By Amrita Sharma as part of the Anxiety Disorders

Picnik_collage.jpg


Posttraumatic stress disorder develops after an exposure to any kind of traumatic event. The genetic basis of PTSD involves several single-nucleotide polymorphisms in fujimycin binding protein 5 interacting with childhood trauma predicting severity of adult PTSD[1] . Also alteration of PACAP – PAC1 pathway is involved in abnormal stress responses in PTSD[2] . An increased level of CRH[3] , a higher number of glucocorticoid receptors and an increased sensitivity of HPA axis are also underlying factors of this disorder[4] . Moreover, at the peak of emotional intensity, when amygdala activity is the highest, encoding in the hippocampus is suppressed and this is consistent with the peri-traumatic amnesia and dissociation observed in PTSD[5] . Several animal models are used to find the best treatments for PTSD, which include psychotherapeutic interventions and medications.














General Overview







Symptoms

According to the Diagnostic and Statistical Manual of Mental Disorders (DSM - IV) and helpguide.org, the symptoms are sub-divided into three categories as followings:
  1. Re-experiencing the traumatic event, which includes intrusive memories, flashbacks, nightmares and intense distress.
  2. Avoidance and numbing include avoiding of activities, places, thoughts and feelings that remind individual of the trauma, unable to remember important aspects of the traumatic event, loss of interest and hopelessness towards future.
  3. Increased anxiety and emotional arousal include difficulty sleeping, anger management problems, difficulty concentrating and easily startled.

Prevalence

In United States, the prevalence rate is approximately 8% to 9% and women are affected in a greater amount.
[6] According to National Center for PTSD, in other countries, the estimated of PTSD prevalence ranges from 0.3% in China to 6.1% in New Zealand. Among Vietnam veterans 30.9% men and 26.9% women are considered to have a lifetime prevalence of PTSD. Also 12.1% of Gulf War veteran and 13.8% of Operation Iraqi freedom are victims of this prevalence rates.

Genetics


Hereditary information

There is evidence that PTSD is related to genetic predispositions. For adult offsprings of Holocaust survivors, parental PTSD was found to be a risk factor.[7]

16317095752983343916.jpg
Figure 1. Parental Holocaust exposure and parental PTSD in relation to PTSD, depressive and anxiety disorders in offspring. Source: Yehuda et al., 2001
Earliest studies done on war veterans also showed family history of psychopathology among PTSD patients.[8] Twin studies also provide evidence of genetic component to PTSD vulnerability. In a study on male and female twin pairs of nonveteran volunteers, PTSD symptoms in combat veterans and noncombat trauma were seen to be heritable with the influence of same genes towards susceptibility of PTSD.[9]


FKBP5 SNPs

Protein_FKBP5_PDB_1kt0.png
Figure 2. Protein FKBP5. Source: Wikimedia Commons
FK506 binding protein 5 (FKBP5), a co-chaperone regulator of glucocorticoid receptor,
[10] was seen to have reduced expression in PTSD.[11] Four particular single nucleotide polymorphisms (SNPs) of the FKBP5 gene were involved in the severity of child abuse in a cross-sectional study on childhood abuse and were thought to be a predictor of adult PTSD symptoms[12] These four SNPs are identified as rs3800373, rs9296158, rs1360780, and rs9470080 from a study done on European Americans and American Americans who were originally screened for lifetime PTSD.[13] All of these four SNPs show similar linking pattern[14] , which proves the genetic involvement with environmental factors seen in childhood abuse leading to adult PTSD.

Pituitary adenylate cyclase – activating polypeptide (PACAP) – PAC1 pathway

PACAP is known to be a regulator of cellular stress response and PACAP – PAC1 receptor has been found to be involved in abnormal stress response underlying PTSD[15] . Examination was done on heavily traumatized population by analyzing blood levels of PACAP, genetic variation and methylation of the PACAP, and PAC1 receptor genes[16] . The study also showed a sex-specific result, where women seemed to be more vulnerable. However, work needs to be done on investigating the neuronal mechanism of this potential biomarker associating the pathological response to stress.

