Biology of Risk of PTSD in Holocaust Survivor Offspring

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DESCRIPTION (provided by applicant): This application is based on preliminary, but compelling data, implicating parental PTSD as a putative risk factor for PTSD among offspring of Holocaust survivors. The data, fully described in this application, lead us to examine biologic correlates of risk for PTSD. To determine whether and to what extent biological alterations observed in PTSD are related to the risk factor of parental PTSD, we will compare clinical data and biological data in individuals with the risk factor of parental PTSD to those without this risk factor. We also seek to differentiate between biologic variables associated with risk for PTSD and those associated with the pathophysiology of this disorder. This will be accomplished by comparing individuals with the risk factor for PTSD (but have not developed PTSD) with those that have developed PTSD. Further, we propose to study whether individuals with trauma-exposed parents who never developed PTSD are similar to persons whose parents were not exposed to extreme trauma (i.e., the Holocaust). This will allow a determination of whether parental exposure, separate from parental PTSD, might also be a risk factor associated with biologic sequelae. Finally, we wish to study whether biologic alterations are different in persons with and without depressive disorders that principally involve the same neuroendocrine systems as PTSD, under any of the specific conditions of having or not having parental PTSD, one's own PTSD, or parental exposure to trauma. Two neuroendocrine stimulation tests, developed in our laboratory, will be performed in each study subject. The low-dose dexamethasone suppression test (DST) will be used to evaluate negative feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis. The metyrapone stimulation test (MST) will be used to assess suprapituitary activation (e.g., CRF release) via examination of the ACTH and 11-deoxycortisol response to metyrapone administration. In each test, we will characterize lymphocytic glucocorticoid receptor (GR) number under basal conditions, and in response to dexamethasone (DEX) and metyrapone administration, respectively, as a way of obtaining indices of GR sensitivity (or reactivity). We will also perform chronobiologic studies to characterize the circadian rhythm of cortisol, adrenocorticotropin (ACTH) and norepinephrine (NE). To accomplish these aims, we will examine data from 240 subjects over five years: 80 offspring with the risk factor of parental PTSD, 80 offspring without parental PTSD, and 80 demographically comparable subjects (whose parents were not in Europe after 1935). The subjects will be further subdivided so that there are 40 in each group with and without PTSD; half of each subgroup will have a current depressive disorder. Thus, we will recruit a total of 20 subjects in each of 12 subgroups.