middotV v- _ _ _ -shy ~

Emergence of antidepressant induced suicidality David Healy

North Wales Department of Psychological Medicine Hergest Unit Bangor LL57 2PW UIC

ReceiVed 22 J4I1uary 2000 accepted 14 March 2000

Keywords Reboxetlne SertrUiDe Suicide

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Introduction

rn 1990 Teicher and coJlelgues reponed on the emergence of stlicishydality on fluoxcrine in l group of bc patients Ill middot These reporrs wtre folshylowed-up by r(ports from King ei aL 121 Creanq et aL [3j RothschHd and Locke [4) and Wirhing et aL 151 unong omen reporting other cases where suiddaliry appeared to emerge in individuals raking fluoxttine

There were a number of fuctorgt associated with these tlse reporti that argued for do scrong C1I~a1 connection In general there was consirency across che [(pores as to me time of unset of the problems following intake of nuoxetim Ihere appeared (0 he a doe respone relationship wieh pmblems liable co emerge on a highcr close There wa

some agreement as rcgu-ds (he probable mechanism l=ding to the difficulties This was termed akarhiSia although whether it was quite rhe same phenomenon as akathisia trlciitionali5-as-sociatcd with neuroleptics Was kss clear The phemiddot

In the conrse ofa randomised doobl~bli1ld aOssoV(r study comparilIg the effect5 of reboxctine andsertralinc in a group of healthy voluntccri [W()

volonte=s ~camc sW(ida on sertraline- This paper descrlbes tlle cb=acshytcrlstlc=s Of the reactions experienced by both subjects These problems were associared with a combination of akath1sla aud disinltibition ~ric or akathisic respowes on their own to either drug did not lead Co suIdda1ity in this group of subjects Irim3ry Coo 15d1rry 2000 6l~28 Wpyrigtu (l ZOOO by librolPlurm UlnilCtl

nomenon in general cleared up on discominLlltion of treaunent and re-emcrged in a number of cases on re-cxposurc to the original treatshymemo In cases where ir rt-fmetged there were reportgt that agents which theoretically might block the appearnnce of a 5liT mediated probshylem were lble to minimise or block the emergence of suiddatity on teshyexposure

Nevenhdess despite a lumshyber of indicuors for very clear Clusal linkage between the intake of fiuoxeshytine and sUicidality there were aL~o a number of aspects of the reportS which argued middotfor some caution in th~ interpremtion of what was hapshypening One was that some but not all of the patients were em other mediotion Anorher was thOle some but nO all h2d lengthy psychiarric histories with evidence of personalshyity problems Te was 10 genernI less than clear whae the description of thio problem emerging in tertiary care centres might meatl for me wider world of primary care amideshypressanr prescribing

Folluwing Ule release of fluoxshyetine a number of other SSRIs appeared on the market induding scrtralinc and paroxetine It seems clear char in general mese drugs arc associated with common profiles of both miln clfati and side effects All have received licens~ for a similltlr sa of nervous conditions All proshyduced a set of side effects induding extm-pyramicW side eITeCL~ which are nocgenerally seat with other antidepn=ssants 161 Both sertrline and-p-aroxerine have been aiSociated with reports of akaulisia [67810 IlUIJJ

On his hasis [here would seem rhertfore co be 01 possibility chac other SSRh might similarly induce suidcWiry A me~-lf1alysis of tri2Is involving (he SNRl milnadpmn compartd wirh SSRlo showeU a sigshynificantly increased nre of suidctllity on rtedtmene with SSRJs 141 A ranshydomised placebu (ooIrol trial of paroxetine in renUfent major depre1Sion shoVICd a higher rate of suidde ateempti on parottine than on placebo in this group of patient

~-middot -----~----p~----a-tty--2-0-00---V-ol-6--N-O-l----~---------------------------------------~

~J ~-- - gt~gt- 7_~ bull~-~~bull - ~- - -

-- -- - --- - shyf shy

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[15J ThC$C data suppkment unpubshylished RCT data from Lilly suggesting a significuuly higher rate of suicide attempts in patients wking fIuoxeshytine compant1 with placebo or other non-SSRI antidep==ts [1617

Against this backgmuntl we report the findings Tom a tl(lublcshyblind rmdomised crossover trial of senr1iine and reboxetine in he3lthy volumetTi This WolS aimed at explorshying modes of acrion of antidcpnsshysam drugs on levels ofweUbeing and in particulu- the screnic effect thar appCIri a~5ociltcd with the usc of SSRls which may mediate their mershy3peUiLc effeCt

Methods

Twenty healthy vuluntcers aged between 28 lnd S2 with a mcan age of 378 yea~ were recIlired tl I

study comparing reboxe[ine with ~LTtrlline on a lJIlge of pcrsonality selfreport ltlnd quality of life meshySUre5 The srudy was aimed a[ esrwshy(ishing the clfttts uf antidepreSiams on levels elf wdlbdng in suhjects not-i currently depressed There were

~ 9 males and 11 fem31es recruited from among the adminisrlTive medical and nursing membees of the North West Wales district general hospital pgtyduo1tric unit as well as four ()ther known t(l memlxn of the unit EthIcal permission had been obtaincd [rom th~ North Wcst Wues Ethical Committce Written consent (0 indusion was oboined from each subject All volunteers were free of medical condieions None we-re on concurrem drug treatshymemo NOne had a history of previous psychilluic illnL~s The two volunshytecr whose exreriemeo arc rcporred here hlVe given (lns(~nr for (hiS informarion [0 be reporTed

Subjecu were r mdomised [0

reboxlttine a selective norltlrcnaline rctJprake inhibitor or senfltlline a selective 51-IT reuprake inhibitOr in a crossover liQign SU that a proporshyticgtn received reboxerine for TWO

w=1G fnl1(gtoed by l rwo week dmg me period and rherfafter sertralinf for twu week or alrernatively scrtrmiddotmiddot lil)e [ollowct1 by rehoxetine The

dose of the drug~ wJS 6ther 4mgs of rtb(Jtctine for the first lve days of the reboxetine arm with an option tel

increase to 4mgs bel if wIera[ed or semaline SOmgs for the fuse five days of the sertraline period with an option tu incr=~euro [0 SOm~ bd if tolshycltcci

At baseline subjects commiddot plered a Karolinska Personality Questionnaire (18 a Tridimensional Personality Qucstionnalre 19 a Profile of Mood Srates (POM$) (201 a PosItive and Negarive Affect icale (PANAS) (21J a Social Adaptation Self EvlI1lation Soles (SASS) [22 and a SIS-SAS scale [23] The effern ofhoth drugs in the whole group on mood scales personality inventories side effect rating ca1~ and other meashysure will be reported d~ewhen

rOMS PANAS and SASS i(Ies

were completed on a daily basis as well as a daily diary of impressiollS of me functional and phyica1 effects of each drug Volunteers were actively encouraged to consult their pmners Or- ochcn IS til any chmgcs that eliCic other noticed in them over- each two-week period II focus grotlP was conducted at [he end of (he study aimed at establishing whether there wen efects chlrlCtcristic of either drug All ratings wert done blind The blinu wa only broktn twO wctks after thE study WltIlt completed

Results

A preliminary analysis of the results indiClres that cwomiddotthirds of subjeCts responded ro one or other of the tWO drugs but nOl the other with a bctter than well responsc RepClnse arpears to have heen f1rcmiddot dicted by personaliry factor similar ro those outlined by Joyce in a study of depressed subjects Cndomised (Q

either reitiveiy sdecrive nOrldrenshyergic or scrtltnnergilt nuptake inhibitors (2~ 1he WOllD also showed changes on the KSP that have been reported ill depressed pIrienrs following 5SRlo [25 Finilly in the group as a whole a gnater number of 5ubjecrs txpn~~ed ltl

preference for sertrlim than for reboxctinc

When on reboxeLine twO subshyjects reportt-d bltcorning depressed_ In both Cltl5es they likened the expeshyrience to post-lthildbirtb baby-blues Neither of these cwo subjects Or any ocher subjecL while taking nbaxcshytine had uicicJal ideation rn conshytraSt two liubjeLts taking sertmline devtloped clear SUicidal ideatlon one ofwhich reached extremely seri shyous proportions 130th thee individshyuals lpptII to haV had elements of akathisil and emotional blunting but other subjecrs had either akathisia or emoriorrul blunting without becomshying uicidal We report on these case in more detail reconstructing events from the diaries kept by both subjects

Case A The first Cltl5e was a 30 year old WOffiW She was lJndomi~cd to reboxetine initially This made her conspicuously relaxed and slighlly seda ted on Ule first dJy She describtd the effect as I ch ill pill 1n subsequent cltJys she found nomlaly strlt~lting events less streSSful She described [he effect as keeping her norm11 tempcrunental self on the straighr and lurrDw She had [Jonr sleep but was uncertlin if this was owing to childcare or the drug During the two weeks on what turned ouc [0 be reboxetine ~hf(

reported dry mouth sleeplessness reduced appetire nausea and COl1SUshy

pation which she attributed to the drug

After mndomLoui(lIl to sertl3shyline within [he first few days she appc-md (l become aVOidant She complain~d of a stiff jaw (an cxtrlpYrlmidal sidemiddoteffect smc vuimt of which W-Ji rqmrted in 15 of [he group while on ertrlline) She had I migrline which she did nor attribute to the drug along with nHlsea malaise rtSt(L~s[Jess OIgita [ion anxiety vivid emotions racing thoughts and ruminarions which she did atlribute to the drug

From (he- end of the firt wlck he wlS reportcd uy colleague to he somewhat restles anu fidgety To some she appeared akathisic but not

PriDlary Care PsythQtry 2000 Vol 6 No l

so dearly tha t everyone would notice She recogtlisLd her rcstlcsmiddot ness and rutd foUIld tlult with a degree of concemrItion and fu1dling she could disguise the dIect She also rimed other changfS in he~f that she cc)uld not initially dearly describt

In view ofthe side dfecrs up to this point the blind guesses of study monitors taking intO account both dnlgs were that she wl- On reboxeshytine rawer seru-ilinc She was noticed by the monitor by the end of the tim week to have become needy of time and company There were moments when she appeared lO lx-come preoccupied and emoshytionaI but on questioning would mention thaI she would be well in a short while as hcr mood hpd been swinging one minute doom and gloom the next ~nshine and Iaughshy

lCiinLS5 of herlegs She said that she was nor doing much work mat she couldnt cope with anyones emomiddot tion and she tried [0 occupy hergtelf by doing paper work but found it difshyficuIt ro focus her attention She describ~ swings of emotion with miscry predominating but she was not depressed She was advised to stop the drug and agreed to do so She did not Stop In ntrospect it was almOSt as if she could not srop herself from cling the tablets A number of (lther disinhibited dtings happened induding ldling her life history to a colleague whom she did flot know well leaving him conshycemed

Her diary record5 impllIsiveshyness initlbility over-senSitiVity as well as muked suspidon It also records a sense thac she had an old me and another The orner was like

tcr lOwrd the end of the first week middot a bit of her dlildhood sdf EaSily on treltltment her diary records and moved to emotion Simplistic aware she reported to a study mOnitOr two of sociJl etiquette but noc inclined [0

incidenrs involving quite atypical follow it impatient selfish and im behuviour for her She reported asponible The old me could only lack of gUilt about something she vras concemd she might be guilty about whtn she came off we maiiauion and was herself This as it turned out was the case

