Memantine – yet another failed Autism Trial

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

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

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

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

What is going on?

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

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

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

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

In other words it does not work.

The drug itself now carries this note:-

8.4 Pediatric Use

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

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

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

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

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

OBJECTIVE:

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

METHODS:

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

RESULTS:

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

CONCLUSIONS:

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

  

Dr Chez? 

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

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

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

 

Abstract

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

Making sense of Memantine

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

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

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

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

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

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

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

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

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

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

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

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

      

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

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

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

Combatting Brain Calcification in Some Autism (and Bipolar and Schizophrenia) and Osteoprotegerin (OPG) as a potential biomarker, implicating Cav1.2

In today’s post there is more supposition than normal, but plenty of anecdotal evidence.  It follows on from the previous post that suggested calcification might be an issue in some types of autism.  As we know, many unrelated biological dysfunctions can lead to autism, but there do seem to be some commonly affected pathways.

This subject is definitely worthy of much more detailed study than my post, which is based on an initial review of the science.  Some leading researchers, like Persico and Courchesne are fully aware of the issue.  I am not sure who would undertake such a study.  There is no physician specialty dedicated solely to osteoporosis, so we are lacking experts.  The bone-vascular axis is worthy of more study, as much for heart disease as autism.

A variety of medical specialists treat people with osteoporosis, including internists, gynecologists, family physicians, endocrinologists, rheumatologists, physiatrists, orthopaedists, and geriatricians.  If you do not know what a physiatrist is, I also had to look it up.  Physical Medicine and Rehabilitation (PM&R) physicians, also known as physiatrists, treat a wide variety of medical conditions affecting the brain, spinal cord, nerves, bones, joints, ligaments, muscles, and tendons.

 

Overview

There is more support for the potential use of calcium channel blockers that affect Cav1.2, via its effect on calcification by modulating Osteoprotegerin (OPG).  OPG is known to be elevated in autism and its two older brothers schizophrenia and bipolar.

It appears that in some people with severe brain calcification, that shows up on CT scans, biphosphanate drugs can be helpful, but do not actually shrink the calcification, perhaps they stop it growing.

Biphosphanate drugs used to treat osteoporosis are not without side effects in some people.

Some people have disturbed calcium homeostasis as a result of drugs they are taking, for example antiepileptic drugs.

So-called “chelation” using powerful intravenous antioxidants has been shown in the TACT clinical trial to reduce future heart problems, but only in people with diabetes. Diabetics are known to have disturbed calcium homeostasis leading to calcification, heart disease and osteoporosis.

In some counties intravenous antioxidants have long been given to people with diabetes to treat its main side effects but not to clear calcification.  In those countries this is seen as perfectly safe and routine. Preventative care for diabetics is actually rather poor in the UK and US.

Vitamin K plays a key role in calcium homeostasis and in some people just giving large amounts of this vitamin has the required therapeutic effect.  Unless given alongside blood thinning drugs, it is claimed that high dose Vitamin K does not have side effects.

Perhaps the most common osteoporosis therapy, calcium plus vitamin D is shown in some trials to be of no value whatsoever.  This therapy would most likely be ill advised in autism.

Osteoprotegerin (OPG)

Osteoprotegerin (OPG) is a cytokine involved in calcification and inflammation.

Osteoprotegerin has been used experimentally to decrease bone resorption in women with postmenopausal osteoporosis.

 It has been particularly related to the increase in cardiovascular risk in patients suffering from diabetes

Interestingly it has been shown that the L type calcium channel Cav1.2 regulates Osteoprotegerin (OPG) expression and secretion.

A NASA space shuttle flight in 2001 tested the effects of osteoprotegerin on mice in microgravity, finding that it did prevent increase in resorption and maintained bone mineralization.  Space flight is not good for your bones.

Osteoprotegerin levels are elevated in people with bipolar and schizophrenia.

