The safety and efficacy of semaglutide in people with schizophrenia spectrum disorders: systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: People with schizophrenia spectrum disorders (SSDs) experience high rates of obesity and metabolic dysfunction, contributing substantially to excess morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide and tirzepatide have demonstrated substantial efficacy for weight and glycaemic outcomes in the general population, but evidence in people with SSDs remains limited. AIMS: To synthesise all placebo-controlled, randomised controlled trials (RCTs) examining semaglutide and/or tirzepatide in people with SSDs. METHOD: A preregistered systematic review and meta-analysis of RCTs examining the efficacy and safety of semaglutide and/or tirzepatide in adults with SSDs was conducted. Outcomes and adverse events were pooled using random-effects meta-analysis. Certainty of evidence was assessed using the GRADE criteria. RESULTS: Three trials ( = 258) met inclusion criteria, examining semaglutide dosages of 1.0-2.0 mg over 26-36 weeks. No trials examining tirzepatide were found. Semaglutide significantly reduced body weight (-11.32 kg; 95% CI -15.35 to -7.29), body mass index (-3.58 kg/m; 95% CI -4.86 to -2.30), haemoglobin A1c (-0.37%; 95% CI -0.51 to -0.22) and fasting glucose (-0.54 mmol/L; 95% CI -0.94 to -0.13). In adverse event analyses, semaglutide was associated with increased risks of abdominal pain (risk ratio 2.93; 95% CI 1.13-7.60), vomiting (risk ratio 2.57; 95% CI 1.39-4.77) and constipation (risk ratio 3.23; 95% CI 1.14-9.18). There was no evidence of increased risk of serious adverse events. CONCLUSIONS: Semaglutide produces clinically meaningful improvements in weight and glycaemic outcomes in people with SSDs, with an adverse event profile consistent with known gastrointestinal effects of GLP-1 RAs in the general population. These findings support semaglutide as a promising adjunctive metabolic intervention in this population, although larger and longer trials, specifically those testing tirzepatide, are needed to better characterise heterogeneity of effects and long-term safety of these promising pharmacological treatments.