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 fastest and most effective therapies for patients with difficult-to-treat depression. The study is the largest direct comparison of the two treatments.

Patients who do not respond to at least two antidepressants: about one third of clinically depressed patients: have a condition doctors refer to as “treatment resistant.” Your relief options are limited. Doctors usually recommend up to 12 ECT sessions, which has a long-established efficacybut is tainted by the stigma of historical misuse and scary hollywood images of people tied to tables, writhing in pain. Today’s ECT is much safer and is performed under general anesthesia, but the procedure remains underused.

The study, published Wednesday in The New England Journal of Medicine, found that ketamine, when administered intravenously, is 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.)

“We were very surprised by the results,” said Dr. Amit Anand, the study’s lead author 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 almost as effective as ECT. Instead, Dr. Anand said, they found that ketamine worked even better than that.

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

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

Previous studies have shown that both treatments can be effective in patients with difficult-to-treat depression, but that research has mostly 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 kind of real-world, randomized, rigorous pragmatic data that is robust and highly clinically significant,” said Dr. McIntyre.

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

Six months later, the quality of life scores of 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 Daniel F. Maixner, MD, director of the ECT program in Michigan Medicine at the University of Michigan. , who was not affiliated with the study.

Study subjects began their ECT course by receiving electrical currents to 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 are more improvements, keep going,” Dr. Maixner said.

Patients starting bilaterallystimulating both sides at the same time, often need fewer sessions. If the patients had completed more ECT sessions, then a higher proportion of them might have responded to the treatment, Dr. Anand said, but that would also likely have caused more side effects.

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

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

previous evidence suggests that remission rates for ECT may be much higher, often at least 60 percent, but these studies may have included a higher percentage of hospitalized patients and patients with psychotic depression, for whom ECT appears to be particularly effective.

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

Unfortunately, because IV ketamine is a generic drug, “it’s unlikely that anyone would try to get FDA approval to make it more reimbursable to insurers,” he added.

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

Dr. Maixner, of Michigan Medicine, said the research suggests intravenous ketamine, which he has also used to treat patients, may have some strong emerging benefits for difficult-to-treat depression, “providing options for people”.