The Ketamine Challenge

When practice leaps ahead of science.

Posted Dec 21, 2014

When is an experimental treatment ready for prime time ? The growing popularity of ketamine as a treatment for mental disorders has posed this question and created an interesting challenge for clinicians, patients and policy makers. The drug, an anesthetic that has traditionally been prescribed for pediatric patients undergoing minor surgical procedures and burn victims, has been used over the last few years for severe difficult to treat cases of mental disorders such as depression and obsessive compulsive disorder (OCD). And its use is on the rise. At the same time, because of its mind bending and euphoriant effects, ketamine has also found favor as a recreational or “club drug” that many refer to as “Special K.”

Ketamine is related to the drug phencyclidine, more commonly known as PCP. Both medications act by blocking the excitatory effects of the neurotransmitter glutamate, which is integral to information processing and memory formation in the brain.  PCP was a popular recreational hallucinogen in the late 1970’s and 80’s before the medical community recognized its toxicity and understood the severe, and sometimes, psychotic reactions it caused.

I vividly remember my own experience, as a psychiatric resident, seeing desperate, maniacal patients intoxicated with PCP brought into the emergency room by police or ambulance. Many were wildly agitated and completely detached from reality. Even the most potent medications seemed to have no effect on them. Most were recreational users who, through their abuse of PCP, had developed psychotic behaviors as a result of the drug.

Research has shown that PCP and Ketamine do have genuine therapeutic uses, but a narrow therapeutic index. This means that the difference in the dose of the drug at which it will produce therapeutic (beneficial medical) effects and that at which it will cause adverse or toxic effects, is very small. So if too much is taken, the drug can result in adverse, and potentially disastrous, consequences. There is a fine line between a medicinal substance producing salutary and toxic effects.

When research with ketamine first showed dramatic therapeutic potential in alleviating the symptoms of depression which had resisted all approved forms of treatment (psychotherapy, antidepressant medications, even electroshock therapy-ECT), desperate patients began to seek and demand the treatment, and clinicians were eager to utilize it.  But the question is how can this new therapeutic option be best applied to serve patients in a beneficial way as we continue to learn about its potential and its consequences.

Ketamine is usually given by injection in single doses. Yet the conditions for which it is used (depression, OCD, etc.) require ongoing and often life long therapy. The dosing intervals for ketamine, to maintain improvement in patients, are not yet understood. Although the results of research with ketamine appear promising, we must determine what the consequences are of repeated administrations and long-term use. We need to know how much and how often.

The pressure to use promising new treatments for clinical purposes before they have been fully tested is not unique to psychiatry or ketamine. And it’s not hard to understand this pressure or the urgency. People are suffering from disabling and often life threatening conditions, and they want—and deserve—appropriate treatment. We have experienced the same phenomenon with treatments for AIDS/HIV in the late 1980’s, treatments for cancer over the last half- century, and recent responses to the devastating Ebola outbreak in Africa.

I believe that we must translate new research findings as rapidly as we can into treatments to improve patients’ lives, but we must be cautious about moving too quickly to apply therapies we don’t completely understand into clinical practice. We must resist the temptation and pressure, and be deliberate and careful. In mental illness, as in every form of human disease, we must stay true to our oldest and most essential principle: primum non nocere. First, do no harm.