In 2004, the Food and Drug Administration (FDA) issued a black-box warning on antidepressants indicating that they were associated with an increased risk of suicidal thinking, feeling, and behavior in young people. The agency's decision was immediately controversial: many members of the medical community worried that this warning would do more harm than good because it would discourage depressed patients from seeking help and discourage doctors from prescribing antidepressants when they were clinically indicated. Now, 10 years later, there are substantial epidemiologic data to address these important concerns. What effect has the FDA warning had on the rates of detection and treatment of depression? And is there any evidence that rates of suicide or suicide attempts have changed?

In retrospect, it seems that the FDA had little choice but to issue its black-box warning. The agency had conducted a series of meta-analyses of 372 randomized clinical trials of antidepressants involving nearly 100,000 participants, which showed that the rate of suicidal thinking or suicidal behavior was 4% among patients assigned to receive an antidepressant, as compared with 2% among those assigned to receive placebo,1 although none of the suicide attempts documented in the trials were fatal. Subsequent age-stratified analyses showed that this increased risk was significant only among children and adolescents under the age of 18 years; there was no evidence of increased risk among adults older than 24 years, and among adults 65 years of age or older, antidepressants had a clear protective effect against the development of suicidal ideation and behavior.

The meta-analyses provoked considerable debate about various methodologic issues. In particular, some experts questioned the validity of the assessment of suicidality in the trials that were included, which were generally not designed to prospectively assess suicidality.

The FDA was obviously mindful of the need to balance the small risk associated with antidepressant treatment against its proven benefits: an expanded black-box warning issued in 2007 stated that depression itself was associated with an increased risk of suicide. Has this well-intended warning accomplished its task — to educate clinicians about risk without discouraging appropriate treatment of depression?

Some worrisome trends in the rates of treatment of depression, diagnoses of new cases of depression, and suicide attempts since the black-box warning was issued suggest that the answer may be no. In a very large cohort study — including 1.1 million adolescents, 1.4 million young adults, and 5 million older adults — researchers examined automated health care claims data (for 2000 to 2010) derived from 11 health plans in the U.S. Mental Health Research Network.2 The study revealed significant reductions in antidepressant use within 2 years after the FDA advisory was issued: relative reductions of 31.0%, 24.3%, and 14.5% among adolescents, young adults, and adults, respectively. Although the downward trend in antidepressant use among adolescents reversed somewhat after 2008, utilization stayed below 2004 rates. In all age groups, rates of antidepressant use since the FDA warning was issued appear to have remained below the levels that would have been expected on the basis of pre-warning patterns.

Similar trends were reported in earlier studies, which showed that prescription rates for selective serotonin-reuptake inhibitors for children decreased by approximately 20% between 2003 and 2005. The proportion of adults with depression who did not receive an antidepressant increased from 20% to 30% during the same period. Primary care physicians were writing a growing proportion of antidepressant prescriptions before the black-box warning was issued (an annual increase of 4.97%), but such prescribing dropped markedly (decreasing by 4.61% annually) after the advisory was issued. Thus, although the FDA advisory focused on children and adolescents, it appears likely to have had an effect on the community treatment of adults with depression — a population that was never the target for the advisory and for whom there is solid evidence of a positive effect of antidepressant medication on suicide risk.3

Moreover, it is not only antidepressant prescribing rates that have fallen in the wake of the black-box warning, but also the rate of diagnosis of new cases of depression. For example, one nationally representative study showed significant post-warning reductions in the rate of new diagnoses of depression by primary care providers: 44% among children, 37% among young adults, and 29% among all adults. This downward trend is clearly the result of case finding, not a change in the actual prevalence of depression. And as antidepressant-prescribing rates declined, there was no compensatory increase in the use of other depression treatments, such as psychotherapy or other psychotropic drugs.4

Of course, these observational data show only that these trends correlate with the issuing of the black-box warning; they cannot establish a causal link between the warning and changes in depression diagnosis and treatment. It's also important to recognize that all these observational studies have methodologic limitations. For example, projections of trends in rates of antidepressant use or depression diagnoses that are based on historical trends are subject to error.

Still, it is certainly plausible that the declines in depression diagnoses and antidepressant prescriptions might reflect the attitudes of both patients and physicians in the face of the controversy over, and media coverage of, the FDA advisory: patients might be reluctant to disclose symptoms that could lead to a diagnosis of depression and subsequent antidepressant treatment, and physicians might be hesitant to prescribe these drugs. But other factors could also explain these trends — for instance, increased restrictions placed on managed mental health care visits or the antidepressant prescribing by managed-care plans, or unmeasured changes in mental health care coverage for the U.S. population.

In addition to the decreased diagnosis and prescribing rates, another disturbing trend emerged in the wake of the FDA advisory: a statistically significant increase in psychotropic-drug poisoning, which was used in one study as a proxy measure for suicide attempts.2 In the second year after the warning was issued, the rate of such poisonings increased by 21.7% among adolescents (10 to 17 years of age) and by 33.7% among young adults (18 to 29 years of age). Insofar as such poisonings represent a reasonable proxy for suicide attempts, it's possible that the downward trend in antidepressant use resulted in an increase in such attempts; one cannot be certain, however, whether any given psychotropic-drug poisoning was intentional or accidental. In contrast, rates of completed suicide among people 10 to 34 years of age increased gradually between 1999 and 2010, without any sudden changes around the time of the FDA warnings, so there is little evidence that actual suicide rates have changed in the wake of the advisory.5

Nevertheless, given the overall direction of these trends, it is critically important for primary care providers, who see and treat a substantial proportion of depressed patients, to know that the risk posed by untreated depression — in terms of morbidity and mortality — has always been far greater than the very small risk associated with antidepressant treatment. We need to better educate physicians, to help them understand that although they cannot ignore that small risk, they can safely manage it by carefully monitoring their patients, particularly children and adolescents, during pharmacotherapy.

What should the FDA do in light of these observational data? Given that the agency's 2007 modification of the black-box warning has not been sufficient to prevent what seems to be a chilling effect on depression treatment — perhaps the mere presence of a warning speaks louder than any clarification it may contain — I believe it's unlikely that further modification would be helpful. I would therefore argue that the FDA should consider removing the warning entirely. At the very least, the medical profession should have a discussion about this possibility. I believe we cannot ignore the weight of these epidemiologic data or the very real possibility that the FDA advisory has unintentionally discouraged depressed patients from seeking treatment and doctors from prescribing antidepressants.