The FDA has recently extended the black-box warning to young adults aged 18 to 24 years based on a meta-analysis of RCTs25 that showed increased rates of suicidal ideation in young adults under 25 years, but either no effects or protective effects in adults older than 25. However, Gibbons and colleagues36 showed that in a comparison of 18- to 25-year-olds who were treated with an SSRI alone versus those who had no antidepressant therapy, there was one third the risk of a serious suicide attempt in the treated group (odds ratio, 0.35; confidence interval, 0.14 to 0.85; P < .021). In this age group, treatment with an SSRI alone produced a 57% decrease in suicide attempts relative to the same young adult age group before antidepressant treatment was initiated.

Similar protective effects of antidepressant treatment were found for adults who were older than 25 years. The findings revealed that when active treatment was compared with no treatment rather than a placebo control condition, and the patients were not excluded on the basis of having preexisting suicidal behavior, antidepressants had a protective effect on suicidal behavior in both younger and older adult populations. Simon and Savarino37 have also shown that both antidepressant therapy and psychotherapy significantly reduce the risk of attempted suicide in the general population as well as in young adults aged 18 to 24 years.

Results of black-box warning

Taken as a whole, these ecological data on suicide rates suggest that decreases in newer antidepressant prescriptions (SSRIs and serotonin-norepinephrine reuptake inhibitors [SNRIs]), in response to the FDA warnings, will lead to increases in the suicide rate. Unfortunately, just such a natural experiment has taken place. Between 2003 and 2005, SSRI prescription rates decreased by approximately 20% in children in the United States in response to public health advisories from the FDA and the MHRA in the United Kingdom as well as the 2004 FDA black-box warning (Figure 1).38 Smaller decreases have also been observed in SSRI prescription rates in adults younger than 60 years.

Suicide rate data published by the CDC have recently been released for 2004.38,39 In youths (aged 5 to 19 years), there was a 14% increase in suicide rates from 2003 to 2004 (2.83 of 100,000 vs 3.23 of 100,000, P < .0001). Except for minor fluctuations in 1994 (1% increase) and in 2000 (3% increase), there had been a consistent reduction in youth suicide rates from 4.4 of 100,000 in 1988 to 2.83 of 100,000 in 2003 (Figure 2). If SSRIs were causing suicides in the general population, we would expect the reverse. In contrast to these results for youth, it was noted that at the same time prescription rates continued to rise for adults older than 60 years and their suicide rates continued to fall.38 In Europe, similar findings have been reported for SSRI prescription and suicide rates in youths.38

Furthermore, the treatment as well as the diagnosis of childhood depression also decreased since the black-box warning took effect.40 Based on predictions from preadvisory data, SSRI prescriptions are 58% lower than predicted (had the warnings not taken place) and the rate of diagnosis of major depressive disorder by both pediatricians and primary care physicians is 32% lower.40 These reductions in antidepressant treatment and diagnosis of depression have "spilled over" to the adult population where significant decreases in the percentage of adults with new depressive episodes have been observed since the black-box warning was released.38,41

In addition, the investigators found that there was a significant increase in the percentage of depressed adult patients who did not receive antidepressant treatment (from 20% before the black-box warning to 30% after the black-box warning).41 These findings fill in an intermediate step related to the observed decrease in antidepressant prescriptions, namely a decreased rate of diagnosis of new episodes of depression in both pediatric and adult populations.

The findings of this natural experiment support the hypothesis that the effect of the black-box warning has been to lower antidepressant prescription rates, which in turn has resulted in more untreated depression and a corresponding increase in suicide rates for children and adolescents.38 The FDA sought to improve treatment of depression, but an overall decline in diagnosis and treatment of depression implies that the black-box warning did not achieve this goal, and the decline is consistent with the possibility that the black-box warning has had the opposite effect.

Summary

Although unintended, the FDA's black-box warning has led to a decrease in the pharmacological treatment of pediatric depression and a decrease in the diagnosis of pediatric depression. At the same time, we have seen the largest increase in child, adolescent, and teen suicide since the CDC began recording these data in 1979. In the event that these results are further confirmed by 2005 suicide rate data, it becomes clear that the black-box warning should be reconsidered and replaced by an effort to improve diagnosis of major depression, improved access to treatment, and more careful monitoring of treatment with antidepressants where indicated.

A black-box warning has only been rescinded once in history, for the drug omeprazole in 2003, but given the mortality of youth suicide and the need to reverse these alarming trends and loss of life, such a step may prove necessary for antidepressant labeling in children and young adults.
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