SAN FRANCISCO — When it came to improving treatment-resistant major depression in outpatients without psychotic features, ketamine worked just as well as electroconvulsive therapy (ECT), the ELEKT-D randomized trial found.

Following a 3-week treatment period, 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a treatment response, a 14.2% difference (95% CI 3.9-24.2) that fell well within the trial’s noninferiority threshold (P<0.001), reported Amit Anand, MD, of Brigham and Women’s Hospital in Boston, and colleagues.

Response was defined as a 50% or greater drop from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16).

The results were presented at the American Psychiatric Association (APA) annual meeting and simultaneously published in the New England Journal of Medicine.

“That ketamine was noninferior was in itself surprising, as ECT is the gold standard for 80 years for treatment of resistant depression,” Anand told MedPage Today. “And actually, ketamine’s effectiveness, in the aggregate results, looks a bit better than ECT for major depression not associated with psychotic features.”

“However, our starting hypothesis and study design was to find whether ketamine was noninferior to ECT,” Anand explained. “So in the paper, we cannot comment on ketamine’s superiority compared to ECT for treatment of non-psychotic resistant depression.”

In an accompanying editorial, Robert Freedman, MD, of the University of Colorado School of Medicine in Aurora, pointed out that “[i]t is noteworthy that all the patients who were considered for trial entry were initially referred for ECT because they and their clinicians thought that ECT was their best option.”

Similar findings were seen when looking at treatment response measured by at least a 50% decrease in Montgomery-Åsberg Depression Rating Scale (MADRS) score. This was achieved by 50.8% of ketamine-treated patients and 41.1% of ECT patients.

Remission of depression measured by the QIDS-SR-16 (score of 5 or less) was achieved by 32.3% of the ketamine group and 20% of the ECT group. When remission was measured using MADRS score (score of 10 or less), this was achieved by 37.9% of the ketamine group and 21.8% of the ECT group.

Both treatment methods yielded significant improvements in patient-reported quality of life, which was one of the secondary trial outcomes. Measured using the 16-item Quality-of-Life Scale, the ketamine and ECT treatment groups saw changes of 12.3 and 12.9 points, respectively.

At the end of treatment, memory function was lower in the ECT group compared with the ketamine group (difference 1.1 points lower, 95% CI 0.9-1.2). This also included a decline from baseline in delayed-recall score for the ECT group. Fewer ketamine-treated patients also reported cognitive symptoms than the ECT group at the end of the treatment phase.

Ketamine Before ECT?

“The study is important for both ECT and ketamine treatment for treatment-resistant depression,” Anand added. “First, it shows that ECT in day-to-day outpatient treatment of resistant depression is not as effective as reported in research studies, which have mainly included inpatient populations or not made the distinction. It also shows that ketamine can be at least as effective and can be a treatment option before a person goes for ECT treatment.”

“It also shows that even patients who are resistant to multiple antidepressant treatment trials have about a 50% chance of getting much better with either treatment that will improve their quality of life,” he pointed out.

A total of 25.1% of the ketamine group and 32.4% of the ECT group experienced at least one moderate or severe adverse event during treatment, though no deaths occurred during the trial. More ECT patients experienced muscle pain or weakness, while more ketamine-treated patients experienced dissociative symptoms. Four of the 200 ketamine-treated patients reported new suicidal ideation versus six of the 203 patients in the ECT arm, and one patient in the ketamine-treated group had a suicide attempt during follow-up.

Participants were recruited at one of five trial sites: Baylor College of Medicine in Houston, Johns Hopkins Medical Institute in Baltimore, Cleveland Clinic Lutheran Hospital, Mount Sinai School of Medicine in New York City, and Yale University School of Medicine in New Haven, Connecticut.

Pointing out that these are “leading clinical centers” in the U.S., Anand said that in “other places where there may not be that many resources, ECT may be given less rigorously and possibly have even lower response rates.”

Trial Details

The open-label trial randomized 403 patients with non-psychotic treatment-resistant major depression to either ketamine or ETC. The average age was 46 and the average baseline MADRS and QIDS-SR-16 scores were 32 and 18, respectively. A small percentage of both groups had previous ECT (11.5% of the ketamine group and 10.3% of the ECT group) and prior ketamine treatment (7% and 3.9%). For the primary endpoint, the statistical design allowed for a 10% lower rate of response in the ketamine arm.

During the 3-week treatment phase, ketamine patients were treated twice per week via IV at a subanesthetic dose of 0.5 mg/kg of body weight over a 40-minute period, which was modified if needed. In IV form, ketamine is only FDA approved as a sedative, analgesic, and general anesthetic. Esketamine (Spravato) nasal spray is approved alongside an oral antidepressant for treatment-resistant depression.

ETC patients were recommended to receive three sessions per week, specified as right unilateral ultra-brief pulse at six times the seizure threshold determined at the first visit, but modified subsequently if needed.

About 93% of both treatment groups completed full treatment. Ketamine dosing was kept constant in nearly all patients, but 39% of ECT patients changed from right unilateral to bilateral treatment.

After the 3-week treatment phase, patients who had a treatment response were followed up for another 6 months. During this time, relapse occurred in 19.0% of the ketamine group and in 35.4% of the ECT group at month 1 and in 34.5% and 56.3%, respectively, by month 6.

Freedman commented that this 6-month follow-up wasn’t very long. Another trial limitation was that the researchers didn’t look for future drug-seeking behavior among the ketamine receivers.

“Patients in an ECT-referral clinic may seem to be an unlikely nidus for a wave of drug addiction, but even in this trial, treatment with ketamine was continued during the 6-month follow-up period in 41% of the participants who had been assigned to receive ketamine in the initial 3-week treatment phase,” he noted.

Freedman suggested that as a longer duration of treatment could increase the chance of dependence and side effects like dissociation and paranoia, ketamine receivers should be thoroughly cautioned about potential downsides to treatment.

Anand said “the next steps are to do comparative effectiveness of ECT versus ketamine in other treatment settings and populations where ECT is recommended as the only option.”

“One [study] is depression associated with acute suicidal thoughts and behaviors,” he said. “Other steps are to develop new treatments, which work like ketamine but have fewer side effects and do not have an addiction potential.”

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