Ketamine and the disinhibition hypothesis - how subanesthetic doses may trigger excitatory mechanisms and therapeutic effects

[Neuropharmacist]

Greetings!

I'm a neuropharmacologist studying the mechanisms of rapid-acting antidepressant treatments like ketamine. I've been reading bluelight occasionally for the past 15 years. Having recently started a Youtube-channel discussing various neuropharmacological topics, I thought there might be people interested in my content on the board. Please let me know if self-promotion is not allowed, I couldn't quickly find anything in the rules.

Let's get to the topic of the title: Ketamine and the disinhibition hypothesis. This is one of the most central hypotheses regarding the ability of subanesthetic doses of ketamine to produce therapeutic effects. Essentially, it states that at lower doses, ketamine preferentially binds to NMDA-receptors on GABAergic interneurons, leading to the disinhibition of excitatory neurons, facilitation of glutamate bursting and ultimately the activation of cellular signaling mechanisms that promote synaptic plasticity. High anesthetic doses, at least based on rodent studies and some human evidence, cause the opposite (e.g. inhibition and reduction of glutamate release) by blocking NMDARs all over. But I also believe that once the high doses start to come down, there may still exist a "sweet spot" where ketamine starts to disinhibit again. This may be similar to other anesthetics, which often cause emergence delirium and excitatory effects upon waking from the anesthesia.

I'd love to hear any thoughts on these putative mechanisms, as well as personal experiences from those suffering from depression and having experienced different ketamine doses.

 

[MsDiz]

Greetings!

I'm a neuropharmacologist studying the mechanisms of rapid-acting antidepressant treatments like ketamine. I've been reading bluelight occasionally for the past 15 years. Having recently started a Youtube-channel discussing various neuropharmacological topics, I thought there might be people interested in my content on the board. Please let me know if self-promotion is not allowed, I couldn't quickly find anything in the rules.

Let's get to the topic of the title: Ketamine and the disinhibition hypothesis. This is one of the most central hypotheses regarding the ability of subanesthetic doses of ketamine to produce therapeutic effects. Essentially, it states that at lower doses, ketamine preferentially binds to NMDA-receptors on GABAergic interneurons, leading to the disinhibition of excitatory neurons, facilitation of glutamate bursting and ultimately the activation of cellular signaling mechanisms that promote synaptic plasticity. High anesthetic doses, at least based on rodent studies and some human evidence, cause the opposite (e.g. inhibition and reduction of glutamate release) by blocking NMDARs all over. But I also believe that once the high doses start to come down, there may still exist a "sweet spot" where ketamine starts to disinhibit again. This may be similar to other anesthetics, which often cause emergence delirium and excitatory effects upon waking from the anesthesia.

I'd love to hear any thoughts on these putative mechanisms, as well as personal experiences from those suffering from depression and having experienced different ketamine doses.

I liked the video, it’s not for the layman but we have plenty of scientist’s on the forum that will take something out of it.

I have actually piloted several rodent studies involving ketamine. Whilst there are interesting results I still haven’t seen enough data from human trials to make any solid statements in regards to ketamine’s role in helping depression.

 

[Neuropharmacist]

I liked the video, it’s not for the layman but we have plenty of scientist’s on the forum that will take something out of it.

I have actually piloted severely rodent studies involving ketamine. Whilst there are interesting results I still haven’t seen enough data from human trials to make any solid statements in regards to ketamine’s role in helping depression.

Thank you!

What do you mean by saying that there isn't enough human data to make solid statements about the effects of ketamine in treating depression? It has been studied in this context for the past 20 years and there is an approved formulation in the market for the treatment of depression. Moreover, there are more than 20 clinical trials supporting its antidepressant action. While I agree with the fact that ketamine's role in the treatment hasn't been fully established -- meaning that its unclear how useful it is in the long-term etc. -- I'd still say there is overwhelming evidence to support the notion that subanesthetic ketamine is an effective rapid-acting antidepressant, with surprisingly good efficacy in treatment resistant patients.

 

[MsDiz]

Thank you!

What do you mean by saying that there isn't enough human data to make solid statements about the effects of ketamine in treating depression? It has been studied in this context for the past 20 years and there is an approved formulation in the market for the treatment of depression. Moreover, there are more than 20 clinical trials supporting its antidepressant action. While I agree with the fact that ketamine's role in the treatment hasn't been fully established -- meaning that its unclear how useful it is in the long-term etc. -- I'd still say there is overwhelming evidence to support the notion that subanesthetic ketamine is an effective rapid-acting antidepressant, with surprisingly good efficacy in treatment resistant patients.

