July–August 2012 Update

Selective Serotonin Reuptake Inhibitors for Treatment of Depression and Suicide in Youth: What's a Doctor to Do?

E ven before the FDA put a black box warning on the use of selective serotonin reuptake inhibitors (SSRIs) for youth and young adults, the use of SSRIs to treat depression has had a checkered past that has included triumph, failure, and, surely controversy. Recent reports have suggested publication bias in reporting treatment outcomes (Turner et al. 2008, Matthew et al. 2009) and less efficacy in only mildly depressed patients (Kirsch et al. 2008, Fournier et al. 2010). Despite the Treatment of Adolescent Depression Study (TADS) (March et al. 2004) findings of efficacy, clinicians have been left with understandably unresolved concerns as well as unanswered questions about how best to treat our patients. And, if this were not enough, concerns about suicidality associated with SSRIs have led to both clinical and legal concerns that challenge the maxim of primum non nocere.

Two recent papers by Robert Gibbons and his colleagues may be helpful as one considers treatment options for depression in youth. Using both published and unpublished data on fluoxetine and venlafaxine, in a meta-analysis of intent-to-treat person-level longitudinal data during the first six weeks of treatment, the authors were able to demonstrate not only that SSRIs are effective in treating depression (Gibbons, Hur et al. 2012a). Even more striking was the fact that youth had the largest treated versus control difference. Underlying this report was the analysis of data on over 4,000 patients from both published and unpublished studies of fluoxetine—youth were not treated with venlafaxine. For youth, the treatment versus control difference for response was 24.1% and remission 30.1%. Even though placebo responses were high, these data are striking because there was such significant differentiation from placebo at 6 weeks and that a significant number of patients had remissions in this timeframe. And, there is no evidence that severity of depression accounted for treatment response.

But, what about suicidality? In an accompanying paper, Gibbons, Brown et al. (2012b) showed that for adult and geriatric patients, suicidal thoughts and behaviors decreased over time. However, they found no differences in suicidal thoughts and behaviors for youth. While this is somewhat disappointing and not easily explained, these data provided no evidence that fluoxetine increased suicidal ideation and behavior. This is consistent with the TADS study (March, et al. 2004) which found no increased suicidal behavior among the treated children.

Some may argue that the differences in these data are small and that they only involve two medications; however, these findings are clinically significant even though they are from very early in the course of treatment. Indeed, they might even be construed as reassuring. Therefore, despite the storms in the media and the FDA black box warning, it appears that there are significant signals that supports the use of SSRIs to treat appropriately diagnosed and clinically managed children and adolescents.