Neuroendocrinology


Modulation of CRF concentrations

CRF.jpeg
Figure 3. CRF inducing depression. Source: Nemeroff, 2008

There is an evidence of changes in corticotropin-releasing factor (CRF) concentrations underlying PTSD and the studies were mostly done on animal models. CRF and CRF1 receptor are believed to play an important role in stress[17] . Blocking CRF1 receptor by an antagonist and using a predator stress model of PTSD, it was found that CRF1 activation leads to anxiety-like behaviour[18] . A bi-directional model of CRF-NE (norepinephrine) modulation of stress responses was also suggested for induction of stress related startle reactivity in animal models, and CRF and NE levels are seen to be distorted in post-traumatic stress leading to amplified frighten[19] . The mechanism of this includes α2 and α1 mediating CRF-induced increases in startle reactivity and thus NE transmission if required[20] .

Increased sensitivity in glucocorticoid receptors predicting abnormality in HPA axis

There are evidences of higher glucocorticoid sensitivity of HPA axis and altered regulation of glucocorticoid immune regulation in PTSD patients[21] . In a study peripheral blood mononuclear cells (PBMCs) were obtained to examine the number of glucocorticoid receptors (GRs) before exposure of trauma as an onset of PTSD symptoms and found out that high GR number in PBMCs is a vulnerable factor for development of PTSD[22] .
GCR_allel_pic.jpg
Figure 4. Number of traumatic memories from intensive care unit treatment in relationship with BclI *G polymorphism of GR gene when homozygotes were compared to noncarriers of the G allele. Source: Hauer et al., 2011
Since, in both animal and human studies, it was seen that glucocorticoid is an important factor for memory consolidation and retrieval of traumatic information, in another study ICU patients were examined to association of BcA SNP with hypersensitivity of glucocorticoids, and the result showed that homozygous allele carriers were at a higher risk for developing post-traumatic stress disorder symptoms[23] .

Areas in the brain


brain.ptsd.illustration.jpg
Figure 5. PTSD and the brain - summarizing the main results from neuroimaging studies by Dr. Dave J. Hayes (Mind, Brain Imaging and Neuroethics, Institute of Mental Health Research, University of Ottawa)


Amygdala and hippocampus are the most important brain areas that show abnormalities in PTSD. However, there is evidence of abnormality in components of default mode network (DMN) alterations in PTSD, which include posterior cingulate cortex (PCC), anterior cingulate cortex (ACC), inferior parietal cortex and medial prefrontal cortex(mPFC)
[24] .

Amygdala

Amygdala activation increases as emotional intensity increases in traumatic situation
[25] . An fMRI study was done using neutral and negative pictures on control group and PTSD patients, and the result seemed to have no difference in Amygdala activation in neutral and negative pictures viewing underlying the severity of emotional intensity in PTSD patients[26] . The result also suggests that selectivity of emotional response in amygdala is dysfunctional in PTSD patients[27] . Cell death of is also prevalent in PTSD patients resulting in a smaller amygdala. Single-prolonged stress (SPS) rats were examined to detect apoptosis related gene expressions and cell death in amygdala regions, which are related to abnormal function of amygdala in PTSD consistent with the fMRI study in human[28] .

Amyg-death.png
Figure 6. TEM images of the amygdala region. A: Normal control amygdala neuron, it had abundance of the organelle of mitochondrion, endoplasmic reticulum, ribosome and so on. The nucleus is large and round, density of chromatin is uniform, and nucleolus is clear. B: Chromatin margination, the figure showed crescent formation in nucleus. C: Chromatin dissolved, nuclear envelope subsidence, the cells showed some typical structural changes of apoptosis. Source: Ding et al., 2010

Hippocampus

Screen_shot_2012-04-01_at_9.45.37_PM.png
Figure 7. MRI showing regional gray matter reduction in hippocampus in PTSD survivors. Source: Zhang et al., 2011

Hippocampus is responsible for memory formation and consolidation, while in PTSD this memory is highly related to negative experience from traumatic event. In an fMRI study of hippocampus, PTSD patients were seen to be highly responsive for negative words than the control group[29] . Hippocampal volume reduction might be a cause of this abnormal function of memory consolidation, which was examined on coal mine flood disaster survivors. Survivors with PTSD were seen to have decreased gray matter volume and density in hippocampus than survivors without PTSD by MRI[30] .

