilg treatclinical populations who haveneverbeenexposed ment may recruit processes thar opposethe initial to them. acrte effects of a drug or of receptor atrerations. Further,in clinical studiesmany variableswhich This may explain the onsetof tolerance in some, are difficult to control for may potentially influpatients. Useof antidepressanr drugsmay alsopro-fi) ence the verification of the sensitisationhypothepel the illnessro a mormalignantand trearnrenr/f sis. leadingto spuriausresults. For in.rtance, there unresponsive cour$er as was suggested in bipolar"\ is'increasing evidencetharcognitive behaviourtherdisorder. When drug treatmenl ends,oppo.sitional apy {CBT) reducesthe ri.skof dcpressive relapse processes may operatefor sometime, re.sulling in and rnay have a more durable effect than pharmathe appearance of withdrawalsympromsand incotherapy alofle.thl.ftll However"thedifferencesmay
o Adr kllrfrotfflc{ tinlted. Att rtlhlr rserved. C$JS9ft46 l9!9Ocl; l2 (4)

1.6Withdrowotond Dependence

s 1999Ocl;12({)

e52

Sen:

{
'D a a' 'D l} D 3 3

:.

n'
5 t 3 D

lt
t2 a

)
f

n'
I

3 :r

:D

) f,

5' :t

J D ? l

$
IJ

)
D I

!: t

r .)
I
) ) :
t L

) ,
L

of CBT morethan be dueto someprolectiveeffect$ effectsdue to the to the occurrenceof sen.sitising Therc i* someprelirninary use of antidepressants. evidencesuggestingthat CBT may reduceresidual which is probabtythe most symptomatology,tns-eal powerful risk factor for relapsein unipolar depresthatthecomIt shouldthusbe demon$trated sion-lt2l is bination of psychotherapy and pharmacorherapy * * psyprevention of relapse to in terms inferior patientswith alone.ln a rment study,l6?l chotherapy recurrentdepressionwere allocatedto 3 groups: (2 years)treatment (i) short term and maintenance drugs;{ii} CBT in theshCIrt term with anridepressflnt phases; and (iii) antidepressant and maintenance use in the short lerm phaseand CBT for maintenance.CBT displayeda similar prophylacticeffect The long term to that of maintenance medication. group shon termand receiving both outcome of the with CBT was slightly bettreatment maintenance ter than that of the group which receivedpharmacotherapyfollowed by psychotherapy.ltrl [n additherapyhas lion, an additiveeffectof combination However,all resultsrnay be not bsen shown.ltHl affectedby the presence of palienu who had been previouslyreated with antidepressant drugs. just that is an example of the difficulties This So in testingthis hypothesis, may be encountered far, only one study has specifically attemptedto verify the sensitisation hypothesis. Younget al,l6el investigated the response to desipramine treatment in relation to prior antidepres$ent treatment,Pahadmore tientswith pastantidepressana treatments episodes of depression anda longerdurationof illness;however,this may sirnply reflect the more severe csur$eoftheir illnessandnot an antidspresa santet'fect.Younget al.l6el failed to subslantiate ip betweenprior antideprssant relrtionsh therapy to f'unher theranda lower response antidepressant te consi deruble nrethodolo gical di fficulapy.De.spi strategics ties.severalresearch may yield somevaluableinformiltion asto thesensitisation hypothesis, 3.I Epidemiologiccl Siudies sourceof intormationmay derive An essential trsattiom epidemiologicultrinls. Unfortunately,

episodein itself may conment of the depressed fioundthe results.However, sludies reporting on tend to omit the naturalhistory of major depression drug use as a risk c$nsiderationof antidepressant factor for recurrence. 3,2 Confolled Cltnicol Triols Controlledclinical triols may provide valuablc with an information, but only if they are associated adequate follow-up period (at least2 years)-These validity if theycompcre trialsachieveeonsiderable andplncebo or clinical managemenl drug treatment lo in palientswho have had no previousexposure drugs. anridepressant Three types of trials appearto be particularly suitable:(i) thosethal involvtd children and ado* sincetheseindividualsare more likely to lescents, and in bc at their first episodeof major depression petienls drug treatof this agegroup antidpressant ment does not appearto be superior to placebo;l?0| wheretherewerc tii) thosewhich invslved situations no significant differencesbetweendrug and placebo in thc short tratment(e-g. in minor depression);lztl and (iii) those that involved the use of arly in anxiety disorders (particul antidepres$ants dispanic,socialphobiaandobsessive-compulsive in facl that, despitesubstantial order).lt is possible, clinical improvcmentin anxietysymptomsduring active tteatment,patientstreatedwith antidepresof major deepisodes sant drugs may experience pressiononce drug treatmenthas been discontinr ued more often than patientstreatedwith placebo although there are no datr lo or benzodiazepine.s, confirm this. 3,3 DifferentiotingRefrccloriness cnd Reslstonce As discussed in section1.5,it is nct knownho\r muny of the patientswho arsjudgcd to be retiac' Featmentuctuallydisplay rory to antidepressunt to that treaiment.i,e. they becamereresistance therupy to which they liactory to fln antidepressirnt initially rcsponded.Valuableinlbrmatirrnrnay be wherercchallenge providedby prospective studies. is perlbrmed.lrel with the samedrug upon relapse

