Keeping ahead of the curve in Autism (and Pitt Hopkins syndrome) treatment - the placebo effect, clinical trials, and a promising case study

Since AI is a trending tool in this blog, I decided to let ChatGPT rewrite today's post. It did rather strip out the science bits.  It added the "don't wait for permission at the end"—a little cheeky, I think. It does like to use dashes.

 

Keeping out in front of the pack is not always easy

Today’s post highlights a compelling new case study—one that turns theoretical research into a real therapy.

About time too! That was my reaction when a reader sent me the paper.

This case study reports on the repurposing of a cheap, well-known drug—Nicardipine—to treat Pitt Hopkins syndrome (PTHS). The drug had already shown promise in earlier mouse models.

So why aren’t we doing this more often? Because the system misunderstands risk.

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What About the Risk?

When it comes to trying new treatments, people often fixate on the risk of the therapy itself. But that’s only half the equation. The risk of doing nothing is often much greater—especially in autism.

Most conventional drug repurposing therapies pose minimal long-term risk. Things change only when you start injecting compounds or using untested chemicals. But even then, there’s surprisingly little harm on record.

Only one death has ever been clearly attributed to a therapy for autism:

A 5-year-old autistic boy from the UK died in the US while undergoing chelation therapy. The wrong form of EDTA—disodium EDTA instead of calcium EDTA—was used. The result was fatal hypocalcemia-induced cardiac arrest. The doctor administering the therapy didn’t understand the pharmacology.

Lesson: Always read the label.

Meanwhile, the risk of death from untreated autism is well established:

• In severe autism, common causes include drowning, accidents, and seizures.
• In milder cases, the biggest risk is suicide.

Another overlooked danger, mentioned previously in this blog, is polydipsia—excessive water drinking—which can cause hyponatremia (low blood sodium), leading to seizures, coma, and even death.

Bottom line?

The risks from untreated autism far exceed the risks from science-based, carefully applied therapies.

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The Nicardipine Case Study

A newly published study builds on promising mouse results and shows real benefit in a young child with PTHS. The drug used—Nicardipine—has been around since 1988 and is commonly prescribed to older adults for high blood pressure or angina.

🔗 Read the case study

Highlights:

• Pitt Hopkins syndrome involves loss of function in the TCF4 gene, leading to overactivity of Nav1.8 sodium channels in neurons.
• Nicardipine inhibits Nav1.8, making it a logical therapy.
• In this case study, the child received oral nicardipine for 7 months (0.2–1.7 mg/kg/day).
• Result: Mild to moderate improvement in all developmental areas, and reduced restlessness.
• No significant side effects reported.

It’s not a magic bullet—but it’s a start.
Used as part of polytherapy, this could become a powerful tool for treating PTHS.

And there’s more coming: Vorinostat, another potential therapy, is entering human trials.

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Why Don’t More Therapies Get Adopted?

A recent paper by Antonio Hardan sheds light on this. He’s the researcher who showed that the OTC antioxidant NAC benefits many with autism, and later explored the hormone vasopressin.

This time, he tackled the placebo effect—a real barrier in autism research.

🔗 Placebo Effect in Clinical Trials in Autism: Experience from a Pregnenolone Treatment Study

What They Did:

• A two-week placebo lead-in before the main trial.
• The drug tested was pregnenolone, a neurosteroid.
• They used parent-reported ABC-I scores to measure irritability.

What They Found:

• A 30% reduction in irritability—just from placebo.
• Also improvements in lethargy, hyperactivity, and repetitive speech.
• The placebo effect was strongest in the first two weeks, then plateaued.
• Clinician-rated scores (CGI) did not show this placebo response.

The Takeaway:

Parent expectations strongly shape trial results—at least in the early stages.
A placebo lead-in is a clever way to measure and filter out this noise.

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Early Adopters, Take Note

It pays to be ahead of the curve.

Some Pitt Hopkins parents are already trying nicardipine at home based on this case study. Good luck to them—I hope they find the right specialists and support.

