Fluvoxamine Reduces the Clozapine Dosage Needed in Refractory Schizophrenic Patients
J Clin Psychiatry 2000;61(8):594-599
© Copyright 2014 Physicians Postgraduate Press, Inc.
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Background: Concomitant fluvoxamine use can
potentially reduce the dosage of clozapine needed in
treatment-refractory patients with schizophrenia. Previous
reports have shown that fluvoxamine can increase plasma clozapine
concentrations by inhibition of cytochrome P450 (CYP) 1A2. We
evaluated the safety and efficacy of fluvoxamine, 50 mg/day,
coadministration with clozapine, 100 mg/day, in refractory
Method: In this prospective study, 18
treatment-refractory patients with DSM-IV schizophrenia (10
nonsmokers and 8 smokers) were treated with clozapine at a target
dose of 100 mg h.s. After steady-state conditions of clozapine
had been reached, 50 mg/day of fluvoxamine was then added. Plasma
levels of clozapine, norclozapine, and clozapine N-oxide
were measured prior to fluvoxamine addition and on days 14 and 28
during combined treatment. Side effects and efficacy were
monitored 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 patients
completed the study without significant adverse side effects.
Twelve of the 18 patients achieved plasma clozapine
concentrations of at least 350 ng/mL. While plasma norclozapine
levels also rose (but to a smaller extent), plasma clozapine N-oxide
levels remained unchanged after the add-on therapy. Patients who
smoked had 34% lower plasma clozapine concentrations than
nonsmokers (NS). Three of the 4 patients who did not reach
clozapine 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, 50
mg/day, to low-dose clozapine, 100 mg/day, can raise plasma
clozapine levels to at least 300 ng/mL in most patients. Only
slight dosage adjustments with clozapine may be needed after
fluvoxamine coadministration in some patients who smoke. Plasma
clozapine levels remained stable after 14 days of fluvoxamine
addition. The combined treatment was well tolerated, and clinical
improvement was observed in our patients. Further long-term
studies with this drug combination are needed to determine its