In what signals relief and hope for clinically depressed patients, a recent study suggests that ketamine could be a promising alternative to electroconvulsive therapy, or ECT, being easier to administer and minus ECT’s associated memory loss.
The study is the largest head-to-head comparison of the two, reports The New York Times.
Patients who don’t respond to at least two antidepressants – about one-third of sufferers – are what clinicians refer to as “treatment-resistant”. Their options are limited. Typically, doctors 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 anaesthesia, but the procedure remains under-utilised.
The study, published in The New England Journal of Medicine, found that the anaesthetic 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,” 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 hypothesised that ketamine would be nearly as effective as ECT. Instead, 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 shows that ketamine is easier to administer, with fewer adjustments during treatment and fewer patients dropping out, 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”, he added.
Earlier studies have shown that both treatments can be effective in patients with hard-to-treat depression, but research has primarily looked at the two therapies independently.
In this particular study, 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% of those in the ketamine group and 41% of the patients in the ECT group reported a 50% 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 Maixner, ECT programme 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,” 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 may have responded to the treatment, Anand said, but that also would have probably caused more side effects.
A small number of patients in both groups – under 33% – went into remission, meaning they had only mild depressive symptoms. This suggests additional treatments would be needed for the patients to maintain any relief.
Continued treatment, however, has 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 Robert Freedman, a professor of psychiatry at the University of Colorado, in an accompanying editorial.
Previous evidence suggests ECT remission rates can be much higher – often at least 60% – 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 US Food and Drug Administration (FDA) 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, Anand said.
Unfortunately, because intravenous ketamine is a generic medicine, “it is unlikely anyone is going to try to get FDA approval for it to make it more reimbursable for insurers”, he added.
Later this year, Anand and 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.
Study details
Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression
Amit Anand, Sanjay Mathew, Gerard Sanacora, James Murrough, Fernando Goes, Murat Altinay, Amy Aloysi, Ali Asghar-Ali, Brian S. Barnett, Lee Chang, Katherine Collins, Sara Costi, et al.
Published in New England Journal of Medicine on 24 May 2023
Abstract
Background
Electroconvulsive therapy (ECT) and subanaesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain.
Methods
We conducted an open-label, randomised, non-inferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The non-inferiority margin was −10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period.
Results
A total of 403 patients underwent randomisation at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the non-inferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test–Revised, −0.9±1.1 in the ketamine group vs. −9.7±1.2 in the ECT group; scores range from −300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation.
Conclusions
Ketamine was non-inferior to ECT as therapy for treatment-resistant major depression without psychosis.
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