ACNP Releases Final Task Force Report on Antidepressants and Suicidality Among Adolescents
In the summer of 2003 the U.K. Department of Health warned doctors against prescribing any serotonin reuptake inhibitor (SSRI) except fluoxetine for depressed youths, claiming that other agents were not effective and may increase the risk of suicidal thinking or attempts. Shortly thereafter, the U.S. Food and Drug Administration (FDA) undertook its own analysis of data from clinical trials and in October 2004 decided to require a "black box" warning about clinical worsening and suicide risk for all antidepressants prescribed for adolescents. However, both the U.K. and FDA analyses revealed deficiencies and ambiguities in the data and many questions remained—questions that have since engendered ever-more-detailed analyses and meta-analyses by several research groups.
During this two-year period of inquiry, a task force created in 2003 by the American College of Neuropsychopharmacology (ACNP) has been exhaustively evaluating evidence of the safety and effectiveness of SSRIs for pediatric depression. The task force not only examined all published clinical trial data, but it also reviewed data reported to the U.K. Medicines and Healthcare Products Regulatory Agency as well as the FDA analyses and more recent reports made public online. The final report of the task force was published in the January issue of the journal Neuropsychopharmacology.
The concluding paragraph of the risk evaluation first points to some evidence of increased suicidality on the basis of data from clinical trials, then questions the validity of this evidence, and then counters it with evidence of the benefits of SSRIs indicated by other lines of research: "SSRIs and other new generation antidepressant drugs, in aggregate, are associated with a small increase in the risk of AE [adverse event] reports of suicidal thinking or suicide attempts in youth." However, data from questionnaires used to measure suicidal ideation in clinical trials do not show any increase, "raising concerns over ascertainment artifacts in the AE report method." The paragraph ends: "Three other lines of evidence in youth, epidemiology, autopsy studies, and recent cohort surveys, do not support the hypothesis that SSRIs induce suicidal acts and suicide, instead indicating a possible beneficial effect, and that a negligible number of youth suicides are taking antidepressants at the time of death."
The epidemiologic evidence presented in the report indicating a reduction in suicide risk with SSRIs is based on U.S. and international studies of suicide rates. The World Health Organization found an average decline in the rates among persons aged 15 to 24 years of about 33 percent across 15 countries over the past 14 years. The reduction followed three decades of increases. "In only three countries did the start of the decline precede the introduction of SSRIs, indicating a relationship of prescription of SSRIs to suicide rates," the report notes. U.S. studies have found that counties with the highest prescription rates for SSRIs and the greatest increase in prescription rates have had the lowest suicide rates and the greatest declines in suicide rates among both youths and adults.
In a chilling summary paragraph on the epidemiologic evidence, the report states: "The FDA's recent black box warning could serve to initiate a natural public health experiment. The change in labeling may be accompanied by a reduction in antidepressant prescriptions, particularly for youth. An unintended consequence of this policy could be an increase in youth suicide. That is an empirical question to be examined in the near future."
The evidence from toxicological analyses at autopsy comes from national studies in Sweden, which included both adults and youths, and smaller studies of youths in the United States showing that more than 80 percent of depressed patients at the time of suicide were not taking antidepressants—a figure closer to 90 percent for adolescents. On the basis of these studies the report concludes that "Suicide is more likely when depressed individuals are untreated, rather than on antidepressants, and that may apply even more strongly in youth compared with adults."
Finally, the evidence from cohort studies presented in the report comes from analyses and meta-analyses—and a separate reanalysis by the task force—of data from clinical trials that involved only adults, which have included many more participants than pediatric trials. These studies have found no relationship between suicidality and SSRIs. The task force's reanalysis confirmed the statistical power of these studies and led it to question the power of the pediatric studies and to call for further research focused on higher-risk populations, such as adolescents with a history of suicidal behavior.
The "ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth" is available online at www.nature.com/npp/journal/vaop/ncurrent/full/1300958a.html.
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