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）：用于治疗精神疾病计划的合作药物开发小组（CDDG）创建的主要动力是令人震惊的事实，即对大抑郁症的可用药物治疗在发病速度，有效性和耐受性的速度方面是优越的。当前针对严重的慢性情绪障碍的药物不是基于疾病的病理生理模型，而是基于单胺能疗法的变化。本申请提出了3个实体之间的合作，其重点是加速抗抑郁药发现：（1）西奈山医学院的精神病学和神经科学系，（2）NIMH壁内情绪和焦虑症计划，以及（3）Organon Pharmaceuticals。这种合作的主要目的是在II期概念验证临床试验中测试候选药物ORG 24448，该试验中适中耐药的单极重大抑郁症。 ORG 24448代表了一种新的抑郁症治疗方法，它通过增强离子型谷氨酸受体的AMPA受体亚科。该药物已被证明在临床前模型中具有抗抑郁剂特征以及认知增强的品质。 AMPA受体激活也已显示出增加生长因子（例如脑衍生神经营养因子（BDNF））的表达。由于来自神经影像学和验尸研究的证据越来越多，表明严重的情绪障碍的特征是细胞内信号传导级联反应的改变以及细胞可塑性和弹性的损害，因此促进BDNF可能会为其治疗效率提供一种机制。在这项2个星期，8周，随机，安慰剂对照的临床试验中，我们的目标是将ORG 24448与21至55岁患者的安慰剂进行比较，并诊断出复发性或慢性MDD（没有精神病特征）。 在3年内，每个部位将招募大约90名严重抑郁症患者，以便在每个部位随机70例患者（总共140例）。在相对较短的时间内实现符合条件的患者的样本，需要两个地点。由于重度抑郁症继续构成重大的公共卫生问题，因此发病率和死亡率很高，因此必须进行稳健且耐受良好的新疗法。如果最初的研究是有希望的，则将研究该化合物以进行长期使用，以改善这种毁灭性慢性疾病的长期预后。