5 ms·

Ketamine has turned out to be a pretty effective treatment for episodes of severe depression, particularly when there is a risk of suicide; one reason is that i

Ketamine has turned out to be a pretty effective treatment for episodes of severe depression, particularly when there is a risk of suicide; one reason is that it starts having an effect in hours instead of days or weeks like SSRIs do. See Jessica Gilbert's work over at NIH [1]. One of the big focuses of clinical neuroscience is to find features in the brain that will predict treatment responses (to cognitive behavioral therapy, anti-depressants, and so on). The amygdala is, as is generally known, strongly associated with fear responses, or other negative emotional responses. The subgenual cingulate cortex has been associated with emotion regulation (e.g. down-regulating responses to negative stimuli). I believe that other treatment-prediction studies have found that connectivity between the subgenual cingulate and other brain regions like the amygdala predict treatment responses, so, their result is pretty consistent with the literature as far as I understand. 1. https://scholar.google.com/citations?user=bSXKfxkAAAAJ&hl=en&oi=sra https://scholar.google.com/citations?user=bSXKfxkAAAAJ&hl=en...

bheadmaster 4y ago
This sounds really promising, but one thing that worries me is that ketamine is a sort-of painkiller (dissociative anesthetic). When heroin was first discovered, it was hailed as a wonder-drug, and it was also considered an effective treatment for severe depression. However, after some time, people realized that its addictive properties and high range of potential tolerance make it backfire pretty badly after a certain amount of (ab)use. Can we be sure that a similar thing won't happen with ketamine?
- jonnycomputer 4y ago
  Good question. Ketamine has been a party drug for quite a while now, and as far as I know, hasn't been shown to be particularly dependency-inducing, though low-dose ketamine over the long term might be (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236511/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236511/) Also, as far as I know, ketamine treatment isn't intended as an ongoing medication, like an SSRI, but as a treatment for acute episodes of depression. I might be wrong about that; webmd says, "For treatment-resistant depression, patients usually get the nasal spray twice a week for 1 to 4 weeks; then once a week for weeks 5 to 9; and then once every week or 2 after that." However, the use-cases I know about (from talking to researchers studying it) is as an intervention to prevent suicide during severe depression (since it's relatively fast acting). As always, its a cost-benefit calculation, that should be carefully made in consultation with a professional. The cost of severe depression can be quite high.
  - engined 4y ago
    The WebMD article is referencing esketamine, also known as Spravato, which is an FDA authorized form of ketamine. It's generally indicated for longer-term use in patients with Treatment Resistant Depression (TRD), and has really good results on par with ketamine (IV or intramuscular). At Lumin Health, we treat about 80% of our patients with esketamine, and the rest with ketamine (generally only if they don't meet esketamine criteria). After the initial course, patients tend to find a good balance of ongoing care that helps treat their particular depression / depressive symptoms. This happens less with ketamine since it tends to be prohibitively expensive to continue care (upwards of $1k/month).
    - jonnycomputer 4y ago
      Do appreciate informed commentary; thank you. I work in a research lab studying depression and the brain, but am not a clinician (which is why I threw in a lot of caveats).
    - robocat 4y ago
      Any comments on https://slatestarcodex.com/2019/03/11/ketamine-now-by-prescription/ https://slatestarcodex.com/2019/03/11/ketamine-now-by-prescr... - presumably the doubts Scott had have now been answered?
      - oaktrout 4y ago
        For those who don't want to read the article, the highlights for me were: 1) esketamine may not work as well as ketamine and 2) esketsmine was invented to make pharm companies money because they couldn't do it with ketamine.
      - engined 4y ago
