Antidepressants modestly heighten the risk of suicide in pediatric patients, according to Dr. Tarek A. Hammad and his associates at the Food and Drug Administration's Center for Drug Evaluation and Research in Rockville, Md.
Noting the longstanding concern that these drugs may induce rather than avert suicidality in children and adolescents, the FDA did a metaanalysis of 23 placebo-controlled clinical trials run by the drug manufacturers and 1 placebo-controlled multicenter trial performed by the National Institute of Mental Health. Among the 4,582 subjects, there were 109 suicide-related events in the manufacturers' trials and 11 in the NIMH trial.
Data on fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, bupropion, extended-release venlafaxine, nefazodone, and mirtazapine were pooled and assessed. Most of the studies were done in the late 1990s and ran from 4 to 16 weeks. Thus, this analysis focused on short-term risks and did not address possible suicidality beyond 16 weeks of treatment (Arch. Gen. Psychiatry 2006;63:332–9).
The antidepressants were used to treat major depressive disorder in only 16 of the trials. Other indications included obsessive-compulsive disorder (four trials), generalized anxiety disorder (two trials), social anxiety disorder (one trial), and ADHD (one trial).
The overall relative risk of suicidal ideation or behavior was 1.95, and it was consistent across the studies. The investigators characterized this rise in risk as statistically robust but modest. Its implications for clinical practice remain unclear, Dr. Hammad and his associates noted.
“It is important to be clear that the FDA has not contraindicated any of the antidepressant drugs for pediatric use. Instead, the new labeling warns of the risk of suicidality and encourages prescribers to balance this risk with clinical need. The FDA recognizes that depression and other psychiatric disorders in pediatric patients can have significant consequences if not appropriately treated,” the investigators said.
Although there were no completed suicides among the subjects, that finding “does not provide much reassurance regarding a small increase in the risk of suicide because this sample is not large enough to detect such an effect,” they said.
It is possible that treatment increased the reporting of suicidality rather than suicidality itself, since the drugs often are given in the hope of increasing pediatric patients' verbalization and communication with others. It is also possible that patients assigned to active drug therapy experienced other adverse events that were not induced by the placebo and which drew clinical attention to them and resulted in better assessment for suicidality, the FDA investigators noted.
Some evidence from other sources seems to belie their findings, they added. The rate of adolescent suicide has declined in recent years, and some data suggest that this decrease correlates with an increasing number of prescriptions for antidepressants. Moreover, autopsy studies have failed to find evidence of antidepressant use in most adolescent suicide victims, even those who had been prescribed the drugs.
In an editorial comment accompanying this report, Dr. Ross J. Baldessarini and his associates at McLean Hospital in Belmont, Mass., noted that, when adverse effects do occur in pediatric patients treated with antidepressants, “they are often detectable with close clinical follow-up and psychological support, especially early in treatment, as recommended in recent Food and Drug Administration clinical advisories.
“Moreover, they may be reversed with appropriately modified treatment, including removal of antidepressant drugs and adding agents likely to reduce agitation and aggression (antipsychotic, antimanic, anxiolytic drugs), as well as close follow-up” (Arch. Gen. Psychiatry 2006;63:246–8).
Adverse effects 'are often detectable with close clinical follow-up and' support. DR. BALDESSARINI