Autism & Schizophrenia as the opposite poles of NMDAr dysregulation / dysfunction?

[palmanita]

Autism & Schizophrenia as the opposite poles of NMDAr dysregulation / dysfunction?

Disclaimer: I know it's speculative, there are always countless other factors, etc.

I'm pretty sure to be autistic. Due to my extensive 'research' about the effects of NMDA antagonists and the comparison with the reports of others, I've not only experienced normality* in a way I never could without chemical aid, but also what happens when one pushes it too far. There comes a state that is strikingly similar to schizophrenia.

* (with all these small little things that make up a personality "disorder" like not understanding chit-chat, jokes etc.. then how it is to be able to do normal social interaction, conversation, processing subtle body talk etc. with no effort like all the normal people out there.. or on the other end of the range, deprivation of thoughts, schizo-perception / vision etc)

| autistic --------- normal --------- schizophrenic (negative symptoms) |

Think of it as a range of intensity of NMDA mediated transmission. Normal humans are in the middle. When you add a NMDA antagonist, it shifts to the right. Now take someone with however caused hyperactivity of NMDA, experiencing autism spectrum symptoms. Give him a NMDA antagonist in the right dosage, and he'll approach the middle, normality. Give him more, and he'll also develop schizo like symptoms. Other way round, NMDA agonists do a shift to the left. That will help against (negative?) symptoms of schizophrenia. Like sarcosine.

NMDA mediates association <-> dissociation (somehow this is about ego perception and the intensity thereof) but also excitation.

Too much NMDA current means a strong ego, separation from the outside world, sensory overload, hyper-focus to details and awkwardness due to too much excitatory inhibition (blank mind in social situations). Also it means strong personal drive, energy. Being isolated behind some wall, yet having no 'buffer zone' and little things hitting you so hard deep directly emotional.

Too little NMDA current means dissolution of the ego, dimmed sensory input, forgetting about things that are far away, diminished cognitive abilities and due to the lack of a strong ego, little self-related drive and energy. Nothing touches you, one is like just an empty shell or non-existant. The surrounding is a scenery made out of paper and reality feels like a prank. I do understand now why schizophrenics tend to develop certain delusions.

(Also this is just an over-generalization, as there are of course many different brain areas with NMDAr's all over, and these symptoms can mix & match as they desire. My mother certainly is autistic too, but she also has some symptoms of schizophrenia & is misdiagnosed as such.)

Sorry as English isn't my mother tongue, hope it's more or less understandable. Don't know whether this already is a settled theory or not but it's so dazzling to experience all this by myself, puzzling things together and all .. I think very few concerned people (autists / schizophrenics) have the chance to experience the other side and to draw conclusions about all that.

At least it's why I can't rest and accept my natural state. It's not drug delusions (and oh well, I have had them too). This is real. And I can't talk about to these who should be professionals of this subject - psychiatrists, neurologists etc.. I'm searching desperately for someone who could understand me. But I also fully understand that if I begin to talk about me having experienced reality differently when taking drugs, especially research drugs, well.. nobody will believe me.

But the relevant question is, why don't these receptors work as they should? Biology is so genious in always restoring equilibrium. So is it genetically predicted, or an infection, an inflammation, whatever?

 

[Anxious.Individual]

Disclaimer: I know it's speculative, there are always countless other factors, etc.

I'm pretty sure to be autistic. Due to my extensive 'research' about the effects of NMDA antagonists and the comparison with the reports of others, I've not only experienced normality* in a way I never could without chemical aid, but also what happens when one pushes it too far. There comes a state that is strikingly similar to schizophrenia.

* (with all these small little things that make up a personality "disorder" like not understanding chit-chat, jokes etc.. then how it is to be able to do normal social interaction, conversation, processing subtle body talk etc. with no effort like all the normal people out there.. or on the other end of the range, deprivation of thoughts, schizo-perception / vision etc)

| autistic --------- normal --------- schizophrenic (negative symptoms) |

Think of it as a range of intensity of NMDA mediated transmission. Normal humans are in the middle. When you add a NMDA antagonist, it shifts to the right. Now take someone with however caused hyperactivity of NMDA, experiencing autism spectrum symptoms. Give him a NMDA antagonist in the right dosage, and he'll approach the middle, normality. Give him more, and he'll also develop schizo like symptoms. Other way round, NMDA agonists do a shift to the left. That will help against (negative?) symptoms of schizophrenia. Like sarcosine.

