University of Pittsburgh School of Medicine, Pittsburgh (Price, Spotts, Panny, Griffo, Degutis, Cruz, Bell, Do-Nguyen, Wallace, Howland); Baylor College School of Medicine and Michael E. DeBakey VA Medical Center, Houston (Mathew).
Am J Psychiatry. 2022 Dec 1;179(12):959-968. doi: 10.1176/appi.ajp.20220216. Epub 2022 Sep 21.
Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. The authors tested whether an automated, computer-based approach could efficiently leverage enhanced neuroplasticity to extend the durability of rapid clinical response.
A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active "automated self-association training" [ASAT]; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One day after a single infusion of intravenous ketamine (0.5 mg/kg over 40 minutes) or inert placebo (saline), active ASAT-targeting self-worth through automated "evaluative conditioning" training delivered by computer-or sham ASAT (consisting of identical computer tasks that included no positive or self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight sessions, ≤20 minutes per session). The prespecified primary outcome measure throughout the main (30-day) study period was score on the Montgomery-Åsberg Depression Rating Scale (MADRS).
Ketamine rapidly and significantly reduced depression scores at 24 hours postinfusion (group-by-time interaction: standardized beta [β]=-1.30, 95% CI=-1.89, -0.70; t=-4.29, df=150). In intent-to-treat linear mixed models, depression scores in the ketamine+ASAT group remained significantly and stably low over the 30-day study period relative to those of the saline+ASAT group (β=-0.61, 95% CI=-0.95, -0.28; t=-3.62, df=148). By contrast, depression scores following ketamine+sham treatment followed a significant, increasing linear trajectory from 24 hours to 30 days, approaching the levels observed in the saline+ASAT group (group-by-time interaction relative to the saline+ASAT group: β=0.015, 95% CI=0.003, 0.03; t=2.35, df=568).
After priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine's rapid antidepressant effects.
静脉注射氯胺酮具有快速抗抑郁的特性，据推测可以通过快速增强神经可塑性来逆转抑郁。作者测试了一种自动化的计算机方法是否能够有效地利用增强的神经可塑性来延长快速临床反应的持续时间。
共有 154 名年龄在 18-60 岁之间的治疗抵抗性单相抑郁症患者，采用双盲、平行臂设计，随机分为两组：一组接受活性/活性治疗联合（氯胺酮加活性“自动自我关联训练”[ASAT]；n=53），另一组接受两种对照治疗：一种缺乏活性药物成分（生理盐水加活性 ASAT；n=51），另一种缺乏活性行为成分（氯胺酮加假 ASAT；n=50）。在单次静脉注射氯胺酮（0.5mg/kg，40 分钟）或无活性安慰剂（生理盐水）1 天后，接受计算机介导的主动 ASAT-通过自动“评价性条件作用”训练针对自我价值，或假 ASAT（由包含无阳性或自我参照刺激的相同计算机任务组成），每天两次，连续 4 天（8 次，每次≤20 分钟）。整个主要（30 天）研究期间的主要预设结果测量是蒙哥马利-阿斯伯格抑郁评定量表（MADRS）的评分。
氯胺酮在输注后 24 小时迅速显著降低抑郁评分（组间时间交互作用：标准化β[β]=-1.30，95%置信区间[-1.89，-0.70]；t=-4.29，df=150）。在意向治疗线性混合模型中，与生理盐水+ASAT 组相比，氯胺酮+ASAT 组在 30 天的研究期间，抑郁评分持续显著且稳定降低（β=-0.61，95%置信区间[-0.95，-0.28]；t=-3.62，df=148）。相比之下，氯胺酮+假治疗后的抑郁评分从 24 小时到 30 天呈显著、递增的线性轨迹，接近生理盐水+ASAT 组的水平（相对于生理盐水+ASAT 组的组间时间交互作用：β=0.015，95%置信区间[0.003，0.03]；t=2.35，df=568）。
用氯胺酮对大脑进行预处理后，训练积极的自我联想可以提供一种有效、低成本、便携、非侵入性和高度易于传播的策略，以利用和延长氯胺酮的快速抗抑郁作用。
