Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Post-traumatic stress disorder

Abstract

Post-traumatic stress disorder (PTSD) occurs in 5–10% of the population and is twice as common in women as in men. Although trauma exposure is the precipitating event for PTSD to develop, biological and psychosocial risk factors are increasingly viewed as predictors of symptom onset, severity and chronicity. PTSD affects multiple biological systems, such as brain circuitry and neurochemistry, and cellular, immune, endocrine and metabolic function. Treatment approaches involve a combination of medications and psychotherapy, with psychotherapy overall showing greatest efficacy. Studies of PTSD pathophysiology initially focused on the psychophysiology and neurobiology of stress responses, and the acquisition and the extinction of fear memories. However, increasing emphasis is being placed on identifying factors that explain individual differences in responses to trauma and promotion of resilience, such as genetic and social factors, brain developmental processes, cumulative biological and psychological effects of early childhood and other stressful lifetime events. The field of PTSD is currently challenged by fluctuations in diagnostic criteria, which have implications for epidemiological, biological, genetic and treatment studies. However, the advent of new biological methodologies offers the possibility of large-scale approaches to heterogeneous and genetically complex brain disorders, and provides optimism that individualized approaches to diagnosis and treatment will be discovered.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The prevalence of PTSD.
Figure 2: The function of the HPA axis in PTSD and controls.
Figure 3: Emotional undermodulation and overmodulation in PTSD.
Figure 4: The default mode, salience and central executive networks in PTSD.
Figure 5: Consequences of reduced cortisol signalling in acute aftermath of trauma.
Figure 6: The timing of treatment of PTSD.
Figure 7: Timing of quality of life issues with PTSD.
Figure 8: Systems biology approach to biomarker discovery and validation.

References

  1. 1

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: (DSM-5) (American Psychiatric Association, 2013).

  2. 2

    Kessler, R. C. & Wang, P. S. The descriptive epidemiology of commonly occurring mental disorders in the United States. Annu. Rev. Publ. Health 29, 115–129 (2008).

    Article  Google Scholar 

  3. 3

    Michopoulos, V. 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 172, 353–362 (2015).

    Article  Google Scholar 

  4. 4

    Lohr, J. B. et al. Is post-traumatic stress disorder associated with premature senescence? A review of the literature. Am. J. Geriatr. Psychiatry 23, 709–725 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Rosenbaum, S. et al. The prevalence and risk of metabolic syndrome and its components among people with posttraumatic stress disorder: a systematic review and meta-analysis. Metabolism 64, 926–933 (2015).

    Article  CAS  Google Scholar 

  6. 6

    Kessler R. C. Posttraumatic stress disorder: the burden to the individual and to society. J. Clin. Psychiatry 61 S4–S12; discussion S13–S14 (2000).

    Google Scholar 

  7. 7

    Yehuda, R. & LeDoux, J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56, 19–32 (2007).

    Article  CAS  Google Scholar 

  8. 8

    Charney, D. S., Deutch, A. Y., Krystal, J. H., Southwick, S. M. & Davis, M. Psychobiologic mechanisms of posttraumatic stress disorder. Arch. General Psychiatry 50, 295–305 (1993).

    CAS  Google Scholar 

  9. 9

    Charney, D. S. Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am. J. Psychiatry 161, 195–216 (2004).

    Article  Google Scholar 

  10. 10

    Kulka, R. A. Contractual Report of Findings From the National Vietnam Veterans Readjustment Study (Research Triangle Institute, 1988).

    Google Scholar 

  11. 11

    Dohrenwend, B. P. et al. The psychological risks of Vietnam for US veterans: a revisit with new data and methods. Science 313, 979–982 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Marmar, C. R. et al. Course of posttraumatic stress disorder 40 years after the Vietnam War: findings from the National Vietnam Veterans Longitudinal Study. JAMA Psychiatry 72, 875–881 (2015). This is the most important longitudinal study of the Vietnam War generation.

    Article  Google Scholar 

  13. 13

    Kok, B. C., Herrell, R. K., Thomas, J. L. & Hoge, C. W. Posttraumatic stress disorder associated with combat service in Iraq or Afghanistan: reconciling prevalence differences between studies. J. Nerv. Mental Dis. 200, 444–450 (2012).

    Article  Google Scholar 

  14. 14

    Sundin, J. et al. Mental health outcomes in US and UK military personnel returning from Iraq. Br. J. Psychiatry 204, 200–207 (2014).

    Article  Google Scholar 

  15. 15

    Hoge, C. W. et al. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N. Engl. J. Med. 351, 13–22 (2004). This is the initial paper that showed the effect of the recent war in Iraq and highlighted the importance of stigma and barriers to help-seeking.

    Article  CAS  Google Scholar 

  16. 16

    Smid, G. E., Mooren, T. T., van der Mast, R. C., Gersons, B. P. & Kleber, R. J. Delayed posttraumatic stress disorder: systematic review, meta-analysis, and meta-regression analysis of prospective studies. J. Clin. Psychiatry 70, 1572–1582 (2009).

    Article  Google Scholar 

  17. 17

    Kessler, R. C., Sonnega, A., Bromet, E., Hughes, M. & Nelson, C. B. Posttraumatic stress disorder in the National Comorbidity Survey. Arch. General Psychiatry 52, 1048–1060 (1995). Results from this study indicate that trauma exposure is common but only a minority of exposed individuals develop PTSD. Findings also showed that conditional PTSD varied by trauma type and that the disorder is highly comorbid with other psychiatric conditions.

    Article  CAS  Google Scholar 

  18. 18

    Resnick, H. S., Kilpatrick, D. G., Dansky, B. S., Saunders, B. E. & Best, C. L. Prevalence of civilian trauma and posttraumatic stress disorder in a representative national sample of women. J. Consult. Clin. Psychol. 61, 984 (1993).

    Article  CAS  Google Scholar 

  19. 19

    American Psychiatric Association. DSM-III: Diagnostic and Statistical Manual of Mental Disorders, Third Edition (American Psychiatric Association, 1985).

  20. 20

    Mills, K. L. et al. Assessing the prevalence of trauma exposure in epidemiological surveys. Austral. N. Z. J. Psychiatry 45, 407–415 (2011).

    Article  Google Scholar 

  21. 21

    De Jong, J. T. et al. Lifetime events and posttraumatic stress disorder in 4 postconflict settings. JAMA 286, 555–562 (2001).

    Article  CAS  Google Scholar 

  22. 22

    Atwoli, L. et al. Trauma and posttraumatic stress disorder in South Africa: analysis from the South African Stress and Health Study. BMC Psychiatry 13, 182 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Karam, E. G. et al. Cumulative traumas and risk thresholds: 12-month PTSD in the World Mental Health (WMH) surveys. Depress. Anxiety 31, 130–142 (2014).

    Article  Google Scholar 

  24. 24

    Hobfoll, S. E. et al. Five essential elements of immediate and mid-term mass trauma intervention: empirical evidence. Psychiatry 70, 283–315; discussion 316–369 (2007).

    Article  Google Scholar 

  25. 25

    Lowe, S. R., Galea, S., Uddin, M. & Koenen, K. C. Trajectories of posttraumatic stress among urban residents. Am. J. Commun. Psychol. 53, 159–172 (2014).

    Article  Google Scholar 

  26. 26

    Ressler, K. J. et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470, 492–497 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Kessler, R. C., Chiu, W. T., Demler, O. & Walters, E. E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. General Psychiatry 62, 617–627 (2005).

    Article  Google Scholar 

  28. 28

    Hoge, C. W., Terhakopian, A., Castro, C. A., Messer, S. C. & Engel, C. C. Association of posttraumatic stress disorder with somatic symptoms, health care visits, and absenteeism among Iraq war veterans. Am. J. Psychiatry 164, 150–153 (2007).

    Article  Google Scholar 

  29. 29

    Pole, N. The psychophysiology of posttraumatic stress disorder: a meta-analysis. Psychol. Bull. 133, 725–746 (2007).

