Ketamine Shows Promise for Hard-to-Treat Depression in New Study

A new study suggests that, for some patients, the anesthetic ketamine is a promising alternative to electroconvulsive therapy, or ECT, currently one of the quickest and most effective therapies for patients with difficult-to-treat depression. The study is the largest head-to-head comparison of the two treatments.

Patients who don’t respond to at least two antidepressants — about one-third of clinically depressed patients — have a condition that clinicians refer to as “treatment-resistant.” Their options for relief are limited. Doctors typically recommend up to 12 sessions of ECT, which has a long-established efficacy, but is tainted by the stigma of historical misuse and frightening Hollywood images of people strapped to tables, writhing in agony. Today’s ECT is much safer and done under general anesthesia, but the procedure remains underutilized.

The study, published on Wednesday in The New England Journal of Medicine, found that ketamine, when administered intravenously, was at least as effective as ECT in patients with treatment-resistant depression who do not have psychosis. (For people with psychosis, ketamine, even in very low doses, can worsen psychosis-like symptoms.)

“The results were very surprising to us,” said Dr. Amit Anand, lead author of the study and a professor of psychiatry at Harvard Medical School who studies mood disorders at Mass General Brigham. His team had initially hypothesized that ketamine would be nearly as effective as ECT. Instead, Dr. Anand said, they found that ketamine performed even better than that.

This is significant in part because some patients are uncomfortable with ECT’s potential side effects, such as temporary memory loss, muscle pain or weakness. (In rare cases it can result in permanent gaps in memory.)

The study, which was sponsored by the Cleveland Clinic Foundation, shows that ketamine is easier to administer, with fewer adjustments during treatment and fewer patients dropping out, Dr. Anand said. “More importantly, it shows that ECT, as expected, is associated with memory problems, while ketamine is not.” Intravenous ketamine also has side effects, like dissociation, but this is “not usually an unpleasant experience for patients,” Dr. Anand said.

Earlier studies have shown that both treatments can be effective in patients with hard-to-treat depression, but that research has primarily looked at the two therapies independently. Dr. Roger S. McIntyre, a professor of psychiatry and pharmacology at the University of Toronto who is not affiliated with the study, called it “groundbreaking.”

“It’s this type of rigorous, randomized, real-world pragmatic data that is robust and very clinically meaningful,” Dr. McIntyre said.

The researchers randomly assigned intravenous ketamine or ECT to 365 patients. Nearly half received ketamine twice a week while the others received ECT three times a week. By the end of the three-week treatment, 55 percent of those in the ketamine group and 41 percent of the patients in the ECT group reported a 50 percent or greater reduction in symptoms.

Six months later, the quality-of-life scores for both groups were similar.

One limitation of the study was that the number of ECT treatments may not have been sufficient because the treatment period was only three weeks, said Dr. Daniel F. Maixner, the ECT program director at Michigan Medicine at the University of Michigan, who was not affiliated with the study.

The study subjects started their course of ECT by receiving electric currents on one side of the brain, which may require 10 or 12 sessions, as opposed to the nine used in the study, he added.

“If there’s more improvement to be had, you continue,” Dr. Maixner said.

Patients who start out bilaterally, stimulating both sides at the same time, often need fewer sessions. If the patients had completed more ECT sessions, then a greater proportion of them may have responded to the treatment, Dr. Anand said, but that also would have likely caused more side effects.

A small number of patients in both groups — under 33 percent — went into remission, meaning they had only mild depressive symptoms. This suggests that additional treatments would be needed in order for the patients to maintain any relief.

Continued treatment, however, comes with additional risks. With ketamine, for example, longer treatment “increases the likelihood of both drug dependence and cognitive adverse effects, including dissociation, paranoia and other psychotic symptoms,” Dr. Robert Freedman, a professor of psychiatry at the University of Colorado, wrote in an editorial published with the study.

Previous evidence suggests that ECT remission rates can be much higher — often at least 60 percent — but these studies may have included a higher percentage of inpatients as well as patients with psychotic depression, for which ECT appears to be particularly effective.

Researchers and clinicians are using intravenous ketamine off label because it has not been approved by the Food and Drug Administration for treatment of mood disorders, unlike its cousin esketamine, also known as Spravato, which is administered nasally. Among clinicians, intravenous ketamine is widely considered to be as effective or more so than esketamine for treatment-resistant depression, Dr. Anand said.

Unfortunately, because intravenous ketamine is a generic medicine, “it is unlikely that anyone is going to try to get F.D.A. approval for it to make it more reimbursable for insurers,” he added.

Later this year, Dr. Anand and his colleagues will recruit patients for a larger study comparing ECT to intravenous ketamine in 1,500 acutely suicidal and depressed patients, most of whom are likely to be inpatients. They will also look at how the effects differ by age groups, Dr. Anand said.

Dr. Maixner, at Michigan Medicine, said that research suggests that intravenous ketamine, which he has also used to treat patients, may have some emerging and strong benefits for hard-to-treat depression, which “gives people options.”