One possible explanation for the identical remission rates in the venlafaxine-mirtazapine arm and the escitalopram arm is that the combination arm was again underdosed. Several studies supporting the superiority of this combination consistently used higher dosages. The mean of the daily doses of mirtazapine was only 20 mg in the CO-MED study, which is below its minimal effective daily dose of 30 mg. The mean of the daily doses of venlafaxine was 192 mg, which is below its noradrenergic range of 225 mg/day (3). Rush et al. (1) point out that no difference in remission rates was observed between the 86 patients who reached the daily regimen of 225 mg of venlafaxine and 30 mg of mirtazapine and those who were in the escitalopram arm. However, the authors indicate that this regimen was achieved “at any time during treatment.” It is unclear how long these dosages were maintained. In two double-blind studies (4, 5), we doubled the remission rates using adequately dosed combinations of mirtazapine and other antidepressants, and the dropout rates were below 15%; no patients in the fixed venlafaxine (225 mg) and mirtazapine (30 mg) group dropped out because of side effects. The double-blind structure of our studies likely contributed to patients tolerating side effects because neither they nor the investigators knew if a dosage titration was used. On the one hand, the CO-MED study results may reflect the underdosing that can happen in a community sample. On the other hand, this approach limits our ability to validate the superiority of the venlafaxine-mirtazapine combination because most patients were on a dosage of venlafaxine that did not inhibit norepinephrine reuptake and a sedative/non-antidepressant dosage of mirtazapine during the trial.