17 replies to this topic

[vere]

I wanted to start a discussion about mGluR 2 & 3 antagonists as a potential treatment for depression. I am finding a lot of promising research in this area for treating my own depression, which is mostly emotional flatness and anhedonia. I think this could potentially help a lot of people with depression like my own, and I’m curious to hear what others think.

 

Note:

 

I am focusing specifically on mGluR 2 & 3 antagonists here because it relates to my knowledge of what has helped my depression, and it may help other people with conditions like my own. But, there is also evidence that mGluR 2 & 3 agonism, as well as mGlur 5 antagonism could be helpful for different types of depression and I’d welcome people to discuss those as well if they feel it would help them.

 

I’m loosely summarizing some important points that I’ve gathered from reading through a bunch of studies and articles, as well as making some of my own conclusions based on my own experiences. Some sources that have been helpful to me are at the bottom of this post. As a disclaimer, I’m no professional on this, so please correct me or dispute if I’ve made connections that are incorrect/misunderstood something/phrased something improperly/oversimplified theories. I’m just someone trying to help myself and others by collecting and trying to make sense of all this information.

 

• Metabotropic glutamate receptors (mGluRs 1-8) are being investigated as potential targets for depression because they modulate the glutamate transmission in various ways. They are possibly a more natural alternative to NMDA antagonists in affecting the glutamate system, since they are responsible for modulation, but not fast neurotransmission like the ionotropic glutamate receptors (NMDA, AMPA, kainate.)

 

• The normal function of mGluRs 2 & 3 is the inhibition of presynaptic glutamate release. So, when mGluRs 2 & 3 are agonized/potentiated, it results in inhibition of glutamate release.

 

• Conversely, antagonizing enhances presynaptic glutamate release, which is what I am focusing on here and what I believe to have a lot of therapeutic potential for those who are worsened by conventional antidepressants like myself.

 

• It seems that upregulation of mGluRs 2 & 3 may even be involved directly in the pathology of depression. mGluRs 2 & 3 are thought to upregulate with “aversive stimuli”/chronic stress.

 

• It seems to me that some of the long-term effects of administering convential antidepressants like SSRIs focus on reducing or moderating overactive glutamate transmission. mGluR 2 & 3 agonists would support this mechanism, as would mGluR 5 antagonism. This may help certain types of depression.  

 

I have not been helped by this theory, but likely worsened by it, as have many others, which is why I am looking to mGluR 2 & 3 antagonists, which result in the same kind of increase in pre-synaptic glutamate release as is seen with ketamine. Ketamine is one of the only treatments that has given me my ability to care and my feelings back (albeit for a short time period) and I think it helps a lot of people who don’t respond to anything else.

 

• Similar to ketamine, mGluR 2 & 3 blockade results in an increase in presynaptic glutamate release, which stimulates AMPA receptor activation and then enhances mTOR signaling. mTOR signaling is the pathway which is thought to lead to synaptic growth.

 

• mGluR 2&3 antagonists like research chemical LY341495 are actually said to enhance the antidepressant effects of ketamine when administered with it and have been studied as an adjunct to ketamine in order to be able to use lower doses of ketamine.

 

• Blockade of mTOR by mTOR antagonist rapamycin with administration of mGluR 2&3 antagonists blocks the sustained antidepressant effects. But, it does not block the acute effects, indicating that mTOR is not responsible for these acute effects.

 

• Blockade of AMPA receptors with administration of mGluR 2 & 3 antagonists blocks the acute antidepressant effects, just like with ketamine. This suggests that the antidepressant effects of both ketamine and mGluR 2&3 antagonists are mediated by AMPA somehow.

 

• Blocking AMPA also results in the blockade of dopamine release in the nucleus accumbens. So it is thought that the AMPA receptor activation with mGluR 2 & 3 antagonists is what contributes to the release of dopamine in the nucleus accumbens. Dopamine release in the nucleus accumbens is said to be a key part of the brain for motivation/reward. So mGluR 2&3 antagonists cause this release of dopamine that may also in part be important to its antidepressant effects as well.

 

• Personally, I tend to believe there is something more behind the direct, or downstream, effects of increasing presynaptic glutamate release that is not addressed yet by these studies. If the acute antidepressant effects seen with ketamine were majorly due to AMPA activation, you would think that AMPAkine like drugs, glycine agonists like sarcosine that indirectly potentiate AMPA, as well as positive allosteric modulators of glycine that potentiate AMPA (like racetams) would result in strong antidepressant effects, but most are just pro-cognitive.

 

I have tried all of those categories of AMPA medicines and not had any notable results. Unless I am missing something here that differentiates these from other antidepressants that supposedly work through AMPA. Partial glycine agonists like GLYX-13 and NRX-1074 are being sought after as upcoming promising antidepressants for the way they also indirectly activate AMPA. Maybe someone can help explain something here?

 

• It is theorized that depression may not be able to be simplified into simply glutamatergic hyper/hypofunction, but rather might be divided based on parts of the brain (i.e. hypofunction in some areas, hyperfunction in others.) The importance is placed on normalizing the glutamatergic system.

 

I believe this is probably true, but in general I have a feeling that depression presents (mostly) in a certain way. There are many different types of depression, I believe, but I do tend to see a defining difference between a type that tends to be more overactive, emotional, and anxious, versus one that tends to be more underactive, flat, and anhedonic.

