Autism/ASD is not a valid Biological Diagnosis

It's September again and about time most Autism “Experts”, therapists, advocates, charities and journalists went back to school as well

Today’s post is a brief one to highlight a mainstream scientific paper that highlights what regular readers will have already determined; autism/ASD is not a valid diagnosis.  Hundreds of different biological dysfunctions may lead to behaviors, in some shape or form, that will be diagnosed as autism.

So a behavioral diagnosis of autism is just the start of the process to determine what the biological problem(s) are.

Several readers have already highlighted the paper, but it is important enough for its own post.

This also means that clinical trials that are based on a group of subjects with completely different biological dysfunctions, but vaguely similar behavioral issues, are likely often to be of little value.

Fortunately, there are shared pathways affected by many of these numerous biological dysfunctions, so there will be some therapies that apply to clusters of subjects. 

ASD Validity

ASD research is at an important crossroads. The ASD diagnosis is important for assigning a child to early behavioral intervention and explaining a child’s condition. But ASD research has not provided a diagnosis-specific medical treatment, or a consistent early predictor, or a unified life course. If the ASD diagnosis also lacks biological and construct validity, a shift away from studying ASD-defined samples would be warranted. Consequently, this paper reviews recent findings for the neurobiological validity of ASD, the construct validity of ASD diagnostic criteria, and the construct validity of ASD spectrum features. The findings reviewed indicate that the ASD diagnosis lacks biological and construct validity. The paper concludes with proposals for research going forward.

PAK inhibitors and potentially treating some Autism using Grandpa’s Medicine Cabinet

I wrote several posts about why PAK1 inhibitors should be beneficial in some autism and indeed some schizophrenia.

We also saw that PAK1-blocking drugs could be potentially useful for the treatment of neurofibromatosis type 2, in addition to RAS-induced cancers and neurofibromatosis type 1.

One problem with drugs developed for cancer is that, even if they finally get approved, they tend to be ultra-expensive.  Production volumes are low because even if they “work” they do not prolong life for so long and cancer has numerous sub-types.

Cheap drugs are ones used to treat common chronic conditions like high blood pressure, high cholesterol and indeed treatment of male lower urinary tract symptoms (LUTS), like benign prostatic hyperplasia (BPH).

A small number of readers of this blog have confirmed the beneficial effect of PAK inhibitors in their specific sub-types of autism.  The problem is that there are no potent PAK1 inhibitors suitable for long term use that are readily available.

The anti-parasite drug Ivermectin is an extremely cheap PAK1 inhibitor, but cannot be used long term, due to its other effects.

Propolis containing CAPE (Caffeic Acid Phenethyl Ester) is a natural PAK1 inhibitor, but may not be sufficiently potent as is reported by people with neurofibromatosis.

You would think somebody would just synthesize CAPE (Caffeic Acid Phenethyl Ester) artificially and then higher doses could be achieved.

PAK Inhibitors and Treatment of Prostate Enlargement

I was rather surprised that research has recently been published suggesting that PAK inhibitors could be used to treat the prostate enlargement, common in most older men. 

P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

Abstract

Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients’ adherence is particularly low to combination therapies of 5α-reductase inhibitors and α₁-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1–10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.

It looks like a PAK inhibitor could potentially solve both the key problems in BPH and so replace the current therapies.

Existing Drugs for LUTS/BPH

Undoubtedly someone is going to wonder whether existing drugs for LUTS/BPH might improve autism.  This is actually possible, but totally unrelated to PAK1 inhibition and RASopathies.

Existing drugs are in two classes, 5α-reductase inhibitors and α₁-adrenoceptor antagonists.

α-adrenoceptor antagonists

Alpha blockers relax certain muscles and help small blood vessels remain open. They work by keeping the hormone norepinephrine (noradrenaline) from tightening the muscles in the walls of smaller arteries and veins, which causes the vessels to remain open and relaxed. This improves blood flow and lowers blood pressure.

