Drug treats depression in hours

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Photo by Karen Tian.


A drug known on the street as “Special K” could be the newest innovation in anti-depression treatment.

In a review article published in “Science” on Oct. 5, Ronald Duman and George Aghajanian, psychiatry professors at the Yale School of Medicine, brought together more than a decade of research on the drug ketamine and its potential to become the first new class of anti-depressant medication in over 50 years. Though ketamine causes psychosis in high doses, scientists have found that low doses can reverse the signs of depression — and even suicidal urges — in just a few hours.

“The idea that a drug could produce a rapid improvement rather than taking several months to feel better is really an important idea and it really challenges the thinking about how anti-depressant medications might work,” Yale Chair of Psychiatry John Krystal said. “I think [it provides] a lot of hope for the future for the treatment of depression.”

Krystal, along with his collaborator Dennis Charney, was the first to link ketamine to the alleviation of depression in the 1990s. Ketamine has long been used as a pediatric and veterinary anesthetic and was originally explored by psychiatrists as a way to study schizophrenia, Krystal said.

Traditional anti-depressants, known as SSRIs, have been shown to take an average of seven weeks to produce improvement in major depressive disorder, Krystal said. Patients must take medication daily, and for one third of these patients, current medications provide no relief, he added. By contrast, ketamine rapidly reverses the disease’s physiological and behavioral effects. Ketamine has been shown to alleviate symptoms of depression in 70 percent of those patients who previously did not respond to treatment, Duman said.

Duman’s work has contributed to the understanding of the pathway by which ketamine works. While SSRIs block the re-uptake of serotonin, a neurotransmitter commonly thought to contribute to feelings of well-being, ketamine acts on the glutamate neurotransmitter system, which mediates the fast transfer of information in the brain.

“We think that’s why ketamine is able to produce such a rapid response,” Duman said.

While chronic stress and depression lead to the loss of synapses ­— key connections between cells that play a critical role in all brain function, including mood and emotion — ketamine reverses this degenerative process. The drug both stimulates synaptic growth and removes inhibitions to regeneration.

“Ketamine effectively takes your foot off the break and steps on the gas,” Krystal said.

The review’s findings are “totally against what we’ve always believed about degenerative disorders,” said Aghajanian, the paper’s coauthor.

“Depression is a neurodegenerative disease, and people long thought that it was very hard to reverse such a thing,” Aghajanian said. “That’s the amazing thing about ketamine — it reverses the changes within 24 hours.”

Ketamine is already FDA-approved as an anesthetic, which has led some doctors to begin prescribing it “off-label” to severely depressed or suicidal patients. This practice is concerning, Krystal said, because the drug is still in the experimental stages and has considerable risks, from potential abuse to side effects that may resemble schizophrenia. In addition, patients relapse after one to two weeks, losing the new synapses formed and the corresponding improvement in their depression. Research into the safety of re-administering the drug is still ongoing.

Aghajanian said researchers are now looking for safer alternatives to ketamine. These alternatives — several of which are currently in clinical trials — would hopefully follow the same pathway as ketamine but cause fewer side effects, he added. Another area for further development is the drug’s method of administration. Ketamine is currently administered intravenously, but future research will explore ways to deliver the drug orally or intra-nasally.

“All this work has really stimulated a back and forth between bench and bedside research around the world,” said Carlos Zarate, a researcher in the Mood and Anxiety Disorders Program at the National Institute of Mental Health (NIMH). “So that’s the exciting part — it’s actually luring industry back into psychiatry, at least on the depression side.”

Each year, major depressive disorder affects 14.8 million Americans over the age of 18 — 6.7 percent of the U.S. population, according to the NIMH.

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