from Hacker News

Ketamine no better than placebo at alleviating depression, unusual trial finds

by theNewMicrosoft on 5/22/23, 4:35 AM with 189 comments

• by cameronh90 on 5/22/23, 11:11 AM

  > They gave volunteers ketamine while they were under general anesthesia, theoretically preventing the participants from going on a trip.

  Maybe it's the trip that helps.

• by throwawaaarrgh on 5/22/23, 12:09 PM

  Amazingly, talk therapy also is no better at reducing depression than placebo while under general anesthesia.

• by cypherpunks01 on 5/22/23, 12:53 PM

  This is rubbish. Ketamine is a life-saver and has been proven to relieve depression, regardless of the administration setting. It is not magic and does not work in every case, but the effects are proven across countless studies. S-ketamine has even gone fully through FDA approval.

  Personally I have used it at home, and at a treatment center. There is no difference in the antidepressant properties, whether someone was helping me administer it in a medical setting, or not. The antidepressant properties do not relate to the effects of simply being in a clinical trial.

  I strongly believe the antidepressant properties arise from the psychedelic/dissociative experience, and not directly from the physical effects. I'm not terribly surprised that ketamine may not produce strong antidepressant effects if the patient is not conscious.

  Anyone looking to read more about ketamine antidepressant properties should read "The Ketamine Papers: Science, Therapy, and Transformation" by Phil Wolfson, M.D., and Glenn Hartelius, Ph.D.

• by mtlmtlmtlmtl on 5/22/23, 11:35 AM

  Unusual is an understatement. This just seems ill-conceived to me. You can't eliminate one effect on the brain by introducing other effects on the brain that might have their own consequences for the results.

  All this shows is that ketamine while under general anaesthesia is not more efficacious than placebo. Ok then. This just seems like a failed attempt to introduce better blinding to me. I'm not convinced it sheds any light on the mechanism by which ketamine is effective.

• by rozab on 5/22/23, 11:55 AM

  I think the criticism of this is unfair, and this result will help shed light on the mechanism. Look at the current theories for molecular mechanisms:

  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999402/

  If these are accurate does it make sense for them to be entirely inhibited by general anesthetic?

• by dimal on 5/22/23, 6:08 PM

  Terribly misleading link-bait headline. The authors were specifically trying to determine whether the hallucinogenic effects are related to the antidepressant effects, so they blunted the hallucinogenic effects by applying ketamine while under general anesthesia. They found that in that case, there was no effect on depression. So the study showed that the hallucinations are a key part of the depression treatment, not that ketamine is no better than placebo. But now I’m sure that this will be cited by people in shitposts based on the title. Science should know better.

• by peterlk on 5/22/23, 11:07 AM

  > In a new study that is yet to be peer reviewed

  Thank you very, very much to the author for saying this

• by cubefox on 5/22/23, 1:29 PM

  > But it’s a problem for researchers running double-blinded clinical trials, as participants can usually tell whether they have received ketamine or a placebo. [...] The scientists gave the volunteers ketamine or saline as placebo right after they were put under anesthesia, but before their surgery, essentially blinding them to any psychedelic or dissociative effects.

  That's a genius way to avoid unblinding. All psychoactive treatment trials have this problem: placebo controlled studies rely on patients not being able to distinguish whether they are in the test group or the control group. I hope future studies (say, for psilocybin) can also use this study design.

• by arthur2e5 on 5/22/23, 12:24 PM

  This kind of headline made some round in Twitter a while ago and got justifiably ridiculed, so let me repeat those old points here.

  The study states "agents used for anesthetic maintenance included intravenous propofol and inhaled sevoflurane or isoflurane." All three have some known antidepressant activity:

  - propofol: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276046/ (This story was pretty big back then, as propofol's a common electeoconvulsion anesthetic.)

  - sevoflurane: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851135/ (tiny sample, but idea comes from other tiny samples where it worked)

  - isoflurane: https://pubmed.ncbi.nlm.nih.gov/23922809/

  Does it mean this study is meaningless? No, but it definitely does not prove what the abstract wants to say. What it does show is well-summarized in https://news.ycombinator.com/item?id=36030251.

  See replies under https://twitter.com/jonahdavids1/status/1654842991331213313.

  (And no, having general anesthesia work about as well as ketamine does not make ket useless either. Ket is less likely to stop you from breathing. And you can stay awake, even non-hallucinating [see: nasal sprays], while it works.)

• by MagicMoonlight on 5/22/23, 12:37 PM

  Hmm so people report better symptoms when they know they’re being given recreational drugs but report no change when they’re not sure what they got.

• by zosima on 5/22/23, 6:18 PM

  Some points:

  1. Depression is measured by severity on the MADRS scale. But the Ketamine group seems to have started out less depressed than the Placebo group. Thus the placebo group had further to fall. Normally this will be adjusted away when calculating treatment effect, but seems not to have been done here. I think if it had been done ketamine would have had a slight (but highly nonsignificant) edge over placebo in the linear model.

  2. Many of the patients are already on some kind of depression treatment, going into the study. This is kind of odd.

  3. 5 of the patients in the ketamine group had experience with ketamine previously, but only 1 in the placebo group. Were those having experience with ketamine insensitive to it, as they seem to have become depressed again? Or did they believe they'd be insensitive to it?

  4. Sample sizes are small, and usually larger sample sizes are needed to see efficacy in depression trials, even in highly efficacious treatments.

  5. The so-called routine surgery may have been fairly anxiety-inducing for the patients and getting it done could have made them feel quite a lot better by itself. That effect may be stronger than any medication effect.

  6. Yeah, of course, this doesn't tell anything on whether ketamine has efficacy against MDD or not. Just that it could look like the efficacy of ketamine +(extra) anesthesia is about the same as anesthesia by itself against MDD, upto 14 day post-treatment.

