Editorial(1).fm

Editorial
How Can We Know Whether
Antidepressants Increase Suicide Risk?
In this issue of the Journal, Gibbons and colleagues use pharmacy records and mortal- ity data to examine the association between rates of antidepressant use and rates of sui-cide death in children and younger adolescents. They find that U.S. counties with higherrates of SSRI antidepressant use had lower rates of suicide death, and that this relation-ship persisted after accounting for potential confounding factors. This finding is consis-tent with two other observational studies (1, 2) finding that increasing rates of antide-pressant use among adolescents were accompanied by stable or declining suicide rates.
These findings seem to conflict with a meta-analysis of data from randomized pla- cebo-controlled trials (3) and with a recent case/control study (4). Using data from allplacebo-controlled antidepressant trials in chil-dren and adolescents, Hammad and colleaguesat the U.S. Food and Drug Administration (FDA) “Even if randomized trials found that risk of suicidal ideation and suicidal behavior was nearly twice as high during treat- ment with several newer antidepressants com-pared with placebo (3). It is important to note that the number of actual suicide attempts in those placebo-controlled trials was too small to compare and that the number of suicide deathswas zero. Olfson and colleagues used a case/ control design to examine the association be- tween antidepressant use and suicide attemptsin adolescents previously hospitalized for de-pression (4). Probability of antidepressant use was significantly greater in those at-tempting suicide after hospital discharge than in those not attempting suicide.
Data from adult antidepressant trials tell a somewhat different story. The combined population in placebo-controlled adult studies is nearly 50,000, or 10 times as large asthat for studies of children and adolescents. Several meta-analyses of those adult stud-ies found no significant difference (neither an increase nor a decrease) in risk of suicideattempt or suicide death in adults exposed to active antidepressants compared withthose exposed to placebo (5–7).
Different findings in pediatric and adult studies are not the only source of complexity and potential confusion. Recent evidence suggests that effects on suicidality may differacross antidepressants. In the FDA meta-analysis of pediatric trials, risk ratios compar-ing individual drugs to placebo ranged from 1.4 to 5.5 (3). Venlafaxine was the only in-dividual drug for which the increase in risk was statistically significant (3). Two meta-analyses of adult paroxetine studies suggest an increased risk of suicidal behavior orsuicide attempt (8, 9). One meta-analysis of adult sertraline studies found no increase inrisk of suicidal ideation or behavior (10).
It is unlikely that additional randomized trials will provide a final answer to this ques- tion, either for adolescents or adults. A randomized trial to definitively determinewhether a specific antidepressant increases or decreases risk of suicide death wouldneed to include several hundred thousand patients. Such a study will never occur. Ob-servational studies using computerized pharmacy data can include such large popula-tions, but those studies are always subject to confounding or other biases. For example,the finding by Gibbons and colleagues that counties with higher antidepressant use This article is featured in this month’s AJP Audio .
Am J Psychiatry 163:11, November 2006 EDITORIAL
tend to have lower suicide rates may simply mean that suicide rates are lower in areaswith more progressive attitudes toward mental health care. Conversely, the finding byOlfson and colleagues (4) that suicide attempters were more often using antidepres-sants than non-attempters may simply mean that use of antidepressants is a marker formore severe depression. Despite these limitations, observational studies can providesome reassurance. The risk of serious suicide attempt during the first 6 months of anti-depressant treatment is less than 1 per 1,000 for adults and less than 1 in 300 for adoles-cents (11). Increasing use of newer antidepressants (compared across time or place) hasbeen accompanied by lower rates of suicide mortality in adolescents and in adults (1,12). Average risk of suicide attempt actually declines after starting antidepressant treat-ment (11), but this more likely reflects the natural history of help-seeking than a protec-tive effect of medication.
Finally, it is likely that effects of antidepressants on suicidal ideation or suicide risk differ across individuals. Most experienced clinicians have heard patients describe sud-den onset of agitation and suicidal thoughts after starting antidepressants. The initialFDA advisory was motivated in part by numerous similar reports (13, 14). While theseanecdotes cannot prove causation, they certainly suggest that some patients may be es-pecially sensitive to this particular adverse effect. Even if randomized trials and largeobservational studies find no effect of antidepressants on average rates of suicide at-tempt or suicide death, average effects may not apply to all individuals.
