Analysis of Suicidality Data from Adult Antidepressant Trials Litigated by Law Firm Baum Hedlund December 13, 2006

Analysis of Suicidality Data from Adult Antidepressant TrialsPDAC Regarding the Results of FDA’s Ongoing Meta- analysis of Suicidality Data from Adult Antidepressant Trials Baum Hedlund client, Kim Witzcak, also testified at the FDA hearing. To: Psychopharmacologic Drugs Advisory Committee (PDAC) members December 1, 2006 For: December 13, 2006 Excerpts of Baum Hedlund’s Submitted Written CommentsFor the past decade and a half (since 1990), Baum Hedlund has represented more than 100 individuals across the country in suicide and suicide attempt cases involving SSRI antidepressants, including Paxil, Zoloft and Prozac. Through our litigation, we have obtained internal company documents to which no one else has access, not even the FDA. Almost all of these documents are labeled confidential by the drug companies. Generally speaking, the only time these documents become publicly available is when a case goes to trial (only 3 have gone to trial). Nevertheless, short of trial, we have fought the companies to get the documents out from under confidentiality seal by seeking court orders to release the documents or by getting the companies to concede that the documents should never have been designated as confidential to begin with. As a result, a number of documents are now available to the public (although too many remain hidden and secret). Internal Documents Show that German Regulators Would Not Approve Prozac Without Stronger Suicide Warning 20 Years Ago All of the Documents referenced in this submission can be found at ​Baum Hedlund’s SSRI Documents

Prozac TimelineAccording to documents obtained in litigation, as early as 1984, Germanregulators had expressed concerns about Prozac and an increased risk ofsuicidality:May 25, 1984internal memorandum from Eli Lilly and Company (“Lilly,” themaker of Prozac) regarding Lilly’s efforts to obtain registration of Prozac inGermany: “During the treatment with the preparation [fluoxetine] 16 suicideattempts were made, 2 of these with success. As patients with a risk ofsuicide were excluded from the studies, it is probable that this high proportioncan be attributed to an action of the preparation in the sence (sic) of andeterioration of the clinical condition, which reached its lowest point.”(VIEW FULL DOCUMENT)











June 26, 1984​, item # 10: “The BGA [German equivalent of FDA] suspects fluoxetine [Prozac] to be a stimulating/activating drug (side-effect profile, suicides, suicide attempts).” Item # 14 states: “This is a very serious issue in the opinion of the BGA. It might well be that we will have to recommend concomitant tranquilizer intake for the first 2 or 3 weeks in the package literature.” (​VIEW FULL DOCUMENT​)







January 29, 1985 ​states: “Two major concerns seem to be the reason that the registration was not accepted,” “efficacy questioned” and “suicidal risk.” (​VIEW FULL DOCUMENT​)





February 26, 1985states: “The use of the preparations seemsobjectionable, as the increase in agitating effect occurs earlier than themood elevating effect and therefore an increased risk of suicide exists.”(VIEW FULL DOCUMENT)





April 1, 1986 ​memorandum, under a discussion of safety issues: “Still not resolved is the fact that suicide attempts have been observed more frequently on fluoxetine as compared to imipramine. According to the today’s knowledge [fluoxetine’s “favourable” side effect spectrum] is negatively affected by the increased suicidal risk.” (​VIEW FULL DOCUMENT​)









August 30, 1989, Additional Feedback Regarding the FluoxetineReview by Commission A (an expert working/consultant group toBGA), Item 3 states: “The counterindication because of acutesuicidality should become a warning whereby the physicians should beadvised that in the absence of sedation, the risk of higher suicidalityshould be taken into account.”(VIEW FULL DOCUMENT)





1985: FDA Safety Officer Recognized Dangerous Side Effect Profile According to FDA’s March 1985 Safety Review of Prozac, conducted by Dr. Richard Kapit: “It is fluoxetine’s particular profile of side effects which may perhaps, in the future, give rise to the greatest clinical liabilities in the use of this medication to treat depression.” (​VIEW FULL DOCUMENT​)















Under “Catastrophic and Serious Events,” Dr. Kapit noted: “… 52 cases were [] subjected to review of case reports on microfiche. Certain additional adverse events, ​not reported by the Company​, which were revealed on microfiche, are also included in this tabulation. In most cases, these adverse events involved the onset of an unreported psychotic episode.​” (​VIEW FULL DOCUMENT​)



Dr. Kapit explained: “[F]luoxetine’s profile of adverse effects more closely resembles that of a stimulant drug than one that causes ​ ​sedation and gain of weight,” therefore, “fluoxetine treatment might, ​ ​at least temporarily, make their illness worse.” ​ ​(​VIEW FULL DOCUMENT​)



