Dose-dependent smoking effects on depression inflammatory mediation and substantial prevention potential

BackgroundDepressive disorders represent a leading cause of disability worldwide, yet prevention efforts have had limited success. Smoking is a modifiable risk factor frequently co-occurring with depression, but we lack quantitative evidence on dose-response relationships, cessation timelines, mediating biological pathways, and preventable disease burden. MethodsWe followed 169,741 UK Biobank participants free of baseline depression for 15 years (2006-2023), identifying 3,241 incident events. Using Cox models, we quantified associations between smoking phenotypes (status, intensity, pack-years, cessation timing) and depression incidence, mapped dose-response curves, and tested effect modification. We assessed inflammatory mediation, calculated population attributable fractions, and tested sensitivity to unmeasured confounding. ResultsCurrent smoking nearly doubled depression risk (HR 1.84, 95% CI 1.65-2.04), while previous smokers showed moderately elevated risk (HR 1.23, 95% CI 1.14-1.33). Cessation progressively reduced risk over subsequent decades. Dose-response was steep: 40 pack-years conferred 2.2-fold risk (HR 2.21, 95% CI 1.89-2.57), and 30 cigarettes daily doubled hazard (HR 2.16, 95% CI 1.71-2.72). Inflammatory biomarkers mediated 12.9% of the association (neutrophils HR 1.12, 95% CI 1.08-1.15; white blood cells HR 1.05, 95% CI 1.04-1.07), showing that most effects arise from non-inflammatory pathways. The population attributable fraction was 13.3%, representing one in eight preventable cases. Sensitivity analyses confirmed temporal stability and consistency across multiple analytical approaches; associations were unlikely to be explained by unmeasured confounding (E-value 3.08). ConclusionsSmoking elevates depression risk in a dose-dependent manner, and cessation yields rapid, sustained reductions. Integrating tobacco cessation into mental health care could prevent one in eight depression cases. Inflammation mediates a minority of this effect; interventional studies are needed to test whether anti-inflammatory approaches provide additional benefit. Routine cessation services should be integrated into psychiatric and primary care settings.