Rave Drug "Special K" Holds Promise for Treating Depression Fast

Companies and clinicians turn to ketamine to treat mental-health disorder as pipeline of new drugs dries up

January 8, 2015 |By Sara Reardon and Nature magazine

Used clinically as an anaesthetic in animals and humans, ketamine has proved an extremely effective treatment for depression, bipolar disorder and suicidal behaviour. 
Credit: kzenon/Thinkstock

Ketamine, a psychoactive ‘party drug’ better known as Special K, has pharma­ceutical companies riding high. Used clinically as an anaesthetic in animals and humans, it has proved an extremely effective treatment for depression, bipolar disorder and suicidal behaviour.

It also works incredibly fast. Unlike conventional antidepressants, which generally take weeks to start working, ketamine lifts depression in as little as two hours. “It blew the doors off what we thought we knew about depression treatment,” says psychiatrist James Murrough at Mount Sinai Hospital in New York City.

Companies are racing to develop patentable forms of the drug, and researchers are battling to understand how it affects the brain. An increasing number of clinicians are prescribing ketamine off-label for their patients, even as some of their colleagues worry that too little is known about its long-term effects.

The excitement over ketamine shows how badly new depression drugs are needed, says Thomas Insel, director of the US National Institute of Mental Health (NIMH) in Bethesda, Maryland. Many drug companies have closed their mental-health divisions in the past five years, and there have been no significant advances in medication for depression in decades.

Today’s most common antidepressants target the brain’s serotonin or noradrenaline pathways (some target both). Ketamine blocks the signalling molecule NMDA, a component of the glutamate pathway, which is involved in memory and cognition. Before ketamine was studied, no one even knew that the pathway was involved in depression, Murrough says.

In 2013, his group published the largest trial of off-label ketamine carried out so far, with 73 participants. The trial found that the drug reduced depression 24 hours after treatment in 64% of patients who had tried three or more other medications with unsuccessful results. A second group received the sedative midazolam; in that case, the reduction was 28% (J. W. Murroughet al. Am. J. Psychiatry 170, 1134–1142; 2013). Murrough’s group is now imaging the brains of patients receiving ketamine treatment to try to dissect just how the drug works.

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He already prescribes ketamine off-label for some patients, and guesses that dozens of physicians across the country do the same. At therapeutic doses, it often produces a dissociative, out-of-body sensation that lasts less than an hour. At higher doses, recreational users report experiencing a ‘K-hole’, a deeply disoriented state accompanied by vivid hallucinations.

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Last month, a company called Naurex, based in Evanston, Illinois, released results from a 386-person trial showing that its own ketamine-like drug, GLYX-13, successfully treated depression in about half of patients, without hallucinatory side effects. Roche of Basel, Switzerland, is also expected to release results early this year from a 357-person trial of a drug called decoglurant, which targets the glutamate pathway.

It is unclear why ketamine’s psychoactive effects are considered a drawback, Sisti says. He questions the ethics of making patients pay more for a patented, non-dissociative drug if unmodified ketamine works just as well.

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