Post-Traumatic Stress Disorder Clinical Trial
Official title:
Glucocorticoid and Mineralocorticoid Receptor Function in Post Traumatic Stress Disorder
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).
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.
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N/A
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