Cited by 89Posttraumatic Stress Disorder ResearchStress Responses and CortisolPsychoanalysis and Psychopathology Research

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Recent Progress in Understanding the Pathophysiology of Post-Traumatic Stress Disorder: Implications for Targeted Pharmacological Treatment

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Bailey, Christopher R., Cordell, Elisabeth, Sobin, Sean M., Neumeister, Alexander·2013·CNS Drugs

DOI 10.1007/s40263-013-0051-4PMC PMC3629370

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Abstract

Post-traumatic stress disorder (PTSD) is a common and chronic anxiety disorder that can result after exposure to a traumatic event. Though our understanding of the aetiology of PTSD is incomplete, several neurobiological systems have been implicated in the pathophysiology and vulnerability towards developing PTSD after trauma exposure. We aimed to provide a concise review of benchmark findings in important neurobiological systems related to the aetiology and maintenance of PTSD symptomology. Specifically, we discuss functional aetiologies in the noradrenergic, serotonergic, endogenous cannabinoid and opioid systems as well as the hypothalamic-pituitary adrenal (HPA) axis. This article provides a succinct framework to appreciate the current understanding of neurobiological mechanisms related to the pathophysiology of PTSD and how these findings may impact the development of future, targeted pharmacological treatments for this debilitating disorder.

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Xie, P., Kranzler, H. R., Poling, J., Stein, M. B., Anton, R. F., Brady, K., Weiss, R. D., Farrer, L., & Gelernter, J. (2009) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2009.153 · Cited by 264
A 6-Week Randomized, Placebo-Controlled Trial of CP-316,311 (a Selective CRH 1 Antagonist) in the Treatment of Major Depression
Binneman, B., Feltner, D., Kolluri, S., Shi, Y., Qiu, R., & Stiger, T. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2008.07071199 · Cited by 254 · cited 1×
“CRF-1 receptor antagonism is a treatment modality that has been explored for the treatment of MDD [166], while an initial open-label study suggested promising efficacy data, these results were not confirmed in follow-up placebo-controlled trials [167].”
Result
Emerging treatments for PTSD
Cukor, J., Spitalnick, J. S., Difede, J., Rizzo, A., & ROTHBAUM, B. O. (2009) · Clinical Psychology Review · doi:10.1016/j.cpr.2009.09.001 · Cited by 251
Pharmacotherapy to prevent PTSD: Results from a randomized controlled proof‐of‐concept trial in physically injured patients
Stein, M. B., Kerridge, C., Dimsdale, J. E., & Hoyt, D. B. (2007) · Journal of Traumatic Stress · doi:10.1002/jts.20270 · Cited by 249
Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment
Hill, M. N., Carrier, E. J., McLaughlin, R. J., Morrish, A. C., Meier, S. E., Hillard, C. J., & Gorzalka, B. B. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05567.x · Cited by 246
kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system.
Simonin, F., Gavériaux‐Ruff, C., Befort, K., Matthes, H. W. D., Lannes, B., Micheletti, G., Mattéi, M., Charron, G., Bloch, B., & Kieffer, B. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.15.7006 · Cited by 245
The role of serotonin receptor subtypes in treating depression: a review of animal studies
Carr, G. V., & Lucki, I. (2010) · Psychopharmacology · doi:10.1007/s00213-010-2097-z · Cited by 244
Differential effects of chronic unpredictable stress on hippocampal CB1 receptors in male and female rats
Reich, C. G., Taylor, M. E., & McCarthy, M. M. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.05.013 · Cited by 244
Randomized, Double-Blind Comparison of Sertraline and Placebo for Posttraumatic Stress Disorder in a Department of Veterans Affairs Setting
Friedman, M. J., Marmar, C. R., Baker, D. G., Sikes, C. R., & Farfel, G. M. (2007) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v68n0508 · Cited by 243
CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents
