Ketamine Shows Promise as Therapy for Brain Trauma and Mood Disorders

Jed Hartings, PhD, in his office. Behind him are a few of the studies he has published in the last year. Photo by Cindy Starr / Mayfield Clinic.

Patients who are fighting for their lives as a result of conditions as diverse as major depression, stroke and traumatic brain injury may benefit from an established drug that is drawing new attention from researchers at the University of Cincinnati Gardner Neuroscience Institute.

Ketamine, commonly used as an anesthetic, is showing promise in its ability to treat a subset of patients with bipolar disorder and to cause sudden improvement in people with depression who have not responded to other treatments. Equally exciting, neurotrauma researchers at the UC Gardner Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health, recently co-authored a study that showed that ketamine halted the damaging electrical activity known as brain tsunamis after traumatic brain injury and stroke.

Cal Adler, MD

“Ketamine is an anesthetic that is commonly used in children and widely used in veterinary practice,” says Cal Adler, MD, Associate Professor of Psychiatry and Behavioral Neuroscience and an expert at the UC Mood Disorders Center. “It is also a drug of abuse. ‘Special K,’ the club drug, is ketamine.”

The drug is known to lower body temperature and to improve cerebral blood flow. It also can cause symptoms of disassociation – a feeling of an out-of-body experience – as well as hallucinations. Although it is being investigated as a potential therapy for patients with severe depression and anxiety disorders that do not respond well to other treatments, it is not currently prescribed by physicians at the UC Mood Disorders Center.

Ketamine works by controlling glutamate, a neurotransmitter that normally plays an important role in memory and learning. If glutamate is present in excessive amounts, however, it overstimulates brain cells, causing them to die from “excitotoxicity.”

Ketamine blocks the neuro-excitatory effects of glutamate by interfering with one of its receptors, known as NMDA (N-methyl D-aspartate). In scientific parlance, ketamine is an NMDA receptor antagonist, which means that it works by antagonizing, or inhibiting, the ability of the NMDA receptor to act. Because the NMDA receptor is involved in several areas of brain regulation, the result of this activity may have different results for different types of patients.

Erik Nelson, MD

“When you block this NMDA receptor, you get a sudden increase in signaling through a different receptor, AMPA, which is thought to underlie the rapid antidepressant effect,” says Erik Nelson, MD, Associate Professor of Psychiatry and Behavioral Neuroscience.

Limiting glutamate might also slow the spread of damage following brain trauma or stroke.

“Glutamate enables one cell’s firing to communicate with the next cell and cause it to fire as well,” explains Jed Hartings, PhD, Assistant Professor in the Department of Neurosurgery. “After a head injury or stroke, the brain becomes hyper-excitable, and we believe that an excess amount of glutamate or the disregulation of ions in the brain is what is causing them to fire too much. This disregulation can lead to seizures and also to electrical disturbances called spreading depolarizations (or brain tsunamis).”

Decades of research in animal models have shown that blocking the NMDA receptor is the best way to stop spreading depolarizations. Last year, for the first time, Dr. Hartings and his colleagues from the international group COSBID (Co-Operative Studies of Brain Injury Depolarizations) accumulated brain-monitoring data of patients who had suffered spreading depolarizations after head trauma or stroke. During the observational, retrospective study, which included patients treated at the UC Medical Center, the researchers compared spreading depolarizations in patients who were treated with various medications during their hospitalization.

“There was no intention to treat spreading depolarizations with ketamine,” Dr. Hartings said. “But some patients in the European population were given ketamine for other reasons. And we found that when that drug was given, the depolarizations stopped.”

The group’s study was published in the August 2012 issue of the journal Brain.

The next step for Dr. Hartings and his team is to conduct a study that administers ketamine to patients with an intention to treat spreading depolarizations. An application is in process with the U.S. Department of Defense. If the study is funded, Dr. Hartings said, it would be the first “selective inclusion trial” ever for a brain trauma therapy. Whereas study therapies for brain trauma previously have been given to all study participants, ketamine would be delivered only to those who are known to be experiencing spreading depolarizations.

At the same time, the ability of ketamine and ketamine-like drugs to block the NMDA receptor is attracting widespread interest within the psychiatric community. UC is a study site for an investigational medicine that was discovered and is being developed by AstraZeneca Pharmaceuticals. The medication, given as an infusion (by IV) to study patients with treatment-resistant depression, resembles ketamine in that it blocks glutamate receptors, but its side-effects are fewer.

Meanwhile, an NMDA antagonist called memantine is being used in the treatment of moderate to severe Alzheimer’s disease. In Alzheimer’s disease, as in neurotrauma, an excessive amount of glutamate appears to kill nerve cells through excitotoxicity.

“The story of the NMDA antagonists is exciting, and we may be using more of these drugs therapeutically in the not-too-distant future,” Dr. Adler says. “We’re still pretty early in process, but ketamine represents the first really new treatment for depression since the advent of serotonin reuptake inhibitors (SSRIs).

— Cindy Starr

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