risk of suicidality in clinical trials of antidepressants in adults

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RESEARCH

Risk of suicidality in clinical trials of antidepressants inadults: analysis of proprietary data submitted to US Foodand Drug AdministrationMarc Stone, medical officer, Thomas Laughren, director, division of psychiatry products, M Lisa Jones,medical officer, Mark Levenson, mathematical statistician, P Chris Holland, mathematical statistician,Alice Hughes, associate director for safety, division of neurology products, Tarek A Hammad, associatedirector, division of epidemiology, Robert Temple, associate director for medical policy, George Rochestmathematical statistics team leader

ABST RACT

Objective To examine therisk of suicidalbehaviourwithinclinical trials of antidepressants in adults.Design Meta-analysis of 372 double blind randomisedplacebo controlled trials.Setting Drugdevelopment programmes for any indicationin adults.Participants 99 231 adults assigned to antidepressantsor placebo. Median age was 42 and 63.1% were women.Indications for treatment were major depression(45.6%),other depression (4.6%), other psychiatric disorders(27.6%), and non-psychiatric disorders (22.2%).Main outcome measures Suicidal behaviour (completedsuicide, attempted suicide, or preparatory acts) andideation.Results For participants with non-psychiatric indications,suicidal behaviour and ideation were extremely rare. For those with psychiatric indications, risk was associatedwith age. For suicidal behaviour or ideation and for suicidal behaviour only, the respective odds ratios were1.62 (95% confidence interval 0.97 to 2.71) and 2.30(1.04 to 5.09) for participants aged


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presentedto a joint meeting of twoFDAadvisorycom-mittees in 2004.4 It showed a relative risk for suicidalbehaviouror ideation of 1.95 (95% confidence interval1.28 to 2.98) for those treated with antidepressantscompared with those given placebo. The committeesrecommended that the FDA add a boxed warning to

antidepressant labelling (implemented early in 2005)and review clinical trials of antidepressants in adultsto look for similar effects. Two previous publishedmeta-analyses in adults did not have access to primarydata, could not validate the identification and classifi-cation of suicidal events, and had limited means toestablishboth theappropriatenessof theincludedtrialsandthe inclusionof allrelevant trials.5 6 Inaddition,theoutcomes considered were not comparable with thoseused in the FDA study of paediatric trials. We carriedouta reviewto respond to the committees requestandaddress limitations of the published meta-analyses.

METHODS

Data collectionTheFDAaskedeightindustrysponsorsof12marketedantidepressant products (bupropion, citalopram,duloxetine, escitalopram, fluoxetine, fluoxetine/olan-zapine (ultimately excluded from theanalysis), fluvox-amine, mirtazapine, nefazodone, paroxetine,sertraline, andvenlafaxine)fordatasets from alldoubleblind randomised placebo controlled trials of anti-depressant in adults for any indication.

The variables included in these datasets provideddetailed information about individual participants.Sponsors dataset submissions were received by the

FDA between September 2005 and September 2006as electronic files (in SAS transport file format).Data were requested from completed, double blind

randomised placebo controlled trials with at least 20participants in each treatment arm. Trials limited toknown drug responders, such as those using rando-mised withdrawal designs, were not included;such stu-dies do not examine the effects of initiating treatment and would eliminate as non-responders those whohadshown suicidality during drug treatment.

We asked sponsors to provide a list of all knowntrials, indicating which trials the sponsor planned toinclude and which they intended to exclude from the

dataset and why. We then provided feedback to thesponsors on which trials should be included in thefinal dataset. Sponsors summarised the characteristicsof the trials included in the datasets in the form of twotables: one providing the dose, duration, and numberof participants per trial, and the other providing thetrial exclusion criteria.

Other than dataset formats, instructions for identify-ing and classifying events possibly related to suicidality(suicidal thoughts and actions) and the event classifica-tion process, we did not specify whoor howcompaniesshould retrieve or compile the information werequested.Eachcompanyhasitsownsystemforarchiv-

ing andmaintaining its records of clinical studies. Theyare in thebest positionto judge theoptimalapproachto

completingthesetasks.Eachcompanydesignatedaperson to serve as the main contact with the FDA.

