Plasma concentrations of clozapine and its major metabolites during combined treatment with paroxetine or sertraline

The effect of paroxetine or sertraline on steady-state plasma concentrations of clozapine and its major metabolites was studied in 17 patients with schizophrenia or schizoaffective disorder stabilized on clozapine therapy (200-400 mg/day). In order to treat negative symptomatology or concomitant depression, 9 patients received additional paroxetine (20-40mg/day) and 8 patients sertraline (50-100 mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% (p<0.01) and by 20% (p<0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapine/clozapine and clozapine N-oxide/clozapine ratios were not modified during paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. Clozapine coadministration with either paroxetine or sertraline was well tolerated. Our findings suggest that the metabolism of clozapine is not affected by sertraline treatment at typical therapeutic doses, while paroxetine, a potent inhibitor of CYP2D6, appears to inhibit the metabolism of clozapine, possibly by affecting pathways other than N-demethylation and N-oxidation. While sertraline may be added safely to patients on maintenance treatment with clozapine, careful clinical observation and monitoring of plasma clozapine levels may be useful whenever paroxetine is coadministered with clozapine.