Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD).
Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD).
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DOI：
10.1038/s41380-018-0256-5
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发表时间：
2020-07
影响因子：
11
通讯作者：
Papakostas GI
中科院分区：
文献类型：
--
作者：
Fava M;Freeman MP;Flynn M;Judge H;Hoeppner BB;Cusin C;Ionescu DF;Mathew SJ;Chang LC;Iosifescu DV;Murrough J;Debattista C;Schatzberg AF;Trivedi MH;Jha MK;Sanacora G;Wilkinson ST;Papakostas GI
许多安慰剂对照研究已证明，氯胺酮（一种NMDA受体拮抗剂）以亚麻醉剂量（0.5 mg/kg，40分钟内）静脉（IV）给药时，能够诱导快速（数小时内）、一过性抗抑郁作用。然而，最佳抗抑郁剂剂量仍然未知。我们的目的是在难治性抑郁症（TRD）门诊患者中比较广泛亚麻醉剂量IV氯胺酮与活性安慰剂的速效抗抑郁药特性。在40分钟内单次输注后的3天内，将一系列IV氯胺酮剂量与活性安慰剂治疗成人TRD进行了比较。这是一项在美国6个学术中心进行的门诊研究。18-70岁的TRD门诊患者，定义为未能达到满意的缓解（例如，抑郁症状改善不足50%），在当前抑郁发作期间接受至少两个充分的治疗疗程。洗脱期后，99例合格受试者以1：1：1：1：1的方式随机分配至5个组之一：单次静脉注射氯胺酮0.1 mg/kg（n=18）、单次静脉注射氯胺酮0.2 mg/kg（n=20）、单次静脉注射氯胺酮0.5 mg/kg（n=22）、单次静脉注射氯胺酮1.0 mg/kg（n=20），和单剂量咪达唑仑0.045 mg/kg（活性安慰剂）（n=19）。研究评估（HAM-D-6，MADRS.在第0、1、3（终点）、5、7、14和30天进行SDQ、PAS、CGI-S和CGI-I），以评估安全性和疗效。总体组 * 时间相互作用效应对于主要结局指标HAM-D-6是显著的。在控制多重比较的事后成对比较中，标准剂量（0.5 mg/kg）和高剂量（1 mg/kg）静脉注射氯胺酮上级活性安慰剂;低剂量（0.1 mg/kg）仅在调整前具有显著性（第1天p=0.02，p-adj=0.14，d=-0.82）。大部分相互作用效应是由于第1天的差异，第3天无显著的校正成对差异。这种模式通常适用于次要结局。与活性安慰剂相比，氯胺酮输注的耐受性相对较好，但较高剂量时分离症状和一过性血压升高更严重。我们的结果表明，有证据表明0.5 mg/Kg和1.0 mg/Kg亚麻醉剂量的IV氯胺酮的疗效，没有明确或一致的证据表明较低剂量的IV氯胺酮具有临床意义的疗效。试验注册：NCT 01920555。
Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5mg/kg over 40 minutes). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 minutes. This was an outpatient study conducted across six US academic sites. Outpatients 18–70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n=18), a single dose of ketamine 0.2 mg/kg (n=20), a single dose of ketamine 0.5 mg/kg (n=22), a single dose of ketamine 1.0 mg/kg (n=20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n=19). The study assessments (HAM-D-6, MADRS. SDQ, PAS, CGI-S and CGI-I) were performed at Days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group*time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post-hoc pairwise comparisons controlling for multiple comparisons standard- (0.5 mg/kg) and high-doses (1 mg/kg) of intravenous ketamine were superior to active placebo; a low-dose (0.1 mg/kg) was significant only prior to adjustment (p=0.02, p-adj=0.14, d=−0.82 at Day 1). Most of the interaction effect was due to differences at Day 1, with no significant adjusted pairwise differences at Day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/Kg and 1.0 mg/Kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.
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影响因子：
10.6
作者：
O'Reardon, John P.;Solvason, H. Brent;Sackeim, Harold A.
通讯作者：
Sackeim, Harold A.
影响因子：
17.7
作者：
Posner, Kelly;Oquendo, Maria A.;Davies, Mark
通讯作者：
Davies, Mark
DOI：
10.1176/appi.ajp.2013.13030392
发表时间：
2013-10
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Murrough JW;Iosifescu DV;Chang LC;Al Jurdi RK;Green CE;Perez AM;Iqbal S;Pillemer S;Foulkes A;Shah A;Charney DS;Mathew SJ
通讯作者：
Mathew SJ
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
影响因子：
3.3
作者：
Pedrelli P;Blais MA;Alpert JE;Shelton RC;Walker RS;Fava M
通讯作者：
Fava M