1991 – FDA’s Failure to Take ActionNotwithstanding the German government’s recognition in themid-1980’s of an increased risk of suicidality and Dr. Kapit’s concernover Prozac’s side effect profile, the public concern over the risk ofantidepressant-induced suicidality did not emerge until 1990 whentwo prominent Harvard psychiatrists, Drs. Martin Teicher andJonathan Cole, published a study entitled “Emergence of IntenseSuicidal Preoccupation During Fluoxetine [Prozac] Treatment.” Fromtheir personal observations of patients taking Prozac, Drs. Teicherand Cole, after first noting that four of the six patients referenced intheir study experienced akathisia (a condition marked by profoundinner restlessness and agitation), found that “persistent, obsessive,and violent suicidal thoughts emerged in a small minority of patientstreated with fluoxetine.”(VIEW FULL DOCUMENT)

EmergenceofIntenseSuicidalPreoccupationDuringFluoxetineTreatmentMartin H.Teicher,M.D., Ph.D., CarolGlod, R.N., M.S.C.S., and JonathanO.Cole, M.D. Sixdepressedpatientsfreeofrecentserioussuicidalideationdevelopedintense,violentsuicidalpreoccupa-tionafter2—7 weeksoffluoxetinetreatment.Thisstatepersistedforaslittleas3daystoaslongas3monthsafterdiscontinuationoffluoxetine. Noneofthesepa-tientshadeverexperiencedasimilarstateduringtreat-mentwithanyotherpsychotropicdrug.(AmJPsychiatry1990;147:207-210)Antidepressantsoccasionallypromotesuicidalac-tionsinseverelydepressed-patientsbyenhancingdriveandcounteractingpsychomotorretardation(1).However,standardantidepressantsarenotknowntoinducesevereandpersistentsuicidalideationinde-pressedpatientsfreeofsuchthoughtsbeforetreat-ment.Wehaverecentlyobservedseveralcomplexpa-tientswhoappeartohavehadseriousparadoxicalresponsestofluoxetinethatwerecharacterizedbyin-tense, violentsuicidalthoughts.CASEREPORTSCase1. Ms. A,a62-year-oldwoman,hada17-yearhis-toryofmajordepressionwithmelancholia.Previouslyshehad been cheerful, outgoing, and successfulin herprofession.She had noevidence of personalitydisorder butoccasionallyabused alcohol. Previous treatmenttrials had includedmostavailabletricyclicantidepressants,phenelzine,tranylcypro-mine, trazodone, alprazolam,carbamazepine, lithium,meth-ylphenidate, and five investigationalcompounds. Ms. A had had a moderate response toa courseof ECT and toa trial of amoxapine, but the benefits were short lived. Hersymptomsincludedfatigue, lethargy, hypersomnia, psychomotorretar-Received Jan. 17, 1989; revision received July 17,1989; accepted July 26,1989. From the Department of Psychiatry, Harvard Medical School, the Hail Mercer Snider Programin DevelopmentalBiopsy-chiatry,theMailmanLaboratoriesforPsychiatricResearch,theAdultOutpatientClinic,andtheAffectiveDiseaseProgram,McLeanHospital.AddressreprintrequeststoDr.Teicher,HallMercerSniderPrograminDevelopmentalBiopsychiatry,McLeanHospital, Belmont,\"MA 02178. Supportedin partby NIMHgrantMH-43743andbyfundingfromthe Hall Mercer Foundationand the Snider Family. The authors thank Ross Baldessarini, M.D., for his comments and criticisms. Copyright © 1990 American Psychiatric Association. dation,anhedonia,guilt,andoccasionalpassivesuicidalthoughtswithoutanysuicideartempts.Beforetreatmentwith, fluoxetine,Ms.Ahadreceivedasecondtrialofamoxapine,withlorazepamandtemazepamavailable for sedation. Aftera 4-week medication-freeperiodand witha baseline score on the Hamiltondepressionratingscale(2)of23,shewasenrolledinatherapeuticstudyoffluoxetine.Shereceived 20nig/dayin thefirsr week, 40mg/day on days8—10, and60 mg/day thereafter.Gnday11 she begantoexperienceforcedobsessionalsuicidalthoughtsconsistingofintenseandincessant wishes tokill herselfanddescribedbyMs.Aas\"uniquelybad.\"Thisledtosuchsignificantanxiety,fear,andturbulence thatshe felt\"deathwould be a welcomeresult.\"She alsofelt like \"jumpingoutofherskin\"buthadnosignsofmotorrestlessness.HerdepressivesymptomsandHamiltondepressionscorere-mainedthe same, exceptforthese intolerableforcedsuicidalthoughts. Fluoxetine treatment was discontinued, and after3daystheintensityandobsessionalqualityofhersuicidalthoughtsabated.Case 2. Mr.B, a 39-year-oldsuccessfulprofessionalman,hada 21-yearhistoryofdysthymiaandepisodicmajorde-pression, but no previous suicidal ideation. He hadmanagedsuccessfullywithpsychotherapyuntil2 years ago, whenhisdepressionworsenedafteradivorceandamedicationtrialwasinitiated.Isocarboxazid(50mg/day)enhancedhis.en-ergy,mood,andself-confidenceanddiminishedhisangerandirritability.Six months later rolerance emerged andMr.Bdevelopedhyperphagia,anergia,poorconcentration,di-minishedlibido,andpassivesuicidalthoughts.Aftera2-weekwashout,fluoxetinewasinitiatedatadoseof20mgevery otherdayfor7days, thendaily. OnemonthlaterhisHamiltondepressionscorewas32andhehadseveralnewcomplaints, including anxious unproduaiveenergy,nausea,severe lossofappetite, andabulia. Mostalarming, however, was the emergence of nearly constant suicidal preoccupation, violentself-destructivefantasies,and Mr.B's resignationtothe inevitabilityof suicide. This was sucha dramaticchangein his behavior and attitude that both his elderly motherandhis formerwifemade emergency telephonecalls to his treat-ers because they were worried about his risk for suicide. Two weeksoflirhiumpotentiation(600mg/day)enhancedhisenergyslightly,butheremainedintenselysuicidal,sobothagents were discontinued. During the next 3 months, trials of imipramine,doxepin,andmerhylphenidateprovidedlittlerelief, and Mr.B's intense suicidal thoughts persisted until2weeksaftertreatmentwithtranylcyprominewasinitiated.Despite ongoing depression and a Hamiltondepression score of16, all tracesof active suicidalideationvanished.AmJPsychiatry147:2,February1990207

