SSRIs, Adolescent Suicide, and the Black Box: Lingering Questions

In “SSRI Prescribing Rates and Adolescent Suicide: Is the Black Box Hurting or Helping?” (Psychiatric Times, October 2007, page 33) Gibbons and associates primarily use data from their American Journal of Psychiatry article that appeared in September 2007, in a not very veiled attempt to influence doctors and the FDA to roll back the “black-box” warning on the prescription of SSRIs for adolescents.¹ One week later, the New York Times reported that this effort to link an uptick in adolescent suicide rates with the influence of the black-box warnings on decreased prescribing rates of SSRIs was undermined by data that showed that during the 2004 period in question, prescribing rates of SSRIs to adolescents had not yet fallen.² Dr Gibbons in the New York Times maintained that despite this crucial error, the study is still “suggestive” of a link between falling SSRI use rates and increased rates of adolescent suicide.

Unsupported by its own data, the publication of this study with its strong condemnation of the FDA decision should be an embarrassment to its authors and the editors of the American Journal of Psychiatry. If the editors of Psychiatric Times knew of the New York Times’ challenge to this article before the press run of their October issue, then they too are guilty of promoting disinformation in the continuing controversy over SSRI use for the treatment of depression in adolescents.

Lawrence Diller, MD
Walnut Creek, Calif

The authors respond:

We would like to thank Dr Diller for giving us the opportunity to respond to the New York Times’ misrepresentation of our work and their mischaracterization of the antidepressant prescription rate data in 2004.

Dr Diller suggests that we incorrectly concluded that decreases in prescriptions were associated with increases in suicide rates in children and adolescents. He cites the New York Times article that reported that for the US data, there was no significant drop in prescriptions in 2004, the last year for which suicide data in the United States are available. In fact, our data do reveal substantial decreases already in 2004, particularly for new antidepressant prescriptions. (Readers who are interested in the data are referred to our study.¹)

Decreases in antidepressant prescriptions following the FDA’s strong warning in March 2004 have also been reported throughout the remainder of the year.^2,3 In light of these findings, our overall comparisons between 2003 and 2004 underestimate the true effect of the FDA warning because they represent a combination of early increases in antidepressant prescriptions in the first 3 months of 2004 and decreases in the following 9 months. Furthermore, our analysis of the data from the Netherlands, where age-stratified data were available from 1998 to 2005 for both antidepressant prescription rates and suicide rates, identified a statistically significant inverse association between antidepressant prescription rates and suicide rates, and confirmed that a 22% decrease in SSRI prescription rates from 2003 to 2005 was associated with a 49% increase in youth suicide rates during that same period. We note that it is quite feasible for a higher rate increase for suicides to be caused by a smaller rate decrease in overall prescription rates if those at higher risk are not being treated.

We are well aware of the limitations of using national time-trend data in suicide rates and prescription use to infer causality. But these trends can have major public health significance. For more than a decade, youth suicide rates were consistently going down, but from 2003 to 2004 there was a 14% increase in this rate, a change that was far greater than any since the beginning of such data collection. We found this record increase, along with sizable decreases in all antidepressant prescriptions, to be too large to ignore without commenting on the potential for early evidence on unintended population-level effects of the FDA and European warnings. The 2005 data recently released by the CDC confirm the earlier 2004 finding. In 2003, the rate of suicide in the United States for 5 to 17 year olds was 1.72/100,000, which increased to 1.93/100,000 in 2004 (P = .01) and remained essentially constant at 1.91/100,000 in 2005 (a significant increase over 2003; P = .02).

Another potential consequence of the FDA warnings may be in reducing the chance for depressed individuals to receive treatment. Valuck and coworkers⁴ showed in their study of half a million adults who were having depressive episodes that primary care physicians and pediatricians were less likely to make diagnoses of depression when the warnings began, and those in whom depression was diagnosed were less likely to receive antidepressant prescriptions. These changes were not associated with compensatory increases in psychotherapy or prescription of atypical antipsychotics or anxiolytics. Unlike primary care physicians, psychiatrists continued to prescribe antidepressants at similar rates, but because most patients who were depressed are seen in primary care, the net result is lower psychotherapeutic or pharmacological treatment for those with depression.

It is important to note that our concern regarding the effects of the black-box warning is not simply based on ecological data. In our recent study of 226,000 veterans who were depressed, we found that those receiving antidepressants had one-third the rate of a serious suicide attempt relative to veterans who did not receive pharmacological treatment.⁵ Furthermore, the likelihood of a suicide attempt before treatment was reduced by about 50% following treatment with antidepressants. Simon and Savarino⁶ reported similar findings. Most important, similar decreases were found for the subset of veterans aged 18 to 24-the age group that the FDA recently expanded the black-box warning to include.

The primary data that led the FDA to include the warning were based on a very modest number of youths enrolled in 25 randomized controlled trials of antidepressants. Clinical records from these data showed that suicidality was higher in youths randomized to an antidepressant (4%) than to controls (2%), with no suicides in either arm. While clinical trial data are generally subject to less internal bias than uncontrolled studies, these trial data are severely limited in that they exclude all youths who had ideation or attempted suicide. Thus, they tell us nothing about those at highest risk for suicide.

In addition, there are no differences in self-reports of suicidality for those taking antidepressants versus placebo. It has been noted that the contradictory finding from the clinic records could well be due to ascertainment bias, because those taking active medication are more likely to be seen by their clinician for adverse effects of the medication, thus increasing the chance that their clinician would hear about suicidality.^1,7

On balance, the existing data support the statement that antidepressant use is not leading to population-level increases in the rate of suicide, which was the concern that led to the black-box warning. If anything, decreases in the availability of treatment for children and adolescents who are depressed have been associated with increases in their rates of suicide. For the clinician and patient, the choice of treatment for depression should weigh both risks and benefits. Monitoring patients who are depressed for suicidality is still important, whether or not medication is prescribed.

Robert D. Gibbons, PhD Chicago
C. Hendricks Brown, PhD Tampa, Fla
J. John Mann, MD, New York

References:

References

1. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164:1356-1363.
2. Berenson A, Carey B. Experts question study on youth suicide rates. New York Times. September 14, 2007;1.

Author Responds References

1. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warning on
SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164:1356-1363.
2. Rosack J. New data show declines in antidepressant prescribing. Psychiatr News. 2005;40:1-6.
3. Nemeroff CB, Kalali A, Keller MB, et al. Impact of publicity concerning pediatric suicidality data on physician practice patterns in the United States. Arch Gen Psychiatry. 2007;64:466-472.
4. Valuck RJ, Libby AM, Orton HD, et al. Spillover effects on treatment of adult depression in primary care after FDA advisory on risk of pediatric suicidality with SSRIs. Am J Psychiatry. 2007;164:1198-1205.
5. Gibbons RD, Brown CH, Hur K, et al. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration datasets. Am J Psychiatry. 2007;164:1044-1049.
6. Simon GE, Savarino J. Suicide attempts among patients starting depression treatment with medications or psychotherapy. Am J Psychiatry. 2007;164:1029-1034.
7. Posner K, Oquendo MA, Gould M, et al. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of antidepressants.
Am J Psychiatry. 2007;164:1035-1043.