Disentangling semaglutide's effects on motivation in major depressive disorder: A mediation analysis
Gill H, Badulescu S, Shah H, et al. (2026). Journal of Affective Disorders.
Summary
An exploratory post-hoc analysis of a 16-week, double-blind, placebo-controlled human trial (NCT04466345) of adjunctive oral semaglutide against placebo in 72 adults with major depressive disorder and overweight or obesity. On the Effort-Expenditure for Rewards Task, people on semaglutide became more willing to work for rewards than people on placebo (lower effort discounting; treatment-by-visit estimate -1.78, 95% confidence interval -3.34 to -0.23). Changes in body mass index, percent body fat, HbA1c, insulin resistance, depressive symptoms and cognition did not account for that difference. The authors describe the pattern as consistent with an effect separate from the metabolic changes they measured, and they do not claim a proven brain mechanism. It is a small analysis of a human trial: the mediation models used 46 to 53 people, comparisons were not adjusted for multiple testing, and the authors note possible functional unblinding. Published online on 9 November 2026. Funding for the trial is not stated in the abstract.
Peptides in this study
Semaglutide in the United Kingdom · Semaglutide in the United States · Semaglutide in Australia