Risperidone (RIS) is one of the first-line treatments for schizophrenia. However, its short half-life and adverse effects, which are induced by the fluctuation of the drug concentration, limited its wide application. The PLGA microsphere was a rapidly developing delivery system for sustained release, which can extend the releasing time of drugs and decrease the fluctuation of the drug concentration. In this study, series of in vivo evaluation were performed to verify the improved efficacy of RIS through PLGA microspheres. The RIS loaded PLGA microspheres (RIS-MS) were prepared by the ultra-fine particle processing system (UPPS) - a novel technique was self-developed to fabricate microspheres. A pharmacokinetic study was employed to verify the sustained release of RIS-MS, and the head-twitch test and pole-climbing test were performed to explore the pharmacodynamics of RIS-MS. Pharmacokinetics showed the a 10-day sustained drug release was achieved by RIS-MS, and the correlation between the in vitro dissolution profile and in vivo absorption of RIS-MS was established successfully (R-2= 0.9356). Moreover, the head-twitch test revealed a continuous release of RIS-MS for 5 d, and the pole-climbing test demonstrated that less adverse effects were caused by RIS-MS compared to the RIS solution. Briefly, RIS-MS prepared by UPPS successfully achieved the in vivo sustained release and amended the adverse effects of RIS. (C) 2018 Elsevier B.V. All rights reserved.