Abstract
BACKGROUND: Depression represents a major global disease burden. While the Center for Epidemiologic Studies Depression Scale (CES-D) is widely used, it relies on subjective self-reporting. Saliva enables non-invasive metabolite analysis, but existing metabolomics studies have focused on clinical depression using blood or urine, with limited investigation of salivary metabolites in community populations. This study investigated associations between CES-D scores and salivary metabolite concentrations in Tokyo residents. METHODS: This cross-sectional study collected CES-D responses and morning saliva samples from Tokyo residents. Salivary metabolites were analyzed using capillary electrophoresis time-of-flight mass spectrometry. Statistical analyses included permutational multivariate analysis of variance (PERMANOVA) for overall metabolite-CES-D associations, pathway enrichment analysis using fast gene set enrichment analysis (FGSEA), and principal component analysis, adjusted for age and sex. RESULTS: Analysis included 107 participants (40 males, 67 females; mean age 55.3 ± 14.2 years). PERMANOVA revealed significant association between 112 salivary metabolites and CES-D scores (F = 2.870, p = 0.003), with metabolites explaining 7.7% of depressive symptom variance. Pathway enrichment analysis identified significant alterations in amino acid metabolism (normalized enrichment score =-1.750, q = 0.007). Glycolysis and amine/polyamine metabolism showed trend-level enrichment (both q = 0.066). Principal component analysis revealed significant correlations between CES-D scores and pathway activity for amino acid metabolism (r = 0.216, p = 0.027) and amine/polyamine metabolism (r = 0.216, p = 0.027). CONCLUSION: This study demonstrates significant associations between salivary metabolite profiles and depressive symptoms in a nonclinical community population, with amino acid metabolism emerging as the most robustly altered pathway. These findings provide preliminary evidence for associations between salivary metabolomic profiles and depressive symptoms in a nonclinical community population.