Porl sion havr gitu, irnpr this resp alier drug of il1 pre.s! sion may sitisi

4. Sr tf
wils r

evide Treat woulr ed us, 4.1

Th establ ever.l in rhe or der sidera bccau therrir aboutI thana prrtie n ceive in tern I'rom c Prnduc tntrh be rou

SensitisingEffwts trf Antidepr6s*,,t,0,

25.i

self mny c$n; reportingon )ntendt(}omil : useas a risk

3,4 BiologicolStudies The ure of biclogicalmarkers husprovidetlimporlanlinsighls into the psychobiology of depression. Unlbrtunalely, however, nlostol'the studies huvc beencross-sccti$nal und did not includelongitudinallbtlow-upot'patients. very Neverrheless. impnnantclinicalresuhs with havebeen achieved Fcr instuncs, rever.siorr this strategy. {o an ubnormal tc,the dexarnetha$one response suppression test after it-sinitial normali.,intion $pon $nlidepre.rsont drug treatnreol may either reflect the progression of illnessor a delayedsensitising effecrof antidepressanl drugson the HPA a1i5.lz:l Fosilronemis* sion tornography imagingof serotonin transporters may be anotherhelpful modalityfor di.ssecting sensitisingeffecrs.

iuappropriats useol'unlidepressunt drugsn:ay leird lo senn'itisation u'ithoulany clearbenel'it. 4.2 Dependence versus$nsitisotion The issucol'dependencc in r shili hasresultcd in thc drugreilinrcntol'anxiety. f'mnrbencliserrders zodinzepi nesto ilntidepressilnls. ion by I l' sensitisat antidepre*sants is asrunlcd !o cxist.the useol'arrtidepressant.\ tn lreill irnxiet-r, could irrdisordcr"s crcase vulnerabililyto dcpr'ession in anxiouspulients.Paradoxically, nright thcn benzodiazepines be re-evaluated. could be regard' sincedependence ed us the lesserof the two problems. 4.3 FullversusSubtheropeutic Dosoges of Anfidepressonts

rvidevaluable with an ciated years). These "they compare lmanagement t0 rs exposure re perticulafly dren and adomorc likely to rrssion and in ;antdrug tralto Ptacebo;Fttl fleretherewer drug and plaminor depresff 'te use of s ..*rticularty disrmpulsive pite substantial during nptom$ ith antidepres* s of major deeen discontinI with placcbo are no data to

Thereis increasing consensus aboutthe advanpiltientson the dosagcof antitageof nrnintaining depressant that was lbund to be effectiveas iicute If the sensitisation hypothesis of anridepressants treatment.lsll The rationalefor thi.sapproachis was substantiated. in parr or in total, by research the insufficienl protective eft'ects of subtherapeutic evidence, a numberofclinicalissues couldemerge. doses,In addition,keepinga patienton low-dose Treatment of deprcssion with antidepressant drugs anfidepressanls for a long tinre (a very common would not bequestionedprrse, practice, particulurlyamongnonpsychiatric physibut a moreinformed useof pharmacotherapy patientsto the risks may ensue. ciansin Eurcpe)could expose protective of .sensitisation, withoutan adequate el'4.1 Inappropriote Useof Antidepressonls fect.

