BackgroundRisperidone is an atypical antipsychotic drug that has been marketed in France since 1996. Therapeutic failures have been observed with risperidone.ObjectiveTo investigate whether interactions with the cytochrome P450 (CYP) isoenzymes implicated in risperidone metabolism could explain these treatment failures.Design and SettingThis was a retrospective study of clinical and drug monitoring data from 50 patients treated by five psychiatrists in northern France.MethodsThe concentration of active drug (risperidone + 9-hydroxy-risperidone) in serum was evaluated by high performance liquid chromatography and radio receptor assay. Clinical efficacy was assessed by the global improvement (CGI2) item of the Clinical Global Impression rating scale.ResultsStatistical analysis revealed a significant increase in efficacy when the serum concentration of active drug was between 25 and 150 micro;g/L compared with when it was out of this range. Carbamazepine, a CYP3A4 inducer, dramatically decreased the concentration of the active moiety of risperidone; on the contrary, CYP3A4 inhibitors (alprazolam and valproic acid) increased the concentration of active drug. The metabolism of risperidone by CYP3A4 did not lead to the formation of metabolite(s) with anti-D2dopaminergic activity. Drugs interacting with CYP2D6 altered the risperidone/9-hydroxy-risperidone ratio but did not change the total amount of active drug.ConclusionsWe have established a therapeutic range for risperidone. CYP3A4 is a major pathway for risperidone metabolism. Consideration of these factors in clinical practice should lead to improved outcomes for patients treated with risperidone.
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