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Is Ketamine the Next Big Thing for Depression?


I was going to write about the Stop Online Piracy Act and why such a law would be bad for freedom of expression and for the collective mental health of the Internet, but ketamine got in the way.

It’s been a few years since I first heard about the use of i.v. ketamine leading to instant relief of depression symptoms, relief that lasts longer than the ketamine does. It sounds like a miracle cure. Dr. William B. Lawson wrote a Commentary about the drug here in Clinical Psychiatry News, and a subsequent news article about an open-label pilot study also was published here by CPN. This week I’ve been hearing about it nearly daily, especially on National Public Radio (NPR).

While turning to Google and PubMed to examine the latest evidence, I am simultaneously wondering why I’ve not heard of anyone I know using it to treat depression. After all, ketamine is a Food and Drug Administration-approved drug, and thus can be used off-label. It is available as an oral drug, which I know mostly because “Special K” has been used as a rave drug for years. And people are out there with treatment-resistant depression who could benefit from it if the risks are not too high. Note: The dose used for depression is only 1/10th (0.5mg/kg) of the common hallucinogenic dose used on the street (350 mg according to Erowid.)

As it turns out, ketamine has been featured on many of NPR’s various shows over the past week. Jon Hamilton’s story on Morning Edition features a man who has had numerous medications to treat his major depression, which he rattled off. “Klonopin, Ativan, Valium, Xanax, Remeron, Gabapentin, Buspar, and Depakote.” I actually heard this story in the car and thought to myself that only one of those eight drugs is actually considered to be an antidepressant. That’s one of the problems we face: inadequate depression treatment. Either the wrong drug (Xanax) or the wrong dose (50 mg of Zoloft).

Neal Conan on NPR’s Talk of the Nation did a whole show about ketamine this week. The transcript is worth reading (or listening to). This most recent blast of publicity about ketamine is likely fueled by Dr. Carlos A. Zarate Jr.’s recent article in Biological Psychiatry using ketamine in a double-blind, placebo-controlled trial with 15 people who have severe bipolar depression. Seventy-nine percent had a “rapid and robust antidepressant response,” while placebo had no effect.

While ketamine’s effects could be related to its glutamate receptor antagonism, another potential mechanism has been invoked. The mammalian target of rapamycin (mTOR) is activated by ketamine, and preventing its activation also prevents the antidepressant effects (at least, in animals). See this 2010 full-text review by Zarate et al. on possible ketamine mechanisms of action in depression.

Anyway, Dr. Zarate, of the National Institute of Mental Health, is featured in some of the NPR stories, and he thinks that ketamine’s tendency to induce hallucinations will prevent it from being widely used for depression. But, until we have another FDA-approved NMDA antagonist to use, there are surely many people “living with the black dog” who would gladly risk a bad trip to cut the dog’s leash. A Yale study used open-label ketamine for acute depression with suicidal ideation in the ER. Which makes me wonder how many psychiatrists reading this article have tried using ketamine on their patients, or how many patients out there have tried it, whether in its prescribed or illicit form. Comment here or on Shrink Rap to let us know.

<[QM]—Steven Roy Daviss, M.D., DFAPA

Dr. Daviss is chair of the department of psychiatry at the University of Maryland’s Baltimore Washington Medical Center, chair of the APA Committee on Electronic Health Records, co-chair of the CCHIT Behavioral Health Work Group, and co-author of Shrink Rap: Three Psychiatrists Explain Their Work, published by Johns Hopkins University Press. He is found on Twitter @HITshrink, at, and on the Shrink Rap blog.

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