The substance in ketamine responsible for its antidepressant effects has been identified by scientists. The discovery has the potential to be a "major breakthrough" for drug development, as the chemical has been shown to alleviate depression, with none of the adverse side effects.
Ketamine has long been known for its potential to treat depression. It has major advantages on currently available treatments as it acts within hours, rather than weeks or months. However, it also has major side effects - including hallucinations - and has the potential to be abused because of its addictive nature.
A team of researchers from the US were looking to work out exactly how ketamine relieves depression. They tested several of the chemicals that form when ketamine is broken down on mice. Known as metabolites, they eventually focused on one that was thought to have no psychoactive effects.
This metabolite – called hydroxynorketamine (HNK) – was then used in a series of experiments to test its antidepressant properties. Their findings, published in Nature, showed that when HNK was blocked, so to were the antidepressant effects of ketamine.
Next, they administered mice with HNK and found it induced the antidepressant effects of ketamine, but with none of the side effects. When they gave the mice the option of self-administering, researchers found they would self-administer ketamine, but not HNK. This suggests the metabolite is non-addictive.
Senior author Todd Gould, from the University of Maryland School of Medicine, said: "This is potentially a major breakthrough. It could allow depressed patients to get the rapid benefits of ketamine, while at the same time avoiding the risks."
He told IBTimes UK he was not expecting one specific metabolite to give ketamine its antidepressant properties: "I was surprised that the metabolism of ketamine in general was responsible, and that the antidepressant actions could be reproduced by a single metabolite."
In a statement, he added: "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."
Carlos Zarate, from the National Institute of Mental Health, said: "This discovery fundamentally changes our understanding of how this rapid antidepressant mechanism works, and holds promise for development of more robust and safer treatments. By using a team approach, researchers were able to reverse-engineer ketamine from the clinic to the lab to pinpoint what makes it so unique."
The researchers hope to start testing HNK to see if it works in humans: "Otherwise, it is just a mouse antidepressant," Gould said. However, he added there are still a number of hurdles to overcome first including a number of FDA requirements, including dose-range toxicology studies, before they can begin human trails. He confirmed there are both plans and a timeline, but "we may be overly optimistic".
Regardless, the team are still hopeful their work will open up a new avenue of drug development. Scott Thompson, also from the University of Maryland School of Medicine, said: "For years, we have been searching for ways to treat depression faster and more effectively. These results open up exciting new vistas for the first new generation of antidepressant compounds in the last 30 years."