NMDAR inhibition-independent antidepressant actions of ketamine metabolites

• Published in: Nature (London) 2016-05, Vol.533 (7604), p.481-486
• Main Authors: Zanos, Panos, Moaddel, Ruin, Morris, Patrick J., Georgiou, Polymnia, Fischell, Jonathan, Elmer, Greg I., Alkondon, Manickavasagom, Yuan, Peixiong, Pribut, Heather J., Singh, Nagendra S., Dossou, Katina S. S., Fang, Yuhong, Huang, Xi-Ping, Mayo, Cheryl L., Wainer, Irving W., Albuquerque, Edson X., Thompson, Scott M., Thomas, Craig J., Zarate Jr, Carlos A., Gould, Todd D.
• Format: Article
• Language: English
• Subjects: 631/154/436/1729; 631/378/1689/1333; 631/378/1689/1414; 64/60; 9/30; 9/74; Animals; Antidepressants; Antidepressive Agents - adverse effects; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Brain; Cell receptors; Drug dosages; Female; Humanities and Social Sciences; Ketamine; Ketamine - adverse effects; Ketamine - analogs & derivatives; Ketamine - metabolism; Ketamine - pharmacology; Male; Mental depression; Metabolism; Metabolites; Methyl aspartate; Mice; multidisciplinary; Pharmaceutical research; Physiological aspects; Psychopharmacology; Receptors, AMPA - agonists; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Science; Side effects; Time Factors; World population
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature17998

Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR ( N -methyl- d -aspartate receptor) antagonist ( R , S )-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of ( R , S )-ketamine to (2 S ,6 S ;2 R ,6 R )-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2 R ,6 R )-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2 R ,6 R )-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of ( R , S )-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants. The metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and the (2R,6R)-HNK enantiomer lacks ketamine-related side effects but exerts rapid and sustained antidepressant actions in mice; these antidepressant effects are independent of NMDAR inhibition but require AMPAR activity. Antidepressant action of a ketamine metabolite The NMDAR antagonist ketamine has rapid and sustained antidepressant effects; this has prompted a search for alternative NMDAR antagonists that have the same antidepressant properties but lack the undesirable side effects of ketamine. Todd Gould and colleagues now show that the metabolism of ( R , S )-ketamine to (2 S ,6 S ;2 R ,6 R )-hydroxynorketamine (HNK) is essential for its antidepressant activity, and that the (2 R ,6 R )-HNK enantiomer exerts rapid and sustained antidepressant actions in mice. These effects are NMDAR-independent but require AMPAR activation. Importantly, (2 R ,6 R )-HNK lacks the side effects associated with ketamine. These findings suggest new options for the development of novel rapid-acting antidepressants.