Monoamine neurotransmitter-related gene-based genome-wide association study of low-dose ketamine in patients with treatment-resistant depression.
Chung-Feng Kao, Shih-Jen Tsai, Tung-Ping Su, Cheng-Ta Li, Wei-Chen Lin, Chen‐jee Hong, Ya-Mei Bai, Pei-Chi Tu, Mu-Hong Chen
Journal of psychopharmacology (Oxford, England) March 24, 2025 DOI: 10.1177/02698811251326939 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 65 |
| Population | Patients with treatment-resistant depression |
| Intervention | ketamine |
| Dose | 0.5 mg/kg, 0.2 mg/kg |
| Topics | Depression Ketamine Esketamine |
| Keywords | Neurotransmitter studies Psychiatric genomics Antidepressant mechanisms Taiwan Genome-wide association study Monoamine neurotransmitters Ketamine research |
| Citations | 1 |
| Key findings | Low-dose ketamine's antidepressant effect is associated with multiple monoamine neurotransmitter systems, including cholinergic, dopaminergic, serotonergic, opioid, cannabinoid, and σ1 receptor pathways. |
Abstract
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.