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Thursday, 5 December 2019

Cleveland Clinic Training Video - Psychopharmacology and Autism Spectrum Disorder



    
Today we look at the progressive end of mainstream medicine’s current take on treating autism, a 45 minute training for doctors treating children with autism, produced by the Cleveland Clinic.






Click on the above link and then on the begin activity box, to start the video.  They even have a quiz at the end.


In the pipeline is a relatively simple post all about dietary autism and a complicated one that tries to apply/simplify genetic models of autism. Sigma-1 receptor agonists will get examined; there is a very interesting Russian one called Afobazole, which I was surprised to see is currently sold on Amazon and eBay.  There are many Sigma-1 receptor agonists (Memantine, Donepezil, Sertraline, Haloperidol, Fluvoxamine etc) but they all have other effects that you likely do not want. Afobazole has a different set of other effects (MT1, MT3, NGF, BNDF, GABAergic etc), but most importantly is reported to be well tolerated and non-addictive.  Afobazole was very recently shown to alleviate cognitive rigidity in an experimental model of ASD.

You might get prescribed Memantine, Donepezil, Sertraline, Haloperidol or Fluvoxamine at the Cleveland Clinic, but there is zero chance of being prescribed Afobazole.

Afobazole also looks potentially interesting for Parkinson's, schizophrenia and anywhere there is ER-stress (Endoplasmic Reticulum stress).  More about ER stress in that future post.

















Wednesday, 27 November 2019

PolyPill v6 for Severe Autism and now for Smartphones




From my blog statistics I know that many people rely on their smartphone to figure out autism.  Most people look at diets and supplements; I can see that from what words people have put in their Google searches. This blog is about anything that actually works and very often that ends up being a pharmaceutical, which is the last thing most people want to hear.


Today we have a video post on YouTube.  It is a power PowerPoint presentation with narration;  this seems to be the best way to view something on a smart phone.

You can skip through it with volume off, or if you are interested in certain parts listen to the narration.

It is not supposed to be a masterpiece, more of an experiment, without any script/rehearsal/editing. There is a preamble since not everyone is a regular reader of the blog. It is really just another way to spread the word that severe autism is treatable, even if that does open Pandora's box. 





You can either click the image at the start of this post, or the link below:-

                  https://youtu.be/T8-ukM2uuQ4


You may need to scroll the video back to the start, if it re-starts in the middle. 

I have added Clemastine and DMF in version 6 of my Polypill.  Some items remain for completeness (they do work), but are no longer in use.

For any techies among you, this is how people view this blog; quite a lot of a lot of iPhones and android phones, not many iPads.  I use Windows and a big screen.








Wednesday, 20 November 2019

Ordinary Gifted or Gifted with Asperger’s Syndrome? And Treatment options for Aspies



Asperger with his Little Professors

This blog is focused more on severe autism, but today it is turn for the Aspies.  The post does rather ramble, because I included some old unused material on micro-dose LSD that may be Aspie-relevant.

Most people diagnosed with autism these days do not have severe autism and so their ideal medical therapy may be very different to the Polypill, I developed for my son.

For a young Aspie he might just need a single intervention like Sertraline (Zoloft) and nothing else, or perhaps Amantadine.

There is more than twenty years of experience medically treating people with Asperger’s, but it very much remains a case of trial and error to find what works.

It does look like most translational research in autism is now focused on those without problems with speech or cognition. That is good news for people with Asperger’s, not so good for the other end of the spectrum.

The paper below is 20 years old, but the medical treatment has not become out of date.






Behavior Problems. Children with AS usually have some behavior problems. They may be compulsive or hyperactive. They may be prone to tantrums or aggressive outbursts. They may routinely hit other children without provocation or touch people in inappropriate ways. Some AS children suffer from anxiety attacks or specific phobias. They may be sensitive to teasing, but consistently demonstrate provocative behaviors that invite teasing. Some AS children will engage adults in endless arguments if given the opportunity. Parents especially may find themselves trapped in repeated discussions about the same events or disagreements. Adults should not attempt to reason for more than a minute with such children (Barron & Barron, 1992; Dewey, 1991; Klin & Volkmar, 1995). Brief, concrete directives are most effective. Visual supports like pictograms can be posted on a child's notebook, desk, or on the wall to visually cue the child regarding expected behaviors. The addition of visual supports can be remarkably effective in helping AS students organize their behavior. Teachers and parents should consult with an augmentative communication specialist to learn more about visual supports.

In addition to behavioral and educational approaches, medications may be helpful in treating specific problematic behaviors. Medications can significantly improve the quality of life of AS children when they exhibit compulsive or aggressive behaviors that interfere with school adjustment or family life. Medication may also be needed to alleviate symptoms of depression, thought disorder, or anxiety attacks. Tofranil and Prozac have been recommended (Grandin, 1992). Beta blockers have been helpful for some aggressive AS children, and Anafranil, Luvox, or one of the SSRIs (e.g., Zoloft) can be useful in reducing obsessive-compulsive tendencies (Gragg & Francis, 1997; Rapoport, 1989).

