Depression: Ketamine Eyes Hath Seen The Glory?

By Neuroskeptic | February 8, 2014 12:09 pm

Ketamine: club drug, ‘horse-tranquillizer’, and… miracle antidepressant?

I’ve blogged about the research behind the claim that ketamine has rapid-acting antidepressant effects several times. Since 2009, my view has been that it is impossible to tell whether ketamine has specific antidepressant properties, because ketamine has never been compared against an ‘active placebo‘ control. In trials, patients given ketamine report feeling better than patients given no drug.

But these trials weren’t really double-blind, because ketamine is psychoactive: it causes hallucinations and other subjective effects. Patients feeling these effects will have known that they had got the real drug, not the inactive control, potentially leading to a greater placebo effect. I’ve also speculated that experiencing the consciousness-altering effects of a psychoactive drug could help depressed people through psychological mechanisms – for example, by giving patients hope that it is possible for them to feel better.

Now, in October last year, James Murrough and colleagues of New York revealed the first published data comparing ketamine to an ‘active control’. They reported that ketamine was more effective. I didn’t blog about it at the time, but this week a very interesting paper appeared in Drug and Alcohol Dependence from Dakwar et al and taken together, they make quite a story.

Murrough et al compared ketamine (dose: 0.5 mg/kg) to midazolam. In a ‘double-blind’, randomized, between-subjects trial, ketamine was substantially more effective than midazolam at relieving major depression. Here’s the symptom ratings on the MADRS scale:

murrough_ketamine

The difference between the two drugs was certainly statistically significant. But what does it signify?

To answer this question, we need to look more closely at the ‘active control’, midazolam. Midazolam is a benzodiazepine, much like Valium (diazepam) but with a shorter duration of action. Like all benzodiazepines, it’s a sedative, anxiolytic and, at higher doses, an anaesthetic. Oh, and it’s made the headlines lately for getting drafted in as a component of American lethal injections because the executioners had trouble sourcing other sedatives.

How does that place it as an active control for ketamine? How do the contenders match up?

ketamine_midazolam

Not very well, in my opinion. That’s not just my opinion after seeing the results of the Murrough trial (although, as we’ll see, the results confirm that.) Two years ago I warned that:

An active comparator has to “make an impression” on the patient equal to that produced by the real drug…

Would a benzodiazepine make as big an impression as 0.5 mg/kg ketamine? It’s impossible to predict, really; so we’d need to ask people about the subjective strength of the drug effect. Personally, I worry that a lot of people just get sleepy on benzodiazepines and don’t really feel much…

So why use midazolam? Murrough et al’s justification is that both ketamine and midazolam are used in anaesthesia. But this is not very meaningful. Ketamine is popular among the dance music community not because it’s an anaesthetic at high doses, but because it’s hallucinogenic at the moderate doses that people take. Midazolam isn’t.

Murrough and colleagues do not appear to have compared the subjective impact of the drugs in any systematic way, using questionnaires. Asking patients (and the attending researchers) whether they could tell which drug they’d been given (checking the blind) would also have helped.

So lacking a direct measure of psychoactivity, the best we can do is look at the side effects. Out of 26 side effects measured, 18 were more common in the ketamine group. More people on midazolam experienced 2, and for 6 there was no difference. Of these, the most ‘psychoactive’ effects were poor concentration (ketamine 26%, midazolam 8%), restlessness (ketamine 21%, midazolam 20%) and anxiety (ketamine 15% midazolam 0%). We’re also told that 17% of the ketamine group experienced ‘significant dissociative [consciousness-altering] symptoms’; no such effects are mentioned for the midazolam group.

In sum, we don’t know how much of a subjective impact these two drugs made, however it seems very plausible that ketamine made a greater impression. The Murrough et al paper is therefore a missed opportunity, which doesn’t answer the big question: are the antidepressant effects of ketamine separable from its psychoactive effects?

Bummer. But it’s doubly disappointing because it could so easily have been different. That Dakwar et al paper I mentioned was much more sophisticated. The title gets right to the point: “Therapeutic infusions of ketamine: Do the psychoactive effects matter?”.

Dakwar et al took 8 crack cocaine addicts who wanted to go clean. They gave them three injections (in a random order, within-subjects). These were ketamine 0.41 mg/kg, ketamine 0.71 mg/kg, and lorazepam 2 mg. The ketamine doses are, respectively, slightly lower than, and substantially higher than, the dose used in depression studies (0.5 mg/kg). Lorazepam is similar to midazolam but with a longer duration.

