Ketamine for The Rapid Treatment of Major Depression and Alcohol Use Disorder

氯胺酮用于快速治疗重度抑郁症和酒精使用障碍

• 批准号: 10709651
• 负责人: Gihyun Yoon
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10709651
• 关键词: Afghanistan; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcohols; Anesthetics; Antidepressive Agents; Area; Back; Categories; Clinical; Country; Data; Development; Disease; Disease remission; Dose; Ecological momentary assessment; Exclusion; Feeling suicidal; General Population; Glutamates; Goals; Healthcare Systems; Income; Infusion procedures; Intravenous; Intravenous infusion procedures; Iraq; Ketamine; Laws; Literature; Major Depressive Disorder; Measures; Medical; Mental Depression; Mental Health Services; Mental disorders; Meta-Analysis; Midazolam; Military Personnel; Mission; Montgomery and Asberg depression rating scale; NMDA receptor antagonist; Odds Ratio; Outcome; Patients; Pharmacotherapy; Phase; Placebos; Population; Prevalence; Questionnaires; Randomized; Randomized, Controlled Trials; Reporting; Research Priority; Safety; Severities; Substance abuse problem; Suicide; Suicide prevention; System; Testing; Therapeutic; Time; United States; Veterans; War; Work; active duty; alcohol comorbidity; alcohol craving; alcohol use disorder; antidepressant effect; binge drinking; comorbidity; completed suicide; craving; depressed patient; depressive symptoms; double-blind placebo controlled trial; drinking; effective therapy; follow-up; health service use; improved; interest; military veteran; mortality; novel; pharmacologic; preventive intervention; psychiatric comorbidity; reduced alcohol use; reducing suicide; response; service member; severe mental illness; standard care; suicidal risk

Major depressive disorder (MDD) and alcohol use disorder (AUD) are serious mental illnesses and commonly co-occur among Veterans. Adequate treatment of depression and comorbid AUD is of major clinical importance at the VA, yet the efficacy of current pharmacotherapy for depression is only modest and remission rates are particularly low in depressed patients with AUD. The delay of weeks or months before the onset of antidepressant effects of traditional antidepressants is also problematic, particularly given the elevated risk for suicide in this population. Furthermore, despite the fact that 40% of patients with MDD have comorbid AUD in their lifetime, AUD patients have been excluded from most antidepressant trials for depression. Thus, there is a critical need to develop effective pharmacotherapy for MDD and AUD. There is a growing body of literature showing that a subanesthetic single intravenous (IV) infusion of ketamine has rapid and robust antidepressant effects. Ketamine was also associated with a rapid reduction in suicidal thoughts in randomized controlled trials. In addition to treating MDD, emerging evidence indicates that ketamine, an NMDA receptor antagonist, might be an effective treatment for AUD by stabilizing glutamatergic system. Building on this evidence, we recently tested ketamine in patients with comorbid MDD and AUD. Our pilot data showed that ketamine may be safe and effective in reducing depression and alcohol consumption. The primary goal of this proposal is to test repeated intravenous ketamine (0.5 mg/kg; once a week; a total of 4 ketamine infusions) as a treatment for MDD and AUD in a total of 60 Veterans. We propose an 8- week, randomized, double-blind, placebo-controlled trial. The study will have two phases: 1) a 4-week treatment phase and 2) a 4-week follow-up phase. All patients will be evaluated daily by using ecological momentary assessment and will receive usual standard care during this trial. There are five objectives. Aim #1: To evaluate whether ketamine is superior to active placebo (midazolam) in treating depression in Veterans with comorbid MDD and AUD. We hypothesize that ketamine is superior to active placebo in clinical response for treating depression. The clinical response will be defined as a ≥ 50% improvement from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Aim #2: To evaluate whether ketamine is superior to active placebo (midazolam) in reducing alcohol use in Veterans with comorbid MDD and AUD. We hypothesize that ketamine is superior to active placebo in reducing drinking as measured by the Time Line Follow Back (TLFB). Aim #3: To evaluate whether ketamine is superior to active placebo (midazolam) in reducing alcohol craving during the 8-week study period. We hypothesize that ketamine is superior to active placebo (midazolam) in reducing alcohol craving as measured by the Alcohol Urges Questionnaire (AUQ). Aim #4: To evaluate whether ketamine is superior to active placebo (midazolam) in reducing suicidal ideation. We hypothesize that ketamine is superior to active placebo (midazolam) in reducing suicidal ideation as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation category. Aim #5: To evaluate the safety and tolerability of repeated ketamine infusions in Veterans with comorbid MDD and AUD. We hypothesize that repeated ketamine infusions are safe and well tolerated in this population. Conclusion: This is the first randomized controlled trial examining the therapeutic potential of repeated ketamine for comorbid MDD and AUD. If successful, our pharmacological approach could help Veterans suffering from this condition.

