As GLP-1 receptor agonists (GLP-1 RAs) are increasingly used worldwide, concerns about their association with mood disorders have grown. Yet real-world observational studies have produced conflicting findings. This study aims to fully examine the link between GLP-1 RAs and emotional/behavioral outcomes.

Disproportionality analysis of GLP-1 RA adverse events was conducted using FAERS data. Mendelian randomization (MR) employed GLP1R cis-eQTLs as instrumental variables to assess links with mood/behavior-related disorders. Summary-data MR (SMR) was then performed using GLP1R cis-eQTL data.

275,718 adverse events (AEs) associated with GLP-1 RAs were retrieved and analyzed. A mild signal for suicide-related AEs was observed only in the obesity indication subgroup (ROR:1.65, 95% CI: 1.28–2.12). Genetic evidence showed that GLP-1 RAs were likely associated with reduced risks of anxiety, depression, emotional lability, bipolar disorder, and suicide. Mediational analysis indicated that weight loss partially mediated the causal effects of GLP-1 RAs on depression and emotional lability, accounting for 18.28% (95% CI: 9.46–27.10%, P = 0.038) and 7.65% (95% CI: 5.66–9.64%, P < 0.001) of the total effects, respectively. SMR analysis showed that genetically predicted GLP1R expression was negatively associated with anxiety (OR: 0.79, 95% CI: 0.64–0.98, P = 0.031), with no significant associations for other emotional or behavioral outcomes.

Both observational and MR analyses showed that patients treated with GLP-1 RAs may have no increased risk of emotional and behavioral disorders. Instead, genetic proxy activation of GLP-1 RAs may reduce the risk of anxiety, depression, and emotional lability.