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Showing posts with label Bumetanide. Show all posts
Showing posts with label Bumetanide. Show all posts

Sunday, 14 June 2020

Summertime Autism Raging and Dumber in the Summer


By far the most read post in this blog is one about histamine and allergies, which means many people are searching on Google for “histamine, allergy and autism”.

Our reader Kei recently commented that his daughter, without allergy, was again showing signs of summertime raging and that his neurologist confirmed that summertime raging does indeed happen and nobody knows why.

I did figure out how to deal with our version of “summertime raging” and the post-bumetanide “dumber in the summer” phenomena.  There were several posts on this subject.  The lasting solution was to treat the raging as if it was caused by inflammation driven by pollen allergy and to note that inflammation will further worsen the KCC2/NKCC1 imbalance in Bumetanide-responsive autism, making those people appear “dumber in the summer”.  This also accounts for the “Bumetanide has stopped working” phenomenon, reported by some parents.  You need to minimize inflammation from allergy and increase Bumetanide (or add Azosemide).  My discovery was that Verapamil was actually more effective than anti-histamines and actual mast cell stabilizers. Mast cells degranulate via a process dependent of the L-type calcium channels that Verapamil blocks. Mast cells release histamine and inflammatory cytokines like IL-6.

This spring when Monty’s brother asked why Monty was acting dumber, it was time to implement the “dumber in the summer” therapies.  Add a morning tablet of cetirizine (Zyrtec) and a nasal spray of Dymista (Azelastine + Fluticasone).

Dymista is inexpensive and OTC where we live, but I see in the US it is quite an expensive prescription drug.  It is a favourite of Monty’s pediatrician and his ENT doctor. 



Summertime Regression in the Research Literature

I recently came across two very relevant papers on this subject by a proactive American immunologist called Dr Marvin Boris.  If you live in New York, he looks like a useful person to know.

In his first study he investigated whether the onset of the allergy season caused a deterioration in behavior of children with autism or ADHD; in more than half of the trial subjects, it did.

In his second study he went on to make a double‐blind crossover study with nasal inhalation of a pollen extract or placebo on alternate weeks during the winter.  This was his way to recreate the pollen season during winter.

Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms.

In other words, half of children with autism regress when exposed to pollen, even though they may not show any symptoms of allergy, or test positive for allergy.  This should be of interest to Kei and his neurologist.



Purpose: To determine whether children with autistic spectrum disorders (ASD) or attention deficit hyperactive disorder (ADHD) exhibit neurobehavioral regressive changes during pollen seasons.
Design: A behavioral questionnaire‐based survey, with results matched to pollen counts; an uncontrolled, open non‐intervention study.
Materials and Methods: Twenty‐nine children identified with ASD and 18 children with ADHD comprised the study population. The parents of the study children completed the Allergic Symptom Screen for 2 weeks during the winter prior to the pollen allergy season under investigation. The parents of the ASD children also completed the Aberrant Behavior Checklist and the parents of the ADHD children completed Conners' Revised Parent Short Form for the same periods. The parents completed the respective forms weekly from 1 March to 31 October 2002. Pollen counts from the geographical area of study were recorded on a daily basis during this period.
Results: During natural pollen exposure, 15 of 29 (52%) children with ASD and 10 of 18 (56%) children with ADHD demonstrated neurobehavioral regression. There was no correlation with the child's allergic status (IgE, skin tests and RAST) or allergy symptoms.
Conclusions: Pollen exposure can produce neurobehavioral regression in the majority of children with ASD or ADHD on a non‐IgE‐mediated mechanism. Psychological dysfunction can be potentiated by environmental exposures. 


Pollen Exposure as a Cause for the Deterioration of Neurobehavioral Function in Children with Autism and Attention Deficit Hyperactive Disorder: Nasal Pollen Challenge 

Purpose: In a previous study it was established that children with attention deficit hyperactive disorder (ADHD) and autistic spectrum disorders (ASD) had regressed during pollen seasons. The purpose of this study was to determine if these children regressed on direct nasal pollen challenge. 

Design: A double‐blind crossover placebo‐controlled nasal challenge study. Materials and Methods: Twenty‐nine children with ASD and 18 with ADHD comprised the population. The study was a double‐blind crossover with nasal instillation of a pollen extract or placebo on alternate weeks during the winter. The pollens used were oak tree, timothy grass and ragweed. The dose insufflated into each nostril was 25 mg (±15%) of each pollen. 

Results: Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. 

Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms. There was no correlation to the child's IgE level, positive RAST pollen tests, or skin tests.


Conclusion

When I was figuring out Monty’s summertime raging and cognitive decline, several years ago, there were no significant signs of allergy present.  Nowadays there are far more visible signs of allergy.

Dr Boris does not suggest any therapy for summertime raging, but he did show that it can be driven by pollen in half of those with autism, even children who have no signs of having any allergy.

His studies were published more than a decade ago and seem to have been forgotten.  This seems a pity, but it says a lot.

I only stumbled upon his papers because I was reading another of his decade old papers.  That paper is based on his early use of Pioglitazone in autism, which resulted in several hundred children being successfully prescribed this drug.  Pioglitazone selectively stimulates the peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.

There was a bladder cancer scare, lots of hungry lawyers and I suppose people stopped prescribing Pioglitazone for autism a decade ago.  The numerous subsequent safety studies and meta-analysis show either a small increased risk, or no increased risk, very much dependent on who financed the research.  Pioglitazone is given to people with type 2 diabetes, and they are already at an increased risk of bladder cancer.  In those people, that risk increases between 0 and about 20%, depending on the study.  We are talking about 0.07% to 0.1% of people with T2 diabetes taking Pioglitazone later developing bladder cancer.

