Alan Schatzberg - US grants

The long-term objective of this research is to test the hypothesis that the development of delusions in major depression is due to the effects of patients' own HPA axis overactivity on central dopamine (DA) systems. Major Depression with psychotic features (PMD), a syndrome with marked morbidity, is characterized by both increased hypothalamic-pituitary - adrenal (HPA) axis activity and increased levels of plasma and cerebrospinal fluid (CSF) homovanillic acid (HVA). This research has major implications for understanding the pathogenesis of PMD, identifying potential genetic risk factors, and developing new, more effective and less toxic treatments. The specific aims include: l.) To characterize the circadian rhythm of plasma homovanillic acid (HVA) in healthy human subjects and its relationship to the circadian rhythm of plasma cortisol and adrenocorticotropic hormone (ACTh). 2.) To compare the circadian rhythms and relative amplitudes of plasma HVA in PMD patients, non psychotic major depressed (NPMD) patients and healthy volunteers; to assess the relationships between components of the HPA axis and HVA in PMD patients; and to more precisely characterize the HPA overactivity in PMD as compared to NPMD patients and healthy controls. 3.) To compare the effects of the administration of oCRH, ACTH, hydrocortisone and saline on plasma HVA levels over the 48 hours post-injection in healthy controls, PMD patients, and NPMD patients. 4.) Utilizing intact, hypophysectomized, and adrenalectomized rats to determine which components of the HPA axis independently increase central dopamine activity, particularly in the mesocortical and mesolimbic DA systems, and to explore the mechanisms underlying such increases. Forty PMD patients, 40 NPMD patients, and 40 controls will be studied in G-CRC settings. Subjects will have blood collected for determination of ACTH, cortisol and HVA on an hourly basis for 24 consecutive hours before they receive one of the following: saline, ACTH, oCRH or hydrocortisone. Bloods will then be collected hourly for the next 24 hours and bi-hourly for the following 24 hours. Comparisons among groups of subjects will be made on basal ACTh, cortisol and HVA levels as well as on changes in these measures in response to specific challenges. Similar experiments will be conducted in intact, hypophysectomized, and adrenalectomized rats. Rats will be sacrificed at multiple time points post-challenge. Monoamines and metabolites as well as mRNA activity and protein levels primarily for tyrosine hydoxylase will be measured in specific brain regions and the periphery by RNase protection assay, radioenzymatic assay and immunotitration respectively. Where differences are found in mRNA, activity, and protein, they will be further localized cellularly by in situ hybridization and immunohistochemistry.

DESCRIPTION (provided by applicant): This is an application for competitive renewal of an institutional training grant. The intent of this training program is to prepare clinically-trained MD's, MD/PhD's, and PhD's for a career in preclinical, clinical and translational research in mood, eating, or anxiety disorders. Physicians are eligible if they have completed the PGY 3 year of psychiatry training or PGY 4 year of neurology; psychologists if they have completed a clinical internship. The program is centered on three disease entities: mood disorders, anxiety disorders, and eating disorders, reflecting the ongoing and long-standing research interests of the core faculty involved in the program. Fellows work with a mentor who is a member of the Stanford University faculty for a period of two years on projects related to the phenomenology, clinical biology (including brain imaging), basic neuroscience (including optigentics), treatment, and outcome in the three major classes of disorders. The Program includes formal seminars in research methodology, and clinical research design. All fellows are required to take a course focused on ethics in medical research. Trainees also have access to a wide array of more specialized course work. All Fellows are expected to design and conduct their own research projects. Assistance is given in preparing trainees to apply for their own funding to support their research post fellowship. Program oversight and continual review of both the program and the trainees progress is provided by an Executive Committee representing the principal areas of research and the training sites. In addition, the program has summer stipends for predoctoral fellow/medical students invested in psychiatry. The Program is now in its 19th year. Thirty-six trainees have been entered into the program in the past 10 years (6 MD/PhD's, 11 MD's and 16PhD's), including 5 Fellows (1 MD/PhD, 1 MD and 3 PhD's) who are currently in the program. Thus, the program has been successful in recruiting MD's, MD/PhD's, and PhD's, in filling the funded positions available, and in retaining fellows accepted to the program. Fellows have been successful in obtaining faculty positions around the US and Canada, Career Development Awards, R01's; NARSAD Young Investigator Awards, etc. Four post-doctoral fellows who left before completing the full 2 years: three obtained K-awards or other funding with faculty position and one obtained a full-time clinical academic position. The program has had 20 pre-doctoral medical students as well.

