Cardiazol, a failed Schizophrenia treatment from the 1930s, repurposed at low doses as a Cognitive Enhancer in Down Syndrome and likely some Autism

Italy has many attractions, one being Lake Como (Villa Clooney). 

It is also the only western country still using Cardiazol, where it is used in a cough medicine

Varanasi and the Ganges, not a place you could forget, particularly the smell.

India is the only other country using Cardiazol

Today’s post draws on clever things going on in Down Syndrome research to improve cognitive function, but puts them in the perspective of the faulty GABA switch. 

In the United States it is estimated that 250,000 families are affected by Down Syndrome.  It is caused by a third copy of chromosome 21, resulting in up-regulation of around 300 genes.  A key feature is low IQ, this is partly caused by a physically smaller cerebellum and it appears partly by the GABA switch.  Research has shown that the cerebellum growth could be normalized, but this post is all about the GABA switch. 

In an earlier very science heavy post we saw how a faulty GABA switch would degrade cognitive function in many people with autism, schizophrenia or Down Syndrome. Basmisanil is a drug in Roche’s development pipeline.

The GABA Switch, Altered GABAa Receptor subunit expression in Autism and Basmisanil

   

More evidence to show the GABA switch affects schizophrenia was provided by our reader Natasa.

Gain-of-function missense variant in SLC12A2, encoding thebumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia

Perturbations of γ-aminobutyric acid (GABA) neurotransmission in the human prefrontal cortex have been implicated in the pathogenesis of schizophrenia (SCZ), but the mechanisms are unclear. NKCC1 (SLC12A2) is a Cl^--importing cation-Cl^- cotransporter that contributes to the maintenance of depolarizing GABA activity in immature neurons, and variation in SLC12A2 has been shown to increase the risk for schizophrenia via alterations of NKCC1 mRNA expression. However, no disease-causing mutations or functional variants in NKCC1 have been identified in human patients with SCZ. Here, by sequencing three large French-Canadian (FC) patient cohorts of SCZ, autism spectrum disorders (ASD), and intellectual disability (ID), we identified a novel heterozygous NKCC1 missense variant (p.Y199C) in SCZ. This variant is located in an evolutionarily conserved residue in the critical N-terminal regulatory domain and exhibits high predicted pathogenicity. No NKCC1 variants were detected in ASD or ID, and no KCC3 variants were identified in any of the three neurodevelopmental disorder cohorts. Functional experiments show Y199C is a gain-of-function variant, increasing Cl^--dependent and bumetanide-sensitive NKCC1 activity even in conditions in which the transporter is normally functionally silent (hypotonicity). These data are the first to describe a functional missense variant in SLC12A2 in human SCZ, and suggest that genetically encoded dysregulation of NKCC1 may be a risk factor for, or contribute to the pathogenesis of, human SCZ.

This study showed that some with schizophrenia will likely benefit from Bumetanide, but that the underlying reason for excessive NKCC1 activity in schizophrenia is not the same as in ASD.  Different cause but the same end result and the same likely therapy, repurposing an old existing drug.

α3 and α5 sub-units of GABA_A

The science is rather patchy, but it seems that the α3 sub-unit of GABA_A receptors is under-expressed in some autism and there is a fair chance that the α5 sub-unit is correspondingly over-expressed.

We know that over-expression of α5 is associated with cognitive impairment.

Down regulating α5 is currently a hot topic in Down Syndrome and at least two drugs are in development.

Reading the Down Syndrome research suggests that those involved have not really understood what is going on.  They do seek to modify GABA signaling, but have not realized that likely problem is the miss-expression of GABA_A subunits in the first place, exactly as in autism.  As in autism, this faulty “GABA switch” has more than one dimension.  An incremental benefit can be expected from correcting each one.


Further support for the use of low dose Clonazepam in some Autism

In previous posts we saw how Professor Catterall's idea to use low dose clonazepam to treat some autism does translate from mice to humans.  This was based on up-regulating the α3 sub-unit of GABA_A receptors.

There is some new research on this subject and Japanese research is very often of the highest quality.