SUICIDAL PREOCCUPATIONAND FLUOXETINE Case 3.Ms.C,a19-year-oldcollegefreshman,washos-pitalizedforthefirsttimewithsymptomsofdepression,paranoia,bulimia,agoraphobia,and dissociation. She had.a historyofmildsuicidalgesturesthathadbeenmanagedwithout hospitalization.Pastmedicationsincludedhaloper-idol andtrifluoperazine,whichalleviatedthe paranoia(butledtosubstantialextrapyramidalsideeffects),andimipra-mine, which relievedherdepression.InthehospitalMs.Cexperiencedoccasionalsuicidalthoughts but had noactive plan or intent. Perphenazine(4—12mg/day)alleviatedher paranoiaandenabledhertosus-tain meaningfulrelationshipsand to obtain employmentaf-ter3months.However,depressionemergedandtreatmentwithtranylcypromine(20—30mg/day)wasinitiated,butitwas discontinued because of orthostatic hypotension. Passive suicidal ideation reemerged, along with irritability, hopeless-ness, andincreasedpurging.Two weeks later, fluoxetine(20 mg/day) was added totheperphenazine(12-20mg/day). During the next 2 weeks Ms. C becamemore paranoid,depressed,andirritable,andshedevelopeddisturbingself-destructivethoughtsbut noactivesuicidality. The fluoxetinedose was increased to 40mg/day,andthe perphenazinedose wasloweredfrom20to16 mg/ daybecauseofworseningakathisia.After3weeksMs.Cimpulsivelyranawayandsuperficiallyscratchedherfore-arms.Overthe nextweekshebecamemoredepressedand-- preoccupiedwith thoughtsof death. After1 monthoftreat-ment, the dose of fluoxetine was increased to 60 mg/day. She then sufferedfromhypersomnia, poor concentration,diurnalvariation,anhedonia,anergy,fatigue,and increasedbingingandpurging.Duringweek5sheescapedfromthehospitaland plannedtocommitsuicide, but she was locatedby hos-pital security staff. Afterthe fluoxetinedose wasincreasedto80mg/dayshe becameviolent,banging herheadandmuti-lating herself, and physical restraint was necessary. Although lithiumcarbonateaugmentationwasbrieflyattempted,flu-oxetine treatment was discontinuedaftera totalof6 weeks. DuringthenextweekMs.Claceratedherforearmsandrequiredemergencyroomtreatment.Althoughlesslabile,she remainedextremelysuicidalandrequiredrestraintperi-odically.Heractiveself-destructiveurgesabated1monthafterfluoxetinetreatmentwasstopped,althoughintermit-tent suicidal ideation persisted. Improvement continuedoverthe next 2 months with perphenazine treatment(32 mg/day), although Ms. C scratched her armsafterlearningof the sale of her family home. Nortriptyline was added to her regimen, and over the next month she had no furthersuicidal ideas or intention.Herabilitytofunctionmarkedlyimproved,andshe was discharged 3monthsafterfluoxetinetreatmentwasdiscontinued. Case 4. Ms. D,a 39-year-oldformerexecutive, hada his-toryofrecurrentmajordepression,episodicalcoholabuse(inremission),andborderlinepersonalitydisorder.Duringthelast8yearsshereceivedaggressivepharmacologicaltreatmentwithlittlebenefit.Trialsofmonoamineoxidaseinhibitors(MAOIs) were moderately successfulbut were ac-companiedbyintolerablesideeffects,andECTproducedmarked but short-lived improvement. Ms. D hadbeeninter-mittentlysuicidalandhadtakendrugoverdosesonthreeoccasions while enraged. However,each suicide attempt, al-though serious, was a direct request for help, and her suicidal .statedissipated rapidlyafterhospitalization.Before treatment withfluoxetine, Ms. D hadrelapsedintomajor depression aftera transient recovery that hadfolloweddiscontinuationofnortriptylinetreatment.Hersymptoms208 