Why is the evidence for Early Intensive Behavioral Intervention for Autism so weak?

One to one autism therapy is pricey – is it worth it?

Only a handful of countries widely apply behavioral interventions to treat toddlers diagnosed with autism.  Behavioral interventions include Applied Behavioral Analysis (ABA), Verbal Behavior (VB), Pivotal Response Treatment (PRT) and the Denver model.

Even after several decades, the published evidence that these interventions actually work is quite weak.  This explains why most countries do not readily provide public funds for ABA.

In the US, efforts are being made to diagnose autism at younger and younger ages, because the child can then benefit from these “proven” interventions, that other countries do not believe work.  Who is right?  

You can read Manuel Casanova’s perspective at the end of this post.  He is not such a fan of expensive US developed therapies and concludes:-

"spending time with your children and group socialization, in my experience, have provided the most favorable outcomes"

Does ABA work?  If so, why can’t you prove it?

From my personal experience, behavioral intervention was very beneficial as a teaching method, but it does not make autism go away.

In today’s study the aim was to determine if behavioral intervention is cost effective.  The conclusion based on all the studies considered is that there is no conclusive evidence that behavioral intervention is cost effective.  So logically the countries that do not widely fund it, like the UK, can be reassured that they are on the “right side” of the argument.

My view is that is that autism is so heterogeneous you can prove almost nothing, with any degree of certainly.  It is always going to be a case of ifs, buts and maybes.  This also very much applies to clinical trials of drugs to treat autism.

Why did ABA ever catch on in the first place?  People want hope and the more expensive something is, the more people want it.  Forty hours a week of ABA is very expensive and nice to have, if someone else is paying.  

We saw in an earlier post that Lovaas (the founding father of ABA) later admitted to selectively retiring non-responders from his clinical trials, to improve the apparent success of his methods.  This pretty much means you have to ignore all his data and his papers should be retracted. 

Many parents want curative treatments for autism.

Lovaas claimed that ABA is curative and that the treated kids end up like typical kids.  Sadly, this is an exaggeration.

Is two years of ABA cost effective for severe autism?  I guess it depends whose money is paying for it.  Is two years of ABA going to be life changing for a person with severe autism?  Unfortunately, even after 20 years of ABA, that person will likely still have severe autism, if you have not treated their underlying biological problems.

Some parents rave about ABA and make comments like “after two years of ABA my son now makes eye contact”.  Great, but would you pay $120,000 of your own money for that?  I think not.  Should your local government regard that as money well spent?  I think they should be more demanding; the results of just $1,000 spent on the right personalized medicine will be much more impressive.

Today most people currently being diagnosed with autism have mild cases.  If they can talk and do not have intellectual disability (ID) / mental retardation (MR), they will likely see little benefit from 40 hours a week of discrete trial training.  It would be a huge waste of money and probably just annoy the child.  

Many children with mild autism need a different kind of therapy, they need to learn social and emotional skills they may not naturally possess - how to make friends, how to avoid making enemies and so how not to get bullied at school.  This will only be effective started very young, before being a victim becomes a badge of honour.

Interventions based on early intensive applied behaviour analysis for autistic children: a systematic review and cost-effectiveness analysis

Autism is a lifelong condition that affects how people understand the world and interact with others. Early intensive applied behaviour analysis-based interventions are an approach designed to help young (preschool) autistic children. This approach is often delivered on a one-to-one basis, for 20–50 hours per week, over a period of several years.

This project obtained and analysed the original data from studies of early intensive applied behaviour analysis-based interventions, to determine whether or not these interventions are beneficial. It also investigated whether or not the interventions represent good value for money.

The results suggest that early intensive applied behaviour analysis-based interventions may improve children’s intelligence, communication, social and life skills more than standard approaches. However, some results could be inaccurate or incorrect, and there was no evidence about other important outcomes, such as the severity of autism and where children went to school. Most studies lasted for around 2 years, which means that it is not known if early intensive applied behaviour analysis-based interventions have meaningful long-term benefits.

It was not possible to fully assess whether or not these interventions provided value for money, as the benefits of early intensive applied behaviour analysis-based interventions were unclear, although the available evidence suggested that they did not. Early intensive applied behaviour analysis-based interventions may, however, provide value for money if their effects were to last into adulthood, or if receiving early intensive applied behaviour analysis had a large impact on the type of school children attended.

