Importance. 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.

Objective

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.

Data Sources. Systematic review of observational studies in PubMed and PsycInfo up to February 2^nd, 2020.

Study Selection. Case-control studies reporting inflammatory mediators' levels in BD and controls.

Data Extraction and Synthesis. 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).

Main Outcomes and Measures. 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.

Results

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 than in HCs for CRP during depressive episodes, lower for IL-6 during euthymia, and higher during manic episodes for CRP, IL-6, and TNF-α. Sensitivity analyses after excluding outliers identified with funnel plot visual inspection, low-quality studies, and considering only studies matched per body mass index confirmed the main results. Meta-regression showed that age (IL-6, TNF-α), gender (CRP), duration of illness (CRP) moderated elevated individual inflammatory levels.

Conclusions and Relevance Peripheral pro-inflammatory marker elevations were confirmed in BD. CRP and TNF-α could represent state markers, as they were only elevated during mood episodes, while IL-6 appeared to be a trait marker for BD. Increased variability of specific inflammatory mediators in specific disease active states suggests that a subset of subjects with BD may exhibit elevated inflammation as part of a manic or depressive episode.

中文翻译：

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双相情感障碍情绪谱中 C 反应蛋白、肿瘤坏死因子-α、白介素-6 和白介素-1β 的外周水平：平均差异和变异性的荟萃分析

重要性。与健康对照相比，尚不清楚双相情感障碍 (BD) 不同阶段和 BD 受试者之间促炎介质的量级和变异性是否存在差异。

客观的

对 BD 与健康对照中的 C 反应蛋白 (CRP)、IL-1、IL-6、TNF-α 进行比较荟萃分析，测量对所有受试者的平均和变异性影响。敏感性分析包括疾病活动。

数据源。在考研和PsycInfo观察性研究的系统评价高达2月2日^第二年，2020年。

研究选择。病例对照研究报告了 BD 和对照中炎症介质的水平。

数据提取和综合。提取了 BD 参与者和对照组中循环 CRP、IL-1β、IL-6、TNF-α 的汇总分布指标。基于个体研究/中介效应大小 (Hedge's g) 进行随机效应多变量荟萃分析。

主要成果和措施。共同主要结果是 BD 参与者在情绪谱和对照组之间的炎症介质水平 (Hedge's g) 和变异性 (变异系数 (CVR)) 差异。

结果

在最初的 729 篇论文中，72 篇被评估，然后在全文审查后排除，最终 53 项研究被纳入系统评价，49 项研究被纳入荟萃分析。平均年龄为 36.96 (SD: 9.29) 岁，平均女性百分比为 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），BD 与 HC 受试者的 TNF-α（g=0.49，95% CI 0.19-0.78，k=49，BD=2,231 与 HC=3,017）升高，但 IL-1β（g=-0.28）不升高, 95% CI -0.68-0.12, k=4, BD=87 vs HC=66)。当分别考虑心境正常、抑郁和躁狂发作时，CRP 和 TNF-α 在抑郁和躁狂发作中均升高，但在心境正常时不升高，而无论疾病状态如何，IL-6 均保持升高。CRP、IL-1β 和 TNF-α 的 CVR 没有差异，而对于 IL-6 观察到较低的 CVR。在考虑疾病阶段时，BD 患者在抑郁发作期间 CRP 的 CVR 高于 HC，在 euthymia 期间 IL-6 的 CVR 较低，而 CRP、IL-6 和 TNF-α 在躁狂发作期间的 CVR 较高。排除通过漏斗图目视检查、低质量研究确定的异常值并仅考虑与每个体重指数匹配的研究后的敏感性分析证实了主要结果。Meta 回归显示年龄（IL-6、TNF-α）、性别（CRP）、病程（CRP）可减轻个体炎症水平的升高。排除通过漏斗图目视检查、低质量研究确定的异常值并仅考虑与每个体重指数匹配的研究后的敏感性分析证实了主要结果。Meta 回归显示年龄（IL-6、TNF-α）、性别（CRP）、病程（CRP）可减轻个体炎症水平的升高。排除通过漏斗图目视检查、低质量研究确定的异常值并仅考虑与每个体重指数匹配的研究后的敏感性分析证实了主要结果。Meta 回归显示年龄（IL-6、TNF-α）、性别（CRP）、病程（CRP）可减轻个体炎症水平的升高。

结论和相关性 在 BD 中证实了外周促炎标志物升高。CRP 和 TNF-α 可以代表状态标记，因为它们仅在情绪发作期间升高，而 IL-6 似乎是 BD 的特征标记。特定疾病活动状态下特定炎症介质的变异性增加表明，一部分患有 BD 的受试者可能表现出炎症升高，作为躁狂或抑郁发作的一部分。