Because alpha blockers also relax other muscles throughout the body, these medications can help improve urine flow in older men with prostate problems.

Selective α₁-adrenergic receptor antagonists are often used in BPH because it is the α₁-adrenergic receptor that is present in the prostate.

 α ₂-adrenergic receptors are present elsewhere in the body

Alpha-2 blockers are used to treat anxiety and post-traumatic stress disorder (PTSD). They decrease sympathetic outflow from the central nervous system. Post-traumatic stress disorder is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system.

Alpha-2 receptor agonists for the treatment of post-traumatic stress disorder

So a nonselective alpha blocker, like one given to an older man with high blood pressure and BPH, might well have an effect on some kinds of anxiety.

You would think that a selective alpha 2 blocker might be interesting, how about Idazoxan?

Idazoxan is a drug which is used in research. It acts as both a selective α2 adrenergic receptor antagonist, and an antagonist for the imidazoline receptor. Idazoxan has been under investigation as an antidepressant, but it did not reach the market as such. More recently, it is under investigation as an adjunctive treatment in schizophrenia. Due to its alpha-2 receptor antagonism it is capable of enhancing therapeutic effects of antipsychotics, possibly by enhancing dopamine neurotransmission in the prefrontal cortex of the brain, a brain area thought to be involved in the pathogenesis of schizophrenia.

Mirtazapine is a cheap generic drug used at high doses for depression.  It happens to be a selective alpha 2 blocker, but it has numerous other effects as well.  One reader of this blog does respond very well to Mirtazapine.

So realistically in Grandpa’s medicine cabinet there might a selective alpha 1 agonist or a non-selective alpha agonist, it is the latter type that might have an effect on some kinds of autism.

5α-reductase inhibitors

The pharmacology of 5α-reductase inhibition involves the binding of NADPH to the enzyme followed by the substrate. Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone.

Beyond being a catalyst in testosterone reduction, 5α-reductase isoforms I and II reduce progesterone to 5α-dihydroprogesterone (5α-DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC).

In vitro and animal models suggest subsequent 3α-reduction of DHT, 5α-DHP and DHDOC lead to neurosteroid metabolites with effect on cerebral function.

These neurosteroids, which include allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 5α-androstanediol, act as potent positive allosteric modulators of GABA_A receptors, and have anticonvulsant, antidepressant, anxiolytic, prosexual, and anticonvulsant effects.

Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT.

This, in turn, results in slight elevations in testosterone and estradiol levels. 

In BPH, DHT acts as a potent cellular androgen and promotes prostate growth; therefore, it inhibits and alleviates symptoms of BPH. In alopecia, male and female-pattern baldness is an effect of androgenic receptor activation, so reducing levels of DHT also reduces hair loss.

A new look at the 5alpha-reductase inhibitor finasteride

Finasteride is the first 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5alpha-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5alpha-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3alpha-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA(A) receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5alpha-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.

This would suggest that a 5α-reductase inhibitor, like finasteride, that might be among Grandpa’s tablets might very well have an effect on someone with GABAa dysfunction, this includes very many people with autism, schizophrenia and Down Syndrome.

Whether the effect will be good or bad is hard to say, and may well depend on whether other drugs that target GABA or NMDA receptors are being used. Due to their other effects, 5α-reductase inhibitors are usually only used in adults.

Merck developed a lower dose form of finasteride, called Prospecia to treat baldness, usually in men.  It is 20% the normal potency used for BPH.

Side effects

The current BPH drugs cause side effects in some people.  PAK1 inhibitors may also have some side effects.

Conclusion

Going back in the days of living with your extended family might make treating many people’s autism much simpler.  It looks like many older people’s drugs can be repurposed for some types of autism (ion channel modifying diuretics, calcium channel blockers, statins, even potentially intranasal insulin in some).  Because older people’s drugs are so widely used they are well understood and inexpensive.  

