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

Area of Science:

• Neuroscience
• Psychiatry
• Pharmacology

Background:

• Glucagon-like peptide-1 receptor (GLP-1 R) activation influences reward processes.
• Limited research exists on GLP-1 R agonists (GLP-1 RAs) effects on motivated behavior in major depressive disorder (MDD).

Purpose of the Study:

• To evaluate the impact of the GLP-1 RA, semaglutide, on reward-related dysfunction in individuals diagnosed with MDD.

Main Methods:

• A 16-week, double-blind, placebo-controlled randomized clinical trial involving 72 participants with MDD and BMI ≥ 25.
• Participants received either oral semaglutide (14 mg) or a placebo, in addition to their usual treatment.
• The primary outcome measure was performance on the Effort-Expenditure for Rewards Task (EEfRT).

Main Results:

• Semaglutide treatment led to increased willingness to exert physical effort for higher rewards (P=.02).
• Computational modeling revealed that semaglutide reduced effort discounting.
• A significant reduction in sensitivity to effort was observed with semaglutide (P=.03), but not probability.

Conclusions:

• Semaglutide significantly enhanced motivation in MDD patients by reducing the perceived cost of effort.
• These findings suggest semaglutide's potential utility in treating neuropsychiatric disorders characterized by reward dysfunction.