If you now look at what is recommend today, two decades later it is pretty much the same.

From the Kennedy Krieger Institute:

  
For core anxiety symptoms, her group listed four possible SSRI antidepressants, sertraline (Zoloft), Prozac, Celexa, or escitalopram (Lexapro). That listing was based upon data on children and teenagers who do not have a developmental disorder. The researchers noted that youth with autism often report one particular side effect with SSRI drugs: "behavioral activation," which may appear as hyperactivity, impulsiveness, or trouble sleeping.14 Other possible side effects, which are not unique to autism, are suicidal thoughts in adolescents, or worsening of mood problems in people with bipolar disorder. So these drugs "should be prescribed cautiously in youth with ASD, with close monitoring," the researchers advised. Their article, in the journal Pediatrics, includes starting and maximum doses for doctors to consider. (See Additional Resources below for a link to the article, to share with your health care provider.)

Over at the MIND Institute at UC Davis:-

Specifying and Treating Anxiety in Autism Research (STAAR) Study

At least 50 percent of children with autism spectrum disorder (ASD) exhibit clinically significant anxiety symptoms. These are associated with increased social deficits, depression, irritability, and stereotyped and self-injurious behaviors. While it is clear that anxiety represents a substantial problem for those with ASD, there are important issues that need to be clarified before effective treatment becomes widespread. This project of the ACE will explore better ways to detect anxiety in children with ASD and determine whether cognitive behavioral therapy or medication can better alleviate their symptoms

  
Studies often appear to show no benefit, but it depends what you choose to measure (the primary outcome) and how large the sample is.



At first, the fluoxetine group appeared to show a slight but significant easing of obsessive-compulsive symptoms after four months compared with the placebo. But after the researchers controlled for factors including age, sex and the severity of symptoms at the start of the trial, the difference vanished. Fluoxetine did no better than the placebo.
The relatively small sample size could have limited the researchers’ ability to detect a benefit from the drug, Neumeyer says. “It’s possible that, with higher numbers, they would’ve found subgroups who benefit from SSRIs,” she says. “That’s the painful part of this [kind of] research though; you’re left wondering.”

Interesting to see low dose Prozac (fluoxetine) used successfully in severe French autism:-

Low-Dose Fluoxetine in Four Children with Autistic Spectrum Disorder Improves Self-Injurious Behavior, ADHD-Like Symptoms, and Irritability


In this article, the authors present four clinical cases of ASD-diagnosed children with ADHD-like symptoms and/or SIB and/or other heteroaggressive behaviors and/or irritability and impulsivity. Each was treated with low doses of fluoxetine, specified as follows: 2.5 mg/d (liquid formulation) in the morning for the first week, followed by a flexible titration schedule based on weight and tolerability. The Hollander et al. protocol [3] is reproduced here, in which children with ASD were given low doses of fluoxetine. Patients were assessed using the Clinical Global Impression Scales (CGI) [12] during the time of fluoxetine introduction and observation. None had tried an SSRI treatment before the reported trial.

In conclusion, in these case reports, we found that the prescription of fluoxetine, in addition to valproate and cyamemazine (Case 1) or to risperidone (Cases 2, 3 and 4), could be effective on severe behavioral symptoms associated with ASD in children. It is important to inform child psychiatrists about this therapeutic possibility even if it would be difficult to predict the rate of responders on the basis of this cases and the literature. The role of comedication remains unanswered as none of our cases was on fluoxetine monotherapy.
  
Recall this old post:- 

When is an SSRI not an SSRI? Low dose SSRIs as Selective Brain Steroidogenic Stimulants (SBSSs) via Allopregnanolone modifying GABAa receptors and neonatal KCC2 expression




Micro-dosing LSD for Aspies?

Since we are on the subject of Aspies, I will insert a post that I never finished.  It is very much for the genuine Aspie, the one with a high IQ, the type working over at Google HQ. Usually male, does not strictly need any medical treatment, but may seek some out nonetheless.

Even though LSD was used at high doses in people with severe autism in the 1960s at UCLA, current interest involves micro-doses taken by people without any severe disability. 

A trial is about to start at Imperial College in London that may particularly interest Californian and Dutch Aspies.



Silicon Valley geeks say it sharpens their thinking and enhances creativity. Other people say it lifts the fog of depression. A novel experiment launching 3 September 2018 will investigate whether microdosing with LSD really does have benefits – or whether it’s all in the mind.
Microdosing using psychedelic drugs – either LSD or magic mushrooms – is said to have become very popular, especially with people working in the Californian digital tech world, some of whom are said to take a tiny amount one or more days a week as part of their routine before heading to work. It’s not for a psychedelic high, though – it’s to make them more focused.
Microdosers tend to use either tiny amounts of LSD – as little as one-fifteenth of a tab – or of psilocybin, the active ingredient in magic mushrooms. The study is recruiting just those who use LSD, because of the difficulty in disguising even ground-up mushrooms in a capsule.
But it’s illegal. So how many people are microdosing is unknown and there is only anecdotal evidence of the effects and any downsides. In a bid to learn more, the Beckley Foundation, which was set up to pioneer research into mind-altering substances, and the unit it funds at Imperial College London, will launch the first ever placebo-controlled trial of microdosing on Monday, 3 September 2018.

