But while the potential benefits are similar and ketamine is easier to administer than ECT, the addiction risks of long-term ketamine treatments are not well established, leading some doctors to urge caution. “It’s a matter of risk assessment for each individual patient,” said Boris Heifets, who studies ketamine at Stanford University and was not involved in the new research. “None of these things are risk-free, nor is they transformative.”
The findings, presented Wednesday at the meeting of the American Psychiatric Association and published in the New England Journal of Medicine, showed that intravenous ketamine was “non-inferior” to ECT. Patients randomly assigned to take ketamine twice a week for three weeks actually had slightly better results: 55.4% responded to treatment. That compared to a 41.2% response rate for those who had ECT three times a week during the same period.
The study, with 403 participants, was significantly larger than previous ketamine comparison studies; a meta-analysis of these smaller studies, published last year and focusing on major depression rather than treatment-resistant depression, found that ECT had better outcomes. But the new paper is both more powerful and arguably aimed at sicker patients, enrolling only those with major depression without psychosis who failed to respond to SSRIs, providing strong evidence of ketamine’s equivalence to ECT. Ketamine, a long-lasting sedative, has gained popularity in recent years as a treatment for depression.
The implications of the findings are “enormous,” said Patrick Oliver, medical director of MindPeace’s ketamine clinics, who has been investigating the drug as a treatment for depression but was not involved in the study. Although it was structured to show “non-inferiority,” he said the data suggests ketamine worked better than ECT.
“I would say without a doubt that this should change the practice of interventional psychiatry,” Oliver said, moving ketamine from last to first choice for patients who don’t respond to SSRIs. That said, he added, neither result is great. “We’re on a C-minus.”
Others, however, have been more cautious about future use of ketamine, pointing to its addictive potential. ECT, which is performed while the patient is under general anesthesia, is hardly risk-free, as it has been shown to cause cognitive impairment, including long-term memory loss. Ketamine, on the other hand, is known to be addictive, although the exact risks have not been well researched. With no regulation or more data, some worry that the widespread use of ketamine could lead to another addiction epidemic like the opioid crisis.
“The follow-up period of the current study was not long, nor did it evaluate future drug-seeking behavior among those who responded or did not respond to ketamine,” Robert Freedman, a professor of psychiatry at the University of Colorado Denver School of Medicine, wrote in a NEJM editorial published in conjunction with the study. “We must remember that only a minority of physicians were responsible for the oxycodone epidemic.”
Amit Anand, lead author of the study and director of psychiatry translational clinical trials at Mass General Brigham, said there was minimal evidence of addictive potential, especially at the trial’s subanesthetic dose of 0.5 milligrams per kilogram of body weight. “I don’t think there is any hard data that people misuse,” he said. “But we have to take it into account.”
However, in the study, 41% of the participants who were required to take ketamine continued to do so over a six-month follow-up period. “That’s a warning to me,” Heifets said, adding that it’s not a short-term treatment “we fix you and you’re done.” “This is a subscription model.”
Both ketamine and ECT work quickly for patients in acute need, which is extremely valuable for an emergency situation. But Anand agreed that the long-term use of ketamine has not been well studied. “The challenges with ECT and ketamine are, you can have an acute response, but how do you actually maintain it?”
Ketamine, popular in higher doses as the “Special K” party drug, can also cause bladder damage in some patients.
Freedman called for detailed informed consent, while Heifets said there should be regulations on how the medication is dispensed and those taking ketamine on a long-term basis should be carefully monitored. Both warned of lessons to be learned from the opioid crisis. “Why do we think ketamine will be different? If you ignore risk and expand access as aggressively as possible, we’ll be in the same place 10 years from now,” Heifets said. “Ketamine is not oxycodone. But it does have a liability for misuse. Even if it’s relatively modest, if you give it to enough people, the math is staggering.”
That said, these concerns must be weighed against ECT’s potential for amnesia. ECT is associated with long-term cognitive problems, including permanent memory loss, in some patients. Patients in the study temporarily had worse memory after ECT treatment, but improved during the six-month follow-up. They were also more likely to experience musculoskeletal side effects, while dissociation was reported as a side effect in patients receiving ketamine.
Ketamine is not approved as a treatment for depression, despite evidence for its effectiveness; the drug is generic, meaning there is no financial incentive for a drug manufacturer to assume the cost of submitting ketamine to the Food and Drug Administration for approval. Instead, esketamine, a modified version of ketamine patented by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, has been approved as a treatment for depression. This drug costs more but, unlike ketamine, may be covered by insurance.
The study’s author, Anand, agreed with Oliver’s view that ketamine could be tried before ECT. “There’s an equal chance you’ll get better with ketamine,” he said. The results are strong enough, he said, to prompt insurers to consider covering ketamine, despite the lack of FDA approval.
That would give patients and doctors more options. “It becomes a matter of which side effects you’re more comfortable with,” Heifets said. “None of these treatments are perfect.”