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Monday, 3 April 2017

Different Types of Excitatory/Inhibitory Imbalance in Autism, Fragile-X & Schizophrenia


There is much written in the complex scientific literature about the Excitatory/Inhibitory (E/I) imbalance between neurotransmitters in autism. 

Many clinical trials have already been carried out, particularly in Fragile-X.  These trials were generally ruled as failures, in spite of a significant minority who responded quite well in some of these trials.

As we saw in the recent post on the stage II trial of bumetanide in severe autism, there is so much “background noise” in the results from these trials and it is easy to ignore a small group who are responders.  I think if you have less than 40%, or so, of positive responders they likely will get lost in the data. 

You inevitably get a significant minority who appear to respond to the placebo, because people with autism usually have good and bad days and testing is very subjective.

There are numerous positive anecdotes from people who participated in these “failed” trials.  If you have a child who only ever speaks single words, but while on the trial drug starts speaking full sentences and then reverts to single words after the trial, you do have to take note. I doubt this is a coincidence.

Here are some of the trialed drugs, just in Fragile-X, that were supposed to target the E/I imbalance:-

Metabotropic glutamate receptor 5 (mGluR5) antagonist

·        Mavoglurant

·        Lithium

mGluR5 negative allosteric modulator

·        Fenobam

N-methyl-D-aspartic acid (NMDA) antagonist

·        Memantine

Glutamate re-uptake promoter

·        Riluzole

Suggested to have effects on NMDA & mGluR5 & GABAA

·        Acamprosate

GABAB agonist

·        Arbaclofen

Positive allosteric modulator (PAM) of GABAA receptor

·        Ganaxolone


Best not to be too clever

Some things you might use to modify the E/I imbalance can appear to have the opposite effect, as was highlighted in the comments in the post below:-



So whilst it is always a good idea to try and figure things out, you may end up getting things the wrong way around, mixing up hypo and hyper.

The MIT people who work on Fragile-X are really clever and they have not figured it all out.


Fragile-X and Idiopathic Autism

Fragile-X gets a great deal of attention, because its biological basis is understood.  It results in a failure to express the fragile X mental retardation protein (FMRP), which is required for normal neural development.

We saw in the recent post about eIF4E, that this could lead to an E/I imbalance and then autism.




Our reader AJ started looking at elF4E and moved on to EIF4E- binding protein number 1.

In the green and orange boxes below you can find elF4E and elF4E-BP2.

This has likely sent some readers to sleep, but for those whose child has Fragile-X, I suggest they read on, because it is exactly here that the lack of fragile X mental retardation protein (FMRP) causes a big problem.  The interaction between FMRP on the binding proteins of elF4E, cause the problem with neuroligins (NLGNs), which causes the E/I imbalance.  Look at the red oval shape labeled FMRP and green egg-shaped NLGNs.

In which case, while AJ might naturally think Ribavirin is a bit risky for idiopathic autism, it might indeed be very effective in some Fragile-X.  You would hope some researcher would investigate this.




Can you have more than one type of E/I imbalance?

Readers whose child responds well to bumetanide probably wonder if they have solved their E/I imbalance.

I think they have most likely improved just one dysfunction that fits under the umbrella term E/I imbalance.  There are likely other dysfunctions that if treated could further improve cognition and behavior.

On the side of GABA, it looks like turning up the volume on α3 sub-unit and turning down the volume on α5 may help. We await the (expensive) Down syndrome drug Basmisanil for the latter, given that the cheap 80 year old drug Cardiazol is no longer widely available. Turning up the volume on α3 sub-unit can be achieved extremely cheaply, and safely, using a tiny dose of Clonazepam.

It does appear that targeting glutamate is going to be rewarding for at least some of those who respond to bumetanide.

One agonist of NMDA receptors is aspartic acid. Our reader Tyler is a fan of L-Aspartic Acid, that is sold as a supplement that may boost athletic performance.  

Others include D-Cycloserine, already used in autism trials; also D-Serine and L-Serine.

D-Serine is synthesized in the brain from L-serine, its enantiomer, it serves as a neuromodulator by co-activating NMDA receptors, making them able to open if they then also bind glutamate. D-serine is a potent agonist at the glycine site of NMDA receptors. For the receptor to open, glutamate and either glycine or D-serine must bind to it; in addition a pore blocker must not be bound (e.g. Mg2+ or Pb2+).

D-Serine is being studied as a potential treatment for schizophrenia and L-serine is in FDA-approved human clinical trials as a possible treatment for ALS/Motor neuron disease.  