In the paper below, highlighted by our reader Tyler, they use low dose clonazepam to reduce autistic behavior in a rare condition called Jacobsen syndrome.  While Professor Catterall and several readers of this blog are using low dose clonazepam to upregulate the α3 sub unit of GABA_A receptors, the Japanese attribute the benefit to the γ2 subunit.

Whichever way you look at it, another reason to support trial of low dose clonazepam in autism.  When I say low, I mean a dose 100 to 1,000 times lower than the standard doses.

PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking 

Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood.

ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABA_AR agonist (Clonazepam)

   

A curative effect of clonazepam on autistic-like behaviour

 These results demonstrate that ASD-like behaviour in PX-RICS^−/− mice is caused by impaired postsynaptic GABA signalling and that GABA_AR agonists have the potential to treat ASD-like behaviour in JBS patients and possibly non-syndromic ASD individuals.

“Correcting GABA” in Down Syndrome

I expect there may be four different methods, all relating to GABA_A, to improve cognition in Down Syndrome just as there appear to be in autism:-

·        Reduce intracellular Cl- by blocking NKCC1 with bumetanide

 ·        Down regulate α5 sub-units of GABA_A

 ·        Damp down GABAA receptors with an antagonist

 ·        Upregulate α3 sub-units of GABA_A

Two of the above are being pursued in Down Syndrome research, but two do not seem to be.

Enhancing Cognitive Function in Down Syndrome

These are the sort of headlines that appeal to me:-

IQ-Boosting Drugs Aim to Help Down Syndrome Kids Learn

Cognitive-enhancing drugs may have a significant impact, doctors say. An IQ boost of just 10 to 15 points could greatly increase the chance that someone with the syndrome would be able to live independently as an adult, said Brian Skotko, co-director of the Down syndrome program at Massachusetts General Hospital in Boston, who has a sister with the condition.

In 2004, Stanford University neurobiologist Craig Garner and a student of his at the time, Fabian Fernandez, realized scientists might be able to counteract the Down Syndrome with drugs…

Researchers did a test in mice using an old GABA-blocking drug called PTZ. After 17 days, the treatment normalized the rodents’ performance on mazes and certain object recognition and memory tasks for as long as two months, according to results published in 2007 in Nature Neuroscience….

“It was bloody amazing,” Garner said by telephone. “It was shocking how well it worked.”

  

Inhibiting Inhibition to Treat Down Syndrome Symptoms

In their work, Hernandez, who is at Roche AG, and colleagues both at Roche and in academia chronically treated mice that have an animal version of Down syndrome with RO4938581, a drug that targets GABA receptors containing an alpha5 subunit. GABA is the major inhibitory transmitter in the brain, and in Down syndrome, there appears to be too much inhibitory signaling in the hippocampus – where, it so happens, GABA receptors with the alpha5 subunit are concentrated.

Treatment with RO4938581 improved the animals' memory abilities in a maze, decreased hyperactivity and reversed their long-term potentiation deficit. In the hippocampus, which is an important brain structure for memory and cognition, it also increased the birth rate of neurons back to the levels seen in normal animals, and led to a decrease in the number of inhibitory connections between cells.

  

In short there are two methods being developed, both potentially applicable to some autism:-

METHOD 1.   Dampen GABA_A receptors with an antagonist

METHOD 2.   Dampen GABA with an inverse agonist of α5 sub-unit  

Initially it was thought method 1 could not be used because of the risk of seizure/epilepsy.

“these drugs (GABA_A antagonists) are convulsant at high doses, precluding their use as cognition enhancers in humans, particularly considering that DS patients are more prone to convulsions”

From:-

Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice

  

However this seems to have been overly conservative.

In the 2007 Stanford study they make a big point of their dosing being far lower than that used to induce seizures.

While you may need for a decade to get hold of Basmisanil (method 2), Cardiazol/PZT (method 1) is available in some pharmacies today.  The only complication is that it is in a cough medicine that also contains Dihydrocodeine.

In some countries Dihydrocodeine is used in OTC painkillers along with paracetamol or ibuprofen, while in other countries it is a banned substance.

In Italy and India Cardiazol, with Dihydrocodeine, is given to toddlers as a cough medicine.

