Few FDA approved drugs have a reputation as controversial as Ketamine. This reputation is well earned. Originally developed in the 1960s as a short-acting anesthetic for battlefield use, in recent decades it has become notorious as a date-rape drug (‘Special K’)*, a club drug (‘Vitamin K’) and for its use in veterinary medicine (‘horse tranquilizer’).
However, I venture to bet that Ketamine is about to be rehabilitated for legitimate human uses. Here is why.
The reason for this belief is a most severe crisis in mental health and our approach to treating mental illness. It is not polite to say this, but given the gravity of the situation it needs to be said: It’s not working out. Not really.
Certainly a strong statement, but this sobering reality is becoming increasingly apparent. Every year, upwards of 10 million people experience a major depressive episode in the US alone. The number of people who never see a professional – and are thus never diagnosed – is likely much higher. Each of these episodes can be expected to last for months to years and is characterized by utter misery; a substantial number is terminal (the number of suicides in the US outnumbers the number of violent non-self gun deaths by about 3:1). Currently available “antidepressants” (a term I would use only in quotation marks, as most struggle to beat placebo except for the most extreme cases and might appear statistically more effective than they actually are) – these days usually a selective serotonin reuptake inhibior (SSRI) – can be expected to help one in ten people, and only after a trial period of 4 weeks to several months. Of course, if the depression happens to coincide with an underlying bipolar tendency, treatment with an SSRI will likely trigger a dysphoric mania. In other words, one will never reach the end of the interval that the SSRI needs to take to work (if it ever does). Instead, one will – at best – need to be hospitalized. So-called “treatment resistant depression” (in reality, depression that didn’t respond to treatment with a few SSRIs or SNRIs as MAO-inhibitors and tricyclics have largely fallen out of favor due to their side effect profile) is either allowed to take its course (with devastating consequences for the individual) or treated with electroshock therapy (ECT). ECT is remarkably effective in addressing this kind of depression, but the “side effects” (more aptly called treatment effects) like deleterious memory loss are a steep price to pay.
This state of affairs is obviously unacceptable. The good news is that it is increasingly being recognized as unacceptable. The National Institute of Mental Health (NIMH) recently announced that it would no longer fund research based on diagnostic criteria as outlined in the DSM. Psychiatric disorders are the only medical conditions that – for historical reasons – are diagnosed entirely based on subjectively reported symptoms. Doing this for any other condition, e.g. cancer or infectious diseases would obviously be absurd. Molecular biology has seen to that. In the 21st century, this simply will no longer do and the NIMH is essentially willing to start over from scratch.
Enter Ketamine. When Ketamine was used as a battlefield anesthetic in Vietnam and the first Gulf war, it was anecdotally noted that wounded soldiers such treated developed far fewer cases of PTSD than soldiers with similar injuries that were treated with other anesthetics. A couple of years ago, systematic studies showed that the vast majority of patients suffering from major depressive disorders made a rapid recovery when given a low, sub-anesthetic dose (most studies show a dose of 0.5 mg/kg to be effective) of Ketamine.
The clinical effectiveness of Ketamine in these scientific reports sounds too good to be true, particularly when compared with anything else on the market. The effects take hold within days (if not hours, compared with weeks to months for SSRIs), they seem to work for most people, there seem to be few discernible side effects (bladder issues seem to be a concern, but mostly at “recreational” doses and frequency of use) in stark contrast to – for instance – ECT), and it seems to be equally effective in the treatment of bipolar depression (which is notoriously hard to treat).
So what is the catch? Given the crushing disease burden inflicted by major depressive disorders, the question why this treatment is not readily available arises immediately.
The issue does not seem to be primarily medical in nature. Ketamine *is* a dissociate anesthetic, so the immediate effects on the conscious experience are rather extreme. Based on reports from people who have received low sub-anesthetic doses of Ketamine, the Kantian a priori categories of space and time seem to unravel shortly after the injection. They report that it becomes obvious that shared reality is a construct – brought about by the normal operation of the brain – but that Ketamine suspends this normal construction process, allowing for different reconstructions of reality. At higher doses, the reports speak of “leaving flatland” and becoming aware of higher dimensional objects that only appear to be separate when projected onto a low-dimensional space (such as the one we commonly perceive). Whether these experience reports sound scary or intriguing, there is no question that these experiences do not last very long. Given the short half-life of Ketamine and depending on individual metabolism and route of administration (IM or IV), these dissociative effects last for an hour or two, not longer.
