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.
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.
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)
- D-Alanine (trialed in schizophrenia)
NMDA antagonists
·
Ketamine (trialed intra-nasal in autism)
Glutamate re-uptake promoters via GLT-1
·
Riluzole
·
Bromocriptine
·
Beta-lactam antibiotics