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.