Advisers to the FDA have told the agency to issue a sweeping new warning about the risks of all antidepressants in children. The warning—an elevation from warning labels adopted by the FDA in March, which say that antidepressant drugs are associated with a risk of suicide in children but do not necessarily cause it—would state that such medicines can cause suicidal behavior in some children. The warning would appear on all antidepressants on the market, as well as those approved in the future. The committee said antidepressants should also be sold with a guide that tells parents to monitor children taking the drugs for suicidal tendencies.

The advisers came to their conclusions after a two-day hearing in which they examined data from 24 clinical trials and heard testimony from patients, parents, and physicians who work with depressed children. The FDA convened the hearing on September 13 to ask its advisory committee how to interpret the clinical trials, which examined the effect in children and teenagers of nine antidepressant medications (fluoxetine, paroxetine, sertraline, citalopram, venlafaxine, bupropion, mirtazapine, nefazodone, and fluvoxamine) on depression, obsessive-compulsive disorder, generalized anxiety disorder, insomnia, and migraine.

CHILDHOOD DEPRESSION, SUICIDE, AND ANTIDEPRESSANTS

About 5% of children and adolescents in the general population suffer from depression, according to the American Academy of Child and Adolescent Psychiatry, said David Fassler, MD, in his testimony at the FDA hearing. “Many children and adolescents who struggle with depression have thoughts about hurting themselves, and each year more than 500,000 young people attempt suicide,” said Dr. Fassler, Clinical Associate Professor of Psychiatry at the University of Vermont in Burlington. Approximately 2,000 children and adolescents commit suicide each year—though this number has been in steady decline in recent years, he noted.

Treatment of depression “should be individualized to the needs of the child and family,” Dr. Fassler said. Treatment will often include individual therapy and may also include family or school-based therapy. “Medication—including the SSRI [selective serotonin reuptake inhibitors] antidepressants—can also be an important component of treatment, but medication alone is rarely an appropriate intervention.”

SUICIDE RECLASSIFICATION

The FDA worked with researchers at Columbia University in New York City to reanalyze the adverse event data presented in pediatric trials of nine antidepressants. Columbia’s reclassification of adverse events found 22 pertinent adverse events in addition to those listed in sponsors’ submissions.

Additionally, Columbia developed a 10-category Suicidality Classification Scale, which “expert raters” used to reclassify the 427 adverse event narratives submitted by sponsors. The raters found 109 cases of possible suicidal behavior or ideation; the FDA reclassified the narratives on its own and determined that the results of Columbia’s scale are reproducible.

The FDA found that when all the studies were considered, there was a relative increase of 1.78 times in the combined category of “suicidal thinking and/or behavior.” However, there were no actual suicides in any of the clinical trials reviewed. The advisory committee voted 25 to one, with one abstention, that the FDA’s reanalysis of the data “demonstrates a causal relationship between nine antidepressants and suicidality.”

However, “the data are far from conclusive,” Dr. Fassler observed. “Research also suggests that this phenomenon may not be specific to these medications. Nonetheless, it’s important and appropriate for parents and patients to receive comprehensive information explaining that such a reaction, although unlikely, is a potential risk with any form of treatment,” he added.

THE BLACK BOX

Such thinking is reflected in the FDA advisory committee’s concern regarding the information drug companies distribute about their products. The committee voted 15 to eight that the FDA issue a “black-box” warning—the strongest possible warning released by the agency. Drug companies must post black-box warnings prominently in any television or magazine advertisements for their products.

Some members of the advisory committee said that black-box warnings might be the only way to get patients and doctors to pay attention to negative information about the drugs in the face of a deluge of advertisements that tout the drugs’ benefits even though most of the drugs have not been shown to help children with depression. “It is almost a penalty for the intense direct-to-consumer advertising, which does play a huge role in driving sales for some of these drugs,” said Bruce G. Pollock, MD, PhD, a Professor of Psychiatry at the University of Pittsburgh School of Medicine.

PRO AND CON

Committee members who voted against the black-box warning were concerned that it could deter physicians from using the medications to treat children with depression and thereby actually increase the children’s danger of suicide. “I fear the black box would impede access to treatment,” said Matthew Rudorfer, MD, of the National Institute of Mental Health.

Other committee members, however, pointed out that the clinical trials they examined showed that most of the drugs do not work in children. Additionally, they were concerned by reports from the families who testified at the FDA hearing that pediatricians had prescribed the drugs for relatively minor ailments, such as insomnia. “That somebody would get Zoloft for insomnia is beyond anything I can understand,” said child psychiatrist James McGough, MD, of the David Geffen School of Medicine at the University of California, Los Angeles. He said the purpose of the black-box warning would be “to inform physicians that this group of medicines can cause problems.”

Dr. Fassler added, “Any increased risk of suicidal thoughts or behaviors, no matter how small, must be taken very seriously.” However, he noted that—based on the data currently available—“most clinicians believe, and I would concur, that for children and adolescents who suffer from depression, the potential benefit of these medications far outweighs the risk.”

FDA APPROVAL?

Though no decision has yet been reached on the black-box issue, the FDA “has begun working expeditiously to adopt new labeling to enhance the warnings associated with the use of antidepressants and to bolster the information provided to patients when these drugs are dispensed,” a spokesperson for the agency said. The FDA usually adopts its advisory committee’s recommendations but will discuss them internally before announcing a decision, added Robert Temple, MD, Director of the Office of Drug Safety in the agency’s drug evaluation center.

—C. Justin Romano

Suggested Reading
Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004;292:338-343.
Whittington CJ, Kendall T, Fonagy P, et al. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet. 2004;363:1341-1345.

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