Peripheral levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-1β across the mood spectrum in bipolar disorder: A meta-analysis of mean differences and variability

• Published in: Brain, behavior, and immunity behavior, and immunity, 2021-10, Vol.97, p.193-203
• Main Authors: Solmi, Marco, Suresh Sharma, Manu, Osimo, Emanuele F., Fornaro, Michele, Bortolato, Beatrice, Croatto, Giovanni, Miola, Alessandro, Vieta, Eduard, Pariante, Carmine M., Smith, Lee, Fusar-Poli, Paolo, Shin, Jae Il, Berk, Michael, Carvalho, Andre F.
• Format: Article
• Language: English
• Subjects: Bipolar disorder; C-reactive protein; Cytokine; Depression; IL-1β; IL-6; Inflammation; Interleukin; Mania; Mental disorders; Meta-analysis; Neuroscience; Psychiatry; TNF-α
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2021.07.014

•A meta-analysis of mean differences and variability assessing peripheral levels of CRP, TNF-α, IL-1β, and IL-6 in individuals with BD and controls was conducted.•Levels of IL-1β were unaltered relative to controls.•Levels of IL-6, TNF-α and CRP were elevated in acute mood states relative to controls.•Only levels of IL-6 were elevated regardless of mood states (trait marker).•Our findings provide evidence that BD is characterized by peripheral immune activation. It is unclear whether differences exist in the magnitude and variability of pro-inflammatory mediators in the different phases of bipolar disorder (BD) and among subjects with BD, as compared to healthy controls. To run a comparative meta-analysis of C-Reactive Protein (CRP), IL-1, IL-6, TNF-α in BD vs healthy controls, measuring mean and variability effects on all subjects. Sensitivity analyses include disease activity. Systematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020. Case-control studies reporting inflammatory mediators' levels in BD and controls. Summary distribution measures of circulating CRP, IL-1β, IL-6, TNF-α in participants with BD and control groups were extracted. Random-effects multivariate meta-analyses were conducted based on individual study/mediator effect sizes (Hedge’s g). Co-primary outcomes were inflammatory mediators' levels (Hedge’s g) and variability (coefficient of variance ratio (CVR)) differences between participants with BD across the mood spectrum and controls. Out of the initial 729 papers, 72 were assessed and then excluded after full-text review, and ultimately 53 studies were included in the systematic review, while 49 were included in the meta-analysis. The mean age was 36.96 (SD: 9.29) years, and the mean female percentage was 56.31 (SD: 16.61). CRP (g = 0.70, 95% CI 0.31–1.09, k = 37, BD = 2,215 vs HC = 3,750), IL-6 (g = 0.81, 95% CI 0.46–1.16, k = 45, BD = 1,956 vs HC = 4,106), TNF-α (g = 0.49, 95% CI 0.19–0.78, k = 49, BD = 2,231 vs HC = 3,017) were elevated in subjects with BD vs HC, but not IL-1β (g = -0.28, 95% CI −0.68–0.12, k = 4, BD = 87 vs HC = 66). When considering euthymic, depressive, and manic episodes separately, CRP and TNF-α were elevated in both depressive and manic episodes, but not in euthymia, while IL-6 remained elevated regardless of the disease state. No difference in CVR emerged for CRP, IL-1β, and TNF-α, while a lower CVR was observed for IL-6. When considering disease phases, CVR was higher in BD