Despite “Flurry of Interest,” Ketamine Remains Unproven For Depression

Justin Karter
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In 2014, then National Institute of Mental Health (NIMH) director, Thomas Insel, speculated that ketamine “might be the most important breakthrough in antidepressant treatment in decades.” A recent review of the research suggests that while ketamine may produce a rapid short-term improvement in depression, the effect is short-lived and the potential for addiction and dependence warrants considerable caution.

Ketamine was developed in 1962 and came into regular use in the 1970s as a fast-acting anesthetic for use on the battlefield in Vietnam. Soldiers realized that the drug produced an “out-of-body” experience that some found uncomfortable and its use in medical settings decreased.  By the 1980s, however, ketamine began to be used as a recreational drug and, as a result, the US federal government added ketamine to the list of schedule III controlled substances in 1999.

Ketamine_10ml_bottleIn an article published in this month’s American Journal of Psychiatry, researchers led by Dr. Jeffrey Newport review randomized control trials on the use of the drug ketamine for depression. They note that ketamine, also known as the street drug “special K,” has been met with a “flurry of interest.” This interest, they write, is largely driven by the fact that currently available antidepressants have “less than optimal efficacy.” This problem is compounded by the fact the search for alternative antidepressant compounds has been “remarkably unsuccessful” over the past decade.

The researchers identified twelve reports of randomized control trials examining the use of ketamine for depression, including studies that used ketamine alone and ketamine combined with ECT. The studies consistently showed a rapid improvement in the first 24 hours, but the effect declined steadily. The studies also revealed that ketamine use often induced a dissociative state in participants, where they felt as though they had become detached from reality.

In five studies, where ketamine was used to as an anesthetic prior to ECT, participants showed an immediate improvement in symptoms but the improvement did not last over the course of the study and ketamine was not found to improve the effects of ECT.  Some of these studies also reported that the use of ketamine increased the duration of ECT-induced seizures and was associated with delirium and fear upon waking up.

While ketamine infusion centers are popping up all over the country, the research does not support their use for depression. Relapse rates for people with depression who get a ketamine injection are “up to nearly 90%” after only four weeks.  The researchers also caution that “widespread dissemination in the outpatient setting could readily produce physiological and psychological dependence on ketamine.” Increasing access to ketamine, they warn, has the potential cause, “or even exceed, problems currently encountered with prescription opiates and sedative-hypnotics.”

“It should be noted that the history of pharmacology is replete with examples of new drug development with the promise of major therapeutic advances leading instead to disastrous public health consequences (e.g., heroin as a less addictive and more effective analgesic than morphine).”

 

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Newport, D. J., Carpenter, L. L., McDonald, W. M., Potash, J. B., Tohen, M., & Nemeroff, C. B. (2015). Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. American Journal of Psychiatry172(10), 950-966. (Abstract)

 

Conflicts of Interest:

Dr.Newport has received research support from Eli Lilly, GlaxoSmithKline, Janssen, NARSAD, NIH, and Wyeth; he has served on speakers’ bureaus for AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, and Wyeth; and he has served on the advisory board for GlaxoSmithKline.

Dr. Carpenter has served as a consultant for AbbVie, Magstim, Naurex, Taisho (Helicon), and Takeda/Lundbeck; and she has received research support from Cervel Neurotech, NeoSync, Neuronetics, and NIH. Dr. McDonald has received research support from Cervel Neurotherapeutics, the Health Resources and Services Administration, NIMH, the National Institute of Neurological Disease and Stroke, Neuronetics, Soterix, and the Stanley Foundation; he has served as a consultant for the Center for Devices and Radiological Health, the Food and Drug Administration, and the Neurological Devices Panel of the Medical Devices Advisory Committee; he is a member of the APA Council on Research and Quality representing ECT and Neuromodulation Therapies; he holds a contractwith Oxford University Press to co-edit a book on the Clinical Guide to Transcranial  Magnetic Stimulation in the Treatment of Depression; he serves on the editorial boards of the American Journal of Geriatric Psychiatry and the Journal of ECT; and he is Section Editor for Current Psychiatry Reports.

