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Friday 25 September 2015

OPN-300 Oxytocin and Autism



This post is about nasal spray drugs and Oxytocin.

Monty, aged 12 with ASD, uses a conventional anti-histamine nasal spray and I do sometimes wonder just how much of the drug reaches its target.  

With inhalers for asthma this is a well known problem and often even adults do not use them correctly; they are proven to work much better when they are fitted with a spacer chamber, that way the drug ends up in your lungs and not stuck to the inside of your mouth.






Many adults with asthma and COPD nowadays use spacers.

So my interest was drawn to a company called Optinose that is developing drugs for nasal delivery using a novel dispenser.  I was particularly surprised that in its small drug pipeline is an oxytocin spray for autism.

If you look on the US National Institute of Health website listing clinical trials of oxytocin and autism, you will find that thirty, yes three zero, studies are listed.


According to their website, Optinose intend to be the first to bring a product to the market approved for autism.











On the clinical trials website you may notice that other trials use an existing drug called Syntocinon that is a synthetic form of Oxytocin already approved for other purposes.






I did mention in an earlier post that the US rights to Syntocinon were sold to a company hoping to develop a therapy for Schizophrenia and Autism.


Retrophin Signs U.S. License Agreement for Syntocinon™ Nasal Spray (Oxytocin)


In Europe Syntocinon is available in most countries as a prescription drug.


The Optinose idea is that their dispenser can much more reliably dispense the correct amount of drug and have it reach the membrane deep inside the nose.  None gets in the mouth and less should get stuck at the entrance to the nose.

Previous trials of Oxytocin have yielded very mixed results.  Perhaps part of this is due to the nature of the spray pump being used?  It is certainly plausible.


The Optinose Spray

The Optinose spray is inserted in one nostril and your mouth.  You blow out through mouth, sealing the nasal cavity in the process, and the spray is forced out into your nose.  This should ensure it goes deep inside to the nasal membrane, where the oxytocin can cross directly into the blood stream.





Click on the link below and then click to play the short video.



As the video points out, this kind of drug delivery can “enable new and improved brain treatments”


They are talking about direct nose-to-brain drug delivery, bypassing the blood brain barrier (BBB).  This is not fantasy and is already quite well studied.

Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: an excellent platform for brain targeting.

Coming back to Oxytocin ...

Not only is Oxytocin a well-known hormone affecting social behavior, but it also plays a role in switching the neurotransmitter GABA between excitatory and inhibitory.


Oxytocin and GABAA

Oxytocin has a role at birth in the GABA “switch”, but it also has an ongoing role via binding to a particular subunit of GABAA receptors.



We report that the oxytocin-mediated neuroprotective γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.

Further evidence as to the precise effect of Oxytocin on GABA receptors was found by chance.  It was found that having dosed rats with Oxytocin, they did not get drunk when fed alcohol.





Specifically, oxytocin (1 µg i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire-hanging test, and righting-reflex test in male rats.

Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at δ-GABAARs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at δ-GABAARs

The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence.



Is Oxytocin a useful Autism Therapy?

Given the large number of trials and the number of people already taking Oxytocin, some people clearly believe in the therapeutic potential of Oxytocin.

What is clear is that there a numerous modes of action for Oxytocin, some of which relate to GABAA receptors.

So why is it taking so very long for these trials to come to any usable conclusion? Well just looking at the long list of researchers, it includes some of those who have spent twenty years "researching" autism and producing absolutely nothing tangible, just papers concluding more research is needed or even producing, supposedly therapeutic, cartoons (Cambridge University).

We have the usual problem that numerous different dysfunctions lie at the root of “autism” and so only a moderate proportion, at best, would be expected to benefit from any therapy.

In the case of nasal sprays we have the question of how much actually gets delivered to the right place deep inside the nose where there is a very thin membrane that allows the Oxytocin to cross over into the blood.


OPN-300 Clinical Trials

The Phase 1 trial for OPN-300 was actually on healthy adults, and looked at things like dosing.  Low doses were more effective than high doses.  Next follows the trial on people with autism.  




Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel ‘Breath Powered’ nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8IU (international units) or 24IU OT, 1IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8IU OT in comparison to both placebo and 24IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.


