Very High Cytochrome P4501A2 Activity and Nonresponse to Clozapine

Clozapine is an efficient atypical antipsychotic drug mostly devoid of extrapyramidal adverse effects, with a response rate of about 60% in those with no or partial response to classical neuroleptics.¹ Recent studies have suggested optimum clozapine plasma levels in treatment-resistant schizophrenia to be at least 350 ng/mL (3 trials), at least 370 ng/mL (1 trial) and at least 420 ng/mL (1 trial).¹ However, considerable interindividual variations of clozapine plasma levels were found for a given dose, depending on factors such as age, sex, and smoking.¹ Recently, it has been shown that the addition of selective serotonin reuptake inhibitors such as fluvoxamine improves the efficacy of clozapine in clozapine-resistant schizophrenia.^2- 3 These improvements can be explained either by pharmacokinetic (increase of clozapine blood concentrations by fluvoxamine) or pharmacodynamic (treatment of negative symptoms by fluvoxamine) effects, but the latter mechanism has been considered the likeliest.^2- 3 The hypothesis of a very rapid metabolism of clozapine in some nonresponders has never, to our knowledge, been stated or demonstrated.