Abstract
BACKGROUND: Depression has become one of the major global public health burdens. In recent years, lipid metabolic abnormalities have garnered increasing attention as potential influencing factors. Among these, the ratio of non-high-density lipoprotein to high-density lipoprotein cholesterol (NHHR) is regarded as an integrated indicator for assessing atherosclerosis risk. Obesity, as a hallmark of metabolic dysregulation, has a complex interplay with depression. This study aimed to investigate the association between NHHR and depression among obese adults and to evaluate the mediating role of body mass index (BMI) in this relationship. METHODS: This study utilized data from the 2013-2023 National Health and Nutrition Examination Survey (NHANES), ultimately including 13,991 adult participants with BMI ≥ 25 kg/m². NHHR was analyzed both as a continuous variable and by quartiles, while depression was assessed using the PHQ-9 scale. The primary analyses were conducted without weighting to explore within-sample associations, with core analyses including nonlinear fitting and mediation analysis. To assess the robustness of the findings, sensitivity analyses incorporated NHANES sampling weights and complex survey design, applied multiple imputation for missing covariates, and performed stratified analyses to evaluate the generalizability of the results to the representative population. RESULTS: After multivariable adjustment, NHHR showed a significant nonlinear positive association with depression risk. Threshold effect analysis identified NHHR = 2.95 as the inflection point. To the left of this threshold, higher NHHR was significantly associated with increased depression risk (OR = 1.19, 95% CI: 1.06-1.09), whereas the association changed beyond this point. Mediation analysis indicated that 15.81% of the total effect of NHHR on depression was mediated indirectly through BMI (β = 0.0013, 95% CI: 0.0008-0.0018). However, given the cross-sectional design, reverse causality cannot be ruled out. Sensitivity analyses further demonstrated that the association was more pronounced among individuals without diabetes, those with prediabetes, and ever-smoker, with evidence of interaction effects (P for interaction < 0.05). Notably, the core findings were consistent in direction and overall trend with the unweighted analyses, further supporting the robustness of our results, although the effect sizes were not identical. CONCLUSIONS: Among obese adults, higher NHHR levels are significantly associated with an increased risk of depression, with BMI partially mediating this relationship and diabetes status and smoking history serving as moderators. These findings suggest that NHHR may provide valuable insight for early intervention in mental health disorders among obese populations.