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.

严重的抑郁症（MDD）和酒精使用障碍（AUD）是严重的精神疾病， 在退伍军人中通常同时发生。抑郁症和合并症的适当治疗是主要的临床 在VA上的重要性，但是当前药物治疗抑郁症的效率仅适度而缓解 抑郁症患者的速度尤其低。发作前几周或几个月的延迟 传统抗抑郁药的抗抑郁作用也有问题，尤其是考虑到较高的风险 自杀。此外，使命是40％的MDD患者合并AUD 他们的一生，AUD患者已被排除在大多数抗抑郁药试验之外的抑郁症。那有一个 为MDD和AUD开发有效的药物治疗的迫切需要。 越来越多的文献表明，下觉单一静脉（IV）输注 氯胺酮具有快速且强大的抗抑郁作用。氯胺酮也与快速减少有关 随机对照试验中的自杀思想。除了治疗MDD外，新兴证据表明 氯胺酮是NMDA受体拮抗剂，可能是通过稳定谷氨酸能的有效治疗方法 系统。在此证据的基础上，我们最近在合并MDD和AUD的患者中测试了氯胺酮。我们的 试验数据表明，氯胺酮可以安全有效地减少抑郁和饮酒。 该提案的主要目标是反复测试静脉注射氯胺酮（0.5 mg/kg；每周一次； A 总共4氯胺输注）作为MDD和AUD的治疗，总共有60名退伍军人。我们提出了8- 周，随机，双盲，安慰剂对照试验。该研究将有两个阶段：1）4周 治疗阶段和2）为期4周的随访阶段。所有患者将每天使用生态学评估 暂时评估，并将在此试验期间获得常规的标准护理。 有五个目标。 目的＃1：评估氯胺酮在治疗抑郁症中是否优于活跃的安慰剂（咪达唑仑） 与合并MDD和AUD的退伍军人。我们假设氯胺酮在临床中优于活跃的安慰剂 治疗抑郁症的反应。临床反应将定义为比基线提高50％ 在蒙哥马利 - 奥斯伯格抑郁评分量表（MADRS）中。 目标＃2：评估氯胺酮在减少酒精饮酒时是否优于活跃的安慰剂（咪达唑仑） 与合并MDD和AUD的退伍军人。我们假设氯胺酮优于活跃的安慰剂 减少饮酒，按时间线跟随（TLFB）。 目的＃3：评估氯胺酮在减少酒精的渴望中是否优于活跃的安慰剂（咪达唑仑） 在8周的研究期间。我们假设氯胺酮优于活跃的安慰剂（咪达唑仑） 通过饮酒敦促调查表（AUQ）来减少渴望酒精的渴望。 目标＃4：评估氯胺酮在减少自杀式想法方面是否优于活跃的安慰剂（米物唑）。 我们假设氯胺酮在降低自杀念头中优于活跃的安慰剂（咪达唑仑） 通过哥伦比亚自由卫生的严重程度评级量表（C-SSRS）自杀构想类别来衡量。 目标＃5：评估与合并MDD的退伍军人中重复氯胺酮输注的安全性和耐受性 和aud。我们假设重复的氯胺酮输注在该人群中是安全且耐受性的。 结论：这是第一次检查重复的治疗潜力的随机对照试验 合并MDD和AUD的氯胺酮。如果成功，我们的药物方法可以帮助退伍军人 患有这种情况。