Rachel Yehuda, Ph.D. - US grants

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).

DESCRIPTION (Adapted from the Applicant's Abstract) PTSD, as defined by DSM-III-R, is an anxiety disorder involving both somatic and psychological symptoms which occur in response to severe trauma, including combat, natural and man-made disasters, hostage situations, rape and assault. The disorder is notoriously difficult to diagnose and treat due to the severity and recurrent nature of the syndrome and the frequent concurrent diagnoses of depression, anxiety disorder, and/or substance abuse. The results of the Principal Investigator's (PI's) previous studies have suggested that combat veterans with chronic PTSD can be differentiated from other groups of psychiatric patients on the basis of differences in several neuroendocrine and neurotransmitter measures, including urinary, cortisol, norepinephrine, epinephrine, dopamine, and testosterone. The PI has been able to utilize the statistical techniques of Stepwise Discriminant Analysis and Multidimensional Scaling to correctly classify Vietnam Veterans with PTSD from other diagnostic groups.She has also found associations between many of the hormonal changes and severity of specific PTSD symptom clusters. Given the distinct constellation of hormonal changes in war-related PTSD, the findings have implications as a biological approach which may offer information relevant to the definition and differential diagnosis of this disorder in symptomatic individuals. The proposed study is designed to explore the generalizability of this hormone profile in other stressed populations with chronic PTSD by applying the same methodology utilized in studies of combat veterans to the study of Holocaust survivors. The hypothesis is that the Holocaust survivors with PTSD will manifest stable, hormonal changes similar to those observed in combat veterans, even 45 years following chronic stress exposure. To test this hypothesis, hormonal assessments will be made in Holocaust survivors and in a group of demographically matched controls. Two Holocaust survivor groups, one with PTSD and one without PTSD, will be used in order to examine whether the hormonal changes observed are a reflection of exposure to stress, or rather are indications of a traumatic stress disorder, and as such can be diagnostically useful. Furthermore, both males and females will be studied in order to test the applicability of the hormone methodology to the study of women with PTSD.

This study will use a well known panic-causing drug called CCK-4 (cholecystokinin-tetrapeptide) in individuals with posttraumatic stress disorder (PTSD). The purpose of this study is to see whether this naturally occurring poly-peptide will also cause flashbacks and panic attacks in patients with PTSD.

This protocol will attempt to (1) evaluate feedback inhibition of the HPA axis in elderly combat veterans and controls; (2) assess suprapituitary activation of the HPA axis using the metyrapone stimulation test; (3) characterize lymphocyte glucocorticoid receptor activity as a measure of the dynamics of the HPA axis; and (4) charctarize the circadian rhythm of cortisol, ACTH, NE, and MHPG using chronobiological techniques.

This application is submitted jointly but separately by Dr. Rachel Yehuda of Mount Sinai Medical School and Dr. Edna Foa of the University of Pennsylvania in response to Program Announcement PA-98-017 inviting collaborative research efforts on Collaborative R0-1 for Clinical Studies in Mental Health. Previously this grant was submitted as an R0-1 with Dr. Foa and PI and Dr. Yehuda as subcontractor. Following review, in consultation with the Chief of the Adult Psychopathology and Prevention Research Branch, we have changed the funding mechanism. Thus, this grant represents the first submission for Dr. Yehuda and a resubmission of R01 MH62003 for Dr. Foa. The grant proposes to employ a longitudinal design to examine alterations in the biology of PTSD in individuals whose symptoms are expected to improve following prolonged exposure therapy (PE). Because a great majority of trauma victims who receive PE show significant improvement in clinical symptoms, examining biological parameters before, during, and after this manipulation provides an opportunity to explore the relationships among biological alterations, changes in PTSD symptom severity, and cognitions related to the disorder. Thus, this study is interested in the relationship between biological alterations and psychological factors (including dysfunctional cognitions about the danger of the world and self-incompetence) that have been implicated in chronic PTSD, particularly as they may change with reduction in PTSD symptoms. Furthermore, the study will assess whether biological alterations associated with chronic PTSD predict, or are altered in relation to, therapeutic outcome. The longitudinal design with multiple measurements will allow us to obtain data that address the temporal relationship between changes in symptom severity with biological and cognitive variables. If biological alterations are principally related to symptom severity and/or cognitive factors that maintain PTSD, then successfully treating the symptoms should alter biological findings in the direction of normality. However, it is possible that changes in symptom severity may occur in the absence of significant shifts in neuroendocrine profile, suggesting a pattern related to underlying risk rather than to symptomatic expression in this disorder. The resolution of these questions has important implications for understanding the pathophysiology of PTSD, and may provide insight into the mechanisms associated with successful psychological treatment for this disorder.