        In general, esketamine has been shown to have about the same efficacy as ketamine for Treatment Resistant Depression (TRD) and MDD. There seem to be some minor differences in bioavailability between esketamine and ketamine, but from experience, if one work, the other will, and if one doesn't, the other won't. Anecdotally, we've seen great results in a matter of weeks with patients who have had no success through numerous antidepressants, TMS, ECT, and other treatments. There is a long-term trial now in its 4th year with esketamine (https://clinicaltrials.gov/ct2/show/NCT02782104 https://clinicaltrials.gov/ct2/show/NCT02782104). I'm not sure how much has been published yet, but early data I saw supported immediate relief and long term benefit over the 4 years. In terms of it being a sinister ploy by pharma, it's definitely priced higher than its ketamine generic counterpart, but for the vast majority of our patients, ketamine treatment out of pocket (since its not covered by insurance) is absolutely unaffordable, and pursuing the insurer-covered version of treatment is a high-value option.
- etiam 4y ago
  From what I've heard ketamine is already (ab)used as a recreational drug since decades back and does have addiction risk. Not addiction risk anything like heroin though, and the trips are apparently mostly unpleasant. Ketamine in its present form is decidedly not ideal for depression treatment, but probably a tradeoff often worth considering compared to the risks of severe and enduring depression. Amine neurotransmittor reuptake inhibitors have quite substantial problems associated with them too (there we arguably really have had a case of the mistaken and excessive wonder-drug status you allude to). The true excitement of ketamine-based depression treatment is perhaps more in that it is something different. It quickly affects the problematic state, by some mechanism which appears to be quite different from the now "classical" antidepressants. That has potential both as a basis for more refined drugs and more importantly to better understand the real mechanisms underpinning depression.
  - cmrdporcupine 4y ago
    Exactly. Ketamine as a "party drug" is more something taken "to get f*cked up" rather than "to feel good." I've always found it odd that it caught on as a party drug, TBH. It's likely more to do with availability.
- chimeracoder 4y ago
  > one thing that worries me is that ketamine is a sort-of painkiller (dissociative anesthetic). The fact that two drugs both can be used as an anesthetic doesn't tell you very much besides that, especially when comparing across different drug classes. For example, cocaine and novocaine are both anesthetics that belong to the same drug class, and yet they have radically different risk profiles, despite both being commonly used in outpatient medical settings. Ketamine is in a completely different category of drugs from cocaine and novocaine, which are also totally different from opiates. It's a fallacy to assume that ketamine would be subject to the same issues as opiates just because both happen to be usable as anesthetics.
  - DontchaKnowit 4y ago
    I dont think its a fallacy. Its definitely a consideration. Ever met an nmda receptor agonist addict? its real shit. It aint pretty. And ive definitely seen it done as a sort of depression-relief-addiction. Had a close friend who I found out had been drinking like 2 or 3 bottles of cough syrup (over the counter, dextromethorphan) daily. She had a hell of a time kicking it. Idk if she ever did. People on these type of drugs long term end up with severe memory issues, fogfy brained all the time, and if its ketamine add in a completely obliterated bladder. I dont think this is an idea that can be dismissed trivially as a fallacy.
    - chimeracoder 4y ago
      > I dont think this is an idea that can be dismissed trivially as a fallacy. "Opiates are dangerous and they are anesthetics; therefore ketamine is dangerous because it's an anesthetic" is, literally, a textbook logical fallacy. If you'd like to argue that ketamine is dangerous based on some other reasoning, go ahead, but that doesn't change the fact that OP's logic is prima facie fallacious. > Ever met an nmda receptor agonist addict? I used to work in drug counseling, so, yes.
      - bheadmaster 4y ago
        > "Opiates are dangerous and they are anesthetics; therefore ketamine is dangerous because it's an anesthetic" is, literally, a textbook logical fallacy. Except that I never made that exact argument. Textbook strawman fallacy.
- trashface 4y ago
  Recreational users take it at far higher doses and that is why they are they are primarily at risk for addiction and other health complications. https://astralcodexten.substack.com/p/drug-users-use-a-lot-of-drugs https://astralcodexten.substack.com/p/drug-users-use-a-lot-o...

