Fluvoxamine Reduces the Clozapine Dosage Needed in Refractory Schizophrenic Patients

Background: Concomitant fluvoxamine use canpotentially reduce the dosage of clozapine needed intreatment-refractory patients with schizophrenia. Previousreports have shown that fluvoxamine can increase plasma clozapineconcentrations by inhibition of cytochrome P450 (CYP) 1A2. Weevaluated the safety and efficacy of fluvoxamine, 50 mg/day,coadministration with clozapine, 100 mg/day, in refractoryschizophrenic patients.

Method: In this prospective study, 18treatment-refractory patients with DSM-IV schizophrenia (10nonsmokers and 8 smokers) were treated with clozapine at a targetdose of 100 mg h.s. After steady-state conditions of clozapinehad been reached, 50 mg/day of fluvoxamine was then added. Plasmalevels of clozapine, norclozapine, and clozapine N-oxidewere measured prior to fluvoxamine addition and on days 14 and 28during combined treatment. Side effects and efficacy weremonitored with standardized rating instruments.

Results: After 14 days of combined treatment,the mean ± SD plasma clozapine level increased 2.3-fold to 432.4± 190.9 ng/mL without further elevation on day 28. All patientscompleted the study without significant adverse side effects.Twelve of the 18 patients achieved plasma clozapineconcentrations of at least 350 ng/mL. While plasma norclozapinelevels also rose (but to a smaller extent), plasma clozapine N-oxidelevels remained unchanged after the add-on therapy. Patients whosmoked had 34% lower plasma clozapine concentrations thannonsmokers (NS). Three of the 4 patients who did not reachclozapine plasma levels of at least 300 ng/mL were smokers.Plasma norclozapine/clozapine ratios, especially in smokers,declined significantly with fluvoxamine addition.

Conclusion: The addition of fluvoxamine, 50mg/day, to low-dose clozapine, 100 mg/day, can raise plasmaclozapine levels to at least 300 ng/mL in most patients. Onlyslight dosage adjustments with clozapine may be needed afterfluvoxamine coadministration in some patients who smoke. Plasmaclozapine levels remained stable after 14 days of fluvoxamineaddition. The combined treatment was well tolerated, and clinicalimprovement was observed in our patients. Further long-termstudies with this drug combination are needed to determine itseconomic impact.