The proposed research is designed to study the long term consequences of being exposed to psychosocial stress (episodic vs. chronic) during infancy using a well controlled nonhuman primate model. It is based upon two recent findings from this laboratory's mother-infant (m-i) research program. First, we have found that squirrel monkey infants that had experienced repeated brief m-i separations prior to weaning displayed an earlier onset of puberty and a reduced biobehavioral response to the stress of social isolation when examined as juveniles. Second, we have established a paradigm that produces chronic stress that can be imposed m-i squirrel monkey dyads to study the long term effects of chronic stress during infancy. Increasing the difficulty to obtain food (without restricting the amount of food consumed) resulted in chronic elevation of plasma cortisol levels in both mother infants, and disruption of social relationships. The specific aims of this proposal are: 1) To assess the long term consequences of exposure to the acute and episodic stress of repeated m-i separations. We will investigate whether these effects are simply a response to removal from the mother or whether the degree of the stress associated with the separation is important. The length of separation and the environment into which the infant is placed following separation will be varied in ways that have been shown to increase or decrease the indices of stress. In addition to studying the undisturbed behavioral and physiological development of these differentially-reared monkeys, we will assess their biobehavioral responses to a variety of psychosocial stimuli (e.g., social isolation, exposure to a novel stimuli in the home cage, placement in a novel environment alone or with unfamiliar conspecifics) beginning at weaning and continuing through early adulthood. 2) To investigate the long term consequences of exposure to chronic stress during infancy. Specifically, this study will assess the long term effects of the stress associated with being reared under conditions of increased difficulty to obtain food. These offspring will be subjected to a similar battery of tests as referred to above. 3) To examine the interaction of the acute stress of m-i separation with the chronic stress of increased difficulty to obtain food. In addition to determining the long term consequences of being separated under a chronic stressful environment, this study will examine the immediate response of the m-i dyad to the challenge of brief separation and its subsequent effect on the m-i relationship upon reunion under conditions of chronic stress.

DESCRIPTION: (Adapted from applicant's abstract) This is application is competing renewal to continue previously funded studies of hypothalamic-pituitary-adrenal (HPA) dysregulation in major depression using a model of hypercortisolism in monkeys. The studies proposed are based on the assumption that this animal model will provide insights into multiple aspects of depression that are difficult to study experimentally in humans. Preliminary data from this laboratory indicates that squirrel monkeys from groupings of paternal half-siblings demonstrate prolonged hypercortisolism after removal of mothers at 9-months of age. When re-evaluated 2-4 years later these monkeys subsequently exhibit impaired performance on tests of reversal learning and memory, and smaller hippocampi based on magnetic resonance imaging (MRI). These findings are similar to neuroimaging results reported in patients with recurrent depression, and they suggest that the smaller hippocampi detected in monkeys years after assessing separation induced hypercortisolism may reflect irreversible neuron loss. However, an alternative explanation may be that smaller hippocampi are a cause, and not a consequence of sustained secretion of cortisol and related impairments seen in major depression. To date studies of hippocampal atrophy in depression have relied on cross-sectional designs, and MRI based assessments of hippocampal atrophy have not been examined at the cellular level. The aim of the research proposed is to map and quantify glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) mRNA expression in the brains of squirrel monkeys stratified by stress (social separation) and genotype (high-responsive vs. low-responsive). The focus will be on two brain regions: hippocampal subfields (CA1, CA2, CA3/4 and dentate) and hypothalamic subnuclei, particularly the paraventricular nucleus. These regions have previously been demonstrated to be critical in corticosteroid hormone mediated feedback regulation of the stress axis in rodent models. However, despite some apparent similarities between rodent and primate brain circuits, there is a paucity of data regarding CNS modulation of stress response in primates.

bipolar depression; cognition; psychosis; pathologic process; cortisol; clinical research; human subject;

This study uses the glucocorticoid -receptor antagonist RU 486 (mifepristone) to treat patients with psychotic major depression. It is hypothesized that these patients have elevated levels of cortisol which leads to a hyperdopaminergic state which in turn results in cognitive dysfunction and psychosis. There is evidence that high-dose mifepristone rapidly resolves psychotic major depression.

This study evaluates hormonal function and mental processing in individuals who are HIV+. We hope to learn which individuals will benefit significantly from group psychotherapy. The characteristics of an individual that may make them more ( or less) likely to benefit from group psychotherapy are not well understood. We hope to learn how to better recognize the physiological features (such as heart rate and blood chemistry) that differentiate some research participants who are HIV+ from others who are (or are not) HIV+. HIV+ participants are selected because they have agreed to participate in Drs Spiegel and Koopmanis' study "An Evaluation of Group Psychotherapy for People with HIV.

