A specific substance formed from the breakdown of ketamine is responsible for the rapid and sustained antidepressant effects of the drug, reports a paper published in Nature this week. A single administration of this metabolite in mice is shown to induce the antidepressant effects of ketamine without its associated side effects.

Current pharmacological treatments for severe depression can take weeks to alleviate symptoms, and some patients do not respond to these treatments at all. The drug ketamine has been studied as a promising alternative to existing antidepressants and has shown efficacy in clinical trials, but it has the potential to be abused and can cause feelings of detachment from the environment and self (dissociation), which limits its potential for widespread clinical use.

Todd Gould and colleagues found that a single administration of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) in mice had antidepressant effects that were similar to those induced by ketamine and that persisted for at least three days. The authors further showed that (2R,6R)-HNK did not have the side effects observed following ketamine administration and that, when given the option, mice self-administered ketamine, but not (2R,6R)-HNK. The study also reveals that ketamine's antidepressant properties are in fact due to the metabolite rather than ketamine itself and that its antidepressant effects are not dependent on the inhibition of a particular receptor in the brain that was previously thought to be involved.

Identifying the molecular target of HNK and elucidating its mechanism of action "might further the development of more-specific and effective treatments, allowing people with depression to step out of the darkness of this disease," concludes Roberto Malinow in an accompanying News & Views article.

Nature. DOI: 10.1038/nature17998. http://nature.com/articles/doi:10.1038/nature17998. Corresponding Author: Todd Gould