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Brain Receptor Function in Post-Traumatic Stress Disorder

2014-07-23 21:52:38 | BioPortfolio

Summary

The purpose of this study is to examine the function of cortisol receptors in post-traumatic stress disorder (PTSD).

Patients with PTSD have neurobiological dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis function. High corticotrophin releasing hormone (CRH) levels and decreased hippocampal volume are major features of the disorder. The mechanisms responsible for these alterations are not known. This study will evaluate the function of cortisol receptors to determine their roles in maintaining PTSD HPA axis dysregulation. Three groups of subjects will take part in the study: Patients with PTSD, healthy control subjects who were exposed to trauma in the past and remained healthy and healthy control subjects who were never traumatized

At study entry, the cerebral spinal fluid (CSF) of all participants will be sampled and evaluated. Participants will also undergo a magnetic resonance imaging (MRI) scan of the brain as well as eye blink trace conditioning and neuropsychological tests.

Participants will be admitted to the Clinical Center for two nights on three different occasions. At each overnight visits, blood levels of stress hormones will be measured every hour for 26 hours after medication or placebo are given. This will be the end of the study for both groups of healthy control subjects, with the exception that they may be asked to repeat neuropsychologic and eye blink tests after 12 weeks.

Participants with PTSD will receive paroxetine for 10 weeks. After 10 weeks these participants will be reevaluated in exactly the same way as before treatment (except they will not repeat the MRI scan).

Description

We propose to investigate the underlying mechanisms that account for neurobiological dysregulation of HPA axis function in PTSD. Paradoxically, low or normal plasma and urinary cortisol despite high corticotrophin releasing hormone (CRH) levels are a major feature of this disorder. Some investigators report decreased hippocampal volume in patients with PTSD. The mechanisms responsible for these alterations are not known. One possibility is that patients with PTSD have an increased number of glucocorticoid receptors (GR) and/or increased GR sensitivity, causing hyper-suppression of HPA axis. Another possibility is that high CRH levels lead to increased mineralocorticoid receptor (MR) levels and this up-regulation of MR is responsible for the low cortisol secretion seen in PTSD. Elevated CRH levels could also result in reduced hippocampal volume.

In order to evaluate MR and GR function, we will examine the effect of RU486 (Mifepristone; a GR antagonist), spironolactone (Aldactone; an MR antagonist), and placebo, on cortisol and ACTH plasma levels in patients with PTSD, trauma exposed, and non-trauma exposed healthy controls. The extent of increase in cortisol and/or ACTH after administration of antagonists will reflect the inhibition ordinarily imposed by GR and MR. We will also examine subjects' cerebral spinal fluid (CSF), CRH levels, and hippocampal volume. Following this evaluation, patients with PTSD will be treated with paroxetine for 8 weeks. The assessments performed before treatment will then be repeated.

The first aim of the present study is to elucidate the pathophysiology of PTSD through the examination of the roles of GR and MR in maintaining PTSD HPA axis dysregulation. The second aim is to compare CSF CRH levels across groups in an effort to extend previous findings and determine whether CRH levels in PTSD are higher than levels in trauma exposed healthy subjects. The present investigation will also evaluate the relationship between CRH levels in PTSD, MR/GR function, hippocampal volume and hippocampally-mediated cognitive tasks. Finally, we will examine the effects of long-term paroxetine treatment in PTSD on HPA axis function, hippocampal volume, and hippocampally-mediated cognitive tasks.

Study Design

N/A

Conditions

Post-Traumatic Stress Disorder

Intervention

RU-486 (Mifepristone)

Location

National Institute of Mental Health (NIMH)
Bethesda
Maryland
United States
20892

Status

Completed

Source

National Institutes of Health Clinical Center (CC)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-07-23T21:52:38-0400

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A class of traumatic stress disorders that is characterized by the significant dissociative states seen immediately after overwhelming trauma. By definition it cannot last longer than 1 month, if it persists, a diagnosis of post-traumatic stress disorder (STRESS DISORDERS, POST-TRAUMATIC) is more appropriate.

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Anxiety disorders manifested by the development of characteristic symptoms following a psychologically traumatic event that is outside the normal range of usual human experience. Symptoms include re-experiencing the traumatic event, increased arousal, and numbing of responsiveness to or reduced involvement with the external world. Traumatic stress disorders can be further classified by the time of onset and the duration of these symptoms.

Syndromes which feature DYSKINESIAS as a cardinal manifestation of the disease process. Included in this category are degenerative, hereditary, post-infectious, medication-induced, post-inflammatory, and post-traumatic conditions.

A benzyl-indazole having analgesic, antipyretic, and anti-inflammatory effects. It is used to reduce post-surgical and post-traumatic pain and edema and to promote healing. It is also used topically in treatment of RHEUMATIC DISEASES and INFLAMMATION of the mouth and throat.

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