Let’s not forget: the big autism trials of recent years—Bumetanide, Memantine, Balovaptan, Oxytocin, Arbaclofen—all officially “failed.”

But the drugs didn’t fail—the trial designs did.

Each of these drugs helped some individuals. The problem?
The trials weren’t structured to identify responder subgroups. We wasted time, money, and hope by not tailoring inclusion criteria more carefully.

Consider Trofinetide, the first FDA-approved drug for Rett syndrome (2023). It helps only 20% of patients, but was still approved.

I’d argue that Bumetanide has an even higher response rate in severe autism, particularly with intellectual disability—and that the best outcome measure is IQ, not a generalized autism scale.

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My Own Example: No Placebo Here

How do I know I wasn’t misled by the parental placebo effect?

Simple. No one knew I was trialing treatments—not even the teachers or therapists. That meant their feedback was objective and uninfluenced by my hopes.

My son Monty went from being unable to do basic subtraction at age 9, to later passing his externally graded IGCSE high school math exam.

Not bad for a therapy that mainstream medicine still ignores.

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Final Thoughts

• Drug repurposing is safe, smart, and often effective.
• The placebo effect is real—but it’s measurable and manageable.
• If we want progress in autism treatment, we need smarter trial designs, not just more of them.
• Being ahead of the curve isn’t risky—it’s essential.

💡 Stay informed, stay curious, and don’t wait for permission.

Thanks for the guest post, ChatGPT !!

One point to add to the risk assessment: by my estimation, each year in the US, around 200 to 300 people die from drowning, seizures, accidents, and suicides related to autism. In living memory, only one person has died as a result of visiting an autism doctor in the US and that death was entirely preventable.

Vorinostat, a potent HDAC inhibitor trialed in several autism models, was mentioned in the above post. Interestingly, there is a recent comment from a reader who finds it resolves 80% of his autism but only for about 2 hours. The half-life of this drug is about 2 hours. There are discussions on Reddit by people using it for autism, anxiety, PTSD etc. It is about 1,000 times more potent than HDAC inhibitors people typically might try at home. Perhaps there should be trials of micro-dosing Vorinostat? I think daily use of high-dose Vorinostat may not work well, due to side effects.  Human trials will soon inform us better. It is often older people who struggle with drug side effects, not children.  

Vorinostat may not only correct Differentially Expressed Genes (DEGs) but also:

• Increase synaptic plasticity
• Improve synaptic morphology (the shape and function of neuronal connections)
• Improve memory and cognition 

The main research interest is in single gene autisms, where one specific gene is under-expressed (eg Pitt Hopkins, Rett, Fragile-X etc) but the general ideas are equally applicable to broader autism. 

Genetic Mutations vs Differentially Expressed Genes (DEGs) in Autism

 

Genes make proteins and you need the right amount in the right place

at the right time.

I should start this post by confessing to not having carried out genetic testing on Monty, now aged 18 with autism.  When I did mention this to one autism doctor at a conference, I was surprised by her reply:- “ You did not need to.  Now there’s no point doing it”.

I got lucky and treated at least some of Monty’s Differentially Expressed Genes (DEGs) by approaching the problem from a different direction.

People do often ask me about what diagnostic tests to run and in particular about genetic testing.  In general, people have far too high expectations regarding such tests and assume that there will be definitive answers, leading to effective therapeutic interventions.

I do include an interesting example today where parent power is leading a drive towards an effective therapeutic intervention in one single gene type of autism.  The approach has been to start with the single gene that has the mutation and look downstream at the resulting Differentially Expressed Genes (DEGs). The intervention targets one of the DEGs and not the mutated gene itself.

This is a really important lesson.

It can be possible to repurpose existing drugs to treat DEGs quite cheaply.  Many DEGs encode ion channels and there are very many existing drugs that affect ion channels.

Entirely different types of autism may share some of the same DEGs and so benefit from the same interventions.