    Article  Google Scholar 

  30. 30

    Pitman, R. K. et al. Biological studies of post-traumatic stress disorder. Nat. Rev. Neurosci. 13, 769–787 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Zoladz, P. R. & Diamond, D. M. Current status on behavioral and biological markers of PTSD: a search for clarity in a conflicting literature. Neurosci. Biobehav. Rev. 37, 860–895 (2013).

    Article  Google Scholar 

  32. 32

    Yehuda, R. Post-traumatic stress disorder. N. Engl. J. Med. 346, 108–114 (2002).

    Article  CAS  Google Scholar 

  33. 33

    Zannas, A. S., Provencal, N. & Binder, E. B. Epigenetics of posttraumatic stress disorder: current evidence, challenges, and future directions. Biol. Psychiatry 78, 327–335 (2015).

    Article  CAS  Google Scholar 

  34. 34

    Daskalakis, N. P., Lehrner, A. & Yehuda, R. Endocrine aspects of post-traumatic stress disorder and implications for diagnosis and treatment. Endocrinol. Metab. Clin. North Am. 42, 503–513 (2013).

    Article  Google Scholar 

  35. 35

    Galatzer-Levy, I. R. et al. Cortisol response to an experimental stress paradigm prospectively predicts long-term distress and resilience trajectories in response to active police service. J. Psychiatr. Res. 56, 36–42 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    van Zuiden, M. et al. Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment. Am. J. Psychiatry 168, 89–96 (2011). This is the first biological prospective study in PTSD that showed that combat veterans who developed PTSD post-deployment had a higher number of glucocorticoid receptors at pre-deployment.

    Article  Google Scholar 

  37. 37

    de Quervain, D. J., Aerni, A., Schelling, G. & Roozendaal, B. Glucocorticoids and the regulation of memory in health and disease. Front. Neuroendocrinol. 30, 358–370 (2009).

    Article  CAS  Google Scholar 

  38. 38

    Parsons, R. G. & Ressler, K. J. Implications of memory modulation for post-traumatic stress and fear disorders. Nat. Neurosci. 16, 146–153 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Duits, P. et al. Updated meta-analysis of classical fear conditioning in the anxiety disorders. Depress. Anxiety 32, 239–253 (2015).

    Article  Google Scholar 

  40. 40

    Jovanovic, T. & Ressler, K. J. How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Am. J. Psychiatry 167, 648–662 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Pietrzak, R. H. et al. Association of in vivo κ-opioid receptor availability and the transdiagnostic dimensional expression of trauma-related psychopathology. JAMA Psychiatry 71, 1262–1270 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Neumeister, A., Seidel, J., Ragen, B. J. & Pietrzak, R. H. Translational evidence for a role of endocannabinoids in the etiology and treatment of posttraumatic stress disorder. Psychoneuroendocrinology 51, 577–584 (2015).

    Article  CAS  Google Scholar 

  43. 43

    O'Donovan, A., Slavich, G. M., Epel, E. S. & Neylan, T. C. Exaggerated neurobiological sensitivity to threat as a mechanism linking anxiety with increased risk for diseases of aging. Neurosci. Biobehav Rev. 37, 96–108 (2013). This is a comprehensive review of the relationship of threat sensitivity and inflammation to increased risk for diseases of ageing in PTSD.

    Article  Google Scholar 

  44. 44

    Baker, D. G. et al. Plasma and cerebrospinal fluid interleukin-6 concentrations in posttraumatic stress disorder. Neuroimmunomodulation 9, 209–217 (2001).

    Article  CAS  Google Scholar 

  45. 45

    Bonne, O. et al. Corticotropin-releasing factor, interleukin-6, brain-derived neurotrophic factor, insulin-like growth factor-1, and substance P in the cerebrospinal fluid of civilians with posttraumatic stress disorder before and after treatment with paroxetine. J. Clin. Psychiatry 72, 1124–1128 (2011).

    Article  CAS  Google Scholar 

  46. 46

    Uddin, M. et al. Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc. Natl Acad. Sci. USA 107, 9470–9475 (2010).

    Article  Google Scholar 

  47. 47

    Gill, J. M., Saligan, L., Woods, S. & Page, G. PTSD is associated with an excess of inflammatory immune activities. Perspect. Psychiatr. Care 45, 262–277 (2009).

    Article  Google Scholar 

  48. 48

    O'Donovan, A. et al. Transcriptional control of monocyte gene expression in post-traumatic stress disorder. Dis. Markers 30, 123–132 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Hill, M. N. & McEwen, B. S. Endocannabinoids: the silent partner of glucocorticoids in the synapse. Proc. Natl Acad. Sci. USA 106, 4579–4580 (2009).

    Article  Google Scholar 

  50. 50

    Hill, M. N. et al. Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks. Psychoneuroendocrinology 38, 2952–2961 (2013).

    Article  CAS  Google Scholar 

  51. 51

    Neumeister, A. et al. Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol. Psychiatry 18, 1034–1040 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Neylan, T. C., Otte, C., Yehuda, R. & Marmar, C. R. Neuroendocrine regulation of sleep disturbances in PTSD. Ann. NY Acad. Sci. 1071, 203–215 (2006).

    Article  CAS  Google Scholar 

  53. 53

    Agorastos, A., Kellner, M., Baker, D. G. & Otte, C. When time stands still: an integrative review on the role of chronodisruption in posttraumatic stress disorder. Curr. Opin. Psychiatry 27, 385–392 (2014).

    Article  Google Scholar 

  54. 54

    Yehuda, R., Teicher, M. H., Trestman, R. L., Levengood, R. A. & Siever, L. J. Cortisol regulation in posttraumatic stress disorder and major depression: a chronobiological analysis. Biol. Psychiatry 40, 79–88 (1996).

    Article  CAS  Google Scholar 

  55. 55

    Cohen, H. et al. The neuropeptide Y (NPY)-ergic system is associated with behavioral resilience to stress exposure in an animal model of post-traumatic stress disorder. Neuropsychopharmacology 37, 350–363 (2012).

    Article  CAS  Google Scholar 

  56. 56

    Serova, L. I. et al. Single intranasal neuropeptide Y infusion attenuates development of PTSD-like symptoms to traumatic stress in rats. Neuroscience 236, 298–312 (2013).

    Article  CAS  Google Scholar 

  57. 57

    Yehuda, R., Flory, J. D., Southwick, S. & Charney, D. S. Developing an agenda for translational studies of resilience and vulnerability following trauma exposure. Ann. NY Acad. Sci. 1071, 379–396 (2006).

    Article  Google Scholar 

  58. 58

    Vermetten, E., Baker, D. & Yehuda, R. New findings from prospective studies. Psychoneuroendocrinology 51, 441–443 (2015).

    Article  Google Scholar 

  59. 59

    Delahanty, D. L. & Nugent, N. R. Predicting PTSD prospectively based on prior trauma history and immediate biological responses. Ann. NY Acad. Sci. 1071, 27–40 (2006).

    Article  Google Scholar 

  60. 60

    Bonne, O. et al. Prospective evaluation of plasma cortisol in recent trauma survivors with posttraumatic stress disorder. Psychiatry Res. 119, 171–175 (2003).

    Article  CAS  Google Scholar 

  61. 61

    Yehuda, R. et al. Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am. J. Psychiatry 171, 872–880 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Yehuda, R., McFarlane, A. C. & Shalev, A. Y. Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biol. Psychiatry 44, 1305–1313 (1998).

    Article  CAS  Google Scholar 

  63. 63

    Yehuda, R., Morris, A., Labinsky, E., Zemelman, S. & Schmeidler, J. Ten-year follow-up study of cortisol levels in aging holocaust survivors with and without PTSD. J. Trauma Stress 20, 757–761 (2007).

    Article  Google Scholar 

  64. 64

    Olff, M., de Vries, G. J., Guzelcan, Y., Assies, J. & Gersons, B. P. Changes in cortisol and DHEA plasma levels after psychotherapy for PTSD. Psychoneuroendocrinology 32, 619–626 (2007).

