Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder: Design,Definitions,and Ongoing Challenges for Child and Adolescent Psychopharmacology Research

To the Editor:

We read with interest the article by Weihs et al. (2018) that reported the results of a placebo-controlled and fluoxetine-referenced study of desvenlafaxine in youth with major depressive disorder (MDD). However, some aspects of the study design as well as its classification as a “failed trial” warrant closer attention.

Recently, Walkup (2017) suggested that large multisite trials of antidepressants in youth with few patients randomized per site and investigators without significant experience in pediatric populations may distort study results. In the desvenlafaxine trial, almost half of the principal investigators (46%) were not child and adolescent psychiatrists, a large number of sites were required, and the variance in enrollment was sequoian, with many sites only randomizing several patients. Also, only 12% of patients were enrolled from academic/hospital sites, which is noteworthy in that having fewer nonacademic sites decreases the likelihood of detecting drug–placebo differences in MDD (Dunlop et al. 2012).

The assertion that this is a “failed trial” is further problematic. Fluoxetine, at 20 mg/day, is likely an insufficient reference dose (Emslie et al. 2015). Yet, the Clinical Global Impressions-Improvement response rate for fluoxetine was statistically superior to placebo (p = 0.017). Furthermore, the odds of being randomized to active treatment were 2:1, which increases “expectation bias” and enhances placebo response in pediatric patients (Strawn et al. 2017).

Studies with a large number of sites, low randomization per site, and investigators without significant experience in pediatric populations are unlikely to produce meaningful results. This presents ethical quandaries, including whether or not patients should participate in research studies that are unlikely to generate meaningful or interpretable results.

Child and adolescent psychopharmacology has made tremendous progress over the past several decades. However, clinical trials require significant scientific, clinical, and regulatory effort. Clinical trials are costly and time intensive; yet they are urgently needed. We are hopeful that study sponsors, clinicians, scientists, academics, federal regulatory agencies, and other stakeholders will collaborate to solve these problems moving forward.