Charles Raison - US grants

DESCRIPTION (provided by applicant): The training and research components of this Research Career Development Award application are designed to prepare the applicant for a career as an independent investigator in the area of mind-body interactions. The long-term objectives are to examine bi-directional relationships between the hypothalamic-pituitary-adrenal (HPA) axis and the immune system and determine the effect of these interactions on the regulation of mood and related neurovegetative functions in medically ill patients. The applicant will devote the 5-year K23 project period to combining his expertise in clinical diagnosis and treatment with rigorous training in neuroimmunology and neuroendocrinology, as well as in research methodology, data organization, biostatistics, and the ethical conduct of research. The training program will consist of an integrated curriculum of formal didactic course work and tutorials with the sponsor and other consultants. The applicant's immediate research goal during the award period will be to examine the relationship between immune system activation and glucocorticoid resistance in patients who develop depressive symptoms during treatment with interferon (IFN)-alpha for chronic hepatitis C virus (HCV) infection. The hypotheses to be tested are as follows: 1) Chronic treatment with IFN-alpha will induce resistance to the inhibitory effects of endogenous glucocorticoids leading to unrestrained release of corticotropin-releasing hormone (CR1-I) and proinflammatory cytokines in the CNS, which in turn will lead to depressive symptoms and 2) Impaired glucocorticoid feedback inhibition at baseline (prior to IFN-alpha treatment) will predict depressive symptoms as a result of relatively unrestrained immune system activation and release of CRH during IFN-alpha therapy. To test these hypotheses, the following specific aims are proposed: 1) To measure concentrations of the proinflammatory cytokines interleukin (IL)-l, IL-6 and tumor necrosis factor-alpha (TNF-alpha), and CRH in cerebrospinal fluid (CSF) of 100 patients with HCV, randomized to receive IFN-alpha treatment or to post-pone treatment until study completion, 2) To determine the correlation among CSF concentrations of proinflammatory cytokines and CRH and behavioral endpoints in these patients, and 3) To explore the effect of chronic IFN-alpha treatment on sensitivity to glucocorticoid-mediated inhibition and to determine the relationship between glucocorticoid-mediated negative feedback and concentrations of IL-1, IL-6, TMF-alpha and CRH in CSF of IFN-alpha-treated patients. All subjects will undergo in vivo and in vitro assessment of sensitivity to glucocorticoid inhibition of the HPA axis and immune system at baseline (prior to beginning IFN-alpha for subjects randomized to active treatment) and again one month later. At study week 12, subjects will receive a lumbar puncture to measure CSF concentrations of CRH, arginine vasopressin and proinflammatory cytokines. Results from this study will enable further understanding of the pathways by which mood disorders arise out of conditions of immune activation and will provide the foundation for the development of novel strategies to treat depression in the medically ill.

hepatitis C; interferon alpha; phenotype; psychoneuroimmunology; microorganism disease chemotherapy; drug adverse effect; clinical depression; immunotherapy; body temperature; interleukin 1; sleep; basal metabolism; interleukin 6; tumor necrosis factor alpha; clinical research; human subject;

DESCRIPTION (provided by applicant): Increasingly recognized as a health burden of global proportions, depression is especially devastating in the context of medical illness. Indeed, depression increases morbidity and hastens mortality across a range of medical disorders. Recent conceptual developments regarding the pathophysiology of depression in the medically ill have focused on the potential role of immune activation/inflammation and the associated release of proinflammatory cytokines. Proinflammatory cytokines induce symptoms of sickness that overlap with major depression and induce the production and release of central nervous system (CNS) corticotropin-releasing hormone (CRH), which is believed to be a key mediator of depression. The long term objective of this R01 application (the Pl's first R01 application) is to further understand the potential role of cytokine-induced CRH in the development of depression in the medically ill. As a model system, we propose to study patients receiving the cytokine, interferon-alpha (IFN-alpha) for the treatment of hepatitis C virus infection (HCV). IFN-alpha potently induces proinflammatory cytokines and leads to depressive symptoms in 30-50% of patients, depending on the dose. In animals, IFN-alpha stimulates the production and release of CRH within the CNS, and blocking CNS CRH attenuates IFN-alpha induced sickness behavior. Our preliminary data indicates that patients who demonstrate hyperactivity in CRH-mediated neuroendocrine pathways in response to a first dose of IFN-alpha have an increased risk of developing depression during IFN-alpha therapy. We have also shown that early life stress (ELS) is associated with sensitization of CRH pathways, indicating a potential link between stress sensitivity and the risk for developing depression during cytokine therapy. We hypothesize that a) patients who demonstrate CRH hyperacitvity in response to an immune challenge will also demonstrate hyperactivity in response to a psychological stressor, and b) hyperactivity to both types of stressors will be associated with the development of IFN-alpha induced depression. Moreover, we anticipate that patients with a history of ELS, current life stress and/or a personal or family history of depression will demonstrate increased CRH reactivity to immunological and psychological stressors. To test these hypotheses, 50 subjects receiving IFN-alpha/ribavirin for HCV will be evaluated for neuroendocrine responses to an immune challenge (first dose of IFN-alpha) and a laboratory psychological stressor (Trier Social Stress Test). Depressive symptoms will be evaluated at baseline and during 12 weeks of treatment with IFN-alpha/ribavirin. All assessments will be conducted in parallel in 25 HCV+ patients randomized to postpone IFN-alpha during the study period (HCV+ controls). Results from these studies will provide important new data on CRH as a potential vulnerability factor for depression in the medically ill and will establish a foundation for developing novel treatment strategies for depression in these patients.