Adverse events in these trials were solicited by general inquiry andrecorded incase report forms.Follow-ing the approach used in the paediatric study,4

sponsors were asked to search their electronic data

bases for adverse events reported during the doubleblind phase of treatment for terms related to suicidality. Because it was difficult to determine whethevents represented a change in condition or resultedfrom a pre-existing condition, all events reported during the double blind phase were included. Events thaoccurred more than a day after the randomised treatment stopped were excluded.

Thedata requestletterasked sponsors to searchclin-ical trial databases forpreferredterms,verbatim termsand any comment fields for the following text string accident- , attempt , burn , cut , drown , gas , gun , hang , hung , immolat , injur- , jump ,

monoxide

,

mutilat-

,

overdos-

,

self damag-

, self harm , self inflict , self injur- , shoot , slash , suic- , poison , asphyxiation , suffoca-tion , firearm . All events identified by this searchwere considered as possibly related to suicidalityunless they were identified as false positive results:events that included any of these text strings but wernot related to suicidality. For example, epigastricpain would be identified in the search for the texstring gas. Sponsors submitted listings of the eventthey classified as false positives, which werereviewed by FDA staff.

Thedatasets included 406clinicaltrials with 103491

participants. Six trials were duplicated in the submissions. We excluded 28 other trials: 23 because at leasone trial arm contained fewer than 20 participantsthree because data at the patient level were not available, and two because the study drug was a combineantidepressant/antipsychotic. We also excluded parti-cipants assigned to a non-antidepressant activecontroldrug (608), leaving a totalof 372 trials with 99231 participants (fig 1). Most of the studies were unpublishethose that had been published in some form seldomcontained information concerning suicidality in thepublication. None of the studies was included in thprevious study of paediatric trials.

Determination of suicidality outcomesSponsors prepared case narratives for each event possibly related to suicidality (suicidal thoughts anactions). Details that might bias classification (such treatment assignment) were removed. Because of thlarge number of participants, the sponsors and not theFDA adjudicated events. Adjudicators, who werblinded to treatment assignment, classified eventusing the approach of Posner et al.7 Eventswere classi-fied into seven mutually exclusive categories: 1 completed suicide, 2 suicide attempt, 3 preparatory acttowards imminent suicidal behaviour, 4 suicidal idea

tion, 5 self injurious behaviour, intent unknown, 6 noenough information (fatal), and 7 not enough

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information (non-fatal). For participants with multipleevents,wecodedonlythemostsevereevent(forexam-ple, completedsuicide would be coded rather thansui-cide attempt if both had occurred).

Three individuals with appropriate training andexpertise independently rated events. Sponsorsengaged outside contractors experienced in themethod of Posner et al,7 either to conduct the rating process or to train the sponsor s staff. If the three raterswere not unanimous in their ratings, a discussionamong the raters, led by a fourth rater, was conductedwith the goal of achieving consensus. If consensus wasnot achieved, the event was rated as indeterminate(category 6 or 7).

Statistical analysis

The primary outcome was defined as suicidal ideation

or worse (categories 1, 2, 3, or 4). This corresponded tothe primary outcome (definitive suicidal behaviour/ideation) used in the FDA s paediatric analysis of sui-cidality. The second outcome variable, considered inparallel with the primary outcome, was preparatoryactions or worse (categories 1, 2, or 3), also calledsuici-dalbehaviour. Welookedat ideation alone for thesakeofcomparisonbutdidnotconsideritaclinicallyimpor-tant outcome becausethe categoryexcludes both thosewho had neither suicidal ideation nor behaviour andthose who had both. Because of the previous finding of increased suicidality with antidepressant use in chil-dren and adolescents, we considered findings within

the general outcomes of suicidal ideation or worseand suicidal behaviour or worse that would be

consistent with this observation in a set order. The pri-mary hypothesis for each outcome was that the out-come would be increased among all adults using antidepressants. The principal secondary hypothesis,contingent on rejection of the primary hypothesis,was that the subpopulation of adults most similar to

children and adolescents

that is, young adults(defined as age


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observation was 15505 person years. Table 2 showsthe numbers of participants by drug, drug class, andtreatment assignment. Table 3 shows the incidence

of suicidality by indication group. There were eight reported completed suicides, 134 reported suicideattempts, 10 reports of preparationswithout attemptedsuicide, and 378reported suicidal ideation alone that is, without any action. The incidence rates for suicidal-ity in those with major depression were higher than inthe other indication groups; incidence rates for otherdepressive disorders and psychiatric disorders otherthan depression were about two thirds of that formajor depression. The rates for non-psychiatric disor-ders were much lower than for psychiatric disordersand consisted almost entirely of suicidal ideationalone. For the psychiatric categories, the ratio of parti-

cipants with ideation only to participants whoattempted suicide was about three to one (360/133).In the non-psychiatric categories there were 18 casesof ideation alone but only one suicide attempt.

