From the beginning of the neuropsychiatric drug era, the development of antidepressants has been mostly based on serendipity. One of the first examples, iproniazid, was an antitubercular drug observed to induce euphoric effects in individuals with tuberculosis. Investigators who pursued this intriguing finding argued that similar compounds might have antidepressant properties, ultimately paving the way to developing monoamine oxidase inhibitors (MAOIs) for treating depression. This discovery ushered in the era of monoaminergic-based antidepressants, and the next 5060 years consisted mainly of developing ‘‘me too’’ drugs that were largely monoaminergically-based. These medications typically yielded only minor refinements – for instance, improved side-effect profiles – to existing antidepressants without offering significant advantages in terms of efficacy or remission and recovery rates. While it is certainly true that these ‘‘conventional antidepressants’’ did help many, it is equally true that not all were helped. Furthermore, these agents are associated with notable limitations, including low remission rates, slow onset of therapeutic effects, and lower efficacy in comorbid psychiatric conditions and syndromes. In addition, many of the patients who did respond – or partially responded – to these treatments continued to relapse despite ongoing treatment, developed treatment resistance, attempted suicide, or had impaired functioning. Given the urgent need for better treatments, several targets for new, non-monoaminergic-based antidepressants have been pursued over the decades; few, if any, novel ones reached the clinic. In this context, one of many targets of interest is the glutamatergic system. Trullas & Skolnick were among the first to examine the possible link between depression and glutamatergic system dysfunction and, building on their preclinical work, Berman et al. discovered that ketamine exerted rapid, robust, and relatively sustained antidepressant effects in depressed patients. Despite the pioneering nature of the results, the paper did not have an immediate dramatic impact on the field. Researchers might have viewed the reported rapid and robust antidepressant effects as a ‘‘fluke’’ or perhaps did not want to test a drug that possessed abuse potential and psychotomimetic effects. Nevertheless, since then, numerous placebo-controlled studies have shown that subanesthetic-dose ketamine has rapid, robust, and relatively sustained antidepressant effects in individuals with treatment-resistant major depressive disorder and bipolar depression. Building on this growing evidence, investigators wondered whether other N-methyl-D-aspartate receptor (NMDAR) antagonists might exert antidepressant effects similar to those of ketamine. Unfortunately, NMDAR antagonists or modulators of the NMDAR complex (e.g., GLYX-13, CERC301) have failed in the clinic. Generally speaking, no other tested NMDAR antagonists have shown the same rapid, robust, and sustained antidepressant effects as ketamine; in other words, they are simply not ketamine. Despite these setbacks, ketamine itself has led to much more focused research seeking to identify promising characteristics of next-generation treatments. In particular, because ketamine’s antidepressant effects are so rapid, and because the onset and offset of its therapeutic effects are fairly predictable, investigators began using ketamine as a tool – both clinically and preclinically – to decipher its mechanistic effects and identify biomarkers of treatment response. For instance, one series of studies implicated glutamate and gamma aminobutyric