Antidepressants double suicidality in children, says FDA

doi:10.1136/bmj.332.7542.626-c

BMJ 2006;332:626 (18 March), doi:10.1136/bmj.332.7542.626-c

News roundup

Antidepressants double suicidality in children, says FDA

New York Jeanne Lenzer

Children and adolescents treated with antidepressants are nearly twice as likely to develop suicidality—suicidal thinking and behaviour—as similar children treated with placebo. This is the finding of a meta-analysis of 24 studies by the US Food and Drug Administration. The studies tested 4582 patients taking nine antidepressants versus placebo for major depressive disorder, obsessive-compulsive disorder, generalised anxiety disorder, attention deficit or hyperactivity disorder, and social anxiety disorder.

The FDA’s analysis, published in this month’s Archives of General Psychiatry is the final review of data that were previously analysed but not released by the FDA (2006;63:332-9). News of the secret data emerged in August 2004, and led to criticism of the FDA when it was learnt that Andrew Mosholder, an expert in the FDA’s office of drug safety, concluded that antidepressants doubled the risk of suicidality in children, but he was not allowed to publish his findings (BMJ 2004;329:307, 7 Aug). FDA advisory hearings in September 2004 led FDA officials to require “black box warnings” about the risk of increased suicidality on all antidepressants for children.

The FDA used newly obtained electronic data at the level of the patient and stricter definitions of suicidality to calculate the risk in this final analysis. This was necessary, said the agency, to rule out confounding variables that might have affected Dr Mosholder’s earlier findings.

After excluding 260 of 427 events originally deemed to be potentially related to suicide, the agency still found that the risk ratio for suicidality for all drugs across all indications was 1.95 (95% confidence interval 1.28 to 2.98). The overall risk ratio for selective serotonin reuptake inhibitors in depression trials was 1.66 (1.02 to 2.68). No suicides were completed in any of these trials.

Ross Baldessarini, professor of psychiatry at Harvard and author of an accompanying editorial (p 246-8) told the BMJ that he was not surprised by the results of the FDA analysis, which he said was “probably done about as well as one would expect.” But he expressed concerns that exposure times in patients taking the active drug might have been different from patients taking placebo—a problem that could lead to an overestimation of risk for children taking antidepressants.

Professor Baldessarini said that the risk profile is “only one-half of a potential problem. The other half is that the evidence that antidepressants are effective in juvenile depression is quite weak in children and adolescents—even for fluoxetine, the only currently FDA-approved [selective serotonin reuptake inhibitor] antidepressant for this indication.”

He added, “Nonetheless, it would be a mistake to conclude that it’s wrong to use antidepressants for children, and it would be unfortunate if the FDA’s findings were to discourage appropriate clinical evaluation and treatment of depressed juveniles at risk for suicide, and especially adolescents.”

Irving Kirsch, professor of psychology at the University of Plymouth is one of only two researchers to have published reviews of antidepressants based on the FDA database. Dr Kirsch analysed data from all published placebo controlled trials of antidepressants and reported that 80% of the drugs’ effects were placebo effect (Prevention & Treatment 2002;5:23).

In view of the FDA’s finding that the risk of suicidality is doubled, Dr Kirsch said, “There are three things to consider: the risk, the benefit, and the alternatives. The benefits of antidepressants over placebo in children are not clinically significant. On the other hand, the placebo response is substantial. That means that one should be able to obtain the same benefits with just about any treatment. So why choose one that may increase the risk of suicide?”