FDA Black Box Warning and Suicide

Project Name:
Longitudinal Analysis of SSRI Warnings and Suicide in Youth
Principal Investigator
Stephen Soumerai, ScD
Principal Investigator Contact Information:          
Principal Investigator institution:
Harvard Pilgrim Health Care
Funding Period:
09/10 – 07/2013
Approximately 14-25% of youth experience major depression before adulthood; about 9% of adolescents attempt suicide and 2.9% make a suicide attempt requiring medical attention. Treatment with antidepressant medications has been shown to improve mood and decrease suicidal ideation. However, there has been concern that antidepressants paradoxically increase the risk of suicidal behaviors following initiation of SSRI treatment. The FDA issued several public health advisories and a boxed warning since October of 2003 and, beginning in 2005, all SSRI labeling has required a “black box” warning (BBW) regarding the increased risk of suicidality in children and adolescents taking antidepressants. However, conflicting evidence concerning the true effects of SSRIs on the risk of suicidal behaviors in youth has generated much controversy. Studies following the BBW reported decreased rates of pharmacologic treatment for depression. Another study reported an 18% increase in completed suicides among youth in 2004 and 2005.

This research will contribute to research regarding unintended consequences of regulatory actions. The secondary aim is to assess the utility of sequential analysis for prospectively assessing signals of health policy impacts using the antidepressant warnings as a policy example.
Grant Number:
Participating Sites:
Harvard Pilgrim Health Care Institute (Lead Site)
Harvard Medical School
Northeastern University
Baylor Scott & White Health jointly with Central Texas Veterans Health Care System
Kaiser Permanente Washington
HealthPartners Institute
Henry Ford Health System
Kaiser Permanente Colorado
Georgia State University
Kaiser Permanente Hawaii
Kaiser Permanente
Kaiser Permanente Northwest
Kaiser Permanente Southern California
University of Tennessee Health Science Center
Harvard Medical School
Brigham and Women’s Hospital
Stephen B. Soumerai, ScD
Christine Y. Lu, PhD
Sengee Toh, ScD
Jessica L. Sturtevant, ScM
Jeanne M. Madden, PhD
Laurel Anne Copeland, PhD
Gregory Simon, MD, MPH
Rebecca Rossom, MD, MS
Brian K. Ahmedani, PhD
Gregory Clarke, PhD
Marsha A. Raebel, PharmD
Ashli Owen-Smith, PhD
Beth Waitzfelder, PhD
Yihe Daida, PhD
Robert Davis, MD, MPH
Stacy Sterling (Enid M. Hunkeler retired), MA, FAHA
Frances Lynch, PhD
Karen J. Coleman, PhD
Robert Penfold
Martin Kulldorff, PhD
Major Goals: Examine the combined effects of FDA warnings and media coverage on changes in antidepressant use, suicide attempts, and suicides among children/adolescents, young adults and adults. Evaluate the utility of sequential analysis for prospectively assessing signals of health policy impacts using FDA antidepressant warnings and related media coverage as policy example.
Description of study sample:
Records data from 11 MHRN health systems were used to examine time trends in rates of antidepressant use, suicide attempt, and suicide death before, during, and after FDA advisories regarding suicidality during antidepressant treatment.  The combined sample included approximately 1.1 million adolescents aged 10-17, 1.4 million adults aged 18-29, and 5 million adults aged 30-64.
Current Status: (write 1-2 sentences describing the project status; include current date)
Our latest publication in May 2018 evaluated the utility of sequential analysis for prospectively assessing signals of health policy impacts. As a policy example, we studied the consequences of the widely publicized Food and Drug Administration’s warnings cautioning that antidepressant use could increase suicidal risk in youth. Prospective, periodic evaluation of administrative health care data using sequential analysis can provide timely population-based signals of effects of health policies (see below). This method may be useful to use as new policies are introduced. Along with this publication Drs. Lu, Soumerai, Simon, and Kulldorff published point and counterpoint articles in Medical Care regarding the importance of surveillance (see below). Analysis for this project is complete and there will be no more publications. Using 28 years of US death certificate data collected and validated by the US CDC from 1990 to 2017, we are conducting the first longitudinal study of discontinuities in the trends of suicide rates before and after the warnings among adolescents and young adults. We hypothesized that the warnings and reductions in depression diagnosis and treatment would be associated with an increase in completed suicides among adolescents and young adults in the US. There are no extant national longitudinal data on the effects of this policy on completed suicides.
Study Registration:
Publications:Lu CY, Stewart C, Ahmed AT, Ahmedani BK, Coleman K, Copeland LA, Hunkeler EM, Lakoma MD, Madden JM, Penfold RB, Rusinak D, Zhang F, Soumerai SB. How complete are E-codes in commercial plan claims databases? Pharmacoepidemiol Drug Saf. 2014 Feb;23(2):218-20. doi: 10.1002/pds.3551.Lu CY, Zhang F, Lakoma MD, Madden JM, Rusinak D, Penfold RB, Simon G, Ahmedani BK, Clarke G, Hunkeler EM, Waitzfelder B, Owen-Smith A, Raebel MA, Rossom R, Coleman KJ, Copeland LA, Soumerai SB. Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study. BMJ. 2014 Jun 18;348:g3596. doi: 10.1136/bmj.g3596.Lu, CY, Penfold RB, Toh S, Sturtevant J, Madden JM, Simon G, Ahmedani BK, Clarke G, Coleman KJ, Copeland L, Daida Y, Davis RL, Hunkeler EM, Owen-Smith A, Raebel MA, Rossom MA, Soumerai SB, Kulldorff M. Near real-time surveillance for consequences of health policies using sequential analysis. Med Care. 2018 May;56(5):365-372.Lu, CY, Simon, G, Soumerai, SB, Kulldorff, M. Early warning systems are imperfect, but essential.  Med Care. 2018 May;56(5):382-383.Lu, CY, Simon, G, Soumerai, SB. Staying honest when policy changes backfire. Med Care. 2018 May;56(5):384-390.
Lessons Learned: Completeness of e-codes varies significantly over time, across treatment settings and across study sites. Improvements in e-coding in commercial health plan datasets are critical for injury research. In the meantime, poisoning by psychotropic drugs appears to be a useful proxy for identifying suicide attempts leading to emergency room visits and hospitalizations. There were substantial reductions in antidepressant use among all age groups and simultaneous, small increases in psychotropic drug poisonings, a validated measure of suicide attempts, among adolescents and young adults following the FDA warnings. These results were consistent across 11 geographically diverse U.S. study sites. Media exaggeration about FDA reports of drug risks may reduce appropriate drug use and increase adverse outcomes. We did not detect changes in completed suicides after the warnings, which is an extremely rare outcome.
What’s Next?
The Virtual Data Warehouse (VDW) provides a rich resource for multi-site research.  The longitudinal nature of the VDW enables longitudinal analyses that are necessarily part of the interrupted time series method, a strong quasi-experimental study design for studying impacts of health policies. MHRN hosts a health policy special interest group for discussing these research ideas.