Efficacy of Glucagon-Like Peptide-1 Receptor Agonists for Psychological Well-Being and Depressive Symptoms: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic disorders. Howeve, their effects on depressive symptoms and psychological well-being remain uncertain. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials evaluating the effects of GLP-1RAs on depressive symptoms and psychological well-being. Random-effects models were used to calculate standardized mean differences (SMDs). Subgroup and meta-regression analyses were performed to explore heterogeneity. The protocol was registered with PROSPERO (CRD42024566217). RESULTS: In total, 25 trials (17,751 participants) evaluated psychological well-being and 11 trials (1961 participants) evaluated depressive symptoms. GLP-1RA treatment was associated with a small but significant improvement in psychological well-being compared with control conditions (SMD = 0.374, 95% CI 0.093-0.656), whereas no significant effect was observed for depressive symptoms (SMD = 0.079, 95% CI -0.024-0.182). Improvements in psychological well-being were consistently observed in studies using semaglutide, tirzepatide or liraglutide, subcutaneous administration, and in populations with type 2 diabetes mellitus or obesity. CONCLUSIONS: GLP-1RA treatment was associated with modest improvements in psychological well-being but not depressive symptoms. These findings should be interpreted cautiously and suggest that any observed psychological benefits are likely indirect, potentially reflecting improvements in metabolic status or general health, rather than direct mood-improving effects.