4. Clinlcol lmplleotioncof lhe tensilfsotion Hypofhesis

is rot known how ,d to be refrac:tually display ey became reI to which they n&tion may be ererechallcnge performed.l$l
rrw6 l999mi 12(4)

The effectiveness of antidepressant drugsis firmly I Howestablished in majordepressive disorders"l?r ever, thereis a growing tendencyto also use them in the settingof a collectionof dysphoric complaints or demoralisarion.l?rl This tendencyhasbeenconriderablyincreased by theintroduction of rheSSRIs. because of their bettertolerabilitycompared with the rricyclic antidepressa6s.l?{J5l CarrolllTbl warned aboutinappropriate useofantideprcssant drugsmore thana decade ago: '...we srronglysuspect that many patientswho are simply unhappyor dysphoric receive these drugs, with predictableconsequences in terms of morbidity from side effects. morraliry from overdose, economicwasteand irrational.unproductive clinicaltrnanagemenr'. To the.same ex* tent that the awareness that antibioticsshouldnot be routinely prescribedfsr minor viml ailments,
O Aft krlernotxrrrcd Unlld. Al nhb fGlawed.

4.4 Acute versusProphyloctic Effect Of Antidepre$sonts trestDespite their benefits, full-dosecontinuation meil strategies endorsea hiddenconeeptual modcl, i"e- what is effectiveacutely in depression is also This inrthebestoptionforcontinuatioqtreatment. plies that the stages of dcvelopmentof a disorder shouldnot be influential in guiding trefiment, There is evidence, howevcr, to call such views in ques1is6.lfia's6l Different stage.s of illness may requirc a hypodifferenttypesof treirtmcnt.For instance. the.sis is whetherdrugsthat thathasnot beentested act primarily as seroronins-HTl receptorantagoritanserinor mianserin)may prove nist.s tsuch a.s rnoresuimblefor continuationtreatnenl. whereas traditionalantidcprssants rnsybe moresuitablein
Ct{sftJ46 lmocir 12(d)

?s4

Sensit

theacutephaseAntagonists of 5-HT1recsptors, in fact, rnay act Egainstthe enhanced S-HTI receptor function prodromal to the onset or relapseof depression.l53l This, or a prychotherapeutic approach airnedat the residualphaseofmooddisorders,lil.ffil may be particulflrlyimportantif a wlnerability phase for sensitisationwere to be discovered, 4.5 Discontlnuotion of Antidepreisont Drugs Baldessarinilrl the risks and implicadescribed tions of abruptly interruptingmaintenance drug thegradual rapy and the clinical advantages deofa It is astonishing crease. how little is known about very practicalissue.s suchasdiscontinuation of anIn phnned" tideprcssant drugs. a controlled disconwith detinuationof antidepressants in 40 patients pression,l6ll my colleagues and I did not observe any clearcutwithdrawalreaction$. most Horvever, of our patientswerereceivingtricyclic antidepressanlsand decreases werevery stow (25mgof arnitriptyline or its equivale ntseveryotherweek).The fact that withdrawalreactions, because of vary slow nver several weeks, tapering did not occurdoesnot impty that sensitisation necessarily is avoided. Therc is a hck of good,controlledstudies of differentschedules redr-rctionof antidepre$$ants Similarly,thereis insuflicientbiological exploration of withdrawal.lsl Howevei the issue sntidepresssnt of withdrawalphenomena is gettinginereasing atwi:h the tention useof SSRIs.t454el Are withdrawal phenomena .simplybothsrsorne and selfl imiti ng reactions, or are they a maaifestation of nn increased vulnerabilityto relapse oncedrug trcatmen( husbeen Thereis evidenee din-ontinued? tharcertainSSRIs flremoreIikely to inducewithdrawal reactions than Accordingto the .sensitisarion others,l{sl hypother (or fuil sis,this would meanthat theyalsofacilirare to protectfrom) relapse oncetheyarediscontinue d. Thi.rcould expluinthe high rateol'retap.sc upon switching from an SSRIto Flacebo,lnlwhich may be difl'erentl'rom one drug to unotherund be disclasedby follow-up studies.

