Intravenous Sub-anesthetic Ketamine Treatment in Treatment-Resistant Depression

静脉亚麻醉氯胺酮治疗难治性抑郁症

• 批准号: 9029172
• 负责人: Paulo R. Shiroma
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029172
• 关键词: Acute; Adverse effects; Adverse event; Affinity; Agonist; Alcohols; Anesthesia procedures; Anesthetics; Antidepressive Agents; Anxiety; Barbiturates; Behavioral; Bipolar Depression; Bipolar Disorder; Cessation of life; Characteristics; Clinic; Clinical Trials; Cognitive; Data; Depressed mood; Discipline of Nursing; Disease; Disease remission; Dose; Drug Kinetics; Eligibility Determination; Evaluation; Event; Exclusion Criteria; Failure; Female; Frequencies; Glutamate Receptor; Goals; Health Care Costs; Hour; Infusion procedures; Intervention; Interview; Intravenous; Intravenous Anesthetics; Intravenous infusion procedures; Ketamine; Life; Major Depressive Disorder; Manic; Measures; Medical; Mental Depression; Mental Health; Midazolam; Military Personnel; Monoamine Oxidase Inhibitors; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Names; Outcome; Pain intensity; Parkinson' s Dementia; Participant; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Population; Post-Traumatic Stress Disorders; Pregnancy; Prevalence; Procedures; Process; Psychotic Disorders; Quality of life; Randomized; Randomized Controlled Trials; Recruitment Activity; Registries; Relapse; Reporting; Research; Research Design; Research Personnel; Risk; Sampling; Schedule; Seizures; Severities; Staging; Substance Use Disorder; Symptoms; Testing; Time; Traumatic Brain Injury; Unipolar Depression; Veterans; Visit; accomplished suicide; antidepressant effect; base; depressed patient; depressive symptoms; effective therapy; follow-up; functional disability; health administration; hemodynamics; hypomania; improved; indexing; male; novel; placebo controlled study; public health relevance; response; screening; secondary outcome; suicidal; suicidal risk; treatment duration; treatment responders; treatment-resistant depression; trial comparing

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.

描述（由申请人提供）： 最近的研究发现，单次氯胺酮输注对治疗难治性抑郁症（TRD）具有快速且高效的抗抑郁作用，但单次输注似乎不足以维持反应，因为大多数患者在一周内恢复到先前的抑郁状态。输注以提高疗效和维持抗抑郁效果尚未在随机对照试验中进行系统评估。拟议的研究是一项单中心、干预性、疗效研究，旨在确定连续输注氯胺酮的抗抑郁效果。与患有 TRD 的退伍军人中单次氯胺酮输注相比，我们发现六次输注在减轻抑郁症状的严重程度和维持反应方面都优于单次氯胺酮输注。 ）任何时代或军事背景的患有 TRD 的患者，TRD 被定义为在至少 2 次不同药理学类别的抗抑郁药试验中未能获得缓解的潜在参与者将从心理健康诊所招募并筛选资格。使用两阶段流程（电话/图表审查，然后进行访谈），排除标准包括筛查前 6 个月患有创伤后应激障碍、精神病相关障碍、躁郁症、酒精/药物滥用障碍；即将自杀/杀人的风险；帕金森病、痴呆、癫痫；当前发作期间服用禁忌药物（例如 MAO 抑制剂、巴比妥类药物）；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至两种平行治疗条件之一：1) 6 次 0.5 mg/kg 氯胺酮输注或 2) 单次 0.5 mg 氯胺酮输注。考虑到与 0.045 mg/kg 的咪达唑仑相似的药代动力学和解离效应特征，选择 5 次咪达唑仑输注作为活性安慰剂。每次干预将按周一-周三-周五的时间表进行总共 12 天的输注阶段，前 4 周每周一次，后续每两周一次。接下来的 8 周，以及在剩余 12 周内每隔 4 周一次或直到复发，主要终点是最后一次输注后 24 小时的蒙哥马利-斯伯格抑郁评定量表 (MADRS) 评分。治疗阶段的次要结果包括 MADRS<10 定义的缓解，以及基线 MADRS 评分降低 50% 的缓解。定义为“复发时间”至该访视时 MADRS 评分低于基线的 50%。独立评估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）将在基线、输注期间的几个时间点和随访时确定。在输注当天，受试者将在隔夜禁食后的早晨到达，每 10 分钟记录一次血流动力学测量。输注前 10 分钟开始 1 小时，然后在输注前和输注后 24 小时内获得抑郁症状的严重程度、疼痛强度、焦虑程度。每次输注开始前 30 分钟和输注结束时（t0+40 分钟）以及 t0+120 分钟和 t0+180 分钟再次测量解离效应、躁狂/轻躁狂症状和拟精神效应。输注将停止。如果发生重大不良事件，将进行第 3、5、8、10 和 12 天的后续输注程序。与第一次输注相同。