Biological studies of post-traumatic stress disorder

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 3rd edn (American Psychiatric Association, 1980).

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Press, 2000).

Dobbs, D. & Wilson, W. P. Observations on persistence of war neurosis. Dis. Nerv. Syst. 21, 686–691 (1960).

Orr, S. P., Metzger, L. J., Miller, M. W. & Kaloupek, D. G. in Assessing Psychological Trauma and PTSD: A Handbook for Practicioners 2nd edn (eds Wilson, J. P. & Keane, T. M.) 289–343 (Guilford Publications, 2004).

Metzger, L. J., Gilbertson, M. W. & Orr, S. P. in Neuropsychology of PTSD: Biological, Clinical, and Cognitive Perspectives (eds Vasterling, J. & Brewin, C.) 83–102 (Guilford Publications, 2005).

Pole, N. The psychophysiology of posttraumatic stress disorder: a meta-analysis. Psychol. Bull. 133, 725–746 (2007). A comprehensive review and meta-analysis of the most important psychophysiological research in PTSD as of that date.

Keane, T. M. 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. 66, 914–923 (1998).

Pitman, R. K., Orr, S. P., Forgue, D. F., de Jong, J. B. & Claiborn, J. M. Psychophysiologic assessment of posttraumatic stress disorder imagery in Vietnam combat veterans. Arch. Gen. Psychiatry 44, 970–975 (1987). This study introduced a novel symptom provocation technique for PTSD that has come into widespread psychophysiologic, neuroimaging and other research use.

Blanchard, E. B. et al. Psychophysiology of posttraumatic stress disorder related to motor vehicle accidents: replication and extension. J. Consult Clin. Psychol. 64, 742–751 (1996).

Kleim, B., Wilhelm, F. H., Glucksman, E. & Ehlers, A. Sex differences in heart rate responses to script-driven imagery soon after trauma and risk of posttraumatic stress disorder. Psychosom. Med. 72, 917–924 (2010).

Orr, S. P. et al. Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: association with posttraumatic stress disorder. Arch. Gen. Psychiatry 60, 283–288 (2003).

Shalev, A. Y. et al. Auditory startle response in trauma survivors with posttraumatic stress disorder: a prospective study. Am. J. Psychiatry 157, 255–261 (2000).

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

Griffin, M. G., Resick, P. A. & Galovski, T. E. Does physiologic response to loud tones change following cognitive-behavioral treatment for posttraumatic stress disorder? J. Trauma Stress. 25, 25–32 (2012).

Peri, T., Ben-Shakhar, G., Orr, S. P. & Shalev, A. Y. Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder. Biol. Psychiatry 47, 512–519 (2000).

Blechert, J., Michael, T., Vriends, N., Margraf, J. & Wilhelm, F. H. Fear conditioning in posttraumatic stress disorder: evidence for delayed extinction of autonomic, experiential, and behavioural responses. Behav. Res. Ther. 45, 2019–2033 (2007).

Lissek, S. & Grillon, C. in The Oxford Handbook of Traumatic Stress Disorders (eds Beck, J. G. & Sloan, D. M.) 175–190 (Oxford Univ. Press, 2012).

Wessa, M. & Flor, H. Failure of extinction of fear responses in posttraumatic stress disorder: evidence from second-order conditioning. Am. J. Psychiatry 164, 1684–1692 (2007).

Milad, M. R. et al. Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J. Psychiatr. Res. 42, 515–520 (2008).

Metzger, L. J., Pitman, R. K., Miller, G. A., Paige, S. R. & Orr, S. P. Intensity dependence of auditory P2 in monozygotic twins discordant for Vietnam combat: associations with posttraumatic stress disorder. J. Rehabil. Res. Dev. 45, 437–449 (2008).

Grillon, C. & Morgan, C. A. Fear-potentiated startle conditioning to explicit and contextual cues in Gulf War veterans with posttraumatic stress disorder. J. Abnorm. Psychol. 108, 134–142 (1999).

Griffin, M. G. A prospective assessment of auditory startle alterations in rape and physical assault survivors. J. Trauma. Stress 21, 91–99 (2008).

Buhlmann, U. et al. Physiologic responses to loud tones in individuals with obsessive-compulsive disorder. Psychosom. Med. 69, 166–172 (2007).

Guthrie, R. M. & Bryant, R. A. Auditory startle response in firefighters before and after trauma exposure. Am. J. Psychiatry 162, 283–290 (2005).

Guthrie, R. M. & Bryant, R. A. Extinction learning before trauma and subsequent posttraumatic stress. Psychosom. Med. 68, 307–311 (2006).

