The joint and interactive effects of the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and body mass index on the risk of depression, as well as the mediating role of NHHR: results from NHANES 2005-2023.

Background: Various research in the past has indicated that the NHHR, which represents the ratio of non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C), and body mass index (BMI) each act independently as contributors to depression risk. Nonetheless, studies exploring the combination of NHHR with BMI in relation to depression are limited. Consequently, the central aim of this study is investigating the joint and interactive effects of NHHR and BMI on depression risk, as well as the mediating role of NHHR.

Methods: Encompassing participants aged 20 years or over, this research incorporated a total of 39,704 individuals from the National Health and Nutrition Examination Survey (NHANES), which covered the period of 2005 to 2023. To analyze the impact of NHHR and its combination with BMI on depression, our analytical approach included multivariate logistic regression, restricted cubic spline modeling, interaction testing and subgroup analyses. Additionally, we studied the joint effects of NHHR and BMI. Finally, we applied a four-way decomposition analysis method to examine the interactions and mediating effects within the aforementioned relationships.

Results: Among all participants in this study, the prevalence of depressive disorder (Patient Health Questionnaire-9 score ≥ 10) was 9.2%. Both the NHHR and BMI were associated with depression, which remained significant even after full adjustment for covariates [NHHR, OR (95% CI): 1.07 (1.04-1.09); BMI, OR (95% CI): 1.02 (1.02-1.03)]. Compared with the reference group, the OR (95% CI) for the highest groups of NHHR, BMI, and their product term NHHR-BMI were 1.41 (1.24-1.61), 1.35 (1.18-1.54), and 1.59 (1.37-1.84), respectively. Participants with NHHR in the fourth quartile and BMI exceeding 30 kg/m², had higher depression risk compared to other participants with NHHR in the first quartile and BMI below 25 kg/m² [OR (95% CI): 1.64 (1.34-2.00)]. Results of the four-way decomposition analyses indicated that NHHR played a mediating role in the association between BMI and depression, with the mediating effect accounting for 17.6%. Similarly, NHHR also mediated 11.0% of the mediating effect between BMI and PHQ-9 score. However, no interaction between NHHR and BMI related to depression was found in the general population. After stratifying by gender, it was found that the mediated interaction between NHHR and BMI had a statistically significant effect on depression and PHQ-9 score in males.

Conclusions: Depression risk is linked to both NHHR and BMI, and NHHR has a significant mediating impact on the association between BMI and depression. Notably, there is a non-negligible mediated interaction effect between BMI and NHHR in male participants. Compared to considering NHHR or BMI individually, participants had a higher risk of depression when the combined terms of the two were in the higher quartiles. These findings suggest that the combined assessment of these two indicators may help deepen the understanding and evaluation of depression, enhance the accuracy of risk stratification, and is worthy of further research.