Importantly, the current findings are the first to suggest that a low dose of OT is more effective than a higher dose in modulating social cognition

Converging biological and behavioral evidence suggests that lower OT doses may be more efficacious than higher doses. For instance, compared with higher doses, lower doses increased peripheral levels of OT in saliva,65 attenuated cortisol stress responses66 and increased eye gaze in patients with Fragile X syndrome.67 In animals, a low dose of OT administered shortly after birth increased partner preference later in life, whereas higher doses did not.68 Similarly, lower doses have been associated with stronger increases in social recognition compared with higher doses.69, 70 The dose–response data reported here provide useful preliminary evidence concerning the optimal dose for social cognition modulation; however, extrapolation from healthy individuals to patients must be with caution. Patients with social-cognitive deficits may respond differently than healthy volunteers, so future studies should explore effects in patient populations to determine the generalizability of these findings to target illnesses. Future work should also further investigate the role of different delivery devices, administration routes, dosages and social cognition tasks on the efficacy of intranasal OT, ideally using larger sample sizes given the limitation of a relatively small sample size in the present study.
In addition, this study provides preliminary evidence that a lower dose (8IU) may offer greater efficacy than a higher dose (24IU) when administered with the Breath Powered device.

There are a number of interpretations regarding why no effect was observed at the 24IU OPN-OT dose, in contrast to the 8IU dose. For example, a higher OT dose is more likely to influence the balance of AVP/OT, as evidenced by the decrease in AVP concentration after 24IU OPN-OT (but not 8IU OPN-OT) observed in the present study, which can modulate social behavior.



OptiNose reports positive results from Phase 1 trial of intranasal oxytocin for autism

Jul 15 2015

OptiNose has announced that a study comparing OPN-300 intranasal oxytocin to intravenous oxytocin for the treatment of autism showed the achievement of similar blood levels but significantly greater social-cognitive effects after intranasal administration. The results were published online July 14, 2015 in Translational Psychiatry.
The randomized, placebo-controlled, double-blind, double-dummy, 4-arm cross-over study involved 16 healthy volunteers who received either intravenous oxytocin or two doses of OPN-300 delivered using OptiNose’s bi-directional breath powered intranasal delivery device. Social-cognitive effects were measured by emotional rating of facial images.
Researcher Ole A. Andreassen of the University of Oslo said, “The OptiNose technology significantly changes the way drug is delivered high up in the nose, and may be the drug delivery solution we’ve been looking for. If we can improve social cognition in healthy people with OPN-300 low-dose oxytocin, then we may be able to address a core symptom suffered by millions of patients worldwide with autism.”
OptiNose Chief Scientific Officer Per Djupesland commented, “Although animal data has been encouraging, many would argue that medication transport from the nasal cavity directly to the brain has not been previously proven in humans. Today’s results are quite promising and bolster our belief that we can enable and enhance the treatment of common brain disorders with OptiNose delivery technology.”
The company says that it is initiating a Phase 2 trial of OPN-300 in autism patients in Norway. OptiNose is also developing intranasal fluticasone for chronic sinusitis and recently reported positive results from a Phase 3 trial of that product.
Read the OptiNose press release.
Read the Translational Psychiatry article.




Conclusion

Some parents already use the Syntocinon version of oxytocin for autism; some tried it in one of the earlier clinical trials and found it did not help.  There is nothing surprising in that. 

The people at OptiNose seem to be a bit more motivated than some of the other oxytocin researchers, in relaxed leafy universities, to actually get to the finishing line.  They are initiating Phase 2 trials of OPN-300 in autism patients in Norway.  Some of the other studies have been going on for several years and are still not finished.

Hopefully we will soon have some data on what percentage of people with “autism” respond to OPN-300 and then we could compare that to the response to Syntocinon.

As we have seen several times before, it seems that smaller doses of oxytocin are more effective than larger doses.  Larger doses seem to change (reduce) vasopressin levels, which will also affect social behavior.

One you start changing the level of one hormone, like oxytocin, you are very likely to affect others.  There are many interrelations and feedback loops.  

Oxytocin may well be part of the solution for some people with autism, but I expect in others it may make them worse.  Hopefully in the later trial(s) they will try and indentify biomarkers for the responder group.








Sunday 20 September 2015

A New School Year – Still keeping up








Before I return to the science-heavy posts, this is another post to encourage people not just to read about autism, but to treat it.  No pseudoscience or great expense is required.

After close to three years of using biology, rather than just behavioral therapy, where have we got to?

