Semaglutide and Effort-Based Decision-Making in Major Depressive Disorder: A Randomized Clinical Trial
Gill H, Badulescu S, Shah H, Brudner RM, Phan L, Di Vincenzo JD
JAMA Psychiatry (2026) · n=72
Across 72 adults with major depressive disorder and BMI ≥25, 16 weeks of adjunctive oral semaglutide (14 mg) significantly reduced the perceived cost of effort relative to monetary reward on the Effort-Expenditure for Rewards Task — the first RCT to show GLP-1RA modulation of reward-related motivation in clinical depression.
This 16-week double-blind placebo-controlled parallel-group RCT, conducted at the Mood Disorders Psychopharmacology Unit of the University Health Network in Toronto by Mansur, McIntyre, Rosenblat and colleagues, is the first randomised trial to evaluate whether a GLP-1 receptor agonist modulates effort-based decision making in patients with major depressive disorder.
72 participants with DSM-5 MDD and a BMI of 25 or higher were randomised 1:1 to adjunctive oral semaglutide (14 mg/day, titrated from 4 mg over 4 weeks) or matched placebo on top of treatment-as-usual psychiatric care. The preregistered secondary-analysis outcome was performance on the Effort-Expenditure for Rewards Task (EEfRT).
Semaglutide-treated participants showed a significantly increased willingness to exert physical effort for higher-expected-value rewards (treatment × visit × expected value interaction χ² = 12.024; p = 0.02). Computational modelling localised the effect to a reduction in effort sensitivity (β = −1.737; p = 0.03) rather than a change in probability sensitivity (β = −0.776; p = 0.51) — semaglutide reduced the perceived cost of effort, not the perception of reward likelihood.
Modest sample size (n=72) limits statistical power, particularly for the computational-model parameter estimates. The trial recruited from a single specialist Toronto mood-disorders clinic, biasing toward severe / treatment-resistant MDD — generalisability to community MDD is limited.
Participants were required to have BMI ≥25, which restricts the result to overweight / obese MDD, the same indication-overlap question as in the Klausen AUD trial: the trial cannot disentangle metabolic from neuropsychiatric mechanism. The EEfRT is the preregistered outcome of a secondary analysis, not the trial's primary endpoint — the reported result is the strongest signal but the depression-symptom primary outcomes are not yet visible in the abstract.
The 16-week duration is short relative to typical antidepressant trial timelines; durability and relapse-protection are not addressed. The McIntyre laboratory has industry relationships across the GLP-1 manufacturers; the standard sponsor-affiliation framing applies. Computational modelling parameters require independent replication before the "reduced effort discounting" mechanistic interpretation should be taken as settled.
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