bheadmaster 4y ago

This sounds really promising, but one thing that worries me is that ketamine is a sort-of painkiller (dissociative anesthetic). When heroin was first discovered, it was hailed as a wonder-drug, and it was also considered an effective treatment for severe depression. However, after some time, people realized that its addictive properties and high range of potential tolerance make it backfire pretty badly after a certain amount of (ab)use. Can we be sure that a similar thing won't happen with ketamine?

jonnycomputer 4y ago
Good question. Ketamine has been a party drug for quite a while now, and as far as I know, hasn't been shown to be particularly dependency-inducing, though low-dose ketamine over the long term might be (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236511/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236511/) Also, as far as I know, ketamine treatment isn't intended as an ongoing medication, like an SSRI, but as a treatment for acute episodes of depression. I might be wrong about that; webmd says, "For treatment-resistant depression, patients usually get the nasal spray twice a week for 1 to 4 weeks; then once a week for weeks 5 to 9; and then once every week or 2 after that." However, the use-cases I know about (from talking to researchers studying it) is as an intervention to prevent suicide during severe depression (since it's relatively fast acting). As always, its a cost-benefit calculation, that should be carefully made in consultation with a professional. The cost of severe depression can be quite high.
- engined 4y ago
  The WebMD article is referencing esketamine, also known as Spravato, which is an FDA authorized form of ketamine. It's generally indicated for longer-term use in patients with Treatment Resistant Depression (TRD), and has really good results on par with ketamine (IV or intramuscular). At Lumin Health, we treat about 80% of our patients with esketamine, and the rest with ketamine (generally only if they don't meet esketamine criteria). After the initial course, patients tend to find a good balance of ongoing care that helps treat their particular depression / depressive symptoms. This happens less with ketamine since it tends to be prohibitively expensive to continue care (upwards of $1k/month).
  - jonnycomputer 4y ago
    Do appreciate informed commentary; thank you. I work in a research lab studying depression and the brain, but am not a clinician (which is why I threw in a lot of caveats).
  - robocat 4y ago
    Any comments on https://slatestarcodex.com/2019/03/11/ketamine-now-by-prescription/ https://slatestarcodex.com/2019/03/11/ketamine-now-by-prescr... - presumably the doubts Scott had have now been answered?
    - oaktrout 4y ago
      For those who don't want to read the article, the highlights for me were: 1) esketamine may not work as well as ketamine and 2) esketsmine was invented to make pharm companies money because they couldn't do it with ketamine.
    - engined 4y ago
      In general, esketamine has been shown to have about the same efficacy as ketamine for Treatment Resistant Depression (TRD) and MDD. There seem to be some minor differences in bioavailability between esketamine and ketamine, but from experience, if one work, the other will, and if one doesn't, the other won't. Anecdotally, we've seen great results in a matter of weeks with patients who have had no success through numerous antidepressants, TMS, ECT, and other treatments. There is a long-term trial now in its 4th year with esketamine (https://clinicaltrials.gov/ct2/show/NCT02782104 https://clinicaltrials.gov/ct2/show/NCT02782104). I'm not sure how much has been published yet, but early data I saw supported immediate relief and long term benefit over the 4 years. In terms of it being a sinister ploy by pharma, it's definitely priced higher than its ketamine generic counterpart, but for the vast majority of our patients, ketamine treatment out of pocket (since its not covered by insurance) is absolutely unaffordable, and pursuing the insurer-covered version of treatment is a high-value option.
etiam 4y ago
From what I've heard ketamine is already (ab)used as a recreational drug since decades back and does have addiction risk. Not addiction risk anything like heroin though, and the trips are apparently mostly unpleasant. Ketamine in its present form is decidedly not ideal for depression treatment, but probably a tradeoff often worth considering compared to the risks of severe and enduring depression. Amine neurotransmittor reuptake inhibitors have quite substantial problems associated with them too (there we arguably really have had a case of the mistaken and excessive wonder-drug status you allude to). The true excitement of ketamine-based depression treatment is perhaps more in that it is something different. It quickly affects the problematic state, by some mechanism which appears to be quite different from the now "classical" antidepressants. That has potential both as a basis for more refined drugs and more importantly to better understand the real mechanisms underpinning depression.
- cmrdporcupine 4y ago
  Exactly. Ketamine as a "party drug" is more something taken "to get f*cked up" rather than "to feel good." I've always found it odd that it caught on as a party drug, TBH. It's likely more to do with availability.
chimeracoder 4y ago
> one thing that worries me is that ketamine is a sort-of painkiller (dissociative anesthetic). The fact that two drugs both can be used as an anesthetic doesn't tell you very much besides that, especially when comparing across different drug classes. For example, cocaine and novocaine are both anesthetics that belong to the same drug class, and yet they have radically different risk profiles, despite both being commonly used in outpatient medical settings. Ketamine is in a completely different category of drugs from cocaine and novocaine, which are also totally different from opiates. It's a fallacy to assume that ketamine would be subject to the same issues as opiates just because both happen to be usable as anesthetics.
- DontchaKnowit 4y ago
  I dont think its a fallacy. Its definitely a consideration. Ever met an nmda receptor agonist addict? its real shit. It aint pretty. And ive definitely seen it done as a sort of depression-relief-addiction. Had a close friend who I found out had been drinking like 2 or 3 bottles of cough syrup (over the counter, dextromethorphan) daily. She had a hell of a time kicking it. Idk if she ever did. People on these type of drugs long term end up with severe memory issues, fogfy brained all the time, and if its ketamine add in a completely obliterated bladder. I dont think this is an idea that can be dismissed trivially as a fallacy.
  - chimeracoder 4y ago
    > I dont think this is an idea that can be dismissed trivially as a fallacy. "Opiates are dangerous and they are anesthetics; therefore ketamine is dangerous because it's an anesthetic" is, literally, a textbook logical fallacy. If you'd like to argue that ketamine is dangerous based on some other reasoning, go ahead, but that doesn't change the fact that OP's logic is prima facie fallacious. > Ever met an nmda receptor agonist addict? I used to work in drug counseling, so, yes.
    - bheadmaster 4y ago
      > "Opiates are dangerous and they are anesthetics; therefore ketamine is dangerous because it's an anesthetic" is, literally, a textbook logical fallacy. Except that I never made that exact argument. Textbook strawman fallacy.
trashface 4y ago
Recreational users take it at far higher doses and that is why they are they are primarily at risk for addiction and other health complications. https://astralcodexten.substack.com/p/drug-users-use-a-lot-of-drugs https://astralcodexten.substack.com/p/drug-users-use-a-lot-o...