The Need to Take a Staging Approach to the Biological Mechanisms of PTSD and its Treatment
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Despite the substantial body of neurobiological research, no specific drug target has been developed to treat PTSD and there are substantial limitations with the available interventions. We propose that advances are likely to depend on the development of better classification of the heterogeneity of PTSD using a staging approach of disease. A primary rationale for staging is to highlight the probability that distinct therapeutic approaches need to be utilised according to the degree of biological progression of the disorder. Prospective studies, particularly of military populations, provide substantial evidence about the emerging biological abnormalities that precede the full-blown disorder. These need to be targeted with tailored interventions to prevent disease progression. Equally, the neurobiology of chronic unremitting PTSD needs to be differentiated from the acute disorder which emerges across a spectrum of severity, and this range of presentations correspondingly needs to be addressed with differing therapeutic strategies. The staging approach also needs to take account of the range of somatic pathological outcomes that are being identified as a consequence of traumatic stress exposure. PTSD should be conceptualised as a systemic disorder underpinned a range of biological dysregulation, including metabolic and altered immune function, reflected in the increased rates of cardiovascular and autoimmune disease. The effectiveness of novel treatments needs to be judged across their effectiveness in addressing the spectrum of trauma-related pathology.
KeywordsPTSD Staging Subsyndromal Neurobiology Inflammation Medical comorbidity Duration of illness Longitudinal course Delayed onset Treatment
The editors would like to thank Dr. Betty Pfefferbaum for taking the time to review this manuscript.
Compliance with Ethics Guidelines
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This research was funded by program grant number 568970 of the National Health Medical and Research Council of Australia.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 1.Australian Centre for Posttraumatic Mental Health. Australian Guidelines for the Treatment of Acute Stress Disorder and Posttraumatic Stress Disorder. ACPMH. 2007.Google Scholar
- 2.• 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. This paper represents a comprehensive overview of the spectrum of neurobiology that underpins PTSD and highlights biological domains for advances in the treatment.CrossRefPubMedGoogle Scholar
- 7.• McGorry P, Keshavan M, Goldstone S, Amminger P, Allott K, Berk M, et al. Biomarkers and clinical staging in psychiatry. World Psychiatry. 2014;13(3):211–23. An excellent description of the staging approach and the disadvantages of current classification systems that do not address the progression of neurobiology in disorder.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Kaczkurkin AN, Burton PC, Chazin SM, Manbeck AB, Espensen-Sturges T, Cooper SE, Sponheim SR, Lissek S. Neural substrates of overgeneralized conditioned fear in PTSD. Am J Psychiatry. 2016:appiajp201615121549.Google Scholar
- 29.Steudte-Schmiedgen S, Stalder T, Schönfeld S, Wittchen HU, Trautmann S, Alexander N, et al. Hair cortisol concentrations and cortisol stress reactivity predict PTSD symptom increase after trauma exposure during military deployment. Psychoneuroendocrinology. 2015;59:123–33.CrossRefPubMedGoogle Scholar
- 30.van Zuiden M, Kavelaars A, Vermetten E, Olff M, Geuze E, Heijnen C. Pre-deployment differences in glucocorticoid sensitivity of leukocytes in soldiers developing symptoms of PTSD, depression or fatigue persist after return from military deployment. Psychoneuroendocrinology. 2015;51:513–24.CrossRefPubMedGoogle Scholar
- 33.• Bryant RA, Nickerson A, Creamer M, O’Donnell M, Forbes D, Galatzer-Levy I, et al. Trajectory of post-traumatic stress following traumatic injury: 6-year follow-up. Br J Psychiatry. 2015;206(5):417–23. The long period of observation of this cohort demonstrates the unexpected prevalence of delayed onset PTSD that many studies with shorter periods of follow up miss which need addressing in causal models.CrossRefPubMedGoogle Scholar
- 44.Keane TM, Kolb LC, Kaloupek DG, Orr SP, Blanchard EB, Thomas RG, et al. Utility of psychophysiological measurement in the diagnosis of posttraumatic stress disorder: results from a Department of Veterans Affairs Cooperative Study. J Consult Clin Psychol. 1998;66(6):914–23.CrossRefPubMedGoogle Scholar
- 48.• Yehuda R, Flory JD, Bierer LM, Henn-Haase C, Lehrner A, Desarnaud F, et al. Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder. Biol Psychiatry. 2015;77(4):356–64. The epigenetic mechanisms of glucocorticoid sensitivity is a central to understanding the emerging shifts in the neurobiology of the stress response that underpin PTSD.CrossRefPubMedGoogle Scholar
- 57.Michopoulos V, Rothbaum AO, Jovanovic T, Almli LM, Bradley B, Rothbaum BO, et al. Association of CRP genetic variation and CRP level with elevated PTSD symptoms and physiological responses in a civilian population with high levels of trauma. Am J Psychiatry. 2015;172(4):353–62.CrossRefPubMedGoogle Scholar
- 59.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. doi: 10.1186/1471-244×-13-40.PubMedPubMedCentralGoogle Scholar
- 61.Kardiner A. The traumatic neuroses of war. National Academies; 1941.Google Scholar
- 65.• 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(Pt B):133–40. An important paper setting out the emerging therapeutic possibilities and the interactions between the glucocorticoid system and immunological reactivity.CrossRefPubMedGoogle Scholar
- 72.• O’Donovan A, Cohen BE, Seal KH, Bertenthal D, Margaretten M, Nishimi K, et al. Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry. 2015;77(4):365–74. A large cohort study sufficiently powered to highlight the burden of immunological dysregulation in PTSD on the prevalence of autoimmune disorders.CrossRefPubMedGoogle Scholar
- 77.Shucard JL, Cox J, Shucard DW, Fetter H, Chung C, Ramasamy D, et al. Symptoms of posttraumatic stress disorder and exposure to traumatic stressors are related to brain structural volumes and behavioral measures of affective stimulus processing in police officers. Psychiatry Res. 2012;204(1):25–31.CrossRefPubMedGoogle Scholar