Shifting the paradigm in bipolar disorder: moving beyond conventional inflammatory markers to novel EBI3-containing heterodimeric cytokines.

Background: Research shows immune dysregulation in bipolar disorder (BD), but clinical heterogeneity and variable treatment responses persist around inflammatory markers like IL-6, TNF-α, and CRP. Newly identified EBI3-containing cytokines (IL-27, IL-35, IL-39) can be proinflammatory or immunoregulatory/putatively neuroprotective, and their role in BD remains unexplored. Methods: Serum levels of EBI3-containing inflammatory cytokines (IL-27, IL-35, IL-39, and EBI3) and conventional inflammatory markers (CRP, TNF-α, IL-6, and IL-10) were measured in this case-control, observational study using a high-sensitivity enzyme-linked immunosorbent assay (ELISA) in a cohort of 60 patients with acute mania and 60 healthy controls. Results: Compared with controls, patients with BD showed significantly higher serum levels of CRP (FDR-p = 0.008), IL-6 (FDR-p = 0.004), IL-10 (FDR-p = 0.008), IL-27 (FDR-p = 0.008), and IL-35 (FDR-p = 0.0027). TNF-α initially reached significance (p = 0.041) but did not remain significant after FDR correction (FDR-p = 0.0547). IL-39 (FDR-p = 0.473) and EBI3 (FDR-p = 0.713) showed no difference between patients and controls. These results highlight a pattern of heightened inflammatory and regulatory cytokine activity in BD. Conclusions: This study suggests that IL-27 and IL-35 dysregulation characterizes the acute manic state of bipolar disorder and reflects a possible imbalance between pro- and anti-inflammatory responses. While these EBI3-containing cytokines may hold promise as state-related markers, their broader relevance across mood phases remains to be determined. Further longitudinal research is needed to evaluate state- versus trait-dependent immune alterations and their potential implications for personalized immunomodulation in BD.