Estimates of risk of suicidality associated withantidepressant treatmentTable 4 shows the estimated odds ratios and risk dif-ferences for suicidal ideation or worse associated withassignment to antidepressant drug treatment com-pared with placebo. For the entire dataset, the oddsratio was 0.85 (95% confidence interval 0.71 to 1.02).The estimated odds ratio for preparatory acts or worse

was 1.12 (0.79 to 1.58). The odds ratio for completedsuicide (2.13) was higher for those treated with an

antidepressant, but this was based on just eight evenand was not significant (0.41 to 10.99).

Table 4 also compares risk of suicidality by indication. The psychiatric indication categories seemremarkably similar, while the non-psychiatric categories seem similar to each other but distinct from th

psychiatric categories.The differencebetween the psychiatric diagnoses and the non-psychiatric diagnoseshowever, was not significant (P = 0.25). As there werefew events in the non-psychiatric categories, an estmate combining observations across all categoriewould be largely determined by the events in psychiatric trials; it might be misleadingly applied to peoplwith non-psychiatric indications. Therefore, we havlimited further analyses presented to the 77207 participants in 295 clinical trials for psychiatric indication

Table 5 showstheodds ratiosand risk differences forsuicidality for antidepressant treatment in psychiatridisorders by drug and drug class. For the entire population with psychiatric disorders, there was a decreasin suicidality with treatment. Other statistical techniques showed nearly identical results. Statistical tesfor differences in effect among drugs and drug classehad negative results, with the exception of some indcationof differences among SSRIs.There was littledifference between older and newer drugs. The oddsratios for suicidal behaviour were slightly higher thathose observed for suicidality.

Estimatesofheterogeneityintreatmenteffectamongtrialsandofinteractionoftreatmenteffectwithstatusoa drug as test drug or active control, trial location, sexand ethnicity were all non-significant (P>0.35).

Table 1 |Demographic data for 99 231 people included inrandomised placebo controlled trials on antidepressants

Percentage*

Age (years):

Mean 43.1

Median (range) 42 (15-99)


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Table 6 and figure 2 showthe risks by age for suicid-ality associated with assignment to antidepressant treatment for adults with psychiatric disorders. Themost striking observation is the higher odds ratio andrisk difference with antidepressant treatment than withplacebo in those aged under 25 but lower odds ratioand risk difference in those aged 25 or older. Theremight also be a further distinction between a modest protective effect of antidepressants in people aged 25-

64 and a strongerprotectiveeffect in those aged65andolder.Whenwemodelledageasacontinuousvariable,the oddsratiodeclined at a rate of 2.6%per year ofage(3.9% to 1.3%, P = 0.001).

Table 6 also shows risks by age for suicidal ideationand suicidal behaviour. The decline in odds ratio andrisk difference with age for suicidal ideation alone wasrelatively slight; the differences between major agecategories were not significant (table 7), except whenwe modelled age as a continuous variable (change inodds ratio 1.8% per year of age, 3.3% to 0.4%,P = 0.014, table 8). For suicidal behaviour, with a smal-lernumberofevents,thedeclineinoddsratioswithageseems steeper and the differences between age cate-gories were more significant. When we modelled ageas a continuous variable, the odds ratio declined at a rateof4.6%peryearofage(7.4% to1.8%, P = 0.001).Table 9 shows the odds ratios and risk differences forsuicidality, suicidal ideation alone, and suicidal beha-viour broken down by age and indication category. Apattern of increase in both odds ratio and risk differ-ence with decreasing age is generally apparent acrossall outcomes and diagnostic categories. The largest increase in risk associated with antidepressants seemsto have been in those aged under 25 with psychiatricdisorders other than depression.

