Iadarola Nicolas D, Niciu Mark J, Richards Erica M, Vande Voort Jennifer L, Ballard Elizabeth D, Lundin Nancy B, Nugent Allison C, Machado-Vieira Rodrigo, Zarate Carlos A
National Institutes of Health/National Institute of Mental Health, Experimental Therapeutics and Pathophysiology Branch, Bethesda, MD, USA.
National Institutes of Health/National Institute of Mental Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Dr., Building 10/CRC, Room 7-5545, Bethesda, MD 20892, USA.
Ther Adv Chronic Dis. 2015 May;6(3):97-114. doi: 10.1177/2040622315579059.
Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine's clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine's antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine's antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.
目前用于治疗重度抑郁症（MDD）和双相抑郁症（BDep）的药物疗法起效明显滞后，这可能给患者带来巨大痛苦和功能损害。此外，多项现实世界有效性试验表明，这些疗法的疗效有限。所有获批用于治疗MDD的抗抑郁药物主要通过单胺能机制发挥作用，即对5-羟色胺、去甲肾上腺素和多巴胺具有不同亲和力的激动剂或拮抗剂。近年来，谷氨酸系统作为开发新型疗法的途径受到了广泛关注。单次亚麻醉剂量输注非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮已被证明在难治性MDD和BDep中具有快速且强效的抗抑郁作用。在反向转化框架中，氯胺酮的临床疗效激发了许多临床前研究来探索抗抑郁作用的谷氨酸能机制。这些研究通过多种分子和细胞机制揭示了突触可塑性/突触生成增强：解除对脑源性神经营养因子的局部翻译抑制并从树突棘释放、雷帕霉素哺乳动物靶点激活以及糖原合酶激酶-3抑制。目前的工作重点是扩大氯胺酮的抗抑郁疗效，揭示在生物学富集亚组中负责氯胺酮抗抑郁活性的神经生物学机制，并确定治疗反应生物标志物以实现抗抑郁药物选择的个性化。其他NMDA受体拮抗剂已在临床前和临床研究中进行了研究，结果显示与氯胺酮相比，其抗抑郁作用相对较弱，但可能具有其他有利特性，例如解离或拟精神病作用降低；因此，开发具有更高靶点特异性和/或更低不良反应的新型谷氨酸能抗抑郁药备受关注。
