Dr. Masand Replies.

Sir: I read with interest the letter to the editor by Dr. Ahmed and colleagues at the Lilly Research Laboratories in Indianapolis, Indiana, regarding our article1 in the last issue of the journal. I agree with the authors that olanzapine has the best available data for efficacy in bipolar disorder, which is the reason, as they point out, that it has approval from the U.S. Food and Drug Administration (FDA) for the treatment of acute mania. However, the authors are incorrect in stating that there is no clinical trial demonstrating risperidone's efficacy as a monotherapeutic agent in bipolar disorder. In fact, there is a randomized, double-blind, controlled trial comparing risperidone, lithium, and haloperidol in the treatment of acute mania, which found equal efficacy of all 3 active groups.2 There is also a double-blind, randomized, placebo-controlled trial of ziprasidone in acute mania showing efficacy superior to placebo.3 There are ongoing double-blind, randomized, placebo-controlled trials of risperidone monotherapy in the treatment of acute mania. The authors describe 3 head-to-head monotherapy studies of olanzapine versus FDA-approved mood stabilizers in acute mania showing either equal or superior efficacy to lithium or divalproex sodium. Conveniently, however, the authors fail to mention that weight gain with olanzapine was twice as much as with divalproex. One of the very important considerations in choosing a novel antipsychotic, in any psychiatric illness—including bipolar illness—is not just efficacy but tolerability and safety. Olanzapine is the novel antipsychotic most likely to be associated with weight gain.4 In fact, in a recent study, comparing olanzapine and risperidone, the average weight gain with olanzapine at the end of 12 weeks was 24 lb (11 kg) versus 4 lb (2 kg) with risperidone.5 Weight gain is a particularly problematic side effect of olanzapine in bipolar disorder since these patients are usually on mood stabilizers like divalproex sodium or lithium, which, in and of themselves, can cause significant weight gain. Among the mood stabilizers, topiramate is perhaps the least likely to cause weight gain.6 In addition, there are now data accumulating from several large epidemiologic studies,7–10 double-blind, randomized, head-to-head, comparison trials,11 and the FDA MedWatch database12 showing that olanzapine, among the atypical antipsychotics, is among the most likely to be associated with diabetes mellitus, which can be potentially life threatening. In a recent article published in the journal Pharmacotherapy, Koller and Doraiswamy13 reported on 237 cases of diabetes mellitus associated with olanzapine, including 80 patients with diabetic ketoacidosis and 15 deaths. Hence, while I agree with the authors that the published efficacy data for olanzapine in bipolar disorder are more extensive than they are for the other atypical antipsychotics, in my experience, the other atypical antipsychotics are as efficacious but safer and better tolerated than olanzapine, particularly with respect to weight gain and diabetes mellitus, which are perhaps the most problematic side effects of some novel antipsychotic medications. Since clinicians now have a choice of 4 first-line novel antipsychotics and a fifth one, aripiprazole, which also showed superiority to placebo in acute mania14 and will be available in the very near future, clinicians need to weigh the risk-benefit ratio of these agents, not just the benefits that the authors have alluded to. In fact, I agree with the authors that it is premature to place these agents into a single category particularly with respect to safety and tolerability since olanzapine appears to be the most problematic.