Channelopathies in Autism - treating Cav1.2 with Verapamil

 

In December 2013 I wrote about a leading Italian researcher and clinician called Professor Antonio Persico and gave a link to an excellent presentation he gave in the US, about his views on the underlying biological process behind autism.

Excess Calcium and Calcium Signaling in the Autistic Brain

  

He had a nice graphic in which he depicted the puzzle that is autism.

  

One of his findings was that in the autistic brain there is an excess of both physical calcium and calcium signaling (via ion channels). He did not draw any therapeutic conclusions, which as I said was a pity.

In fact, Persico is far from the first scientist to point the finger at calcium channelopathies.

A few months before this, I had decided I would apply myself to see if there were any safe, practical therapies that could be applied, based on all the scientific research about calcium ion channels; incomplete as it might be.

After a few hours, or so, of reading about the biology of calcium channels, the available drugs and the existing research in their use in conditions other than autism, I came to the conclusion that Verapamil looked a very likely candidate.

Verapamil is a so-called L-type calcium channel blocker (L representing long-lasting length of activation); it particularly affects a type of voltage-gated calcium channel called Cav1.2.  For various reasons, I had deduced that these Cav1.2 channels were possible open more often than they should be in the brain of Monty, aged 10 with ASD.  I proposed that over activation of these channels resulted in extreme agitation that leads to aggression and self-injurious behavior in autism.

Back in September 2013, Monty was still having behavioral problems, apparently brought about by summertime pollen allergies.  I did write extensively about this and how I had narrowed the problem down to mast cell degranulation and histamine.  Treating the allergy did a lot of good, but was never a complete solution, since the standard allergy drugs worked for only a couple of hours, rather than the 24 hours they claimed.

So I had Monty in a state of near explosion by mid-afternoon most days, with a red face and letting us all know he was not feeling good.  He would say things including “be nice”, “I want to be nice”, “to hit your head” or even, on a good day, “to hit your head and see birdies”.  By then, he was also having Rupatadine, a mast cell stabilizer, which did seem to help.  The eruptions were far less often and less severe than in July, but it was clear that more could be done.

One afternoon, I decided to give a very small dose (20mg) of Verapamil, and before my eyes, the anger and agitation began to fade and was replaced by calm.  It was the most amazing experiment that I have witnessed and within 20 minutes there was complete calm.

In the following weeks, I would still hear Monty say “be nice”, but this was no longer followed by any aggressive behaviour.  The trigger was still there to energize these channels, but they had blocked by Verapamil.  It was like firing a gun, but with no ammunition; there was a “click”, but no “bang”.

This is the reason that Verapamil is in the PolyPill, in case anyone has wondered.

Before you start googling, there is absolutely no published research to support the use of Verapamil in autism.  This is part of the reason I did not to write about it at the time.

Verapamil is also a blocker of certain voltage-gated potassium channels and has the effect of raising potassium levels in the blood.  We have seen in earlier posts that potassium channel dysfunction is also present in autism and that raising potassium levels helps reduce sensory overload.  One effect of bumetanide is that it lowers levels of potassium, so bumetanide and verapamil are in that way very complementary.

Subsequently, I have read that mutation of the CACNA1C gene is associated with schizophrenia, which is like adult-onset autism.  The calcium channel produced from the CACNA1C gene is Cav1.2.  So this might be a case of what helps in autism might help in schizophrenia.

The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia.

 If you are interested in why I decided to test Verapamil, read on.

 

Observations

Anger & SIB

Anger, leading to violence against others and to yourself are behaviours that arise in many people with autism.  There are undoubtedly many causes, and many are behavioral.  If a non-verbal person cannot express what he wants, or a partially verbal child has some pain (e.g. toothache) and does not understand it, things are likely to get out of control.

But there are other times, when for no apparent reason, nasty behaviour can occur, so I presumed that there might be a biological explanation.  If there was one, then I would think about a biological intervention.

My wife always asked Monty if his head was hurting when these kinds of behaviors popped up.  He would usually say “yes”, but it could well have been to avoid any other questions.  But why not consider it as possible that there is a pain prior to SIB.

Fever Effect

Then we have the recurring observation about autistic behaviours changing when the person has a high temperature; the fever effect.  This has now been studied by literally warming people up in hot water and then carrying out behavioural test.

Hyperthermia and the Amelioration of AutismSymptoms

As usual in autism, this effect applies much more to some people than to others.  Monty is moderately affected, but some people are dramatically improved.

Headaches

Headaches are very common, but some people do seem to get far more than their fair share.  Migraines are particular nasty and so is another type, the cluster headache.