It will be unique, says Balázs Szigeti, the study leader. The cost and the illegality of LSD would make a conventional study prohibitively expensive. So he has hit on a way of running it by inviting those who already microdose to join a “self-blinded” study. They will take either what they usually use in a capsule or an identical dummy capsule instead, without knowing which is which. They will complete questionnaires and tests and play cognitive games online, and only at the end will they learn whether they were happy and focused because of LSD or because they thought they were using LSD.

Conclusion

The big difference between treating mild autism (Asperger’s) and severe autism is whether cognitive function is a target.  For severe autism raising cognitive function is the most important target, because it has the potential to improve all other behavioral issues. 

Aspies have been self-treating for decades and in some countries have a helpful psychiatrist happy to prescribe off-label (SSRIs, bet-blockers etc).  They often seem to like 5HT2A agonists.

The effective drugs for mild autism (Asperger’s) may have only limited value to those with severe autism.  Unless you resolve cognitive impairment, you will not transform the developmental trajectory.

It would be helpful if during the initial observational autism diagnosis, the doctor made clear to parents, what kind of autism the child has.   This often is not the case.

It is clear that most people diagnosing autism in very young children do not attempt to measure IQ, or even use an autism ratings scale, like CARS.  There are understandable reasons for this, but it still looks lazy to me.  Nowadays people struggle less hearing the word “autism”, but nobody wants to hear about MR/ID in their 3 year old.  So better to keep silent and avoid parents bursting into tears.

You really do need to be told where you are on the scale from Aspie to the other extreme of Autistic disorder/ Kanner’s/Classic/SDA.  You might think this would be obvious, but it is not.  If you have a 4 year old Aspie, start with Aspie therapies, not therapies for severe autism.

We saw in Catherine Lord’s study that all of those in her 20 year longitudinal study of children with an autism diagnosis, also had an IQ , when measured, indicating MR/ID.  Her study group was a random selection of those diagnosed with autism where she worked.  Back then autism meant autism.  Her “top performing” 40% have normal IQ as adults, but even in that group their measured IQ at age 3 or 4 was less than 70.  This group are not Aspies, they would have had normal/high IQ when tested at the age of 3 or 4.

The meaning of the diagnosis has changed so much in 20 years that the research now talks of autism with a developmental disorder and autism without a developmental disorder.

Actually, “autism” is supposed to be a developmental disorder; that was the whole point. But never mind.

Aspies have had a wide range of treatment options for more than 20 years and they also stand to benefit for the new generation of “autism” drugs, which are actually mainly for mild autism.

As with severe autism, treating an Aspie will also require personalized medicine, or just call it trial and error.  Prozac might be hopeless, but Zoloft work wonders.  ADHD meds might help, or just make things worse.  Oxytocin might improve empathy, or do absolutely nothing.  Perhaps the study at Imperial will show micro-dose LSD does have a benefit.  Since you are fully verbal and have a high IQ it is not hard to establish whether there is a benefit or not, move on and perfect your personal therapy.

It is the other end of the spectrum, where there is a big problem.  You may need to look at the new drugs being developed for Down Syndrome, Fragile-X and the numerous rare single gene autisms. Those drugs will not be cheap.






Wednesday, 13 November 2019

Dentistry Gangnam-Style vs Native American (Papoose) - Style

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There have been previous posts in this blog about dental treatment for those with autism.  I am sure readers with older children have already found what works for them.  Many people are not regular readers, so there is some repetition in today’s post.

There is no single best solution for the dentist because your options are very different depending on where you live and your budget.

In the US you have the widest choice, but they are all pricey.

In other countries there are more legal restrictions. Some countries with universal healthcare have well organised free solutions for those with special needs, but you may have little choice.

In many countries all the options are pretty bad.

It looks like US dentists are taught two broad options: -

·        Sedation

·        Immobilization


I think they are often missing a missing a third option, D-Termined or similar, which I think is the best one.


Sedation

There are several levels of sedation, all the way up to deep sedation and finally general anesthetic.

There are legal restrictions on how far dentists can go with sedation and this varies widely depending on where you live.

Where we live the dental clinic can give you local anesthetic and no more. In the UK light sedation and moderate sedation is permitted.  For a higher degree of sedation, you need to be in a hospital, with all the emergency back-up.

Intravenous (I/V) sedation is quite common for those with anxiety, but you have to sit still while you are connected up.

General anesthetic seems to be very commonly used for special needs kids and I presume the adults they become, of whom we hear very little.


Immobilization

I had never heard of immobilization, probably because in many countries it is illegal.
In the US immobilization is widely known.  Some people think it is great and some people do not.

