High-sensitivity C-reactive protein fails to capture cellular immune dysregulation in major depressive episodes: A preliminary study.
BACKGROUND High-sensitivity CRP (hsCRP) is the most widely used biomarker to operationalize the concept of "inflammatory depression" and has been proposed to define biologically meaningful subgroups of major depressive disorder. However, CRP is a nonspecific acute-phase reactant, and whether CRP-based stratification captures the cellular immune dysregulation increasingly implicated in active major depressive episodes (MDE) remains unclear. METHODS We conducted a secondary analysis of a deeply immunophenotyped cohort including patients with active MDE and healthy controls (HC). Participants were stratified by high-sensitivity CRP (hsCRP) level (<3VS. ≥ 3 mg/L). Adaptive and innate immune cell profiles were compared between diagnostic groups within each hsCRP stratum, focusing on T-cell activation, inhibitory checkpoint expression, and monocyte subset distributions. RESULTS Elevated hsCRP (≥3 mg/L) was observed in both HC and MDE participants and was not associated with depressive symptom severity. Across hsCRP strata, patients with MDE exhibited marked alterations in adaptive immunity, including increased T-cell activation (CD69 expression) and inhibitory checkpoint signaling (PD 1 and LAG-3), particularly within the CD8+ compartment. MDE was also associated with a characteristic redistribution of circulating monocyte subsets. These cellular immune alterations were evident even among individuals with hsCRP levels within the conventionally non-inflammatory range, whereas HC with elevated hsCRP did not display an MDE-like immune phenotype. CONCLUSIONS In this preliminary study (MDE: n = 39; HC: n = 41), hsCRP stratification did not capture the cellular immune dysregulation associated with an active MDE. While hsCRP may reflect a broader systemic inflammatory or metabolic burden, cellular immune signatures appear more closely linked to depressive pathophysiology. These findings are preliminary and require replication in larger cohorts, but support moving, beyond hsCRP alone toward integrated immune signatures - combining cellular immunophenotyping with myeloid-derived mediators - to define immune-related subtypes of depression.