Post-Traumatic+Stress+Disorder

//By Amrita Sharma as part of the Anxiety Disorders//



** P ** **osttraumatic 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. Also alteration of PACAP – PAC1 pathway is involved in abnormal stress responses in PTSD. An increased level of CRH, a higher number of glucocorticoid receptors and an increased sensitivity of HPA axis are also underlying factors of this disorder. 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. Several animal models are used to find the best treatments for PTSD, which include psychotherapeutic interventions and medications.

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=General Overview =

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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.  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.

Earliest studies done on war veterans also showed family history of psychopathology among PTSD patients. <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">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.

<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">FKBP5 SNPs
<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">[|FK506 binding protein 5 (FKBP5)], a co-chaperone regulator of glucocorticoid receptor, <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">was seen to have reduced expression in PTSD. <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;"> 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 <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;"> 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. <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;"> All of these four SNPs show similar linking pattern <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">, which proves the genetic involvement with environmental factors seen in childhood abuse leading to adult PTSD.

<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">Pituitary adenylate cyclase – activating polypeptide (PACAP) – PAC1 pathway
<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">[|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 <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">. Examination was done on heavily traumatized population by analyzing blood levels of PACAP, genetic variation and methylation of the PACAP, and PAC1 receptor genes <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">. 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.

=<span style="color: #0000ff; font-family: 'Times New Roman',Times,serif; font-size: 16pt;">Neuroendocrinology =

<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">Modulation of CRF concentrations
<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;"> <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">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 <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">. 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 <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">. 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 <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">. The mechanism of this includes α2 and α1 mediating CRF-induced increases in startle reactivity and thus NE transmission if required <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">.

==<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">Increased sensitivity in [|glucocorticoid receptors] predicting abnormality in [|HPA axis] == <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">There are evidences of higher glucocorticoid sensitivity of HPA axis and altered regulation of glucocorticoid immune regulation in PTSD patients <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">. 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 <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">. <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">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 <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">.

=<span style="color: #0000ff; font-family: 'Times New Roman',Times,serif; font-size: 16pt;">Areas in the brain =



<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> [|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) <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 12pt;">.

<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">Amygdala
media type="youtube" key="6GdALwuYtG8" height="251" width="336" align="right"<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">Amygdala activation increases as emotional intensity increases in traumatic situation <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">. 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 <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">. The result also suggests that selectivity of emotional response in amygdala is dysfunctional in PTSD patients. 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.



<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">Hippocampus
<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;"> 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 <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">. 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 <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 12pt;">.

=<span style="color: #0000ff; font-family: 'Times New Roman',Times,serif; font-size: 16pt;">Animal models =

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<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;"> 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.



<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> 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.

=<span style="color: #0000ff; font-family: 'Times New Roman',Times,serif; font-size: 16pt;">Treatments =

<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">Psychotherapeutic interventions
<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">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 <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">.

<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 16px;">Medications
<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 12pt;">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 [|reboxetine]showed reverse effects <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 12pt;">. Other medications, according to [|NIMH], include [|benzodiazepine] to help patients relax and sleep, and [|antipsychotics], for people with other mental disorders.

=<span style="color: #0000ff; font-family: 'Times New Roman',Times,serif; font-size: 16pt;">External links =

<span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 12pt;">[|National Institute of Mental Health] <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> [|National Center for PTSD] <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> [|Helpguide.org] <span style="color: #000000; font-family: 'Times New Roman',Times,serif; font-size: 12pt;"> [|Wikipedia: The free encyclopedia]