Orr, S. P. et al. Predicting post-trauma stress symptoms from pre-trauma psychophysiologic reactivity, personality traits and measures of psychopathology. Biol. Mood Anxiety Disord. 2, 8 (2012).

O'Donnell, M. L., Creamer, M., Elliott, P. & Bryant, R. Tonic and phasic heart rate as predictors of posttraumatic stress disorder. Psychosom. Med. 69, 256–261 (2007).

Suendermann, O., Ehlers, A., Boellinghaus, I., Gamer, M. & Glucksman, E. Early heart rate responses to standardized trauma-related pictures predict posttraumatic stress disorder: a prospective study. Psychosom. Med. 72, 301–308 (2010).

Shalev, A. Y. et al. A prospective study of heart rate response following trauma and the subsequent development of posttraumatic stress disorder. Arch. Gen. Psychiatry 55, 553–559 (1998).

Kobayashi, I., Boarts, J. M. & Delahanty, D. L. Polysomnographically measured sleep abnormalities in PTSD: a meta-analytic review. Psychophysiology 44, 660–669 (2007).

Sapolsky, R. M., Uno, H., Rebert, C. S. & Finch, C. E. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J. Neurosci. 10, 2897–2902 (1990).

Bremner, J. D. et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am. J. Psychiatry 152, 973–981 (1995).

Gurvits, T. V. et al. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol. Psychiatry 40, 1091–1099 (1996).

Stein, M. B., Koverola, C., Hanna, C., Torchia, M. G. & McClarty, B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol. Med. 27, 951–959 (1997).

Kitayama, N., Vaccarino, V., Kutner, M., Weiss, P. & Bremner, J. D. Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J. Affect. Disord. 88, 79–86 (2005).

Wang, Z. et al. Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder. Arch. Gen. Psychiatry 67, 296–303 (2010). This was the first study in humans to use high-resolution sMRI to determine more specific volume diminutions within selected hippocampal subfields and to delineate those regions specific to PTSD versus ageing effects.

Smith, M. E. Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: a meta-analysis of structural MRI studies. Hippocampus 15, 798–807 (2005).

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

Woon, F. & Hedges, D. W. Gender does not moderate hippocampal volume deficits in adults with posttraumatic stress disorder: a meta-analysis. Hippocampus 21, 243–252 (2011).

Gilbertson, M. W. et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nature Neurosci. 5, 1242–1247 (2002). This study used data from monozygotic twins discordant for combat exposure and PTSD to suggest that smaller hippocampal volume in PTSD represents a pre-existing vulnerability factor.

Bonne, O. et al. Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am. J. Psychiatry 158, 1248–1251 (2001).

Fennema-Notestine, C. Stein, M. B., Kennedy, C. M., Archibald, S. L. & Jernigan, T. L. Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder. Biol. Psychiatry 52, 1089–1101 (2002).

De Bellis, M. D., Hall, J., Boring, A. M., Frustaci, K. & Moritz, G. A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder. Biol. Psychiatry 50, 305–309 (2001).

Emdad, R. et al. Morphometric and psychometric comparisons between non-substance-abusing patients with posttraumatic stress disorder and normal controls. Psychother. Psychosom. 75, 122–132 (2006).

Bonne, O. et al. Reduced posterior hippocampal volume in posttraumatic stress disorder. J. Clin. Psychiatry 69, 1087–1091 (2008).

Schuff, N. et al. Abnormal N-acetylaspartate in hippocampus and anterior cingulate in posttraumatic stress disorder. Psychiatry Res. 162, 147–157 (2008).

Karl, A. & Werner, A. The use of proton magnetic resonance spectroscopy in PTSD research — meta-analyses of findings and methodological review. Neurosci. Biobehav. Rev. 34, 7–22 (2010).

Myslobodsky, M. S. et al. Changes of brain anatomy in patients with posttraumatic stress disorder: a pilot magnetic resonance imaging study. Psychiatry Res. 58, 259–264 (1995).

Bremner, J. D. Hypotheses and controversies related to effects of stress on the hippocampus: an argument for stress-induced damage to the hippocampus in patients with posttraumatic stress disorder. Hippocampus 11, 75–81 (2001).

Vermetten, E., Vythilingam, M., Southwick, S. M., Charney, D. S. & Bremner, J. D. Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol. Psychiatry 54, 693–702 (2003).

Woon, F. L., Sood, S. & Hedges, D. W. Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 1181–1188 (2010).

Kasai, K. et al. Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol. Psychiatry 63, 550–556 (2008).