 

I wonder if glutamatergic hyperfunction is seen more with an ‘overactive’ depression and hypofunction with an ‘underactive’ depression. Both are equally troubling conditions but from my own experience and reading a lot of anecdotes, I do find a lot of depressions labeled “treatment resistant” tend to be more underactive and anhedonic, and it seems like there are less medicines available currently that would effectively address this glutamatergic hypofunction.

 

• It is possible that mGluR 2&3 antagonists may cause some of the dissociative effects/adversely affect locomotion in similar ways to ketamine, but likely only at high doses. It is said that unlike ketamine, low doses of mGluR 2&3 antagonists exhibit antidepressant effects still, without these dissociative effects. As far as safety goes, some mGluR 2&3 antagonists have made it onto Phase II trials in humans, so it is unlikely that it would have progressed otherwise.

 

So what is available to antagonize mGluRs 2&3? Pretty much nothing at the moment, unfortunately. Some chemicals with this mechanism are research chemicals that have been purely used in preclinical models with animal studies. Others have been in clinical trials but the studies are now completed. Here are the main ones I have come up with.

 

• LY341495 - a research chemical that seems to be potent and selective for mGluRs 2&3, but seems to have never been trialed in humans.

• MGS-0039. Also known as BCI-632 and its other prodrug variants, like BCI-838. These have had clinical trials run on them and it seems like they were doing well.

• Decoglurant also known as RG1578 and RO4995819. This is actually a negative allosteric modulator of mGluRs 2&3. It was in clinical trials but it seems like the studies haven’t had results posted yet.

 

None of this is super new research, but for some reason it’s not really out in the mainstream and there aren’t any antidepressants currently in the pipeline that act as mGluR 2 & 3 antagonists. Maybe other approaches at the ketamine idea have won out as being more promising? I still find myself really interested in this because it seems like it is more related to an underlying pathology of depression, and a more endogenous way of fixing glutamatergic dysfunction. But, I could be wrong and I’d like to hear others’ thoughts on this.

 

If others do think this is promising, maybe we could try to find a lab that would synthesize chemicals like these? I have no idea how to get something like this started myself, so if anyone who is more familiar with how to run group buys and get this started would like to take up the cause, I am all for it.

 

Although LY341495 seemed like the most selective mGluR 2&3 antagonist and the one that interested me the most initially, it hasn’t been in human trials so figuring out dosing might be difficult.

 

The BCI drug variants seem a little more mainstream and are selective mGluR 2&3 antagonists as far as I understand. Maybe these would be a good candidate?

 

Decoglurant has been in trials, but I am not sure of the efficacy of a negative allosteric modulator as opposed to an antagonist of mGluR 2&3. I would have more hope in an antagonist.

 

As far as natural supplements goes, I know there are things that act as mGluR 2 & 3 agonists, like Acetyl-L-Carnitine, but I haven’t found any that are antagonists. If anyone knows anything like this, that would be interesting to hear as well.

 

Some sources I’ve read, and many others are probably not listed but these give a pretty good overview of some of the topics I summarized here:

 

https://www.researchgate.net/publication/225068456_MGlu23_and_mGlu5_receptors_Potential_targets_for_novel_antidepressants

 

This is a pretty thorough article on a variety of mechanisms to treat depression, including mGluR 2&3 agonism, antagonism, and mGluR 5 antagonism.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981731/#!po=31.0127

 

Study on the mechanisms of MGS0039 in depression.

 

https://www.firstwordpharma.com/node/956370?tsid=17

 

Article talking about the successes of clinical trials with BCI-632 and BCI-838.

 

https://www.researchgate.net/publication/268985757_Novel_metabotropic_glutamate_receptor_23_antagonists_and_their_therapeutic_applications_A_patent_review_2005-present

 

Article that focuses more heavily on the chemical nature of various mGluR 2&3 antagonists.

 

http://www.sciencedirect.com/science/article/pii/S0028390811003674?via%3Dihub

 

Article that discusses the different mechanisms between sustained and acute antidepressant effects in mGluR 2&3 antagonists.

 

https://www.ncbi.nlm.nih.gov/pubmed/27189960

 

Commonalities shared between ketamine and LY341495’s effects on dopamine circuits.

 

https://www.ncbi.nlm.nih.gov/pubmed/27286960

 

LY341495 enhances antidepressant-like effects of ketamine.

 

All in all, I’m interested in hearing what other people think on all of these theories, and if this mechanism has any place in the future of treating depression. I have been through a huge variety of treatments and my depression worsened in spite, or because of, most of them. I have found partial help through the kappa antagonist CERC-501 through a group buy on this forum, but it still doesn’t address my depression in full. I think a lot of mental health conditions converge in the area of some sort of glutamate dysfunction and it’s about time that the people who could be potentially helped greatly by medicines like this are able to try them.

[PeaceAndProsperity]

You risk psychosis by doing that. That's the mechanism of psychosis induced by 5ht2a activation.

You also risk memory deficits and other issues. But go ahead and try if you can. We can learn from your experiences.

 

FYI theanine in tiny amounts before bed seems to prevent morning depression induced by serotonin overactivity.