This study uses the glucocorticoid-receptor antagonist RU486 (mifepristone) to treat patients with a diagnosis of schizoaffective disorder. It is hypothesized that these patients have elevated levels of cortisol which leads to a hyperdopaminergic state which in turn results in cognitive dysfunction and psychosis. There is evidence that high-dose mifepristone rapidly resolves these symptoms. Clinicals were begun in mid-1998 and continue. We have collected data on 2 patients with a diagnosis of schizoaffective disorder.

This study uses the glucocorticoid-receptor antagonist RU486 (mifepristone) to treat patients with a diagnosis of psychotic major depression or schizoaffective disorder. This is a follow-up treatment step (or, "compassionate use" study) for our current mifepristone-use protocols ("Treatment of Schizoaffective Disorder Using Mifepristone"GCRC #537 and "Rapid Reversal of Psychotic Depression Using Mifepristone" GCRC #484). It is a non-randomized study providing short-term pharmaco-therapy and measuring effects over an eight-day treatment period. Clinicals were begun in mid-1998 and continue. We have collected data on 1 patient with a diagnosis of schizoaffective disorder.

hypothalamic pituitary adrenal axis; mifepristone; human therapy evaluation; major depression; dopamine; mental disorder chemotherapy; psychosis; drug screening /evaluation; clinical research; human subject;

DESCRIPTION: Recruitment Core - under Alan Schatzberg - will help recruit both patients and healthy controls. By establishing a new site in San Francisco, it will allow for a 30-40% increase in the recruitment rate and will broaden the ethnic mix by helping to recruit Asian - and Afro-Americans to the studies.

DESCRIPTION (Adapted from the Applicants Abstracts): This is an application for four years of CoGent funding to support 7 NIMH-funded R01's led by six PI's in the Departments of Psychiatry and Behavioral Sciences of Psychology at Stanford University. The R01's focus on a number of disorders - major depression with and without psychotic features, obsessive compulsive disorder, post-traumatic stress disorder, fragile X and other neurogenetic syndromes, and schizophrenia. This CoGent will increase the efficiency of the approved research of each of the studies, expand their scope, and allow for significant cross study collaborations. It consists of 3 cores - Recruitment, Statistics and Data Management, and Neuroimaging. The Recruitment Core will be located across three sites (two in Palo Alto and one in San Francisco) to increase recruitment of subjects. The San Francisco site will provide greater numbers of ethnic minority subjects for the Base Grants. The Core will facilitate subjects participating in more than one study. The Statistic and Data Management Core will assist in developing methods that can be used across studies for accessing longitudinal course and outcome (e.g. random regression models), response in randomized clinical trials (e.g. Reciever Operating Characteristics Curve Methodology), and the relative contributions of multiple risk factors. The Neuroimaging Core will offer prestudy exposure to a simulator and provide for additional scan time. A major feature of this CoGent is the application of fMRI across different populations being studied in the Base Grants. Several of the studies already use fMRI to study affect and cognition in specific disorders - e.g., schizophrenia, nonpsychotic and psychotic major depression, social phobia, fragile X, etc. The CoGent will permit utilization of standard fMRI experiments in these patient groups that will allow comparisons to be made across projects - e.g., hallucinating schizophrenic patients with hallucinating psychotic depressives. In two studies, the use of fMRI will significantly enhance the research design by exploring the specific effects of treatment on brain function.

DESCRIPTION (provided by applicant): The chronic depressive disorders, which afflict 3 percent to 5 percent of the adult population of the U.S., are potentially disabling conditions that adversely affect physical health and performance in social and vocational roles. Research conducted by our team since 1991 has documented 50 percent acute phase intent-to-treat response rates to standard antidepressants and 75 percent prophylaxis with maintenance therapy. Many experts have suggested that a combination of psychotherapy and pharmacotherapy may be the optimal treatment for chronic depression and, indeed, we have completed a study (n=681) in which the combination of nefazodone and a model of psychotherapy developed for chronic depression (Cognitive Behavioral Analysis System of Psychotherapy; CBASP) was significantly more effective than either monotherapy (intent-to-treat response rates: 75 percent vs. 48 percent vs. 45 percent). These findings have limited generalizability because of the highly restrictive nature of the protocol. Moreover, it is not clear if the more expensive combined approach ultimately results in a greater proportion of fully recovered patients, especially when compared to an optimized sequential, algorithm-guided approach to pharmacotherapy. It also appears that while CBASP alone may have a slower onset of action than pharmacotherapy alone, those who do respond to this form of psychotherapy have a more durable or enduring response. We now propose to extend these findings in an innovative multicenter trial of a diverse and representative sample of 450 chronically depressed patients, The study will encompass both acute and continuation phases of treatment. During the acute phase (lasting up to 28 weeks), patients will be randomized to one of three modalities: 1) sequential algorithm-guided pharmacotherapy (n=150), 2) CBASP alone (n=150), or 3) pharmacotherapy plus CBASP (n=150). During both the acute and continuation phase trials we predict that combined treatment will yield superior outcomes on symptom, syndromal (i.e., remission, recovery, and relapse rates), and functional measures. Across the full study duration, the treatments will be contrasted on a variety of quality of life and health economic outcomes. We predict that the extra cost of combined treatment will be at least partly offset by faster and more complete remissions. We also predict pharmacotherapy alone will have faster effects (at lower costs) than CBASP alone during the acute phase but that the CBASP group will "catch up" by the end of the continuation phase. This two stage study bridges conventional efficacy and services models of research and will make a significant impact on public health by evaluating both the utility and cost of these well-characterized treatment approaches. The study also will provide the foundation for a subsequent application evaluating longer term, maintenance phase treatments of chronic depression.

