title: Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis.
abstract: BACKGROUND
  Bipolar disorder may be associated with peripheral immune system dysfunction; however, results in individual studies are conflicting. Our aim was to systematically review evidence of peripheral cytokine alterations in bipolar disorder integrating findings from various affective states.
  
  
  METHODS
  We conducted a meta-analysis of studies comparing peripheral cytokine concentrations in patients with bipolar disorder with healthy control subjects. Results were reported according to the PRISMA statement.
  
  
  RESULTS
  Eighteen studies with a total of 761 bipolar disorder patients and 919 healthy controls were included. Overall, concentrations of soluble Interleukin (IL)-2 receptor (sIL-2R), tumor necrosis factor-α (TNF-α), soluble tumor necrosis factor receptor type 1 (sTNFR1) (p < 0.001 each), sIL-6R (p = 0.01) and IL-4 (p = 0.04) were significantly higher in bipolar patients compared with healthy controls. There were no significant differences between bipolar disorder patients and healthy control subjects for IL-1, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12, IL-1β, IL-1 receptor antagonist (IL-1RA), interferon-γ (IFN-γ), transforming growth factor-β1 (TGF-β1) and sTNFR2.
  
  
  CONCLUSIONS
  Employing a global approach, incorporating evidence across affective states, this meta-analysis found some support for peripheral inflammatory alterations in bipolar disorder. Results were limited by heterogeneity between studies, insufficient standardization and lacking control for confounders in individual studies. Further research exploring the role of the peripheral inflammatory system in relation to neuroinflammation is warranted.
authors.affiliation: Psychiatric Center Copenhagen, Rigshospitalet, University of Copenhagen, Denmark. klaus.munkholm@regionh.dk
authors.forename: Klaus
authors.initials: K
authors.lastname: Munkholm
authors.forename: Julie Vestergaard
authors.initials: JV
authors.lastname: Braüner
authors.forename: Lars Vedel
authors.initials: LV
authors.lastname: Kessing
authors.forename: Maj
authors.initials: M
authors.lastname: Vinberg
mesh_terms: D001714:Bipolar Disorder / Q000378:metabolism*; D016207:Cytokines; D016208:Databases, Factual; D006801:Humans
chemical_list: D016207:Cytokines
keywords: Biomarker; Bipolar disorder; Cytokines; Inflammation; Meta-analysis; Review