Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, China.
Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China.
Neuropharmacology. 2022 Nov 1;218:109219. doi: 10.1016/j.neuropharm.2022.109219. Epub 2022 Aug 14.
The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine causes rapid onset and sustained antidepressant actions in treatment-resistant patients with major depressive disorder (MDD) and other psychiatric disorders, such as bipolar disorder and post-traumatic stress disorder. (R,S)-ketamine is a racemic mixture consisting of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine), with (S)-enantiomer having greater affinity for the NMDAR. In 2019, an esketamine nasal spray by Johnson & Johnson was approved in the USA and Europe for treatment-resistant depression. In contrast, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. Importantly, the side effects, i.e., psychotomimetic and dissociative effects and abuse liability, of arketamine are less than those of (R,S)-ketamine and esketamine in animals and humans. An open-label study demonstrated the rapid and sustained antidepressant effects of arketamine in treatment-resistant patients with MDD. A phase 2 clinical trial of arketamine in treatment-resistant patients with MDD is underway. This study was designed to review the brief history of the novel antidepressant arketamine, the molecular mechanisms underlying its antidepressant actions, and future directions.
N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂（R，S）-氯胺酮在治疗抵抗性重度抑郁症（MDD）和其他精神障碍（如双相情感障碍和创伤后应激障碍）的患者中引起快速起效和持续的抗抑郁作用。（R，S）-氯胺酮是一种由（R）-氯胺酮（或阿立哌唑）和（S）-氯胺酮（或艾司氯胺酮）组成的外消旋混合物，其中（S）对映体对 NMDAR 的亲和力更大。2019 年，强生公司的艾司氯胺酮鼻喷雾剂在美国和欧洲获得批准，用于治疗抵抗性抑郁症。相比之下，越来越多的临床前研究表明，在啮齿动物中，阿立哌唑比艾司氯胺酮具有更强的效力和更持久的抗抑郁样作用，尽管阿立哌唑对 NMDAR 的结合亲和力较低。重要的是，阿立哌唑在动物和人类中的副作用，即致幻和分离作用以及滥用倾向，低于（R，S）-氯胺酮和艾司氯胺酮。一项开放标签研究表明，阿立哌唑在治疗抵抗性 MDD 患者中具有快速和持续的抗抑郁作用。一项阿立哌唑治疗 MDD 治疗抵抗患者的 2 期临床试验正在进行中。本研究旨在回顾新型抗抑郁药阿立哌唑的简要历史、其抗抑郁作用的分子机制以及未来方向。
