FDA Black-Box Warnings on Antidepressants Linked to Reduced Treatment, Increased Risk of Suicide Among Youth

A significant decline among youth in depression diagnoses, pharmacotherapy, and clinical visits for depression as well as an increase in psychotropic drug poisonings and completed suicides are among the unintended consequences of FDA pediatric antidepressant advisories that led to the requirement for Black Box Warnings on all antidepressant labeling.¹

The findings, from a large systematic review led by the Harvard Pilgrim Health Care Institute, are contrary to the original intent of the warnings which were meant to increase monitoring for suicidal thoughts and behaviors by physicians treating children and young adults.

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The FDA in 2003 advised the medical and lay public that antidepressants may be associated with suicidal thoughts and behaviors shortly after treatment initiation among youth aged 18 years and younger. The advisory was escalated in 2005 to a permanent black box warning of the risk on antidepressant labeling and in media advertisements as well. In 2007 the boxed warning was expanded to include risk among young adults through age 24, a labeling requirement that remains in effect.¹

Despite the agency’s desire to promote caution in the treatment of young people with depression, the terminology included in the warnings, ie, “suicidality” could lead to the perception that use of the medications causes suicide, according to the study authors.¹ “…the warnings may have the unintended effect of frightening both physicians and youth,” lead investigator Stephen Soumerai, ScD, professor of population medicine at Harvard Medical School and the Harvard Pilgrim Health Care Institute, and colleagues wrote in the study published online October 7 in the journal Health Affairs.¹

The warnings with the original language persist on labels, across media including internet resources, and in patient drug information, the researchers emphasized.¹

“Our goal was to assess the intended and unintended outcomes of the youth antidepressant warnings by conducting a systematic review of the most credible evidence in the field,” Soumerai, said in a statement.² “We screened all available research reports on the warnings, focusing on those that met rigorous research design criteria and synthesized the most trustworthy data available.”²

The team screened 1841 research reports published about antidepressant warnings from January 1, 2003, to October 31, 2022. Of the total, 11 reports included studies measuring abrupt changes in outcome trends following the October 2003 FDA advisory and/or January 2005 Black-Box Warnings, according to the study.¹ These outcomes included monitoring for suicidality, physician visits for depression, depression diagnoses, psychotherapy visits, antidepressant treatment and use and psychotropic drug poisonings (a proxy for suicide attempts), and suicide deaths.

FINDINGS

Monitoring. The study’s findings are a dramatic portrait of the warning’s effects. Soumeria et al reported that fewer than 5% of pediatric patients were monitored for symptoms of suicidality using the contact schedule the FDA recommended after warning were put into effect. This rate was unchanged from that before the warnings. Nor did any of the post-warning studies document improvements in mental health care or reduced levels of suicide attempts or completions, according to the results.¹

Visits, diagnoses. The researchers found substantial reductions in clinic visits for depression and depression diagnoses of between 20% and 45% among more than 12 million children and adolescents across 4 of the studies.

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Antidepressant use. In the years before the first FDA advisory, the majority of the 11 studies showed increasing prescriptions for antidepressants, a trend “followed by abrupt, sustained reductions” including a slide in antidepressant treatment that ranged between 20% and 50%, the team reported. In 3 studies investigators found an increase in proxies for suicide attempts and deaths by suicide among pediatric patients¹

Among the study’s limitations the authors point to the potential for variation in the strength of the relationship between the FDA’s actions and reported outcomes despite the use of interrupted time series analyses. The factor most likely to undermine their findings, they wrote, is the potential for events other than FDA warnings to have contributed to suicide attempts and completions. After careful consideration and analysis of potential confounding variables such as the opioid epidemic, social media influence, and the recession of 2008, however, the research team remained confident in the findings.¹

“The sudden, simultaneous, and sweeping effects of these warnings––the reduction in depression treatment and increase in suicide––are documented across 14 years of strong research,” Soumerai said in the statement.² “The consistency in observed harms and absence of observed benefits after the black-box warnings indicate this is not a coincidence. We recommend that the FDA consider incorporating the black-box warnings into the list of routine warnings that pose fewer health risks, or potentially removing the warnings altogether.”²

References
1. Soumerai, S, Kappel, R, Naci, H, et al. Intended and unintended outcomes after FDA pediatric antidepressant warnings: a systematic review. Health Affairs. 2024. doi:10.1377/hlthaff.2023.0026
2. Systematic review highlights decline in mental health care and increase in suicides following FDA youth antidepressant warnings. EurekAlert! October 7, 2024. Accessed October 8, 2024. https://www.eurekalert.org/news-releases/1060134