Higher Lipopolysaccharide Levels Are Linked to Less Anhedonia and Lower Severity of Major Depressive Disorder

Background: Inflammatory mechanisms contribute to major depressive disorder (MDD) in a subset of patients. Lipopolysaccharide (LPS), a potent inflammatory endotoxin, can induce depressive-like symptoms, but its relationship with specific depressive symptom profiles remains unclear. Methods: In total, 95 adults with MDD (mean age was 44 ± 14 years) were recruited from psychiatric inpatient and outpatient services. Depressive symptom severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Serum concentrations of LPS, IL-10, TNF-α, IL-6, and IFN-γ were measured by ELISA. Associations between inflammatory markers and depressive symptoms were examined using group comparisons, correlation analyses, multivariable linear regression, quantile regression, and mediation analyses adjusted for demographic and clinical covariates. Results: Patients with severe depression exhibited significantly lower circulating LPS levels than those with mild-to-moderate depression (95.6 vs. 165.2 pg/mL, p = 0.007), despite no significant differences in cytokine concentrations. LPS levels were inversely associated with depression severity, anhedonia factor score, and MADRS item 8 ("inability to feel"). Lower LPS concentrations were independently predicted by higher inability to feel, reduced appetite and combined pharmacotherapy use. Quantile regression demonstrated heterogeneity across the LPS distribution, with symptom-LPS associations evident among patients with higher LPS concentrations. Higher LPS levels were associated with greater apparent sadness, concentration difficulties, and reduced sleep, but lower levels of anhedonia, less reduced appetite, less lassitude, lower inner tension, and lower suicidality. Mediation analyses indicated that anhedonia mediated the association between LPS levels and depression severity. Conclusions: Higher circulating LPS may characterize a biologically distinct subgroup of MDD patients with lower symptom severity and less anhedonia, supporting biological heterogeneity within MDD.