Large-Scale Study Finds Comparable Neuropsychiatric Risk for Tirzepatide and Semaglutide
A retrospective cohort study published on July 8, 2026, in Diabetes, Obesity & Metabolism assessed the neuropsychiatric safety of tirzepatide, semaglutide, and other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in adults with type 2 diabetes, obesity, or both. Solomon Chih-Cheng Chen and colleagues analyzed data from the TriNetX Global Federated Network, which includes records from more than 192 million patients worldwide.
The study addressed concerns about possible neuropsychiatric side effects, such as depression and suicidal ideation, as use of incretin-based therapies increases. The researchers compared risks among newer and older GLP-1 receptor agonists. They included adults who started tirzepatide, semaglutide, or other GLP-1 RAs between July 2022 and June 2025, applying a new-user design and a 12-month washout period. Propensity score matching was used to balance demographic and clinical characteristics among the groups.
The analysis focused on two main comparisons: tirzepatide versus semaglutide (85,546 matched pairs) and semaglutide versus other GLP-1 RAs (80,115 matched pairs). The team tracked depression, anxiety, and suicidal ideation over two years, with separate results for Year 1 and Year 2 after starting treatment.
Tirzepatide and semaglutide showed similar risks for the composite psychiatric outcome in both years (Year 1 hazard ratio [HR] 0.984, 95% CI 0.950–1.019; Year 2 HR 1.002, 95% CI 0.960–1.046). Tirzepatide was linked to a slightly higher risk of anxiety in Year 2 (HR 1.052, 95% CI 1.001–1.106), but the authors advised caution in interpreting this finding due to multiple comparisons.
Semaglutide, when compared to earlier-generation GLP-1 RAs, was associated with lower risks of depression, anxiety, suicidal ideation, and the composite psychiatric outcome during Year 1. The hazard ratio for depression was 0.811 (95% CI 0.770–0.855), for anxiety 0.915 (95% CI 0.871–0.961), for suicidal ideation 0.488 (95% CI 0.339–0.702), and for the composite outcome 0.866 (95% CI 0.832–0.901).
The authors concluded that tirzepatide and semaglutide have similar neuropsychiatric safety profiles over two years in routine clinical settings. Semaglutide was linked to lower psychiatric event rates compared to earlier GLP-1 receptor agonists. The study recommends ongoing post-marketing surveillance as these medications are prescribed for diabetes and obesity.
Additional research may help clarify the significance of the observed differences and provide more information on neuropsychiatric outcomes over longer periods or in specific patient groups. The full study is available at the provided PubMed link.