重度抑郁症（MDD）和酒精使用障碍（AUD）是严重的精神疾病， 通常发生在退伍军人中。充分治疗抑郁症和共病的AUD是主要的临床 在VA的重要性，但目前的药物治疗抑郁症的疗效是只有适度和缓解 在患有AUD的抑郁症患者中发生率特别低。延迟数周或数月才发作， 传统抗抑郁药的抗抑郁作用也是有问题的，特别是考虑到 在这个人群中自杀。此外，尽管事实上40%的MDD患者合并有AUD， 在他们的一生中，AUD患者被排除在大多数抑郁症抗抑郁药试验之外。由此可见，有一 迫切需要开发有效的药物治疗MDD和AUD。 越来越多的文献表明，亚麻醉单次静脉（IV）输注 氯胺酮具有快速和强大的抗抑郁作用。氯胺酮也与快速减少 随机对照试验中的自杀想法。除了治疗MDD，新出现的证据表明， 氯胺酮是一种NMDA受体拮抗剂，可能通过稳定多巴胺能神经元， 系统基于这一证据，我们最近在MDD和AUD共病患者中测试了氯胺酮。我们 试验数据显示，氯胺酮可安全有效地减少抑郁症和饮酒。 本提案的主要目标是测试重复静脉注射氯胺酮（0.5 mg/kg;每周一次; 共4次氯胺酮输注）治疗MDD和AUD，共60例退伍军人。我们提出了一个8- 周、随机、双盲、安慰剂对照试验。该研究将分为两个阶段：1）为期4周的 治疗阶段和2）4周随访阶段。所有患者将每天通过使用生态 暂时评估，并将在本试验期间接受常规标准治疗。 有五个目标。 目的#1：评价氯胺酮在治疗抑郁症方面是否上级活性安慰剂（咪达唑仑）， 患有MDD和AUD共病的退伍军人。我们假设氯胺酮在临床上上级活性安慰剂， 治疗抑郁症的反应。临床应答定义为较基线改善≥ 50% 在蒙哥马利抑郁量表（MADRS）评分中。 目的#2：评价氯胺酮在减少酒精使用方面是否上级活性安慰剂（咪达唑仑）， 患有MDD和AUD共病的退伍军人。我们假设，氯胺酮上级活性安慰剂， 根据时间线追踪（TLFB）的测量，减少饮酒。 目的#3：评价氯胺酮在减少酒精渴求方面是否优于活性安慰剂（咪达唑仑）上级 在8周的研究期间。我们假设，氯胺酮上级活性安慰剂（咪达唑仑）， 减少酒精渴望，通过酒精冲动问卷（AUQ）测量。 目的#4：评价氯胺酮在减少自杀意念方面是否上级活性安慰剂（咪达唑仑）。 我们假设氯胺酮在减少自杀意念方面上级活性安慰剂（咪达唑仑）， 通过哥伦比亚自杀严重程度评定量表（C-SSRS）自杀意念类别测量。 目的5：评价在合并MDD的退伍军人中重复氯胺酮输注的安全性和耐受性 和AUD。我们假设，重复氯胺酮输注在这一人群中是安全的，耐受性良好。 结论：这是第一个随机对照试验，检查重复的治疗潜力。 氯胺酮用于合并MDD和AUD。如果成功，我们的药理学方法可以帮助退伍军人 患有这种疾病。