Kitayama, N., Quinn, S. & Bremner, J. D. Smaller volume of anterior cingulate cortex in abuse-related posttraumatic stress disorder. J. Affect. Disord. 90, 171–174 (2006).

Carrion, V. G., Weems, C. F., Richert, K., Hoffman, B. C. & Reiss, A. L. Decreased prefrontal cortical volume associated with increased bedtime cortisol in traumatized youth. Biol. Psychiatry 68, 491–493 (2010).

Kim, S. J. et al. Asymmetrically altered integrity of cingulum bundle in posttraumatic stress disorder. Neuropsychobiology 54, 120–125 (2006).

Sekiguchi, A. et al. Brain structural changes as vulnerability factors and acquired signs of post-earthquake stress. Mol. Psychiatry 22 May 2012 (doi:10.1038/mp.2012.51).

Morrow, B. A., Elsworth, J. D., Rasmusson, A. M. & Roth, R. H. The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat. Neuroscience 92, 553–564 (1999).

Herry, C. et al. Neuronal circuits of fear extinction. Eur. J. Neurosci. 31, 599–612 (2010).

Milad, M. R. & Quirk, G. J. Fear extinction as a model for translational neuroscience: ten years of progress. Annu. Rev. Psychol. 63, 129–151 (2012).

Liberzon, I. et al. Brain activation in PTSD in response to trauma-related stimuli. Biol. Psychiatry 45, 817–826 (1999).

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).

Bremner, J. D. et al. Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychol. Med. 35, 791–806 (2005).

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).

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).

Felmingham, K. et al. Neural responses to masked fear faces: sex differences and trauma exposure in posttraumatic stress disorder. J. Abnorm. Psychol. 119, 241–247 (2010).

Shin, L. M. et al. Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch. Gen. Psychiatry 61, 168–176 (2004).

Felmingham, K. et al. Changes in anterior cingulate and amygdala after cognitive behavior therapy of posttraumatic stress disorder. Psychol. Sci. 18, 127–129 (2007). This article used fMRI to reveal functional brain changes in response to cognitive behavioural therapy in PTSD.

Milad, M. R. et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol. Psychiatry 66, 1075–1082 (2009).

Shin, L. M. et al. An fMRI study of anterior cingulate function in posttraumatic stress disorder. Biol. Psychiatry 50, 932–942 (2001).

Rougemont-Bucking, A. et al. Altered processing of contextual information during fear extinction in PTSD: an fMRI study. CNS Neurosci. Ther. 17, 227–236 (2011).

Bryant, R. A. et al. Neural networks of information processing in posttraumatic stress disorder: a functional magnetic resonance imaging study. Biol. Psychiatry 58, 111–118 (2005).

Pannu, H. J., Labar, K. S., Petty, C. M., McCarthy, G. & Morey, R. A. Alterations in the neural circuitry for emotion and attention associated with posttraumatic stress symptomatology. Psychiatry Res. 172, 7–15 (2009).

Fonzo, G. A. et al. Exaggerated and disconnected insular–amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorder. Biol. Psychiatry 68, 433–441 (2010).

Shin, L. M. et al. Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch. Gen. Psychiatry 66, 1099–1107 (2009).

Shin, L. M. et al. Exaggerated activation of dorsal anterior cingulate cortex during cognitive interference: a monozygotic twin study of posttraumatic stress disorder. Am. J. Psychiatry 168, 979–985 (2011).

Bremner, J. D. et al. MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am. J. Psychiatry 160, 924–932 (2003).

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

Simmons, A. N. et al. Functional activation and neural networks in women with posttraumatic stress disorder related to intimate partner violence. Biol. Psychiatry 64, 681–690 (2008).

Strigo, I. A. et al. Neural correlates of altered pain response in women with posttraumatic stress disorder from intimate partner violence. Biol. Psychiatry 68, 442–450 (2010).

Aupperle, R. L. et al. Dorsolateral prefrontal cortex activation during emotional anticipation and neuropsychological performance in posttraumatic stress disorder. Arch. Gen. Psychiatry 69, 360–371 (2012). This paper linked functional brain activation patterns with neuropsychological test performance in PTSD.

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).

Elzinga, B. M. & Bremner, J. D. Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)? J. Affect. Disord. 70, 1–17 (2002).

Rauch, S. L., Shin, L. M. & Phelps, E. A. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research--past, present, and future. Biol. Psychiatry 60, 376–382 (2006).

Pitman, R. K. Combat effects on mental health: the more things change, the more they remain the same. Arch. Gen. Psychiatry 63, 127–128 (2006).