The goal was to see whether ketamine increased the ‘motivation to quit’ crack. But Dakwar et al also used questionnaires to formally assess the psychoactive effects. The key finding was that both doses of ketamine caused much stronger ‘mystical experiences’ than lorazepam, as measured with the HMS scale. Participants reported feeling “a new view of reality”, “incapable of being expressed in words”, “a feeling of awe”… pretty impressive, basically.

dakwar

Furthermore, there was a strong correlation between the intensity of the injection-induced mystical experience, and subsequent motivation to quit. This is consistent with (although not proof of) the idea that the clinical effect of ketamine in addiction is an indirect effect of its psychoactive properties, rather than a direct pharmacological effect.

Of course, this doesn’t directly tell us anything about the ketamine in depression question. But it’s suggestive and the paper is a good example of how to approach these issues (although it would have been even better to have had an inactive placebo injection as well.)

Unfortunately, ‘the race goes not to swift’ in science these days. Dakwar and colleagues published in the humdrum journal Drug and Alcohol Dependence (Impact Factor: 3.14) while Murrough et al scored a place in the American Journal of Psychiatry (Impact Factor: 14.7). Incidentally, one of the authors of the new study, Sanjay J Mathew, was the senior author on the Murrough et al paper.

In summary I think the question is still very much open whether ketamine’s antidepressant effects are ‘psychological’ or ‘physiological’ in origin. I’m genuinely agnostic on the issue; I would love to know the answer, but at present we don’t have it.

You might ask – and many commenters on my previous ketamine posts have asked – so what? Isn’t the whole psychological-vs.-physiological question dualistic anyway? If ketamine works, it works, right? Does it matter why it works?

I think it does matter. For one thing, if ketamine has a ‘physiological’ antidepressant effect, via its action on glutamate receptors, then that would have major research implications: it would imply that other glutamate drugs might be as effective without the hallucinogenic effects. Drug companies and neuroscientists would have a research agenda mapped out for them (and indeed this is already underway.) If it’s a ‘psychological’ antidepressant, this would be misguided.

But it also matters clinically. If ketamine treatment is, in fact, acting as a kind of latter-day psychedelic therapy, that would imply that ensuring a comfortable atmosphere and encouraging positive expectations would be crucial. On this view, the smile on the face of the doctor giving the injection might be as important as the drug in the syringe.

Finally, I’d like to mention some mysterious ‘loose ends’ in these results. In Murrough et al, the midazolam group improved substantially, dropping by about 8 points on the MADRS scale after getting their injection. That’s not a huge effect, but it’s notable because the inactive placebo groups in previous ketamine trials have not tended to improve at all. Midazolam’s effect was also greater than that of 150 mg AZD6765, a non-psychoactive ketamine-like drug, in a prior study.

One interpretation of this is that midazolam is a quite good rapid-acting antidepressant. The other interpretation is in terms of the placebo effect: patients taking a given antidepressant are known to report greater improvement if they’re in a double-blind trial comparing two different drugs, as opposed to a trial comparing drug to placebo, perhaps because they know that they’re getting ‘a real treatment’ and therefore expect to get better.

ResearchBlogging.orgMurrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, & Mathew SJ (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. The American Journal of Psychiatry, 170 (10), 1134-42 PMID: 23982301

Dakwar E, Anerella C, Hart CL, Levin FR, Mathew SJ, & Nunes EV (2014). Therapeutic infusions of ketamine: Do the psychoactive effects matter? Drug and Alcohol Dependence PMID: 24480515

  • templeruins

    So much of this is truly stretching the definition of science I question the legitimacy of method. But anyway, for so many patients the traditional drugs for depression are ineffective, even worsening, and often creating a new addiction. Ketamine would not create addicts to ketamine, one thing I don’t believe you mentioned, the dependency on traditional drugs depression sufferers can feel. It may even only need to be used a few times at most in treatment, rather than the lifelong pill popping of other depression drugs. That’s not good for business.

    • Otteg

      We see a lot of therapy resistant depressions nowadays (resistant to SSRI’s et al) maybe due to genetic variants in BDNF or otherwise. Anyhow, clinically these patients suffer graviously and are nowadays met in Belgium with “generous” euthanasia proposals. Yet ketamine and even rTMS is denied to them ?!!
      Am i stranded on an alien planet ? Killing patients is ok but a trial on Ketamine (or psilocybine cf John Hopkins) is denied “because it could induce addiction ???

      Surely Jim, this must be earth but not the planet we once knew.

