METS-IR and SII as mediators in the association between smoking and depressive symptoms: insights from NHANES...

Depression is associated with smoking and inflammation. However, whether inflammation and metabolic insulin resistance mediate the relationship between smoking and depression remains unclear.

We analyzed 15,391 participants from the 2005-2018 National Health and Nutrition Examination Survey (NHANES), representing approximately 92,321,194 individuals in the USA. Data on depressive symptoms (assessed by the Patient Health Questionnaire-9 [PHQ-9]), smoking (assessed via smoking questionnaire), and Systemic Immune-Inflammation Index (SII) and metabolic insulin resistance score (METS-IR) were evaluated. Additionally, the effect of smoking on all-cause mortality among individuals with depressive symptoms was assessed.

Weighted logistic regression analysis showed that current smoking was significantly associated with a higher risk of depressive symptoms (OR = 3.02, 95% CI: 2.46-3.69, P < 0.001), with consistent findings across subgroups. Weighted generalized linear regression indicated that smoking upregulates SII and METS-IR levels. Specifically, current smokers had SII and METS-IR levels 86.1 (95% CI: 67.5-104.8) and 0.01 (95% CI: 0.005-0.02) units higher than never-smokers, respectively. Restricted cubic spline models demonstrated nonlinear dose-response relationships between SII, METS-IR, and depressive symptom severity (P for nonlinear < 0.05). SII and METS-IR mediated 0.69% and 0.86% of the relationship between smoking and depressive symptoms, respectively. Lastly, smoking appeared to increase all-cause mortality in individuals with depressive symptoms.

The positive association between smoking and depressive symptoms is partly mediated by SII and METS-IR. Smoking cessation may alleviate depressive symptoms and improve survival in individuals with depressive symptoms.