Haller, J., Varga, B., Ledent, C., & Freund, T. F. (2004) · Behavioural Pharmacology · doi:10.1097/01.fbp.0000135704.56422.40 · Cited by 241 · cited 1×
“cological disruption of CB1 receptor signalling, which is required for normal fear extinction [121–123], results in an anxious PTSD phenotype [126, 127], and brain CB1 receptor signalling controls extinction of aversive memo-”
Background
The Role of the Dorsal Hippocampal Serotonergic and Cholinergic Systems in the Modulation of Anxiety
File, S. E., Kenny, P. J., & Cheeta, S. (2000) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(00)00198-2 · Cited by 239
Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice
Rademacher, D. J., Meier, S. E., Shi, L., Vanessa Ho, W.-S., Jarrahian, A., & Hillard, C. J. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.06.012 · Cited by 233
Treatment of Posttraumatic Stress Disorder With Venlafaxine Extended Release
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Noradrenergic enhancement of reconsolidation in the amygdala impairs extinction of conditioned fear in rats-a possible mechanism for the persistence of traumatic memories in PTSD
Dębiec, J., Bush, D. E. A., & LeDoux, J. E. (2011) · Depression and Anxiety · doi:10.1002/da.20803 · Cited by 227
Anxiolytic-Like Effects of κ-Opioid Receptor Antagonists in Models of Unlearned and Learned Fear in Rats
Knoll, A. T., Meloni, E. G., Thomas, J. B., Carroll, F. I., & Carlezon, W. A. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.127415 · Cited by 227
Psychiatric Comorbidity of Full and Partial Posttraumatic Stress Disorder Among Older Adults in the United States: Results From Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions
Pietrzak, R. H., Goldstein, R. B., Southwick, S. M., & Grant, B. F. (2011) · American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e31820d92e7 · Cited by 217
Imaging of opioid receptors in the central nervous system
Henriksen, G., & Willoch, F. (2008) · Brain · doi:10.1093/brain/awm255 · Cited by 214
Regulation of endocannabinoid signaling by stress: Implications for stress-related affective disorders
Gorzalka, B. B., Hill, M. N., & Hillard, C. J. (2008) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.03.004 · Cited by 211
A Study of the Protective Function of Acute Morphine Administration on Subsequent Posttraumatic Stress Disorder
Bryant, R. A., Creamer, M. C., O'Donnell, M. L., Silove, D. M., & McFARLANE, A. C. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.10.032 · Cited by 210
CRF1-R Activation of the Dynorphin/Kappa Opioid System in the Mouse Basolateral Amygdala Mediates Anxiety-Like Behavior
Bruchas, M. R., Land, B. B., Lemos, J. C., & Chavkin, C. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008528 · Cited by 209
Serotonin type-1A receptor imaging in depression
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Early post-stressor intervention with propranolol is ineffective in preventing posttraumatic stress responses in an animal model for PTSD
Cohen, H., Kaplan, Z., Koresh, O., Matar, M. A., Geva, A. B., & Zohar, J. (2010) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2010.11.011 · Cited by 204
The combined effect of gender and age on post traumatic stress disorder: do men and women show differences in the lifespan distribution of the disorder?
Ditlevsen, D. N., & Elklit, A. (2010) · Annals of General Psychiatry · doi:10.1186/1744-859x-9-32 · Cited by 204
Physiology of the Hypothalamic-Pituitary-Adrenal Axis in Health and Dysregulation in Psychiatric and Autoimmune Disorders
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Gender differences in depression and PTSD symptoms following combat exposure
Luxton, D. D., Skopp, N. A., & Maguen, S. (2010) · Depression and Anxiety · doi:10.1002/da.20730 · Cited by 198
Pharmacological treatment of PTSD – Established and new approaches
Steckler, T., & Risbrough, V. B. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.06.012 · Cited by 188
Awakening the sleeping giant: anatomy and plasticity of the brain serotonergic system.
