Semaglutide significantly reduces weight and improves glycemic control in schizophrenia spectrum disorders

People with schizophrenia spectrum disorders (SSDs) face disproportionately high rates of obesity and metabolic dysfunction, often exacerbated by antipsychotic medications like clozapine and olanzapine. These metabolic comorbidities contribute significantly to excess morbidity and mortality, creating a critical treatment gap. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) like semaglutide have proven highly effective for weight and glycemic management in the general population, their safety and efficacy specifically within the SSD population have remained less clear, limiting their clinical application.

This preregistered systematic review and meta-analysis synthesized all placebo-controlled, randomized controlled trials (RCTs) investigating semaglutide and/or tirzepatide in adults with schizophrenia spectrum disorders. The analysis pooled data from three trials (n = 258), all examining semaglutide dosages of 1.0-2.0 mg administered over 26-36 weeks. No trials involving tirzepatide met the inclusion criteria. Outcomes and adverse events were analyzed using random-effects meta-analysis, and the certainty of evidence was assessed via GRADE criteria.

Semaglutide demonstrated clinically meaningful improvements across key metabolic parameters in people with SSDs. It significantly reduced body weight by -11.32 kg (95% CI -15.35 to -7.29), body mass index by -3.58 kg/m2 (95% CI -4.86 to -2.30), and improved glycemic control. Hemoglobin A1c (HbA1c) decreased by -0.37% (95% CI -0.51 to -0.22), and fasting glucose dropped by -0.54 mmol/L (95% CI -0.94 to -0.13). The adverse event profile was consistent with known GLP-1 RA effects in the general population. > 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). Importantly, there was no evidence of an increased risk of serious adverse events.