Comparative Effectiveness of Antipsychotic Drugs

To the Editor: We read with interest the study by Dr. Volavka and colleagues comparing three second-generation antipsychotics and haloperidol in patients with chronic schizophrenia. In this study, olanzapine was randomly assigned to a second cohort of patients after the study had been in progress for 15 months. The result of the combined cohorts was that olanzapine had the largest effect size for total scores on the Positive and Negative Syndrome Scale.

The authors found no cohort effect. For their statistical analysis, they assumed that if a cohort effect were present, the three first-cohort medications (i.e., haloperidol, risperidone, and clozapine) should have all fared better in the second cohort. We question this assumption. If the second cohort consisted of patients with a better prognosis for second-generation antipsychotics, we would have expected the following: haloperidol should not have been effective in either cohort because both cohorts were selected to be resistant to neuroleptics, clozapine should have performed well in both cohorts, and risperidone should have been inferior to clozapine in the first cohort (1) and comparable in the second cohort (2, 3). The reported results fit these assumptions fairly well. Haloperidol was indeed ineffective in both cohorts. Clozapine did moderately well in both cohorts, with scores on the Positive and Negative Syndrome Scale increasing only a small amount in the second cohort (6.48 versus 7.05, respectively). The risperidone group’s improvement scores increased from –0.03 in the first cohort (N=25) to 7.93 in the second cohort (N=16). The latter appears comparable to the improvement with olanzapine (9.1, N=39). In summary, the cohort results appear too different to be validly combined.

Other analyses in this article seem to favor olanzapine. The authors reported that two patients had seizures while taking risperidone, but none had seizures while taking olanzapine. However, the authors did not note the discordance of the results for their small group of patients with seizure rates in the premarketing trials of these antipsychotics. According to the package inserts, there was a higher rate of seizures with olanzapine than with risperidone (0.9% and 0.3%, respectively). Two patients developed neutropenia with risperidone, and the authors cited a published report of another instance. They did not mention that olanzapine is associated with at least 10 cases, which we found in a PUBMED search.

Finally, the article’s abstract stated—without qualification—that improvements in negative symptom scores “were superior” with clozapine and olanzapine. The supporting evidence seems weak at best. Negative symptom scores on the Positive and Negative Syndrome Scale decreased from 21.7 at baseline to 20.1 after 14 weeks of olanzapine, including 6 weeks at the top dose of 30 mg/day. The risperidone patients’ negative symptoms did not improve at 8 mg/day nor at the 11.6-mg/day dose taken between weeks 8 and 14. But risperidone might have equaled or exceeded the tiny improvement produced by olanzapine had the dose been kept at 8 mg/day or reduced during weeks 8–14. Notwithstanding the authors’ two citations (one unpublished), suggesting that 8 mg/day of risperidone may be better than 4 mg/day, most data and expert opinions indicate better results with risperidone doses below 8 mg/day (4–8; Marder and Meibach, 1994). For a more balanced and appropriately cautious interpretation of the data in this study, this deserved acknowledgment.