Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review Article
  • Published:
Molecular Psychiatry Submit manuscript

Abstract

Post-traumatic stress disorder (PTSD) has been associated with persistent, low-degree inflammation, which could explain the increased prevalence of autoimmune conditions and accelerated aging among patients. The aim of the present study is to assess which inflammatory and oxidative stress markers are associated with PTSD. We carried out a meta-analytic and meta-regression analysis based on a systematic review of studies comparing inflammatory and oxidative stress markers between patients with PTSD and controls. We undertook meta-analyses whenever values of inflammatory and oxidative stress markers were available in two or more studies. Overall, 28,008 abstracts were identified, and 54 studies were included, with a total of 8394 participants. The Newcastle-Ottawa Quality Assessment Scale was used to evaluate the quality of the studies. Concentrations of C-reactive protein (SMD = 0.64; 95% CI: 0.21 to 1.06; p = 0.0031; k = 12), interleukin 6 (SMD = 0.94; 95% CI: 0.36 to 1.52; p = 0.0014; k = 32), and tumor necrosis factor-α (SMD = 0.89; 95% CI: 0.23 to 1.55; p = 0.0080; k = 24) were significantly increased in patients with PTSD in comparison with healthy controls. Interleukin 1β levels almost reached the threshold for significance (SMD = 1.20; 95% CI: –0.04 to 2.44; p = 0.0569; k = 15). No oxidative stress marker was associated with PTSD. These findings may explain why PTSD is associated with accelerated aging and illnesses in which immune activation has a key role, such as cardiovascular diseases and diabetes. In addition, they pointed to the potential role of inflammatory markers as therapeutic targets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2: Subgroup meta-analysis of interleukin 6 with comorbid MDD as a predictor.
Fig. 3: Subgroup meta-analysis of tumor necrosis factor-α with comorbid MDD as a predictor.
Fig. 4: Subgroup meta-analysis of interleukin 6 with use of psychotropic medications as a predictor.
Fig. 5: Subgroup meta-analysis of tumor necrosis factor-α with use of psychotropic medications as a predictor.

Similar content being viewed by others

References

  1. Yehuda R, Hoge CW, McFarlane AC, Vermetten E, Lanius RA, Nievergelt CM, et al. Post-traumatic stress disorder. Nat Rev Dis Primers. 2015;1:15057.

    Article  PubMed  Google Scholar 

  2. Tortella-Feliu M, Fullana MA, Pérez-Vigil A, Torres X, Chamorro J, Littarelli SA, et al. Risk factors for posttraumatic stress disorder: an umbrella review of systematic reviews and meta-analyses. Neurosci Biobehav Rev. 2019;107:154–65.

    Article  PubMed  Google Scholar 

  3. Koenen KC, Ratanatharathorn A, Ng L, McLaughlin KA, Bromet EJ, Stein DJ, et al. Posttraumatic stress disorder in the World Mental Health Surveys. Psychol Med. 2017;47:2260–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gradus JL. Posttraumatic stress disorder and death from suicide. Curr Psychiatry Rep. 2018;20:98.

    Article  PubMed  Google Scholar 

  5. Lohr JB, Palmer BW, Eidt CA, Aailaboyina S, Mausbach BT, Wolkowitz OM, et al. Is post-traumatic stress disorder associated with premature senescence? A review of the literature. Am J Geriatr Psychiatry. 2015;23:709–25.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Dams J, Rimane E, Steil R, Renneberg B, Rosner R, König H-H. Health-related quality of life and costs of posttraumatic stress disorder in adolescents and young adults in Germany. Front Psychiatry. 2020;11:697.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Michopoulos V, Powers A, Gillespie CF, Ressler KJ, Jovanovic T. Inflammation in fear- and anxiety-based disorders: PTSD, GAD, and beyond. Neuropsychopharmacology. 2017;42:254–70.

    Article  CAS  PubMed  Google Scholar 

  8. Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015;2:1002–12.