Any scientist will tell you, it’s too early to tell how ketamine will preform long term in regards to treatment for depression. We don’t even know the method of action fully.

Is it an interesting and exciting treatment option now? Of course and the human trials are great but I remain skeptical, as any scientist should.

I’m excited to see what you’re going to bring to the forum. I encourage you to read the threads and get involved.

 

[thegreenhand]

it’s too early to tell how ketamine will preform long term in regards to treatment for depression

That hasn’t stopped doctors from throwing SSRIs at us either, to be fair


@Neuropharmacist any thoughts on esketamine? I know there was some hype in the US when it was approved. Do you think there is any benefit of S over racemic or R ketamine?

 

[Neuropharmacist]

@Neuropharmacist any thoughts on esketamine? I know there was some hype in the US when it was approved. Do you think there is any benefit of S over racemic or R ketamine?

I don't think S-ketamine has any significant advantage over racemic. However, while there are many studies showing the effectiveness of racemic ketamine, there aren't that many looking at the effects of the S-isomer. As far as I remember, there are some studies that have demonstrated non-inferiority of e.g. 0.25 mg/kg of S-ketamine when compared to 0.5 mg/kg racemic iv.

The intranasal S-ketamine studies gave me the impression it was rather ineffective -- at least when compared to intravenous racemic ketamine. But then again, there aren't that many studies with intranasal racemic, and even less, if any, well designed head-to-head comparisons between routes of administration. And as a side note, the price for the intranasal formulation is out of this world, given that ketamine doesn't really cost any money to produce.

 

[Neuropharmacist]

Any scientist will tell you, it’s too early to tell how ketamine will preform long term in regards to treatment for depression. We don’t even know the method of action fully.

Is it an interesting and exciting treatment option now? Of course and the human trials are great but I remain skeptical, as any scientist should.

I’m excited to see what you’re going to bring to the forum. I encourage you to read the threads and get involved.

I've been talking to some of the leading researchers in the field, both clinical and preclinical, and I think we all agree that ketamine is here to stay. There just aren't that many options for certain situations, where you need rapid relief of depression (or suicidality). I don't think people working with ketamine research and actually treating patients have any doubts about the effectiveness of ketamine. I place ketamine right next to ECT. The discussion of whether ketamine will ever become a drug that is used weekly for the rest of your life is a different story.

And I do appreciate healthy skepticism, but with ketamine, I think we've reached the threshold where we can actually say it's a rapid-acting antidepressant.

Happy to join the discussion!

 

[thegreenhand]

I don't think S-ketamine has any significant advantage over racemic. However, while there are many studies showing the effectiveness of racemic ketamine, there aren't that many looking at the effects of the S-isomer. As far as I remember, there are some studies that have demonstrated non-inferiority of e.g. 0.25 mg/kg of S-ketamine when compared to 0.5 mg/kg racemic iv.

The intranasal S-ketamine studies gave me the impression it was rather ineffective -- at least when compared to intravenous racemic ketamine. But then again, there aren't that many studies with intranasal racemic, and even less, if any, well designed head-to-head comparisons between routes of administration. And as a side note, the price for the intranasal formulation is out of this world, given that ketamine doesn't really cost any money to produce.

yeah that was sort of my thought too. it seemed like a money grab. but here in the US IV ketamine is ridiculously expensive too so who knows.

 

[AnnEOakley]

I've been talking to some of the leading researchers in the field, both clinical and preclinical, and I think we all agree that ketamine is here to stay. There just aren't that many options for certain situations, where you need rapid relief of depression (or suicidality). I don't think people working with ketamine research and actually treating patients have any doubts about the effectiveness of ketamine. I place ketamine right next to ECT. The discussion of whether ketamine will ever become a drug that is used weekly for the rest of your life is a different story.

And I do appreciate healthy skepticism, but with ketamine, I think we've reached the threshold where we can actually say it's a rapid-acting antidepressant.

Happy to join the discussion!

