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
mGluR5 negative allosteric modulator
N-methyl-D-aspartic acid (NMDA) antagonist
Glutamate re-uptake promoter
Suggested to have effects on NMDA & mGluR5 & GABAA
Positive allosteric modulator (PAM) of GABAA receptor
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:-
NMDAR hypo-function causing E/I imbalance in Autism and Schizophrenia – Baclofen, Sodium benzoate and Cinnamon (again)
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.
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.
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.
· 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.
D-Cycloserine an antibiotic with similar structure to D-Alanine (D-Cycloserine was trialed in autism and schizophrenia)
· Aspartic acid (trialed and used by Tyler, suggested for schizophrenia)
· D-Serine (trialed in schizophrenia)
- D-Alanine (trialed in schizophrenia)
· Ketamine (trialed intra-nasal in autism)
Glutamate re-uptake promoters via GLT-1
· Beta-lactam antibiotics