Semaglutide and Effort-Based Decision-Making in Major Depressive Disorder

Importance: Consistent results from preclinical and clinical studies indicate that activation of glucagon-like peptide-1 receptors (GLP-1 Rs) affects reward processes; however, to our knowledge, no study has previously evaluated whether a GLP-1 R agonist (GLP-1 RA) affects motivated behavior in individuals with major depressive disorder (MDD) in a randomized clinical trial. Objective: To assess the effects of a GLP-1 RA, semaglutide, on reward-related dysfunction in a population with MDD. Design, Setting, and Participants: This study was a 16-week, double-blind, placebo-controlled, parallel-group randomized clinical trial. A total of 72 participants with a diagnosis of MDD and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 25 or higher were randomized to oral semaglutide (n = 35) or placebo (n = 37). Participants were recruited from the Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, a university-based mood disorders program. Participants were enrolled between March 14, 2022, and July 26, 2024. Data analysis was performed from January 7, 2025, through February 3, 2025. Intervention: Patients were randomized 1:1 to receive placebo or oral semaglutide, 14 mg (initiated at 4 mg and titrated using a 4-week dose-escalation regimen), adjunctive to their treatment as usual. Main Outcome and Measure: The preregistered outcome of this secondary analysis was performance on the Effort-Expenditure for Rewards Task (EEfRT). Results: A total of 72 participants were randomized to oral semaglutide (n = 35 [49.7%]; mean [SD] age, 38.17 [11.79] years; 18 female participants [51.4%]) or placebo (n = 37 [51.3%]; mean [SD] age, 40.27 [9.32] years; 19 female participants [51.3%]). Semaglutide-treated participants exhibited a pattern of increased willingness to exert physical efforts with higher expected values of reward (treatment × visit × expected value interaction: χ2 = 12.024; P = .02). Computational modeling indicated that semaglutide's effects on choice behavior were a result of reduced effort discounting. Sensitivity to effort was significantly reduced by treatment with semaglutide (β = -1.737; P = .03), whereas there was no treatment effect on sensitivity to probability (β = -0.776; P = .51). Conclusions and Relevance: In this secondary analysis of a double-blind randomized clinical trial, treatment with semaglutide significantly improved measures of motivation in patients with MDD. Semaglutide reduced the perceived cost of effort, relative to the monetary reward; the results of this trial have implications for the treatment of multiple neuropsychiatric disorders, which are characterized by varied reward dysfunctions. Trial Registration: ClinicalTrials.gov Identifier: NCT04466345.