includedhypersomnia,socialwithdrawal,irritability,andpsychomotorretardation,withoutsuicidalideation.Fluox-etinetreatmentwasstartedatadoseof20mg/day.Twoweeks later, Ms. Dwas more depressedand wasexperienc-ingextremefatigue,daytimesedation,andpersistentnega-tive thoughts that progressed to intense suicidal ideation. For thefirsttimeshecontemplatedobtainingaguntocommitsuicide. Her treatment was also complicated by the develop-mentofatruncalerythematouspruriticrash,whichwasinitiallytreatedwithdexamethasone, thenterfenadine.Thefluoxetinedose was gradually increased to60mg/day over2months. She began to think fluoxetine was a\"deadlydrug,\"and she developed a strong desire todrink. Despite her poor response,shewishedtocontinuetakingfluoxetine,assheknewofotherpatientswhohadrespondedtoitonlyaftermonthsoftreatment.By her thirdmonthof treatment,ata doseof80mg/day,Ms.Dremainedprofoundlydepressed.Anger,frustration,andpersistentsuicidal ideationpredominated.After5yearsofsobriety,shedrank.Fluoxetinetreatmentwasdiscontin-ued,buthersymptomsintensifiedandailminated2weekslaterinasecretsuicide attemptinvolving diazepamandal-cohol.Incontrasttoherpriorattempts,whenshe hadim-mediatelycalledforhelp,shewasdiscoveredbyhersisteronly whenhertelephonewent unanswered.Inthehospital,she disclosedthefullextentof her self-destructivethoughts.Theyincludedsevere suicidalruminations,dissociativefeel-ings,andthebeliefthatshecould notfightorcontrolhersuicidal impulses.She believed thatfluoxetinewouldenableher to successfullycommit suicide, and she hid thisinforma-tionfromothers.Inthehospital,Ms. D'sprofounddistressandagitationwerepartiallyrelievedbychlorprothixene,aneurolepticwith prominentserotonin antagonisteffects(3). Hersuicidalthoughts diminished over 3 weeks, but profoundfatigueandpsychomotor retardationreturned. Eight weeks after the dis-continuationoffluoxetinetreatment,tranylcyprominewasaddedtothechlorprothixene,herresidualsuicidalideationremitted,andshe improvedsufficientlyto bedischarged.Case 5.Ms.E,a 39-year-oldwomanwithmajordepres-sion,borderlinepersonalitydisorder, andtemporallobe ep-ilepsy,hadbeensuccessfullytreatedwithMAOIs,carba-mazepine(1200mg/day),andclonazepam(0.5mgeveryother day). Persistent suicidal thoughts predatedpharmaco-logical treatment but had been absent for at least 2 years. She had never madeany suicide attempts. Unfortunately,MAOItherapywascomplicatedbyweightgainandvirtualanor-gasmia. Fluoxetine was substitutedforisocarboxazidafterawashout periodof2 weeks; the initialdose was 20mg/day,which was increased after 3 weeks to 40 mg/day. During this rimeMs.Ewasdepressed,apathetic,fatigued,andhyper-somnolent.Suicidalthoughtsreemergedafteryearsoftheirabsence. Pemoline(37.5 mg/day)wasaddedtoincreaseherenergy, but the suicidal ideation worsenedand she begantofantasizeaboutpurchasinga gunforthefirst time. Theflu-oxetinedosewasincreasedto60mg/day in the sixthweekand to80 mg/day in the eighth week. Ms. E then complained ofprominentdissociativesymptoms,sedation,andabulia.Fluoxetinetreatmentwasdiscontinued,andmethylpheni-date(5 mg/day)was substitutedfor the pemoline. Although Ms.Efeltlessdepressed,hersevereobsessivesuicidalthoughtscontinued.In contrasttoher past experiencewithsuicidalfeelings,she nowembracedtheseimpulses andhidthemfromtheclinicians.She checkedthePhysician'sDesk,Referencetoseeifany\" of her medicationswereparticularly/AmJPsychiatry147:2,February1.

