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

• 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
• 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

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.

项目一：脑啡肽能化合物治疗重度抑郁症：越来越多的证据表明，与非焦虑性抑郁症患者相比，焦虑性重度抑郁症（AMDD）患者的抑郁程度更严重，功能障碍，自杀风险增加，社会困扰更严重，酒精和药物滥用发生率更高，治疗反应和结局更差。越来越多的文献报道内源性阿片系统参与抑郁症及其治疗。δ-阿片受体作为治疗抑郁和焦虑的可能靶标的鉴定始于临床观察，即在δ-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加。许多研究人员发现，选择性δ阿片受体激动剂在强迫游泳试验等模型中具有抗抑郁药样特性。在AMDD的概念验证临床研究中，为了寻找一种选择性δ阿片受体激动剂进行测试，AZD 2327是一种强效的、一流的、高亲和力的脑啡肽能激动剂，在动物模型中具有抗焦虑和抗抑郁活性。AZD 2327在焦虑和抑郁啮齿动物模型中的疗效分别与地西泮和丙咪嗪相当。I期研究已经完成，并已表明可接受的安全性特征。 年龄18 - 65岁、诊断为重度抑郁症（无精神病特征）且符合AMDD标准的男性和女性患者将随机接受双盲治疗，以2：1的比例接受AZD 2327（3 mg BID）或安慰剂治疗，持续4周。此外，将获得一系列替代神经生物学标志物，以确定它们是否能够预测治疗反应。约96例急性重度抑郁症患者将入组研究。 项目二：重性抑郁症患者外周血细胞p11蛋白水平与西酞普兰治疗反应相关性的研究 重度抑郁症（MDD）是一种严重的，使人衰弱的，缩短寿命的疾病，影响所有年龄和背景的许多人。 虽然治疗对大部分MDD患者有效，但开发更有效治疗方法的进展滞后。此外，关于现有的抗抑郁药物，还没有可靠的预测缓解的可能性，响应或不响应与抗抑郁药物的初始试验。识别可能预测反应的因素将具有针对特定个体的个性化治疗的优势;也就是说，选择最有可能产生有利结果的最大概率的抗抑郁药物。 5-羟色胺系统与抑郁症的病理生理学和现有有效抗抑郁治疗的作用机制有关。到目前为止，已经鉴定出14种不同的5-羟色胺受体。其中之一，5-HT1B，在调节5-羟色胺神经传递中起重要作用。最近，发现p11（S100蛋白家族成员）与5-HT1B受体相互作用（Svenningsson et al 2006; Svenningsson and Greengard 2007）。无助的H/Rouen小鼠前脑中p11 mRNA水平显著降低，抑郁症患者前扣带皮层中p11 mRNA水平下调。p11 mRNA的分布与5-HT 1B受体mRNA的分布非常相似，包括皮质、海马、下丘脑和中缝核。长期服用抗抑郁药丙咪嗪、反苯环丙胺和西酞普兰可显著增加皮质中p11的水平。最后，我们发现氟西汀长期治疗可增加猴外周血单个核细胞中p11的表达。 我们现在将研究健康个体和患有单相抑郁症的患者的血细胞p11水平是否不同。此外，我们将研究p11的水平是否会受到选择性5-羟色胺再摄取抑制剂西酞普兰治疗的影响。其他实验室将继续进行补充工作，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、死后研究）。 此外，我们还将在基线和第8周时对45名同质性抑郁受试者和45名匹配的健康对照者进行一系列磁共振成像（MRI）扫描。 越来越多的证据表明，在重性抑郁症的病理生理学中，存在可通过MRI测量的形态测量和生理异常。 我们将评估抑郁症受试者和健康对照者之间的基线差异、治疗效果，并寻找预测治疗反应的可能MRI标记物。 这是一项开放标签研究，将在美国国家精神卫生研究所进行。 总共将从社区招募82名18至65岁的重度抑郁症成人受试者。 此外，我们将在64名健康对照受试者的血细胞中进行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障碍（MAP）研究的数据库协议，包括遗传学，神经心理学测试，结构和脑成像，电生理学研究和外周血测量正在检查诊断和治疗反应的标志物。 项目4。心境障碍和焦虑障碍新疗法的靶点验证 a. NR2B拮抗剂治疗难治性抑郁症 B.难治性重性抑郁症的低捕获NMDA通道阻滞剂