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

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

Liberzon, I. et al. Altered central mu-opioid receptor binding after psychological trauma. Biol. Psychiatry 61, 1030–1038 (2007).

Murrough, J. W. et al. The effect of early trauma exposure on serotonin type 1B receptor expression revealed by reduced selective radioligand binding. Arch. Gen. Psychiatry 68, 892–900 (2011).

Southwick, S. M. et al. Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol. Psychiatry 46, 1192–1204 (1999).

Pitman, R. K. Post-traumatic stress disorder, hormones, and memory. Biol. Psychiatry 26, 221–223 (1989).

Rasmusson, A. M. et al. Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD. Biol. Psychiatry 47, 526–539 (2000).

Perry, B. D., Giller, E. L. Jr & Southwick, S. M. Altered platelet α2-adrenergic binding sites in posttraumatic stress disorder. Am. J. Psychiatry 144, 1511–1512 (1987).

Maes, M. et al. Serotonergic and noradrenergic markers of post-traumatic stress disorder with and without major depression. Neuropsychopharmacology 20, 188–197 (1999).

Blanchard, E. B., Kolb, L. C., Prins, A., Gates, S. & McCoy, G. C. Changes in plasma norepinephrine to combat-related stimuli among Vietnam veterans with posttraumatic stress disorder. J. Nerv. Ment. Dis. 179, 371–373 (1991).

Southwick, S. M. et al. Abnormal noradrenergic function in posttraumatic stress disorder. Arch. Gen. Psychiatry 50, 266–274 (1993).

Mellman, T. A., Kumar, A., Kulick-Bell, R., Kumar, M. & Nolan, B. Nocturnal/daytime urine noradrenergic measures and sleep in combat-related PTSD. Biol. Psychiatry 38, 174–179 (1995).

Liberzon, I., Abelson, J. L., Flagel, S. B., Raz, J. & Young, E. A. Neuroendocrine and psychophysiologic responses in PTSD: a symptom provocation study. Neuropsychopharmacology 21, 40–50 (1999).

Bremner, J. D. et al. Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch. Gen. Psychiatry 54, 246–254 (1997).

Taylor, F. B. et al. Daytime prazosin reduces psychological distress to trauma specific cues in civilian trauma posttraumatic stress disorder. Biol. Psychiatry 59, 577–581 (2006).

Raskind, M. A. et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol. Psychiatry 61, 928–934 (2007).

Vaiva, G. et al. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol. Psychiatry 54, 947–949 (2003).

Stein, M. B., Kerridge, C., Dimsdale, J. E. & Hoyt, D. B. Pharmacotherapy to prevent PTSD: results from a randomized controlled proof-of-concept trial in physically injured patients. J. Trauma Stress. 20, 923–932 (2007).

Hoge, E. A. et al. Effect of acute posttrauma propranolol on PTSD outcome and physiological responses during script-driven imagery. CNS Neurosci. Ther. 18, 21–27 (2012).

Southwick, S. M. et al. Noradrenergic and serotonergic function in posttraumatic stress disorder. Arch. Gen. Psychiatry 54, 749–758 (1997).

Baumann, M. H., Mash, D. C. & Staley, J. K. The serotonin agonist m-chlorophenylpiperazine (mCPP) binds to serotonin transporter sites in human brain. Neuroreport 6, 2150–2152 (1995).

Murphy, D. L., Lesch, K. P., Aulakh, C. S. & Pigott, T. A. Serotonin-selective arylpiperazines with neuroendocrine, behavioral, temperature, and cardiovascular effects in humans. Pharmacol. Rev. 43, 527–552 (1991).

Kennett, G. A. et al. Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function. Neuropharmacology 33, 1581–1588 (1994).

Britton, K. T., Akwa, Y., Spina, M. G. & Koob, G. F. Neuropeptide Y blocks anxiogenic-like behavioral action of corticotropin-releasing factor in an operant conflict test and elevated plus maze. Peptides 21, 37–44 (2000).

Zhou, Z. et al. Genetic variation in human NPY expression affects stress response and emotion. Nature 452, 997–1001 (2008).

Morgan, C. A. et al. Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report. Biol. Psychiatry 52, 136–142 (2002).

Sah, R. et al. Low cerebrospinal fluid neuropeptide Y concentrations in posttraumatic stress disorder. Biol. Psychiatry 66, 705–707 (2009).

Yehuda, R., Brand, S. & Yang, R. K. Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping. Biol. Psychiatry 59, 660–663 (2006).

Dunn, A. J. & Berridge, C. W. Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res. Brain Res. Rev. 15, 71–100 (1990).

