Phenotyping Major Depression with Increased Inflammation

炎症加剧的重度抑郁症表型分析

基本信息

批准号：
8625336
负责人：
ANDREW H MILLER
金额：
$ 42.75万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8625336
关键词：
Acetic Acids American Heart Association Anti-Cytokine Therapy Antidepressive Agents Basal Ganglia Behavioral Bioinformatics Biological Markers Blood Blood specimen Body mass index Cardiovascular Diseases Centers for Disease Control and Prevention (U.S.)Cerebrospinal Fluid Characteristics Classification Clinical Communicable Diseases Complement Corticotropin Cytokine Signaling Data Depressed mood Depressive Syndromes Development Diabetes Mellitus Diagnosis Digit structure Dioxygenases Disease Dopamine Early-life trauma Elements Equipment and supply inventories Exhibits Fatigue Fingers Flow Cytometry Fostering Gene Activation General Hospitals Genes Glucocorticoid Receptor Glucocorticoids Guidelines Homovanillic Acid Hour Hydrocortisone Immune Immunologics In Vitro Inflammation Inflammatory Inflammatory Response Inpatients Interferon-alpha Interleukin 2 Receptor Interleukin 6 Receptor Interleukin-1 beta Interleukin-6 Kynurenic Acid Kynurenine Life Stress MAPK14 gene Major Depressive Disorder Malignant Neoplasms Massachusetts Measures Medical Mental Depression Messenger RNA Metabolism Methods Microarray Analysis Monocyte Chemoattractant Protein-1 Montgomery and Asberg depression rating scale NF-kappa B Neurobiology Neurocognitive Neuropsychological Tests Neurosecretory Systems Neurotransmitters Nitric Oxide Norepinephrine Pathway interactions Patient Self-Report Patients Pattern Performance Peripheral Blood Mononuclear Cell Phenotype Plasma Play Polysomnography Population Prevention Protein Isoforms Proteins Psychosocial Stress Questionnaires Quinolinic Acid Reaction Time Relative (related person)Research Resistance Resources Risk Risk Factors Role Sampling Serotonin Signal Pathway Sleep Speed Staging Stress Subgroup Symptoms Testing Therapeutic Intervention Tryptophan Tumor Necrosis Factor-alpha anakinra base cancer therapy chemokine cytokine depressive symptoms design disorder prevention endophenotype glucocorticoid receptor alpha glucocorticoid receptor beta human MAPK14 protein hydroxyindole improved indexing indoleamine inflammatory marker monoamine neurocognitive test neuropsychiatry neuropsychological neurotransmitter metabolism novel novel strategies patient population pediatric trauma peripheral blood pleasure public health relevance receptor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): To facilitate the development of a personalized approach to the treatment of patients with major depression, this study is designed to elaborate the clinical and neurobiological phenotype of depressed patients with increased inflammation. Mounting data suggest that inflammation may play an important role in the development of major depression. For example, cytokines released as part of the inflammatory response have been found to interact with virtually every pathophysiologic domain relevant to depression including neuroendocrine function and neurotransmitter metabolism. Of note, depressed patients with increased inflammation may be less responsive to conventional antidepressant therapy and may be at increased risk for other medical disorders. Preliminary data from our group suggest that depending on the patient population one third or more of patients with major depression exhibit increased inflammation as reflected by a plasma c- reactive protein (CRP) concentration >3mg/L. Nevertheless, the clinical and neurobiological phenotype of depressed patients with increased inflammation has yet to be established. Data on the impact of the inflammatory cytokine, interferon (IFN)-alpha, on patients with infectious diseases and cancer may provide important clues regarding features that may be uniquely associated with increased inflammation in patients with major depression including 1) prominent neurovegetative symptoms such as psychomotor retardation and fatigue; 2) flattening of the diurnal cortisol curve; and 3) increased plasma and cerebrospinal fluid (CSF) concentrations of metabolites of indoleamine 2,3 dioxygenase including kynurenine, quinolinic acid and kynurenic acid, which has been shown to reduce dopamine release in the basal ganglia. These neurobiologic changes in turn have been associated with IFN-alpha-induced increases in peripheral blood and/or CSF concentrations of tumor necrosis factor-alpha and interleukin-6 and their soluble receptors as well as chemokines such as monocyte chemoattractant protein-1. In addition, relevant cytokine signaling pathways including p38 mitogen activated protein kinase appear to be involved. To test the hypothesis that these clinical and neurobiological features associated with IFN-alpha will also be associated with increased inflammation in patients with major depression, 150 depressed patients with high (n=50), medium (n=50) and low (n=50) inflammation (as defined by a CRP >3, 1-3 and <1 mg/L, respectively) will be examined. All subjects will undergo neuropsychiatric assessments and blood and CSF sampling for the above noted variables during a 2- day inpatient stay. In addition, given the association of early life stress, increased body mass index, treatment resistance and dysregulated sleep with inflammation, these factors will also be examined. Elaboration of pathophysiologic pathways (and related endophenotypes) specific to depressed patients with increased inflammation will foster development of new therapies and biomarkers relevant to an individualized approach to diagnosis, treatment and prevention of major depression.