Osteoprotegerin levels in patients with severe mental disorders

Severe mental disorders are associated with elevated levels of inflammatory markers. In the present study, we investigated whether osteoprotegerin (OPG), a member of the tumour necrosis factor receptor family involved in calcification and inflammation, is elevated in patients with severe mental disorders.

Methods

We measured the plasma levels of OPG in patients with severe mental disorders (n = 312; 125 with bipolar disorder and 187 with schizophrenia) and healthy volunteers (n = 239).

The mean plasma levels of OPG were significantly higher in patients than in controls (t₅₃₁ = 2.6, p = 0.01), with the same pattern in bipolar disorder and schizophrenia. The increase was significant after adjustment for possible confounding variables, including age, sex, ethnic background, alcohol consumption, liver and kidney function, diabetes, cardiovascular disease, autoimmune diseases and levels of cholesterol, glucose and C-reactive protein.

Conclusion

Our results indicate that elevated OPG levels are associated with severe mental disorders and suggest that mechanisms related to calcification and inflammation may play a role in disease development.

As shown in the study below, many inflammatory cytokines are elevated in autism, just look at those insulin-like growth factor binding proteins.  Osteoprotegerin is a modest 500% of what it might be expected to be in non autism.

Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism

Chelation

Because of the continuing non-debate in scientific terms about vaccines and autism, it is unlikely that there will ever be any study about calcium chelation and autism.  Rather than admit that in a small number of cases vaccination may trigger mitochondrial disease and result in autism, there is complete denial, at least in public. In private it is an open secret.

The planned chelation trial in autism was banned, on “safety grounds”.

It looks to me that the enemy is not mercury or other heavy metals, the problem is much less exotic. 

Oxidative Stress

Most people with autism have oxidative stress, which should be improved by any potent antioxidant.  Agents used to chelate metals have to be potent antioxidants.

Calcification

In some yet to be determined percentage of people they potentially have disturbed calcium homeostasis resulting in some calcium deposits in the brain.  Those chelating to remove, most likely non-existing, “toxins” may sometimes be reducing harmful calcification.

Fortunately there has been a very large study, called TACT, on de-calcification (calcium chelation) in Coronary Heart Disease.

One large group of people at risk from low bone density are those with diabetes.

Patients with diabetes, who made up approximately one third of the 1,708 TACT participants, had a 41 percent overall reduction in the risk of any cardiovascular event; a 40 percent reduction in the risk of death from heart disease, nonfatal stroke, or nonfatal heart attack; a 52 percent reduction in recurrent heart attacks; and a 43 percent reduction in death from any cause.

   

Chelation for Coronary Heart Disease

§  Patients with diabetes, who made up approximately one third of the 1,708 TACT participants, had a 41 percent overall reduction in the risk of any cardiovascular event; a 40 percent reduction in the risk of death from heart disease, nonfatal stroke, or nonfatal heart attack; a 52 percent reduction in recurrent heart attacks; and a 43 percent reduction in death from any cause. In contrast, there was no significant benefit of EDTA treatment in participants who didn't have diabetes.

Source:  https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_446204.pdf

From the Mayo Clinic:-

          Results of trial to assess chelation therapy (TACT) study presented

 A further review from TACT just looking at patients with diabetes:- 

The Effect of an EDTA-based Chelation Regimen on Patients with Diabetes and Prior Myocardial Infarction in TACT

Patients with diabetes:-

Patients without diabetes (no benefit over placebo):-

Treatment

The 10 component 500 mL intravenous solution in TACT consisted of 3 g of disodium EDTA, adjusted downward based on estimated glomerular filtration rate; 7 g of ascorbic acid; 2 g of magnesium chloride; B-vitamins, and other components (eTable 4). The placebo solution consisted of 500 mL of normal saline and 1.2% dextrose (2.5 g total). The solution was infused over at least 3 hours through a peripheral intravenous line weekly for 30 weeks and then biweekly to bimonthly to complete 40 infusions.

