Target validation of novel therapeutic agents in mood disorders

情绪障碍新型治疗药物的靶点验证

• 批准号: 8342185
• 负责人: Carlos Zarate
• 金额: $ 76.84万
• 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/8342185
• 关键词: Acute; Adult; Adverse effects; Affect; Affective; Affinity; Age; Agonist; Alcohol abuse; Anhedonia; Animal Model; Animals; Anterior; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; BI-1; Behavior; Biochemical; Biological Markers; Bipolar Disorder; Blood Cells; Brain imaging; Calcium; Cells; Cerebrospinal Fluid; Chronic; Citalopram; Clinical; Clinical Research; Communities; Databases; Depressed mood; Diagnosis; Diazepam; Disease; Disease remission; Distress; Double-Blind Method; Drug abuse; Endoplasmic Reticulum; Enrollment; Experimental Models; Female; Fluoxetine; Fright; Functional disorder; Genetic; Habenula; Hamilton Rating Scale for Depression; Hippocampus (Brain); Homeostasis; Hypothalamic structure; Imipramine; Incidence; Individual; Investigation; Knockout Mice; Laboratories; Lead; Life; Literature; Magnetic Resonance Imaging; Major Depressive Disorder; Measurement; Measures; Mental Depression; Messenger RNA; Modeling; Monkeys; Mononuclear; Mood Disorders; Mus; National Institute of Mental Health; Nerve Growth Factors; Neurobiology; Neuropsychological Tests; Outcome; Patients; Pattern; Peripheral; Persons; Pharmaceutical Preparations; Physiological; Pilot Projects; Placebo Control; Placebos; Play; Post-Traumatic Stress Disorders; Probability; Process; Property; Prosencephalon; Protein Biosynthesis; Protocols documentation; Randomized; Recruitment Activity; Reporting; Research Personnel; Resolution; Rewards; Risk; Rodent Model; Role; S100 Proteins; S100 family protein p11; Safety; Selective Serotonin Reuptake Inhibitor; Series; Serotonin; Serotonin Receptor 5-HT1B; Severities; Signal Transduction; Site; Sleep Deprivation; Stress; Substance P; Substance P Receptor; Suicide; Swimming; System; Testing; Therapeutic; Therapeutic Agents; Tranylcypromine; Treatment outcome; Unipolar Depression; Validation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Work; cingulate cortex; clinically significant; combat; delta opioid receptor; depressive symptoms; double-blind placebo controlled trial; effective therapy; endogenous opioids; functional disability; improved; inhibitor/antagonist; insight; male; meetings; member; monoamine; neurotransmission; novel; novel therapeutics; open label; peripheral blood; phase 1 study; pre-clinical; raphe nuclei; resilience; response; serotonin receptor; social; trafficking; 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. A recent report by STAR*D emphasizes the worse outcome of patients with this type of depression. The investigators found that remission was significantly less likely and to take longer to occur in patients with anxious versus nonanxious depression. Current antidepressants are largely "me too" drugs in as much as they exert their primary biochemical effects by increasing the intrasynaptic levels of monoamines, and as such, there has been limited (if any) progress in developing medications with improved efficacy. 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. In summary, clear preclinical signals for efficacy and an acceptable safety profile in Phase I studies to date have been seen with the enkephalinergic agonist AZD2327 suggesting that it might be a highly novel and effective therapy in both anxiety and depression. Furthermore, understanding the mechanism of action of enkephalinergic agonists' antidepressant effect may ultimately lead to further insight into the pathophysiology of mood disorders in general. 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

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。STAR*D最近的一份报告强调了这类抑郁症患者更糟糕的结果。研究人员发现，焦虑型抑郁症患者与非焦虑型抑郁症患者相比，缓解的可能性要小得多，而且需要更长的时间。目前的抗抑郁药在很大程度上是“我也是”的药物，因为它们通过增加突触内单胺的水平来发挥其主要的生化作用，因此，在开发提高疗效的药物方面进展有限（如果有的话）。