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A promising experimental antidepressant may work differently than scientists had previously thought, potentially explaining multiple failed drug trials over the past decade.

Ketamine has been known since the turn of the millennium to have powerful antidepressant effects — it relieves symptoms in a matter of hours, while other antidepressants take weeks or months, and it can treat depression even when other drugs are ineffective. But it also has hallucinogenic side effects, which give it value as an illegal street drug.


New research published Wednesday in Nature demonstrates how to use a derivative of ketamine to achieve the same benefit without the side effects, at least in mice.

“I think there’s going to be a lot of individuals in industry who are thinking very carefully about this,” said Dr. Todd Gould, a neurobiologist at the University of Maryland School of Medicine, who led the study.

Ketamine was originally used as an anesthetic, interacting in the brain via a particular receptor called NMDA, which is involved in learning and memory. So, scientists presumed that the same receptor was also responsible for ketamine’s anti-depressive qualities, said Gould.


That led more than a dozen companies to try to develop other drugs that also target the NMDA receptor — but some of those drugs haven’t worked as well as ketamine. AstraZeneca’s highly touted lanicemine, for example, failed to show long-term benefits, and the company pulled the plug on the drug’s development in 2013.

Gould’s study suggests that these companies may have been looking in the wrong place. His team showed that, in mice, ketamine’s effectiveness as an antidepressant doesn’t come from the NMDA receptors. Instead, something else happens.

In the body, ketamine turns into a molecule called hydroxynorketamine — or HNK — and that molecule is actually what treats the depression. Gould’s team also found that HNK does not interact with the NMDA receptor, and it doesn’t have some of the side effects that ketamine does.

Of course, these results come with the giant caveat that they came from experiments in mice. But Gould is already forging ahead on a path to human trials.

“We have a game plan in place to move forward with clinical development of HNK,” said Gould, who, along with his various coauthors, filed a patent application for certain uses of the ketamine derivative.

Most outside researchers STAT contacted expressed support for this research, characterizing it as well-done science that could open up new areas for treatment.

But they aren’t convinced it’s time to ditch the NMDA receptor as a drug target for depression quite yet.

“In my view, it is quite premature to move away from the hypothesis that NMDA receptor antagonists have antidepressant activity based on this single study,” said Dr. John Krystal, a psychiatrist and neuroscientist at Yale University, who consults for companies developing NMDA-targeted drugs and has been in the field for decades.

Uli Hacksell, chief executive of Cerecor, a Baltimore company that has a Phase 2 drug candidate directed at the NMDA pathway, also took issue with the claim that such drugs might be going after the wrong target, and he said that the paper will have no implications for his company’s development plans. “We think that the clinical data we get with our molecule will speak for themselves,” he said.

Meanwhile, other companies are pursuing variants of ketamine and have had preliminary success.

For example, Janssen Pharmaceuticals has a nasal spray in development that contains a certain variety of ketamine called esketamine. It’s now being tested in five ongoing Phase 3 trials.

Dr. Husseini Manji, global therapeutic head for neuroscience at Janssen, said that Gould’s paper presents some exciting possibilities for additional ways to treat depression, but that’s secondary to what matters most for patients.

“We have clear evidence that esketamine works in people,” Manji said.