Kato Taro
Pharmacology Research Unit, Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka, 554-0022, Japan.
Neuropharmacology. 2023 Feb 1;223:109325. doi: 10.1016/j.neuropharm.2022.109325. Epub 2022 Nov 9.
Conventional antidepressant medications act on monoaminergic systems and have important limitations, including a therapeutic delay of weeks to months and low rates of efficacy. Recently, clinical findings have indicated that ketamine, a dissociative anesthetic that blocks N-methyl-d-aspartate receptor channel activity, causes rapid and long-lasting antidepressant effects. Although the exact mechanisms underlying the antidepressant effects of ketamine are not fully known, preclinical studies have demonstrated a key role for mechanistic target of rapamycin complex 1 (mTORC1) signaling and a subsequent increase in synapse formation in the medial prefrontal cortex. In this review, we discuss the role of mTORC1 and its subsequent signaling cascade in the antidepressant effects of ketamine and other compounds with glutamatergic mechanisms of action. We also present the possibility that mTORC1 signaling itself is a drug discovery target.
传统抗抑郁药物作用于单胺能系统，存在重要局限性，包括数周数月的治疗延迟以及低效的疗效。最近，临床研究结果表明，氯胺酮这种阻断N-甲基-D-天冬氨酸受体通道活性的解离性麻醉剂，能产生快速且持久的抗抑郁效果。尽管氯胺酮抗抑郁作用的确切机制尚不完全清楚，但临床前研究已证明雷帕霉素复合物1（mTORC1）信号传导起关键作用，且随后内侧前额叶皮质中的突触形成会增加。在本综述中，我们讨论了mTORC1及其后续信号级联在氯胺酮及其他具有谷氨酸能作用机制的化合物的抗抑郁作用中的作用。我们还提出了mTORC1信号传导本身是一个药物发现靶点的可能性。
