New class of antidepressants shows promise

The patient was only in his 20s but had been battling depression all his life—sometimes he felt so bad he would stay in bed for weeks. Finally he joined a clinical trial and took a drug that may turn out to be the biggest breakthrough in depression in decades. In a matter of hours he felt normal for the first time in his life.

The drug is called ketamine. Primarily used for inducing and maintaining anesthesia, ketamine has yet to be FDA-approved as an antidepressant. Nearly all existing antidepressant medications, including Zoloft, Prozac, and Cymbalta, target the serotonin and norepinephrine neurotransmitter systems and take weeks to work. Ketamine primarily affects a set of receptors in the central nervous system that are responsible for memory formation and learning, as well as other functions. These receptors utilize glutamate (glutamic acid), the most abundant excitatory neurotransmitter in the human brain.

Patients who have taken ketamine for depression in clinical trials at Yale report striking results almost immediately. “People will make comments like they feel their shoulders relax for the first time in years within a day of receiving the treatment,” says psychiatrist Gerard Sanacora, PhD, MD, who directs the Yale Depression Research Program at the Yale School of Medicine. “

On the cusp of ‘a game changer’

“It seems like we’re on the cusp of something very exciting that may be a game changer for depression,” says psychiatrist John Krystal, MD, chair of the Department of Psychiatry at the Yale School of Medicine, who led the first ketamine trial for depression along with Dennis Charney, MD, a former colleague at Yale who is now at the Icahn School of Medicine at Mount Sinai.

An estimated one in 10 American adults report symptoms of depression, and as many as a third of people don’t respond to currently available medications. Ketamine and ketamine-like drugs may offer new hope as well as rapid relief, especially for those who may be suicidal or require hospitalization, says Dr. Sanacora.

However, more research is needed to test the longer-term effectiveness of this new class of drugs and to determine the risks and benefits of treating mild and moderate depression. One concern is that, at some dosages, ketamine—which has been abused as a party drug under the name “Special K”—produces such unwanted side effects as euphoria, hallucinations, disorientation, and amnesia. Another is that ketamine’s antidepressant effect can wear off in a week to 10 days, and there is little information on the safety of repeated doses.

The most recent research aims to develop medications based on findings from the ketamine trials that will be safer and easier to administer than ketamine, and ultimately capable of maintaining long-lasting clinical benefits. Lanicemine, a drug that belongs to the same general chemical class as ketamine, showed similar antidepressant effects as ketamine without many of the unwanted side effects in an initial study reported by Dr. Sanacora.

The lanicemine study, published earlier this year in the journal Molecular Psychiatry, was funded by AstraZeneca Pharmaceuticals, which is developing the medication. In addition to lanicemine, Dr. Sanacora’s program has tested several other drugs under development by pharmaceutical companies that target the glutamate neurotransmitter system. He is currently investigating another glutamatergic drug called riluzole.

Looking at depression from a different angle

The glutamate system is the key to the new class of medications because it represents a different route to treat depression. “For the last 50 years, we’ve sort of looked at depression through one window,” says Dr. Sanacora. “Now I think we’re aware that there are many other avenues that could be pursued.”

Glutamate first intrigued Dr. Krystal early in his career when he wanted to learn what role it might play in schizophrenia and alcoholism. While most drugs prescribed for depression focus on such neurotransmitters as serotonin or norepinephrine, which are active in the brain stem, glutamate is the chemical used for communication by the cortex, the outermost and most highly evolved structure of the brain.

Dr. Sanacora frequently collaborates with Ronald Stanton Duman, PhD, a molecular neuroscientist, to understand precisely what happens in the brain when a person takes ketamine or a ketamine-like drug. Dr. Duman’s work has begun to elucidate the molecular changes occurring in the brain in response to ketamine and how these changes may help to reverse some of the pathology associated with depression. That knowledge will be critical to understanding depression and developing more effective treatments.

Sign up for a clinical trial

The safest way for patients to try the new drugs would be to sign up for a clinical trial that includes close monitoring, he says. To find out about clinical trials at Yale involving ketamine and ketamine-like drugs, visit Clinical Trials at Yale and type the word “depression” into the search box.

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This article was submitted by Mark Santore on January 31, 2014.

Related People

Ronald Stanton Duman

Elizabeth Mears and House Jameson Professor of Psychiatry and Professor of Neuroscience

John H. Krystal

Robert L. McNeil, Jr. Professor of Translational Research and Professor of Psychiatry and of Neuroscience

Gerard Sanacora

Professor of Psychiatry