title: Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression.
abstract: 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.
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  None.
authors.affiliation: 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.
authors.forename: Ives Cavalcante
authors.initials: IC
authors.lastname: Passos
authors.affiliation: 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.
authors.forename: Mirela Paiva
authors.initials: MP
authors.lastname: Vasconcelos-Moreno
authors.affiliation: Interdisciplinary Laboratory of Clinical Neurosciences, Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Leonardo Gazzi
authors.initials: LG
authors.lastname: Costa
authors.affiliation: 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.
authors.forename: Maurício
authors.initials: M
authors.lastname: Kunz
authors.affiliation: Interdisciplinary Laboratory of Clinical Neurosciences, Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Elisa
authors.initials: E
authors.lastname: Brietzke
authors.affiliation: 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; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, Brazil.
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
authors.affiliation: Graduation Program in Psychiatry and Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Salum
authors.affiliation: 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.
authors.forename: Pedro V
authors.initials: PV
authors.lastname: Magalhães
authors.affiliation: 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. Electronic address: flavio.kapczinski@gmail.com.
authors.forename: Flávio
authors.initials: F
authors.lastname: Kapczinski
authors.affiliation: 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.
authors.forename: Márcia
authors.initials: M
authors.lastname: Kauer-Sant'Anna
mesh_terms: D015415:Biomarkers / Q000097:blood*; D006801:Humans; D007249:Inflammation / Q000097:blood*; D012044:Regression Analysis; D013313:Stress Disorders, Post-Traumatic / Q000097:blood*
chemical_list: D015415:Biomarkers