Dr. Tohen has been employed with Eli Lilly; he has received honoraria from or consulted for Abbott, Alkermes, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Elan, Eli Lilly, Forest, Geodon Richter Plc., Janssen/Johnson and Johnson, Lundbeck, Merck, Pamlab, Otsuka, Roche, Sepracor Wyeth, Sunovion, Teva, and Wiley Publishing; and his spouse has been employed with Eli Lilly. Dr. Nemeroff has received research/grant support from NIH; he has served as a consultant for Allergan, Clintara LLC, Eli Lilly, Gerson Lehrman Group Healthcare and Biomedical Council, Lundbeck, Mitsubishi Tanabe Pharma Development America, Prismic Pharmaceuticals, Roche, Shire, SK Pharma, Taisho Pharmaceutical, Takeda, Total Pain Solutions, and Xhale; he is a shareholder with Abbvie, Celgene, OPKO Health, Seattle Genetics, Titan Pharmaceuticals, and Xhale; he has served on scientific advisory boards for American Foundation for Suicide Prevention, Anxiety Disorders Association of America, Brain and Behavior Research Foundation (formerly NARSAD), Clintara LLC, RiverMend Health LLC, Skyland Trail, and Xhale; he holds patents forMethod and devices for transdermal delivery of lithium (U.S. 6,375,990B1) and Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (U.S. 7,148,027B2); he serves on the Board of Directors of American Foundation for Suicide Prevention, Anxiety Disorders Association of America, and Gratitude America; and he has received income sources or equity of $10,000 or more from American Psychiatric Association Publishing, Clintara, CME Outfitters, Takeda, and Xhale.

Dr. Potash reports no financial relationships with commercial interests.

22 COMMENTS

  1. “might be the most important breakthrough in antidepressant treatment in decades.”

    That presupposes there were earlier breakthroughs in antidepressant treatments… there weren’t. Non-biased studies from Kirsch and Moncrieff show that neither the older nor newer antidepressants have ever had much efficacy over placebo. This one is just as doomed.

    • Exactly! And it was Thomas Insel who said that! As near as I can see the entire efficacy of ADs is accounted for when we consider they are active placebos, just as Kirsch found. It is well known that depression has a large placebo effect. I’ll never understand how people in the field overlook this and conclude the drug itself actually affects depression. They work because they are active placebos and also because depression can remit on its own.

  2. Addicted to i’m K, is moderation ever going to be possible?
    A friend of mine has been seriously mentally addicted to ketamine on and off for 5 years. Droughts in the UK are the only thing that has interrupted his consistent k use.

    As with most people it all started with tiny lines. After a mind blowing first k hole binging it began. This is back when you could buy 12.5g for a reasonable price. Tolerance builds up dramatically quickly with ketamine and the effects he used to get from 100mg soon needed 1000mg to achieve. Eventually the amount binged was getting too much for his nostrils and he moved onto a more efficient way to consume it.

    Injecting ketamine is where the problems really got bad. Anyone who has experience binging k will know you sometimes over shoot the dose and can have black out periods. This is extremely dangerous when you are using needles. Anyway injecting k was a whole new experience. Suddenly from one gram he was getting multiple k holes again and the rush was unbelievable. However just like with sniffing it the tolerance goes up and you get to a stage where lines wont touch you. Its comparable to smoking joints or hitting bongs I suppose.

    After a series of unfortunate events and inconvenient truths and after more grams than he can possible comprehend or imagine, he is a 11 days clean. His sources have dried up and the only way to obtain it would be online which hes managed to resist doing so far. However he still thinks about it all the time, multiple times a day and wonders if that craving will ever go away? He had a few months off it before, but the cravings would not go.

    He would like to know if anyone else has experience with quitting ketamine after long term use? Is moderation possible or is that just wishful thinking? In an ideal world he would use moderately one injection a week at most but just like an alcoholic cant risk one drink he is worried he cant risk one gram.

    Read the thread https://drugs-forum.com/forum/showthread.php?t=271988

    Read the Ketamine forum https://drugs-forum.com/forum/forumdisplay.php?f=92

    I never took the stuff and have no idea if its a good or bad thing.