    Article  CAS  Google Scholar 

  65. 65

    Walsh, K. et al. Cortisol at the emergency room rape visit as a predictor of PTSD and depression symptoms over time. Psychoneuroendocrinology 38, 2520–2528 (2013).

    Article  CAS  Google Scholar 

  66. 66

    Delahanty, D. L., Raimonde, A. J. & Spoonster, E. Initial posttraumatic urinary cortisol levels predict subsequent PTSD symptoms in motor vehicle accident victims. Biol. Psychiatry 48, 940–947 (2000).

    Article  CAS  Google Scholar 

  67. 67

    van Zuiden, M. et al. Glucocorticoid receptor pathway components predict posttraumatic stress disorder symptom development: a prospective study. Biol. Psychiatry 71, 309–316 (2012).

    Article  CAS  Google Scholar 

  68. 68

    Eraly, S. A. et al. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry 71, 423–431 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Yehuda, R. et al. Glucocorticoid-related predictors and correlates of post-traumatic stress disorder treatment response in combat veterans. Interface Focus 4, 20140048 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Rauch, S. A. et al. Biological and symptom changes in posttraumatic stress disorder treatment: a randomized clinical trial. Depress. Anxiety 32, 204–212 (2015).

    Article  Google Scholar 

  71. 71

    Levy-Gigi, E., Szabo, C., Kelemen, O. & Keri, S. Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy. Biol. Psychiatry 74, 793–800 (2013).

    Article  CAS  Google Scholar 

  72. 72

    Afifi, T. O., Asmundson, G. J., Taylor, S. & Jang, K. L. The role of genes and environment on trauma exposure and posttraumatic stress disorder symptoms: a review of twin studies. Clin. Psychol. Rev. 30, 101–112 (2010).

    Article  Google Scholar 

  73. 73

    Stein, M. B., Jang, K. J., Taylor, S., Vernon, P. A. & Livesley, W. J. Genetic and environmental influences on trauma exposure and posttraumatic stress disorder: a twin study. Am. J. Psychiatry 159, 1675–1681 (2002).

    Article  Google Scholar 

  74. 74

    Koenen, K. C., Duncan, L. E., Liberzon, I. & Ressler, K. J. From candidate genes to genome-wide association: the challenges and promise of posttraumatic stress disorder genetic studies. Biol. Psychiatry 74, 634–636 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    True, W. J. et al. A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch. General Psychiatry 50, 257–264 (1993).

    Article  CAS  Google Scholar 

  76. 76

    Sartor, C. E. et al. Common heritable contributions to low-risk trauma, high-risk trauma, posttraumatic stress disorder, and major depression. Arch. General Psychiatry 69, 293–299 (2012).

    Article  Google Scholar 

  77. 77

    Sartor, C. E. et al. Common genetic and environmental contributions to post-traumatic stress disorder and alcohol dependence in young women. Psychol. Med. 41, 1497–1505 (2011).

    Article  CAS  Google Scholar 

  78. 78

    Gilbertson, M. W. et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat. Neurosci. 5, 1242–1247 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Wolf, E. J., Mitchell, K. S., Koenen, K. C. & Miller, M. W. Combat exposure severity as a moderator of genetic and environmental liability to post-traumatic stress disorder. Psychol. Med. 44, 1499–1509 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Binder, E. B. et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299, 1291–1305 (2008). This paper describes that genetic variants of a chaperone protein involved in glucocorticoid signalling, together with exposure to child trauma, predict adult PTSD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Klengel, T. et al. Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nat. Neurosci. 16, 33–41 (2013).

    Article  CAS  Google Scholar 

  82. 82

    Nugent, N. R., Amstadter, A. B. & Koenen, K. C. Genetics of post-traumatic stress disorder: informing clinical conceptualizations and promoting future research. Am. J. Med. Genet. C Semin. Med. Genet. 148, 127–132 (2008).

    Article  Google Scholar 

  83. 83

    Yehuda, R., Bell, A., Bierer, L. M. & Schmeidler, J. Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors. J. Psychiatr. Res. 42, 1104–1111 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Mehta, D. et al. Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proc. Natl Acad. Sci. USA 110, 8302–8307 (2013).

    Article  Google Scholar 

  85. 85

    Almli, L. M. et al. A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces. Am. J. Med. Genet. B Neuropsychiatr. Genet. 168, 327–336 (2015).

    Article  CAS  Google Scholar 

  86. 86

    Heijmans, B. T. & Mill, J. Commentary: the seven plagues of epigenetic epidemiology. Int. J. Epidemiol. 41, 74–78 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Yehuda, R. et al. Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Front. Psychiatry 4, 118 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Yehuda, R. et al. Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks. Biol. Psychiatry 66, 708–711 (2009). This is the first genome-wide gene expression study in PTSD that identified genes associated with glucocorticoid receptor functioning, such as FKBP5.

    Article  CAS  Google Scholar 

  89. 89

    Sipahi, L. et al. Longitudinal epigenetic variation of DNA methyltransferase genes is associated with vulnerability to post-traumatic stress disorder. Psychol. Med. 44, 3165–3179 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Schmidt, U., Keck, M. E. & Buell, D. R. miRNAs and other non-coding RNAs in posttraumatic stress disorder: a systematic review of clinical and animal studies. J. Psychiatr. Res. 65, 1–8 (2015).

    Article  Google Scholar 

  91. 91

    Zhou, J. et al. Dysregulation in microRNA expression is associated with alterations in immune functions in combat veterans with post-traumatic stress disorder. PLoS ONE 9, e94075 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Logue, M. W. et al. A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor-α (RORA) gene as a significant risk locus. Mol. Psychiatry 18, 937–942 (2013).

    Article  CAS  Google Scholar 

  93. 93

    Xie, P. et al. Genome-wide association study identifies new susceptibility loci for posttraumatic stress disorder. Biol. Psychiatry 74, 656–663 (2013).

    Article  CAS  Google Scholar 

  94. 94

    Guffanti, G. et al. Genome-wide association study implicates a novel RNA gene, the lincRNA AC068718.1, as a risk factor for post-traumatic stress disorder in women. Psychoneuroendocrinology 38, 3029–3038 (2013).

    Article  CAS  Google Scholar 

  95. 95

    Nievergelt, C. M. et al. Genomic predictors of combat stress vulnerability and resilience in U. S. Marines: a genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene. Psychoneuroendocrinology 51, 459–471 (2015).

    Article  CAS  Google Scholar 

  96. 96

    Button, K. S. et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat. Rev. Neurosci. 14, 365–376 (2013).

    Article  CAS  Google Scholar 

  97. 97

    Almli, L. M., Fani, N., Smith, A. K. & Ressler, K. J. Genetic approaches to understanding post-traumatic stress disorder. Int. J. Neuropsychopharmacol. 17, 355–370 (2014).

    Article  Google Scholar 

  98. 98

    Logue, M. W. et al. The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: posttraumatic stress disorder enters the age of large-scale genomic collaboration. Neuropsychopharmacology 40, 2287–2297 (2015). This paper describes the formation of a large-scale GWAS consortium dedicated to the study of PTSD genetics that will lead the search for replicable genetic associations.

    Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Bremner, J. D. Does stress damage the brain? Biol. Psychiatry 45, 797–805 (1999).

    Article  CAS  Google Scholar 

  100. 100

    Bremner, J. D. et al. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse — a preliminary report. Biol. Psychiatry 41, 23–32 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    van Rooij, S. J. et al. Smaller hippocampal volume as a vulnerability factor for the persistence of post-traumatic stress disorder. Psychol. Med. 45, 2737–2746 (2015).

    Article  CAS  Google Scholar 

  102. 102

    Shin, L. M. & Liberzon, I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35, 169–191 (2010).

    Article  Google Scholar 

  103. 103

    Shin, L. M. et al. Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: a PET investigation. Am. J. Psychiatry 156, 575–584 (1999).