    Article  PubMed  Google Scholar 

  9. Roberts AL, Malspeis S, Kubzansky LD, Feldman CH, Chang S-C, Koenen KC, et al. Association of trauma and posttraumatic stress disorder with incident systemic lupus erythematosus in a longitudinal cohort of women. Arthritis Rheumatol. 2017;69:2162–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Song H, Fang F, Tomasson G, Arnberg FK, Mataix-Cols D, Fernández de la Cruz L, et al. Association of stress-related disorders with subsequent autoimmune disease. JAMA. 2018;319:2388–400.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Miller MW, Sadeh N. Traumatic stress, oxidative stress and post-traumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis. Mol Psychiatry. 2014;19:1156–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yang R, Wu GWY, Verhoeven JE, Gautam A, Reus VI, Kang JI, et al. A DNA methylation clock associated with age-related illnesses and mortality is accelerated in men with combat PTSD. Mol Psychiatry. 2021;26:4999–5009. https://doi.org/10.1038/s41380-020-0755-z.

  13. Miller MW, Wolf EJ, Sadeh N, Logue M, Spielberg JM, Hayes JP, et al. A novel locus in the oxidative stress-related gene ALOX12 moderates the association between PTSD and thickness of the prefrontal cortex. Psychoneuroendocrinology. 2015;62:359–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yang J-J, Jiang W. Immune biomarkers alterations in post-traumatic stress disorder: a systematic review and meta-analysis. J Affect Disord. 2020;268:39–46.

    Article  CAS  PubMed  Google Scholar 

  15. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–12.

    Article  CAS  PubMed  Google Scholar 

  17. Ottawa Hospital Research Institute. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 13 Jan 2021.

  18. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36:1–48.

    Article  Google Scholar 

  19. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions. Chichester, UK: John Wiley & Sons; 2019.

  20. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta‐analysis. Stat Med. 2002;21:1539–58.

  21. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updated September 2006]. In: The Cochrane Library. Chichester, UK: John Wiley & Sons, Ltd. 2006.

  23. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Team RC. R: a language and environment for statistical computing. 887. Vienna, Austria: R Foundation for Statistical Computing; 2017.

  25. Spivak B, Shohat B, Mester R, Avraham S, Gil-Ad I, Bleich A, et al. Elevated levels of serum interleukin-1 beta in combat-related posttraumatic stress disorder. Biol Psychiatry. 1997;42:345–8.

    Article  CAS  PubMed  Google Scholar 

  26. Muhtz C, Godemann K, von Alm C, Wittekind C, Goemann C, Wiedemann K, et al. Effects of chronic posttraumatic stress disorder on metabolic risk, quality of life, and stress hormones in aging former refugee children. J Nerv Ment Dis. 2011;199:646–52.

    Article  PubMed  Google Scholar 

  27. Atli A, Bulut M, Bez Y, Kaplan İ, Özdemir PG, Uysal C, et al. Altered lipid peroxidation markers are related to post-traumatic stress disorder (PTSD) and not trauma itself in earthquake survivors. Eur Arch Psychiatry Clin Neurosci. 2016;266:329–36.

    Article  PubMed  Google Scholar 

  28. Küffer A, Straus LD, Prather AA, Inslicht SS, Richards A, Shigenaga JK, et al. Altered overnight levels of pro-inflammatory cytokines in men and women with posttraumatic stress disorder. Psychoneuroendocrinology. 2019;102:114–20.

    Article  PubMed  Google Scholar 

  29. Vidović A, Gotovac K, Vilibić M, Sabioncello A, Jovanović T, Rabatić S, et al. Repeated assessments of endocrine- and immune-related changes in posttraumatic stress disorder. Neuroimmunomodulation. 2011;18:199–211.

    Article  PubMed  Google Scholar 

  30. Smith AK, Conneely KN, Kilaru V, Mercer KB, Weiss TE, Bradley B, et al. Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:700–8.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Baker DG, Ekhator NN, Kasckow JW, Hill KK, Zoumakis E, Dashevsky BA, et al. Plasma and cerebrospinal fluid interleukin-6 concentrations in posttraumatic stress disorder. Neuroimmunomodulation. 2001;9:209–17.

