Depression is a disease that affects millions of Americans, and as many as a third of Americans suffering from depression are at least partially resistant to the current standard of care. The anesthetic ketamine has been discovered to have unique antidepressant properties, including the ability to successfully treat those patients who are resistant to standard antidepressants. However, ketamine’s side effects limit its ability to be widely prescribed for depression.
In a collaboration with the National Institute on Aging, the National Institute for Mental Health and the University of Maryland School of Medicine, NCATS discovered that a key metabolite of ketamine, (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), replicated ketamine’s antidepressant effects in mice. Moreover, when the metabolism of ketamine was impeded, ketamine lost its antidepressant effects in mice. This implies that the metabolite is responsible for ketamine’s antidepressant effects in humans. Lastly, this metabolite had none of the side effects that ketamine had in mouse models.
- Ruin Moaddel, Ph.D., National Institute of Aging, NIH
- Carlos Zarate, Jr., M.D., National Institute on Mental Health, NIH
- Todd Gould, Ph.D., University of Maryland School of Medicine
- Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr., Gould TD. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481–6.
(2R,6R)-HNK has been found to be a safe, effective next-generation antidepressant in several different mouse models of depression. Work toward human clinical trials with (2R,6R)-HNK is currently underway.
Public Health Impact
Depression remains a serious medical illness for more than 10 million Americans annually. For a large percentage, the existing treatment options fail, and there are no current options for these individuals. The goal of this project is to develop a treatment for patients with resistant depression.