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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 \u00b1 14 years) were recruited from psychiatric inpatient and outpatient services. Depressive symptom severity was assessed using the Montgomery\u2013\u00c5sberg Depression Rating Scale (MADRS). Serum concentrations of LPS, IL-10, TNF-\u03b1, IL-6, and IFN-\u03b3 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 (\u201cinability to feel\u201d). 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\u2013LPS 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.<\/jats:p>","DOI":"10.3390\/brainsci16080852","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T14:45:06Z","timestamp":1786545906000},"page":"852","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Higher Lipopolysaccharide Levels Are Linked to Less Anhedonia and Lower Severity of Major Depressive Disorder"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3136-9064","authenticated-orcid":false,"given":"Egle","family":"Milasauskiene","sequence":"first","affiliation":[{"name":"Laboratory of Behavioral Medicine, Neuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"},{"name":"Department of Psychiatry, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3928-2151","authenticated-orcid":false,"given":"Julius","family":"Burkauskas","sequence":"additional","affiliation":[{"name":"Laboratory of Behavioral Medicine, Neuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simonas","family":"Jesmanas","sequence":"additional","affiliation":[{"name":"Department of Radiology, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rymante","family":"Gleizniene","sequence":"additional","affiliation":[{"name":"Department of Radiology, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilmante","family":"Borutaite","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nijole","family":"Raskauskiene","sequence":"additional","affiliation":[{"name":"Laboratory of Behavioral Medicine, Neuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Skemiene","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginija","family":"Adomaitiene","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5086-8893","authenticated-orcid":false,"given":"Brigita","family":"Gradauskiene","sequence":"additional","affiliation":[{"name":"Department of Immunology and Allergology, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3610-1730","authenticated-orcid":false,"given":"Guy C.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, Cambridge CB21QW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesta","family":"Steibliene","sequence":"additional","affiliation":[{"name":"Laboratory of Behavioral Medicine, Neuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"},{"name":"Department of Psychiatry, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/s41398-024-02921-z","article-title":"Inflammatory mediators in major depression and bipolar disorder","volume":"14","author":"Poletti","year":"2024","journal-title":"Transl. 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