[vere]

Ketamine also risks psychosis in some populations by the same means as mGluR 2 & 3 antagonism (increasing pre-synaptic glutamate release), but yet it is a very effective antidepressant in a large amount of depressed patients who respond to nothing else. It's been so revolutionary to theories about depression for a reason. This mechanism is what newer glutamatergic antidepressants are targeting in a variety of ways. Any of the articles and studies I've listed and sourced are discussing mGluR 2 & 3 antagonism as a clinically valid way of enhancing presynaptic glutamate release - just as ketamine does - to reap its therapeutic effects in certain depressed patients. 

 

I wouldn't say this mechanism is desirable for people who have, for example, schizophrenia, where it might exacerbate psychosis in people who already have issues with this. But that doesn't mean it's not incredibly valid for the people who don't.

 

I would guess 5HT2A is a problem in this kind of depression, but a reduced activity of 5HT2A. 5HT2A downregulation by chronic SSRIs is probably one of the reasons why people who have a depression like this are worsened and feel more numbed by SSRIs. mGluRs 2 & 3 also have a complex interrelationship with 5HT2A as far as I understand, which might be some more evidence that glutamate suppression might be linked to this type of depression. SSRIs intentionally try to mute this activity, which could be helpful for some but detrimental in others where 5HT2A expression is already muted.

 

Regardless of the theory though, my point is that something that might be horrible for one type of depression might be the reason for another, and vice versa. I am also not proposing there are only two categories. I think someone can also be anhedonic/emotionally flat and have it based in some other variety of imbalances as well, and that variety probably even extends to over/underactivity in different parts of the brain between different people. The subtleties of peoples' conditions are too complicated to describe with broad terms. But in general we can sort of learn about our specific conditions and compare to others based on how medications affect us in different ways, and this mechanism would mainly appeal to people who are helped by ketamine and not helped by things that oppose its main mechanisms.

 

Theanine is an mGluR 5 antagonist which would inhibit glutamate release, and it's also an AMPA antagonist. So it's in contrast to what I am trying to address here. This doesn't mean it's not a valid mechanism for some types of depression/anxiety as well - I know it is because my best friend is helped by it. But as you might expect, our conditions are very different, and I have personally tried theanine in varying doses before and I have felt zero effects from it. People who are helped by theanine might be helped by something like Basimglurant which is also an upcoming med that's an mGluR 5 antagonist, and all are welcome to discuss that here too. I'm just against saying it's the answer to others' problems that are clearly not benefited by it.

 

Back to the topic though, I'd like to expand this thread beyond just mGluR 2 & 3 antagonists to other glutamatergic antidepressants in the pipeline being based around ketamine. Although I am personally more interested in mGluRs 2 & 3 in the pathology of some types of depression, I understand that they may be more difficult to pursue since they may be even less readily available and less well studied in clinical trials than other, more mainstream, upcoming antidepressants. So it might be more worthwhile to think about accessibility of some of these other ones, if they would be easier to synthesize anywhere. I've been trying to look into this the best I can. Really anything that would have a shot at helping people in this realm of things is something to consider I think. These are the ones I can think of off the top of my head that I am interested in, feel free to mention others that I haven't listed:

NMDA partial glycine agonists:
Rapastinel (GLYX-13) and its counterpart Apimostinel (NRX-1074)

 

NMDA glycine antagonists:
AV-101

Selective NR2B subunit NMDA antagonists:

Traxoprodil

CERC-301

 

[jack black]

the problem with this discussion is there are many types of depression and without splitting depression into biologic subtypes (using biomarkers) first, we will never make any progress in treatment of depression, that should differ based on a sub-type.

however, after saying that, based on the efficacy of tianeptine (anti-glutamate drug), mGluR 2/3 agonism (presynaptic, hence inhibitory) seems the way to go.  what was your personal history with mGluR 2/3 antagonism?

[ThreeKings12341]

vere u did a great work with your researches - great to have u back. since we have very similiar symptoms i hope we will have sucess in future, hopefully this thread gets popular

[vere]

I really don't want this topic to get derailed by posts like these but I feel like I have to address this because both of the first two posts have started to shut down this conversation before it even begins by making overstatements. It's unhelpful and irrelevant to the cause of discussing this research, and I'm afraid it's going to discourage and confuse people who probably could benefit from this.

 

But thank you ThreeKings for your support! I'll continue to look into this until I find something and of course keep you posted on what works for me.

 

Yes, depression is extremely varied and that makes generalized conversation about depression very difficult, which is why I was speaking to mGluR 2 & 3 antagonism as something that would help others who were helped by ketamine and things of that nature, who are not helped by other standard monoamine theory treatments like SSRIs/SNRIs/SNDRIs, etc. This would be a common thread, a reference point for people to relate to. People can find out more about how to treat their depression through some trial and error and learning from the anecdotes of people who have similar issues to them as well. 

 

Despite not knowing what specific biologic subtype of depression you belong to, I would say that's irrelevant. While of course it would make things a lot easier to know for sure what type of depression someone has scientifically, it shouldn't prevent us from discussing what might help and trying to address their issues to the best of our ability.

 

My experience with mGluR 2 & 3 antagonism is that the mechanisms converge with ketamine's (enhancement of pre-synaptic glutamate release), which is the only treatment I've tried that gave me my emotions back and made me feel completely normal again. I am not unique in this, considering this is exactly where a lot of the research is target right now in developing new antidepressants that function in a similar way to ketamine.

