The mechanistic basis for the rapid antidepressant-like effects of ketamine: From neural circuits to molecular pathways

Conventional antidepressants that target monoaminergic receptors require several weeks to be efficacious. This lag represents a significant problem in the currently available treatments for serious depression. Ketamine, acting as an N-methyl-d-aspartate receptor antagonist, was shown to have rapid antidepressant-like effects, marking a significant advancement in the study of mood disorders. However, serious side effects and adverse reactions limit its clinical use. Considering the limitations of ketamine, it is crucial to further define the network targets of ketamine. The rapid action of ketamine an as antidepressant is thought to be mediated by the glutamate system. It is believed that synaptic plasticity is essential for the rapid effects of ketamine as an antidepressant. Other mechanisms include the involvement of the γ-aminobutyric acidergic (GABAergic), 5-HTergic systems, and recent studies have linked astrocytes to ketamine's rapid antidepressant-like effects. The interactions between these systems exert a synergistic rapid antidepressant effect through neural circuits and molecular mechanisms. Here, we discuss the neural circuits and molecular mechanisms underlying the action of ketamine. This work will help explain how molecular and neural targets are responsible for the effects of rapidly acting antidepressants and will aid in the discovery of new therapeutic approaches for major depressive disorder.