The patient is physically attached to the dental chair so that they cannot move.



D-Termined or similar

There is a third option, which you might just call “good dentistry”.  I eventually found two dentists like this.  They break everything down into steps and make sure the child gets familiarized with each step, before moving on to the next.  They are not in a hurry and they try to make the experience as fun as possible, inflating surgical gloves like a balloon etc.

One US dentist developed his own system in the belief that most people with special needs can be treated conventionally and should not need to resort to general anesthetic.

Dr Tesini named his method the D-Termined program. More than a decade ago he made a training DVD for fellow dentists which was available for free, thanks to a supportive charity. Much more recently he published a peer-reviewed paper showing its effectiveness at reducing the need for general anesthetic.

D-Termined is ABA applied to dentistry.  Everything is broken down into simple steps.  Once you have mastered being able to sit still in the chair and keep your arms still, you move on to learn about all the gadgets the dentist can use.  Eventually, after a few visits, you move on to a simple actual procedure, like polishing/de-scaling teeth.    
Keeping you arms still is step our new dentist does not teach/insist on.  This is a mistake, since it can be taught and flapping arms can be dangerous.

I did acquire the DVD training by Dr Tesini ten years ago and tried without success to find a local dentist interested to apply it.

You might wonder while all pediatric dentists are not at least aware of the D-Termined program.  Apparently having learned with D-Termined most patients can successfully transfer to any other dentist.  This would save a huge amount of money in admissions to hospital for dental work.

Effectiveness of the D-TERMINED Program of Repetitive Tasking for Children with Autism Spectrum Disorder. 

PURPOSE:

The purpose of this study was to compare the effectiveness of the D-TERMINED Program with standard behavior guidance techniques (SBGTs) used for children with autism spectrum disorder (ASD) in a private dental setting.

METHODS:

A retrospective data analysis was performed from records of children with ASD who received treatment using either the D-TERMINED program or SBGTs at two private dental practices. Data were analyzed using chi-square, Fisher's exact, Wilcoxon Signed Rank, and Mann-Whitney U tests and logistic regression.

RESULTS:

Forty-four charts (22 in each group) were selected from office visits between 1999 and 2012. Children in the D-TERMINED group were significantly younger (P=0.01). There were no significant differences between groups regarding gender and dental care characteristics. Patients treated with the D-TERMINED program showed a significantly greater improvement in behavioral scores compared to the control group (P=0.03). Additionally, children treated with the D-TERMINED program had significantly lower referrals for dental treatment under general anesthesia (P=0.04).

CONCLUSION:

The D-TERMINED program may help children with ASD learn the cooperation skills necessary to receive treatment in a dental practice, which might impact health care cost effectiveness.

In Monty’s dental training program, we practised at home with an electric drill. Monty made a burning smell drilling into some old pieces of oak. So, he got used to strange sounds, vibrations and smells.  We practised with a syringe how the anesthetic is applied.


Costs in the US

A survey by TheWealthyDentist.com reports an average cost of $482 for IV sedation. General anesthesia can cost $300-$1,000 or more and averages about $600-$700, depending on the complexity of dental procedure.


Monty and the Dental Marathon

About a month ago Monty finished his dental marathon of fifteen visits to the dentist since March.  It was entirely successful but it did take much longer than I had expected.

I got to learn about restorative dentistry. In Monty’s case his decay was deep and could not be repaired leaving the nerve intact in a single visit to the dentist.  A live tooth has the nerve intact and has its own blood supply.  I wanted his two problematic teeth to retain their nerves.

The dentist drills out as much decay as possible and then adds layer of Calcium Hydroxide, which is very alkaline.  This then causes the nerve to withdraw slightly and slowly the pulp above the nerve is converted to dentine (so-called reparative dentine), you add a temporary filling and wait for 6-7 weeks.  Then you remove the temporary filling, drill a bit deeper, again avoiding the nerve, add a layer of calcium hydroxide and another temporary filling and wait another 6-7 weeks. The end result is that you can remove deep decay without removing the nerve.

On two rear teeth Monty had temporary fillings four times before he got the final permanent filling.  That means being injected with local anesthetic ten times and ten trips to the dentist.

In addition, he has visits for fissure sealant to be applied on the remaining teeth.

Our original “nice dentist” from 4 years ago went on an extended maternity leave and it was toothache that prompted the need for a different one. Fortunately, we found a nice new dentist who in the last couple of years developed an interest in treating autistic kids. Even she was not keen to work on the rear teeth.  She can only give local anesthetic; she cannot use US-style physical immobilization. Her suggestion was to make an appointment for dentistry under general anesthetic.  So off we went to the local University hospital where, as expected, they wanted to extract both teeth under general anesthetic, all they do is so-called “radical dentistry”, but even for this option you wait 3-4 months for an appointment.

I asked why can you not save the teeth?  Like with a typical child.

I was told that Monty would struggle with local anesthetic, the rear teeth are particularly difficult.  Some kids with autism can struggle with the loss of sensation and end up biting themselves quite badly.

