Scientists have identified a key protein that helps trigger ketamine’s rapid anti-depressant effects in the brain, a crucial initial step to developing alternative treatments to the controversial drug being dispensed in a growing number of depression clinics across the country.

Ketamine is drawing intense interest in the psychiatric field after multiple studies have demonstrated it can quickly stabilize severely depressed patients. But ketamine – illicitly used for its psychedelic properties – could also impede memory and other brain functions, spurring scientists to identify new drugs that would safely replicate its anti-depressant response without the unwanted side effects.

A new study from the Peter O’Donnell Jr. Brain Institute has jumpstarted this effort in earnest by answering a question vital to guiding future research: What proteins in the brain does ketamine target to achieve its effects? “Now that we have a target in place we can research the pathway and develop drugs that safely recreate the anti-depressant effect,” said Dr. Lisa Monteggia, Professor of Neuroscience at UT Southwestern Medical Center’s O’Donnell Brain Institute.

The study published in Nature shows that ketamine blocks a protein responsible for a range of normal brain functions. The blocking of the N-methyl-D-aspartate (NMDA) receptor creates the initial antidepressant reaction, and a metabolite created by the ketamine is responsible for extending the duration of the effect.

The blocking of the receptor also induces many of ketamine’s hallucinogenic responses. The drug – used for decades as an anesthetic – is sometimes used illicitly and can distort senses and impair coordination.

But if taken with proper medical care, ketamine may help severely depressed or suicidal patients in need of a quick, effective treatment, Dr. Monteggia said.

Studies have shown ketamine can stabilize patients within a couple of hours, compared to other antidepressants that often take a few weeks to respond – if they respond at all.

“People are demanding it. They’re willing to take the risk of potential side effects just to feel better,” Dr. Monteggia said. “And that demand is over-riding all the questions we still have about ketamine. How often can you have an infusion? How long can it last? There are a lot of things that are still unclear.”

Dr. Monteggia’s lab continues researching these questions as UT Southwestern conducts two clinical trials with ketamine, including an effort to administer the drug through a nasal spray as opposed to intravenous infusions.

The results will have major implications for the millions of depressed patients seeking help, in particular those who have yet to find a medication that works.

A major national study UT Southwestern led more than a decade ago (STAR*D) gives insight into the prevalence of the problem: Up to a third of depressed patients don’t improve during their first medication, and about 40 percent of people who start taking antidepressants stop taking them within three months.

Ketamine, due to the potential side effects, is mainly being explored as a treatment only after other antidepressants have failed. But for patients on the brink of giving up, waiting weeks to months to find the right therapy may not be an option.

“Ketamine opens the door to understanding how to get rapid action and to stabilize people quickly. Because the (NMDA) receptor is not involved in how other classical serotonin-based antidepressants work, this study opens up a new avenue of drug discovery,” said Dr. Monteggia, who holds the Ginny and John Eulich Professorship in Autism Spectrum Disorders.

The study was supported by the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the International Mental Health Research Organization. Collaborators at UT Southwestern include Dr. Ege Kavalali, Professor of Neuroscience and Physiology and holder of the Rosewood Corporation Chair in Biomedical Science, Dr. Kevin Hunt, Director of Biopharmaceutical Product Development, Dr. Elena Nosyreva, Instructor of Neuroscience and Physiology, and Dr. Kanzo Suzuki, a postdoctoral fellow.