Over the fir-a wedand he had a nighanlre about having her throat slit so that it gaped open and she bled to death in the bed She didnt gel back to oleep She did nOl increase the dose of sertrnline over the weekend Versions of this nightshymare recurred on two succeeding middot rughr~

At the start of week twO she remained resdess wilhdrrwn and preoccupied The po1i)ibility of h(jlt~ iJg me drug was raised but she Opted [() carry on despite feeling as thuugh she had a combination of bad PMi and pre-=m nerves Htr diuy record~ thlt she thought she mighr have an infetuon that wlS

a~ldVltlting rhings and 1 hnpe thlt when lhal clearet she wOlld feeJ beITer

By Wednesday she had become withdrawn was ruminating over impulsive disinhibired things she had dune wc [Crful and not herelf She had very nhvioll re5[shy

watch what WJS happening and was helpless to MOp the ocher bit which was in concrol

Jhe following day it turned Ollt

~he had not stopped the ablets and the mediotion WoI-~ discontinued by study monitors She looked tJllwell but seemed to be making a great eflortat trying to appear nonnal She

wc still lkatrusic at a level that would be apparent to mosc j observers That night she was serishyously suicidal although the tablet she was due to take mal night had been stopped

On the Friday she telephoned early in the morning distressed and learful after the previous nighL Her converation wa- garbled She de5cribed almust going OlJr lI1d killing hersell~ She Wli vi~itcd at home She recounted that the night previously she had fclt camplere blackness aU around her All she could foUlS on was the pen and the qUQtionnaire in front of her but she couldnt write lOyrhing down She felt hopcleii and alone II scemcd [hal all she could do was [0 follow a thought that had been planted 10 her brain from some ilien force She

~uddenly decided she should go ant tlllOW hcrsclf in front of a car that chis was the only answer It was as if there was nothing out mere apmt from the car which sh~ was going to Lhrow herself under She didnc think ofher partner or child She was walkshying ouc of the door when the phone went 11lis scopped the tunnd of suishycidal ideation She later becune disshyrraught at what she had nearly done and guilry that she had not thought of hcr fumi1y

She ~s taken for a walk and appeared to gather hersdf Larer in the day $he completed a diary entry foe the night before LO supplement the brief entries of the previous Pay which included a hope [hac she would make it through the rughl In chi she described being jumpy lnXshy

ious and suspicious Her mind was racing and spiralling Out of contrOl Then jt wem blank except for the clear mought thar he mu~t kill hershyself viokntly by thrOWing herself beneath a Cilr or u-ain This cl=r thought appeared irrcsitible ltlnd its apptJrance seemed to put an end lO

the ~ety It was crancemiddotlike and J only broken by a phone-GIll which came when she WLi felc she was about to out Oil the basis of this idea

Contact was maintained ovcr me weekend By the Monday she dcdared herself co be back [Q her sdf She looked berrer but nmained vulnerable and wa dearlyapprehenshysive about Cilking lIbom what had happened_ 80th study motlitOrs and the research subject wert still blind at this point as [0 the identity of the medication The slbject herself remaini very_disturbed at what ha~

hoIppened During [his period daily POMS

and PANAS rAting were underraken On che POMS thE words mOST conshysiscently cndo~ed were lively active cheerful and vigorous during the reboxctlne block On middot senraline e-pccially in the second week the words endorsed wert [ense worn out unhappy fatigued sad conmiddot fused shaky discouraged on cC1ge miserable bewildered and nervous were regularly endorsed On [he PANAS she had a mc-an po~i[ive woro score of 197 in week une and

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203 ill week 2 on rcboxetine and bur most probably was IS he to fmd her mother extremely frightshy253 in week one on crtrlline ftillilg to 194 in week 2 Her negative word score was 10 in wttk one on rebaxcshytine 114 in wttk two rising to 127 fur week One on serrraline and 229 for week twO

CaseS

B was a 28-yetr old woman at the time bf enrry to the st1ldy She had no history of psychiatric or medi=l problems She moked and took apprOldtnateiy twO ururs of alcohol her week Her only significmt peiiod of -tress WL5 three yeus previollsly when she sepuatttI from a parmer At tfur point in time the thought of suicide bld crossed her mind bur without my iment p lans or active ideation of any sort

She was randomised fJJ reboxshycLine followed by sertrLIine 50mgs for five dar increasing up to lOOmgs On reboxerine at some point during the twO weeks she sufshyfered from sleepJcssness conotipashydon dry mouth with some reduction

-f appetite sexual dysfunction ant _impairment ofconcentration In genshy

er3I however she found herself more confident calm and energetic

On going on sertraline she noticed the following effecrs which she attributed to the drug nawea lethargy malaise paniC and min in her jaw Within twO days she also noted in her diary that gthe had betume snappy and much more likely to say things thal CAme to mind and that [hiS had been noticed by her colie-tgUes By the third day she records herself as more J5serrive She also ~ported her mood as liable to drop that generAlly her emotions were liable to swing mm she was sluggish that she had become irritashyble It the slighrest liuJe rhing and WA~ Habie to take commcnrs personshyally Her mood does not appeared to hrve been depressed hur colleagucs noted her swings [rom cheerIulnei~ 0 withdrawal

She also found herself restless U1d reponed that she didn( Imow if he wl5 com or going This did lor appear to be an obviOUS aklthisil

endorsed agimtion as a side e1lect of the drug Close collelgues atld her mother nouccd this and other diS inshyhibired eventS of the kind described below All agreed that she was adversely affected by the L-cond pill and ~he was advised particularly by her mother never to go on anything like tlllt again

There was a reluctance to mention any of this to othergt and only a brief mcntion in a post-study fcx~ group led to a Sub~cqllent disshycussion in which these details became dear One of the intriguing fcLmres of this woman S experishyenced endorsed by ClSe A wo1S 41 conshyCcrn that elahof(1tlng on what WlS

trJppening her wouldlearl to others thinking she WlS cr=y - no-one had warned her bdorehand that this could possibly happeo on this drug Her diary entries and her rating scales wcre therefore economical with [hI truth

While on rcboxetine on the POMS this subject endolScd the worcl~ wom Out and weary during the first (WO weeks switching to sad annoyed miser3blt unhappy and angry during week two On the PANAS her positive scores dropped from 176 anu 154 on reboretinc to 114 and 126 on scrtraline Her negshyative scores did noc chanRe However there i~ a group of over 6 co-habifees work colleagues and s tudy monitors who had become aw-tre of rIle changes listed above atld below

8 briefly in her diary and at greater length subsequently descrilxd finding hereff ill a s~e

ltwhere she didnt think through theI ~)nequencc of what she did or SltLid She tlidn r appear to feel tfraidjFor =mple on one occasion wh ile driving home with her mother in he ar a grou p of 18 ycJr old boy by tbe idc of he road rrulde obscene geshyture Iod houtL-d af rhem while Un car wa5 moving slowly at a ttich juncture in the mad She toppctlIIthe car in rhe middk of moving trafshy

fico went over to them and grabbctl one of Them tdling hitn if he did anything like that again she would dak him She came back to the car

ened about what had hltlppened )There was a contra5r between reboxshyetine and sertr3line in this regard in I that rebaxetine had fIUde her feel I calm bur in a manner that Jefr her still able ro fcel feu In com1St on scrtraline she felt Wessive middot and fearless She found herself thinking on several occasions when fJced with situations wirh peopJe that she could deck them

She increased her dose of seIshytrallne ltJ 100 mg as per protocol Thereafter she fdt worse 0 thar she reduced the duse blck to SO mg three days before the end of the study_ -Following the incrcagte in dose she had tWO disrurbing nocturshynal episodes on consccurive nights She is a woman prone to lucid dreaming and both sleep walking and sleep talking with atensivt memory tile following day for what hlcl happened the previOUS night Her partner regularJy reportS her as bong awake during these cpisodes It is dilliL-ulr therefore o dctermine what happened but her rtcollection is while awake or lucidly dreaming that she spcnt long period lyinR in hltT bed funtasising about hanging herself from l beam across the bedshyroom ceiling She was aware tJc these thoughts were acCtJmpanied byln abnormal fade of concern as to whether her partner mother or othmiddot ergt might find her She is not aW~e

of eva having mmparmle thoughts before -rne reason-she did nothing she explaiJled afterwards WrlS Ibecaue she was a coward and had a vestigial concern about being foulld by her son-This episode repeated itself the following night

There wI5 a strong feeling thal while on the drug in some way she was being cOnLrolled and that suicide might happen She mtionaJisec1 rhat she had only a few days lefr on rhe drugmd was probably therefore ~fe to LOnrinue pacricularly with the dose reduclitm The fL-clings clcJred (0 some extent on the Iow~r dose and clCllred complecIy after the drug hld been discontinued In her opinion had the drug been cunrjnmiddot ued fur longer in a sitU2tion where she WoIS a patient seeking heJp rarher

Pri=ry Care PSYchiatry 2000 Vol 6 No 1

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than l volunteer who could disconshy(inut the drug that then might bav~ been an up to 50150 chance of a self hrm episode h3ppcning

A fln-al poillt of note about thiS Cil5e is that the suhject was awlre nfterwttd of perceptions mat the instibiltty she had shown on the drug would reflect on h(T She would be thought to middot be Ilnsrable rlther than to have had a drugmiddotinduatl instabiliry Both subjects felt this They are almost certainly accumte to

some exrcnr

Discussion

TIleslt cases which emerged in the courre of a blind contrblled study shed new light on the issue of drug induced suicidal ideatiOn Hitherro one of the arguments of the sceptics has been tliu depression leads to suishycidal ideation and against this backshyground it is difficult [Q make a causal connection between antidepre=t imake tnd suicidal ideation 125

The =mple of reserpine is of ~ interest here ReSErpine a psyshyj chorropic drug with RCT evidence of

mtidepressam cfficacy WJ) associshyated with an emergence of suicicJal ideltion and a number uf compkted suicides during the 19505 when il was widely used At the time it was argued chat it must he triggering a depressive disorder A recem reanalysis of (hoc early studies sugshyRestS rhltlt in fua it prEcipitated akathi~ia and this mmy have mcdishyared the suiodaJiry 1261 Of particular imeror is the fuel mat the probltITlS and $~Iicjdcs occurred in non-p$ychishyatrie patients being creued with reserpine fur hypertension permitshyting a SHang c~lIst1 claim to be made

In a recem he3lrhy volunteer study involving tlndumisation [l

droplt-ridol l()r17~p3m and placclJo we also wilnessed all emergence of suiddaJi(y lhat apPca(-d w be linked to agitation or akathliil 1271 This antidepfC5smt srudy provides support for the afpumcm that psycilmropic drugs in certain cirrumshyStances may induce ltl suidrlUiry thou would mherwise nut hl happened

The ctSes described in rnL5 paper appear to have bccome suidshydal on ~ertrJ1jne with no easy mons of cxplaining wha[ happened other

