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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 重度抑郁症 (MDD) 是一种常见、严重、慢性且常常危及生命的疾病，导致显着的发病率和死亡率。尽管抗抑郁药物种类繁多，但 30% 至 40% 的重度抑郁症患者对一线抗抑郁药物（例如选择性血清素再摄取抑制剂 [SSRI]）没有反应，尽管有足够的剂量、持续时间和依从性。目前关于抑郁症神经生物学的病理生理学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，例如脑源性神经营养因子（BDNF），可能为抑郁症的治疗提供一种机制。表明谷氨酸受体在抗抑郁治疗作用中的调节作用的新信息表明了开发一类新型抗抑郁药的新方法。研究表明，联芳基丙基磺酰胺 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。多项研究表明，AMPA 受体激活可以在体外和体内增加 BDNF 的表达，从而为通过 AMPA 受体增强剂进行治疗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 与安慰剂治疗 MDD 进行比较。年龄在 21 至 55 岁之间、诊断为 MDD（无精神病特征）的患者将被随机分配接受 Org 24448 或安慰剂的双盲治疗，为期 8 周。急性疗效将通过使用指定标准证明与安慰剂相比更高的反应率来确定。 主要具体目标 根据 DSM-IV 标准，评估 AMPA 受体增强剂与安慰剂相比，急性治疗对于无精神病特征的重度抑郁症患者的急性治疗在改善整体抑郁症状方面的疗效。这将通过测量两组之间蒙哥马利-阿斯伯格抑郁量表 (MADRS) 总分从基线分数到 8 周治疗结束时分数的平均变化来实现。 假设：与随机接受安慰剂的受试者相比，随机接受 Org 24448 急性治疗的受试者将具有更高的缓解率。 次要具体目标[探索性（预期低功率）]： 1. 探讨与随机接受安慰剂的受试者相比，随机接受 Org 24448 急性治疗的重度抑郁症受试者是否会表现出认知功能（尤其是记忆力）的改善（通过神经心理学测试测量）。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. 探讨给予 Org 24448 的受试者与接受安慰剂的受试者相比，脑脊液中测量的 BDNF 是否会增加。