  

METHOD 1.   Dampen GABA_A receptors with an antagonist

  

As seems to be the case quite often, you can sometimes repurpose an old drug rather than spend decades developing a new one.  This is the case with Cardiazol/ Pentylenetetrazol that was used in the Stanford trial.

Confusing Medical Jargon, (again)

Cardiazol, the name an elderly psychiatrist would recognize, is also called:-

·        Pentylenetetrazol
·        Pentylenetetrazole
·        Metrazol
·        Pentetrazol
·        Pentamethylenetetrazol
·        PTZ
·        BTD-001 

·        DS-102

Other than to confuse us, why do they need so many names for the same drug?

Cardiazol/ Pentylenetetrazol is a drug that was widely used in the 1930s in Mental Hospitals to trigger seizures that were supposed to treat people with Schizophrenia.  At much lower doses, it found a new purpose decades ago as an ingredient in cough medicine.

Electroconvulsive therapy later took the place of Cardiazol, as psychiatrists sought to treat people by terrifying them.  It was later concluded that the only benefit in giving people Cardiazol was the fear associated with it. Electroconvulsive therapy is still used today in autism.

  

For a background into Cardiazol as a schizophrenia therapy, the following is not very pleasant reading:-

  

‘A violent thunderstorm’: Cardiazol treatment in British mental hospitals

  

The 2007 Stanford trial of Cardiazol (there called PTZ) also trialed another GABA_A antagonist called picrotoxin (PTX).  Picrotoxin is, not surprisingly, a toxin, it is therefore a research drug but it has been given to horses to make them run faster.

Pharmacotherapy for Cognitive Impairment in a Mouse Model of Down Syndrome

  

Recent neuroanatomical and electrophysiological findings from a

mouse model of Down syndrome (DS), Ts65Dn, suggest that there is

excessive inhibition in the dentate gyrus, a brain region important for

learning and memory. This circuit abnormality is predicted to compromise normal mechanisms of synaptic plasticity, and perhaps mnemonic processing. Here, we show that chronic systemic administration of noncompetitive GABAA antagonists, at non – epileptic doses, leads to a persistent, post drug, recovery of cognition in Ts65Dn mice, as well as recovery of deficits in long – term potentiation (LTP). These data suggest that excessive GABAergic inhibition of specific brain circuits is a potential cause of mental retardation in DS, and that GABAA antagonists may be useful therapeutic tools to facilitate functional changes that can ameliorate cognitive impairment in children and young adults with the disorder.

One important things is that this cognitive enhancing effect persisted for a couple of months.

As you will see in the human clinical trial at the end of this post, they are comparing single doses with daily doses to understand the pharmokinetics.

The lead author, Craig Garner went on to start his own company because nobody seemed interested in his findings.

http://balance-therapeutics.com/

“Balance is now testing a GABA-blocking drug, BTD-001, on 90 adolescents and adults with Down syndrome in Australia, with results expected by early next year, said Lien, chief executive officer of the company.”

GABA_A agonists and antagonists

The jargon does get confusing, if you want to stimulate GABA_A receptors, you would use an agonist like GABA itself, or something that mimics it.

If you want to damp down the effect of GABA_A receptors you would need an antagonist.

So if GABA_A receptors are “malfunctioning”, you could either fix the malfunction or turn them down to reduce their effect.

If you cannot entirely repair the malfunction you could always do both.  The overall effect might be better, or might not be, and it might well vary from person to person depending on the degree and nature of malfunction.

We saw in a previous post the idea of using drugs like bumetanide, diamox, and potassium bromide to restore E/I balance and then give GABA a little boost with a GABA agonist like Picamillon.  This is very easy to test.  In our case that little boost, did not help.

In those people who do not respond well, we can take the idea developed by Stanford for Down Syndrome and do the opposite, use a tiny amount of an antagonist, to see if that fine tuning has any beneficial effect.  We now see this is both simple and safe.

METHOD 2.   Inverse agonists of α5 sub-unit GABA_A

I do like method 2, but would prefer not to wait another decade.

Method 2 sets out to improve cognitive function by dampening the activity of α5 sub-unit GABA_A.

The Downs Syndrome researchers at Roche are developing Basmisanil/RG-1662 for this purpose.  It will be a long while till it appears on the shelf of your local pharmacy.

