Treatment-resistance to clozapine in association with ultrarapid CYP1A2 activity and the C -> A polymorphism in intron 1 of the CYP1A2 gene: Effect of grapefruit juice and low-dose fluvoxamine

Antipsychotic response to clozapine varies markedly among patients with sch izophrenia. The disposition of clozapine is dependent, in part, on the cyto chrome P-450 (CYP) 1A2 enzyme in vivo. In theory, a very high CYP1A2 activi ty may lead to subtherapeutic concentrations and treatment resistance to cl ozapine. This prospective case study evaluates the clinical significance of ultrarapid CYP1A2 activity and a recently discovered single nucleotide (C --> A) polymorphism in intron 1 of the CYP1A2 gene (CYP1A2*F) for treatment resistance to clozapine. In addition, we describe the effect of grapefruit juice or low-dose fluvoxamine (25-50 mg/d) coadministration on clozapine a nd active metabolite norclozapine steady-state plasma concentration and ant ipsychotic response.