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: 9330790
• 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/9330790
• 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; Dental crowns; 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; Homicide; Hour; Infusion procedures; Intervention; Interview; Intravenous; Intravenous infusion procedures; Ketamine; Major Depressive Disorder; Manic; Measures; Medical; Mental Depression; Mental Health; Methodology; Midazolam; Military Personnel; Monoamine Oxidase Inhibitors; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Names; Nurses; Outcome; Pain intensity; Parkinson' s Dementia; Participant; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phonation; 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; Substance Use Disorder; Symptoms; Telephone; Testing; Time; Traumatic Brain Injury; Treatment Efficacy; Treatment outcome; Unipolar Depression; Veterans; Visit; accomplished suicide; antidepressant effect; 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，单个氯胺酮输注在耐治疗抑郁症（TRD）中的快速且高效的抗抑郁作用。但是，随着大多数患者在一周内恢复到以前的抑郁状态，单个输注似乎不足以维持反应。在RCT中，尚未系统地评估多种输注以提高有效性和维持抗抑郁作用的策略。拟议的研究是一项单中心的，介入的，有效性研究，旨在确定与TRD的退伍军人相比，与单个氯胺酮输注相比，连续氯胺酮输注的抗抑郁剂结果。我们假设，六种输注量将优于氯胺酮的单一输注，这既降低了抑郁症状的严重程度和保持反应。参与者将是任何ERA或军事背景的男性/女退伍军人（18至75岁），他们的TRD被定义为未能从至少2次对不同药物类别的抗抑郁药试验中缓解。潜在的参与者将从心理健康诊所招募，并使用两个阶段过程（电话/图表评论，随后进行访谈）筛选资格。排除标准包括创伤后应激障碍，与精神病相关的疾病，躁郁症，酒精/药物使用障碍前6个月；不稳定的医学疾病；严重/迫在眉睫的自杀/杀人风险；帕金森氏病，痴呆，癫痫发作；创伤性脑损伤；禁忌的药物（例如，毛抑制剂，巴比妥类药物）；在当前情节中获得了ECT；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给以下两个平行治疗条件之一：1）以0.5 mg/kg或2）为0.5 mg/kg的单酮输注以0.045 mg/kg为0.5 mg/kg。咪达唑仑被选为具有类似的药代动力学和与氯胺酮的分离效果的活性安慰剂。每种干预措施将在周一至周五的时间表中总共提供12天的输液相。后续访问将在最初的4周内每周进行一次，在接下来的8周内以2周的间隔以及剩余的12周或直到复发的4周间隔进行。主要终点是蒙哥马利抑郁量量表（MADRS）在最后一次输注后24小时得分，氯胺酮发生了峰值抗抑郁作用。治疗阶段的次要结果包括由MADR <10定义的缓解，而响应定义为降低基线MADRS评分E 50％。在后续期间，抗抑郁反应的耐用性将由“救济时间”定义为在此访问时的MADRS得分<50％。将在基线，输注期间和随访时确定抗抑郁作用的抑郁症状严重程度和抗抑郁作用的潜在协变量（例如疼痛强度，焦虑程度）的独立评估。在输液的那天，经过一夜之间过夜后，受试者将在早晨到达。在输注前10分钟开始，每10分钟将每10分钟记录一次血液动力学措施。然后，受试者将在40分钟内接受IV输注。抑郁症状的严重程度，疼痛强度，焦虑程度将在输注前和24小时后获得。在每次输注开始前30分钟，在输注结束时（T0+40分钟），将测量急性解离效应，躁狂/躁狂症状和心理症状，并在T0+120分钟和T0+180分钟处进行测量。在发生重大不良事件的情况下，输液将中止。第3、5、8、10和12天后输注的程序将与第一次输注的程序相同。