I said not to worry about the local anesthetic, we would easily get him through that part.  Yes, he has autism, but he is no longer typically autistic - he is now "different".  We do not avoid challenges; we try to overcome them.

Our new dentist basically said she would only try and repair the teeth if there was a plan B for emergency extraction.  Such an extraction is not possible at the government hospital and she would not be able to do it either.

More than 10 years ago when Monty needed emergency dental work, we had to take him to a neighbouring country where it is legal to have general anesthetic in a dental clinic.

Fortunately, a local private medical clinic that does minor operations has recently started doing some dentistry and they can offer general anaesthetic.  So off I went there to see if they would help.  I met a very pleasant dental surgeon who had just relocated home from Chile and he also thought teeth should be repaired and not extracted.  He was happy to provide the plan B.

Feeling much happier, our dentist agreed to proceed and our dental marathon began.

We started in winter, so no allergy-affected behaviour, and things went very well.  The dentist told me “it was exactly as you said it would be”, Monty could comply with treatment like any typical teenager.  Anaesthetic no problem, drilling no problem.  Monty get to choose the music during the dental procedures.  It was stress free.

As we moved to spring and then summer, compliance did fade slightly.  The worst day and in fact the only really tough visit was the for the final drilling and filling on the lower tooth.  The anesthetic did not seem to have gone in exactly the right place, Monty was not happy, the anesthetic was repeated, to no avail.  I had to keep him and indeed the dentist as calm as possible.  I had to stand in front of the dental chair and talk to Monty the entire time, reassuring him, counting up to 20, down from 20, having him pick the number etc to distract him from the procedure.
  
That was a visit the dentist will not forget.  Monty on the other hand got out of the chair as if nothing had happened.

For dental visit number 15 and the final drilling and filling on the upper tooth I had started to use DMF and Azosemide; there was no anxiety, everything was like in the winter.  Monty was a model patient and the dentist was sad that we had finished our marathon.

Dentistry is not expensive where we live, so our 15 visits probably cost about the price of one composite adult filling in the US.


Gangnam Style

Monty became very comfortable with his visits to the dentist, getting the dental assistant to put his favourite music to play. For his final visit getting permanent filling number two, he requested “Gangnam Style”. With his mouth full of cotton wool (saliva absorbers) I had no idea what he was saying, but the dentist understood and it was time for K-pop.



Papoose Board









Until very recently I had never heard of the Papoose Board and its use in dentistry; where I come from it is actually illegal to use it.

A papoose means a native American child. A papoose board is like a straight jacket, but it immobilizes the entire body, including your head.  It is like being encased in Velcro straps.

During my many visits to the dentist I learnt that a common problem treating children with autism is that they do not sit still in the dental chair and they flap their arms about which can make it difficult to get any work done.  It usually requires the help of the dental assistant so that the dentist has two arms available for her work.

So, you can see where the idea if strapping the child to the chair comes from.

Personally, I cannot think of anything worse during visit to the dentist than having my arms strapped to my body for 30-60 minutes. What if you want to itch your nose? You are non-verbal so you cannot ask the dentist to do it for you.  That is just me.

There are horror stories in the US media about the use of a Papoose board, but there was a recent post on the NCSA website saying how great it was for one child with severe autism.  It is a case of finding what works for your n=1 case.


In Dental Care for Severe Autism, a Papoose Board Comes to the Rescue



Conclusion

Finding dental care for someone with autism is very often a huge problem.  In some countries you get free care that is well organized, but you may not get any choice as to what is done, or indeed how.

Many people with autism routinely have all procedures using general anesthetic, that is OK if you have a qualified anesthetist monitoring the situation.  It must be better to learn how to sit in the chair and have regular dentistry using local anesthetic.  It is much cheaper and much safer.

I personally think Gangnam style dentistry is much more preferable to the native American style.  Yes, it will take longer, at least until the first filling has been completed successfully.

There clearly are people with autism who accept being strapped to the dental chair with Velcro and some who enjoy it. Temple Grandin is a big fan of squeezing/pressure therapy, so I expect she would enjoy being strapped to a Papoose Board.

Another thing I came across was that parents in some countries are not present while the child is having the dental procedure. I came across one lady furious to find out that her child was strapped up in a Papoose board, she was totally unaware it was being used, until she left the waiting room to look for her child.  I suppose it depends if having the parent present is helpful, or just adding to the stress - both cases are possible.  

An old post from 2014:-


       A Surprise at the Dentist





Wednesday, 6 November 2019

Metformin to raise Cognition in Fragile X and some other Autisms?




I started to write this post a long time ago, when Agnieszka first highlighted an interview with Dr Hagerman from UC Davis.  Hagerman is experimenting in using Metformin to treat Fragile-X.

Having again be reminded about Metformin, I realized that I never finished my post on this subject. With some extras about autophagy and a nice graphic courtesy of Ling’s excellent paper, here it is. 

Metformin has already been covered in 5 previous posts.


