COMMENTARY

Ketamine in Psychiatry: Take Care

Jeffrey A. Lieberman, MD

Disclosures

February 06, 2015

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Hello. This is Dr Jeffrey Lieberman of Columbia University, speaking to you for Medscape. The title of my comments today could be called "The Ketamine Challenge, or When Practice Leapfrogs Science." The reason I want to address this is because we are in a time when, fortunately, there is an exciting new pharmacologic agent being used in the treatment of mental disorders, and that opens up a new pathway for future drug development.

I'm referring to the use of the agent ketamine, which has been used as an anesthetic previously for children with pediatric conditions and also for burn victims. It acts specifically by virtue of its blocking the activity of glutamate on the N-methyl-D-aspartate (NMDA) receptor.

Recent research pioneered by a variety of investigators from Dennis Charney and Carlos Zarate[1,2,3] and Sanjay Mathew[4,5,6,7] have demonstrated that people who have treatment-resistant depression for which all medications have failed—and in most cases electroconvulsive therapy too—can show a dramatic reversal of their symptoms in some cases, with even a single dose of ketamine.

This work has been extended to other disorders, and promising results have been seen with conditions like severe obsessive-compulsive disorder by virtue of the work of Caroline Rodriguez and Blair Simpson.[8,9] Now, this is cause for satisfaction and excitement, but it also raises some worrisome concerns. The reason for this is that ketamine—which has been repurposed to extend its uses beyond its traditional anesthetic and pain-relieving purposes to neuropsychiatric disorders—is a pharmacologic cousin to phencyclidine or PCP.

Now, you might remember that PCP was a drug that had a certain popularity in the late 1970s and 1980s as a recreational drug, a hallucinogen, which in many cases had catastrophic adverse effects. I can remember my own experiences as a resident in the emergency room seeing patients brought in who were wildly agitated and floridly psychotic under the intoxication of PCP. It is an agent that was used in veterinary medicine as an animal tranquilizer. PCP acts as an NMDA receptor antagonist, as does ketamine, but perhaps more potent. PCP, in addition to being psychotoxic, was shown in human and animal studies to have certain neurotoxic effects. So there is reason to be concerned about the potential toxicity of these pharmacologic agents.

Ketamine has been used safely for anesthetic purposes and is now being applied for treatment of refractory neuropsychiatric conditions, all of which is good, But because of the dramatic results in a very dire population (people with treatment-refractory mental disorders), the use of ketamine has really expanded before the research can define or answer all of the questions related to incorporating a new treatment agent into standard practice.

Innovative psychiatrists are responding to the pleas of patients to make treatment with ketamine available in one form or another. You have different ways in which it is being provided. But bare in mind that ketamine, which is approved by the US Food and Drug Administration for anesthetic purposes, is not available orally. It is only administrable in parenteral fashion.

Because ketamine is given as a single parenteral dose for anesthesia, the dosing parameters for psychiatric illness, which presumably require ongoing or maintenance treatment after acute treatment, haven't been fully worked out. If we are talking about something that is used as an anesthetic given parenterally, usually intravenously, can it be given in an office? Does it have to be given in a hospital? Do you have to have an anesthesiologist present? Can psychiatrists administer it? What is the appropriate dose to be used? What is the appropriate dosing interval if it needs to be repeated? These are questions that haven't been answered and are beginning to be, or are in the process of being studied.

Also, because an NMDA antagonism has been demonstrated as a therapeutic mechanism, many companies have begun to pursue a NMDA antagonist for an NMDA receptor as their goal for drug development. We hope to have agents available in the near future that are practically applicable to the treatment of psychiatric disorders by oral administration, with a longer duration of action—and with dosing that has been established. This is all in process right now. We don't know exactly when it's going to come to fruition.

I think the question now is, how do we safely utilize the finding that ketamine can be helpful for certain psychiatric conditions in the form that it's available in now? We must try to use the treatment as we can now, but in a very cautious and careful way so as not to overstep the level of our knowledge.

Using new treatments that have some potential risks and that aren't fully studied is not something unique to psychiatry. This has been done for many dire illnesses before. Probably the most dramatic application was for the AIDS epidemic. There was such an urgent need for treatments to forestall eventual mortality, that treatments were being applied even before they went through even the most rudimentary kinds of investigational testing. We also see it with other conditions—with cancers, with autism, with chelation therapy, and things of this sort. The most recent instance was with the outbreak of Ebola, when treatments that had barely been used needed to be rushed into service to try to stem this infectious disorder scourge.

It is understandable that there would be the same kind of rush to try a novel treatment that is effective even for the most refractory patients. But we always must do this cautiously, particularly in the area of psychiatry, where we have a bit of a notorious history to overcome. Remember malaria fever therapy; remember lobotomies; remember the use of LSD and how it spun out of control.

Ketamine has opened up a new therapeutic pathway for the treatment of depression and potentially other psychiatric disorders. But we must use it carefully and in a very professional and rigorous way now, while we are trying to extend our knowledge about the mechanism of action and trying to develop analog agents that have been more practically applied to the treatment of psychiatric disorders.

I'm Dr Jeffrey Lieberman from Columbia University, speaking to you today for Medscape. Please leave your comments below. Thank you for your attention.

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