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  • Ketamine Loudoun

The brain on ketamine

"Had no major side effects compared to

electroconvulsive therapy, considered the ‘gold

standard’ treatment"

In a clinical trial of 403 patients, Massachusetts General Brigham investigators found

that 55 percent of those who received ketamine treatment experienced a sustained

improvement in depressive symptoms without major side effects.

The new MGB-led study compared subanesthetic intravenous ketamine to

electroconvulsive therapy (ECT) for the treatment of non-psychotic, treatment-resistant

depression. The results are published in the New England Journal of Medicine.

“ECT has been the gold standard for treating severe depression for over 80 years,” said

Amit Anand, director of Psychiatry Translational Clinical Trials at Mass General Brigham

and professor of psychiatry at Harvard Medical School. “But it is also a controversial

treatment because it can cause memory loss, requires anesthesia, and is associated

with social stigma. This is the largest study comparing ketamine and ECT treatments for

depression that has ever been done, and the only one that also measured impacts to


Major depressive disorder (MDD) is a leading cause of disability worldwide and is

estimated to affect 21 million adults in the U.S. ECT involves inducing a seizure via

electrical stimulation of the brain. Ketamine is a low-cost dissociative drug approved by

the Food and Drug Administration as a sedative/analgesic and general anesthetic.

Previous studies have suggested that low doses of the drug may have rapid

antidepressant effects for people with MDD.

The trial was conducted from March 2017 to September 2022 at five sites with 403

patients randomized one-to-one to receive either ECT three times per week or ketamine

twice per week for three weeks. Patients were followed for a period of six months after

treatment and responded to a depressive symptom self-assessment questionnaire,

which also included memory tests and questions about quality of life.

This is the largest study comparing ketamine and ECT treatments for

depression that has ever been done, and the only one that also measured impacts to


The researchers found that 55 percent of those receiving ketamine and 41 percent of

those receiving ECT had at least a 50 percent improvement in their self-reported

depressive symptoms and an improvement in their self-reported quality of life that lasted

throughout the six-month monitoring period. ECT treatment was associated with memory

loss and musculoskeletal adverse effects. Ketamine treatment was not associated with

side effects other than an experience of transient dissociation at the time of treatment.

The current study is the largest-to-date real-world comparative effectiveness trial of ECT

vs. ketamine. The trial took a patient-centered approach, with three types of

independent depression ratings (patient, rater, and clinician) captured and no active

solicitation of participants.

“For the ever-growing number of patients who do not respond to conventional psychiatric

treatments and need a higher level of care, ECT continues to be the most effective

treatment in treatment-resistant depression,” said psychiatrist Murat Altinay, lead of the

trial site at Cleveland Clinic. “This study shows us that intravenous ketamine was not inferior to ECT for treatment of nonpsychotic treatment resistant depression and could

be considered as a suitable alternative treatment for the condition.”

The authors note that their findings are based on self-reported outcomes and that the trial’s open-label design could have influenced response rates. But its patient centeredness and real-world design may also be a strength, allowing the findings to be

more easily translated into clinical practice.

Anand’s team is now working on a follow-up study comparing ECT and ketamine

treatments for patients with acute suicidal depression to see if the same promising

impact is found in that population.

“People with treatment-resistant depression suffer a great deal, so it is exciting that

studies like this are adding new options for them,” said Anand. “With this real-world trial,

the results are immediately transferable to the clinical setting.”

This study was funded by the Patient Centered Outcome Research Institute (TRD-1511-

33648) and sponsored by the Cleveland Clinic.

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