Zachary N. Stowe - US grants

This proposal outlines a Multi-Institutional Collaborative Research (R-10) Project in which we will evaluate the risk of relapse in pregnancy among women with a history of major depression who either maintain or discontinue antidepressant treatment around the time of conception. The primary aims of this investigation are (1) to establish whether relapse/recurrence rates are lower in women who maintain versus discontinue antidepressant treatment during pregnancy; (2) to identify clinical and psychosocial predictors of relapse during pregnancy in those who maintain or discontinue antidepressants; and (3) to assess perinatal outcome and its relationship to depressive symptomatology in pregnancy. The three participating sites for this investigation include the Perinatal and Reproductive Psychiatry, Clinical Research Program, Massachusetts General Hospital, Harvard Medical School (Dr. Cohen), Women's Life Center and Mood Disorders Research, UCLA (Dr. Altshuler), Emory University School of Medicine (Dr. Stowe). Subjects who have euthymic for at least three months and who have not discontinued antidepressant more than six weeks prior to conception will be accessioned early in their pregnancy and will be followed longitudinally from the first trimester of pregnancy through delivery. Given the prevalence of major depression during the childbearing years and the growing numbers of women who receive treatment with antidepressants, it is crucial to identify those women who may be able to safely discontinue antidepressant treatment during pregnancy as well as those who are particularly vulnerable to relapse. Delineating of these subgroups provides an opportunity to screen for women "at risk" for relapse and allows for thoughtful treatment plan.

DESCRIPTION (provided by applicant): This is an application for RFA-OD-02-002 to fund a Specialized Center of Research on Sex and Gender Factors Affecting Women's Health representing the collaborative efforts of five departments and two academic institutions. The central theme of the application is "pharmacokinetic, pharmacodynamic, and pharmacogenetic (PK/PD/PG) modeling of anti-epileptic drugs (AED) and psychotropic medications during pregnancy and lactation using both human and rodent paradigms: defining fetal/neonatal exposure and influence on obstetrical outcome" ' The primary objectives of the center include: 1) PK/PD/PG modeling of anti-epileptic drugs (AED) and psychotropic medications antidepressants, lithium) during pregnancy and lactation. These novel data will provide information about the metabolism, distribution, and extent of fetal/neonatal exposure to these medications. The data for this modeling will be obtained from women with neurological disorders (Epilepsy, Tourette's Syndrome) and mental illness (Bipolar Disorder, Major Depression, Obsessive Compulsive Disorder, Panic Disorder). These patient populations were selected based on the typical chronic course of illness and utilization of similar medications between the groups. The PK/PD modeling from subjects with different illnesses and ethnic groups enhances the pharmacogenetic (PG) comparison of metabolic capacity and protein binding. 2) These clinical data will be complemented by a series of laboratory animal studies in two strains of rodent (one deficient in 2D6 activity) to provide fetal and neonatal central nervous system (CNS) tissue concentrations, neonatal CNS clearance, and neurotransmitter receptor effects of antenatal and postnatal exposure to AEDs and psychotropic medications. 3) Prospective assessment of these women will provide documentation of all additional exposures (prescription medications, over the counter preparations, herbal remedies, maternal illness events, environmental toxins) and delineation of the course of illness during pregnancy and postpartum. The ultimate clinical import of these data will be clarification of the factors influencing medication metabolism and distribution, thereby providing an estimate fetal/neonatal exposure, factors influencing such exposure, and novel data regarding the potential "dose versus outcome" comparison. The multidisciplinary team of this center application represent two academic medical centers and five departments organized into 2 clinical projects, 1 laboratory investigation, supported by 3 core components and an executive committee with extensive research/clinical experience. The achievement of the objectives address several research priority areas noted in ORWH Agenda for Research on Women's Health for the 21st century.

