To the Editor: We read with great interest the article by Pinkhas Sirota, M.D., and colleagues (1) on the use of ondansetron in the treatment of neuroleptic-induced tardive dyskinesia. The findings are especially remarkable in light of reports on the efficacy of clozapine and olanzapine in treating tardive dyskinesia (2, 3); these drugs having some affinity for the serotonin 5-HT₃ receptor.

In the Method section of their article, the authors stated that their patients had received a stable psychotropic drug regimen for at least 6 months before study entry. It would, however, be interesting to know what type of antipsychotics the patients had been receiving, especially if clozapine or olanzapine could have biased the results. It would also be interesting to know if concomitant medications could have induced an increase in plasma concentrations of the given antipsychotics. Increasing a dose of antipsychotics may, although transiently, alleviate tardive dyskinesia.

A literature search by the authors did not reveal any effects of ondansetron on the metabolism of other medications. In vitro studies have, however, shown that ondansetron is a competitive inhibitor of the CYP2D6-dependent O-demethylation of dextromethorphan, with a K_i value of 29 μM, and a competitive inhibitor of the CYP3A4-dependent metabolism of cyclosporine A, with a K_i of 31 μM (4). Pharmacokinetic interactions between ondansetron and antipsychotic drugs, whose metabolism largely depends on CYP2D6 and CYP3A4, cannot therefore be excluded.