DISCUSSION

In contrast with the results of the review of paediatricstudies on suicide andantidepressants by the US Foodand DrugAdministration (FDA),4 pooledestimates forthe adult population did not show an increased risk of suicidality.When weanalysed results by age, however,wefoundanincreasedriskamongadultsagedunder25that approached the risk seen in children and adoles-cents. The net effect seems moderately protective for

adults aged 25-64 and more strongly protective inthose aged 65 and older. This age related gradient seemedsteeper forsuicidalbehaviourthan forideationalone.

Because the relation between antidepressant useandsuicidality seems to be age related, the overall result isprobably a consequence of the particular age distribu-tion of the participants in the study population. Thispopulation was not chosen to be representative of theage distribution of antidepressant users. If the popula-tion had skewed younger, the overall result wouldprobably have shown a higher risk; if the populationhad skewed older, the overall risk would probablyhave been lower. The overall estimates are thereforenot generalisable.

Strengths and limitations of this study

Our study has several features not present in most other systematic reviews. We were able to apply a uni-form approach to the detection of possible suiciderelated events across hundreds of studies and used a validated method with proved inter-rater reliabilityfor classification of events.

Thisstudydiffersinimportantwaysfrommostmeta-analyses, which rely on the published results of ana-lyses performed in individual studies and combines

Table 3 |Incidence of suicidal behaviour or ideation by indication group. Figures are numbers (percentages) of participants

Major depression Other depression Other psychiatric Behavioural All other Total

Completed suicide 6 (0.01) 0 2 (0.01) 0 0 8 (0.01)

Attempted, not completed 90 (0.20) 7 (0.15) 36 (0.13) 1 (0.01) 0 134 (0.14)

Preparation, no attempt 7 (0.02) 1 (0.02) 2 (0.01) 0 0 10 (0.01)

Ideation alone 238 (0.53) 14 (0.30) 108 (0.39) 8 (0.06) 10 (0.12) 378 (0.38)

Total 341 (0.76) 22 (0.47) 148 (0.54) 9 (0.07) 10 (0.12) 530 (0.54)

Table 4 |Suicidality risk for active drug relative to placebo (ideation or worse) in all adults by indication

Indication category

Drug Placebo

Odds ratio (95% CI), P value Risk difference/1000 (95% CI), P valueEvents Participants Event s Participants

All indications 326 63 327 204 35 904 0.85 (0.71 to 1.02), 0.08 0.87( 1.89 to 0.15), 0.10

Psychiatric indications:

All 314 50 043 197 27 164 0.83 (0.69 to 1.00), 0.05 1.28( 2.57 to 0.00), 0.05

Major depression 218 30 485 123 14 728 0.85 (0.67 to 1.07), 0.16 1.42( 3.23 to 0.40), 0.12

Other depression 13 2744 9 1863 0.90 (0.38 to 2.14), 0.81 0.15( 4.40 to 4.11), 0.95

Other 83 16 814 65 10 573 0.79 (0.56 to 1.11), 0.17 1.37( 3.33 to 0.59), 0.17

Non-psychiatric indications 12 13 284 7 8740 1.47 (0.57 to 3.79), 0.42 0.28 ( 0.50 to 1.05),0.48

Behavioural indications 6 8144 3 5218 1.43 (0.35 to 5.86), 0.62 0.16 ( 0.72 to 1.03),0.72

Other indications 6 5140 4 3522 1.51 (0.42 to 5.40), 0.53 0.38 ( 0.96 to 1.73),0.58

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them into a single estimate of effect. Our study, in con-trast, analysed the primary data from adverse event reports on individual subjects to identify suicidalityevents occurring within a collection of clinical trials.(Some of the trials included in the analysis were thebasis of articles published in peer reviewed journalsbut the question of suicidality was not considered inany detail by the authors or reviewers.) We analysedthe data as primary data even though we were not directly involved in the data collection. We believethat our approach provided a high level of assuranceas to the completeness and accuracy of the data. Fed-eral law requires that any research study of a drug that has not been licensed for sale in the US and that involves humans in the US must be reviewed inadvance by the FDA. This requirement is extendedto drugs already licensed for sale if the study in ques-tion is intended to support commercial use, such as a possible application for a new indication or changing information in the drug label about safety or efficacy.ThismeansthattheFDAhasarecordofvirtuallyeverycompanysupported clinical trialperformed on peoplein the US as well as reports of the results of those stu-

dies. In addition, anystudy performed entirely outsidethe US that provides information used in a licensing

application will also be reported. In many cases thstudy reports included the original datasets andadverse event reports. This provided us with an excellent reference source with which to confirm the accuracy and completeness of the submissions that werspecifically requested for our study. FurthermoreFDAstaff are experts on the clinical development pro-grammes for these drugs and were already familia