 

It seems like you are generalizing that tianeptine/anti-glutamate is the way to go for depression, because of its success rate. I agree it's a decent medicine and it helps a good deal of people, and I would say it is a better alternative for most to a lot of the other mainstream, standardly prescribed antidepressants out there. Its mechanisms are totally valid in treating some depressions. I just hope you are not saying that its general success rate is a basis for mGluR 2 & 3 agonism being helpful for everyone, and that the best we can do is look at treating depression from this kind of generalized approach.

 

Did anyone read anything from the articles I included, or even just google search mGluR 2 & 3 antagonism themselves? There is research that clearly shows that both ends of the spectrum of the mechanisms of these receptors (agonism and antagonism, inhibitory and excitatory) are valued equivalently but in different patients. But even without the studies, this should be common sense.

 

Are you implying it wouldn't be worthwhile to at least try to discuss and identify some of these types of depression based on the characteristics of someone's depression and looking to treat their specific nature? The only way that I see to make progress IS to address the different types of depression and not to generalize them.

 

Depression is varied, but I can guarantee you it's not that varied that we wouldn't be able to categorize by some characteristics and find the most appropriate medicine available for the majority of people, than had we not tried at all. Medications will never perfectly address all of everyone's issues, but there needs to at least be an attempt to find something that's in the right line of thought for them and not do something that makes them feel worse. 

 

The alternative to that is what we already have: the messed up state of psychiatry which prescribes a pretty standardized treatment across the board for anyone who walks into a psychiatrist's office and says they're depressed, regardless of what symptoms they describe. It stems from that dangerous ideology that lumps all depressed people together, and that because something has a 30% success rate and limited side effects across a huge population, that's the best they can do. Really the answer to helping people with depression is to stop assuming the patient is within that global 30% of a broad diagnosis and listen to their actual symptoms to figure out what has the best chance of helping THEM, not everyone. 

 

When someone isn't helped by that standard treatment, should they just accept that's okay because medicines aren't made for their type of depression and they must just be wrong? We can't make a drug for everyone, so let's just compromise and give everyone the same crappy drug that "might work" instead? I have been blunted by so many medications that try the same tired theories over and over again. So should I keep trying the things that make me worse because everyone else says they're the way to go for depression, or find something different? Mental illnesses don't compromise to common ground, which is why there are so many people left insufficiently treated.

 

I even understand that we can't change the way psychiatry and drug development is as a whole, I'm just saying that within this community I thought the point of this was to learn from and relate to others so that we can come to conclusions we couldn't otherwise by seeing ill-informed, generic psychiatrists in isolation.

 

If most people are interested in mGluR 2 & 3 agonism, I wouldn't argue that it wouldn't help people. Just don't be close minded and say that's best for everyone. But, I wanted to bring some attention to it considering there a lot of people with a type of depression that is not addressed by currently available meds, that may be addressed by these mechanisms. On the other hand, neuroprotective, anti-glutamate substances are more commonly available, so if that were going to help someone in need, they'd probably know by now.

 

This discussion is intended to help people and I've opened it up for anyone to discuss what kinds of new glutamatergic drugs they feel are best for them, because I feel like discussion of these newer medicines is pretty limited right now and a lot of people could benefit from them - but I don't feel like the first couple posts here are contributing to this.

Edited by vere, 10 July 2017 - 10:00 PM.

[jack black]

Fine with me. I'll shot up. Over and out.

[PeaceAndProsperity]

Theanine is an mGluR 5 antagonist

Wow are you sure about that? It doesn't seem to be the case for me (because mglur5 activation induces autistic rage fits and theanine doesn't do anything to remove it).

I'm not saying that you are wrong but I'd really love if you could find the source of that.

[vere]

https://www.research...399a393eb4c.pdf

 

"In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors."

 

Group 1 mGluRs being 1 and 5, antagonizing them being inhibitory to glutamate release. But actually you have me unsure about this, since everywhere states it's just "possible" that's a way it produces its neuroprotective effects. I'm not sure anyone's really confident about the exact mechanisms of theanine. It could be a very minor effect on those receptors? Didn't mean to state it so strongly since it seems like even the research is a little questionable, but the point being it is definitely in contrast to mGluR 2 & 3 antagonism because it tends to be enforce inhibition of glutamate release.

 

[echopraxia]

I've tried 5-6 antidepressants and 5 ADHD drugs, and microdosing Psilocybin (5ht2a agonism/mGluR2 antagonism) is by far the most effective anxiety and depression treatment for me. I'll make a longer post about this later with links to research, just posting now so I don't forget. Somehow the combination results in actually feeling serotonin-esque emotions, where every SSRI failed to do that.

[jack black]

I've tried 5-6 antidepressants and 5 ADHD drugs, and microdosing Psilocybin (5ht2a agonism/mGluR2 antagonism) is by far the most effective anxiety and depression treatment for me. I'll make a longer post about this later with links to research, just posting now so I don't forget. Somehow the combination results in actually feeling serotonin-esque emotions, where every SSRI failed to do that.

 

I tried microdosing for a couple of weeks and there were some subtle improvemnts, but nothing earth shattering. since one rapidly develops tolerance to psychodelics, doesn't chronic dosing/microdosing work by downregulating 5HT2a receptors? downregulating 5HT2a is linked to antianxiety and antidepressive effects. Not sure how mGluR are affected by microdosing.

[Mind_Paralysis]

It's a very interesting discovery this - I'm sure it'll be able to help a subset of depressed patients.