One of the most remarkable figures I’ve ever seen. Dissociative symptoms over time. x-axis is nonlinear. Differences at all time points other than the 40 minute mark are not significant. Adapted from Diazgranados, Nancy, et al. “A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.” Archives of general psychiatry 67.8 (2010): 793.
It is also reassuring that the patients could *answer* the CADSS, so they couldn’t have been too far gone. Intriguingly, while there was no significant difference between placebo and ketamine group except for the 40 minute mark, *all* the mean scores of the placebo group seem to be slightly above the ketamine group. The CADDS features items like: “Do objects look different than you would expect?”. It is not inconceivable that, the experience properly calibrated the scale of the Ketamine group.
Obviously, there are no studies on long term effects in humans at this point, but similar studies on monkeys are encouraging. Animals which had received similar doses for long periods of time on a daily basis show that the dose has to be relatively high and the period of time relatively long to demonstrate impairment. Moreover, the doses involved in the treatment of pain are usually considerably higher, without reports of long term ill effects. To be clear: *Any* potential neurotoxicity is obviously cause for serious concern. However, all medical decisions involve tradeoffs. Depression in itself is increasingly linked to neurotoxicity. Moreover, the spectre of neurotoxicity can lurk where one least expects it, e.g. from antibiotic treatments. In addition, Ketamine seems to potentially *reverse* depression (or stress) induced brain damage via synaptogenesis. The moral of the story is that one should not embark on a course of medical treatment unless the expected upside (far) exceeds the expected downside.
Of course, there is a rub. More than one, actually. The two biggest and uncontested issues seem to be unclear mechanism of action as well as sustainability.
The first issue is that we do not really know or understand how Ketamine seems to bring about its antidepressant magic. Many theories are currently being explored in active research. Some of the hottest trails are NMDA antagonism, neurogenesis and dentritic sprouting. Personally, I believe there might be something to the notion that one is “growing a prefrontal forest”, strengthening prefrontal networks that are in turn able to better quench aberrant activity originating in evolutionary older structures (amygdala, limbic system, etc.) One way or the other, glutamate seems to be involved. While it may sound unsettling that we do not understand the mechanism of a treatment, this situation is far from unique. As a matter of fact, we do not understand the mechanism of action of *any* anesthetic drug. Similarly, there is plenty of evidence that even SSRIS don’t work the way we thought they do. There is mounting empirical support for the notion that the Serotonin action is largely incidental, and that neurogenesis is really behind their therapeutic effects.
The second issue – that of sustainability – is more serious. Curiously, the effects don’t seem to last. While Ketamine can rapidly pull someone out of a serious depression, the depression seems to return in time, requiring a “booster” shot to banish the demons again, even for a short while. The time until relapse is different from individual to individual, ranging from weeks to months, but it is intriguing that there is a time constant at all.
However, there are many chronic diseases that require daily administration of medications, including injections. In this regard, Ketamine isn’t even all that different from most other antidepressants, which are – more often that not – a pretty permanent deal. Many have to keep taking them, for fear of relapse. The real issue why these treatments are not more readily available seems to be economic in nature.
Ketamine is an extremely cheap drug, as it has been off patent for almost 40 years. Put differently, there is no money to be made here. The FDA is tasked with protecting the public from harmful treatments. Thus, the approval process is lengthy and costly. In reality, only a major pharmaceutical company has the financial resources to spearhead the approval of a drug. In the case of Ketamine, this is unlikely to happen, as these companies could never realistically expect to recover their expenses. To be clear, Ketamine already *is* FDA approved, but not for the treatment of depression. There are already some courageous pioneers who will administer Ketamine today (for a king’s ransom) in its off-label use for depression. This is not in itself unusual. Many drugs – once FDA approved – are prescribed for off-label uses. For instance, Modafinil was initially approved for the treatment of narcolepsy. Today, the vast majority of prescriptions are not issued by neurologists for narcoleptics, but rather by primary care physicians for people who feel a little tired – or simply because people want to use it. So in principle, Ketamine already is available for the treatment of depression, off-label. However, the overwhelming majority of psychiatrists is unlikely to touch a drug that is a PCP derivative and needs to be injected, no matter how effective. This problem is not unique to Ketamine. Once a drug has acquired a certain infamy, it is hard to change minds. For instance, Thalidomide is now being explored as an effective cancer treatment, precisely because its such a potent inhibitor of angiogenesis. But that’s a hard sell, given its historical record.
