Comparison of Blood-Based and Skin Advanced Glycation End Products in Schizophrenia: a Systematic Review and Meta-Analysis Exploring Metabolic Heterogeneity

BACKGROUND & OBJECTIVE:Elevated advanced glycation end products (AGEs) are linked to metabolic dysfunction in schizophrenia-spectrum disorders, but previous studies have shown methodological heterogeneity and overlapping cohorts. We systematically reviewed and quantified differences in blood-based and skin AGE levels between patients and healthy controls. METHODS:Following PRISMA 2020, databases were searched up to January 2025. Independent case-control studies with quantitative AGE measurements were analysed using random-effects models, strictly excluding overlapping cohorts. RESULTS:Nine independent studies (584 patients, 630 controls; N = 1,214) were included. Patients exhibited significantly higher AGE levels than controls (SMD = 0.63, 95% CI 0.26-1.00; p = 0.0008), with substantial heterogeneity (I2 = 88.4%). Subgroup analyses showed significant elevations in both blood-based measurements (k = 6, SMD = 0.47) and skin (k = 4, SMD = 0.87). Measurement modality was not a significant moderator (p = 0.20). The association remained significant in high-quality studies (k = 5, SMD = 0.70). CONCLUSIONS:AGE levels are significantly elevated in schizophrenia-spectrum disorders, although substantial heterogeneity remains. Further longitudinal studies controlling for metabolic and geographic factors are needed.