First synthesized in 1962, ketamine was initially used for pain relief and as an anaesthetic before drifting into recreational circles due to its dissociative and hallucinogenic properties. In recent years the drug has been discovered to have notable rapid-acting effects as an anti-depressant. Despite growing anecdotal support, scientists have not had a clear understanding of how ketamine's anti-depressant effects actually work. A new study has finally solved a key part of the ketamine mystery, discovering how it triggers its anti-depressant effects.

A small, but landmark, study in 2006 showed that ketamine triggered significantly positive effects in patients with treatment-resistant depression within two-hours of intravenous treatment. The study kickstarted a whole new generation of research investigating the drug's unexpected ability to treat a broad variety of mood disorders from depression to obsessive-compulsive disorder.

Over the last decade a multitude of research has barrelled along, solidifying a positive connection between ketamine and depression, but medical research is a slow beast. Too slow for many in fact. A number of "ketamine clinics" have opened in the last few years across the United States offering infusions to patients, for a price.

As an anaesthetic ketamine is approved by the FDA, but using it for depression is not approved. This means that it is not illegal for clinicians to deliver the drug in this "off-label" way, but insurance companies will not cover it.

These ketamine clinics are, not surprisingly, expensive options out of reach to many without big wallets. The drug also has significant hallucinogenic side-effects that, while alluring to recreational users, are not ideal in clinical scenarios.

A team from the Peter O'Donnell Jr Brain Institute at UT Southwestern has recently made a major breakthrough in understanding the neurological process at play between ketamine and depression. The hope is that this research could lead to the development of a more targeted treatment that achieves the anti-depressant qualities of ketamine without the unwanted side effects.

The study discovered that ketamine blocks a protein receptor in the brain called N-methyl-D-aspartate (NMDA). It's this action that reportedly causes the drug's fast-acting anti-depressant effects and a metabolite found in ketamine also extends the duration of the effect.

"Ketamine opens the door to understanding how to achieve rapid action and to stabilize people quickly," says one of the study's authors, Dr Lisa Monteggia. "Because the (NMDA) receptor that is the target of ketamine is not involved in how other classical serotonin-based antidepressants work, our study opens up a new avenue of drug discovery."

Dr Monteggia's team is also conducting two clinical trials investigating the efficacy of ketamine delivered through a nasal spray instead of the more invasive intravenous infusion. These studies, alongside a myriad of concurrent trials around the world, are working towards building a body of clinical evidence to help legitimize the treatment.

"This demand is overriding all the questions we still have about ketamine," explains Dr Monteggia. "How often can you have an infusion? How long can it last? There are a lot of aspects regarding how ketamine acts that are still unclear."

This study is only one piece of the ketamine puzzle, as other scientists dig around to work out how this mysterious drug works. Last year a team from the National Institute of Mental Health and the University of Maryland identified a metabolite called hydroxynorketamine, created as the body breaks down ketamine, and showed it to reverse depression-like symptoms in mice without any of the dissociative side effects of ketamine.

A whole new avenue of treatment is quickly opening up thanks to the unexpected benefits of this 50-year old drug. With most 20th century anti-depressant drugs working on serotonin pathways, often with only mild success, hopes are high that ketamine can reveal entirely new ways to treat depression and anxiety disorders.

The new study was published in the journal Nature.

Source: UT Southwestern