FDA scrutinizes antidepressants,risk of suicidality

Warning may be applied to young adults. Concerns about the risk of suicidality in patients on antidepressant therapy have deepened as a result of a Food and Drug Administration advisory panel’s recommendation to expand a black box warning to include young adults. The proposal also sparked concern, expressed by some of the panelists, that extension of the warning might discourage appropriate antidepressant prescribing. The December 13 recommendation by the FDA’s Psychopharmacologic Drugs Advisory Committee would extend the warning of increased risk of suicidality associated with selective serotonin reuptake inhibitors and other antidepressants to include patients up to age 25, rather than just children and adolescents.

The panel’s recommendation was based on new evidence that the elevated risk of suicidality (suicidal behavior or ideation) seen in children and adolescents persists through young adulthood. The evidence is from an FDA meta-analysis of data requested from antidepressant manufacturers on almost 100,000 adult patients in 372 randomized, controlled trials of 11 antidepressants. Most of the trials lasted up to 12 weeks. The meta-analysis found a clear association between age and the risk of suicidality. The increased short-term risk of suicidality, compared with placebo, appeared to extend up to the age of 25 only.

After the age of 30, the antidepressants begin to show a protective effect that was most pronounced after age 65. The studies included patients with major depressive disorder and other depressive disorders, as well as other indications for antidepressants. As with pediatric studies, data on completed suicides were insufficient to support conclusions about the risk of suicide and antidepressant therapy. At the meeting, the right voting panel members agreed that the label should be modified in some way to reflect these new data.

All but two panel members voted to include this new information in the black box warning, with the caveat that it would also include a statement about what the data do not say about the risk of suicidality and untreated depression. Doctor noted that the FDA meta-analysis did not address the issue of suicidality associated with untreated depression. Also, the risk among those on placebo in these trials is not the same as the risk in an untreated, undiagnosed population of people with depression. Director of the division of research at the American Psychiatric Association, referred to a Centers for Disease Control and Prevention report documenting an increase in pediatric suicides after a decade-long decline. The increase could be a result of the drop in antidepressant prescribing that occurred after the black box warning about pediatric suicidality was added in early 2005.

Black box panic is real. Citing the drop in prescribing after the warning was added to the label, it was acknowledged that some prescriptions may not have been appropriate. But when you see a decline that is being reversed and furthermore, is increasing, that is very, very significant. The APA remains concerned about unintended consequences of the black box warning. But it was added that it was encouraged by the panel’s recommendation to add positive information about antidepressant therapy to the black box warning, and to include a caveat about the risk of suicidality associated with untreated depression.

The meeting was a follow-up to the September 2004 meeting of the same panel on suicidality associated with antidepressants in pediatric patients. In that meeting, the panel recommended a boxed warning and a patient medication guide alerting patiens, families, and caregivers about the increased risk of suicidality in short-term placebo-controlled trials of children and adolescents, and advising prescribers and families to observe patients for worsening suicidality and unusual changes. The FDA''s meta-analysis found that among people aged 18-24 years, there were roughly four additional suicidality events per 1,000 patients treated, above the background level, but there was a reduction of roughly six such events per 1,000 patients treated among those 65 and older, the FDA''s director of the division of psychiatry products.

However, we still feel it is good advice for clinicians to observe all patients of all ages who are being treated with antidepressants for emergence of suicidality and other behaviors that might suggest suicidality. The new information would also be added to the patient medication guide for antidepressants, which explains the risks of antidepressants and is supposed to be provided to patients with each prescription.