Fibromyalgia and, perhaps, What Happened to the Missing Females with Autism

This post is about a condition about Fibromyalgia, a condition that affects 2-4% of the population. It affects women eight times more often than men, but it does, bizarrely, appear to be related to autism and is seen by some as a comorbidity.  I would go further and suggest that perhaps I have stumbled upon the missing females with autism. 

When you look at all the proposed drugs and supplements, there is a 90% overlap between the two conditions, even things like low dose naltrexone and flavonoids, like quercetin, crop up.

As we have seen earlier in this blog, autism is a disease related to the auto-immune system and inflammatory pathways.  There are many other diseases with similar origins, one example being arthritis.  Fibromyalgia tends to get lumped together with arthritis.  Families with autism present tend to have higher levels of arthritis and there are even some overlapping therapies, such as vagus nerve stimulation.

Fibromyalgia caught my attention, because it seems to be uncannily closely related to autism, but there are some distinct differences.  Classic “full-on” fibromyalgia is a disease about pain, whereas in autism people tend to have a high pain threshold.  Nonetheless, if you Google “Fibromyalgia with Autism” you will find no shortage of people suffering from both and pondering a connection.

Comorbidities are interesting, because they can indicate possible new therapies.  The people researching fibromyalgia are not generally the same people as the autism researchers.  The underlying pathologies though are very likely overlapping, even though neither is fully understood.

Fibromyalgia is neither degenerative nor curable, but it is treatable.

Here is a link to an article by a US doctor who came to the same conclusion.  (The article itself is not great)

Symptoms of Fibromyalgia

We can split these into two categories, pain-related and pain-unrelated.  In the case of autism we should look at pain-unrelated, but in the case of relatives we should look at both.  You will probably be able to diagnose a non-autistic family member with symptoms of this syndrome.

 
Pain-related:-

·        Widespread muscle pain and joint pain, the effects of these symptoms varies from person to person and from day to day.  Many people have flare-ups.  There are specific pain areas, and these are shown below:

 

·        Long-term studies suggest that it is not progressive, it does not cause permanent damage to your muscles, bones, joints or organs.

 

Pain-unrelated:-

This is a long list and typically only some will apply to any one person:-

·        Cognitive dysfunction, such as:

o   Difficulty following directions when driving

o   Losing your train of thought in the middle of a sentence

o   Difficulty paying attention

o   Memory problems

o   Difficulty expressing ideas in words

·        Depression, anxiety, irritability,  overreaction, anger outbursts, unpredictable mood swings, phobias and personality changes

·        Difficulty swallowing

·        Headaches

·        Restless leg syndrome

·        Sensitivity to the cold, and/or having cold hands and feet

·        Palpitations

·        Chest pain and costochondritis    

·        Sensitivity to light and noise intolerance.

·        Clumsy walking, dropping things

·        Hair loss

Fibromyalgia vs autism

There are some other similarities/differences with autism.

·        It often takes years to get a diagnosis and some doctors do not believe the condition exists

·        There is a specialist doctor that should know about it – the Rheumatologist, although Neurologists sometimes get involved

·        It is not curable, but it is treatable

·        It is usually diagnosed on very subjective measures

·        A blood test does now exist in the US  - the FM/a test  

The firm with the blood test is called, interestingly, “Epigenetics”.  If you make a blood test for Fibromyalgia, there is a good chance that the same researchers could develop one for autism.  They are measuring the level of pro-inflammatory cytokines.

The test is expensive, about $750.  Who knows how accurate the result is; they claim 99%.

In the UK, the National Health Service maintains that no test for Fibromyalgia exists.

A Neuro-immuno-endocrine disorder

Evidence exists that fibromyalgia is a neuro-immuno-endocrine disorder. Elevations in substance P, IL-6 and IL-8 as well as corticotropin-releasing hormone have been found in the cerebral spinal fluid of fibromyalgia suffering individuals. Increased numbers of mast cell numbers have been found in skin biopsies of some individuals with fibromyalgia.

