Ketamine for Treatment-Resistant Depression: A Better Alternative to ECT? (Podcast)

Dr. Amit Anand shares his journey from a 1990s discovery to an ongoing randomized trial

Ketamine may be a more desirable alternative to electroconvulsive therapy (ECT) for treatment-resistant depression. It seems to work fast — similar to ECT — even decreasing suicidal ideation, says Amit Anand, MD, Vice Chair for Research in Cleveland Clinic’s Center for Behavioral Health.

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In the newest episode of Cleveland Clinic’s Neuro Pathways podcast, Dr. Anand shares details about the five-year, 400-patient, multicenter randomized trial he’s leading to compare the two treatments.

“The question we are trying to answer is: Will a patient referred for ECT get equally better if they receive ketamine instead?” he says. “And even if they get a little less better, is ketamine still worthwhile because it doesn’t cause memory problems, doesn’t require anesthesia and most of the time is a more pleasant experience compared to ECT?”

During the podcast, Dr. Anand also discusses:

  • How best to define “treatment-resistant depression”
  • How depression therapy has evolved in recent decades
  • His memories as part of the team that discovered ketamine’s antidepressant effects in the 1990s
  • Use of intranasal esketamine

Click the player below to listen to the podcast now, or read on for a short edited excerpt. Check out more Neuro Pathways episodes at or wherever you get your podcasts.

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Excerpt from the podcast

Dr. Anand: Ketamine for depression was found through serendipity. Ketamine is a derivative of phencyclidine (PCP), which was thought to be an anesthetic agent initially, but it caused psychosis. Ketamine was developed as a similar anesthetic that caused milder psychedelic experiences or psychosis.

At Yale, scientists were studying the effects of ketamine in healthy subjects. They were trying to make a model of psychosis or schizophrenia by giving intravenous ketamine. This use in psychiatry was with subanesthetic doses, now 0.5 mg/kg over 30 to 40 minutes, not high enough to put somebody to sleep. Because it was given as an infusion, subjects would have mild psychedelic experiences. The researchers were trying to use other medications to decrease the psychosis and use it as a model for developing treatments for schizophrenia.

At the time, I was in the mood disorders group at Yale. There was some indication that NMDA antagonists may have some antidepressant properties. Medications like amantadine were around at that time. There was some evidence that they had some mood-elevating effects.

The researchers therefore thought, “Let’s try out ketamine in depressed patients.” Originally people were skeptical. We had a bit of a hard time getting it through the regulatory system, but we finally got it. A colleague of mine, Angela Cappiello, an Italian psychiatrist who had just come to the U.S., did the first study. I still remember, she came to our group and said, “It’s pretty amazing. I gave ketamine to this depressed person. It’s been three days, and he’s saying he’s not depressed at all.” So we started a small study of about eight to 10 patients.

There were a lot of other medications, like amphetamines, which could cause euphoria and other things, but with ketamine we gave one dose and then at least for seven days, subjects reported, “I don’t have depression anymore.”

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Usual antidepressants took four to six weeks or more to act. We thought we had found something that could work very fast, just like electroconvulsive therapy.

However, as I said, the duration of the antidepressant effects of a single infusion was about seven days. After seven days, the person relapsed back into depression. It was still a short period of alleviation of depression — more than the immediate effect of a stimulant like amphetamine, but not as much as usual antidepressants, which if taken for a longer term have an effect for many months or years.