• by ketaminethrow on 5/22/23, 12:04 PM

  I've been taking oral ketamine for about 2 years now. Not super frequently, probably ~6-10x/year. I feel like it's been a pretty helpful addition to my life, but it's not what I expected at all.

  To me, ketamine isn't really "enjoyable" or seem to modify my mood directly or anything like that. What it does do is shift my perspective for a few minutes and makes me introspective in ways I can only see as healthy.

  Sometimes I think about my wife, my children, my finances, my work, my parents, cleaning the bathroom, whatever life issues I might be struggling with at that moment but the perspective shift brings a clarity to the issue and the solution seems obvious. I often want to jump off the couch and feel invigorated and motivated. (Of course ketamine also makes you fatigued so it's a bit of a strange mix of feelings). I mentally want to do things but physically I am not able to—that's fine though.

  I'm also an experienced meditator and have done traditional psychedelics, neither of those have improved my life as much as ketamine has. Meditation is simply really hard for me despite over a decade of trying and failing to make it a daily habit. Psychedelics work very well for introspection, but they're also terrifying and in my mid-30's I am pretty sure this is something I'm content with not needing to deal with again.

  I once heard someone say that psychedelics are like color TV and ketamine is black-and-white. Somehow this describes the feeling exactly to me. Ketamine isn't nearly as intense as LSD/psilocybin and that's the best part IMO.

  My life is in relatively good shape, but a monthly-ish tune-up with ketamine seems to have really been effective.

• by blcknight on 5/23/23, 2:39 AM

  Ketamine saved my life. It’s proven to be extremely effective against suicidal ideation. The trip is definitely part of it.

  I’ve switched to shrooms and one trip every 3-6 months seems to reliably keep depression and panic disorder at bay. It did require some work and I really had to process some awful memories from my childhood.

  But these things did more for me than years of psychiatric meds ever did - literally dozens of them. Mirtazapine made me gain weight - 60 lbs in a year. Prozac gave me bruxism and I cracked 3 dental crowns in a month. Effexor turned me into a suicidal yet somehow also emotionless zombie. I got addicted to Ativan and couldn’t sleep without it. I’m off it all, and happier than I’ve ever been.

• by zone411 on 5/22/23, 11:59 AM

  Nothing against the study, it seems interesting. But the article title is quite misleading considering that ketamine is not typically administered under general anesthesia for treating depression.

• by insane_dreamer on 5/22/23, 1:32 PM

  Interesting study. However, I would argue that the study introduces an additional confound (anesthesia) rather than removing a confound (in order to isolate the effectiveness of ketamine).

• by kraussvonespy on 5/22/23, 7:12 PM

  n=1 and all but ketamine is the only med out of 30+ that I've tried for my TRD over the last 40+ years that actually helped me long term. Every other med either had side effects that were worse than being depressed or they just didn't work beyond the first few weeks which I attribute to the initial placebo effect.

  What I try to stress to people who ask is that ketamine is a powerful agent of neuroplasticity. So, so many people expect to take a pill and just feel better. With ketamine, you have to stay as positive as you can before, during and for days afterwards to reprogram your brain to be more positive. The people that I know that have had success with ketamine are those that either had therapists working with them during or right after the experience, or those who followed the "must work hard at being positive for 2-3 days after taking ketamine" advice.

  This is a med that I suspect you could actually damage yourself permanently if you just take the med and then go right back to doomscrolling social media or something similarly negative. The initial experience can make you feel better for a day or two, which is huge because no other antidepressant has that kind of quick impact. But if you work at it during that 2-3 days after, you can become a more positive person permanently.

  I'm hoping that it gets more accepted over time and can be prescribed by psychiatrists because compared to most other "here's some pills, hopefully you'll feel better in 6 weeks and if not, we'll give you more pills that will hopefully work in 6 weeks" depression meds, it works really fast. For someone on the verge of suicide, it can be a truly miracle med.

• by EMM_386 on 5/22/23, 5:22 PM

  Got Ketamine in the ER to reduce my dislocated shoulder.

  Fell into what addicts refer to as the "k-hole".

  Felt I was falling into a complete void. All I can remember is yelling "no, no, NO!".

  Highly NOT recommended.

• by waythenewsgoes on 5/22/23, 12:58 PM

  This study seems inherently flawed to me, how are you isolating what is happening while simultaneously administering other brain—chemistry altering drugs to the patient? These patients are all undergoing surgery, yet another variable with drastic consequences on mental health. Just taking the drug alone doesn’t even seem to accurately reflect the primary treatment path of having talk therapy while the drug is taking effect. What if the anesthesia simply inhibits the drug from working? Additionally the sample size (40 people) is extremely small to extrapolate this to the general population. I’m not sure how these flaws can be reconciled.

• by 1letterunixname on 5/22/23, 4:15 PM

  Did they double blind all 4 combinations? K+A, K, A, and control?

  IIRC, K is primarily useful for TRD when nothing else works.

• by ablyveiled on 5/22/23, 5:49 PM

  As an ex-depressive, the best cure for depression I've found is a period of ketogenic dieting.

• by huuhee3 on 5/22/23, 11:19 AM

  Then it's still no worse than widely used SSRI's, which also mostly don't differ from placebo

• by hprotagonist on 5/22/23, 11:56 AM

  which form of ketamine?

• by bjt2n3904 on 5/22/23, 12:44 PM

  Psychiatry, having failed to measurably solve any "mental health" problem is so desperate to find a solution that it's sampling the recreational drug cabinet. This isn't science. This isn't medicine. This is rolling back the clock to witch doctors and medicine men.

  Can't be depressed if your mind has been chemically lobotomized.