Key Takeaways:

• A new systematic review led by the Harvard Pilgrim Health Care Institute examined a wide body of evidence documenting pediatric mental health outcomes in the period following FDA Black-Box Warnings that antidepressants may be associated with suicidal thoughts and behaviors among youth.
• The data indicate that these warnings, meant to increase monitoring of suicidal thoughts and behaviors, resulted in reduced essential medication use and mental health treatment of pediatric depression and increased suicide attempts and deaths.
• The findings support a re-evaluation of the Black-Box warning.

The longstanding epidemic of severe pediatric depression is a significant public health concern, with only one third of the affected population receiving any mental health care. A new systematic review suggests that FDA-issued warnings about antidepressant use, intended to increase monitoring of suicidal thoughts among youth, have led instead to unintentional harm.

The study was led by the Harvard Pilgrim Health Care Institute with collaborators from the University of Pennsylvania, London School of Economics and Political Science, Northeastern University, Drexel University, and The University of Sydney.

The findings are published in the October issue of Health Affairs.

Since 2003, the FDA has advised that antidepressants might be linked to suicidal thoughts and behaviors in young people. These warnings, upgraded to a Black-Box Warning (the most serious level of warning) in 2005 for those under 18 and an expansion in 2007 to include young adults up to the age of 24, were intended to encourage physician vigilance in monitoring patients for suicidal thoughts and behaviors. However, experts say evidence shows they resulted in a decline in pediatric mental health.

“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,” says lead author Stephen Soumerai, Harvard Medical School professor of population medicine at the Harvard Pilgrim Health Care Institute. “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.”

The study team screened a total of 1,841 research reports published about the warnings spanning the period between January 1, 2003 and October 31, 2022. Of these, 34 measured the outcomes of the warnings, 11 of which met well-recognized research design criteria. These 11 reports included studies measuring abrupt changes in outcome trends following the October 2003 FDA advisory and/or January 2005 Black-Box Warnings.

Suicidality symptom surveillance

The review found that fewer than 5% of pediatric patients were monitored in accordance with FDA’s recommended contact schedule recommendations following the advisory. This low rate remained unchanged from the rate prior to the warnings. Zero studies documented improvements in mental health care or declines in suicide attempts or suicides after the warnings went into effect.

Unintended consequences
Four studies, including a total of over 12 million patients, reported substantial reductions in doctor visits for depression and depression diagnoses. Most studies showed increasing use of antidepressants in the years before the FDA Advisory, followed by abrupt, sustained reductions in use after the warnings. Seven studies showed the relative reduction in antidepressant treatment and use ranging from 20% to 50%. Three studies showed increases in psychotropic drug poisonings (a proxy for suicide attempts) and suicide deaths among pediatric patients. While young adults from age 18 to 24 were not included in the studies of younger pediatric patients, the effects of these warnings “spilled over” to young adults who frequently experienced declines in mental health care and increases in suicides.

Because it is unlikely that any one outside factor can account for the multiple sudden and parallel effects on depression care, suicidal behavior, and deaths by suicide, the authors suggest that allowing the warnings to stand may contribute to the continuing pediatric mental health crisis.

“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. The consistency in observed harms and absence of observed benefits after the Black-Box Warnings indicate this is not a coincidence,” adds Dr. Soumerai. “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.”