- than by invoking an SSRr-induced suicidality The mechanism through which this was mediatcti appear ro have been a combination of aknthisia and emotional blunting as well as other features suggestive of an amomatism_ The disinhibition reponed appears comparable to that reponed by Hoehn-Saric et al 2RJ on fluVOxarnIDE and fluClXetule To dare the phenomenology of what can happen has nor been explored ill any decaJl It is notable mat neither dnlg-induced depression nor drugmiddot induced akachisia experienced alone necessarily Jed to suicidaUry in this study Indeed in me case of the [wo volunteers who became suicidal they do not seem to have been depressed

One of the messages of the reSerpine stOry appear to have been [hat those who did not suffer from a p~ychiatric illness may have be~n at more risk from chis drug rhan others This hdthy volullteer study sugmiddot gests that individuals who are not frankly depressed may also be at incrc4ISed rL5k of drug-indllced problems compared [0 others Concomitan[ drug prescription may in middotfucr in nuny cases minimise the ri~ks Given that antidepressants arc commonly prescribed for stress relCshy

tion~ particularly when given alone chis point wnllld seem to be of some importance

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Ilchod for cljniCll description 2nd dasilk1(iOIl tif pcnon2lity vuilnrs a JltUpc=INCb Centtrallgtycbimry 4457j-SSS __

20 Me Nair DM nrr M amp Drupplcmatl U(l988) M=utl (ot the ProfIle of MnocI 5= $m DiCRO Cili[ EcuCUiunaJ Inri IndusCriIJ Tring SetviClOi

21 WllSOu D CI~tk 1 amp TcJleru II (1988) The dcvcloplTlenr uuI YJliddtion nr brier llltuuICS o( ptLltilive ~nd mgaivc aff~

The PANAS SaJcj hgtr=nality 6- Sltxial Psycbolo$V HW6j-1070

22 B~ M Duhini A Polin V (1997) PlupmenT ~llcl vaJiduiO of a gtOd21 funCtiOning ~~le lhe i(gtct21 Adaptation 5cJ[-FvaIuuion S(lk European IIcllropycixJpbarnuuukJhY 7 ~uppl S7-~70

23 ClrveCS Whil n (1994) lkhJviorll inhibiijon bchilviurnJ 3CriVllliOn and lifCtivc rCpoHe to lmrcnding trWlfd 3nri ~uni-hrncm lhe RLilMS sc-uc J ~rgtOnality ant Xxlall5yclJoiagy 67319-333

PrUnu-y Care Psychiatry 2000 Vol 6 No 1

s--~ = o-~- - - -- - - -

~-

_~_L - ) ~ ~

[15J ThC$C data suppkment unpubshylished RCT data from Lilly suggesting a significuuly higher rate of suicide attempts in patients wking fIuoxeshytine compant1 with placebo or other non-SSRI antidep==ts [1617

Against this backgmuntl we report the findings Tom a tl(lublcshyblind rmdomised crossover trial of senr1iine and reboxetine in he3lthy volumetTi This WolS aimed at explorshying modes of acrion of antidcpnsshysam drugs on levels ofweUbeing and in particulu- the screnic effect thar appCIri a~5ociltcd with the usc of SSRls which may mediate their mershy3peUiLc effeCt

Methods

Twenty healthy vuluntcers aged between 28 lnd S2 with a mcan age of 378 yea~ were recIlired tl I

study comparing reboxe[ine with ~LTtrlline on a lJIlge of pcrsonality selfreport ltlnd quality of life meshySUre5 The srudy was aimed a[ esrwshy(ishing the clfttts uf antidepreSiams on levels elf wdlbdng in suhjects not-i currently depressed There were

~ 9 males and 11 fem31es recruited from among the adminisrlTive medical and nursing membees of the North West Wales district general hospital pgtyduo1tric unit as well as four ()ther known t(l memlxn of the unit EthIcal permission had been obtaincd [rom th~ North Wcst Wues Ethical Committce Written consent (0 indusion was oboined from each subject All volunteers were free of medical condieions None we-re on concurrem drug treatshymemo NOne had a history of previous psychilluic illnL~s The two volunshytecr whose exreriemeo arc rcporred here hlVe given (lns(~nr for (hiS informarion [0 be reporTed

Subjecu were r mdomised [0

reboxlttine a selective norltlrcnaline rctJprake inhibitor or senfltlline a selective 51-IT reuprake inhibitOr in a crossover liQign SU that a proporshyticgtn received reboxerine for TWO

w=1G fnl1(gtoed by l rwo week dmg me period and rherfafter sertralinf for twu week or alrernatively scrtrmiddotmiddot lil)e [ollowct1 by rehoxetine The

dose of the drug~ wJS 6ther 4mgs of rtb(Jtctine for the first lve days of the reboxetine arm with an option tel

increase to 4mgs bel if wIera[ed or semaline SOmgs for the fuse five days of the sertraline period with an option tu incr=~euro [0 SOm~ bd if tolshycltcci

At baseline subjects commiddot plered a Karolinska Personality Questionnaire (18 a Tridimensional Personality Qucstionnalre 19 a Profile of Mood Srates (POM$) (201 a PosItive and Negarive Affect icale (PANAS) (21J a Social Adaptation Self EvlI1lation Soles (SASS) [22 and a SIS-SAS scale [23] The effern ofhoth drugs in the whole group on mood scales personality inventories side effect rating ca1~ and other meashysure will be reported d~ewhen

rOMS PANAS and SASS i(Ies

were completed on a daily basis as well as a daily diary of impressiollS of me functional and phyica1 effects of each drug Volunteers were actively encouraged to consult their pmners Or- ochcn IS til any chmgcs that eliCic other noticed in them over- each two-week period II focus grotlP was conducted at [he end of (he study aimed at establishing whether there wen efects chlrlCtcristic of either drug All ratings wert done blind The blinu wa only broktn twO wctks after thE study WltIlt completed

Results

A preliminary analysis of the results indiClres that cwomiddotthirds of subjeCts responded ro one or other of the tWO drugs but nOl the other with a bctter than well responsc RepClnse arpears to have heen f1rcmiddot dicted by personaliry factor similar ro those outlined by Joyce in a study of depressed subjects Cndomised (Q

either reitiveiy sdecrive nOrldrenshyergic or scrtltnnergilt nuptake inhibitors (2~ 1he WOllD also showed changes on the KSP that have been reported ill depressed pIrienrs following 5SRlo [25 Finilly in the group as a whole a gnater number of 5ubjecrs txpn~~ed ltl

preference for sertrlim than for reboxctinc

When on reboxeLine twO subshyjects reportt-d bltcorning depressed_ In both Cltl5es they likened the expeshyrience to post-lthildbirtb baby-blues Neither of these cwo subjects Or any ocher subjecL while taking nbaxcshytine had uicicJal ideation rn conshytraSt two liubjeLts taking sertmline devtloped clear SUicidal ideatlon one ofwhich reached extremely seri shyous proportions 130th thee individshyuals lpptII to haV had elements of akathisil and emotional blunting but other subjecrs had either akathisia or emoriorrul blunting without becomshying uicidal We report on these case in more detail reconstructing events from the diaries kept by both subjects

Case A The first Cltl5e was a 30 year old WOffiW She was lJndomi~cd to reboxetine initially This made her conspicuously relaxed and slighlly seda ted on Ule first dJy She describtd the effect as I ch ill pill 1n subsequent cltJys she found nomlaly strlt~lting events less streSSful She described [he effect as keeping her norm11 tempcrunental self on the straighr and lurrDw She had [Jonr sleep but was uncertlin if this was owing to childcare or the drug During the two weeks on what turned ouc [0 be reboxetine ~hf(

reported dry mouth sleeplessness reduced appetire nausea and COl1SUshy

pation which she attributed to the drug

After mndomLoui(lIl to sertl3shyline within [he first few days she appc-md (l become aVOidant She complain~d of a stiff jaw (an cxtrlpYrlmidal sidemiddoteffect smc vuimt of which W-Ji rqmrted in 15 of [he group while on ertrlline) She had I migrline which she did nor attribute to the drug along with nHlsea malaise rtSt(L~s[Jess OIgita [ion anxiety vivid emotions racing thoughts and ruminarions which she did atlribute to the drug

From (he- end of the firt wlck he wlS reportcd uy colleague to he somewhat restles anu fidgety To some she appeared akathisic but not

PriDlary Care PsythQtry 2000 Vol 6 No l

so dearly tha t everyone would notice She recogtlisLd her rcstlcsmiddot ness and rutd foUIld tlult with a degree of concemrItion and fu1dling she could disguise the dIect She also rimed other changfS in he~f that she cc)uld not initially dearly describt

In view ofthe side dfecrs up to this point the blind guesses of study monitors taking intO account both dnlgs were that she wl- On reboxeshytine rawer seru-ilinc She was noticed by the monitor by the end of the tim week to have become needy of time and company There were moments when she appeared lO lx-come preoccupied and emoshytionaI but on questioning would mention thaI she would be well in a short while as hcr mood hpd been swinging one minute doom and gloom the next ~nshine and Iaughshy

lCiinLS5 of herlegs She said that she was nor doing much work mat she couldnt cope with anyones emomiddot tion and she tried [0 occupy hergtelf by doing paper work but found it difshyficuIt ro focus her attention She describ~ swings of emotion with miscry predominating but she was not depressed She was advised to stop the drug and agreed to do so She did not Stop In ntrospect it was almOSt as if she could not srop herself from cling the tablets A number of (lther disinhibited dtings happened induding ldling her life history to a colleague whom she did flot know well leaving him conshycemed

Her diary record5 impllIsiveshyness initlbility over-senSitiVity as well as muked suspidon It also records a sense thac she had an old me and another The orner was like

tcr lOwrd the end of the first week middot a bit of her dlildhood sdf EaSily on treltltment her diary records and moved to emotion Simplistic aware she reported to a study mOnitOr two of sociJl etiquette but noc inclined [0

incidenrs involving quite atypical follow it impatient selfish and im behuviour for her She reported asponible The old me could only lack of gUilt about something she vras concemd she might be guilty about whtn she came off we maiiauion and was herself This as it turned out was the case

Over the fir-a wedand he had a nighanlre about having her throat slit so that it gaped open and she bled to death in the bed She didnt gel back to oleep She did nOl increase the dose of sertrnline over the weekend Versions of this nightshymare recurred on two succeeding middot rughr~

At the start of week twO she remained resdess wilhdrrwn and preoccupied The po1i)ibility of h(jlt~ iJg me drug was raised but she Opted [() carry on despite feeling as thuugh she had a combination of bad PMi and pre-=m nerves Htr diuy record~ thlt she thought she mighr have an infetuon that wlS

a~ldVltlting rhings and 1 hnpe thlt when lhal clearet she wOlld feeJ beITer

By Wednesday she had become withdrawn was ruminating over impulsive disinhibired things she had dune wc [Crful and not herelf She had very nhvioll re5[shy

watch what WJS happening and was helpless to MOp the ocher bit which was in concrol

Jhe following day it turned Ollt

~he had not stopped the ablets and the mediotion WoI-~ discontinued by study monitors She looked tJllwell but seemed to be making a great eflortat trying to appear nonnal She

wc still lkatrusic at a level that would be apparent to mosc j observers That night she was serishyously suicidal although the tablet she was due to take mal night had been stopped