I did look to see if there any clever ways to down regulate the α5 sub-unit of GABA_A , other than those drugs being developed for Down Syndrome. 

Inverse agonists of of α5 sub-unit GABA_A

• α₅IA
• Basmisanil (RG-1662, RO5186582): derivative of Ro4938581, negative allosteric modulator at GABA_A α₅, in human trials for treating cognitive deficit in Down syndrome.^[3]
• L-655,708
• MRK-016
• PWZ-029: moderate inverse agonist^[4]
• Pyridazines^[5]
• Ro4938581^[6]
• TB-21007^[7][8]

The only option today would be the Pyridazines, which include cefozopran (a 4^th generation antibiotic), cadralazine (reduces blood pressure), minaprine (withdrawn antidepressant), pipofezine (a Russian a tricyclic antidepressant), hydralazine (reduces blood pressure, but has problems), and cilazapril (ACE inhibitor).

Pipofezine looks interesting.

Now we can compare Pipofezine with Mirtazapine.   They are both this tricyclic antidepressants, so both closely related to H1 antihistamine drugs.  We saw in earlier posts that Mirtazapine helps some people with autism in quite unexpected ways.

  

To be classed as a Pyridazines there has to be the benzene ring with two adjacent nitrogen atoms

So mirtazapine is not quite a Pyridazine, so may not directly affect the α5 sub-unit; but it does have potent effects elsewhere on the same receptor.  It is will increase the concentration of neuroactive steroids that act as positive allosteric modulators via the steroid binding site on GABA_A receptors.

  

We saw this in earlier posts that changes in progesterone levels affect not only the function of GABA_A but even the subunit composition and hence indirectly possibly α5 sub-unit expression.

I previously suggested both progesterone and pregnenalone as potential autism therapies.  Pregnenalone has since been trialed at Stanford.

The problem with these substances is that they are also female hormones and giving them in high doses to young boys is not a good idea.  Stanford used adults in their trial.

However, affecting the metabolites of progesterone rather than increasing the amount of progesterone itself may give the good, without the bad.  Also, perhaps there is a reason, oxidative stress perhaps, why progesterone metabolism might be disturbed in autism?

Anyway, it is yet another plausible reason why mirtazapine helps some people with autism.

Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3-hydroxysteroid dehydrogenase activity

Certain 3-reduced metabolites of progesterone such as 3,5-tetrahydroprogesterone (3,5-THP, 5-pregnan-3-ol-20-one, allopregnanolone) and 3,5-tetrahydroprogesterone (3,5-THP, 5-pregnan-3-ol-20-one, pregnanolone) are potent positive allosteric modulators of the -aminobutyric acid_A (GABA_A) receptor complex.^1, 2, 3

 Mirtazapine affects neuroactive steroid composition similarly as do SSRIs. The inhibition of the oxidative pathway catalyzed by the microsomal 3-HSD is compatible with an enhanced formation of 3-reduced neuroactive steroids. However, the changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of this antidepressant rather than clinical improvement in general.

So there may indeed be an effect on α5 sub-unit GABA_A, but there is also an effect on another α5 subunit, this time the nicotinic acetylcholine receptors (nAChR).  Those I looked at in earlier posts.  This is getting rather off-topic.

The gene that encode the α5 sub-unit of nAChR is called CHRNA5.  It is associated with nicotine dependence (and hence lung cancer), but is also linked to anxiety.  GABA sub-units expression also plays a key role in anxiety.  So a reason Mirtazapine should help reduce anxiety.

  

Progesterone modulation ofα5 nAChR subunits influences anxiety-related behavior during estrus cycle 

 It has already been shown that GABA_A receptor subunit expression and composition is modulated by progesterone both in vitro and in vivo(Biggio et al. 2001; Griffiths & Lovick 2005; Lovick 2006; Pierson et al. 2005; Weiland & Orchinik 1995) but this is the first report showing an effect of physiological concentrations of progesterone on nAChR subunit expression levels.

Pharmokinetics of Cardiazol

Since mouse experiments indicated an effect that continues after stopping using the drug, the clinical trials are particularly looking at the so called pharmokinetics.  What is best a small daily dose or occasional larger doses?

