Semaglutide May Improve Motivation in MDD, Small Trial Finds
Key Clinical Summary
- Oral semaglutide improved measures of motivation in adults with major depressive disorder (MDD) and a body mass index of 25 or higher.
- The 16-week randomized clinical trial included 72 participants at University Health Network in Toronto.
- Semaglutide reduced effort sensitivity, suggesting potential effects on reward-related dysfunction in depression.
A randomized clinical trial published in JAMA Psychiatry found that oral semaglutide may improve effort-based decision-making in adults with major depressive disorder (MDD). The Toronto-based study evaluated whether a glucagon-like peptide-1 receptor (GLP-1 R) agonist could affect reward-related dysfunction, a feature relevant to motivation and functioning in depression.
Study Findings
The 16-week, double-blind, placebo-controlled, parallel-group randomized clinical trial enrolled 72 adults with MDD and a body mass index of 25 or higher. Participants were recruited from the Mood Disorders Psychopharmacology Unit at University Health Network in Toronto between March 14, 2022, and July 26, 2024.
Participants were randomized 1:1 to oral semaglutide or placebo, added to treatment as usual. Semaglutide was given at 14 mg after a 4-week dose-escalation regimen beginning at 4 mg. The preregistered outcome for this secondary analysis was performance on the Effort-Expenditure for Rewards Task (EEfRT).
Semaglutide-treated participants showed greater willingness to exert physical effort when expected reward values were higher (treatment × visit × expected value interaction: χ2 = 12.024; P = .02). Computational modeling indicated that semaglutide’s effect on choice behavior reflected reduced effort discounting. Sensitivity to effort was significantly reduced with semaglutide (β = −1.737; P = .03) while sensitivity to probability was not significantly affected (β = −0.776; P = .51).
Clinical Implications
For clinicians treating MDD, the findings suggest that semaglutide may influence motivational processes rather than only metabolic outcomes. Reward-related dysfunction, including reduced willingness to expend effort for reward, can contribute to impaired daily functioning in depression.
The study does not establish semaglutide as a depression treatment. The findings are therefore most relevant as early clinical evidence that GLP-1 Rs may affect neuropsychiatric reward pathways.
The authors stated that the trial has implications for multiple neuropsychiatric disorders characterized by reward dysfunction. Further studies are needed to clarify clinical efficacy, patient selection, durability of benefit, and safety in psychiatric populations.
Expert Commentary
“Treatment with semaglutide modulated effort-based decision-making in patients with MDD by increasing the willingness to exert effort with higher expected values of reward and reducing the perceived cost of effort relative to the reward,” wrote Hartej Gill, PhD, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada, and colleagues. “Results from this trial reinforce the involvement of metabolic mechanisms in effort-based motivation in patients with MDD.”
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