Objective To observe the effect of perospirone hydrochloride combined with low dose amisulpride on refractory schizophrenia and explore its application value.Methods A total of 120 patients with refractory schizophrenia who received treatment in Zhumadian Second People's Hospital from February 2022 to February 2023 were selected and divided into control group (n=60) and observation group (n=60), respectively. The improvement of psychiatric symptoms, fasting blood glucose (FBG), serum prolactin (PRL), blood lipids and social function were compared between the two groups.Results After 3 months of intervention, the scores of the three dimensions of the Positive and Negative Syndrome Scale ( PANSS ) decreased in both groups, the observation group was lower than the control group, and the difference was statistically significant (P<0.05). After 3 months of intervention, the levels of FBG, PRL, total cholesterol (TC) and triglyceride (TG) increased in both groups. The levels of FBG, TC and TG in the observation group were lower than those in the control group, and the level of PRL was higher than that in the control group (P<0.05). After 3 months of intervention, the scores of four dimensions in the Personal and Social Performance (PSP) scale increased in both groups, and the observation group was higher than the control group (P<0.05).Conclusion Perospirone hydrochloride combined with low dose amisulpride is beneficial to the improvement of clinical symptoms in patients with refractory schizophrenia, which can maintain the stability of glucose and lipid metabolism, and is also conducive to the improvement of patients' social function.