Ketamine — should we believe the hype?
It is really hard to underestimate the hype that has surrounded the development of ketamine as a potential antidepressant drug. In the first seconds of a Google search I found statements like “Get your life back” and “Reset your brain, reset your life”. Perhaps we should not be that surprised. Psychiatry, as I have recently written, is crying out for new options for patients with depression. I want to spend a little time to explore if ketamine is the answer and whether it lives us to the hype.
First, a few words of history and context. What is ketamine and why the excitement? Ketamine is most commonly used as an anesthetic drug, in humans, especially children, and in animals. It was first approved for clinical use in 1970, was popular as a battlefield drug in the Vietnam war but is not used widely as an anesthetic in adults as patients often wake in an overexcited state or experiencing disturbing symptoms including hallucinations. Off the back of the Vietnam war, ketamine was a not uncommon drug of abuse in certain circles: within the new age movement in the 1970s and dance culture in the following decades.
There are some relatively well known books from the new age movement published in the late 1970’s describing the experiences of authors like Marcia Moore and John Lilly who used the drug extensively. Moore, the self-proclaimed ‘priestess of the Goddess Ketamine’, told Lilly after being warned about her use that she would “ride this comet through to the end”. She disappeared not long after, on a winters night in 1979, and froze to death in forest having injected a copious amount of the drug.
From the 1990’s ketamine became increasingly popular as a treatment for patients with chronic pain, something it is still used for. When used in this way, the drug is administered as an intravenous infusion, but at a dose too low to induce anesthesia. It was in the late 1990’s when the idea of using ketamine as an antidepressant was first considered. Ketamine is a blockers of a specific receptor for the neurochemical glutamate, known as the NMDA receptor. It was proposed that blocking the NMDA receptor might help depression and ketamine was the most suitable drug with which to do this available at the time.
Thus the modern use of ketamine in depression began: first with a small trial in 9 patients conducted at Yale and published in 2000[1]. These patients received 2 infusions for 40 minutes each, a week or more apart: one of ketamine and one of a placebo, just salt water. 4 of the 8 patients who received the real drug ‘responded’: they had a substantial reduction in depression and just one patient after placebo treatment.
This response was dramatic and quick — within 24 hours — was still there after three days but had faded away by one week follow up. This pattern seems to characterize the response to intravenous ketamine and has been reported in several other studies, in patients with both unipolar and bipolar depression. However, there are major problems understanding the significance of this. First, most of the studies to date are of just single doses and do not give an idea of how this will or can translate to longer term treatment outcomes if therapy is repeated. There have been a very small number of studies, all with limited patient number, providing repeated doses, for example six infusions over three weeks, but not all of these studies have actually showed benefits. A study published last year from the Massachusetts General Hospital in Boston failed to show any difference between active ketamine and placebo despite using the same standard dose that has been utilised in most previous studies[2].
There are also serious concerns about the ‘blinding’ of these studies: are patients unaware of whether they receive active drug or placebo and can this affect response to the active drugs. If patients are aware they are getting ketamine, are they more likely to think they have gotten better? This is especially a problem as patients receiving ketamine often experience a variety of fairly obvious symptoms. They can get headaches, dizziness and nausea. More prominent though, is the dissociation: a change in their sense of reality of themselves and / or their bodies.
At this stage it would only be fair to conclude that intravenous ketamine probably has short term antidepressant effects but we have no idea if these can translate into long term clinical outcomes with repeated administration. Repeated infusions are costly and also not very convenient.
However, there may be alternatives. Despite issues with how it is absorbed and processed by the body, taking ketamine in a tablet form may be an option. There have been few studies exploring this so far but amongst other research, Douglas Pharmaceuticals from New Zealand is currently evaluating an extended release oral form of ketamine.
An option, which has progressed much more, is the use of a nasal spray. This is the approach adopted by the Janssen Pharmaceutical company, part of Johnson & Johnson. Over recent years they have conducted a series of trials evaluating Spravato, their intranasal ketamine drug esketamine.
At this point in the story we need to take a little detour into chemistry to understand the difference between ketamine and esketamine. Ketamine is effectively made up of two “enantiomers” which are referred to as the S-ketamine and R-ketamine molecules. Enantiomers are a pair of molecules that are the identical mirror images of one another, just as one of your hands is the mirror image of the other. They are the same but not the same. A number of different drugs are made up of two enantiomers and in some cases the enantiomers have been separated to allow one of these to be marketed as a separate drug. For example, the antidepressant citalopram is made up of two enantiomers and one of these was isolated and produced as a separate antidepressant, escitalopram, around the time that the original drug was coming out of patent protection.
