David Rubinow - US grants

DESCRIPTION (provided by applicant): Our prior work indicates that women with premenstrual dysphoric disorder (PMDD) may be more vulnerable to dysphoric mood states induced by changes in gonadal hormones and their neuroactive metabolites, and not resulting from absolute levels per se. One objective of the proposed research is to determine if a continuous oral contraceptive (OC) regimen that eliminates the pill free interval (PFI) and produces stable, low endogenous hormone levels will prevent the expression of PMDD symptoms. A second objective is to demonstrate that changing hormones trigger affective symptoms in PMDD, and to establish which gonadal hormones and their neuroactive metabolites are associated with symptoms. Eighty one women with prospectively confirmed PMDD will be randomized and complete one of three, 13 week treatment arms: Treatment #1) continuous administration of 20 ug ethinyl estradiol/3mg drospirenone [EE/P];Treatment #2) interrupted EE/P, substituting placebo for EE/DRP during weeks 4, 8, &12;Treatment #3) continuous placebo. The primary outcome measure will be the total PMDD symptom score assessed daily at baseline and throughout the treatments. Secondary measures will include Response Rate, mood and social adjustment scales. Serum levels of estradiol (E2) and P, as well as plasma levels of neuroactive steroids, allopregnanolone, allotetrahydroDOC, pregnanolone and pregnenolone sulfate, all potent modulators of the GABAA receptor will be sampled on cycle days 17, 21, 25, 2, &5 at pretreatment and also during treatment month 3. Primary predictions are: 1) Continuous EE/P (arm #1) will be associated with a significant reduction in PMDD symptoms relative to pretreatment levels, and will be associated with lower symptom levels in months 2 and 3 of treatment relative to both placebo and interrupted EE/P (arms #2 and #3);2) Women treated with interrupted OC (arm #2) will show symptom severity similar to women treated with placebo (arm #3), and will continue to show cyclicity of symptoms though there will be a shift in peak symptoms to the follicular phase, corresponding primarily to the changes in E2 induced during the PFI;3) the increase in E2 during the PFI in women treated with interrupted OC (arm #2) will predict the development and severity of symptoms in that group;and 4) since OCs suppress the synthesis of neurosteroids, the magnitude of the change in neuroactive steroids from days 17 - 25 to days 2- 5 will predict PMDD symptoms in the placebo group, but not in the women treated with OCs (arms #1 and #2). The results of this study are expected to advance our knowledge on the pathophysiology of PMDD and help illuminate a substrate for affective dysregulation in women. Confirmation of the role of hormonal change in precipitating PMDD will suggest therapeutic targets for future research.

Affective Disorders; Behavior; Behavioral; CRISP; Clinical; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Control Groups; Diagnosis; ELIG; Eligibility; Eligibility Determination; Endocrine; Evaluation; Follicular Phase; Funding; Grant; Institution; Interview; Investigators; Luteal Phase; Menses; Menstrual Cycle, Follicular Phase; Menstrual Cycle, Luteal Phase; Menstrual Cycle, Secretory Phase; Menstrual Proliferative Phase; Menstrual Secretory Phase; Menstrual cycle, proliferative phase; Menstrual fluid; Menstruation; Mood Disorders; Moods; NIH; National Institutes of Health; National Institutes of Health (U.S.); Population; Postovulatory Phase; Preovulatory Phase; Protocol Screening; Purpose; Recruitment Activity; Research; Research Personnel; Research Resources; Researchers; Resources; Source; Symptoms; Testing; United States National Institutes of Health; Visit; Woman; day; disease control; disorder control; experience; menstrual period; monthly period; proliferative phase Menstrual cycle; recruit

