Body mass index mediates the relationship between depression and triglyceride levels: Evidence from a large national cohort

BACKGROUND: Major Depressive Disorder (MDD) is linked to adverse metabolic outcomes, including elevated triglycerides and body mass index (BMI). However, mechanisms underlying this relationship-and their variation by age or sex-remain unclear. METHODS: Using data from over 200,000 participants in the All of Us Research Program, we examined associations between MDD (defined by SNOMED-coded diagnoses), BMI, and lipid biomarkers (triglycerides, HDL, LDL). Causal mediation analyses tested whether BMI mediated the MDD-triglyceride relationship, adjusting for age, sex, and alcohol intake. Sex differences and age-stratified effects (ages 25, 45, 65) were also explored. RESULTS: Individuals with MDD had higher BMI and triglyceride levels than those without (BMI SMD = 0.234; triglycerides SMD = 0.195; both p < 0.001). BMI significantly mediated the MDD-triglyceride association (ACME = 5.46, 95 % CI [2.95, 8.17], p < 0.001), accounting for 34.1 % of the total effect. The direct effect was not statistically significant (ADE = 10.55, p = 0.084). Mediation effects were consistent across sexes. Stronger mediation was observed at older ages (e.g., ACME = 6.07 at age 65, p < 0.001) but not at younger ages (e.g., ACME = 5.09 at age 25, p = 0.076). Multiple imputation analyses confirmed these findings (ACME = 3.71, 95 % CI [3.09, 4.33], p < 0.001; proportion mediated = 24.9 %). HDL and LDL levels differed modestly by MDD status. CONCLUSIONS: BMI partially mediates the relationship between MDD and triglycerides, particularly in older adults. These results support integrating metabolic risk management into mental health care.