This post
will be mainly of interest to the small number of people using low-dose
clonazepam for autism and those considering doing so.
This therapy
modifies the excitatory/inhibitory (im)balance between the GABA and Glutamate
neurotransmitters. The big advantage is
that it should be very safe, is extremely inexpensive and, unlike Bumetanide,
does not cause diuresis. The
disadvantage is that the effective dose is only in a narrow window, and you
have to find it by trial and error.
Does it work?
It certainly
does work in some children with autism.
It also
appears to have an additional effect over Bumetanide alone, at least my son.
Questions
remain:
·
Does
it work with everyone who responds to bumetanide?
·
Does
it only work in people with a Nav1.1 dysfunction?
·
Will
bumetanide work in everyone who responds to Clonazepam?
One of my
earlier, detailed, posts on this subject is this one:-
Just google
“clonazepam epiphany” or use the site index, for the other posts.
Professor Catterall
I have already
covered the science behind low-dose Clonazepam and Professor Catterall’s trials
in two mouse models. It is quite a
complex subject and in the end most people just want to know does it work in
humans with autism or not.
Catterall’s
research was funded by the Simons Foundation, so no surprise really that he
made a Webinar for SFARI. It covers the
ground of those two papers and indicates the next steps for his research.
It is a bit
lighter going than his papers, but it is a full hour of science.
Catterall
plans to trial it in humans with autism, starting with those known to have
sodium channel dysfunction. So he is following the same pattern he used with
his mice.
The first
mouse model he used was Dravet syndrome, a rare condition leading to epilepsy
and autism which is caused by a sodium ion channel (Nav1.1) dysfunction. The second experiment used a standard mouse model of autism called the
BTBR mouse model, so no connection with sodium channels.
My
question to Catterall was whether this therapy would only work in people with a
Nav1.1 dysfunction. He did respond via the comments on the post,
but did not really answer the question.
The fact that he plans to trial his idea on humans with autism with a
known sodium ion channel dysfunction, does suggest something at least.
I think that
since the actual mechanism of the drug is on a sub-unit of the GABAA receptor,
sodium channels may actually be more of a coincidence, meaning that while autism
Nav1.1 dysfunction may indeed indicate this therapy, it may be applicable
in other autism where GABA is dysfunctional.
Bumetanide Use
The downside
of bumetanide use to correct the E/I imbalance often found in autism is the
diuresis and excessive loss of potassium in about 20% of people.
If you
revisit the original paper suggesting an
E/I imbalance might be fundamental to many kinds of autism, you will see
that this E/I imbalance is not just an ongoing issue, it is potentially an
avoidable cause of disruption at key points in the brain’s development prior to maturation. In simpler terms, an E/I imbalance during development may cause the physical brain abnormalities often observed in autism.
That would
suggest you should try and reverse E/I imbalance as soon as possible, well before
maturation of the brain.
One day an
analog of bumetanide may be developed, that avoids the diuresis; it is already being discussed.
Bumetanide (or low dose Clonazepam)
use, even before autism has become established ?
In something
like 30% of cases of classic autism there is macrocephaly (a big head), which
even shows up on ultrasound scans of the pregnant mother. A big head does not necessarily mean autism,
but specific types of autism are clearly associated with big heads.
There are many other well known risk factors, like siblings with autism, siblings with other
disabilities, older parents, family history (schizophrenia, bipolar, auto-immune
conditions, COPD, Nobel Laureates, math prodigies) etc.
Since we
also know that an indicator of this kind of E/I imbalance is that
benzodiazepine drugs can show paradoxical effects (they work in reverse), it
should be possible to make some kind of predictive diagnostic test.
So it would
not be rocket science to identify many babies at elevated risk of autism and then treatment
could be started very early and well before brain maturation.
This is rather like the Japanese researchers in the previous post suggesting that sulforaphane consumption in childhood might prevent susceptible people developing schizophrenia in adulthood.