Efficacy and safety of pharmacological and non-pharmacological interventions for antipsychotic-induced weight gain in individuals with schizophrenia: A systematic review and network meta-analysis of 55 clinical trials.

INTRODUCTION: Schizophrenia is a severe mental disorder that impacts thoughts, emotions, and behavior, affecting 0.32% of the global population. While antipsychotic medications are crucial for managing symptoms, nearly half of individuals with schizophrenia experience weight gain, leading to treatment non-compliance and further health complications. Our systematic review and network meta-analysis aim to provide comprehensive evidence on the safety and efficacy of pharmacological and non-pharmacological interventions for antipsychotic-induced weight gain. METHODS: We conducted this study in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, following our protocol (CRD42024599597). We searched PubMed, Scopus, Web of Science, and Cochrane Library until July 2025. Only randomized placebo-controlled trials were included. We focused on anthropometric measurements and safety profiles. The primary outcome was weight change, while the secondary outcomes included waist-hip ratio, waist circumference, and hip circumference. RESULT: Fifty-five studies were included in the meta-analysis, with a total of 2977 individuals. Regarding the weight change, the highest three interventions hold the highest probability of being the most effective therapy in weight loss compared to the Usual care group were Semagultide (MD: -13.5 [-17.3, -9.57], followed by Metformin + NutriEx (MD: -6.34, [-9.85, -2.9]), then Nizatidine (MD: -5.46 [-7.77, -2.76]). According to non-pharmacological interventions, all interventions showed significant reductions in weight (-value < 0.05). CONCLUSION: We found that Semaglutide has the highest probability of being the most effective therapy in the reduction of weight gain and BMI. Liraglutide was associated with mild adverse effects. Additional trials focusing on non-pharmacological approaches are essential.