Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish.
Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish.
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DOI：
10.1017/s1092852914000686
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发表时间：
2016-02
期刊：
影响因子：
3.3
通讯作者：
Arnsten AF
中科院分区：
文献类型：
--
作者：
Opler LA;Opler MG;Arnsten AF
本文综述了N-甲基-D-天冬氨酸谷氨酸受体(NMDAR)拮抗剂氯胺酮的抗抑郁作用，并基于NMDAR在非人灵长类前额叶皮质(PFC)中的关键作用，为氯胺酮鼻腔超快速作用提供了潜在的神经机制。虽然静脉注射氯胺酮可以在几个小时内提升情绪，但目前的综述描述了鼻腔注射氯胺酮如何具有超快速的抗抑郁效果，从几分钟(5-40分钟)开始，持续几个小时，但需要重复治疗才能持续抗抑郁作用。对啮齿动物的研究表明，从给药几小时后开始，前额叶核内突触生成的增加可能有助于氯胺酮给药的长期益处。然而，这些数据不能解释鼻腔注射氯胺酮后几分钟内出现的缓解。我们推测，人类鼻腔给药的超快速效应可能是由于氯胺酮阻断了NMDAR回路，该回路产生了疼痛的情绪表征(例如，Brodmann区24和25，岛叶皮质)，这些皮质区域在抑郁时可能过度活跃，位于鼻部上皮之上。相反，全身给药氯胺酮后，阻断背外侧PFC的NMDAR可能导致认知功能障碍。这一新的观点可能有助于解释静脉注射氯胺酮如何治疗抑郁症的症状，但却会恶化精神分裂症的症状。
This paper reviews the anti-depressant actions of the N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, ketamine, and offers a potential neural mechanism for intranasal ketamine’s ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5–40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (e.g. Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.