Tumor Necrosis Factor-alpha and its association with bipolar disorder: a systematic review and meta-analysis

OBJECTIVE: The objective of this study is to conduct a systematic review and meta-analysis of the association between bipolar disorder (BD) and levels of Tumor Necrosis Factor-alpha (TNF-alpha) and its receptors. METHODS: A systematic review and meta-analysis was conducted for studies analyzing TNF-alpha and its receptors, according to the PRISMA guidelines. Studies evaluating protein and gene expression levels in peripheral blood or in postmortem brain tissue were included. PubMed, PsycINFO, and Embase databases were searched, and a total of 97 studies were included. RESULTS: The meta-analysis results showed that levels of TNF-alpha, and soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFR1 and sTNFR2) were all elevated in individuals with BD when compared to a healthy control group. Additional analysis for bipolar subgroups revealed an increase in TNF-alpha, sTNFR1, and sTNFR2 levels in individuals with mania, depression, BD type 1 and BD type 2 when compared to healthy controls. In contrast, none were elevated when comparing euthymic individuals and healthy controls. CONCLUSIONS: This study found increased levels of TNF-alpha, sTNFR1 and sTNFR2 supporting the notion of inflammation playing a major role in BD. The pathophysiological pattern of TNF-alpha and its receptors being significantly increased during mood episodes lends support to increased immune dysregulation in BD.