Phenotyping Major Depression with Increased Inflammation

炎症加剧的重度抑郁症表型分析

• 批准号: 8257183
• 负责人: ANDREW H MILLER
• 金额: $ 43.31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257183
• 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; Health; 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; receptor; treatment strategy

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)：为了促进开发一种个性化的方法来治疗重度抑郁症患者，这项研究旨在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，炎症可能在严重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几乎所有与抑郁症相关的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，炎症增加的抑郁症患者可能对传统的抗抑郁药物治疗反应较差，并可能面临其他内科疾病的风险增加。来自我们小组的初步数据表明，根据患者群体的不同，三分之一或更多的重度抑郁症患者表现出炎症增加，反映为血浆C-反应蛋白(CRP；3 mg/L)浓度。然而，伴有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。有关炎性细胞因子干扰素(干扰素)-α对感染性疾病和癌症患者的影响的数据，可能提供有关可能与严重抑郁症患者炎症增加独特相关的特征的重要线索，这些特征包括：1)显著的神经植物症状，如精神运动迟缓和疲劳；2)白天皮质醇曲线变平；3)吲哚胺2，3双加氧酶代谢产物血浆和脑脊液浓度增加，包括犬尿氨酸、喹啉酸和犬尿酸，这已被证明可以减少基底节中的多巴胺释放。这些神经生物学变化反过来与干扰素-α诱导的外周血和/或脑脊液中肿瘤坏死因子-α和白介素6及其可溶性受体以及单核细胞趋化蛋白-1等趋化因子浓度的增加有关。此外，包括p38丝裂原活化蛋白激酶在内的相关细胞因子信号通路似乎也参与其中。为了验证与干扰素-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炎症增加相关的假设，将检查150名高度(n=50)、中度(n=50)和低(n=50)炎症(分别由C反应蛋白3、1-3和1 mg/L定义)的抑郁症患者。在为期两天的住院期间，所有受试者都将接受神经精神评估以及血液和脑脊液采样，以检测上述变量。此外，考虑到早期生活压力、体重指数增加、治疗阻力和睡眠失调与炎症的关联，这些因素也将被检查。阐述炎症增加的抑郁症患者特有的病理生理途径(和相关的内表型)将促进与诊断、治疗和预防严重抑郁症的个体化方法相关的新疗法和生物标记物的发展。 与公共卫生相关：最近的数据表明，炎症增加可能在相当大比例的抑郁症患者的严重抑郁症的发展中发挥作用。数据还表明，炎症增加的抑郁症患者可能对传统的抗抑郁药物治疗策略反应较差，并可能增加发生其他医学疾病的风险，包括心血管疾病、糖尿病和癌症。本项目旨在阐述伴有炎症增加的抑郁症患者潜在的独特临床和神经生物学特征，以揭示与诊断、治疗和预防严重抑郁症的个性化方法相关的新疗法和生物标记物的开发新靶点。