    Article  CAS  PubMed  Google Scholar 

  32. Ogłodek EA, Just MJ. The association between inflammatory markers (iNOS, HO-1, IL-33, MIP-1β) and depression with and without posttraumatic stress disorder. Pharmacol Rep. 2018;70:1065–72.

    Article  PubMed  Google Scholar 

  33. Ogłodek EA. Evaluation of ADMA, carbonyl groups, CAT and NKA in depressed patients with and without posttraumatic stress disorder. Pharmacol Rep. 2017;69:730–7.

    Article  PubMed  Google Scholar 

  34. Ogłodek EA. The role of PON-1, GR, IL-18, and OxLDL in depression with and without posttraumatic stress disorder. Pharmacol Rep. 2017;69:837–45.

    Article  PubMed  Google Scholar 

  35. Ogłodek EA. Changes in the concentrations of inflammatory and oxidative status biomediators (MIP-1 α, PMN elastase, MDA, and IL-12) in depressed patients with and without posttraumatic stress disorder. Pharmacol Rep. 2018;70:110–8.

    Article  PubMed  Google Scholar 

  36. Eswarappa M, Neylan TC, Whooley MA, Metzler TJ, Cohen BE. Inflammation as a predictor of disease course in posttraumatic stress disorder and depression: a prospective analysis from the Mind Your Heart Study. Brain Behav Immun. 2019;75:220–7.

    Article  PubMed  Google Scholar 

  37. Gill J, Vythilingam M, Page GG. Low cortisol, high DHEA, and high levels of stimulated TNF-alpha, and IL-6 in women with PTSD. J Trauma Stress. 2008;21:530–9.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gill J, Luckenbaugh D, Charney D, Vythilingam M. Sustained elevation of serum interleukin-6 and relative insensitivity to hydrocortisone differentiates posttraumatic stress disorder with and without depression. Biol Psychiatry. 2010;68:999–1006.

    Article  CAS  PubMed  Google Scholar 

  39. Gill JM, Saligan L, Lee H, Rotolo S, Szanton S. Women in recovery from PTSD have similar inflammation and quality of life as non-traumatized controls. J Psychosom Res. 2013;74:301–6.

    Article  PubMed  Google Scholar 

  40. Gola H, Engler H, Sommershof A, Adenauer H, Kolassa S, Schedlowski M, et al. Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells. BMC Psychiatry. 2013;13:40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Guo M, Liu T, Guo J-C, Jiang X-L, Chen F, Gao Y-S. Study on serum cytokine levels in posttraumatic stress disorder patients. Asian Pac J Trop Med. 2012;5:323–5.

    Article  CAS  PubMed  Google Scholar 

  42. Toft H, Bramness JG, Lien L, Abebe DS, Wampold BE, Tilden T, et al. PTSD patients show increasing cytokine levels during treatment despite reduced psychological distress. Neuropsychiatr Dis Treat. 2018;14:2367–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Söndergaard HP, Hansson L-O, Theorell T. The inflammatory markers C-reactive protein and serum amyloid A in refugees with and without posttraumatic stress disorder. Clin Chim Acta. 2004;342:93–98.

    Article  PubMed  Google Scholar 

  44. Park J, Marvar PJ, Liao P, Kankam ML, Norrholm SD, Downey RM, et al. Baroreflex dysfunction and augmented sympathetic nerve responses during mental stress in veterans with post-traumatic stress disorder. J Physiol. 2017;595:4893–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sumner JA, Chen Q, Roberts AL, Winning A, Rimm EB, Gilsanz P, et al. Cross-sectional and longitudinal associations of chronic posttraumatic stress disorder with inflammatory and endothelial function markers in women. Biol Psychiatry. 2017;82:875–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Miller K, Driscoll D, Smith LM, Ramaswamy S. The role of inflammation in late-life post-traumatic stress disorder. Mil Med. 2017;182:e1815–e1818.