DESCRIPTION (provided by applicant): Accumulating data suggest that activation of the innate immune inflammatory response may contribute to the development of major depression. Medically healthy patients with depression exhibit increased plasma concentrations of inflammatory mediators including cytokines of the innate immune system, and administration of innate immune cytokines to animals and humans induces behavioral alterations that overlap with major depression. In addition, cytokines of the innate immune response interact with pathways implicated in the pathophysiology of depression. Increasing interest in targeting the immune system for the treatment of depression has focused on tumor necrosis factor (TNF)-alpha. Plasma concentrations of TNF-alpha have been found to be elevated in patients with major depression, and TNF-alpha is known to activate signaling pathways that alter HPA axis function, monoamine metabolism and synaptic plasticity;all of which are pathophysiologic domains relevant to the development of major depression. Furthermore, laboratory animals with the TNF-alpha receptor gene knocked out exhibit an antidepressant-like phenotype, and the efficacy of traditional antidepressants (i.e. monoamine reuptake inhibitors) has been shown to be related in part to effects on TNF. Finally, antagonism of TNF-alpha activity has been shown to improve depressive symptoms in patients with autoimmune disorders. The long-term goal of the proposed work is to test the cytokine hypothesis of depression using a TNF-alpha antagonist. In the current project, we plan to measure the behavioral response of depressed patients to a single infusion of the TNF-alpha antagonist, infliximab. Given the potential health risks of TNF-alpha antagonism, the proposed study will focus on medically healthy patients with both treatment resistant depression (TRD) and evidence of activation of the innate immune response. TRD is a common and significant public health concern with debilitating consequences in terms of both morbidity and mortality. Interestingly, patients with TRD also appear to be more likely than treatment responsive patients to demonstrate innate immune system activation. We hypothesize that 1) infliximab infusion will decrease depressive symptoms in patients with TRD and increased markers of inflammation and 2) that decreases in depression will correlate with infliximab-induced decreases in TNF-alpha activity and other downstream elements of the innate immune inflammatory response. To test these hypotheses, sixty antidepressant-free subjects with TRD will be randomized in double-blind fashion to a single infusion of infliximab versus saline. Subjects will undergo regular neurobehavioral, immunologic and safety assessments at baseline and at weeks 1, 2, 4, 6 and 8 following infliximab infusion. The proposed translational research will provide novel insights into the role of TNF-alpha in depression and will help define potential biomarkers that predict or monitor success of anti-TNF-alpha therapy.Major depression is the fourth leading cause of overall health burden in the world. Non-response to currently available therapies in up to 30% of depressed patients is a primary contributor to the human and economic cost of the disease. This application proposes to evaluate the novel therapeutic strategy of blocking the cytokine tumor necrosis factor (TNF)-alpha as an intervention for treatment-resistant depression, based on data suggesting that overactive immune system responses, including excessive release of cytokines like TNF- alpha, may contribute to the pathophysiology of the disorder.