Clearly the research on PAK inhibitors for LUTS/BPH is at an early stage, but there is a huge potential market.   A widely available PAK1 inhibitor might be a big help to some people with autism, neurofibromatosis, other RASopathies, not just Grandpa’s prostate.

In addition to FRAX486 and IPA3, why doesn’t someone try synthetic CAPE, i.e. without the bees, as a PAK inhibitor?

Bioactivity and chemical synthesis of caffeic acid phenethyl ester and its derivatives.

There is far more chance of a PAK1 inhibitor coming to market for LUTS/BPH, or certain cancers than for autism.  That is a fact of life.

As for 5α-reductase inhibitors, like finasteride, we know from Hardan’s study on Pregnenolone at Stanford that this hormone can have a positive effect and we know that various natural steroid metabolites will modulate GABA subunits.  So it is quite likely that finasteride is going have a behavioral effect.  Perhaps Hardan would like to trial finasteride 5mg and 1mg (Prospecia) in some adults with autism. I suspect it will make some people “worse” and others somewhat “better”; so please do not report the “average” response, highlight the nature of the positive responders.

Wandering & Forever Young

Today’s post is rather light on the usual science.

One reader recently suggested a post on wandering. Wandering off and getting lost is a common event for many with more severe autism and while for some it may be an issue only in childhood, for many it will continue to adulthood.  US news reports frequently feature this kind of wandering, but it occurs everywhere.

Minions like to wander too

The broader issue here is that many people with severe autism remain child-like their entire lives.  So they continue to face many of the same risks as a neuro-typical toddler. If you do not pay great attention to your typical two year they also may have all kinds of accidents, but they soon figure out that roads are dangerous and falling from a window is going to hurt.

There are lots of clever high tech tracking solutions to help find your child, but the ideal solution must be not to lose him in the first place.

We have a high fence around our garden; we have a cover on our pool that even an adult cannot fall through and a number coded lock on the way out to the garage. So it would be hard for any toddler to wander off from our house and hard to fall from an upper window.

I think we have reached a developmental age where wandering is not likely, this is likely in part due to pharmacological intervention.

Many years ago I used to travel on business to Warsaw, in Poland, and we were fortunate to stay in a very upmarket hotel in the reconstructed old town called the Bristol.  You would think this would be a very safe place.  Some years later a friend was telling me how our former colleague was staying there over one weekend with his wife and their typical toddler son.  The boy was left unattended and somehow fell to his death from an upper window.

We do not electronically tag all two year olds, the idea is that they are given near constant supervision and hopefully things work out well. 

The big risks for kids with autism are drowning and seizures; in some cases it is a seizure while in the bath unattended that causes drowning.  Drowning should be preventable.  I think that with the appropriate treatment the onset of seizures in many people with autism might be prevented.

In the US on average 10 people drown each day, of whom two will be under 14 years old. Another 10 children receive emergency department care each day for nonfatal submersion injuries.

Life is a risky business.

Tracking Devices

There are numerous types of tracking device, but most have the drawback that they are removable.  To be genuinely effective the device would have to some kind of bracelet that cannot be removed.

In some countries by law all pet dogs have to be microchipped. If the dog gets lost a small inexpensive scanner reads the number on the chip which is looked up on an online database revealing the owner's details.

Our neighbour’s dog wanders off on regular basis, but thanks to his chip he has made it home so far.

It would be possible to microchip non-verbal people.  The problem here is that who would have a scanner?  Who would know that the person was chipped?  If you have to have a mark saying “I’m chipped” you might as well just write the person’s name and address indelibly on their forearm.  Better still don’t lose them.

Sense of Danger

Some people say that their child with autism has no sense of danger, but is that because he has not yet developed one, or he will never have one?  I remember being in an outdoor green market with Monty when we met an older boy who was in our mainstream school for a year or two.  He was non-verbal, autistic and had seizures. We usually saw him strapped into an oversized pushchair.  He could walk, but clearly it was deemed preferable to keep him strapped in.