 

Genetic Testing 

Genetic testing has not proved to be the holy grail in diagnosing and treating autism, but it remains a worthwhile tool at a population level (i.e. maybe not in your specific case).  What matters most of all are Differentially Expressed Genes (DEGs), which is something different.

A paper was recently published that looked into commercially available genetic testing.  Its conclusion was similar to my belief that you risk getting a “false negative” from these tests, in other words they falsely conclude that there is no genetic basis for the person’s symptoms of autism. 

 

Brief Report: Evaluating the Diagnostic Yield of Commercial Gene Panels in Autism

Autism is a prevalent neurodevelopmental condition, highly heterogenous in both genotype and phenotype. This communication adds to existing discussion of the heterogeneity of clinical sequencing tests, “gene panels”, marketed for application in autism. We evaluate the clinical utility of available gene panels based on existing genetic evidence. We determine that diagnostic yields of these gene panels range from 0.22% to 10.02% and gene selection for the panels is variable in relevance, here measured as percentage overlap with SFARI Gene and ranging from 15.15% to 100%. We conclude that gene panels marketed for use in autism are currently of limited clinical utility, and that sequencing with greater coverage may be more appropriate.

 

To save time and money, the commercial gene panels only test genes that the company defines as autism genes.  There is no approved list of autism genes. 

You have more than 20,000 genes and very many are implicated directly, or indirectly, in autism and its comorbities. To be thorough you need Whole Exome Sequencing (WES), where you check them all.  

There are tiny mutations called SNPs ("snips") which you inherit from your parents; there are more than 300 million known SNPs and most people will carry 4-5 million.  Some SNPs are important but clearly most are not.  Some SNPs are very common and some are very rare. 

Even WES only analyses 2% of your DNA, it does not consider the other 98% which is beyond the exome.  Whole Genome Sequencing (WGS) which looks at 100% of your DNA will be the ideal solution, but at some time in the future.  The interpretation of WES data is often very poor and adding all the extra data from WGS is going to overwhelm most people involved. 

Today we return to the previous theme of treating autism by treating the downstream effects caused by Differentially Expressed Genes (DEGS).

Genetics is very complicated and so people assume that is must be able to provide answers. For a minority of autism current genetics does indeed provide an answer, but for most people it does not.

Early on in this blog I noted so many overlaps between the genes and signaling pathways that drive cancer and autism, that is was clear that to understand autism you probably first have to understand cancer; and who has time to do that!

Some people’s cancer is predictable. Chris Evert, the American former world No. 1 tennis player, announced that she has ovarian cancer.  Her sister had exactly the same cancer.  Examining family history can often yield useful information and it is a lot less expensive that genetic testing.  Most people’s cancer is not so predictable; sure if you expose yourself to known environmental triggers you raise its chances, but much appears to be random.  Cancer, like much autism, is usually a multiple hit process. Multiple events need to occur and you may only need to block one of them to avoid cancer. We saw this with a genetic childhood leukemia that you can prevent with a gut bacteria. 

Learning about Autism from the 3 Steps to Childhood Leukaemia

What is not random in cancer are the Differentially Expressed Genes (DEGs).

We all carry highly beneficial tumor suppressing genes, like the autism/cancer gene PTEN.  You would not want to have a mutation in one of these genes.

What happens in many cancers is that the individual carries two good copies of the gene like PTEN, but the gene is turned off. For example, in many people with prostate cancer, the tumor suppressor gene PTEN is turned off in that specific part of the body.  There is no genetic mutation, but there is a harmful Differentially Expressed Gene (DEG). If you could promptly turn PTEN expression back on, you would suppress the cancer.

Not surprisingly, daily use of drugs that increase PTEN expression is associated with reduced incidence of PTEN associated cancer.  Atorvastatin is one such drug.

 

DEGs are what matter, not simply mutations

 

In many cases genetic mutations are of no clinical relevance, we all carry several on average.  In some cases they are of immediate critical relevance.  In most cases mutations are associated with a chance of something happening, there is no certainty and quite often further hits/events/triggers are required.

