Neuroendocrine studies examining hypothalamic-pituitary adrenal (HPA) activity under both baseline conditions and in response to neuroendocrine challenges have suggested a dysregulation of this axis in war veterans with chronic post-traumatic stress disorder (PTSD). To date, there is much debate regarding whether these alterations suggest a specific pathophysiology of PTSD, or rather, reflect a comorbid major depressive disorder (MDD). Our previous work has shown that HPA axis abnormalities are present in PTSD, and that these abnormalities appear to be distinct from those observed in MDD. For example, in two separate studies from our laboratory, a lower mean 24-hour urinary cortisol excretion was observed in combat veterans with PTSD compared to patients with MDD and normal males. Two studies are proposed to further characterize HPA axis abnormalities in PTSD. The first study will examine basal circadian secretion of cortisol and corresponding changes in lymphocyte glucocorticoid receptors (GR) in combat veterans with PTSD compared to patients with MDD and both combat and nonveteran nonpsychiatric, healthy males. Based on our pilot data, it is hypothesized that combat veterans with PTSD will show an increased number of lymphocyte GR compared to all other groups, which is consistent with low ambient levels of circulating glucocorticoids. In the second study, the possibility of an enhanced negative feedback sensitivity of the HPA axis in PTSD will then be investigated using a low-dose dexamethasone (DEX) challenge paradigm. For this study, cortisol and corresponding changes in lymphocyte CR in response to 0.50 mg and 0.25 mg of DEX will be measured. Based on pilot data, it is hypothesized that patients with PTSD will show an enhanced suppression of cortisol to both doses of DEX compared to both patients with MDD and nonpsychiatric controls. Furthermore, a significant relationship between lymphocyte GR number and the cortisol response to DEX is hypothesized (i.e., patients with high GR numbers will show low cortisol secretion following low dose DEX).
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