  3. Good thing you disclosed the conflicts of interest relating to this article. There are so many conflicts it takes away all credibility of this article…over a decade of 100+ independent clinical trials of IV Ketamine infusion therapy have been conducted by leading medical institutions including Yale, Massachusetts General, National Institute of Mental Health, Black Dog Institute, and countless others, all consistently showing IV Ketamine’s efficacy of around 70%. Its ability to end suicidal thinking within hours is unmatched by anything else available today. Patients who want to kill themselves when they come into our clinic leave not wanting to hurt themselves anymore. We have an 80+% success rate and our patients are getting an average of 3 months of total relief from their symptoms, not weeks. Most of the early research was around a single infusion which did show about 7 days of relief. We provide a series of 6 and we’re seeing long-term benefits. Patients are able to exercise, eat more healthily, participate in talking therapy, and make other important lifestyle changes while they are symptom free, or at least have a substantial reduction of symptoms, that produce long-term benefits.

    We’ve administered well over 1,000 IV infusions and not a single patient has demonstrated any signs of addictive behavior. While the experience during an infusion can be pleasant at times, it’s a strange one people do not seek. It is very different from abusing Ketamine on the street. This is a medical procedure; people do not become “hooked” on their infusions.

    Ketamine is safe, effective, fast-acting, and has no long-term side effects. It is imperfect. It is not a cure. Still, It is the best option we currently have for those suffering from MDD, especially if treatment-resistant. Most of our patients have not only tried countless medications to no avail, but also ECT and/or TMS and they haven’t gotten the relief they deserve. Ketamine infusions really work for them. See ketamineclinics.com for more information.

    • What was ketamine developed from? I’ve been told that it was originally used as a horse tranquilizer. If that’s true I don’t think I’d want to touch the stuff. Just like the original drugs that led to the first so-called “antipsychotics” were developed from dyes for synthetic fabric and insecticides. I can’t believe that drugs created from stuff like this can be healthy for the human body and brain.

      • I agree. They were developed for other reasons, and have been found to work for depression. The reason they work is the placebo effect, nothing more. And the guy who is doing the injections is using an extremely effective placebo procedure. It is an established fact that what he is doing will give good results even if the injected liquid were water. But I have no doubt he believes it is the ketamine.

    • Instead of slapping another bandaid (and a potentially danderous one- Ketamine- a drug) on depression…when we know so very little about the human brain. Why don’t we start looking for the root cause of their depression. Before injecting these people w/ Ketamine does anyone look at their diet? Their lifestyle? Do they try exercise, therapy, support? I follow a lot in paleo community and post after post, I see people leaving testimonies that their depression and anxiety completely resolved after they changed their diet.

      What are the long-term consequences of this Ketamine use? Do we even know?

      And what if someone is lacking the enzyme to metabolize Ketamine? Do you even test for that? Or just throw the drug at patients like a dart to a dartboard and see what happens?

      I’ll pass. Already had one psycho-pharmaceutical nightmare- and that’s one too many.

    • Forgive my skepticism but these are the same arguments that have been made previously for the latest, greatest, psych med.

      And when you talk about long term results, what are you referring to? Any links to an unbiased study that could confirm your claims?

      By the way, Steve M, an MIA writer, has spoken about being able to end patient’s depression very quickly. His novel idea? Listen to the patient and ask them for the source of the distress. And not treating them as someone with a lifetime brain disease.

    • I would think that using the drug Ketamine to get to a happy place would remind a depressed person that happy exists and that would have a beneficial effect.

      But this,

      clinical trials… Yale, Massachusetts General, National Institute of Mental Health, Black Dog Institute…

      “Massachusetts General” , you have to be kidding me, “Dr” Bidermans little playground of child drugging .

      The ‘ADHD Drug’ That Gives Boys Breasts http://www.thedailybeast.com/articles/2015/06/12/the-adhd-drug-that-gives-boys-breasts.html

      Why in the world would you list Massachusetts General ? Crimes against humanity come out of that place.