Baker, D. G. et al. Higher levels of basal serial CSF cortisol in combat veterans with posttraumatic stress disorder. Am. J. Psychiatry 162, 992–994 (2005).

de Kloet, C. S. et al. Elevated plasma corticotrophin-releasing hormone levels in veterans with posttraumatic stress disorder. Prog. Brain Res. 167, 287–291 (2008).

Geracioti, T. D. Jr et al. Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder. Psychoneuroendocrinology 33, 416–424 (2008).

Yehuda, R. et al. Low urinary cortisol excretion in patients with posttraumatic stress disorder. J. Nerv. Ment. Dis. 178, 366–369 (1990).

Yehuda, R. Post-traumatic stress disorder. N. Engl. J. Med. 346, 108–114 (2002). This article reviewed a highly influential body of research involving hyper-responsiveness of glucocorticoid receptors, enhanced negative feedback of the hypothalamus–pituitary–adrenal cortical axis and lower circulating cortisol levels in PTSD.

Yehuda, R., Boisoneau, D., Lowy, M. T. & Giller, E. L. Jr. Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Arch. Gen. Psychiatry 52, 583–593 (1995).

Yehuda, R., Lowy, M. T., Southwick, S. M., Shaffer, D. & Giller, E. L. Jr. Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder. Am. J. Psychiatry 148, 499–504 (1991).

Yehuda, R. Status of glucocorticoid alterations in post-traumatic stress disorder. Ann. NY Acad. Sci. 1179, 56–69 (2009).

Mehta, D. et al. Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies. Arch. Gen. Psychiatry 68, 901–910 (2011).

Young, E. A. & Breslau, N. Cortisol and catecholamines in posttraumatic stress disorder: an epidemiologic community study. Arch. Gen. Psychiatry 61, 394–401 (2004).

Young, E. A. & Breslau, N. Saliva cortisol in posttraumatic stress disorder: a community epidemiologic study. Biol. Psychiatry 56, 205–209 (2004).

Rasmusson, A. M. et al. Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder. Biol. Psychiatry 50, 965–977 (2001).

Schelling, G. et al. Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. Biol. Psychiatry 55, 627–633 (2004).

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).

de Quervain, D. J. Glucocorticoid-induced inhibition of memory retrieval: implications for posttraumatic stress disorder. Ann. NY Acad. Sci. 1071, 216–220 (2006).

McIntyre, C. K. & Roozendaal, B. in Neural Plasticity and Memory: From Genes to Brain Imaging (ed. Bermúdez-Rattoni, F.) 265–284 (CRC, 2007).

Sandi, C. Glucocorticoids act on glutamatergic pathways to affect memory processes. Trends Neurosci. 34, 165–176 (2011).

Hou, Y. T., Lin, H. K. & Penning, T. M. Dexamethasone regulation of the rat 3α-hydroxysteroid/dihydrodiol dehydrogenase gene. Mol. Pharmacol. 53, 459–466 (1998).

Rasmusson, A. M., Picciotto, M. R. & Krishnan-Sarin, S. Smoking as a complex but critical covariate in neurobiological studies of posttraumatic stress disorders: a review. J. Psychopharmacol. 20, 693–707 (2006).

Yehuda, R. et al. Cortisol metabolic predictors of response to psychotherapy for symptoms of PTSD in survivors of the World Trade Center attacks on September 11, 2001. Psychoneuroendocrinology 34, 1304–1313 (2009).

Rasmusson, A. M., Vythilingam, M. & Morgan, C. A. The neuroendocrinology of posttraumatic stress disorder: new directions. CNS Spectr. 8, 651–657 (2003).

Chalbot, S. & Morfin, R. Dehydroepiandrosterone metabolites and their interactions in humans. Drug Metabol. Drug Interact. 22, 1–23 (2006).

Balazs, Z., Schweizer, R. A., Frey, F. J., Rohner-Jeanrenaud, F. & Odermatt, A. DHEA induces 11β–HSD2 by acting on CCAAT/enhancer-binding proteins. J. Am. Soc. Nephrol. 19, 92–101 (2008).

Spivak, B. et al. Elevated circulatory level of GABAA — antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder. Psychol. Med. 30, 1227–1231 (2000).

Sondergaard, H. P., Hansson, L. O. & Theorell, T. Elevated blood levels of dehydroepiandrosterone sulphate vary with symptom load in posttraumatic stress disorder: findings from a longitudinal study of refugees in Sweden. Psychother. Psychosom. 71, 298–303 (2002).

Rasmusson, A. M. et al. An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD. Neuropsychopharmacology 29, 1546–1557 (2004).