Background

The Trial to Assess Chelation Therapy (TACT) showed clinical benefit of an ethylene diamine tetraacetic acid (EDTA-based) infusion regimen in patients 50 years or older with prior myocardial infarction (MI). Diabetes prior to enrollment was a pre-specified subgroup.

Methods and Results

Patients received 40 infusions of EDTA chelation or placebo. 633 (37%) had diabetes (322 EDTA, 311 placebo). EDTA reduced the primary endpoint (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina) [25% vs 38%, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.44, 0.79), p<0.001] over 5 years. The result remained significant after Bonferroni adjustment for multiple subgroups (99.4% CI (0.39, 0.88), adjusted p=0.002). All-cause mortality was reduced by EDTA chelation [10% vs 16%, HR 0.57, 95% CI (0.36, 0.88) p=0.011], as was the secondary endpoint (cardiovascular death, reinfarction, or stroke) [11% vs 17% HR 0.60, 95% CI (0.39, 0.91), p=0.017]. After adjusting for multiple subgroups, however, those results were no longer significant. The number needed to treat to reduce one primary endpoint was 6.5 over 5 years (95% CI (4.4, 12.7). There was no reduction in events in non-diabetics (n=1075, p=0.877), resulting in a treatment by diabetes interaction (p=0.004).

Conclusions

Post-MI diabetic patients age 50 or older demonstrated a marked reduction in cardiovascular events with EDTA chelation. These findings support efforts to replicate these findings and define the mechanisms of benefit. They do not, however, constitute sufficient evidence to indicate the routine use of chelation therapy for all post-MI diabetic patients.

Effect of the Polypill on Calcification

Oral antioxidants like NAC and Alpha lipoic Acid given daily will have both a direct and indirect “chelating” effect.

Alpha-Lipoic Acid Promotes Osteoblastic Formation in H2O2 -Treated MC3T3-E1 Cells and Prevents Bone Lossin Ovariectomized Rats.

 

Alpha-lipoic acid (ALA), a naturally occurring compound and dietary supplement, has been established as a potent antioxidant that is a strong scavenger of free radicals. Recently, accumulating evidences has indicated the relationship between oxidative stress and osteoporosis (OP). Some studies have investigated the possible beneficial effects of ALA on OP both in vivo and in vitro; however, the precise mechanism(s) underlying the bone-protective action of ALA remains unclear. Considering this, we focused on the anti-oxidative capacity of ALA to exert bone-protective effects in vitro and in vivo. In the present study, the effects of ALA on osteoblastic formation in H(2)O(2) -treated MC3T3-E1 pre-osteoblasts and ovariectomy (OVX)-induced bone loss in rats were investigated. The results showed that ALA promoted osteoblast differentiation, mineralization and maturation and inhibited osteoblast apoptosis, thus increasing the OPG/receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) ratio and leading to enhanced bone formation in vitro and inhibited bone loss in vivo. Further study revealed that ALA exerted its bone-protective effects by inhibiting reactive oxygen species (ROS) generation by down-regulating Nox4 gene expression and protein synthesis and attenuating the transcriptional activation of NF-κB. In addition, ALA might exert its bone-protective effects by activating the Wnt/Lrp5/β-catenin signaling pathway. Taken together, the present study indicated that ALA promoted osteoblastic formation in H(2)O(2) -treated MC3T3-E1 cells and prevented OVX-induced bone loss in rats by regulating Nox4/ROS/NF-κB and Wnt/Lrp5/β-catenin signaling pathways, which provided possible mechanisms of bone-protective effects in regulating osteoblastic formation and preventing bone loss. Taken together, the results suggest that ALA may be a candidate for clinical OP treatment.

Statins are known to promote bone health.

Statins and osteoporosis:new role for old drugs.

Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case-control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted.

Verapamil via the effect on OPG should have positive effect on bones and reduce vascular calcification.

