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

重度抑郁症(MDD)和酒精使用障碍(AUD)是严重的精神疾病和 通常在退伍军人中共同发生。充分治疗抑郁症和伴发的AUD具有重要的临床意义 在退伍军人事务部的重要性，但目前的药物治疗抑郁症的疗效仅为温和和缓解 在患有AUD的抑郁症患者中，这一比例尤其低。发病前的几周或几个月的延迟 传统抗抑郁药的抗抑郁效果也是有问题的，特别是考虑到 在这群人中自杀。此外，尽管40%的MDD患者患有AUD 在他们的一生中，AUD患者被排除在大多数抗抑郁药物试验之外。因此，有一个 迫切需要为MDD和AUD开发有效的药物疗法。 越来越多的文献表明，麻醉下单一静脉(IV)输注 氯胺酮具有快速而有力的抗抑郁作用。氯胺酮也与快速减少的 随机对照试验中的自杀念头。除了治疗MDD外，新出现的证据表明 氯胺酮是一种NMDA受体拮抗剂，可能通过稳定谷氨酸能而有效治疗AUD 系统。基于这一证据，我们最近在患有MDD和AUD的患者中测试了氯胺酮。我们的 试点数据显示，氯胺酮在减少抑郁和饮酒方面可能是安全有效的。 这项提议的主要目标是测试重复静脉注射氯胺酮(0.5毫克/公斤；每周一次； 共输注氯胺酮4次)，用于治疗MDD和AUD，共60名退伍军人。我们建议8- 每周，随机、双盲、安慰剂对照试验。研究将分两个阶段进行：1)为期4周 治疗阶段和2)为期4周的随访阶段。所有患者每天都将接受生态评估 即时评估，并将在此试验期间接受通常的标准护理。 有五个目标。 目的1：评价氯胺酮治疗抑郁症是否优于活性安慰剂(咪达唑仑)。 患有MDD和AUD的退伍军人。我们假设氯胺酮在临床上优于活性安慰剂。 对治疗抑郁症的反应。临床反应将被定义为≥较基线改善50% 采用蒙哥马利-奥斯伯格抑郁量表(MADRS)评分。 目的2：评估氯胺酮在减少酒精使用方面是否优于活性安慰剂(咪达唑仑)。 患有MDD和AUD的退伍军人。我们假设氯胺酮在以下方面优于活性安慰剂 通过时间线跟踪(TLFB)来衡量减少饮酒量。 目的3：评估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) 在为期8周的研究期间。我们假设氯胺酮在以下方面优于活性安慰剂(咪达唑仑) 通过酒精刺激问卷(AUQ)测量减少酒精渴求。 目的#4：评价氯胺酮在减少自杀意念方面是否优于活性安慰剂(咪达唑仑)。 我们假设氯胺酮在减少自杀念头方面优于活性安慰剂(咪达唑仑)，因为 由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：评估反复输注氯胺酮对患有MDD的退伍军人的安全性和耐受性 和澳元。我们假设，重复输注氯胺酮在该人群中是安全和耐受性良好的。 结论：这是首个检验重复试验治疗潜力的随机对照试验。 氯胺酮治疗MDD和AUD并存。如果成功，我们的药理学方法可以帮助退伍军人 患有这种病症的。

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.