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：
7986778
负责人：
ANDREW H MILLER
金额：
$ 44.34万
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 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7986778
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 Interferons Interleukin 2 Receptor Interleukin 6 Receptor Interleukin-1 beta Interleukin-6 Interleukins 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 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. PUBLIC HEALTH RELEVANCE: Recent data suggest that increased inflammation may play a role in the development of major depression in a significant percentage of depressed patients. Data also suggest that depressed patients with increased inflammation may be less responsive to conventional antidepressant treatment strategies and may be at increased risk for the development of other medical disorders including cardiovascular disease, diabetes and cancer. This project seeks to elaborate potentially unique clinical and neurobiological features of depressed patients with increased inflammation in order to reveal novel targets for the development of new therapies and biomarkers relevant to a personalized approach to diagnosis, treatment and prevention of major depression.

描述（由申请人提供）：为了促进开发治疗重度抑郁症患者的个性化方法，本研究旨在详细阐述炎症增加的抑郁症患者的临床和神经生物学表型。越来越多的数据表明，炎症可能在重度抑郁症的发展中发挥重要作用。例如，作为炎症反应的一部分释放的细胞因子被发现与抑郁症相关的几乎所有病理生理领域相互作用，包括神经内分泌功能和神经递质代谢。值得注意的是，炎症加剧的抑郁症患者可能对传统抗抑郁治疗反应较差，并且患其他疾病的风险可能增加。我们小组的初步数据表明，根据患者群体，三分之一或更多的重度抑郁症患者表现出炎症增加，血浆 C 反应蛋白 (CRP) 浓度 >3mg/L 反映了这一点。然而，炎症增加的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 对传染病和癌症患者影响的数据可能提供重要线索，了解可能与重度抑郁症患者炎症增加唯一相关的特征，包括 1) 突出的植物神经症状，例如精神运动迟缓和疲劳； 2) 日间皮质醇曲线变平； 3) 吲哚胺 2,3 双加氧酶代谢物（包括犬尿氨酸、喹啉酸和犬尿酸）的血浆和脑脊液 (CSF) 浓度增加，已被证明可以减少基底神经节中多巴胺的释放。这些神经生物学变化反过来与 IFN-α 诱导的外周血和/或脑脊液中肿瘤坏死因子-α 和白细胞介素 6 及其可溶性受体以及趋化因子（如单核细胞趋化蛋白-1）浓度的增加有关。此外，包括 p38 丝裂原激活蛋白激酶在内的相关细胞因子信号传导途径似乎也参与其中。为了检验以下假设：这些与 IFN-α 相关的临床和神经生物学特征也与重度抑郁症患者的炎症增加有关，研究了 150 名抑郁症患者，分别为高 (n=50)、中 (n=50) 和低 (n= 50) 将检查炎症（分别由 CRP >3、1-3 和 <1 mg/L 定义）。所有受试者将在 2 天的住院期间接受神经精神评估以及针对上述变量的血液和脑脊液采样。此外，考虑到早期生活压力、体重指数增加、治疗抵抗和睡眠失调与炎症之间的关系，这些因素也将受到检查。详细阐述炎症增加的抑郁症患者特有的病理生理学途径（和相关的内表型）将促进与诊断、治疗和预防重度抑郁症的个体化方法相关的新疗法和生物标志物的开发。公共卫生相关性：最近的数据表明，炎症的增加可能在相当大比例的抑郁症患者发展为重度抑郁症的过程中发挥了作用。数据还表明，炎症加剧的抑郁症患者对传统抗抑郁治疗策略的反应可能较差，并且患心血管疾病、糖尿病和癌症等其他疾病的风险可能增加。该项目旨在详细阐述炎症增加的抑郁症患者潜在独特的临床和神经生物学特征，以揭示与诊断、治疗和预防重度抑郁症的个性化方法相关的新疗法和生物标志物开发的新靶标。