FDA Reanalyzes Data as Controversy Continues Over Antidepressant Use by Children and Adolescents

Published reports of antidepressant trials among children and adolescents have consistently exaggerated the benefits of the drugs and downplayed serious adverse effects, including suicidality, according to a meta-analysis of data from efficacy trials that was published in the British Medical Journal (BMJ) in April. The authors cited "disturbing shortcomings" in the studies' methods and reporting and concluded that "confidently recommending these drugs as a treatment option, let alone as first line treatment, would be inappropriate."

The data reviewed came from six placebo-controlled trials of three antidepressants—fluoxetine, sertraline, and paroxetine—among patients under age 18. The authors found that improvement in the group receiving placebo was strong and that the additional benefit from the drugs was of doubtful clinical significance, which led them to conclude that the evidence was not sufficient to justify risking the adverse effects observed in the trials.

The study, from a group of Australian researchers, received widespread media attention, in part because any pediatric use of psychotropic drugs continues to be a hotly debated issue. However, the use of antidepressants has been of particular concern in the wake of media reports of suicide attempts and suicides among youths taking antidepressants, a British ban in December on all antidepressants except fluoxetine for pediatric depression, and two public health advisories in the past six months from the U.S. Food and Drug Administration (FDA). The first FDA advisory, issued in October 2003, warned clinicians to closely monitor pediatric patients for suicidal thoughts and behaviors because FDA's preliminary review of reports for eight antidepressants could not rule out the possibility of an increased risk of suicidality associated with these medications.

The second FDA advisory, issued on March 22 of this year, was stronger and asked manufacturers of medications used to treat pediatric depression to change the drug labeling to include a statement recommending "close observation of adults and pediatric patients treated with these agents for worsening depression or the emergence of suicidality." It also presented a more specific warning to health care providers, patients, and their families "to watch for symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania when these symptoms are severe or abrupt in onset or were not part of a patient's presenting symptoms." The drugs are fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, bupropion, venlafaxine, nefazadone, and mirtazapine. In an accompanying fact sheet, FDA stressed that only fluoxetine has been approved for treatment of depression among youths; that fluoxetine, sertraline, and fluvoxamine have FDA approval for treatment of pediatric obsessive-compulsive disorder; and that the other drugs have no approved uses in this population.

The more strongly worded advisory was the outcome of a day-long hearing convened by FDA on February 2 to hear public comments on pediatric antidepressant use as well as to discuss a joint report from two FDA advisory groups. After the first FDA warning in October 2003, the two groups conducted a more comprehensive review of the data. They examined findings from additional published and unpublished clinical trials—24 in all—involving pediatric use of nine antidepressants. The groups reported that they still did not have the data they needed to reach definitive, evidence-based conclusions. However, testimony at the February hearing by representatives of the advisory groups noted a "signal" in the data of a link between these drugs and suicidality and urged FDA to err on the side of caution and issue the stronger advisory.

Because the "signal" is not clear or consistent either between or within the clinical trials and because the data analyzed by the FDA panels were incomplete, the agency has asked drug companies for deidentified patient-level data for the more than 4,000 children and adolescents who participated in the 24 clinical trials. The task of analyzing these data has been given to a group of suicidality experts at Columbia University, and their report is due to be completed by late summer. One challenge they will face is to agree on which adverse events represent suicidal behavior and apply a standard terminology across the 24 trials. In one trial, a child who slapped herself on the head was classified as a case of suicidal behavior, whereas in another, a child who stabbed himself in the neck with a pencil was classified as an accidental injury.

Public and media reaction to the FDA advisories and to the continued uncertainty about what the data indicate has been strong in some quarters. An April 10 story in the Los Angeles Times accused senior FDA officials of hiding evidence of the link between antidepressants and suicidality and of not allowing the author of the preliminary report, Andrew Mosholder, M.D., to present the full findings at the February FDA hearing. According to the CBS Evening News and the San Francisco Chronicle, two congressional committees—the House Energy and Commerce Subcommittee on Investigations and the Senate Finance Committee—have ordered FDA to hand over relevant documents, including the Mosholder report and all e-mails and correspondence related to pediatric use of antidepressants. These news agencies also reported that "FDA bosses" pressured Mosholder to make his conclusions "less definitive" and that FDA has launched a criminal investigation to find the employee who leaked the full report to the media.

Among the many media entities that participated in the outcry over the BMJ's meta-analysis concluding that no antidepressant is safe for children, only HealthDay, a daily Internet news feed from ScoutNews, LLC, of Norwalk, Connecticut, noted that two of the article's six authors are the chair and the director of Healthy Skepticism, a nonprofit organization whose main aim is "to improve health by reducing harm from misleading drug promotion." (These affiliations are noted as a "competing interest" at the end of the BMJ article.) Healthy Skepticism was founded in 1983 as the Medical Lobby for Appropriate Marketing and changed its name in 2001. The organization's Web site refers to the BMJ article as "our publication."

The responses of mental health care providers and researchers have been more balanced, perhaps reflecting their familiarity with and greater toleration of ambiguity in clinical data. A statement by Marcia K. Goin, M.D., president of the American Psychiatric Association, noted that "it would be tragic if publicity around the FDA advisory … caused parents to hesitate in seeking needed help for their children. Suicidal thoughts and behaviors are all-too-common symptoms of depression. The biggest threat to a depressed person's well-being is to receive no care at all." A New York Times story on the Australian review in BMJ quoted Dr. Laurence Greenhill, a professor of psychiatry at Columbia University, who said "I think that these medications are neither as much of a silver bullet as the advocates would have it nor as terrible as the critics would say." And even Dr. Mosholder, in his testimony at the FDA hearing in February, pointed out that "the largest problem here is that the outcome of interest that we are tracking, which is suicidality, is also an outcome of the indication for which the drug is prescribed."

About 5 percent of children and adolescents in the U.S. population suffer from depression, and 7 percent of Americans who are taking antidepressants are under age 18. In 2002, a total of 2.7 million antidepressant prescriptions were for children younger than 12, and 8.1 million were for adolescents, according to FDA, although some individuals received more than one prescription.

From 1980 to 1997, the rate of suicide among adolescents increased by 11 percent. Suicide is rare but growing among younger children. The suicide rate for ten- to 14-year-olds increased by 109 percent between 1980 and 1997, according to the Centers for Disease Control and Prevention. No suicides were reported among the more than 4,000 youths in the clinical trials. However, the Australian researchers asserted that the follow-up periods in the trials were too short to determine an association.

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