Theoharides, who I have quoted extensively in early post on mast cells and autism, appears here too:- 

Fibromyalgia--new concepts of pathogenesis and treatment.

Lucas HJ, Brauch CM, Settas L, Theoharides TC.

Abstract

Fibromyalgia (FMS) is a debilitating disorder characterized by chronic diffuse muscle pain, fatigue, sleep disturbance, depression and skin sensitivity. There are no genetic or biochemical markers and patients often present with other comorbid diseases, such as migraines, interstitial cystitis and irritable bowel syndrome. Diagnosis includes the presence of 11/18 trigger points, but many patients with early symptoms might not fit this definition. Pathogenesis is still unknown, but there has been evidence of increased corticotropin-releasing hormone (CRH) and substance P (SP) in the CSF of FMS patients, as well as increased SP, IL-6 and IL-8 in their serum. Increased numbers of activated mast cells were also noted in skin biopsies. The hypothesis is put forward that FMS is a neuro-immunoendocrine disorder where increased release of CRH and SP from neurons in specific muscle sites triggers local mast cells to release proinflammatory and neurosensitizing molecules. There is no curative treatment although low doses of tricyclic antidepressants and the serotonin-3 receptor antagonist tropisetron, are helpful. Recent nutraceutical formulations containing the natural anti-inflammatory and mast cell inhibitory flavonoid quercetin hold promise since they can be used together with other treatment modalities.

Treatment

Classic treatment involves tricyclic antidepressants, which are actually very closely related to the early antihistamine drugs. 

Even though low brain serotonin is a feature of the disease, counter-intuitively, it has been found that serotonin-3 receptor antagonists are effective; this is the opposite of what was expected.  Tropisetron is a favoured antagonist, but there are several others.  Tropisetron is also a α₇-nicotinic receptor agonist, which you may recall, I highlighted as interesting in posts on the cholinergic system and autism.

Oral treatment of fibromyalgia with tropisetron given over 28 days: influence on functional and vegetative symptoms, psychometric parameters and pain.

This blog is about autism, so let us go back to a previous paper I looked at.

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

 

In that paper tropisetron is put forward as a potential autism treatment.

 

10.1.2 ᾳ7 nAChRs

It is possible to use ᾳ7 nAChR agonists to treat neuroinflammation in ASD. There is strong evidence that activation of the ᾳ7 nAChR expressed on monocytes and macrophage, by inhibiting NF-kappaB nuclear translocation, suppresses cytokine release by them, and that this cholinergic anti-inflammatory pathway that provides a bidirectional link between the nervous and immune system, inhibits the innate immune response. Hence, a reasonable case can be made for the use of ᾳ7 nAChR agonists to treat neuroinflammation in ASD.

A second candidate drug, Tropisetron is a partial agonist of the ᾳ7 nAChR. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. In a clinical trial with 33 schizophrenic patients administration of tropisetron, without placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. In mice, the early postnatal period represents a critical time window essential for brain development. The administration of tropisetron from postnatal days 2-12

(P2-P12) in mice did not induce significant cognitive, schizophrenia-like or emotional alterations in tropisetron-treated animals as compared to controls, when tested in multiple behavioral assays.

 

It is the non-conventional treatments that overlap with autism, things like GH, IGF-1 and low dose naltrexone etc.  The interesting therapies relate to treating the non-pain symptoms. There are many such therapies and some have been used for decades, one or two may be interesting for autism; they may indeed be more effective in autism that in fibromyalgia.  There is even an overlap with therapies I am already investigating.

 

 

Melatonin for Kids with Autism, and indeed their Parents

I have long heard about kids with autism having sleeping problems; these range from difficulty falling asleep, waking frequently during the night and waking up very early in the morning.  The same problems apparently occur in ADHD.

I think some of the sleep related problems are behavioral in nature; some children with ASD live actually with less structure than typical kids.  Some kids with ASD do not get much physical exercise to tire them out by bed time.  

Having said all that, there does seem to be something else going on.