Use of Biphosphanate Drugs to Treat Brain Calcification

Primary brain calcification in patients undergoing treatment with the biphosphanate alendronate

Brain calcification might be associated with various metabolic, infectious or vascular conditions. Clinically, brain calcification can include symptoms such as migraine, Parkinsonism, psychosis or dementia. The term Primary Brain Calcification was recently used for those patients without an obvious cause (formerly idiopathic) while Primary Familial Brain Calcifications was left for the cases with autosomal dominant inheritance. Recent studies found mutations in four genes (SLC20A2,PDGFRB, PDGFB and XPR1). However, these genes represent only 60% of all familial cases suggesting other genes remain to be elucidated. Studies evaluating treatments for such a devastating disease are scattered, usually appearing as single case reports. In the present study, we describe a case series of 7 patients treated with Alendronate, a widely prescribed biphosphanate. We observed good

tolerance and evidence of improvements and stability by some patients. No side effects were reported and no specific symptoms related to medication. Younger patients and one individual continuing a prescription (prior to study commencement) appeared to respond more positively with some referred improvements in symptoms. Biphosphanates may represent an excellent prospect for the treatment of brain calcifications due to their being well tolerated and easily available. Conversely, prospective and controlled studies should promptly address weaknesses found in the present analysis.

Patient 3. A 43-year-old man, one of seven children born to the same mother (described below as Patient 4), presented with rapid progression of parkinsonism. In the last 5 years, a progressive presentation of general bradykinesia, rigidity, and paresis in the right arm had developed. He had previously been an active individual with regular employment. Prior to recruitment, this patient had been on carbidopa/levodopa, which was continued throughout the duration of the present study. Genetic screening identified a SLC20A2 mutation (c.1483 G > A)3, and the patient was placed on alendronate therapy.

Patient 4. This 84-year-old woman presented with mild depression, late-stage parkinsonism, and large calcifications (10.85 cm3) in the basal ganglia and cerebellum. She is the mother of Patient 3 and carries the same SLC20A2 mutation. This patient had been taking alendronate for 10 years due to a diagnosis of osteoporosis. Intriguingly, she presented with fewer symptoms than her son, despite being 41 years old older.

We chose alendronate due to its availability, safety, and comfortable dosing schedule (oral administration, once a week). Etidronate probably works via a different mechanism (bulk action binding to hydroxyapatite) than

the newer amino bisphosphonate alendronate (inhibition of osteoclasts). This might explain why the effects seen in our series were less dramatic than those seen in patients treated with etidronate. Thus, while alendronate has a more convenient dosing schedule and, possibly, fewer side effects, a larger clinical trial should consider the choice of bisphosphonate carefully.

To date, there is no specific treatment for primary brain calcification; the main goal is symptom management.

Clinicians should make sure that the idiopathic/primary profile is accurately defined to rule out any underlying organic cause, e.g., in non-idiopathic basal ganglia calcification caused by abnormal calcium regulation, such as in primary endocrine disorders.

Bisphosphonates represent the only effective (although still anecdotal) treatment that could have wider applications in basal ganglia calcification. Prospective, controlled studies should be conducted to address the weaknesses of the present manuscript and establish a definitive analysis of bisphosphonate therapy for primary brain calcification. Furthermore, the excellent tolerability profile of alendronate in primary brain calcifications suggests that a trial in asymptomatic patients could help address the potential benefit of this strategy to control symptoms in younger patients.

Conclusion

Bisphosphonates may be applicable, safe and change the natural progression of primary brain calcifications, especially in younger patients and across prolonged periods. Nevertheless, future studies with adequate design should answer remaining questions.

Metabolic Bone Diseases

There are numerous things that can affect the bone-vascular axis including various  metabolic diseases.  This is rather beyond the scope of an autism blog, but if you are interested here is a link.

Imaging Findings and Evaluation of Metabolic Bone Disease

Conclusion

Unless you have evidence of osteoporosis, or a brain scan showing calcification, it might be rather extreme to take a biphosphanate drug like Fosamax.