Acquiring new skills is effortless for clever typical kids; we have also got one of those.  For kids with classic autism, even the most basic skills need to be taught and taught again, until eventually, they might sink in.  I do not think this has anything to do with permanent MR/ID (mental retardation/intellectual disability), although I can see why it often gets diagnosed as such; it turns out to be treatable.

In the race to keep up with the typical kids, or at least keep them in sight, we started with ABA and about 1,800 hours a year of 1:1 time with an assistant.  After a few years the typical kids had pulled far ahead.

At age 9, I started to correct the underlying dysfunctions, first with Bumetanide, using very recent findings in the scientific literature.  This coincided with the decision to change his (neurotypical) peer group at school to those 2-3 years his junior.  Time was reset.

We still had the 1,800 hours a year of 1:1 time with an assistant, half at school and half at home.

At age 12, the original peer group is now far out of sight, but after three years we are still keeping up academically with the new “friends at school”.

Monty, now aged 12 with ASD, is in the same small mainstream international school he has attended for eight years.  Three years ago I held him back two years, since he was becoming completely “un-includable”.  So we went Year 1, Year 2, Year 3 then back to Year 2, then Year 3, Year 4 and now Year 5. 

Since most readers are American, where school starts one year later, to convert UK school year to US grade, just subtract one.  UK Year 5 = US 4th grade.  In the US you finish in 12th Grade whereas in the UK system you finish in Year 13, both typically in your 18th year. (so in the US system, he went K, 1st, 2nd, then 1st, 2nd 3rd and now 4th)

Many kids with autism are now “included” in mainstream education, but in reality some are just having a private 1:1 lesson with their assistant at the back of the class. This is not a good idea; for the last three years Monty has been able to follow the teacher.  If you cannot follow the teacher, you really should not be in that class.

We have a new class teacher, an American, he has been teaching for 15 years, but has never had a special needs kid before; that in itself tells you something.  Now he has Monty, aged 12 with “treated” classic autism, something he probably will never see again.

After a couple of weeks, his conclusion is “he can read nicely and do the exercises”.  This makes it sound rather a non-event.  A few short years ago, his school teachers were rather stunned that his 1:1 assistant got him to read very simple words.  Now he can read aloud from “chapter books” to the rest of the class.   

When they had a spelling test (words like graduate, icicles, sausages) he got 18/20 and one of the new girls in class told her mother how clever Monty is.  When told he has “special needs” and an assistant, she replied “special needs … no special needs”.  That was nice, but Monty does still have plenty of special needs, but for three years he has been able to move forward academically at a similar rate to his classmates, albeit that they are all 2 years his junior.  That progression is quite extraordinary, if you know about outcomes in classic autism. 

Having been using ABA for five years prior to starting with the biology/pharmacology, and seen steady but slow progress and so falling ever further behind his peers, I never expected to be here in 2015 with Monty being able to subtract 7,794 from 9,621, or add up 8,756 + 4,326 + 7,832, interpret data from graphs and use x,y coordinates.  Until five years ago he did not even attend numeracy/math classes at school, because we had to focus on basic speech, basic reading and things like standing in line and changing shoes.

I have no idea how far he can go. I was expecting by now to again have to repeat a school year, but it has not been necessary.


Behavioral problems (SIB, anxiety, aggression etc.) were generally rooted in biology and have been more than 90% treatable.

With neither behavioral, nor pharmacological intervention, it would not now be a pretty sight.

It is sad that almost nobody treats Classic Autism pharmacologically; there are so many unnecessary, unhappy, consequences, lives sometimes lost to what can be a treatable condition.

It also appears likely that by treating the dysfunctions in Classic Autism, you may avoid the possible later progression to epilepsy/seizures and all the problems that may cause (even SUDEP, drowning etc).  This was something we had been warned might develop, but now looks much less likely.  For some people, seizures are a bigger issue than their autism. Some data, for those interested:-




This is among the largest studies to date of children with ASD and co-occurring epilepsy. Our sample includes 5,815 participants with ASD, 289 of whom had co-morbid epilepsy. Using statistical modeling in this well-powered sample of patients we have made several important observations about a contemporary group of individuals with ASD and epilepsy. We identified several correlates of epilepsy in children with ASD including older age, lower cognitive and adaptive functioning, poorer language skills, a history of developmental regression, and more severe ASD symptoms. Through multivariate logistic regression we found that only age and cognitive ability were independent predictors of epilepsy.

