C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis

Background Inflammatory processes and neural-immune interactions have been implicated in the pathogenesis of psychiatric conditions, but studies in bipolar disorder are inconclusive so far. We aimed to investigate whether peripheral concentrations of C-reactive protein (CRP), an acute-phase response protein of inflammatory activity, are increased in bipolar disorder across the mood spectrum. Methods In this systematic review and meta-analysis, we searched MEDLINE, the Cochrane Library, Scopus, and Web of Knowledge from database inception to Aug 14, 2016, for studies that measured serum and plasma CRP concentrations in adult patients with bipolar disorder (as defined by DSM-IV-TR) and healthy controls. We extracted data from published reports. We did three between-group meta-analyses comparing CRP concentrations in patients in mania, depression, or euthymia, with those in healthy controls (cross-sectional studies), and two within-group meta-analyses comparing changes in CRP concentrations before and after treatment of an index manic or depressive episode (longitudinal studies). We used Hedges' adjusted g to calculate effect sizes and pooled results using random-effect models. We also did meta-regression analyses by mood state to investigate possible moderators of CRP concentrations. Findings We identified 27 studies representing 2161 patients with bipolar disorder and 81 932 healthy controls. Compared with healthy individuals, CRP concentrations were moderately increased in people with bipolar disorder during depression (g 0.67, 95% CI 0.23 to 1.11; p = 0.003) and euthymia (0.65, 0.40 to 0.90; p < 0.0001) and more substantially increased during mania (0.87, 0.58 to 1.15; p < 0.0001). The extent of the increases in CRP concentrations in mania and depression was not related to symptom severity (p = 0.256 for mania and p = 0.626 for depression). CRP concentrations were moderately decreased after resolution of an index manic episode (-0.36, -0.66 to -0.05; p = 0.022) and slightly decreased after resolution of an index depressive episode (-0.18, -0.30 to -0.07; p = 0.002). Interpretation CRP concentrations are increased in bipolar disorder regardless of mood state, but are higher during mania than in depression and euthymia, suggesting an increased inflammatory burden in mania.