Glucagon-Like Peptide 1 Receptor Agonists and Mental Health
Authors: Aureliane C. S. Pierret, Yuya Mizuno, Pippa Saunders, Eshaya Lim, Riccardo De Giorgi, Oliver D. Howes, Robert A. McCutcheon, Barbara McGowan, Piya Sen Gupta, Daniel Smith, Khalida Ismail, Toby Pillinger
Journal: JAMA Psychiatry (2025)

Importance People with obesity and diabetes have poorer psychiatric and cognitive outcomes and lower quality of life (QOL) compared with those without. Glucagon-like peptide 1 receptor agonists (GLP1-RAs) are treatments for diabetes and obesity that may also influence psychiatric outcomes. Objective To conduct a meta-analysis of randomized placebo-controlled trials to evaluate psychiatric, cognitive, and QOL outcomes with GLP1-RA treatment. Data Sources MEDLINE, Embase, PsycINFO, and CENTRAL databases were searched from inception through June 24, 2024. Study Selection Double-blind placebo-controlled trials comparing GLP1-RA to placebo in adults with overweight/obesity and/or diabetes, reporting on psychiatric, cognition, or QOL outcomes, were included. Data Extraction and Synthesis Data extraction was performed in parallel by 2 reviewers. Random-effects meta-analysis was performed. Effect size measures were log risk ratios (log[RR]) and standardized mean differences (Hedges g ). The quality of studies was appraised using the Cochrane risk-of-bias tool (RoB2). Certainty of evidence was assessed via GRADEpro. Main Outcomes and Measures Main outcomes were risk of psychiatric adverse events (serious and nonserious) and change in mental health symptom severity, health-related quality of life, and cognition. Results Eighty randomized clinical trials involving 107 860 patients were included in the meta-analysis. The mean (SD) age of participants across studies in the meta-analysis was 60.1 (7.1) years; 43 251 were female (40.1%) and 64 608 male (59.9%). GLP1-RA treatment was not associated with a significant difference in risk of serious psychiatric adverse events (log[RR] = −0.02; 95% CI, −0.20 to 0.17; P = .87) and nonserious psychiatric adverse events (log[RR] = −0.03; 95% CI, −0.21 to 0.16], P = .76), or depressive symptom change ( g = 0.02; 95% CI, −0.51 to 0.55; P = .94), compared with placebo. GLP1-RA treatment was associated with improvements in restrained eating ( g = 0.35; 95% CI, 0.13 to 0.57; P = .002) and emotional eating behavior ( g = 0.32; 95% CI, 0.11 to 0.54; P = .003) and in mental health–related QOL ( g = 0.15; 95% CI, 0.07 to 0.22; P &amp;amp;lt; .001), physical health–related QOL ( g = 0.20; 95% CI, 0.14 to 0.26; P &amp;amp;lt; .001), diabetes-related QOL ( g = 0.23; 95% CI, 0.15 to 0.32; P &amp;amp;lt; .001), and weight-related QOL ( g = 0.27; 95% CI, 0.18 to 0.35; P &amp;amp;lt; .001) compared with placebo. Conclusions and Relevance In patients with overweight/obesity and/or diabetes , GLP1-RA treatment is not associated with increased risk of psychiatric adverse events or worsening depressive symptoms relative to placebo and is associated with improvements in QOL, restrained eating, and emotional eating behavior. These findings provide reassurance regarding the psychiatric safety profile of GLP1-RAs and suggest that GLP1-RA treatment contributes to both physical and emotional well-being.