    CAS  PubMed  Google Scholar 

  104. 104

    Gold, A. L. et al. Decreased regional cerebral blood flow in medial prefrontal cortex during trauma-unrelated stressful imagery in Vietnam veterans with post-traumatic stress disorder. Psychol. Med. 41, 2563–2572 (2011).

    Article  CAS  Google Scholar 

  105. 105

    Lanius, R. A. et al. Recall of emotional states in posttraumatic stress disorder: an fMRI investigation. Biol. Psychiatry 53, 204–210 (2003).

    Article  Google Scholar 

  106. 106

    Etkin, A. & Wager, T. D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Sartory, G. et al. In search of the trauma memory: a meta-analysis of functional neuroimaging studies of symptom provocation in posttraumatic stress disorder (PTSD). PLoS ONE 8, e58150 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Taber, K. H., Rauch, S. L., Lanius, R. A. & Hurley, R. A. Functional magnetic resonance imaging: application to posttraumatic stress disorder. J. Neuropsychiatry Clin. Neurosci. 15, 125–129 (2003).

    Article  Google Scholar 

  109. 109

    Hayes, J. P., Hayes, S. M. & Mikedis, A. M. Quantitative meta-analysis of neural activity in posttraumatic stress disorder. Biol. Mood Anxiety Disord. 2, 9 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Lanius, R. A., Bluhm, R., Lanius, U. & Pain, C. A review of neuroimaging studies in PTSD: heterogeneity of response to symptom provocation. J. Psychiatr. Res. 40, 709–729 (2006).

    Article  CAS  Google Scholar 

  111. 111

    Nicholson, A. A. et al. The dissociative subtype of posttraumatic stress disorder: unique resting-state functional connectivity of basolateral and centromedial amygdala complexes. Neuropsychopharmacology 40, 2317–2326 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Lanius, R. et al. Emotion modulation in PTSD: clinical and neurobiological evidence for a dissociative subtype. Am. J. Psychiatry 167, 640–647 (2010). This article focuses on the neural manifestations of the dissociative subtype in PTSD and compares them to those underlying the re-experiencing and hyperaroused subtype. These findings have important implications for the treatment of PTSD, including the need to assess patients with PTSD for dissociative symptoms and to incorporate the treatment of dissociative symptoms into stage-oriented trauma treatment.

    Article  Google Scholar 

  113. 113

    Menon, V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn. Sci. 15, 483–506 (2011).

    Article  Google Scholar 

  114. 114

    Patel, R., Spreng, R. N., Shin, L. M. & Girard, T. A. Neurocircuitry models of posttraumatic stress disorder and beyond: a meta-analysis of functional neuroimaging studies. Neurosci. Biobehav. Rev. 36, 2130–2142 (2012).

    Article  Google Scholar 

  115. 115

    Sripada, R. K. et al. Neural dysregulation in posttraumatic stress disorder: evidence for disrupted equilibrium between salience and default mode brain networks. Psychosomat. Med. 74, 904–911 (2012).

    Article  Google Scholar 

  116. 116

    Rabellino, D. et al. Intrinsic connectivity networks in post-traumatic stress disorder during sub- and supraliminal processing of threat-related stimuli. Acta Psychiatr. Scand. 35, 258–266 (2015).

    Google Scholar 

  117. 117

    Daniels, J. K. et al. Switching between executive and default mode networks in posttraumatic stress disorder: alterations in functional connectivity. J. Psychiatry Neurosci. 35, 258–266 (2010).

    Article  Google Scholar 

  118. 118

    Geuze, E. et al. Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder. Mol. Psychiatry 13, 74–83, 3 (2008).

    Article  CAS  Google Scholar 

  119. 119

    Murrough, J. W. et al. Reduced amygdala serotonin transporter binding in posttraumatic stress disorder. Biol. Psychiatry 70, 1033–1038 (2011).

    Article  CAS  Google Scholar 

  120. 120

    Yehuda, R. et al. Changes in relative glucose metabolic rate following cortisol administration in aging veterans with posttraumatic stress disorder: an FDG-PET neuroimaging study. J. Neuropsychiatry Clin. Neurosci. 21, 132–143 (2009).

    Article  Google Scholar 

  121. 121

    Brewin, C. R. Episodic memory, perceptual memory, and their interaction: foundations for a theory of posttraumatic stress disorder. Psychol. Bull. 140, 69–97 (2014).

    Article  Google Scholar 

  122. 122

    Yehuda, R. & McFarlane, A. C. Conflict between current knowledge about posttraumatic stress disorder and its original conceptual basis. Am. J. Psychiatry 152, 1705–1713 (1995). This is a seminal review showing that biological measures from PTSD do not conform to predictions from known acute stress biology.

    Article  CAS  Google Scholar 

  123. 123

    American Psychiatric Association. DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (American Psychiatric Association, 1994).

  124. 124

    Friedman, M. J., Resick, P. A., Bryant, R. A. & Brewin, C. R. Considering PTSD for DSM-5. Depress. Anxiety 28, 750–769 (2011).

    Article  Google Scholar 

  125. 125

    Hoge, C. W., Riviere, L. A., Wilk, J. E., Herrell, R. K. & Weathers, F. W. The prevalence of post-traumatic stress disorder (PTSD) in US combat soldiers: a head-to-head comparison of DSM-5 versus DSM-IV-TR symptom criteria with the PTSD checklist. Lancet Psychiatry 1, 269–277 (2014).

    Article  Google Scholar 

  126. 126

    McFarlane, A. C. PTSD and DSM-5: unintended consequences of change. Lancet Psychiatry 1, 246–247 (2014).

    Article  Google Scholar 

  127. 127

    Stein, D. J. et al. DSM-5 and ICD-11 definitions of posttraumatic stress disorder: investigating ‘narrow’ and ‘broad’ approaches. Depress. Anxiety 31, 494–505 (2014). This paper highlights the conceptual questions of validity with the existence of different sets of diagnostic criteria and the need to consider the challenge of the lack of overlap of DSM and ICD systems.

    Article  Google Scholar 

  128. 128

    Bryant, R. A., O'Donnell, M. L., Creamer, M., McFarlane, A. C. & Silove, D. A multisite analysis of the fluctuating course of posttraumatic stress disorder. JAMA Psychiatry 70, 839–846 (2013).

    Article  Google Scholar 

  129. 129

    Bunting, B. P., Murphy, S. D., O'Neill, S. M. & Ferry, F. R. Lifetime prevalence of mental health disorders and delay in treatment following initial onset: evidence from the Northern Ireland Study of Health and Stress. Psychol. Med. 42, 1727–1739 (2012).

    Article  CAS  Google Scholar 

  130. 130

    McFarlane, A. C. The long-term costs of traumatic stress: intertwined physical and psychological consequences. World Psychiatry 9, 3–10 (2010). This paper shows that the prevalence of delayed-onset PTSD and the associated physical comorbidities highlight the need for the long-term effect of traumatic stress exposure to be a clear focus in clinical settings.

    Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Kendler, K. S., Thornton, L. M. & Gardner, C. O. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the ‘kindling’ hypothesis. Am. J. Psychiatry 157, 1243–1251 (2000).

    Article  CAS  Google Scholar 

  132. 132

    Collip, D., Myin-Germeys, I. & Van Os, J. Does the concept of ‘sensitization’ provide a plausible mechanism for the putative link between the environment and schizophrenia? Schizophr. Bull. 34, 220–225 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    Adler, A. B., Wright, K. M., Bliese, P. D., Eckford, R. & Hoge, C. W. A2 diagnostic criterion for combat-related posttraumatic stress disorder. J. Trauma. Stress 21, 301–308 (2008).

    Article  Google Scholar 

  134. 134

    Brady, K. T., Killeen, T. K., Brewerton, T. & Lucerini, S. Comorbidity of psychiatric disorders and posttraumatic stress disorder. J. Clin. Psychiatry 61 S22–S32 (2000).

