Psychiatric Safety of Tirzepatide in People With Obesity and No Known Major Psychopathology: A Post Hoc Analysis of SURMOUNT

Objective This post hoc analysis assessed psychiatric changes with tirzepatide in adults with obesity, without known major psychopathology, from SURMOUNT‐1, SURMOUNT‐2, and SURMOUNT‐3. Methods In participants ( N = 4056) treated with tirzepatide (5/10/15 mg or maximum tolerated dose 10/15 mg) versus placebo, depressive symptoms and suicidal ideation and behavior (SI/SB) were measured using the Patient Health Questionnaire‐9 (PHQ‐9) and Columbia‐Suicide Severity Rating Scale (C‐SSRS), respectively. Nervous system and psychiatric disorder adverse events (AEs) were collected. Results Mean (SD) baseline PHQ‐9 scores were 2.7 (3.0) for tirzepatide and 2.6 (3.1) for placebo, indicating no/minimal symptoms of depression. At week 72, scores were 1.9 (2.7) and 2.4 (3.3), respectively (estimated treatment difference [SE]: −0.6 [0.1]); p < 0.001. Tirzepatide‐treated participants were less likely to shift to a more severe PHQ‐9 category (18.2% vs. 24.3%; p < 0.001). Using the C‐SSRS, 0.6% of participants in each group reported SI, most of which was considered low risk. SB (nonfatal) occurred in 0.1% of tirzepatide‐treated participants versus none with placebo. AEs were generally similar across groups. Conclusions In this post hoc analysis, tirzepatide versus placebo did not appear to be associated with an increased risk of depression in participants with overweight/obesity and without known major psychopathology. Rates of SI/SB observed with tirzepatide were similar to those of other incretin‐based therapies. Further study of tirzepatide's safety in persons with significant psychiatric illness may be warranted. Trial Registration ClinicalTrials.gov identifiers: NCT04184622, NCT04657003, and NCT04657016