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.

posttraumatic stress disorder; human therapy evaluation; corticosteroid receptors; depression; dexamethasone; cortisol; mental disorder chemotherapy; immune response; cytokine; hormone regulation /control mechanism; lymphocyte; comorbidity; receptor binding; stress; behavioral /social science research tag; clinical research; human subject;

DESCRIPTION (provided by applicant): The New York Academy of Sciences (NYAS) is planning a major interdisciplinary scientific conference entitled, "Psychobiology of PTSD: A Decade of Progress." The conference is being organized by Rachel Yehuda, Ph.D., Department of Psychiatry, Bronx VA Medical Center, Mount Sinai School of Medicine. In September 1996, NYAS hosted a conference entitled: The Psychobiology of PTSD, chaired by Rachel Yehuda and Alexander C. McFarlane held at Rockefeller University in New York City. The upcoming symposium will provide a comprehensive and up date examination of the many significant research advances that have occurred over the past decade. Remarkably most of the biologic findings presented at 1996 conference in extremely preliminary form have withstood the test of time and replication, and almost without exception, the researchers who presented at the previous conference are still active (now more senior) researchers in the field of PTSD. One of the main issues occurring in the field is the dramatic improvement of the quality of findings - issues that appeared to be relatively simple ten years ago when only limited data were available have now turned out to be far more complex. On the other hand, strategies for examining the psychobiology of PTSD have allowed the field to keep pace with these complexities. The symposium will integrate basic science and clinical research so that both bench researchers and clinicians can develop a mutual understanding of recent progress in post traumatic stress research. Conference attendees will achieve an understanding of molecular biology, pathophysiology, neurology, epidemiology, clinical care and psychosocial management of PTSD. Expected participants to this conference include clinicians - Ph.D., M.D., M.S.W., R.N.'s who work with trauma survivors and wish to update their knowledge about the biology of PTSD, as well as basic and clinical researchers working in the field. We also expect the conference to be attractive to educated lay individuals such as consumers, family members, advocates, and members of the press who are interested in tracking the development of knowledge in this area.

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DESCRIPTION (provided by applicant): This proposal seeks to examine gene-environment interactions that contribute to the development of PTSD in 960 persons selected from a well-characterized sample of 2750 men and women in the New York metropolitan area, exposed to the World Trade Center attacks. This cohort was initially recruited six months after September 11th, has been followed longitudinally for the purpose of determining mental health consequences resulting from this event, and is sufficiently large enough to undertake a comprehensive investigation of risk factors for this disorder. We will examine clinical and neuroendocrine measures previously hypothesized or demonstrated to be associated with risk for PTSD, related to alterations in cortisol signaling. Since genetic factors contribute to the function of this biological system, we will examine polymorphisms of several genes related to glucocorticoid activity, as well as peptidergic and monoaminergic neurotransmission implicated in PTSD pathophysiology. To determine the involvement of other relevant genes, we will examine expression profiles using microarray techniques and quantitative polymerase chain reaction. The subset of genes that are validated will also be genotyped for association with PTSD. Additionally, based on recent evidence for non-genetic intergenerational transmission of PTSD and cortisol alterations associated with PTSD (i.e., from trauma-exposed parents with PTSD to their offspring), we will examine stable individual differences in gene activity that are subject to 'programming' by experience via epigenetic mechanisms (e.g., DNA methylation). These studies will focus on specific promoter regions of the glucocorticoid receptor (GR) in lymphocytes, a tissue demonstrated to be more responsive to glucocorticoids in PTSD. It will therefore be possible to associate epigenetic alterations in DNA methylation at GR promoter sites with" genetic and non-genetic risk factors, and their interaction with trauma severity, towards the aim of understanding the simple, but as yet unanswered question of the role of trauma in the development of PTSD, and the even more complex one of why some persons develop PTSD following trauma exposure while others do not. The coincidence of this unique and representative cohort, together with the expertise reflected in this multi-institutional team, will provide unambiguous information concerning the molecular- genetic basis of PTSD, PTSD vulnerability, and stress resistance. Relevance to Public Health: There is a major gap in knowledge regarding why only some exposed to trauma develop PTSD, while the majority do not. This gap results from an over-emphasis on PTSD as a response to an event and an under-emphasis on differences in genetic or early environmental influences that make some more vulnerable. The development of models of prevention and treatment of PTSD can only occur following an understanding of individual risk factors and their interactions with event exposure.