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Serotonin neurons, neuroplasticity, and homeostasis of neural tissue
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Localization of 5‐HT1A receptors to astroglial cells in adult rats: Implications for neuronal‐glial interactions and psychoactive drug mechanism of action
Whitaker‐Azmitia, P. M., Clarke, C., & Azmitia, E. C. (1993) · Synapse · doi:10.1002/syn.890140303 · Cited by 181
Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task
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Glutamate Receptors in Extinction and Extinction-Based Therapies for Psychiatric Illness
Myers, K. M., Carlezon, W. A., & Davis, M. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.88 · Cited by 177
Chronic Pain in Women Survivors of Intimate Partner Violence
Wuest, J., Merritt-Gray, M., Ford-Gilboe, M., Lent, B., Varcoe, C., & Campbell, J. C. (2008) · The Journal of Pain · doi:10.1016/j.jpain.2008.06.009 · Cited by 175
Effect of Acute Posttrauma Propranolol on PTSD Outcome and Physiological Responses During Script‐Driven Imagery
Hoge, E. A., Worthington, J. J., Nagurney, J. T., Chang, Y., Kay, E. B., Feterowski, C. M., Katzman, A. R., Goetz, J. M., Rosasco, M. L., Lasko, N. B., et al. (2012) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2010.00227.x · Cited by 174 · cited 1×
“Clinical evidence has shown a similar trend regarding propranolol as a PTSD prophylactic [44, 45] with several contrary findings [46, 47].”
Result
Medical Comorbidity of Full and Partial Posttraumatic Stress Disorder in US Adults
Pietrzak, R. H., Goldstein, R. B., Southwick, S. M., & Grant, B. F. (2011) · Psychosomatic Medicine · doi:10.1097/psy.0b013e3182303775 · Cited by 174
Noradrenergic Mechanisms in the Pathophysiology of Post-Traumatic Stress Disorder
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Gender differences in PTSD symptoms: An exploration of peritraumatic mechanisms
Irish, L. A., Fischer, B., Fallon, W. F., Spoonster, E., Sledjeski, E. M., & Delahanty, D. L. (2010) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2010.09.004 · Cited by 165
Modulation of the firing activity of noradrenergic neurones in the rat locus coeruleus by the 5‐hydroxtryptamine system
Haddjeri, N., De Montigny, C., & Blier, P. (1997) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0700968 · Cited by 164
Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropinreleasing hormone
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Venlafaxine Extended Release in Posttraumatic Stress Disorder: A Sertraline- and Placebo-controlled Study
Davidson, J., Rothbaum, B. O., Tucker, P., Asnis, G., Benattia, I., & Musgnung, J. J. (2006) · Journal of Clinical Psychopharmacology · doi:10.1097/01.jcp.0000222514.71390.c1 · Cited by 157
Full and partial PTSD among young adult survivors 10 months after the L'Aquila 2009 earthquake: Gender differences
Dell’Osso, L., Carmassi, C., Massimetti, G., Daneluzzo, E., Tommaso, S. D., & Rossi, A. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.11.023 · Cited by 155
Interactions between Kappa Opioid Agonists and Cocaine: Preclinical Studies
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Psychiatric implications of altered limbic-hypothalamic-pituitary-adrenocortical activity
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Early maternal deprivation induces gender‐dependent changes on the expression of hippocampal CB1 and CB2 cannabinoid receptors of neonatal rats
Suárez, J., Llorente, R., Romero‐Zerbo, S., Mateos, B., Bermúdez‐Silva, F. J., de Fonseca, F. R., & Viveros, M. (2008) · Hippocampus · doi:10.1002/hipo.20537 · Cited by 142
Stimulation of astroglial serotonin receptors produces culture media which regulates growth of serotonergic neurons
Whitaker‐Azmitia, P. M., & Azmitia, E. C. (1989) · Brain Research · doi:10.1016/0006-8993(89)90972-4 · Cited by 141
Limited efficacy of propranolol on the reconsolidation of fear memories
Muravieva, E. V., & Alberini, C. M. (2010) · Learning & Memory · doi:10.1101/lm.1794710 · Cited by 135
Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior
Krebs-Kraft, D. L., Hill, M. N., Hillard, C. J., & McCarthy, M. M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1005003107 · Cited by 130
Sex differences and the HPA axis: implications for psychiatric disease.
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Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in Wistar Kyoto Rats
Carr, G. V., Bangasser, D. A., Bethea, T. T., Young, M., Valentino, R. J., & Lucki, I. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2009.183 · Cited by 124
The Endocannabinoid System and Extinction Learning
Lutz, B. (2007) · Molecular Neurobiology · doi:10.1007/s12035-007-8004-x · Cited by 124
Noradrenergic vs Serotonergic Antidepressant with or without Naltrexone for Veterans with PTSD and Comorbid Alcohol Dependence
Petrakis, I. L., Ralevski, E., Desai, N., Trevisan, L. A., Gueorguieva, R. V., Rounsaville, B. J., & Krystal, J. H. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.283 · Cited by 122
The VA/DOD Clinical Practice Guideline for Management of Post-Traumatic Stress (update 2010): development and methodology.