DESCRIPTION (provided by applicant): The postpartum period is a time of heightened risk for the emergence of psychiatric illness, particularly in women who already have a history of mood disorder. Given the prevalence of depressive disorders during the childbearing years, it is crucial to identify women who are at highest risk for new onset or recurrence of depression during the postpartum period. Identification of those women at greatest risk for postpartum depression may allow for interventions that would limit maternal morbidity associated with untreated postpartum depression. This proposal outlines a multi-institutional collaborative research project (R01) in response to PA-00-074, in which risk for postpartum depression will be evaluated in women with histories of major depressive disorder. Subjects who have had at least one episode of DSM-IV major depression will be followed prospectively from late pregnancy (32-36 weeks gestation) up to six months after delivery using a series of standardized instruments. The primary aims of this investigation are (1) to identify clinical and psychosocial predictors of postpartum depression and functional impairment and (2) to determine the extent to which treatment (pharmacologic, nonpharmacologic or a combination) proximate to delivery modulates risk for postpartum relapse. How clinical and psychosocial variables including history of postpartum depression, severity of past depression, number of previous episodes, age at illness onset, depression during pregnancy, and social support affect risk for postpartum depression, as well as psychosocial functioning, will be investigated. The current submission is a natural extension of an ongoing academically productive collaboration in which risk for depressive relapse is evaluated in pregnant women with histories of major depression who either discontinue or maintain antidepressant treatment. This proposal provides an opportunity to study a rigorously followed population into a period of risk -- the postpartum period -- and to investigate the factors that confer or modulate risk for depression at this time. The three participating sites for this investigation include the Perinatal and Reproductive Psychiatry Clinical Research Program at the Massachusetts General Hospital, Harvard Medical School (Drs. Cohen, Nonacs and Otto), the Women's Life Center and Mood Disorders Research Program at UCLA (Dr. AItshuler, Dr. Hendrick), and the Emory Women's Mental Health Program at Emory University School of Medicine (Dr. Stowe).

The primary focus of this project is to measure stress reactivity in infants of mothers' with major depression, a form of ELS, in a controlled laboratory setting. The literature is replete with studies of the effects of maternal depression, anxiety, and stress on infant well-being that includes >32,000 mother-infant pairs. Studies in infants with genetic vulnerability for affective disorders have been reported to have lower vagal tone, as well as higher salivary cortisol concentrations following lab tasks, when compared with control infants. There appears to be a mismatch between their passive or nonreactive behaviors, and their supersensitive physiological responses to stress. Remarkably, there are few investigations that have measured behavioral and psychophysiological functioning of infants of depressed mothers in response to controlled laboratory stress stimuli, and no study of this type has controlled for maternal co-morbid anxiety, maternal medications in pregnancy and/or lactation, obstetrical events, early life trauma and recent maternal stressful life events. This study is designed to further this important area of research by assessing behavioral and cortisol stress reactivity of infants of women with a history of major depression at six months of age. The prospective assessment of psychiatric morbidity during pregnancy and the postpartum period, comorbid anxiety, obstetric complications,early life trauma and maternal stressful life events will address the sparse date regarding maternal factors mediating infant reactivity. The study population will include 25 infants of women with no history of depression to serve as controls, that will be compared to infants from three age matched cohorts; 1) Women undergoing antidepressant treatment (monotherapy) for major depression during pregnancy and the postpartum period; 2) Women with a history of prenatal depression who choose not to take antidepressants; and 3) Women with a history of major depression who remain euthymic during pregnancy without antidepressant exposure. These later cohorts will be derived from ongoing NIH-funded investigations (Specialized Center of Research on Sex and Gender Effects focusing on PK/PD Modeling in Pregnancy and focusing on predictors of relapse of Depression during the Postpartum). At six months of age the infants will be exposed to laboratory stressors (noise burst, arm restraint), and their behavioral and physiological reactivity (heart rate variability, salivary cortisol) will be assessed. The novelty of these data is enhanced by the pre-natal and postnatal prospective assessment of variables that could influence response to these stressors.

CORE A - Abstract The Administrative Core (Core A) will be primarily operated from the Women's Mental Health Program (WMHP) at Emory University School of Medicine. The Core will provide administrative support for the operation of the Center including: budgeting, communication with internal regulatory offices (OSP, IRB, IACUC), communication with NIH, and scheduling of Center meetings. As part of this function, the Administrative Core will provide agendas and reports for each Center meeting and coordination of the interim Center meeting. Core A will include an Executive Committee, Internal Advisory Board (IAB), External Advisory Board (EAB), Statistical Methods and Data Management (SMDM) subunit, and Education & Career Development (ECD) subunit. The SMDM subunit will provide a central data repository and statistical support for the Center. The ECD subunit will assure that educational and career development opportunities are coordinated among the Cores and Projects. Each subunit is charged with specific objectives for supporting and evaluating the Center. The primary responsibility for overseeing the progress of the individual cores and projects will be specifically delegated to and shared by the Executive Committee, IAB, and EAB. Reports from these committees will be included in the Center's annual progress report to NIH. The process for providing information about Center projects and results will be monitored by the Administrative Core and approved information and project results will be listed on the WMHP web site www.emorvwomensprogram.org. The process for data sharing will be discussed and approved by NIH in accordance with data sharing policy.