  • Helge Ha
    • http://blogs.discovermagazine.com/neuroskeptic/ Neuroskeptic

      I had read it, but thanks for mentioning it because it gives me chance to discuss it here. For those who haven’t clicked the link, it’s a paper from the Czech Republic, authors

      • larry mccoy

        Hello.
        So, my question has been asked before and my reason is the same as many others. I am in my 40′s and have suffered from depression since I was young. To be honest, nothing has changed. It is still Prozac and the stigmatism still exists. This is even true within my own family with a mother who died last year who suffered from depression since the 70′s before there was even medicine for it AND who’s Father is a physician, yet refused to embrace it.
        My entire life has never amounted to much. I have never been able to keep a job or even stay in a relationship for longer than a few months. All the while watching my siblings and friends attain wonderful careers and experience love, marriage and families and happiness while I have stayed in my room for every holiday , birthday or any type of celebration for the last 25 years.I recently heard a commercial in the last year from a drug company who described depression as “something you can’t hear, feel, see or touch” I have described it exactly like that to anyone that would listen, but to no avail.
        So, I have decided to help myself now. I read about the research on Ketamine and as it related to depression. I want to try it. I guess it is illegal. But, if I can get it from outside the US, like Seniors do with medicine from Canada and gamblers do with online companies in Central America, I am willing to try. I am tired, lonely and deserve the right to feel better.
        Can anyone tell me where to get this? I imagine there is risk involved with getting scammed. I do not even know what to ask for or how much.
        Thank you very much for any advice anyone can give me.

        • Travis

          I share your same story Larry and I too would like information regarding this matter. If anyone knows the method to obtain and the dosage, it would be greatly appreciated. Thanks

        • kerherven

          Hi Larry
          Sorry to hear about your life. My GF had chronic depression for years.i found this article about how to use ketamine, and after following tbis regimen, she has like hm 20% of issue she used to have. I live in Montenegro, small country in Europe, we found K illegally with one veterinary as here theyre allowed to havs it. Try with them in USA? heres the link on regime http://www.bluelight.org/vb/threads/669468-Experience-with-ketamine-therapy-for-depression
          For all i can say, its by far most effective, cheap, least side effects treatment for depression. Its a bllody miracle if u ask me. Pitty big farma screwed system so u cant have it legally.

        • http://blogs.discovermagazine.com Longmire

          Try Silk Road unless the righteous agents of our government have shut it down again in which case go to a local rave and ask around. Needlessly suffering for that long is a travesty. Also try working out if you don’t already your body effects your mind more than is currently realized, heck just smile when you feel the worst it infuriates “depression”.

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  • http://www.amazon.com/Rolf-Degen/e/B001K1NBP4/ref=ntt_athr_dp_pel_2 Rolf Degen

    The fact that the real drug produces more and different side effects than the placebo, perhaps even an active one, is a problem in lot of double blind research. One could say “double blind is not blind enough.” But to a certain degree this could be remedied if the expectations in both the experimental and the placebo group were controlled. Ask the subjects in both groups how sure they are they got the real thing.

  • Gerald Gaines

    We can’t believe the amount of misinformation about ketamine. We are a clinic founded by a bipolar/PTSD person – me – who happened to have the personal resources to do something better than wait for pharma to develop a patented version of ketamine. I have no axe to grind other than for things that stand in the way of an effective treatment for depression.

    Where to start? It is clear to any objective observer that ketamine functions at both the mind (physical) and brain (emotional) level. With regard to effect on the mind, there are no psychedelic effects of ketamine at .5 mg, unless you have screened poorly and have someone who suffers from a disease in the schizophrenia family. For everyone else, all you feel is mild disassociation – a sense of floating in the room. I am speaking as both a patient and as an observer of over 300 treatments. NO psychedelic effects in a single patient. What people are mistaking as a “mythical” experience is actually a therapeutically valuable dropping of the patients’ ego boundaries, a known “side-effect” of ketamine, which by the way matches up well with the definition of depression as being “ego death”.

    At the physical level of the brain, the work from Duman at Yale shows the functional impact of ketamine is to rapidly grow neurons in the areas of the brain that drive emotion. A natural consequence of that would be the return to normal of the brain’s neurotransmitters. It is not clear at this point HOW ketamine builds nerves, but there are three disparate theories being pursued quietly in private labs across the country.

    The most frustrating thing for me is that the standard of judgment being applied to ketamine efficacy and safety is one not applied to any other drug that has been used for 50 years in large single dosages for surgery with little incident. It has also been used for over ten years for multiple, large doses for the illness CRPS.

