Clozapine toxicity in a CYP2D6 poor metaboliser: Additive effects of haloperidol and valproate on clozapine metabolism

Abstract

Objective: To illustrate the complexities of clozapine metabolism with the use of therapeutic drug monitoring. Methods: We describe a case of clozapine toxicity in a patient with schizophrenia treated with the combination of clozapine, valproate and haloperidol. Results: A 24-year-old CYP2D6 poor metaboliser developed clozapine toxicity corresponding to the additive effects of haloperidol, and increasing clozapine and valproate doses. Saturation of metabolism, evidenced by a high clozapine/norclozapine ratio, was present at this time. Conclusions: Clozapine metabolism is complex and influenced by multiple factors, including interactions with hepatic P450 enzyme inducers/inhibitors, genetic polymorphisms and the potential for saturation of the N-demethylation metabolic pathway.