To the Editor: In their randomized, double-blind trial comparing ziprasidone and olanzapine for the treatment of acutely ill inpatients with schizophrenia or schizoaffective disorder, George M. Simpson, M.D., et al. (1) provided important information showing that olanzapine-treated patients have a greater risk of weight gain and lipid abnormalities than patients treated with ziprasidone. However, the dosing protocol in this study raised a number of questions. First, there appeared to be a potential for unblinding. Each blister pack of study medication was labeled "A," "B," or "C," corresponding to a "low," "medium," or "high" dose of each drug. All ziprasidone-treated patients were to receive the "high" dose at the end of 1 week, whereas the olanzapine-treated patients received the "medium" dose. During the trial, the treating clinician would need to know the current dose classification each week to decide whether it should or could be increased or decreased. A "medium" dose after the end of the first week would clearly indicate olanzapine treatment, whereas a "high" dose would indicate ziprasidone treatment. It is possible that unpublished procedures were used to prevent this potential problem. If so, knowledge of these procedures would be helpful in interpreting the results of the trial.

A second concern with regard to the dosing protocol is one that is not uncommon in trials sponsored by pharmaceutical companies, that of a suboptimal dose of a comparator drug. In this trial, the patients could receive a maximum olanzapine dose of only 15 mg/day, although the product labeling recommended doses up to 20 mg/day (2). The patients received 10 mg/day at the end of 1 week, and the mean dose of olanzapine throughout the trial was only 11.3 mg/day. In contrast, ziprasidone was titrated to the maximum dose recommended by the product labeling (3), 160 mg/day, by the third day of the trial. In order to reduce bias in studies comparing drugs of a sponsor and competitor, available doses should include the entire range recommended by the product labeling.