Intravenous Sub-anesthetic Ketamine Treatment in Treatment-Resistant Depression

描述(由申请人提供)： 最近的研究发现，单次输注氯胺酮对难治性抑郁症(TRD)具有快速高效的抗抑郁作用。然而，一次输液似乎不足以维持反应，因为大多数患者在一周内恢复到以前的抑郁状态。多次输注以提高疗效和维持抗抑郁效果的策略尚未在随机对照试验中进行系统评估。这项拟议的研究是一项单中心的干预性疗效研究，旨在确定与单次输注氯胺酮相比，连续输注氯胺酮对患有TRD的退伍军人的抗抑郁效果。我们假设，在降低抑郁症状的严重程度和维持反应方面，六次输注都优于单次输注氯胺酮。参与者将是任何时代或军事背景的男性/女性退伍军人(18至75岁)，他们患有TRD，其定义为未能在至少两个不同药理类别的抗抑郁药物试验中获得缓解。潜在的参与者将从精神卫生诊所招募，并通过两个阶段的过程(电话/图表审查，然后进行面试)筛选资格。排除标准包括创伤后应激障碍、精神病相关障碍、躁郁症、酒精/物质使用障碍筛查前6个月；不稳定的内科疾病；严重/迫在眉睫的自杀/凶杀风险；帕金森氏病、痴呆症、癫痫发作；创伤性脑损伤；违禁药物(如MAO抑制剂、巴比妥类)；在当前病程中接受ECT检查；怀孕/护理。基线评估将在开始治疗前1-2周完成。参与者将被随机分配到两种平行治疗条件中的一种：1)6次注射0.5毫克/公斤的氯胺酮或2)单次注射0.5毫克/公斤的氯胺酮，然后再注射5次0.045毫克/公斤的咪达唑仑。咪达唑仑被选为活性安慰剂，其药代动力学和解离效应与氯胺酮相似。每项干预措施将按周一至周三至周五的时间表提供总计12天的输液阶段。前4周每周一次，接下来的8周每2周一次，其余12周每4周一次，直到复发为止。主要终点是最后一次输液后24小时的Montgomery-�sberg抑郁评定量表(MADRS)评分，此时氯胺酮的抗抑郁效果达到顶峰。治疗阶段的次要结果包括MADRS&lt；10定义的缓解，以及定义为基线MADRS评分下降50%的应答。在随访期内，抗抑郁药物反应的持久性将由“复发时间”定义为MADRS评分的50%。将在基线、输液期内的几个时间点和随访时确定抑郁症状严重程度和抗抑郁效果的潜在协变量(例如，疼痛强度、焦虑水平)的独立评估。在输液当天，受试者将在隔夜禁食后于早上到达。从输液前10分钟开始，每10分钟记录一次血流动力学指标，持续1小时。然后，受试者将接受超过40分钟的静脉输液。观察输液前和输液后24小时抑郁症状的严重程度、疼痛强度、焦虑程度。在每次输液开始前30分钟和输液结束时(t0+40分钟)，在t0+120分钟和t0+180分钟再次测量急性分离效应、躁狂/躁狂症状和拟精神分裂效应。如果发生严重不良事件，将停止输液。随后在第3、5、8、10和12天的输液程序将与第一次输液相同。

DESCRIPTION (provided by applicant): Recent studies have found rapid and highly efficacious antidepressant effects of a single ketamine infusion in treatment-resistant depression (TRD). However, a single infusion appears insufficient to maintain response as most patients return to previous depressive state within a week. The strategy of multiple infusions to increase efficacy and sustain antidepressant effects has not yet been systematically evaluated in an RCT. The proposed study is a one-center, interventional, efficacy study designed to determine antidepressant outcomes of serial ketamine infusions compared to a single ketamine infusion among veterans with TRD. We have hypothesized that six infusions will be superior to a single infusion of ketamine in both decreasing severity of depressive symptoms and maintaining response. Participants will be male/female veterans (18 to 75 years old) of any era or military background who suffer from TRD defined as failure to achieve remission from at least 2 antidepressant trials of different pharmacological classes. Potential participants will be recruited from Mental Health clinics and screened for eligibility using a two stage process (phone/chart review, followed by interview). Exclusion criteria includes post-traumatic stress disorder, psychosis-related disorder, bipolar disorder, alcohol/substance use disorder 6 months prior to screening; unstable medical illness; serious/imminent suicidal/homicidal risk; Parkinson's disease, dementia, seizures; traumatic brain injury; contraindicated medications (e.g., MAO inhibitors, barbiturates); received ECT during current episode; pregnancy/nursing. Baseline assessments will be completed 1-2 weeks prior to starting treatment. Participants will be randomly assigned to one of two parallel treatment conditions: 1) six ketamine infusions at 0.5 mg/kg or 2) single ketamine infusion at 0.5 mg/kg preceded by five midazolam infusions at 0.045 mg/kg. Midazolam was chosen as an active placebo given similar pharmacokinetics and dissociative effect profile to ketamine. Each intervention will be provided for a total of 12-day infusion-phase on a Monday-Wednesday-Friday schedule. The, follow-up visits will occur at weekly intervals for the first 4 weeks, at 2-week intervals for the next 8 weeks, and at 4-week intervals for the remaining 12 weeks or until relapse. The primary end point is the Montgomery- �sberg Depression Rating Scale (MADRS) score 24 hours following the last infusion where the peak antidepressant effects of ketamine occur. Secondary outcomes for the treatment phase include remission defined by MADRS<10, and response defined as a reduction in the baseline MADRS score e 50%. For the follow-up period, durability of antidepressant response will be defined by "time to relapse" to a MADRS score <50% of baseline at that visit. Independent evaluation of depressive symptom severity and potential covariates of antidepressant effect (e.g., pain intensity, level of anxiety) will be ascertained at baseline, at several time points during infusion period, and at follow-up. On the day of infusion, subjects will arrive in the morning after an overnight fast. Hemodynamic measures will be recorded every 10 min for 1 hour beginning 10 min before infusion. Subjects will then receive IV infusion over 40 minutes. Severity of depressive symptoms, pain intensity, level of anxiety will be obtained before and 24 hours after infusion. Acute dissociative effects, manic/hypomanic symptoms, and psychotomimetic effects will be measured 30 minutes before the start of each infusion and at the end of infusion (t0+40 mins) and again at t0+120mins and t0+180mins. The infusion will be discontinued in the event of significant adverse events. Procedures for the subsequent infusions at days 3, 5, 8, 10, and 12 will be identical to those of the first infusion.