NMDA glutamate receptors

[pgoody]

Hi there. I was doing some looking into NMDA receptors as the role of glutamate is possibly an important factor in OCD. For anyone that likes to read about this stuff, I found a good article I would like to share talking about a number of neuronal pathways throughout our brain. This article is specifically about schizophrenia, which I have read about a good amount and this is the best, most up to date, and easy to understand overview of the disease that I have found in regards to the NMDA hypofunction vs Dopamine hypothesis.

http://www.frontiersin.org/Neuropharmacology/10.3389/fphar.2012.00195/full

 

[pgoody]

Here is a very nice simplified overview of schizophrenia and current hypotheses. http://www.nmdainschizophrenia.com/understanding-pathways?cid=bit_we_F000500_P001031#glutamate8

I have been reading a lot into the schizophrenic hypothesis because there is some overlap in glutamatergic dysfuction in both OCD and schizophrenia. In fact, if you head on over to schizophrenia.com and read the posts on that forum, there are a good number of people who are advocating the use of sarcosine, which is a GlyT1 inhibitor, inhibiting the uptake of glycine which then acts as an NMDA co-agonist. If you look into these links you will see that in some cases NMDA agonism will increase dopamine (prefrontal cortex) and in some cases decrease it (mesolimbic region). Apparently sarcosine is a more potent method of delivering glycine then just taking glycine itself. People taking glycine take somehting between 30-50g daily and there are some issues with stomach upset. A standard sarcosine dose seems to be something up to 2g at least. So far I have read that there are no side effects to taking sarcosine which seems very promising.

As to how this pertains to OCD, there are currently trials being done using sarcosine for OCD treatment. Here is an older study of sarcosine for OCD:
http://www.ncbi.nlm.nih.gov/pubmed/21508860

Also, a new GlyT1 inhibiting medicine called Bitopertin (rg1678), more potent in its effect than sarcosine for therapeutic purposes has been developed and should be available for prescription in the next couple of years. This medication is being developed for the purpose of treating schizophrenia but is also going to be used for the treatment of OCD.
http://www.roche.com/research_and_development/pipeline/roche_pharma_pipeline.htm

They say this is going to be something schizophrenics will take alongside with a antipsychotic, but from some of the people on the forums I have been reading it seems that bitopertin might be good enough to take alone, depending on the case.

 

[aaron_c]

@pgoody

Hi

I know this post is a little old...old but good! I have a question I'm hoping you can help me with:

So I did a bit of that reading--which was fascinating. I seem to be heterozygous for the main GAD mentioned in a related article. As far as I can tell, they looked at a bunch of mutations in GAD for relevance to schizophrenia, and for mathematical reasons that I honestly don't understand, they found that one of them was really important and some others were a little important. But the important one, rs3749034, decreases GAD1 expression, which should--if I am getting this right-- have the effect of decreasing GABA levels.

I was under the impression that Glutamate and GABA exist in some kind of balance. In healthy people they are easily transformed into one another, so if you have very little of one, usually people have a lot of the other. Yasko in particular seems to think that this is a problem for Autistic kids, in that they typically have too much glutamate and not enough gaba.

So if the GAD1 snp is indicated in schizophrenia, I would expect GABA to be low and Glutamate to be high. So here is my confusion: The stuff you are talking about, the entire glutamate theory in fact...it's based on the observation that NMDA antagonists like ketamine cause symptoms close to schizophrenia. To me, this says that they don't have enough either glutamate or glycine (an oversimplification, I know). But in this abstract, after explaining more or less what I just did, in the same breath they go on to say that drugs that lower the resting glutamate levels (in the neuronal gap, I assume?) I think by lowering NMDA receptor activity would provide a promising treatment for schizophrenia.

I guess my question is: If the glutamate hypothesis in schizophrenia is about low NMDA activity causing schizophrenia, why does the major schizophrenia GAD1 snp seem to cause an increase in glutamate? And why do other treatments try to lower NMDA activity?

I realize that I don't have this whole picture--I doubt the whole thing is wrong. I think I am just missing something.