short term memory; war /peace

(11Beta,16alpha)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione; 1-Dehydro-16alpha-methyl-9alpha-fluorohydrocortisone; 16Alpha-methyl-9alpha-fluoro-1,4-pregnadiene-11beta,17alpha,21-triol-3,20-dione; 16Alpha-methyl-9alpha-fluoro-delta1-hydrocortisone; 16Alpha-methyl-9alpha-fluoroprednisolone; 9Alpha-fluoro-11beta,17alpha,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione; 9alpha-Fluoro-16alpha- methylprednisolone; ACTH; ACTH (1-39); Aacidexam; Adexone; Adrenocorticotropic Hormone; Adrenocorticotropin; Aeroseb-HC; Affect; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Ambene; Ammon Horn; Amplidermis; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Anemul mono; Anterior; Antimicotico; Aquapred; Area; Attention; Auditory; Auxiloson; Azona; Baycuten; Baycuten N; Bosnia; Bosnia and Hercegovina; Bosnia-Herzegovina; Brain; CDC; CRISP; California; Centers for Disease Control; Centers for Disease Control (U.S.); Centers for Disease Control and Prevention; Centers for Disease Control and Prevention (U.S.); Cetacort; Characteristics; Chronic; Chronic Disease; Chronic Illness; Cognition; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Condition; Confidence Intervals; Cornu Ammonis; Corson; Cort-Dome; Cortef; Cortenema; Corticotropin; Corticotropin (1-39); Cortidexason; Cortisol; Cortispray; Cortisumman; Cortril; DST; Data; Decacort; Decadrol; Decadron; Decalix; Decameth; Decasone R.p.; Dectancyl; Deenar; Dekacort; Deltafluorene; Depressed mood; Dermacort; Deronil; Desamethasone; Desameton; Dex-4; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexace; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Digit; Digit structure; Dinormon; Dose; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Eldecort; Encephalon; Encephalons; Exposure to; Fatigue; Feeling; Fluoro-9alpha Methyl-16alpha Prednisolone; Fluorodelta; Fortecortin; Funding; Gammacorten; Glucocorticoid Receptor; Glucocorticoids; Grant; Gulf War; HPA; Health; Herzegovina; Hexadecadrol; Hexadrol; Hippocampus; Hippocampus (Brain); Hydrocortisone; Hydrocortone; Hytone; Infusion; Infusion procedures; Ingestion; Institution; Investigators; Kosovo; Lack of Energy; Letters; Link; Literature; Lokalison-F; Loverine; Low Prevalence; Lymphocyte; Lymphocytic; Major Depressive Disorder; Measures; Mediating; Medical; Memory; Memory, Immediate; Memory, Short-Term; Memory, Shortterm; Methylfluorprednisolone; Millicorten; Moods; Musculoskeletal; Mymethasone; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Neuranatomies; Neuranatomy; Neuroanatomies; Neuroanatomy; Neuroendocrine; Neuroendocrine System; Neuropsychologic Tests; Neuropsychological Tests; Neurosecretory Systems; Neuroses, Post-Traumatic; Neuroses, Posttraumatic; Numbers; Nutracort; Ocasa; Operation Desert Shield; Operation Desert Storm; Orgadrone; PBO; PTSD; Performance; Persian Gulf War, 1991; Placebo Control; Placebos; Post-Traumatic Stress Disorders; Predni-F; Pregn-4-ene-3,20-dione, 11,17,21-trihydroxy-, (11beta)-; Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11beta,16alpha)-; Procedures; Process; Proctocort; Rate; Regulation; Research; Research Personnel; Research Resources; Researchers; Resources; Role; Savings; Sham Treatment; Short-Term Memory; Sleep; Source; Spersadex; Spersadox; Stress; Stress Disorders; Stress Disorders, Post-Traumatic; Stress Disorders, Posttraumatic; Stress Disorders, Traumatic; Symptoms; System; System, LOINC Axis 4; Testing; Therapeutic Glucocorticoid; Therapeutic Hydrocortisone; Thinking; Thinking, function; Trauma; Traumatic Stress Disorders; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; United States National Institutes of Health; Verbal Learning; Veterans; Visumetazone; War; amygdaloid nuclear complex; auricularum; base; brain volume; chronic disease/disorder; chronic disorder; cognitive function; cohort; day; depressed; design; designing; dexamethasone suppression test; feelings; hippocampal; hypothalamic-pituitary-adrenal (HPA) axis; hypothalamic-pituitary-adrenal axis; hypothalmus-pituitary-adrenal axis; improved; indexing; lymph cell; major depression; memory retention; response; sadness; sham therapy; social role; traumatic neurosis; visual memory; working memory