Project 1 will focus on the fetal and obstetrical consequences of maternal stress, depression, and anxiety during pregnancy. Information that better informs the clinical decision potentially affects >400,000 women in the United States annually. The treatment of maternal depression and anxiety during pregnancy continues to stimulate vigorous debate with the emphasis on the reproductive safety of antidepressant medications. Recently, there have been reports of purported "antidepressant neonatal withdrawal", and a renewed attention with respect to potential teratogenic effects (e.g. ventral septal defects). Unfortunately, the potential impact of maternal stress, depression, and anxiety on the fetus and obstetrical outcome is seldom included in these reports. The extant literature on the impact of maternal mental illness typically uses single point assessments (predominantly in mid to late pregnancy) of maternal depression and anxiety. While such studies have demonstrated alterations in fetal activity, fetal heart rate, and an increase in obstetrical complications (low birth weight, preterm labor, preterm delivery), they have only speculated about the mechanisms based on cross sectional assessment. Similarly, these investigations have failed to account for other exposures that may influence outcome (medications, tobacco, etc). Project 1 will fill these gaps utilizing the well characterized women from Core B. We will determine the impact of maternal depression and anxiety, in any, on biological indices of stress (both acute and cumulative) and the relationship of these measures and maternal symptoms with uterine blood flow, fetal activity, fetal heart rate, obstetrical outcome, neonatal outcome. The center design permits blinded assessments of these relationships - an incremental advance over previous investigations. The focus on a clinical population will provide a cohort of pregnant women with antidepressant exposure. The modulatory effects, if any, of antidepressants on our outcome variables are unknown. Blinded assessment of obstetrical and neonatal outcome will directly address many of the concerns recently reported. The potential impact of exposure (e.g. ng/ml in cord blood) will be included in data analysis. The novel data generated from Project 1 will serve as candidate phenotypes for Project 2, and additional potential moderators of infant outcome in Project 3.

[unreadable] DESCRIPTION (provided by applicant): This Center application responds to PAR-04-151: Translational Research Centers in Behavioral Sciences (TRCBS). Based in the Department of Psychiatry and Behavioral Sciences of the Emory University School of Medicine, the center includes 3 cores and 4 projects led by an investigative team (consisting of multi- departmental, multi-institutional, and community practitioners) with a proven track record of productivity and commitment to career development. The highly interactive translational design will "elucidate the role(s) of perinatal events, susceptibility genes, and fetal exposures on the vulnerability of the offspring to later psychopathology." [unreadable] [unreadable] The intrauterine environment can be altered by maternal stress, depression, and anxiety. The constituents of this initial developmental milieu depend on the metabolic capacities, sensitivities, and affinities of the maternal, placental, and fetal compartments. The Center will prospectively follow women at risk for peri-partum depression, biological fathers, and offspring through pregnancy and the first postnatal year - gathering DMA trios, biological indices of maternal stress, and maternal symptoms. Perinatal assessments will include uterine blood flow, fetal activity, and obstetrical outcome. Behavioral/affective, neurobiological, and psychophysiological measures will be gathered on infants at several post-natal time points. The impact of fetal antidepressant exposure will be incorporated into statistical models to determine the potential moderating role of such exposure on the vulnerability of the offspring. [unreadable] [unreadable] The clinical population will be modeled in rats by characterizing maternal behavior, and gathering invasive assessments of neurobiological mechanisms mediating exposure to maternal stress and antidepressants. These rat models will provide unique insights into the behavioral, physiological, and genetic consequences of perinatal stress and antidepressant exposure. [unreadable] [unreadable] The proposed Center will test our broad hypothesis that maternal mental illness during pregnancy constitutes an early environmental exposure that alters vulnerability of offspring to later psychopathology in a genetically vulnerable population. The work will advance our understanding of the influence of genes and early environment on the developmental trajectory of offspring. In addition, the Center will potentially identify gestational windows of enhanced fetal susceptibility. Data that quantifies the impact of maternal depression/anxiety and antidepressant use during pregnancy has direct clinical implications for the care of >400,000 women each year in the United States. [unreadable] [unreadable] Overall Center [unreadable] [unreadable] [unreadable]