The average prevalence of epilepsy among children aged 2 to 17 years in our population-based sample, the NSCH, was 12.5%. This estimate is comparable to a recent report of a 15.5% rate of epilepsy in another population-based sample of children with ASD. While the prevalence was 10% or lower in children under 13 years of age, by adolescence it reached 26.2%. Therefore, the best estimate of the cumulative prevalence of epilepsy in ASD through 17 years of age is 26%. Our study replicates findings from prior studies that have followed children with ASD into adolescence/early adulthood and reported epilepsy prevalence rates from 22% to 38%


Note that Classic Autism accounts for about 30% of ASD; it is not hard to guess where you would find most of the 26% with ASD who later develop epilepsy.  

Odd epileptiform activity (seen on an EEG), falling short of epilepsy, is common in young children with autism and I think might be considered as pre-epilepsy.  Just as someone who has prediabetes has the chance to do something about it, before it progresses to type II diabetes, unusual EEG activity should prompt consideration of a treatable excitatory/inhibitory imbalance. 


Conclusion

At least I have treated the only autism case I am responsible for. I encourage others to do the same; it is never too late, even in adulthood.  We have one reader, Roger, who got his core biological autism dysfunction diagnosed and treated in adulthood.

If you prefer to wait for 100% FDA-guaranteed solutions, you will wait forever.  







Friday 18 September 2015

The Benefit of Defining Severity in Autism






 
We have seen in this blog that many hundreds of different dysfunctions can lead to symptoms broadly diagnosed as autism.  At the same time, the boundary at which people seek to medicalize behavioral problems continues to shift (more ADHD, more autism etc.), making it now hard to know what people mean by “autism”.

Rather than grading autism severity 1, 2 or 3, which is the new clinical practice under the American psychiatrists’ DSM5, my scheme might be more useful, since it would also show the variability of the symptoms.

I would rate “autism” on a scale of 1 to 100, but would state typical and peak values.  This could be established via an intelligent questionnaire given to parents and teachers.  It certainly would remain subjective and be far from perfect.



0 to 100 scale, with typical to peak

Some examples:-


Asperger’s plus Sensory

Somebody with what used to be called Asperger’s, who attends mainstream school, but has now developed sensory issues that the parents and child find troubling might be 5/15.

This would mean that most of the time the child is at 5, but when the problems arise from sensory issues he moves up to a 15.  The increase of 10 is a shock to the parents and would be noticed in mainstream school, but to someone at the other end of the scale, it would be like a hiccup.


Boy on the Bus

The nonverbal teenager with “autism” in the US, who the school bus driver forgot on the bus and was found dead a few hours later, still on the bus, parked back at the depot, might be 85/90.  This person needed assistance to wash, toilet and dress himself.  Clearly his issues were quite different from the 5/15 child.

85/90 should mean never be left alone and do not hand over to the “care” of the unknown relief bus driver.


Classic Autism at Special School

In most countries children with Classic Autism are in special schools.  What is interesting is that in this group there are often big variations over time.  These variations, just like all those comorbidities, are big signposts as to what the underlying neurological dysfunctions are.

A child might be 40/70; meaning that much of the time (i.e. at 40) things are nicely under control, but sometimes things get much worse.  Some parents describe this as “my child raves like a lunatic”, for others it might be aggression towards others and in some it might be self injury.

By far the most read posts on this blog come from people searching on google “autism + histamine”, so it looks likely that very many people find that summertime allergies cause big spikes in autism, as odd as that may sound.

There appear to be many other reasons for this temporary change 40/70 or 70/90 or even 10/30.  These big changes can be caused by all kinds of things.

In a future post I will look at the inflammatory response to GAS (Group A Streptococcus) and aberrant immunological reactions to GAS antigens.  The first of these might well cause the “raving loony” effect, while the second might the produce the facial grimacing and tics, observed by some readers of this blog.  If there was an effective rating scale, you could easily distinguish between the two.  Is the change 40/45 or 40/70 for example?


Double tap autism

In an earlier post I gave the term “double tap” autism to those people who started out with regular classic autism, say 40, who then suffer a sharp (permanent, if not treated) regression taking them to say 70 or even higher.

The internet is full of untreated examples of just this phenomenon.