Future studies of early interventions may be helpful, but should consider looking at which components of early applied behaviour analysis-based interventions are the most important, rather than at whether or not they work better than other interventions. Future studies should also follow best current research practice and evaluate outcomes that matter to autistic people and their families. 

Economic evaluation

Using National Institute for Health and Care Excellence decision rules to benchmark the results of the cost-effectiveness analysis and adopting a £30,000 (USD 40,000) per quality-adjusted life-year threshold, these results indicate that early intensive applied behaviour analysis-based interventions would need to generate either further benefits or cost savings to be considered cost-effective.

Implications for service provision

Although individual participant data meta-analyses have shown small to moderate improvements in child cognitive ability and adaptive behaviour for early intensive applied behaviour analysis-based interventions relative to treatment as usual or eclectic approaches, all of the identified studies were at risk of bias, limiting the strength of conclusions that can be drawn from these results. Furthermore, results from individual studies varied considerably, with some showing no relative benefit of early intensive applied behaviour analysis-based interventions. 

Conclusion

For cases of severe autism, if you can afford intensive (and expensive) 1:1 intervention of any credible kind (Floortime, ABA, Denver etc - whatever works best in your case) it makes sense to use it.  It should improve skill acquisition and will make the parents feel better.

None of these interventions are curative, the child will still have autism.  When you no longer pay for the 1:1 intervention, the effects most definitely will start to fade away.  Don’t mortgage your house to pay for ABA.

Nothing stops you making your own 1:1 intervention program using family, friends and volunteers.  This does not cost much and is sustainable over many years; it is likely to be much for effective that 2 years of "professional" therapy.

I do find it odd that in the US there is free early intervention for toddlers and then provision just stops, as if it suddenly is no longer needed.

If you use ABA to teach a child to tie shoe laces, he/she will retain the skill as long as you keep buying shoes with laces.  If you do not practice/apply the skill for 6 months, do not be surprised if it has to be re-taught.

Our final ABA consultant was very experienced, she worked for 10+ years in the US before moving home to Athens, Greece.  She told me that in her experience all children with autism benefit from ABA, but the level of progress they make varies widely.  If a child does not respond to ABA, it very likely is not being done correctly.  ABA should be seen as fun, not like a punishment. If your child hates ABA sessions, they have no chance of working.

I come back to my earlier recommended strategy. Find your most effective novel medical treatment, which will inevitably be a polytherapy and combine this with a method of learning that works best for your particular child.

Then just keep going and let time do its work.

In countries like the UK, with free health and education provision, the government does not generally pay for early intervention because their medical advisors do believe it to be cost effective, which really means they think it does not work and so do not want to pay for it.  The cynic might just say they do not want to fund it. 

The idea was supposed to be that by investing upfront in ABA during the early years, you save money later on, by having a more functional child and then adult who requires less expensive provision.  Unfortunately, there is absolutely no proof this is true.  

If you go from early intervention, to an ABA special school and then ABA college, things clearly did not work out.

In the US early intervention is assumed to be very effective and the current idea is that doctors should hurry to diagnose autism before 24 months so as to get into the intervention program as soon as possible.  Where is the evidence to support the US view?  Are US outcomes any better?

We saw in recent research from UC Davis that looked at outcomes over time in autism that the best outcomes are not associated with any particular therapy.  The best outcomes happen because of the biological characteristics of that child, rather than any amount of behavioral intervention.

I expected the UC Davis study to show a relative benefit for those who received ABA therapy, but it did not.  We do have to take note.  I am actually pro-ABA and have spent a vast amount of money on this kind of therapy and 1:1 instruction.   

Ignoring treating the biological dysfunctions in autism while spending hundreds of thousands of dollars on 1:1 therapy and special education does not make a lot of sense.

Here is a relevant excerpt from a recent post by the neurologist, autism researcher and autism Grandfather, Manuel Casanova, from his Cortical Chauvinism blog: -

AUTISM: HOW CULTURE INFLUENCES OUTCOMES

Despite marked differences in geography, non-Westernized countries see autism as a social responsibility rather than a medical condition.  These countries offer a collectivist perspective that downplays individuality and prioritizes maintaining relationships within a given group of people.  In this regard, I have often marveled as to how vastly different countries, like Colombia and the more desolate regions of Eastern Russia (Siberia), share similar perspectives regarding autism. Indeed, due to a lack of resources, interventions in these countries are usually parent-mediated and heavily influenced by cultural norms.  Lack of personnel trained in behavioral analysis has been supplanted by art and music instruction.  Classes are provided in group settings where outperforming other members is not seen as conductive to the overall benefit of the group. Members are encouraged to adopt the norms of the group while teachers emphasize cooperation and nurturing. Students arrive early to school to participate in team building exercises.

