Cytokine alterations in bipolar disorder: A meta-analysis of 30 studies

Background: We conducted a meta-analysis of studies comparing cytokine concentrations between patients with bipolar disorder (BD) and healthy control subjects (HCs). Methods: We searched ISI Web of Science, MEDLINE, BIOSIS Previews, Scopus, Current Contents Connect, and Biological Abstracts for relevant studies. Based on heterogeneity status, we used fixed-effect or restricted maximal likelihood model to perform meta-analysis. Results: Thirty studies with a total of 2599 participants (1351 BD and 1248 HCs) were eligible for the analysis. Concentrations of interleukin (IL)-4 (p =.008), IL-6 (p =.073), IL-10 (p =.013), soluble IL-2 receptor (sIL-2R; p<.001), sIL-6R (p =.021), tumor necrosis factor (TNF)-α (p =.010), soluble TNF receptor-1 (sTNFR1; p<.001), and IL-1 receptor antagonist (p value in mania<.001 and euthymia =.021) were significantly elevated in patients compared with HCs. Moreover, IL-1β (p =.059), and IL-6 (p =.073) tended to show higher values in patients. Levels of IL-2 (p =.156), interferon (INF)-γ (p =.741), C-C motif ligand 2 (p =.624), and IL-8 (p =.952) did not significantly differ between patients and HCs. Subgroup analysis based on mitogen stimulation status partially or completely resolved heterogeneity for most of the cytokines. Concentrations of IL-2, IL-4, sIL-6R, and INF-γ were unrelated to medication status. Phasic difference was present for TNF-α, sTNFR1, sIL-2R, IL-6, and IL-1RA, whereas it was absent for IL-4 and IL-10. Conclusions: This meta-analysis provides evidence for significant elevation of proinflammatory, anti-inflammatory, and regulatory cytokines in BD.