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.