The largest study to date confirms that ketamine — a “club drug” that is also legally used as an anesthetic — could be a quick and effective way to relieve depression.
The results were presented at the annual meeting of the American Psychiatric Association and represent growing excitement about ketamine’s potential. The study included 72 patients who had previously failed to respond to at least two other medications. After receiving a single intravenous (IV) dose of ketamine, 64% of patients reported fewer depression symptoms within one day compared to 28% of those given midazolam — an anesthetic drug that was used as a control.
“[This research] reports the largest controlled evaluation of the antidepressant effects of ketamine to date,” says Dr. John Krystal, professor of psychiatry at Yale, who published the first study in 2000 suggesting that ketamine could quickly lift depression, but was not associated with this trial.
Antidepressants typically take weeks to improve mood — and that’s a time when people with the disorder are at an especially high risk of suicide. “Among people who respond to antidepressants, it takes on average 7 weeks to produce this response,” Krystal says, “When simply getting through a single day can be difficult, waiting 7 weeks to get better can be daunting.” Ketamine— and similar drugs currently being tested by pharmaceutical companies could help relieve suffering faster and potentially reduce the suicide risk associated with the mood disorder.
And because the doses used were lower than those taken by clubbers or used in anesthesia, most patients didn’t have the extreme experiences of “out of body” sensations or profoundly distorted perceptions of reality. “Nobody freaked out,” says Murrough, adding that most described the experience of the infusion as being similar to having had a few drinks. About 10%, however, did have some dissociative effects. “One patient [reported] wondering whether time still existed during the infusion,” he says.
The results are especially noteworthy because ketamine was compared to another anesthetic with similar psychoactive effects, not just a placebo. Such comparisons are important because drugs that result in highly noticeable responses like sedation also tend to have strong placebo effects. Researchers had argued that without such a comparison, it would be difficult to tell whether ketamine was actually relieving depression.
“This design was elegant because midazolam briefly made patients feel better, but did not produce a real antidepressant effect,” Krystal says, “In contrast, ketamine produced the robust antidepressant effects that have been observed in every study of ketamine since our initial preliminary observations. This is the first direct evidence that the antidepressant effects of ketamine are specific, increasing our confidence in importance of this clinical observations.”
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Since the study has not been published, however, the results have not yet been subject to peer review. But Krystal and others are encouraged by the apparently lasting effects of the drug; the study showed that seven days after the infusion, 46% of those who received ketamine were still experiencing significant relief— compared to just 18% of those who received the midazolam.
The findings also follow about half a dozen smaller trials that tested the drug for depression or bipolar disorder. Murrough and his colleagues also published a study last year in Biological Psychiatry that could pave the way for broader use of the drug. In that analysis, his team examined whether ketamine could be used repeatedly for longer term results, perhaps as a replacement for, or addition to, electroconvulsive therapy (ECT). In that study, 24 patients with treatment-resistant depression who were not taking any other medications received several daily doses of ketamine; after 12 days, 71% of the patients showed a 50% reduction in depression symptoms, with relief typically coming within 2 hours of the treatment. On average, the patients who responded remained well for 18 days following the last infusion.
But because ketamine distorts consciousness, it likely would not be practical as a daily medication, as Prozac is currently used. In cases of profoundly disabling depression, however, it might be helpful if given several days a week, the way ECT is now prescribed. While ECT is the best existing treatment for cases of depression that do not respond to medication and therapy, the stimulation can interfere with memory and it requires general anesthesia. Murrough envisions ketamine could be administered in conjunction with talk therapy and in combination with other medications to try to maintain recovery.
In fact, since ketamine is already FDA-approved, some clinicians have started to offer infusions to their patients, but that’s not a practice that Murrough condones. “There are physicians carrying out this procedure in nearly every major American city,” Krystal notes, “[But] I think that ketamine infusion is still an experimental procedure.”
Indeed, Krystal’s colleagues recently reported some significant negative side effects in his trial of using ketamine to treat obsessive-compulsive disorder (OCD). Two of three participants who had OCD, who did not have current depression but had suffered from it in the past, developed new symptoms the day after ketamine treatment, which included suicidal thoughts, anxiety and severe distress.
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The researchers agree that while promising, ketamine-based therapy is probably still best conducted in an experimental setting— but that any clinicians who use it outside of research must, at the very minimum, carefully monitor patients. Krystal is planning to urge the National Institute on Mental Health to collect more data on all patients currently being treated for mental illness with ketamine. “The largest study of repeated ketamine administration ever published has only 24 patients in it,” he says, “This is an extremely thin and somewhat risky evidence-base to launch a national treatment program.”
With more data, however, researchers may become more confident in how best— and safely— to use the drug. And the latest study is an important first step toward that goal. “It seems that a new antidepressant approach has been identified that may expand the scope of effective antidepressant treatment,” Krystal says, “We look forward to larger and more definitive clinical trials that will help to determine whether more patients will be effectively treated through this mechanism and whether the possibility of rapid improvements in depression substantially reduces the burden of this disease.”