Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe.

ClinicalTrials.gov: Treatment Resistant Depression (Pilot), NCT01179009.

氯胺酮在超过 50% 的难治性抑郁症成人中产生快速的抗抑郁反应。长期输注氯胺酮可持久缓解抑郁症状，但其安全性、有效性和神经生物学相关性尚不清楚。在这项开放标签、原理验证研究中，患有难治性抑郁症的成年人 ( N = 23) 接受了 96 小时静脉注射氯胺酮（0.15 mg/kg/h 滴定至 0.6 mg/kg/h）。共同给予可乐定以减少拟精神病作用。我们测量了输注后 8 周的临床反应。静息态功能磁共振成像用于评估输注前和输注后 2 周患者以及匹配的非抑郁对照中的功能连接性（N= 27). 我们假设对治疗有反应的人会表现出依赖于反应的连通性变化，而所有受试者都会表现出依赖于治疗的连通性变化。大多数参与者完成了输注（21/23；平均最终剂量 0.54 mg/kg/h，SD 0.13）。输液耐受性良好，认知和拟精神病副作用最小。抑郁症状显着减少（基线时的 MADRS 29 ± 4 至输注后一天的 9 ± 8），持续时间为 2 周（13 ± 8）和 8 周（15 ± 8）。成像显示膝下前扣带回皮层与默认模式网络的超连接性随反应而降低，边缘系统（海马、杏仁核、内侧丘脑、伏隔核）内的超连接性随治疗而降低。在探索性分析中，边缘系统和额叶区域之间的连通性增加，基线时右侧海马体积较小预示着 MADRS 变化较大。单次长时间输注氯胺酮可对难治性抑郁症产生耐受、快速和持续的反应，并使边缘系统和额叶中与抑郁症相关的超连接正常化。

ClinicalTrials.gov ：治疗抵抗性抑郁症（试点），NCT01179009。