TEICHER, GLOD, ANDCOLEleriial, and she repeatedly poured out her pills and struggled over takingthem.Elevendaysafterdiscontinuationofflu-oxetine, hersuicidal thoughts diminished, but she remained quitedepressed.Isocarboxazidtreatmentwasresumed6weeks later, andafter month her energy, sociability, work 1performance, and mood were substantially improved and she had no moresuicidal thoughts. Case 6.Ms.F,a30-year-oldwoman,hadahistoryofbipolar disorder, multiple personality disorder, pseudotumor cerebri, hypothyroidism secondary to propylthiouracil treat-ment,andanabnormalEECHerhistoryincludedthreesignificantsuicide gestures, the first atage 17 and the last 5 years ago. Intermittent suicidal thoughts had continueddur-ing the past 5 years. Past medicationtrials includedtricyclicantidepressants,whichwereoflittlebenefit,andMAOIs,whichled tosignificanttherapeutic responses. Withdailydosesofhaloperidol(4mg),carbamazepine(600 mg), clonidine(0.4mg), thyroxine(150n-g), acetazo-lamide (750 mg), and diazepam(40 mg), severe anxiety and depressionemerged,withself-loathing,anergy,fatigue,hopelessness,suicidalideation,andsocialwithdrawal.Flu-oxetine was added to her complex regimen, and the dose was gradually increased to 40 mg/day over 1 month. After Ms. F developedanerythematousrash,herfluoxetinedosewasdecreasedto20mg/day.Duringthisperiodherconditionworsened,withincreasedfeelingsofanxiety,dissociation,lethargy, and incapacity. A briefattempt to potentiate treat-ment by adding pemoline(18.75mg/day)wasunsuccessful.By week 7 she was severely depressed, detached, withdrawn, -resdess, and agitated; fluoxetine was discontinued. Two days later her internal personalities started shouting at her to com-mit suicide. During the next 2 weeks she remained depressed and had a Hamiltondepressionscoreof 28; hospitalization was recommended, but she declined. Herself-destructivenesscontinued to intensify;she planned a lethal overdose and put a loaded gun to her head. \"With family intervention and daily telephonecontact,shecontinuedinoutpatienttreatment.She remained depressed, anxious, and intensely suicidal for 1 month afterfluoxetine treatment was abandoned. The sever-ityofherself-destructivethoughtsandherneedtoactondiem thenabated.DISCUSSION Five depressedoutpatientsandone inpatient,19-62yearsofage,developedintensesuicidalthoughtsameanof 26days(range,12—50) afterinitiationof flu-oxetine treatment.This state wasmoreintense, obses-sive,andviolentthananythingtheypreviouslyhadexperienced.Onepatienthadnopriorsuicidalide-ation(case 2),andonlythreepatientshadevermadepreviousattempts(cases4and6) orgestures(case 3). These intenseself-destructivethoughtspersisted,andevenworsenedtemporarily,afterdiscontinuationoffluoxetinetreatment.Theyfadedinintensityanaver-ageof 27days(range,3-49)later,buttheydidnotfullyabateinmostpatientsuntilameanof87days(range,60—106days)aftercessationoftreatment.Four patients received relativelyhighdoses offluox-etine(60—80 mg/day),buttwopatientsreceivedonly20-40 mg/day. Two patients(cases1 and 2)developedAmJPsychiatry147:2,February1990suicidalideationwhilereceivingonlyfluoxetine.Theremainderweretakinga varietyof othermedications,whichincludedcarbamazepine(cases 5 and6), neuro-leptics(cases 3 and 6), benzodiazepines(cases Jand 6), andthyroxine(case6).Threepatientsalsoreceivedstimulanttrialstocombatfluoxetine-inducedanergia(cases 4-6), and lithium potentiation wasunsuccessfulintwopatientsaftersuicidalpreoccupationhademerged(cases2and3).AllpatientshadpreviouslybeentreatedwithMAOIs,andforthree(cases2,3,and5),an MAOIhadbeenthelasttreatmentbeforefluoxetine.ResumptionofMAOItreatment(afteratleast a6-weekfluoxetinewashout period) appearedtoresult in rapid abatementof persistent suicidal ideation indiethreecasesinwhichthiswastried(cases2,4,and5).In no case was thereevidence that strongpreexistingself-destructiveurgeswereactivatedandenergizedbyfluoxetine. No patient was actively suicidal at thetimefluoxetinetreatmentbegan.Rather,allwerehopefulandoptimistic,andthestrongobsessivesuicidalthoughtsapparentlyemergeddenovoafterweeksormonthsof treatment. Infourpatients(cases2and4—6), these thoughtswereaccompaniedbyabjectaccep-tanceanddetachment.Twopatients(cases4and5)tried to conceal their suicidal feelings and impulses and tocontinuefluoxetinetreatment,believingthatthedrug wouldeventuallyenable themtosuccessfullykillthemselves!•A great deal has been writtenon the possible roleofserotonininviolence,suicide,andobsessivebehavior(4—7),andfluoxetineisknowntobeapotentandselectiveserotonergicuptakeinhibitor(8,9).Giventhisbackground,wewereespeciallysurprisedtowit-nesstheemergenceofintense,obsessive,andviolentsuicidalthoughtsinthesepatients.Theirsuicidalthoughtsappeartohavebeenobsessive,astheywererecurrent,persistent,andintrusive.Theyemergedwithout reason but were the patients' own thoughts. It was also remarkable howviolentthese thoughts were. Twopatientsfantasized,forthefirst time,aboutkill-ingthemselveswithagun(cases4and5),andonepatient(case6)actuallyplacedaloadedgunto- her head.One patient(case 3)neededtobe physicallyre-strained to prevent self-mutilation.Patient 2, whohadhad no prior suicidal thoughts, fantasizedabout killing himselfinagasexplosionoracarcrash.Serotoninmay. wellbe relatedtoviolentsuicidalideationorac-tionandtoobsessionalthinking,buttherelationshipmay be complexandfluoxetinemayexertaparadox-ical responsein somepatients.Itisalwaysdifficulttoknowwhetheruntowardef-fectsthatemergeduringpharmacologicaltreatmentare a consequenceofdrug treatmentorarecoinciden-tal.Alternativeexplanationsshouldalsobeconsid-ered. Suicidal thoughtsmay have emerged in these pa-tientsbecausethey were notresponding tofluoxetine;theirunderlyingdepressionmayhaveworsenedandledtotheirsuicidalstates.Thisisnotacompellingargument.Patientl'sHamiltondepressionscorere-209