Susskind, O., Ruzek, J., & Friedman, M. (2012) · Journal of rehabilitation research and development · doi:10.1682/jrrd.2011.12.0241 · Cited by 119
μ-, δ- and κ-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer’s disease patients
Mathieu-Kia, A.-M., Fan, L.-Q., Kreek, M. J., Simon, E. J., & Hiller, J. M. (2001) · Brain Research · doi:10.1016/s0006-8993(00)03302-3 · Cited by 118
Interpersonal friction and PTSD in female victims of sexual and nonsexual assault
Zoellner, L. A., Foa, E. B., & Brigidi, B. D. (1999) · Journal of Traumatic Stress · doi:10.1023/a:1024777303848 · Cited by 117
Corticotropin-Releasing Factor in the Basolateral Amygdala Enhances Memory Consolidation via an Interaction with the -Adrenoceptor-cAMP Pathway: Dependence on Glucocorticoid Receptor Activation
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The Effect of Early Trauma Exposure on Serotonin Type 1B Receptor Expression Revealed by Reduced Selective Radioligand Binding
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Gender differences in probable posttraumatic stress disorder among police responders to the 2001 World Trade Center terrorist attack
Bowler, R. M., Han, H., Gocheva, V. V., Nakagawa, S., Alper, H., DiGrande, L., & Cone, J. E. (2010) · American Journal of Industrial Medicine · doi:10.1002/ajim.20876 · Cited by 112
Noradrenergic enhancement of amygdala responses to fear
Onur, O. A., Walter, H., Schlaepfer, T. E., Rehme, A. K., Schmidt, C., Keysers, C., Maier, W., & Hurlemann, R. (2009) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsn049 · Cited by 111
The Neuropharmacology of Serotonin
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Chronic Stress Increases the Plasmalemmal Distribution of the Norepinephrine Transporter and the Coexpression of Tyrosine Hydroxylase in Norepinephrine Axons in the Prefrontal Cortex
Miner, L. H., Jedema, H. P., Moore, F. W., Blakely, R. D., Grace, A. A., & Sesack, S. R. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4450-05.2006 · Cited by 107
Pharmacology and Distribution of Norepinephrine Transporters in the Human Locus Coeruleus and Raphe Nuclei
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Impulsivity and alcohol use coping motives in a trauma-exposed sample: the mediating role of distress tolerance
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Guideline Watch (March 2009): Practice Guideline for the Treatment of Patients with Acute Stress Disorder and Posttraumatic Stress Disorder
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The 5-HT1B Receptor: A Novel Target for the Pathophysiology of Depression (Supplementary Tables)
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Sex-dependent alterations in response to maternal deprivation in rats
Viveros, M., Llorente, R., López‐Gallardo, M., Suárez, J., Bermúdez‐Silva, F. J., la Fuente, M. D., de Fonseca, F. R., & García‐Segura, L. M. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.05.015 · Cited by 99
Preliminary Evidence for the Effects of Morphine on Posttraumatic Stress Disorder Symptoms in One- to Four-Year-Olds With Burns
Stoddard, F. J., Sorrentino, E. A., Ceranoglu, T. A., Saxe, G., Murphy, J. M., Drake, J. E., Ronfeldt, H. M., White, G. W., Kagan, J., Snidman, N. C., et al. (2009) · Journal of Burn Care & Research · doi:10.1097/bcr.0b013e3181b48102 · Cited by 98
Atomoxetine and Adult Attention-Deficit/Hyperactivity Disorder: The Effects of Comorbidity
Spencer, T. J., Faraone, S. V., Michelson, D., Adler, L. A., Reimherr, F. W., Glatt, S. J., & Biederman, J. (2006) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v67n0312 · Cited by 94 · cited 1×
“Early clinical evidence suggests that atomoxetine, which has a high affinity for the NET, increases inhibitory response control [62] and reduces attention-deficit hyperactivity disorder (ADHD) symptoms with co-morbid anxiety [63] and PTSD [64] diagnoses.”
