Nature
April 24, 2016
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,602 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), produces rapid and sustained antidepressant-like effects in mice without the side effects associated with ketamine itself. These effects do not rely on blocking NMDA receptors but instead involve early and ongoing activation of AMPA receptors. This finding points to a new mechanism for developing faster-acting antidepressants with fewer unwanted effects.
Pharmacological Reviews
June 26, 2018
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,272 citations
Ketamine, in clinical use since 1970, is best known as a dissociative anesthetic but also has analgesic, anti-inflammatory, and antidepressant effects. This review covers its therapeutic uses by dose, route, and time course, along with side effects from short-term or prolonged exposure and recreational use. Ketamine is rapidly metabolized into norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK). While anesthetic and analgesic actions stem from inhibition of N-methyl-D-aspartate receptors, other targets include GABA, dopamine, serotonin, sigma, opioid, and cholinergic receptors, plus ion channels. HNK metabolites show antidepressant efficacy in preclinical studies, suggesting broader clinical relevance. Understanding these targets may help develop new drugs with ketamine's benefits but fewer side effects.
Molecular Psychiatry
March 13, 2018
P. Zanos, T. Gould
1,112 citations
A single low dose of the anesthetic ketamine can rapidly and lastingly relieve depression, but its abuse potential and dissociative side effects limit widespread use. This review examines proposed molecular mechanisms for ketamine's antidepressant action, including inhibition of specific N-methyl-D-aspartate receptors (NMDARs), effects on GABAergic interneurons, and suppression of burst firing in the lateral habenula. It also discusses downstream pathways involving brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mTOR, and GSK-3, as well as the roles of ketamine's (R)-ketamine enantiomer and the metabolite (2R,6R)-hydroxynorketamine. These mechanisms likely work together to trigger lasting changes in synaptic plasticity that underlie the antidepressant effects.
Molecular Psychiatry
February 27, 2018
A. Nugent, Elizabeth D. Ballard, T. Gould et al.
254 citations
In a double-blind, placebo-controlled, randomized cross-over trial with 35 unmedicated people with major depressive disorder (MDD) and 25 healthy controls, ketamine (0.5 mg/kg) improved depressive symptoms in MDD subjects but caused modest, temporary increases in depressive symptoms in healthy controls. Both groups showed increased resting gamma power measured by magnetoencephalography. Among MDD subjects, gamma power did not directly predict the size of the antidepressant effect. However, baseline gamma power moderated the link between post-ketamine gamma and response: higher post-ketamine gamma was tied to better response in those with low baseline gamma, but the opposite pattern appeared in those with high baseline gamma. This suggests biological subtypes based on homeostatic dysregulation and cautions against inferring ketamine's mechanism solely from studies of healthy controls.
Biochemical Pharmacology
December 1, 2021
E. Hess, L. Riggs, M. Michaelides et al.
167 citations
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.
Proceedings of the National Academy of Sciences of the United States of America
February 22, 2019
E. Lumsden, Timothy A. Troppoli, S. J. Myers et al.
159 citations
A single low dose of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) produces rapid antidepressant-like effects in mice without blocking NMDA glutamate receptors (NMDARs), unlike ketamine itself. At a dose of 10 mg/kg, which triggers antidepressant-related behavioral and cellular responses, (2R,6R)-HNK reaches hippocampal concentrations of about 8 µM—far below the levels needed to inhibit NMDARs in vitro. The dose required to prevent NMDA-induced lethality was 228 mg/kg for (2R,6R)-HNK versus 6.4 mg/kg for ketamine, indicating weak NMDAR inhibition. These findings suggest that (2R,6R)-HNK's antidepressant effects occur through alternative molecular targets, potentially avoiding ketamine's adverse effects such as dissociation and abuse potential.
Annual Review of Clinical Psychology
February 9, 2021
L. Riggs, T. Gould
87 citations
Traditional antidepressants can take weeks to work and often fail for many patients. In contrast, a single low dose of ketamine can relieve depression symptoms within hours, even in people who have not responded to other treatments. Ketamine is thought to repair damaged neural circuits by boosting glutamate signaling and promoting the release of neurotrophic factors that strengthen synaptic connections. This review covers the history of antidepressant development leading up to the ketamine discovery, critically evaluates proposed mechanisms for ketamine's rapid effects, and discusses how these insights are guiding current drug discovery.