On the Friday she telephoned early in the morning distressed and learful after the previous nighL Her converation wa- garbled She de5cribed almust going OlJr lI1d killing hersell~ She Wli vi~itcd at home She recounted that the night previously she had fclt camplere blackness aU around her All she could foUlS on was the pen and the qUQtionnaire in front of her but she couldnt write lOyrhing down She felt hopcleii and alone II scemcd [hal all she could do was [0 follow a thought that had been planted 10 her brain from some ilien force She

~uddenly decided she should go ant tlllOW hcrsclf in front of a car that chis was the only answer It was as if there was nothing out mere apmt from the car which sh~ was going to Lhrow herself under She didnc think ofher partner or child She was walkshying ouc of the door when the phone went 11lis scopped the tunnd of suishycidal ideation She later becune disshyrraught at what she had nearly done and guilry that she had not thought of hcr fumi1y

She ~s taken for a walk and appeared to gather hersdf Larer in the day $he completed a diary entry foe the night before LO supplement the brief entries of the previous Pay which included a hope [hac she would make it through the rughl In chi she described being jumpy lnXshy

ious and suspicious Her mind was racing and spiralling Out of contrOl Then jt wem blank except for the clear mought thar he mu~t kill hershyself viokntly by thrOWing herself beneath a Cilr or u-ain This cl=r thought appeared irrcsitible ltlnd its apptJrance seemed to put an end lO

the ~ety It was crancemiddotlike and J only broken by a phone-GIll which came when she WLi felc she was about to out Oil the basis of this idea

Contact was maintained ovcr me weekend By the Monday she dcdared herself co be back [Q her sdf She looked berrer but nmained vulnerable and wa dearlyapprehenshysive about Cilking lIbom what had happened_ 80th study motlitOrs and the research subject wert still blind at this point as [0 the identity of the medication The slbject herself remaini very_disturbed at what ha~

hoIppened During [his period daily POMS

and PANAS rAting were underraken On che POMS thE words mOST conshysiscently cndo~ed were lively active cheerful and vigorous during the reboxctlne block On middot senraline e-pccially in the second week the words endorsed wert [ense worn out unhappy fatigued sad conmiddot fused shaky discouraged on cC1ge miserable bewildered and nervous were regularly endorsed On [he PANAS she had a mc-an po~i[ive woro score of 197 in week une and

igtdlnary Can Psychiatry 2000 Vol 6 No 1

- - - - - -- - -- - - -

203 ill week 2 on rcboxetine and bur most probably was IS he to fmd her mother extremely frightshy253 in week one on crtrlline ftillilg to 194 in week 2 Her negative word score was 10 in wttk one on rebaxcshytine 114 in wttk two rising to 127 fur week One on serrraline and 229 for week twO

CaseS

B was a 28-yetr old woman at the time bf enrry to the st1ldy She had no history of psychiatric or medi=l problems She moked and took apprOldtnateiy twO ururs of alcohol her week Her only significmt peiiod of -tress WL5 three yeus previollsly when she sepuatttI from a parmer At tfur point in time the thought of suicide bld crossed her mind bur without my iment p lans or active ideation of any sort

She was randomised fJJ reboxshycLine followed by sertrLIine 50mgs for five dar increasing up to lOOmgs On reboxerine at some point during the twO weeks she sufshyfered from sleepJcssness conotipashydon dry mouth with some reduction

-f appetite sexual dysfunction ant _impairment ofconcentration In genshy

er3I however she found herself more confident calm and energetic

On going on sertraline she noticed the following effecrs which she attributed to the drug nawea lethargy malaise paniC and min in her jaw Within twO days she also noted in her diary that gthe had betume snappy and much more likely to say things thal CAme to mind and that [hiS had been noticed by her colie-tgUes By the third day she records herself as more J5serrive She also ~ported her mood as liable to drop that generAlly her emotions were liable to swing mm she was sluggish that she had become irritashyble It the slighrest liuJe rhing and WA~ Habie to take commcnrs personshyally Her mood does not appeared to hrve been depressed hur colleagucs noted her swings [rom cheerIulnei~ 0 withdrawal

She also found herself restless U1d reponed that she didn( Imow if he wl5 com or going This did lor appear to be an obviOUS aklthisil

endorsed agimtion as a side e1lect of the drug Close collelgues atld her mother nouccd this and other diS inshyhibired eventS of the kind described below All agreed that she was adversely affected by the L-cond pill and ~he was advised particularly by her mother never to go on anything like tlllt again

There was a reluctance to mention any of this to othergt and only a brief mcntion in a post-study fcx~ group led to a Sub~cqllent disshycussion in which these details became dear One of the intriguing fcLmres of this woman S experishyenced endorsed by ClSe A wo1S 41 conshyCcrn that elahof(1tlng on what WlS

trJppening her wouldlearl to others thinking she WlS cr=y - no-one had warned her bdorehand that this could possibly happeo on this drug Her diary entries and her rating scales wcre therefore economical with [hI truth

While on rcboxetine on the POMS this subject endolScd the worcl~ wom Out and weary during the first (WO weeks switching to sad annoyed miser3blt unhappy and angry during week two On the PANAS her positive scores dropped from 176 anu 154 on reboretinc to 114 and 126 on scrtraline Her negshyative scores did noc chanRe However there i~ a group of over 6 co-habifees work colleagues and s tudy monitors who had become aw-tre of rIle changes listed above atld below

8 briefly in her diary and at greater length subsequently descrilxd finding hereff ill a s~e

ltwhere she didnt think through theI ~)nequencc of what she did or SltLid She tlidn r appear to feel tfraidjFor =mple on one occasion wh ile driving home with her mother in he ar a grou p of 18 ycJr old boy by tbe idc of he road rrulde obscene geshyture Iod houtL-d af rhem while Un car wa5 moving slowly at a ttich juncture in the mad She toppctlIIthe car in rhe middk of moving trafshy

fico went over to them and grabbctl one of Them tdling hitn if he did anything like that again she would dak him She came back to the car

ened about what had hltlppened )There was a contra5r between reboxshyetine and sertr3line in this regard in I that rebaxetine had fIUde her feel I calm bur in a manner that Jefr her still able ro fcel feu In com1St on scrtraline she felt Wessive middot and fearless She found herself thinking on several occasions when fJced with situations wirh peopJe that she could deck them

She increased her dose of seIshytrallne ltJ 100 mg as per protocol Thereafter she fdt worse 0 thar she reduced the duse blck to SO mg three days before the end of the study_ -Following the incrcagte in dose she had tWO disrurbing nocturshynal episodes on consccurive nights She is a woman prone to lucid dreaming and both sleep walking and sleep talking with atensivt memory tile following day for what hlcl happened the previOUS night Her partner regularJy reportS her as bong awake during these cpisodes It is dilliL-ulr therefore o dctermine what happened but her rtcollection is while awake or lucidly dreaming that she spcnt long period lyinR in hltT bed funtasising about hanging herself from l beam across the bedshyroom ceiling She was aware tJc these thoughts were acCtJmpanied byln abnormal fade of concern as to whether her partner mother or othmiddot ergt might find her She is not aW~e

of eva having mmparmle thoughts before -rne reason-she did nothing she explaiJled afterwards WrlS Ibecaue she was a coward and had a vestigial concern about being foulld by her son-This episode repeated itself the following night

There wI5 a strong feeling thal while on the drug in some way she was being cOnLrolled and that suicide might happen She mtionaJisec1 rhat she had only a few days lefr on rhe drugmd was probably therefore ~fe to LOnrinue pacricularly with the dose reduclitm The fL-clings clcJred (0 some extent on the Iow~r dose and clCllred complecIy after the drug hld been discontinued In her opinion had the drug been cunrjnmiddot ued fur longer in a sitU2tion where she WoIS a patient seeking heJp rarher

Pri=ry Care PSYchiatry 2000 Vol 6 No 1

- ~

- - ---- -

than l volunteer who could disconshy(inut the drug that then might bav~ been an up to 50150 chance of a self hrm episode h3ppcning

A fln-al poillt of note about thiS Cil5e is that the suhject was awlre nfterwttd of perceptions mat the instibiltty she had shown on the drug would reflect on h(T She would be thought to middot be Ilnsrable rlther than to have had a drugmiddotinduatl instabiliry Both subjects felt this They are almost certainly accumte to

some exrcnr

Discussion

TIleslt cases which emerged in the courre of a blind contrblled study shed new light on the issue of drug induced suicidal ideatiOn Hitherro one of the arguments of the sceptics has been tliu depression leads to suishycidal ideation and against this backshyground it is difficult [Q make a causal connection between antidepre=t imake tnd suicidal ideation 125

The =mple of reserpine is of ~ interest here ReSErpine a psyshyj chorropic drug with RCT evidence of

mtidepressam cfficacy WJ) associshyated with an emergence of suicicJal ideltion and a number uf compkted suicides during the 19505 when il was widely used At the time it was argued chat it must he triggering a depressive disorder A recem reanalysis of (hoc early studies sugshyRestS rhltlt in fua it prEcipitated akathi~ia and this mmy have mcdishyared the suiodaJiry 1261 Of particular imeror is the fuel mat the probltITlS and $~Iicjdcs occurred in non-p$ychishyatrie patients being creued with reserpine fur hypertension permitshyting a SHang c~lIst1 claim to be made

In a recem he3lrhy volunteer study involving tlndumisation [l

droplt-ridol l()r17~p3m and placclJo we also wilnessed all emergence of suiddaJi(y lhat apPca(-d w be linked to agitation or akathliil 1271 This antidepfC5smt srudy provides support for the afpumcm that psycilmropic drugs in certain cirrumshyStances may induce ltl suidrlUiry thou would mherwise nut hl happened

The ctSes described in rnL5 paper appear to have bccome suidshydal on ~ertrJ1jne with no easy mons of cxplaining wha[ happened other

- than by invoking an SSRr-induced suicidality The mechanism through which this was mediatcti appear ro have been a combination of aknthisia and emotional blunting as well as other features suggestive of an amomatism_ The disinhibition reponed appears comparable to that reponed by Hoehn-Saric et al 2RJ on fluVOxarnIDE and fluClXetule To dare the phenomenology of what can happen has nor been explored ill any decaJl It is notable mat neither dnlg-induced depression nor drugmiddot induced akachisia experienced alone necessarily Jed to suicidaUry in this study Indeed in me case of the [wo volunteers who became suicidal they do not seem to have been depressed

One of the messages of the reSerpine stOry appear to have been [hat those who did not suffer from a p~ychiatric illness may have be~n at more risk from chis drug rhan others This hdthy volullteer study sugmiddot gests that individuals who are not frankly depressed may also be at incrc4ISed rL5k of drug-indllced problems compared [0 others Concomitan[ drug prescription may in middotfucr in nuny cases minimise the ri~ks Given that antidepressants arc commonly prescribed for stress relCshy

tion~ particularly when given alone chis point wnllld seem to be of some importance

References

I ni~her MIt Clod C ColeJO Erl1erJCn~e

of intense 5uiCithl prcoccu~tion (lun~ lluoXttine rtI(ment AmIrgtorhiafr)l 1910 H7207-110

L (jog RA Riddle MA Chappell rll H~din

Xl And=n GM Lumbrmn P F~cc of sdf-ltlc-rv~ti IhcnonlC-l in hildrltn U1ltJ dolcnr c1uritlll tluOlC~lin u=unC1i(j ~nj Aliltd CbildAdd Prycbialrv 1991 30171middot 1-6