Long ago people found out that Melatonin, a hormone available cheaply without prescription in many countries, had a very positive effect on sleeping patterns.

What is also interesting, is the other properties of Melatonin and the other types of people who can benefit from it.  This does take us some way from our core theme of autism, towards treating cancer and other illnesses of older age.  I expect most my readers are parents of a child with ASD, well this time science has some news for you too.

What is Melatonin?

Melatonin is a hormone secreted by the Pineal Gland in the brain. It helps regulate other hormones and maintains the body's internal clock. The circadian rhythm is an internal 24-hour clock, that plays a critical role in when we fall asleep and when we wake up. When it is dark, your body produces more melatonin; when it is light, the production of melatonin drops. Being exposed to bright lights in the evening or too little light during the day can disrupt the body’s normal melatonin cycles.

Melatonin helps control the timing and release of female reproductive hormones. Some researchers also believe that melatonin levels may be related to aging.

Young children have the highest levels of night time melatonin. Researchers believe these levels drop as we age. Some people think lower levels of melatonin may explain why some older adults have sleep problems.

Melatonin has powerful antioxidant effects. Research suggests that it may help strengthen the immune system.

Melatonin is derived from serotonin. Serotonin levels in autism are often high in the blood, but can be low in the brain.  Serotonin cannot cross the blood brain barrier.  The Pineal Gland is inside the brain, but outside the blood brain barrier.

 

Dose Response

One clever study tried to establish the dose at which Melatonin had an effect on sleep.  It is interesting that they found the dosage was not correlated to weight.  The vast majority of drugs are dosed on how big you are, and often trials assume this to be the case.

Melatonin for Sleep in Childrenwith Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

Dose-response

All 24 children who completed study procedures obtained a satisfactory response (as defined above) to melatonin at doses between 1 mg and 6 mg. Seven children obtained a satisfactory response at 1 mg, 14 at 3 mg, and only 3 required 6 mg. The child’s age or weight was not associated with melatonin dose response. The mean age/weight (standard deviation) of children responding to 1 mg was 5.9 (1.9) years/26.4 (11.1) kg; and to 3 or 6 mg was 5.9 (2.3) years/25.4 (11.2) kg.

In effect you are treating a hormone deficiency, like any other.  Just as a small person may need more thyroid hormone than a very big person; the same appears to be true with Melatonin.

Much of the “specialist advice” from "doctors" on the web looks incorrect on this subject:-

Melatonin. This naturally occurring peptide released by the brain in response to the setting of the sun has some function in setting the circadian clock. It is available without prescription at most pharmacies and health food stores. Typically the dosage sizes sold are too large. Almost all of the published research on Melatonin is on doses of 1 mg or less, but the doses available on the shelves are either 3 or 6 mg. Nothing is gained by using doses greater than one milligram. Melatonin may not be effective the first night, so several nights' use may be necessary for effectiveness.

(this was advice for people with ADHD, which I regard as part of ASD)

 

Abnormal Melatonin Synthesis in ASD and in Parents

A surprising amount of work has been done looking at abnormalities in melatonin synthesis in both kids with ASD and their parents.  Hence the title of this post.

The low level of melatonin synthesis is acquired from one or more parent, who will probably also have a sleep disorder.  Not only that, but low melatonin is also linked to increased risk to some serious health conditions, more on that later. 

Abnormal Melatonin Synthesis in ASD

"In autism spectrum disorders (ASD), low melatonin levels have been reported by three independent groups,^13–15 but the underlying cause of this deficit and its relationship to susceptibility to ASD was unknown

the serotonin level was significantly higher in individuals with ASD (P=2×10⁻¹¹) and their parents (P=10⁻⁸) than in controls

 Our results confirm that low plasma melatonin concentration (half the mean of the control values) is a frequent trait in ASD patients, as observed in 65% of the patients tested, a proportion very similar (63%) to that previously reported by Tordjman et al.¹⁵ We show for the first time that abnormal melatonin levels are also present in the unaffected parents of ASD patients, suggesting a genetic origin. Indeed, the melatonin deficit observed in the patients was associated with low ASMT activity, suggesting that variations in the ASMT gene could be the cause of this deficit."