If you already take oral NAC , ALA or L-carnitine you have a pretty potent therapy which would target any calcification, if indeed it existed.  Intravenous ALA, as used my Monty’s Grandad for years, should be even more effective as it is for diabetic neuropathy.

Those using verapamil appear to have another layer of protection against calcification. I did suggest to Agnieszka that elevated OMG might indeed be the biomarker needed for the use of verapamil in Autism. Remember to contact her to participate in her study.

Verapamil use in Autism – Request for Case Reports from Parents

Vitamin K2 is claimed to be extremely safe unless you are taking a blood thinning drug like Warfarin, that are Vitamin K antagonists.

Some studies claim great results from K2, while some others are more mixed.  It is likely that depending on what underlying dysfunction exists, high dose K2 may help or do nothing.  It is clear that low amounts of K2 are damaging.

So K2 would seem worthwhile trialing.  It is found in the not so pleasant tasting Natto.  Vitamin K (more K1 than K2) is found in broad-leafed vegetables.  The excellent Linus Pauling Institute reviewed all the vitamin K evidence and concluded people should:-

 “eat at least one cup of dark green leafy vegetables daily”

This brings me back to where I started the previous post with the Mediterranean diet, rich in dark green leafy vegetables.

Intravenous infusion of antioxidants looks like a very good idea for people with diabetes.  Where we live this has been standard practice for years, where Monty’s grandad goes twice a year for 10 days of ALA infusion, the rest of the year he is prescribed oral ALA.  This is given to control diabetic neuropathy, but clearly a side effect is that it will reduce the likelihood of a heart attack or stroke.

I have no doubt IV infusion of ALA would be beneficial for some with autism, but I think they might get sufficient benefit from oral ALA or indeed NAC.

I wish the FDA would permit the “chelation” autism trial in the US, I have no doubt it would show a positive effect, but not for the reasons put forward by DAN doctors and the chelation cults. 

The TACT chelation trial in older people showed that the therapy was very well tolerated.  IV ALA therapy is also well tolerated.

Public health officials should not fear the truth.  In the long run the truth is the best policy and when given all the facts the public are not stupid.  If vaccination is in the interest of their child, enough parents will happily cooperate. The Herd Immunity Threshold (HIT) is the percentage of people who need to be vaccinated.  HIT is 95% for measles.  Therapies used at Johns Hopkins exist to minimize the possible damaging effect on mitochondria and never give paracetamol/acetaminophen to children after a vaccination.

Treating Adults with Autism?

 

Almost the entire focus of treating autism is targeted at young children; only rarely do you hear about clinical trials involving adults, yet we are often reminded that autism is a lifelong condition.

For those of you that read the proposed guidelines to drug companies developing autism therapies, this issue raised its head again.  Will therapies effective in children be effective in adults (and vice versa)?

There are many issues here.  On the one hand there is great caution about giving drugs to very young children, but there is the realization that many therapies may only be effective if given at an extremely young age.

I only started treating the biological dysfunctions in Monty, now aged 12, when he was 9 years old.  By good fortune the first therapy (bumetanide) I tried was highly effective, otherwise this blog would not exist.

Had that Bumetanide clinical trial been published 5 years earlier, would I have given my then 4 year old son that same drug?  Probably not.

With what I now know, I would be happy to give Bumetanide as soon after birth that autism was even suspected.  (To the trained eye, this is but a few months old)

The effect of no treatment

For three years I have been developing a personalized autism treatment, Monty’s Polypill, and I think it works well, but a few weeks ago we decided to see what happens with no treatment at all.

This did provide some useful insights into treating young adults, as opposed to young children.

The first thing is that all the new skills that have been acquired, at close to neurotypical speed, in the last three years, did not just fade away. 

The old obvious repetitive behaviors/stimming/stereotypy did not return, but more subtle new ones did.  (no NAC)

He could still play his piano nicely with his teacher, but his interest in playing out of lessons faded away as did his skill level out of lessons.

