On May 2, 2007, the Food and Drug Administration (FDA) ordered that all antidepressant medications carry an expanded black-box warning incorporating information about an increased risk of suicidal symptoms in young adults 18 to 24 years of age. Since October 2004, antidepressants have been required to have a black-box warning indicating that they are associated with an increased risk of suicidal thinking, feeling, and behavior in children and adolescents.

The new warning also states that there is no evidence of an increased risk for adults older than 24 years of age and that the risk is actually decreased for adults 65 years of age or older. Strikingly, the label states that “depression and other serious psychiatric disorders are themselves associated with increases in the risk of suicide,” which makes it the first black-box warning to note that a disease itself carries risk - and implies that there is risk in not using the very medication being warned about.

The new warning was developed in the wake of a December 2006 meeting of the FDA’s Psychopharmacologic Drugs Advisory Committee, which focused on the controversial link between antidepressants and suicide risk in adults. During an often contentious public session, the advisory committee heard from psychiatric experts and from aggrieved family members, who sometimes expressed outrage at the FDA when they spoke of the death of loved ones who had taken antidepressants. In the end, the committee voted 6 to 2 in favor of extending the black-box warning to include adults 18 to 24 years of age.

The notion that antidepressants might be associated with an increased risk of suicidality (suicidal ideation, behavior, or both) in some patients is hardly new. Clinicians have known for years that during the first few weeks of treatment with antidepressants, some patients become “activated” —energized and agitated — before their depressed mood lifts, and that combination makes them more likely to act on preexisting suicidal impulses. But because suicidal thinking, feeling, and behavior are core symptoms of depression, there is no way to know whether suicidal symptoms that develop during treatment are due to the underlying illness or the medication.

The FDA used the best available data in attempting to disentangle the effects of treatment from those of illness by comparing the rates of suicidal symptoms among patients taking antidepressants with rates among those taking placebo. The advisory committee considered the results of comprehensive meta-analyses of an enormous data set: data on 99,839 participants who had enrolled in 372 randomized clinical trials of antidepressants conducted by 12 pharmaceutical companies during the past two decades.

The primary analyses were restricted to participants in trials for psychiatric disorders. There were 8 suicide deaths: in 5 of 39,729 participants assigned to the investigational drug, 2 of 27,164 assigned to placebo, and 1 of 10,489 assigned to an active comparator. In addition, 501 participants had suicidal feelings or thoughts or nonfatal suicide attempts — 243 while receiving an investigational drug, 194 while receiving placebo, and 64 while receiving an active comparator. No increased risk of suicidal behavior or ideation was perceptible when analyses were pooled across all adult age groups. In age-stratified analyses, however, the risk for patients 18 to 24 years of age was elevated, albeit not significantly (odds ratio, 1.55; 95% confidence interval, 0.91 to 2.70).

Why, then, did the committee recommend expanding the black-box warning to include this age group? First, the threshold for threat to safety is generally lower than that for efficacy, and the data did not provide strong evidence of an absence of risk. Second, and most important, the trend across age groups toward an association between antidepressants and suicidality was convincing, particularly when superimposed on earlier analyses of data on adolescents from randomized, controlled trials.

Richard A. Friedman, M.D., and Andrew C. Leon, Ph.D.

References
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  2. Harris G. Study finds less antidepressant use. New York Times. September 21, 2004:C1.
  3. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry 2006;163:1898-1904.
  4. Leon AC, Marzuk PM, Tardiff K, Bucciarelli A, Markham Piper T, Galea S. Antidepressants and youth suicide in New York City, 1999-2002. J Am Acad Child Adolesc Psychiatry 2006;45:1054-1058. [CrossRef][ISI][Medline]
  5. American Psychiatric Association practice guideline for the assessment and treatment of patients with suicidal behaviors. Am J Psychiatry 2003;160:Suppl:11-11.

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