You would hope they will be keeping a watchful eye on seizures.

I do not know what doses was used in those mental hospitals in the 1930s, but it must be well documented somewhere.

Safety and Efficacy Study of Orally Administered DS102 in Healthy Subjects

Experimental doses in adults vary widely from a “one off” 100mg to a daily dose of 2000mg. Look how they treat the 7 cohorts in the trial.

The cough medicine has 100mg of Cardiazol per 1ml

The usual dose is one drop per year of age, so a 12 year old would have a 0.6ml  dose containing 60mg of Cardiazol.  That is dosage is give 2 to 4 times a day, so up to 240mg a day

This dose is well up there with the dosage used in the above clinical trial, which starts at a one off dose of just 100mg or daily doses of 500mg in adults.

The above trial has been completed but the results have not been published.

If the trial is positive at the lower dose range, the cough medicine is a very cheap alternative.

Conclusion

I wish a safe inverse agonist of the α5 sub-unit of GABA_A existed for use today.

I do not know anyone with Down Syndrome and this blog does not have many readers from Italy.  The standard pediatric dose of Cardiazol Paracodina  cough medicine might be well worth a try for both those with Down Syndrome and some autism with cognitive dysfunction. 

We actual have quite a few readers from India and that is the only other country using this drug.  In India the producer is Nicholas Piramal and the brand name is Cardiazol Dicodid, it cost 30 US cents for 10ml.  So for less than $1, or 70 rupees, you might have a few months of cognitive enhancement, that is less than some people pay for 1 minute of ABA therapy.

If a few drops of this children’s cough medicine improves cognition please lets us all know.

Benfotiamine for Autism

by Seth Bittker

In recent decades populations of wild bird species in the Baltic Sea have been dying off in large numbers from a paralytic disease.  When some of the birds with signs of this disease are given thiamine, they rapidly improve.  So it would appear the immediate cause of these large scale population decreases among the birds of the Baltic is thiamine deficiency [1]. The same thing appears to be happening to large mammals like elk [2].

Setting aside the question of underlying cause, could it be another mammal high up the food chain also has many members of its population suffering  from thiamine deficiency?  There is no good standardized test for thiamine deficiency that does not involve supplementing with thiamine.  So whether individual humans are somewhat deficient in thiamine is not obvious.  However, a particular constellation of symptoms was recognized as the disease “beriberi” before it was understood that the underlying cause was thiamine deficiency.  And what are the signs of beriberi?  The symptoms are variable but some that have been observed are mental confusion, irritability, difficulty moving, loss of sensation, loss of muscle function, rashes, involuntary eye movements, digestive issues, abdominal pain, and sometimes lactic acidosis [3].

Many of these symptoms match the symptoms of some with autism.  So one might naturally wonder whether some cases of autism are in fact unrecognized cases of beriberi and perhaps more likely that thiamine deficiency could play a role in other cases of autism depending upon other genetic and environmental factors.  A Dr. Luong and Dr. Nguyen previously noticed this similarity and developed this idea into a paper from 2013 which is available here [4].

Pulling from their Abstract:

“A relationship between thiamine status and the development of autism has been established, with thiamine supplementation exhibiting a beneficial clinical effect on children with autism. Thiamine may involve in autism via apoptotic factors (transcription factor p53, Bcl-2, and caspase-3), neurotransmitter systems (serotonin, acetylcholine, and glutamate), and oxidative stress (prostaglandins, cyclooxygenase-2, reactive oxygen species, nitric oxide synthase, the reduced form of nicotinamide adenine dinucleotide phosphate, and mitochondrial dysfunction). In addition, thiamine has also been implicated in autism via its effects on basic myelin protein, glycogen synthetase kinase-3β, alpha-1 antitrypsin, and glyoxalase 1.”

A researcher named Derrick Lonsdale found in 2003 that a set of 8 of 10 children with autism had clinical improvement on suppositories containing thiamine tetrahydrofurfuryl disulfide (TTFD), a thiamine derivative [5].  There was no control group on this study.  So one should be cautious when interpreting these results.  In addition Lonsdale was interested in metals excretion – TTFD can serve as a chelator.  He found that TTFD increased excretion of such toxic metals but it also would increase thiamine levels as well.

