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.

Protective Stabilization for Pediatric Dental Patients

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

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.

https://epiphanyasd.blogspot.com/search/label/metformin

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.

Diabetes Medicine MetforminMay Improve Cognition, Behavior Symptoms in Fragile X Syndrome Patients, Case Study Reports

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.

                                                              

Diabetes drug delivers multiple benefits forpeople with fragile X syndrome

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. 

Metformin as targeted treatment in fragile X syndrome 

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 a metformin trial at the University of California at Davis MIND Institute.

A Trial of Metformin in Individuals with Fragile X Syndrome (Met)

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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635566/

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.