Gill, J., Vythilingam, M. & Page, G. G. Low cortisol, high DHEA, and high levels of stimulated TNFα, and IL-6 in women with PTSD. J. Trauma Stress 21, 530–539 (2008).

Morgan, C. A. et al. Relationships among plasma dehydroepiandrosterone sulfate and cortisol levels, symptoms of dissociation, and objective performance in humans exposed to acute stress. Arch. Gen. Psychiatry 61, 819–825 (2004).

Morgan, C. A., Rasmusson, A., Pietrzak, R. H., Coric, V. & Southwick, S. M. Relationships among plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate, cortisol, symptoms of dissociation, and objective performance in humans exposed to underwater navigation stress. Biol. Psychiatry 66, 334–340 (2009).

Yehuda, R., Brand, S. R., Golier, J. A. & Yang, R. K. Clinical correlates of DHEA associated with post-traumatic stress disorder. Acta Psychiatr. Scand. 114, 187–193 (2006).

Rasmusson, A. M. et al. Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol. Psychiatry 60, 704–713 (2006). This article reported deficits in the synthesis of GABAergic neuroactive steroids in PTSD, suggesting a mechanism that may confer resistance to SSRI treatment and contribute to comorbidities, such as depression and chronic pain.

Genazzani, A. D. et al. Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuroactive steroids. Fertil. Steril. 80, 1495–1501 (2003).

Schmidt, P. J. et al. Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch. Gen. Psychiatry 62, 154–162 (2005).

Semyanov, A., Walker, M. C., Kullmann, D. M. & Silver, R. A. Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci. 27, 262–269 (2004).

Pinna, G., Dong, E., Matsumoto, K., Costa, E. & Guidotti, A. In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine. Proc. Natl Acad. Sci. USA 100, 2035–2040 (2003).

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

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

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).

Lyons, M. J. et al. Do genes influence exposure to trauma? A twin study of combat. Am. J. Med. Genet. 48, 22–27 (1993).

Jang, K. L., Stein, M. B., Taylor, S., Asmundson, G. J. & Livesley, W. J. Exposure to traumatic events and experiences: aetiological relationships with personality function. Psychiatry Res. 120, 61–69 (2003).

Cornelis, M. C., Nugent, N. R., Amstadter, A. B. & Koenen, K. C. Genetics of post-traumatic stress disorder: review and recommendations for genome-wide association studies. Curr. Psychiatry Rep. 12, 313–326 (2010).

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

Purcell, S. M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).

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

Chang, S. C. et al. No association between ADCYAP1R1 and post-traumatic stress disorder in two independent samples. Mol. Psychiatry 17, 239–241 (2012).

Segman, R. H. et al. Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol. Psychiatry 10, 500–513 (2005).

Zieker, J. et al. Differential gene expression in peripheral blood of patients suffering from post-traumatic stress disorder. Mol. Psychiatry 12, 116–118 (2007).

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).

Uddin, M. et al. Gene expression and methylation signatures of MAN2C1 are associated with PTSD. Dis. Markers 30, 111–121 (2011).

Kilpatrick, D. G. et al. The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. Am. J. Psychiatry 164, 1693–1699 (2007). This was the first study to document a genotype by environment interaction in risk of PTSD. The data suggested that the low expression variant of the serotonin transporter gene increases risk of PTSD under conditions of high stress and low social support but not under low stress conditions.

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).

Uddin, M. et al. Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc. Natl Acad. Sci. USA 107, 9470–9475 (2010). This study provided evidence of a biological model of PTSD aetiology in which an externally experienced traumatic event induces downstream alterations in immune function by reducing methylation levels of immune-related genes.

Smith, A. K. et al. Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 700–708 (2011).

Xie, P. et al. Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations. Arch. Gen. Psychiatry 66, 1201–1209 (2009).

Xie, P., Kranzler, H. R., Farrer, L. & Gelernter, J. Serotonin transporter 5-HTTLPR genotype moderates the effects of childhood adversity on posttraumatic stress disorder risk: a replication study. Am. J. Med. Genet. B Neuropsychiatr. Genet. 159B, 644–652 (2012).

Koenen, K. C. et al. Modification of the association between serotonin transporter genotype and risk of posttraumatic stress disorder in adults by county-level social environment. Am. J. Epidemiol. 169, 704–711 (2009).

Philibert, R. A. et al. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 543–549 (2008).

Koenen, K. C. et al. SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder. Depress. Anxiety 28, 639–647 (2011).

Trollope, A. F. et al. Stress, epigenetic control of gene expression and memory formation. Exp. Neurol. 233, 3–11 (2012).