One interesting point is that the researchers at UC Davis are using the measurement of IQ as one of the outcome measures in their trial of Metformin.  I have been suggesting the French Bumetanide researchers do this for a long time.

It is my opinion that simple medical interventions can have a profound impact on the IQ of some people with severe autism. I mean raising IQ not by 5-10 points as at UC Davis, but by 20-50 points.  IQ can be measured using standardized tools and is far less subjective than any autism rating scale.

The big-time potential IQ enhancers we have seen in this blog include: -

·        Bumetanide/Azosemide
·        Statins (Atorvastatin, Lovastatin, Simvastatin, but they are not equivalent and the effect has nothing to do with lowering cholesterol)
·        Micro-dose Clonazepam
·        Clemastine
·        It seems DMF, in n=2 trial

The good news is that these drugs are all off-patent cheap generics (except DMF), as is metformin.  No need for drugs costing $50,000 a year.

For those that do not know, metformin is the first line medication for type-2 diabetes. It was introduced as a medication in France in 1957 and the United States in 1995.  In many countries Metformin is extremely cheap, with 30 x 500 mg tablets costing about $2 or Eur 2. In the US it costs about $10 for generic, so not expensive. 

There are sound reasons why Metformin could increase IQ in someone with autism or Fragile-X. In the case of idiopathic autism is there a likely biomarker to identify a likely responder? One has not yet been identified.

Clearly Metformin will not work for all people with autism and MR/ID, but even if it only works for 10% that would be great.

Are all parents going to notice an increase in IQ of 5-10 points?  You might think so, but I doubt it.  I would hope therapists, teachers and assistants would notice.

I think basic mental maths is the best way to notice improved cognitive function in people with IQ less than 70.  You can easily establish a baseline and then you can notice/measure improvements.

Improved cognitive function does not just help with maths, it helps with learning basic skills like tying shoe laces, brushing teeth and later shaving.  This does also involve many other types of skill.





In the study, researchers from the UC Davis Medical Investigation of Neurodevelopmental Disorders Institute in California tested the long-term effects of metformin, delivered at 1,000 milligrams (mg) twice a day, for one year in two male patients, 25 and 30 years old. Genetic analysis confirmed that both patients had mutations in the FMR1 gene, confirming their fragile X syndrome diagnoses.

The younger patient had autism and was also diagnosed with generalized anxiety disorder. First prescribed metformin at 22, he is currently taking 500 mg of metformin twice a day and 10 mg per day of simvastatin — used to lower the level of cholesterol in the blood.
The second patient was also diagnosed with anxiety and exhibited socially nervous behaviors, including panic attacks. He had severe limitations in language use, and communicated in short sentences and by mumbling. He had been on an extended-release formulation of metformin, taking 1,000 mg once a day for one year.

Both patients showed significant cognitive and behavioral improvements. After one year of treatment with metformin, test results revealed an increase in the patients’ IQ scores, from 53 to 57 in the younger patient and from 50 to 58 in the second patient.

Verbal and nonverbal IQ — the ability to analyze information and solve problems using visual or hands-on reasoning — were also improved in both patients. Non-verbal IQ increased from 50 to 52 in the younger patient and from 47 to 51 in the other. Verbal IQ went from 61 to 66 in the first patient, and from 58 to 68 in the second.

                                                              

Researcher Randi Hagerman is a big proponent of metformin — a diabetes drug that helps people manage their weight. In fact, Hagerman takes the drug herself as a preventive measure against cancer.
Metformin has also unexpectedly shown promise for improving cognition in people with fragile X syndrome, a leading genetic cause of autism characterized by severe intellectual disability.

A study published in 2017 linked impaired insulin signalling in the brain to cognitive and social deficits in a fruit fly model of fragile X, and the flies improved on metformin. A second paper that year showed that metformin reverses abnormalities in a mouse model of the syndrome, including the number of branches the mice’s neurons form. It also improved seizures and hyperactivity in the mice — issues we also see in people with fragile X.
I began prescribing metformin to people with fragile X syndrome to help curb overeating. Many of the people I treat are overweight because of this habit — it’s one of the symptoms of a subtype of fragile X called the Prader-Willi phenotype, not to be confused with Prader-Willi syndrome.
I was surprised when the families of these individuals told me they could talk better and carry out conversations, where they couldn’t before. That really gave us impetus to conduct a controlled clinical trial.
It’s not a cure-all, but we do see some positive changes. It doesn’t resolve intellectual disability, but we have seen IQ improvements of up to 10 points in two boys who have been treated with metformin. We are very excited about that.

Individuals on metformin tend to start eating less, and often lose weight as a result. I could kick myself, because metformin has been approved to treat obesity for many years, but I never thought to use it in fragile X syndrome. Oftentimes children with fragile X syndrome have so many problems that you aren’t thinking about obesity as the top priority.
We’ve also seen a gradual effect on language, which we can detect after two to three months. Sometimes there are improvements in other behaviors too; I’ve seen mood-stabilizing effects. Many people with fragile X syndrome have issues with aggression, and it’s possible these could be moderated with metformin too. 

