As with many other psychiatric drugs, the antidepressant effects of ketamine were discovered by accident.
In the late 1990s, Dennis Charney and John Krystal, then at Yale University, wanted to find a chemical probe that could help them explore what role the neurotransmitter glutamate might play in depression and alcoholism.
They settled on an anesthetic known as ketamine, which targets a brain receptor that glutamate normally interacts with. When they tried it, they found to their surprise that the patients suddenly started feeling much more optimistic. "We weren't expecting it to act as an antidepressant," said Dr. Charney, now the dean of the Icahn School of Medicine at Mount Sinai Hospital in New York. "But luckily we measured depression, and we saw that these patients were getting dramatically better in a couple hours and the effect lasted for a couple days."
A paper on ketamine's antidepressant boost was published in 2000, but then, Dr. Charney said, further research "went silent" for the next six years, partly because ketamine's brain effects were similar to those of the notorious street drug PCP, also known as angel dust, and because ketamine already was being used as a recreational drug called Special K.
In higher doses, ketamine produces mild hallucinations and a feeling of euphoria, which made it popular at raves and parties.
After Dr. Charney went to the National Institutes of Mental Health to head up mood disorders research programs, he worked to duplicate the original ketamine study, and when that was successful in 2006, he said, labs around the world began working to replicate the results.
The problem with ketamine so far, though, is that its effects only seem to last a couple of weeks, and then they fade away. That has triggered a wave of research at trying to find versions of ketamine, or similar drugs, that could sustain the antidepressant effect. It also has led to research trying to unravel what is going on in the brain to lift depression.
In a breakthrough paper in 2010, Yale researcher Ronald Duman and his team found that low doses of ketamine in rodents actually stimulated the growth of new synapses in the animals' frontal brain regions, while also reducing stress-related behaviors.
The same kind of synapse growth is seen in human beings when they learn new skills, he said in an interview last month, and it seems ketamine may be creating a similar impact in the brain's prefrontal cortex, which may help control overactivation of emotional centers in the brain. The growth of the synapses in the rat brains "occurred in a matter of hours," he said.
Scientists already knew that stress could destroy synapses in the same parts of the brain, and postmortem studies of the brains of people who had depression showed they had fewer synapses than others in the prefrontal cortex.
It appeared ketamine was allowing the brain to bounce back from that damage, said Mr. Duman, who grew up in Western Pennsylvania. Unfortunately, after several days, the new synapses disappeared and the antidepressant effects left along with them, like spring flowers in a cold snap.
Researchers are now focused on how to extend ketamine's effects, either by reformulating it or finding substitutes. Johnson & Johnson is developing a nasal spray version of ketamine that may have fewer side effects. Another Yale group is exploring a drug called Lanicemine, which targets the same receptors as ketamine. And the Duman group just published a paper showing that the anti-nausea drug scopolamine may have similar effects.
As that work continues in the lab, private clinics across the nation are giving ketamine to desperate patients. While it is not specifically authorized for depression, it is legally available for pain treatment, and many of the clinics dispensing it also handle patients with chronic pain.
Rather than criticize this "off-label" use, Dr. Charney said, his researchers have been inviting these clinic operators in to see how their patients have reacted. "They claim with intermittent ketamine doses, they've been able to maintain the [antidepressant] response."
Even though the drug has side effects, including brief periods of the same "zoned out" sensations that Special K provided, Dr. Charney said the benefits may be worth the risk. "We give chemotherapy for cancer and there are side effects with chemotherapy, but we give it anyway, because people need it to get better from cancer.
"Ketamine does not have the side effects chemotherapy does, yet we're using it for a disease that has a defined mortality; there is a suicide rate associated with severe depression."
Mr. Duman said ketamine is the most exciting new possible treatment for depression in decades.
"I've seen videos of people who have been sick for years and get a single dose of this and can't believe how good they feel," he said. "You're no longer feeling like you're totally worthless and you have nothing to live for -- all of a sudden all that's lifted."