To the Editor: In the July 2011 issue of the Journal, Susan M. Essock et al. (1) provided valuable information on an important clinical paradox: the widespread use of antipsychotic polypharmacy in the treatment of schizophrenia, despite the lack of evidence to support it. However, the study had an essential limitation that was not addressed in the article: the matter of dosing.

The total daily dose of antipsychotic drugs at baseline was comparable between groups, as shown in Table 1 of the article. The total dosage at 6 months follow-up and at treatment discontinuation (for those discontinuing before 6 months) was not reported in the article, but it is highly likely that this dosage was significantly lower in the monotherapy group because one of the prescribed antipsychotics had been discontinued (medication dosing was not constrained by the protocol). If this was the case, there was a bias favoring the polypharmacy group with regard to effectiveness. This is emphasized by the fact that all the study participants had residual symptoms and were candidates for change of medication. Decreasing the total dosage of antipsychotic drugs (as is the most probable scenario in the switch to monotherapy group) in such a study population would a priori be expected to be less effective than continuing the same dosage (as in the stay on polypharmacy group). Thus, future studies should include a mandatory increase in the dosage of the remaining antipsychotic drug when switching from polypharmacy to monotherapy to compensate for the dosage reduction. If possible, the dosage should be reduced at a later point in time, but initially the dosage in the monotherapy group has to equal the dosage in the polypharmacy group. If not, the lack of effectiveness observed in this study might merely reflect the effect of dosage reduction and not the effect of the reduced number of drugs. If the question of dosing is not taken into consideration, the main conclusion of the study ("Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued") might be strongly biased in favor of antipsychotic polypharmacy—and might prevent some clinicians from trying to switch their patients from polypharmacy to monotherapy, even though the secondary conclusion of the study ("two-thirds of participants successfully switched, the groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss") strongly supports such effort.