You may be thinking, my kid has autism, what has this got to do with ALS/Motor neuron disease (from the ice bucket challenge)? Well one of the Fragile-X trial drugs at the beginning of this post is Riluzole, a drug developed for specially for ALS.  Although it does not help that much in ALS, it does something potentially very useful for some autism, ADHD and schizophrenia; it clears away excess glutamate.


Fragile-X is likely quite different to many other types of autism

I suspect that within Fragile-X there are many variations in the downstream biological dysfunctions and so that even within this definable group, there may be no universal therapies.  So for some people an mGluR5 antagonist may be appropriate, but not for others.

Even within this discrete group, we come back to the need for personalized medicine.

I do not think Fragile-X is a good model for broader autism.


Glutamate Therapies

There are not so many glutamate therapies, so while the guys at MIT might disapprove, it would not be hard to apply some thoughtful trial and error.

You have:

mGluR5

     ·        mGluR5 agonists (only research compounds)

·        mGluR5 positive allosteric modulators (only research compounds)

·        mGluR5 antagonists (Mavoglurant, Lithium)

·        mGluR5 negative allosteric modulators (Fenobam, Pu-erh tea decreases mGluR5 expression )

Today you can only really treat too much mGluR5 activity.  It there is too little activity, the required drugs are not yet available.  I wonder how many people with Fragile-X are drinking Pu-erh tea, it is widely available.


NMDA agonists

D-Cycloserine an antibiotic with similar structure to D-Alanine (D-Cycloserine was trialed in autism and schizophrenia)

ɑ-amino acids:

·         Aspartic acid (trialed and used  by Tyler, suggested for schizophrenia)

·         D-Serine (trialed in schizophrenia)




NMDA antagonists


·        Memantine (widely used off-label in autism, but failed in clinical trials)


·        Ketamine (trialed intra-nasal in autism)


Glutamate re-uptake promoters via GLT-1


·        Riluzole


·        Bromocriptine


·        Beta-lactam antibiotics









28 comments:

  1. Thankyou Peter for the post and the link,and the image post,another that made me laugh.
    Valentina

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  2. Hi Kritika,

    I remember you were trying to see if Cardiazol was available in India? Is it? Do you know if KBr is available there as well?

    Many thanks.

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    Replies
    1. Hi RG,

      Yes, in fact I had tried to find out about the availability of cardiazol but it seems difficult to procure through local chemists..even the ones around premier hospitals. In fact they deny evem keeping the drug. But I think it was availabe online and very cheap at that..with a doctors prescription though. I did not pursue it further...you have reminded me to try and get a peesctiption if possible. I never enquired about kbr but its easily available online..as a veterinary med!

      Regards

      Delete
  3. Hey Peter we recently had a discussion about trehalose bioavailability and I just came across a very recent study on humans using what you might consider a megadose of trehalose (100g/d) which when finished showed significant effects and improvements in arterial microvasculature in healthy middle aged and older adults (MA/O):

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931825/

    Ironically most Americans consume more calories in the form of sucrose per day so who is to say it is a megadose, but I am guessing they use this large dose to overwhelm the trehalase enzyme which is present in considerable quantities in the upper intestine, liver, and blood.

    What they found is for adults who did not gain more than 2.3kg in weight over 12 weeks, their endothelium-dependent dilation (EDD) improved by 30%. In other words, they found no improvements in the macrovasculature (as they expected) but considerable improvements in the microvasculature, a topic relevant to autism especially with regards to the microvasculature of the blood brain barrier. It is also interesting (and with respect to autism and some interventions suggested on this blog) that the improvements in EDD were abolished from nitric oxide inhibition which suggests obviously that trehalose's positive effects on the microvasculature are nitric oxide dependent. If oxidative stress (in some autisms) is a direct cause of BBB permeability, perhaps megdose trehalose could be a magic bullet in this regard (one can only hope).

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  4. One more thing for anyone who might consider megadose trehalose. Here is a link to the brand I have at home:

    https://www.swansonvitamins.com/swanson-ultra-pure-trehalose-1-lb-454-grams-pwdr

    If you were to do 100 grams a day (which you would probably scale down for a child), that would cause you to run through 2 of those containers in 9 days which comes out to be roughly $2.67 (American) per day which is obviously not cheap and considering it eventually is metabolized to 400 calories a day in glucose, you obviously would want to cut back on carbs in other areas because you will be getting plenty from trehalose. One nice thing about trehalose is that unlike pretty much every other sugar I am aware of, it is not absorbed really fast in the stomach, rather it does not get broken down into glucose until it gets to the small intestine and any trehalose not broken down by trehalase is absorbed passively by the intestinal lumen (which is the idea behind the megadosing) or else excreted.