NMDA mediates association <-> dissociation (somehow this is about ego perception and the intensity thereof) but also excitation.

Too much NMDA current means a strong ego, separation from the outside world, sensory overload, hyper-focus to details and awkwardness due to too much excitatory inhibition (blank mind in social situations). Also it means strong personal drive, energy. Being isolated behind some wall, yet having no 'buffer zone' and little things hitting you so hard deep directly emotional.

Too little NMDA current means dissolution of the ego, dimmed sensory input, forgetting about things that are far away, diminished cognitive abilities and due to the lack of a strong ego, little self-related drive and energy. Nothing touches you, one is like just an empty shell or non-existant. The surrounding is a scenery made out of paper and reality feels like a prank. I do understand now why schizophrenics tend to develop certain delusions.

Sorry as English isn't my mother tongue, hope it's more or less understandable. Don't know whether this already is a settled theory or not but it's so dazzling to experience all this by myself, puzzling things together and all .. I think very few concerned people (autists / schizophrenics) have the chance to experience the other side and to draw conclusions about all that.

At least it's why I can't rest and accept my natural state. It's not drug delusions (and oh well, I have had them too). This is real.

I completely agree with this. Autism consists of excess logical thinking, where as schizophrenia is the opposite, lack of logical thought due to NMDA hypofucntion, which can cause serious delusions to form. Also schizophrenic individuals have serious acetylcholine hypo function, which is responsible for psychosis/delirium that they experience, which also explains why a lot of schizophrenics smoke, since nicotine actually reduces a lot of these symptoms.

NMDA antagonists that also act as dopamine agonists, like PCP have been used to simulate schizophrenia.

 

[palmanita]

Thanks! Yes, that's a good point about the acetylcholine.

And a big obstacle for research because most if not all the NMDA antagonists used are choline antagonists too, so the glu mediated effects get confused with these caused by choline disruption and probably important results overlooked. Even memantine is an anticholinergic.

NMDA antagonist treatment (imo) only shines when the choline part is circumvented as I currently do with nicotine.

I think a core part is about evaluation, the nitty-gritty of neuronal processing, how our brain forms thoughts for us, pre-selects which options we have to choose from etc. Maybe it's better to draw this:

You know what I mean?

 

[aced126]

I buy into this theory

 

[serotonin2A]

I completely agree with this. Autism consists of excess logical thinking, where as schizophrenia is the opposite, lack of logical thought due to NMDA hypofucntion, which can cause serious delusions to form. Also schizophrenic individuals have serious acetylcholine hypo function, which is responsible for psychosis/delirium that they experience, which also explains why a lot of schizophrenics smoke, since nicotine actually reduces a lot of these symptoms.

NMDA antagonists that also act as dopamine agonists, like PCP have been used to simulate schizophrenia.

You are conflating the effects of muscarinic and nicotinic systems. Muscarinic blockade causes delirium. Schizophrenics smoke cigarettes because nicotine enhances cognition in schizophrenia, not because it reduces delirium. Nicotine has absolutely no effect on delirium -- good luck trying to treat scopolamine induced delirium with nicotine.

You are also wrong about most abused NMDA-R blocking ACh. To put it bluntly, that action doesn't appreciably contribute to the effects of most NMDA-Rs -- at least in non-overdose situations. Some NMDA-R antagonists, like MK-801 and diphenidine, are highly selective vs. muscarinic sites.

 

[palmanita]

One more thought construct: Phantom pain. The inventor of MXE (who I'd now believe to be on the left end of the range, say, ASD) found relief in dissociatives, and said he finds them corrective. This is very true. But only for these who are on the left half, and only as long as you don't push the NMDA antagonism too far.

There is always a loop running in our brain, which saves the current state so that we know we have a door behind us, even when we don't see it. How we have to type on the keyboard to write this. If we focus on something, then the filters allow new input to enter this loop. Say, you look very close at your keyboard and suddenly notice how dirty it is. From this point of time on, you'll always know there is dirt (unless you or your brain decides this information to be irrelevant, and it gets sorted out again).

