Lipopolysaccharide and cytokine levels differ by disease severity in major depressive disorder

Abstract Background Major depressive disorder (MDD) lacks established biological markers, although immune dysregulation and gut-derived inflammation have been implicated in a subset of patients; however, their diagnostic utility across levels of depression severity and impact of psychotropic treatment remain unclear. Methods This cross-sectional study examined circulating lipopolysaccharide (LPS) and cytokines (TNF-α, IL-6, IL-10, IFN-γ) in 95 patients with MDD and 51 healthy controls (HC), evaluating their diagnostic utility across depression severity and the influence of psychotropic medication. Depression severity was assessed using the Montgomery–Åsberg Depression Rating Scale, with patients stratified into mild-to-moderate and severe groups. Results Compared with HC, patients with MDD showed elevated LPS and TNF-α levels and reduced IL-10, while IL-6 and IFN-γ did not differ. LPS elevation was specific to mild-to-moderate MDD, whereas TNF-α was consistently elevated across all severity levels. A combined model including LPS, TNF-α, and IL-10 demonstrated the highest diagnostic accuracy for MDD (AUC = 0.778) and mild-to-moderate MDD (AUC = 0.818). TNF-α alone was the strongest predictor of severe MDD (AUC = 0.677), while LPS alone distinguished mild-to-moderate from severe MDD (AUC = 0.679). These associations remained significant after adjusting for age, sex, BMI, smoking status, and psychotropic medication use. LPS levels were higher in mild-to-moderate MDD during antidepressant monotherapy and lower with combination therapy regardless of severity. Conclusions Mild-to-moderate MDD is associated with elevated LPS, reflecting gut-derived inflammation and a distinct subtype, whereas severe MDD is linked to TNF-α. These biomarkers may aid in distinguishing MDD subtypes and inform targeted therapeutic strategies.