PHARMACOKINETIC INTERACTIONS OF CLOZAPINE WITH SELECTIVE SEROTONIN REUPTAKE INHIBITORS - DIFFERENTIAL-EFFECTS OF FLUVOXAMINE AND PAROXETINEIN A PROSPECTIVE-STUDY

Pharmacokinetic interactions of clozapine and its metabolites N-desmet hylclozapine and clozapine N-oxide with the selective serotonin reupta ke inhibitors (SSRIs) fluvoxamine and paroxetine were investigated in a prospective study in schizophrenic patients under steady-state condi tions. Thirty patients were treated with clozapine at a target dose of 2.5 to 3.0 mg/kg of body weight. After gradual dose escalation, serum concentrations of clozapine and two metabolites were determined twice at 7-day intervals after steady-state conditions had been reached. Th en, fluvoxamine (50 mg/day) or paroxetine (20 mg/day) was added in 16 and 14 patients, respectively. Serum concentrations of clozapine and i ts metabolites were measured after 1, 7, and 14 days of coadministrati on with the SSRI. Mean trough concentrations of steady-state serum con centrations of clozapine, N-desmethylclozapine, and clozapine N-oxide were markedly elevated under fluvoxamine by about threefold of baselin e concentrations whereas paroxetine induced only minor, nonsignificant changes. Estimation of the mean elimination half-life of clozapine 2 weeks after start of fluvoxamine comedication revealed an increase fro m 17 hours to about 50 hours whereas there was no change under paroxet ine coadministration. The N-desmethylclozapine/clozapine ratio did not change significantly with either SSRI. Under monotherapy, clozapine m ean serum concentrations in smokers were significantly lower by 32% co mpared with nonsmokers. Similarly, N-demethylation ratios were about 2 0 to 50% higher in smokers. Thus, in all patients, fluvoxamine induced relevant increases in serum concentrations of clozapine and its metab olites, probably by the inhibition of enzymes catalyzing the degradati on of clozapine and N-desmethylclozapine, whereas paroxetine, at a usu al clinically effective dosage of 20 mg/day, did not cause significant pharmacokinetic interactions.