Ketamine shows promise for hard-to-treat depression in a 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 hard-to-treat depression. The study is the largest direct 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 doctors call treatment resistant. Their options for relief are limited. Doctors typically recommend up to 12 sessions of ECT, which has an established efficacy, but is tainted with the stigma of historic abuse and scary Hollywood images of people tied to tables, writhing in agony. Today\’s ECT is much safer and is performed under general anesthesia, but the procedure remains underutilized.

The study, published Wednesday in the New England Journal of Medicine, found that ketamine, when given intravenously, was at least as effective as ECT in patients with treatment-resistant depression who don\’t have psychosis. (For people with psychosis, ketamine, even in very low doses, can make psychosis-like symptoms worse.)

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

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

The study, sponsored by the Cleveland Clinic Foundation, shows 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, such as dissociation, but this is usually not 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 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 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. Nearly half received ketamine twice a week while the rest received ECT three times a week. At the end of the three-week treatment, 55% of those in the ketamine group and 41% of patients in the ECT group reported a 50% or greater reduction in symptoms.

Six months later, 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 enough because the treatment period was only three weeks, said Dr. Daniel F. Maixner, director of the ECT program at Michigan Medicine at the University of Michigan who was not affiliated with the study.

Study subjects began their course of ECT by receiving electrical currents to one side of the brain, which can take 10 or 12 sessions, up from the nine used in the study, he added.

If there\’s more improvement to be had, continue, Dr. Maixner said.

Patients who start bilaterally, stimulating both sides simultaneously, often need fewer sessions. If patients completed more ECT sessions, a higher proportion of them might have responded to treatment, Dr. Anand said, but that would also likely have caused more side effects.

A small number of patients in both groups below 33% went into remission, meaning they had only mild depressive symptoms. This suggests that further treatments would be needed for patients to maintain some relief.

Continued treatment, however, carries additional risks. With ketamine, for example, longer treatment increases the likelihood of both addiction and negative cognitive effects, including dissociation, paranoia and other psychotic symptoms, wrote Dr. Robert Freedman, a professor of psychiatry at the University of Colorado, in an editorial published with the studio.

Previous evidence suggests that ECT remission rates can be much higher, often at least 60%, but these studies may have included a higher proportion of inpatients and patients with psychotic depression, for whom ECT it seems to be particularly effective.

Researchers and doctors are using intravenous ketamine off label because it hasn\’t 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 nasally. Among clinicians, intravenous ketamine is widely considered as effective as or more than esketamine for treatment-resistant depression, Dr. Anand said.

Unfortunately, because intravenous ketamine is a generic drug, it\’s unlikely anyone will seek FDA approval 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 with intravenous ketamine in 1,500 depressed and acutely suicidal patients, most of whom are likely to be hospitalized. They will also look at how the effects differ across age groups, said Dr. Anand.

Dr. Maixner, of Michigan Medicine, said research suggests 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.

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