    Article  Google Scholar 

  135. 135

    Debell, F. et al. A systematic review of the comorbidity between PTSD and alcohol misuse. Soc. Psychiatry Psychiatr. Epidemiol. 49, 1401–1425 (2014).

    Article  Google Scholar 

  136. 136

    Rytwinski, N. K., Scur, M. D., Feeny, N. C. & Youngstrom, E. A. The co-occurrence of major depressive disorder among individuals with posttraumatic stress disorder: a meta-analysis. J. Trauma. Stress 26, 299–309 (2013).

    Article  Google Scholar 

  137. 137

    Rasmussen, A., Keatley, E. & Joscelyne, A. Posttraumatic stress in emergency settings outside North America and Europe: a review of the emic literature. Soc. Sci. Med. 109, 44–54 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Brewin, C. R. et al. Promoting mental health following the London bombings: a screen and treat approach. J. Trauma. Stress 21, 3–8 (2008). This paper shows the underestimation of the clinical significance of distress and symptoms by general practitioners when diagnosing PTSD, despite patients seeking help and benefiting from treatment when identified in a population-based screening and treatment intervention.

    Article  PubMed  PubMed Central  Google Scholar 

  139. 139

    Gupta, M. A. Review of somatic symptoms in post-traumatic stress disorder. Int. Rev. Psychiatry 25, 86–99 (2013).

    Article  Google Scholar 

  140. 140

    Liebschutz, J. et al. PTSD in urban primary care: high prevalence and low physician recognition. J. Gen. Intern. Med. 22, 719–726 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Battaglia, S. et al. Elevated NCOR1 disrupts PPARα/γ signaling in prostate cancer and forms a targetable epigenetic lesion. Carcinogenesis 31, 1650–1660 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Lehrner, A. & Yehuda, R. Biomarkers of PTSD: military applications and considerations. Eur. J. Psychotraumatol. 5, 23797 (2014).

    Article  Google Scholar 

  143. 143

    Searle, A. K. et al. The validity of military screening for mental health problems: diagnostic accuracy of the PCL, K10 and AUDIT scales in an entire military population. Int. J. Methods Psychiatr. Res. 24, 32–45 (2015).

    Article  Google Scholar 

  144. 144

    Lee, D. J., Warner, C. H. & Hoge, C. W. Advances and controversies in military posttraumatic stress disorder screening. Curr. Psychiatry Rep. 16, 467 (2014).

    Article  Google Scholar 

  145. 145

    Terhakopian, A., Sinaii, N., Engel, C. C., Schnurr, P. P. & Hoge, C. W. Estimating population prevalence of posttraumatic stress disorder: an example using the PTSD checklist. J. Trauma Stress 21, 290–300 (2008).

    Article  Google Scholar 

  146. 146

    Australian Centre for Posttraumatic Mental Health. Australian Guidelines for the Treatment of Acute Stress Disorder and Posttraumatic Stress Disorder (ACPMH, 2013).

  147. 147

    Warner, C. H., Appenzeller, G. N., Parker, J. R., Warner, C. M. & Hoge, C. W. Effectiveness of mental health screening and coordination of in-theater care prior to deployment to Iraq: a cohort study. Am. J. Psychiatry 168, 378–385 (2011).

    Article  Google Scholar 

  148. 148

    Institute of Medicine. Preventing Psychological Disorders in Service Members and Their Families: An Assessment of Programs (The National Academies Press, 2014).

  149. 149

    McCabe, O. L. et al. Building a national model of public mental health preparedness and community resilience: validation of a dual-intervention, systems-based approach. Disaster Med. Publ. Health Prep. 8, 511–526 (2014).

    Article  Google Scholar 

  150. 150

    Yehuda, R. Learning from September 11, 2001. CNS Spectr. 7, 566–567 (2002).

    Article  Google Scholar 

  151. 151

    Roberts, N. P., Kitchiner, N. J., Kenardy, J. & Bisson, J. Multiple session early psychological interventions for the prevention of post-traumatic stress disorder. Cochrane Database Syst. Rev. 3, CD006869 (2009).

    Google Scholar 

  152. 152

    Vermetten, E., Zhohar, J. & Krugers, H. J. Pharmacotherapy in the aftermath of trauma; opportunities in the ‘golden hours’. Curr. Psychiatry Rep. 16, 455 (2014).

    Article  Google Scholar 

  153. 153

    Sijbrandij, M., Kleiboer, A., Bisson, J. I., Barbui, C. & Cuijpers, P. Pharmacological prevention of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis. Lancet Psychiatry 2, 413–421 (2015). This is the first systematic review to examine the effects of pharmacotherapies (for example, β-blockers, hydrocortisone and selective serotonin reuptake inhibitors) given within the first month after a traumatic or aversive event to prevent PTSD or acute stress disorder compared with no pharmacotherapy or a placebo control.

    Article  Google Scholar 

  154. 154

    Marin, M. F., Lonak, S. F. & Milad, M. R. Augmentation of evidence-based psychotherapy for PTSD with cognitive enhancers. Curr. Psychiatry Rep. 17, 39 (2015).

    Article  Google Scholar 

  155. 155

    Merlo, E., Milton, A. L. & Everitt, B. J. Enhancing cognition by affecting memory reconsolidation. Curr. Opin. Behav. Sci. 4, 41–47 (2015).

    Article  Google Scholar 

  156. 156

    Saxe, G. et al. Relationship between acute morphine and the course of PTSD in children with burns. J. Am. Acad. Child Adolesc. Psychiatry 40, 915–921 (2001).

    Article  CAS  Google Scholar 

  157. 157

    Bryant, R. A., Creamer, M., O'Donnell, M., Silove, D. & McFarlane, A. C. A study of the protective function of acute morphine administration on subsequent posttraumatic stress disorder. Biol. Psychiatry 65, 438–440 (2009).

    Article  CAS  Google Scholar 

  158. 158

    Pitman, R. K. et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol. Psychiatry 51, 189–192 (2002).

    Article  CAS  Google Scholar 

  159. 159

    Amos, T., Stein, D. J. & Ipser, J. C. Pharmacological interventions for preventing post-traumatic stress disorder (PTSD). Cochrane Database Syst. Rev. 7, CD006239 (2014). This Cochrane Database Systematic Review focuses on the effects of pharmacological interventions for the prevention of adult PTSD. Evidence suggests that hydrocortisone might be moderately effective for the prevention of PTSD. There was no evidence to support the use of propranolol, temazapam, gabapentin and escitalopram in the prevention of PTSD onset.

    Google Scholar 

  160. 160

    McFarlane, A. C., Barton, C. A., Yehuda, R. & Wittert, G. Cortisol response to acute trauma and risk of posttraumatic stress disorder. Psychoneuroendocrinology 36, 720–727 (2011).

    Article  CAS  Google Scholar 

  161. 161

    Mouthaan, J. et al. The role of acute cortisol and DHEAS in predicting acute and chronic PTSD symptoms. Psychoneuroendocrinology 45, 179–186 (2014).

    Article  CAS  Google Scholar 

  162. 162

    Schelling, G. et al. The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder in survivors. Biol. Psychiatry 50, 978–985 (2001).

    Article  CAS  Google Scholar 

  163. 163

    Zohar, J. et al. High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies. Eur. Neuropsychopharmacol. 21, 796–809 (2011).

    Article  CAS  Google Scholar 

  164. 164

    Delahanty, D. L. et al. The efficacy of initial hydrocortisone administration at preventing posttraumatic distress in adult trauma patients: a randomized trial. CNS Spectr. 18, 103–111 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  165. 165

    Holbrook, T. L., Galarneau, M. R., Dye, J. L., Quinn, K. & Dougherty, A. L. Morphine use after combat injury in Iraq and post-traumatic stress disorder. N. Engl. J. Med. 362, 110–117 (2010).

