Smoking and depressive symptoms: the mediating role of systemic inflammation in a US nationally representative sample

BACKGROUND: Smoking and depressive symptoms are strongly associated, but the underlying biological mechanisms remain incompletely understood. Systemic inflammation has been proposed as a potential mediator linking smoking behavior to depressive symptoms. However, few studies have simultaneously examined multiple inflammatory biomarkers in large, nationally representative samples. OBJECTIVE: This study aimed to investigate whether systemic inflammation, measured by C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR), mediates the association between current smoking and depressive symptoms in a US nationally representative sample. METHODS: I analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2005-2018, including 28,456 adults aged 20 years and older. Smoking status was categorized as current, former, or never smoker. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). Serum CRP levels and NLR were used as inflammatory biomarkers. Mediation analysis was performed using the Baron and Kenny approach with bootstrap methods to estimate indirect effects. RESULTS: Current smokers had significantly higher prevalence of depressive symptoms. compared to never smokers (12.8% vs. 7.2%, p < 0.001). Both CRP levels and NLR were significantly elevated in current smokers compared to never smokers (CRP: 3.2 ± 0.1 vs. 2.1 ± 0.1 mg/L; NLR: 2.4 ± 0.1 vs. 2.0 ± 0.1, both p < 0.001). In mediation analysis, CRP mediated 15.3% (95% CI: 12.1-18.7%) and NLR mediated 8.7% (95% CI: 6.2-11.4%) of the association between current smoking and depressive symptoms. The combined mediation effect of both inflammatory markers was 21.2% (95% CI: 17.8-24.9%). CONCLUSIONS: Systemic inflammation, as measured by CRP and NLR, partially mediates the association between smoking and depressive symptoms in US adults. These findings support the inflammatory hypothesis of depression and suggest that anti-inflammatory interventions may be beneficial for smokers with depressive symptoms.