氯胺酮及其衍生物的抗抑郁研究进展

中国药物评价 ›› 2024, Vol. 41 ›› Issue (5): 372-376.

氯胺酮及其衍生物的抗抑郁研究进展

赖增燕1，钱妍1，赵春景1，邹品文1，蒋为薇1，龚雪3，4，毛强1，2*

1.重庆医科大学附属第二医院，重庆 400010；

2.澳门科技大学医学院药学院，澳门 999078；

3.重庆医科大学附属第一医院，国家卫健委功能性脑疾病诊治重点实验室，重庆 400016；

4.中山大学附属第五医院，广东珠海 519000

收稿日期:2024-04-22 修回日期:2024-09-03 出版日期:2024-10-28 发布日期:2024-10-28
基金资助:
重庆市自然科学基金面上项目《氯胺酮介导AKT/GSK3β/NLRP3信号通路缓解青幼期小鼠抑郁样行为机制研究》（项目编号：CSTB2022NSCQ-MSX1165）；重庆市自然科学基金（博士后）联合资助项目《基于PPARa/RXR/CREB通路探讨共轭亚油酸缓解抑郁样行为的机制研究》（项目编号：CSTB2022NSCQ-BHX0010）

Advanced in Antidepressant Research of Ketamine and Its Derivatives

1.The Second Affiliated Hospital of Chongqing Medical University， Chongqing 400010， China；

2.School of Pharmacy， Faculty of Medicine， Macau University of Science and Technology， Macau 999078， China；

3. NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases， The First Affiliated Hospital of Chongqing Medical University， Chongqing 400016， China；

4.Department of Neurology， The Fifth Affiliated Hospital of Sun Yat-sen University， Guangdong Zhuhai 519000， China

Received:2024-04-22 Revised:2024-09-03 Online:2024-10-28 Published:2024-10-28
Supported by:
氯胺酮介导AKT/GSK3β/NLRP3信号通路缓解青幼期小鼠抑郁样行为机制研究

摘要/Abstract

摘要： 抑郁症是一种常见的精神疾病，主要表现为显著而持久的心境低落、快感缺失，给患者及其家庭带来沉重负担。抑郁症的治疗主要以单胺类抗抑郁药物为主，但这类药物起效慢、治愈率低、复发率高。近年来，大量研究证实氯胺酮及其对映异构体具有快速而持久的抗抑郁作用，且艾司氯胺酮已经被国内外批准用于治疗成人难治性抑郁患者。同时，研究还发现氯胺酮的代谢物可能是其发挥抗抑郁作用机制的关键步骤，如S-去甲基氯胺酮、(2R，6R)-羟基去甲氯胺酮、(2S，6S)-羟基去甲氯胺酮等代谢物具有抗抑郁作用。然而，氯胺酮及其衍生物的具体作用机制和作用特点不清。本文旨在总结氯胺酮及其衍生物（氯胺酮的对映异构体和活性代谢物）的研究进展，重点关注其抗抑郁作用机制和作用特点，以期为后续临床研究提供理论基础及为重度抑郁症的治疗提供新方法。

关键词: font-size:medium, ">抑郁症；氯胺酮；对映异构体；代谢物；快速抗抑郁供新方法。

Abstract: Major depressive disorder（MDD) is a common mental disease， characterized by significant and lasting depressed moods and anhedonia， which imposes a heavy burden on the patients and their families. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder， although with antidepressant effect to be slowed down， low cure rate and high recurrence rate. Over the past two decades， a larger number of studies have confirmed the rapid and robust antidepressant effects of ketamine and its enantiomers for patients with depression， and esketamine has been approved for the treatment of treatment-resistant depression（TRD). Meanwhile， it was also reported that the metabolites of ketamine may be a key step in the mechanism of its anti-depressant action， such as S-norketamine，（2R，6R)-hydroxynorketamine，（2S，6S)-hydroxynorketamine and other metabolites have anti-depressant effects. However， the specific mechanism and characteristics of ketamine and its derivatives are unclear. Thus， our review aims to summarize the advanced research of ketamine and its derivatives（enantiomers and active metabolites of ketamine)， mainly focusing on the mechanism and characteristics of its antidepressant action， which is to provide a theoretical basis for subsequent clinical studies and provide new therapeutic approaches for major depressive disorder.

Key words: font-size:medium, ">Major depressive disorder（MDD)； Ketamine； Enantiomers； Metabolites； Rapid antidepressant

中图分类号:

赖增燕1, 钱妍1, 赵春景1, 邹品文1, 蒋为薇1, 龚雪3, 4, 毛强1, 2. 氯胺酮及其衍生物的抗抑郁研究进展[J]. 中国药物评价, 2024, 41(5): 372-376.

