Kao Chung-Feng, Tsai Shih-Jen, Su Tung-Ping, Li Cheng-Ta, Lin Wei-Chen, Hong Chen-Jee, Bai Ya-Mei, Tu Pei-Chi, Chen Mu-Hong
Department of Agronomy, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung, Taiwan.
Advanced Plant Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.
J Psychopharmacol. 2025 Jun;39(6):593-602. doi: 10.1177/02698811251326939. Epub 2025 Mar 24.
Low-dose ketamine is an N-methyl-D-aspartate receptor antagonist that exerts an antidepressant effect on patients with treatment-resistant depression (TRD). This antidepressant effect may extend beyond the glutamatergic hypothesis. Nevertheless, the roles of genes encoding other monoamine neurotransmitters (i.e., serotonin and dopamine) in the neuromechanism of low-dose ketamine remain unknown.
In this clinical trial, which involved 65 patients with TRD, 21 patients received 0.5 mg/kg ketamine, 20 received 0.2 mg/kg ketamine, and 24 received normal saline. All patients were genotyped for 684,616 single-nucleotide polymorphisms (SNPs). A total of 50 monoamine neurotransmitter-related candidate genes, including HTR2A and HTR2C from the serotoninergic system, CHRM4 and CHRNB1 from the cholinergic system, and DRD2 from the dopaminergic system, were selected to conduct a gene-based genome-wide association study of the antidepressant effects of ketamine.
Gene-set enrichment analysis revealed that the pathway underlying neuroactive ligand-receptor interaction (KEGG) played a pivotal role in the biomechanisms underlying ketamine's antidepressant effect. Specifically, the genes and SNPs related to the cholinergic system (e.g., rs2644247 in CHRM5), μ1 opioid receptor (e.g., rs2473546 in OPRM1), dopaminergic system (e.g., rs2617577 in SLC6A3), serotonergic system (HTR2A), cannabinoid receptor (CNR2), and σ1 receptor (SIGMAR1) were associated with the antidepressant effect of low-dose ketamine.
Low-dose ketamine has an antidepressant effect, which may be associated with multiple monoamine neurotransmitter systems and the σ1 receptor.
低剂量氯胺酮是一种N-甲基-D-天冬氨酸受体拮抗剂，对难治性抑郁症（TRD）患者具有抗抑郁作用。这种抗抑郁作用可能超出了谷氨酸能假说。然而，编码其他单胺类神经递质（即血清素和多巴胺）的基因在低剂量氯胺酮的神经机制中的作用仍不清楚。
在这项涉及65例TRD患者的临床试验中，21例患者接受0.5mg/kg氯胺酮，20例接受0.2mg/kg氯胺酮，24例接受生理盐水。所有患者均进行了684,616个单核苷酸多态性（SNP）的基因分型。总共选择了50个与单胺神经递质相关的候选基因，包括来自5-羟色胺能系统的HTR2A和HTR2C、来自胆碱能系统的CHRM4和CHRNB1以及来自多巴胺能系统的DRD2，以进行基于基因的全基因组关联研究，探讨氯胺酮的抗抑郁作用。
基因集富集分析表明，神经活性配体-受体相互作用（KEGG）途径在氯胺酮抗抑郁作用的生物机制中起关键作用。具体而言，与胆碱能系统（如CHRM5中的rs2644247）、μ1阿片受体（如OPRM1中的rs2473546）、多巴胺能系统（如SLC6A3中的rs2617577）、5-羟色胺能系统（HTR2A）、大麻素受体（CNR2）和σ1受体（SIGMAR1）相关的基因和SNP与低剂量氯胺酮的抗抑郁作用有关。
低剂量氯胺酮具有抗抑郁作用，这可能与多个单胺神经递质系统和σ1受体有关。