4.6 Psychotheropeulic versus Phormocologicol Chonges pi6pditrulemphasised how both acutestressors and psychotherapycan induce biological modificationsat the centrallevel and how psychotropic drugsandpsychological arcprobably interventions pathways. aclingon cornmon neurotransmitter The exlsnt and type of action, however, may be differcnt. and from this differcntial thcrapeutic effons both exposurctherapyand may ensue.For inslance, meimipraminemay sharethe sameneurochemical chanismin severe cases of panicdisorderwith agwhartheydo not share oraphobia.l;el However, {the generally fact that changes long-lastingafier are exposure andshort*lived after imipraminel]'ll)may be as importanllTel evidence Substantial supports theefficacy of long with retmr antidepressanl medication in patients I I Suchevidcncehasbeen currentdepression.l??t$0'il guidelincsfbr the treatment translate d into practice of majordepressive disorders,{t:l However,recent researchlf6.il1indicrte.s that CBT may yield similar resultsin recurrenl whereas the role of depression, yet in bipolar disorderis such strategies to be establi.shed,l8sl lf the sensitisation hypothesiswere correcr.nanpharmacologic*lstratrgiesfor maintewould achieve nance evengrearer importrealment tance.

the sr impor bale : Rl

I. Lc
I

2. Fx.

'
I 3. Mi 4. Scr
ll

5. Far i{ t 6, Bul n
0 7. Far
$1

t,
E. Picr n 9. Pay ln is 1! lO. Loh dc I l. Ran

an
13. Fav, ch l-1. Tcdl Pn
1A

5. Conclusions
Al present. thereare no robus(data to support to depression by antidethe view that sensitisation pressonl drugsexistsmd * if it does* whetherit is Howa generalised or very lirnited phenomenon. phenomena in fte v:rrious reporled ev*r. clinical suspicion that literatureprovide a high degreeul" sensitisation may exist.Also. thereore no robusl dces nol datato supportthe view lhill sensitisuiion takeplaceentailscon' The scicntificstudyol'.sensilisation I problerns. Neverthcless, siderabl e rnethodologica many importontdilta have proh*trly treeninadver' on depre$duringclinictl $tudies tently collec:ed in (e.g. and on antidepressants rrion on resilitance)

lJ, Rotr to Pr' 15.Brul

tilt

l9 16. Shcri
lot l7- Bllcl Itr -15

r8. D; b
ind l9( 19. Van I Ne :{r. Af0n san Jl. Fux I dur tflf lt8: ll, Btrntj t99

il

Fni'n

SensitisingEffectsof Aniidepressants?

?55

lcutestressorJi rgicalmodifipsycholropic sareprohahly rathways. Thc nuy b ditlerpeulic elTorts re therapyand rchemical nrerrderwith agnot share {the :-lastingafier minell{l)rnay 'ficacy of long ientswith re:nce hasbeen the treatment wever,recenl yield similar as the role of yet to be es,r i.r were :s for mainlerea{erimpor-

ot"anxiety disorders, thesettinB Civen theclinicll of the issues. importance lhe tinre ha.s conreto dcbaternd explorethenrnrorefully.

References
L Lcr1, 58. Tlr rnlihiotirt p:rrndnx: hon mirarle drugs arc drstrcying lhe miritclc. Ncw Yorli {NY}: Plcnunr-l99l l" Flhn S. Lctodofil-induced ncurotoricirl,. Drxs il rcprcrctrr ;r Jtrohlcnrlbr thc trultrnrnt nf Plrlinron's dirsasr'l CNS Drugr 1997:!l: -376-93 .?. }llitchcll EA, ls cuc*nt trcatment incrca*ing aslhnra nrtrrtalir.r lnd morbidiry?Thorrs l9$9:'l{: El-J {.,St'irsi M R. Lon g-actine trctir-agon ists. tlchl'ph1,laxi r. rnd cor. ticostcroids. Chcsr 1996: l(19:862-{ 5. fu va GA. Do antideprrsxnt and anriln xiay drugsincrca-sc clronicitf i n affccri ve dislrdcni? Fs1'choth*rPr;'chrrsom l f 9l l 6 | :

|:5-31
6, Bcldcsslrini Rl. Ri:rls rnd hnplicationsof intcrrupting maintc. nancc prtychatropic drug thcmpy. Psychothcr Psychorom t995; b3: l3?-41 7. Fava GA. Holding on: dcprc**ion. senrltization by mtidrpres.santdrugti. and thc prudiXal cxpen.r. Prycloth* Psychostrm 1995:64: 5?-61 8. Piccirclli M, Wilkinson C. Outcome of dcpression in psychinrir xcnings.Br I Psychiatry199{l lf{: :97-}0d 9. Palkcl ES. Rclap*c. rccurencc and chroniciry in deprcsrion. ln: Langcr SZ. Brunello N, RncagniG. cr al., cditors.Crirical issues in the trratmcnt of lffcctir,c di.rorders,Ba*el; Karger. | 99il: 9-20 l(1. Llbba(e LA, Doylc ME. Rccidivism in mrjor dcprcssivc disordcr. Psychother Prychosom 199?:66: 145-9 I l. Rlrnana R. Faykcl E5, Coopcr Z. ct al. Rcmixsion tnd rclapr;c in majordeprtsion. PxychslMcd l99l; 35: I 16l-70 | 2. Fava OA. Thc corlccpt of rccovcry in aflcctitc dirordcrs. Pry" chothcr Psychosom t9!16;65: 2- | 3 1.1.Tedlow J. Fava M. Udrchckcf L et al. Ourcomc definitionsand prcdictors in dcpreision. Psychcthcr Psycho:*orn 1998: 6T;