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  5. Just came across a novel bit of research that explores the brain-gut axis, rather than the more conventionally known gut-brain axis:

    Press Release (No Paper):

    https://www.sciencedaily.com/releases/2017/04/170403123508.htm

    What they did in this research is apply a new use of Transcranial Magnetic Stimulation they call "Deep Transcranial Magnetic Stimulation" or dTMS to an area of the brain in obese subjects that is very difficult to target with regular TMS called the insula. This stimulation ended up changing the gut microbiota of the subjects to have a composition more reflective of healthy/skinny subjects and caused a 3% average weight loss over the study period.

    Now what is interesting here is not really the technique but the idea of changing the gut microbiome via the brain itself. The stimulation area they chose was the insula and one interesting thing is that the area they likely targeted which included the prefrontal cortex (which means they focused on the anterior insula) is also parallel to many endocrine subcortical nuclei, including the hypothalamus. There is no paper available, so I am just speculating that in addition to stimulating the insula, they likely stimulated feeding centers in the brain which primarily are master regulated via the hypothalamic nuclei even though reward areas of the brain are very important, not to mention parts of the insula involved in whether you "feel" one way or another toward a food (i.e. is it good, bad, disgusting, etc.).

    With respect to autism where impaired endocrine signaling and a compromised microbiome is just part of the story, the idea of using the brain to change the microbiome, rather than the other way around is intriguing. It also suggests, simply supplementing with probiotics in some people may not be enough as the gut microbiota could be constantly pushed back into a compromised state via the brain itself.

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    Replies
    1. Hi Tyler,

      Thanks for posting this! The gut/brain axis was interesting enough, but the idea that there is two way communication versus one, is big. The fact that the brain can impact the but microbiome is fascinating - and to your point, interventions aimed at changing the gut microbiome of ASD patients may be inadequate if the brain keeps sending messages to turn the good microbiome bad. The key then would be to change the message from the brain.

      AJ

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  6. Hi everyone,

    Thought you'd be interested in this:

    http://www.telegraph.co.uk/news/2017/04/05/marmite-may-boost-brain-even-help-stave-dementia/

    Marmite appears to boost GABA - could it be helpful to us?

    It can never be something tasty like a KitKat bar that our kids would actually crave - it has to be something that will taste odd to them.

    Hope you find this interesting!

    AJ

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    1. Hi AJ,

      I was just curious about the effects you could perceive, of the many naturally occurring compounds...astaxanthin, apigenin I remember..you were trialling on your daughter. Any breakthrough with any other intervention. Would be grateful for a brief summary.

      Wishes

      Delete
    2. Hi Kritika,

      Hope all is well with you. Kritika, I would say that the only compound I can say for sure has had an impact on my daughter is 5-HTP. The impact is really noticeable. I give her 0.5mg/kg twice a day (1 mg/kg total per day) and the difference is noticeable. I had bought it and held onto it, not sure if I sure try it, and then I read something Peter had written and that gave me more confidence - tried and it and wow. My daughter's mood improved a lot. She was already a happy kid, but she immediately became a lot happier, less cranky, etc. I don't know if it'll work for your son, but it worked for us.

      My daughter is constantly improving in terms of her speech, but I don't know if its her natural progression or my treatment protocol. I recently added Huperzine and Citicoline and school just said they see recent improvements in her speech, but again, I can't say if its related. All that to say, I haven't yet had a "WOW" where I give a supplement and she immediately improves a lot.

      I will say that I just read something Peter wrote about improved Oxytocin with Biogastrus Protectis. I will likely try that next.

      Hope that's helpful Kritika, and all the best to you and your family!

      AJ

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    3. Hi AJ,

      Thanks. I am currently trying, rather finishing off my bottle of Biogaia protectis, on alternate days, as i had opened it and then stopped using it and it is to be consumed within a certain time period following opening.

      But the dramatic mood enhancement and communication improvement which we had seen with bio amicus reuteri was missing with protects. Not sure if its because of difference in strain or my sons changed biochemistry or change in weather. After this, I am done with L. Reuteri as I am unable to decide what kind of positive effects I am looking for to justify its long term use.

      Currently just trying to revisit basic supplementation... Plus some methylation stuff.