Knowing that this person is 40/70, might then prompt the clinician to look for what had happened to cause this step change in autism symptoms.  If you managed to get to 4 years old before the regression to 70 occurred, there should be a good chance of finding out what happened, treating it and getting back to at least 40.

      
Autism Secondary to Mitochondrial Disease (AMD)

This young child might appear as 0/50, showing that before the onset of mitochondrial disease he was a typical child, but he regressed over a few weeks/months to something similar to classic autism.  It is the big change from 0 to 50 that should sound alarm bells.

The sooner it is treated, the better the final result. 



Primary and Secondary Causes of Autism

This all fits nicely with the segmentation I suggested in a previous post, regarding Primary and Secondary causes of autism.

If someone is 40/70, the 40 represents the primary cause(s) of their autism and the increase by 30 to 70 is the effect of the secondary dysfunctions when they are active.

Note that many people have commented that their therapy for Primary autism ceases to be effective when the secondary dysfunction(s) become active.  Hence “NAC has stopped working”, “Bumetanide has stopped working” etc.




Primary Dysfunctions in Autism
Secondary (some transient) Dysfunctions



Excitatory/Inhibitory GABA imbalance
Food allergy (e.g. gluten)
Oxidative stress
Pollen allergy
Neuroinflammation
Mast cell activation disorder
Activated microglia (over-activated immune system) inviting secondary dysfunctions
Mastocytosis
Vitamin B7 (biotin) related dysfunctions
Reaction to GAS and/or GAS antigens
Vitamin B9 (folate) related dysfunctions
Reaction to candida
Vitamin B12 related dysfunctions
Mitochondrial dysfunction
Central hormonal dysfunction (T3, TRH, Serotonin, IGF-1, BDNF etc)
Inflammatory events raising IL6 (e.g. slowly losing milk teeth)
Ion channel dysfunctions
Disturbed gut microbiota
Mitochondrial disease
Leaky Blood Brain Barrier (BBB) & leaky gut
etc …
etc…



The thing to remember is that while the some of the above may be relevant to most people exhibiting “autism”, many will be irrelevant to any one person.  So in many people candida, gluten and disturbed gut microbiota are not an issue at all, but in a small number one may be.

I think that some mild cases nowadays defined as autism are likely caused by just one of the secondary dysfunctions that may, on occasion, fade by themselves, or by dietary modification.


Resource Allocation

Since there will never be enough resources to go around, authorities have to prioritize where money is spent.  Do you start with the worse affected and then work down?  Do you invest the limited resources where the impact is greatest?

One thing we know for sure is that there will never be enough money and often those who complain the most, get the most resources.  Those without lawyers and parents who can write long letters get what is left.

If there was a severity scale, it could be used to better allocate resources and also to differentiate between those affected.

For example, you could say people rated > 30 should receive some ongoing financial support, or people < 10 do not need publicly funded services, or people > 50 need constant supervision, or people >70 cannot travel on the school bus without an assistant.  It is not rocket science.


Employment

You regularly hear about some big software company or another wanting to hire people with autism.  This further adds to the confusion of what autism is.  What they really mean is that they want people with a high IQ and autism 5/7.  So they have Asperger’s and have the occasional off-day, but nothing severe.  They are not going to throw the coffee jug at someone, or pee in the elevator.

The car wash where they hire people with “autism” is talking about the 30/40 type where everyone is glad that person is getting out of the house to work and in a loosely supervised environment, the odd behavioral “event” is acceptable.


Travel on Planes

You do hear horror stories about people with autism having tantrums on planes.  You could have a rule saying that people with autism peaking at 50 should have to notify the airline in advance, and then the pilot and crew are forewarned.  The airline can then make, and publish, its own policy of whether to accept such passengers.

Small children going berserk on a plane can be dealt with, but fully grown “children” may not be so easily controlled by their, then older, parents.


Conclusion

The better you can define a problem, the closer you are to a solution.  If other people use the same definition the easier it is to identify shared solutions.

Given the complex nature of autism and the huge numbers of people affected, it should be possible to do much better, so that similar clusters can be identified and people can then be more accurately treated.  As it stands today what might help 5% of people is tried on 100% and then, after a few failures, people give up.  We need to know more about those 5%; that applies to all the therapies that do seem to help some people. 

No fancy genetic testing is required to grade severity of autism and it is the most obvious place to start.

Change in severity of autism can really tell you a lot.

As usual, I should add, I do not expect any of this to happen.