    Article  CAS  Google Scholar 

  166. 166

    Markowitz, J. C. et al. Is exposure necessary? A randomized clinical trial of interpersonal psychotherapy for PTSD. Am. J. Psychiatry 172, 430–440 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  167. 167

    Bisson, J. & Andrew, M. Psychological treatment of post-traumatic stress disorder (PTSD). Cochrane Database Syst. Rev. 3, CD003388 (2007). This Cochrane Database Systematic Review reports the effects of randomized controlled trials of individual trauma-focused treatments for adult PTSD. Results indicate that individual trauma-focused CBT and EMDR were superior to wait-list and usual care in reducing clinician-assessed PTSD symptoms.

    Google Scholar 

  168. 168

    Bisson, J. I., Roberts, N. P., Andrew, M., Cooper, R. & Lewis, C. Psychological therapies for chronic post-traumatic stress disorder (PTSD) in adults. Cochrane Database Syst. Rev. 12, CD003388 (2013).

    Google Scholar 

  169. 169

    Mello, P. G., Silva, G. R., Donat, J. C. & Kristensen, C. H. An update on the efficacy of cognitive-behavioral therapy, cognitive therapy, and exposure therapy for posttraumatic stress disorder. Int. J. Psychiatry Med. 46, 339–357 (2013).

    Article  Google Scholar 

  170. 170

    Rauch, S. A., Eftekhari, A. & Ruzek, J. I. Review of exposure therapy: a gold standard for PTSD treatment. J. Rehabil. Res. Dev. 49, 679–687 (2012).

    Article  Google Scholar 

  171. 171

    McLean, C. P. & Foa, E. B. Prolonged exposure therapy for post-traumatic stress disorder: a review of evidence and dissemination. Expert Rev. Neurother. 11, 1151–1163 (2011).

    Article  Google Scholar 

  172. 172

    Morkved, N. et al. A comparison of narrative exposure therapy and prolonged exposure therapy for PTSD. Clin. Psychol. Rev. 34, 453–467 (2014).

    Article  CAS  Google Scholar 

  173. 173

    Leer, A., Engelhard, I. M., Altink, A. & van den Hout, M. A. Eye movements during recall of aversive memory decreases conditioned fear. Behav. Res. Ther. 51, 633–640 (2013).

    Article  Google Scholar 

  174. 174

    Engelhard, I. M. et al. Reducing vividness and emotional intensity of recurrent ‘flashforwards’ by taxing working memory: an analogue study. J. Anxiety Disord. 25, 599–603 (2011).

    Article  Google Scholar 

  175. 175

    Seidler, G. H. & Wagner, F. E. Comparing the efficacy of EMDR and trauma-focused cognitive-behavioral therapy in the treatment of PTSD: a meta-analytic study. Psychol. Med. 36, 1515–1522 (2006).

    Article  Google Scholar 

  176. 176

    Schottenbauer, M. A., Glass, C. R., Arnkoff, D. B. & Gray, S. H. Contributions of psychodynamic approaches to treatment of PTSD and trauma: a review of the empirical treatment and psychopathology literature. Psychiatry 71, 13–34 (2008).

    Article  Google Scholar 

  177. 177

    Ehlers, A. et al. Predicting response to exposure treatment in PTSD: the role of mental defeat and alienation. J. Trauma Stress 11, 457–471 (1998).

    Article  CAS  Google Scholar 

  178. 178

    Schnurr, P. P. et al. Cognitive behavioral therapy for posttraumatic stress disorder in women: a randomized controlled trial. JAMA 297, 820–830 (2007).

    Article  CAS  Google Scholar 

  179. 179

    Stein, D. J., Ipser, J. & McAnda, N. Pharmacotherapy of posttraumatic stress disorder: a review of meta-analyses and treatment guidelines. CNS Spectr. 14, 25–31 (2009).

    PubMed  Google Scholar 

  180. 180

    Eisenman, D. et al. The ISTSS/Rand guidelines on mental health training of primary healthcare providers for trauma-exposed populations in conflict-affected countries. J. Trauma Stress 19, 5–17 (2006).

    Article  Google Scholar 

  181. 181

    Weine, S. et al. Guidelines for international training in mental health and psychosocial interventions for trauma exposed populations in clinical and community settings. Psychiatry 65, 156–164 (2002).

    Article  Google Scholar 

  182. 182

    Cloitre, M. et al. Treatment of complex PTSD: results of the ISTSS expert clinician survey on best practices. J. Trauma Stress 24, 615–627 (2011).

    Article  Google Scholar 

  183. 183

    Rosen, C. S. et al. VA practice patterns and practice guidelines for treating posttraumatic stress disorder. J. Trauma Stress 17, 213–222 (2004).

    Article  Google Scholar 

  184. 184

    Susskind, O., Ruzek, J. I. & Friedman, M. J. The VA/DOD clinical practice guideline for management of post-traumatic stress (update 2010): development and methodology. J. Rehabil. Res. Dev. 4, xvii–xxviii (2012).

    Article  Google Scholar 

  185. 185

    Wolf, E. J., Lunney, C. A. & Schnurr, P. P. The influence of the dissociative subtype of posttraumatic stress disorder on treatment efficacy in female veterans and active duty service members. J. Consult Clin. Psychol. http://dx.doi.org/10.1037/ccp0000036 (2015).

  186. 186

    Cloitre, M. et al. Treatment for PTSD related to childhood abuse: a randomized controlled trial. Am. J. Psychiatry 167, 915–924 (2010).

    Article  Google Scholar 

  187. 187

    Cloitre, M., Petkova, E., Wang, J. & Lu Lassell, F. An examination of the influence of a sequential treatment on the course and impact of dissociation among women with PTSD related to childhood abuse. Depress. Anxiety 29, 709–717 (2012).

    Article  Google Scholar 

  188. 188

    Lanius, R. A., Frewen, P. A., Tursich, M., Jetly, R. & McKinnon, M. C. Restoring large-scale brain networks in PTSD and related disorders: a proposal for neuroscientifically-informed treatment interventions. Eur. J. Psychotraumatol. 6, 27313 (2015).

    Article  Google Scholar 

  189. 189

    Dorahy, M. J. et al. Dissociation, shame, complex PTSD, child maltreatment and intimate relationship self-concept in dissociative disorder, chronic PTSD and mixed psychiatric groups. J. Affect. Disord. 172, 195–203 (2014).

    Article  Google Scholar 

  190. 190

    Albucher, R. C. & Liberzon, I. Psychopharmacological treatment in PTSD: a critical review. J. Psychiatr. Res. 36, 355–367 (2002).

    Article  Google Scholar 

  191. 191

    Schoenfeld, F. B., Marmar, C. R. & Neylan, T. C. Current concepts in pharmacotherapy for posttraumatic stress disorder. Psychiatr. Serv. 55, 519–531 (2004).

    Article  Google Scholar 

  192. 192

    Drici, M. D. & Priori, S. Cardiovascular risks of atypical antipsychotic drug treatment. Pharmacoepidemiol. Drug Saf. 16, 882–890 (2007).

    Article  CAS  Google Scholar 

  193. 193

    Hageman, I., Andersen, H. S. & Jorgensen, M. B. Post-traumatic stress disorder: a review of psychobiology and pharmacotherapy. Acta Psychiatr. Scand. 104, 411–422 (2001).

    Article  CAS  Google Scholar 

  194. 194

    Watanabe, Y., Sakai, R. R., McEwen, B. S. & Mendelson, S. Stress and antidepressant effects on hippocampal and cortical 5-HT1A and 5-HT2 receptors and transport sites for serotonin. Brain Res. 615, 87–94 (1993).

    Article  CAS  Google Scholar 

  195. 195

    Yehuda, R. et al. Hippocampal volume in aging combat veterans with and without post-traumatic stress disorder: relation to risk and resilience factors. J. Psychiatr. Res. 41, 435–445 (2007).