I have often marveled at the achievements of troupes of autistic children performing autochthonous musicals and their accompanying choreography.  Adopting the norms of the group have served them far better than any Westernized behavioral intervention.  Participants in these groups seem genuinely happy; in part, given the sense of achievement at contributing to a piece of artistic expression.  In addition, the structured activities in such groups offer norms that minimize uncertainty.  Participants feel a sense of security in a group that fast becomes their extended family.

Autism is a medical condition but, without a cause that we can target, treatment options have remained symptomatic.  This is one of the reasons for looking at other countries and learning what has worked for them.  Indeed,  I believe that we can gain from adopting the cultural perspective of other countries to benefit our own children. Whether it is an improvisation on an autism chair, electroacupuncture, or using a zen bowl, spending time with your children and group socialization, in my experience, have provided the most favorable outcomes.

Manuel is one of a very small group of thoughtful researcher-clinicians, who have been working in the field of autism for decades, like Dr Kelley from Johns Hopkins and that psychologist Dr Siegel who wrote the Politics of Autism and revealed how Lovaas really did his "research". 

Manuel's researcher son-in-law is interested in precision medicine and drug re-purposing, I guess driven by his own young son's rare genetic "autism", NGLY1 deficiency. This very severe condition leads to the body not being able to breakdown and remove damaged and misfolded proteins.  You would think that reducing Endoplasmic Reticulum (ER) stress, that produces misfolded proteins, might be useful. This was covered here, along with a long list of possible therapeutics:-

https://epiphanyasd.blogspot.com/2019/12/er-stress-and-protein-misfolding-in.html

Some readers are following the details of the Covid-19 situation.

The Indian Experiment rather than the Swedish Experiment

A recent study suggests that more than half of the 6 million slum dwellers in Mumbai have had Covid-19; another 6 million do not live in slums. Government research showed that in the capital Delhi 23% have Covid-19 antibodies.

Mumbai slums have an extremely high population density, extreme poverty and so not much social distancing. So they show what Covid-19 does with no serious intervention, better than Sweden does.  Mumbai has reported 6,200 deaths in total.

You can extrapolate from the data (57% of slum dwellers and 16% of non slum dwellers with Covid antibodies) for the total 12 million population of Mumbai.  4.4 million had the virus and 0.14% died.  In the worst case scenario, when everyone finally gets infected in the next few years, there would be another 7.4 million with the virus and another 10,800 deaths.  The death/mortality rate for the city would be 0.14%.  (In reality it will probably be less than 0.14%, because some people will not get the virus)

The 0.14% Covid-19 mortality rate compares to the 2.5% mortality rate of the 1918/9 global flu pandemic; worse still that flu pandemic affected fit young people the most, making the demographic impact huge. 

The crude death rate from all causes in the US is around 0.8% each year (just 0.7% in India).  That puts the 0.14% from Covid-19 into some perspective. If Americans are as healthy as Indians and India did not under-report the number of Covid deaths in Mumbai (both are big ifs), you could apply the 0.14% mortality from Covid-19  to 330 million Americans and get 460,000 people. I think the realistic number would be higher, given deaths to date in the US.  

I think the world has been very lucky to have been affected by a pandemic that has such a low mortality rate.  It could easily have been 20 times worse, perhaps next time?  In the Middle Ages, the Black Death killed hundreds of millions of people - a truly apocalyptic pandemic.

There is no certainty that a vaccine is going solve the Covid-19 problem, indeed the UK government is buying 12 different vaccines, in the hope that one is effective.  Vaccines are often least effective in older people, who are main risk group for Covid-19.

If no vaccine turns out to be 90% effective, the Mumbai slum dwellers and the Swedes will have been the smart ones.


