Low Dose Clonazepam for Autism - SFARI Webinar with William Catterall

Click this link  http://sfari.org/sfari-community/community-blog/webinar-series/2015/webinar-william-catterall-examines-anxiety-drugs-for-autism/

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:-

Channelopathies in Autism - Treating Nav1.1 with Clonazepam

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 GABA_A 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.

Modified Use of Anti-Epileptic Drugs (AEDs) at Low Doses in Autism

As readers will be aware, many people with more severe autism are also affected by epilepsy.  Siblings of those with autism also seem to be at greater risk of epilepsy.

There are frequent comments that once starting on AEDs (Anti-Epileptic Drugs) aspects of autism also seem to improve.  This should not be surprising given the suggested action of these drugs and the overlapping causes of epilepsy and autism.

Today’s post is prompted by the observation that in very low, apparently sub-therapeutic, doses some AEDs seem to improve autism in some cases.  This is relevant because the usual high doses of these drugs are associated with some side effects and indeed a small number can be habit forming.

What is epilepsy?

The cause of most cases of epilepsy is unknown.

Genetics is believed to be involved in the majority of cases, either directly or indirectly. Some epilepsies are due to a single gene defect (1–2%); most are due to the interaction of multiple genes and environmental factors.  Each of the single gene defects is rare, with more than 200 in all described.  Most genes involved affect ion channels, either directly or indirectly. These include genes for ion channels themselves, enzymes, GABA, and G protein-coupled receptors.

Much of the above applies equally to autism, including the genetic dysfunctions associated with GABA.  The ion channel dysfunctions in epilepsy are thought to be mainly sodium channels, like Nav1.1.  We previously came across this channel when looking at Dravet Syndrome.

Dravet Syndrome

Dravet Syndrome is rare form of epilepsy, but is highly comorbid with autism.  It is cause by dysfunctions of the SCN1A gene, which encodes the sodium ion channel Nav1.1.  There is a mouse model of this condition, used in autism research.  Dravet Syndrome is known to cause a down-regulation of GABA (the neurotransmitter) signaling.  We saw how tiny doses of Clonazepam corrected this dysfunction in mice.

Known ASD-associated mutations occur in the genes CACNA1C, CACNA1F, CACNA1G, and CACNA1H, which encode the L-type calcium channels Cav1.2 and Cav1.4 and the T-type calcium channels Cav3.1 and Cav3.2, respectively; the sodium channel genes SCN1A and SCN2A, which encode the channels Nav1.1 and Nav1.2, respectively; and the potassium channel genes KCNMA1 and KCNJ10, which encode the channels BKCa and Kir4.1, respectively.

Channelopathies in Autism - Treating Nav1.1 with Clonazepam

Dr Catterall, the researcher, then went on to test low dose clonazepam in a different mouse of autism model and found it equally effective.  It also appears to work in some human forms of autism.

Sodium Valproate

Valproate is a long established epilepsy drug that has also been used widely as a mood stabilizer and particularly to treat Bipolar Disorder.

One side effect can be hair loss.  Hair loss/growth and also hair greying are frequently connected with drugs and genes linked to autism (BCL-2, biotin, TRH etc).

One regular reader of this blog has pointed out that a tiny dose of Valproate, when combined with Bumetanide, appeared to have a significant and positive effect.  We know that bumetanide works via NKCC1 and the GABA_A receptor to make GABA more inhibitory.

Many modes of action are proposed for Valproate, but the most mentioned one is that it increases GABA “turnover”; so it would make sense that having shifted the balance from excitatory to inhibitory, a stimulation to increase GABA signaling might be beneficial.

What is odd is that this is happening at a dose 20 times less than used in epilepsy, bipolar or mood disorders.

The use of Clonazepam, discovered by Dr Catterall, is also at a dose 20 to 50 times less than the typical dose.

Clonazepam and Valproate are both AEDs.  There are not so many of these drugs and while using them at high doses, without dire need, might be highly questionable, their potential effectiveness at tiny doses is very interesting.

Clonazepam is a Benzodiazepine in the table below.

The above table is from the following paper:-

 Mechanisms of action of antiepileptic drugs

Low Dose Clonazepam

Low dose Clonazepam was shown to be effective by its action of modulating the GABA_A receptor to make it more inhibitory.  There are different types of GABA_A receptor and the low dose effect was sub-unit specific.  Other benzodiazepine drugs were found to have the opposite effect.

The mouse research showed that the effect only appeared with a narrow range of low dosages.

Low Dose Valproate

Valproate is known to affect sodium channels like Nav1.1, but also some calcium channels.

For an insight into some known potential effects of Valproate, here is a paper from the US National Institute of Mental Health:-

Therapeutic Potential of MoodStabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

In the paper it highlights the less well known effects of Valproate:-

inhibits HDACs

Modulates Neurotrophic and Angiogenic Factors (BDNF, GDNF, VEGF)

PI3K/Akt Pathway

Wnt/β-Catenin Pathway

MEK/ERK Pathway

Oxidative Stress Pathways

Enhanced Neuroprotection

Enhancing the Homing and Migratory Capacity of Stem Cells

Here is a list of the suggested new applications of Valproate, many highly appropriate to many types of autism:-

       Repurposing Mood Stabilizers for CNS Disorders Beyond BD

       A. Stroke

       1. Lithium-Induced Effects in Experimental Stroke Models

       a. Neuroprotection and behavioral improvement

       b. Anti-excitotoxic and anti-apoptotic effects

       c. Anti-inflammation

       d. Angiogenesis

       e. Neurogenesis

       f. Effects on MSC migration after transplantation

       2. VPA-Induced Effects in Experimental Stroke Models

       a. Neuroprotective effects and behavioral benefits

       b. Anti-inflammation

       c. BBB protection

       d. Angiogenesis

       e. Neurogenesis

       B. TBI

       1. Lithium-Induced Effects on Neurodegeneration, Neuroinflammation, Behavioral Improvement, and Aβ Accumulation in Models of TBI

       2. VPA-Induced Effects on Neurodegeneration, Neuroinflammation, and Functional Recovery in Models of TBI

       3. Clinical Trials of VPA Treatment in TBI

Having read that paper I am now not surprised that a tiny dose of valproate can have a positive behavioral effect in autism.  What would be interesting to know is how the effects and dominant modes of action vary with dosage.  I presume the dosage has been optimized to control/prevent seizures.

Valproate is a cheap drug and is available as a liquid, so accurate low dosing is possible.  It has been shown to be neuro-protective, even shown promise as a treatment for traumatic brain injury.

While not written about autism, some of you may find the following collection of research interesting:-

Brain Protection in Schizophrenia, Mood and Cognitive Disorders

It does talk about the wider potential use of Valproate, but not at tiny doses.

Stiripentol

Interestingly, an orphan drug was developed in the European Union to treat Dravet Syndrome.  It is included on the list of AEDs above.

Even though that drug, Stiripentol, is not approved by the FDA, most sufferers in the US are able to acquire it under the FDA’s Personal Importation Policy(PIP).

So it is indeed possible to acquire drugs prior to approval in your home country.

Hopefully, once Bumetanide is approved for autism in Europe, similarly people will be able to access it easily in the US.

I wonder if anybody with Dravet Syndrome has tried low dose Clonazepam.  In theory it should be helpful.