MAPS (Multidisciplinary Association for Psychedelic Studies) has a long article explaining the history of ketamine and it's use in treating depression. A very worthwhile read. Ketamine Stirs Up Hope—and Controversy—as a Depression Drug
IN THE 1950S, a physician at Montefiore Medical Center in the Bronx made a prescient discovery. He found that a tuberculosis drug called cycloserine had the unanticipated side effect of lifting patients' moods. (It also caused convulsions and hallucinations in some.) The antibiotic, scientists would later discover, blocked glutamate receptors. This was perhaps the first evidence that the glutamate system might be important in depression.
Forty years later, scientists at the University of Mississippi found that people who'd committed suicide—arguably the end result of a battle with severe depression—had abnormalities in their NMDA receptors compared to controls of the same age. At the same time, researchers were zeroing in on this receptor subtype in rodent models of depression. In 1990, Phil Skolnick, a scientist at the National Institutes of Health, discovered that when he treated animals with drugs that dampened NMDA receptor activity, they fared better in stressful tests, indicating an antidepressant-like effect.
SSRIs had just come on the market and while many hailed them as a godsend, it remained puzzling why they took so long to work. Skolnick's research again implicated the glutamate system. In animals treated with SSRIs, serotonin went up immediately, but it was only when the activity of their NMDA receptors became suppressed that the antidepressant effect emerged.
These observations suggested that maybe serotonin didn't matter in depression so much as glutamate. They also implied that SSRIs weren't working quite the way many scientists thought they did. Yes, they increase serotonin, "but that by itself is not sufficient. And it's not necessary either," says Skolnick, who's now chief scientific officer at Opiant Pharmaceuticals. Perhaps targeting the glutamate pathway directly could yield a faster-acting antidepressant.
What's remarkable about the story of ketamine is that, despite knowing that the glutamate system might be important in depression by the 1990s, and despite having drugs on hand, like ketamine, that targeted NMDA receptors, no one investigated the possibility in people for years. When scientists at Yale finally tested ketamine on depressed people in the late 1990s, their primary goal was seeing how the drug might affect perception and the ability to think. Seven depressed patients received intravenous ketamine infusions. The researchers were surprised when every patient's mood improved quickly and dramatically.
The results seemed so over-the-top that even Dennis Charney, one of the study's senior scientists and now dean of the Icahn School of Medicine at Mt. Sinai in New York City, didn't quite believe them. Neither did anyone else, he thinks. No one replicated the research—until, in 2006, when Charney, by then at NIMH, teamed up with researcher Carlos Zarate and repeated it. Of 17 patients treated, 12 improved within a day compared to a placebo group, which saw no response. Five saw their depression completely disappear for the duration of the study.
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