rs6-70

\ I ta to support on by antidewherher it is :lenon.Howrorted in thc .rspicionthat rre no robust tion doesnot r entailscoft,{evertheless. een inadvers on depres:pressants in
p le99Oct; l2 (d)

14. Rotschild R.. analysis QuitkinFM. Rcviewof rhe**c of pauern to diffcrcntiatc tr*ponscs, Psychothcr lruc drug andplaccbo Psycbomm l?G? 1992;58: 15. Brughl TS. tscbbingron PE MrcCarrhyB. ct al. Antidcprersonlrmayno{arlristrccor.cry in pracrict,Acu PsychhtrScand 1992: 86:5-lI 16, Shcr MT. Elkin I, lmbcrSD,cI al. Councof dcprcssive symp. tomsovcr follary-up.ArchGcn Psychiatry 199tr; 49: 782-l 17. Baldvin RC.Anddcpreisant* *har difdcprcrision: in gcdarric fcrsncehaverhcy mdc? Int Psychogcriau 1995;7 Supp!.t 55-68 lS. Di MnscioA, Mcyer RE, Stiflcr L. Effcctsof imipraminc on individualsvaryingin lcvcl of degrcssion. Am I Psychiatry 1968: t27 Suppl.:55-t 19, V1n$qhsyp6 JE. R*uncnt vitaldeprcssions. Neurol P.sychiatr Ncurochir l9?3;16:93-l l3 ?0. AronsonTA. Tmatment.mcrgnr with rntidcprtrdeprcssion srnus in prnicdisordcr. CompP.ychiulry1989: 30: 267-?l 21. Fux M, Tub M, ZoharJ, Erncrgcncc of dcJncsrive symFtoms duringtrcalnuntfor pmic dircrdcrwirh sfrcific 5-hydmx1.trypophanrcuptakcinhihiton. Acra F*ychirtr Scand199-1: $E:ll5-7 ll. BondAJ. Drug-induced bchavioural dirinhibition.CNS Drugs 1998:9:41-57