Monty was used to exploring the stalls in the market and often he would be given something to taste.  The other boy was there with his mother and his assistant. I started talking to the mother, Monty started to move the next stall and then the assistant “pounced”, like Monty was about to walk in front of a bus.  I explained that is was OK, he was not about to run away; he had already learned a sense of danger from experience.

Clearly people are very different, but you do have to give people some space to develop and explore, if you expect them to learn.

Monty likes fire, but rather than hide him from it he is one who lights our open fire at home.  He is now fully aware that you can burn yourself (and your house). We do have several smoke detectors.

So I think some people may be over protective and not allowing the child to develop a sense of danger, while some others let their moderately autistic young child roam the street in front of their home and are surprised when trouble occurs.

Dressed to Kill

Many people like to be snappy dressers; I think people should be equally attentive to how they dress their adult-sized offspring with severe autism.

I recall a news article a while back when a mother let her adult son with severe non-verbal autism wander from home.  He was dressed in green military attire, like a big version of Rambo.  He wandered into a neighbour’s garden and the occupant saw the intruder and called the police.  The police arrived and tackled the non-responsive, threateningly-dressed, intruder to the ground.  The mother turned up and was upset that the officer had man handled her child.  I think this was in Canada, a little further south and the officer might have shot him.

Had the youth been dressed in shorts and a Mickey Mouse sweatshirt I doubt the home owner would have called the police in the first place, rather “it’s just that boy Jimmy from down the street wandering again, I must call his mother, she did tell me that he wanders”.

It does matter how you are dressed and how you behave.  I recall another parent commenting that adults with autism are not cute, that sounded odd to me.  An 8 year old with autism banging his head against the wall certainly is not cute.  A well behaved adult-sized person with classic autism can be cute, more than likely he is just a big kid, or a gentle giant.  If he is a permanent “big kid”, dress him like one and nobody is going to feel threatened by any unexpected behaviours.

Conclusion

Wandering can be deadly; if someone with non-verbal autism is prone to wander technology can only be of limited help.

The tendency to wander has to be matched by the level of supervision.

This blog is usually about pharmacological therapies and in many cases these should be able to improve cognition and self-awareness so that wandering is much less likely.

There will always be curious or adventurous types that will find a way over the fence and out into the wider world. Better make sure they know how to cross roads and know how to swim.  Even if they are only minimally verbal, from a very early age they need to know their name and address.  If they are totally non-verbal, you need a better fence, a tracking device that cannot be removed, or that permanent marker.

Memantine – yet another failed Autism Trial

Memantine (Namenda/ Ebixa) is an Alzheimer’s drug that has been used off-label in autism for many years; but does it actually work?

More than a thousand people with autism have completed clinical trials and yet more trials are in progress. 

A few years ago, at the FDA’s request, the producer of the drug, Forest Laboratories, funded two clinical trials enrolling 903 children with autism.  The results were never fully published because the trials were deemed to have failed to find any positive effect and a note to reflect this is included in each pack of Namenda.

A quick look at ClinicalTrials.gov website shows yet more autism trials in the pipeline.

What is going on?

When Dr Chez made a trial in 2007 he found Memantine to be effective; he has since moved on to stem cell therapy which he also finds to be effective.

The latest study to be published includes Dr Hardan from Stanford, who published that study showing NAC to be effective in autism.  This time his study shows no positive effect.

If you look on the clinical trials site you can see some data for the primary endpoint used in the very big trial funded by Forest Laboratories.  It seems to show 517 responders.

By the time the results were reviewed in detail the conclusion drawn by Forest was “there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo”. 

In other words it does not work.

The drug itself now carries this note:-

8.4 Pediatric Use

The safety and effectiveness of memantine in pediatric patients have not been established.