El-Sayed, A. M., Halossim, M. R., Galea, S. & Koenen, K. C. Epigenetic modifications associated with suicide and common mood and anxiety disorders: a systematic review of the literature. Biol. Mood Anxiety Disord. 2, 10 (2012).

Pitman, R. K., Orr, S. P. & Shalev, A. Y. Once bitten, twice shy: beyond the conditioning model of PTSD. Biol. Psychiatry 33, 145–146 (1993).

Adamec, R. E. & Shallow, T. Lasting effects on rodent anxiety of a single exposure to a cat. Physiol. Behav. 54, 101–109 (1993). An early and influential study of the PredEx animal model for PTSD.

Zoladz, P. R., Conrad, C. D., Fleshner, M. & Diamond, D. M. Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder. Stress 11, 259–281 (2008).

Cohen, H., Zohar, J. & Matar, M. The relevance of differential response to trauma in an animal model of posttraumatic stress disorder. Biol. Psychiatry 53, 463–473 (2003).

Mesches, M. H., Fleshner, M., Heman, K. L., Rose, G. M. & Diamond, D. M. Exposing rats to a predator blocks primed burst potentiation in the hippocampus in vitro. J. Neurosci. 19, RC18 (1999).

Liberzon, I., Lopez, J. F., Flagel, S. B., Vazquez, D. M. & Young, E. A. Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J. Neuroendocrinol. 11, 11–17 (1999). This study demonstrated the construct validity of the SPS animal model of PTSD.

Kohda, K. et al. Glucocorticoid receptor activation is involved in producing abnormal phenotypes of single-prolonged stress rats: a putative post-traumatic stress disorder model. Neuroscience 148, 22–33 (2007).

Servatius, R. J., Ottenweller, J. E., Bergen, M. T., Soldan, S. & Natelson, B. H. Persistent stress-induced sensitization of adrenocortical and startle responses. Physiol Behav. 56, 945–954 (1994).

Pynoos, R. S., Ritzmann, R. F., Steinberg, A. M., Goenjian, A. & Prisecaru, I. A behavioral animal model of posttraumatic stress disorder featuring repeated exposure to situational reminders. Biol. Psychiatry 39, 129–134 (1996).

Rau, V. & Fanselow, M. S. Exposure to a stressor produces a long lasting enhancement of fear learning in rats. Stress 12, 125–133 (2009).

Li, X., Han, F., Liu, D. & Shi, Y. Changes of Bax, Bcl-2 and apoptosis in hippocampus in the rat model of post-traumatic stress disorder. Neurol. Res. 32, 579–586 (2010).

Kozlovsky, N., Matar, M. A., Kaplan, Z., Zohar, J. & Cohen, H. A distinct pattern of intracellular glucocorticoid-related responses is associated with extreme behavioral response to stress in an animal model of post-traumatic stress disorder. Eur. Neuropsychopharmacol. 19, 759–771 (2009).

Zhe, D., Fang, H. & Yuxiu, S. Expressions of hippocampal mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the single-prolonged stress-rats. Acta Histochem. Cytochem. 41, 89–95 (2008).

Adamec, R., Muir, C., Grimes, M. & Pearcey, K. Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress. Behav. Brain Res. 179, 192–207 (2007).

Adamec, R., Fougere, D. & Risbrough, V. CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predator stress model of PTSD. Int. J. Neuropsychopharmacol. 13, 747–757 (2010).

Cohen, H., Matar, M. A., Buskila, D., Kaplan, Z. & Zohar, J. Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biol. Psychiatry 64, 708–717 (2008).

Kaouane, N. et al. Glucocorticoids can induce PTSD-like memory impairments in mice. Science 335, 1510–1513 (2012).

Knox, D., Perrine, S. A., George, S. A., Galloway, M. P. & Liberzon, I. Single prolonged stress decreases glutamate, glutamine, and creatine concentrations in the rat medial prefrontal cortex. Neurosci. Lett. 480, 16–20 (2010).

Harvey, B. H., Oosthuizen, F., Brand, L., Wegener, G. & Stein, D. J. Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology (Berl.) 175, 494–502 (2004).

Yamamoto, S. et al. Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder. J. Psychiatr. Res. 44, 1069–1074 (2010).

Yamamoto, S. et al. Effects of single prolonged stress and d-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD. Neuropsychopharmacology 33, 2108–2116 (2008).

Blundell, J. & Adamec, R. The NMDA receptor antagonist CPP blocks the effects of predator stress on pCREB in brain regions involved in fearful and anxious behavior. Brain Res. 1136, 59–76 (2007).