    As for efficacy, the gold standard of a double-blind trial is a mirage. ALL of the pharma submissions for anti-depressants were double-blind trials, albeit with small numbers of patients. The trick was to submit the 2 out of 5 that showed positive results and to sit on the others. Double-blind trial results are advertising for the masses unless you know the totality of the drug’s development history, which you almost never have unless you have the resources for a Freedom of Information Request.

    But back here in the real world, ketamine is working just fine. Even in our unfinished state of refining the protocols, we see almost complete remission in 60% of our patients and partial and slow remission in many of the others. The response to placebo in depression in general has been consistently measured at about 1/3 of the patient population for standard, non treatment resistant patients. The placebo response rate for this sub-population would obviously be less than 1/3.

    Also, one cannot use the standard depression tests to measure the short term impact of ketamine appropriately. All of the tests force the respondent to measure depression over time as that is how clinicians distinguish depression from sadness. We’ve developed a more contemporaneous test, given frequently during treatment, and then benchmarked it with standard tests given at the beginning of treatment and about a month later. Then you get valid results on the standard tests – before that they understate by a large margin the level of improvement the patient is feeling, or they confuse him so much that the result is invalid.

    In sum, we have researchers who are reporting out on ketamine who have vested, financial interests in seeing analogs of ketamine, but not ketamine itself, become big sellers.

    We have psychiatrists who have a vested interest in a business model that can’t be used for ketamine treatment.

    We have a solution with a Political problem, not a clinical one. If ketamine were still under patent it would be re-submitted to the FDA for depression approval. Instead we have to wait for the functionally identical S-ketamine trials from J and J.

    • http://blogs.discovermagazine.com/neuroskeptic/ Neuroskeptic

      Thanks for the informed comments.

      I agree with you about the political aspects of this. And I agree that ketamine therapy is safe. I think it should be available for anyone who wants to try it (under medical supervision.)

      But on the question of how it works, I remain agnostic.

    • Doubthelout

      I’m not sure where you got your information that mystical (or “mythical” as you called it) effects are not seen with that dose of ketamine when you have a study by disinterested scientists indicating that it does. But that is only one of many claims you make that seems pompous and frankly unscientific. Your impression of efficacy giving the drug to desperate and paying patients is hardly sufficient to make the case. This is why large-scale randomized controlled trials are conducted. And the authors on the cited paper by Murroughs indicate that there is inadequate evidence at present to definitively state that ketamine is effective.

      As for founding a clinic to treat depression and PTSD, I’m not sure we have enough information to know how to give ketamine safely in a clinical setting, especially as nearly all studies to date involved hospitalized participants. Entrepreneurs such as yourself are not the best authority on scientific matters. Your diatribe against financial interests influencing perspective is perhaps too much like a pot calling the kettle black.

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  • ohwilleke

    I have to agree with those concerned about excessive dualism and who are not too worried about lack of understanding of mechanism. What lots of studies show is that a particular dose of ketamine rapidly alleviates the symptoms of depression, and what lots of direct comparisons and prior research shows is that a great many of regularly used anti-depression drugs are not fast acting.

    The reality is that there are lots of commonly used, fairly effective mental health treatments that appear to work even though we don’t really know quite why they work (at least at first). Psychiatrists discovered that (counter-intuitively) general nervous system stimulants were effective at treating ADHD at a point when the approach was based on little more than a heuristically motivated hunch. AFAIK, we still don’t really understand why lithium is an effective (and now generic and hence cheap) mental health drug for lots of people. We have only the dimmest idea of why electroshock therapy is effective in certain cases.

    Also, when you are looking at different drugs chosen for the express purpose of having an impact on one’s psychological state (something that we don’t understand terribly well in the non-pathological state either), in somewhat different ways, the distinction between psychoactive and pharmacological sounds like a distinction without a difference. Yes, they are clear different in experience and mechanism, but yes they also affect the problematic symptoms.

    Maybe its like sneezing and staring. If you sneeze, you can’t continue to stare uninterrupted. Maybe that’s totally wrong. But, the fact that not knowing how a drug works means we don’t know whether some hypothetical future alternative will work too doesn’t strike me as a particularly salient criticism.

    The point that the control group has to have some physiological effect so that they know that they have a real drug doesn’t imply that the effect must be similar in kind or effect to serve as a valid placebo. And, saying that a drug works due to psychoactive effects is not at all the same thing as saying that its benefits are a mere placebo. Instead, it says that psychoactive drugs may be effective at promptly alleviating depression.