Memantine failed to demonstrate efficacy in two 12-week controlled clinical studies of 578 pediatric patients aged 6-12 years with autism spectrum disorders (ASD), including autism, Asperger’s disorder, and Pervasive Development Disorder — Not Otherwise Specified (PDD-NOS). Memantine has not been studied in pediatric patients under 6 years of age or over 12 years of age. Memantine treatment was initiated at 3 mg/day and the dose was escalated to the target dose (weight-based) by week 6. Oral doses of memantine 3, 6, 9, or 15 mg extended-release capsules were administered once daily to patients with weights < 20 kg, 20-39 kg, 40-59 kg and ≥ 60 kg, respectively.

In a randomized, 12-week double-blind, placebo-controlled parallel study (Study A) in patients with autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total raw score between patients randomized to memantine (n=54) and those randomized to placebo (n=53). In a 12-week responder-enriched randomized withdrawal study (Study B) in 471 patients with ASD, there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo (n=158).

So if it does not work, why do researchers continue to carry out further trials, like the recent one below, including Hardan?

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension

OBJECTIVE:

Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension.

METHODS:

A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day.

RESULTS:

There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks.

CONCLUSIONS:

This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

  

Dr Chez? 

So how reliable then are Dr Chez’s other findings?  He is a "big name" in autism research.

Back in 2007 Dr Chez published a very positive study on the use of Memantine in autism. 

Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observationof initial clinical response and maintenance tolerability.

 

Abstract

Autism and Pervasive Developmental Disorder Not Otherwise Specified are common developmental problems often seen by child neurologists. There are currently no cures for these lifelong and socially impairing conditions that affect core domains of human behavior such as language, social interaction, and social awareness. The etiology may be multifactorial and may include autoimmune, genetic, neuroanatomic, and possibly excessive glutaminergic mechanisms. Because memantine is a moderate affinity antagonist of the N-methylD-aspartic acid (NMDA) glutamate receptor, this drug was hypothesized to potentially modulate learning, block excessive glutamate effects that can include neuroinflammatory activity, and influence neuroglial activity in autism and Pervasive Developmental Disorder Not Otherwise Specified. Open-label add-on therapy was offered to 151 patients with prior diagnoses of autism or Pervasive Developmental Disorder Not Otherwise Specified over a 21-month period. To generate a clinician-derived Clinical Global Impression Improvement score for language, behavior, and self-stimulatory behaviors, the primary author observed the subjects and questioned their caretakers within 4 to 8 weeks of the initiation of therapy. Chronic maintenance therapy with the drug was continued if there were no negative side effects. Results showed significant improvements in open-label use for language function, social behavior, and self-stimulatory behaviors, although self-stimulatory behaviors comparatively improved to a lesser degree. Chronic use so far appears to have no serious side effects.

Making sense of Memantine

Personally, I think it likely that Memantine may indeed have a positive effect in some people with autism.  For most people it probably does no good, but no harm, so it is a harmless placebo that may make the parents feel better and gives the doctor something to prescribe.

Memantine and the very similar Galantamine probably do deserve a place in the long list of drugs and supplements that may be effective in some people.  But how great is that “effect”?  I suspect this is the problem; it is big enough for Dr Chez but not big enough for the others.

I suspect this will be a recurring problem in almost all future autism drug trials.  What is a responder?  How big an effect is a worthwhile effect?

I think a better approach would be to focus on the so-called responders identified by Dr Chez and others.  Document the claimed positive effects and then see if these effects continue when the responders are given a dummy placebo.

This is the approach I use in my trials; when I stop a therapy, I look to see if there is a change.  When you suspend an effective therapy things should get worse.

The hundreds or thousands of kids currently on Memantine should do the same; take a break and see if there is any change, be it positive or negative. 

Many people believe no valid treatments for autism exist and that those thinking otherwise are all deluded.

I think that many people are giving their kids drugs and supplements of no therapeutic value and in some cases are making the situation worse.

