The basic and clinical pharmacology of ketamine

Abstract

Ketamine, an N-methyl-D-aspartic acid (NMDA) glutamate receptor antagonist developed as an anesthetic, has shown efficacy as an antidepressant in a number of studies since 2000. Multiple routes of ketamine administration, each with unique pharmacokinetics, have been investigated in the treatment of depression, including intravenous, intramuscular, intranasal, sublingual, and oral delivery. Ketamine is most commonly administered as (R, S)-ketamine, a 1:1 racemic mixture. Ketamine’s most important antidepressant activity is believed to stem from its antagonism of NMDA receptors, which are widely expressed in the brain. When NMDA receptors on gamma-aminobutyric acid (GABA)-ergic neurons are antagonized, downstream glutamatergic neurons are disinhibited. This increased glutamatergic activity impacts neural signaling, synaptic plasticity, and connectivity. Ketamine-induced synaptic potentiation and proliferation may play a key role in eliciting antidepressant effects. Ketamine also impacts other neurotransmitter systems, affecting cholinergic, opioidergic, monoaminergic, and GABAergic function.