From the Journals

Ketamine may be a viable alternative to ECT for severe depression



Electroconvulsive therapy (ECT) is the standard treatment for resistant depression, but results of 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 somebody is being referred for ECT, the treating clinician should think of offering ketamine first,” study investigator Amit Anand, MD, professor of psychiatry, Harvard Medical School, Boston, said in an interview.

The study was published online in the New England Journal of Medicine.

‘Preferred treatment’

More than one-third of cases of depression are treatment resistant, said Dr. Anand, who is also director of Psychiatry Translational Clinical Trials at Mass General Brigham. He noted that ECT has been the “gold standard for treating severe depression for over 80 years.”

Ketamine drug with syringe Julia Hiebaum/Alamy

He added that although ECT is very effective and is fast acting, “it requires anesthesia, can be socially stigmatizing, and is associated with memory problems following the 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 may be a viable alternative to ECT.

To date, no large, head-to-head trials have compared ECT to intravenous ketamine. A recent meta-analysis showed that ECT was superior to ketamine for major depression, but the total number of patients included in the analysis was small, Dr. Anand said.

In addition, most of the participants in that trial were drawn from a single center. Approximately 95 patients were enrolled in each arm of the trial, which included some participants with features of psychosis. “ECT is very effective for depression associated with psychotic features, which may be one reason ECT had a better response in that trial,” said Dr. Anand.

The investigators 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 either ketamine or ECT (n = 200 and 203, respectively; 53% and 49.3% women, respectively; aged 45.6 ± 14.8 and 47.1 ± 14.1 years, respectively).

Patients were required to have had an unsatisfactory response to two or more adequate trials of antidepressant treatment.

Prior to initiation of the 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 per week or ketamine (0.5 mg/kg of body weight) twice per week.

The primary outcome was treatment response, defined as a decrease of 50% or more from baseline in the16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16). Secondary outcomes included scores on memory tests and patient-reported quality of life.

Patients who had a response were followed for 6 months after the initial treatment phase.

More research needed

Following the 3-week treatment period, a total of 55.4% patients who received ketamine and 41.2% of patients who underwent ECT responded to treatment, which translates into a difference of 14.2 percentage points (95% confidence interval, 3.9-24.2; P < .001) – a finding that fell within the noninferiority threshold set by the investigators.

ECT was associated with decreased memory recall after the 3 weeks of treatment, with a mean (standard deviation) decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test–Revised of –0.9 (1.1) in the ketamine group vs. –9.7 (1.2) in the ECT group (difference, –1.8 points [–2.8 to –0.8]).

Remission, determined on the basis of QIDS-SR-16 score, occurred in 32% of the ketamine group and in 20% in the ECT group. Similar findings were seen on the Montgomery-Åsberg 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 investigators note.

During the 6-month follow-up period, there were differences in relapse rates between the groups (defined as QIDS-SRS-16 score > 11). At 1 month, the rates were 19.0% for those receiving ketamine and 35.4% for those receiving ECT. At 3 months, the rates were 25.0% and 50.9%, respectively; at 6 months, the rates were 34.5% and 56.3%, respectively.

ECT has been shown to be effective for older adults, patients with MDD and psychosis, and in inpatient and research settings. Future studies are needed to determine the comparative effectiveness of ketamine in these populations, the authors note.

Not life-changing

In a comment, Dan Iosifescu, MD, professor of psychiatry, NYU Langone Health, New York, called it an “extraordinarily important and clinically relevant study, large, well-designed, and well-conducted.”

Dr. Iosifescu, director of the clinical research division, Nathan Kline Institute, Orangeburg, N.Y., who was not involved with the study, noted that the study wasn’t powered to determine whether one treatment was superior to the other, but rather it assessed noninferiority.

“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 getting ketamine first because it is somewhat easier in terms of side effects and logistics and consider ECT afterwards if the ketamine doesn’t work.”

In an accompanying editorial, Robert Freedman, MD, clinical professor, University of Colorado at Denver, Aurora, noted that although “3 weeks of lightened mood is undoubtedly a gift ... the results of this current trial suggests that the 3-week treatment was not life-changing,” since effects had largely worn off by 6 months in both groups.

Longer-term treatment with ketamine “increases the likelihood of both drug dependence and cognitive adverse effects, including dissociation, paranoia, and other psychotic symptoms,” Dr. Freedman said.

He recommends that informed consent documents be used to caution patients and clinicians considering ketamine “that temporary relief may come with longer-term costs.”

The study was supported by a grant from PCORI to Dr. Anand. Dr. Freedman has disclosed no relevant financial relationships. In the past 2 years, Dr. Iosifescu has been a consultant for Axsome, Allergan, Biogen, Clexio, Jazz, Neumora, Relmada, and Sage. He has also received a research grant from Otsuka.

A version of this article first appeared on

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