Cluster headaches are severe headaches that are clustered together.

Cluster headaches are occasionally referred to as "alarm clock headaches" because of the regularity of their timing and they may awaken individuals from sleep. Both individual attacks and the cluster grouping can have a metronomic regularity; attacks striking at a precise time of day each morning or night is typical. This has prompted researchers to speculate involvement, or dysfunction of the brain's hypothalamus, which controls the body's "biological clock" and circadian rhythm.

Now I have noted that in some literature it is claimed that parents of children with autism often have a history of headaches (and I do not mean caused by dealing with their child’s autism).  

Note that most younger people with autism have a “faulty” biological clock, so they have trouble sleeping through the night.

 

Febrile seizures

Seizures and autism are closely related.  Febrile seizures occur in some children when they have a temperature greater than 38 °C (100.4 °F).  They are twice as common in Japanese children than they are in Western children, occurring in up to 9% of children and mainly in boys.

It is not agreed exactly what causes febrile seizures, Japanese research points to voltage-gated sodium channels, which does not really support my theory.  However, rather than delete this part of the post, I did a little more digging and found a paper in the Journal of Neuroscience that does neatly fit by theory.

Temperature-sensitive Cav1.2 calcium channels support intrinsic firing of pyramidal neurons andprovide a target for the treatment of febrile seizures.

Comorbidities

It is well documented that poor cardiac health is associated with autism.  I have commented before that it is not entirely by coincidence that some drugs that help autism were actually developed as drugs for heart problems.  By treating the autism, a side benefit is that you may also be treating (and perhaps avoiding) the heart disease that would otherwise likely to develop at quite a young age.

So, while giving statins and calcium channel blockers to a healthy young person would be irresponsible, the same may not true for people with autism.  In the same way that people with type 1 diabetes have been recognized as being at high risk of heart disease and are put on preventative drugs at a much younger age than the wider public. Patients with type 1 diabetes are 10 times more at risk from heart disease than other healthy patients.  They are recommended statins, aspirin therapy and an ACE inhibitor.  An ACE inhibitor reduces blood pressure in a different way to how Verapamil also lowers blood pressure.

Due to the severity of neurological/behavioral problems of autism, medical practitioners are not really worrying about cardiac health.

Too Much Calcium

There are opposing views about the role of vitamin D in autism; in other words, too much or too little.  There have been some interesting thoughts about milk and autism, and not about whether or not it is fortified with extra vitamin D; the point was the role played by calcium.

Then there is the mother who found that supplementing her autistic child with calcium had some frightening consequences, producing profound regression.

Basic Biology

If you want to read about the basic biology of calcium channels, here are links to Wikipedia;-

Calcium Channels

L-type Calcium Channels

Calcium Channel Blockers

Connections with the biology

One of the things that drew my attention was the fact that the behaviour of some calcium channels is temperature dependent.  There are other ion channels that are also temperature dependent.  The Cav1.2 channels are known to behave differently according to their temperature.

Connections within the literature

Timothy syndrome

I have covered Timothy syndrome previously in this blog.

This is a, thankfully, extremely rare condition in which the most people do not survive to childhood; those few that do are likely to have autistic-like symptoms.

The syndrome is caused by severe mutations of the CACNA1C gene.  As a result it is also associated with severe heart problems, since this gene expresses the Cav1.2 channel that is found in the heart and the brain.

The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels

In the following article, Dr Ricardo Dolmetsch used an experimental L-type calcium channel blocker, called Roscovitine, to “successfully” treat his model of Timothy Syndrome.

Scientists identify defect in brain cell channel that may cause autism-like syndrome 

Dolmetsch is now Head of Neuroscience at the Novartis Institute for Biomedical Research.  I did write to him once, when he was still at Stanford, to ask if he was interested in discussing some of my ideas – no answer, I guess he was busy curing autism.

Headaches

It has been known for many years that some L-type calcium channel blockers are effective in treating both migraine headaches and cluster headaches.

Individualizing treatment with verapamil for cluster headache patients

 

CONCLUSIONS:

Providing the dosage for each individual is adequate, preventing CH with verapamil is highly effective, taken three (occasionally with higher doses, four) times a day. In the majority (94%) with episodic CH steady dose increase under supervision, totally suppressed attacks. However in the chronic variety only 55% were completely relieved, 69% men, but only 20% women. In both groups, for those with partial attack suppression, additional prophylactic drugs or acute treatment was necessary.

This study found that some people required 5 times higher dose than others and doses were up to 960mg per day.

