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.
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.
Molecular Psychiatry
September 14, 2020
A. Mkrtchian, Jennifer W. Evans, C. Kraus et al.
110 citations
Ketamine increased fronto-striatal functional connectivity in people with treatment-resistant major depression toward levels seen in healthy volunteers, while shifting connectivity in healthy volunteers toward a state similar to depressed participants under placebo. These effects occurred largely without changes in inflammatory markers (C-reactive protein) and were associated with both acute and sustained symptom improvements in the depressed group. Ketamine thus normalized reward-related brain circuitry in depression but disrupted it in healthy individuals, highlighting the potential importance of this circuitry in ketamine's mechanism of action for motivational symptoms.