      Beet wishes

      Delete
  7. Peter
    I started my 6 year old son autism on Bumetanide 1mg Two times a day 2 weeks ago. I am seeing changes with him on this. Urination is just more volume not that much more often. He is calmer, has much less OCD and better balance already, also better sentence structure when talking. These changes are coupled with some unusual episodes in which he seems to be laughing & totally on another planet about 3 times a day for about 10 minutes. My son is an unusual kid as far as responding to things. Many things that other kids respond to he has had a bad response to. NAC made him stare off & make strange noises for long durations where you could get him to hear us. This seems to happen with other amino acids that we have tried. Broccoli Sprout Powder (Enduracell) seems to make him calm yet happy. So this one has been pretty good.
    I am hopeful about the Bumetanide since I see that it does have an effect on him. School considers him autistic with hyperlexia since he is a good learner with gifts in reading and math. He has a negative part of his personality in which he accomplishes great things if you are not watching him but will NOT share his gifts. An example he will count by 9 s or even 8 s to 100 but if you say " that's great can you do that again, he will scream very loudly "NO, I won't " . The same with reading & the same with playing his instruments. Peter I know you are not a doctor, by when reading his description are their any other compounds that may help him? Also I know to just stick with the Bumetanide to see those changes all the way through. I am supplementing potassium. Also is your son still using Bumetanide.

    Thank you

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    Replies
    1. Pierrette, my son has been taking Bumetanide since December 2012, so we are committed to it.

      Your son sounds like he has Asperger's.

      I would continue with the bumetanide. If he does not have big issues, I would not get carried away with therapies.

      5-HTP is widely used and does correct a common biological dysfunction. It is very cheap and easy to trial. You can get it in gelatin capsules and just pour out the correct amount into a drink. I would try 0.5mg/kg at breakfast and see if you have a more cheerful son later in the day. People who do respond seem to use 0.5mg/kg twice a day, but once may be enough.

      When he is older and if he has more behavioral issues you could try baclofen, which many people with Asperger's respond to; but not all of them.

      If you want to make him more emotional/loving/caring, the Biogaia Protectis probiotic produces oxytocin among other effects. It really does have this effect in many people. Biogaia Gastrus has a second bacteria in it. We use Protectis, but not every day.

      Delete
    2. Pierrette, how you describe your son being resistant to sharing his gifts - a kind of performance anxiety - you might be interested in what Donna Williams has to say on this. She is an Australian woman on the spectrum who has written several books and works with families - she describes this scenario as "exposure anxiety". My son is the same - except he will say "go away" or leave me alone please"... I find her insights so helpful. She shares her very personal experiences and addresses the emotional health, not just the biology, and how that impacts so much. Give her a google.Of all the adults on the spectrum writing books and speaking at seminars, I always found her insights and experiences more like my son - very creative soul, sensitive, and deep in to the sensory stuff. Best wishes!

      Delete
    3. Peter:

      I appreciate the great recommendations, I am not knowledgeable on what supplement could improve mood and less anxiety, so thanks for these, I will wait 30 more days on this bumetanide to see if mood is improved with less sodium chloride in his cells!!! If not I will try these! He is currently on a probiotic Lacto Rueteri which I chose because it is supposed to positively effect mood & oxytocin. I will have to track it and see if the days I don't give it may be his more problematic days. The Biogaia Protectis may be even more effective then Lacto Rueteri. I have not tried the 5-HTP. After 30 more days I will try the dosage you suggested if needed. As far as issues go. He is a great learner but a very poor communicator. He is in Half mainstream Kindergarten/ Half Hyperlexia class, (he prefers the hyperlexia class with just 5 other kids) and since he does not share and show I had to tell school that he could read & do math & after he was there for months they let me know that he was quite gifted at reading & math, they thought they were informing me of something I did not know. So communication is a BIG problem for him. He does make autism noises so they tend to think that he has problems learning and his not wanting to talk to them made it that much harder. Thank you Peter & Thank you for a very informative blog

      Tanya:
      I am glad you wrote that post I really never had someone explain this as "exposure anxiety" & yes his other phrases are "please leave me alone", "please close the door behind you", & "I would like some privacy, please leave". Like I said I am hoping the bumetanide relieves some of this anxiety and I will look up Donna Williams for more insight!

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  8. The NMDA antagonist Amantadine has proved very helpful for my son... however after two years we have reached max dose and tolerance is waning... any suggestions on how to achieve the same effect?

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    1. Audrey, Amantadine also increases dopamine release, and blocks dopamine reuptake. It may be this effect that gave the benefit. I think you said L-DOPA did not help, there is also Carbidopa. I did a post on dopamine.

      https://epiphanyasd.blogspot.com/2017/02/secondary-monoamine-neurotransmitter.html

      Amantadine is used off-label in MS.

