RANDOMIZED,PLACEBO-CONTROLLED TRIAL OF AN AMPAKINE IN MAJOR DEPRESSIVE DISORDER

安帕金治疗重度抑郁症的随机、安慰剂对照试验

• 批准号: 7605345
• 负责人: Dennis S. Charney
• 金额: $ 2.31万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605345
• 关键词: AMPA Receptors; Acute; Age; Animal Model; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Chronic; Class; Computer Retrieval of Information on Scientific Projects Database; DSM-IV; Diagnosis; Double-Blind Method; Funding; Glutamate Receptor; Grant; Growth Factor; Impairment; In Vitro; Institution; Life; Major Depressive Disorder; Measures; Memory; Mental Depression; Montgomery and Asberg depression rating scale; Morbidity - disease rate; Neurobiology; Neuropsychological Tests; Patients; Placebos; Randomized; Range; Rate; Receptor Activation; Research; Research Personnel; Resources; Score; Selective Serotonin Reuptake Inhibitor; Signal Transduction; Source; Specific qualifier value; United States National Institutes of Health; Week; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; cognitive function; depressive symptoms; dosage; improved; in vivo; mortality; neuropsychological; novel strategies; randomized placebo controlled trial; receptor; resilience; response; theories

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Major depressive disorder (MDD) is a common, severe, chronic and often life-threatening illness that contributes to significant morbidity and mortality. Although there is a wide range of antidepressant drugs, 30% to 40% of patients with major depression fail to respond to first-line antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs]), despite adequate dosage, duration, and compliance. Current pathophysiological theories regarding the neurobiology of depression include alterations in intracellular signaling cascades, and impairments of cellular plasticity and resilience. There is recent evidence suggesting that promoting growth factors, such as brain derived neurotrophic factor (BDNF), may provide a mechanism for the treatment of depression. New information indicating modulation of glutamate receptors in the actions of antidepressant treatments suggests a novel approach to develop a new class of antidepressants. Studies have shown that the biarylpropylsulfonamide AMPA receptor potentiators (LY392098 and LY451616) have antidepressant effects in animal models of depression. Several studies have demonstrated that AMPA receptor activation can increase expression of BDNF both in vitro and in vivo, thus providing one possible new approach for treatment via an AMPA receptor potentiator. In this study we propose to compare the ampa receptor potentiator Org 24448 to placebo for the treatment of MDD. Patients, ages 21 to 55 with a diagnosis of MDD (without psychotic features), will be randomized to double-blind treatment with either Org 24448 or placebo for an 8-week period. Acute efficacy will be determined by demonstrating a greater response rate vs. placebo using specified criteria. Primary Specific Aim To assess the efficacy of acute therapy with an AMPA receptor potentiator compared to placebo in patients with major depression without psychotic features according to the DSM-IV criteria, in improving overall depressive symptomatology. This will be achieved by measuring the mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline score to the score at the end of 8 weeks of therapy between the 2 groups. Hypothesis: Subjects randomized to acute therapy with Org 24448 will have greater response rates compared to subjects randomized to placebo. Secondary Specific Aims [exploratory (anticipate low power)]: 1. To explore whether subjects with major depression randomized to acute therapy with Org 24448 will manifest improved cognitive function, especially memory, as measured by neuropsychological testing compared to subjects randomized to placebo. This will be measured by statistical evidence in change in neuropsychological function from baseline to the end of treatment. 2. To explore whether the subjects who are administered Org 24448 compared to those who receive placebo will have in an increase in BDNF as measured in the CSF.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 重度抑郁症（MDD）是一种常见，严重，慢性且经常危及生命的疾病，有助于大量发病率和死亡率。尽管有广泛的抗抑郁药，但尽管有足够的剂量，持续时间和合规性，但有30％至40％的严重抑郁症患者未能对一线抗抑郁药反应（例如选择性5-羟色胺再摄取抑制剂[SSRIS]）。有关抑郁神经生物学的当前病理生理理论包括细胞内信号级联的改变以及细胞可塑性和弹性的损害。 最近有证据表明，促进生长因子（例如脑衍生的神经营养因子（BDNF））可能提供了一种治疗抑郁症的机制。新信息表明在抗抑郁药治疗的作用中调节谷氨酸受体表明一种新的方法来开发一种新的抗抑郁药。研究表明，双丙基磺胺AMPA受体增强剂（LY392098和LY451616）在抑郁症动物模型中具有抗抑郁作用。几项研究表明，AMPA受体激活可以在体外和体内增加BDNF的表达，从而通过AMPA受体增强剂提供了一种可能的新方法。 在这项研究中，我们建议将AMPA受体增强剂ORG 24448与安慰剂进行比较，以治疗MDD。 21至55岁的患者诊断为MDD（无精神病特征），将在8周期间用ORG 24448或安慰剂随机分配给双盲治疗。急性功效将通过使用指定标准证明更高的应答率与安慰剂来确定。 主要目的 根据DSM-IV标准，与安慰剂相比，用AMPA受体增强剂评估AMPA受体增强剂的急性治疗的功效，以改善总体抑郁症状。这将通过衡量蒙哥马利 - 阿斯伯格抑郁量表（MADRS）的平均变化在两组之间治疗的8周结束时总分从基线得分到得分。 假设：与随机分配给安慰剂相比，用ORG 24448随机对急性治疗的受试者将具有更大的反应率。 次要特定目的[探索性（预期低功率）]： 1。探索与随机的受试者相比，与随机分配给安慰剂相比，通过神经心理学测试衡量的严重抑郁症受试者是否会改善认知功能，尤其是记忆。这将通过从基线到治疗结束的神经心理功能变化的统计证据来衡量。 2。探索与接受安慰剂的受试者相比，受试者是否会增加BDNF，如CSF中所测量是否会增加。