Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide

A single subanesthetic dose of ketamine, a glutamate NMDA receptor channel blocker, produces a rapid antidepressant response within hours that lasts about a week, even in treatment-resistant patients, and also treats suicidal ideation. Efforts are developing ketamine-like drugs with fewer side effects, including ketamine metabolites, stereoisomers, NMDA allosteric modulators, and mGluR2/3 autoreceptor blockers. Other targets enhancing glutamate neurotransmission or synaptic function, such as scopolamine and mTORC1 signaling activators, are being investigated. This discovery heralds a new era for developing rapid and efficacious antidepressant medications.

Study at a glance

Abstract

Therapeutic medications for the treatment of depression have serious limitations, particularly delayed onset and low rates of efficacy. However, the discovery that a single subanesthetic dose of ketamine, a glutamate NMDA receptor channel blocker, can produce a rapid (within hours) antidepressant response that is sustained (about 1 week), even in patients considered treatment-resistant, has invigorated the field. In addition to these remarkable actions, ketamine has proven effective for the treatment of suicidal ideation. Efforts are under way to develop ketamine-like drugs with fewer side effects as well as agents that act at other sites within the glutamate neurotransmitter system. This includes ketamine metabolites and stereoisomers, drugs that act as NMDA allosteric modulators or that block mGluR2/3 autoreceptors. In addition, targets that enhance glutamate neurotransmission or synaptic function (or both), which are essential for the rapid and sustained antidepressant actions of ketamine in rodent models, are being investigated; examples are the muscarinic cholinergic antagonist scopolamine and activators of mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is required for the actions of ketamine. The discovery of ketamine and its unique mechanisms heralds a new era with tremendous promise for the development of novel, rapid, and efficacious antidepressant medications.