Controlled Infection vs Vaccination

If I was a dentist I would be seriously worried about Covid-19. I would favor a small infection today, caught from my party-going offspring, rather than in two year's time catch it while peering into a stranger's mouth during an hour long procedure, and get a huge initial exposure, leading to a more severe infection.  The fact that Mumbai policemen, London bus drivers and of course doctors and nurses without good PPE have had so many fatalities does suggest the amount of virus you are initially exposed to is a critical factor to the outcome.  This would be logical anyway.

I am really glad at least my older son and myself have had Covid-19.  If I was a dentist, I would be hugely relieved. A few months ago we assumed Covid-19 was both highly infectious and often deadly, now we know the reality.  If you are youngish, slim and healthy the risk is very low.  Many in rich societies are old, overweight and in poor health.

I did take my younger son Monty, aged 17 with autism, for a visit to the dentist two months ago and I really felt sorry for her.  She was wearing a mask, but that is no guarantee of her safety.  

    

How to increase Oxytocin (OT) effects in the autistic brain? OT nasal spray, L. reuteri DSM 17938, Magnesium, Estradiol, Nicotinamide riboside …

 Struggle to make friends? Consider Oxytocin

Today’s post was going to be about FMT super-donors, but instead we have a post about new insights into using oxytocin to treat autism.  From personal experience I can say that you really can target oxytocin receptors to affect mood/behavior; I have no personal experience of FMT (fecal microbiota transplants), but thousands of people use it for many conditions.  The FMT post will be next.

Oxytocin and vasopressin are two hormones, made in the hypothalamus, that are established targets for autism treatment. They are released into the bloodstream where they carry out their best-known functions, but they are also released from the hypothalamus directly into the brain where these hormones have entirely different functions.

Both oxytocin and vasopressin can be given as nasal sprays to enter the central nervous system (CNS) rather than just the blood stream.  This means you get the brain effects of the hormone, also known as the “central effects”.

As was discussed previously in this blog and is highlighted more recently in the article below, you can use certain bacteria in the gut to signal to the hypothalamus to produce more oxytocin.  This is really clever and it works in humans, not just research animals.  It also has the advantage of producing a more continuous effect than is found using the intranasal method to deliver oxytocin. 

When you sever the vagus nerve, the bacteria in the gut continues to produce the required chemicals, but the signal to the brain has been lost. The hypothalamus no longer produces increased oxytocin and so the behavioral/mood effect is lost. This has been proven in the research.

Gut microbes may treat social difficulties in autism mice

In science speak, “the results suggest that a peptide or metabolite produced by bacteria may modulate host oxytocin secretion for potential public or personalized health goals”.  It also appears that oxytocin improves wound healing. So perhaps old people with leg ulcers, which never seem to get better, might benefit from a daily dose of L. reuteri DSM 17938, it also might make them feel better due to those central effects.

Oxytocin in the brain acts via oxytocin receptors

As we learned years ago in this blog, you can increase the effect (turn up the volume) of receptors using a PAM (positive allosteric modulator).  Interestingly, magnesium is a PAM of the oxytocin receptor (OTR).  Many people with autism are supplementing magnesium, perhaps those using intranasal oxytocin should join them. 

A very recent paper has investigated in detail how oxytocin receptors function.

Crystal structure of the human oxytocin receptor

The peptide hormone oxytocin modulates socioemotional behavior and sexual reproduction via the centrally expressed oxytocin receptor (OTR) across several species. Here, we report the crystal structure of human OTR in complex with retosiban, a nonpeptidic antagonist developed as an oral drug for the prevention of preterm labor. Our structure reveals insights into the detailed interactions between the G protein–coupled receptor (GPCR) and an OTR-selective antagonist. The observation of an extrahelical cholesterol molecule, binding in an unexpected location between helices IV and V, provides a structural rationale for its allosteric effect and critical influence on OTR function. Furthermore, our structure in combination with experimental data allows the identification of a conserved neurohypophyseal receptor-specific coordination site for Mg2+ that acts as potent, positive allosteric modulator for agonist binding. Together, these results further our molecular understanding of the oxytocin/vasopressin receptor family and will facilitate structure-guided development of new therapeutics. 

Magnesium and mood disorders: systematic review and meta-analysis

Another consequence of ERβ under-expression in autism

Also interesting to those following autism research, is the role of ERβ (estrogen receptor beta).  It is well known that in the brains of those with autism, there is a lack of ERβ.  A lack of ERβ is likely to lead to lower oxytocin in the brain and CSF (spinal fluid).  In many types of autism, we know that the level of oxytocin in CSF is reduced.