l-\. Portl RM. Dcrtrcaft KD. Lcvr:rich (iS. ct :rl. Dru!-tnd$ced \$ itching in hiprlar dixrnl*r. CNS Drugs lll97l 8: .151-65 !J. Angsl J. Swikb lnnn dcprcssiorr trr rnrnil, A rs{rord slud} rrt' dc!'rdcr hetllccn l9?tlanrl l9tl3" Prychogrthologl' l9t{5: ll{: l{(}'.55 !5. Kuhoputus A. Regirratrli Lr. L:rddonradaP. ct ll. Crrurr ot th* nranic-dcprcsilc cyclc lnrt chunges causcd b-r' IrdJlrufolr, Phlnnllioprl'chi:rtr Nr:urrrysl,choplurlultol | 9l{(}: 1.1 t.l l: I56-67 J6. Ku\ttpulor A. Clti:rri 8. Tundo A, t r al. Rapidcyclcrs. lcnrp*ranxnl, andirntitlcprcrsuntr.Conrpr Ps-r [hiut+, l9lt.'l: ]J: l{9-iX 17" CrtrJu'in FK. Thc hkrfirg1 ol'recurrcncc-J Clin Ps;-uhiutrl' l9lit]: 5 U{ l 3 S u p p l . t: J{}-{ 18. Cahcn BM. Brldcl.,iarini RJ. Tolerlncr (o theropcutic cffcctr of anlidcprcssantr. Am J Ps.vchintry 1985: l.l?: {89-9{} 19. Frlr M. Rappc Str'|.Puvl JA. et al. Rclrpse in paticnts on lonir. lcrm nuoxftinr trculmeql: rg,ipqns{l to incrcascd fluoxetinc do*. J Clin Ps1'chiatry 1995: -16:5l-5 J{1. l\tulrn JJ. Loss nfarrtidcprcssant clTect \r'ith long tcrm mcntraminc oxidasc inhibition..f Clin Prychoph:rrmacol198.11 3: ^16-1{ ll. LicbJ. BirltcrA. Anlidcprcsrirntt+tihtphlhri$. Med Hypothcscs l9E,l: lJ: 179-91 ll. Fra*l E, KulLr DJ, Pcrcl JM, ct iil. Thrct-yclr otrcomcs for main{cnlncc th+mpics in rccurrcnl dcprc*sion. Arch Gen Prychirtry 1990: .l?: 109.1-9 .1.1.Byroe SE. Rothschild AJ. Loss nf antideprassanrefticacy during muintcranrc therupy. J Clin Ps)chialr.y 19981 59: 279-8{t J"l. MarLs lM. Echatioral und drug arcltrhcnts of phobic and oh. scssire-conpul.rilc d ircrderu. Prycho{hcr Fsychosorn | 9Eil: 46r l5-4{ f5. Favr GA. Frrdingof thcnpcutic cflccts of rlpeazolam in agoruphobia. Prog Ncuroprychoph:rrmacol Biol Psychiltry | 988 : l2: 109-ll 36. Post RM- Lrvcrich GS, Altschuler L. ct al. Lilhium discontinudlios-induced rcl'nrtorin*s. Anr J Psycbiatry 199} I{9; l7?7-9 17. M{j M, Pimrzi R- Mlgliano L. Non rasponsc to rciolitituted lithium prophyluris in previounly rcspor.ritc bipohr patienls. Am, p$ychiltD* 1 9 9 5 : 1 5 2 :l 8 l 0 - l 3 8. Fucddl GL, Tondo L. B uldcssarini RJ, ct rl. Outcome aftcr rupid vri grudrraldisconlinurdon of lithium rrcatmcnt in bipolardisordcrs. Arch Ccn P.sychiatry 1993t 5O: 4{E-55 39. fiva 6A. Rafanclli C, Grandi S. ct El, Six-yclr oulcomc for cognilivt bcho!'isd trcetmcnt of rq{i*ual symploms in mojor dcprcnsion. Am I Psychisuty l99E; 155: l,14-1-5 .10. Flvr M. Davidrcn KG. Dcfirition lnd pidcmiology of trcatnaat - rcsisul dcprcr.sion. P.rychiur Clin Nonh Am 1996; l9: 179.200 ll. Amath J. Trcrtmcnt rcsistant dcprcsrion: Psychorbcr Psycho. *om I99E:67:6I-?O ;ll. Donaldson SR. Tolcrsncc to phcnclzi nr and ru br,cqacnt rcfracttry dcp,rcrriicn.J Clin Psychiotrl. l9E9: 50: 33-5 43. KramcrJC. Klci* DF. Fink M. \ilithdru*ol sympoms following discontinuation of imipraminc rhcrap;'. Am J Psychiory l!)61 I I I 8; 549-50 4,{. Dhalvcr $C. Hctcrccplic antideprclninn(.moroarninc otidasc inhibircr rnd netrolcptic withdruu'rl phcnomc,nu.Pro4l Ncuropsychopharmlcol Biol Pxychiltr)' 1990: 14: l17-61 ,tI " LcJoyur M, Adirt J, Mosrsd l. ct ;rl. A nt idtprcssul wilhdn',rru I syndmme. CNS Drugs 1996: 5: 378-91 .16. Z.{cctl J. Trmy KA. Mirchcll S. Dix-ontinuation symptom!; oflcr trcllmcnl $,ith scrdonin rcuprakc inhrbiton. J Clin Psyc h i a t r y 1 9 9 ? ; 5 8 :2 9 1 - ?

S Ac$ hternaR)nd Ufttd, Al|righErasrr/ed.

