Dose-dependent pharmacokinetic interaction of clozapine and paroxetine in an extensive metabolizer

A 53-year-old patient suffering from delusional disorder developed an anticholinergic syndrome 19 days after initiation of paroxetine in addition to a steady dose of clozapine. The clozapine plasma concentration had doubled and was in the toxic range. On re-exposition with a lower clozapine dosage the increase was significantly lower. The importance of a dose-dependent interaction of both drugs is emphasized and a possible pharmacological explanation described. With regard to interactions of SSRIs and clozapine, fluvoxamine, a potent inhibitor of cytochrome P4501A2, gives rise to higher clozapine levels at an earlier time, compared to other SSRIs (paroxetine, fluoxetine and sertraline), which are potent cytochrome P4502D6 inhibitors.