'Major' Ketamine Discovery May Lead to New Antidepressants

Pam Harrison

May 10, 2016

The possibility of an antidepressant that delivers ketamine's rapid antidepressant effects but none of its potential harms may be one step closer, new research shows.

Investigators at the National Institute of Health (NIMH) have discovered that ketamine rapidly lifts depression via a by-product of its metabolism. This metabolite singularly reversed depressionlike behaviors in mice without triggering any of the anesthetic, dissociative, or addictive side effects associated with ketamine.

"This discovery changes our understanding of how this rapid antidepressant mechanism works and holds promise for the development of more robust and safer treatments," study investigator Carlos Zarate, MD, National Institute of Mental Health, Methesda, Maryland, said in a statement.

"Ketamine is a reasonable option to consider when patients have tried everything else, as long as it's in the right hands and given at the right time," Dr Zarate told Medscape Medical News.

"But if you had an alternative drug that works rapidly but which doesn't have any risk of addiction or cause any of ketamine's side effects, you open up the possibility of many others being able to receive an alternative to ketamine," he added.

The study, led by Panos Zanos, PhD, University of Maryland School of Medicine, Baltimore, was published online May 4 in Nature.

No Side Effects

It was long assumed that ketamine works as an antidepressant by directly inhibiting the N-methyl-D-aspartate glutamate receptor (NMDAR), the researchers note.

However, in clinical trials, alternative NMDAR inhibitors have not demonstrated the same robust, rapid, or sustained antidepressant activity as ketamine. Researchers therefore used reverse- engineering techniques to examine the precise antidepressant action of NMDAR blockade.

Using mouse models of depressionlike behavior, the researchers broke down into its two chemical forms first the molecule and then its two metabolites to identify which chemical form, or which metabolite, was responsible for the desirable and undesirable effects of ketamine.

Previous research established that female mice respond well to much lower doses of ketamine than do males. This sex-based treatment response could not be explained by different levels of ketamine in the brain. Researchers found that levels of a key metabolite, (2S,6S;2R,6R)-hydroxynorketamine (HNK), were about three times higher in the brains of female mice than in those of males after ketamine administration, "suggesting a role of (2S,6S;2R,6R-HNK in the antidepressant effects of the drug."

To confirm this finding, the team chemically blocked the overall metabolism of ketamine to prevent the formation of its key metabolite.

They found that administration of chemically altered ketamine did not produce any antidepressant effects, a clear signal that the metabolite itself was responsible for the antidepressant activity attributed to ketamine.

Importantly, the key metabolite comes in two forms, and researchers eventually zeroed in on one of these metabolites, (2R,6R)-HNK, as the key player responsible for producing ketamine's antidepressant effects.

Researchers also showed that, similar to ketamine, a single dose of (2R,6R)-HNK led to antidepressant effects lasting for at least 3 days in treated mice.

Further exploration revealed that this pivotal metabolite activates another type of glutamate receptor, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). When AMPA is blocked, the antidepressant effects of (2R,6R)-HNK are neutralized in mouse models of depression.

Importantly, this singular metabolite was shown not to affect any of the usual changes in locomotion or coordination usually elicited by the administration of ketamine in mice.

Even given at high doses, mice did not display any of the usual changes in sensory processing commonly seen with ketamine.

In another experimental situation in which mice were allowed to self-administer medication, they did so with ketamine but not with the (2R,6R)-HNK metabolite, suggesting that the metabolite responsible for producing the antidepressant effects of ketamine is not addictive.

"So the metabolite of ketamine activates AMPA, and you get the antidepressant effects of ketamine without the liability of its side effects, because this metabolite doesn't do anything to NMDA. Side effects from ketamine are largely produced through NMDA inhibition," said Dr Zarate.

"Major Advance"

"The finding that the antidepressant effects of ketamine are not mediated through its actions on the NMDAR is a major advance," Roberto Malinow, MD, PhD, University of California, San Diego, writes in an accompanying commentary.

"Zanos et al show that HNK does not elicit several of the cognitive and motor side effects that have been linked to ketamine. As such, this study represents important progress."

Proof that researchers are on the right track will have to be shown in human studies, which NIMH investigators plan to start next year.

So far, the research has generated considerable interest from pharmaceutical companies, which see great potential in the exploitation of this newly defined pathway.

"I'm getting a lot of phone calls," said Dr Zarate.

"Now that we know that ketamine's antidepressant actions in mice are due to a metabolite, not ketamine itself, the next steps are to confirm that it works similarly in humans and determine if it can lead to improved therapeutics for patients," NIMH grant recipient Todd Gould, MD, University of Maryland School of Medicine, Baltimore, said in a statement.

Nature. Published online May 4, 2016. Abstract, Commentary

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