I have not experimented with TTFD, but Lonsdale’s work did get me thinking about oral supplementation of thiamine.  I tried experimenting with my son on regular thiamine hydrochloride.   I thought there may have been a very modest effect in terms of increasing his energy but it was not a sizeable effect.  However, there are other forms of thiamine.  One lipid soluble form that has been used with some modest success in diabetic neuropathy is benfotiamine [6].

There are case reports of neuropathy in cases of autism [7].  In addition one symptom of some with autism that are significantly affected is arm flapping.  It seems to me a person may flap his arms if he is feeling numbness and he is trying to get blood flowing to reduce the discomfort.  For the same reason somebody who is cold may move his limbs rhythmically.  In other words, I think arm flapping may typically be a sign of neuropathy and that neuropathy is an under-recognized and often comorbid condition with autism.

My son does not have neuropathy, but we did try benfotiamine on him.  My experience is that on it he had a significant reduction in irritability, increased cuddliness, and more energy.  I also feel he was mentally sharper initially but this diminished with higher doses.  Another result was he had flatulence some of which was pungent soon after starting supplementation.  In retrospect I take this as a sign that his digestion was beginning to operate more efficiently and relatedly he may have been dumping xenobiotics into his bowel when starting benfotiamine but this is pure speculation on my part.

After about a week on benfotiamine he got a rash and I began to feel that his mental acuity was leveling off.  I found that if I gave him biotin the rash went away and his mental acuity became sharper again.  Biotin and thiamine are both sulfur containing B-vitamins  and there are genetic diseases where both are involved [8].   My experience with my son suggests to me that there may be some common pathways with these nutrients.  In other words, I think befotiamine supplementation may exacerbate biotin deficiency.  As some may be aware, biotin deficiency is also sometimes seen in autism [9].  So for this reason I think they should be taken together when given for autism.

Thus, if you do a trial of benfotiamine, I would include biotin as well.  I am currently giving my son about 120 mg of benfotiamine per day and 5 mg of biotin per day.  He is about 90 pounds.  I give these to him in a juice smoothie because benfotiamine tastes a bit tangy.  You might also consider providing them in something sweet.

In interest of full disclosure when communicating about benfotiamine in the comment section of a separate post, Agnieska Wroczynska mentioned that benfotiamine had a positive effect on her child but increased hyperactivity.  So she found it was not ultimately helpful, and RG reported no positive affect whatsoever.  So it is possible that the experience that I have had with it with my son is highly unusual.

If you do wish to do a trial, as with any other supplement, start with low doses first to avoid risk and increase modestly if you see positive effects.  I am interested in others experiences with it and hope if you try it you will leave a comment here with some color on the results.

I thank Peter Lloyd-Thomas for the opportunity to write this guest blog and for providing a wonderful forum on autism treatment and autism research.

Treating Adults with Autism?

 

Almost the entire focus of treating autism is targeted at young children; only rarely do you hear about clinical trials involving adults, yet we are often reminded that autism is a lifelong condition.

For those of you that read the proposed guidelines to drug companies developing autism therapies, this issue raised its head again.  Will therapies effective in children be effective in adults (and vice versa)?

There are many issues here.  On the one hand there is great caution about giving drugs to very young children, but there is the realization that many therapies may only be effective if given at an extremely young age.

I only started treating the biological dysfunctions in Monty, now aged 12, when he was 9 years old.  By good fortune the first therapy (bumetanide) I tried was highly effective, otherwise this blog would not exist.

Had that Bumetanide clinical trial been published 5 years earlier, would I have given my then 4 year old son that same drug?  Probably not.

With what I now know, I would be happy to give Bumetanide as soon after birth that autism was even suspected.  (To the trained eye, this is but a few months old)

The effect of no treatment

For three years I have been developing a personalized autism treatment, Monty’s Polypill, and I think it works well, but a few weeks ago we decided to see what happens with no treatment at all.

This did provide some useful insights into treating young adults, as opposed to young children.

The first thing is that all the new skills that have been acquired, at close to neurotypical speed, in the last three years, did not just fade away. 