However, effective therapies do exist for many people with autism and they stand up to scrutiny.  The effect is apparent to third parties, like teachers and therapists, and when you stop the therapy the positive effect is lost and people notice, only to return when it is restarted.  Then you know it is not wishful thinking and at that point what the FDA says does not really matter and you do not need bother with what subsequent trials say.

So when a reader asked me what I thought about the recent “failed” trial of NAC, to treat social impairment in autism, I took a very relaxed view.  If they had identified 50 kids with classic autism and stereotypy and looked at whether NAC reduced this, I would take note.  They choose the wrong primary endpoint, social impairment, and wasted a lot of money.

A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder

Conclusions
The results of this trial indicate that NAC treatment was well tolerated, had the expected effect of boosting GSH production, but had no significant impact on social impairment in youth with ASD.

      

I only wait to see what happens when Ben Ari publishes the results of his large trial on Bumetanide.  Whatever data they choose to collect, is it going to convince the European Medicines Agency that it is an effective therapy?  I hope so, but nothing would surprise me.

I would love to know how Dr Chez rationalizes the fact that so many others cannot replicate his positive research findings.  But he keeps on going.

Rather off-topic, a recent comment on my post on Clonidine, informed us that this drug, often prescribed off-label in autism and ADHD, really is acting as a sedative to calm the person down. So no effect on core autism.  Sedation does have a role to play in some people’s disorders.  Very low doses of Mirtazapine (Remeron) are also sedating via its effect of central H1 receptors; it occurred to me that this might be a safe long term therapy for some "out of control" people with severe autism; likely safer than the usual antipsychotics. 

Autism, Allergies and Summertime Raging in 2016

  

This time of year many parents in the northern hemisphere are looking up “autism and allergy” on Google and more than 20,000 have ended up at my post from 2013 on this subject.

Not just for Stomach Health

It is clear that many people have noticed that allergy makes autism worse, even if your family doctor might think you are imagining it.

This year, thanks to our reader Alli from Switzerland, there is a new innovation in my therapy for Monty, now aged 13 with ASD.  Now we are firm believers in a specific probiotic bacteria to dampen the immune system (more IL-10, less IL-6 and likely more regulatory T cells) and minimize the development of pollen allergy and all its consequences.

There is a wide range of H1 antihistamines, mast cell stabilizers and inhaled steroids available and many readers of this blog are using a combination of some or all of these to control allergy and mast cell activation.

By using the Bio Gaia probiotic bacteria the magnitude of the allergic response to allergens is substantially reduced, so whatever problems allergy worsens in your specific subtype of autism, these should become much milder.

In our case the allergy will trigger summertime raging and loss of cognitive function.

The use of the calcium channel blocker Verapamil very effectively halts/prevents the raging, but it does not reduce the other effects of the allergy or the loss of cognitive function.

The use of the Bio Gaia probiotic reduces the problem at source; it greatly reduces the allergy itself.  Less allergy equals less summertime raging and equals less loss of cognitive function.

So for anyone filling up on antihistamines, steroids and mast cell stabilizers it could be well worth reading up on the studies on probiotics and allergy, or just make a two day trial with Bio Gaia.

Prior to Bio Gaia, we used Allergodil (Azelastine mast cell stabilizer and antihistamine) nasal spray or the more potent Dymista (Azelastine plus Fluticasone) nasal spray, plus oral H1 antihistamine (Claritin or Xyzal) and sometimes quercetin.  Verapamil was introduced to halt the raging/SIB caused by the allergy, which it does within minutes or can be given preventatively.

Each year the pollen allergy got worse than the previous year, starting five years ago at almost imperceptible and ending up with blood red sides of his nose.  With Bio Gaia there is just a faint pinkness at the side of his nose.

There are additional positive effects of Bio Gaia beyond the allergy reduction, but they do seem to vary from person to person.  In our case there is an increase in hugging and singing.  The research on this bacteria does show it increases the hormone oxytocin in mice.

