Semaglutide and Effort-Based Decision-Making in Major Depressive Disorder: A Randomized Clinical Trial

What Was Tested

This randomized controlled trial paper looks at Semaglutide.

To assess the effects of a GLP-1 RA, semaglutide, on reward-related dysfunction in a population with MDD.

Why It Was Studied

Consistent results from preclinical and clinical studies indicate that activation of glucagon-like peptide-1 receptors (GLP-1 Rs) affects reward processes; however, to their 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.

Who Took Part

According to the abstract, 72 participants were involved.

The age groups tagged for this paper are adults and middle-aged adults, both men and women.

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.

How the Study Was Run

The researchers set it up as a randomized, double-blind, placebo-controlled and parallel-group study.

The participants were allocated by chance, so the Semaglutide group and the comparison group should start out alike.

As a double-blind Semaglutide study, the assignments were hidden from both participants and investigators until the end.

The comparison arm used a placebo, so changes seen with Semaglutide could be set against what happens without it.

Groups ran in parallel: each of the participants stayed in one arm throughout.

This study was a 16-week, double-blind, placebo-controlled, parallel-group randomized clinical trial.

Participants were enrolled between March 14, 2022, and July 26, 2024.

Data analysis was performed from January 7, 2025, through February 3, 2025.

What Was Measured

Consistent results from preclinical and clinical studies indicate that activation of glucagon-like peptide-1 receptors (GLP-1 Rs) affects reward processes; however, to their 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.

Topics PubMed links to this paper include Semaglutide, Major Depressive Disorder, Glucagon-Like Peptides, Reward, Motivation and Glucagon-Like Peptide-1 Receptor Agonists.

What This Means in Plain Language

The paper is a randomized, double-blind and placebo-controlled study of Semaglutide in 72 participants.

Its findings take up roughly 7 sentences of the abstract and are left out here on purpose; the source paper is the place to read them.

The publication is from 2026 (JAMA psychiatry), a journal based in United States.

More context: the Semaglutide compound page, all human trials.