Browne Caroline A, Lucki Irwin
Department of Psychiatry, University of Pennsylvania Philadelphia, PA, USA.
Department of Psychiatry, University of Pennsylvania Philadelphia, PA, USA ; Department of Pharmacology, University of Pennsylvania Philadelphia, PA, USA.
Front Pharmacol. 2013 Dec 27;4:161. doi: 10.3389/fphar.2013.00161.
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.
许多患有重度抑郁症（MDD）的个体对治疗反应不佳，且由于治疗效果出现前有数周的延迟，因此需要新型抗抑郁药。临床试验的最新证据表明，N-甲基-D-天冬氨酸（NMDA）拮抗剂氯胺酮是一种革命性的新型抗抑郁药，因为它起效迅速且对难治性患者有效。单次注射氯胺酮可在数小时内缓解难治性抑郁症患者的抑郁症状，且这些效果可持续长达2周。尽管氯胺酮作用的发现重塑了抗抑郁药的药物研发，但该化合物的拟精神病特性将这种疗法的使用限制在病情最严重的患者中。为了开发像氯胺酮这样的其他抗抑郁药，需要建立并使用适用于速效抗抑郁药的临床前行为筛选范式，以识别潜在的神经机制。本综述考察了试图模拟氯胺酮抗抑郁样作用的临床前文献。氯胺酮的急性给药在诸如强迫游泳试验、进食新奇抑制等抗抑郁药行为筛选以及抑郁症啮齿动物模型中产生了效果。据报道，氯胺酮单次治疗后会出现持续数天的行为效应。这种时间模式与其临床效果相似，可能成为人类快速抗抑郁作用的一种新动物范式。此外，介导突触可塑性的分子的长期变化与氯胺酮的抗抑郁样行为效应的介导有关。当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，以便开发出没有氯胺酮致幻副作用或滥用潜力的其他速效抗抑郁药。
