Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9111, USA.
Nature. 2011 Jun 15;475(7354):91-5. doi: 10.1038/nature10130.
Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.
临床研究一致表明，单次亚致幻剂量的氯胺酮，一种离子型谷氨酸能 NMDA 受体（N-甲基-D-天冬氨酸受体）拮抗剂，可在患有重度抑郁症的患者中产生快速抗抑郁反应，尽管其潜在机制尚不清楚。抑郁患者报告说，在单次、低剂量静脉输注氯胺酮后两小时内，主要抑郁症状得到缓解，其效果可持续长达两周，与传统抗抑郁药（选择性 5-羟色胺再摄取抑制剂）不同，后者需要数周才能达到疗效。这种延迟是目前治疗重度抑郁症的主要缺点，需要更快起效的抗抑郁药，特别是对于有自杀风险的患者。氯胺酮能够在抑郁患者中产生快速起效、持久的抗抑郁反应，这为研究潜在的细胞机制提供了独特的机会。在这里，我们表明氯胺酮和其他 NMDA 拮抗剂在小鼠模型中产生快速起效的行为抗抑郁样效应，并且这些效应依赖于脑源性神经营养因子的快速合成。我们发现，静息状态下氯胺酮介导的 NMDA 阻断会使真核延伸因子 2（eEF2）激酶（也称为 CaMKIII）失活，导致 eEF2 磷酸化减少和脑源性神经营养因子翻译去抑制。此外，我们发现 eEF2 激酶抑制剂可诱导快速起效的行为抗抑郁样效应。我们的研究结果表明，自发神经传递对蛋白质合成的调节可能成为开发快速起效的抗抑郁药的可行治疗靶点。
