Ketamine Noninferior to Electroconvulsive Therapy for Treatment-Resistant Depression


New prospective data show more adult patients achieved clinical response with ketamine than the historic standard ECT over a 6-month regimen.

Ketamine Noninferior to Electroconvulsive Therapy for Treatment-Resistant Depression

Amit Anand, MD

Credit: Boston University

Intravenous ketamine may provide similar benefit to electroconvulsive therapy (ECT) for treatment-resistant major depression, according to data from the ELEKT-D clinical trial program.1

In findings from a team of US investigators, a subanesthetic dose regimen of 0.5 mg/kg of the rapid-acting N-methyl-D-aspartate receptor antagonist ketamine provided noninferior benefit to the historically standard ECT in treatment response in patients with treatment-resistant major depression without psychosis.

The outcomes implicate potentially greater use for the once-controversial therapy, which has been approved by the US Food and Drug Administration (FDA) as a sedative, analgesic and general anesthetic.

“Ketamine is an attractive alternative for patients because it does not require general anesthesia and is not associated with clinically significant memory impairment,” investigators wrote. “However, ketamine is a schedule III medication with liability for potential abuse. Because treatment with ketamine can lead to transient changes in perception and thinking, it is mainly used in patients with treatment-resistant major depression without psychotic features.”

Led by Amit Anand, MD, of the department of psychiatry at Brigham and Women’s Hospital and Harvard Medical School, investigators sought compare the efficacy of ECT and subanesthetic intravenous ketamine in patients with treatment-resistant depression. They noted that, though the antidepressant drug class is robustly available in the US market, their efficacy is suboptimal in approximately one-third of the estimated 21 million American patients.

“ECT has a track record of nearly 80 years as one of the most effective and rapid strategies for treatment-resistant major depression,” they wrote. “However, ECT remains underused owing to limited availability, social stigma, and concerns regarding the adverse effect of cognitive impairment.”

Anand and colleagues’ prospective, open-label, randomized, noninferiority trial was designed to address concerns regarding ketamine and lessen the gap in clinical evidence for its use in major depression. The team conducted a 3-week initial treatment phase of either twice-weekly ketamine or 3 times weekly ECT to patients at 1 of 5 clinical sites. Following the initial treatment phase, patients who reported a clinical response to care were followed for a 6-month period during which thy received ketamine or ECT regimens as defined by their physician.

The team conducted follow-up visits at months 1, 3, and 6, seeking a primary outcome of treatment response defined as ≥50% decrease from baseline in 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16). The patient-reported assessment gauges status of depressive symptoms on a scale ranging from 0 – 27, with greater scores indicating greater depression.

To interpret ketamine’s noninferiority to ECT, investigators set a margin of -10 percentage-point change in QIDS-SR-16. Key secondary outcomes from the assessment included memory test and patient-reported quality of life scores.

The trial recruited 403 patients randomized 1:1 at the 5 clinical sites; patients were generally in their late 40s, with a body mass index of approximately 30. Nearly 90% were White. Approximate mean age at first major depressive episode onset was 19 years old; patients and a median 5 previous episodes of major depression at the time of the trial.

Investigators reported 55.4% of patients receiving ketamine reported a clinical response, versus 41.2% of those receiving ECT (difference, 14.2; 95% CI, 3.9 – 24.2; P <.001 for noninferiority). In the secondary outcome, ECT was associated with a decreased memory recall after 3 weeks compared to ketamine. Both treatment arms reported improved quality of life versus baseline scores.

Regarding adverse events, patients receiving ECT were more likely to report musculoskeletal effects (5.3%), while patients receiving ketamine were more likely to report gastrointestinal events (6.7%) or headaches (8.2%).

Interestingly, the supportive noninferiority findings come only 1 month after clinical data suggested ECT significantly improved the mean rate of major depressive episodes in patients versus ketamine.2

“However, the advantage is small, and therefore, for many patients, especially those who want to be protected against cognitive risks, a trial of ketamine may be worth considering before a trial of ECT,” investigators wrote at the time.

Indeed, Anand and colleagues concluded that their latest contribution to the ketamine psychiatric field suggests a narrow advantage for the subanesthetic drug over its staple competitor agent—though with more questions to be answered.

“The current trend in the United States is for ECT to be administered on an outpatient basis to patients with treatment-resistant major depression,” investigators wrote. “ECT is recommended as being highly effective for rapid treatment of late-life, catatonic, and suicidal depression. Future studies will need to be conducted to determine the comparative effectiveness of ketamine and ECT in older patients, patients with bipolar depression, and in emergency inpatient settings.”


  1. Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression [published online ahead of print, 2023 May 24]. N Engl J Med. 2023;10.1056/NEJMoa2302399. doi:10.1056/NEJMoa2302399
  2. Walter K. Electroconvulsive Therapy Bests Ketamine in Treating Major Depressive Episodes. HCPLive. Published April 12, 2023. Accessed May 27, 2023.
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