mifepristone; human therapy evaluation; schizophrenia; antipsychotic agents; mental disorder chemotherapy; major depression; cognition; adrenocorticotropic hormone; cortisol; patient oriented research; human subject; clinical research;

[unreadable] DESCRIPTION (provided by applicant): The proposed research continues previously funded studies of behavioral, cellular, and molecular genetic aspects of hypothalamic-pituitary-adrenal (HPA)-axis regulation and post-stress recovery. The central hypothesis is that diminished hippocampal volume is a cause and not just an effect of stress-related psychopathology as modeled in adult female monkeys. Female animal models of stress-related depressive disorders are important because prevalence rates of depression in women are nearly two-times higher than in men. There is also a need to bridge the gap between brain imaging studies of humans with major depression and animal models that focus on cellular and molecular levels of neuroscience research. In this regard, nonhuman primates offer attractive opportunities for cross-disciplinary translational research. The studies proposed here test in monkeys the following specific predictions. Adult females with small hippocampal volumes (i.e., selected from the bottom third of a normal distribution) determined before initiation of the study will respond to repeated exposure to cycles of social isolation-induced hypercortisolism with impaired spatial memory, increased anhedonia, and HPA-axis dysregulation as compared to females with large hippocampi (i.e., top third of the distribution) exposed to cycles of social isolation, or matched female monkey controls housed continuously in pairs. In response to subsequent social stimulation after each cycle of social isolation, females with small hippocampi will show an impaired capacity for recovery. Females exposed to cycles of isolation and social stimulation will also exhibit hippocampal volume loss as compared to matched female controls housed continuously in pairs. The behavioral and neuroendocrine effects of hippocampal atrophy will be greatest in females with initially small hippocampal volumes as predicted by a threshold model described in the Research Plan. Adult females with initially small hippocampi will respond to repeated isolation and social stimulation with diminished hippocampal neurogenesis and increased glucocorticoid receptor gene expression compared to females with equally small hippocampi housed in stable pairs. These studies cross the boundaries of molecular, cellular, and behavioral neuroscience with the ultimate goal of building a foundation for improved treatments and the prevention of major depression by elucidating the relationship between hypercortisolism and hippocampal volume. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The goal of the ongoing NIMH funded multi-site study entitled "Research Evaluating the Effect of Augmenting Medication with Psychotherapy" (REVAMP) is to investigate psychotherapeutic strategies for treating chronic forms of major depression unresponsive to medication alone. Patients (n = 909) are treated initially with one of several pharmacologic strategies, as guided by a staged algorithm. Those who do not remit after up to 12 weeks of treatment (estimated n = 500) receive the next algorithm-guided pharmacotherapy. In addition they are randomized to Cognitive Behavioral Analysis System of Psychotherapy (CBASP), Supportive Psychotherapy (SP), or Clinical Management (CM). At exit from this 12-week randomized therapy trial all consenting patients enter a 24-month naturalistic follow-up to investigate the durability of the acute approaches in keeping patients well. It is hypothesized that patients who received augmentation with CBASP in addition to switching medication will have better long-term outcomes (e.g., more time in remission, lower symptom ratings, better social adjustment) than patients receiving a medication switch alone, and patients who received SP augmentation will fall in between. We also hope to test whether the long-term effects of CBASP are mediated by teaching patients more effective social problem-solving skills. We now are submitting a competing continuation application to complete the final 3 years of the follow-up. Some prior studies have showed enduring effects of psychotherapy in depressed patients (although not in chronic forms of MOD), but other studies have failed to find such an effect, including the NIMH Collaborative Treatment Study. This follow-up study will address the important question of whether augmentation with 12 weeks of CBASP, a therapy developed specifically for chronic depression, leads to enduring effects in a chronic sample over that provided by pharmacotherapy alone or in combination with a less specific form of psychotherapy.