DESCRIPTION (provided by applicant): The increasingly widespread use of meditation for stress-related emotional and medical conditions highlights the urgent need to rigorously evaluate mechanisms through which the benefits of practice might be conferred. Primary challenges in this regard include evaluating dose response relationships between practice time and outcomes; clarifying whether physiological and behavioral effects of meditation derive primarily from non-specific aspects of training or result from specific meditation practices; and identifying molecular mechanisms by which meditation might affect physiological responses relevant to stress-related illness. Recent findings from a cross-sectional study by our group indicate that young adults who are randomized to, and practice, compassion meditation demonstrate reduced inflammatory responses, less emotional distress, and reduced autonomic responses to a standardized laboratory psychosocial stressor (Trier Social Stress Test [TSST]) when compared to subjects randomized to an active control condition. However, as a result of the cross-sectional study design and lack of a meditation comparator arm, these results provide only partial insight into key issues outlined above regarding the role played by specific meditation procedures and/or practice time in observed physiological and behavioral outcomes. The primary hypothesis of the proposed work is that practicing a meditation procedure specifically designed to enhance empathic concern for others (i.e. compassion meditation) will optimize autonomic reactivity to psychosocial stress in a manner that results in diminished activation of peripheral inflammatory signaling pathways and reduced behavioral distress. To test this hypothesis, the following aims are proposed: Aim 1: to use a longitudinal design to definitively establish that practice time contributes to the effect of compassion meditation on in vivo inflammatory and behavioral responses to psychosocial stress; Aim 2: To examine whether the effect of compassion meditation on behavioral and inflammatory responses to psychosocial stress results specifically from training in the generation of empathic concern for others or derives more generally from learning the basic meditative practices of focused attention and mindfulness; and Aim 3: to investigate autonomic mechanisms by which meditation may attenuate stress-induced inflammation. To accomplish these aims, the current study will randomize 360 medically healthy adults to 6 weeks of either compassion meditation training, Mindful Attention Training (to control for exposure to the basic meditation practices of attention and mindfulness) or a health education discussion group (to control for potential non-specific elements such as group support). Prior to, and upon completion of these interventions, all subjects will undergo TSST testing in order to assess inflammatory, autonomic and behavioral responses to psychosocial stress. Health-relevant behavioral and lifestyle factors will also be assessed to evaluate their contribution to the effect of meditation on inflammation. The long-term health implications of this study will likely be far reaching given evidence that inflammatory pathways represent an important mechanism by which stress promotes and/or worsens many medical and psychiatric conditions.

DESCRIPTION (provided by applicant): Excluding certain insects, humans are the Earth's supremely social species. Befitting this status, it is increasingly clear that social processes are a prime determinant of human health. Whether conceptualized as social integration or social support, positive social connectivity (PSC) has been shown in hundreds of studies to protect against illness development, to reduce morbidity once illness is established and to reduce mortality from an array of natural causes. Conversely, negative social processes (NSP)-whether measured as loneliness, social isolation or interpersonal conflict-predict disease development and concomitant increases in disease-related morbidity and mortality. The current proposal has been designed to identify behavioral and physiological mechanisms through which PCS/NSP interact with psychosocial stress to promote resilience in the context of illness, A central innovation of the current project is that assessments of social processes and stress reactivity will not rely on first person report, on generalizations across a number of circumstances or on retrospective reporting. Rather, PSC/NSP and stress reactivity will be assessed objectively-that is from a third person perspective-in real time and in specific situations. Similarly, rather than relying on the vagaries and complexities of natural disease processes to supply health-relevant behavioral outcomes, we model inflammation (a central element of all disease states) through the use of treatment with interferon (IFN)-alpha, which provides a standardized regimen of chronic cytokine exposure known to produce profound behavioral disturbances, including depression, fatigue and sickness, in a high percentage of individuals. To objectively assess social processes, the current project will employ the Electronically Activated Recorder (EAR), which periodically and unobtrusively records snippets of ambient sounds in people's momentary environments. Participants wear the device while going about their lives. In tracking moment-to-moment ambient sounds, it yields acoustic logs of their behaviors and interactions as they naturally unfold. To objectively assess behavioral and physiological responses to psychosocial stress the current project will employ the Trier Social Stress Test (TSST), a standardized laboratory stressor known to reliably activate behavioral, neuroendocrine and inflammatory responses. These novel methodologies and model systems will be employed to test the hypotheses that (a) pre-existing affiliative and prosocial behavior will promote resilience in the context of chronic inflammation and that (b) -conversely-chronic inflammation will reduce affiliative and prosocial behavior via effects on stress reactivity, neuroendocrine function and sleep. Finally, it will explore (c) the potential mediating role of stress physiology. To test these hypotheses, 120 subjects with chronic hepatitis C virus infection will be randomized to receive treatment with pegylated IFN-alpha plus ribavirin or to postpone treatment for 8 weeks. Prior to randomization and 8 weeks later all subjects will be evaluated with the EAR in their home environments and will undergo TSST, 14 hour diurnal neuroendocrine and immune measurement and overnight sleep polysomnography in the Atlanta Clinical and Translational Science Institute Clinical Interactions Network site at Emory University.