Adamec, R., Holmes, A. & Blundell, J. Vulnerability to lasting anxiogenic effects of brief exposure to predator stimuli: sex, serotonin and other factors-relevance to PTSD. Neurosci. Biobehav. Rev. 32, 1287–1292 (2008).

Harvey, B. H., Brand, L., Jeeva, Z. & Stein, D. J. Cortical/hippocampal monoamines, HPA-axis changes and aversive behavior following stress and restress in an animal model of post-traumatic stress disorder. Physiol. Behav. 87, 881–890 (2006).

Kesner, Y. et al. WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model. Mol. Psychiatry 14, 86–94 (2009).

Luo, F. F., Han, F. & Shi, Y. X. Changes in 5-HT1A receptor in the dorsal raphe nucleus in a rat model of post-traumatic stress disorder. Mol. Med. Report. 4, 843–847 (2011).

Harvey, B. H., Naciti, C., Brand, L. & Stein, D. J. Endocrine, cognitive and hippocampal/cortical 5HT1A/2A receptor changes evoked by a time-dependent sensitisation (TDS) stress model in rats. Brain Res. 983, 97–107 (2003).

Wang, H. T., Han, F. & Shi, Y. X. Activity of the 5-HT1A receptor is involved in the alteration of glucocorticoid receptor in hippocampus and corticotropin-releasing factor in hypothalamus in SPS rats. Int. J. Mol. Med. 24, 227–231 (2009).

Harada, K., Yamaji, T. & Matsuoka, N. Activation of the serotonin 5-HT2C receptor is involved in the enhanced anxiety in rats after single-prolonged stress. Pharmacol. Biochem. Behav. 89, 11–16 (2008).

Olson, V. G. et al. The role of norepinephrine in differential response to stress in an animal model of posttraumatic stress disorder. Biol. Psychiatry 70, 441–448 (2011).

Takei, S. et al. Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder. J. Psychiatr. Res. 45, 460–468 (2011).

Kozlovsky, N. et al. Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response. Int. J. Neuropsychopharmacol. 10, 741–758 (2007).

Roth, T. L., Zoladz, P. R., Sweatt, J. D. & Diamond, D. M. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. J. Psychiatr. Res. 45, 919–926 (2011).

Pitman, R. K. & Orr, S. P. in Posttraumatic Stress Disorder in Litigation: Guidelines for Forensic Assessment (ed. Simon, R. I.) 207–223 (American Psychiatric Press, 2003).

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).

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).

Brunet, A. et al. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J. Psychiatr. Res. 42, 503–506 (2008).

Brunet, A. et al. Trauma reactivation under the influence of propranolol decreases posttraumatic stress symptoms and disorder: 3 open-label trials. J. Clin. Psychopharmacol. 31, 547–550 (2011).

Schiller, D. et al. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463, 49–53 (2010).

Milad, M. R. et al. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol. Psychiatry 62, 446–454 (2007).

Milad, M. R. et al. A role for the human dorsal anterior cingulate cortex in fear expression. Biol. Psychiatry 62, 1191–1194 (2007).

Goldstein, L. E., Rasmusson, A. M., Bunney, B. S. & Roth, R. H. Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat. J. Neurosci. 16, 4787–4798 (1996).

Arnsten, A. F. Stress signalling pathways that impair prefrontal cortex structure and function. Nature Rev. Neurosci. 10, 410–422 (2009).

Rosenkranz, J. A. & Grace, A. A. Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo. J. Neurosci. 22, 324–337 (2002).

Chhatwal, J. P., Myers, K. M., Ressler, K. J. & Davis, M. Regulation of gephyrin and GABAA receptor binding within the amygdala after fear acquisition and extinction. J. Neurosci. 25, 502–506 (2005).

Heldt, S. A. & Ressler, K. J. Training-induced changes in the expression of GABAA-associated genes in the amygdala after the acquisition and extinction of Pavlovian fear. Eur. J. Neurosci. 26, 3631–3644 (2007).

Rosenkranz, J. A. & Grace, A. A. Dopamine attenuates prefrontal cortical suppression of sensory inputs to the basolateral amygdala of rats. J. Neurosci. 21, 4090–4103 (2001).

Braga, M. F., Aroniadou-Anderjaska, V., Manion, S. T., Hough, C. J. & Li, H. Stress impairs α1A adrenoceptor-mediated noradrenergic facilitation of GABAergic transmission in the basolateral amygdala. Neuropsychopharmacology 29, 45–58 (2004).

Buffalari, D. M. & Grace, A. A. Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of α-2 and β receptor activation. J. Neurosci. 27, 12358–12366 (2007).