The U.S. Food and Drug Administration (FDA) has reminded prescribers and patients alike that adults who take antidepressant medications should be watched closely for worsening of depression and the possibility of suicidal thoughts and behaviors, especially early in treatment or when dosing is either increased or decreased.

In addition, the agency said in a Public Health Advisory issued June 30, adults whose symptoms worsen while taking antidepressant medications should be promptly evaluated by their health care professional. The recommendations, the FDA said, "are consistent with existing warnings for treated adults in the approved labeling (package insert) for antidepressant medications...."

The advisory and an accompanying FDA Talk Paper were issued as an interim step while the agency awaits results of an in-depth analysis of large amounts of clinical-trials data on antidepressant use in adults. That analysis will mirror the full review of child and adolescent data completed last year by suicide experts at Columbia University (Psychiatric News, March 19, 2004; March 5, 2004).

At press time the FDA was unable to confirm whether the same Columbia researchers would play a part in the adult-data analysis.

The FDA said that rather than going another year without clear advice for adults taking antidepressants, it was prompted to issue the advisory by the publication of two research articles earlier this year that "suggested the possibility of an increased risk for suicidal behavior in adults who are being treated with antidepressant medications" (see article at left).

Last fall, prior to the agency's becoming aware of the adult analyses, which were subsequently published in February, the agency announced that it would undertake a full reclassification of all adverse-event data from clinical trials involving antidepressant use in adults.

Last year researchers at Columbia reviewed all available adverse-event data from clinical trials involving antidepressants in children and adolescents. The experts reclassified each of the adverse-event reports to determine whether it represented a true suicidal/self-harming event.

Based on the reclassified adverse-event data, an FDA internal analysis last summer found that there was about a twofold increase in the occurrence of suicidal thoughts or behaviors in children and adolescents taking antidepressants in clinical trials compared with subjects taking placebo. However, the FDA also found that there was no difference in the emergence of suicidality or in worsening of existing suicidality between the two groups of clinical-trial participants. The FDA has acknowledged the apparent contradiction in the findings but to date has not offered any explanation.

The results of that analysis prompted the FDA to require black-box warnings on labels of all antidepressants marketed in the United States (Psychiatric News, November 5, 2004).

Earlier this year, the FDA asked the manufacturers of all marketed antidepressants to "fully evaluate the risk of suicidality in adults treated with these drugs," the public health advisory explained. Manufacturers were asked to identify all placebo-controlled trials conducted in adults for any antidepressant product, regardless of whether the trial was specifically evaluating the use of the drug for depression. Trials investigating the use of the drugs for anxiety disorders, personality disorders, eating disorders, chronic pain, diabetic neuropathy, stress urinary incontinence, and any other indication will be included in the new adult analysis.

Manufacturers were asked for detailed information on all adverse events recorded in all trials, following the same format as that used in collecting the child and adolescent data last year. It was important, the agency noted, to include all available data, regardless of the indication, because some drugs have been associated with an increased risk of suicidal thoughts and behaviors in trials for one indication, but not others (see box above).

The FDA said its "comprehensive review will involve many hundreds of individual clinical trials and many thousands of adult patients." The analysis will take "a year or more to complete" because of the large number of trials and thousands of adverse-event records that must be individually reclassified.

"FDA will make the results of its review available to the public once its analyses are complete and will update this advisory in the meantime if more definitive information becomes available," the advisory stated.

"FDA Public Health Advisory: Suicidality in Adults Being Treated With Antidepressant Medications" is posted at<www.fda.gov/cder/drug/advisory/SSRI200507.htm>. More information about the analysis of child and adolescent data is posted at<www.fda.gov/cder/drug/antidepressants/default.htm>.▪