      “The key to the treatment of bipolar disorder (whether bipolar I or bipolar II) remains pharmacological. This is because bipolar disorder is a biological condition with a strong genetic component…

      One of the main issues in management for any clinician (GP or psychiatrist) is helping patients to remain ON medication…

      Although strictly a physical therapy and not a medication, it is worth mentioning as ECT plays an important role in treating both acute mania (and psychosis) and severe depression on occasions…”

      http://www.blackdoginstitute.org.au/healthprofessionals/bipolardisorder/managingbipolardisorder/medicationsinbipolardisorder.cfm

      The Black Dog Institute is at the forefront of research
      into therapeutic benefits of drug treatments, and works closely with
      pharmaceutical companies… http://www.blackdoginstitute.org.au/docs/PharmaceuticalCospolicy.pdf

      Your references are scary dude.

    • most of your patients have tried countless medications, ECT and or TMS to no avial. Not very surprising and none of these are very effective and have considerable dangers.

      Indpendant peer reviewed reports published in reputable journals please so we can assess the eveidence. Otherwise you just sound the advertising manager for some private outlet trying to drum up customers.

      • “Still, It is the best option we currently have for those suffering from MDD, especially if treatment-resistant.” – I don’t agree. There are lots of other options a person might use – but these options would be non medical. Non medical options can also work longterm.

  4. As Dr Mandel has said there is considerable evidence accumulated over the past 15 years that ketamine is a safe and effective treatment for depression that is not helped by other therapies. Ketamine can be administered by a variety of routes including oral, sublingual, subcutaneous, intramuscular and intravenous.
    Low dose sublingual ketamine is a promising development as it’s use enables all psychiatrists to include it as part of a comprehensive treatment plan. After an initial monitored test dose patients can safely take follow up doses at home.
    It is important to know that although the recreational use of ketamine can lead to tolerance dependence and addiction for some, there are no reports of this occurring with the medically prescribed use of ketamine over the past 50 years.
    Further details can be found in the recently published book “Ketamine for Depression.”

    • Every drug trial result for antidepressants I’ve ever seen can be accounted for by the placebo effect. They have a lot of difficulty outperforming placebo and often don’t. The drug is administered and the patient gets better. It is natural to think the drug worked. It appears it is the drug, but it is not. The active chemical does nothing for depression. The patient has been given an expensive and potentially dangerous placebo. Why does this fact get swept aside?

      • This fact gets swept away because of money and greed, plain and simple. It’s quite fine and okay to experiment on the so-called “mentally ill” since society at large does not care a fat damn about what happens to us. And I do not accept the fact that depression is an “illness”. I know, from my own experience, that it is a result of what is going on, or not going on, in my life and in what’s impinging on my life from things going on in my society. It is not some illness and there is no “chemical imbalance”. It’s time that we stop all this foolishness and get on with helping people to deal with their lives in effective and useful ways.

  5. I would like to offer a few points of clarification and a minority opinion–I hope that ketamineclincics and steve1930, especially, might read and respond. For starters, I am deeply suspicious of psychiatric drugs (and have been massively harmed by them myself) but feel it is important not to throw the baby out with the bathwater and believe ketamine has real value.

    I think the most important point that is often missed in these discussions is that, while the chemical imbalance theory is a terrible fallacy that has caused great harm, there are still biophysical issues at play. Intense abuse or neglect in childhood causes what can be considered a brain injury. For some people, psychological difficulties and historical trauma do not heal and progress the way they do for others–these are the people who seem to suffer endlessly despite trying different approaches, drug and non-drug. That doesn’t mean assisted brain-plasticity (which I believe is essentially what ketamine does) is necessary for everyone, or always necessary for anyone, but I think it is a serious mistake to simply kick this substance out with a jerk of the knee, given the fact that there really are people who’ve been suffering terribly and cannot find relief elsewhere. (And also that ketamine has been used at low doses for chronic pain for years and so far appears to be pretty safe.) Personally, I feel it can also be very helpful for people not in that category, especially because it does not inhibit psychological healing and growth the way most other psych drugs do, but can actually make it more possible, and thus does not necessarily need to be used long term. (There’s a recent issue of the journal of transpersonal psychology that speaks to this.)