CNSeugs l90q Ocl: 12(a)

ul

E I ol
(Dl
U'I

sl
8 l ol
dl 3l
{ol rrl
51

(Dl o. l

g 6"1 5l

{?, Medlw:r C. Thc lntirlcprr:s}nnt$.b, lnt .l Rirk Safcty Med l9A7:l():75-l16 {l|. Rosenbrunr JF. Fava M. Htug $L. et al. Sclectivc srrolonin reuprlkc inhibitcr d i*-ontinuutioo syndrurne: u rcndonrizcd clinical triitl. Bitrl Pryr'hiatry l99E: *l: 77.87 {9. Fava OA. Grandi S" WitMrar+at syadromcsoficr porore tinr and *crtralinc discrmrinurtion. J Clin Psychoph:nmrcol 1995: l5: :74-.5 r{ l. SuppcsT. Saldtrsarini RJ-Mutoha$i i.l. ct ol. Spcciul trelrtmcnt isrues: mointuining ard tli:aontinuing psychotropic nrcdicatirm*, In: Rush AJ. cditrrt, Mrrld disordcrs. Ba*cl: Kargcr, It|97: !.ri-S-l .5l. Young AM. Goudie A.l. Arlupti vr p(>crx$csrrgulatin g tolcranrc totrhavioral effcctr ofdrugs. In: Blaom FE, Kupfcr DJ. editon;. Prychuphurmucology, New York (NY): Ravcn Prc*, 1995:?IlJl 5?. Pop HG. Jacohr A. Miatct JP.ct rl. Evidcncc l'or r scr:$ccifi( rcsidpal cflctr ol'canmhir oo tisu*spa{irl memory- P.*ychothrr Ps)'choxom1997:66: t79-$.{ 1-1.Leonurd BE, Scnttonin rcccptors and thcir funcrion in slcep. anxietv disnrders. md rlcprcrsion.Psychothcr F:ychosom l916: 65:66-75 5J. BcrendscnHC. ldtcrirclions txt*ecn s-hydrorylrlFtaminc rcceptor ruhlvrrcs. Phnrnrucol'Tlrer | 995: 66: I 7- 19 55. Kpob GF. Cador il|" h;ychonnrtorstimulantscnsitization; the conir$lnrprn-r*lc:rring l'irctrrr-stemitl rrytneclicn. Bchat Phirrl -{ mocol 1993:J; -15 .56"Ritrmann Rf;. Colbcm DL,Zimrncrfirnn EG. ct al. Neumhyp$phyfcirl hornronts in tolernnec and physicll rlcpendrnce. Pharmlcol Thrr 198'l:ll:]tl-lll of Cushiag's dis57. Sonino N. Fut'r GA. Prvchoxrmltic ',rspects ease.P*ychother Ps1'chosom 1998:67: ll()'6 5E. Stcwsrt J. Brdirni A. Tolcrgnce und sensitizarionto thr bchai ioml cfitcts of drugs. Eehav Phrrmn'ol l99l: .l: 189-l I l 59. Grcscs PIt. Thornpvrn RF. Hchituation: I durlpruccss thcory. PsycholRer' l9?{l:77: dl9-54} 6t1. Antclman Sbl- GcrshonS. Clinir..al rpplitrrrtionof tinrcdrpcdcnt s+nsitir.arion(o rntideprei\rnt rhr'rlpy. Prog Ncurop;ychopharmacal Binl Psychiirtr.vl99ll: 3l:65-78 6 1. Scutl J, Cognitivc therapyofaffcctivediscrrdcn. J Affcct Disord l98S:17: l-l I fr]. Anlnnuccio DO. DirntrrnWG. Dr Nr:hk1 GY. ct rl. Rairing que$ti(rn:afxrut antirJclxrrsurxr''. PsychothcrPsrchosonr l*99: 6 E :l - t { 6J. Fin'l CA. (irmrJi 5. Ziclczoy il{. ct ll. Cognitir,: hchuvior;rl IteJtnrcntol'reridual synryitotrts in pritrun uujrrr delressilc disordcr-Arn,l Pqchiltry ltI)J: l5l: l195-9 Fuln CA" Grnndi $, Zigl{/.n) M. *t ul. Frrrr-1,r:irotttr'lrrr}L' ,or crrgnitir'r ht'har irrr;rllrr:llnrcnl cfrcsidull 11'nrptorlsin rrl$or drpft .\\ llr. Attt J Ps,r,chi irtr-r I tjt)6: Li-l : 9{J" 7 Fallr CA. 5:l rurr$. Or;rndiS. tt irl. Cornitirc hlnrirrul ntanir$clr!'nt r)l dfu.i-rc\iililnl nrirjor dcpn'ssiyc distnllr. J Clrn ItI)7: jl{: l?H.fi: P.s;-chiatr-r'

