Optimization of IV Ketamine for Treatment Resistant Major Depression

静脉注射氯胺酮治疗难治性重度抑郁症的优化

• 批准号: 8102809
• 负责人: SANJAY J MATHEW
• 金额: $ 28.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-23 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102809
• 关键词: Acute; Adult; Adverse effects; Adverse event; Affinity; Analgesics; Anesthetics; Animal Model; Antidepressive Agents; Childhood; Clinical Trials; Crossover Design; Disease remission; Dose; Double-Blind Method; Elements; Excitatory Amino Acid Antagonists; Hour; Infusion procedures; Intervention; Intervention Studies; Intravenous; Intravenous infusion procedures; Investigation; Ketamine; Major Depressive Disorder; Masks; Measures; Medical Staff; Mental Depression; Midazolam; Modification; Montgomery and Asberg depression rating scale; Mood Disorders; Morbidity - disease rate; N-Methylaspartate; National Institute of Mental Health; Outcome; Outcome Measure; Participant; Patients; Pharmaceutical Preparations; Placebo Control; Property; Public Health; Randomized; Relapse; Reporting; Research; Research Proposals; Resistance; Safety; Saline; Sampling; Severities; Site; Specificity; Subgroup; Testing; Therapeutic; Unipolar Depression; active control; arm; comparative efficacy; depressive symptoms; design; discontinuation trial; hypnotic; innovation; meetings; mortality; novel; pilot trial; public health relevance; response; sedative; treatment effect

DESCRIPTION (provided by applicant): Existing treatments for major depressive disorder (MDD) may require several weeks to months to exert their maximal benefit. Ketamine, a high-affinity NMDA glutamate receptor antagonist, is an anesthetic and analgesic medication commonly used in pediatric and adult patients. Ketamine has antidepressant properties in animal models, and may have rapid antidepressant activity for patients with severe mood disorders. A recent placebo-controlled investigation in patients with treatment-resistant unipolar depression (TRD) showed robust antidepressant efficacy of a single subanesthetic dose of intravenous (IV) ketamine (0.5 mg/kg), findings which replicated a previous small pilot trial. Strikingly, a high proportion of patients maintained the acute response to IV ketamine for several days or longer. In this 4-year single-site study, we will conduct a triple-masked, randomized, parallel-arm active control investigation of the acute efficacy and safety of IV ketamine in TRD. Specific Aims: (1) To test whether a single IV infusion of ketamine has superior antidepressant efficacy compared to an active control agent (IV midazolam) in patients with TRD. (2) To characterize the durability of benefit and test whether IV ketamine is associated with superior antidepressant effects at the 7-day timepoint. (3) To examine the safety and tolerability of the interventions. The intent-to-treat sample is comprised of 64 TRD patients, conservatively defined as insufficient response to = 3 adequate antidepressant trials in the current episode. After a medication-free period = 2 weeks, patients are randomized to receive an infusion of either IV ketamine (0.5 mg/kg over 40 min) or IV midazolam (0.045 mg/kg over 40 min). Efficacy and safety is evaluated over the following 7 days. Non responders at the 7-day endpoint exit the study, while patients meeting response criteria are followed bi-weekly until relapse or for an additional 4 weeks. The primary efficacy measure is reduction in depression severity as assessed by the Montgomery- Asberg Depression Rating Scale (MADRS) scale 24 hours following IV infusion; additional outcome measures include response and remission rates, durability of benefit (7-day endpoint), side effects, and adverse events. PUBLIC HEALTH RELEVANCE: There is an urgent public health imperative to develop safe, well-tolerated, and rapidly-acting treatments for MDD. This research application seeks to benefit the public health by identifying a novel therapy for highly symptomatic and treatment-resistant patients that may decrease the morbidity and mortality associated with this common and serious illness.

描述(由申请人提供)：现有的治疗重度抑郁障碍(MDD)可能需要几周到几个月的时间才能发挥其最大益处。氯胺酮是一种高亲和力的NMDA谷氨酸受体拮抗剂，是一种麻醉和止痛药物，通常用于儿童和成人患者。氯胺酮在动物模型中具有抗抑郁特性，对患有严重情绪障碍的患者可能具有快速抗抑郁活性。最近在难治性单相抑郁(TRD)患者中进行的一项安慰剂对照研究显示，单次静脉注射(IV)氯胺酮(0.5 mg/kg)具有强大的抗抑郁效果，这一发现重复了之前的一项小型试点试验。引人注目的是，很高比例的患者对静脉注射氯胺酮保持了几天或更长时间的急性反应。在这项为期4年的单点研究中，我们将对静注氯胺酮治疗TRD的急性疗效和安全性进行三重掩蔽、随机、平行臂主动对照研究。具体目的：(1)测试与有效对照药物(咪达唑仑)相比，单次静脉输注氯胺酮是否具有更好的抗抑郁疗效。(2)确定疗效的持久性，并测试静注氯胺酮是否与7天时间点的抗抑郁效果有关。(3)检查干预措施的安全性和耐受性。意向治疗样本由的TRD患者组成，保守地定义为对当前事件中的3次足够的抗抑郁药物试验反应不足。在停药2周后，患者随机接受静注氯胺酮(40分钟内注射0.5毫克/公斤)或咪达唑仑(40分钟内注射0.045毫克/公斤)。在接下来的7天内对疗效和安全性进行评估。7天终点的无反应者退出研究，而符合反应标准的患者每两周进行一次跟踪，直到复发或再持续4周。主要的疗效衡量标准是用蒙哥马利-阿斯伯格抑郁评定量表(MADRS)在静脉注射24小时后评估的抑郁严重程度的降低；其他结果衡量标准包括反应和缓解率、受益的持久性(7天终点)、副作用和不良事件。 与公共卫生相关：开发安全、耐受性好、见效快的MDD治疗方法是公共卫生的当务之急。这项研究应用寻求通过为高度症状和治疗抵抗的患者确定一种新的疗法来造福公众健康，该疗法可以降低与这种常见和严重疾病相关的发病率和死亡率。