Individuals with fragile X syndrome (FXS) have both behavioral and medical comorbidities and the latter include obesity in approximately 30% and the Prader‐Willi Phenotype (PWP) characterized by severe hyperphagia and morbid obesity in less than 10%. Metformin is a drug used in individuals with type 2 diabetes, obesity or impaired glucose tolerance and it has a strong safety profile in children and adults. Recently published studies in the Drosophila model and the knock out mouse model of FXS treated with metformin demonstrate the rescue of multiple phenotypes of FXS.

Materials and Methods

We present 7 cases of individuals with FXS who have been treated with metformin clinically. One case with type 2 diabetes, 3 cases with the PWP, 2 adults with obesity and/or behavioral problems and, a young child with FXS. These individuals were clinically treated with metformin and monitored for behavioral changes with the Aberrant Behavior Checklist and metabolic changes with a fasting glucose and HgbA1c.

Results

We found consistent improvements in irritability, social responsiveness, hyperactivity, and social avoidance, in addition to comments from the family regarding improvements in language and conversational skills. No significant side‐effects were noted and most patients with obesity lost weight.

Conclusion

We recommend a controlled trial of metformin in those with FXS. Metformin appears to be an effective treatment of obesity including those with the PWP in FXS. Our study suggests that metformin may also be a targeted treatment for improving behavior and language in children and adults with FXS.

Recruiting: Clinical Trial of Metformin for Fragile X Syndrome


While a growing number of families are trying metformin and reporting mixed results, metformin has not yet been systematically studied in patients with Fragile X syndrome. This open-label trial is designed to better understand the safety and efficacy of this medicine on behavior and cognition, and to find the best dosages for children and adults.

20 children and adults with Fragile X syndrome will take metformin 250mg twice a day for the first week, followed by metformin 500mg twice a day for the next 8 weeks.
The study will measure changes in the total score on the Aberrant Behavior Checklist-Community (ABC-C) after 9 weeks of metformin treatment. The ABC-C is a 58-item behavior scale which is filled out by a caregiver. In addition, Transcranial Magnetic Stimulation (TMS) will be used to look for changes in cortical excitability and Electroencephalography (EEG) will assess levels of synaptic plasticity.
Participants in this study must be Canadian residents and be able to travel to the University of Sherbrooke in Quebec, Canada, for several visits. If you are interested in metformin but this trial is not convenient, there are two alternatives. FRAXA is funding a new trial of metformin in New Jersey, and Dr. Randi Hagerman is currently recruiting for metformin trial at the University of California at Davis MIND Institute.



Metformin has emerged as a candidate drug for the targeted treatment of FXS based on animal studies showing rescue of multiple phenotypes in the FXS model. Metformin may contribute to normalizing signalling pathways in FXS in the central nervous system, which may include activities of mTOR and PI3K, both of which have shown to be pathogenically overactive in FXS. In addition, metformin inhibits phosphodiesterase, which would lead to correction of cAMP levels, and MMP9 production, which is also elevated in FXS. Looking at the potential signalling pathways, metformin appears to be a good candidate for targeting several of the intracellular functions in neurons disrupted in FXS and, therefore, has potential to rescue several types of symptoms in individuals with FXS. The researchers have utilized metformin in the clinical treatment of over 20 individuals with FXS between the ages of 4 and 58 years and have found the medication to be well tolerated and to provide benefits not only in lowering weight gain and normalizing appetite but also in language and behavior. In this controlled trial, the researchers hope to further assess metformin's safety and benefits in the areas of language and cognition, eating and weight loss, and overall behavior.


mTOR and P13K

Hagerman highlights Metformin’s effects on mTOR and P13K pathways.

This is a highly complex subject and the graphic below from an early post shows how interconnected everything is.  If mTOR is not working correctly you can expect many things not to work as nature intended.

Numerous things can cause an imbalance in mTOR and so there are numerous ways to re-balance it.

Not surprisingly much of this pathway plays a role in many types of cancer.

Hagerman herself is taking Metformin to reduce her chances of developing cancer. I think that is a good choice, particularly if you are overweight.  My anticancer choice, not being overweight, is Atorvastatin which targets inhibition of PI3K signalling through Akt and increases PTEN.

Hagerman is 70 years old and I think many cancers actual initiate years before they are large enough to get noticed and to be effective any preventative therapy needs to be started before that initiation has occurred. Hopefully she started her Metformin long ago. 

Given that 50% of people are likely to develop one cancer or another, I am with Dr Hagerman on the value of prevention, rather than treatment/cure.







The Wrong Statin for Fragile-X?