      I think you once mentioned you use Minocycline. This should reduce microglial activation.

      One reader of this blog uses the Japanese drug Ibudilast. In Japan it is used to treat asthma, so it is a drug for long term use.

      Ibudilast has been found to stabilize microglia and in the US is now being trialed as a therapy for MS.

      So while Ibudilast is not the same as Amantadine, it might be interesting.

      Delete
    2. thanks Peter. Yes we use minocycline too... though it also seems to have tapered off in effectiveness. And I'm never quite sure about the dose. Yes... Zandopa, a natural form of L-dopa based on Mucuna was quite impressvie for my son... increased movement, language, etc. But only once... the next day it did not work. I waited a few weeks and tried again... and never got that same amazing response as the first time. :( I will look into ibudilast... thank you Peter

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    3. Hi Peter, and all. My Ibudilast arrived today from Japan. Can anyone give me advice on dosing for a 40lb, 6 y.o.?
      Thanks so much

      Delete
    4. Audrey, in Japan the dose for asthma is 10mg twice a day. Your son is 1/3 the weight of a Japanese adult.
      It is experimental use, but the current trial in the US to treat MS is going well and has been extended. At least one reader of this blog finds Ibudilast helpful for autism, but I do not know her dose.

      Delete
  9. Peter, have you seen this article?

    https://www.ncbi.nlm.nih.gov/pubmed/27645286
    It first sounds as if it is just about stuttering, but it seems that adrenocorticotropic hormone (ACTH) has good effects on autism as well. The common denominator is epileptic activity (electrical status epilepticus in sleep - ESES).
    I stumbled on this while looking for information on transcranial direct current stimulation and epilepsy.
    /Ling

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    Replies
    1. Ling, thanks for the link.

      That link would be very interesting for Tanya and Agnieszka.

      There is also interest regarding corticotropin releasing hormone (CRH) and autism.

      Stuttering is a troubling feature for many with autism.

      Central hormonal dysfunction is one of my suggested core issues in autism. ACTH is part of the hypothalamic-pituitary-adrenal axis. A problem with one hormone then disturbs many others.

      The problem with hormones is that they are controlled by feedback loops and it is hard to find solutions that are long lasting and without negative consequences.

      ACTH is interesting. Low ACTH and cortisol levels are symptoms of ACTH deficiency, which is treatable.

      Delete
    2. ESES might be underdiagnosed in autism, but I think it’s important to consider even if it’s only a kind of epiphenomenon. I am not sure, but I think they used high dose ACTH as in infantile spasms, a severe early childhood epilepsy and it was suggested that ACTH might be anitiinflammatory/immunomodulatory in such case.

      Recently Diamox was also found effective for ESES and improved communication, school performance and behavior in children included here:
      https://www.ncbi.nlm.nih.gov/pubmed/26230617

      Ling, I saw you considered EEG for your daughter. I think these papers (and many others) show that it is really a good idea and the best would be prolonged sleep EEG, otherwise things like ESES might not appear in the result. Good luck with finding help for your daughter.

      Paradoxically, speech disfluency in my son developed along with improvement in EEG and huge cognitive step forward. His sleep epileptiform discharges disappeared on acetazolamide. His awake EEG abnormal slowing reduced gradually on Bumetanide and is now considered borderline.

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    3. Thanks Agnieszka!
      Actually it was this publication that made me insist on having an EEG for my daughter: http://treatingautism.org.uk/wp-content/uploads/2017/04/Seizures-in-Autism-information-sheet.pdf
      I am sure you know it well... :-)
      /Ling

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  10. Peter - I noticed earlier that you said that Biogaia Protectis increases Oxytocin - I didn't realize that and would love that effect. I looked online and found that they have both drops and tablets. Is one more effective than the other between the drops and the tablet in your opinion? And what dosage would you recommend for a 35 pound 4 year old? If my daughter's sociability at school improves due to this product, it would be great news for us.

    Thanks in advance Peter!

    AJ

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    1. AJ, Bioamicus are in Toronto and you might want to try their L.reuteri and compare with Protectis.

      In our 50kg (110 pounds)case, just one tablet is enough to make the effect I assume comes from oxytocin. I think 5 drops = 1 tablet.

      The Bioamicus bacteria is very slightly different and it is entirely plausible that different people might respond better to different versions. Diet may also have an influence.

      Delete
    2. Hi Peter, Thank you! I will definitely try it and didn't realize there was an option (Bioamicus) in my own backyard. I will certainly try it. Much appreciated Peter!

      AJ

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