Reanalyzing a Randomized Controlled Trial of Combination Antidepressant Treatment With Mirtazapine: Confidence Intervals Suggest Substantial Uncertainty

Abstract

This article subjects a randomized controlled trial (RCT) published in the American Journal of Psychiatry to a methodological and statistical critique, including a reanalysis of the effect size statistics presented. The published trial tested the use of combination antidepressants (mirtazapine coprescribed with either bupropion, venlafaxine, or fluoxetine) at treatment initiation as compared with fluoxetine monotherapy. The authors report that combination therapy was effective, with a number-needed-to-treat (NNT) statistic of 3–5, a strong effect size. Scrutiny of the methodology and clinical trial registration shows that 4 of 6 preregistered outcomes were statistically nonsignificant, 1 outcome was not reported, and 1 unregistered outcome was published. The well-critiqued Hamilton Depression Inventory was the only positive outcome measure. Calculating confidence intervals for the reported NNT demonstrates substantial uncertainty (95% CI for NNT = 2.3–18.0). In an era of evidence-based psychiatric practice, there is insufficient evidence to recommend combination therapy at initiation of treatment.