3 Ct=ruy ~ MurrIy I Holy 0 Antidcpresgm induced suicidlll ideliun Hum lgtychopbarmacoll99l ltO329-33l

4 kolhschilcl N Lodltc (A nt~gtltpu U

nuctxetine uter ~cnou suiciltl 3CIltnlIL hy 3 patientS [he mle at 1lcuhisiaCin fsyltigti(lrTy 1991 52491-193

5 Wirshing we In Puntn T RoscnbagJ MLrdec $ Nnelaquo () HiclG-CrI) T Eluogttint aJcIlhlsia anU uicjdauly is there a UtusU conn~n Arch Grn Pltychlalry 1992 95lj(-5B1

6 Lane lW SSRlmiddotnduced =pyramicla1 sidlt 5= ~nd ikuhisil implications (of rtltWllcnrjJgtyrbophannacoll998 12192-214

7 Scttlc C Akathis~ ~nd scrtrgtJincJGin PsychlltlIry 1993 S~3Zl

8 Klce fl Kronig MH Clsc report of probiltble scrrraJinc indvced okuhli~ Am J PsycbiaJry 1993150 986-987

9 Kva m Drug induced aklthisi3 ~1Jhj=M experience and objecuve

Bndings Milil Med 1994159A10 to 1clorulJ) Scrtralille inducc(l ~lcjhiiL

J Cli JsyCbopbarmacol 199413219-220

1L Uo RJ Disordcfs associl1Cd With the sero(onin sdccriltle reuptllce inhibitor Cllrric frchlalry 1996 57449-15-1

12 Altshul U Pi=JM WUShing we Ames DScruaJine and akailiisiL I aln Psychopbarmacoll99414278-279

D IlonnetmiddotBrilluult F TItiWut P tepricLll A Petir M II eac of Paroxttine inducrd kl[hiSi2 md a revUew otSSRI induccd 1kalhiii Europ Psychlalry 1991l13 109-111

14 JUpcr S he p13Cl of lniliuclprnn in the tnItTI~m ufdepresSiOn HU11I

~cbopharmacol 199712Sl3S-141 15 B3ldwin D l11e Uemmcnt of rltCurrent

boa (1~pnsion Europem 0gtlI~ oj NeurOpycoopbarmacoiagp Meeting nncon Sept 241994

16 LiUy Memo n sUiCidesznd suidck 3Cmpts OltTo~r 1986 Forsyth Vgti Eli lilly Pwntiffi ethibit 73

17 He-ly D Guesl EditnritJ A F3ilurc (0 W1m n~mation11 Risk Saftty Ntlt (in p=)

18 ~ellui 1 von Knorring L (1999) Challi in prOl2lity trilis uuring (rGllmcm With =Ilne or cit2l0pr3n BriJishj Piychiatry 1744-448

19 CloninsCf CJ (19R7) I )ltcm~tic

Ilchod for cljniCll description 2nd dasilk1(iOIl tif pcnon2lity vuilnrs a JltUpc=INCb Centtrallgtycbimry 4457j-SSS __

20 Me Nair DM nrr M amp Drupplcmatl U(l988) M=utl (ot the ProfIle of MnocI 5= $m DiCRO Cili[ EcuCUiunaJ Inri IndusCriIJ Tring SetviClOi

21 WllSOu D CI~tk 1 amp TcJleru II (1988) The dcvcloplTlenr uuI YJliddtion nr brier llltuuICS o( ptLltilive ~nd mgaivc aff~

The PANAS SaJcj hgtr=nality 6- Sltxial Psycbolo$V HW6j-1070

22 B~ M Duhini A Polin V (1997) PlupmenT ~llcl vaJiduiO of a gtOd21 funCtiOning ~~le lhe i(gtct21 Adaptation 5cJ[-FvaIuuion S(lk European IIcllropycixJpbarnuuukJhY 7 ~uppl S7-~70

23 ClrveCS Whil n (1994) lkhJviorll inhibiijon bchilviurnJ 3CriVllliOn and lifCtivc rCpoHe to lmrcnding trWlfd 3nri ~uni-hrncm lhe RLilMS sc-uc J ~rgtOnality ant Xxlall5yclJoiagy 67319-333

PrUnu-y Care Psychiatry 2000 Vol 6 No 1

s--~ = o-~- - - -- - - -

~-

so dearly tha t everyone would notice She recogtlisLd her rcstlcsmiddot ness and rutd foUIld tlult with a degree of concemrItion and fu1dling she could disguise the dIect She also rimed other changfS in he~f that she cc)uld not initially dearly describt

In view ofthe side dfecrs up to this point the blind guesses of study monitors taking intO account both dnlgs were that she wl- On reboxeshytine rawer seru-ilinc She was noticed by the monitor by the end of the tim week to have become needy of time and company There were moments when she appeared lO lx-come preoccupied and emoshytionaI but on questioning would mention thaI she would be well in a short while as hcr mood hpd been swinging one minute doom and gloom the next ~nshine and Iaughshy

lCiinLS5 of herlegs She said that she was nor doing much work mat she couldnt cope with anyones emomiddot tion and she tried [0 occupy hergtelf by doing paper work but found it difshyficuIt ro focus her attention She describ~ swings of emotion with miscry predominating but she was not depressed She was advised to stop the drug and agreed to do so She did not Stop In ntrospect it was almOSt as if she could not srop herself from cling the tablets A number of (lther disinhibited dtings happened induding ldling her life history to a colleague whom she did flot know well leaving him conshycemed

Her diary record5 impllIsiveshyness initlbility over-senSitiVity as well as muked suspidon It also records a sense thac she had an old me and another The orner was like

tcr lOwrd the end of the first week middot a bit of her dlildhood sdf EaSily on treltltment her diary records and moved to emotion Simplistic aware she reported to a study mOnitOr two of sociJl etiquette but noc inclined [0

incidenrs involving quite atypical follow it impatient selfish and im behuviour for her She reported asponible The old me could only lack of gUilt about something she vras concemd she might be guilty about whtn she came off we maiiauion and was herself This as it turned out was the case

Over the fir-a wedand he had a nighanlre about having her throat slit so that it gaped open and she bled to death in the bed She didnt gel back to oleep She did nOl increase the dose of sertrnline over the weekend Versions of this nightshymare recurred on two succeeding middot rughr~

At the start of week twO she remained resdess wilhdrrwn and preoccupied The po1i)ibility of h(jlt~ iJg me drug was raised but she Opted [() carry on despite feeling as thuugh she had a combination of bad PMi and pre-=m nerves Htr diuy record~ thlt she thought she mighr have an infetuon that wlS

a~ldVltlting rhings and 1 hnpe thlt when lhal clearet she wOlld feeJ beITer

By Wednesday she had become withdrawn was ruminating over impulsive disinhibired things she had dune wc [Crful and not herelf She had very nhvioll re5[shy

watch what WJS happening and was helpless to MOp the ocher bit which was in concrol

Jhe following day it turned Ollt

~he had not stopped the ablets and the mediotion WoI-~ discontinued by study monitors She looked tJllwell but seemed to be making a great eflortat trying to appear nonnal She

wc still lkatrusic at a level that would be apparent to mosc j observers That night she was serishyously suicidal although the tablet she was due to take mal night had been stopped

On the Friday she telephoned early in the morning distressed and learful after the previous nighL Her converation wa- garbled She de5cribed almust going OlJr lI1d killing hersell~ She Wli vi~itcd at home She recounted that the night previously she had fclt camplere blackness aU around her All she could foUlS on was the pen and the qUQtionnaire in front of her but she couldnt write lOyrhing down She felt hopcleii and alone II scemcd [hal all she could do was [0 follow a thought that had been planted 10 her brain from some ilien force She

~uddenly decided she should go ant tlllOW hcrsclf in front of a car that chis was the only answer It was as if there was nothing out mere apmt from the car which sh~ was going to Lhrow herself under She didnc think ofher partner or child She was walkshying ouc of the door when the phone went 11lis scopped the tunnd of suishycidal ideation She later becune disshyrraught at what she had nearly done and guilry that she had not thought of hcr fumi1y

She ~s taken for a walk and appeared to gather hersdf Larer in the day $he completed a diary entry foe the night before LO supplement the brief entries of the previous Pay which included a hope [hac she would make it through the rughl In chi she described being jumpy lnXshy

ious and suspicious Her mind was racing and spiralling Out of contrOl Then jt wem blank except for the clear mought thar he mu~t kill hershyself viokntly by thrOWing herself beneath a Cilr or u-ain This cl=r thought appeared irrcsitible ltlnd its apptJrance seemed to put an end lO

the ~ety It was crancemiddotlike and J only broken by a phone-GIll which came when she WLi felc she was about to out Oil the basis of this idea

Contact was maintained ovcr me weekend By the Monday she dcdared herself co be back [Q her sdf She looked berrer but nmained vulnerable and wa dearlyapprehenshysive about Cilking lIbom what had happened_ 80th study motlitOrs and the research subject wert still blind at this point as [0 the identity of the medication The slbject herself remaini very_disturbed at what ha~

hoIppened During [his period daily POMS

and PANAS rAting were underraken On che POMS thE words mOST conshysiscently cndo~ed were lively active cheerful and vigorous during the reboxctlne block On middot senraline e-pccially in the second week the words endorsed wert [ense worn out unhappy fatigued sad conmiddot fused shaky discouraged on cC1ge miserable bewildered and nervous were regularly endorsed On [he PANAS she had a mc-an po~i[ive woro score of 197 in week une and

igtdlnary Can Psychiatry 2000 Vol 6 No 1

- - - - - -- - -- - - -

203 ill week 2 on rcboxetine and bur most probably was IS he to fmd her mother extremely frightshy253 in week one on crtrlline ftillilg to 194 in week 2 Her negative word score was 10 in wttk one on rebaxcshytine 114 in wttk two rising to 127 fur week One on serrraline and 229 for week twO

CaseS

B was a 28-yetr old woman at the time bf enrry to the st1ldy She had no history of psychiatric or medi=l problems She moked and took apprOldtnateiy twO ururs of alcohol her week Her only significmt peiiod of -tress WL5 three yeus previollsly when she sepuatttI from a parmer At tfur point in time the thought of suicide bld crossed her mind bur without my iment p lans or active ideation of any sort

She was randomised fJJ reboxshycLine followed by sertrLIine 50mgs for five dar increasing up to lOOmgs On reboxerine at some point during the twO weeks she sufshyfered from sleepJcssness conotipashydon dry mouth with some reduction

-f appetite sexual dysfunction ant _impairment ofconcentration In genshy

er3I however she found herself more confident calm and energetic

On going on sertraline she noticed the following effecrs which she attributed to the drug nawea lethargy malaise paniC and min in her jaw Within twO days she also noted in her diary that gthe had betume snappy and much more likely to say things thal CAme to mind and that [hiS had been noticed by her colie-tgUes By the third day she records herself as more J5serrive She also ~ported her mood as liable to drop that generAlly her emotions were liable to swing mm she was sluggish that she had become irritashyble It the slighrest liuJe rhing and WA~ Habie to take commcnrs personshyally Her mood does not appeared to hrve been depressed hur colleagucs noted her swings [rom cheerIulnei~ 0 withdrawal