Background
Treatment of PTSD: An Assessment of the Evidence
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Activation of basolateral amygdala corticotropin-releasing factor 1 receptors modulates the consolidation of contextual fear
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Yohimbine — facilitated acoustic startle reflex in humans
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A High Risk Twin Study of Combat-Related PTSD Comorbidity
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Ultrastructural interactions between terminals expressing the norepinephrine transporter and dopamine neurons in the rat and monkey ventral tegmental area
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Pharmacologic treatment of acute and chronic stress following trauma: 2006.
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Gender Differences in the Clinical Presentation of PTSD and Its Concomitants in Survivors of Interpersonal Assault
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Effects of Early-Life Stress on Serotonin1A Receptors in Juvenile Rhesus Monkeys Measured by Positron Emission Tomography
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Laminar distribution of the multiple opioid receptors in the human cerebral cortex
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Identification, course, and treatment of depression after admission for a cardiac condition: rationale and patient characteristics for the identifying depression as a comorbid condition (IDACC) project
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Extending pharmacological spectrum of opioids beyond analgesia: Multifunctional aspects in different pathophysiological states
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Serotonin 1B Receptor Imaging in Alcohol Dependence
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Self-citation
CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predator stress model of PTSD
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Predictors of posttraumatic stress in children following injury: The influence of appraisals, heart rate, and morphine use
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Serotonin 1B Autoreceptors Originating in the Caudal Dorsal Raphe Nucleus Reduce Expression of Fear and Depression-Like Behavior
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The Role of the Glutamatergic System in Posttraumatic Stress Disorder
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Hurt people who hurt people: Violence amongst individuals with comorbid substance use disorder and post traumatic stress disorder
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Dynorphin and the kappa 1 ligand [3H]U69,593 binding in the human epileptogenic hippocampus
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Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline in Tourette's syndrome: A pilot study
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Prevalence and features of panic disorder and comparison to posttraumatic stress disorder in VA primary care
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5-HT1B Receptor-Mediated Presynaptic Inhibition of GABA Release in the Suprachiasmatic Nucleus
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Altered adrenergic receptor signaling following traumatic brain injury contributes to working memory dysfunction
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5‐HT1A Receptors and 5‐HT1A‐Mediated Responses: Effect of Treatments That Modify Serotonergic Neurotransmission
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Gender Differences in Traumatic Event Exposure and Mental Health Among Veteran Primary Care Patients
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Authors: Bailey, C. R., Cordell, E., Sobin, S. M., & Neumeister, A.
Affiliations: Johns Hopkins University (US)
NYU Langone Health (US)
Corresponding author: Neumeister, Alexander
ORCID: Bailey, Christopher R.
Venue: CNS Drugs
Publisher: Springer Science and Business Media LLC
Published: 2013-03
Volume: 27
Issue: 3
Pages: 221-232
ISSN: 1172-7047 (ISSN-L)
1179-1934
DOI: 10.1007/s40263-013-0051-4
PMC: PMC3629370
OpenAlex: W2085725087
Cited by: 89
References: 203
Citations by year: 2026: 2 · 2025: 5 · 2024: 4 · 2023: 8 · 2022: 4 · 2021: 10 · 2020: 9 · 2019: 9 · 2018: 7 · 2017: 7 · 2016: 8 · 2015: 7 · 2014: 7 · 2013: 2
FWCI: 1.17
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
Locations: CNS Drugs (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute of Mental Health (R21MH085627, R01MH096876, R21MH081103, R21MH096105)
Topics: Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Social Sciences › Psychology › Clinical Psychology › Psychoanalysis and Psychopathology Research
Keywords: post-traumatic stress disorder, pathophysiology, noradrenergic system, serotonergic system, endocannabinoid system, opioid system, hypothalamic-pituitary-adrenal axis, trauma exposure
MeSH terms: Animals, Female, Humans, Hypothalamo-Hypophyseal System, Male, Pituitary-Adrenal System, Stress Disorders, Post-Traumatic, Drug Design, Molecular Targeted Therapy

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Recent Progress in Understanding the Pathophysiology of Post-Traumatic Stress Disorder: Implications for Targeted Pharmacological Treatment

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