Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients

Rationale: Clozapine is a unique antipsychotic drug, outstanding for its la ck of extrapyramidal side-effects and its superior efficacy in refractory s chizophrenia. However, an unambiguous concentration-response relationship h as not yet been established. Objective: We investigated serum concentration s of clozapine, norclozapine and clozapine-N-oxide in psychiatric in- and o utpatients to identify particular metabolic patterns in clozapine responder s and non-responders and putative threshold levels for clozapine response. Methods. Psychiatric assessments, CYP2D6 genotype, and weekly serum concent rations of clozapine, norclozapine and clozapine-N-oxide were obtained in 3 4 adult schizophrenic in-and outpatients (18 men, 16 women) during 10 weeks of clozapine treatment with a naturalistic dose design. Results: Responder s (n=21) displayed significantly lower serum concentrations of clozapine co rrected for dose compared to non-responders (n=13; P<0.05), while none of t he other parameters (absolute clozapine concentration, metabolite ratios, g ender) were different. Smokers had significantly lower dose-corrected cloza pine concentrations. A positive correlation was observed between age and av erage steady state clozapine concentrations. Conclusions: These findings in dicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentia tes responders from non-responders. Thus, clozapine TDM seems ineffective f or predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine dispos ition.