:
{D TD

o o) E

s
o
(D a d't a g ll :t

o a)
t, :1

of rrcurrcnt C. Crandi S. ct al. Frcvcntion 6O.F;rvr64. Rrfaraclli drprcssion wirhragnitivutrchuvianl lhcrapy. Arch GenPrychiatry1998:55: tl6-2fi 67. BhrtrburnlM, MoorcRG. Conlrollcdocutt md follow-uptrial of cogniriw ilrrapy and plu,rmEcoth*lpy in wt-poticlrs wittt rtcurcnl dcprexiion.Br J hychiary | 997: I ? l: ']?8.3.f 6E. Wcxler BE. NclqonJC. Th. Itcrtrrrnl of rnljor &prcs*ivc dissrdsr$. lnlJ Mcr*al Hcolth 19931 22: ?-{l 69. Young IJ[,Cookt RG,ttritt AJ,c!ol. Priorantidcpr$salllr!trrrtnt docs not hlvr uo impart on Erponlrc to dcaipraminc lrcslrficilt in major dcpftssion. Biol Prychirlry 1995:38: .{ t0-12 ?0. Hlrcl P.O'Coamll D. llclrhcotc D. ct al. Efficmy of tticyclic BMJ l99J: dnrE ia trrutingchiHandeddlcsccnr dcprcsltioa. 3 r& 897-90r of thcra7 l. PoykclES,Hollynan f d. Frcclingfl ct al" Prcdicrom Furis b.ftslit fmm amitriptylincin mild dcprcrriot. J Affect Disod l9Eft l.l: EI-J axis dis71. Far':r 64, SoninoN. Hypothdamic-pituitry-bdrcncl turbarrces iRCS Mcd Sci l9E6; l{: 10586t in drprcssion, of dcprcsrion. Dis Manngc ?3. FavaGA. Scrccning lnd diagno*i:t Healrh 1997:?: l -7 Outcomcs f l. Roshol nrf U. OremLF.l.racsson G. rt r l. Chlngasin thc pattcrns ontidcprts. ofantidcprrsonluseuFtn thcinttodu$iono[ nEr^' 1997:52: 205-9 sanu.EurJ Clin Pharrnscol prc75. OlfsonM. Munrc $C, PincusHA. ct rl. Anridcprcssmt srribingproctices of oulprrti{nrpsychirtrists, Arch Gcn Psychiatry1998:55:310-6 ofdcprcssion dinrcnsionr lnd mania, 76. Canoll BJ.Neurotriologk tn: Angstl. cditor.Thc origins of dcpre.rrion. Berlin: SpringcrVcrllg.l9E3: l6l-86 ?7. Montgomcry 5A. Thr ncedfor long tcrm ltcalmntof dcprcsI 997: 7 Suppl,3: S.?r{)9sion.Eur Ncurop;ychophurmmol Il ?8. Siondi M, Bcyondthc brain-mind dichotomy and lowa{d I rnd prycommonorgrnieingprinciptr of phurmrcological chologicalucrrlmcnili.PsychothcrPsychosom| 995: 6,{: l -5 79. Frva GA. MangelliL. Subctioicol symptonlro[ pirilicdisordrr. 19991 Pryr{msom 6t: 381-9 P.*ychother lre&tmcnt in rccurrnt dcprssion. Br 80. Kopfer DJ.Maialcoanct 1991: 16l: 3tl9-16 J Psychiltry of 81. Flta M. Krji J. Continurtionund mainrenlncctncutdlcntri !-l; lf, l-9t) mljor dcpnssir'*disordcn*Fsyshirtr Ann 199.1; guidclim lbr ntujor Asrrrxiution. Pracrice 81. Amcricu P*yrbiatric t5(l Suppl' dirorder in atlults. Anr I Psychiltry1993', dcprerisivc f: l-16 t1.1. ColomF.Vietl E. Murtinul A, ct irl, Whari; *re rolc of priychoPsyrhothcr Psy' thcrupy in thr trri{nhrtl of biprlir rliscrrlcr:t cho:om 19981 67: .1-t)

o
CI
Tre
Mnrt
lKe

PsJ

Conl
Abr

I
I

2.C 2.
1.

2.
1... t",

Crrrrespondence anri rePrints: Dr Gitr;'nrrrliA. Fartn' Oipartirnenttr di Psicrrlr6ia, Unir'ersith di &rlt1gn.r, Viale ltalll Bcrti Fichat 5. "t01278nlcrg,n.r.

2.r 3. Ps 3.
,J.i

;, 6 * r

4, Ph 4.t

4.2

al,