The episodes caught the attention of the US Food and Drug Administration, which requested the randomized clinical trial data from GlaxoSmithKline, the manufacturer of paroxetine. Eventually, the FDA requested data from manufacturers of all antidepressants utilized for children, specifically Celexa, Luvox, Prozac, Zoloft, Effexor XR, Remeron, Serzone, and Wellbutrin.

This effort was driven by the Pediatric Exclusivity Provision established under the FDA Modernization Act of 1997, which incentivized pharmaceutical companies to study medications already approved for adults for use in children. The provision aimed to generate safety and efficacy data specific to children, leading to the development of several exploratory clinical trial models for pediatric depression.

After a series of internal deliberations, the FDA convened a two-day advisory committee meeting in September 2004, where attendees considered mixed and inconclusive data about suicidality (a term created by the FDA meaning “suicidal thinking and behavior”) that failed to showcase statistical significance. Nonetheless, the committee decided that a permanent “black box” warning should appear on the drug’s label — a high-visibility warning as opposed to a “Warnings and Precautions” note elsewhere on the label — when the medications are prescribed to young people, to highlight this concern. Committee members defended this decision by claiming it was pertinent to convey any sort of risk to clinicians, patients, and families about the medications to promote open conversation and discussion about benefits and potential risks of taking the medications. A subsequent advisory meeting in May 2006 likewise failed to adduce statistically significant data showing suicidality, yet the committee decided the black box warning should continue and extend to the antidepressants Lexapro and Cymbalta, and expanded it to include young adults up to 24 years of age.

However, as we will soon explain, instead of tamping down on the risk of youth suicide, the FDA decision appears to have increased it.

The Black Box Warning

Figure 1 shows the three versions of the warning (implemented in 2006, 2013, and 2024) used over the past two decades for Wellbutrin, the branded version of bupropion. The original label followed the standardized wording used across most antidepressants, as determined by the Psychopharmacologic Drugs Advisory Committee in 2004. Similar boxed warnings appeared on Wellbutrin labels until 2013, when the FDA implemented the Physician Labeling Rule, which required boxed warnings to be more concise. In 2016, the FDA removed the neuropsychiatric events warning after a large trial showed that bupropion did not increase serious neuropsychiatric risks compared to placebo or nicotine replacement therapy, even in patients with psychiatric histories. As a result, the FDA concluded the boxed warning overstated the risk and moved that information to the “Warnings and Precautions” section of the label.

The Opposite of the Intended Effect

Two decades later, despite the FDA’s well-intentioned efforts to promote patient safety, youth suicide has climbed rather than fallen. Figure 2 shows the suicide rate among 10–14 year-olds has tripled since the period 2001–2005, just prior to the warning’s introduction. This suggests the black box label is having the unintended consequence of discouraging the drugs’ use when they would help young people, with tragic results. This should prompt reconsideration of the black box warning. These data are particularly important because they were independently generated and analyzed by the Centers for Disease Control and Prevention. This provides an external and unbiased perspective on outcomes observed since the warnings were implemented.

The excess deaths of 2,365 children and 3,593 young adults is nothing but a national tragedy. Moreover, other countries have adopted similar warnings, suggesting they too could be experiencing an increase in suicides by young people (Fornaro et al. 2019).

Why did this happen? Simply put, the FDA physicians and scientists were not practicing as clinicians. Rather, their decisions reflect how they view medical practices in local communities in the United States: that the FDA is simply providing information to wise health care providers instead of contributing to risk-misperception.

This thinking is displayed in a response we received when we submitted our concerns and data on the black box warning to the FDA. It read in part:

The purpose of the boxed warning is frequently misunderstood… . Its intent is not to stigmatize antidepressants or to imply that they are categorically harmful. Rather, it serves to alert clinicians to a counterintuitive and clinically dangerous possibility: that new or worsening suicidality shortly after treatment initiation may represent an adverse drug reaction rather than inadequate treatment response. Without this awareness, clinicians may respond by increasing the dose or persisting with treatment under the assumption that symptoms will improve with time, thereby potentially exacerbating harm. This risk of mismanagement justifies the prominence of a boxed warning.

The warnings appear to have led to significant shifts in the evaluation and management of pediatric and young adult patients. The reality is that almost every suicide or self-induced harm reaction leads to a medical malpractice lawsuit in the United States. The warnings thus put physicians — including primary care specialists, pediatricians, nurse practitioners, and psychiatrists — in a difficult position. The federal government’s actions exposed them to litigation without any specific guidance they could use in their defense, while not prescribing the medication could be defended by citing the warning.

So, what happened? The diagnosis of major depression — which would have led the health care provider to consider prescribing an antidepressant — dropped dramatically, thereby preventing legal exposure for clinicians. Since medical guidelines did not have any specific strategies — like using antidepressants — for managing mood disorder, the legal exposure to clinicians was minimal, unlike the diagnosis of major depression.

Multiple sources provide abundant evidence that this occurred. Figure 3 likewise shows an increase in suicides when the warning was extended to older youths and young adults. Meanwhile, as shown in Figure 4, though the suicide rates for people age 55 and older — who are not subject to the black box warning — increased, the increase was much smaller than for youth.

Call for Action

We propose the FDA recall/​remove the black box warning for all antidepressants to prevent further unnecessary deaths among young people who suffer various mood disorders. There is a long history of correcting such errors in the United States, as was seen with hormone replacement therapy (Howard and Goodman 2025) and antiepileptics (Yan 2008). If the FDA maintains that health care providers need information about this possible risk, it can be addressed in the “Warnings and Precautions” section of the label rather than a boxed warning.

