Ketamine for the treatment of depression and other anxiety-related disorders

2016

Challenge

Ketamine and its analogs have been found to provide rapid anti-depressive relief in depression and other anxiety-related disorders. Despite legitimate medical uses, ketamine also has dissociative, euphoric, and addictive properties, making it a potential drug of abuse and limiting its usefulness. This has prompted a search for metabolites that retain antidepressant properties, but lack the undesirable side effects of ketamine.

Advance

IRP researchers led by Carlos Zarate, M.D., and collaborators found that the (2R,6R)-2-amino-2-(2-chlorophenyl)-6- hydroxycyclohexanone ((2R,6R)-hydroxynorketamine (HNK)) metabolite reverses depression-like behaviors in mice without triggering the undesirable side effects. In contrast to the prevailing view that ketamine produces its antidepressant effects by blocking glutamatergic N-methyl-D-aspartate (NMDA) receptors, the team found that the rapid antidepressant-like effects required activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

Impact

A stereospecific bioactive ketamine metabolite (2R, 6R-HNK) was identified that exerts rapid-acting antidepressant effects and is devoid of addictive properties. This metabolite and associated methods of treatment are available for collaboration and licensing. Further, by elucidating the molecular target, the results of this study open new avenues for further antidepressant drug discovery and development.

Publications

Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KSS, Fang Y, Huang X, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA, Gould TD. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 533:481-6.