New Insight Into How Ketamine Works in Depression

Megan Brooks

July 05, 2017

Ketamine exerts an initial antidepressant effect by blocking the N-methyl-D-aspartate receptor (NMDAR), and the ketamine metabolite hydroxynorketamine (HNK) may extend the duration of the effect. The findings could lead to the development of safer alternatives.

Several studies have shown that the psychoactive drug, which is an anesthetic, has rapid antidepressant effects in patients with treatment-refractory major depression.

"But it's been unclear exactly what the target is, how the drug acts to deliver that effect," lead investigator Lisa Monteggia, PhD, a neuroscientist with the O'Donnell Brain Institute at UT Southwestern Medical Center in Dallas, Texas, told Medscape Medical News.

"If we understand what that target is, exactly how the drug works, it might allow us to think about drugs that hopefully will have the same rapid response of ketamine without the potential side effects," she said.

Dr Monteggia and colleagues at UT Southwestern compared the actions of ketamine (50 μM) with the ketamine metabolite HNK (10 and 50 μM) in cultured hippocampal neurons.

At the higher dose, they found that HNK blocks synaptic NMDA receptors, similar to ketamine. This triggers a cascade of intracellular signaling previously believed to underlie the antidepressant effects.

The study, published online June 21 in Nature, suggests that HNK is "an open-channel blocker of NMDARs," the authors write.

Dr Monteggia and colleagues acknowledge that their findings are somewhat at odds with a recent study in mice by Panos Zanos, PhD, and colleagues suggesting that HNK acts in an NMDAR-independent manner.

"Contrary to the study suggesting it is NMDA-independent, we showed that it does indeed block the NMDA receptor, so it refocuses attention back to NMDA receptor as the target for what needs to be engaged to trigger a rapid antidepressant response," said Dr Monteggia.

In a reply published online June 21 in Nature, Dr Zanos, Todd Gould, MD, both of the University of Maryland School of Medicine in Baltimore, and colleagues say that this new study in fact confirms their previous findings that HNK does not functionally inhibit the NMDAR "at concentrations relevant to its antidepressant actions recently reported in mice (that is, 10 μM)."

"We don't think [the findings] differ in a substantial way," Dr Gould told Medscape Medical News. "Basically, their finding is NMDAR inhibition at concentrations much higher than those required to exert antidepressant actions. We did not assess such high concentrations because of their irrelevance," he added.

"Although development of (2R,6R)-HNK as an antidepressant drug, which does not induce NMDAR-mediated side effects, can proceed independently of target identification, it remains important to identify its primary pharmacological target at antidepressant-relevant concentrations (~10 μM)," Dr Gould and colleagues conclude.

Dr Monteggia noted that at this point the "relevant dose is unclear."

"In fact, we don't even know with ketamine. There hasn't been strong dose-response curves done clinically to really know. That work is ongoing now," she said.

The study was supported by the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the International Mental Health Research Organization. The authors have disclosed no relevant financial relationships.

Nature. Published online June 22, 2017. Study abstract, Reply


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