Table 5 |Suicidality risk for active drug relative to placebo (ideation or worse) in adults with psychiatric disorders by drug and drug class

Drug class

Drug Placebo

Odds ratio (95% CI), P value Risk difference/1000 (95% CI), P valueEvents Participants Events Participants

All drugs 314 50 043 197 27 164 0.83 (0.69 to 1.00), 0.05 1.28( 2.57 to 0.00), 0.05

Selective serotonin reuptake inhibitor:

All 205 31 440 141 21 225 0.86 (0.69 to 1.06), 0.16 0.60( 2.07 to 0.88), 0.43

Citalopram 24 2 661 7 1 371 2.11 (0.90 to 4.94), 0.09 4.05 ( 1.38 to 9.49), 0.14

Escitalopram 10 3 130 5 2 604 2.44 (0.90 to 6.63), 0.08 1.27 ( 1.38 to 3.93), 0.35

Fluoxetine 81 7 180 67 4 814 0.71 (0.52 to 0.99), 0.04 3.39( 7.61 to 0.82), 0.11

Fluvoxamine 22 2 187 13 1 828 1.25 (0.66 to 2.39), 0.49 3.13 ( 2.80 to 9.06), 0.30

Paroxetine 50 9 919 29 6 972 0.93 (0.62 to 1.42), 0.75 0.50 ( 1.56 to 2.55), 0.64

Sertraline 18 6 363 28 5 081 0.51 (0.29 to 0.91), 0.02 2.50( 4.99 to 0.01), 0.05

Serotonin-noradrenaline reuptake inhibitor:

All 54 7 920 48 5 364 0.81 (0.56 to 1.19), 0.28 2.45( 5.69 to 0.80), 0.14

Duloxetine 25 2 327 18 1 460 0.88 (0.47 to 1.63), 0.68 2.23( 9.11 to 4.65), 0.52

Venlafaxine 29 5 593 30 3 904 0.71 (0.44 to 1.16), 0.17 2.55( 6.02 to 0.92), 0.15

Other modern antidepressants:

All 27 6 511 24 4 225 0.83 (0.49 to 1.41), 0.49 1.18( 4.09 to 1.74), 0.43

Bupropion 7 2 659 4 1 800 1.35 (0.45 to 4.06), 0.59 0.50( 3.15 to 2.14), 0.71

Mirtazapine 8 1 016 6 644 0.97 (0.34 to 2.78), 0.96 0.02( 9.14 to 9.11), 1.00

Nefazodone 12 2 836 14 1 781 0.65 (0.30 to 1.41), 0.28 3.38( 8.36 to 1.61), 0.18

Tricyclicantidepressants:

All 27 4 023 39 3 941 0.71 (0.45 to 1.12), 0.14 3.98( 8.06 to 0.10), 0.06

Amitriptyline 0 625 1 627 0 (0 to ), 0.99 1.59( 4.72 to 1.54), 0.32

Clomipramine 5 632 12 617 0.49 (0.18 to 1.34), 0.17 11.48 ( 24.4 to 1.41),0.08

Desipramine 1 315 2 298 0.63 (0.06 to 6.25), 0.69 3.56 ( 14.76 to 7.64), 0.53

Dosulepin 0 106 1 95 0 (0 to ), 0.99 10.53 ( 31.0 to 1.00),0.32

Imipramine 21 2 345 23 2 304 0.88 (0.50 to 1.53), 0.64 2.38( 8.19 to 3.43), 0.42

Other antidepressants:

All 1 149 2 153 0.61 (0.06 to 5.95), 0.67 6.58( 29.6 to 16.4), 0.58

Mianserin 1 28 1 28 1.00 (0.06 to 16.8), 1.00 0 ( 97.2 to 97.2), 1.00

Trazodone 0 121 1 125 0 (0 to

), 0.99

9.03(

23.3 to 5.27), 0.22


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Results of other studiesSeveral case-control studies have addressed the ques-tion of a differential risk of antidepressant induced sui-cidalityacrossthe agespectrum.Olfsonetal found that antidepressant treatment was not associated with sui-cide attempts or suicide in severely depressed adults

requiring admission to hospital.10

In patients aged 6-18, however, there was a significant association withdrug treatment and both suicide attempts and com-pleted suicide. Martinez et al found no overall differ-ence in risk between SSRIs and tricyclicsbutdid find a suggestion of an increasedrisk of suicidality in patientsaged 18 andyounger.11 Juurlink et al found greater riskof suicide in patients treated with an SSRI comparedwith patients receiving other antidepressants only inthe first month of treatment.12 The case-control meth-ods used in these studies is subject to confounding notably, differential prescribing to patients perceivedto be sicker and at greater risk of suicidal behaviour.

Apart from the finding of age related risk, the resultsare consistent with published meta-analyses of clinicaltrials of SSRIs in adults conducted by Gunnell et al5

and Fergusson et al.6 Despite considerable differencesin theavailabilityof data, statisticalmethods, andevent classification, the odds ratios were remarkably similarto those we obtained in subsets of our data that weremost comparable with those used by these authors:odds ratios for SSRIs compared with placebo were0.855 versus0.86 (current study)for completedsuicide,1.295 versus1.25 fornon-fatal self harm, and 0.795 ver-sus 0.76 for suicidal ideation. For a comparison of SSRIs with tricyclics the odds ratios for fatal or non-

fatal suicide attempts were 0.886

versus 1.11 (current study).Numerous population based studies in recent years

have compared patterns of antidepressant prescribing and suicide rates.13 Studies in Finland, Sweden, Hun-gary, Australia, one study in Britain, and a Europe-wide study showed an inverse correlation betweenantidepressant use and suicide rates, but studies inItaly, Iceland, and Denmark did not show a relation.A study fromNorthern Ireland showedan inverse cor-relation in adults over age 30 but found no relationbetween antidepressant use and suicide in adults aged20-30.14 In England and Wales Gunnell et al found no

decrease in suicides among men aged 25-34, despite a small increase in antidepressant prescribing, but a

large reduction in suicide rates in adults over 60 thacorrelated with increased antidepressant use.15 In theUS, Gibbons et al looked at county-level suicide ratewith adjustments for age, sex, income, and race.16

There was no overall relation with antidepressant prescribing, but the prescribing of SSRIs and other newe

antidepressantswasassociated with lower suicide rateand tricyclicprescribing wasassociated with increasedsuicide rates. Grunebaum et al noted a fourfoldincrease in antidepressant prescribing coincident withan overall decrease in the suicide rate of 13.5% from1985 to 1999.17 Milane et al looked at fluoxetine pre-scribing between 1988 and 2002 and observed adecline in suicide rates since its introduction.18 Thefindings in non-US studies were generally similaThe ecological approach taken by these studies, however, does not allow causal conclusions. For exampleincreased use of SSRIs and lower suicide rates coulboth be consequences of economic prosperity ogreater availability of mental health services.

Explanations and implicationsSome have argued that an observed increase in suicidality with drug treatment could be the result of ascertainment bias: an increase in reporting of suicidalitrather than a true increase. This could occur if peoplwere so depressed that they could not articulate suicidal thoughts or report suicidal behaviour until reliewas obtained from drug treatment or if they reportedsuicidal thinking or behaviour only because they alssought medical attention for drug side effects. Thieffect would need to be greater than a similar bia

that could operate in the opposite direction: people ina placebo group who, because of lack of therapeutieffect, sought treatment for non-suicidal symptomand, when examined, disclosed suicidal symptoms awell. Our findings argue against this explanationAscertainment bias cannot easilyexplain the observedagerelatedness of the findingsor thestronger apparentincrease in suicidality in non-depressed psychiatripatients in the youngest age group than in depressepatients of the same age. It also cannot explain anapparently greater effect on promoting the reportingof suicidal behaviour than the reporting of suicidaideation.