He showed an occasional aversion to doing anything new, for example when his assistant came in the afternoon, I told him to go outside and meet her.  He could happily open the front door (his normal routine) but was not able to walk though it and meet her by the gate.  (no statin)

When I offered to go with him, he had a brief tantrum. 

He started asking permission to do things he knew how to do, which some people saw as a positive.  When lying in bed at 9pm he called out “Mum can I read a book”, rather than just picking one from the shelf by his bed and when at a small birthday party he had to bend down to light the candles, he turned round and said “can I squat?”  Most people thought that was good use of vocabulary, I was thinking “just do it”.  (statin effect)

I received comments like “how patient he is”, or at school  words like “peace” and “peaceful”.  I was thinking how passive he was. (no bumetanide/low dose clonazepam)

While there was no glaring loss of cognitive function and spelling tests and maths test at school were not showing any deficit, I noticed a loss of ability to develop new skills. 

We use an excellent online program called Math Whizz and one thing we were learning was to how to use the calendar.

Typical questions would be:-

“What date is the second Friday in May?”

“What date if the first Monday in December?”

“What day (of the week) is the last day in June?”

You first have to click on “May” to get the calendar to turn to the correct month and then you can figure out the answer.

To my surprise, while still on the Polypill, Monty was getting pretty good at this exercise, on his first attempt.

However, a few days later, when we tried with no Polypill, he was struggling and as the days passed he got worse and worse.  (chloride levels gradually rising?)

There was even a return of the sensory overload that causes many problems for some people with autism and also Asperger’s.  Even the sound of a crow became disturbing.  Both Acetazolamide and Bumetanide are used to treat Hypokalemic Periodic Paralysis, which is a more severe form of Hypokalemic Sensory Overload and at least some types of Autistic Sensory Overload are a subset of this.

After two weeks of Bumetanide and Potassium the sound over-sensitivity has gone again.  It did not go away immediately.

Pleiotropic effect of Verapamil

While I initially identified the calcium channel blocker, Verapamil, as an effective inhibitor of aggression and SIB triggered by allergy/mast cell degranulation, I was once asked if I thought Verapamil might have pleiotropic effects in Monty.  Having stopped using Verapamil and then restarted it, all outside of the problematic allergy season, I have all the proof I need in my n=1 case.  Life is better with a little Verapamil; his calcium channel dysfunction goes beyond those in mast cells.

Verapamil was the last element of the Polypill that I re-started; I was rather hoping it would show no effect outside the allergy season.  Only after adding it back did things really return to what has become our "normal".

There is after all a vast amount of evidence linking calcium ion channel dysfunction and autism.

My Verdict

I think many people would be very happy to have a passive child, who can sit for two hours in restaurant.

Most people do not notice the fading of good behavior, because their overriding concern is the lack of any “bad” behavior.  So a bad behavior is followed by a “is this better?”, rather than a “Wow, do you know Monty did today …”.

I prefer a child who can learn, even if that means he may get fed up from time to time, and show it.

I was pleased to come home earlier this week and find Monty sitting alone playing his piano beautifully (no prompting, no reinforcement needed), with his music book laid out in front of him, playing one melody, turning the page and playing the next one, while his big brother had gone upstairs to play his computer games, because little brother does not need him. 

  

Intervention in Adults

Other than halting self injurious behavior (SIB), I am far from convinced that most people would even notice the difference if you took an adult with classic autism and started to treat him.

At that age, passive and patient is what most caregivers want.

So I see little prospect that “corrective biological therapy” will ever be initiated in many adults with more serious autism;  they will continue to be “tranquilized”.

Many adults with Asperger’s and high IQ do their own research and self-treat; some even read this blog. For them, even a small biological "improvement" can have a welcome effect on well-being. Good for them.

Intervention in Young Children

The best way forward is to intervene immediately after diagnosis.  In the US/Canada that might be two years old, but more like four years old in Europe.

If I was a Roche or Novartis, this would be my target:- non-verbal, non toilet-trained toddlers who make no eye contact, possibly cry a lot and tend to be kept at home.