 

It should be noted though, that if mGlur-antagonism was a valid mechanism for MANY depressed patients, then it should stand to reason that mGlur-AGONISM should be VERY DANGEROUS FOR VERY MANY PEOPLE.

This does not appear to be the case... Enter my good old friend FASORACETAM! : ) If you check the clinical data on it, you will find that depression is NOT a very common side-effect, in fact, it's so rare that it's not considered a valid side-effect.

 

If you check the Fasoracetam-thread, you will notice that pretty much no-one there reports depressive symptoms - it's extremely rare. I myself used Fasoracetam and did NOT experience any acute depressive symptoms, in fact, I'd say the opposite! : O I actually felt less negative thoughts-wise while taking it. Now, of course, Fasoracetam isn't an entirely selective mGlur-agonist, it also has some weak effects on dopamine, norepinephrine, and Acetylcholine - but its main MOA is considered to be mGlur-agonism.

 

There's also the fact that a sub-set of Schizophrenics, which is one of the most severely depressed sub-sets of patients out there - the suicide-statistics speak for themselves, have been noted to have decreased activity in the mGlur-receptors in the frontal lobe - possibly responsible for their negative symptoms. These people should obviously not use mGlur-antagonists. I don't think mGlur-antagonism is a good mechanism for people with ADHD either, since Dr. Hakon Hakonarson have proven with GENETIC data and medical trials, that there is indeed a subset of ADHD-ers whom gain tremendous benefits from mGlur-antagonism.

 

 

Hence, I rather agree with Jack_Black that it's a good idea to at least get SOME sense of what subset of patients mGlur-antagonism is useful for - remember, many ADHD-ers and most Schizophrenics are depressed - who are these drugs safe to administer to? How does someone with treatment-resistant depression figure out if these particular drugs is the drug to try? Remember, there is an ENORMOUS amount of new, exciting and novel antidepressants out there, or on the way out there.

 

 

Let's start with the OP: how would you describe yourself? What kind of response have you had to other antidepressants? Do you suspect any neurodevelopmental, or neuropsychiatric disease?

You could help others whom are like you, if you can figure out why this helps you in particular! = )

 

It should also be noted, that effects on the AMPA and NMDA-receptors, which is theorized to be the actions of both Ketamine and Tianeptine, is NOT the same as actions on the mGlur-receptors.

 

 

I'll try and provide references for my claims at a later date - at the moment, SCT-symptoms is overloading any such attempts, so I understand if you consider this post somewhat light-weight on the science.

[jack black]

I'll try and provide references for my claims at a later date - at the moment, SCT-symptoms is overloading any such attempts, so I understand if you consider this post somewhat light-weight on the science.

I don't know about SCT. Your posts are very focused, insightful and eloquent.

[vere]

Hmm, this is an interesting discussion. Maybe it really is true that I am of a more specific subset of depression than I think, and I should have titled this thread differently. But, I thought that this would have applied to more people given the success of ketamine and other medicines that have caused a burst in glutamate release, and an increase in glutamate cycling, and the mechanism is shared by mGluR 2/3 antagonism (i.e. mGluR 2/3 antagonism enhances antidepressant affects of ketamine, both prompt those changes in glutamate transmission.) These things seem to be crucial to some sort of antidepressant response, but maybe antidepressant is not the right word for it?

 

I do agree with you Stinkorninjor, that it's important to know what subset this mechanism would be helpful for. So in that sense I apologize to Jack Black if that's what you meant before and I took it the wrong way. But again, I do think it is important to find these subtypes by making correllations, rather than ignoring them and say that one type of antidepressant is all we can do for people. I think the misunderstanding does come from the fact that I was speaking to it as a treatment for depression (albeit a certain type), but not being aware that people do not commonly associate the kind of depression I experience -- with the term depression.

 

I refuse to call myself treatment-resistant because it sounds like I have failed treatment, where treatment has failed me. But the term overall is uniting in a way, because the term does address a subset of people like myself. The reason that treatment-resistant depressions have not been affected by antidepressants is because the antidepressants currently available are in polar opposition to the kind of "depression" or emotional deficit that I and others experience. But, we get lumped under the condition of depression when maybe this truly is not where we belong. 

 

So maybe the problem is that we really are having a discussion about two different conditions altogether that seem to be pretty in opposition to each other. But I know I am also not alone in whatever subset I am in either. There's apparently not a clinical name for whatever it is yet, I think eventually there will be, and that it needs to start being acknowledged. I hope this information applies to someone, because it seems like there is a severe shortage of potential treatments out there or even upcoming for people like myself, and I think this might be key to something.

 

To speak for myself: never been of the suicidal type of depression by any means, sometimes I feel hopeless but never sad. Never anxious, but I do feel stress and can feel easily frustrated (my only "emotion".) I don't have trouble getting out of bed in the morning or doing daily tasks, or doing the things I used to do. I just can't feel anything from them. Motivation doesn't even seem to be too much of a problem, or wouldn't stand in my way if I could just feel something about the things I am supposed to care about. Never emotional at all. I am just flat, no emotion, cannot enjoy anything positive, anhedonic, etc. If I would be able to cry or have some emotional breakdown, it would be therapeutic because I am so stopped up all the time - this is why ketamine was so cathartic.