I’m my experience, yes ketamine is as if not more effective than ECT for my depression. Problem is that I can get the antidepressant effect to last more than 3 days so far. That is an exquisitely difficult roller coaster: to feel so alive and free from despair for 3 days only to want to curl up in despair on day 4 until the next treatment. I really am looking for any information on how to extend the duration of the antidepressant effect … even if just to 7 days would be amazing. This is like miraculously life saving except then suddenly it’s heartbreakingly over.

 

[G_Chem]

I was talking to a physician recently that runs a “memory clinic” and he was saying they are seeing major positive outcomes in comparison to ECT. He said himself patients who undergo ECT seems to turn their brain to mush with many memory deficits, but K gives all the benefits with none of drawbacks.

@Neuropharmacist or anyone for that matter. What’s the thoughts on the antidepressant efficacy of K when administered intranasal VS IV/IM?

-GC

 

[AnnEOakley]

Yes. I had memory loss from ECT. I wouldn’t say it turns your brain to mush but there can be memory issues. I’ve had no cognitive issues with ketamine. However, ECT has a much more guaranteed efficacy for ultimate success of alleviating depression. Ketamine has a lower efficacy rate. When it works it’s better than ECT but they are apples and oranges in a way.

 

[G_Chem]

Yes. I had memory loss from ECT. I wouldn’t say it turns your brain to mush but there can be memory issues. I’ve had no cognitive issues with ketamine. However, ECT has a much more guaranteed efficacy for ultimate success of alleviating depression. Ketamine has a lower efficacy rate. When it works it’s better than ECT but they are apples and oranges in a way.

My apologies that was rude language and not accurate as you said, he meant it in the context of memory issues not in a literal sense. But unfortunately doctors have a way of saying things almost too crudely.

When I had cancer come back the doctor said quote: “you’ve got a tumor the size of a pear in your stomach.” After seeing the dimensions he was exaggerating and if anything talking about a very small pear, but simply saying it like that really is far from helpful.

-GC

 

[Neuropharmacist]

@Neuropharmacist or anyone for that matter. What’s the thoughts on the antidepressant efficacy of K when administered intranasal VS IV/IM?

-GC

I did a quick review last year (https://link.springer.com/article/10.1007/s43440-021-00232-4) and at the time of writing I could not find any solid evidence to draw proper conclusions on the matter. My general feeling is that intranasal racemic might be somewhat comparable to IV. With S-ketamine, however, there are some studies that suggest it might not be very effective, at least intranasally. If I remember correctly, some studies suggest racemic IV is superior to intranasal esketamine.

 

[Skorpio]

Greetings!

I'm a neuropharmacologist studying the mechanisms of rapid-acting antidepressant treatments like ketamine. I've been reading bluelight occasionally for the past 15 years. Having recently started a Youtube-channel discussing various neuropharmacological topics, I thought there might be people interested in my content on the board. Please let me know if self-promotion is not allowed, I couldn't quickly find anything in the rules.

Let's get to the topic of the title: Ketamine and the disinhibition hypothesis. This is one of the most central hypotheses regarding the ability of subanesthetic doses of ketamine to produce therapeutic effects. Essentially, it states that at lower doses, ketamine preferentially binds to NMDA-receptors on GABAergic interneurons, leading to the disinhibition of excitatory neurons, facilitation of glutamate bursting and ultimately the activation of cellular signaling mechanisms that promote synaptic plasticity. High anesthetic doses, at least based on rodent studies and some human evidence, cause the opposite (e.g. inhibition and reduction of glutamate release) by blocking NMDARs all over. But I also believe that once the high doses start to come down, there may still exist a "sweet spot" where ketamine starts to disinhibit again. This may be similar to other anesthetics, which often cause emergence delirium and excitatory effects upon waking from the anesthesia.

I'd love to hear any thoughts on these putative mechanisms, as well as personal experiences from those suffering from depression and having experienced different ketamine doses.

I'm probably a bit late on this, but I'm fine with you promoting your videos. I am always happy to have voices in this forum that are close to the bench.

I've got a few questions for you, as you seem pretty involved in the whole ketamine scene. I kind of scanned a few of your publications, but I didn't go beyond abstracts so forgive me if these are obvious questions.

What are your thoughts on the Monteggia v Zarate " feud" regarding HNK as a mediator of antidepressive effects?

Your 2019 Neuropharmacology paper talks about how HNK doesn't impinge on Trkb and gsk3b signaling, do you believe that the AMPA signaling and the effects on mTOR contribute to the total antidepressant power of ketamine (ie the 2016 Zanos Nature paper) ? (I guess as a followup to that, do you know any studies that compare the deuterated ketamine vs HNK with behavioral assays?)

