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Increase in Suicidality Associated With FDA Black Box Warning Implementation
Black box warnings on antidepressants from the US Food and Drug Administration (FDA) warning of increased risk of suicidality were associated with a decline in mental health treatment and an increase in suicide attempts and deaths in young people, according to a systematic review published in Health Affairs.
In October 2003, the FDA issued an advisory warning that antidepressants may be associated with suicidality in those under the age of 18 soon after the initiation of treatment, and beginning in January 2005, permanent black box warning was required on product labels and in advertising materials for antidepressant drugs. In May 2007, the warning was expanded to include young adults through the age of 24.
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“FDA officials should review the totality of evidence and err on the side of caution in acknowledging possible harms of the antidepressant warnings,” noted lead author Stephen B. Soumerai, ScD, Harvard University, and co-authors. “High-quality studies support reevaluation and possible replacement of the FDA black box warning with routine warnings in product labeling. Moreover, such warnings should be evaluated rigorously by independent scientists to yield objective evidence on their intended and unintended consequences.”
Researchers searched the Medline Ovid, Embase Ovid, and PsycINFO Ovid databases for studies from January 1, 2003, to October 31, 2022, investigating changes in specified youth outcomes associated with the FDA’s antidepressant warnings. The included studies were based on data from state Medicaid programs; death certificates for all US counties, captured in the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (WONDER) database; nationwide managed care plan data sets; and nationally representative surveys.
Database searches found 1841 studies that discussed the FDA antidepressant warnings, of which 34 examined the warnings’ outcomes. Of those, 11 total studies were included in the final analysis, all of which measured changes in outcomes after the October 2003 FDA advisory or January 2005 black box warnings. In the 11 studies, both warnings were associated with unintended outcomes, such as reduced physician visits and depression diagnoses (ranging from 20% to 45%), psychotherapy visits, and antidepressant treatment and use (ranging from 20% to 50%) as well as an increase in psychotropic drug poisonings and suicide deaths. One study showed a reduction in total depression visits by almost half in the 3 years after the black box warning, which suggests “a likely reduction in monitoring of suicidal thoughts and behaviors in youth with depression,” authors said.
There was no documentation of improvements in mental health care or declines in suicide attempts or suicides after the warnings were issued.
Authors acknowledged some limitations with the results, particularly the potential influence of co-occurring events on outcomes. While the FDA warnings were linked to increases in psychotropic drug poisonings and suicide deaths, alternative explanations such as increased social media use, the opioid epidemic, and the 2008 recession were carefully considered and deemed unlikely to have confounded the findings. Data on these factors showed trends inconsistent with the outcomes reviewed, suggesting that they did not significantly impact the associations observed. Authors found only one study investigating the FDA-intended effect on prescriber monitoring for suicidal thoughts and behaviors, “the scarcity of published research on this outcome means that caution must accompany conclusions about such monitoring.”
“It has been more than 15 years since studies began documenting these outcomes, using the most rigorous quasi-experimental methods. Now, the overwhelming evidence suggests that the ongoing use of these warnings may result in more harms than benefits,” concluded Dr Soumerai.