DESCRIPTION (provided by applicant): This is an application in response to RFA-Recovery Act Limited Competition: Supporting New Faculty Recruitment to Enhance Research Resources through Biomedical Research (P30) ~ to provide support for recruitment of a junior faculty clinician scientist to work in and further develop a multidisciplinary program in the area of biomarkers of mood disorders. We are currently searching for an assistant professor to work on functional brain imaging biomarkers of mood disorders across the lifespan. The faculty member will have a primary appointment in the Department of Psychiatry and Behavioral Sciences at Stanford University Medical School and will be a member of the Stanford University Mood Disorders Center. The specific aims of the proposal are: 1. To provide start up funding for an assistant professor, clinician scientist with a primary interest in mood disorders with a particular emphasis on functional magnetic resonance imaging (f-MRI) studies aimed at elucidating the neurobiology of these disorders. 2. To provide an enriched interdisciplinary environment to support the continued research career development of junior faculty member(s). 3. To provide funding for interdisciplinary pilot studies on f-MRI of depressed and/or anxious patients and controls across the lifespan. An example of the type of indisciplinary research proposed is reflected in recent work pointing to potential differences in the processing and regulation of emotion in patients with major depression or generalized anxiety disorder, and to test these biomarkers on noncomorbid and comorbid cohorts of patients with these disorders. Anxiety- and depression-related biomarkers identified in this core set of experiments will then be applied in adolescent and geriatric pilot studies. Taken together, these studies may help our understanding of the pathophysiology of depression across the life span. PUBLIC HEALTH RELEVANCE: Mood disorders are extremely common and are associated with great morbidity. Interdisciplinary research involving brain imaging can help understand the biological bases of major depression and aid in differential diagnosis and treatment development. A junior faculty will be supported to conduct research that can help our understanding of the development of depression across the lifespan.

DESCRIPTION (provided by applicant): In the past two decades, the reduced number of clinical scientists who pursue mental health research coupled with a high rate of attrition among those who enter the field are threatening our nation's ability to leverage advances in basic biomedical and behavioral sciences into improvements in public health. The specific aim of the Research Career Development Institute for Psychiatry (CDI), to be accomplished through this R25 application, is to provide the necessary skill set and support to a nationally selected broad-based group of promising young psychiatrists and PhD researchers in order to launch and maintain successful research careers in academic psychiatry. The program is geared toward individuals at the critical transition point between the completion of research training and their initial faculty appointment or very early in the initial appointment. The proposed program will help fill this training gap by providing the necessary skill set and guidance in a multi-faceted longitudinal training experience, including a comprehensive program of career and skills self-assessment, individualized career goal setting, a four-day workshop, structured long- distance career mentoring and goal tracking, webinars (online meetings) and tutorials, and a multi-tiered program evaluation. Targeted career skills identified as critical to beginning and maintaining a successful career in research psychiatry will include: writing (grants, particularly a K-series award, and manuscripts), negotiating (for a faculty position, salary, benefits, space, facilities, research time, etc.), time management (particularly for writing) and juggling multiple demanding responsibilities, responsible conduct of research, networking, project management (such as hiring staff, supervision, budgeting, lab management), and mentoring. Career development activities will occur in four phases over a 24-month period for each annual class of 20 participants: online baseline career and skills self-assessment, didactic learning and preparations for four-day in-person workshop and goal setting, long-distance structured mentoring and online continued learning, and post-program career progress and process evaluation. The CDI program website, www.CDIPsych.org, will be the portal through which career goals and progress are measured and monitored, coaching and mentoring sessions take place, and virtual meetings are held throughout the 24- month training period. A Peer Advisory Council consisting of past CDI participants provides two-fold added value: (1) attendees get to hear from colleagues just a few years ahead of them in their research career trajectory and may identify more with them than with established investigators, and (2) it gives the PAC member an early career opportunity to provide mentoring to others and to participate at a faculty/teacher level. The proposed longitudinal program of education, training, mentoring, peer support, and communications for individuals making the transition to academic research should potentially help increase the number of scientists committed to research careers in mental health. PUBLIC HEALTH RELEVANCE: The number of physician scientists experienced in mental health research in this country is dwindling yet the number of people experiencing mental illness is on the rise. The Career Development Institute for Psychiatry proposes a longitudinal program of education, training, mentoring, peer support, and communications to support these individuals in carrying out their research career paths and to potentially increase the number of scientists committed to research careers in mental health.