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.
Proceedings of the National Academy of Sciences
March 13, 2019
Panos Zanos, Jaclyn N. Highland, Brent W. Stewart et al.
153 citations
A single subanesthetic dose of ketamine produces rapid (within hours) and sustained antidepressant effects, unlike standard antidepressants that take months and fail in about 30% of patients. The ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant candidate with fewer adverse effects. Using behavioral, genetic, pharmacological approaches and EEG measurements, the study found that antidepressant-relevant actions of (2R,6R)-HNK involve metabotropic glutamate receptor subtype 2 (mGlu2) signaling and identified high-frequency EEG oscillations as a marker of rapid antidepressant responses. The findings suggest clinical trials combining subtherapeutic doses of mGlu2 receptor inhibitors with ketamine or (2R,6R)-HNK for depression treatment.
Translational Psychiatry
May 2, 2022
Ruin Moaddel, Panos Zanos, Cristan Farmer et al.
32 citations
Subanesthetic-dose ketamine produces rapid antidepressant effects, but its mechanism remains unclear. A targeted metabolomic analysis of plasma and cerebrospinal fluid from nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg), along with parallel analysis in mice given ketamine, (2R,6R)-hydroxynorketamine (HNK), or saline, found that both ketamine and HNK affect multiple inflammatory pathways. Some changes were unique to humans or mice, suggesting species differences. Consistently implicated mechanisms across both species and sample types include LAT1, IDO1, NAD+, nitric oxide signaling, and the sphingolipid rheostat.
Neuropharmacology
November 1, 2024
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix et al.
3 citations
Ketamine produces rapid and lasting antidepressant effects in depressed patients. A metabolite called (2R,6R)-hydroxynorketamine (HNK) may contribute to these effects. In anxious male mice, blocking the liver enzyme cytochrome P450 with fluconazole before ketamine or HNK altered drug metabolism: it raised ketamine and norketamine levels in blood and brain but sharply reduced HNK levels. Fluconazole also prevented ketamine's sustained antidepressant-like actions in behavioral tests and its enhancement of cortical GABA levels 24 hours after injection. Giving (2R,6R)-HNK alone reversed fluconazole's blockade of ketamine's antidepressant-like activity. The findings suggest that HNK is essential for ketamine's sustained antidepressant effects and that drug interactions with cytochrome P450 inhibitors may affect ketamine treatment in patients.
bioRxiv Preprint Server
April 3, 2024
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix et al.
preprint
Ketamine's rapid antidepressant effects in depressed patients may depend on a specific metabolite, (2R,6R)-hydroxynorketamine ((6)-HNK). In male BALB/cJ mice with high anxiety, blocking liver enzymes that break down ketamine (using fluconazole) raised ketamine and norketamine levels in blood and brain but sharply reduced (6)-HNK levels. This blockade prevented ketamine's sustained antidepressant-like effects 24 hours later in behavioral tests and stopped the increase in cortical GABA levels. Giving a single dose of (2R,6R)-HNK alone restored the antidepressant-like activity. The findings indicate that (6)-HNK is essential for ketamine's lasting antidepressant effects and suggest that drug interactions affecting ketamine metabolism could matter in patients.
British journal of pharmacology
July 1, 2019
Panos Zanos, Jaclyn N Highland, Xin Liu et al.
In mice, (R)-ketamine's metabolism to (2R,6R)-hydroxynorketamine (HNK) enhances its antidepressant-relevant actions. A deuterated form of (R)-ketamine that blocks this metabolism had less potency in antidepressant-sensitive behavioral tests, while (2R,6R)-HNK itself produced dose-dependent sustained antidepressant effects. However, (R)-ketamine also caused NMDA receptor-mediated adverse effects—including locomotor stimulation, conditioned-place preference, prepulse inhibition deficits, and motor incoordination—at sub-anaesthetic doses, with about half the potency of racemic ketamine. These findings indicate that while antidepressant-relevant effects occur at lower doses, there is a potential risk for sensory dissociation and abuse liability at higher doses.