Semaglutide Not Linked to Suicidal Risks in Those Without Major Psychiatric Disorders

Thomas Wadden, PhD

Credit: Penn Medicine

Taking semaglutide for weight management does not increase the risk of depression or suicidal thoughts among individuals without a known major mental health disorder, a post-hoc analysis discovered.

This contradicts a recent disproportionality analysis that uncovered semaglutide may be linked to increased suicidal ideation, the first study reaching this finding with sufficient power. This study had assessed the association of potential signals for suicidal and self-harm adverse drug reactions with semaglutide and liraglutide. This analysis detected participants had 45% greater odds of reporting semaglutide-associated suicidal ideation.

However, this recent post-hoc analysis, led by Thomas A. Wadden, PhD, from Perelman School of Medicine at University of Pennsylvania, reached a different conclusion.

“Our new analyses provide assurance that the medication, when taken by individuals who are free of significant mental health concerns, does not increase the risk of depression, suicidal thoughts, or suicidal behavior,” Wadden said in a statement.

Obesity is linked to several psychosocial complications. Thus, investigators emphasize the importance of considering psychiatric safety when treating patients with obesity.

Wadden and colleagues sought to determine whether taking semaglutide 2.4 mg once weekly would affect the risk of developing symptoms of depression, suicidal ideation, or suicidal behavior in individuals who were overweight or obese and without a known major psychopathology. The team conducted a post-hoc analysis of the randomized, double-blind, placebo-controlled, multicenter phase 3a STEP 1, 2, and 3 trials over 68 weeks (2018 – 2020) and the STEP 5 trial over 105 weeks (2018 – 2021).

The study included 3377 participants in the STEP 1, 2, and 3 trials with 69.9% women, 71.5% White, and a mean age of 49 years. STEP 5 included 304 participants, with 77.6% women, 93.1% White, and the mean age 47 years. Common comorbidities included hypertension (43.8% and 38.8%, respectively) and dyslipidemia (44% and 35.2%, respectively).

Participants in STEP 1,2, and 3 trials had mean baseline Patient Health Questionnaire 9 (PHQ-9) scores of 2.0 and 1.8 for participants on semaglutide and placebo, respectively, which indicates participants had minimal symptoms of depression. In these trials, 25% of participants receiving semaglutide and 25% receiving placebo reported concurrent psychiatric disorders.

Investigators saw no clinically meaningful differences in depressive symptoms between the active arm and placebo arm throughout the trials, reflected in the mean PHQ-9 scores. At week 69, participants on semaglutide and placebo had PHQ-9 scores of 2.0 and 2.4, respectively, and the estimated treatment difference between groups was -0.56 (95% confidence interval [CI], -0.81 to -0.32; P < .001). Participants treated with semaglutide were less likely to shift from baseline to week 68 to a more severe category of PHQ-9 depression (odds ratio [OR], 0.63; 95% CI, 0.50 – 0.79; P < .001).

The groups had a similar proportion of participants reporting suicidal ideation or behavior, as evaluated by the Columbia-Suicide Rating Scale. Only ≤ 1% of participants reported suicidal ideation or behavior during treatment, and investigators saw no differences between semaglutide and placebo. Ultimately, similar psychiatric adverse events were seen between groups, and the team observed similar results in STEP 5.

The main limitation of the study was excluding individuals with lifetime suicide attempts, current high-risk suicidal ideation, recently diagnosed major depressive disorder, and other clinically significant psychopathology.

“It is certainly possible that individuals with overweight or obesity who take semaglutide may experience depressive symptoms or suicidal ideation or behavior, but the data suggest that persons not taking semaglutide—in the placebo group in this study—are equally likely to experience these conditions,” said Gregory Brown, PhD, a study co-author and director of the Penn Center for the Prevention of Suicide at the Perelman School of Medicine.

References

1. ^{Wadden TA, Brown GK, Egebjerg C, et al. Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology: Post Hoc Analysis of the STEP 1, 2, 3, and 5 Trials. JAMA Intern Med. Published online September 03, 2024. doi:10.1001/jamainternmed.2024.4346}
2. ^{Derman, C. Semaglutide Linked to Suicidal Ideation, New Study Reveals. HCPLive. August 23, 2024. https://www.hcplive.com/view/semaglutide-linked-to-suicidal-ideation-new-study-reveals. Accessed September 4, 2024.}