Neurobiology and Target validation of novel therapeutic agents in mood disorders

情绪障碍新型治疗药物的神经生物学和靶标验证

基本信息

批准号：
8745751
负责人：
Carlos Zarate
金额：
$ 89.63万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8745751
关键词：
Acute Adult Adverse effects Affect Affinity Age Agonist Alcohol abuse Animal Model Animals Anterior Anti-Anxiety Agents Antidepressive Agents Anxiety Anxiety Disorders Behavior Biological Markers Bipolar Disorder Blood Cells Brain imaging Cells Chronic Citalopram Clinical Clinical Research Communities Cyclic AMP Databases Depressed mood Development Diagnosis Diazepam Disease remission Distress Double-Blind Method Drug abuse Enrollment Face Family Female Fluoxetine Functional disorder Genetic Hamilton Rating Scale for Depression Hippocampus (Brain)Hypothalamic structure Image Imipramine Incidence Individual Investigation Ketamine Knockout Mice Laboratories Licensing Life Literature Longevity Magnetic Resonance Imaging Major Depressive Disorder Manic Measurement Measures Mediating Mental Depression Messenger RNA Modeling Monkeys Mononuclear Mood Disorders Motor Mus N-Methylaspartate National Institute of Mental Health Neurobiology Neuropsychological Tests Oral Outcome Patients Pattern Peripheral Persons Pharmaceutical Preparations Physiological Placebos Play Probability Property Prosencephalon Protocols documentation Randomized Recruitment Activity Research Personnel Resistance Risk Rodent Model Role Rolipram S100 Proteins S100 family protein p11 Safety Selective Serotonin Reuptake Inhibitor Series Serotonin Serotonin Receptor 5-HT1B Severities Signal Transduction Suicide Swimming System Testing Therapeutic Therapeutic Agents Tranylcypromine Treatment outcome Unipolar Depression Validation Work channel blockers cingulate cortex clinically significant delta opioid receptor depressive symptoms effective therapy endogenous opioids functional disability male meetings member neural circuit neurotransmission novel novel therapeutics open label peripheral blood phase 1 study phosphodiesterase IV population based raphe nuclei response serotonin receptor single episode major depressive disorder social treatment effect treatment response

Acute Adult Adverse effects Affect Affinity Age Agonist Alcohol abuse Animal Model Animals Anterior Anti-Anxiety Agents Antidepressive Agents Anxiety Anxiety Disorders Behavior Biological Markers Bipolar Disorder Blood Cells Brain imaging Cells Chronic Citalopram Clinical Clinical Research Communities Cyclic AMP Databases Depressed mood Development Diagnosis Diazepam Disease remission Distress Double-Blind Method Drug abuse Enrollment Face Family Female Fluoxetine Functional disorder Genetic Hamilton Rating Scale for Depression Hippocampus (Brain)Hypothalamic structure Image Imipramine Incidence Individual Investigation Ketamine Knockout Mice Laboratories Licensing Life Literature Longevity Magnetic Resonance Imaging Major Depressive Disorder Manic Measurement Measures Mediating Mental Depression Messenger RNA Modeling Monkeys Mononuclear Mood Disorders Motor Mus N-Methylaspartate National Institute of Mental Health Neurobiology Neuropsychological Tests Oral Outcome Patients Pattern Peripheral Persons Pharmaceutical Preparations Physiological Placebos Play Probability Property Prosencephalon Protocols documentation Randomized Recruitment Activity Research Personnel Resistance Risk Rodent Model Role Rolipram S100 Proteins S100 family protein p11 Safety Selective Serotonin Reuptake Inhibitor Series Serotonin Serotonin Receptor 5-HT1B Severities Signal Transduction Suicide Swimming System Testing Therapeutic Therapeutic Agents Tranylcypromine Treatment outcome Unipolar Depression Validation Work channel blockers cingulate cortex clinically significant delta opioid receptor depressive symptoms effective therapy endogenous opioids functional disability male meetings member neural circuit neurotransmission novel novel therapeutics open label peripheral blood phase 1 study phosphodiesterase IV population based raphe nuclei response serotonin receptor single episode major depressive disorder social treatment effect treatment response

