Semaglutide for the treatment of cognitive dysfunction in major depressive disorder: A randomized clinical trial

Evidence suggests that glucagon-like peptide 1 receptor agonists (GLP-1RAs) might have pro-cognitive effects. No prior study has evaluated the efficacy and safety of a GLP-1RA for the treatment of cognitive dysfunction in adults with major depressive disorder (MDD) in a randomized clinical trial.

This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345). Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese. Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide. The primary outcome was an executive function composite score comprising the digit symbol substitution test, the Stroop test, and the n-back test. Secondary outcomes included a global cognition composite score, measures of functioning, depressive symptom severity, suicidality, and body weight.

72 participants were randomized to oral semaglutide (n = 35) or placebo (n = 37). Semaglutide did not improve executive function (adjusted Z score difference [semaglutide - placebo]: 0.32, 95% confidence interval [CI]: -0.92 to 1.58, p = 0.60). Preplanned secondary analysis showed treatment effects for global cognition (2.39, 95% CI: 0.19 to 4.60, p = 0.03) and body weight (kg) (adjusted mean difference -6.03, 95% CI: -8.76 to -3.29, p < 0.001). Treatment did not affect depressive symptom severity or the frequency of suicidal ideation. Gastrointestinal side effects were common in the semaglutide group, with no serious adverse events.

Semaglutide did not improve executive function; results from secondary analyses suggested effects on specific domains of cognition. Semaglutide was safe for patients with MDD.

This work was supported by the Physicians' Services Incorporated Foundation.