If you activate ERβ you both increase expression of oxytocin receptor (OTR) and also increase the level of oxytocin measured in the CSF.  You can activate ERβ with estrogens, like estradiol or even phytoestrogens like soy.  The ideal therapy to use would be DHED.

https://epiphanyasd.blogspot.com/2018/02/dhed-delivering-estradiol-only-to-brain.html

The cheap diuretic spironolactone may very well indirectly increase the level of oxytocin in CSF.

Oxytocin and Estrogen Receptor β in the Brain: An Overview

Oxytocin (OT) is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release OT into the bloodstream to promote labor and lactation; however, OT neurons also project to other brain areas where it plays a role in numerous brain functions. OT binds to the widely expressed OT receptor (OTR), and, in doing so, it regulates homeostatic processes, social recognition, and fear conditioning. In addition to these functions, OT decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter OTR expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase OT peptide transcription, suggesting a role for OT in this estrogen receptor β-mediated anxiolytic effect. Further research is needed to identify modulators of OT signaling and the pathways utilized and to elucidate molecular mechanisms controlling OT expression to allow better therapeutic manipulations of this system in patient populations.

NAD and Nicotinamide Riboside to boost Oxytocin

Today we see that recent research from Japan shows that in those people with autism who have reduced NAD, they may well be able to improve behavior/mood by increasing the level of their oxytocin using Nicotinamide Riboside (NR).

Nicotinamide riboside (NR) is a special form of vitamin B3, sold as an expensive supplement.  The FDA say it is safe for use in humans.

Nicotinamide riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder

Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of nicotinamide riboside, a recently discovered vitamin precursor of nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with nicotinamide riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.

NR elevates brain NAD⁺ and cerebrospinal OT

Social preference deficit and anxiety of CD157KO males are best corrected at a relatively low dose of NR

The results demonstrated that the daily oral administration of NR rescued the social behavioural impairments observed in male CD157KO mice. NR had essentially no effects on social behaviour in wild-type male mice. The beneficial effects of NR appear to depend on restoration of CSF OT levels because the NR-induced OT elevation was only detected in CD157KO mice, which have a CSF OT deficit.

In the course of identifying a nutritional intervention for CD157KO mice, we reproduced the anxiety-like and social-avoidance-like deficits reported previously. Reproducibly lower levels of CSF OT in male CD157KO mice make these mice an attractive model of autism, anxiety disorder, or social avoidance in neurodegenerative diseases. Significantly, this model responds to both OT and NR as a treatment.

The challenge of polygenic diseases of incomplete penetrance is that they are difficult to understand mechanistically. Multiple genetic and environmental (biochemical) factors may converge to dysregulate pathways that are altered in common conditions such as ASD. We note that one potentially hopeful point when studying polygenetic diseases is that brain systems are redundant, and thus, it may be possible to increase normal functions that are only partially encoded by genetically damaged circuitry.

NAD⁺ is consumed by CD38 in formation of cyclic ADP-ribose. It then participates in OT release in the hypothalamus. In our study, ADP-ribosyl cyclase activity was maintained at a similar range as that in wild-type animals (data not shown). A recent study suggested that NR supplementation did not change CD38 expression. However, in vitro studies have shown that NAD⁺ applied to the mouse hypothalamus leads to OT release. It is reasonable to assume that an elevation in NAD⁺ levels by NR in the hypothalamus is responsible for repair of the OT release.

Future work will probe CD38 dependence and the cell-type dependence of the beneficial effects of NR on CD157KO behaviour, the potential benefits of NR in other ASD models, and the potential of NR to become a safe nutritional intervention, in addition to OT, for at least some types of ASD in human populations.

NAD+ is reduced in older people

There is a lot of research into combating the effects of aging.  It is agreed that the older you get, the less NAD+ you have and so research has looked at numerous ways to raise it.

The CD157KO mice model of autism does feature reduced NAD+, but nobody knows how common reduced NAD+ is in autism.

If you have low levels of NAD+ there will be negative consequences.

I think you can consider NAD+ depletion in a similar way to oxidative stress, both are inevitable and damaging features of aging.

Most healthy younger people are likely wasting their time and money worrying about oxidative stress and NAD+.  These are the people with “detox” diets and juices.

However, most old people and some young people with autism really stand to benefit from correcting oxidative stress and any reduced NAD+.