Effect of Hormone Supplementation on the Pineal Gland

If you start interfering with human hormones, you need to be aware of the possible consequences.  For example, a relatively common autism therapy in the US is to give thyroid hormones T4 and T3 to children who are not clinically hypothyroid.  Some parents report great improvements, but some comment that over time they have to increase the dosage.  This is because the feedback loops that control the thyroid gland are telling it to gradually shut down.  Over time, such a child might become entirely dependent on the T4/T3 tablets.

So, if you have a pineal gland that does not produce enough melatonin, what happens to it when you take supplements?  I do not think anyone can tell you with certainty.

There have been long term trials over a few years in sleep disorders.  When supplementation stops the sleep disorder returns.  Nothing bad was reported.

Natural release of melatonin is controlled by exposure to light and dark.  To what extent does this change when supplements are added?

To what extent to supplements interfere with other less well understood melatonin mechanisms?  

On balance, common sense would tell you to leave a fully functioning pineal gland well alone; but if you have an autistic child with a challenging sleep disorder, this would be suggest that the pineal gland needs some external help.  In an ideal world, your doctor would test the pineal gland function and check Melatonin levels were age appropriate.

Melatonin and Behaviours

Research in ADHD suggests that while Melatonin improves sleep disorders it does not improve behaviour.

Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. 

Abstract

OBJECTIVE:

To investigate the effect of melatonin treatment on sleep, behavior, cognition, and quality of life in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia.

METHOD:

A total of 105 medication-free children, ages 6 to 12 years, with rigorously diagnosed ADHD and chronic sleep onset insomnia participated in a randomized, double-blind, placebo-controlled trial using 3 or 6 mg melatonin (depending on body weight), or placebo for 4 weeks. Primary outcome parameters were actigraphy-derived sleep onset, total time asleep, and salivary dim light melatonin onset.

RESULTS:

Sleep onset advanced by 26.9 +/- 47.8 minutes with melatonin and delayed by 10.5 +/- 37.4 minutes with placebo (p < .0001). There was an advance in dim light melatonin onset of 44.4 +/- 67.9 minutes in melatonin and a delay of 12.8 +/- 60.0 minutes in placebo (p < .0001). Total time asleep increased with melatonin (19.8 +/- 61.9 minutes) as compared to placebo (-13.6 +/- 50.6 minutes; p = .01). There was no significant effect on behavior, cognition, and quality of life, and significant adverse events did not occur.

CONCLUSION:

Melatonin advanced circadian rhythms of sleep-wake and endogenous melatonin and enhanced total time asleep in children with ADHD and chronic sleep onset insomnia; however, no effect was found on problem behavior, cognitive performance, or quality of life.

 

The studies in autism indicate a different story; behaviours do improve.  After a good night’s sleep, most people’s behaviour improves; it would be odd if it did not.

I think this is another case of ADHD disorders being of a different magnitude to disorders further along the autistic spectrum.  

For the impact in autism, it best to read the studies; here is an excerpt from Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes:-

“The behavioral outcome measures that showed change with melatonin (e.g., attention-deficit hyperactivity, withdrawn, affective problems, stereotyped behaviors, compulsive behaviors) resemble that of prior work. The literature emphasizes that the behavioral construct of hyperactivity is affected by sleep disturbance—this had been documented in ASD populations (Goldman et al 2009; Mayes and Calhoun 2009) as well as typically developing children treated for obstructive sleep apnea (Chervin et al 2006). Other behavioral parameters which have been associated with poor sleep in children with ASD include repetitive behavior, including compulsive behavior, and oppositional and aggressive behavior, anxiety, depression, and mood variability (Malow et al 2006; Goldman et al, 2009; Mayes and Calhoun 2009). In an intervention study of parent education, hyperactivity and restricted behaviors showed improvements with treatment (Reed 2009).”

