Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for the management of type 2 diabetes mellitus (T2DM) due to their metabolic and cardiovascular benefits; however, concerns have emerged regarding potential neuropsychiatric effects, including depression. This systematic review and meta-analysis aimed to evaluate the association between GLP-1 RA use and the risk of developing depression in adults with T2DM. A systematic search of PubMed, Embase, Scopus, Web of Science, and the Cochrane Library was conducted from database inception through April 2025 to identify randomized controlled trials and observational studies comparing GLP-1 RAs with other antidiabetic therapies. The primary outcome was incident depression. Secondary outcomes included anxiety-related outcomes and reported adverse events. Risk of bias was assessed using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool and the Newcastle-Ottawa Scale, where appropriate. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Nine studies involving 1,735,325 patients met the inclusion criteria, of which five contributed to the quantitative synthesis. The meta-analysis demonstrated no statistically significant difference in the risk of incident depression between GLP-1 RA users and those receiving other antidiabetic agents (HR 1.05; 95% CI 0.97-1.14), with substantial heterogeneity observed (I² = 83.2%). Sensitivity analysis showed that exclusion of one influential study increased the pooled estimate to a statistically significant hazard ratio (HR 1.09; 95% CI 1.01-1.19; p = 0.035). Limited evidence suggested potential benefits in anxiety-related outcomes in some studies, although findings were heterogeneous and not amenable to quantitative synthesis. Reported adverse events were predominantly gastrointestinal. Overall, the available evidence suggests that GLP-1 RA use is not associated with an increased risk of depression in adults with type 2 diabetes, though heterogeneity across studies highlights the need for further prospective research with standardized psychiatric outcome assessment.
