Effect of Glucagon-Like-Peptide-1 Receptor Agonists (GLP-1 RA) on Neuropsychiatric Outcomes: A Systematic Review and Meta-Analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials and observational studies
PubMed 41862354 · doi:10.1016/j.clinthera.2026.02.010
What was done
A systematic review and random-effects meta-analysis (PROSPERO CRD420251025534) searched MEDLINE, SCOPUS, CENTRAL, and Web of Science through October 30, 2025. The authors evaluated randomized controlled trials and observational studies examining the effects of GLP-1 receptor agonists versus placebo, standard care, or other glucose-lowering drugs on neuropsychiatric outcomes. Study quality was evaluated using RoB2 and ROBINS-I, with certainty assessed via GRADE.
What was found
From 82 included studies (screened from 10,037 records): - Parkinson's Disease (PD): Associated with reduced PD risk (pooled HR 0.70, 95% CI: 0.53–0.92, I² = 38%), but no significant motor improvement in established PD (MDS-UPDRS Part III off-medication mean difference: -3.29, 95% CI: -7.84 to 1.26, I² = 80%) and no consistent improvement in non-motor symptoms, dyskinesia, or quality of life. - Substance & Eating Disorders: Associated with reduced risk of cannabis use disorder (pooled HR 0.55, 95% CI: 0.39–0.77, I² = 71%) but not opioid use disorder (pooled HR 0.61, 95% CI: 0.24–1.52, I² = 91%). Liraglutide reduced binge frequency in binge eating disorder versus placebo (mean difference: -1.28, 95% CI: -1.67 to -0.89, I² = 53%). - Suicidality & Affective Disorders: Observational comparisons to non-users suggested lower suicidality risk (pooled OR 0.34, 95% CI: 0.18–0.63, I² = 99%), but no association appeared for semaglutide alone (pooled OR 0.71, 95% CI: 0.29–1.73, I² = 99%), active-comparator studies (pooled HR 0.96, 95% CI: 0.81–1.15, I² = 0%), or RCTs (pooled RR 1.13, 95% CI: 0.53–2.41, I² = 0%). No associations were seen for depression or anxiety. - Cognitive Outcomes: Dementia risk was not reduced versus SGLT2 inhibitors (pooled RR 1.07, 95% CI: 0.73–1.56, I² = 78%), though Alzheimer's risk appeared lower versus unmatched/non-exposed controls (pooled RR 0.37, 95% CI: 0.14–0.96, I² = 98%).
Why it matters
This review indicates that purported neuroprotective and psychiatric benefits of GLP-1 RAs are highly outcome-specific (such as Parkinson's incidence and binge eating frequency) and frequently disappear when tested in RCTs or against active comparators like SGLT2 inhibitors.
Limits
Most findings are rated low to very low certainty on GRADE due to high statistical heterogeneity (I² up to 99%) and wide confidence intervals. Apparent protective signals for suicidality and dementia were restricted to observational comparisons against non-exposed controls and were absent in active-comparator or RCT designs. The abstract does not report the total participant sample size across the 82 included studies.
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