Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants.
Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants.
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DOI：
10.3389/fphar.2013.00161
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发表时间：
2013-12-27
影响因子：
5.6
通讯作者：
Lucki I
中科院分区：
文献类型：
--
作者：
Browne CA;Lucki I
许多患有重度抑郁症（MDD）的个体需要更新的抗抑郁药，这些个体对治疗没有充分的反应，并且因为治疗效果出现前的延迟数周。最近的临床试验证据表明，NMDA拮抗剂氯胺酮是一种革命性的新型抗抑郁药，因为它作用迅速，对难治性患者有效。单次输注氯胺酮可在数小时内缓解难治性抑郁症患者的抑郁症状，这些作用可持续长达2周。虽然氯胺酮作用的发现重塑了抗抑郁药的药物发现，但这种化合物的拟精神病特性限制了这种疗法对最严重患者的使用。为了开发更多的抗抑郁药，如氯胺酮，需要建立足够的临床前行为筛选模式，快速作用的抗抑郁药，并用于确定潜在的神经机制。本文综述了临床前文献试图模拟氯胺酮的抗抑郁样作用。氯胺酮的急性给药在抗抑郁药的行为筛选中产生了影响，如强迫游泳试验，喂养的新奇抑制和啮齿动物抑郁模型。据报道，氯胺酮的预防性行为作用在持续数天的单次治疗后出现。这种时间模式与其临床效果相似，可作为人类快速抗抑郁作用的新动物范例。此外，介导突触可塑性的分子的长期变化与介导氯胺酮的抗抑郁样行为效应有关。目前的临床前研究正在研究对谷氨酸受体和突触具有更特异性药理作用的化合物，以开发其他快速起效的抗抑郁药，而不会产生氯胺酮的致幻副作用或滥用潜力。
Newer antidepressants are needed for the many individuals with major depressive disorder (MDD) that do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent evidence from clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel antidepressant because it acts rapidly and is effective for treatment-resistant patients. A single infusion of ketamine alleviates depressive symptoms in treatment-resistant depressed patients within hours and these effects may be sustained for up to 2 weeks. Although the discovery of ketamine's effects has reshaped drug discovery for antidepressants, the psychotomimetic properties of this compound limit the use of this therapy to the most severely ill patients. In order to develop additional antidepressants like ketamine, adequate preclinical behavioral screening paradigms for fast-acting antidepressants need to be established and used to identify the underlying neural mechanisms. This review examines the preclinical literature attempting to model the antidepressant-like effects of ketamine. Acute administration of ketamine has produced effects in behavioral screens for antidepressants like the forced swim test, novelty suppression of feeding and in rodent models for depression. Protracted behavioral effects of ketamine have been reported to appear after a single treatment that last for days. This temporal pattern is similar to its clinical effects and may serve as a new animal paradigm for rapid antidepressant effects in humans. In addition, protracted changes in molecules mediating synaptic plasticity have been implicated in mediating the antidepressant-like behavioral effects of ketamine. Current preclinical studies are examining compounds with more specific pharmacological effects at glutamate receptors and synapses in order to develop additional rapidly acting antidepressants without the hallucinogenic side effects or abuse potential of ketamine.
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影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
影响因子：
3.8
作者：
Carlos da Silva, Francisca Charliane;de Oliveira Cito, Maria do Carmo;Florenco de Sousa, Francisca Clea
通讯作者：
Florenco de Sousa, Francisca Clea
影响因子：
3.4
作者：
Bechtholt-Gompf, Anita J.;Smith, Karen L.;Oenguer, Dost
通讯作者：
Oenguer, Dost
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
影响因子：
3.4
作者：
Dagestad, Grethe;Kuipers, Sjoukje D.;Bramham, Clive R.
通讯作者：
Bramham, Clive R.