Glucagon-like peptide-1 receptor agonists and risk of depression: a systematic review and meta-analysis

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven effectiveness in stimulating weight loss, as well as enhancing metabolic parameters. Nevertheless, the information available on the possible effects on mood and the risk of depression is not consistent, and it is possible that further research should evaluate the psychiatric safety of GLP-1RA usage. To conduct a systematic review and quantitatively assess whether the usage of GLP-1RA is associated with the increased risk of having depression-related adverse events and to learn more about the sources of heterogeneity. In accordance with the PRISMA guidelines, we systematically searched PubMed, Embase, Cochrane Library, Web of Science, Scopus, and LILACS for randomized controlled trials and observational studies published between 2000 and 2025. Studies were eligible if they enrolled adults with overweight or obesity and reported outcomes related to depression or mood. Random-effects models were used for meta-analysis, with heterogeneity, sensitivity analysis, meta-regression, and publication bias assessments conducted. A total of 19 studies were included in this systematic review. Combined findings revealed that the risk of depression was linked to the utilization of GLP-1RA (OR = 1.49, 95% CI: 1.18–1.88). Between-study heterogeneity was very high (I² = 99.21%) although sensitivity analysis revealed that the findings were robust. The heterogeneity was not explained by a single factor, indicating a multifactor interaction, as found in meta-regression. None of the publications exhibited any considerable bias. The current evidence suggests a possible association between use of GLP-1RA and an increased risk of depression, but overall risk seems to be dominated by population characteristics, drug class, and how mood outcomes are assessed. Given the metabolic benefits of GLP-1RAs, caution is advised in patients with a history of depression or psychiatric vulnerability and a heightened vigilance for these events is warranted. High-quality studies are warranted with psychiatric outcomes as primary endpoints in order to determine whether there is a causal relationship and to identify high-risk subpopulations.