Cytokines in bipolar disorder: A systematic review and meta-analysis

Background: Current research and hypothesis regarding the pathophysiology of bipolar disorder suggests the involvement of immune system dysfunction that is possibly related to disease activity. Our objective was to systematically review evidence of cytokine alterations in bipolar disorder according to affective state. Methods: We conducted a systemtic review of studies measuring endogenous cytokine concentrations in patients with bipolar disorder and a meta-analysis, reporting results according to the PRISMA statement. Results: Thirteen studies were included, comprising 556 bipolar disorder patients and 767 healthy controls, evaluating 15 different cytokines-, cytokine receptors- or cytokine antagonists. The levels of tumor necrosis factor-alpha (TNF-alpha), the soluble tumor necrosis factor receptor type 1 (sTNF-R1) and the soluble inlerleukin-2 receptor (sIL-2R) were elevated in manic patients compared with healthy control subjects (p < 0.01 for each). Levels of sTNF-R1 and TNF-alpha were elevated in manic patients compared to euthymic patients (p=0.01 and p=0.04, respectively). sTNF-R1 levels were elevated in euthymic patients compared with healthy control subjects (p < 0.01). There were no significant findings for other comparisons, including intra-individual alterations of cytokine levels. Limitations: Stratification according to mood state resulted in small study numbers for some cytokines. Findings were limited by heterogeneity, small sample sizes and a lack of control for confounding factors in individual studies. Conclusions: This meta-analysis found some support for immune dysregulation in bipolar disorder. Future research is warranted to elucidate the role of endogenous cytokine alterations in bipolar disorder. Clinical studies examining longitudinal changes within individuals are recommended. (C) 2012 Elsevier B.V. All rights reserved.