In normality, there is the right balance between inner input, memory, and outer input.

When you enter dissoverse (shift to the right) this loop becomes more and more free running (this is very well explained in White's DXM FAQ) and imaginated things will become less and less sorted out, they will become more and more real. On the other side, when you go to the left, then things and personality will become more rigid. It's less about the sum but about details. Prejudices and preconceptions will become more and more important.

Like in computers, every "packet" of information carries some meta-data to help the evaluation circuits decide which information is important, neutral, useless etc.. this applies to memory too, if you remember something then the most important memory of this certain topic comes into your mind at first. Small things like the color of a car will be sorted out quickly. Other things are more important. And then we have a traumatic information, that has an importance of 10'000 in a range of 1-100.

Now, this all is recursive. White uses the example of a camera recording a TV screen that displays the output of the camera (or, simplified, two mirrors that are oppositing).

Usually, when some information enters the loop, at some point it will fade away again when the input is removed.
But if you have some small but traumatic pain input package with an importance, or weight, of 10'000 then even when it was just a brief amount of time, it will instantly "burn in" through long term potentiation. It will remain there, like a dead pixel.

Usually the filter mechanisms will sort out imperfect information and replace them with the backup copy. But what if the backup copy also has this faulty information in it? And we deal with backup copies of backup copies. Well, the more we are on the left of the GLU processing level, the more such "faulty" information will manifest.

Do you get what I try to say? I'm currently loosing my own thoughts a bit in the loop. Might have to redose to continue but that's for another time.

 

[serotonin2A]

One thing that perplexes me about theories like this one is that they totally ignore the fact that there is a scientific literature on the topic. Even a quick google search reveals the following review:

http://www.ncbi.nlm.nih.gov/pubmed/25636159

So there apparently is evidence that NMDA-R alterations MAY contribute to autism. The review, however, states that there may be both increases and reductions in NMDA-R function in autism. Since you have put autism and schizophrenia on different ends of a NMDA-R activity continuum, I'm not sure how you can reconcile your view with the evidence that autism isn't simply caused by NMDA-R overactivity.

 

[Anxious.Individual]

One thing that perplexes me about theories like this one is that they totally ignore the fact that there is a scientific literature on the topic. Even a quick google search reveals the following review:

http://www.ncbi.nlm.nih.gov/pubmed/25636159

So there apparently is evidence that NMDA-R alterations MAY contribute to autism. The review, however, states that there may be both increases and reductions in NMDA-R function in autism. Since you have put autism and schizophrenia on different ends of a NMDA-R activity continuum, I'm not sure how you can reconcile your view with the evidence that autism isn't simply caused by NMDA-R overactivity.

My theory on this, is that in individuals with autism there is serious NMDAr hyperfucntion in the nucleus accumbens and the amygdala, while at the same time there is mild NMDAr hypo function throughout the prefrontal cortex. While in schizophrenic individuals, it's the exact opposite. Hypo function in the nucleus accumbens, with hyperfucntion throughout the prefrontal cortex.

NMDA blockade in the nucleus accumbens leads to a hyperglutamatergic state at other glutamate receptors and an increase in dopamine release, which is seen in schizophrenia.

 

[serotonin2A]

My theory on this, is that in individuals with autism there is serious NMDAr hyperfucntion in the nucleus accumbens and the amygdala, while at the same time there is mild NMDAr hypo function throughout the prefrontal cortex. While in schizophrenic individuals, it's the exact opposite. Hypo function in the nucleus accumbens, with hyperfucntion throughout the prefrontal cortex.

Except that schizophrenia is associated with NMDA-R hypofunction in PFC:

http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2207&context=smhpapers
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041270/
http://www.nature.com/nm/journal/v12/n7/full/nm1418.html
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608949/
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061278

To some degree, schizophrenia is thought to be a spine pruning disorder where pyramidal neurons and interneurons in PFC do not receive sufficient glutamatergic input. Hence why schizophrenia tends to develop during late adolescence when there is a huge amount of cell and synaptic pruning.

Note that spine pruning abnormalities are also thought to contribute to autism spectrum disorders:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530413/

That is just one review but you really need to read about the complexity of these systems. You are markedly oversimplifying the brain if you think that autism and schizophrenia can be explained by a continuum of NMDA-R dysfunction.


