Dominique L. Musselman - US grants

DESCRIPTION (Adapted from the Applicant's Abstract): The training and research components of this application for a Scientist Development Award for New Minority Faculty are designed to prepare the applicant for a career as an independent investigator at the interface of the basic and clinical sciences. The career development plan, modeled after the Ph.D. program in biological sciences, will provide the scientific knowledge base and specific laboratory techniques required to conduct the proposed research. Supervised case management in addition to tutorials in hematology, cardiology, and psychiatric assessment will develop the applicant's clinical skills. The research plan focuses on the relationship between major mood disorders and thrombotic disease. Not only are platelets a source of vasoactive mediators that regulate vascular tone, but they also play a role in intravascular thrombus formation and dynamic coronary constriction that results in myocardial ischemia. There is considerable evidence that patients with ischemic heart disease (IHD) and concurrent major depression have a less favorable prognosis than patients with IHD alone. Recent studies have revealed that major depression is a very significant risk factor for death after myocardial infarction and stroke and not simply a nonspecific emotional response to cardiovascular illness. The overall objective of the proposed work is to investigate further this interaction between major depression and the hemostatic system, especially major depression. The research aims are to determine: 1) whether depressed patients without cardiovascular disease exhibit exaggerated platelet reactivity under basal conditions, 2) whether platelet responsiveness to orthostatic challenge and standard inducers of aggregation are altered in patients with major depression, and 3) if pharmacologic treatment of depressed patients with paroxetine (a potent and selective serotonin reuptake inhibitor) is associated with alteration of platelet responsiveness to orthostatic challenge, and to standard inducers of aggregation. To accomplish these aims, platelet function and severity of depression willbe evaluated longitudinally before and after treatment with either placebo or paroxetine. Additionally, the in vitro activity of paroxetine on platelet activity will be evaluated. Future investigators would expand these findings to depression by evaluation and treatment of depressed patients at risk for IHD (e.g., those with hypertension, hyperlipidemia, etc...) and patient post-myocardial infarction with comorbid depression. These studies will provide novel information on the biological basis for the apparent increased vulnerability of depressed patients to IHD.

Several studies have shown that major depression and associated symptoms, such as hopelessness, are a major independent risk factor in development of ischemic heart disease (IHD), and for death after an index myocardial infarction. Not only do platelets play a central role in hemostasis, atherosclerosis, and acute coronary syndromes, but patients with major depression exhibit increased numbers of the functional platelet GPIIb/IIIa receptor, the receptor for fibrinogen and other ligands, and the final common pathway by which platelet aggregation and adhesion occurs. The overall goal is to determine in patients with major depression, the specific molecular pathways, and relative contributions of these pathways, whereby the platelet GPIIb/IIIa receptor is converted from a low- affinity to high-affinity conformation. To accomplish this goal, we will scrutinize in men with unipolar, recurrent, major depression, not only depression severity and platelet GPIIb/IIIa receptors, but characterize platelet autocrine "feed forward" pathways via: platelet serotonin (5HT) and 5HT2 receptors, platelet adenosine triphosphate (ATP) release, and urinary excretion of 11-dehydrothromboxane beta2: (1) under controlled basal conditions, (2) after the Trier Social Stress Test (a sustained mental stressor which will stimulate platelet function via peripheral release of the platelet agonist epinephrine). Moreover we will determine the molecular mechanisms whereby antidepressant treatment reduces numbers of high-affinity GPIIb/IIIa receptors, using randomized, double-blind, treatment with paroxetine (a selective 5HT reuptake inhibitor) in comparison to desipramine (a noradrenergic tricyclic). State-of- the-art techniques will be used, including fluorescence activated flow cytometry (FAFC), platelet calcium mobilization, and evaluation of in vitro antidepressant direct "drug effects" of upon platelet function. Novel information will be gleaned regarding not only the biological basis for the increased vulnerability of depressed patients to IHD, but also potential thrombovascular targets whereby psychopharmacologic interventions might reduce the future risk of heart attack and sudden death in patients with major depression.

DESCRIPTION (provided by applicant): African-Americans have increased prevalence of both diabetes and diabetes complications, reflecting combined psychobehavioral and metabolic dysfunction. Depression may contribute to both the genesis of Type 2 diabetes, and difficulties in management; we find that many African-Americans with diabetes also have depression, that depression is a factor in nonadherence, and that nonadherence leads to poor glycemic control- a major cause of complications. (1) To establish the prevalence, socioecoloqic associates, and. qlycemic impact of depression, we will study patients presenting to the Grady Diabetes Clinic; evaluate socioeconomic status, literacy, and access to care; and relate depression to these factors and to metabolic control both at presentation and after one year of care. (2) To define the pathways through which depression contributes to metabolic imbalance, we will study patients exposed to progressive psychobehavioral challenge (depression and/or early life stress), and assess (a) hypothalamic-pituitary-adrenal activation; (b) counter-regulatory hormones; and (c) immunoinflammatory cytokines; in relation to (d) insulin resistance. (3) To determine the psychobehavioral and neurohormonal mechanisms of treatment, we will conduct a randomized, placebo-controlled, double-blind trial: patients with depression will receive stress management videotapes and either placebo or the selective serotonin reuptake inhibitor (SSRI) citalopram, and we will assess (a) overall glycemic control (HbAlc levels), and (b) patient adherence -to a prescribed diet/exercise program, to use of medications, and to scheduled return appointments; in relation to (c) depressive symptoms and (d) neurometabolic function as defined in Aim #2. These questions will be addressed by a multidisciplinary team with experience in both neuroendocrine analysis, clinical psychiatry, and diabetes management. The goal of this proposal is to use state-of-the-art psychobiological techniques to define the neurobehavioral and neurometabolic abnormalities and their response to treatment in urban African-Americans with type 2 diabetes and depression, as needed to improve basic understanding of disordered metabolism in this patient population and to help relieve their disparity in health.

