A Mystery Partly Solved: How the ‘Club Drug’ Ketamine Lifts Depression So Quickly

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Glass capsules containing ketamine

A new study sheds light on why the anesthetic and “club drug” ketamine can relieve depression rapidly — in hours, instead of weeks or months. The findings may help provide new targets for developing antidepressants and increase researchers’ understanding of the devastating disorder.

The study, published in the journal Nature, offer support for wider use of ketamine in depression and suggests new leads for scientists aiming to create fast-acting drugs with fewer side effects. A drug that could relieve depression quickly has long been sought by pharmaceutical companies and patients: for the 20 million Americans suffering from depression, the early weeks of treatment are a high-risk time for suicide, which kills nearly 35,000 people each year.

The new research involved numerous experiments in mice aimed at teasing out what happens to both brain and behavior when ketamine takes effect. In one such test, mice were forced to swim in a water-filled tube that they cannot escape. Previous research has shown that mice given antidepressants swim longer before giving up: a sign that the drugs are working.

The new study found that just one dose of ketamine produced the same effect in a half an hour — compared with the weeks or months this can take with standard antidepressants, in mice as well as in humans. Further, the new study found that the antidepressant effect of a single dose of ketamine lasted for a week.

(More on TIME.com: How a Study of a Failed Antidepressant Shows That Antidepressants Really Work)

“It’s a nice, elegant experiment,” says Carlos Zarate, chief of experimental therapeutics of the mood and anxiety disorders program at the National Institute of Mental Health and author of an early randomized trial of ketamine for depression. He was not associated with the study. “It’s very good work,” he adds.

The researchers, led by Lisa Monteggia, an associate professor of psychiatry at the University of Texas Southwestern Medical Center, also measured brain changes after animals underwent behavioral tests. Monteggia and her colleagues found that ketamine acted by increasing synthesis of BDNF, a nerve growth factor that supports the health of brain cells, helps them grow and can promote the development of new neurons.

Some researchers have previously theorized that all effective antidepressants ultimately act by promoting nerve cell growth, which would help explain the fact that although the drugs change neurotransmitter levels within hours, it takes much longer to lift mood. Nerve cells take time to grow, they argued, and that accounts for the delay. But the rapid action of ketamine shows that this certainly can’t be the whole story, whether or not the growth of new cells matters for long-term recovery.

Digging further, Monteggia’s group found that ketamine increases BDNF by deactivating a chemical called eEF2 kinase (also known as CAMKIII), which normally suppresses BDNF production. Consequently, when eEF2 kinase is inactivated, brain cells produce more BDNF.

“We know that ketamine can produce a fast-acting antidepressant response in treatment-resistant patients, but no one really knows how that works. What we found is a necessary pathway for ketamine to trigger [that response],” says Monteggia. “We’ve identified a novel pathway never before linked to any behavior, let alone an antidepressant response — that could be a novel drug target.”

That means drugs that inhibit or block eEF2 kinase could potentially work as antidepressants — ones that would take effect faster than any current medication and possibly without the “trippy” side effects that make ketamine desirable to some recreational users. Compounds like this currently exist.

“It sounds very, very exciting,” says Emery Brown, professor of computational neuroscience at MIT, who was not associated with the research. “If they’re correct, it most certainly could lead to new drug development. This is the first time I’ve heard of this possible mechanism.”

(More on TIME.com: Treating Depression: How Bright Light Can Help)

However, none of these compounds are currently on the market for any use and it’s not known what other kinds of side effects they might have, Monteggia says.

The implications of the research go beyond possible drugs based on eEF2 kinase. The research shows that ketamine acts on brain circuits that are constantly active “in the background” — cells that are activated not when you do something or have an experience, but that are always sort of humming along, no matter what else you are doing or thinking.

“That background stuff might not just be the background,” Monteggia says. “It might be important. The problem in mental illness may be a function of background neurotransmission.”

“This is bringing a whole new insight into how we might want to construct these types of drugs,” says Brown. “It could make us rethink how we approach this entire problem.”

Ketamine is already widely used in anesthesia and for pain treatment. But it is not yet widely available to the 5% of Americans over 12 who suffer severe depression, even though such “off-label” use is legally allowed.  rown and Zarate say that one reason may be that while anesthesiologists are comfortable using the drug, psychiatrists do not have much experience with it and may be scared about side effects.

However, with another recent study suggesting that ketamine may be useful for treating the depression associated with bipolar disorder as well, it could be time for some psychiatrists to offer compassionate use in people whose depression hasn’t responded to existing treatments.

(More on TIME.com: Drugging the Vulnerable: Atypical Antipsychotics in Children and the Elderly)

“In good hands and perhaps in a specialized clinic and with larger controlled trials, we can start to figure out how and when to use it,” says Zarate.

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