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The combination of atypical antipsychotics and selective serotonin reuptake inhibitors is an effective strategy in the treatment of certain psychiatric disorders. However, pharmacokinetic interactions between the two classes of drugs remain to be explored. The present study was designed to determine whether there were different effects of steady-state fluvoxamine on the pharmacokinetics of a single dose of olanzapine and clozapine in healthy male volunteers. One single dose of 10 mg olanzapine (n = 12) or clozapine (n = 9) was administered orally. Following a drug washout of at least 4 weeks, all subjects received fluvoxamine (100 mg/day) for 9 days, and one single dose of 10 mg olanzapine or clozapine was added on day 4. Plasma concentrations of olanzapine, clozapine, and N-desmethylclozapine were assayed at serial time points after the antipsychotics were given alone and when added to fluvoxamine. No bioequivalence was found in olanzapine alone and cotreatment with fluvoxamine for the mean peak plasma concentration (Cmax), the area under the concentration-time curve from time 0 to last sampling time point (AUC0-t), and from time 0 to infinity (AUC0-∞. Under the cotreatment, Cmax of olanzapine was significantly elevated by 49%, with a 32% reduced time (tmax) to Cmax, whereas the Cmax and tmax of clozapine were unaltered. The cotreatment increased the AUC0-t and AUC0-∞ of olanzapine by 68% and 76%, respectively, greater than those of clozapine (40% and 41 %). The presence of fluvoxamine also prolonged the elimination half-life (t1/2) of olanzapine by 40% and, to a much greater extent, clozapine by 370% but reduced the total body clearance (CL/F) of clozapine (78%) more significantly than it did for olanzapine (42%). The apparent volume of distribution (Vd) was suppressed by 31 % in olanzapine combined with fluvoxamine but was unaltered in the clozapine regimen. A significant reduction in the N-desmethylclozapine to clozapine ratio was present in the clozapine with fluvoxamine regimen. The effects of fluvoxamine on different aspects of pharmacokinetics of the two antipsychotics may have implications for clinical therapeutics.