Pooled SURMOUNT analysis finds no rise in depression risk with tirzepatide
Pooled results from three trials found no sign tirzepatide worsened depression in people without major psychiatric illness, a group the study excluded and one that monitoring guidance still covers.
A pooled analysis of three large tirzepatide trials found no sign that the drug raises the risk of depression in adults with overweight or obesity who had no known major psychiatric illness, according to results published January 15, 2026 in the journal Obesity [1].
The post hoc analysis combined SURMOUNT-1, SURMOUNT-2 and SURMOUNT-3, covering 4,056 participants who received tirzepatide — the drug sold as Mounjaro and Zepbound — at 5, 10 or 15 mg, or a maximum tolerated dose of 10 or 15 mg, and compared them with placebo [1]. Depression symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9) and suicide risk with the Columbia-Suicide Severity Rating Scale (C-SSRS) [1].
Mean PHQ-9 scores at the start were 2.7 for tirzepatide and 2.6 for placebo, which the authors describe as no or minimal symptoms of depression [1]. By week 72, scores were 1.9 and 2.4, an estimated treatment difference of −0.6 (standard error 0.1), with p < 0.001 [1]. Tirzepatide-treated participants were less likely to shift into a more severe PHQ-9 category: 18.2% versus 24.3% on placebo [1]. The paper describes the differences between groups in mean score changes as not clinically meaningful [1].
On suicidal thoughts and behaviors, 0.6% of participants in each group reported suicidal ideation, most of it rated low risk [1]. Nonfatal suicidal behavior was reported by 0.1% of tirzepatide-treated participants, or two people, and by none in the placebo group [1]. The paper also notes that a numerically greater percentage of tirzepatide-treated participants reported moderate-risk ideation, while overall rates of ideation and behavior were low and similar to those seen in pooled analyses of other incretin-based weight-management drugs [1]. Nervous system and psychiatric adverse events were generally similar across groups [1].
Two limits stand out. The comparison was post hoc, designed after the trials were run rather than as a pre-specified endpoint [1]. And people with known major psychiatric illness were excluded, so the findings do not describe them; the authors wrote that further study of tirzepatide's safety in people with significant psychiatric illness may be warranted [1].
The authors support recommendations from regulatory authorities that health care professionals monitor mood and behavior in patients prescribed incretin-based therapies for weight management, together with continued post-marketing surveillance [1]. The paper cites a January 2024 FDA review of GLP-1 receptor agonists that concluded the agency had "not found evidence that use of these medications causes suicidal thoughts or actions" [1].
Why it matters for patients
People considering or already taking tirzepatide often hear that weight-loss drugs can affect mood. In this analysis, a group that started with minimal depression symptoms saw PHQ-9 scores drift slightly downward on the drug over 72 weeks, and suicidal ideation was reported at the same rate as placebo — 0.6% in each group [1]. About 18% of tirzepatide-treated participants versus 24% of those on placebo moved into a more severe symptom category [1].
The group studied matters. Because participants had no known major psychiatric illness and began with very low scores, the results say little about someone already living with depression, anxiety or a history of suicidal thoughts. Those people were not included, and the paper says studying them further may be warranted [1]. The small average score change also does not show that tirzepatide lifts mood [1].
What the paper does not change is monitoring. It backs existing regulatory advice that clinicians watch for changes in mood and behavior in anyone prescribed these drugs [1].
What happens next
The analysis appears in Obesity, volume 34, issue 3, pages 565-578, first published January 15, 2026 [1]. The three trials it draws on are registered as NCT04184622, NCT04657003 and NCT04657016 [1]. Whether new studies focused on people with significant psychiatric illness are planned has not been disclosed in the paper [1].
Sources
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