One of the Holy Grails of depression drug research has been finding a safe, nonaddictive version of ketamine that could have a durable impact on patients. Now investigators at the NIH say that they’ve made a breakthrough discovery in an animal study that could point the way to the promised land. And they’re headed straight into human studies to see if they’re right--and everyone else is wrong.
Ketamine, a generic sedative known in party circles as Special K, has shown time and again that it can almost instantly lift large percentages of patients out of the most severe cases of depression. But it got to be a party drug because of the hallucinations and dissociative behavior that made it impossible to use for a disease that afflicts millions.
The NIH team, led by Carlos Zarate, found in reverse engineering ketamine in the lab that there are two mirror chemical forms of the drug. One of those forms is good at blocking NMDA receptors, influencing glutamate, a well known chemical messenger in the brain. That’s where many investigators have been concentrating their attention, looking for NMDA receptor drugs that could do the therapeutic work that ketamine performs.
But that was a red herring, says the NIH team. It’s the other chemical form of ketamine which creates a metabolite--HNK (hydroxynorketamine)--that triggers the antidepressant function. Instead of blocking NMDA receptors, this metabolite activates a different glutamate receptor: glutamate receptor, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). And it works without the illicit drug response that makes ketamine so problematic.
“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,” explained Todd Gould, a researcher at the University of Maryland School of Medicine working with Zarate.
The next step is completing a safety study in humans, and then start efficacy trials.
If they’re right, and preclinical studies are typically ultrahigh-risk when it comes to making a switch from mice to humans, the NIH team may open a door that could have profound consequences for a group of companies doing late-stage depression research. J&J has been working on a late-stage study for its intranasal version of ketamine called esketamine. And Allergan ($AGN) recently acquired Naurex’s NMDA drug--GLYX-13--in a $560 million-plus deal.
It's going to take more than an animal study to persuade these companies that they're on the wrong track. Midstage clinical trials have raised evidence of success in treating depression, and they're making major investments to prove they work in pivotal studies.
- here's the release