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

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 5 2.3-18.0). In an era of evidence-based psychiatric practice, there is insufficient evidence to recommend combination therapy at initiation of treatment. Keywords: evidence-based practice; mirtazapine; antidepressant; statistical reform The limitations of antidepressant monotherapy in the treatment of major depression are well established (Leventhal & Antonuccio, 2009). No more than 30% of depressed patients will have full remission of their depression in response to a single antidepressant (Pigott, 2011; Trivedi et al., 2006). Given these acknowledged limitations, there is a need for treatments that have demonstrated evidence of superiority over antidepressant monotherapy. In a recent issue of the American Journal of Psychiatry, Blier and colleagues (2010) reported a randomized controlled trial (RCT) sponsored by Organon Pharmaceuticals, the manufacturer of mirtazapine. The investigators claim that combining mirtazapine with fluoxetine, venlafaxine, or bupropion is more effective in the treatment of major depression than fluoxetine monotherapy 1 placebo. The clinical implication is that prescribers should consider prescribing two antidepressants (one of them mirtazapine) at treatment initiation. This is a reasonable conclusion given the findings as presented, in that combination treatment "yielded a number needed to treat of 3 to 5 over fluoxetine monotherapy, which is similar to the advantage of clozapine over conventional antipsychotics" (Blier et al., 2010, p. 286). An editorial in the same issue states, while noting limitations, "The results are striking, and the message is encouraging" (Rush, 2010, p. 241). As reported, these are robust findings, and given the potential ramifications of these findings for clinical practice,1 they warrant detailed consideration. METHODOLOGICAL CRITIQUE Antidepressant trials have been frequently critiqued for methodological problems ( Moncrieff, 2001), and this trial is no exception. The dosing of fluoxetine monotherapy was not optimized, and most of the patients had depression with melancholic features, both of which may have disadvantaged fluoxetine monotherapy (Rush, 2010). Unsurprisingly, this type of confound favors mirtazapine, the drug manufactured by the sponsor of the trial (see Smith, 2005). The basic design of this trial has been questioned. A letter to the editor published in response to this study (El-Mallakh, Kaur, & Lippman, 2010) argues that because the trial lacked a mirtazapine 1 placebo group, the authors' conclusions are invalid. This argument is critically important-if it is correct, other analyses may be beside the point. This trial was preregistered, as is required of all contemporary trials (De Angelis et al., 2005). Trial registration consists of the investigators preregistering their outcome variables, so that the selective reporting so common in psychiatric trials (e.g., Turner, Matthews, Linardatos, Tell, & Rosenthal, 2008) can be prevented or at least identified. …