Oral Semaglutide Shows Promise for Motivation in Depression, Finds Research
Canada: Researchers have found in secondary analysis of a randomized trial that treatment with Semaglutide (Rybelsus) was associated with significant improvement in motivation in patients with Major Depressive Disorder. This is particularly relevant for addressing anhedonia, a symptom that is often inadequately managed with conventional antidepressants.
While the findings appear promising, further validation through larger and more rigorous studies is needed, and they may hold broader relevance for neuropsychiatric conditions marked by impaired reward processing.
The brief report published in JAMA Psychiatry by Hartej Gill and colleagues explored whether semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), could influence reward-related dysfunction in individuals with major depressive disorder (MDD). Although GLP-1 receptor activation has previously been linked to reward pathways in preclinical and clinical settings, its effect on motivated behavior in MDD had not been examined in a randomized clinical trial until now.
The study was designed as a 16-week, double-blind, placebo-controlled, parallel-group trial involving 72 adults diagnosed with MDD and a body mass index of 25 or higher. Participants were randomly assigned to receive either oral semaglutide or placebo alongside their usual treatment. The semaglutide group received a target dose of 14 mg, initiated at a lower dose and gradually increased over four weeks. The trial was conducted at a university-based mood disorders program in Toronto, with participant enrollment spanning from March 2022 to July 2024.
To evaluate motivation and reward processing, researchers used the Effort-Expenditure for Rewards Task (EEfRT), a validated behavioral measure assessing willingness to exert effort for potential rewards.
The trial revealed the following findings:
- Individuals treated with semaglutide were more likely to engage in physically demanding tasks when higher rewards were expected.
- This pattern reflects improved motivation and goal-directed behavior.
- Computational analysis indicated that these effects were due to reduced effort discounting.
- Participants perceived the cost of effort as lower relative to the reward.
- Semaglutide significantly decreased sensitivity to effort.
- There was no significant effect on sensitivity to reward probability.
- These findings suggest a targeted action of semaglutide on motivational deficits.
According to the authors, the study is among the first clinical investigations to demonstrate the multidimensional impact of a GLP-1 receptor agonist on reward-related abnormalities in patients with MDD. The findings suggest that semaglutide may help address core symptoms such as reduced motivation and anhedonia, which are often resistant to standard therapies.
Overall, the study provides early evidence supporting the potential role of semaglutide in modulating reward processing in depression. These results open new avenues for research into novel treatment strategies for MDD and other neuropsychiatric disorders characterized by disrupted reward systems, although larger trials are essential to confirm these observations.
Reference:
Gill H, Badulescu S, Shah H, et al. Semaglutide and Effort-Based Decision-Making in Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. Published online April 29, 2026. doi:10.1001/jamapsychiatry.2026.0594
Next Story