 

I think it is right that maybe mGluR 2/3 agonism is more traditionally anti-depressive, anti-anxiety. I wouldn't argue that mGluR 2/3 agonism is depressive per se either, it doesn't seem to be the case even in myself. But for people like myself, I think it is still harmful or at the very least does nothing at all to help. The word for their effects, I wouldn't consider to be "depressive" though, you're right.

 

mGluR 2/3 antagonism and similar mechanisms that result in a glutamate burst and increase in glutamate cycling (like ketamine as well) are also in direct opposition to schizophrenia because they seem to mimic the pathology of it, or at least maybe that increase in glutamate cycling is something that is seen by default in schizophrenics. 

 

Personally, I have tried things that work in the direction of mGluR 2/3 agonism and glutamate inhibition. I usually feel nothing at all from them. When I first tried things of this nature, I read that they were supposed to be anti-depressive, so I wondered why they weren't working and would try higher doses. But if anything, they make me feel more robotic and bored than even usual. They make me feel more "depressed" in my own sense of the word - which is emotionally flat - but I know this definition of depression doesn't apply for many people. I think if taken long term they would have similar flattening effects for me as to SSRIs.

 

I wanted to bring up the idea of cognition vs. emotion, and the two being opposed to each other. I know many people here have probably tried a lot of nootropics and found them at least mildly anti-depressive as well. mGluR 2/3 agonists are most likely pro-cognitive, as are (most?) antidepressants. Cognitive deficits also seem to be common in traditional depression. Cognition being more than just mental performance, but of organization, clarity, focus, reason, logic. Emotion being the opposite - disorder, passion, chaos, raw impulse.

 

Very emotional, or depressive, people - probably need this kind of restraint that cognition brings, to get through the day, feel lifted and good. I wouldn't say it depletes them completely of their emotion by taking things like this either, I think it maybe brings them back to a normal, manageable level.

 

But taking myself as an example, I feel that I'm plagued by too much cognition, and no emotion. I feel like a robot. This isn't how I used to be. I would like to feel more unrestrained, unaware, be surprised by things again, instead of going outside and not even lifting my head because I already know what everything looks like, and it's flat, and I'm so bored of it. Everything is so predictable. 

 

One of the reasons NMDA antagonism, being anti-cognitive, is helpful to me is because it does put me out of it a little more, makes my perception of things nicer. The niceness of it makes things more bearable than usual, but NMDA antagonism alone doesn't make me feel emotional or connected to it like I care deeply, just a shallow appreciation that I don't usually have, and a change in perspective which is refreshing.

 

I don't think this is just a binary balance either though, so I apologize if I'm portraying this too simply. It's not just less pro-cognitive, anti- emotion vs. pro-emotion, anti-cognitive. It's about the positivity of the emotion, the meaning behind it. Emotions that are too polarized and only negative are destructive. That's why it is helpful in traditionally depressed people to clamp emotion in a way. But really the key would to be able to pinpoint what enhances the positive emotions (positive emotions can even be sadness as well, but the right kind of sadness). The goal would be to enhance the kinds of feelings that make you care about life.

 

There is a subset of people helped by psychedelics and I would think they are the same people that would be helped by mGluR 2/3 antagonism, ketamine, and things of that nature. I would probably be one of them, though I have never tried them. Thanks echopraxia, for bringing that up, and looking forward to your post. I think the connection between 5HT2a and mGluR 2/3 antagonism is an important one to make.

 

I would argue that 5HT2A agonism itself is the direct mechanism that yields the short-term effects of psychedelics, and that 5HT2A activation plays a huge role in emotions. The benefits of long-term 5HT2a downregulation would be more akin to SSRIs, which tend to strip people like myself of their emotions.

 

I remember reading that 5HT2a agonism downregulates with both agonism and antagonism, which is the only reason I'm hesitant to try 5HT2a agonism myself - fear of further downregulation. I am curious to know if microdosing or taking it less frequently circumvents this at all - can anyone comment on their experience with this? I thought that mGluR 2/3 antagonism would be a more sustainable approach than 5HT2a agonism in meeting the same end. I am not sure of its effects on 5HT2a short-term or long term, but I am guessing that by affecting it indirectly it would be positive for people like myself. 

 

5HT2a downregulation is anti-anxiety, and anti-depressive, and I think helpful to people who are suffering from that. I do remember reading that postmortem studies of suicidal people showed an increase in density of 5HT2a receptors, and that alone made me question this theory. But, this is completely on one end of the spectrum of depressive disorders, maybe a more traditional, deep depression.

 

Keep in mind also though, that it is an effect of many SSRIs to downregulate 5HT2a, and it is not uncommon for an entire population to be negatively affected by SSRIs - becoming emotionally numb and anhedonic. This other end of the spectrum is an entirely different form of torture than those of the suicidally depressed. I am not saying that suicidality isn't more concerning to address -no one should have to go through feeling that death would be more desirable than continuing to live because of the pain. But that the fear of the idea of that end of the spectrum, should not take away validity or weight from the other people who need the opposite and are living in an eternal dry, dull, prison that they can't break from. This also makes life not worth living, but maybe not in a way that provokes ideas of suicide.

 

To comment again for myself, I didn't even realize how badly I was doing on SSRIs because they did not feel "bad" at the time. They just made me feel complacent and restrained, more calm but more numb, more bored, more apt to do the same thing every day and not even notice I was even doing that, too dumbly satisfied to care to change it and instead spend time on the things I care about. This is my default state now. 

