Despite the fact that increasing numbers of scientists are now experimenting with psychoactive drugs to treat psychiatric disorders, the use of these substances remains a pretty controversial topic. One such drug, ketamine, has been shown to rapidly and radically reduce symptoms of depression, yet its “druggy” side effects – which include sensory discombobulation and addictiveness – make it something of a hot potato.
However, a team of scientists funded by the National Institute of Health has now isolated a single compound, produced when the body breaks the drug down, that appears to be responsible for this antidepressant effect without producing any undesirable side-effects.
After confirming the efficacy of the compound in depressed mice, study co-author Todd Gould explained that “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.”
Because ketamine works by blocking a particular type of receptor in the brain, known as NMDA receptors, scientists had until now focused on these receptors in their attempts to replicate the drug’s antidepressant properties. In doing so, they hoped to develop new treatments that could alleviate depression without producing the mental and emotional distortions for which ketamine is famous.
However, while studies have repeatedly highlighted ketamine’s fast-acting and long-lasting ability to relieve depression, all attempts to recreate this with other NMDA inhibitors had produced disappointing results. As such, some scientists began to suspect that the key to ketamine’s efficacy must lie in some other mode of action.
Publishing their study in the journal Nature, the team behind this latest research describe how, when treating depressed mice with the drug, its antidepressant effects tended to be much more noticeable in females than in males. This was measured by observing the animals’ response to being given a series of electric shocks, both before and after receiving ketamine. Those that displayed a sense of “hopelessness” by not moving away from the source of the shocks were deemed to be heavily depressed.
Because of its psychoactive properties, ketamine has become a popular recreational drug. wavebreakmedia/Shutterstock
Analyzing the compounds present in the rodents’ brains once they had metabolized the ketamine, the researchers noted that levels of one particular metabolite, known as (2R,6R)-HNK, was three times higher in female than male mice.
They then administered (2R,6R)-HNK to another group of mice, finding that this reduced behaviors associated with depression just as effectively as ketamine itself, without getting the mice “high” like the drug does.
Importantly, (2R,6R)-HNK does not inhibit NMDA receptors, but instead works by activating another type of receptor known as AMPAR receptors. To confirm this, the researchers supplied the mice with a compound that inhibits AMPAR activity, before giving them either ketamine or (2R,6R)-HNK. As expected, this blocked the drug’s antidepressant effects, suggesting that this is indeed the main mechanism by which it treats the condition.
Furthermore, even after receiving high quantities of (2R,6R)-HNK, the mice showed no tendency to self-administer the drug, indicating that, unlike ketamine itself, the substance is non-addictive. Commenting on these results, study co-author Carlos Zarate stated that “this discovery fundamentally changes our understanding of how this rapid antidepressant mechanism works and holds promise for development of more robust and safer treatments.”