Animal models
















Although animal models are necessary to understand various conditions reflected in humans, they might not be enough to understand every mechanism related to brain mechanism and circuitry which is well shown in Table 1 below.

2011.Neumann.Animal.models.depress.anx.examples.jpg
Table 1. Validity of the animal models. Source: Neumann et al., 2011


However, one of the excellent examples of a rat model was used to show the efficacy of propranolol in blocking β– adrenergic receptors which seem to be involved in creating aversive memories in stressful situations with the measurements taken from spatial memory task and conditioned stimulus[31] .

Treatments


Psychotherapeutic interventions

According to National Institute of Mental Health (NIMH), many types of psychotherapy can either target symptoms of PTSD directly, or focus on social problems surrounding patients. The treatment usually takes place in a combination of different therapies. Cognitive Behavioral Therapy (CBT) is proven to be the best therapy for patients with PTSD, which includes exposure therapy to help them controlling their fear, cognitive restructuring to make them try to understand the bad memories and avoid imaginations, and stress inoculation training helping patients to reduce anxiety. A meta-analysis study of psychotherapy has shown that patients gain large initial improvement from baseline, however, majority of them continue having residual symptoms even after the treatment, suggesting follow-up research[32] .

Medications

PTSD medications mainly involve antidepressants, such as sertraline, fluoxetine, citalopram and paroxetine according to NIMH. These medications are also used in depression suggesting that these help PTSD patients to cope up with anxiety, anger, sadness and heightened emotion. However, there are side effects to these medicines, which include, headache, nausea, sleeplessness, agitation and sexual problems. In a study with depressed patients, placebo induction showed reduced recognition of facial expression and decreased response on positive experiences, however, antidepressant reboxetineshowed reverse effects[33] . Other medications, according to NIMH, include benzodiazepine to help patients relax and sleep, and antipsychotics, for people with other mental disorders.

External links


National Institute of Mental Health
National Center for PTSD
Helpguide.org
Wikipedia: The free encyclopedia