Where does this leave us? In an uncomfortable (as millions are suffering right now), but hopeful position. The evidence for the antidepressant effectiveness of Ketamine (for whatever, yet to be understood reason) is so overwhelming that quite a few pharmaceutical companies are feverishly working on Ketamine analogues and delivery methods (e.g. nasal sprays) as well as alternative NMDA modulators that *can* be patented and thus would be worthwhile to put through the highly demanding FDA approval process. Preliminary results are so promising that one can reasonably hope to have truly effective antidepressants available within another decade or so. If this happens, a mental health revolution will be at hand. And it will be sorely needed. Having rapidly acting and unequivocally effective antidepressants widely available and covered by insurance (akin to antibiotics) will make all the difference.
Note: There is no question that Ketamine is a crude drug when it comes to addressing the pathology that underlies depression. Nevertheless, it is a promising and encouraging start, not necessarily the end. Further drug development will need to hone in on the underlying biological target systems (which is why a mental illness classification based on biomarkers is so sorely needed). Moreover, it has not escaped my notice that this discussion has focused on psychopharmacological aspects of depression. There are other aspects that are social, psychological and nutritional in nature, among others. Etiology is likely complex. Breakdown in social coping structures? Sedentary lifestyles? Overfeeding? Intense and chronic stress? Extreme social competition and comparison? Sleep deprivation? Light pollution? Hormone disruption? There certainly is a discussion to be had about these aspects, but not now. It will take a while for research to disentangle these causal links. Meanwhile, it is important to lighten the burden of disease. Thus, the focus was deliberate and we will save a deliberation of other factors for later.
On a final note, it is quite unsettling that virtually all truly effective treatments for mental disorders (e.g. Lithium, ECT, Ketamine, etc.) and psychoactive substances in general (e.g. LSD, Benzos, etc.) were discovered entirely by chance, by pure serendipity. Conversely, all mental health treatments *designed* to do a certain thing, based on our current understanding of the nervous system (e.g. SSRIs, but not just SSRIs – one can always do worse) basically failed to deliver. This suggests that we do not currently understand it very well. Recognizing this should break a lance for pioneering (some call it basic, but there is nothing basic about it) neuroscience research.
PS: This is another installation in an ongoing series on how language really does matter. Most people suffering from depression would reasonably turn to antidepressants, not dissociative anesthetics for help. But just because marketing calls them that doesn’t make it so (whatever one’s position, they are on average so ineffective that a vigorous debate whether or not they are more effective than placebo is even possible. A debate we didn’t see regarding the effectiveness of penicillin. Regardless, there are so many vested interests involved here that the debate is likely to go on. So it is certainly premature to write “Listening to Ketamine” even as people are sick of listening to overhyped BS. Yet, the suffering of the suffering is so severe that I remain hopeful that reason will prevail in the struggle to make depression history. The notion to have effective antidepressants available is a powerful one). As it turns out, the antidepressant effects of some dissociative anesthetics are in all likelihood much more potent than that of current “antidepressants”. Go figure.
Be it as it may, it is downright scandalous to have people suffer every day, some of them killing themselves and have a safe solution (at the right dose) readily available, yet not allow it to be used. That this is even a possible – and ongoing – state of affairs does not instill confidence in the way things are in general. Downright scary, actually.
Update: The story has now hit the mainstream. Also, there is now solid evidence that repeated low dose administration of Ketamine seems to keep depression at bay, akin to maintenance ECT and without mounting side effects.
Update: In the piece, I expressed surprise at the fact that patients have not been more forceful in advocacy and outreach, demanding the FDA approval of this treatment on an emergency basis. This now seems to be happening. The website also compiles a – growing – directory of health care providers willing to administer Ketamine infusions. Given how bad the suffering can be – note this case of a woman enduring 273 (mostly bilateral) ECT treatments – without an appreciable effect on the depression, but dramatic and sustainable effects from low-dose Ketamine infusions on a maintenance schedule every 3 weeks. Note that dosage seems to be *critical*, with a very narrow therapeutic range between 0.4-0.6 mg/kg.
*It is possible that Ketamine acquired this reputation somewhat unfairly, as legislators might have confused it with the date-rape drug GHB when passing emergency legislation in August 1999 (classifying it as a schedule-3 substance in the US). Interestingly enough, GHB is now legally available as a drug for narcolepsy, Xyrem.