Esketamine is effectively the S-ketamine component of the full mix of S and R ketamine. Therefore, it is not necessarily possible to directly compare the results of studies using more traditional intravenous R+S ketamine to the intranasal esketamine developed by Janssen. Interestingly, there have been studies that would have suggested that using R-ketamine may have been a more effective strategy then S-ketamine alone. A very early study conducted in the 1990s indicated that S-ketamine was associated with significant psychiatric side-effects including dissociation and hallucinations but these same adverse effects were not produced with R-ketamine. More recent studies have suggested that R+S ketamine may have longer acting therapeutic action compared to S-ketamine alone. However, let’s get back on track.
Janssen have conducted a series of clinical trials evaluating the use of Spravato, comparing this to a placebo nasal spray. Of the three trials conducted testing its use in the treatment of depression, using repeated doses several times per week over four weeks, only one found that the active drug (added to an antidepressant started simultaneously) was better than the placebo.
This alone is a little worrying. If you add to this the concerns about the likelihood or otherwise of the success of blinding in these trials it is of even more concern. To top it off, in the one study which did find a benefit, the difference between active drug and placebo was really limited, only 4 points on the MADRS scale. Unfortunately it gets worse. There were three deaths of patients by suicide in the study: all three of these were in patients taking the active drug, but not when taking it. These all occurred within three weeks of the patients stopping treatment, raising serious concerns about the possibility they were related to drug withdrawal.
Despite these concerns Spravato was approved for use in the US by the FDA in 2019. The FDA abandoned their traditional approach which requires two positive trials showing efficacy and instead accepted the one trial described and a second showing reduced relapse rates in Spravato responders continued on the drug compared to Spravato responders transitioned to placebo. This process certainly attracted considerable attention with President Donald Trump quoted as saying:
“You have people calling for help and if those people had that (esketamine), I’m hearing like instantaneously they’re in better shape.” [3]
Despite these concerns about safety and efficacy, both intravenous ketamine and Spravato have become increasingly commonly used, throughout the US especially. There are a multitude of adds on the internet strongly proclaiming the benefits of injected ketamine and offering this at between $300 and $1,000 a shot. These are run by a mixture of anesthetists, psychiatrists or even nurses, with few showing any evidence of having the sort of multi-disciplinary team you would want. This is not trivial: a considerable mixture of professional skills are required to assess patients with complex mental health needs, administer an intravenous drug, manage behavioral and other complications and address suicidal ideation, existing or emerging. The use of Spravato has also escalated rapidly with over 850 centres ‘certified’ by a program mandated by the FDA already and a cost of treatment of over $30,000 per year.
How do we understand these contradictions? We have an expensive drug or group of drugs with strong and potentially dangerous side effects and questionable long term effectiveness that is being rapidly taken up into clinical use. Is this a good thing or not?
Well we need to remember the context, referred to right at the start of this piece. Depression is a really challenging illness for many patients and our current treatments just don’t work in many patients. Ketamine produces powerful short term effects in some patients and according to the many testimonies of patients, does seem to make a great difference for some in the long term, despite what the data says so far. We really need new therapies like ketamine but this is not a reason to rush them into use prematurely if there are safety and efficacy concerns.
We end up with the much too common and unsatisfying conclusion: that we just need more research. Fortunately, there is a lot going on at the moment and hopefully this will provide clarity. In the meantime, patients considering ketamine treatment should seek out as much information as they possibly can, get second or third opinions. Make sure whomever is suggesting this is also providing sensible information about alternatives such as repetitive transcranial magnetic stimulation: this does not work in everyone but has a much greater evidence base in terms of both safety and efficacy at this stage.
[1] Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 47(4), 351–354. doi: 10.1016/s0006–3223(99)00230–9
[2] Ionescu DF, Bentley KH, Eikermann M, et al. Repeat-dose keta-mine augmentation for treatment-resistant depression with chronic suicidal ideation: a randomized, double blind, placebo controlled trial. J Affect Disord.2019;243:516–524. doi:10.1016/j.jad.2018.09.037
[3] https://www.bloomberg.com/news/articles/2019-06-12/trump-offers-to-negotiate-price-of-j-j-anti-depressant-for-va