Another problem with your hypothesis is that it treats autism and schizophrenia as polar opposites. If that is the case then there should be no overlap in symptoms between the two disorders, and they could never be co-morbid. Of course, that is not true. Individual patients can suffer from autism and schizophrenia and there is some evidence of that some symptoms may converge:

http://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-015-0494-x
http://www.nature.com/pr/journal/v69/n5-2/full/pr9201190a.html
http://www.clinicalneuropsychiatry.org/pdf/Fitzgerald.pdf

NMDA blockade in the nucleus accumbens leads to a hyperglutamatergic state at other glutamate receptors and an increase in dopamine release, which is seen in schizophrenia.

Actually, it is the complete opposite -- NMDA-R blockade in the PFC leads to a hyperglutamatergic state in PFC. The PFC is a source of descending glutamatergic input to the ventral tegmental area (VTA), so hyperglutamatergic effects in PFC can lead to increased dopamine release from VTA neurons.

http://www.ncbi.nlm.nih.gov/pubmed/12700703

 

[Cotcha Yankinov]

I doubt that NMDA antagonism would improve the recognition of facial affect deficits and other social deficits seen in ASD...

It seems to me that just because a drug is changing your thought patterns/conscious experience in a way that you like, it doesn't necessarily mean that that drug's mechanism of action is directly affecting the root cause of the symptoms that you dislike.

 

[Cotcha Yankinov]

Individual patients can suffer from autism and schizophrenia and there is some evidence of that some symptoms may converge

My question relates to overlap of Alzheimer's disease related genetics (Such as the APOE4 allele - which I apparently have one of) with symptoms of ASD and schizophrenia. If the APOE4 allele can contribute to excess pruning, does it stand to reason that this could result in vaguely similar symptoms that we see in the other "pruning disorders"?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846754/ - "ApoE4 Decreases Spine Density and Dendritic Complexity in Cortical Neurons in vivo"

Edit: From this meta-analysis, there might be a modest association between APOE4 and schizophrenia http://www.schres-journal.com/article/S0920-9964(06)00082-X/abstract

Also, inside the review of pruning abnormalities you linked, the authors write "Such findings are consistent with an emerging hypothesis that the brains of individuals with ASD are characterized by hyperconnectivity in local circuits and hypoconnectivity between brain regions¹⁰", and I have a pondering with this in regards to the finding that children with a APOE4 allele + APOE3 allele have increase volume of the medial orbitofrontal cortex (http://www.neurology.org/content/early/2016/07/13/WNL.0000000000002939)

Could the increased volume of the medial orbitofrontal cortex be due to increased stimulation because of the aforementioned hyperconnectivity in local circuits?

 

[WSH]

I don't think that autism and schizophrenia are opposites.
I actually think that they are more similar than different!

For example, both autism and schizophrenia are associated with stereotypies.

Plus the fact that antipsychotics are effective for both schizophrenia and autism:

An update on pharmacotherapy for autism spectrum disorder in children and adolescents

Atypical antipsychotics, particularly risperidone and aripiprazole, are effective in reducing irritability, stereotypy and hyperactivity.

 

[palmanita]

Please forget about this "theory" that was made out of a crazy day's thoughts.

But if we continue with this, then WSH might be on a right direction. In that the same preconditions with just some changes at glutamatergic procession can lead to an ASD-alike or schizo-alike perception. It's striking that altering the kinetics of one receptor circuit can shift consciousness from one 'disorder' to another.. indeed confirming similarities.

A conclusion could be that I hope for very specific NMDAr agents one day being able to help some heavily suffering individuals (wow, what a life changing statement).

 

[Limpet_Chicken]

Wel OBVIOUSLY antipsychotics are going to reduce activity. They are a chemical baseball bat to the skull. And IMO should ONLY be given to autistic children if there is something that must for the kid's own good, be contained. Or for the good of others. As in, to protect them from violence. Although far better would be to attempt at least to find the root cause of the frustration that is generating the violence. And use APs as a last resort. In OLDER members of the breed, then the picture is a little different, if they themselves find them helpful then obviously, go ahead.

As for stereotypy, its not a disorder, its hawt