Passos Ives Cavalcante, Vasconcelos-Moreno Mirela Paiva, Costa Leonardo Gazzi, Kunz Maurício, Brietzke Elisa, Quevedo João, Salum Giovanni, Magalhães Pedro V, Kapczinski Flávio, Kauer-Sant'Anna Márcia
UT Center of Excellence on Mood Disorder, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA; Bipolar Disorder Program, Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil; Graduation Program in Psychiatry and Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
Bipolar Disorder Program, Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil; Graduation Program in Psychiatry and Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
Lancet Psychiatry. 2015 Nov;2(11):1002-12. doi: 10.1016/S2215-0366(15)00309-0.
Studies investigating inflammatory markers in post-traumatic stress disorder (PTSD) have yielded mixed results. The aim of our study was to compare concentrations of inflammatory markers in patients with PTSD compared with healthy controls.
We did a meta-analysis and meta-regression of studies comparing inflammatory markers between patients with PTSD and healthy controls by searching PubMed, Embase, Scopus, Web of Science, and PsycINFO for articles published between Jan 1, 1960, and April 7, 2015. From eligible studies (ie, cross-sectional studies or baseline data from longitudinal studies of peripheral blood cytokine concentrations that compared adults with PTSD with healthy controls), we extracted outcomes of interest, such as mean and SD of peripheral blood cytokines, the time of day blood was collected, whether the study allowed patients with comorbid major depressive disorder in the PTSD group, whether patients were medication free, and severity of PTSD symptoms. We undertook meta-analyses whenever values of inflammatory markers were available in two or more studies. A random-effects model with restricted maximum-likelihood estimator was used to synthesise the effect size (assessed by standardised mean difference [SMD]) across studies.
8057 abstracts were identified and 20 studies were included. Interleukin 6 (SMD 0.88; p=0.0003), interleukin 1β (SMD 1.42; p=0.045), and interferon γ (SMD 0.49; p=0.002) levels were higher in the PTSD group than in healthy controls. Subgroup meta-analysis of patients who were not given medication showed higher tumour necrosis factor α (TNFα; SMD 0.69, 95% CI 0.35-1.02; p<0.0001) in the PTSD group than the control group in addition to the aforementioned cytokines. TNFα (SMD 1.32, 0.13-2.50; p=0.003), interleukin 1β (SMD 2.35, 0.01-4.68; p=0.048), and interleukin 6 (SMD 1.75, 0.97-2.53; p<0.0001) levels remained increased in the PTSD group in a subgroup meta-analysis of studies that excluded comorbid major depressive disorder. Illness duration was positively associated with interleukin 1β levels (b=0.33, p<0.0001) and severity with interleukin 6 (b=0.02, p=0.042). A model composed of several variables-presence of comorbid major depressive disorder, use of psychotropic medications, assay used, and time of day blood was collected-explained the large amount of heterogeneity between interleukin 1β, interleukin 6, and C-reactive protein studies. Egger's linear regression test revealed a potential publication bias for interleukin 1β. Additionally, for most inflammatory markers, study heterogeneity was reported to be high (I(2)>75%).
PTSD is associated with increased interleukin 6, interleukin 1β, TNFα, and interferon γ levels. This information might be useful for consideration of chronic low-grade inflammation as a potential target or biomarker in PTSD treatment. Use of psychotropic medication and presence of comorbid major depressive disorder were important moderators that might explain the inconsistency between results of previous studies. Our search strategy used a range of databases and we made exhaustive effort to acquire data by contacting the authors. Notably, high levels of between-study heterogeneity were recorded for most cytokine variables measured in our analysis. However, meta-regression analysis could explain a large amount of this heterogeneity.
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关于创伤后应激障碍（PTSD）炎症标志物的研究结果不一。我们研究的目的是比较PTSD患者与健康对照者炎症标志物的浓度。
我们通过检索PubMed、Embase、Scopus、Web of Science和PsycINFO数据库，对1960年1月1日至2015年4月7日发表的比较PTSD患者与健康对照者炎症标志物的研究进行了荟萃分析和荟萃回归。从符合条件的研究（即比较PTSD成年患者与健康对照者外周血细胞因子浓度的横断面研究或纵向研究的基线数据）中，我们提取了感兴趣的结果，如外周血细胞因子的均值和标准差、采血时间、PTSD组是否允许合并重度抑郁症患者、患者是否未用药以及PTSD症状的严重程度。只要两项或更多研究中有炎症标志物的值，我们就进行荟萃分析。采用限制最大似然估计的随机效应模型来综合各研究的效应量（通过标准化均值差[SMD]评估）。
共识别出8057篇摘要，纳入20项研究。PTSD组白细胞介素6（SMD 0.88；p = 0.0003）、白细胞介素1β（SMD 1.42；p = 0.045）和干扰素γ（SMD 0.49；p = 0.002）水平高于健康对照组。对未用药患者的亚组荟萃分析显示，除上述细胞因子外，PTSD组肿瘤坏死因子α（TNFα；SMD 0.69，95%CI 0.35 - 1.02；p < 0.0001）高于对照组。在排除合并重度抑郁症的研究亚组荟萃分析中，PTSD组TNFα（SMD 1.32，0.13 - 2.50；p = 0.003）、白细胞介素1β（SMD 2.35，0.01 - 4.68；p = 0.048）和白细胞介素6（SMD 1.75，0.97 - 2.53；p < 0.0001）水平仍升高。病程与白细胞介素1β水平呈正相关（b = 0.33，p < 0.0001），严重程度与白细胞介素6呈正相关（b = 0.02，p = 0.042）。一个由几个变量组成的模型——合并重度抑郁症的存在、精神药物的使用、所用检测方法以及采血时间——解释了白细胞介素1β、白细胞介素6和C反应蛋白研究之间的大量异质性。Egger线性回归检验显示白细胞介素1β存在潜在的发表偏倚。此外，对于大多数炎症标志物，研究异质性据报道较高（I²>75%）。
PTSD与白细胞介素6、白细胞介素1β、TNFα和干扰素γ水平升高有关。这些信息可能有助于将慢性低度炎症作为PTSD治疗的潜在靶点或生物标志物进行考虑。精神药物的使用和合并重度抑郁症的存在是重要的调节因素，可能解释了先前研究结果之间的不一致。我们的检索策略使用了一系列数据库，并通过联系作者竭尽全力获取数据。值得注意的是，我们分析中测量的大多数细胞因子变量的研究间异质性水平较高。然而，荟萃回归分析可以解释大量这种异质性。
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