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in women, and currently kills more women than men in the U.S. due to the greater burden of cardiovascular risk after menopause. Depression increases risk for CVD by two-fold. Understanding the depression-CVD link has particular relevance for women since they suffer from depression at a rate twice that of men. Estrogen (E2) withdrawal not only increases cardiovascular risk in women, but is also involved in depression. The planned study will examine the biological mediators of risk that are common to both CVD and depression (inflammation, endothelial dysfunction, cardiac autonomic dysregulation, and metabolic disturbance) within the context of E2 withdrawal during the perimenopause. Heightened cardiovascular, neuroendocrine and inflammatory reactivity to stress also define a profile of risk and adversely impacts the mediators of risk described above. While E2 is associated with beneficial effects on the mediators of risk common to depression and CVD and on stress reactivity, and is also effective in reducing depressive symptoms, there is substantial variance in both the cardioprotective and antidepressant responses to E2. The planned research intends to identify a profile of risk that would predict the greatest benefits of E2 in the prophylaxis of the progression of cardiovascular risk and appearance of depression in perimenopausal women. Based on the shared mediators of risk for CVD and depression, we predict that perimenopausal women with histories of recurrent depression will show greater progression of cardiovascular risk and suffer from more depression over 12 months than never depressed women, and show cardiovascular benefit of E2. A total of 320 perimenopausal women (45-55 years of age;STRAW stage-1) who are eligible candidates for E2 will be studied. Based on SCID interview, one half (n=160) will have a history of recurrent depression (2+ depressive episodes, 1+ must be major depression), but in remission (>2 yrs and with current CES-D score d 8) and 160 will be recruited as never depressed perimenopausal women (also CES-D d 8). Following medical and psychiatric evaluation, including assessment of lifetime trauma exposure, women will be tested for baseline cardiovascular risk profiles which include: 1) Cardiac Autonomic Tone - defined by baroreceptor sensitivity involving the non-invasive measurement of HR and beat-to-beat change in BP;2) Stress Reactivity - based on a composite score involving cardiovascular (blood pressure and vascular resistance), neuroendocrine (cortisol), and inflammatory (IL-6) responses to the Trier Social Stress Test;3) Endothelial Function - based on ultrasound measurement of flow mediated dilatation of the brachial artery during reactivity hyperemia;and 5) Metabolic Risk - determined based on meeting standard criteria for the metabolic syndrome or exhibiting insulin resistance in response to the oral glucose tolerance test. Using double-blind procedures, subjects will then be randomized to either transdermal 172-E2 (100ug/day) or placebo for 12 months, and micronized progesterone (P) will be given every 3 months to women on active ERT (placebo P given on 2 out of 3 months) and placebo P will be given every month to women on placebo ERT. Subjects will be assessed at regular intervals during the intervention for depression, compliance, vitals, and side effects. At months 6 and 12 of the treatment period, all cardiovascular procedures conducted at the baseline assessment will be repeated. This is a mechanistic study designed to examine the predictors (history of recurrent depression) and moderators (trauma exposure) of cardiovascular risk progression in untreated perimenopausal women over 12 months, and the mediators (stress reactivity profile) of the beneficial effects of E2 treatment on depression and cardiovascular risk. The results of this study are intended to identify potential targets for behavioral or biological intervention and provide mechanistic hypotheses that can be tested in depressions that occur during other stages of life as well as help advance the goals of individualized medicine. PUBLIC HEALTH RELEVANCE: Despite the prevalence and human costs of cardiovascular disease and depression in women, there are few known mediators or predictors of the increased risk of these inter-related disorders during the perimenopause. The existence of such predictors (e.g., history of depression), moderators (e.g., lifetime trauma exposure), biomarkers (e.g., insulin resistance) or mediators (e.g. stress reactivity) would identify targets for intervention and potentially influence the lives and health of millions of women. Additionally, identification of predictors of benefits associated with short-term ERT would advance the goal of individualized medicine.

DESCRIPTION (provided by applicant): In contrast to progress for autism, bipolar disorder, and schizophrenia, discerning the biological basis of major depressive disorder (MDD) has been difficult. Genetic studies of MDD using genome-wide linkage, candidate gene, and GWAS (with Ns > 20,000 subjects) have not been successful in identifying risk loci that meet contemporary standards for replication. Major lessons are that genetic approaches for higher prevalence/lower heritability diseases like MDD may be suboptimal given the likely role of etiological heterogeneity. We propose here an alternative strategy to identify networks and pathways involved in the etiology of MDD. To minimize heterogeneity, we will study postpartum depression (PPD), a more homogenous type of MDD. Although most women have mild mood symptoms in the first few days to weeks postpartum (the baby blues), these symptoms usually resolve spontaneously. In contrast, PPD is a severe and persistent form of MDD that is one of the most frequent complications of childbirth (prevalence 15-20%) and is the leading cause of maternal death. Practically, pregnant women are straight-forward to identify, as they have frequent contact with the healthcare system and are willing to participate in research on perinatal problems. The study of PPD should decrease heterogeneity in multiple ways (females only, age-banded, all subjects exposed to the same biopsychosocial event). Moreover, we have moved to the rigorous study of the biomarker space to identify the distinguishing features of PPD of potential clinical relevance. DNA methylation markers are appealing because methylation is directly related to gene expression. RNA expression signatures add complementary data on the state of a tissue and even of an organism. Finally, the comprehensive study of neuroendocrine hormones is of clear salience for PPD. We propose: (1) to ascertain and sample 1,000 PPD cases and 1,000 euthymic controls, all self-reported African-American; (2) conduct discovery analyses using an unbiased/screening biomarker assessment for 500 PPD cases and 500 controls (methylomics and transcriptomics via next-generation technologies on peripheral blood), and state-of-the-art statistical analyses will identify multivariate biomarker signatures for PPD; and (3) conduct validation assays of biomarkers meeting liberal significance criteria in independent samples (500 PPD cases and 500 controls). Our focus on African American women is optimal as this US minority group is manifestly under-studied, the prevalence of PPD is higher in African-American women, and in contrast to genetic studies where ancestry heterogeneity is a major source of false positive signals, it can be a strength in biomarker studies. MDD is a first-rank public health problem due to the associated morbidity, mortality, and personal/societal costs. Studying the MDD sub-form PPD is particularly appealing due to the inherent control for multiple sources of heterogeneity - we propose to study women of child-bearing years who are all exposed to the major risk factor of pregnancy. Moreover, PPD is itself an important and under-studied human health concern, particularly in African-American women. Successful completion of the proposed research will yield strong and replicable biomarker signatures for PPD. This new knowledge would provide insight into state-related alterations characteristic of PPD and potentially to trait-related vulnerabilities to MDD (particularly in combination with GWAS findings). Future research could evaluate whether a biomarker signature is of predictive utility and, if so, rational primary prevention may become feasible. PUBLIC HEALTH RELEVANCE: Postpartum depression causes enormous human suffering and cost to society. Our goal is rapidly to learn more about the biological basis of postpartum depression by studying the blood of African-American women with and without postpartum depression.

