One Doctor's Ketamine Concern

Hello. This is Dr Jeffrey Lieberman of Columbia University in New York City, speaking to you for Medscape.

My comments today could be called, "When Clinical Practice Leaps Ahead of Research and Evidence." It's occasioned by the growing interest in utilizing the treatment ketamine for psychiatric disorders.

Ever since it was first researched by groups at Yale, the National Institute of Mental Health, and Mount Sinai School of Medicine, ketamine has proven a real boon to those with treatment-resistant depression. However, things have moved along at such an accelerated pace as to pose a concern—and, frankly, a real danger—to the field of psychiatry.

Our field doesn't need any more missteps. In the past we've suffered from a lot of unfounded theories and ineffective or harmful treatments. This has given us what could be called a checkered or notorious history, which thankfully we resoundingly emerged from in the latter part of the 20th century on a wave of scientific research. We now have an array of treatments for most mental disorders that are effective, safe, and make huge differences in peoples' lives. However, we can't afford to shoot ourselves in the foot again and undermine the credibility that has been slow and hard won, and of which many people are still skeptical.

Questionable Ketamine Clinics

What pushed my button was receiving an email from a colleague to whom I referred a patient suffering from depression. The colleague was updating me on the patient's history and progress, and noted that he was going to be referring the patient for ketamine treatment which was to be administered by a private center called the Ketamine Treatment Centers of America. This particular clinic was operated by a physician who had retrained in psychiatry from another field of medicine at an advanced age.

When I looked at the proposed treatment protocol, I saw that the patient was going to receive a course of up to 12 treatments in a relatively short period of time. That clearly raised a red flag in my mind, in terms of what the standard research supports regarding the prudent way to use ketamine.

About the same time I was looking at the clinic's website, by coincidence or fate, I received an email from the Ketamine Treatment Centers of America. It was inviting me to attend a dinner meeting in one of the various cities in which this was being offered. [At the event] they would personally describe the benefits of ketamine and how they use it. Obviously, this was a solicitation for me to refer patients to them.

The principals in this organization are a psychiatrist who trained at American University but has no particular academic expertise, and an anesthesiologist who is early in his career and has no particular expertise in psychiatry. They work alongside psychiatrists to administer ketamine, which, as you know, has previously been used as a dissociative anesthetic. They recommend that this treatment be considered for a variety of disorders—not just treatment-resistant depression, but also anxiety, post-traumatic stress disorder, obsessive-compulsive disorder, and pain disorders, including fibromyalgia. I think this is really problematic.

Waiting for the Evidence to Arrive

When we in medicine see new advances, treatments, and technologies, there is certainly a tendency to leap on the bandwagon. It's one thing to do that with a new technological advancement (eg, robotic surgery) and to use it at greater expense but not necessarily knowing whether it provides any incremental benefit and efficacy. Surgeons have certainly done this, and there doesn't seem to be a downside other than cost.

Ketamine is different. The research is still ongoing to see what it safely provides in terms of rapidity of recovery and any added benefit in efficacy. It's a dissociative anesthetic which acts as an uncompetitive antagonist at the N-methyl-D-aspartate (NMDA) glutamate receptor. This receptor has been studied in a variety of contexts and it is known that it can mediate something called excitatory neurotoxicity if stimulated too much or too frequently.

Probably the most scholarly and informative publication about the current state of ketamine treatment for depression and other mental disorders was published in the April 2017 issue of JAMA Psychiatry by Gerard Sanacora and colleagues.^[1] It was initiated at the behest of the American Psychiatric Association to give clinicians an understanding of what we currently know and how it should be used. It's a very prudent and scholarly communication.

There's a companion paper^[2] in the same issue from Drs Charles Zorumski and Charles Conway of the Washington University School of Medicine in St. Louis, Missouri. The significance of this report coming from Washington University is that this is where some of the first studies took place that elucidated the pharmacology of the glutamate NMDA receptors and what their potential benefits and risks are in terms of utilizing different pharmacologic compounds to modulate them. These classic studies showed that too much activation of NMDA receptors could produce toxicity resulting in cell process ablation and possibly even cell death. In their commentary, the authors write that "there is little doubt that ketamine is having a major effect on psychiatry" and should be used. However, while the science is being elucidated, it should be used prudently and very cautiously.

Basic science studies that are being done indicate that it may not even be ketamine acting at the glutamate receptor which is producing the therapeutic antidepressant effect. It may be that ketamine is a prodrug, and it is a metabolite of ketamine that is producing the therapeutic effect at a different receptor, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid class of glutamate receptors.

Proceed With Caution

This is a work in progress, and for clinicians to engage in this kind of reckless application and leaping ahead of evidence is very, very dangerous, in my opinion. I'm very sorry to have to say that it's not just that people are being overzealous in their application of what they think might be a panacea, but it's driven by the profit motive. When you have treatment centers distributed in different cities soliciting referrals of people through the same kind of promotional activities for which the pharmaceutical companies were dinged by conflict of interests, criticisms, and governmental panels of inquiry in the past, this is just bad.

When you then see that many of the principal proprietors of these for-profit entities are physicians in mid or late career who retrain in order to leap on what may be a profitable gravy train, it really doesn't pass the smell test. I certainly wouldn't be sending my patients to these places unless they were thoroughly vetted and I could be assured of their competence and the fidelity of their principal motivations.

It's imperative that we bear in mind that when a potential breakthrough innovation comes about that can mean all the difference in the world for some patients in whom existing therapies haven't worked, we must manage their application in a responsible, professional way that doesn't endanger [patients] or the reputation of our field.

I recommend that you read the consensus statement by Dr Sanacora^[1] and the accompanying editorial^[2] in the April 2017 JAMA Psychiatry. And if you receive solicitations for these companies like I did, I would not go for a free meal in order to hear their pitch, but decline because it's not prudent practice and the last chapter on this story hasn't yet been written. Hopefully, it'll end in a way that is positive and helpful without causing any injury to people in the meantime. Until we know all that we need to about these treatments, they have to be administered in an extremely careful way and according to what the evidence that we are in possession of currently supports.

Thank you for listening. This is Dr Jeffery Lieberman, speaking to you for Medscape.

The views and opinions expressed in this article are those of the author and do not necessarily reflect the views and opinions of Medscape.

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