Dr. Marder and Colleagues Reply

To the Editor: The authors raise two important questions: first, about the dose equivalence of risperidone and haloperidol; and second, concerning how clinicians can use the research literature to reach conclusions about the most effective dose of an antipsychotic.

The optimal study design for reaching conclusions about the relative efficacy and side effects of different doses of two antipsychotic agents would involve random assignment of patients to different doses of both agents. Unfortunately, this type of comparison has not been done in the case of haloperidol versus risperidone.

Instead, evidence regarding the dose equivalency of risperidone and haloperidol has been drawn from less optimal study designs. In the North American trials of Chouinard et al. and Marder and Meibach, as well as in the large multinational trial of Peuskens and colleagues, the researchers randomly assigned patients to different doses of risperidone but used fixed doses of haloperidol (20 mg/day and 10 mg/day, respectively). While these studies indicate that risperidone in the 4–8 mg range was most effective, they provide little data concerning the optimal dose of haloperidol. Other studies containing no risperidone treatment arm, in which patients were randomly assigned to a variety of haloperidol doses, provide mixed results. A study by Van Putten et al. (1) suggested that 10 and 20 mg of haloperidol were only marginally better than 5 mg and that the 20-mg doses were associated with high levels of side effects. In a trial by Zimbroff and colleagues (2), patients were randomly assigned to three doses of sertindole, three doses of haloperidol, or placebo; for haloperidol, there was a small and nonsignificant advantage for 8 mg/day over 4 mg/day or 16 mg/day.

Results from flexible dose studies, such as those cited by Remington and colleagues, have been interpreted as supporting a lower dose range for haloperidol. However, data from other flexible dose studies indicate that higher dose ranges are needed. For example, a recently concluded study by Marshal and colleagues (unpublished) found that final doses of haloperidol were considerably higher than those for risperidone. Results from any flexible dose study should be interpreted cautiously. One problem is that the lower doses prescribed for haloperidol patients can be related to a tendency of clinicians to titrate doses according to extrapyramidal side effects rather than efficacy. Therefore, the meta-analysis of Bolini et al. for haloperidol dosing may reflect doses that are associated with fewer extrapyramidal symptoms rather than the most effective doses.

In any case, Remington and his colleagues have raised an important issue regarding the dose equivalency of newer and older antipsychotics. We look forward to additional interaction and exchange of views on this topic.