Ketamine shows promise for hard-to-treat depression in new study

A new study suggests that for some patients, the anesthetic drug 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 head-to-head comparison of the two treatments.

Patients who fail to respond to at least two antidepressants — about one-third of clinically depressed patients — have a condition that clinicians call “treatment resistant.” Their lighting options are limited. Doctors typically recommend up to 12 sessions of ECT, which have long been proven effective but are tainted by the stigma of historical abuse and terrifying Hollywood images of people tied to tables, writhing in pain. Today’s ECT is much safer and performed under general anesthesia, but the procedure remains underused.

The study, published Wednesday in The New England Journal of Medicine, finds 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 at very low doses, can exacerbate psychosis-like symptoms.)

“The results were very surprising to us,” says 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 initially hypothesized that ketamine would be nearly as effective as ECT. Instead, said Dr. Anand, they found that ketamine performed even better than that.

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

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, said Dr. Anand. “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,” said Dr. Anand.

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

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

The researchers randomly assigned intravenous ketamine or ECT to 365 patients. Almost half received ketamine twice a week, the others 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 patients in the ECT group reported a reduction in symptoms of 50 percent or more.

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

A 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 subjects began their ECT course by receiving electrical currents on one side of the brain, which may have required 10 or 12 sessions, as opposed to the nine used in the study, he added.

“If there’s still more improvement to be had, keep going,” Dr. Maixner said.

Patients who start bilaterally and stimulate both sides at the same time often need fewer sessions. If the patients had completed more ECT sessions, a higher proportion of them may have responded to treatment, said Dr. Anand, but that would probably have caused more side effects as well.

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 are needed to allow patients to maintain some relief.

However, continued treatment carries 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,” wrote Dr. Robert Freedman, a professor of psychiatry at the University of Colorado, published an editorial with the study.

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

Researchers and clinicians use intravenous ketamine off-label because it is not approved by the Food and Drug Administration for the treatment of mood disorders, unlike its cousin esketamine, also known as Spravato, which is administered nasally. It is widely believed among clinicians that intravenous ketamine is as effective or more effective than esketamine for treatment-resistant depression, said Dr. Anand.

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

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

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

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