A good example is epilepsy. Epilepsy is usually caused by an ion channel dysfunction (sodium, potassium or calcium) that is caused by a defect in the associated gene. Most people are not born with epilepsy, the onset can be many years later.  Some parents of a child with autism/epilepsy carry the same ion channel mutation but remain unaffected. 

 

Follow the DEGs from a known mutation 

There is a vanishingly small amount of intelligent translation of autism science to therapy, or even attempts to do so.  I set out below an example of what can be done.

 

Pitt Hopkins (Haploinsufficiency of TCF4) 

The syndrome is caused by a reduction in Transcription factor 4, due to mutation in the TCF4 gene.  One recently proposed therapy is to repurpose the cheap calcium channel blocker Nicardipine. Follow the rationale below.

 

↓  means down regulated

↑ means up regulated

1.     Gene/Protein TCF4 (Transcription Factor 4) ↓↓↓↓

2.     Genes SCN10a  ↑↑    KCNQ1 ↑↑

3.     Encoding ion channels  Na_v1.8   ↑↑     K_v7.1   ↑↑

4.     Repurpose approved drugs as inhibitors of K_v7.1 and Na_v1.8 

5.     High throughput screen (HTS) of 1280 approved drugs.

6.     The HTS delivered 55 inhibitors of K_v7.1 and 93 inhibitors of Na_v1.8

7.     Repurposing the Calcium Channel Inhibitor Nicardipine as a Na_v1.8 inhibitor 

           

The supporting science: 

Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1

  

Highlights

•TCF4 loss of function alters the intrinsic excitability of prefrontal neurons 

•TCF4-dependent excitability deficits are rescued by SCN10a and KCNQ1 antagonists 

•TCF4 represses the expression of SCN10a and KCNQ1 ion channels in central neurons 

•SCN10a is a potential therapeutic target for Pitt-Hopkins syndrome

  

Na_v1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene

K_v7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the KCNQ1 gene.

  

Transcription Factor 4 (TCF4) is a clinically pleiotropic gene associated with schizophrenia and Pitt-Hopkins syndrome (PTHS).  

SNPs in a genomic locus containing TCF4 were among the first to reach genome-wide significance in clinical genome-wide association studies (GWAS) for schizophrenia  These neuropsychiatric disorders are each characterized by prominent cognitive deficits, which suggest not only genetic overlap between these disorders but a potentially overlapping pathophysiology.

We propose that these intrinsic excitability phenotypes may underlie some aspects of pathophysiology observed in PTHS and schizophrenia and identify potential ion channel therapeutic targets.

Given that TCF4 dominant-negative or haploinsufficiency results in PTHS, a syndrome with much more profound neurodevelopmental deficits than those observed in schizophrenia, the mechanism of schizophrenia risk associated with TCF4 is presumably due to less extreme alterations in TCF4 expression at some unknown time point in development

The pathological expression of these peripheral ion channels in the CNS may create a unique opportunity to target these channels with therapeutic agents without producing unwanted off-target effects on normal neuronal physiology, and we speculate that targeting these ion channels may ameliorate cognitive deficits observed in PTHS and potentially schizophrenia.

 

 

Disordered breathing in a Pitt-Hopkins syndrome model involves Phox2b-expressing parafacial neurons and aberrant Nav1.8 expression

Pitt-Hopkins syndrome (PTHS) is a rare autism spectrum-like disorder characterized by intellectual disability, developmental delays, and breathing problems involving episodes of hyperventilation followed by apnea. PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (Tcf4). Despite the severity of this disease, mechanisms contributing to PTHS behavioral abnormalities are not well understood. Here, we show that a Tcf4 truncation (Tcf4^tr/+) mouse model of PTHS exhibits breathing problems similar to PTHS patients. This behavioral deficit is associated with selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO₂/H⁺. We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in Tcf4^tr/+ mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS. 

