Electroconvulsive therapy (ECT) is the gold standard treatment for resistant depression, but results from a new randomized head-to-head trial suggest intravenous ketamine is at least as effective and has fewer side effects.
“The take-home message right now is that if someone is being referred for ECT, the treating physician should think about offering ketamine first,” said study researcher Amit Anand, MD, professor of psychiatry, Harvard Medical School. , Boston, Mass Medscape Medical News.
The study was published online on May 24 The New England journal of medicine.
More than a third of depression cases are resistant to treatment, said Anand, who is also director of Psychiatry Translational Clinical Trials at Mass General Brigham. He noted that ECT has been the “gold standard for the treatment of major depression for over 80 years.”
He added that although ECT is very effective and fast-acting, it “requires anesthesia, can be socially stigmatizing and is associated with memory problems after treatment.”
An anesthetic agent, ketamine has been shown to have rapid antidepressant effects and does not cause memory loss or carry the stigma associated with ECT, he added. For these reasons, the investigators examined whether it could be a viable alternative to ECT.
To date, no large head-to-head studies have compared ECT with intravenous ketamine. A recent meta-analysis showed ECT was superior to ketamine for major depression, but the total number of patients included in the analysis was small, Anand said.
Also, most of the participants in that trial came from a single center. Approximately 95 patients were enrolled in each arm of the study, which included some participants with features of psychosis. “ECT is very effective for depression associated with psychotic features, which may be one reason why ECT had a better response in that trial,” said Anand.
The researchers compared ECT to ketamine in a larger sample that excluded patients with psychosis. They randomly assigned 403 patients at five clinical sites in a 1:1 ratio to receive ketamine or ECT (n = 200 and 203, respectively; 53% and 49.3% women, respectively; ages 45.6, 14.8 and 47.1 and 14.1 years, respectively).
Patients were required to have had an unsatisfactory response to two or more adequate trials of antidepressant treatment.
Before the start of assigned treatment, 38 patients withdrew, leaving 195 in the ketamine group and 170 in the ECT group.
Treatment was administered over a 3-week period, during which patients received either ECT three times a week or ketamine (0.5 mg/kg body weight) twice a week.
The primary outcome was response to treatment, defined as a 50% decrease from baseline in the 16-item Quick Inventory of Depressive Symptomatology-Self-report (QIDS-SR-16). Secondary outcomes included memory test scores and patient-reported quality of life.
Patients who had a response were followed up for 6 months after the initial phase of treatment.
More research is needed
After the 3-week treatment period, a total of 55.4% of patients receiving ketamine and 41.2% of patients undergoing ECT responded to treatment, which translates into a difference of 14.2 points percentages (95% CI, 3.9 ± 24.2; P <.001) a result that fell within the non-inferiority threshold set by the investigators.
ECT was associated with a decrease in memory recall after 3 weeks of treatment, with a mean (SD) decrease in the Hopkins Verbal Learning TestRevised Delayed Recall T-score of -.9 (1.1) in the ketamine group compared with -9.7 (1.2) in the ECT group (difference, -1.8 points [-2.8 to -.8]).
Remission, as determined by QIDS-SR-16 score, occurred in 32% of the ketamine group and 20% of the ECT group. Similar results were seen on the Montgomery-Sberg Depression Rating Scale.
Both groups showed significant improvements in quality of life, with changes of 12.3 and 12.9 points, respectively, on the 16-item quality of life scale.
“ECT was associated with musculoskeletal adverse events, whereas ketamine was associated with dissociation,” the researchers note.
During the 6-month follow-up period, differences in recurrence rates were found between groups (defined as QIDS-SRS-16 score >11):
|Month||Ketamine group||ECT group|
ECT has been shown to be effective for the elderly, patients with MDD and psychosis, and in hospital and research settings. Future studies are needed to determine the comparative efficacy of ketamine in these populations, the authors note.
It doesn’t change life
Commenting for Medscape Medical NewsDan Iosifescu, MD, professor of psychiatry, NYU Grossman School of Medicine, New York, called it an “extraordinarily important and clinically relevant study that was large, well designed and well conducted.”
Iosifescu, director of the clinical research division, Nathan Kline Institute, who was not involved in the study, noted that the study was not powered to determine whether one treatment was superior to the other, but rather assessed non-inferiority.
“The main point of this study is that the two treatments are largely equivalent, although numerically, ketamine was slightly associated with more beneficial outcomes and fewer cognitive side effects,” he said.
The findings suggest “that people who have no contraindications and are candidates for both ketamine and ECT, which is the vast majority of people with treatment-resistant depression, should consider taking ketamine first because it is a bit easier in terms of side effects and logistics and consider ECT later if ketamine doesn’t work.”
In an accompanying editorial, Robert Freedman, MD, clinical professor, University of Colorado, Denver, noted that although “3 weeks of lightened mood is undoubtedly a gift…the results of this current study suggest that the 3-week treatment it wasn’t life-changing,” as the effects had largely worn off within 6 months in both groups.
Long-term treatment with ketamine “increases the likelihood of both drug addiction and adverse cognitive effects, including dissociation, paranoia and other psychotic symptoms,” Freedman said.
It recommends that informed consent documents be used to warn patients and physicians considering ketamine “that temporary relief may come with long-term costs.”
The study was supported by a grant from PCORI to Anand. Other authors’ revelations are listed in the original article. Freedman disclosed no relevant financial relationships. For the past 2 years, Iosifescu has been a consultant for Axsome, Allergan, Biogen, Clexio, Jazz, Neumora, Relmada and Sage. He has also received a research grant from Otsuka.
N English J Med. Published online May 24, 2023. Abstract, Editorial
Batya Swift Yasgur, MA, LSW is a freelance writer with a consulting firm in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books, as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoirs of two brave Afghan sisters who told their story).
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