Answering why ketamine helps depression could lead to safer drugs
First synthesizedin 1962, ketamine was initially used for pain relief and as ananaesthetic before drifting into recreational circles due to itsdissociative and hallucinogenic properties. In recent years the drughas been discovered to have notable rapid-acting effects as ananti-depressant. Despite growing anecdotal support, scientists havenot had a clear understanding of how ketamine's anti-depressanteffects actually work. A new study has finally solved a key part of theketamine mystery, discovering how it triggers its anti-depressanteffects.
A small, but landmark, study in 2006showed that ketamine triggered significantly positive effects inpatients with treatment-resistant depression within two-hours of intravenoustreatment. The study kickstarted a whole new generation of research investigating the drug's unexpected ability to treat a broad variety of mooddisorders from depression to obsessive-compulsive disorder.
Over the last decade a multitude ofresearch has barrelled along, solidifying a positive connectionbetween ketamine and depression, but medical research is a slow beast.Too slow for many in fact. A number of "ketamine clinics" have opened inthe 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 notapproved. This means that it is not illegal for clinicians to deliverthe drug in this "off-label" way, but insurance companies willnot cover it.
These ketamine clinics are, notsurprisingly, expensive options out of reach to many without bigwallets. The drug also has significant hallucinogenic side-effectsthat, while alluring to recreational users, are not ideal in clinicalscenarios.
A team from the Peter O'Donnell JrBrain Institute at UT Southwestern has recently made a majorbreakthrough in understanding the neurological process at playbetween ketamine and depression. The hope is that this research couldlead to the development of a more targeted treatment that achievesthe anti-depressant qualities of ketamine without the unwanted sideeffects.
The study discovered that ketamineblocks a protein receptor in the brain called N-methyl-D-aspartate(NMDA). It's this action that reportedly causes the drug'sfast-acting anti-depressant effects and a metabolite found in ketamine alsoextends the duration of the effect.
"Ketamine opens the door tounderstanding how to achieve rapid action and to stabilizepeople quickly," says one of the study's authors, Dr LisaMonteggia. "Because the (NMDA) receptor that is the target ofketamine is not involved in how other classical serotonin-basedantidepressants work, our study opens up a new avenue of drugdiscovery."
Dr Monteggia's team is also conductingtwo clinical trials investigating the efficacy of ketamine deliveredthrough a nasal spray instead of the more invasive intravenousinfusion. These studies, alongside a myriad of concurrent trialsaround the world, are working towards building a body of clinicalevidence to help legitimize the treatment.
"This demand is overriding all thequestions we still have about ketamine," explains Dr Monteggia."How often can you have an infusion? How long can it last? Thereare a lot of aspects regarding how ketamine acts that are stillunclear."
This study is only one piece of theketamine puzzle, as other scientists dig around to work out how thismysterious drug works. Last year a team from the National Instituteof Mental Health and the University of Maryland identified ametabolite called hydroxynorketamine, created as the body breaks downketamine, and showed it to reverse depression-like symptoms in micewithout any of the dissociative side effects of ketamine.
A whole new avenue of treatment isquickly opening up thanks to the unexpected benefits of this 50-yearold drug. With most 20th century anti-depressant drugsworking on serotonin pathways, often with only mild success, hopesare high that ketamine can reveal entirely new ways to treatdepression and anxiety disorders.
The new study was published in thejournal Nature.
Source: UT Southwestern