Mechanisms of Ketamine and its Metabolites as Antidepressants

Summary

Ketamine, an anesthetic, produces rapid antidepressant effects in people with treatment-resistant depression when given at sub-anesthetic doses, leading to FDA approval of esketamine. The mechanisms behind these effects remain under investigation, with evidence suggesting that ketamine's metabolites, such as (2R,6R)-hydroxynorketamine (HNK), may play a key role. HNK shows antidepressant potential in preclinical tests without ketamine's dissociative or abuse-related side effects. The review discusses how ketamine and its metabolites influence glutamate signaling through NMDARs and AMPARs, synaptic changes via BDNF, opioid receptor interactions, and enhancement of serotonin, norepinephrine, and dopamine signaling. Targeting these pathways could yield new rapid-acting antidepressants with fewer side effects.

Study at a glance

Abstract

Treating major depression is a medical need that remains unmet by monoaminergic therapeutic strategies that commonly fail to achieve symptom remission. A breakthrough in the treatment of depression was the discovery that the anesthetic (R,S)-ketamine (ketamine), when administered at sub-anesthetic doses, elicits rapid (sometimes within hours) antidepressant effects in humans that are otherwise resistant to monoaminergic-acting therapies. While this finding was revolutionary and led to the FDA approval of (S)-ketamine (esketamine) for use in adults with treatment-resistant depression and suicidal ideation, the mechanisms underlying how ketamine or esketamine elicit their effects are still under active investigation. An emerging view is that metabolism of ketamine may be a crucial step in its mechanism of action, as several metabolites of ketamine have neuroactive effects of their own and may be leveraged as therapeutics. For example, (2R,6R)-hydroxynorketamine (HNK), is readily observed in humans following ketamine treatment and has shown therapeutic potential in preclinical tests of antidepressant efficacy and synaptic potentiation while being devoid of the negative adverse effects of ketamine, including its dissociative properties and abuse potential. We discuss preclinical and clinical studies pertaining to how ketamine and its metabolites produce antidepressant effects. Specifically, we explore effects on glutamate neurotransmission through N-methyl D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), synaptic structural changes via brain derived neurotrophic factor (BDNF) signaling, interactions with opioid receptors, and the enhancement of serotonin, norepinephrine, and dopamine signaling. Strategic targeting of these mechanisms may result in novel rapid-acting antidepressants with fewer undesirable side effects compared to ketamine.