Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders

Two separate studies were carried out to assess the effect of valproic acid on the steady-state plasma concentrations of clozapine and its major metab olites norclozapine and clozapine N-oxide in psychotic patients. In the fir st study, concentrations of clozapine and metabolites were compared between patients treated with clozapine in combination with sodium valproate (n = 15) and control patients treated with clozapine alone (n = 22) and matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated w ith valproate tended to have higher clozapine levels and lower norclozapine levels, but the differences did not reach statistical significance. In a s ubsequent study plasma concentrations of clozapine and its metabolites were determined in 6 patients with schizophrenia stabilized on clozapine therap y (200-400 mg/d) before and after treatment with sodium valproate (900-1200 mg/d) for 4 weeks. Mean plasma concentrations of clozapine and its metabol ites did not change significantly throughout the study, but there was a tre nd for clozapine levels to be higher and for norclozapine levels to be lowe r after valproate. Overall, these findings suggest that valproic acid may h ave an inhibiting effect on the CYP1A2- or CYP3A4-mediated conversion of cl ozapine to norclozapine. However, the interaction is unlikely to be clinica lly significant.