LAI Zeng-yan1, QIAN Yan1, ZHAO Chun-jing1, ZOU Pin-wen1, JIANG Wei-wei1, GONG Xue4, 5, MAO Qiang1, 2. Advanced in Antidepressant Research of Ketamine and Its Derivatives[J]. CHINESE JOURNAL OF DRUG EVALUATION, 2024, 41(5): 372-376.

参考文献

[1] Wu M， Tian T， Mao Q， et al. Associations between disordered gut microbiota and changes of neurotransmitters and short-chain fatty acids in depressed mice[J]. Transl Psychiatry， 2020， 10(1)： 350.
     [2] Nisar A， Yin J， Waqas A， et al. Prevalence of perinatal depression and its determinants in Mainland China： A systematic review and meta-analysis[J]. J Affect Disord， 2020， 277： 1022-1037.
     [3] Friedrich MJ. Depression Is the Leading Cause of Disability Around the World[J]. Jama， 2017， 317(15)： 1517.
     [4] Dwyer JB， Landeros-Weisenberger A， Johnson JA， et al. Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression： A Randomized Midazolam-Controlled Trial[J]. Am J Psychiatry， 2021， 178(4)： 352-362.
     [5] Rao WW， Xu DD， Cao XL， et al. Prevalence of depressive symptoms in children and adolescents in China： A meta-analysis of observational studies[J]. Psychiatry Res， 2019， 272： 790-796.
     [6] Shinohara R， Aghajanian GK， Abdallah CG. Neurobiology of the Rapid-Acting Antidepressant Effects of Ketamine： Impact and Opportunities[J]. Biol Psychiatry， 2021， 90(2)： 85-95.
     [7] Yang C， Yang J， Luo A， et al. Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites[J]. Transl Psychiatry， 2019， 9(1)： 280.
     [8] Chen BK， Denny CA. Weapons of stress reduction：（R，S)-ketamine and its metabolites as prophylactics for the prevention of stress-induced psychiatric disorders[J]. Neuropharmacology， 2023， 224： 109345.
     [9] Yao W， Cao Q， Luo S， et al. Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of（R)-ketamine[J]. Mol Psychiatry， 2022， 27(3)： 1618-1629.
     [10] Hua H， Huang C， Liu H， et al. Depression and antidepressant effects of ketamine and its metabolites： The pivotal role of gut microbiota[J]. Neuropharmacology， 2022， 220： 109272.
     [11] Ren L. The mechanistic basis for the rapid antidepressant-like effects of ketamine： From neural circuits to molecular pathways[J]. Prog Neuropsychopharmacol Biol Psychiatry， 2024， 129： 110910.
     [12] Xu S， Yao X， Li B， et al. Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant[J]. Front Pharmacol， 2021， 12： 740996.
     [13] Johnston JN， Henter ID， Zarate CA， Jr. The antidepressant actions of ketamine and its enantiomers[J]. Pharmacol Ther， 2023， 246： 108431.
     [14] Krystal JH， Kaye AP， Jefferson S， et al. Ketamine and the neurobiology of depression： Toward next-generation rapid-acting antidepressant treatments[J]. Proc Natl Acad Sci U S A， 2023， 120(49)： e2305772120.
     [15] Wei Y， Chang L， Hashimoto K. Molecular mechanisms underlying the antidepressant actions of arketamine： beyond the NMDA receptor[J]. Mol Psychiatry， 2022， 27(1)： 559-573.
     [16] Yokoyama R， Higuchi M， Tanabe W， et al.（S)-norketamine and（2S，6S)-hydroxynorketamine exert potent antidepressant-like effects in a chronic corticosterone-induced mouse model of depression[J]. Pharmacol Biochem Behav， 2020， 191： 172876.
     [17] Yokoyama R， Higuchi M， Tanabe W， et al. Long-lasting anti-despair and anti-anhedonia effects of（S)-norketamine in social isolation-reared mice[J]. J Pharmacol Sci， 2024， 154(2)： 72-76.
     [18] Wang Y， Jiang R， Wu Z， et al. Gut microbiota is involved in the antidepressant-like effect of（S)-norketamine in an inflammation model of depression[J]. Pharmacol Biochem Behav， 2021， 207： 173226.
     [19] Can A， Zanos P， Moaddel R， et al. Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release， Dopamine Receptors， and Monoamine Transporters[J]. J Pharmacol Exp Ther， 2016， 359(1)： 159-70.
     [20] Kawatake-Kuno A， Li H， Inaba H， et al. Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular dynamics in aPVT glutamatergic neurons[J]. Neuron， 2024.
     [21] Highland JN， Zanos P， Riggs LM， et al. Hydroxynorketamines： Pharmacology and Potential Therapeutic Applications[J]. Pharmacol Rev， 2021， 73(2)： 763-791.
     [22] Ago Y， Yokoyama R， Asano S， et al. Roles of the monoaminergic system in the antidepressant effects of ketamine and its metabolites[J]. Neuropharmacology， 2023， 223： 109313.