Strangely, when it came to parental stress, they found less impact:-

“Parenting stress, as measured by the Difficult Child Subscale, improved with treatment. We did not find improvement in the PSI parent-related domains (Parental Distress or Parent-Child Dysfunctional Interaction) suggesting that parental stress in autism is multifactorial and may not be addressed with a single intervention.”

 

Why is Melatonin so good for the CNS (Central Nervous System)?

It appears that Melatonin does some very useful things

·        It is an antioxidant/free radical scavenger

·        It stimulates the production of the body’s other key antioxidants

·        It inhibits the production of pro-oxidative enzymes

·        Protects nuclear and mitochondrial DNA

Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.

Abstract

This review briefly summarizes the multiple actions by which melatonin reduces the damaging effects of free radicals and reactive oxygen and nitrogen species. It is well documented that melatonin protects macromolecules from oxidative damage in all subcellular compartments. This is consistent with the protection by melatonin of lipids and proteins, as well as both nuclear and mitochondrial DNA. Melatonin achieves this widespread protection by means of its ubiquitous actions as a direct free radical scavenger and an indirect antioxidant. Thus, melatonin directly scavenges a variety of free radicals and reactive species including the hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide, peroxynitrite anion, and peroxynitrous acid. Furthermore, melatonin stimulates a number of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Additionally, melatonin experimentally enhances intracellular glutathione (another important antioxidant) levels by stimulating the rate-limiting enzyme in its synthesis, gamma-glutamylcysteine synthase. Melatonin also inhibits the proxidative enzymes nitric oxide synthase and lipoxygenase. Finally, there is evidence that melatonin stabilizes cellular membranes, thereby probably helping them resist oxidative damage. Most recently, melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce election leakage and the generation of free radicals. These multiple actions make melatonin a potentially useful agent in the treatment of neurological disorders that have oxidative damage as part of their etiological basis.

 

Why is Melatonin good for the Immune System?

It is known that Melatonin interacts with the immune system, but the mechanism is not fully understood yet.  As you see below, Melatonin is not just produced in the Brain, it is also sythesized by the immune system. 

A review of the multiple actions of melatonin on the immune system

Abstract

This review summarizes the numerous observations published in recent years which have shown that one of the most significant of melatonin's pleiotropic effects is the regulation of the immune system. The overview summarizes the immune effects of pinealectomy and the association between rhythmic melatonin production and adjustments in the immune system as markers of melatonin's immunomodulatory actions. The effects of both in vivo and in vitromelatonin administration on non-specific, humoral, and cellular immune responses as well as on cellular proliferation and immune mediator production are presented. One of the main features that distinguishes melatonin from the classical hormones is its synthesis by a number of non-endocrine extrapineal organs, including the immune system. Herein, we summarize the presence of immune system-synthesized melatonin, its direct immunomodulatory effects on cytokine production, and its masking effects on exogenous melatonin action. The mechanisms of action of melatonin in the immune system are also discussed, focusing attention on the presence of membrane and nuclear receptors and the characterization of several physiological roles mediated by some receptor analogs in immune cells. The review focuses on melatonin's actions in several immune pathologies including infection, inflammation, and autoimmunity together with the relation between melatonin, immunity, and cancer.

 

Anti-aging Treatment

There are all sorts of products and therapies put forward to an eager public to combat the aging process; melatonin is one of these products.   I think, in this case, they may very well have got is right.  Yet again, a drug for older people seems to be effective for kids with ASD. 

In anti-aging, one well known practitioner, Dr Pierpaoli, recommends:-

30-39 years of age             1.5mg at bedtime

40-49 years of age             1.5mg to 3mg at bedtime

50-74 years of age             3mg at bedtime

Above 75 years                   3mg to 6mg at bedtime

 

Other use of Melatonin, related to subjects covered in this blog

Melatonin appears to help in Alzheimer’s by interfering with Amyloid beta, which was covered in an earlier post.

Amyloids, APP, ADAM17 and Autism

Melatonin appears to reduce symptoms in irritable bowel symptom.