This complexity raises many interesting questions for researchers, but it provides little clear guidance to physicians, patients, and family members. Caught between our con-cerns about precipitating a suicide attempt and our concerns about untreated depres-sion, what advice can we give to those who are starting antidepressant treatment? Hereis my best attempt to summarize the complex and sometimes conflicting evidence: The Food and Drug Administration requires a warning that antidepressant medica-tions can sometimes cause or increase thoughts of suicide. Studies in children andadolescents have shown that antidepressants can increase suicidal thoughts. How-ever, other studies have shown that the overall risk of attempting suicide goes downafter starting antidepressant medication. Even if antidepressants help most peoplewho take them, some people may have very negative reactions. Thus, it is importantthat we have regular contact over the next few weeks. If you have thoughts aboutsuicide or about harming yourself, please contact me right away.
References
1. Olfson M, Shaffer D, Marcus S, Greenberg T: Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003; 60:978–982 2. Sondergard L, Kvist K, Anderson P, Kessing L: Do antidepressants precipitate youth suicide? A nationwide pharmacoepidemiological analysis. Eur Child Adolesc Psychiatry 2006; 15:232–240 3. Hammad T, Laughren T, Racoosin J: Suicidality in pediatric patients treated with antidepressant drugs. Arch 4. Olfson M, Marcus S, Shaffer D: Antidepressant drug therapy and suicide in severely depressed children and adolescents. Arch Gen Psychiatry 2006; 63:865–872 5. Hammad T, Laughren T, Racoosin J: Suicide rates in short-term randomized controlled trials of newer anti- depressants. J Clin Psychopharmacol 2006; 26:203–207 6. Gunnell D, Saperia J, Ashby D: Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-anal- ysis of drug company data from placebo-controlled, randomised controlled trials submitted to the MHRA’ssafety review. BMJ 2005; 330:385 7. Khan A, Khan S, Kolts R, Brown W: Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry 2003; 160:790–792 8. GlaxoSmithKline: Important Prescribing Information [Web p]. 2005; Available at www.fda.gov/medwatch/ safety/ 2005/Paxil_dearhcp_letter.pdf . (Accessed 29 June 29, 2006).
9. Aursnes I, Tvete I, Gaasemyr J, Natvig B: Suicide attempts in clinical trials with paroxetine randomised against 10. Vanderburg D, Batzar E, Fogel I, Kremer C: Possibly suicide-related adverse events in placebo-controlled, short-term studies of sertraline in adult patients. American Psychiatric Association Annual Meeting.
Am J Psychiatry 163:11, November 2006 EDITORIAL
11. Simon G, Savarino J, Operskalski B, Wang P: Suicide risk during antidepressant treatment. Am J Psychiatry 12. Gibbons R, Hur K, Bhaumik D, Mann J: The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry 2005; 62:165–172 13. Food and Drug Administration. Psychopharmacologic Drugs Advisory Committee and Pediatric Subcommit- tee of the Anti-Infective Drugs Advisory Committee: Slides [Web p]. 2 Feb 2004; available at www.fda.gov/ohrms/dockets/ac/04/slides/4006s1.htm. (Accessed March 30, 2004) 14. Moynihan R: FDA advisory panel calls for suicide warnings over new antidepressants. BMJ 2004; 328:303 GREGORY E. SIMON, M.D., M.P.H.
Address correspondence and reprint requests to Dr. Simon, Center for Health Studies, 1730 Minor Ave. #1600,Seattle, WA 98101; simon.g@ghc.org (e-mail). Supported by NIMH grant P20 MH-068572. During the last 5years, Dr. Simon has received research grant support from Eli Lilly and Company and has received consultingfees from Wyeth Pharmaceuticals and Bristol Myers Squibb. Dr. Freedman has reviewed this editorial andfound no evidence of influence from these relationships. Am J Psychiatry 163:11, November 2006

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