Exploring inflammatory depression: associations of CRP and NLR with neuroanatomical alterations and symptom dimensions in hospitalized patients with major depressive disorder

Abstract

Growing evidence indicates that immune dysfunction contributes to the heterogeneity of major depressive disorder, yet it remains unclear when inflammation is clinically relevant, how it manifests in symptomatology and brain structure, and for whom immune-related mechanisms may be most important. Clarifying these questions is essential for patient stratification and the development of immunomodulatory treatments. Methods Clinical, biochemical, and neuroimaging data from 176 hospitalized adults with DSM-5 major depressive disorder was involved. Peripheral inflammation was assessed using routinely available markers, including C-reactive protein (CRP) and the neutrophil-to-lymphocyte ratio (NLR), and a high-inflammation subgroup was defined using literature-based thresholds (CRP > 3.0 mg/L and/or NLR > 3.53). Depressive symptoms, functioning, and illness severity were evaluated from structured clinical records. Voxel-based morphometry analyses were conducted to investigate associations between inflammatory markers and gray matter volume. Results Approximately one-third of patients met criteria for an inflammation-associated subtype. In univariate analyses, CRP was nominally higher in patients with anhedonia and suicide attempt, though neither association survived FDR correction. After adjusting for age, sex, and BMI, CRP was independently associated with suicide attempt (OR = 1.221, p = 0.004) and suicidal plan (OR = 1.173, p = 0.021), while the anhedonia association was no longer significant. CRP correlated with higher CGI-S (ρ = 0.193, pFDR = 0.041) and predicted both GAF and CGI-S in covariate-adjusted models. NLR showed no significant associations with any symptom or clinical severity measure. The high-inflammation subgroup was characterized by older age, higher BMI, and later age at illness onset, without significant differences in symptoms, CGI-S, or GAF after covariate adjustment. Exploratory VBM analyses revealed CRP-related gray matter increases in the left middle and inferior temporal gyrus and decreases in occipital and inferior parietal regions, while NLR was associated with increased volume in the right thalamic nuclei and decreased volume in the right superior temporal gyrus; subgroup contrasts indicated greater occipital and cuneus volume in the low-inflammation group and greater temporal pole volume in the high-inflammation group, with all findings reported at uncorrected thresholds. Conclusions Our findings suggest that CRP, a routinely available inflammatory marker, is independently associated with suicidality and clinical severity in severely depressed inpatients, even after accounting for confounders. The divergent neuroanatomical correlates of CRP and NLR, though exploratory, point to distinct inflammatory pathways with regionally specific brain signatures. These findings support the potential utility of CRP in identifying a clinically relevant inflammatory dimension within severe depression. Prospective studies with larger samples are needed to replicate these associations, clarify the temporal dynamics of inflammation in depression, and evaluate whether inflammatory stratification can guide treatment selection.