    As for the article cited here, aside from conflicts of interest mentioned above (of course drug companies want to diss ketamine, it’s off patent and not a money-maker), it doesn’t really offer much, to my mind. I don’t think anyone working with ketamine these days would suggest that a single infusion can be a cure–that’s what the article seems to be evaluating, and it’s beside the point. From everything I can see, and I’ve looked at this carefully as it has evolved, ketclinics, above, is right that multiple infusions can give more lasting relief and periodic later infusions can sustain this for many people, as can more regular use of low doses–which really don’t have the addictive potential alluded to above (we’re talking tiny, tiny amounts compared to addictive street use).

    I also think Steve1930 (who is maybe Steven Hyde?), above, is right that low-dose ketamine is a very important alternative to the expensive medical procedures done at clinics. The book he cites discusses alternative (minority) research using very low doses, and also several doctors and researchers who’ve been working in this mode with considerable success. So why is this approach not even on the radar screen for most people in the states? I suspect it is some combination of war-on-drugs paranoia, the clinics being profitable, and perhaps some a priori assumption among researchers that high doses are necessary because ketamine’s primary use as an anaesthetic uses even much, much higher doses. And perhaps drug company influence–cf. the article at issue here.

    The book, “Ketamine for Depression” is self-published, so that does raise some concerns, but it appears to be an attempt to get the information out quickly and gives a thoughtful account of previous work that to my eye hangs together pretty well.

    So them’s my thoughts. I realize this could turn out to be a dead end, or worse, harmful, but I honestly don’t see much evidence of that, especially given how effective ketamine appears to be–it’s dramatic enough that I can’t see it as placebo at all. Mostly, I think it’s awfully important not to dismiss alternatives out of hand when people are suffering.

    • This is the way it is with the placebo effect. No one believes it and assumes it is the drug. It isn’t! This mistake has opened the door to billions of dollars for the drug industry and they have exploited it masterfully. Yet we know the placebo effect is very strong with depression. Administering ketamine via injection produces a powerful placebo effect. I would want to see the results of an unbiased placebo injection trial…go through all the same motions, but with water, or better, an injection fluid that produces side effects. Without that the claims made are baseless and highly suspect.

      I’ve been through the bio-psychiatry wringer and have given psychiatry a thorough rectal exam. There is a lot of smoke and mirrors going on and it is important to remain deeply skeptical. I see nothing convincing with ketamine that can’t be explained by the placebo effect. It’s the same old story – more unscientific bio-psychiatry nonsense.

      • Spatler, I agree this is important and perhaps I’m not giving enough attention. But is it not possible to write off just about everything this way (hey, maybe setting a broken bone is just placebo–I mean, where’s the double blind trial?) and is it not worth a little closer consideration than simply assuming any effect people find is placebo? My take is based on what I believe are pretty consistently strong positive effects with both infusions and low-dose, oral and adminstration, including a few trials with hospice patients using very low-dose oral for both pain and depression, a situation that would hardly indicate major placebo effect. Overall, the effect certainly seems much stronger than, for instance, SSRIs, which, even if you exclude negative results (as drug companies have done), are barely better than placebo–I think we could agree on that.

        But there is also perhaps something to look inductively vis. the experience of individuals. The accounts are pretty persuasive on a human level–do you feel they should simply be ignored? I mean, what WOULD you say to someone who has suffered for years, tried everything else, is pretty much crippled, and finds ketamine really helpful? Is that simply invalid in your eyes? Why not consider possibilities outside our own personal experience?

        • It works, right? Let’s be clear – that is not in question. I’m questioning the reason it works and am critical of that being presented as a drug effect. Where is the objective proof that ketamine does anything to help depression beyond the placebo response? How does it stack up against therapy, placebo, and nothing at all? Show me objective quantitative results. If it is for real it should be able to withstand this test and that should be done before it is peddled to unsuspecting patients as real medicine. It is simply another in an endless string of examples of the placebo effect being ignored and the results attributed to a mysterious drug effect.