acid (GABA) signaling dysfunction in depression; similarly, convergent evidence from behavioral, cellular, and molecular ketamine studies supported the theory that enhanced a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity – with a concomitant increase in synaptic plasticity – is critical to ketamine’s mechanism of action and may be the key to developing similarly rapidacting antidepressants. On the clinical front, investigating ketamine’s mechanistic properties has led to the exploration of a variety of human biomarkers, as well as treatment options such as scopolamine and electroconvulsive therapy. Ketamine clinics – which typically administer racemic ketamine intravenously – have proliferated globally. As a whole, the field has urged caution regarding the need for more research, and several meetings have been conducted to share clinical experience and standardize ketamine use. Perhaps the most salient recent development is the March 2019 FDA approval of esketamine (Spravato; the S-isomer of ketamine). Spravato can only be dispensed and administered to patients in medicallysupervised healthcare settings that provide monitoring (Risk Evaluation and Mitigation Strategies). This is

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氯胺酮：抗抑郁药发展的新篇章

从神经精神药物时代开始，抗抑郁药的开发大多基于偶然性。最早的例子之一，异烟肼，是一种抗结核药物，观察到可在肺结核患者中引起欣快感。追求这一有趣发现的研究人员认为，类似的化合物可能具有抗抑郁特性，最终为开发用于治疗抑郁症的单胺氧化酶抑制剂 (MAOIs) 铺平了道路。这一发现开创了基于单胺能抗抑郁药的时代，接下来的 5060 年主要包括开发主要基于单胺能的“我也是”药物。这些药物通常只产生微小的改进——例如，改善的副作用特征——与现有的抗抑郁药相比，在疗效或缓解和恢复率方面没有显着优势。虽然这些“传统抗抑郁药”确实对许多人有帮助，但并非所有人都得到了帮助，这同样是正确的。此外，这些药物具有显着的局限性，包括低缓解率、治疗效果起效缓慢以及对共存精神疾病和综合征的疗效较低。此外，许多对这些治疗有反应或部分反应的患者尽管正在进行治疗，但仍继续复发、出现治疗抵抗、企图自杀或功能受损。鉴于迫切需要更好的治疗方法，几十年来一直在追求新的非单胺能抗抑郁药的几个目标；很少（如果有的话）到达诊所。在这种情况下，许多感兴趣的目标之一是谷氨酸能系统。Trullas 和 Skolnick 是最早研究抑郁症和谷氨酸能系统功能障碍之间可能联系的人之一，并且在他们的临床前工作的基础上，Berman 等人。发现氯胺酮在抑郁症患者中发挥了快速、强大和相对持久的抗抑郁作用。尽管结果具有开创性，但该论文并未对该领域产生直接的巨大影响。研究人员可能将所报告的快速而强大的抗抑郁作用视为“侥幸”，或者可能不想测试具有滥用潜力和拟精神病作用的药物。尽管如此，从那时起，许多安慰剂对照研究表明，亚麻醉剂量的氯胺酮具有快速、稳健、对患有难治性重度抑郁症和双相抑郁症的个体具有相对持续的抗抑郁作用。基于这一不断增长的证据，研究人员想知道其他 N-甲基-D-天冬氨酸受体 (NMDAR) 拮抗剂是否可能发挥类似于氯胺酮的抗抑郁作用。不幸的是，NMDAR 复合物的 NMDAR 拮抗剂或调节剂（例如 GLYX-13、CERC301）在临床上失败了。一般来说，没有其他测试过的 NMDAR 拮抗剂显示出与氯胺酮相同的快速、强大和持续的抗抑郁作用；换句话说，它们根本就不是氯胺酮。尽管有这些挫折，氯胺酮本身已经导致了更加集中的研究，试图确定下一代治疗的有希望的特征。尤其是因为氯胺酮的抗抑郁作用如此之快，并且由于其治疗效果的发生和抵消是相当可预测的，研究人员开始使用氯胺酮作为一种工具——无论是在临床上还是在临床前——来解读其机制效应并确定治疗反应的生物标志物。例如，一系列研究表明抑郁症中的谷氨酸和γ-氨基丁酸（GABA）信号功能障碍；同样，来自行为、细胞和分子氯胺酮研究的一致证据支持了以下理论：增强 a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) 受体活性——伴随着突触可塑性的增加——是至关重要的氯胺酮的作用机制，可能是开发类似速效抗抑郁药的关键。在临床方面，对氯胺酮机械特性的研究导致了对各种人类生物标志物以及东莨菪碱和电休克疗法等治疗方案的探索。氯胺酮诊所——通常通过静脉注射外消旋氯胺酮——在全球范围内激增。总体而言，该领域已敦促对进行更多研究的必要性持谨慎态度，并且已经召开了几次会议以分享临床经验和标准化氯胺酮的使用。也许最近最显着的发展是 2019 年 3 月 FDA 批准了 esketamine（Spravato；氯胺酮的 S 异构体）。Spravato 只能在提供监测（风险评估和缓解策略）的医疗监督医疗保健环境中向患者分发和管理。这是 以及治疗方案，如东莨菪碱和电休克疗法。氯胺酮诊所——通常通过静脉注射外消旋氯胺酮——在全球范围内激增。总体而言，该领域已敦促对进行更多研究的必要性持谨慎态度，并且已经召开了几次会议以分享临床经验和标准化氯胺酮的使用。也许最近最显着的发展是 2019 年 3 月 FDA 批准了 esketamine（Spravato；氯胺酮的 S 异构体）。Spravato 只能在提供监测（风险评估和缓解策略）的医疗监督医疗保健环境中向患者分发和管理。这是 以及治疗方案，如东莨菪碱和电休克疗法。氯胺酮诊所——通常通过静脉注射外消旋氯胺酮——在全球范围内激增。总体而言，该领域已敦促对进行更多研究的必要性持谨慎态度，并且已经召开了几次会议以分享临床经验和标准化氯胺酮的使用。也许最近最显着的发展是 2019 年 3 月 FDA 批准了 esketamine（Spravato；氯胺酮的 S 异构体）。Spravato 只能在提供监测（风险评估和缓解策略）的医疗监督医疗保健环境中向患者分发和管理。这是 该领域敦促人们谨慎对待更多研究的必要性，并召开了几次会议以分享临床经验和标准化氯胺酮的使用。也许最近最显着的发展是 2019 年 3 月 FDA 批准了 esketamine（Spravato；氯胺酮的 S 异构体）。Spravato 只能在提供监测（风险评估和缓解策略）的医疗监督医疗保健环境中向患者分发和管理。这是 该领域敦促人们谨慎对待更多研究的必要性，并召开了几次会议以分享临床经验和标准化氯胺酮的使用。也许最近最显着的发展是 2019 年 3 月 FDA 批准了 esketamine（Spravato；氯胺酮的 S 异构体）。Spravato 只能在提供监测（风险评估和缓解策略）的医疗监督医疗保健环境中向患者分发和管理。这是 Spravato 只能在提供监测（风险评估和缓解策略）的医疗监督医疗保健环境中向患者分发和管理。这是 Spravato 只能在提供监测（风险评估和缓解策略）的医疗监督医疗保健环境中向患者分发和管理。这是