  

Therapeutic potential of NAD-boosting molecules: the in vivo evidence

Hallmarks of NAD homeostasis

NAD⁺ is not merely a redox co-factor, it is also a key signaling molecule that controls cell function and survival in response to environmental changes such as nutrient intake and cellular damage. Fluctuations in NAD impact mitochondrial function and metabolism, redox reactions, circadian rhythm, immune response and inflammation, DNA repair, cell division, protein-protein signaling, chromatin and epigenetics.

There are many ways to boost NAD+.

Classes of NAD+ boosting molecules and known effects in humans

NAD+ Precursors              

Niacin/ nicotinic acid (NA), Nicotinamide riboside (NR) Nicotinamide (NAM) etc.

CD38 Inhibitors                 

Flavonoids (Quercetin, Luteolin, Apigenin, fisetin, rutin and naringin)             

Luteolinidin.  Kuromanin/ Chrysanthemin, an anthocyanin (food pigment)    

PARP Inhibitors    

BGB-290, Olaparib, Rucaparib, Veliparib, CEP-9722, E7016, Talazoparib, Iniparib, Niraparib, PJ34, DPQ, 3-aminobenzamide

                       

SARM Inhibitors

XAV939                    

NAMPT Activators

P7C3 

Conclusion

Some readers of this blog do give intranasal oxytocin as a therapy.  There have been numerous studies on children with autism, some discussed in earlier posts.  Oxytocin needs to be kept chilled, not to lose its potency.

Eleven previous posts in this blog refer to Oxytocin.

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

As to whether stimulating oxytocin receptors is going to be worthwhile in your case of autism, you will just have to try it and see.

I found that the Biogaia Protectis probiotic (L. reuteri DSM 17938) had very clear effects, which were very much hallmark effects of oxytocin.  This is easy and inexpensive to try.

Some readers of this blog do use Nicotinamide Riboside (NR), which we saw today can increase oxytocin by increasing NAD+.

There are very many reasons why you do not want to be lacking in NAD+, other than oxytocin, but if you already have plenty NAD+ you will unlikely see a benefit from yet more.

Magnesium is a very common autism supplement; it is often given with vitamin B6; both can be used to treat stress.

Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial

Immune modulatory treatments for autism spectrum disorder

Need a wizard, or your local doctor?

I was intrigued to come across a recent paper on immune modulatory treatments for autism by a couple of doctors from Massachusetts General Hospital for Children.  The lead author has interests in:

·      Autism spectrum disorders

·      Psychopharmacology

·      Developmental Disabilities

·      Williams syndrome

·      Angelman syndrome

·      Down syndrome

Apparently, he is an internationally-recognized expert in the neurobiology and neuropsychopharmacology of childhood-onset neuropsychiatric disorders including autistic disorder.  Sounds promising, hopefully we will learn something new.

The paper is actually a review of existing drugs, with immunomodulatory properties, that have already been suggested to be repurposed for autism. The abstract was not very insightful, so I have highlighted the final conclusions and listed the drugs, by category, that they thought should be investigated further.

All the drugs have already been covered in this blog and have already been researched in autism.

One important point raised in the conclusion relates to when the drugs are used.  Autism is a progressive condition early in life and there are so-called “critical periods” when the developing brain is highly vulnerable.

For example, Pentoxifylline has been found to be most effective in very young children.  This does not mean do not give it to a teenager with autism, it just means the sooner you treat autism the better the result will be.  This is entirely logical.

Some very clever drugs clearly do not work if given too late, for example Rapamycin analogs used in people with TSC-type autism.

Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain

Importantly, each of these developmental abnormalities that are caused by enhanced mTOR pathway has a specific window of opportunity to respond to rapamycin. Namely, dyslamination must be corrected during neurogenesis, and postnatal rapamycin treatment will not correct the cortical malformation. Similarly, exuberant branching of basal dendrites is rectifiable only during the first 2 weeks postnatally while an increase in spine density responds to rapamycin treatment thereafter.  

Back to today’s paper.

Immune modulatory treatments for autism spectrum disorder

The identification of immune dysregulation in at least a subtype ASD has led to the hypothesis that immune modulatory treatments may be effective in treating the core and associated symptoms of ASD. In this article, we discussed how currently FDA-approved medications for ASD have immune modulatory properties.

