To the Editor: We agree with Dr. El-Mallakh et al. that the design of the combination study was not optimal to bring "conclusive evidence for these combination pharmacotherapies as being superior to mirtazapine alone," since this was not the primary or secondary objective of the study. However, the design of the first study was aimed at that specific goal (1). The antidepressant effect of optimized paroxetine and mirtazapine monotherapy was compared with the combination of these two medications at their minimal effective doses from treatment initiation. At the end of week 6, the combination treatment, relative to either medication used alone, produced a significant 10-point greater reduction in Montgomery-Åsberg Depression Rating Scale scores.

In the subsequent study, on which El-Mallakh et al. comment, the primary objective was achieved: to evaluate the possible superiority of combination treatment with two antidepressant medications from treatment initiation, as compared with monotherapy. Specifically, a 25% remission rate with fluoxetine and a 52% remission rate with fluoxetine plus mirtazapine were obtained. The second objective was also achieved: an apparent synergy between a nonselective serotonin reuptake inhibitor and mirtazapine was observed. Given the severity of symptoms in the study patients, it is highly unlikely that superior performance of medication combinations was attributable to mirtazapine alone, although without a pure placebo control, we cannot be sure that mirtazapine alone was effective. Definite and conclusive evidence for this treatment strategy will obviously have to come from larger trials carried out in more than one center with these or other medications. Thus, as reflected in the article as well as the accompanying editorial, much work is still needed to establish whether, which, and for which patients antidepressant combinations are more effective than monotherapy.