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SEMAGLUTIDE IMPROVES HEALTH-RELATED QUALITY OF LIFE IN MAJOR DEPRESSIVE DISORDER INDEPENDENT OF MOOD CHANGE: EVIDENCE FOR METABOLIC AND MOTIVATIONAL PATHWAYS

Cristian-Daniel Llach Lopez — Sebastian Badulescu1, Aniqa Tabassum1, Hiya Shah1, Hartej Gill1, Ryan Brudner1, Riccardo de Giorgi2, Eduard Vieta3, Roger S. McIntyre1, Joshua D. Rosenblat1, Rodrigo Mansur1 1University of Toronto, 2University of Oxford, 3University of Barcelona Cristian-Daniel Llach Lopez, University of Toronto

2026 ASCP Annual Meeting

Background

Health-related quality of life (HRQoL) and motivation are core determinants of functional recovery in major depressive disorder (MDD), yet they remain insufficiently addressed by existing antidepressant treatments. Patients frequently report persistent impairments in motivation, vitality, and day-to-day functioning even when mood symptoms improve, underscoring the need for interventions that target broader dimensions of well-being. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve metabolic health, reward behavior, and HRQoL in obesity and diabetes, raising the possibility that they may influence motivational and functional outcomes in MDD. However, no randomized controlled trial has evaluated the effects of a GLP-1RA on HRQoL, effort-based motivation, or reward behavior in MDD.

Purpose

The objective of this analysis was to determine whether adjunctive semaglutide improves HRQoL in adults with MDD, and to test whether motivational and/or metabolic pathways help explain these effects. This trial therefore aimed to evaluate semaglutide’s potential as a mechanistically novel, patient-centered intervention targeting domains of functioning not captured by conventional antidepressant endpoints.

Methods

This secondary analysis evaluated data from a 16-week, double-blind, placebocontrolled trial of adjunctive oral semaglutide in adults with MDD, cognitive dysfunction, and overweight/obesity. Participants continued stable antidepressant therapy. HRQoL (SF36), depressive symptoms (HAMD-17), cognition, metabolic markers (HbA1c, fasting glucose, HOMA2-IR), and reward-related motivation (Effort Expenditure for Rewards Task; EEfRT) were assessed from baseline to week 20. Generalized estimating equations tested longitudinal effects, and moderation/mediation analyses evaluated motivational and metabolic pathways.

Results

Seventy-two participants were randomized (semaglutide n=35; placebo n=37), with 75% completing week 16. At baseline, lower HRQoL correlated with greater depressive severity, higher BMI and insulin resistance, and poorer cognitive performance. Semaglutide produced significantly greater HRQoL improvement than placebo (Treatment × Time p=0.027), with an adjusted +11.8-point gain at week 16 versus +4.0 points for placebo (p=0.015), exceeding minimal clinically important differences. Improvements were independent of changes in depressive symptoms or weight, indicating a distinct therapeutic signal. Reductions in effort discounting significantly moderated semaglutide’s HRQoL effect (p=0.039), explaining ~19% of within-group variance. These findings support the interpretation that semaglutide may reduce the perceived effort required for daily activities, improving role fulfillment and functional engagement. Mediation analysis showed that reductions in HbA1c partially mediated HRQoL gains (indirect effect = 5.20, 95% CI 0.71– 11.25). This suggests that improvements in chronic glycemic exposure, even within a nondiabetic range, may enhance subjective well-being and vitality.

Conclusions

Adjunctive semaglutide significantly improved HRQoL in adults with MDD and cognitive dysfunction through convergent motivational and metabolic mechanisms. These benefits occurred independently of mood improvement, underscoring therapeutic domains not targeted by conventional antidepressants. Semaglutide may address aspects of day-to-day functioning that are central to recovery and highly valued by patients. This study provides first-in-human evidence supporting GLP-1RAs as mechanistically novel, patientcentered interventions for improving quality of life in mood disorders.

Learning Objective 1: Understand how insulin and glucose metabolism influence neurobiology, physical health, and overall HRQoL in MDD, and how GLP-1 receptor agonists may shape the functional course of depression through these pathways.

Learning Objective 2: Recognize why health-related quality of life (HRQoL) is an essential outcome to measure in future clinical trials and how it captures dimensions of recovery beyond traditional symptom-based endpoints.

References

Badulescu S, Gill H, Shah H, et al. Semaglutide for the treatment of cognitive dysfunction in major depressive disorder: A randomized clinical trial. Med. Published online November 2025:100916. doi:10.1016/J.MEDJ.2025.100916 Mansur RB, Ahmed J, Cha DS, et al. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: A pilot, open-label study. J Affect Disord. 2017;207:114-120. doi:10.1016/J.JAD.2016.09.056 7:00 p.m. - 8:30 p.m. Satellite Symposium: Moving Beyond Sleep: The Broader Connection Between the Orexin System and Psychiatric Disorders