Association between tirzepatide use and risk of suicidal ideation among individuals with obesity and major depressive disorder

Obesity and major depressive disorder (MDD) frequently co-occur and confer mutually reinforcing risks, including elevated suicidality. Tirzepatide has demonstrated substantial metabolic benefits, yet its psychiatric safety in high-risk populations with MDD remains uncertain. This study aimed to compare suicidal ideation outcomes among adults with comorbid obesity and MDD initiating tirzepatide versus non–GLP-1RA anti-obesity medications. This retrospective, propensity score–matched cohort study used deidentified electronic health record data from the TriNetX Global Collaborative Network. Adults (≥18 years) with diagnosed obesity and MDD who initiated tirzepatide or non–GLP-1RA anti-obesity medications were included. The primary outcome was suicidal ideation. Secondary outcomes included anxiety disorders, insomnia disorders, all-cause mortality, and emergency department or inpatient encounters. Among 24,103 matched pairs, tirzepatide use was associated with lower risk of suicidal ideation (HR, 0.63; 95% CI, 0.42–0.93), anxiety disorders (HR, 0.83; 95% CI, 0.81–0.86), insomnia disorders (HR, 0.92; 95% CI, 0.86–0.98), all-cause mortality (HR, 0.38; 95% CI, 0.25–0.58), and emergency department visits or hospitalizations (HR, 0.94; 95% CI, 0.89–0.99). Risk reduction was generally consistent across prespecified subgroups. Control outcome analyses supported the internal validity of the findings. In conclusion, this study provides real-world evidence that tirzepatide initiation was associated with a lower recorded risk of suicidal ideation, as well as reduced anxiety, insomnia, all-cause mortality, emergency department visits, and hospitalizations, among adults with comorbid obesity and MDD. This observational association should not be interpreted as evidence of a direct antisuicidal effect. These findings support the potential for tirzepatide to serve as a metabolically favorable treatment option associated with a lower risk of suicidal ideation in this vulnerable, high-risk population.