Nicotine metabolite ratio and clinically significant depressive symptoms in U.S. adults: A smoker-specific association

Nicotine metabolite ratio (NMR) is a biomarker for the rate of nicotine metabolism and may be linked to depression, but evidence from large, representative populations is scarce. The role of smoking status as a potential effect modifier of this association is poorly understood. Identifying smoker-specific vulnerability may inform risk stratification and integration of mental-health screening within smoking-cessation settings. We aimed to investigate the association between NMR and clinically significant depressive symptoms in U.S. adults and among active smokers. We conducted a cross-sectional, observational analysis of 9287 adults (≥20 years) from the National Health and Nutrition Examination Survey 2013 to 2018. The exposure was the natural ln(NMR). The outcome was clinically significant depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥10). We used survey-weighted modified Poisson regression to estimate relative risks with 95% confidence intervals; missing covariates were addressed using multiple imputation. Analyses were stratified by smoking status using a union definition (self-report or serum cotinine ≥3 ng/mL); robustness was evaluated using a stricter threshold of ≥10 ng/mL. In the overall population, ln(NMR) was not associated with depressive symptoms (per 1- standard deviation [SD] increase, RR 1.03; 95% CI 0.93-1.14). However, among smokers (union definition; cotinine ≥3 ng/mL), a higher ln(NMR) was associated with a higher prevalence of clinically significant depressive symptoms (RR per 1-SD, 1.15; 95% CI, 1.02-1.29). This finding was robust using a stricter cotinine cutoff of ≥10 ng/mL (RR per 1-SD, 1.16; 95% CI, 1.02-1.32). Restricted cubic splines revealed a near-linear dose-response relationship in smokers only. Significant interactions were observed across multiple covariates - including body mass index, poverty-income ratio, race/ethnicity, sex, smoking status, hypertension, diabetes, cotinine level, and stroke - after false discovery rate control. In this study, higher ln(NMR) was associated with a higher prevalence of clinically significant depressive symptoms among active smokers, but not in the overall U.S. adult. These findings highlight a smoker-specific vulnerability and suggest that NMR may be useful for risk stratification to support integrated smoking-cessation and mental-health screening; longitudinal and interventional studies are needed to clarify directionality and clinical utility.