“Risperidone also inhibited the expression of inflammatory signaling proteins, myelin basic protein isoform 3 (MBP1) and mitogen-activated kinase 1 (MAPK1), in a rat model of MIA. Similarly, aripiprazole has been demonstrated to inhibit expression of IL-6 and TNF-α in cultured primary human peripheral blood mononuclear cells from healthy adult donors.”

We then described emerging treatments for ASD which have been repurposed from nonpsychiatric fields of medicine including metabolic disease, infectious disease, gastroenterology, neurology, and regenerative medicine, all with immune modulatory potential. Although immune modulatory treatments are not currently the standard of care for ASD, remain experimental, and require further research to demonstrate clear safety, tolerability, and efficacy, the early positive results described above warrant further research in the context of IRB-approved clinical trials. Future research is needed to determine whether immune modulatory treatments will affect underlying pathophysiological processes affecting both the behavioral symptoms and the common immune-mediated medical co-morbidities of ASD. Identification of neuroimaging or inflammatory biomarkers that respond to immune modulatory treatment and correlate with treatment response would further support the hypothesis of an immune-mediated subtype of ASD and aid in measuring response to immune modulatory treatments. In addition, it will be important to determine if particular immune modulating treatments are best tolerated and most effective when administered at specific developmental time points across the lifespan of individuals with ASD.

Here are the drugs they listed:-

1.     Metabolic disease

Spironolactone

Pioglitazone

Pentoxifylline

Spironolactone is a cheap potassium sparing diuretic. It has secondary effects that include reducing the level of male hormones and some inflammatory cytokines.

Pioglitazone is drug for type 2 diabetes that improves insulin sensitivity.  It reduces certain inflammatory cytokines making it both an autism therapy and indeed a suggested Covid-19 therapy.

Pentoxifylline is a non-selective phosphodiesterase (PDE) inhibitor, used to treat muscle pain.  PDE inhibitors are very interesting drugs with a great therapeutic potential for the treatment of immune-mediated and inflammatory diseases.  Roflumilast and Ibudilast are PDE4 inhibitors that also may improve some autism.  The limiting side effect can be nausea/vomiting, which can happen with non-selective PDE4 inhibitors.

I did try Spironolactone once; it did not seem to have any effect.  It is a good match for bumetanide because it increases potassium levels.

I do think that Pioglitazone has a helpful effect and there will be another post on that.

PDE inhibitors are used by readers of this blog. Maja is a fan of Pentoxifylline, without any side effects. Roflumilast at a low dose is supposed to raise IQ, but still makes some people want to vomit. The Japanese drug Ibudilast works for some, but nausea is listed as a possible side effect.

2.     Infectious disease

Minocycline

Vancomycin

Suramin

Minocycline is an antibiotic that crosses in to the brain.  It is known to stabilize activated microglia, the brain’s immune cells.  It is also known that tetracycline antibiotics are immunomodulatory.

Vancomycin is an antibiotic used to treat bacterial infections, if taken orally it does not go beyond the gut.  It will reduce the level of certain harmful bacteria including Clostridium difficile.

Suramin is an anti-parasite drug that Dr Naviaux is repurposing for autism, based on his theory of cell danger response.

  

3.     Neurology

Valproic acid

Valproic acid is an anti-epileptic drug.  It also has immunomodulatory and HDAC effects, these effects can both cause autism when taken by a pregnant mother and also improve autism in some people.

Valproic acid can have side effects. Low dose valproic acid seems to work for some people. 

4.     Gastroenterology

Fecal microbiota transplant (FMT)

FMT is currently used to treat recurrent Clostridium difficile infection and may also be of benefit for other GI conditions including IBD, obesity, metabolic syndrome, and functional GI disorders.

Altered gut bacteria (dysbiosis) is a feature of some autism which then impairs brain function.  Reversing the dysbiosis with FMT improves brain function.  

5.     Oncology

Lenalidomide

Romidepsin

  

Lenalidomide is an expensive anti-cancer drug that also has immunomodulatory effects.

Romidepsin is a potent HDAC inhibitor, making it a useful cancer therapy.  HDAC inhibitors are potential autism drugs, but only if given early enough not to miss the critical periods of brain development. 

6.     Pulmonology

N-acetylcysteine

Many people with autism respond well to NAC. You do need a lot of it, because it has a short half-life.