Saturday 12 September 2015

“Why Most Published Research Findings Are False” or “Much of the scientific literature, perhaps half, may simply be untrue”






Regular readers of this blog, and the small number of other autism science blogs, will have noticed how often research findings are contradictory.  In autism there is often a good reason why things are contradictory, because in some of the underlying dysfunctions both too much, or too little, (hyper or hypo) both lead to “autism”.     

Take the relatively simple case of GI problems in autism; estimates of prevalence range from 9 to 91%.  Such a variation is of course absurd and on the basis of which study you choose to quote, you can make whatever case you want.
   
Given that autism is not a single disease like say rheumatic fever, another very odd inflammatory disease, it makes anything very much harder to prove.

In the wider world of medical research there is an ongoing debate about research studies in general.  Most of this research is in much simpler types of disease, where you can accurately include in your trial only people with the same single biological dysfunction.

It has been suggested recently in the Lancet, one of the world’s top medical journals, that perhaps as much of half of the findings in research are untrue.



   
The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness. As one participant put it, “poor methods get results”. The Academy of Medical Sciences, Medical Research Council, and Biotechnology and Biological Sciences Research Council have now put their reputational weight behind an investigation into these questionable research practices. The apparent endemicity of bad research behaviour is alarming. In their quest for telling a compelling story, scientists too often sculpt data to fit their preferred theory of the world. Or they retrofit hypotheses to fit their data. Journal editors deserve their fair share of criticism too. We aid and abet the worst behaviours. Our acquiescence to the impact factor fuels an unhealthy competition to win a place in a select few journals. Our love of “significance” pollutes the literature with many a statistical fairy-tale. We reject important confirmations. Journals are not the only miscreants. Universities are in a perpetual struggle for money and talent, endpoints that foster reductive metrics, such as high-impact publication. National assessment procedures, such as the Research Excellence Framework, incentivise bad practices. And individual scientists, including their most senior leaders, do little to alter a research culture that occasionally veers close to misconduct.
Can bad scientific practices be fixed? Part of the problem is that no-one is incentivised to be right. Instead, scientists are incentivised to be productive and innovative. Would a Hippocratic Oath for science help? Certainly don't add more layers of research red-tape. Instead of changing incentives, perhaps one could remove incentives altogether. Or insist on replicability statements in grant applications and research papers. Or emphasise collaboration, not competition. Or insist on preregistration of protocols. Or reward better pre and post publication peer review. Or improve research training and mentorship. Or implement the recommendations from our Series on increasing research value, published last year. One of the most convincing proposals came from outside the biomedical community. Tony Weidberg is a Professor of Particle Physics at Oxford. Following several high-profile errors, the particle physics community now invests great effort into intensive checking and re-checking of data prior to publication. By filtering results through independent working groups, physicists are encouraged to criticise. Good criticism is rewarded. The goal is a reliable result, and the incentives for scientists are aligned around this goal. Weidberg worried we set the bar for results in biomedicine far too low. In particle physics, significance is set at 5 sigma—a p value of 3 × 10–7 or 1 in 3·5 million (if the result is not true, this is the probability that the data would have been as extreme as they are). The conclusion of the symposium was that something must be done. Indeed, all seemed to agree that it was within our power to do that something. But as to precisely what to do or how to do it, there were no firm answers. Those who have the power to act seem to think somebody else should act first. And every positive action (eg, funding well-powered replications) has a counterargument (science will become less creative). The good news is that science is beginning to take some of its worst failings very seriously. The bad news is that nobody is ready to take the first step to clean up the system.


Ten years ago John Ioannidis, a well-known Professor of Medicine now at Stanford, published a much more complex paper saying essentially the same thing.  That paper, below, was recently highlighted to me by one reader of this blog, who is involved in such research.
  




Conclusion
  
Since modern medicine, and indeed some autism therapy, is all about being “evidence based”, this does pose a big problem.

When the experts are telling us not to trust the evidence, what/who do you trust?

Getting into debates about almost anything to do with autism, with anyone, usually gets you nowhere at all.  Even the most basic points are disputed. This is at least one thing that people can agree on.


In the end it comes down to your own experience and judgement; I hope it is good.

In spite of all its shortcomings, I continue to marvel at how easy it is to access what you want from the vast amount of accumulated research, draw your own conclusions and act on them. I wish more people did the same.