citalopram; human therapy evaluation; psychological stressor; psychopharmacology; mental disorder chemotherapy; early experience; clinical depression; desipramine; neuroendocrine system; platelets; patient oriented research; human subject; clinical research;

[unreadable] DESCRIPTION (provided by applicant): D. Increasing data implicate cytokines in the development of behavioral alterations in patients with a wide range of medical illnesses including cancer; patients with medical illnesses exhibit rates of depression 5-10 times higher than the general population. Depression in the medically ill is associated with reduced treatment adherence, impaired quality of life, and in several studies, increased morbidity and mortality. Model systems to study the neurobiology and treatment of cytokine-induced depression are needed to develop new strategies to help diagnose and manage depression in the medically ill. One such model system involves patients receiving the cytokine interleukin (IL)-2. This T cell cytokine is used to treat patients with cancer and causes profound behavioral alterations including depressed mood, anhedonia, anorexia, fatigue, cognitive dysfunction (especially memory impairment), altered sleep and psychosis, symptoms that overlap with many of those of major depression. In addition, IL-2 potently activates the hypothalamic-pituitary adrenal (HPA) axis and alter neuretransmitter metabolism, while activating the release of other cytokines (e.g.lL-6) that have been implicated in mood disorders. We plan to characterize neuropsychiatric, neuroendocrine and immune changes in patients undergoing IL-2 treatment for malignant melanoma and evaluate whether an antidepressant can prevent these changes. 70 patients with Stage IV malignant melanoma (ages of 18 to 75 years old) will be studied before and during intravenous (IV) IL-2 treatment [720,000 units/kg Q8 hours X 5 days (1 cycle) every 3 weeks X 4 cycles]. Two weeks prior to IV IL-2 therapy, patients will enter a randomized, double-blind treatment trial comparing 14 weeks of treatment with the antidepressant paroxetine, versus placebo. We will determine whether paroxetine will: a) diminish IL-2-associated neuropsychiatric symptoms, b) reduce IL-2-associated increases in ACTH and cortisol and increase glucocorticoid sensitivity, c) prevent IL-2-induced decreases in serotonin metabolism as manifested by decreased plasma tryptophan and 5HT and increased plasma kyneurinine, and d) improve the number of IL-2 doses tolerated. We will also correlate specific neuropsychiatric symptoms (including memory impairment and psychosis) with HPA axis and immune function both prior to, and during, IL-2 therapy, and determine the impact of paroxetine on these relationships. These studies will provide insights into differential mechanisms of symptom development and treatment response during cytokine therapies. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): D. Increasing data implicate cytokines in the development of behavioral alterations in patients with a wide range of medical illnesses including cancer;patients with medical illnesses exhibit rates of depression 5-10 times higher than the general population. Depression in the medically ill is associated with reduced treatment adherence, impaired quality of life, and in several studies, increased morbidity and mortality. Model systems to study the neurobiology and treatment of cytokine-induced depression are needed to develop new strategies to help diagnose and manage depression in the medically ill. One such model system involves patients receiving the cytokine interleukin (IL)-2. This T cell cytokine is used to treat patients with cancer and causes profound behavioral alterations including depressed mood, anhedonia, anorexia, fatigue, cognitive dysfunction (especially memory impairment), altered sleep and psychosis, symptoms that overlap with many of those of major depression. In addition, IL-2 potently activates the hypothalamic-pituitary adrenal (HPA) axis and alter neuretransmitter metabolism, while activating the release of other cytokines (e.g.lL-6) that have been implicated in mood disorders. We plan to characterize neuropsychiatric, neuroendocrine and immune changes in patients undergoing IL-2 treatment for malignant melanoma and evaluate whether an antidepressant can prevent these changes. 70 patients with Stage IV malignant melanoma (ages of 18 to 75 years old) will be studied before and during intravenous (IV) IL-2 treatment [720,000 units/kg Q8 hours X 5 days (1 cycle) every 3 weeks X 4 cycles]. Two weeks prior to IV IL-2 therapy, patients will enter a randomized, double-blind treatment trial comparing 14 weeks of treatment with the antidepressant paroxetine, versus placebo. We will determine whether paroxetine will: a) diminish IL-2-associated neuropsychiatric symptoms, b) reduce IL-2-associated increases in ACTH and cortisol and increase glucocorticoid sensitivity, c) prevent IL-2-induced decreases in serotonin metabolism as manifested by decreased plasma tryptophan and 5HT and increased plasma kyneurinine, and d) improve the number of IL-2 doses tolerated. We will also correlate specific neuropsychiatric symptoms (including memory impairment and psychosis) with HPA axis and immune function both prior to, and during, IL-2 therapy, and determine the impact of paroxetine on these relationships. These studies will provide insights into differential mechanisms of symptom development and treatment response during cytokine therapies.