She also found herself restless U1d reponed that she didn( Imow if he wl5 com or going This did lor appear to be an obviOUS aklthisil

endorsed agimtion as a side e1lect of the drug Close collelgues atld her mother nouccd this and other diS inshyhibired eventS of the kind described below All agreed that she was adversely affected by the L-cond pill and ~he was advised particularly by her mother never to go on anything like tlllt again

There was a reluctance to mention any of this to othergt and only a brief mcntion in a post-study fcx~ group led to a Sub~cqllent disshycussion in which these details became dear One of the intriguing fcLmres of this woman S experishyenced endorsed by ClSe A wo1S 41 conshyCcrn that elahof(1tlng on what WlS

trJppening her wouldlearl to others thinking she WlS cr=y - no-one had warned her bdorehand that this could possibly happeo on this drug Her diary entries and her rating scales wcre therefore economical with [hI truth

While on rcboxetine on the POMS this subject endolScd the worcl~ wom Out and weary during the first (WO weeks switching to sad annoyed miser3blt unhappy and angry during week two On the PANAS her positive scores dropped from 176 anu 154 on reboretinc to 114 and 126 on scrtraline Her negshyative scores did noc chanRe However there i~ a group of over 6 co-habifees work colleagues and s tudy monitors who had become aw-tre of rIle changes listed above atld below

8 briefly in her diary and at greater length subsequently descrilxd finding hereff ill a s~e

ltwhere she didnt think through theI ~)nequencc of what she did or SltLid She tlidn r appear to feel tfraidjFor =mple on one occasion wh ile driving home with her mother in he ar a grou p of 18 ycJr old boy by tbe idc of he road rrulde obscene geshyture Iod houtL-d af rhem while Un car wa5 moving slowly at a ttich juncture in the mad She toppctlIIthe car in rhe middk of moving trafshy

fico went over to them and grabbctl one of Them tdling hitn if he did anything like that again she would dak him She came back to the car

ened about what had hltlppened )There was a contra5r between reboxshyetine and sertr3line in this regard in I that rebaxetine had fIUde her feel I calm bur in a manner that Jefr her still able ro fcel feu In com1St on scrtraline she felt Wessive middot and fearless She found herself thinking on several occasions when fJced with situations wirh peopJe that she could deck them

She increased her dose of seIshytrallne ltJ 100 mg as per protocol Thereafter she fdt worse 0 thar she reduced the duse blck to SO mg three days before the end of the study_ -Following the incrcagte in dose she had tWO disrurbing nocturshynal episodes on consccurive nights She is a woman prone to lucid dreaming and both sleep walking and sleep talking with atensivt memory tile following day for what hlcl happened the previOUS night Her partner regularJy reportS her as bong awake during these cpisodes It is dilliL-ulr therefore o dctermine what happened but her rtcollection is while awake or lucidly dreaming that she spcnt long period lyinR in hltT bed funtasising about hanging herself from l beam across the bedshyroom ceiling She was aware tJc these thoughts were acCtJmpanied byln abnormal fade of concern as to whether her partner mother or othmiddot ergt might find her She is not aW~e

of eva having mmparmle thoughts before -rne reason-she did nothing she explaiJled afterwards WrlS Ibecaue she was a coward and had a vestigial concern about being foulld by her son-This episode repeated itself the following night

There wI5 a strong feeling thal while on the drug in some way she was being cOnLrolled and that suicide might happen She mtionaJisec1 rhat she had only a few days lefr on rhe drugmd was probably therefore ~fe to LOnrinue pacricularly with the dose reduclitm The fL-clings clcJred (0 some extent on the Iow~r dose and clCllred complecIy after the drug hld been discontinued In her opinion had the drug been cunrjnmiddot ued fur longer in a sitU2tion where she WoIS a patient seeking heJp rarher

Pri=ry Care PSYchiatry 2000 Vol 6 No 1

- ~

- - ---- -

than l volunteer who could disconshy(inut the drug that then might bav~ been an up to 50150 chance of a self hrm episode h3ppcning

A fln-al poillt of note about thiS Cil5e is that the suhject was awlre nfterwttd of perceptions mat the instibiltty she had shown on the drug would reflect on h(T She would be thought to middot be Ilnsrable rlther than to have had a drugmiddotinduatl instabiliry Both subjects felt this They are almost certainly accumte to

some exrcnr

Discussion

TIleslt cases which emerged in the courre of a blind contrblled study shed new light on the issue of drug induced suicidal ideatiOn Hitherro one of the arguments of the sceptics has been tliu depression leads to suishycidal ideation and against this backshyground it is difficult [Q make a causal connection between antidepre=t imake tnd suicidal ideation 125

The =mple of reserpine is of ~ interest here ReSErpine a psyshyj chorropic drug with RCT evidence of

mtidepressam cfficacy WJ) associshyated with an emergence of suicicJal ideltion and a number uf compkted suicides during the 19505 when il was widely used At the time it was argued chat it must he triggering a depressive disorder A recem reanalysis of (hoc early studies sugshyRestS rhltlt in fua it prEcipitated akathi~ia and this mmy have mcdishyared the suiodaJiry 1261 Of particular imeror is the fuel mat the probltITlS and $~Iicjdcs occurred in non-p$ychishyatrie patients being creued with reserpine fur hypertension permitshyting a SHang c~lIst1 claim to be made

In a recem he3lrhy volunteer study involving tlndumisation [l

droplt-ridol l()r17~p3m and placclJo we also wilnessed all emergence of suiddaJi(y lhat apPca(-d w be linked to agitation or akathliil 1271 This antidepfC5smt srudy provides support for the afpumcm that psycilmropic drugs in certain cirrumshyStances may induce ltl suidrlUiry thou would mherwise nut hl happened

The ctSes described in rnL5 paper appear to have bccome suidshydal on ~ertrJ1jne with no easy mons of cxplaining wha[ happened other

- than by invoking an SSRr-induced suicidality The mechanism through which this was mediatcti appear ro have been a combination of aknthisia and emotional blunting as well as other features suggestive of an amomatism_ The disinhibition reponed appears comparable to that reponed by Hoehn-Saric et al 2RJ on fluVOxarnIDE and fluClXetule To dare the phenomenology of what can happen has nor been explored ill any decaJl It is notable mat neither dnlg-induced depression nor drugmiddot induced akachisia experienced alone necessarily Jed to suicidaUry in this study Indeed in me case of the [wo volunteers who became suicidal they do not seem to have been depressed

One of the messages of the reSerpine stOry appear to have been [hat those who did not suffer from a p~ychiatric illness may have be~n at more risk from chis drug rhan others This hdthy volullteer study sugmiddot gests that individuals who are not frankly depressed may also be at incrc4ISed rL5k of drug-indllced problems compared [0 others Concomitan[ drug prescription may in middotfucr in nuny cases minimise the ri~ks Given that antidepressants arc commonly prescribed for stress relCshy

tion~ particularly when given alone chis point wnllld seem to be of some importance

References

I ni~her MIt Clod C ColeJO Erl1erJCn~e

of intense 5uiCithl prcoccu~tion (lun~ lluoXttine rtI(ment AmIrgtorhiafr)l 1910 H7207-110

L (jog RA Riddle MA Chappell rll H~din

Xl And=n GM Lumbrmn P F~cc of sdf-ltlc-rv~ti IhcnonlC-l in hildrltn U1ltJ dolcnr c1uritlll tluOlC~lin u=unC1i(j ~nj Aliltd CbildAdd Prycbialrv 1991 30171middot 1-6

3 Ct=ruy ~ MurrIy I Holy 0 Antidcpresgm induced suicidlll ideliun Hum lgtychopbarmacoll99l ltO329-33l

4 kolhschilcl N Lodltc (A nt~gtltpu U

nuctxetine uter ~cnou suiciltl 3CIltnlIL hy 3 patientS [he mle at 1lcuhisiaCin fsyltigti(lrTy 1991 52491-193

5 Wirshing we In Puntn T RoscnbagJ MLrdec $ Nnelaquo () HiclG-CrI) T Eluogttint aJcIlhlsia anU uicjdauly is there a UtusU conn~n Arch Grn Pltychlalry 1992 95lj(-5B1

6 Lane lW SSRlmiddotnduced =pyramicla1 sidlt 5= ~nd ikuhisil implications (of rtltWllcnrjJgtyrbophannacoll998 12192-214

7 Scttlc C Akathis~ ~nd scrtrgtJincJGin PsychlltlIry 1993 S~3Zl

8 Klce fl Kronig MH Clsc report of probiltble scrrraJinc indvced okuhli~ Am J PsycbiaJry 1993150 986-987

9 Kva m Drug induced aklthisi3 ~1Jhj=M experience and objecuve

Bndings Milil Med 1994159A10 to 1clorulJ) Scrtralille inducc(l ~lcjhiiL

J Cli JsyCbopbarmacol 199413219-220

1L Uo RJ Disordcfs associl1Cd With the sero(onin sdccriltle reuptllce inhibitor Cllrric frchlalry 1996 57449-15-1

12 Altshul U Pi=JM WUShing we Ames DScruaJine and akailiisiL I aln Psychopbarmacoll99414278-279

D IlonnetmiddotBrilluult F TItiWut P tepricLll A Petir M II eac of Paroxttine inducrd kl[hiSi2 md a revUew otSSRI induccd 1kalhiii Europ Psychlalry 1991l13 109-111

14 JUpcr S he p13Cl of lniliuclprnn in the tnItTI~m ufdepresSiOn HU11I

~cbopharmacol 199712Sl3S-141 15 B3ldwin D l11e Uemmcnt of rltCurrent

boa (1~pnsion Europem 0gtlI~ oj NeurOpycoopbarmacoiagp Meeting nncon Sept 241994

16 LiUy Memo n sUiCidesznd suidck 3Cmpts OltTo~r 1986 Forsyth Vgti Eli lilly Pwntiffi ethibit 73

17 He-ly D Guesl EditnritJ A F3ilurc (0 W1m n~mation11 Risk Saftty Ntlt (in p=)

18 ~ellui 1 von Knorring L (1999) Challi in prOl2lity trilis uuring (rGllmcm With =Ilne or cit2l0pr3n BriJishj Piychiatry 1744-448

19 CloninsCf CJ (19R7) I )ltcm~tic

Ilchod for cljniCll description 2nd dasilk1(iOIl tif pcnon2lity vuilnrs a JltUpc=INCb Centtrallgtycbimry 4457j-SSS __

20 Me Nair DM nrr M amp Drupplcmatl U(l988) M=utl (ot the ProfIle of MnocI 5= $m DiCRO Cili[ EcuCUiunaJ Inri IndusCriIJ Tring SetviClOi

21 WllSOu D CI~tk 1 amp TcJleru II (1988) The dcvcloplTlenr uuI YJliddtion nr brier llltuuICS o( ptLltilive ~nd mgaivc aff~

The PANAS SaJcj hgtr=nality 6- Sltxial Psycbolo$V HW6j-1070

22 B~ M Duhini A Polin V (1997) PlupmenT ~llcl vaJiduiO of a gtOd21 funCtiOning ~~le lhe i(gtct21 Adaptation 5cJ[-FvaIuuion S(lk European IIcllropycixJpbarnuuukJhY 7 ~uppl S7-~70

