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Valproic acid and clozapine are drugs commonly used in the treatment of schizophrenic and schizoaffective disorders. Pharmacokinetic interactions of valproic acid with several drugs are well known, yet results concerning the interaction with clozapine are inconsistent.Steady-state dose-corrected serum concentrations of clozapine and its main metabolite norclozapine were retrospectively analyzed in 45 patients receiving both clozapine and valproic acid. Controls were matched for sex, age, smoking, comedication, and inflammatory response.The group receiving comedication with valproic acid showed significantly lower median dose-corrected serum concentrations of norclozapine (0.44 [0.27–0.58] (ng/mL)/(mg/d) vs 0.78 [0.60–1.07] (ng/mL)/(mg/d)) as well as metabolite to parent compound ratios (0.40 [0.36–0.47] vs 0.71 [0.58–0.84]) by approximately 44%. Dose-corrected serum concentrations of clozapine were not significantly lower. The effect of valproic acid was independent of sex and smoking.Comedication with valproic acid accelerated metabolism of clozapine with predominant effects on the degradation of norclozapine. Therapeutic drug monitoring should be applied to guide individual patient responses upon initiation of comedication.