 

Repurposing Approved Drugs as Inhibitors of K_v7.1 and Na_v1.8 To Treat Pitt Hopkins Syndrome

Purpose:

Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels K_v7.1 and Na_v1.8 which triggers an increase in after-hyperpolarization and altered firing properties.

Methods:

We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (K_V7.1) or HEK293 (Na_v1.8) cells and the HTS used either ⁸⁶Rb⁺ efflux (K_V7.1) or a FLIPR assay (Na_v1.8).

Results:

The HTS delivered 55 inhibitors of K_v7.1 (4.2% hit rate) and 93 inhibitors of Na_v1.8 (7.2% hit rate) at a screening concentration of 10 μM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Na_v1.8.

Conclusions:

This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Na_v1.8, as there are currently no approved treatments for this rare disorder.

  

Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Na_v1.8 inhibitor in vivo for Pitt Hopkins Syndrome

Individuals with the rare genetic disorder Pitt Hopkins Syndrome (PTHS) do not have sufficient expression of the transcription factor 4 (TCF4) which is located on chromosome 18. TCF4 is a basic helix-loop-helix E protein that is critical for the normal development of the nervous system and the brain in humans. PTHS patients lacking sufficient TCF4 frequently display gastrointestinal issues, intellectual disability and breathing problems. PTHS patients also commonly do not speak and display distinctive facial features and seizures. Recent research has proposed that decreased TCF4 expression can lead to the increased translation of the sodium channel Na_v1.8. This in turn results in increased after-hyperpolarization as well as altered firing properties. We have recently identified an FDA approved dihydropyridine calcium antagonist nicardipine used to treat angina, which inhibited Na_v1.8 through a drug repurposing screen.

 

All of the above was a parent driven process.  Well done, Audrey!

Questions remain.

Is Nicardipine actually beneficial to people with Pitt Hopkins Syndrome? Does it matter at what age therapy is started? What about the K_v7.1 inhibitor?

 

Conclusion 

Genetics is complicated, ion channel dysfunctions are complicated; but just a superficial understanding can take you a long way to understand autism, epilepsy and many other health issues.

There is a great deal in this blog about channelopathies/ion channel dysfunctions.

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

Almost everyone with autism has one or more channelopathies. Most channelopathies are potentially treatable.

Parents of children with rare single gene autisms should get organized and make sure there is basic research into their specific biological condition.  They need to ensure that there is an animal model created and it is then used to screen for existing drugs that may be therapeutic.  I think they also need to advocate for gene therapy to be developed.  This all takes years, but the sooner you start, the sooner you will make an impact.

Very likely, therapies developed for some single gene autisms will be applicable more broadly.  A good example may be the IGF-1 derivative Trofinetide, for girls with Rett Syndrome. IGF-1 (Insulin-like growth factor 1) is an important growth factor that is required for proper brain development. In the brain, IGF-1 is broken down into a protein fragment called glypromate (GPE). Trofinetide is an orally available version of GPE.

The MeCP2 protein controls the expression of several genes, such as Insulin-like Growth Factor 1 (IGF1), brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate (NMDA).  All three are implicated in broader autism. 

https://rettsyndromenews.com/trofinetide-nnz-2566/

In girls with Rett Syndrome the genetic mutation is in the gene MeCP2, but one of the key DEGs (differentially expressed genes) is the FXYD1; it is over-expressed. IGF-1 supresses the activity of FXYD1 and hopefully so does Trofinetide.  Not so complicated, after all!

Medicine is often driven by the imperative to do no harm.

In otherwise severely impaired people, perhaps the imperative should be to try and do some good.

In medicine, time is of the essence; doctors in the ER can be heard to say "Stat!", from the Latin word for immediately, statim.  

How about some urgency in translating autism science into therapy? But then, what's the hurry? Why rock the boat?

On an individual basis, much is already possible, but you will have to do most of the work yourself - clearly a step too far for most people.