Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.

中文翻译：

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mTORC1 抑制剂雷帕霉素调节氯胺酮的抗抑郁作用。


给药 24 小时后，氯胺酮发挥快速而强大的抗抑郁作用，这种作用被认为是通过激活雷帕霉素复合物 1 (mTORC1) 的机制靶点介导的。为了检验这一假设，抑郁症患者在接受氯胺酮之前接受了雷帕霉素（一种 mTORC1 抑制剂）预处理。 20 名患有重度抑郁发作的患者在双盲交叉设计中，在静脉注射氯胺酮 0.5 mg/kg 之前 2 小时随机接受口服雷帕霉素（6 mg）或安慰剂预处理，治疗天数至少相隔 2几周。使用蒙哥马利-阿斯伯格抑郁评定量表（MADRS）评估抑郁严重程度。雷帕霉素预处理不会改变氯胺酮在 24 小时时间点的抗抑郁作用。在接下来的两周内，我们发现时间交互作用具有显着的治疗效果（F(8,245) = 2.02，p = 0.04），表明雷帕霉素延长了氯胺酮的抗抑郁作用。服用氯胺酮两周后，我们发现与安慰剂 + 氯胺酮相比，雷帕霉素 + 氯胺酮治疗后的缓解率 (41%) 和缓解率 (29%) 更高（分别为 13%，p = 0.04 和 7%，p = 0.003）。综上所述，单剂量雷帕霉素预处理未能阻断氯胺酮的抗抑郁作用，但延长了氯胺酮的抗抑郁作用。这一观察结果提出了关于全身与局部阻断 mTORC1 在氯胺酮抗抑郁作用中的作用的问题，提供了雷帕霉素可能延长氯胺酮益处的初步证据，从而可能揭示氯胺酮给药后导致抑郁症复发的机制。