The old obvious repetitive behaviors/stimming/stereotypy did not return, but more subtle new ones did.  (no NAC)

He could still play his piano nicely with his teacher, but his interest in playing out of lessons faded away as did his skill level out of lessons.

He showed an occasional aversion to doing anything new, for example when his assistant came in the afternoon, I told him to go outside and meet her.  He could happily open the front door (his normal routine) but was not able to walk though it and meet her by the gate.  (no statin)

When I offered to go with him, he had a brief tantrum. 

He started asking permission to do things he knew how to do, which some people saw as a positive.  When lying in bed at 9pm he called out “Mum can I read a book”, rather than just picking one from the shelf by his bed and when at a small birthday party he had to bend down to light the candles, he turned round and said “can I squat?”  Most people thought that was good use of vocabulary, I was thinking “just do it”.  (statin effect)

I received comments like “how patient he is”, or at school  words like “peace” and “peaceful”.  I was thinking how passive he was. (no bumetanide/low dose clonazepam)

While there was no glaring loss of cognitive function and spelling tests and maths test at school were not showing any deficit, I noticed a loss of ability to develop new skills. 

We use an excellent online program called Math Whizz and one thing we were learning was to how to use the calendar.

Typical questions would be:-

“What date is the second Friday in May?”

“What date if the first Monday in December?”

“What day (of the week) is the last day in June?”

You first have to click on “May” to get the calendar to turn to the correct month and then you can figure out the answer.

To my surprise, while still on the Polypill, Monty was getting pretty good at this exercise, on his first attempt.

However, a few days later, when we tried with no Polypill, he was struggling and as the days passed he got worse and worse.  (chloride levels gradually rising?)

There was even a return of the sensory overload that causes many problems for some people with autism and also Asperger’s.  Even the sound of a crow became disturbing.  Both Acetazolamide and Bumetanide are used to treat Hypokalemic Periodic Paralysis, which is a more severe form of Hypokalemic Sensory Overload and at least some types of Autistic Sensory Overload are a subset of this.

After two weeks of Bumetanide and Potassium the sound over-sensitivity has gone again.  It did not go away immediately.

Pleiotropic effect of Verapamil

While I initially identified the calcium channel blocker, Verapamil, as an effective inhibitor of aggression and SIB triggered by allergy/mast cell degranulation, I was once asked if I thought Verapamil might have pleiotropic effects in Monty.  Having stopped using Verapamil and then restarted it, all outside of the problematic allergy season, I have all the proof I need in my n=1 case.  Life is better with a little Verapamil; his calcium channel dysfunction goes beyond those in mast cells.

Verapamil was the last element of the Polypill that I re-started; I was rather hoping it would show no effect outside the allergy season.  Only after adding it back did things really return to what has become our "normal".

There is after all a vast amount of evidence linking calcium ion channel dysfunction and autism.

My Verdict

I think many people would be very happy to have a passive child, who can sit for two hours in restaurant.

Most people do not notice the fading of good behavior, because their overriding concern is the lack of any “bad” behavior.  So a bad behavior is followed by a “is this better?”, rather than a “Wow, do you know Monty did today …”.

I prefer a child who can learn, even if that means he may get fed up from time to time, and show it.

I was pleased to come home earlier this week and find Monty sitting alone playing his piano beautifully (no prompting, no reinforcement needed), with his music book laid out in front of him, playing one melody, turning the page and playing the next one, while his big brother had gone upstairs to play his computer games, because little brother does not need him. 

  

Intervention in Adults

Other than halting self injurious behavior (SIB), I am far from convinced that most people would even notice the difference if you took an adult with classic autism and started to treat him.

At that age, passive and patient is what most caregivers want.

So I see little prospect that “corrective biological therapy” will ever be initiated in many adults with more serious autism;  they will continue to be “tranquilized”.

Many adults with Asperger’s and high IQ do their own research and self-treat; some even read this blog. For them, even a small biological "improvement" can have a welcome effect on well-being. Good for them.

Intervention in Young Children

The best way forward is to intervene immediately after diagnosis.  In the US/Canada that might be two years old, but more like four years old in Europe.

If I was a Roche or Novartis, this would be my target:- non-verbal, non toilet-trained toddlers who make no eye contact, possibly cry a lot and tend to be kept at home.