Cytokine Alterations in Bipolar Disorder: A Meta-Analysis of 30 Studies

BackgroundWe conducted a meta-analysis of studies comparing cytokine concentrations between patients with bipolar disorder (BD) and healthy control subjects (HCs).MethodsWe 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.ResultsThirty 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.ConclusionsThis meta-analysis provides evidence for significant elevation of proinflammatory, anti-inflammatory, and regulatory cytokines in BD.