Verapamil in prophylactic therapy of migraine

We conducted a double-blind, placebo-controlled crossover study of verapamil HCI in the prophylaxis of chronic migraine headaches. Verapamil significantly reduced both headache frequency and duration with few side effects. The drug may be useful for a segment of the migraine population refractory to other prophylactic agents or for those who cannot tolerate the side effects of other drugs

Mice and SIB (Self Injurious Behaviour)

Lots of people do not like the idea of being compared to mice, or even worse rats.  Nonetheless, this following paper is indeed very relevant, it showed that it you active the L type calcium channels in mice they will engage in self injurious behaviour.

Calcium channel activation and self-biting in mice

The L type calcium channel agonist Bay K 8644 has been reported to cause characteristic motor abnormalities in adult mice. The current study shows that administration of this drug can also cause the unusual phenomenon of self-injurious biting, particularly when given to young mice.

The self-biting provoked by Bay K 8644 can be inhibited by pretreating the mice with dihydropyridine L type calcium channel antagonists such as nifedipine, nimodipine, or nitrendipine.

However, self-biting is not inhibited by nondihydropyridine antagonists including diltiazem, flunarizine, or verapamil.

If Monty was a mouse, verapamil would therefore likely not work and I would probably have had to use nimodipine.

Genes

I do not claim to be an expert in Genetics, but I can uses genes to support my case.

In 2013 a paper was published in the Lancet that looked for genetic links between a range of neurological disorders.

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

In this paper you can find out many things, including:-

•  Gain-of-function mutations in CACNA1C causes Timothy syndrome

•  CACNA1C is a susceptibility gene for bipolar disorder, schizophrenia, and major depressive disorder

• neuroimaging studies have documented effects of CACNA1C variants on a range of structural and functional brain phenotypes, including circuitry involved in emotion processing, executive function, attention, and memory

• Mutation in the CACNB2 gene are associated with Brugada syndrome, autism, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia

• CACNB2 encodes an auxiliary voltage-gated calcium-channel subunit that interacts with L-type calcium-channel subunits (including CACNA1C, CACNA1D, and CACNA1S) to promote their trafficking to the plasma membrane, increase their function, and regulate their modulation by other signaling proteins and molecules

Now “my” Calcium channel, also known as Cav1.2, is encoded by the very same CACNA1C gene.

In a similar paper, autism also gets a mention 

“Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders”

CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease

So all in all the genetic analysis also point to Cav1.2 as a good candidate for some intervention.

Epilepsy

Verapamil is being investigated to treat various forms of epilepsy and seizure.  This is interesting, since seizures are highly comorbid with autism.

Seizures tend to develop in early puberty in many cases of autism.  It appears possible (maybe not probable) that if you can avoid the onset of epilepsy during this time of hormonal change, you may be free of it for life.  The science has shown that the first seizure makes a biological change occur;  the same is indeed true with asthma.  If you can identify the at risk group (i.e. people with autism for epilepsy and atopic dermatitis for asthma) you may indeed be able to avoid it.

I was not aware of this until after Monty, aged 10 with ASD, had developed asthma, but I am well aware of it now.  I am actively taking steps to avoid epilepsy.

The other useful aspect of this research is that they are all clinical trials of Verapamil in children.  This is important from the safety perspective.

Study suggests Verapamil could be used to fight refractory epilepsies

Verapamil as Therapy for Children and Young Adults With Dravet Syndrome

Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy

Calcium channel blocker Verapamil Administration in Prolonged and Refractory Status Epilepticus

Choice of Channel Blocker

In medicine, calcium channel blockers were developed to treat heart conditions.  A common problem in treating autism is the need for drugs to freely cross the blood barrier (BBB); most do not.

Other issues include the half-life of the drug and most importantly the safety of the drug.

Given these considerations, and the fact that I know precisely which calcium channel I want to block, this led to me to Verapamil.

It is very widely used, and is available very cheaply as a generic in sizes down to 40mg.  Adult and indeed child dosages go all the way up to 400+mg a day.

Since the idea is to subtly affect the brain and not dilate blood vessels in the heart, which increases the supply of blood and oxygen; a small dose was envisaged, 20 mg.

On paper, Nimodipine, also looks a very interesting candidate, but it is rarely used in children.  It would be useful to trial it on adults with autism.  It works better than verapamil in mice with SIB.

Conclusion

I must admit that some of my “evidence” was gathered after I had proved my theory was valid, like the mice with SIB after their L-type channels were activated.

Given all of the “evidence” it does amaze me that it did not occur to anyone to try a drug like Verapamil in children with autism.

Clearly all drugs carry a risk, but so does violence and self-injury.

P.S.  Note that magnesium is also a calcium channel blocker