Semaglutide Does Not Increase Depression or Suicidal Ideation Risk in Adults With Overweight, Obesity

New study findings published in JAMA Internal Medicine demonstrate that the risk of developing symptoms of depression or suicidal ideation is similar between treatment with semaglutide (Wegovy; Novo Nordisk) and placebo among individuals with overweight or obesity.¹

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Around 70% of US adults are classified as overweight or obese, which are serious health issues linked to major causes of death, including heart disease, stroke, diabetes, and certain cancers. However, losing 5% to 10% of body weight through lifestyle changes could reduce cardiovascular disease risk, according to the FDA.²

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that was granted FDA approval in 2021 for chronic weight management in adults with obesity or overweight with at least 1 weight-related condition. The under-the-skin injection was approved as a 2.4 mg once-weekly dose in addition to a reduced-calorie diet and increased physical activity.² After 68 weeks of treatment, semaglutide produces approximately a 10% to 15% mean reduction in baseline body weight, demonstrating clinically meaningful improvements in cardiovascular events.¹

Obesity, especially with a body mass index (BMI) of 40 or greater, is also linked to increased risks of depression and other mental illnesses. This is potentially due to weight stigma, a bidirectional relationship between obesity and depression, and increased inflammation, which can negatively impact psychosocial well-being and quality of life.¹

“Concerns about potential psychiatric adverse events in people with clinically significant depression have accompanied the development of medications for chronic weight management, which, except for orlistat, access brain regions that regulate energy intake and may interact with mood-influencing pathways,” the study authors said in a news release.¹

With the increased use of GLP-1s, researchers evaluated the psychiatric safety of subcutaneous semaglutide compared with placebo in a post hoc analysis among individuals without known major psychopathology. The study used pooled data from the randomized, double-blind, placebo-controlled, multicenter phase 3a STEP 1, 2, and 3 trials and phase 3b STEP 5 trial. The analysis included 3377 individuals from the STEP 1, 2, and 3 trials and 304 individuals from the STEP 5 trial.¹

The study authors noted that the depressive symptoms and suicidal ideation and behavior were assessed using the Patient Health Questionnaire (PHQ-9) and Columbia-Suicide Severity Rating Scale (C-SSRS). The PHQ-9 total scores range from 0 to 27, with 0 to 4, 5 to 9, 10 to 14, 15 to 19, and 20 or greater suggesting no or minimal, mild, moderate, moderately severe, and severe symptoms of depression, respectively. The C-SSRS identified suicidal ideation as: a wish to be dead, nonspecific active suicidal thoughts, active suicide ideation with any method (no plan) without intent to act, active suicide ideation with some intent to act without a specific plan, and active suicide ideation with a specific plan and intent.¹

In the STEP 1, 2, and 3 trials, the 2.4 mg semaglutide group and the placebo group both showed minimal depression symptoms at baseline, with mean PHQ-9 scores of 2.0 and 1.8, respectively.¹

The results demonstrated that by week 68, the semaglutide group had a statistically significant lower score of 2.0 compared with 2.4 in the placebo group, with a treatment difference of -.56. Additionally, individuals treated with semaglutide were less likely to worsen in depression severity (odds ratio: .63; P < .001), and suicidal ideation and behavior remained low and similar between both groups.¹

“Most participants in both groups reported no change or improvement in their mood during the in-trial period, results that are similar to those observed with behavioral weight loss interventions. Although in some analyses semaglutide, 2.4 mg, showed statistically greater improvements in depressive symptoms than placebo, we do not consider these differences to be clinically meaningful,” the study authors said in a news release.¹

The findings suggest that treatment with 2.4 mg of semaglutide did not increase the risk of developing suicidal ideation or behavior compared to placebo. However, the study authors noted that individuals with obesity should be monitored for mental health concerns to ensure they receive applicable care.¹

REFERENCES

1. Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology. JAMA Internal Medicine. News release. Published September 3, 2024. Accessed February 13, 2025. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2823084?resultClick=1

2. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA. News release. Published June 4, 2021. Accessed February 13, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014