Semaglutide improves physical quality of life in schizophrenia with prediabetes

BACKGROUND: People with schizophrenia experience markedly reduced health-related quality of life (QoL), partly driven by obesity and metabolic dysregulation. Glucagon-like peptide-1 receptor agonists such as semaglutide induce substantial weight loss in the general population and in patients receiving antipsychotic medication. However, the extent to which semaglutide-associated weight loss mediates changes in QoL and symptom severity in schizophrenia remains unclear. METHODS: This secondary analysis of a randomized, double-blind, placebo-controlled trial included 154 adults with schizophrenia spectrum disorder, prediabetes, and overweight or obesity. Participants were randomized 1:1 to once-weekly semaglutide or placebo for 30 weeks. Outcomes were the SF-36v2 Physical and Mental Component Summary scores (PCS, MCS) and the Positive and Negative Syndrome Scale, 6-item version (PANSS-6). Causal mediation analyses estimated natural direct and indirect effects of semaglutide via weight loss at weeks 15 and 30. RESULTS: Semaglutide improved PCS at weeks 15 and 30, with effect sizes exceeding the minimally important difference. Indirect effects via weight loss were positive but not statistically significant, although at week 30 approximately half of the total PCS effect was estimated to be mediated through weight change. No total or mediated effects were found for MCS. For PANSS-6, no meaningful mediation was observed. CONCLUSIONS: Semaglutide improved physical QoL in patients with schizophrenia, and weight loss may partially contribute to this effect. Longer-term studies are needed to determine whether mental QoL or symptom effects emerge beyond 30 weeks.