The Mediation Effect of Cotinine Between Depression, Inflammation, and Mortality: A National Cohort Study

Background Depression is a major mental health issue that affects millions globally. Inflammation is linked to depression, and smoking is prevalent among depressed individuals. Serum cotinine, a nicotine metabolite, may mediate the effects of smoking on inflammation and mortality in depression. This study aims to explore the mediating role of cotinine between depression, inflammation, and all-cause mortality. Methods This study utilized data from the National Health and Nutrition Examination Survey (NHANES) collected between 2005 and 2014. A total of 24,937 participants were included after excluding individuals with missing data on depressive symptoms, serum cotinine concentration, and mortality outcomes. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), and serum cotinine levels were measured by isotope-dilution HPLC-APCI MS/MS. Multivariable logistic regression was used to assess the association between depression and cotinine. Mediation analysis was conducted to evaluate the mediating role of cotinine in the relationship between depression and WBC count, as well as between WBC count and mortality. Cox proportional hazards models were employed to determine the associations between cotinine, WBC count, and all-cause mortality. Results The analysis showed that individuals with depression had significantly higher serum cotinine levels (95.615 ng/mL vs. 53.546 ng/mL, P < 0.001) and WBC counts (7.665 vs. 7.203, P < 0.001) compared to those without depression. Multivariable logistic regression revealed that serum cotinine was positively associated with depression (OR = 1.002, 95% CI: 1.002–1.002, P < 0.001). Mediation analysis indicated that cotinine significantly mediated the association between depression and WBC count, accounting for 37.01% of the total effect after adjusting for confounders. Higher cotinine levels were also associated with increased all-cause mortality (HR = 1.889, 95% CI: 1.691–2.111, P < 0.001). Furthermore, cotinine mediated the relationship between WBC count and mortality, contributing to 27.39% of the total effect after adjustment. Conclusion This study highlights cotinine's role as a dual mediator in the relationships between depression, inflammation, and all-cause mortality. These findings underscore the need for targeted interventions, including smoking cessation and inflammation management, to improve health outcomes in individuals with depression.