FDA is requesting that manufacturers of antidepressants update "black box" warnings on labeling to advise of an increased risk of suicidal thinking and behavior in young adults ages 18 to 24, while at the same time enhance language on the risks of depression and other psychiatric disorders and their link to suicide.

The agency issued the proposed labeling changes and a corresponding updated medication guide May 2 in a move that highlights the delicate balance of weighing risks and benefits.

Labeling for antidepressants already includes a black box warning on the risk of suicidality in children and adolescents. Now, the FDA is requesting that manufacturers extend that warning to patients ages 18 to 24.

At the same time, the proposed warning notes, "Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older."

The proposal also includes a caution that, "Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide."

In a same-day press alert, Center for Drug Evaluation and Research Division of Psychiatry Products Director Thomas Laughren stated, "The important message to prescribers is that these drugs do have value across the age spectrum, but their use requires certain precautions."

The proposed label also lays out the risk of suicide in a table under the "Warnings' section. According to the table, for every 1,000 patients treated with antidepressants versus placebo, 14 additional cases of suicidality were seen in patients under the age of 18. That figure drops to five among patients 18 to 24. For patients between the age of 24 to 64, there is virtually no difference between drug or placebo, with one fewer case of suicidality. For patients 65 and older, it is six fewer cases.

"The risk is quite small, but we think it is a real risk, and it is something that needs to be paid attention to," Laughren said.

The revised warning is based upon a pooled analysis of placebo-controlled trials including 4,400 children and adolescents and 77,000 adult patients.

Results of the analysis also showed that the increase in suicidality among patients taking antidepressants is typically seen in early treatment for most medications.

The labeling update corresponds with recommendations by FDA's Psycopharmacologic Drugs Advisory Committee, which concluded in December that the data about the risk of suicidality in young adults should be added to labeling, yet also noted that a statement should be added about the risk of suicidality if depression is left untreated (¹ Also see "FDA Should Add Age Modification To Antidepressant Suicidality Warning, Committee Says" - Pink Sheet, 13 December, 2006.).

FDA has acknowledged that the pediatric black box warning may have had a negative impact on prescribing patterns for antidepressants, a concern for the agency.

During the press call, Laughren noted, "We, as others, are concerned about this. It's in part in response to that, that we've made some additional changes to labeling, in particular pointing out that depression itself is a serious illness that is the major cause of suicide."

The revised labeling applies to 36 antidepressants, including Eli Lilly's Cymbalta (duloxetine), Wyeth's Effexor (venlafaxine), Forest's Lexapro (escitalopram), Pfizer's Zoloft (sertraline) and GlaxoSmithKline's Paxil (paroxetine).

Manufacturers have 30 days to submit revised labels and medication guides to FDA.

-Jessica Merrill (j.merrill@elsevier.com)

FDA Extends Antidepressant “Black Box” Warning On Suicidality To Young Adults

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