Also the isoflurane work is pretty cool, how would you compare the antidepressant potential of volatile anesthetics vs ketamine (like do you think the broad range of ion channel effects of the volatiles is beneficial or a negative?)


Do you have thoughts on that 2020 PNAS paper that cites phospholipase D as an upstream regulator of ion channel function for different gaseous anesthetics? I like the simplicity of that explanation, but I am curious to how different anesthetics alter the function of different ion channels in varying manners if this mechanism is truly conserved.

 

[AnnEOakley]

My apologies that was rude language and not accurate as you said, he meant it in the context of memory issues not in a literal sense. But unfortunately doctors have a way of saying things almost too crudely.

When I had cancer come back the doctor said quote: “you’ve got a tumor the size of a pear in your stomach.” After seeing the dimensions he was exaggerating and if anything talking about a very small pear, but simply saying it like that really is far from helpful.

-GC

No offense taken. The memory issues are often distressing. I just like to destigmatize ECT because it can be a lifesaver, when all else fails.

 

[Neuropharmacist]

I'm probably a bit late on this, but I'm fine with you promoting your videos. I am always happy to have voices in this forum that are close to the bench.

I've got a few questions for you, as you seem pretty involved in the whole ketamine scene. I kind of scanned a few of your publications, but I didn't go beyond abstracts so forgive me if these are obvious questions.

What are your thoughts on the Monteggia v Zarate " feud" regarding HNK as a mediator of antidepressive effects?

Your 2019 Neuropharmacology paper talks about how HNK doesn't impinge on Trkb and gsk3b signaling, do you believe that the AMPA signaling and the effects on mTOR contribute to the total antidepressant power of ketamine (ie the 2016 Zanos Nature paper) ? (I guess as a followup to that, do you know any studies that compare the deuterated ketamine vs HNK with behavioral assays?)

Also the isoflurane work is pretty cool, how would you compare the antidepressant potential of volatile anesthetics vs ketamine (like do you think the broad range of ion channel effects of the volatiles is beneficial or a negative?)


Do you have thoughts on that 2020 PNAS paper that cites phospholipase D as an upstream regulator of ion channel function for different gaseous anesthetics? I like the simplicity of that explanation, but I am curious to how different anesthetics alter the function of different ion channels in varying manners if this mechanism is truly conserved.

The HNK debate is interesting. I've made a simple video on HNK as well

I personally have a hard time believing that the antidepressant effects of ketamine would be mediated by HNK. Perhaps it plays some role, at least in the effects observed in rodents, but I still like to think NMDA antagonists in general have antidepressant potential. Clinical trials are underway and will hopefully answer this question in the near future.

The 2019 Neuropharmacology paper did indeed suggest that HNK doesn't contribute to the observed TrkB signaling in terms of increased phosphorylation. The funny thing is that I've never seen a subanesthetic dose of ketamine activate TrkB either, yet this is the prevailing paradigm. There are very few studies that show actually show increased TrkB phosphorylation after subanesthetic ketamine. I have some interesting results coming up related to these neurotrophic pathways in relation to antidepressants, but I will not delve deeper into the results before the papers are published. Indeed, mTOR is also considered another key player (10.1126/science.1190287), but there have also been difficulties in replicating the key findings (https://f1000research.com/articles/5-634). Altogether I'd say that I am not very convinced at any single pathways or molecular markers being as critical as some studies have suggested. The cascade of events is very complex and the understanding of these events is very limited.

Isoflurane appears to have antidepressant potential, but more studies are needed. At this time, any comparisons are impossible, as its clinical efficacy has not even been established.

The 2020 PNAS paper I'm not really familiar with at this time.

 

[ecstacylover]

I personally have a hard time believing that the antidepressant effects of ketamine would be mediated by HNK. Perhaps it plays some role, at least in the effects observed in rodents, but I still like to think NMDA antagonists in general have antidepressant potential. Clinical trials are underway and will hopefully answer this question in the near future.

Not a clinical trial, but HNK plasma levels are negatively associated with antidepressant response to ketamine in humans. [ref] That's pretty suggestive that ketamine's AD effects are HNK-independent. Of course HNK could still have AD activity, it just seems ketamine is much more potent in that regard.