The good news about the anesthetic ketamine is that its administration can alleviate severe, treatment-resistant depression within hours.

The bad news is that ketamine is also a street drug, with high abuse potential, and it has side effects that include dissociation.

Now, researchers at the University of Maryland School of Medicine have shown that ketamine's antidepressant actions may be mediated by one of its metabolites, (2R,6R)-hydroxynorketamine (HNK).

And, in a stroke of good luck, HNK does not appear to have the psychoactive side effects that are part of what is keeping ketamine from being more widely used as an antidepressant.

"In mice, it's possible to separate the antidepressant actions [of ketamine] from the side effects," Todd Gould, an associate professor of psychiatry at the University of Maryland, told BioWorld Today.

Gould is the corresponding author of the paper reporting the findings, which appeared in the May 5, 2016, issue of Nature.

In the work, the team also showed that HNK appeared to act not by inhibiting the NMDA receptor, which is the target of ketamine, but by activating another receptor, the AMPA receptor.

Both NMDA and AMPA are receptors for the neurotransmitter glutamate. NMDA receptors play important roles in learning and neural plasticity – a plasticity that is ultimately encoded partly as changes in AMPA receptor signaling.

Gould said the possibility that AMPA receptor activation may be behind antidepressant effects fits with other scientific studies.

"AMPA receptor antagonists block the antidepressant actions of ketamine," he noted.

And there is also evidence in rodents that long-term administration of selective serotonin reuptake inhibitors (SSRIs) – the current major drug class for the treatment of depression – changes glutamate transmission.

Previous studies had also suggested that NMDA might not be the receptor mediating ketamine's antidepressant effects.

Not all NMDA receptor antagonists show the sorts of antidepressant effects that ketamine does, and several NMDA receptor antagonists, including most recently lanicemine (Astrazeneca plc.), have failed in clinical trials for depression, though others remain in development.

In a News & Views article accompanying the paper, Roberto Malinow, professor of neurosciences at the University of California at San Diego, cautioned that "the molecular target and mechanism of action of HNK remain to be defined," but said that "the finding that the antidepressant effects of ketamine are not mediated through its actions on the NMDA [receptor] is a major advance."

Joseph Moskal, professor of biomedical engineering at Northwestern University and the chief scientific officer at Aptinyx Inc., lauded the work as showing that NMDA receptor blockage "may not be the only way, or the optimal way, that ketamine acts. It forces us to more broadly consider the activation of plasticity mechanisms, rather than being stuck in the mud of NMDA receptor blockage," as a goal of antidepressants.

Moskal is not ready, though, to throw NMDA receptor targeting out as a clinical approach.

For one, NMDA receptor blockade and AMPA receptor activation are not mutually exclusive.

As for HNK's lack of side effects, Moskal told BioWorld Today that "the dark side of the space" is that mouse models of neuropsychiatric disorders are by their nature blunt instruments to see such side effects, while the complexity of transmitter systems means that therapeutic indices are often narrow.

"Ketamine is a spectacular example of that problem," he said, but hardly has the monopoly on it. "These issues will always come up."

Gould and his team are working toward clinical trials of HNK. One advantage of the compound is that although it will be formally treated as a new molecular entity by the FDA, it is a natural metabolite of ketamine, which means that in practice, it has been present in ketamine-treated patients for decades without toxicity issues.

The team hopes to be in clinical trials with HNK by 2017. Initially, HNK will be administered intravenously in clinical testing, as is the case for ketamine. The need for intravenous administration is another obstacle to ketamine's more widespread use, and so the team is also looking at the possibility of an oral formulation.