To the Editor: Herbert Y. Meltzer, M.D., Eugene Rubin, M.D., Eduardo Dunayevich, M.D., and Anjan Chatterjee, M.D., raise three main concerns about our report: 1) study group population; 2) clozapine titration, dosing, and delayed response; and 3) risperidone with treatment-resistant patients and switching from clozapine to risperidone.

1. Our patient group was typical for the standards used when treatment with clozapine is envisaged—i.e., intolerance or nonresponse to previous treatments (see Method). Therefore, our group cannot be compared with that of the Kane et al. study, in which treatment refractoriness was defined more rigorously, both retrospectively and prospectively, and in which nontolerant patients were not included. As outlined in our Discussion section, treatment resistance and treatment intolerance could not be clearly differentiated, and this could indeed be one of the reasons for the higher response rate we found.

As a consequence of the Kane et al. study, the definition of treatment resistance—two rather than three retrospective trial failures with conventional antipsychotics for a 4-to-6-week period, rather than a strict 6-week period—are now accepted (1). Furthermore, now that antipsychotics that are potentially effective and less toxic compared to clozapine are available (2), a less restrictive definition of treatment resistance may be needed; a multiaxial classification of treatment resistance that focuses on specific targets, such as positive and negative symptoms, treatment intolerance, and poor compliance, may be helpful in directing treatment.

2. Questions concerning clozapine doses, plasma levels, and delayed responses were addressed in our report. We emphasized "cultural" differences in clozapine dosing between Europe and the United States, we reported that plasma concentrations of clozapine of less than 350 ng/ml are reportedly sufficient, and we insisted that doses as high as 600 mg/day and 12 mg/day of clozapine and risperidone, respectively, can be given. An adaptation of the clozapine dose on the basis of plasma concentrations was prohibited because the code would have been broken. About the relative rapid titration schedule for clozapine, as outlined in our Discussion section, the differences in side effects observed during the titration period suggest that some bias may have occurred with regard to the blindness of the trial.

3. We think that patients who do well taking clozapine and are able to tolerate its side effects should continue taking it. Otherwise, it seems reasonable to consider a trial of risperidone with treatment-resistant schizophrenic patients before using clozapine. About 30% of such patients show no significant change in either positive or negative symptoms when treated with clozapine (3). Moreover, risperidone efficacy in subpopulations of patients with variously defined treatment resistance may corroborate the hypothesis of heterogeneous physiopathology of resistant schizophrenia, which may be discriminated by pharmacological response to agents with different pharmacodynamic profiles (4).