A single species of gut bacteria can reverse autism-related social behavior in mice

In some people without obvious allergy, Bio Gaia’s effect on the immune system can also be quite dramatic.  In some people the standard dose is effective, but in others a much higher dose is needed.  The good thing is that the effect is visible very quickly and does seem to be maintained.  The main post on Bio Gaia is here.  

Bio Gaia is based on serious science but is available over the counter.

Ongoing Clinical Trial of Vivomixx Probiotic in Children with Autism

Since there is now interest in the potential benefit of probiotic bacteria to treat some autism, I wanted to point out that there actually is a clinical trial underway in Italy.  It is funded the Italian Ministry of Health and by the Tuscany Region.  They use Vivomixx, an OTC probiotic from the Italian speaking region of Switzerland.   

Vivomixx contains:

Streptococcus thermophilus DSM 24731, bifidobacteria (B. breve DSM 24732, B. longum DSM 24736, B. infantis DSM 24737) 
lactobacilli (L. acidophilus DSM 24735, L. plantarum DSM 24730, L. paracaseiDSM 24733, L. delbrueckii subsp. bulgaricus DSM 24734).

Before you start wondering, it is not cheap; the Swiss do not do cheap.

There is a detailed explanation of the trial in the full version of the paper below.  It is due to be completed at the end of 2017.

  
Vivomixx is virtually identical to a well known expensive probiotic called VCL#3, which has been used in research.  Due to some dispute the originator of VCL#3 started a new company which now sells Vivomixx.  In some countries one is available and in other countries it is the other one.  VCL#3 is even more expensive. 

Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters

Background

A high prevalence of a variety of gastrointestinal (GI) symptoms is frequently reported in patients with Autism Spectrum Disorders (ASD). The GI disturbances in ASD might be linked to gut dysbiosis representing the observable phenotype of a “gut-brain axis” disruption. The exploitation of strategies which can restore normal gut microbiota and reduce the gut production and absorption of toxins, such as probiotics addition/supplementation in a diet, may represent a non-pharmacological option in the treatment of GI disturbances in ASD. The aim of this randomized controlled trial is to determine the effects of supplementation with a probiotic mixture (Vivomixx®) in ASD children not only on specific GI symptoms, but also on the core deficits of the disorder, on cognitive and language development, and on brain function and connectivity. An ancillary aim is to evaluate possible effects of probiotic supplementation on urinary concentrations of phthalates (chemical pollutants) which have been previously linked to ASD.

Methods

A group of 100 preschoolers with ASD will be classified as belonging to a GI group or to a Non-GI (NGI) group on the basis of a symptom severity index specific to GI disorders. In order to obtain four arms, subjects belonging to the two groups (GI and NGI) will be blind randomized 1:1 to regular diet with probiotics or with placebo for 6 months. All participants will be assessed at baseline, after three months and after six months from baseline in order to evaluate the possible changes in: (1) GI symptoms; (2) autism symptoms severity; (3) affective and behavioral comorbid symptoms; (4) plasmatic, urinary and fecal biomarkers related to abnormal intestinal function; (5) neurophysiological patterns.

Discussion

The effects of treatments with probiotics on children with ASD need to be evaluated through rigorous controlled trials. Examining the impact of probiotics not only on clinical but also on neurophysiological patterns, the current trial sets out to provide new insights into the gut-brain connection in ASD patients. Moreover, results could add information to the relationship between phthalates levels, clinical features and neurophysiological patterns in ASD.

Trial registration

ClinicalTrials.gov Identifier: NCT02708901. Retrospectively registered: March 4, 2016.

So in the coming years it looks like there will be some actual data with which you can decide whether or not to trial specific probiotic bacteria. 

Hopefully, the Biogaia people in Sweden will provide their products for some independent researchers to trial on humans with autism, probably Swedish ones.