 

I'm thinking 5HT2a agonism would feel good for people like myself because it is in contradiction to what SSRIs do. In traditionally depressed people, there is said to be a lack of serotonin, and so SSRIs mediate this by flooding the brain with extracellular serotonin. 5HT2a, being an auto receptor and playing a role in the feedback loop of the serotonin system, would contribute to the clearing of extracellular serotonin - something that would not be desirable in traditionally depressed people who are trying to raise serotonin concentrations. I feel that I'm naturally in a state of elevated serotonin, or that it has been brought on by the downregulation of serotonin autoreceptors by medications. 

 

I would say that I blatantly disagree with the idea that AMPA activation is the only thing going on with ketamine's antidepressant effects. It's true that this is one of the main theories behind ketamine at the moment, I don't think it would be with no reason. Though, it might be the part that is helping a certain subset of people that would be helped by mGluR 2/3 agonism (traditional depression.) The theory behind it is the increased throughput to AMPA receptors by NMDA blockade - seems like it triggers dopamine release in the short term, and activates the mTOR pathway for long term synaptogenesis. 

 

Again though, for myself, I think it was ketamine's action on a different mechanism, the burst in glutamate release and increase in glutamate cycling, that was therapeutic for me. This is emphasized by the idea that I had no "antidepressant" benefits except for directly post-infusion, right as ketamine was being flushed out with saline. Nothing long-term, if anything I felt worse, and I had quite a few ketamine treatments. 

 

I believed in this idea at first and have tried a bunch of medicines in this direction. There are a lot of things that activate AMPA directly/indirectly. Racetams/positive allosteric modulators of AMPA, glycine agonists (Sarcosine), glycine partial agonists (D-cycloserine at low doses), AMPAkines like IDRA-21. I am less hopeful for things like GLYX/NRX because of their shared mechanisms targeting AMPA (partial glycine agonism), and Rapastinel/GLYX has been shown to not increase glutamate cycling like ketamine. Read here: http://www.biologica...(17)31193-9/pdf

 

Other medicines like scopolamine and D-cycloserine (at high doses) have things in common with ketamine in this way, and are also being studied for antidepressant effects. 

 

Scopolamine is a muscarinic acetylcholine antagonist, which somehow leads to the same inhibition of GABA interneurons, disinhibiting excitatory (glutamate) transmission and increasing glutamate cycling.

 https://www.research...ation-of-mTORC1

https://www.jci.org/...cles/view/85033

 

Ketamine does the same thing - blocks NMDA on GABA interneurons, disinhibiting glutamate. 

 

http://www.nature.co...nm.4050_F4.html Describes ketamine's mechanism in this way, how it is similar to scopolamine's glutamate release by GABA interneuron blockade, also mentions how mGluR 2/3 antagonism similarly produces antidepressant actions via blockade of presynaptic autoreceptors that inhibit release of glutamate.

 

https://www.ncbi.nlm...les/PMC2954603/  This talks about the effects of NMDA antagonists (or NMDA hypofunction) paradoxically causes excitation by GABAergic interneuron inhibition and thus pro-excitatory transmission.

 

NMDA glycine site antagonism of high-dose D-cycloserine triggers a glutamate release as well. I also had great results trying D-cycloserine at a high dose - but it's not really something I want to take long term. The medicine AV-101, a glycine antagonist, is based on the evidence of success of high dose D-cycloserine for depression, and is said to cause the same surge in glutamate as ketamine.

 

It seems like the enhanced release of glutamate is helpful for people (at least ones like myself, if not more types of depression as well), but then of course increased extracellular glutamate is often said to, traditionally, be a bad thing in many ways - and for that there's a very overwhelming anti-glutamate sentiment out there. But there are probably a lot of subtlties in these mechanisms - maybe enhanced glutamate transmission wouldn't be "pro-glutamate" necessarily? Sounds contradictory, but perhaps it is both the release AND the reuptake of glutamate? The glutamate-glutamine cycling process? Enhancing excitatory transmission but at the same time clearing glutamate from the synapse quickly? This cycling is particularly noted in several papers regarding ketamine's antidepressant effects, among other medicines (like scopolamine and D-cycloserine.)

https://www.ncbi.nlm...les/PMC5345902/

 

Things like Riluzole are also being studied in relation to the antidepressant effects of ketamine - and Riluzole appears to inhibit presynaptic glutamate release and enhance reuptake. So maybe there are a couple ways about the same problem? The problem maybe just being high concentrations of extracellular glutamate, stagnant? Lessened release, but also lessened reuptake? I suppose I would have to try it for myself to know if this is desirable for myself or for a different subset of depression. 

 

https://www.ncbi.nlm...les/PMC3055603/ Here is a study on Riluzole, though being studied in relation to Bipolar Depression here, it is found to increase glutamate-glutamine cycling. However, it's also known to inhibit presynaptic glutamate release - so it seems very different in the way that it somehow increases glutamate transmission and cycling.

 

I would really love someone's input here on this area if they are able to elaborate on these ideas I don't understand, all my knowledge of neurochemistry is just trying to put some pieces together from papers I've read and conclusions I've come to for myself from trying different medicines.

 

And additionally, I have been looking into purchasing an mGluR 2/3 antagonist myself. I'll keep this thread updated if I make any progress.

 

Thanks everyone for your comments and fostering this discussion.

Edited by vere, 13 August 2017 - 05:36 PM.