    Article  Google Scholar 

  196. 196

    Neylan, T. C. et al. Insomnia severity is associated with a decreased volume of the CA3/dentate gyrus hippocampal subfield. Biol. Psychiatry 68, 494–496 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  197. 197

    Karl, A. et al. A meta-analysis of structural brain abnormalities in PTSD. Neurosci. Biobehav. Rev. 30, 1004–1031 (2006).

    Article  Google Scholar 

  198. 198

    Raskind, M. A. et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am. J. Psychiatry 170, 1003–1010 (2013).

    Article  Google Scholar 

  199. 199

    Department of Veterans Affairs; VA Puget Sound Health Care System. Prazosin and combat trauma PTSD (PACT). ClinicalTrials.gov[online], (2014).

  200. 200

    de Quervain, D. J. Glucocorticoid-induced reduction of traumatic memories: implications for the treatment of PTSD. Prog. Brain Res. 167, 239–247 (2008).

    Article  CAS  Google Scholar 

  201. 201

    Golier, J. A., Caramanica, K., Demaria, R. & Yehuda, R. A pilot study of mifepristone in combat-related PTSD. Depress Res. Treat. 2012, 393251 (2012).

    PubMed  PubMed Central  Google Scholar 

  202. 202

    Aerni, A. et al. Low-dose cortisol for symptoms of posttraumatic stress disorder. Am. J. Psychiatry 161, 1488–1490 (2004).

    Article  Google Scholar 

  203. 203

    Suris, A., North, C., Adinoff, B., Powell, C. M. & Greene, R. Effects of exogenous glucocorticoid on combat-related PTSD symptoms. Ann. Clin. Psychiatry 22, 274–279 (2010).

    PubMed  PubMed Central  Google Scholar 

  204. 204

    Ipser, J. C. & Stein, D. J. Evidence-based pharmacotherapy of post-traumatic stress disorder (PTSD). Int. J. Neuropsychopharmacol. 15, 825–840 (2012).

    Article  CAS  Google Scholar 

  205. 205

    Management of Post-Traumatic Stress Working Group. VA/DoD clinical practice guideline for the management of post-traumatic stress. U.S. Department of Veteran Affairs[online], (2010).

  206. 206

    Dunlop, B. W. et al. Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial. Trials 15, 240 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. 207

    Cameron, C., Watson, D. & Robinson, J. Use of a synthetic cannabinoid in a correctional population for posttraumatic stress disorder-related insomnia and nightmares, chronic pain, harm reduction, and other indications: a retrospective evaluation. J. Clin. Psychopharmacol. 34, 559–564 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. 208

    Jetly, R., Heber, A., Fraser, G. & Boisvert, D. The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: a preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology 51, 585–588 (2015).

    Article  CAS  Google Scholar 

  209. 209

    Feder, A. et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry 71, 681–688 (2014).

    Article  CAS  Google Scholar 

  210. 210

    de Kleine, R. A., Rothbaum, B. O. & van Minnen, A. Pharmacological enhancement of exposure-based treatment in PTSD: a qualitative review. Eur. J. Psychotraumatol. 4, 21626 (2013).

    Article  Google Scholar 

  211. 211

    Kupferschmidt, K. Can ecstasy treat the agony of PTSD? Science 345, 22–23 (2014).

    Article  Google Scholar 

  212. 212

    Novakovic, V. et al. Brain stimulation in posttraumatic stress disorder. Eur. J. Psychotraumatol. 2, 5609 (2011).

    Article  Google Scholar 

  213. 213

    Karsen, E. F., Watts, B. V. & Holtzheimer, P. E. Review of the effectiveness of transcranial magnetic stimulation for post-traumatic stress disorder. Brain Stimul. 7, 151–157 (2014).

    Article  Google Scholar 

  214. 214

    Steckler, T. & Risbrough, V. Pharmacological treatment of PTSD — established and new approaches. Neuropharmacology 62, 617–627 (2012).

    Article  CAS  Google Scholar 

  215. 215

    Rothbaum, B. O. et al. A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans. Am. J. Psychiatry 171, 640–648 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  216. 216

    Yehuda, R. et al. Cortisol augmentation of a psychological treatment for warfighters with posttraumatic stress disorder: randomized trial showing improved treatment retention and outcome. Psychoneuroendocrinology 51, 589–597 (2015).

    Article  CAS  Google Scholar 

  217. 217

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (American Psychiatric Association, 2000).

  218. 218

    Pietrzak, R. H. et al. Functional significance of a novel 7-factor model of DSM-5 PTSD symptoms: results from the National Health and Resilience in Veterans Study. J. Affect. Disord. 174, 522–526 (2015).

    Article  Google Scholar 

  219. 219

    Rapaport, M. H., Clary, C., Fayyad, R. & Endicott, J. Quality-of-life impairment in depressive and anxiety disorders. Am. J. Psychiatry 162, 1171–1178 (2005).

    Article  Google Scholar 

  220. 220

    Harvey, S. B. et al. The long-term consequences of military deployment: a 5-year cohort study of United Kingdom reservists deployed to Iraq in 2003. Am. J. Epidemiol. 176, 1177–1184 (2012).

    Article  Google Scholar 

  221. 221

    Bosco, M. A., Gallinati, J. L. & Clark, M. E. Conceptualizing and treating comorbid chronic pain and PTSD. Pain Res. Treatment 2013, 1–10 (2013).

    Article  Google Scholar 

  222. 222

    Kaniasty, K. & Norris, F. H. Longitudinal linkages between perceived social support and posttraumatic stress symptoms: sequential roles of social causation and social selection. J. Traumat. Stress 21, 274–281 (2008). Examining a large sample of natural disaster victims in Mexico, the authors of this study find that initially lower social support leads to greater rates of PTSD. However, over time, PTSD erodes social support, making individuals increasingly vulnerable to downstream challenges.

    Article  Google Scholar 

  223. 223

    Yehuda, R., Lehrner, A. & Rosenbaum, T. Y. PTSD and sexual dysfunction in men and women. J. Sex. Med. 12, 1107–1119 (2015).

    Article  Google Scholar 

  224. 224

    Hobfoll, S. E. Traumatic stress: a theory based on rapid loss of resources. Anxiety Res. 4, 187–197 (1991). The theory presented in this paper proposes that individuals experiencing traumatic stress often experience the concordant loss of personal, social and material resources, and this process occurs rapidly.

    Article  Google Scholar 

  225. 225

    Hobfoll, S. E. Stress, Culture, and Community: the Psychology and Philosophy of Stress (Plenum, 1998).

    Book  Google Scholar 

  226. 226

    Hall, B. J., Bonanno, G. A., Bolton, P. A. & Bass, J. K. A longitudinal investigation of changes to social resources associated with psychological distress among Kurdish torture survivors living in Northern Iraq. J. Trauma. Stress 27, 446–453 (2014).

    Article  Google Scholar 

  227. 227

    Goodson, J. T., Lefkowitz, C. M., Helstrom, A. W. & Gawrysiak, M. J. Outcomes of prolonged exposure therapy for veterans with posttraumatic stress disorder. J. Trauma. Stress 26, 419–425 (2013).

    Article  Google Scholar 

  228. 228

    Giacco, D., Matanov, A. & Priebe, S. Symptoms and subjective quality of life in post-traumatic stress disorder: a longitudinal study. PLoS ONE 8, e60991 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. 229

    Lamarche, L. J. & De Koninck, J. Sleep disturbance in adults with posttraumatic stress disorder: a review. J. Clin. Psychiatry 68, 1257–1270 (2007).

    Article  Google Scholar 

  230. 230

    Daskalakis, N. P., Cohen, H., Cai, G., Buxbaum, J. D. & Yehuda, R. Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes. Proc. Natl Acad. Sci. USA 111, 13529–13534 (2014). This paper is important because it uses an unbiased approach to look at convergent pathways in the blood and the brain. Furthermore, this animal model separates biological differences resulting from stress exposure and individual differences in pathological behaviour.