    Article  PubMed  Google Scholar 

  47. Oganesyan LP, Mkrtchyan GM, Sukiasyan SH, Boyajyan AS. Classic and alternative complement cascades in post-traumatic stress disorder. Bull Exp Biol Med. 2009;148:859–61.

    Article  CAS  PubMed  Google Scholar 

  48. Jergović M, Tomičević M, Vidović A, Bendelja K, Savić A, Vojvoda V, et al. Telomere shortening and immune activity in war veterans with posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2014;54:275–83.

    Article  PubMed  Google Scholar 

  49. Jergović M, Bendelja K, Savić Mlakar A, Vojvoda V, Aberle N, Jovanovic T, et al. Circulating levels of hormones, lipids, and immune mediators in post-traumatic stress disorder – a 3-month follow-up study. Front Psychiatry. 2015;6:49.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Maes M, Lin AH, Delmeire L, Van Gastel A, Kenis G, De Jongh R, et al. Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biol Psychiatry. 1999;45:833–9.

    Article  CAS  PubMed  Google Scholar 

  51. Miller MW, Maniates H, Wolf EJ, Logue MW, Schichman SA, Stone A, et al. CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein. Brain Behav Immun. 2018;67:194–202.

    Article  CAS  PubMed  Google Scholar 

  52. Neupane SP, Bramness JG, Lien L. Comorbid post-traumatic stress disorder in alcohol use disorder: relationships to demography, drinking and neuroimmune profile. BMC Psychiatry. 2017;17:312.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Jiang D, Jiang S, Gong F, Yuan F, Zhao P, He X, et al. Correlation between depression, posttraumatic stress disorder, and inflammatory factors in patients with severe burn injury. Am Surg. 2018;84:1350–4.

    Article  PubMed  Google Scholar 

  54. Spitzer C, Barnow S, Völzke H, Wallaschofski H, John U, Freyberger HJ, et al. Association of posttraumatic stress disorder with low-grade elevation of C-reactive protein: evidence from the general population. J Psychiatr Res. 2010;44:15–21.

    Article  PubMed  Google Scholar 

  55. Lindqvist D, Wolkowitz OM, Mellon S, Yehuda R, Flory JD, Henn-Haase C, et al. Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress. Brain Behav Immun. 2014;42:81–88.

    Article  PubMed  Google Scholar 

  56. Lindqvist D, Dhabhar FS, Mellon SH, Yehuda R, Grenon SM, Flory JD, et al. Increased pro-inflammatory milieu in combat related PTSD – a new cohort replication study. Brain Behav Immun. 2017;59:260–4.

    Article  CAS  PubMed  Google Scholar 

  57. Hoge EA, Brandstetter K, Moshier S, Pollack MH, Wong KK, Simon NM. Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder. Depress Anxiety. 2009;26:447–55.

    Article  CAS  PubMed  Google Scholar 

  58. Vidović A, Vilibić M, Sabioncello A, Gotovac K, Rabatić S, Folnegović-Šmalc V, et al. Changes in immune and endocrine systems in posttraumatic stress disorder – prospective study. Acta Neuropsychiatr. 2009;21(Suppl 2):46–50.

    Article  PubMed  Google Scholar 

  59. de Oliveira JF, Wiener CD, Jansen K, Portela LV, Lara DR, Souza LD, et al. Serum levels of interleukins IL-6 and IL-10 in individuals with posttraumatic stress disorder in a population-based sample. Psychiatry Res. 2018;260:111–5.

    Article  PubMed  Google Scholar 

  60. Dalgard C, Eidelman O, Jozwik C, Olsen CH, Srivastava M, Biswas R, et al. The MCP-4/MCP-1 ratio in plasma is a candidate circadian biomarker for chronic post-traumatic stress disorder. Transl Psychiatry. 2017;7:e1025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Newton TL, Fernandez-Botran R, Miller JJ, Burns VE. Interleukin-6 and soluble interleukin-6 receptor levels in posttraumatic stress disorder: associations with lifetime diagnostic status and psychological context. Biol Psychol. 2014;99:150–9.

