Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression

Background 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. Methods 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. Findings 8057 abstracts were identified and 20 studies were included. Interleukin 6 (SMD 0.88; p=0.0003), interleukin 1 beta (SMD 1.42; p=0.045), and interferon. (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 alpha (TNF alpha; 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. TNFa (SMD 1.32, 0.13-2.50; p=0.003), interleukin 1 beta (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 1 beta 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 1 beta, interleukin 6, and C-reactive protein studies. Egger's linear regression test revealed a potential publication bias for interleukin 1 beta. Additionally, for most inflammatory markers, study heterogeneity was reported to be high (I-2>75%). Interpretation PTSD is associated with increased interleukin 6, interleukin 1 beta, TNF alpha, and interferon gamma 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.