Melatonin has been used to treat cluster headaches.

Information for Parents

We have seen earlier in this post that parents of a child with ASD also tend to have a low level of Melatonin.  If you read the layperson’s guide from the University of Maryland, you will see that a low Melatonin level in women is linked to increased risk of breast cancer and in men an increased risk of prostate cancer. 

“Studies show that men with prostate cancer have lower melatonin levels than men without the disease. In test tube studies, melatonin blocks the growth of prostate cancer cells.”

“Laboratory experiments have found that low levels of melatonin stimulate the growth of certain types of breast cancer cells, while adding melatonin to these cells slows their growth”

Since Melatonin is a powerful antioxidant, this may just mean that breast cancer and prostate cancer are linked to oxidative stress and so Melatonin is being used up; but it might also mean that Melatonin is somehow protective.

I read a long time ago that NAC improves outcomes in breast cancer and I expect it does on other types of cancer.

I already take NAC daily, I should probably take some Melatonin as well.  And you?

Conclusion

Melatonin would seem a good candidate for a drug that can make small positive improvements in autism.  Based on an earlier post, it is under consideration for the yellow side of the Polypill.

 

Note that Melatonin has to be given just before bed time.

Note that Melatonin interacts with some drugs used in autism and ADHD.

 

 

How to avoid Autism (and also treat TBI)

It appears that in classic autism, most of the damage is done before birth, but a gradual second decline does often seem to occur between 24 and 54 months, even in a child who you would not think of as suffering from regressive autism.

When people think back about their child with regressive autism, they often recall examples of odd behaviours occurring long before the big regression occurred.

So my "extrapolation" from this, is that there are actually two waves of neurological damage in these two common types of autism. It is just that in one case there is a tidal wave before birth and a smaller change as a toddler.  In regressive autism, the first wave usually passes unnoticed, and the main, unmistakable damage occurs in the second wave.

Perhaps we can avoid this first wave of damage done before birth, in both classic early onset autism and regressive autism.

In an earlier post, I made my case for why girls do not get mild autism and why mothers, who are alpha-females, are more prone to have kids with ASD.

Why Girls don’t get Mild Autism and Why Alpha Females may have Kids with Autism.

This was based on reading that the female hormone progesterone is extremely neuro-protective and that oxidative stress, now seen as a cause of autism, has many causes and is extremely damaging to the brain.  A good example of progesterone use, is its experimental use immediately after a traumatic brain injury.  All I did was extend this to autism.  Now it appears I am not the only one.

Here is a paper I spotted in a corner on Paul Whiteley’s ASD blog.

Low maternal progesterone may contribute to both obstetrical complications and autism

Abstract

Studies show increased autism risk among children born to mothers experiencing obstetrical complications. Although this is usually interpreted as suggesting that the obstetrical complications could be causing autism, it is possible that a single factor could be responsible for both complications and autism. We hypothesized that low levels of the hormone progesterone is responsible since it is supplied to the fetus maternally and does not only support pregnancy but also promotes brain development. Following a review of the literature, we report findings from a survey of mothers of autistic children (n=86) compared to mothers of typically-developing children (n=88) regarding obstetrical histories, including five obstetrical risk factors indicative of low progesterone Using this analysis, the ASD group had significantly more risk factors than controls (1.21 ± 0.09 vs. 0.76 ± 0.08, p< .0001), suggesting low progesterone. Thus, results suggest that low progesterone may be responsible for both obstetrical complications and brain changes associated with autism and that progesterone levels should be routinely monitored in at-risk pregnancies. Our hypothesis also suggests that ensuring adequate levels of progesterone may decrease the likelihood of autism.

The authors’ hypothesis suggests that ensuring adequate levels of progesterone may decrease the likelihood of autism.  Well, I for one, find this interesting.

