Efficacy and safety of semaglutide versus placebo for people with schizophrenia spectrum disorders with obesity or early-stage metabolic abnormalities: A systematic review and meta-analysis of randomized controlled studies
Minahil Rasul, Ahmad Hassan, Ubaid Ur Rehman, Muhammad Sarmad, Abdullah Shahid Farooq, Huzaifa Khalil, Muhammad Asad Jahangir, Zain Ul Abideen, Muhammad Kashif Bashir, Umaima Cheema, Maaz Amir, Mohammad Azeem Malik, Abdul Haseeb Hasan, Ramisha TahirBackground
Individuals with schizophrenia spectrum disorders are at increased risk of cardiometabolic complications, largely due to antipsychotic-associated metabolic effects. Effective management strategies remain limited. Semaglutide, a glucagon-like peptide-1 receptor agonist, has shown metabolic benefits in the general population, but its role in this population remains unclear.
Objective
To evaluate the efficacy and safety of semaglutide compared with placebo in individuals with schizophrenia spectrum disorders receiving antipsychotic therapy and experiencing metabolic abnormalities.
Design
Systematic review and meta-analysis of randomized controlled trials.
Data Sources
and Methods: A systematic review and meta-analysis was conducted following PRISMA guidelines. PubMed, Cochrane Library, Embase, and ScienceDirect were searched from inception to February 2026. Randomized controlled trials comparing semaglutide with placebo were included. The longest follow-up time point from each study was used for pooled analysis. Mean differences (MD) and odds ratios (OR) with 95% confidence intervals (CIs) were calculated using RevMan 5.4. The certainty of evidence for critical outcomes was assessed using the GRADE framework.
Results
Three randomized controlled trials (n = 258) were included. Semaglutide was associated with reductions in body weight (MD: -11.01 kg), BMI (MD: -3.63 kg/m 2 ), and waist circumference (MD: -6.33 cm). Improvements were also observed in body composition. No significant differences were found in lipid or glycemic parameters except HbA1c which showed a significant reduction. Psychiatric outcomes remained unchanged. Gastrointestinal adverse particularly nausea and vomiting events were more frequent with semaglutide.
Conclusion
Semaglutide appears to improve anthropometric outcomes without worsening psychiatric symptoms in individuals receiving antipsychotic therapy. However, evidence is limited, and larger, long-term trials are required. According to the GRADE framework, the certainty of evidence ranged from moderate for key anthropometric and safety outcomes to low or very low for several metabolic and psychiatric outcomes, highlighting the need for larger, long-term randomized trials.