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项目摘要

Project 1: Enkephalinergic compounds for major depression: There is increasing evidence that patients with anxious major depressive disorder (AMDD) have a greater depressive severity, functional impairment, increased risk of suicidality, worse social distress, higher incidence of alcohol and drug abuse, and poorer treatment response and outcome than patients with non-anxious depression. There is increasing literature of the involvement of the endogenous opioid system in major depression and its treatment. Identification of delta-opioid receptor as a possible target in the treatment of depression and anxiety began with clinical observations that a heightened anxiety state and depressive-like behaviors were consistently noted in the delta-opioid receptor knockout mouse. A number of investigators have found that selective delta-opioid receptor agonists have antidepressant-like properties in models such as the forced swim test. In a search for a selective delta-opioid receptor agonist to test in a proof-of-concept clinical study in AMDD, AZD2327 is a potent, first in class, high-affinity enkephalinergic agonist that possesses anxiolytic and antidepressant activity in animal models. AZD2327 has efficacy comparable to diazepam and imipramine in rodent models of anxiety and depression, respectively. Phase I studies have been completed and have indicated an acceptable safety profile. Male and female patients, ages 18 to 65, with a diagnosis of major depression (without psychotic features) meeting criteria for AMDD, will be randomized to double-blind treatment to receive either AZD2327 (3 mg BID) or placebo in a 2:1 ratio for a period of 4 weeks. In addition, a series of surrogate neurobiological markers will be obtained to establish whether they are capable of predicting therapeutic response. Approximately 96 patients with acute major depression will be enrolled in the study. Project 2: An investigation to determine whether levels of p11 protein in peripheral blood cells correlate with treatment response to citalopram in patients with major depressive disorder. Major depressive disorder (MDD) is a serious, debilitating, life-shortening illness that affects many persons of all ages and backgrounds. While treatments are effective for a significant portion of patients with MDD, progress in developing more effective treatments is lagging. Furthermore, with regards to existing antidepressant medications, there are yet no reliable predictors of the likelihood of remission, response or non-response with an initial trial of an antidepressant medication. Identifying factors that are likely to predict response would have the advantage of personalizing treatment to a particular individual; that is, selecting the antidepressant medication that is most likely to give the greatest probability of having a favorable outcome. The serotonin system has been implicated in the pathophysiology of depression and mechanism of action ofexisting effective antidepressant treatments. Fourteen different serotonin receptors have been identified to date. One of them, 5-HT1B, plays an important role in regulating serotonin neurotransmission. Recently, p11 (a member of the S100 family of proteins) was found to interact with 5-HT1B receptors (Svenningsson et al 2006; Svenningsson and Greengard 2007). p11 mRNA levels are markedly reduced in the forebrain in helpless H/Rouen mice and the level of p11 mRNA was down-regulated in the anterior cingulate cortex from depressed patients. p11 mRNA is distributed in an anatomical pattern that closely resembled that of 5-HT1B receptor mRNA, including cortex, hippocampus, hypothalamus and raphe nuclei. Chronic administration of the antidepressants imipramine, tranylcypromine, and citalopram significantly increase the level of p11 in cortex. Finally, we have found that chronic treatment with fluoxetine increases p11 in peripheral mononuclear cells in monkeys. We will now study whether the blood cell levels of p11 differ between healthy individuals and patients suffering from unipolar depression. Moreover, we will study whether the levels of p11 are affected by treatment with the selective serotonin reuptake inhibitor, citalopram. Complementary work will continue at other laboratories to better characterize the role of p11 in the pathophysiology of depression (e.g., animal studies, post-mortem studies). In addition, we will also acquire a battery of magnetic resonance imaging (MRI) scans in a subset of 45 more homogeneous depressed subjects, and 45 matched healthy controls at baseline and at 8 weeks. There is a growing body of evidence implicating morphometric and physiologic abnormalities, measureable by MRI, in the pathophysiology of major depressive disorder. We will assess both baseline differences between depressed subjects and healthy controls, treatment effects, and search for possible MRI markers predicting treatment response. This is an open label study which will be performed at the National Institute of Mental Health. In all, 82 adult subjects with major depressive disorder, between the ages of 18 and 65 years, will be recruited from the community. In addition, we will perform p11 measurements in blood cells from 64 healthy control subjects. Project 3: Identifying biomarkers of diagnosis, illness and treatment response. Using data from the repository protocol from studies conducted in the Mood and Anxiety Disorders (MAP) which includes genetics, neuropsychological testing, structural and brain imaging, electrophysiological studies and peripheral blood measures were are examining markers of diagnosis and treatment response. Project 4. Target validation of novel treatments in mood and anxiety disorders a. NR2B antagonist in treatment-resistant major depressive disorder b. Low-trapping NMDA channel blocker in treatment-resistant major depressive disorder.

