Neuropsychiatric Outcomes With Tirzepatide, Semaglutide, and Other GLP-1 Receptor Agonists.

AIMS: Neuropsychiatric safety concerns, including depression and suicidal ideation, have emerged during the expanding clinical use of incretin-based therapies for type 2 diabetes mellitus (T2DM) and obesity. However, whether risks differ across successive generations of incretin-based therapies remains uncertain. MATERIALS AND METHODS: This retrospective cohort study used the TriNetX Global Federated Network (> 192 million patients). Adults with T2DM, obesity, or both initiating tirzepatide, semaglutide, or other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) between July 2022 and June 2025 were identified using a new-user design with a 12-month washout. Propensity score matching balanced demographic, clinical, and metabolic variables. Two comparisons were conducted: tirzepatide versus semaglutide and semaglutide versus other GLP-1 RAs. Follow-up included Year 1 (day 31-365) and Year 2 landmark analysis (day 366-730). Hazard ratios (HRs) for incident depression, anxiety, and suicidal ideation were estimated using Cox models. RESULTS: After matching, 85 546 pairs were included for tirzepatide versus semaglutide and 80 115 pairs for semaglutide versus other GLP-1 RAs. Tirzepatide and semaglutide showed similar risks for the composite psychiatric outcome (Year 1 HR 0.984 [95% CI 0.950-1.019]; Year 2 HR 1.002 [0.960-1.046]); a nominally higher anxiety hazard was observed with tirzepatide during Year 2 (HR 1.052 [1.001-1.106]), which should be interpreted cautiously given multiple comparisons. Compared with other GLP-1 RAs, semaglutide was associated with lower risks of depression (HR 0.811 [0.770-0.855]), anxiety (HR 0.915 [0.871-0.961]), suicidal ideation (HR 0.488 [0.339-0.702]), and the composite psychiatric outcome (HR 0.866 [0.832-0.901]) during Year 1. CONCLUSIONS: In real-world practice, tirzepatide and semaglutide demonstrated comparable neuropsychiatric risk profiles over 2 years. Semaglutide was associated with lower psychiatric event rates compared with earlier-generation GLP-1 receptor agonists.