Neurobiology and Target validation of novel therapeutic agents in mood disorders

项目1：脑啡能化合物治疗重度抑郁症：越来越多的证据表明，与非焦虑型抑郁症患者相比，焦虑型重度抑郁症（AMDD）患者有更严重的抑郁严重程度、功能障碍、自杀风险增加、社交困扰加重、酗酒和滥用药物发生率更高，治疗反应和预后更差。关于内源性阿片系统参与重度抑郁症及其治疗的文献越来越多。在临床观察中发现，δ阿片受体作为治疗抑郁和焦虑的可能靶点，在δ阿片受体敲除小鼠中持续出现焦虑状态升高和抑郁样行为。许多研究者在强迫游泳试验等模型中发现选择性δ -阿片受体激动剂具有抗抑郁样特性。在寻找选择性阿片受体激动剂以在AMDD的概念验证临床研究中进行测试的过程中，AZD2327是一种有效的，一流的高亲和力脑啡能激动剂，在动物模型中具有抗焦虑和抗抑郁活性。AZD2327在焦虑和抑郁啮齿动物模型中的疗效分别与地西泮和丙咪嗪相当。第一阶段的研究已经完成，并显示出可接受的安全性。男性和女性患者，年龄18至65岁，诊断为重度抑郁症（无精神病性特征），符合AMDD标准，将随机分配到双盲治疗中，以2:1的比例接受AZD2327 （3mg BID）或安慰剂，为期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。大约96名急性重度抑郁症患者将参加这项研究。

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.