SUICIDAL PREOCCUPATIONANDFLUOXETINEmainedthe same, and patient5 mayhave hada slight initialantidepressantresponse.Patients2and4arepresentlyfreefromactivesuicidalideationeventhough they are depressed, and all of these patients had beendepressedpreviouslybuthadneverbeenso vio-lentlysuicidal.Second,itispossiblethatsuicidalthoughtsemergedforreasonsunrelatedtofluoxetinetreatment(e.g., loss or abandonment), although no ev-idencecouldbefoundtosupportthisalternative.Infact,nopatientwasabletoarticulateareasonforfeeling so suicidal. Third, it is possible that otherphar-macological factorsorinteractionsmayhavebeenin-volved.Mostpatientswerereceivingtreatmentwithotherdrugsthatcouldhavealsocontributedtothisresponse,althoughthey werefreefromactivesuicidalthoughtswhiletakingthesedrugsbeforefluoxetinetreatment.Fluoxetinecanmarkedlyalterthemetabo-lismofconcomitandyadministeredmedications(8),anddruginteractionsmaybeanimportantfactor.Similarly, their previous histories of treatment with tri-cyclic antidepressants, MAOIs, or neuroleptics may be relevantriskfactors.There is nosimple explanationof why these patients seemedtoreactsoadversely, tofluoxetine.Itisnote-worthy thattheyall had hypersomnia,fatigue, or psy-chomotor retardationbefore or during treatmentwithfluoxetine. Fourpatientsalso complainedofa disturb-ing sense'ofinnerrestlessness, andtheymay have had aformofakathisia(cases1—3 and6), whichcouldbeacontributingfactor.Noneofthepatientshadaprominenttherapeuticresponsetofluoxetine,andwehave not observed the emergence of suicidalideationinany patient whowasclearlybenefitingfromthisdrug.At the presenttime we can only state thatpersistent,obsessive,andviolentsuicidalthoughtsemergedinasmall minorityof patients treated withfluoxetine.Flu-oxetine wasthesole pharmacologicagentinonlytwocases; the otherpatients were takinga varietyofothermedications,whichmayhavealsocontributedtothisreactionandtherebycomplicateinterpretation.Thepurposeofthisreportis tosuggestthe surprisingpos-sibilitythatfluoxetinemay inducesuicidalideationinsome patients. Only additionalsurveillance willenableus tolearnwhetherthisisa widespreadorvalidcon-cern.Inourownexperience,thissideeffecthasoc-210 ••4 \" curredin 3.5%of patientsreceivingfluoxetine,which ' providesanestimatedincidenceof1.3%—7.5%with-95%confidencelimits.Cliniciansshouldbealertto ' thispossibilityandshouldquerypatientscarefully'aboutsuicidalideation, particularlyif theyare not re-•spondingwell totreatment.Recently we havestartedto inform patientsof this risk and have toldthemthatthismedicationdoes notalwayswork,thatsomepa-tientsfeelworse,andthatafewhavedevelopedsui-cidalthoughts.Theyareinstructedtocalliftheyde-velopsideeffectsorstarttofeelworse.At the present time we recommendthat this drug be usedcautiouslyandthatthepractitionerbeattentivetothe possible emergenceofsuicidal ideation,even in thosepatientswithoutaprevioushistoryofsuicidalthoughts or actions. Patients who have previously been treated withotherantidepressantsorwhodevelopin-tense fatigue, hypersomnia, or restlessness while taking fluoxetinemaybe atrisk.REFERENCES.1.FeuersteinTJ, JackischR:Whydosomeantidepressantspro-motesuicide?(letter). Psychopharmacology(Berlin)1980; 90: 422.2.Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry1960;23:56-623.wanderTJ, NelsonA,OkazakiH,et al:Antagonismbyneu-rolepticsof serotonin 5-HT1Aand J-HT2receptorsofnormalhuman brainin vitro. Eur JPharmacol1987;143:279-2824.Traksman L, Asberg M, Bertilsson L, et al: Monoamine metab-olites in CSF and suicidal behavior. Arch Gen Psvchiatry 1981; 38:631-636 5.MannJJ,StanleyM,McBridePA,et al:Increasedserotonin2arid p-adrenergic receptor binding in the frontalcorticesof sui-cide victims. ArchGenPsychiatry1986;43:954-9596.Insel TR, MurphyDL, CohenRM, et al:Obsessive-compulsivedisorder:adouble-blindtrialofclomipramineandclorgyline.ArchGen Psychiatry 1983; 40:605-612 7.Perse TL, Greist JH, Jefferson JW, et al: Fluvoxamine treatment ofobsessive-compulsivedisorder.Am JPsychiatrv1987;144:1543-1548 8.BenfieldP, Heel RC, Lewis SP: Fluoxetine: a review of its phar-macodynamic and pharmacokinetic properties, andtherapeuticefficacyin depressive illness. Drugs1986;32:481-5089.WongDT,BymasterFP:Subsensitivityofserotoninreceptorsafterlong-termtreatment withfluoxetine.Res CommunChemPathol Pharmacoll981;32:41-51AmJPsychiatry147:2,February1990