描述（由申请人提供）：为了促进对严重抑郁症患者治疗的个性化方法的开发，该研究旨在详细介绍抑郁症患者的临床和神经生物学表型，炎症增加。安装数据表明，炎症可能在重大抑郁症的发展中起重要作用。例如，发现作为炎症反应的一部分释放的细胞因子与几乎所有与抑郁症有关的病理生理结构域相互作用，包括神经内分泌功能和神经递质代谢。值得注意的是，炎症增加的抑郁症患者对常规抗抑郁治疗的反应可能较小，可能会增加其他医疗疾病的风险。我们小组的初步数据表明，根据患者人群三分之一或多个严重抑郁症患者的炎症增加，如血浆C反应性蛋白（CRP）浓度> 3mg/L所反映的那样。然而，尚未确定抑郁症患者的临床和神经生物学表型尚未确定。关于炎症细胞因子，干扰素（IFN） - α，对感染性疾病和癌症患者的影响的数据，可能会提供有关特征的重要线索，这些线索可能与大量抑郁症患者的炎症有关，包括1）突出的神经抑郁症患者，包括1）突出的神经抑郁症状，例如精神抑制和疲劳； 2）昼夜皮质醇曲线的扁平；和3）吲哚美蛋白的代谢产物的血浆和脑脊液（CSF）浓度增加了2,3二氧酶，包括甲磺酰氨酸，喹啉酸和Kynurenaric酸，已显示出可减少基础神经节中多巴胺释放的二尿酸。这些神经生物学的变化又与IFN-alpha诱导的肿瘤坏死因子因子-Alpha和interleukin-6及其可溶性受体以及趋化因子以及诸如单核细胞化学剂蛋白质蛋白-1的趋化因子以及趋化因子以及趋化因子以及趋化因子的增加有关。此外，似乎涉及包括p38促丝因激活蛋白激酶在内的相关细胞因子信号通路。为了检验以下假设：与IFN-α相关的这些临床和神经生物学特征也将与重度抑郁症患者的炎症增加有关，150名抑郁症患者（n = 50），培养基（n = 50）和低（n = 50）炎症（由CRP> 3、1-3、1-3、1-3、1-3和<1 mg/l定义），将与<1 mg/l相关。所有受试者将在2天的住院住院期间对上述变量进行神经精神评估以及血液和CSF取样。此外，鉴于早期生命应力的关联，体重指数增加，治疗耐药性和失调的睡眠与炎症的失调，这些因素也将被检查。针对抑郁症患者的病理生理途径（以及相关的内表型）的阐述将促进与个性化诊断，治疗和预防重度抑郁症相关的新疗法和生物标志物的发展。