Abstract
High-density lipoprotein cholesterol (HDL-C) has been increasingly recognized not only for its established role in cardiovascular health but also for its potential relevance to mental health, particularly depression. Dysregulated lipid metabolism may affect neuroinflammation, oxidative stress, and hypothalamic-pituitary-adrenal axis regulation, thereby influencing mood. This study aimed to investigate the association between HDL-C levels and depression in a nationally representative U.S. population. We analyzed cross-sectional data from 12,310 adults in the National Health and Nutrition Examination Survey (2015-2020). Depression was present in 8.8% of participants. Weighted multivariable logistic regression and generalized additive models with restricted cubic spline regression were applied to examine linear and nonlinear associations, and subgroup analyses were conducted. Models were adjusted for key covariates, including age, sex, race/ethnicity, body mass index (BMI), poverty-income ratio, smoking, alcohol use, and comorbidities such as diabetes, hypertension, and cardiovascular disease. Participants with depression had significantly lower mean HDL-C levels than those without depression (weighted mean: 1.37 vs 1.41 mmol/L, P < .01). Higher HDL-C levels were inversely associated with depression (OR = 0.92, 95% confidence interval (CI): 0.71-1.13). Subgroup analyses indicated a stronger inverse association among men (OR = 1.92; 95% CI: 0.45-3.39) and in participants without hypertension (OR = -3.64; 95% CI:-5.21 to-2.07). A nonlinear relationship between HDL-C and depression was also observed. HDL-C levels were inversely and nonlinearly associated with depression, with particularly strong associations in men and individuals without hypertension. These findings suggest HDL-C may serve as a potentially modifiable biomarker for depression risk, highlighting the need for longitudinal studies to confirm causality and to evaluate whether lipid management strategies could be incorporated into preventive or therapeutic approaches in neuropsychiatry.