  • Colin Hendrie

    Ketamine is about to be reclassified in the UK as a Class B drug (rating it as more harmful than is indicated by its current Class C status) ‘in the face of mounting evidence over its physical and psychological dangers’. Doesn’t bode well for a drug they’re trying to push as a new treatment even if they do ever manage to get some properly controlled studies done.

  • http://blogs.discovermagazine.com Paulette Ward

    Why aren’t we just looking more into marijuana? It’s been on this planet
    forever, no side effects, no animal torture no a lot of things. Doesn’t
    make sense to me. More chemicals in our bodies keeping the
    pharmaceutical companies in big business. Believe me it works a lot
    better than anything I was given.

  • tikitools1

    Then there is Ibrogaine which is a class X drug in America but legal elsewhere, it is another powerful hallucinogenic that can work wonders with breaking addictions, especially heroin! We need to start taking a more pragmatic approach towards addiction, depression and drug use.

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  • Phull Kname

    What ever happened to GLYX-13?

    • http://blogs.discovermagazine.com/neuroskeptic/ Neuroskeptic

      Well, here’s a review paper on it just published: http://informahealthcare.com/doi/pdfplus/10.1517/13543784.2014.852536

      In the only human efficacy trial, 5 and 10 mg/kg GLYX-13 reduced depression more than placebo. However, strangely, 30 mg/kg GLYX-13 was exactly the same as placebo.

      Also, for some reason the placebo effect in this trial was huge (12 points on the HAMD after 1 day), far larger than in any ketamine trial.

  • http://blogs.discovermagazine.com Roy Dempsey

    These new data on Ketamine in depression are very interesting, and not surprising to me (that it is probably effective for some depression). You say several times that you are agnostic about Ketamine, but you clearly show bias and prior negative judgement about ketamine, in several ways, quite obviously. Also, it was ignorant and disquieting for me to see you say that you think the benzodiazepine used in one study (midazolam) just makes people sleepy and tired! As with other medicines not approved for use as anti-depressant therapy (such as opiods), ketamine, opiods, and yes benzodiazepines – all often cause “paradoxical” excitation, activation, and often increased psychomotor activity. Depression is often accompanied by anxiety, and benzodiazepines often give short term relief here as well (one of the early indications in Xanax studies). Do not mention the problems with chemical dependency in any response, these effects for benzo and opiods are obvious, I am talking about activation (mental, psychomotor, affect – this is where you treat depression), perhaps the RAS is activated, the glutamate receptors probably do play a role, but that can not be the only pathway here with ketamine, other studies rule this out with glutamate agonists. Most all of the approved anti-depressants on he market fall into one of 4-5 classes (depending on how you count them), and fail in a huge % of patients, especially if you follow them for more than eight weeks, which is almost NEVER done. You also need to realize that ketamine is not very psychoactive at all at this 0.5 mg/kg dose, and that psychomotor activation is most assuredly a factor in its action. Loss of Energy and fatigue are the hallmarks of depression, although we all know other symptoms are significant in many patients. Most all approved anti-depressants take 6-8 for any onset of action, you NEED to give more emphasis in your articles on the enormous advantage that a fast acting drug for depression like ketamine offers as an enormous advantage, for patients suffering from moderate to severe depression, and when quality of life and true suffering are factored in. Depression, whether endogenous or bi-polar or other types, represent a huge spectrum of illnesses, and undoubtably a significant number of biochemical/neurotransmitter pathways are involved and can be disrupted in a depressed person (autism spectrum, or the range of anxiety disorders are analagous), and the more weapons in the arsenal to treat it the better. Finally, I thought Descartes was dead? Mind/Body Dualism is a flawed concept you seem to stubbornly hold onto, and this attempt to intellectualize a difference in whether ketamine’s effect is “physiological” or “psychological” is moot and almost meaningless. Of couse it is both!! I have little doubt, but await further evidence of course to confirm and extend, that ketamine DOES HAVE a real (also unique mechanism of actions) and reproducible anti-Depressant effect that will prove to be useful.

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  • http://depressionfreeblog.com/ dwinez

    Dealing with severe health problems caused by alcohol is a factor in depression. Alcohol has a serious affect on our physical health and can
    affect almost every organ and system in the body. The liver is one of
    the first organs to be seriously affected by heavy alcohol abuse. Cirrhosis of the liver is a serious problem with heavy binge drinkers. If it progresses enough the liver will eventually fail.

    Lowering the Risk of Depression by Drinking Red wine

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No brain. No gain.

About Neuroskeptic

Neuroskeptic is a British neuroscientist who takes a skeptical look at his own field, and beyond. His blog offers a look at the latest developments in neuroscience, psychiatry and psychology through a critical lens.

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