    Article  CAS  Google Scholar 

  231. 231

    Neylan, T. C., Schadt, E. E. & Yehuda, R. Biomarkers for combat-related PTSD: focus on molecular networks from high-dimensional data. Eur. J. Psychotraumatol. 5, 23938 (2014). This paper explains how big data and novel computational methods from converging data sets will help to identify molecular networks in PTSD. Furthermore, this paper shows how animal and human data can be used together to advance the field.

    Article  Google Scholar 

  232. 232

    Thakur, G. S. et al. Systems biology approach to understanding post-traumatic stress disorder. Mol. Biosyst. 11, 980–993 (2015).

    Article  CAS  Google Scholar 

  233. 233

    De Jong, J. in Broken Spirits: The Treatment of Asylum Seekers and Refugees with PTSD (eds Wilson, J. P. & Drodzek, B. ) 159–179 (Brunner/Routledge Press, 2005).

    Google Scholar 

  234. 234

    Hobfoll, S. E. Resource caravans and resource caravan passageways: a new paradigm for trauma responding. Intervention 12, 21–32 (2014).

    Article  Google Scholar 

  235. 235

    Jewkes, R., Fulu, E., Roselli, T. & Garcia-Moreno, C. Prevalence of and factors associated with non-partner rape perpetration: findings from the UN Multi-country Cross-sectional Study on Men and Violence in Asia and the Pacific. Lancet Glob. Health 1, e208–e218 (2013).

    Article  Google Scholar 

  236. 236

    Alegria, M. et al. Prevalence, risk, and correlates of posttraumatic stress disorder across ethnic and racial minority groups in the United States. Med. Care 51, 1114–1123 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  237. 237

    Moisander, P. A. & Edston, E. Torture and its sequel — a comparison between victims from six countries. Forens. Sci. Int. 137, 133–140 (2003).

    Article  Google Scholar 

  238. 238

    Wolfe, J. & Kimerling, R. in Assessing Psychological Trauma and PTSD (eds Wilson, J. P. & Keane, T. M. ) 192–238 (Guilford, 1997).

    Google Scholar 

  239. 239

    Cortina, L. M. & Kubiak, S. P. Gender and posttraumatic stress: sexual violence as an explanation for women's increased risk. J. Abnorm. Psychol. 115, 753–759 (2006).

    Article  Google Scholar 

  240. 240

    Tolin, D. F. & Foa, E. B. Sex differences in trauma and posttraumatic stress disorder: a quantitative review of 25 years of research. Psychol. Bull. 132, 959–992 (2006).

    Article  Google Scholar 

  241. 241

    Breslau, N., Chilcoat, H. D., Kessler, R. C., Peterson, E. L. & Lucia, V. C. Vulnerability to assaultive violence: further specification of the sex difference in post-traumatic stress disorder. Psychol. Med. 29, 813–821 (1999).

    Article  CAS  Google Scholar 

  242. 242

    Breslau, N. & Anthony, J. C. Gender differences in the sensitivity to posttraumatic stress disorder: an epidemiological study of urban young adults. J. Abnormal Psychol. 116, 607–611 (2007).

    Article  Google Scholar 

  243. 243

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (American Psychiatric Association, 1987).

  244. 244

    Hopper, J. W., Frewen, P. A., van der Kolk, B. A. & Lanius, R. A. Neural correlates of re-experiencing, avoidance, and dissociation in PTSD: Symptom dimensions and emotion dysregulation in responses to script-driven trauma imagery. J. Trauma. Stress 20, 713–725 (2007).

    Article  Google Scholar 

  245. 245

    World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research (Geneva, 1992).

  246. 246

    NICE. Post-traumatic stress disorder: the management of PTSD in adults and children in primary and secondary care. NICE[online], (2005).

  247. 247

    Canadian Psychiatric Association. Clinical practice guidelines: management of anxiety disorders. Canadian J. Psychiatry 51 (Suppl. 2), 9S–91S(2006).

    Google Scholar 

  248. 248

    Bajor, L. A., Ticlea, A. N. & Osser, D. N. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on posttraumatic stress disorder. Harvard Rev. Psychiatry 19, 240–258 (2011).

    Article  Google Scholar 

  249. 249

    Forbes, D. et al. A guide to guidelines for the treatment of PTSD and related conditions. J. Trauma. Stress 23, 537–552 (2010).

    Article  Google Scholar 

  250. 250

    Foa, E. B., Keane, T. M., Friedman, M. J. & Cohen, J. A. Effective treatments for PTSD: Practice Guidelines from the International Society for Traumatic Stress Studies (Guilford Press, 2008).

    Google Scholar 

  251. 251

    Ursano, R. J. et al. Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Am. J. Psychiatry 161, 3–31 (2004).

    Article  Google Scholar 

  252. 252

    Benedek, D. M., Friedman, M. J., Zatzick, D. & Ursano, R. J. Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Psychiatry Online[online], (2009).

  253. 253

    Bernardy, N. C. & Friedman, M. J. 2010 VA/DOD Clinical Practice Guideline for Management of Post-Traumatic Stress: how busy clinicians can best adopt updated recommendations. J. Rehabil. Res. Dev. 49, vii–viii (2012).

    Article  Google Scholar 

  254. 254

    Forbes, D. et al. Australian guidelines for the treatment of adults with acute stress disorder and post-traumatic stress disorder. Aust. N. Z. J. Psychiatry 41, 637–648 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

R.Y. is supported by grants from the US Department of Defense (DOD W81XWH-10-2-0072 and DOD W81XWH-13-1-0071) and a grant from the Lightfighter Trust Foundation (LFT2009-02-1). A.C.M. is supported in part by National Health and Medical Research Council Program Grant number 568970. C.M.N. is supported in part by US National Institutes of Health (NIH) grant R01MH093500. S.E. Hobfoll is partly supported by a grant from the National Institute of Mental Health (RO1MH073687) and the Rush Center for Urban Health Equity (NIH-NHLBI 1P50HL105189). K.C.K. is supported by grants NIH MH078928 and MH093612. T.C.N. is supported in part by a research grant that was awarded and administered by the U.S. Army Medical Research & Materiel Command (USAMRMC; TCN: W81XWH-11-2-0189) and the Mental Illness Research and Education Clinical Center of the US Veterans Health Administration. The authors would like to thank L. M. Bierer for her careful final review of the manuscript, M. E. Bowers for assistance with the development of the graphics and review of references, and H. Bader for administrative coordination and integration of multiple versions of the document.

Author information

Affiliations

Authors

Contributions

Introduction (R.Y.); Epidemiology (K.C.K. and C.W.H.); Mechanisms/pathophysiology (T.C.N., R.Y., C.M.N. and R.A.L.); Diagnosis, screening and prevention (A.C.M.); Management (E.V.); Quality of life (S. E. Hobfoll); Outlook (S. E. Hyman and R.Y.); overview of Primer (R.Y.). All authors contributed to the review and to the editing of the final manuscript.

The views expressed in this article are those of the authors and do not represent an official position of the US Army, US Department of Defense or any of the affiliated institutions listed.

Corresponding author

Correspondence to Rachel Yehuda.

Ethics declarations

Competing interests

R.Y. has a patent entitled Genes Associated with Posttraumatic Stress Disorder (2012/0039,812). A.C.M. receives research funding from the Australian Department of Defense and the Australian Department of Veterans Affairs. He is a Group Captain in the RAAF specialist reserves and is an advisor to the Department of Veterans Affairs. K.C.K. has consulted for Synchroneuron Inc. and Accellient Partners. T.C.N. has consulted for Genentech and has received study medication from Actelion for a study funded by the US Department of Defense, and from Glaxo-Smith-Kline for a study funded by the US Department of Veterans Affairs. S. E. Hyman has consulted on early stage drug discovery for Novartis and Sunovion. C.W.H., E.V., R.A.L., C.M.N. and S. E. Hobfoll declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yehuda, R., Hoge, C., McFarlane, A. et al. Post-traumatic stress disorder. Nat Rev Dis Primers 1, 15057 (2015). https://doi.org/10.1038/nrdp.2015.57

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing