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

## TL;DR

This study found that tirzepatide, a weight-loss drug, did not increase depression or suicidal thoughts in people with obesity and no major mental health issues.

## Contribution

The study provides new evidence on the psychiatric safety of tirzepatide in a large sample of individuals with obesity.

## Key findings

- Tirzepatide was associated with lower depression scores compared to placebo at week 72.
- Suicidal ideation and behavior rates were low and similar between tirzepatide and placebo groups.
- Adverse events were generally similar across treatment groups.

## Abstract

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.

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.

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.

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.

ClinicalTrials.gov identifiers: NCT04184622, NCT04657003, and NCT04657016

Obesity is associated with an increased risk of depression and other psychiatric disorders which health care professionals have been advised to monitor in patients prescribed medications approved for weight management.In the SURMOUNT clinical trial program, robust weight reduction was observed with once weekly tirzepatide treatment, a once weekly dual GIP/GLP‐1 receptor agonist, in people with obesity or overweight, with and without type 2 diabetes, compared to placebo.

Obesity is associated with an increased risk of depression and other psychiatric disorders which health care professionals have been advised to monitor in patients prescribed medications approved for weight management.

In the SURMOUNT clinical trial program, robust weight reduction was observed with once weekly tirzepatide treatment, a once weekly dual GIP/GLP‐1 receptor agonist, in people with obesity or overweight, with and without type 2 diabetes, compared to placebo.

In this post hoc pooled analysis of 4056 participants in SURMOUNT‐1, SURMOUNT‐2, and SURMOUNT‐3, no clinically meaningful differences were observed in mean changes in Patient Health Questionnaire‐9 scores between the pooled tirzepatide (5/10/15 mg) and placebo groups. Reports of overall suicidal ideation (SI), assessed by the Columbia‐Suicide Severity Rating Scale, were similar between groups, although a numerically greater percentage of tirzepatide‐ than placebo‐treated participants reported moderate‐risk SI. Two participants in the tirzepatide group versus none in placebo reported nonfatal suicidal behavior (SB).

In this post hoc pooled analysis of 4056 participants in SURMOUNT‐1, SURMOUNT‐2, and SURMOUNT‐3, no clinically meaningful differences were observed in mean changes in Patient Health Questionnaire‐9 scores between the pooled tirzepatide (5/10/15 mg) and placebo groups. Reports of overall suicidal ideation (SI), assessed by the Columbia‐Suicide Severity Rating Scale, were similar between groups, although a numerically greater percentage of tirzepatide‐ than placebo‐treated participants reported moderate‐risk SI. Two participants in the tirzepatide group versus none in placebo reported nonfatal suicidal behavior (SB).

In this post hoc analysis, tirzepatide relative to placebo was not associated with an increased risk of symptoms of depression. Occurrences of SI/SB were low and similar to those observed in pooled analyses of other incretin‐based therapies approved for chronic weight management.The authors support regulatory authorities' recommendations for health care professionals to monitor mood and behavior in patients prescribed incretin‐based therapies for weight management, combined with continued post‐marketing surveillance.

In this post hoc analysis, tirzepatide relative to placebo was not associated with an increased risk of symptoms of depression. Occurrences of SI/SB were low and similar to those observed in pooled analyses of other incretin‐based therapies approved for chronic weight management.

The authors support regulatory authorities' recommendations for health care professionals to monitor mood and behavior in patients prescribed incretin‐based therapies for weight management, combined with continued post‐marketing surveillance.