In the first article highlighted in this post, there is a case history of a man with FX being treated by a Statin, it looks to me that he has the wrong prescription (Simvastatin). Perhaps Dr Hagerman should read this old post from this blog:-


Choose your Statin with Care in FXS, NF1 and idiopathic Autism







   Simvastatin does not reduce ERK1/2 or mTORC1 activation in the Fmr1-/y hippocampus.
So  ? = Does NOT inhibit

The key is to reduce Ras. In the above graphic it questions does Simvastatin inhibit RAS and Rheb.
                                                                                                     

For anyone really interested, the following graphic from a previous post shows the fragile X mental retardation protein, FMRP.  Lack of FMRP goes on increase neuroligins (NLFNS) this then creates an excitatory/inhibitory imbalance which cause mental retardation and features of autism.





This all suggests that the 25 year-old young man with Fragile X treated at UC Davis (case study above) should switch from Simvastatin to Lovastatin.




Metformin and Autophagy

I also think Dr Hagerman is less likely to get dementia now that she is talking metformin.  If she takes vigorous exercise at least once a week, I think that is also going to keep her grey cells ticking over nicely. Like Dr Ben Ari, Hr Hagerman is working way past normal retirement.  If you love your job, then why not?  As with many things, in the case of neurons, “use them or lose them”.

Autophagy in Dementias


Dementias are a varied group of disorders typically associated with memory loss, impaired judgment and/or language and by symptoms affecting other cognitive and social abilities to a degree that interferes with daily functioning. Alzheimer’s disease (AD) is the most common cause of a progressive dementia, followed by dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia (VaD) and HIV associated neurocognitive disorders (HAND).
The pathogenesis of this group of disorders has been linked to the abnormal accumulation of proteins in the brains of affected individuals, which in turn has been related to deficits in protein clearance. Autophagy is a key cellular protein clearance pathway with proteolytic cleavage and degradation via the ubiquitin-proteasome pathway representing another important clearance mechanism. Alterations in the levels of autophagy and the proteins associated with the autophagocytic pathway have been reported in various types of dementias. This review will examine recent literature across these disorders and highlight a common theme of altered autophagy across the spectrum of the dementias.

Below is an excellent graphic from a paper highlighted by Ling. Note metformin, above AMPK.


Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity









I would highlight the presence of IP3R, the calcium channel proposed by Gargus as being a nexus in autism, for where multiple types of autism meet up, to do damage.

Verapamil, in Monty’s Polypill, increases autophagy independently of mTOR in a complicated mechanism  involving IP3R and likley calpain.  It is proposed as a therapy for Huntington’s Disease via this mechanism. At the lower right of the chart below we see calpain, a group of calcium dependent enzymes, not well understood.  ROS can activate calpains via L-type calcium channels.





I would not worry about the details.  The take home point is that if you have autism, dementia or many other neurological conditions, you might well benefit from increasing autophagy.  There are very many ways to do this.      
                                                           
Conclusion

Fortunately, I am not a doctor.  I do recall when my doctor father was out visiting his sick patients at their homes, he did have not only his medical bag, but also some useful gadgets always kept in his car, that might come in handy.

The autism equivalent is the personalized Polypill therapy for daily use and the autism toolbox to delve into to treat flare-ups in autism as and when they arise.

I do think some people should have metformin in their daily Polypill therapy.

I think we can safely call Fragile-X a type of autism, so we already know it works for at least some autism.  Metformin is a very safe old drug, with minimal side effects and it is cheap.  It ticks all the boxes for a potential autism therapy.  Will it work for your case?  I can tell you with certainty that it does not work for everyone.

Metformin has been trialled to treat people with obesity and autism, since it can reduce appetite.

Metformin forTreatment of Overweight Induced by Atypical Antipsychotic Medication in YoungPeople With Autism Spectrum Disorder: A Randomized Clinical Trial.


INTERVENTIONS:

Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years.

MAIN OUTCOMES AND MEASURES:

The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication.

RESULTS:

Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005).

CONCLUSIONS AND RELEVANCE:

Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD.

My guess is that a minority will be responders, the benefit will manifest itself in different ways and so it will be a useful part of polytherapy for some people, but it will not be a silver bullet.  Other than via an IQ test, I think the benefit will be hard to measure, even when it is very evident. 

In the end there will be a clever way to predict who will respond to which therapy.  Today’s post actually replaces one that will look into genetic testing and DEGs (differentially expressed genes). Most likely testing for DEGs will be the best predictor of what drugs work for whom.

Intelligent, cautious trial and error using safe drugs is an alternative strategy.  It is available today; it is cheap and it does work.

I have not tried Metformin yet, in recent years I have had most success with my own ideas. I have some of Dr Frye's calcium folinate sitting at home waiting for a trial.  Both Metformin and calcium folinate should be trialled.  The other obvious thing to trial is that Japanese PDE4 inhibitor Ibudilast (Ketas).  Thanks to Rene we now know you can acquire this is via any international pharmacy in Germany, with a prescription. It also reappeared on the website of a Japanese online pharmacy. The Western PDE4 inhibitors, like Daxas/Roflumilast are not selective enough and so are emetic (they make you want to vomit). Low dose Roflumilast has been patented as a cognitive enhancer, but you may need to have a bucket with you at all times.