DESCRIPTION (provided by applicant): This grant responds to NIH Challenge 08-MH-103: Understanding the Genomic Risk Architecture of Mental Disorders. This application builds on recent animal and human data on epigenetic mechanisms mediating 'glucocorticoid programming'to address a critical gap in knowledge about how early experience confers increased biological risk for post-traumatic stress disorder (PTSD). The gap in knowledge will be addressed by examining cytosine methylation of the glucocorticoid receptor (GR) gene. The study of epigenetic modifications in relation to PTSD risk represents an important scientific frontier. PTSD occurs in only a proportion of those exposed to trauma, but has a population lifetime prevalence of 10-14%. Maternal PTSD has been identified as a risk factor for PTSD in 2nd generation offspring (F2) allowing examination of biological mechanisms in association with this risk factor. The GR gene is the focus of investigation because alterations reflecting enhanced GR responsiveness have been demonstrated in F2 with maternal PTSD, and in other PTSD samples.The relationships among cytosine methylation, GR gene expression, and neuroendocrine measures associated with PTSD risk (GR sensitivity, negative feedback inhibition, basal cortisol level and metabolism) will be examined in 120 F2 of Holocaust survivors (grouped by presence or absence of maternal and paternal PTSD) and in 30 subjects with no parental Holocaust exposure or PTSD. Since glucocorticoid programming has also been implicated as a mechanism through which [in utero] maternal stress increases risk for the subsequent development of metabolic syndrome (MetS) in their adult offspring, and recent data have linked PTSD to the development of MetS and its consequences, data on MetS will also be obtained. This project can be accomplished in two years because we can recruit from previously studied Holocaust F2 that agreed to be recontacted. Cytosine methylation will be quantified using polymerase chain reaction (PCR) primers developed by Michael Meaney, Ph.D. that selectively amplify variations in the relevant region of the GR gene for DNA methylation and splice variant analysis of mRNA in the human lymphocyte. Dr. Meaney's group has confirmed that the organization of the human GR gene closely resembles the rat GR. Our primary hypothesis is that cytosine methylation will be greater in F2 with maternal than paternal PTSD. A path analysis model will examine the contribution of this epigenetic modification to neuroendocrine and metabolic consequences associated with PTSD risk, incorporating other relevant aspects of early life experience (parental symptoms, childhood abuse and neglect, parental care and overprotection) to assess their contribution. This work is innovative in attempting to use a naturalistic intergenerational 'model system'to examine the role for an epigenetic mechanism in transmitted vulnerability for PTSD and associated health risks, and determine their relationship to other environmental contributors. The results have implications for detecting persons at risk for PTSD, but may also point to novel targets for prophylaxis and early treatment. Adult children of mothers with post traumatic stress disorder (PTSD) are at increased risk for PTSD, and also show changes in their responsiveness to the stress hormone cortisol that appear to reflect early developmental influences, possibly resulting from maternal stress effects. In this grant we investigate whether the biological changes in these offspring reflect an enduring epigenetic modification, induced by early maternal behavior that resulted in 'recalibrating'the cortisol system in a manner that increases risk for subsequent PTSD and possibly other health consequences. If such changes are observed, this research will yield an early (i.e., pretraumatic) biologic marker that can ultimately be used in screening persons at increased risk for PTSD either before or immediately after they are exposed to trauma.