[Mind_Paralysis]

Very well written piece, Vere! = ) I hope to be able to reply in a sufficient manor in the near future.

I would agree that what you're describing isn't what's traditionally called Depression, or even Dysthymia - it's something else. More like Anhedonia, or even DP/DR. This is something I've read some articles about, even - how most antidepressants are created to DAMPEN negative feelings, instead of enhancing positive ones.

 

Have you looked into the research into reward-system modifying antidepressants? There's a couple of them in the works - one of them being CERC-501 - a Kappa-antagonist - presumed to be useful for anhedonia, DP/DR and addiction (alas, it failed to be effective in traditional depression).

 

On another note, going through the research here, and how you describe yourself, I start wondering.. ARE YOU IMMUNE TO PSYCHOSIS?! : O You know, I think you just might be... Because usually, the drugs which you describe as helpful, all cause psychosis - but not necessarily in you... HMMM...! Perhaps you should consider looking into Cannabinoids as well, since they are known to cause psychosis as well, and do seem to modify the reward-mechanisms of the brain. Alas, they could also make things worse, since CB is also known to cause a form of apathy and decreased affect.

 

 

 

 

I'll try and provide references for my claims at a later date - at the moment, SCT-symptoms is overloading any such attempts, so I understand if you consider this post somewhat light-weight on the science.

I don't know about SCT. Your posts are very focused, insightful and eloquent.

 

 

Aww, you're too kind, Jack! ^^
 

[vere]

Thanks for the thoughts, Stinkoninjor! And sorry for the very late reply. Definitely I have some sort of anhedonia. I tend to see emotional numbness as maybe a separate thing from anhedonia, but they are often comorbid it seems. I could be wrong but I identify anhedonia symptoms as apathy, inability to enjoy daily activities, everything seems dreadfully boring or undesirable to do, don't get any enjoyment out of things like music, eating, going for a walk, etc. I think of my emotional flatness on a slightly deeper level - can't care about the things I used to love, no passion, no inspiration, no feeling in my gut when I think about things I like, my perception of the world around me is dulled, looking at everything just looks flat, I'm like a robot. This part of me feels like my personality has changed from what it used to be. My anhedonia fluctuates and sometimes I am without anhedonic symptoms and I can enjoy daily activities a bit more (despite still not being able to care about the things that matter) especially with the use of some medicines like CERC, and some dopaminergic things. .

 

I've thought about cannabinoids too, but was scared off at the knowledge that some people suffer from reduced affect as an effect of using them. I am not sure if I'm immune to psychosis! I have definitely never experienced full blown psychosis or anything but I have experienced (short-lived) bouts of extreme anger infrequently in overwhelming situations as a result of feeling stuck in a spiral of negative thoughts that can make me lose touch with reason (though not disconnected with reality.) Also important is that this happens almost exclusively when my serotonin and norepinephrine levels are increased directly by a medicine, or as a rebound from a medicine. 

 

I did end up trying out fasoracetam to see what an mGluR 2/3 agonist, the opposite of the type of medicine I'm seeking (mGluR 2/3 antagonist) would do for me. I didn't hate it, it didn't make me feel more depressed, just more robotic - which I didn't think was possible. I will say it was relaxing in a way. I found it easier to get things done, not really with any inspiration or feeling about it though, just somewhat mindlessly. Things still felt dull, but I did have the motivation to want to work on things that normally I might not see any point in doing or any redeeming outcome of finishing. I found my thoughts to be a little more organized and it was easier to not get as caught up on small things that might usually make me just quit doing what I was doing. 

 

So while it's not for me, I can see how people would like it as an antidepressant or anxiolytic, and it seems to maybe help the reward system. Normally, without medicine, I'm robotic and I don't get anything done. So at least it fixes one of those issues. But it definitely is not the heart of my issue, and I wouldn't want to take it often for that reason. I still think an mGluR 2/3 antagonist would really give me the kinds of feelings I am missing that no other medicine has addressed (aside from ketamine.) I wonder if anyone else feels this way.

 

I think it's best not to think of mGluR 2/3 agonists/antagonists as  opposites, but as treating different types of depressive symptoms. This also doesn't mean that either or will be effective at addressing everything for any one person. I wouldn't be surprised if mGluR 2/3 antagonism didn't fix everything for me. But I would like to see if it is able to give me a window of emotion.

 

I noticed when I take fasoracetam before I take high dose D-cycloserine, that it makes the D-cycloserine feel even stronger. (D-cycloserine does help me quite a bit, it changes my perception of things and makes everything look more like it used to, which almost starts to make me feel something.) Perhaps the fasoracetam inhibiting presynaptic glutamate release is rebounded more strongly by D-cycloserine at a high dose triggering a glutamate surge. Total guess, but whatever the reason, it seems to be a combination that works pretty well for me.

Edited by vere, 26 September 2017 - 07:23 AM.

[Deaden]

Glutamate is the core of what's causing our anhedonia indeed, but there's a bit more to it. I've been stuck at home for a few days and doing research I believe I found an alternative to needing mGluR antagonists, although those don't seem like too much of a bad idea. I'm working on an updated anhedonia cure guide with a more scientific approach than my previous one. I think I really hit something... A much better approach than trying to rely on antidepressants or stimulants. Should make complete sense will need you guys intake. I'll finish it tomorrow I'm going to sleep now...

[Deaden]

http://www.longecity...nia-cure-guide/