Tuesday 8 September 2015

Time for a new generation of Autism “Experts”?






Farewell to Pingu


I usually succeed in keeping to the science in this blog and refrain from sharing my other wider opinions.  Today I slipped up.

Rather like James Simons, founder of the Simons Foundation, I do not have a high opinion of many supposed experts, particularly when it comes to autism.

Autism is often a backwater, where “academics” can still write the occasional quasi-scientific paper on some touchy-feely aspect that they consider important and make a name for themselves.  On the back of this, they can advocate for their perception of autism and often encourage ever-wider diagnosis in people who are less and less severely affected.

So far this is fine; we are all entitled to have our own opinions, so no comments on Autism Speaks, Autism One, or the various National Autism Societies. They all have the best intentions.

I should highlight the Simons Foundation and the UC Davis MIND Institute as being excellent scientific sources of objective information.

The only reason for today’s post is the comment made by someone who might be seen as the United Kingdom’s top autism expert, Professor Simon Baron-Cohen, Director of Cambridge University's Autism Research Centre. With such a tittle, he should set a high standard.





"We're not looking for a cure  … its part of their genetic and neurological make up," said Professor Simon Baron-Cohen, director of the Autism Research Centre at Cambridge University and vice-president of the National Autistic Society.

And …

“Children with Autism wait on average about three and a half years to get their diagnosis," Mr Baron-Cohen said.



It may come as a surprise to the Professor, but Parkinson’s disease is also a complex condition with a complex genetic element.  

Numerous very bright researchers are working to defeat Parkinson’s disease and, I am informed, that they are quite likely to achieve this end.

They set out to find a cure; they may indeed fall short and just find an effective therapy.

Imagine athletes starting a race, they all aim for gold.  By aiming for first place you might just come 5th, but if you did not train for gold you would come last.

As for the Professor’s comment that people in the UK wait over three years for an autism diagnosis, this is not strictly true and is scaremongering.  People with what used to be autism, i.e. classic autism, Kanner’s autism or autistic disorder go to the front of the assessment queue and get diagnosed for free within a few months.  Some parents keep going back for a second, third, fourth, fifth opinion until they get the result they want; this takes years. 

There is of course nothing to stop someone in the UK paying themselves for the assessment and so waiting a matter of weeks; after all they would happily pay to have someone fix their washing machine.

The UK consultant neurodevelopmental pediatrician, who diagnosed my son, told us at the time that a multidisciplinary assessment is generally not needed and that she can see almost immediately if a 3-4 year old has autism.  With what I now know, I would have to agree with her 100%; to the trained eye it is obvious.  

There are numerous milder dysfunctions that can affect children and there is an ever growing raft of observational diagnoses.  These diagnoses are all highly subjective and some really could be simplified to “I DON’T KNOW”  (PDD NOS = Pervasive Developmental Disorder Not Otherwise Specified).  I rather liked IED = Intermittent Explosive Disorder.

In many cases the troubling symptom in these milder dysfunctions is “just” anxiety.  If the anxiety is severe enough to need treatment, why not try one of the safe (i.e. not Prozac) drugs? There are numerous existing treatments (Propranolol for example) for children with anxiety and some interesting new ones (Baclofen).

Then we would be left with:-

Autism, a disabling developmental disorder diagnosed in early childhood.  Following its diagnoses, based on simple observational/behavioral criteria, a biological diagnosis of the underlying dysfunctions should be sought.  A small minority of these dysfunctions are substantially curable.  Some dysfunctions in the majority of the remaining children are, to a meaningful extent, treatable today.

Having treated what is treatable, use behavioral therapy.

Unable to contribute to finding cures/therapies for the underlying biological dysfunctions, the Professor and many like him have sought to widen the scope of “autism” and diagnose ever more people.  The latest idea being the Broad(er) Autism Phenotype (BAP), where you diagnose almost anyone as a teeny tiny bit autistic.

Now everyone from Nikola Tesla to Fieldmarshal Montgomery is supposed to have been autistic.  Both did rather well for themselves for someone with a disability.

This “mild” autism is extremely subjective, which is why so many assessors will not diagnose it, and so yes, if you keep going for several years you may find someone to tell you that you have “autism”.  But then what?  There are no cures or therapies, apparently.  There are these supposed “services” which are available on diagnosis, depending where you live.

There are indeed valuable services for people with severe autism, like speech therapy, occupational therapy and behavioral therapy.  These are not going to help much with mild autism.