    Article  PubMed  PubMed Central  Google Scholar 

  62. O’Donovan A, Ahmadian AJ, Neylan TC, Pacult MA, Edmondson D, Cohen BE. Current posttraumatic stress disorder and exaggerated threat sensitivity associated with elevated inflammation in the Mind Your Heart Study. Brain Behav Immun. 2017;60:198–205.

    Article  PubMed  Google Scholar 

  63. Olam N, Yasar AB. The relation of trauma type on the levels of plasma C-reactive protein in patients with post-traumatic stress disorder/Travma sonrasi stres bozuklugu hastalarinda travma tipinin plazma C-reaktif protein duzeyi ile iliskisi. Anadolu Psikiyatri Dergisi. 2019;20:573–81.

    Google Scholar 

  64. Tucker P, Ruwe WD, Masters B, Parker DE, Hossain A, Trautman RP, et al. Neuroimmune and cortisol changes in selective serotonin reuptake inhibitor and placebo treatment of chronic posttraumatic stress disorder. Biol Psychiatry. 2004;56:121–8.

    Article  CAS  PubMed  Google Scholar 

  65. Powers A, Dixon HD, Conneely K, Gluck R, Munoz A, Rochat C, et al. The differential effects of PTSD, MDD, and dissociation on CRP in trauma-exposed women. Compr Psychiatry. 2019;93:33–40.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Imai R, Hori H, Itoh M, Lin M, Niwa M, Ino K, et al. Inflammatory markers and their possible effects on cognitive function in women with posttraumatic stress disorder. J Psychiatr Res. 2018;102:192–200.

    Article  PubMed  Google Scholar 

  67. Imai R, Hori H, Itoh M, Lin M, Niwa M, Ino K, et al. Relationships of blood proinflammatory markers with psychological resilience and quality of life in civilian women with posttraumatic stress disorder. Sci Rep. 2019;9:17905.

    Article  PubMed  PubMed Central  Google Scholar 

  68. von Känel R, Hepp U, Kraemer B, Traber R, Keel M, Mica L, et al. Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder. J Psychiatr Res. 2007;41:744–52.

    Article  Google Scholar 

  69. von Känel R, Begré S, Abbas CC, Saner H, Gander M-L, Schmid J-P. Inflammatory biomarkers in patients with posttraumatic stress disorder caused by myocardial infarction and the role of depressive symptoms. Neuroimmunomodulation. 2010;17:39–46.

    Article  Google Scholar 

  70. Song Y, Zhou D, Guan Z, Wang X. Disturbance of serum interleukin-2 and interleukin-8 levels in posttraumatic and non-posttraumatic stress disorder earthquake survivors in northern China. Neuroimmunomodulation. 2007;14:248–54.

    Article  CAS  PubMed  Google Scholar 

  71. Wang Z, Mandel H, Levingston CA, Young MRI. An exploratory approach demonstrating immune skewing and a loss of coordination among cytokines in plasma and saliva of Veterans with combat-related PTSD. Hum Immunol. 2016;77:652–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wang W, Wang L, Xu H, Cao C, Liu P, Luo S, et al. Characteristics of pro- and anti-inflammatory cytokines alteration in PTSD patients exposed to a deadly earthquake. J Affect Disord. 2019;248:52–58.

    Article  CAS  PubMed  Google Scholar 

  73. Teche SP, Rovaris DL, Aguiar BW, Hauck S, Vitola ES, Bau CHD, et al. Resilience to traumatic events related to urban violence and increased IL10 serum levels. Psychiatry Res. 2017;250:136–40.

    Article  CAS  PubMed  Google Scholar 

  74. Chen T, Guo M, Gao Y, Chen F, Guo J, Liu T, et al. A comparative study on the levels of serum cytokines and cortisol among post-traumatic stress disorder patients of Li and Han ethnicities in Hainan. Chin Med J. 2014;127:2771–4.

    CAS  PubMed  Google Scholar 

  75. Tezcan E, Atmaca M, Kuloglu M, Ustundag B. Free radicals in patients with post-traumatic stress disorder. Eur Arch Psychiatry Clin Neurosci. 2003;253:89–91.

    Article  PubMed  Google Scholar 

  76. McD Young R, Lawford B, Mellor R, Morris CP, Voisey J, PTSD Initiative. Investigation of C-reactive protein and AIM2 methylation as a marker for PTSD in Australian Vietnam veterans. Gene. 2021;803:145898.

    Article  CAS  PubMed  Google Scholar 

  77. Mehta ND, Stevens JS, Li Z, Gillespie CF, Fani N, Michopoulos V, et al. Inflammation, reward circuitry and symptoms of anhedonia and PTSD in trauma-exposed women. Soc Cogn Affect Neurosci. 2020;15:1046–55.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Yang L, Wu X, Wang X, Hu S, Liu G, Ma W, et al. Controlled study on serum cytokine levels in stress-related disorders. Chinese Mental Health J. 2001;15:295–6.

    Google Scholar 

  79. Luchini C, Stubbs B, Solmi M, Veronese N. Assessing the quality of studies in meta-analyses: advantages and limitations of the Newcastle Ottawa Scale. World J Metaanal. 2017;5:80.

    Google Scholar 

  80. Hori H, Kim Y. Inflammation and post-traumatic stress disorder. Psychiatry Clin Neurosci. 2019;73:143–53.

    Article  PubMed  Google Scholar 

  81. Daskalakis NP, Cohen H, Nievergelt CM, Baker DG, Buxbaum JD, Russo SJ, et al. New translational perspectives for blood-based biomarkers of PTSD: from glucocorticoid to immune mediators of stress susceptibility. Exp Neurol. 2016;284:133–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Daskalakis NP, Lehrner A, Yehuda R. Endocrine aspects of post-traumatic stress disorder and implications for diagnosis and treatment. Endocrinol Metab Clin North Am. 2013;42:503–13.

    Article  PubMed  Google Scholar 

  83. Edmondson D, von Känel R. Post-traumatic stress disorder and cardiovascular disease. Lancet Psychiatry. 2017;4:320–9.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Edmondson D, Kronish IM, Shaffer JA, Falzon L, Burg MM. Posttraumatic stress disorder and risk for coronary heart disease: a meta-analytic review. Am Heart J. 2013;166:806–14.

    Article  PubMed  Google Scholar 

  85. Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res. 2019;124:315–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hamblen JL, Norman SB, Sonis JH, Phelps AJ, Bisson JI, Nunes VD, et al. A guide to guidelines for the treatment of posttraumatic stress disorder in adults: an update. Psychotherapy. 2019;56:359–73.

    Article  PubMed  Google Scholar 

  87. Starke JA, Stein DJ. Management of treatment-resistant posttraumatic stress disorder. Curr Treat Options Psychiatry. 2017;4:387–403.

    Article  Google Scholar 

  88. Miller MW, Lin AP, Wolf EJ, Miller DR. Oxidative stress, inflammation, and neuroprogression in chronic PTSD. Harv Rev Psychiatry. 2018;26:57–69.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Ebenezer PJ, Wilson CB, Wilson LD, Nair AR, Francis F. The anti-inflammatory effects of blueberries in an animal model of post-traumatic stress disorder (PTSD). PLoS One. 2016;11:e0160923.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Monsey MS, Gerhard DM, Boyle LM, Briones MA, Seligsohn M, Schafe GE. A diet enriched with curcumin impairs newly acquired and reactivated fear memories. Neuropsychopharmacology. 2015;40:1278–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wu Y, Potempa LA, El Kebir D, Filep JG. C-reactive protein and inflammation: conformational changes affect function. Biol Chem. 2015;396:1181–97.

