Dr. Lieberman and Colleagues Reply

To the Editor:

The letter by Dr. Teich includes a number of questions and gives us the opportunity to clarify some of the misconceptions of the CATIE study that have emerged since the initial outcome results were published in the New England Journal of Medicine in September 2005. The first pertains to the doses of medications used. The dose equivalence and range were selected based on the package insert approved by the Food and Drug Administration and the use patterns of the drug in clinical practice at the time the study was designed. The proposed dose equivalence of each capsule and range to be used were then discussed with each drug company and modified (or not) based on its input. The implication that any of the given drugs would have performed differently at higher doses is pure conjecture because there are no published data, to our knowledge, that definitively demonstrate that higher doses than those used are any more effective. Although the patients with tardive dyskinesia could not be randomly assigned to perphenazine, in all analyses of outcomes, the patients with tardive dyskinesia were excluded so as not to bias the comparisons. Therefore, the inclusion of the patients with tardive dyskinesia in the second-generation drug groups could not have influenced the outcomes by genetic factors or otherwise. Treatment adherence was measured in the study by clinical interview, pill counts, and serum drug levels. These will be reported subsequently. Perphenazine was selected as the representative of the first-generation drugs because it was of intermediate potency and was thus expected to cause fewer extrapyramidal side effects than high-potency drugs, such as haloperidol, and less sedation than low-potency drugs, such as chlorpromazine. Our intention was to select a drug that would give the first-generation drugs the fairest chance and provide the truest test. Because there were no data indicating that any first-generation drugs are any better than any of the others, there was no reason not to select perphenazine.

Dr. Basil and colleagues begin the complex process of extending the initial reporting of the efficacy and safety data from the CATIE study to implementation and policy. Although their statements seem reasonable, we suggest that such efforts are premature given that only the first of many reports of the study’s extensive database have been reported. The cost-effectiveness, cognition, and phase II results (including the clozapine comparison) will be reported over the next 6 to 12 months. These will greatly enhance our ability to apply these results in a rational and valid policy.

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