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