23 ClrveCS Whil n (1994) lkhJviorll inhibiijon bchilviurnJ 3CriVllliOn and lifCtivc rCpoHe to lmrcnding trWlfd 3nri ~uni-hrncm lhe RLilMS sc-uc J ~rgtOnality ant Xxlall5yclJoiagy 67319-333

PrUnu-y Care Psychiatry 2000 Vol 6 No 1

s--~ = o-~- - - -- - - -

~-

- - - - - -- - -- - - -

203 ill week 2 on rcboxetine and bur most probably was IS he to fmd her mother extremely frightshy253 in week one on crtrlline ftillilg to 194 in week 2 Her negative word score was 10 in wttk one on rebaxcshytine 114 in wttk two rising to 127 fur week One on serrraline and 229 for week twO

CaseS

B was a 28-yetr old woman at the time bf enrry to the st1ldy She had no history of psychiatric or medi=l problems She moked and took apprOldtnateiy twO ururs of alcohol her week Her only significmt peiiod of -tress WL5 three yeus previollsly when she sepuatttI from a parmer At tfur point in time the thought of suicide bld crossed her mind bur without my iment p lans or active ideation of any sort

She was randomised fJJ reboxshycLine followed by sertrLIine 50mgs for five dar increasing up to lOOmgs On reboxerine at some point during the twO weeks she sufshyfered from sleepJcssness conotipashydon dry mouth with some reduction

-f appetite sexual dysfunction ant _impairment ofconcentration In genshy

er3I however she found herself more confident calm and energetic

On going on sertraline she noticed the following effecrs which she attributed to the drug nawea lethargy malaise paniC and min in her jaw Within twO days she also noted in her diary that gthe had betume snappy and much more likely to say things thal CAme to mind and that [hiS had been noticed by her colie-tgUes By the third day she records herself as more J5serrive She also ~ported her mood as liable to drop that generAlly her emotions were liable to swing mm she was sluggish that she had become irritashyble It the slighrest liuJe rhing and WA~ Habie to take commcnrs personshyally Her mood does not appeared to hrve been depressed hur colleagucs noted her swings [rom cheerIulnei~ 0 withdrawal

She also found herself restless U1d reponed that she didn( Imow if he wl5 com or going This did lor appear to be an obviOUS aklthisil

endorsed agimtion as a side e1lect of the drug Close collelgues atld her mother nouccd this and other diS inshyhibired eventS of the kind described below All agreed that she was adversely affected by the L-cond pill and ~he was advised particularly by her mother never to go on anything like tlllt again

There was a reluctance to mention any of this to othergt and only a brief mcntion in a post-study fcx~ group led to a Sub~cqllent disshycussion in which these details became dear One of the intriguing fcLmres of this woman S experishyenced endorsed by ClSe A wo1S 41 conshyCcrn that elahof(1tlng on what WlS

trJppening her wouldlearl to others thinking she WlS cr=y - no-one had warned her bdorehand that this could possibly happeo on this drug Her diary entries and her rating scales wcre therefore economical with [hI truth

While on rcboxetine on the POMS this subject endolScd the worcl~ wom Out and weary during the first (WO weeks switching to sad annoyed miser3blt unhappy and angry during week two On the PANAS her positive scores dropped from 176 anu 154 on reboretinc to 114 and 126 on scrtraline Her negshyative scores did noc chanRe However there i~ a group of over 6 co-habifees work colleagues and s tudy monitors who had become aw-tre of rIle changes listed above atld below

8 briefly in her diary and at greater length subsequently descrilxd finding hereff ill a s~e

ltwhere she didnt think through theI ~)nequencc of what she did or SltLid She tlidn r appear to feel tfraidjFor =mple on one occasion wh ile driving home with her mother in he ar a grou p of 18 ycJr old boy by tbe idc of he road rrulde obscene geshyture Iod houtL-d af rhem while Un car wa5 moving slowly at a ttich juncture in the mad She toppctlIIthe car in rhe middk of moving trafshy

fico went over to them and grabbctl one of Them tdling hitn if he did anything like that again she would dak him She came back to the car

ened about what had hltlppened )There was a contra5r between reboxshyetine and sertr3line in this regard in I that rebaxetine had fIUde her feel I calm bur in a manner that Jefr her still able ro fcel feu In com1St on scrtraline she felt Wessive middot and fearless She found herself thinking on several occasions when fJced with situations wirh peopJe that she could deck them

She increased her dose of seIshytrallne ltJ 100 mg as per protocol Thereafter she fdt worse 0 thar she reduced the duse blck to SO mg three days before the end of the study_ -Following the incrcagte in dose she had tWO disrurbing nocturshynal episodes on consccurive nights She is a woman prone to lucid dreaming and both sleep walking and sleep talking with atensivt memory tile following day for what hlcl happened the previOUS night Her partner regularJy reportS her as bong awake during these cpisodes It is dilliL-ulr therefore o dctermine what happened but her rtcollection is while awake or lucidly dreaming that she spcnt long period lyinR in hltT bed funtasising about hanging herself from l beam across the bedshyroom ceiling She was aware tJc these thoughts were acCtJmpanied byln abnormal fade of concern as to whether her partner mother or othmiddot ergt might find her She is not aW~e

of eva having mmparmle thoughts before -rne reason-she did nothing she explaiJled afterwards WrlS Ibecaue she was a coward and had a vestigial concern about being foulld by her son-This episode repeated itself the following night

There wI5 a strong feeling thal while on the drug in some way she was being cOnLrolled and that suicide might happen She mtionaJisec1 rhat she had only a few days lefr on rhe drugmd was probably therefore ~fe to LOnrinue pacricularly with the dose reduclitm The fL-clings clcJred (0 some extent on the Iow~r dose and clCllred complecIy after the drug hld been discontinued In her opinion had the drug been cunrjnmiddot ued fur longer in a sitU2tion where she WoIS a patient seeking heJp rarher

Pri=ry Care PSYchiatry 2000 Vol 6 No 1

- ~

- - ---- -

than l volunteer who could disconshy(inut the drug that then might bav~ been an up to 50150 chance of a self hrm episode h3ppcning

A fln-al poillt of note about thiS Cil5e is that the suhject was awlre nfterwttd of perceptions mat the instibiltty she had shown on the drug would reflect on h(T She would be thought to middot be Ilnsrable rlther than to have had a drugmiddotinduatl instabiliry Both subjects felt this They are almost certainly accumte to

some exrcnr

Discussion

TIleslt cases which emerged in the courre of a blind contrblled study shed new light on the issue of drug induced suicidal ideatiOn Hitherro one of the arguments of the sceptics has been tliu depression leads to suishycidal ideation and against this backshyground it is difficult [Q make a causal connection between antidepre=t imake tnd suicidal ideation 125

The =mple of reserpine is of ~ interest here ReSErpine a psyshyj chorropic drug with RCT evidence of

mtidepressam cfficacy WJ) associshyated with an emergence of suicicJal ideltion and a number uf compkted suicides during the 19505 when il was widely used At the time it was argued chat it must he triggering a depressive disorder A recem reanalysis of (hoc early studies sugshyRestS rhltlt in fua it prEcipitated akathi~ia and this mmy have mcdishyared the suiodaJiry 1261 Of particular imeror is the fuel mat the probltITlS and $~Iicjdcs occurred in non-p$ychishyatrie patients being creued with reserpine fur hypertension permitshyting a SHang c~lIst1 claim to be made

In a recem he3lrhy volunteer study involving tlndumisation [l

droplt-ridol l()r17~p3m and placclJo we also wilnessed all emergence of suiddaJi(y lhat apPca(-d w be linked to agitation or akathliil 1271 This antidepfC5smt srudy provides support for the afpumcm that psycilmropic drugs in certain cirrumshyStances may induce ltl suidrlUiry thou would mherwise nut hl happened

The ctSes described in rnL5 paper appear to have bccome suidshydal on ~ertrJ1jne with no easy mons of cxplaining wha[ happened other

- than by invoking an SSRr-induced suicidality The mechanism through which this was mediatcti appear ro have been a combination of aknthisia and emotional blunting as well as other features suggestive of an amomatism_ The disinhibition reponed appears comparable to that reponed by Hoehn-Saric et al 2RJ on fluVOxarnIDE and fluClXetule To dare the phenomenology of what can happen has nor been explored ill any decaJl It is notable mat neither dnlg-induced depression nor drugmiddot induced akachisia experienced alone necessarily Jed to suicidaUry in this study Indeed in me case of the [wo volunteers who became suicidal they do not seem to have been depressed

One of the messages of the reSerpine stOry appear to have been [hat those who did not suffer from a p~ychiatric illness may have be~n at more risk from chis drug rhan others This hdthy volullteer study sugmiddot gests that individuals who are not frankly depressed may also be at incrc4ISed rL5k of drug-indllced problems compared [0 others Concomitan[ drug prescription may in middotfucr in nuny cases minimise the ri~ks Given that antidepressants arc commonly prescribed for stress relCshy

tion~ particularly when given alone chis point wnllld seem to be of some importance

References

I ni~her MIt Clod C ColeJO Erl1erJCn~e

of intense 5uiCithl prcoccu~tion (lun~ lluoXttine rtI(ment AmIrgtorhiafr)l 1910 H7207-110

L (jog RA Riddle MA Chappell rll H~din

Xl And=n GM Lumbrmn P F~cc of sdf-ltlc-rv~ti IhcnonlC-l in hildrltn U1ltJ dolcnr c1uritlll tluOlC~lin u=unC1i(j ~nj Aliltd CbildAdd Prycbialrv 1991 30171middot 1-6

3 Ct=ruy ~ MurrIy I Holy 0 Antidcpresgm induced suicidlll ideliun Hum lgtychopbarmacoll99l ltO329-33l

4 kolhschilcl N Lodltc (A nt~gtltpu U

nuctxetine uter ~cnou suiciltl 3CIltnlIL hy 3 patientS [he mle at 1lcuhisiaCin fsyltigti(lrTy 1991 52491-193

5 Wirshing we In Puntn T RoscnbagJ MLrdec $ Nnelaquo () HiclG-CrI) T Eluogttint aJcIlhlsia anU uicjdauly is there a UtusU conn~n Arch Grn Pltychlalry 1992 95lj(-5B1

6 Lane lW SSRlmiddotnduced =pyramicla1 sidlt 5= ~nd ikuhisil implications (of rtltWllcnrjJgtyrbophannacoll998 12192-214

7 Scttlc C Akathis~ ~nd scrtrgtJincJGin PsychlltlIry 1993 S~3Zl

8 Klce fl Kronig MH Clsc report of probiltble scrrraJinc indvced okuhli~ Am J PsycbiaJry 1993150 986-987

9 Kva m Drug induced aklthisi3 ~1Jhj=M experience and objecuve

Bndings Milil Med 1994159A10 to 1clorulJ) Scrtralille inducc(l ~lcjhiiL

J Cli JsyCbopbarmacol 199413219-220

1L Uo RJ Disordcfs associl1Cd With the sero(onin sdccriltle reuptllce inhibitor Cllrric frchlalry 1996 57449-15-1

12 Altshul U Pi=JM WUShing we Ames DScruaJine and akailiisiL I aln Psychopbarmacoll99414278-279

D IlonnetmiddotBrilluult F TItiWut P tepricLll A Petir M II eac of Paroxttine inducrd kl[hiSi2 md a revUew otSSRI induccd 1kalhiii Europ Psychlalry 1991l13 109-111