DESCRIPTION (provided by applicant): The purpose of the proposed training program, Postdoctoral Training in Reproductive Mood Disorders is to develop researchers with expertise in both the biological basis and clinically relevant (predictive) phenotypes of reproductive mood disorders (perinatal depression, premenstrual dysphoric disorder, and perimenopausal depression). This is a two year training program for MD, PhD and MD/PhD trainees. Training will involve a broad-based and integrative perspective, involving not only psychiatry but cardiology and genetics, endocrinology, neuroscience, and obstetrics/gynecology. With this program's emphasis on training in pathophysiological mechanisms that underlie reproductive mood disorders, trainees will develop mastery in the following: reproductive hormonal physiology and signaling; methods for manipulating the reproductive system; and clinical phenomenology of reproductive mood disorders. Additionally, trainees will develop expertise in at least one of four methodological training tracks: Neurosciences, Genetics, Stress Physiology, or Clinical Trials Methodology. Fellows will have a primary research mentor (representing their training track) and a secondary mentor (from a different track), thereby providing additional exposure to both the interdisciplinarity and collaborative nature of science. In addition to experiential opportunities with program faculty, didactics will be tailored to the individual fellow to ensure that each achieves competence in their chosen research track. A key element of the training as well includes an independent research project. Thus, while the training plan is multidisciplinary, an emphasis is placed on individualizing the training experience for the Fellows. However, through a number of program specific venues designed to bring the Fellows together for exchange of ideas and support, the program will ensure cohesiveness among the trainees. Fellows who complete this program will be poised to become independent researchers, having the unique requisite foundation to examine biobehavioral mechanisms in reproductive mood disorders and the ability to identify therapeutic biologic targets in their future independent research. The University of North Carolina at Chapel Hill represents an ideal setting for the proposed program because it possesses a well-known collaborative infrastructure, a vibrant women's mood disorder clinical program (which includes the first inpatient perinatal depression program in the country), and a critical mass of researchers in reproductive mood disorders with a track record of success.

DESCRIPTION (provided by applicant): Affective disorders, such as postpartum depression (PPD) and other reproductive-related mood disorders, are common and constitute a significant burden for women, children, and society. However, little is known about the neurobiological mechanisms underlying depressive disorders in women. The long-term goal of this research is to 1) advance our understanding of the biological mechanisms underlying both the triggering of and susceptibility to depressive disorders in women; and 2) permit the prediction of those at risk for PPD. The objective of the current project is to examine whether those with a past episode of PPD (at high risk for recurrence) show differences in emotional arousal and reward processing domains relative to healthy control women (without a history of PPD) under baseline and hormone withdrawal-precipitated conditions. Our central hypothesis is that reproductive hormone changes are associated with dysregulation of the neural circuits underlying emotional arousal and reward processing and consequent depressive symptoms in high-risk women. The rationale for the proposed study is that employing a scaled down model of puerperal hormonal events in high-risk women permits the identification of a group of individuals homogeneous for reproductive related affective dysfunction and, hence, the best opportunity for disentangling the specific changes in brain function due to reproductive hormones from those accompanying reproductive hormone-precipitated affective dysfunction. Moreover, identifying a neurophysiologic biomarker for hormone-related affective dysfunction provides a clear pathway for examining mechanisms of susceptibility to affective dysfunction across disorders. We plan to accomplish the objectives of this application by pursuing the following specific aims: 1) to assess the effects of simulated postpartum reproductive hormone withdrawal, compared to baseline, on corticolimbic circuit activation in high-risk and control women; and 2) to examine the effects of reproductive hormone withdrawal, compared to baseline, on reward circuit activation in high-risk and control women. An additional exploratory aim is to identify a neural biomarker, characterized by corticolimbic and reward circuit dysfunction, that can be used to predict the onset of PPD. The proposed study involves experimentally manipulating reproductive hormones in euthymic women to create a scaled down version of the changes that occur at the puerperium. This endocrine manipulation paradigm will be used to examine the neurocircuitry underlying the regulation of affect and reward processing under baseline and hormone withdrawal-precipitated conditions among women who are expected to experience hormone-related affective dysregulation (n=15) and controls (n=15). The expected outcome is the identification of neural circuits underlying both the susceptibility to and mediation of hormone-related affective dysfunction. Understanding these neurobiological mechanisms will subsequently improve our ability to identify those at risk for PPD, which may strengthen prevention efforts and ultimately prevent the deleterious effects of maternal depression on offspring.