Development of (2R,6R)-Hydroxynorketamine as a Treatment for Depression

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.

Scientific Synopsis

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.

This chart demonstrates that ketamine is effective at 10 mg/kg dosing in the learned helplessness model of depression, compared with the placebo (saline). Likewise, (2R,6R)-HNK is effective at 5 mg/kg dosing and above. (Reprinted with permission from Zanos P, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481–6.) Copyright 2016 Nature)

This chart demonstrates that ketamine is effective at 10 mg/kg dosing in the learned helplessness model of depression, compared with the placebo (saline). Likewise, (2R,6R)-HNK is effective at 5 mg/kg dosing and above. (Reprinted with permission from Zanos P, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481–6.) Copyright 2016 Nature)

This figure shows that ketamine is effective in the learned helplessness model of depression at 10 mg/kg, while the placebo (saline) is not. When a deuterium-labelled version of ketamine ((R,S)-d2-KET) is used instead, it is not significantly effective in the learned helplessness model. This provides evidence that the metabolism of ketamine is necessary for its antidepressant effects. (Reprinted with permission from Zanos P, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481–6.) Copyright 2016 Nature)

​This figure shows that ketamine is effective in the learned helplessness model of depression at 10 mg/kg, while the placebo (saline) is not. When a deuterium-labelled version of ketamine ((R,S)-d2-KET) is used instead, it is not significantly effective in the learned helplessness model. This provides evidence that the metabolism of ketamine is necessary for its antidepressant effects. (Reprinted with permission from Zanos P, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481–6.) Copyright 2016 Nature)

Ketamine is an addictive substance. This chart shows that when mice are given the option to self-administer ketamine (by pushing a lever), compared with the placebo (saline), they choose to administer themselves ketamine. However, when mice are allowed to self-administer (2R,6R)-HNK, compared with saline, there is no statistical difference.(Reprinted with permission from Zanos P, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481–6.) Copyright 2016 Nature)

Ketamine is an addictive substance. This chart shows that when mice are given the option to self-administer ketamine (by pushing a lever), compared with the placebo (saline), they choose to administer themselves ketamine. However, when mice are allowed to self-administer (2R,6R)-HNK, compared with saline, there is no statistical difference.(Reprinted with permission from Zanos P, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481–6.) Copyright 2016 Nature)

Lead Collaborators

  • 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

Publication

Outcomes

(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.

Contact

Craig Thomas, Ph.D.