14 JUpcr S he p13Cl of lniliuclprnn in the tnItTI~m ufdepresSiOn HU11I

~cbopharmacol 199712Sl3S-141 15 B3ldwin D l11e Uemmcnt of rltCurrent

boa (1~pnsion Europem 0gtlI~ oj NeurOpycoopbarmacoiagp Meeting nncon Sept 241994

16 LiUy Memo n sUiCidesznd suidck 3Cmpts OltTo~r 1986 Forsyth Vgti Eli lilly Pwntiffi ethibit 73

17 He-ly D Guesl EditnritJ A F3ilurc (0 W1m n~mation11 Risk Saftty Ntlt (in p=)

18 ~ellui 1 von Knorring L (1999) Challi in prOl2lity trilis uuring (rGllmcm With =Ilne or cit2l0pr3n BriJishj Piychiatry 1744-448

19 CloninsCf CJ (19R7) I )ltcm~tic

Ilchod for cljniCll description 2nd dasilk1(iOIl tif pcnon2lity vuilnrs a JltUpc=INCb Centtrallgtycbimry 4457j-SSS __

20 Me Nair DM nrr M amp Drupplcmatl U(l988) M=utl (ot the ProfIle of MnocI 5= $m DiCRO Cili[ EcuCUiunaJ Inri IndusCriIJ Tring SetviClOi

21 WllSOu D CI~tk 1 amp TcJleru II (1988) The dcvcloplTlenr uuI YJliddtion nr brier llltuuICS o( ptLltilive ~nd mgaivc aff~

The PANAS SaJcj hgtr=nality 6- Sltxial Psycbolo$V HW6j-1070

22 B~ M Duhini A Polin V (1997) PlupmenT ~llcl vaJiduiO of a gtOd21 funCtiOning ~~le lhe i(gtct21 Adaptation 5cJ[-FvaIuuion S(lk European IIcllropycixJpbarnuuukJhY 7 ~uppl S7-~70

23 ClrveCS Whil n (1994) lkhJviorll inhibiijon bchilviurnJ 3CriVllliOn and lifCtivc rCpoHe to lmrcnding trWlfd 3nri ~uni-hrncm lhe RLilMS sc-uc J ~rgtOnality ant Xxlall5yclJoiagy 67319-333

PrUnu-y Care Psychiatry 2000 Vol 6 No 1

s--~ = o-~- - - -- - - -

~-

- - ---- -

than l volunteer who could disconshy(inut the drug that then might bav~ been an up to 50150 chance of a self hrm episode h3ppcning

A fln-al poillt of note about thiS Cil5e is that the suhject was awlre nfterwttd of perceptions mat the instibiltty she had shown on the drug would reflect on h(T She would be thought to middot be Ilnsrable rlther than to have had a drugmiddotinduatl instabiliry Both subjects felt this They are almost certainly accumte to

some exrcnr

Discussion

TIleslt cases which emerged in the courre of a blind contrblled study shed new light on the issue of drug induced suicidal ideatiOn Hitherro one of the arguments of the sceptics has been tliu depression leads to suishycidal ideation and against this backshyground it is difficult [Q make a causal connection between antidepre=t imake tnd suicidal ideation 125

The =mple of reserpine is of ~ interest here ReSErpine a psyshyj chorropic drug with RCT evidence of

mtidepressam cfficacy WJ) associshyated with an emergence of suicicJal ideltion and a number uf compkted suicides during the 19505 when il was widely used At the time it was argued chat it must he triggering a depressive disorder A recem reanalysis of (hoc early studies sugshyRestS rhltlt in fua it prEcipitated akathi~ia and this mmy have mcdishyared the suiodaJiry 1261 Of particular imeror is the fuel mat the probltITlS and $~Iicjdcs occurred in non-p$ychishyatrie patients being creued with reserpine fur hypertension permitshyting a SHang c~lIst1 claim to be made

In a recem he3lrhy volunteer study involving tlndumisation [l

droplt-ridol l()r17~p3m and placclJo we also wilnessed all emergence of suiddaJi(y lhat apPca(-d w be linked to agitation or akathliil 1271 This antidepfC5smt srudy provides support for the afpumcm that psycilmropic drugs in certain cirrumshyStances may induce ltl suidrlUiry thou would mherwise nut hl happened

The ctSes described in rnL5 paper appear to have bccome suidshydal on ~ertrJ1jne with no easy mons of cxplaining wha[ happened other

- than by invoking an SSRr-induced suicidality The mechanism through which this was mediatcti appear ro have been a combination of aknthisia and emotional blunting as well as other features suggestive of an amomatism_ The disinhibition reponed appears comparable to that reponed by Hoehn-Saric et al 2RJ on fluVOxarnIDE and fluClXetule To dare the phenomenology of what can happen has nor been explored ill any decaJl It is notable mat neither dnlg-induced depression nor drugmiddot induced akachisia experienced alone necessarily Jed to suicidaUry in this study Indeed in me case of the [wo volunteers who became suicidal they do not seem to have been depressed

One of the messages of the reSerpine stOry appear to have been [hat those who did not suffer from a p~ychiatric illness may have be~n at more risk from chis drug rhan others This hdthy volullteer study sugmiddot gests that individuals who are not frankly depressed may also be at incrc4ISed rL5k of drug-indllced problems compared [0 others Concomitan[ drug prescription may in middotfucr in nuny cases minimise the ri~ks Given that antidepressants arc commonly prescribed for stress relCshy

tion~ particularly when given alone chis point wnllld seem to be of some importance

References

I ni~her MIt Clod C ColeJO Erl1erJCn~e

of intense 5uiCithl prcoccu~tion (lun~ lluoXttine rtI(ment AmIrgtorhiafr)l 1910 H7207-110

L (jog RA Riddle MA Chappell rll H~din

Xl And=n GM Lumbrmn P F~cc of sdf-ltlc-rv~ti IhcnonlC-l in hildrltn U1ltJ dolcnr c1uritlll tluOlC~lin u=unC1i(j ~nj Aliltd CbildAdd Prycbialrv 1991 30171middot 1-6

3 Ct=ruy ~ MurrIy I Holy 0 Antidcpresgm induced suicidlll ideliun Hum lgtychopbarmacoll99l ltO329-33l

4 kolhschilcl N Lodltc (A nt~gtltpu U

nuctxetine uter ~cnou suiciltl 3CIltnlIL hy 3 patientS [he mle at 1lcuhisiaCin fsyltigti(lrTy 1991 52491-193

5 Wirshing we In Puntn T RoscnbagJ MLrdec $ Nnelaquo () HiclG-CrI) T Eluogttint aJcIlhlsia anU uicjdauly is there a UtusU conn~n Arch Grn Pltychlalry 1992 95lj(-5B1

6 Lane lW SSRlmiddotnduced =pyramicla1 sidlt 5= ~nd ikuhisil implications (of rtltWllcnrjJgtyrbophannacoll998 12192-214

7 Scttlc C Akathis~ ~nd scrtrgtJincJGin PsychlltlIry 1993 S~3Zl

8 Klce fl Kronig MH Clsc report of probiltble scrrraJinc indvced okuhli~ Am J PsycbiaJry 1993150 986-987

9 Kva m Drug induced aklthisi3 ~1Jhj=M experience and objecuve

Bndings Milil Med 1994159A10 to 1clorulJ) Scrtralille inducc(l ~lcjhiiL

J Cli JsyCbopbarmacol 199413219-220

1L Uo RJ Disordcfs associl1Cd With the sero(onin sdccriltle reuptllce inhibitor Cllrric frchlalry 1996 57449-15-1

12 Altshul U Pi=JM WUShing we Ames DScruaJine and akailiisiL I aln Psychopbarmacoll99414278-279

D IlonnetmiddotBrilluult F TItiWut P tepricLll A Petir M II eac of Paroxttine inducrd kl[hiSi2 md a revUew otSSRI induccd 1kalhiii Europ Psychlalry 1991l13 109-111

14 JUpcr S he p13Cl of lniliuclprnn in the tnItTI~m ufdepresSiOn HU11I

~cbopharmacol 199712Sl3S-141 15 B3ldwin D l11e Uemmcnt of rltCurrent

boa (1~pnsion Europem 0gtlI~ oj NeurOpycoopbarmacoiagp Meeting nncon Sept 241994

16 LiUy Memo n sUiCidesznd suidck 3Cmpts OltTo~r 1986 Forsyth Vgti Eli lilly Pwntiffi ethibit 73

17 He-ly D Guesl EditnritJ A F3ilurc (0 W1m n~mation11 Risk Saftty Ntlt (in p=)

18 ~ellui 1 von Knorring L (1999) Challi in prOl2lity trilis uuring (rGllmcm With =Ilne or cit2l0pr3n BriJishj Piychiatry 1744-448

19 CloninsCf CJ (19R7) I )ltcm~tic

Ilchod for cljniCll description 2nd dasilk1(iOIl tif pcnon2lity vuilnrs a JltUpc=INCb Centtrallgtycbimry 4457j-SSS __

20 Me Nair DM nrr M amp Drupplcmatl U(l988) M=utl (ot the ProfIle of MnocI 5= $m DiCRO Cili[ EcuCUiunaJ Inri IndusCriIJ Tring SetviClOi

21 WllSOu D CI~tk 1 amp TcJleru II (1988) The dcvcloplTlenr uuI YJliddtion nr brier llltuuICS o( ptLltilive ~nd mgaivc aff~

The PANAS SaJcj hgtr=nality 6- Sltxial Psycbolo$V HW6j-1070

22 B~ M Duhini A Polin V (1997) PlupmenT ~llcl vaJiduiO of a gtOd21 funCtiOning ~~le lhe i(gtct21 Adaptation 5cJ[-FvaIuuion S(lk European IIcllropycixJpbarnuuukJhY 7 ~uppl S7-~70

23 ClrveCS Whil n (1994) lkhJviorll inhibiijon bchilviurnJ 3CriVllliOn and lifCtivc rCpoHe to lmrcnding trWlfd 3nri ~uni-hrncm lhe RLilMS sc-uc J ~rgtOnality ant Xxlall5yclJoiagy 67319-333

PrUnu-y Care Psychiatry 2000 Vol 6 No 1

s--~ = o-~- - - -- - - -

~-

24 Joyce PR Mulder lIT Cloninger CR (19)1) 1Crnperuncnt prcCim clomipramine and dcriprunJne n=spatl5C

III maor depression] affeailll DsonitTS 3035-16

25 Holy D lanlffialClc C SaVgt M (1999) Suid~ in the COUlslt of the [rltlttmcm of depr=ionJPsycbopbarm~oIogy 13106-11L

26 HClly D Savage M (1998) Rotrpinc

EJchumeQ fJririsbJ Psycbiarry 172376-378

27 Healy D F2rquhu-G (1998) nle immcdQle effectS ofdropcriclol Human Pycbopharma~ Bl13-120

28 lioehn-Suc R LipseyJR Mdcod DR (199O) pithy lUld indlfferente in patientS on IllJVOlQmine lnd (luOXttine

J Oinical sycboplxrrmacology 10343--34S

middotjl----------------------------shyPrimary Care Psychiatry WOO Vol 6 No 1

l- _ _ __ 0 --~ shy