Phenotyping Major Depression with Increased Inflammation

描述（由申请人提供）：为了促进重度抑郁症患者个性化治疗方法的发展，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起着重要作用。例如，作为炎症反应的一部分释放的细胞因子已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，炎症加重的抑郁症患者可能对常规抗抑郁治疗反应较差，并且可能增加其他医学疾病的风险。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，这反映在血浆c反应蛋白（CRP）浓度bbb3mg /L上。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。炎症细胞因子干扰素(IFN)- α对感染性疾病和癌症患者影响的数据可能为研究与重度抑郁症患者炎症增加相关的特征提供重要线索，包括1)突出的神经植物症状，如精神运动迟缓和疲劳；2)皮质醇日曲线趋平；3)增加血浆和脑脊液（CSF）中吲哚胺2,3双加氧酶代谢物（包括犬尿氨酸、喹啉酸和犬尿酸）的浓度，这已被证明可以减少基底节区多巴胺的释放。这些神经生物学变化反过来又与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ifn - α相关的这些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的假设，将对150名高（n=50），中（n=50）和低（n=50）炎症（分别由CRP >.3, 1-3和<1 mg/L定义）的抑郁症患者进行检查。在为期2天的住院期间，所有受试者将接受神经精神评估，并对上述变量进行血液和脑脊液采样。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的关联，这些因素也将被研究。对炎症加重的抑郁症患者的病理生理途径（以及相关的内表型）的细化，将促进新疗法和生物标志物的发展，从而为诊断、治疗和预防重度抑郁症提供个性化的方法。

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.