    Article  CAS  PubMed  Google Scholar 

  92. Chen X, Pu J, Liu Y, Tian L, Chen Y, Gui S, et al. Increased C-reactive protein concentrations were associated with suicidal behavior in patients with depressive disorders: a meta-analysis. Psychiatry Res. 2020;292:113320.

    Article  CAS  PubMed  Google Scholar 

  93. Costello H, Gould RL, Abrol E, Howard R. Systematic review and meta-analysis of the association between peripheral inflammatory cytokines and generalised anxiety disorder. BMJ Open. 2019;9:e027925.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Osimo EF, Baxter LJ, Lewis G, Jones PB, Khandaker GM. Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychol Med. 2019;49:1958–70.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Zhou J, Lu Y, Wang S, Chen K. Association between serum amyloid A levels and coronary heart disease: a systematic review and meta-analysis of 26 studies. Inflamm Res. 2020;69:331–45.

    Article  CAS  PubMed  Google Scholar 

  96. Costello EJ, Copeland WE, Shanahan L, Worthman CM, Angold A. C-reactive protein and substance use disorders in adolescence and early adulthood: a prospective analysis. Drug Alcohol Depend. 2013;133:712–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Friend SF, Nachnani R, Powell SB, Risbrough VB. C-reactive protein: marker of risk for post-traumatic stress disorder and its potential for a mechanistic role in trauma response and recovery. Eur J Neurosci. 2020. https://doi.org/10.1111/ejn.15031.

  98. Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, et al. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry. 2014;71:423–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sumner JA, Chen Q, Roberts AL, Winning A, Rimm EB, Gilsanz P, et al. Posttraumatic stress disorder onset and inflammatory and endothelial function biomarkers in women. Brain Behav Immun. 2018;69:203–9.

    Article  CAS  PubMed  Google Scholar 

  100. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6:a016295.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–57.

    Article  CAS  PubMed  Google Scholar 

  102. Winsauer C, Kruglov AA, Chashchina AA, Drutskaya MS, Nedospasov SA. Cellular sources of pathogenic and protective TNF and experimental strategies based on utilization of TNF humanized mice. Cytokine Growth Factor Rev. 2014;25:115–23.

    Article  CAS  PubMed  Google Scholar 

  103. Marsland AL, Gianaros PJ, Abramowitch SM, Manuck SB, Hariri AR. Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults. Biol Psychiatry. 2008;64:484–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Baune BT, Konrad C, Grotegerd D, Suslow T, Ohrmann P, Bauer J, et al. Tumor necrosis factor gene variation predicts hippocampus volume in healthy individuals. Biol Psychiatry. 2012;72:655–62.

    Article  CAS  PubMed  Google Scholar 

  105. Maier A, Dharan A, Oliver G, Berk M, Redston S, Back SE, et al. A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial to assess the efficacy of adjunctive N-Acetylcysteine for treatment-resistant PTSD: a study protocol. BMC Psychiatry. 2020;20:397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Borovac Štefanović L, Kalinić D, Mimica N, Beer Ljubić B, Aladrović J, Mandelsamen Perica M, et al. Oxidative status and the severity of clinical symptoms in patients with post-traumatic stress disorder. Ann Clin Biochem. 2015;52:95–104.

    Article  PubMed  Google Scholar 

  107. Zieker J, Zieker D, Jatzko A, Dietzsch J, Nieselt K, Schmitt A, et al. Differential gene expression in peripheral blood of patients suffering from post-traumatic stress disorder. Mol Psychiatry. 2007;12:116–8.

    Article  CAS  PubMed  Google Scholar 

  108. Tylee DS, Chandler SD, Nievergelt CM, Liu X, Pazol J, Woelk CH, et al. Blood-based gene-expression biomarkers of post-traumatic stress disorder among deployed marines: a pilot study. Psychoneuroendocrinology. 2015;51:472–94.

