This May, the FDA called for a black box warning on antidepressants to indicate that patients aged 18 to 24 years are at heightened risk for treatment-emergent suicidality. But a member of the FDA advisory committee that recommended that warning has issued his own warning, saying that the "real killer in this story is untreated depression and the possible risk from antidepressant treatment is dwarfed by that from the disease."
Andrew Leon, PhD, professor of biostatistics in psychiatry at Weill Cornell Medical College, New York, and member of the FDA Psychopharmacology Drugs Advisory Committee, made this point with coauthor Richard Friedman, MD, in a Perspective article in the June 7 issue of New England Journal of Medicine.1 They affirmed that the data indicate an absolute risk of antidepressant treatment-emergent suicidality of 0.01%; and the committee previously estimated a 1% to 3% occurrence in children receiving antidepressants. Leon and Friedman emphasize, however, that these rates are substantially lower than the estimated 2.2% to 15% lifetime risk of suicidality for patients with major depression.
In an audio interview accompanying the article on the New England Journal's Web site, Leon commented, "Given the data that are available, I think it's important that the FDA has so strongly advised physicians to monitor suicidality in patients who are treated with antidepressants. Yet, at the same time, the FDA warns that untreated depression is a risk for suicide in and of itself."
Leon was among the 6-2 majority of the committee that voted to recommend expanding the warning about children and adolescents to indicate that young adults are also at risk for antidepressant-related suicidality. The committee determined that the meta-analyses of trials involving almost 100,000 patients supported the association between antidepressants and suicidality as well as the trend of heightened occurrence in younger age groups. Although the somewhat elevated rate in patients aged 18 to 24 was not statistically significantly higher than in older adults, it was a sufficiently strong signal for the committee to include this age group in the warning.
"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."
Leon is also concerned, however, about the recently documented trend of reduced antidepressant prescribing that followed the 2003 black box warning of suicidality in children.2 (For a discussion of this issue regarding children, see "Update on Antidepressants and Suicide" by Karen Dineen Wagner, MD [Psychiatric Times, July 2007, page 29]).
"The public health experiment has just begun," Leon declared. "What we want to see is if the black box reduced the distribution of the antidepressants in the United States so much [that] the rates of suicide increase . . . over the next several years. That will give us an indication that the black box warning was a mistake.
"If, on the other hand, suicide rates remain constant or go down," Leon said, "the FDA cannot be criticized for the decision to introduce the black box warning."
With suicide a hazard of untreated depression, and with antidepressant medication a generally effective treatment, Friedman and Leon ask the rhetorical question of why the FDA did not emphasize in the antidepressant label warning that the medication can lessen the greater risk of untreated illness. They point out, however, that such a statement would resemble a treatment recommendation, which is outside the agency's purview.
Friedman and Leon do recommend that clinicians provide this context to patients, explaining that while there is a risk with antidepressant medications, there is a larger risk to patients with untreated depression. They encourage clinicians to carefully monitor patients early in treatment, particularly during the first 4 to 6 weeks after starting an antidepressant.