Child and Adolescent Psychiatry: Update on the Antidepressant Controversy

April 1, 2006

A black box warning about increased suicidality in pediatric patients is now required for all antidepressant medications. This column reviews a number of studies on this topic that were published after the FDA advisory was issued.

The FDA recently issued a public health advisory requiring manufacturers of all antidepressant medications to add a black box warning about increased suicidality in pediatric patients. Since that time, however, a number of clinically important studies that further address this issue have been published. A brief review of the data follows.

Although the FDA analysis focused on antidepressant treatment trials, Bridge and colleagues1 examined the incidence of emergent suicidality in a psychotherapy treatment trial for adolescent depression. In this clinical trial of psychotherapy, depressed adolescents were randomized to receive cognitive-behavioral therapy, systemic behavioral family therapy, or nondirective supportive therapy over a period of 12 to 16 weeks. No adolescents received antidepressant medication during the course of the trial. The incidence of emergent suicidality was assessed in 88 of the depressed patients who denied suicidality at the time of the clinical intake interview.

Suicidality developed in 11 (12.5%) of these adolescents during treatment. Of those, 10 had suicidal ideation without a plan, and 1 made a suicide attempt. Most of the episodes of suicidality occurred within 3 weeks of beginning therapy. The investigators concluded that the rate of emergent suicidality was similar to the rates in pharmacotherapy trials of depressed youths.

Simon and colleagues2 conducted a study to evaluate the risk of serious suicide attempt and suicide death in relation to initiation of antidepressant treatment. These investigators used computerized health plan records to identify 65,103 patients who received antidepressant treatment between 1992 and 2003. Death certificates were used to identify those who had died by suicide. A serious suicide attempt was defined as an attempt that led to hospitalization, which was identified by using hospital discharge data. The age of patients included in the sample ranged from 5 to 105 years (mean, 44 years).

The investigators determined that the highest risk of suicidality occurred in the month before treatment initiation, particularly in the week before starting antidepressant medication. In both adults and adolescents, there was a swift decline in suicide attempts immediately after starting medication treatment and a gradual decline over the next 6 months. The risk of death by suicide did not increase during the first month of antidepressant treatment and remained constant throughout the first 6 months of treatment.

These investigators also compared suicidal risk associated with older antidepressants and with 1 of the 10 newer antidepressants included in the FDA warning. The older antidepressants, primarily tricyclics and trazodone, were associated with a higher risk of suicidality in the first month of treatment; this was not the case for the newer antidepressants. The authors concluded that the available data do not demonstrate an increased risk of suicide or serious suicide attempt after initiation of antidepressant medication, and that the risk is not higher for those treated with newer antidepressants. Based on their findings, Simon and colleagues raised concern that the FDA warnings about antidepressants and emergent suicidality may discourage depressed persons from obtaining needed clinical treatment.

One of the most comprehensive and thoughtful articles on the risks versus benefits of antidepressant treatment for children and adolescents with depression was authored by Bridge and colleagues.3 These investigators reviewed the FDA analysis of antidepressant medication and pediatric suicidality in major depressive disorder. It is important to remember that the increased risk of suicidality found in the FDA analysis of antidepressant trials consisted predominantly of suicidal ideation and less frequently of suicide attempts. There were no completed suicides in these trials.

The investigators assessed whether the benefit of prescribing selective serotonin reuptake inhibitors (SSRIs) is worth the risk. The degree of the effect of treatment was computed using the number-to-treat method. They also examined the number needed to harm. The authors used available data from SSRI trials related to drug-placebo difference in response and drugplacebo difference in suicidality.

The researchers found that the number needed to treat for antidepressants in childhood depression is 9, whereas the number needed to harm with regard to suicidality was 59. Therefore, they concluded that more than 6 times as many youths will respond positively to antidepressants as will have suicidal ideation or behavior. Their findings regarding this risk-benefit analysis are important information for clinicians who must convey to parents of depressed youths the relative risk-benefit ratio associated with the use of antidepressant medication.

Untreated depression in children and adolescents can have fatal consequences. Therefore, it is essential to identify treatments in which the benefits outweigh the risks of an adverse outcome of the treatment. Findings from the FDA analysis regarding increased risk of suicidality with antidepressant medications as well as the report by Bridge and associates1 regarding emergent suicidality during the course of a psychotherapy trial argue for a prospectively designed study aimed at carefully assessing factors that may be related to emergent suicidality in treatment trials.

In the meantime, the Bridge and associates3 study demonstrating that the benefits of antidepressant medication treatment far outweigh the risks of suicidal ideation or behavior provides some reassurance to clinicians and to patients and their families. Of course, any child with depression who is treated with medication and/or psychotherapy must receive careful monitoring during the course of the treatment.

Dr Wagner is the Robert L. StubblefieldProfessor in the department of psychiatryand behavioral sciences and director of childand adolescent psychiatry at the University ofTexas Medical Branch at Galveston.

References:

References


1.

Bridge JA, Barbe RP, Birmaher B, et al. Emergent suicidality in a clinical psychotherapy trial for adolescent depression.

Am J Psychiatry

. 2005;162:2173-2175.

2.

Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment.

Am J Psychiatry

. 2006;163:41-47.

3.

Bridge JA, Salary CB, Birmaher B, et al. The risks and benefits of antidepressant treatment for youth depression.

Ann Med

. 2005;37:404-412.