To the Editor: I thank Drs. Carnahan, Perry, and Ross for their comments on our study and welcome the opportunity to discuss the issues they raise regarding drug administration, concomitant medication, and dosing.

Drs. Carnahan and Perry comment that the medication labeling—"A," "B," and "C," denoting "low," "medium," and "high" doses—would alert investigators at day 7 to treatment assignment because all patients randomly assigned to ziprasidone received 80 mg b.i.d. (the "high" dose) on days 3 to 7 and all patients randomly assigned to olanzapine received 10 mg/day (the "medium" dose). The "A," "B," and "C" labeling was, in fact, employed only during the flexible-dose weeks of the study (weeks 2 to 6). During days 1 to 2 and days 3 to 7, when fixed doses were administered, the medication cards did not contain this labeling. During both the fixed titration and flexible-dose phases of the study, the patients in the two treatment arms received identical quantities of medication of identical appearance; in the olanzapine group, placebo capsules were employed to simulate twice-a-day dosing. For example, a subject who was assigned to olanzapine at 10 mg/day would have received the same number of identical-appearing capsules twice a day as a subject who was assigned to ziprasidone at 80 mg b.i.d. with this "double-dummy" design. Thus, there was no potential for unblinding in the drug-administration protocol.

Dr. Ross questions the use of lorazepam in our trial to treat agitation or insomnia. Clinical trials of antipsychotics in acute schizophrenia have commonly permitted concomitant use of benzodiazepines, although data on their use have not always been reported. The percentages we reported in our article for any use of lorazepam during the study—83.1% in the ziprasidone group and 75.2% in the olanzapine group—reflected lorazepam use during days 1 to 7. During days 8 to 14, the percentages of subjects still taking lorazepam decreased to 51.5% in the ziprasidone group and 51.9% in the olanzapine group. Lorazepam use continued to decrease over subsequent study weeks and remained comparable for the two treatment groups throughout the study.

With regard to the comments on dosing, the olanzapine dosing regimen employed in the trial was consistent with dosing recommendations from the olanzapine prescribing information, as well as with published clinical trial data available at the time the study was designed and conducted (1–4). It should be noted that only olanzapine-naive patients were included in our study. Patients who had more than 14 days of total lifetime exposure to olanzapine or who had received an olanzapine dose above 10 mg/day were excluded. This criterion for entry, together with the fact that patients who are required to provide informed consent in such clinical trials are generally not of the highest level of illness severity, may have moderated the average dosing requirements for subjects in the study. The mean olanzapine dose in our study reached 13 mg/day by days 15 to 21 and remained at that level for the remaining study weeks (the mean dose for the entire length of the study was 11.3 mg/day), indicating that this medication was adequately dosed. As noted in our article, the mean olanzapine dose after week 5 in our study—13.1 mg/day—is virtually identical to the endpoint mean dose in the comparative trial of olanzapine and risperidone reported by Conley and Mahmoud (5).

Although ziprasidone could be administered at up to 160 mg/day, the maximum dose currently recommended in the product labeling (the package insert for Geodon), the mean doses were approximately 140 mg/day at days 15 to 21 and the following weeks, with a mean dose of 130 mg/day for the entire length of the study, indicating that many subjects were judged not to require the maximum recommended dose. The percentages of subjects receiving the maximum dose at endpoint were similar for the olanzapine (59.4%) and ziprasidone (61.8%) groups. In addition to observing comparable efficacy between ziprasidone and olanzapine in the treatment of hospitalized patients with acute schizophrenia, we found differences between treatment groups in body weight, lipid profile, and insulin resistance. Presumably, higher doses would not have ameliorated—and may have exacerbated—these adverse events observed in the olanzapine-treated subjects.