Inducing effect of phenobarbital on clozapine metabolism in patients with chronic schizophrenia

The steady state plasma concentrations of clozapine and its two major metabolites, norclozapine and clozapine N-oxide, were compared in patients with schizophrenia treated with clozapine in combination with phenobarbital (n = 7), and in control patients treated with clozapine alone (n = 15). Patients were matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with phenobarbital had significantly lower plasma clozapine levels than those of the controls (232 ± 104 versus 356 ± 138 ng/ml; mean, SD, p <0.05). Plasma norclozapine levels did not differ between the two groups (195 ± 91 versus 172 ± 61 ng/ml, NS), whereas clozapine N- oxide levels were significantly higher in the phenobarbital group (115 ± 49 versus 53 ± 31 ng/ml, p <0.01). Norclozapine/clozapine and clozapine N- oxide/clozapine ratios were also significantly higher (p <0.001) in patients comedicated with phenobarbital. These findings suggest that phenobarbital stimulates the metabolism of clozapine, probably by inducing its N-oxidation and demethylation pathways.