The association of antidepressant treatment with anincreased risk of suicidality and suicidal behaviouseems paradoxical. If suicide is a response to thesymptoms of depression, treatments proved to reduce thessymptoms ought to reduce the risk of suicide. Oustudy suggests, however, that the relation between sucidality, age, and antidepressant treatment is generalisable beyond those with major depressive disorder to

Table 7 |Comparison of age specific risks for drug effect on suicidality

Age range Ratio (95% CI) P value Riskdifference/1000(95% CI) P value

Ideation or worse


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everyone with psychiatric diagnoses. These findingssupport the idea that antidepressant drugs can havetwo separate effects: an undesirable effect in somepatients that promotes suicidal ideation or suicidalbehaviour and a therapeutic effect in others that alle-viates depression and reduces any suicidal sequelaefrom depression. From the standpoint of clinical deci-sion making, the age dependent increase in suicidalitywould be considered a phenomenon separate fromtherapeutic effect and approached like any otheruncommon but serious adverse effect. Patients whose

illnessespose less risk ofsuicidal ideationorbehaviour,such as those without major depression, could haveless potential to benefit from any effect drug treatmentmight have on reducing suicidal sequelae but be littledifferent from patients with major depression in vul-nerability to adverse effects.

The possibility of separate therapeutic and adverseeffectsfromantidepressantdrugsonsuicideideationorbehaviour should be the subject of further research,particularly in terms of possible mechanisms for agerelated differences. Another possible topic for investi-gation would be differences among drugs. Althoughthis study did not show much evidence for differencesbetween antidepressant drugs in net effect on suicidalbehaviour or ideation, further investigation couldreveal whether some drugs cause relatively substantialincreases in both adverse and therapeutic effects whileother drugs have little effect on either.

When we presented these results at a meeting of thePsychopharmacologicDrugsAdvisoryCommitteein December 2006 [www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-fda.pdf], the committeeagreed with FDA s conclusions that the risk of suicid-ality associated with antidepressants in young adults(under 25) approached that seen in children and ado-lescents, that the net effect seemed to be neutral in

adults aged 25-65, and that the effect on suicidalitywas favourable in adults older than 65. They

Table 9 |Suicidality risk for active drug relative to placebo by age and diagnostic category

Diagnostic category

Age


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recommended that the FDAshouldexpand the suicid-ality warning language in labelling and in the medica-tion guide with this new information, including thestrong age relatedness of the findings. Because of con-cerns of a possible negative impact of the FDA s regu-latory actions on appropriate treatment of depression,

especially in younger patients, the committee alsorecommended that the warnings on the labelling andin medication guides include language making clearthat depression is a serious illness that itself is a strong predictor of suicide. These changes to labelling andmedication guides have now been implemented.We thank Renmeet Grewal, William Bender, and Paul David for theiradministrative and organisational support for this project.Contributors: MS was responsible for statistical design, analysis, andwriting of the manuscript and is guarantor. TL and AH planned andconducted the analysis and contributed to the writing of the manuscript.MLJ prepared the methods section of the manuscript and data foranalysis. ML was responsible for statistical design and reviewed themanuscript. PCH was responsible for data analysis and reviewed themanuscript. TAH planned and executed this study and reviewed themanuscript. RT wrote and edited the manuscript and contributed to theanalysis. GR was responsible for statistical methods and overall analyticalapproaches.Funding:This research received no specific grant from any funding agencyin the public, commercial, or not-for-profit sectors.Competing interests: None declared.Ethical approval: Not required.

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13 HallWD, Lucke J. Howhave theselectiveserotoninreuptake inhibitor antidepressants affected suicide mortality? Aust N Z J Psychiatry 2006;40:941-50.

14 Kelly CB,Ansari T, Rafferty T, StevensonM. Antidepressantprescribing and suicide rate in NorthernIreland. Eur Psychiatry 2003;18:325-8.

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18 Milane MS,SuchardMA, Wong M, LicinioJ. Modelingof thetemporal

patternsof fluoxetine prescriptions and suicide rates in the UnitedStates. PLoS Med 2006;3:1-9.

Accepted: 1 May 2009

RESEARCH

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risk of suicidality in clinical trials of antidepressants in adults

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