Monoamine neurotransmitter-related gene-based genome-wide association study of low-dose ketamine in patients with treatment-resistant depression.

Low-dose ketamine, an N-methyl-D-aspartate receptor antagonist, has an antidepressant effect in treatment-resistant depression that may involve multiple monoamine neurotransmitter systems beyond glutamate. In a trial with 65 patients, those receiving 0.5 mg/kg or 0.2 mg/kg ketamine were compared with those receiving normal saline. Genetic analysis of 50 monoamine-related genes found that variants in the cholinergic, dopaminergic, serotonergic, opioid, cannabinoid, and σ1 receptor systems were associated with ketamine's antidepressant effect. The neuroactive ligand-receptor interaction pathway played a key role. The findings suggest that ketamine's effects involve serotonin, dopamine, and other monoamine systems.

Study at a glance

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.