Abstract
BACKGROUND: Depression is associated with smoking and inflammation. However, whether inflammation and metabolic insulin resistance mediate the relationship between smoking and depression remains unclear. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.