Following the FDA's landmark approval of a ketamine-inspired nasal spray for treatment-resistant depression, new research led by the University of Maryland School of Medicine is offering provocative insights into how the drug exerts such a rapid anti-depressant effect and points to new pathways for research into alternative drugs to treat depression.

It's been known for some time that ketamine blocks a protein receptor in the brain called N-methyl-D-aspartate (NMDA), and it is this process that many have suspected is the cause of the drug's fast-acting anti-depressant qualities. However, a growing body of research is beginning to suggest this hypothesis is overly simplistic, and even potentially wrong.

When ketamine is metabolized by the liver, it is transformed into a number of metabolites that subsequently exert certain effects on the brain. Ketamine, and its primary metabolite norketamine (NK), are known NMDA antagonists. Other secondary metabolites have generally been considered inactive and not relevant to the drug's clinical effects.

A controversial 2016 study proposed a provocative alternative hypothesis. It suggested that a secondary metabolite produced by ketamine is essential to its anti-depressant effects, and it works independently of any action on NMDA receptors.

Called (2R,6R)-hydroxynorketamine (or (2R,6R)-HNK for short), this distinct metabolite was revealed in the 2016 research to exert unique behavioral, electroencephalographic, electrophysiological and cellular antidepressant actions in animal tests. Even more importantly, these effects seemed to lack all the negative psychoactive effects commonly associated with ketamine, most likely due to the fact this particular metabolite did not act on NMDA receptors.

The new research set out to further home in on the specific action of this novel ketamine metabolite. Using a variety of experimental animal tests the researchers ultimately discovered that (2R,6R)-HNK exerts anti-depressant effects by inhibiting activity in glutamate receptors called mGlu2. Most importantly, the study also found that this ketamine metabolite does not interact with NMDA receptors, suggesting these anti-depressant effects are entirely independent, and wholly related to mGlu2 receptors.

This hypothesis is not presented without divisive debate in the scientific community. Some researchers suggest it is premature to discard the NMDA hypothesis, especially based on limited study, and only in animals. But, it has been pointed out that many alternative, non-ketamine-based NMDA-inhibitors have not proven as effective as ketamine in delivering anti-depressant effects. This implies that, at the very least, the beneficial anti-depressant qualities of ketamine are the result of much more than simple NMDA inhibition.

The big takeaway from this new study is that (2R,6R)-HNK may offer promise for a whole new generation of anti-depressant drugs targeting mGlu2 receptors. The major hurdle holding ketamine back from becoming an effective and easily administered anti-depressant is the fact it results in acute dissociative effects immediately after a dose. This makes it challenging to safely administer outside of day-long infusions or treatments requiring significant patient observation. Identifying a specific ketamine metabolite that may deliver anti-depressant effects without these negative side effects offers an excitingly promising pathway to new drugs for treatment-resistant depression.

The new study was published in the journal PNAS.