Methodological Concerns in a Trial of Ziprasidone and Olanzapine

To the Editor: I read with interest the study by Dr. Simpson and colleagues comparing ziprasidone to olanzapine for the treatment of schizophrenia. I commend the authors for completing a head-to-head study that provides some important safety data. However, the study has two important limitations that limit its interpretation.

First, the olanzapine dosing was excessively restricted with respect to the upward titration rate (5 mg/day on days 1 and 2; 10 mg/day on days 3–7) and the maximum dose allowed (15 mg/day). The authors’ argument that this dosing schedule is consistent with the package insert is weak. This dosing schedule falls within the low range of the guidelines on the package insert, which was based on studies performed about 10 years ago and submitted for approval to the Food and Drug Administration. Since that time, there have been many more studies and a vast amount of clinical experience to suggest that a significantly faster upward titration rate and a higher maximum dose often are needed to adequately treat acutely ill schizophrenia patients (1). Therefore, the approach chosen by the authors was biased against finding efficacy in the olanzapine group.

Second, the vast majority of patients in both groups were treated with lorazepam in addition to the antipsychotic. Why were such high rates of lorazepam allowed? Granted, acutely psychotic patients often benefit from a benzodiazepine. But because a major goal of the study was to compare the efficacy of ziprasidone versus olanzapine, then the high rate of use of lorazepam limited the interpretation of the results. Benzodiazepines help to enhance sleep and reduce agitation and anxiety, thus interfering with the interpretations regarding efficacy of the antipsychotics. Furthermore, benzodiazepines suppress antipsychotic-induced movement disorders such as akathisia, thus limiting the interpretation of the results regarding these adverse events.

In summary, this was not simply a study of ziprasidone versus olanzapine; it was a study of ziprasidone plus lorazepam versus suboptimally dosed olanzapine plus lorazepam.