Randomized, placebo-controlled trial/AMPAkine depression

随机、安慰剂对照试验/AMPAkine 抑郁症

• 批准号: 7059114
• 负责人: Dennis S. Charney
• 金额: $ 42.75万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059114
• 关键词: AMPA receptors; adult human (21+); antidepressants; behavioral /social science research tag; brain derived neurotrophic factor; chemosensitizing agent; clinical research; clinical trial phase II; cognition; cooperative study; drug resistance; drug screening /evaluation; human subject; human therapy evaluation; longitudinal human study; major depression; memory; mental disorder chemotherapy; neuropsychological tests; piperidine

DESCRIPTION (provided by applicant): A major impetus for the creation of the Cooperative Drug Development Group (CDDG) for the Treatment of Mental Illness program is the sobering fact that available pharmacotherapies for major depression are suboptimal in terms of speed of onset, efficacy, and tolerability. Current medications for severe, chronic mood disorders are not based on pathophysiological models of illness, but rather are variations of monoaminergic-based therapies. The present application proposes a collaboration between 3 entities with the focused goal of accelerating antidepressant drug discovery: (1) the Departments of Psychiatry and Neuroscience of the Mount Sinai School of Medicine, (2) the NIMH Intramural Mood and Anxiety Disorders Program, and (3) Organon Pharmaceuticals. The primary aim of this collaboration is to test a candidate drug, Org 24448, in a phase II proof-of-concept clinical trial in adult patients with moderately treatment-resistant unipolar major depressive disorder. Org 24448 represents a new treatment approach for depression, by potentiating the AMPA receptor subfamily of ionotropic glutamate receptors. This drug has been shown to have antidepressant features in preclinical models, as well as cognitive-enhancing qualities. AMPA receptor activation has also been shown to increase expression of growth factors such as brain derived neurotrophic factor (BDNF). Since there is growing evidence from neuroimaging and post-mortem studies that severe mood disorders are characterized by alterations in intracellular signaling cascades and impairments of cellular plasticity and resilience, promoting BDNF may provide a mechanism for its therapeutic efficacy. In this 2-site, 8-week, randomized, placebo-controlled clinical trial, we aim to compare Org 24448 to placebo in patients ages 21 to 55, with a diagnosis of recurrent or chronic MDD (without psychotic features). Approximately 90 patients with major depression will be recruited at each site over 3 years, in order to randomize 70 patients at each site (140 patients total). Two sites are necessary to achieve the sample size of eligible patients in a relatively short period of time. As major depressive disorder continues to pose a significant public health problem, with high rates of morbidity and mortality, robust and well-tolerated new treatments are necessary. If initial studies are promising, this compound will be investigated for longer-term use with the aims of improving the long-term prognosis of this devastating chronic illness.

描述（由申请人提供）：创建精神疾病治疗合作药物开发小组 (CDDG) 计划的一个主要推动力是一个令人警醒的事实，即现有的重度抑郁症药物疗法在起效速度、疗效、和耐受性。目前治疗严重、慢性情绪障碍的药物并非基于疾病的病理生理学模型，而是基于单胺能疗法的变体。本申请提出了三个实体之间的合作，其重点目标是加速抗抑郁药物的发现：(1) 西奈山医学院精神病学和神经科学系，(2) NIMH 校内情绪和焦虑症项目，以及 ( 3）欧加农制药公司。此次合作的主要目的是在中度难治性单相重度抑郁症成年患者的 II 期概念验证临床试验中测试候选药物 Org 24448。 Org 24448 通过增强离子型谷氨酸受体的 AMPA 受体亚家族，代表了一种治疗抑郁症的新方法。该药物已在临床前模型中显示出具有抗抑郁特性以及增强认知的特性。 AMPA 受体激活也被证明可以增加生长因子的表达，例如脑源性神经营养因子 (BDNF)。由于神经影像学和尸检研究越来越多的证据表明，严重情绪障碍的特征是细胞内信号级联的改变以及细胞可塑性和弹性的损害，促进 BDNF 可能为其治疗功效提供一种机制。在这项为期 8 周的 2 个中心、随机、安慰剂对照临床试验中，我们的目标是在 21 至 55 岁、诊断为复发性或慢性 MDD（无精神病特征）的患者中比较 Org 24448 与安慰剂。 每个中心将在 3 年内招募大约 90 名重度抑郁症患者，以便在每个中心随机分配 70 名患者（总共 140 名患者）。为了在相对较短的时间内达到合格患者的样本量，需要两个站点。由于重度抑郁症继续构成重大的公共卫生问题，发病率和死亡率很高，因此需要强有力且耐受性良好的新治疗方法。如果初步研究有希望，我们将研究这种化合物的长期使用，目的是改善这种破坏性慢性疾病的长期预后。