Ketamine for Depression: Research versus Marketing

Bioethics in the News logoThis post is a part of our Bioethics in the News series

By Arthur Ward, PhD

Just weeks ago, the U.S. Food and Drug Administration approved Ketamine as the first new drug in decades for treatment of depression. Or rather, while the approval for psychiatric treatment was new, the drug itself has been around as an anesthetic since 1970. The story of why it took so long for this well-known and well-tested drug (millions of patients have received ketamine as anesthesia) reveals the complex interplay between medical practice, the economics of pharmaceuticals, and the challenges of research ethics. Ketamine and other psychoactive drugs hold a great deal of promise for the treatment of depression and suicidality, but we need to be measured in our approach. To that end, I recommend an accelerated pace of research, but a slower rate of FDA approval and therapeutic application until more is known about the long-term effects.

What is so special about ketamine? Traditional pharmaceutical treatments for depression such as SSRIs (selective serotonin reuptake inhibitors) work by increasing the levels of the neurotransmitter serotonin in the brain. Ketamine is totally different, acting instead on the neurotransmitter glutamate. While SSRI medications can take weeks or months to become effective, ketamine can sometimes be effective in hours. That is utterly remarkable and groundbreaking, especially given the urgent nature of a depressive crisis. Meta-analyses of recent clinical trials on short term use show clear promise, with as much as a 50% improvement over placebo after 72 hours.

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Yet there are reasons to think that Janssen’s esketamine nasal spray needs further research before responsibly coming to market. Double-blind randomized controlled clinical trials (RCTs) on psychoactive substances are very difficult to administer when the experimental drug has known mind-altering properties; in short, those that don’t hallucinate will know they’re in the control group! In the four Janssen phase-three clinical trials, all participants were on SSRI medication (it would not be ethical to give a depressed patient no treatment at all), the experimental group received esketamine nasal spray, while a placebo nasal spray was used in the control group. Despite adding an “embittering agent” to the placebo spray, the control group would likely have known they did not receive the esketamine (which is a hallucinogen), and thus a great deal of scientific rigor of the experiment was lost. In ongoing and future clinical trials, Janssen is using an “active placebo,” combining the placebo nasal spray with midazolam (a benzodiazepine sedative) so that the control group might think they took esketamine. While this would be an improvement in the blinding process, ketamine and midazolam do not feel the same: Midazolam a depressant while ketamine has psychedelic properties.

A second concern with the limited research so far has to do with the unknown long-term effects of ketamine use. Millions have experienced the anesthetic in a single dose, but the effects of long-term use are largely untested. The four clinical trials of Janssen’s esketamine nasal spray lasted only four weeks, and of these, only one showed significant results. Could it cause neurological damage long-term to take many repeated doses of esketamine? We don’t know, because the research hasn’t been done yet.

There are also cautionary signals of over-exuberance in therapeutic application that warrant vigilance. We must be mindful of pharmaceutical economics: capitalism craves returning customers. The market tends to reward expensive treatments for chronic conditions, and stifles cheaper treatments that effect a cure. For use as an anesthetic, Ketamine currently is generic and can be acquired quite cheaply. However, the FDA has only approved Janssen pharmaceuticals to release a nasal spray version of the drug, with esketamine, a closely related chemical. In doing so, the FDA grants esketamine patent protection – guaranteeing that treatment will be upwards of $500 a dose (the recommended treatment is eight doses over a month, totaling $4,720 to $6,785). This price is just for the drug alone, and not the accompanying office visit, which requires several hours of observation by a professional, adding extra expense. Granted, if one is freed from the burden and danger of crushing depression, this is well worth the price! And there are many credible anecdotes of ketamine treatment providing rapid, permanent relief. However, looking at the data, this long-lasting effect does not seem to be the norm. Instead, most people require sustained, periodic maintenance sessions every few weeks or months. This then raises the troubling question of whether we might be cultivating a financially crippling chemical dependence for some patients – rather than a cure.

My words of caution should not be interpreted as scolding or alarmist. I am a cheerleader for ketamine research. So far, the best evidence is that ketamine and esketamine are able to help some people who found little relief from other antidepressant treatments, and this is a wonderful turn of events. Alternatively, I think we should perhaps slow the pace of how quickly we bring ketamine drugs to market, but accelerate the related research. We need more clinical trials, and not just on ketamine, but on a variety of other psychoactive drugs as well! The culture wars of the 1960s resulted in the shuttering of promising research into LSD, psilocybin, and MDMA, all psychedelics well-recognized to have efficacy for depression treatment. After decades of lost time, clinical trials of all three chemicals are now underway. As the writer Michael Pollan has recently asserted in interviews and in his book, How To Change Your Mind, we are in the midst of a new renaissance of research into psychoactive chemicals. I suggest that we embrace this experimentation momentum, but simultaneously keep watch over our shoulder, both for possible long-term side-effects and for drug marketing’s problematic economic pressures.

Arthur Ward photoArthur Ward, PhD, is a teaching professor of History, Philosophy, and Sociology of Science in Lyman Briggs College at Michigan State University.

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References

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2 Responses to Ketamine for Depression: Research versus Marketing

  1. Leonard M Fleck says:

    Thank you for a very provocative essay. Here is one question or concern i have. What you describe (and what others seem to have described) sounds amazing, so much so that I can readily imagine lots of patients struggling with major depression demanding this of their physicians. The logic of their request might be this: Why should i have to suffer from my depression for possibly several months before I might get some degree of relief from one of the off-patent anti-depressants already on the market? How are physicians supposed to respond to such requests in such circumstances. Maybe that patient has tried only one anti-depressant which has only been marginally beneficial. Must they try several more before they would be allowed access to one of these drugs? There might also be a resource allocation issue. Ketamine treatment will cost much more than any off-patent anti-depressant. If an off-patent anti-depressant might work almost as well but take longer to achieve a therapeutic effect, does a patient still have a just claim at social expense to ketamine therapy, likely over a very prolonged period of time, just because that is what they want?

  2. Arthur Ward says:

    Len, thanks for the thoughtful question. I can think of a few angles here. The first thought is that in the early days of ketamine anti-depressive treatment, physicians won’t have a very broad body of evidence to know how ketamine will be tolerated by different patients, and so a sensible cautionary stance would recommend trying the more predictably safe SSRI drugs first. Sure, it will be frustrating for a patient to think that a possible quick-fix is being withheld, but prudence recommends trying the known-safe methods first. One exception to this advice might be someone who is acutely suicidal, in which case my own (non-clinical) instinct would lead towards trying the more experimental ketamine more quickly.

    There’s a more ponderous and bureaucratic answer to your question, though, that connects to the intricacies of research ethics. Ketamine is not approved for use in patients that are not ALSO on SSRI drugs. You have to be on SSRIs while you take ketamine (or esketamine). This is because in the design of the clinical trials, clinical equipoise wouldn’t permit a control group that is receiving no treatment (and it wouldn’t have been feasible or ethical to take someone off of SSRIs slowly in order to prep them to be in the experimental treatment group). So, we’ve actually never tested ketamine on people that weren’t also on SSRIs. That’s a roundabout reason why physicians wouldn’t at present be able to prescribe ketamine to someone who hadn’t tried standard SSRIs first.

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