The mother of the child in the above BBC interview said her child is much better now because “he is on the right (anxiety) medication” and is in a school with small classes.  He had previously been given all sorts of diagnoses, Tourette syndrome, OCD etc. in multiple earlier assessments.

Why not take an anxiety medication if you had OCD, or Tourette’s?  Just google it.  Was the doctor only willing to prescribe an anxiety drug with an autism diagnosis?

The key was treating the anxiety and being in a small class at school.  Is that really “autism”?

Many children who are different, in one way or the other, struggle in large classes and many of them also get bullied, sometimes even by the teacher.  By all means call it Asperger’s, but please do not call it autism.

Yes, the Professor would say that autism is a spectrum.  This really means he has no clue what is the underlying biological dysfunction, so let’s call it all “autism” and be done with it.  “Autism” is in fact just a name for almost anything that goes mildly or severely wrong neurologically, in the first few years of life. 

Once you are a teenager, if a new unknown dysfunction occurs, it gets new labels: - schizophrenia, bipolar etc.  These are also just observational diagnoses and within them are numerous different genetic and environment causes, some of which are treatable, if you care to look.


Other Experts

It is not just the Professor; you will come across numerous “local experts” perpetuating misunderstandings regards autism.  Like the dedicated Principal of the autism special school explaining that some of her kids have such terrible anxiety that their stomachs are tied in knots and they have severe GI problems.  Anxiety certainly does not help, but we actually know much about reflux/GERD in autism and the more serious IBS/IBD/ulcerative colitis.  We even know the mechanism that may explain why reflux/GERD is comorbid with autism, it is called mGluR5.

On the subject of ulcerative colitis and autism, just because a certain Dr Wakefield highlighted this link, it is widely assumed to be a falsehood.  The literature is strewn with links between ASD and ulcerative colitis.  I have an anecdote of my own.  One of the few people I hear about with Asperger’s, where we live, was first diagnosed with ulcerative colitis, then followed the Asperger’s diagnosis, and now he needs part of his intestines removed.   This could have been treated years earlier and then there would be no need for surgery now and years of trouble at school could have been avoided.


Clever Scientists

What is needed are hard-core clever scientists, not soft-hearted touchy feely Psychologists. (Apologies to those forward looking Psychologists amongst you, who keep updated by reading the literature)

I could not agree more with James Simons and his Foundation, who choose to fund Nobel Laureates and future Nobel Laureates.  Hopefully, they do actually aim to find cures.  It may take a hundred years, but along the way there will be numerous therapies to improve outcomes in the meantime.

Some of these therapies for specific causes of “autism” already exist.  They are in the literature, but I guess Baron-Cohen does not read it.

Perhaps a little shocking is that even though the Professor is not a medical doctor and so has no medical experience of treating people with autism, he was the 2012 Chair of the National Institute for Health and Care Excellence (NICE) Guideline Development Group for adults with autism.  This is advice that is given to doctors in the UK on how to treat autism.  Not surprisingly, NICE guidelines to doctors in the UK actually tell them not to bother, core autism is not medically treatable.   

In many areas of health, like asthma, the NICE treatment guidelines are excellent and a great resource for clinicians and patients.

How can you attend the top universities, albeit not in medicine, work 25 years in  the field of autism research, travel to all those nice conferences, even edit an autism journal and not have realized/discovered that it is treatable? It is almost criminally negligent.  If cases of autism are treatable, they are potentially preventable and, if caught early enough, potentially reversible.   

If you want a warm feeling, don’t campaign for “Autism Awareness” or wider “Autism Diagnosis”, campaign for free detailed metabolic testing, genetic testing and MRIs (with MR spectroscopy) for all people diagnosed under five with autism (at their first assessment!).

By the way, I have no doubt that many of the highly intelligent researchers who get funding from the Simons Foundation would also have struggled in their childhood had they been in large classes, in non-selective, State-funded, primary schools.  


A wake up call

It is not just me claiming that most types of autism are, to varying degrees, treatable today.

There are a growing number of readers of this blog who have found the same. Most are regular parents, who current “Experts” would totally ignore, but some are actually doctors, medical researchers, and even Professors of Medicine.

If an amateur, with a blog, can figure out usable therapies from the literature, we really do need some new Experts, and then NICE will need to rewrite their guidelines.