GLP-1 and dual GIP/GLP-1 receptor agonists' psychopharmacology and putative neuropsychiatric associated effects: a Bradford Hill-informed, systematic, evaluation

Purpose of review: This review evaluates evidence linking both GLP-1 and GIP/GLP-1RAs' exposure to a range of neuropsychiatric outcomes using the Bradford Hill criteria for causal inference. Recent findings: Glucagon-like peptide-1 (GLP-1) and the dual glucose-dependent insulinotropic polypeptide-GIP/GLP-1 receptor agonists (RAs) are incretin-based medications widely prescribed for type 2 diabetes mellitus and obesity, with demonstrated cardiometabolic benefit and rapidly expanding population exposure. In parallel, post-marketing surveillance and emerging translational research have raised questions regarding potential central nervous system effects, including neuropsychiatric adverse events and psychopharmacological properties. Integrating data from receptor pharmacology, preclinical neuroscience, randomized controlled trials, and observational and pharmacovigilance studies, the strength, consistency, biological plausibility, and experimental support for reported associations with depression, anxiety, suicidality, reward-related behaviour, cognitive effects and retinal/ocular related disturbances were here assessed. Implications for clinical risk-benefit assessment were discussed as well. Current evidence supports potential biological plausibility of a relationship between GLP-1 RAs and a range of psychopathological disorders but remains insufficient to establish causality for most neuropsychiatric outcomes, suggesting the need for prospective, mechanism-informed clinical studies.