项目1：重度抑郁症的ENKephalinagic化合物：有越来越多的证据表明，焦虑的重度抑郁症（AMDD）患者的抑郁症严重程度更大，功能障碍，自杀率更高，社会困扰较差，饮酒和药物滥用率更高，治疗反应较差，治疗反应较差，而疗程较差。内源性阿片类药物系统参与重大抑郁及其治疗的文献越来越多。鉴定三角洲阿片受体是治疗抑郁和焦虑的可能目标，始于临床观察，即在三角洲阿片受体敲除小鼠中始终注意到焦虑状态和抑郁样行为的增强。许多研究人员发现，在强制游泳试验等模型中，选择性的三角洲阿片受体激动剂具有抗抑郁样性能。为了在AMDD的概念验证临床研究中进行选择性的三角洲 - 阿片受体激动剂，AZD2327是一种有效的，首先是类，高亲和力的enkephalinergic激动剂，在动物模型中具有抗焦虑和抗抑郁活性。 AZD2327在焦虑和抑郁模型中具有与地西ep剂和丙咪嗪相当的功效。第一阶段的研究已经完成，并表明可接受的安全性概况。男性和女性患者，年龄在18至65岁之间，诊断出严重抑郁症（无精神病特征）符合AMDD的标准，将随机分为双盲治疗，以接受AZD2327（3 mg BID）或安慰剂的2：1比例，为2：1的比例为4周。此外，还将获得一系列替代神经生物学标记，以确定它们是否能够预测治疗反应。该研究将招募大约96例急性严重抑郁症患者。项目2：一项研究，以确定周围血细胞中P11蛋白水平是否与对大抑郁症患者的治疗反应相关。重度抑郁症（MDD）是一种严重的，令人衰弱的疾病，会影响许多年龄和背景的许多人。虽然治疗对大部分MDD患者有效，但开发更有效治疗的进展仍在落后。此外，关于现有的抗抑郁药，对于抗抑郁药的初步试验，尚无可靠的预测因素。确定可能预测反应的因素将具有个性化对特定人的个性化治疗的优势；也就是说，选择抗抑郁药，最有可能带来有利结果的可能性。 5-羟色胺系统与抑郁症的病理生理学有关，并具有有效抗抑郁药的作用机理。迄今为止，已经确定了14种不同的5-羟色胺受体。其中一个，5-HT1b，在调节5-羟色胺神经传递方面起着重要作用。最近，发现P11（S100蛋白质家族的成员）与5-HT1B受体相互作用（Svenningsson等，2006； Svenningsson和Greengard 2007）。在无助的H/rouen小鼠的前脑中，P11 mRNA水平明显降低，P11 mRNA的水平在抑郁症患者的前扣带回皮层中下调。 P11 mRNA以解剖模式分布，与5-HT1B受体mRNA的分布，包括皮层，海马，下丘脑和Raphe核。长期给药抗抑郁药丙咪胺，宁甲基香气和西酞普兰可显着提高皮质中P11的水平。最后，我们发现氟西汀的慢性治疗在猴子的周围单核细胞中增加了P11。现在，我们将研究健康个体和单极抑郁症患者的P11的血细胞水平是否有所不同。此外，我们将研究P11的水平是否受到选择性5-羟色胺再摄取抑制剂Citalopram治疗的影响。补充工作将继续在其他实验室继续进行，以更好地表征P11在抑郁症病理生理学中的作用（例如动物研究，验尸研究）。此外，我们还将在45个均质抑郁症受试者的子集中获得一系列磁共振成像（MRI）扫描，并在基线和8周时进行45个匹配的健康对照。在主要抑郁症的病理生理学中，越来越多的证据表明形态和生理异常，可通过MRI测量。我们将评估抑郁症受试者和健康对照，治疗效果之间的基线差异，并寻找预测治疗反应的可能的MRI标记物。这是一项开放式标签研究，将在美国国家心理健康研究所进行。总共将从社区招募82名年龄在18至65岁之间的患有重度抑郁症的成年受试者。此外，我们将对来自64名健康对照受试者的血细胞进行P11测量。项目3：确定诊断，疾病和治疗反应的生物标志物。使用来自情绪和焦虑症进行研究的存储库方案的数据（MAP），包括遗传学，神经心理学测试，结构和脑成像，电生理研究和外周血液测量正在检查诊断和治疗反应的标志。项目4。心情和焦虑症的新型治疗方法的目标验证一个。 NR2B抗治疗重大抑郁症的拮抗剂 b。在耐治疗的主要抑郁症中，低捕获NMDA通道阻滞剂。