Antidepressants and Suicidal Ideation, Black-Box Warning Misses the Mark

A 2004 FDA block-box warning indicating that antidepressants were associated with an increased risk of suicidal thinking, feeling, and behavior in young people may have had a negative effect on the detection and treatment of depression, according to an article published in the New England Journal of Medicine (NEJM). Although the warning was issued following analyses of over 372 clinical trials, which demonstrated a significant increase in the occurrence of suicidal thinking among some antidepressant users, the NEJM article contends that the FDA should consider removing the warning because it fails to adequately balance the risks associated with the diagnosis and treatment of depression.

Warning

The FDA conducted a series of meta-analyses of 372 clinical trials that included over 100,000 participants. The findings of those analyses indicated that suicidal thinking and behavior existed in 4 percent of depressed patients taking antidepressants, compared to just 2 percent of patients taking a placebo. Although none of the suicide attempts that took place as a result of the trial were fatal, subsequent analyses revealed that the risk was even higher among younger individuals, under the age of 18. However, according to the NEJM article, the results were met with criticism and the FDA was led to issue an expanded version of the warning in 2007, which indicated that the link between antidepressants and suicide could be misleading because depression itself is associated with an increased risk of suicide.

Antidepressants

Following the issuance of the warning, trends in the rates of treatment of depression suggest that the warning and its expansion were not effective in adequately educating clinicians about the risks associated with antidepressants. For example, one study, derived from health care claims data of 1.1 million adolescents, 1.4 million young adults, and 5 million older adults, revealed that in the two years following the FDA warning, adolescents, young adults, and adults saw reductions of antidepressant use at 31 percent, 24.3 percent and 14.5 percent, respectively. Prescription rates for antidepressants, or serotonin-reuptake inhibitors, also fell following the issuance of the warning. In fact, prior to the FDA warning being issued, antidepressants were being prescribed with an annual increase of 4.97 percent. However, following the issuance of the warning, prescribing rates for antidepressants changed to an annual decrease of 4.61 percent.

Diagnosis

According to the NEJM article, the potential impacts of the warning could be said to extend beyond prescribing rates and even reach diagnoses. One study, which the NEJM article indicates is not reflective of a downward trend in actual prevalence of depression but instead of diagnosis rates, showed that following the warning rates of depression diagnosis fell 44 percent among children, 37 percent  among young adults, and 29 percent among all adults.

Consequence

The NEJM article cautions that none of the trends that follow the date of the 2004 warning can establish a causal link between the warning and the rates of depression diagnosis and treatment. However, as the article suggests, it is also possible that the declines in depression diagnosis and treatment with antidepressant prescriptions might be reflections of patient and physician reactions to the FDA advisory and related media coverage.  Some evidence suggests that the warning, although well intended, may have had a negative effect on depressed populations. For example, rates of psychotropic-drug poisoning, which is sometimes used as a proxy measure for suicide attempts, increased 21.7 percent among adolescents and 33.7 percent among adults in the second year after the warning. The NEJM article contends that to the degree psychotropic-drug poisoning is a reliable proxy for suicide attempts, the results may show that the FDA warning resulted in increased suicide attempts due to the downward trend in the use of antidepressants that the warning may have caused.

Education

According to the article, the observational data reveals a need for education among patients and physicians. Specifically, the NEJM article suggests that the 2007 clarification to the black-box warning has done an insufficient job to eliminate the chilling effect that the 2004 black-box warning had on depression treatment. The article asserts that the FDA’s best option may be to remove the warning altogether, or, at least, engage in a discussion about how the warning is balanced against the “very real possibility” that the warning has become an unintentional barrier separating depressed patients from much needed treatment.