          • Yes, I see that you are questioning the mechanism. I suppose we could both continue repeating “it’s all placebo” and “it’s not placebo,” but that feels to me disturblingly similar to “it’s all chemical imbalance.” There are a host of empirical “objective” studies anyone can find, just look them up or go to the citations of the meta-analysis referenced above and others listed in the book that Steve1930 mentions; I’ve looked them over and believe (as someone highly skeptical of drug approaches) that I see an effect strong enough to suggest something more than placebo. I understand that you disagree, but I’m not seeing a response to the specific points I’ve made, rather just a continued assertion of your belief.

            But also, I think demanding “objective” results in the forms of quantitative analysis is not the answer. “Statistical significance” is important, of course, at the population level (if the research any good), but that’s all about averages. Suffering happens to individuals, not populations, and treatments have variable results, especially so in this realm. So I think it’s important to also look at clinical experience and individual variation that controlled trials generally do not account for–I think we need to look at both, and to consider SUBjective evidence, as well as supposedly objective evidence (it can only ever be “relatively” objective, there is no such thing as purely objective). It’s all imperfect, there is no evidenciary silver bullet in this realm, or at least that’s my view, and it’s why I feel it quite important to stay open to possibilities, even as we can (I hope) agree that the big-pharma juggernaut has done enormous harm–please know that I am with you on that. Differences aside, I think we’re all mostly after the same thing here and so the more dialogue, and disagreement, even (!), the better, which is why I’ve tried to be specific and give others something to respond to.

  6. It’s good to see reasoned debate on a subject which is highly important to those who have not been helped by current treatments.
    On the issue of placebo effects, although there have been multiple double-blind placebo controlled trials these have mainly used saline as the placebo and it is hard to see people not being able to guess whether they are taking the ketamine. Some are now using midazolam as a placebo which is an improvement but it’s not exactly the same as ketamine in terms of it’s effects. Alcohol [most people taking low dose ketamine describe the experience to be like having a half glass of beer or wine] would possibly be better but this may have it’s own issues.
    The main problem in getting the large-scale trials which would provide more certainty is financial. Because ketamine is long out of patent the pharmaceutical companies have no incentive to invest in new indications for it’s use, so all of the recent studies have been done by poorly funded public facilities who have done very well within their limitations.
    As to dosage and the method of administration, most of the research has followed the initial intravenous protocol of the Berman study from 2000 and it is only recently that there has been a growing effort to look for approaches that are more practical and affordable than IV. There are some promising developments in the use of oral ketamine as evidenced by the work of Angelo De Gioannis who has treated over 600 patients in a clinic setting in Brisbane with results similar to the injection routes – his results are due to be published soon.
    So we are faced with the reality that the evidence we have is not perfect and we have people suffering and dying prematurely from treatment-resistant psychiatric illness. For me the benefits of trialing ketamine as part of a comprehensive treatment plan outweigh the short and long term risks about which we know a great deal, as ketamine has been used for round 50 years now in anesthesia, pain medicine and psychiatry.

  7. Steve,

    Perhaps I am missing something but your post seems contradictory to me. You keep saying alot is known about Ketamine but admit on the other hand, it is hard to set up adequate trials to prove its efficiency.

    And interestingly, you haven’t addressed my concerns that your talk about Ketamine sounds so similar to how previous psych meds were praised as the latest and greatest drugs only to fall flat on their face.

    Regarding Ketamine for anesthesia, as one who had practically zero complications with Propofol, h-ll would freeze over before I allowed that drug to be used in surgery.

  8. AA
    I guess I’m meaning that the evidence that ketamine is helpful is available and it is not perfect for some very practical reasons. However what is known is sufficient for doctors and their patients to have a discussion of the risks versus the benefits of trying it for treatment resistant conditions. Professor Collen Loo in Australia has just today received a 2 million dollar grant to conduct a multi-center trial on 200 patients using ketamine versus an active placebo which will give us more information to work with.
    In any field new treatments invariably go through phases of excitement then despondency before eventually settling into “this is useful for some but not all.”
    Ketamine is the most widely used anaesthetic in the world and is on the WHO list of “Essential Medicines” to be stocked at all hospitals. This is because of it’s safety profile due to mimimal effects on respiration and the cardiovascular system. It continues to be used to manage severe pain conditions as well as being widely used in veterinary medicine.