Use of the Wnt/β-catenin Activator Lithium Is Associated with Less Emphysema

RATIONALE: Emphysema is defined by progressive alveolar destruction and impaired tissue repair, with diminished Wnt/β-catenin signaling implicated in its pathogenesis. Preclinical studies suggest that lithium, a pharmacologic activator of Wnt/β-catenin signaling, may attenuate emphysema. However, its effects in humans remain unknown. OBJECTIVES: To investigate whether lithium use is associated with less emphysema compared to users of other neuropsychiatric medications. METHODS: We analyzed cross-sectional data from two large cohorts-the U.K. Biobank and COPDGene-comprising over 800 individuals using oral lithium. Lithium users were compared to individuals using other neuropsychiatric medications. In the U.K. Biobank, outcomes included spirometry and self-reported physician-diagnosed emphysema. In COPDGene, outcomes included spirometry and quantitative CT measures of emphysema. Multivariable regression and propensity score matching accounted for demographics, smoking history, and psychiatric diagnoses. MEASUREMENTS AND MAIN RESULTS: In the U.K. Biobank, lithium use was associated with higher FEV1 and FVC (% predicted) and ∼50% lower adjusted odds of emphysema diagnosis. In COPDGene, lithium users exhibited significantly higher FEV1, FVC, and FEV1/FVC ratios, lower CT-measured emphysema (LAA %F950), and higher lung density. These associations persisted after multivariable adjustment and across sensitivity analyses. CONCLUSIONS: Lithium use is associated with less emphysema in two independent cohorts. These findings align with preclinical evidence supporting Wnt/β-catenin activation as a protective mechanism and warrant further investigation of lithium as a potential therapy for emphysema.