The safety and efficacy of semaglutide in people with schizophrenia spectrum disorders: systematic review and meta-analysis of randomised controlled trials.
This systematic review and meta-analysis synthesized evidence from three placebo-controlled randomized controlled trials (total n = 258) examining semaglutide in adults with schizophrenia spectrum disorders (SSDs). The authors conducted a preregistered search, pooled outcomes using random-effects meta-analysis, and assessed evidence certainty using GRADE criteria. The included trials tested semaglutide over 26–36 weeks. The study found that, compared to placebo, semaglutide was associated with statistically significant reductions in body weight (approximately −11.3 kg), BMI (approximately −3.6 kg/m²), HbA1c (approximately −0.37%), and fasting glucose. On the safety side, semaglutide was associated with meaningfully higher risks of abdominal pain, vomiting, and constipation, consistent with the known gastrointestinal profile of GLP-1 receptor agonists; no elevated risk of serious adverse events was observed. The authors note that the overall evidence base is limited by a small number of trials, modest combined sample size, and relatively short follow-up durations. No trials of tirzepatide in this population were identified. The authors conclude that semaglutide shows promise as an adjunctive metabolic treatment in SSDs but call for larger, longer trials.
Why this grade: The meta-analysis pools data exclusively from placebo-controlled RCTs in humans, supporting a moderate grade, but the evidence is constrained by only three trials with a combined sample of 258 participants and follow-up of under one year.
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 ( n = 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 2 ; 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.
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