In another earlier post, I referred to my advice to Ted, the nom de guerre of my very neuro-typical elder son, on how to avoid autism in the next generation.  I think I can now extend that advice further:-

People like Ted, with a close relative with ASD, could do some of the following:-

·        Find a partner who is calm beta-type female

·        Ensure she avoids emotional stress and shocks during pregnancy (particularly early on)

·       Take maternity leave straight after pregnancy is noticed, rather than mainly after birth; or, best of all, have the partner quit work as soon as pregnancy is noted

·        Ensure high levels of neuro-protective agents throughout pregnancy

·        Progesterone

·        Glutathione GSH (i.e. take NAC)

 

You might be expecting me to have statins on my list, since they are also very neuro-protective, but I do not;  even though:-

Johns Hopkins – a new use for statins

Statins in traumatic brain injury

During pregnancy, statins are detrimental to human placental development.  So although people in high speed skiing accidents, who suffer traumatic brain injuries, would have a clear benefit, for a woman with a 10% chance of having a child with ASD, the risks would outweigh the possible benefit.  Most likely, the primary, cholesterol lowering effect of the statin, is doing the damage, since the baby’s brain does need cholesterol. 

Statin warning for pregnant women

Progesterone would also be a potential therapy for people with ASD.  It might though not be wise for boys around puberty.  There are reports of people with ADHD finding progesterone helpful.
 

Should I happen to have a TBI (traumatic brain injury), please put in my IV drip progesterone, atorvastatin/lovastatin and N-acetylcysteine.


P.S.  During pregnancy, ensuring the mother is not hypothyroid and does take folic acid will also shift the odds away from an outcome with ASD.

 

 

Increasing Good Behaviors and Reducing Bad Behaviors in Autism

This blog is all about clever chemicals that can make life better for people with autism, but for several years I have also been learning all about behavioral therapy to achieve the same goal.  So I thought I should look for any lessons that I might apply from my earlier endeavours.  

Two of the best books in my ABA collection, based on feedback from all of our Assistants/Therapists/Friends are the oldest, and indeed the lightest.  They are more than 30 years old, as you might imagine from the front cover, which is a big turn off for many parents.

They are great books, that tell you what you actually want to know: how to get rid of horrible behaviours and how to encourage nice ones.

Dr Foxx is still going strong and won the 2013 Award for Distinguished Professional Contributions to Applied Research from the American Psychological Association. Foxx is a professor of psychology at Pennsylvania State Harrisburg and an adjunct professor of pediatrics at the Pennsylvania State University College of Medicine.

The thing I always found odd was why Dr. Foxx wrote two separate books, surely it is all the same subject matter.  He had his reasons.

Here is my parallel with my quest to develop a smart combination of safe drugs to help in autism. 

So far, most of what I have been doing is focused on decreasing the bad behaviors, so the blue part of the pill; the remaining work is find to ways to promote the good behaviors, the yellow part of the pill.

This might actually be more relevant that you realize.  While it is clear that bad behaviors in autism vary widely in both type and extent, desirable good behaviors should have much more in common.  We know that many individual drugs on the "blue side" are effective only in a minority of people, but perhaps there will be much more commonality on the "yellow side".  I expect this to be the case.

So my Polypill is taking colour, as well as shape.

Another good piece of news is that I found a precedent for orphan drug designation in classic autism.  It appears that in 1998 the FDA awarded orphan drug status to Naltrexone to treat childhood autism with SIB.  In the US, orphan drug status is only possible for rare diseases affecting less than 200,000 people.  There are other cases of orphan drugs in autism, but they are for rare genetic variants. Currently the FDA website for orphan drugs does not list Autism for Naltrexone.

Also, an interesting Australian drug NNZ-2566,  mentioned in a previous post, has recently been given orphan drug status in the US, this time based on Fragile X designation.  The drug is an analogue of IGF-1 and looks interesting to me.

If you want to see what orphan drug designation in the EU means, here is what Novartis received for its new Fragile X treatment, Mavoglurant.

Orphan drug status reduces the cost of approving a drug.  But how rare is classic autism, these days?

 

Matching Pathology with Behaviours in Autism

 
I think the wrong people are in charge of autism research; forensic scientists or even air-crash investigators might do much better.

