Risperidone (Ris) is a second-generation antipsychotic (SGA) used to treat patients with schizophrenia. Additional interventions that increase plasma d-serine (d-Ser) levels could provide improved amelioration of the negative symptoms of schizophrenia. In the present study, we studied whether Ris pretreatment altered the concentration of plasma d-Ser administered intraperitoneally. In addition, the effects of Ris and its main metabolite, 9-hydroxyrisperidone (9-OHRis), on rat d-amino acid oxidase (DAO) activity were examined in vitro.Ris (0, 0.5, 1.0, or 3.0mg/kg), followed by d-Ser (20mg/kg), were administered intraperitoneally (i.p.) to male Sprague-Dawley rats, and the time-courses of plasma d-Ser, Ris, and 9-OHRis concentrations were examined. Inhibition of DAO activity in rat cerebellar and kidney preparations by Ris and 9-OHRis were measured spectrophotometrically.Significant increases in plasma d-Ser levels were observed in rats treated with both Ris and d-Ser. This effect occurred in a Ris dose-dependent manner, and the areas under the plasma d-Ser concentration-time curves were similar in rats treated with Ris (1.0mg/kg) and with a commercial DAO inhibitor, 3-methylpyrazole-5-carboxylic acid (1.0mg/kg). Rat plasma analyses showed that 9-OHRis was rapidly produced from Ris; however, high concentrations of Ris and 9-OHRis produced weak DAO inhibition in vitro, suggesting that some other pharmacological effect of Ris and/or 9-OHRis might contribute to its effects on plasma d-Ser levels.The combined administration of Ris and d-Ser may increase plasma d-Ser levels, suggesting that this approach could reduce the dose of d-Ser required for these patients.