Readings

• Bridge, Jeffrey A., Joel B. Greenhouse, Andrew H. Weldon, et al., 2008, “Suicide Trends Among Youths Aged 10 to 19 Years in the United States, 1996–2005,” JAMA 300(9): 1025–1026.
• Busch, Susan H., Ezra Golberstein, Ellen Meara, et al., 2014, “The FDA and ABCs,” Journal of Human Resources 49(3): 540–571.
• Carson, Nicholas J., Ana M. Progovac, Ye Wang, et al., 2017, “A Decline in Depression Treatment Following FDA Antidepressant Warnings Largely Explains Racial/​Ethnic Disparities in Prescription Fills,” Depression and Anxiety 34(12): 1147–1156.
• Curtin, Sally C., and Matthew F. Garnett, 2023, “Suicide and Homicide Death Rates among Youth and Young Adults Aged 10–24: United States, 2001–2021,” Data Brief no. 471, National Center for Health Statistics, US Department of Health and Human Services, June.
• Fornaro, Michele, Andre F. Carvalho, Giacomo D’Angelo, et al., 2019, “The FDA ‘Black Box’ Warning on Antidepressant Suicide Risk in Young Adults: More Harm than Benefits?” Frontiers in Psychiatry 10: 294.
• Garnett, Matthew F., Merianne Rose Spencer, and Julie D. Weeks, 2023, “Suicide among Adults Age 55 and Older, 2021,” Data Brief no. 483, National Center for Health Statistics, US Department of Health and Human Services, November.
• Gibbons, Robert D., Kwan Hur, C. Hendricks Brown, et al., 2007, “Early Evidence on the Effects of Regulators’ Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents,” American Journal of Psychiatry 164(9): 1356–1363.
• Greenland, Sander, Mohammad Ali Mansournia, and Douglas G. Altman, 2016, “Sparse Data Bias: A Problem Hiding in Plain Sight,” BMJ 352: i1981.
• Hammad, Tarek A., Thomas Laughren, and Robert Racoosin, 2006, “Suicidality in Pediatric Patients Treated with Antidepressant Drugs,” Archives of General Psychiatry 63(3): 332–339.
• Howard, Jacqueline, and Brenda Goodman, 2025, “ ‘Black Box’ Safety Warning to Be Removed from Hormone Therapy for Menopause,” CNN​.com, November 10, 2025.
• Kurian, Benji T., Karen J. Ray, Hendricks Brown, et al., 2007, “Effect of Regulatory Warnings on Antidepressant Prescribing for Children and Adolescents,” Archives of Pediatrics & Adolescent Medicine 161(7): 690–696.
• Leon, Andrew C., 2007, “The Revised Warning for Antidepressants and Suicidality: Unveiling the Black Box of Statistical Analyses,” American Journal of Psychiatry 164(12): 1786–1789.
• Libby, Anne, 2007, “Decline in Treatment of Pediatric Depression after FDA Advisory on Risk of Suicidality with SSRIs,” American Journal of Psychiatry 164(6): 884–891.
• Lu, Christine Y., Fang Zhang, Stephen B. Soumerai, et al., 2014, “Changes in Antidepressant Use by Young People and Suicidal Behavior after FDA Warnings and Media Coverage: Quasi-Experimental Study,” BMJ 348: 3596.
• Lu, Christine Y., Robert B. Penfold, Fang Zhang, et al., 2020, “Increases in Suicide Deaths among Adolescents and Young Adults following US Food and Drug Administration Antidepressant Boxed Warnings and Declines in Depression Care,” Psychiatric Research and Clinical Practice 2(2): 43–52.
• Nemeroff, Charles B., Alan J. Gelenberg, Martin B. Keller, et al., 2007, “Impact of Publicity Concerning Pediatric Suicidality Data on Physician Practice Patterns in the United States,” Archives of General Psychiatry 64(4): 466–472.
• Olfson, Mark, Benjamin G. Druss, and Sherry A. Marcus, 2015, “Trends in Mental Health Care among Children and Adolescents,” New England Journal of Medicine 372(21): 2029–2038.
• Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee, 2004, Joint Meeting Transcript, US Food and Drug Administration, September 13.
• Robb, Adelaide S., and Leia Foster, 2009, “The Black Box Warning and Its Unintended Consequences,” Child and Adolescent Psychopharmacology News 14(1): 6–9.
• Soumerai, Stephen B., Fang Zhang, Christine Y. Lu, et al., 2024, “Intended and Unintended Outcomes after FDA Pediatric Antidepressant Warnings: A Systematic Review,” Health Affairs 43(10): 1360–1369.
• Stone, Marc, Lisa Jones, Thomas L. Smith, et al., 2009, “Risk of Suicidality in Clinical Trials of Antidepressants in Adults: Analysis of Proprietary Data Submitted to US Food and Drug Administration,” BMJ 339: b2880.
• Valuck, Robert J., Heather A. Libby, Christine Y. Orton, et al., 2007, “Spillover Effects on Treatment of Adult Depression in Primary Care after FDA Advisory on Risk of Pediatric Suicidality with SSRIs,” American Journal of Psychiatry 164(8): 1198–1205.
• Yan, Jun, 2008, “FDA Committees Advise Against Black-Box Warning on Antiepileptics,” Psychiatric News, August 15.