7.     Nutritional medicine and dietary supplements

Omega-3 fatty acids

Vitamin D

Flavonoids

Nutritional supplements can get very expensive.  In hot climates, like Egypt, some dark skinned people cover up and then lack vitamin D.  A lack of vitamin D will make autism worse.

Some people with mild brain disorders do seem to benefit from some omega-3 therapies.

Flavonoids are very good for general health, but seem to lack potency for treating brain disorders.  Quercetin and luteolin do have some benefits. 

8.     Rheumatology

Celecoxib

Corticosteroids

Intravenous immunoglobulin (IVIG)

Celecoxib is a common NSAID that is particularly well tolerated (it affects COX-2 and only marginally COX-1, hence its reduced GI side effects).

NSAIDS are used by many people with autism.

Steroids do improve some people’s autism, but are unsuitable for long term use.  A short course of steroids reduces Covid-19 deaths – a very cost effective therapy.

IVIG is extremely expensive, but it does provide a benefit in some cases. IVIG is used quite often to treat autism in the US, but rarely elsewhere other than for PANS/PANDAS that might occur with autism.

9.     Regenerative medicine

Stem cell therapy

I was surprised they gave stem cell therapy a mention. I think it is still early days for stem cell therapy.

Conclusion

I have observed the ongoing Covid-19 situation with interest and in particular what use has been made of the scientific literature.

There are all sorts of interesting snippets of data. You do not want to be deficient in Zinc or vitamin D, having high cholesterol will make it easier for the virus to enter your cells.  Potassium levels may plummet and blood becomes sticky, so may form dangerous clots. A long list of drugs may be at least partially effective, meaning they speed up recovery and reduce death rates. Polytherapy, meaning taking multiple drugs, is likely to be the best choice for Covid-19.

Potential side effects of some drugs have been grossly exaggerated, as with drugs repurposed for autism.  Even in published research, people cheat and falsify the data. In the case of hydroxychloroquine, the falsified papers were quickly retracted.

The media twist the facts, to suit their narrative, as with autism.  This happens even with Covid-19. Anti-Trump media (CNN, BBC etc) is automatically anti-hydroxychloroquine, and ignores all the published research and the results achieved in countries that widely use it (small countries like China and India). 

Shutting down entire economies when only 5-10% of the population have been infected and hopefully got some immunity, does not look so smart if you are then going to reopen and let young people loose.  They will inevitably catch the virus and then infect everyone else. Permanent lockdown restrictions, if followed by everyone, until a vaccine which everyone actually agreed to take, makes sense and living with the virus makes sense, but anything in between is not going to work. After 3 months without any broad lockdown, and allowing young people to socialize, most people would have had the virus and then those people choosing to shield could safely reemerge. The death rate with the current optimal, inexpensive treatment, as used in India or South Africa is very low, in people who are not frail to start with. Time to make a choice.  Poor people in poor countries cannot afford to keep going into lockdown, they need to eat.

What hope is there for treating a highly heterogeneous condition like autism, if it is not approached entirely rationally and without preconceptions and preconditions?  In a pandemic we see that science does not drive policy and translating science into therapy is highly variable.  The science is there for those who choose to read it.

I frequently see comments from parents who have seen some of the research showing that autism has an inflammatory/auto-immune component.  They ask why this has not been followed up on in the research.  It has been followed up on.  It just has not been acted upon.

Why has it not been acted on?

This missing stage is called “translation”.  Why don’t doctors translate scientific findings into therapy for their patients?

What is common sense to some, is “experimental” to others. “Experimental” is frowned upon in modern medicine, but innovation requires experimentation.

Many people’s severe autism is unique and experimental polytherapy/polypharmacy is their only hope.

The cookie cutter approach is not going to work for autism. 

Thankfully, for many common diseases the cookie cutter approach works just fine.

Do the authors of today’s paper, Dr McDougle and Dr Thom, actually prescribe to their young patients many of the drugs that they have written about?  I doubt it and therein lies the problem.  

Time for that wizard, perhaps? 

A few years ago I did add the following tag line, under the big Epiphany at the top of the page. 

An Alternative Reality for Classic Autism - Based on Today's Science

You can choose a different Autism reality, if you do not like your current one.  I am glad I did. I didn't even need a wizard.  

There are many immuno-modulatory therapies for autism that the Massachusetts doctor duo did not mention, but it is good that they made a start.