  1. ^
    Schinozaki, G., Jowsey, S., Amer, H., Biernacka, J., Colby, C., Walker, D., Black, J., Rundell, J., Stegall, M., & Mrazek, D. Relationship between FKBP5 polymorphisms and depression symptoms among kidney transplant recipients. Depression and Anxiety, 28, 1111 – 1118 (2011).
  2. ^ Ressler, K., Mercer, K., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., Norrholm, S., Kilaru, V., Smith, A., Myers, A., Ramirez, M., Engles, A., Hammack, S., Toufexis, D., Braas, K., Binder, E., & May, V. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature, 470, 492 – 497 (2011).
  3. ^ Kloet, C.S., Vermetten, E., Geuze, E., Lentjess, E.G.W.M., Heijnen, C.J., Stalla, G.K., & Westenberg, H.G.M. Elevated plasma corticotrophin – releasing hormone levels in veterans with posttraumatic stress disorder. Progress in Brain Research, 167, 287 – 291 (2008).
  4. ^ Yehuda, R., Boisoneau, D., Lowy, M., & Giller, E. 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 (7), 583 – 593 (1995).
  5. ^ Layton, B., & Krikorian, R. Memory mechanisms in posttraumatic stress disorder. The Journal of Neuropsychiatry and Clinical Neurosciences, 14, 254–261 (2002).
  6. ^
    Grinage, B.D. Diagnosis and management of Post-traumatic Stress Disorder. American Academy of Family Physicians, 68 (12), 2401 – 2409 (2002).
  7. ^
    Yehuda, R., Halligan, S.L., & Bierer L.M. Relationship of parental trauma exposure and PTSD to PTSD, depressive ans anxiety disorders in offspring. Journal of Psychiatric Research, 35, 261 – 270 (2001).
  8. ^
    Yehuda, R., Halligan, S.L., & Bierer L.M. Relationship of parental trauma exposure and PTSD to PTSD, depressive ans anxiety disorders in offspring. Journal of Psychiatric Research, 35, 261 – 270 (2001).
  9. ^
    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).
  10. ^
    Mehta, D., Gonik, M., Klengel, T., Rex-Haffner, M., Menke, A., Rubel, J., Mercer, K.B., Putz, B., Bradley, B., Holsboer, F., Ressler, K.J., Muller-Myshok, B., & Binder, E.B. Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: Evidence from endocrine and gene expression studies. Arch Gen Psychiatry, 68 (9), 901 – 910 (2011).
  11. ^
    Yehuda, R., Cai, G., Golier, J.A., Sarapas, C., Galea, S., Ising, M., Rein, T., Schmeidler, J., Muller-Myshok, B., Holsboer, F., & Buxbaum, J. Gene expression aptterns associated with posttraumatic stress disorder following exposure to the world trade center attacks. Biol Psychiatry, 66, 708 – 711 (2009).
  12. ^
    Binder, E.B., Bardley, R.G., Liu, W., Epstein, M.P., Deveau, T.C., Mercer, K.B., Tang, Y., Gillespie, C.F., Heim, C.M., Nemeroff, C.B., Schwartz, A.C., Cubells, J.F., & Ressler, K.J. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA, 299 (11), 1291 – 1305 (2008).
  13. ^
    Xie, P., Kranzler, H.R., Poling, J., Stein, M.B., Anton, R.F., Farrer, L.A., & Gelernter, J. Interaction of FKBP5 with childhood adversity on risk for post-traumatic disorder. Neuropsychopharmacology, 35, 1684 – 1692 (2010).
  14. ^
    Schinozaki, G., Jowsey, S., Amer, H., Biernacka, J., Colby, C., Walker, D., Black, J., Rundell, J., Stegall, M., & Mrazek, D. Relationship between FKBP5 polymorphisms and depression symptoms among kidney transplant recipients. Depression and Anxiety. 28, 1111 – 1118 (2011).
  15. ^
    Ressler, K.J., Mercer, K.B., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., Norrholm, S.D., Kilaru, V., Smith, A.K., Myers, A.J., Ramirez, M., Engel, A., Hammack, S.E., Toufexis, D., Braas, K.M., Binder, E.B., & May, V. Post-traumatic stress disorder is associated with PACAp and the PAC1 receptor. Nature, 470, 492 – 497.
  16. ^
    Ressler, K.J., Mercer, K.B., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., Norrholm, S.D., Kilaru, V., Smith, A.K., Myers, A.J., Ramirez, M., Engel, A., Hammack, S.E., Toufexis, D., Braas, K.M., Binder, E.B., & May, V. Post-traumatic stress disorder is associated with PACAp and the PAC1 receptor. Nature, 470, 492 – 497.
  17. ^
    Adamee, R., Fougere, D., & Risbrough, V. CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predeator stress model of PTSD. Internal Journal of Neuropsychopharmacology, 13, 747 – 757 (2010).
  18. ^