The FDA thereafter assembled a group of psychiatrists to serve on its PDAC to discuss the issue. The advisory committee meeting took place on September 20, 1991. Lilly assigned Dr. Gary Tollefson to testify at the September 1991PDAC. According to his November 16, 1994 testimony in the Prozac case, Fentress v. Shea et al., Case No. 90-CI-06033, he did not disclose to the FDA the fact that the issue had been raised by the German government in 1984/1985. Dr. Tollefson testified: Q​.Doctor [Tollefson], to back up a little bit, earlier you said . that the first time the issue of using Prozac and the incidence of suicide was raised [was] in 1990 by Doctor Teicher’s article; correct? A​. It was the first time that I was aware of the issue having arisen at that time. Q​. Okay. So let’s make sure we’re clear on this. That issue was raised by the German government back in 1984; correct? A​. I have heard that indication, yes. * * * Q​. Were you aware in 1991, when you testified before the PDAC, that Lilly had in fact hired experts back in 1985 and 1986 to look at [the suicide] issue with regards to the German government? A​. I had heard that there were some individuals that have consulted previously with Lilly on those issues but did not know specifically whether it was related to the BGA or the issue in general. Q​. Okay. Did you tell the PDAC in 1991, that Lilly had previously – and I’m talking about prior to Doctor Teicher raising the issue, that Lilly had previously hired experts to look at the issue of increased suicide and the use of Prozac? A​. I think as part of the presentation it was made clear that a very thorough and comprehensive analysis of the worldwide data on suicide and Prozac had been made. * * * Q​. Let’s try it one more time. Specifically, did you tell the PDAC that prior to 1990, when the German government raised this issue, that Lilly hired experts to investigate the issue of increased suicide and the use of Prozac, yes or no? A​. That was not a question I was asked by the PDAC, so I did not answer that question. Q​. Did you volunteer it? A​. No. * * * Q​. Did you inform the committee that there was a package insert in use in Germany, on the day of the advisory committee, that recommended the use of sedatives in people who were suicidal or agitated on Prozac? A​. That was not one of the points of discussion. Q​. The answer is you didn’t; right? A​. Again, I did not feel there would be any reason. (Testimony of Dr. Gary Tollefson, transcript, p. 111:9-25; 114:10-115:15; 118:2- 119:2: VIEW FULL DOCUMENT​)

