title: Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress.
abstract: BACKGROUND
  Chronic inflammation may be involved in combat-related post-traumatic stress disorder (PTSD) and may help explain comorbid physical diseases. However, the extent to which combat exposure per se, depression, or early life trauma, all of which are associated with combat PTSD, may confound the relationship between PTSD and inflammation is unclear.
  
  
  METHODS
  We quantified interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and C-reactive protein (CRP) in 51 combat-exposed males with PTSD and 51 combat-exposed males without PTSD, and assessed PTSD and depression severity as well as history of early life trauma. To decrease the possibility of Type I errors, we summed standardized scores of IL-1β, IL-6, TNFα, IFNγ and CRP into a total "pro-inflammatory score". PTSD symptom severity was assessed with the Clinician Administered PTSD Scale (CAPS) rating scale.
  
  
  RESULTS
  Subjects with PTSD had significantly higher pro-inflammatory scores compared to combat-exposed subjects without PTSD (p=0.006), and even after controlling for early life trauma, depression diagnosis and severity, body mass index, ethnicity, education, asthma/allergies, time since combat and the use of possibly confounding medications (p=0.002). Within the PTSD group, the pro-inflammatory score was not significantly correlated with depressive symptom severity, CAPS total score, or with the number of early life traumas.
  
  
  CONCLUSIONS
  Combat-related PTSD in males is associated with higher levels of pro-inflammatory cytokines, even after accounting for depression and early life trauma. These results, from one of the largest studies of inflammatory cytokines in PTSD to date, suggest that immune activation may be a core element of PTSD pathophysiology more so than a signature of combat exposure alone.
authors.affiliation: Department of Psychiatry, University of California, San Francisco (UCSF), School of Medicine, San Francisco, CA, United States; Department of Clinical Sciences, Section for Psychiatry, Lund University, Lund, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindqvist
authors.affiliation: Department of Psychiatry, University of California, San Francisco (UCSF), School of Medicine, San Francisco, CA, United States. Electronic address: Owen.Wolkowitz@ucsf.edu.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Wolkowitz
authors.affiliation: Department of OB/GYN and Reproductive Sciences, University of California, San Francisco (UCSF), School of Medicine, San Francisco, CA, United States.
authors.forename: Synthia
authors.initials: S
authors.lastname: Mellon
authors.affiliation: Department of Psychiatry, MSSM/James J. Peters Veterans Administration Medical Center, NY, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Yehuda
authors.affiliation: Department of Psychiatry, MSSM/James J. Peters Veterans Administration Medical Center, NY, United States.
authors.forename: Janine D
authors.initials: JD
authors.lastname: Flory
authors.affiliation: Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and Traumatic Brain Injury, Department of Psychiatry, NYU, NY, United States.
authors.forename: Clare
authors.initials: C
authors.lastname: Henn-Haase
authors.affiliation: Department of Psychiatry, MSSM/James J. Peters Veterans Administration Medical Center, NY, United States.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Bierer
authors.affiliation: Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and Traumatic Brain Injury, Department of Psychiatry, NYU, NY, United States.
authors.forename: Duna
authors.initials: D
authors.lastname: Abu-Amara
authors.affiliation: Department of Psychiatry, University of California, San Francisco (UCSF), School of Medicine, San Francisco, CA, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Coy
authors.affiliation: Department of Psychiatry, University of California, San Francisco (UCSF), School of Medicine, San Francisco, CA, United States.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Neylan
authors.affiliation: Department of Psychiatry, MSSM/James J. Peters Veterans Administration Medical Center, NY, United States.
authors.forename: Iouri
authors.initials: I
authors.lastname: Makotkine
authors.affiliation: Department of Psychiatry, University of California, San Francisco (UCSF), School of Medicine, San Francisco, CA, United States.
authors.forename: Victor I
authors.initials: VI
authors.lastname: Reus
authors.affiliation: Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and Traumatic Brain Injury, Department of Psychiatry, NYU, NY, United States.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Taylor
authors.affiliation: Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and Traumatic Brain Injury, Department of Psychiatry, NYU, NY, United States. Electronic address: Charles.Marmar@nyumc.org.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Marmar
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States.
authors.forename: Firdaus S
authors.initials: FS
authors.lastname: Dhabhar
mesh_terms: D000328:Adult; D002097:C-Reactive Protein / Q000378:metabolism; D003130:Combat Disorders / Q000097:blood* / Q000150:complications; D016207:Cytokines / Q000097:blood*; D003866:Depressive Disorder / Q000097:blood* / Q000150:complications; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000150:complications; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008016:Life Change Events; D008297:Male; D008889:Military Personnel; D013313:Stress Disorders, Post-Traumatic / Q000097:blood* / Q000150:complications; D013315:Stress, Psychological / Q000097:blood* / Q000150:complications; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D055815:Young Adult
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein
keywords: Combat; Cytokines; Depression; Early life trauma; Inflammation; Post-traumatic stress disorder (PTSD)