    Adamee, R., Fougere, D., & Risbrough, V. CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predeator stress model of PTSD. Internal Journal of Neuropsychopharmacology, 13, 747 – 757 (2010).
  19. ^
    Gresack, J.E., & Risbrough, V.B. Corticotropin – releasing factor and noradrenergic signaling exert reciprocal control over startle reactivity. International Journal of Neuropsychopharmacology, 14, 1179 – 1194 (2011).
  20. ^
    Gresack, J.E., & Risbrough, V.B. Corticotropin – releasing factor and noradrenergic signaling exert reciprocal control over startle reactivity. International Journal of Neuropsychopharmacology, 14, 1179 – 1194 (2011).
  21. ^
    Zuiden, M., Geuze, E., Willemen, H., Vermetten, E., Maas, M., Heijnen, C.J., & Kavelaars, A. Pre-existing high gluccoticoid receptor number predicting development of posttraumatic stress symptoms after military deployment. American Journals of Psychiatry, 168, 89 – 96 (2011).
  22. ^
    Zuiden, M., Geuze, E., Willemen, H., Vermetten, E., Maas, M., Heijnen, C.J., & Kavelaars, A. Pre-existing high gluccoticoid receptor number predicting development of posttraumatic stress symptoms after military deployment. American Journals of Psychiatry, 168, 89 – 96 (2011).
  23. ^
    Hauer, D., Weis, F., Papassotiropoulos, A., Schmoeckel, M., Beiras-Fernandez, A., Leike, J., Kaufmann, I., Kirchhoff, F., Vogeser, M., Roozendaal, B., Briegel, J., Quervain, D., & Schelling, G. Relationship of a common polymorphism of the glucocorticoid receptor gene to traumatic memories and posttraumatic stress disorder in patients after intensive care therapy. Critical Care Medicine and Lippincott Williams & Wilkins, 39, 643 – 650 (2011).
  24. ^
    Daniels, J.K., Frewen, P., McKinnon, M.C., & Lanius, R.A. Default mode alteration in posttraumatic stress disorder related to early-life trauma: a development perspective. J Psychiatry Neurosci, 36(1), 56-59 (2011).
  25. ^
    Layton, B., & Krikorian, R. Memory mechanisms in posttraumatic stress disorder. The Journal of Neuropsychiatry and Clinical Neurosciences, 14, 254 – 261 (2002).
  26. ^
    Brunetti, M., Sepede, G., Mingola, G., Catani, C., Ferretti, A., Merla, A., Gratta, C.D., Romani, G.L., & Babiloni C. Elevated response of human amygdala to neutral stimuli in mild post traumatic stress disorder: Neural correlated of generalized emotional response. Neuroscience, 168, 670 – 679 (2010).
  27. ^
    Brunetti, M., Sepede, G., Mingola, G., Catani, C., Ferretti, A., Merla, A., Gratta, C.D., Romani, G.L., & Babiloni C. Elevated response of human amygdala to neutral stimuli in mild post traumatic stress disorder: Neural correlated of generalized emotional response. Neuroscience, 168, 670 – 679 (2010).
  28. ^
    Ding, J., Han, F., & Shi, Y. Single-prolonged stress induces apoptosis in the amygdala in a rat model of post-traumatic stress disorder. Journal of Psychiatric Research, 44, 48 – 55 (2010).
  29. ^
    Tomaes, K., Dorrespaal, E., Draijer, N., Ruiter, M.B., Elzinga, B.M., Sjoerds, Z., Balkom, A.J., Smit, J.H., & Veltman, D.J. Increased anteorior cingulate cortex and hippocampus activation in complex PTSD during encoding of negative words. SCAN (2011).
  30. ^
    Zhang, J., Tan, Q., Yin, H., Zhang, X., Huan, Y., Tang, L., Wang, H., Xu, J., & Li, L. Decreased gray matter volume in the left hippocampus and bilateral calcarine cortex in coal mine flood disaster survivors with recent onset PTSD. Psychiatric Research: Neuroimaine, 192, 84 – 90 (2011).
  31. ^
    Cohen, H., Kaplan, Z., Koresh, O., Matar, M.A., Geva, A., & Zohar, J. Early post-stressor intervention with propranolol is ineffective in preventing posttraumatic stress responses in an animal model for PTSD. European Neuropsychopharmacology, 21, 230 – 240 (2011).
  32. ^
    Bradley, R., Greene, J., Russ, E., Dutra, L., & Westen, D. A multidimensional meta-analysis of psychotherapy for PTSD. Am J Psychiatry, 162, 214 – 227 (2005).
  33. ^
    Harmer, C., O’Sullivan, U., Favaron, E., Massey-Chase, R., Ayres, R., Reinecke, A., Goodwin, G.M., & Cowen, P.J. Effect of acute antidepressant administration on negative bias in depressed patients. Am J Psychiatry, 166, 1178 – 1184 (2009).