    Article  CAS  PubMed  Google Scholar 

  109. Metelli S, Chaimani A. Challenges in meta-analyses with observational studies. Evid Based Ment Health. 2020;23:83–87.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

TLP has received a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). JVP has received a scholarship from CNPq (Brazilian National Council for Scientific and Technological Development), Brazil. AOS has received a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). ASM has received a scholarship from Institutional Scientific Initiation Scholarship Program (PIBIC) with support from CNPq and Universidade Federal do Rio Grande do Sul, Brazil. VRL has received a scholarship from Federal University of Rio Grande do Sul Scientific Initiation Program (BIC-UFRGS). APA has received a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). ARB receives scholarships and support from FAPESP, the Brazilian National Council of Scientific Development (CNPq-1B), University of São Paulo Medical School (FMUSP), the UK Academy of Medical Sciences (Newton Advanced Fellowship), and the International Health Cohort Consortium (IHCC). FK has received grants from Instituto Nacional de Ciência e Tecnologia – Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Canada Foundation for Innovation (CFI). ICP is CNPq research fellow and supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil and by FIPE (Fundo de Incentivo à Pesquisa e Eventos) from Hospital de Clínicas de Porto Alegre, Brazil. This work was supported by a São Paulo Research State Foundation (FAPESP) grant (20/05441-9).

Author information

Author notes

  1. These authors contributed equally: Tatiana Lauxen Peruzzolo, Jairo Vinícius Pinto, Thiago Henrique Roza.

Authors and Affiliations

  1. Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil

    Tatiana Lauxen Peruzzolo, Jairo Vinícius Pinto, Thiago Henrique Roza, Augusto Ossamu Shintani, Ana Paula Anzolin, Vanessa Gnielka, André Moura Kohmann, Amanda Salvador Marin, Vitória Ruschel Lorenzon, Flávio Kapczinski & Ives Cavalcante Passos

  2. Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Tatiana Lauxen Peruzzolo, Thiago Henrique Roza, Augusto Ossamu Shintani, Ana Paula Anzolin, Vanessa Gnielka, André Moura Kohmann, Amanda Salvador Marin, Vitória Ruschel Lorenzon, Flávio Kapczinski & Ives Cavalcante Passos

  3. University Hospital, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    Jairo Vinícius Pinto

  4. Centro de Pesquisas Clínicas e Epidemiológicas, Hospital Universitário, Universidade de São Paulo, São Paulo, Brasil

    André Russowsky Brunoni

  5. Departamentos de Clínica Médica e Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

    André Russowsky Brunoni

  6. Instituto Nacional de Biomarcadores em Psiquiatria (IMBION), Laboratory of Neurosciences (LIM-27), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

    André Russowsky Brunoni

  7. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada

    Flávio Kapczinski

  8. Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil

    Ives Cavalcante Passos

Authors
  1. Tatiana Lauxen Peruzzolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jairo Vinícius Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thiago Henrique Roza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Augusto Ossamu Shintani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana Paula Anzolin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vanessa Gnielka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. André Moura Kohmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Amanda Salvador Marin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vitória Ruschel Lorenzon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. André Russowsky Brunoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Flávio Kapczinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ives Cavalcante Passos
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JVP was responsible for the statistical analysis. TLP and THR were responsible for writing the article, supervised by ICP and ARB.

Corresponding author

Correspondence to Ives Cavalcante Passos.

Ethics declarations

Competing interests

ICP has received research support from or served as consultant, adviser or speaker for Lundbeck, EMS, Libbs, and receives authorship royalties from Springer Nature and ArtMed.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peruzzolo, T.L., Pinto, J.V., Roza, T.H. et al. Inflammatory and oxidative stress markers in post-traumatic stress disorder: a systematic review and meta-analysis. Mol Psychiatry 27, 3150–3163 (2022). https://doi.org/10.1038/s41380-022-01564-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-022-01564-0

  • Springer Nature Limited

This article is cited by

Search

Navigation