Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the treatment of overweight and obesity because of their established efficacy in achieving clinically meaningful weight loss. However, concerns have emerged regarding their potential association with neuropsychiatric outcomes, including depressive and anxiety symptoms, manic or hypomanic symptoms, and suicidal ideation or behavior. This systematic review aimed to synthesize the available evidence on neuropsychiatric outcomes associated with GLP-1 RA use in adults with overweight or obesity. Methods: A systematic search of PubMed/MEDLINE, Scopus, and Web of Science was conducted following PRISMA 2020 guidelines. Eligible studies included randomized controlled trials, longitudinal observational studies, and cross-sectional studies evaluating neuropsychiatric outcomes associated with GLP-1 RAs in adults with overweight or obesity. Risk of bias was assessed using RoB 2, ROBINS-I, and the Joanna Briggs Institute Critical Appraisal Checklist according to study design. Given the clinical and methodological heterogeneity of the included studies, findings were synthesized narratively in accordance with SWiM guidance, and certainty of evidence was assessed at the outcome level using GRADE. Results: Fourteen studies were included, comprising four randomized studies, nine longitudinal observational studies, and one analytical cross-sectional study. Randomized evidence showed no consistent worsening of depressive symptoms or imbalance in suicide-related outcomes, whereas observational findings were heterogeneous. For depression, observational HRs ranged from 0.63 to 2.95 across different populations and comparators, while randomized studies showed small or no between-group differences in depressive symptoms. For suicide-related outcomes, observational HRs/aHRs ranged from 0.27 to 2.06, while suicidal ideation or behavior was uncommon in randomized studies and showed no consistent treatment imbalance. Anxiety-related findings were also heterogeneous, and manic or hypomanic symptoms were not systematically assessed. GRADE certainty was low for depressive symptoms and very low for anxiety and suicide-related outcomes. Conclusions: Current evidence does not demonstrate a consistent increase in adverse neuropsychiatric outcomes associated with GLP-1 receptor agonists in adults with overweight or obesity. Although some studies reported neutral or potentially beneficial associations, observational findings were heterogeneous, and the certainty of evidence was low or very low across the assessable outcomes. These findings do not establish a class-wide neuropsychiatric safety effect, particularly given differences among individual agents, study populations, and baseline psychiatric characteristics. Further prospective studies specifically designed to assess neuropsychiatric outcomes, including individuals with pre-existing psychiatric disorders, are warranted.
