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Ketamine for Treatment-Resistant Major Depressive Disorder

In patients referred for electroconvulsive therapy (ECT) for treatment-resistant major depression without psychosis, subanesthetic intravenous ketamine was noninferior to ECT for reducing depressive symptoms by 50%, researchers report. “The decline in memory performance appeared to be greater with ECT than with ketamine at the end-of-treatment visit, but the results were similar in the two trial groups at the 1-month follow-up visit,” the authors write. “Both ketamine and ECT appeared to be associated with improved quality of life immediately after the initial treatment phase.”

The open-label, randomized, noninferiority ELEKT-D trial included 403 patients referred to ECT clinics at 5 clinical sites for treatment-resistant major depression without psychosis. Assignment to ECT 3 times per week or ketamine 0.5 mg/kg over 40 minutes twice weekly had these effects on a primary outcome of ≥50% decrease 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(scores range from 0 to 27, with higher scores indicating greater depression): “After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients.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 noninferiority 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.”

Editorial: “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,” writes an editorialist. “A longer duration of treatment increases the likelihood of both drug dependence and cognitive adverse effects, including dissociation, paranoia, and other psychotic symptoms. ECT clinics have informed consent documents that list the various cognitive and other adverse effects of that treatment. A similar informed consent document for ketamine should caution patients and clinicians that temporary relief may come with longer-term costs.”

Source: New England Journal of Medicine