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BackgroundPlatelet dysfunction has been increasingly implicated in the pathophysiology of major depressive disorder (MDD), yet conventional platelet indices have shown inconsistent associations with the disease. The platelet-to-albumin ratio (PAR), a composite biomarker integrating inflammatory and nutritional status, has not been comprehensively investigated in relation to MDD across different populations. This study aimed to examine the association between PAR and depression using two independent cross-sectional cohorts.MethodsWe analyzed data from a population-based NHANES cohort (n = 34,068) and a Chinese clinical cohort (n = 735). Depression in the NHANES cohort was assessed using the Patient Health Questionnaire-9 (PHQ-9), whereas MDD in the clinical cohort was diagnosed by psychiatrists according to DSM-5 criteria. Multivariable logistic and linear regression, subgroup analyses, and restricted cubic spline (RCS) models were used to examine the associations of platelet count (PLT), mean platelet volume (MPV), and PAR with depression. Bonferroni correction was applied to account for multiple comparisons in the regression analyses.ResultsPAR was consistently and positively associated with depression across both cohorts after adjustment for potential confounders and Bonferroni correction. In the fully adjusted model, each unit increase in PAR was associated with higher odds of depression in both the NHANES cohort (OR = 1.047, 95% CI: 1.013–1.081, P = 0.006, Bonferroni-adjusted P = 0.018) and the clinical cohort (OR = 1.446, 95% CI: 1.267–1.659, P < 0.001, Bonferroni-adjusted P < 0.001). In contrast, PLT and MPV showed no consistent associations across the two cohorts. PAR was positively associated with depressive symptom severity in NHANES, whereas no significant association was observed in the clinical cohort. RCS analyses suggested an approximately linear association in NHANES but a nonlinear association in the clinical cohort. Stronger associations were observed among smokers, alcohol drinkers, and individuals without a partner in the clinical cohort.ConclusionsAcross two independent cross-sectional cohorts with different population characteristics and outcome assessments, PAR showed a consistent positive association with depression, whereas conventional platelet indices did not. These findings suggest that PAR may provide additional information on depression-related inflammatory and nutritional alterations beyond individual platelet parameters. Prospective studies are warranted to clarify the temporal relationship and evaluate its potential clinical utility.

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