1 1 NO. 90-CI-06033 JEFFERSON CIRCUIT COURT DIVISION ONE 2 3 4 JOYCE FENTRESS, et al PLAINTIFFS 5 6 VS TRANSCRIPT_OF_THE_PROCEEDINGS __________ __ ___ ___________ 7 8 9 SHEA COMMUNICATIONS, et al DEFENDANTS 10 11 * * * 12 13 14 WEDNESDAY, NOVEMBER 16, 1994 15 VOLUME XXXVII 16 17 * * * 18 19 20 21 _____________________________________________________________ REPORTER: JULIA K. McBRIDE 22 Coulter, Shay, McBride & Rice 1221 Starks Building 23 455 South Fourth Avenue Louisville, Kentucky 40202 24 (502) 582-1627 FAX: (502) 587-6299 25

111 1 other placebo-controlled double-blind studies that were part 2 of the NDA. 3 Q. So other studies could have been done but they 4 just weren't part of the NDA? 5 A. That's possible. 6 Q. Okay. Let me show you what's been marked as 7 Plaintiffs' Exhibit 227. 8 I believe it's already been entered, Judge. 9 Doctor, to back up a little bit, earlier you 10 said when Mr. McGoldrick was asking you questions, that the 11 first time the issue of using Prozac and the incidence of 12 suicide was raised in 1990 by Doctor Teicher's article; 13 correct? 14 A. It was the first time that I was aware of the 15 issue having arisen at that time. 16 Q. Okay. So let's make sure we're clear on this. 17 That issue was raised by the German government back in 1984; 18 correct? 19 A. I have heard that indication, yes. 20 Q. Have you ever seen any information about the 21 BGA? 22 A. No, I had not; I have not. 23 Q. You have not still, even in your position at 24 Lilly now? 25 A. Correct.

114 1 A. Yes, ma'am. 2 Q. Okay. Were you personally aware that in 1984, 3 the German government raised the issue of an increased risk of 4 suicide and the use of Prozac? 5 A. No. I was not aware of that specific question 6 back in 1984. 7 Q. Okay. Did you inform the PDAC that the German 8 government had raised that issue back in 1984? 9 A. I did not. 10 Q. Were you aware in 1991, when you testified 11 before the PDAC, that Lilly had in fact hired experts back in 12 1985 and 1986 to look at this issue with regards to the German 13 government? 14 A. I had heard that there were some individuals 15 that have consulted previously with Lilly on those issues but 16 did not know specifically whether it was related to the BGA or 17 the issue in general. 18 Q. Okay. Did you tell the PDAC in 1991, that Lilly 19 had previously -- and I'm talking about prior to Doctor 20 Teicher raising the issue, that Lilly had previously hired 21 experts to look at the issue of increased suicide and the use 22 of Prozac? 23 A. I think as part of the presentation it was made 24 clear that a very thorough and comprehensive analysis of the 25 worldwide data on suicide and Prozac had been made. In fact,

115 1 I was personally aware of the analyses of the depression 2 studies both from the U. S. and those conducted overseas and, 3 in fact, when those data are combined in analysis, the numbers 4 are even more in the favor of Prozac than what I shared with 5 Mr. McGoldrick that was published in the British medical 6 journal. 7 Q. Let's try it one more time. Specifically, did 8 you tell the PDAC that prior to 1990, when the German 9 government raised this issue, that Lilly hired experts to 10 investigate the issue of increased suicide and the use of 11 Prozac, yes or no? 12 A. That was not a question I was asked by the PDAC, 13 so I did not answer that question. 14 Q. Did you volunteer it? 15 A. No. 16 Q. You talked about a lot of stuff and they didn't 17 ask you questions, didn't you? 18 A. No. I think everything I talked about was 19 relative to the question that the PDAC was addressing; that 20 is, is there any credible evidence. So we shared U. S., 21 O.U.S. data, depression, nondepressed patients, 10,000 22 patients; that's what they saw, that's what they deliberated 23 upon. 24 Q. You didn't think the fact that the BGA had 25 raised this issue back in 1984 and Lilly had investigated it

118 1 although I don't see any purpose in it. 2 Q. Did you inform the committee that there was a 3 package insert in use in Germany, on the day of the advisory 4 committee, that recommended the use of sedatives in people who 5 were suicidal or agitated on Prozac? 6 A. My recollection of that package insert was not a 7 recommendation to use a sedative, merely outlining that as a 8 possible addition to the therapeutic regimen of patients being 9 treated with fluoxetine. To me, that's quite different from a 10 recommendation to do. 11 Q. This, I think, says you may want to use a 12 sedative; correct? 13 A. You may. They were leaving it to the 14 clinician's discretion to determine if it was indicated or not 15 indicated. 16 Q. Did you tell the PDAC that in 1991, when you 17 were there for 45 minutes to an hour talking about how 18 wonderful this drug was and how it didn't cause anybody to 19 commit suicide or violent-aggressive behavior? 20 A. That was not one of the points of discussion. 21 Q. The answer is you didn't; right? 22 A. Again, I did not feel there would be any reason. 23 Q. How about concomitant medication use in the 24 clinical trials? Did you tell the PDAC members about that 25 when you were there?

FDA Officials Treat 1991 PDAC and Suicide Risk as a “Public Relations Problem” Through documents obtained in litigation, we learned that the FDA never took this issue seriously. According to a GlaxoSmithKline (GSK) memorandum dated October 3, 1990, the FDA believed the public controversy that had erupted concerning the potential for antidepressants to increase the risk of suicide in adults was, to the FDA, not “a real issue, but rather “a public relations problem.” The FDA’s Dr. Martin Brecher indicated to GSK that the FDA “does not think it is an issue, but it needs to be addressed.” (​VIEW FULL DOCUMENT​)