We have seen in this blog that many drugs have a positive effect in specific types of autism. In many, but not all cases, the mechanism of that drug and its effect on the pathology of autism is understood. 

If you have followed an ABA programme, you will know that an experienced autism therapist would very easily be able to give a long list of behavioral issues that occur in varying combinations among her clients.

From reading the research, it is clear that the people who understand the biology, often do not understand the psychology and the behavioral issues they are trying to treat - but perhaps they should.  Only then can you target treatments for specific problems.  There can be no single drug for autism, but there can be a drug for obsessive behaviours, and another for self-injury.  You cannot say a low dose of X helps with social cognition, but for aggression you need a high dose of X.  To me at least, this is complete nonsense and shows a complete failure to understand the underlying psychology.

Just as most people struggle with all the jargon of biochemistry, I suppose the medical researchers fail to grasp the nuances of the psychologists’ jargon.  We need to match both sides, because we need science to solve a complex problem that presents itself in hard to describe, odd behaviours and not as nice neat equation to solve.

It is difficult to accurately describe and quantify the behavioral issues of a child with ASD.  It is very hard for a parent, but it is definitely possible for a psychologist using tools like ABBLS and others.  Then you can move towards seeing precisely what behavioral effects a drug has and stop expecting improvements in areas that are completely unrelated.

Having produced the list of deficit areas you can then try and understand the underlying pathology as to why a drug is effective.

I make no claims to have great expertise in this area, but it looks like nobody else does either.

Here are some examples:

Obsessions

Obsessive compulsive behaviours are well known to affect some people with autism.  This is a type of behaviour that most people would understand and would notice if they saw it, although they might find it hard to quantify.

Oxidative stress is a measurable pathological condition that is present in some people with autism.  Oxidative stress exists in other medical conditions and has a known therapy, an antioxidant like NAC.

By chance, it was found that treating someone with obsessive compulsive behaviours with NAC, greatly reduced those behaviours.

In the case of people with autism and obsessive compulsive behaviours, it would be good to know if other deficit areas were also impacted.  Clearly, taking away the obsessive compulsive behaviours, you would expect to see a general improvement, since the person is now much calmer and better able to function and so many behaviours should improve to a certain extent.  But does NAC reduce head banging and other SIB?  I think not.

So we can then conclude that oxidative stress triggers obsessive compulsive behaviours and NAC should be prescribed.  Oxidative stress may exist to a lesser degree in subjects that do not (yet) display obsessive behaviours.

 

Anxiety

I have not tried to treat anxiety in autism, but many people have.  Anxiety lies on the axis running from happy to depressed.  By raising the level of serotonin in the brain you move from depressed towards happy.  The antidepressant Prozac is given to many children with ASD to reduce anxiety. Prozac is a selective serotonin reuptake inhibitor (SSRI).

The problem with such drugs is their side effects and use can result in dependency.  If that was not the case, the advice would be simple.

I think a better and safer way exists to raise brain serotonin levels in autism.

Seizures and SIB

Not all people with SIB (Self-injurious Behavior) have seizures, but I expect many people with seizures have SIB.  Both conditions appear to be channelopathies (ion channel/transporter dysfunctions); but there is more to it than that, what triggers the channelopathy?  It would seem that in both cases the message comes via inflammatory signalling from the vagus nerve.  So to treat these conditions you can block the inflammatory signalling (vagus nerve stimulation), or you can treat the resulting ion channel/transporter dysfunction in the brain; doing both may be quite unnecessary.

If you have neither seizures nor SIB, then using any of the above therapies would be of little effect.

Many open questions remain

All is not clear; for example, where does hyperactivity fit in?  Where does anger fit in?  Is anger just a mild version of SIB?  It is extreme anxiety?  Is it something entirely different?

An interesting finding of mine was that showing affection appears to be pathologically related to self-confidence and lack of inhibition.  The pathology linking them appears to be neuroinflammation, or rather the control of it.