Objective: To investigate the efficacy of aripiprazole orally disintegrating tablets (ODT) combined with sertraline tablets in patients with schizophrenia comorbid with depression.Methods: In this prospective clinical study, 70 patients with schizophrenia and concurrent depression who attended our hospital from January 2022 to May 2025 were enrolled. They were randomly divided into a control group (n = 35) receiving aripiprazole ODT monotherapy and an observation group (n = 35) receiving aripiprazole ODT plus sertraline. PANSS, HAMD and RSA scores, serum levels of 5-HT, DA and NT-3, overall efficacy and adverse events were compared before and after treatment.Results: After 8 weeks, PANSS total and subscale (positive, negative, general psychopathology) scores decreased significantly in both groups, with lower values in the observation group (P < 0.05). HAMD scores declined and RSA scores rose in both groups, and the observation group showed lower HAMD and higher RSA scores than the control group (P < 0.05). Serum 5-HT, DA and NT-3 levels increased in both groups, and the observation group exhibited higher levels than the control group (P < 0.05). The overall response rate was superior in the observation group (P < 0.05). The incidence of adverse reactions did not differ significantly between the two groups (P > 0.05). Conclusion:Aripiprazole ODT combined with sertraline not only markedly ameliorates psychotic and depressive symptoms, enhances psychological resilience and neurotrophic factor levels, but also provides better efficacy than aripiprazole monotherapy with comparable safety, thus deserving wider clinical application.