Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy
Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy
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DOI：
10.1177/2045125313507739
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发表时间：
2014-04-01
影响因子：
4.2
通讯作者：
Tracy, Derek K.
中科院分区：
文献类型：
--
作者：
Caddy, Caroline;Giaroli, Giovanni;Tracy, Derek K.
抑郁症的负担和目前药物治疗的不足是众所周知的。麻醉和致幻药物氯胺酮在过去十年左右引起了人们的极大兴趣，因为它是一种作用非常迅速的抗抑郁药，不会改变“经典”的单胺能受体。目前的证据表明，它可能通过几种方式发挥治疗性抗抑郁作用：阻断谷氨酸能NMDA受体和相对上调α-氨基-3羟基-5-甲基-4-异恶唑丙酸（AMPA）亚型可能改变皮质连接模式;通过细胞内蛋白质表达的变化，包括蛋白质哺乳动物雷帕霉素靶蛋白（mTOR）和脑源性神经营养因子（BDNF）;以及细胞内信号级联的改变。临床证据表明，大多数参与者的情绪和自杀想法迅速改善，尽管研究数量通常很少，许多试验是非盲的，方法学上也很薄弱。有一小部分工作表明氯胺酮也可能增强电休克治疗，并可能在抑郁症患者中作为手术麻醉剂发挥作用。一个主要问题是氯胺酮的作用似乎是暂时的，在几天到几周后就会消失（尽管在一些情况下持续了更长的益处），迄今为止，通过药理学增强来规避这一问题的尝试令人失望。这些令人兴奋的数据为抑郁症的神经生物学模型提供了新的见解，并可能开辟一类新的抗抑郁药，但关于它可能具有的任何未来主流临床作用，都存在重大的实践和伦理问题。
The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established. The anaesthetic and hallucinogenic drug ketamine has provoked much interest over the past decade or so as an extremely rapidly acting antidepressant that does not modify 'classical' monoaminergic receptors. Current evidence has shown several ways through which it might exert therapeutic antidepressant actions: blockade of glutamatergic NMDA receptors and relative upregulation of a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes may alter cortical connectivity patterns; through intracellular changes in protein expression, including the proteins mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF); and alteration of intracellular signalling cascades. The clinical evidence demonstrates rapid improvements in mood and suicidal thinking in most participants, although study numbers have generally been small and many trials are unblinded and methodologically weak. There is a small body of work to suggest ketamine might also augment electroconvulsive therapy and potentially have a role as a surgical anaesthetic in depressed patients. A major problem is that the effects of ketamine appear temporary, disappearing after days to weeks (although longer benefits have been sustained in some), and attempts to circumvent this through pharmacological augmentation have been disappointing thus far. These exciting data are providing new insights into neurobiological models of depression, and potentially opening up a new class of antidepressants, but there are significant practical and ethical issues about any future mainstream clinical role it might have.