Efficacy of pharmacological and nutritional interventions for glucose dysfunction in schizophrenia—A systematic review and network meta-analysis

INTRODUCTION: Individuals with schizophrenia experience disproportionately high rates of impaired glucose tolerance and insulin resistance. While pharmacological strategies have demonstrated efficacy, concerns about polypharmacy and drug-drug interactions highlight the need to evaluate alternative approaches. METHODS: We systematically searched PubMed, EMBASE, Web of Science, and CENTRAL up to February 10, 2025, for randomized controlled trials assessing pharmacological or nutritional interventions on metabolic outcomes in schizophrenia. Eligible trials reported fasting blood glucose, HbA1c, serum insulin, or Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Secondary outcomes included anthropometrics, lipid profiles, and psychopathology (Positive and Negative Syndrome Scale). Data were synthesized using Bayesian network meta-analysis with random-effects, and treatments were ranked using surface under the cumulative ranking curve. Risk of bias was assessed with RoB 2. RESULTS: A total of 102 RCTs including 7278 participants were analyzed. For fasting glucose, topiramate, synbiotic, vitamin E, and probiotic/selenium were beneficial. Metformin improved insulin levels and HOMA-IR, while aripiprazole showed significant improvement in HbA1c. Secondary outcomes revealed reductions in body mass index and body weight with aripiprazole, liraglutide, metformin, nizatidine, sibutramine, topiramate, zonisamide, and berberine. Lipid improvements were observed with aripiprazole, liraglutide, pioglitazone, pravastatin, sitagliptin, topiramate, berberine, synbiotic, and Withania somnifera. Evidence for most nutritional supplements was limited and heterogeneous. CONCLUSIONS: This study provides the first integrated comparison of pharmacological and nutritional interventions for glucose dysfunction in schizophrenia. Metformin showed the most consistent benefits, whereas aripiprazole, topiramate, liraglutide, and select supplements demonstrated additional advantages. These findings highlight the importance of targeting glucose dysregulation as a core therapeutic priority and support the cautious but promising role of nutritional agents alongside established pharmacological strategies.