A decade later and Pioglitazone is again back in fashion with trials in humans with autism and studies in mouse models of autism. The current autism research does not see cancer risk as reason not to use Pioglitazone.  I agree with them. 

It looks like a minority of people taking Pioglitazone are more likely to suffer upper respiratory tract infections.  That is the risk that I consider relevant.  I also note that in trials even the placebo can appear to cause upper respiratory tract infections.

Pioglitazone was covered in earlier posts, 


but there will soon be a new post.  For most people I think histamine, allergy and summertime raging will continue to be of more interest.






Tuesday, 26 May 2020

Bumetanide for TSC-type Autism, Verapamil now for sinusitis, Lower dose Folinic Acid looks interesting for Autism in France, Roche cuts Balovaptan and Basmisanil; Stanford continue repurposing Vasopressin for Autism

 Repurposing what already exists – cheap, safe, effective and sometimes colourful


Today’s post is nice and simple.

Yet another sub-type of autism is shown in a clinical trial to respond to the cheap drug bumetanide, this time it is children diagnosed with TSC (tuberous sclerosis complex); TSC is a leading genetic cause of autism often used in research.

In France researchers repurposed Folinoral, a lower dose equivalent of Dr Frye’s, and our reader Roger’s, Leucovorin to treat autism with a positive result.  Folinoral is Calcium Folinate, but the dose was just 5mg twice a day, much less than the dose used in the US research.

The potential off-label uses for Verapamil, the old calcium channel blocker helpful in some autism, continue to grow.

Original purpose:  

Lower blood pressure by blocking L-type calcium channels

Alternative uses:

·        Treating bipolar disorder
·        Treating cluster headaches and some migraine
·        Halting the loss of insulin production in people with diabetes
·        Treating diarrhea-predominant irritable bowel syndrome (IBS-D)
·        Treating aggression/anxiety in some autism

We can now add, as our reader Lisa discovered by chance,

·        Treating chronic sinusitis

Patients with severe chronic rhinosinusitis show improvement with Verapamil treatment


"Recently, we became aware that some of the inflammation in chronic rhinosinusitis (CRS) with nasal polyps is generated by the nasal lining itself, when a particular protein pump (P-glycoprotein) is overexpressed and leads to the hyper-secretion of inflammatory cytokines," said senior author Benjamin S. Bleier, M.D., a sinus surgeon at Mass. Eye and Ear and an assistant professor of otolaryngology at Harvard Medical School. "Verapamil is a first-generation inhibitor that is well-established in blocking P-glycoprotein. In some patients with CRS with nasal polyps, we saw dramatic improvement in their symptom scores."

Roche ditching experimental autism drugs

Basmisanil which targets the alpha 5 sub-unit of GABAA receptors was originally being developed to improve cognition in Down Syndrome; those clinical trials failed. Now Roche have pulled the plug on the trials to improve cognition in Schizophrenia.
Balovaptan was Roche’s expensive bet on Vasopressin to treat autism, covered in earlier posts; it blocks the activity of the V1a vasopressin receptor.  The Balovaptan phase 3 clinical trials have also been cancelled.



Stanford still pursuing Vasopressin for autism

Stanford’s bet on Vasopressin for autism is still ongoing.  They had the much simpler idea of just putting some pharmaceutical-grade vasopressin in a nasal spray and trialling that.

Intranasal delivery of drugs to target the brain appeals to me, as do eye drops.  Your eyes are part of the central nervous system, in the case of your nose it appears that drugs are transported directly to the brain from the nasal cavity along the olfactory and trigeminal nerves. 

Mechanism of intranasal drug delivery directly to the brain


One feature of this blog is a belief that central hormonal dysfunction is a core feature of much autism.  The big problem is that you cannot easily measure hormone levels in the central nervous system (CNS) and you may get quite contradictory results measuring hormone levels in blood samples.

Plasma oxytocin and vasopressin do not predict neuropeptide concentrations in human cerebrospinal fluid.


I was encouraged to see that the Stanford vasopressin researchers measured vasopressin in samples from spinal fluid.  They found that children who went on to be diagnosed with autism has very low levels of vasopressin in their brains early in life. Making it a potential biomarker.


Autism spectrum disorder (ASD) is a brain disorder characterized by social impairments. ASD is currently diagnosed on the basis of behavioral criteria because no robust biomarkers have been identified. However, we recently found that cerebrospinal fluid (CSF) concentration of the “social” neuropeptide arginine vasopressin (AVP) is significantly lower in pediatric ASD cases vs. controls. As an initial step in establishing the direction of causation for this association, we capitalized upon a rare biomaterials collection of newborn CSF samples to conduct a quasi-prospective test of whether this association held before the developmental period when ASD first manifests. CSF samples had been collected in the course of medical care of 0- to 3-mo-old febrile infants (n = 913) and subsequently archived at −70 °C. We identified a subset of CSF samples from individuals later diagnosed with ASD, matched them 1:2 with appropriate controls (n = 33 total), and quantified their AVP and oxytocin (OXT) concentrations. Neonatal CSF AVP concentrations were significantly lower among ASD cases than controls and individually predicted case status, with highest precision when cases with comorbid attention-deficit/hyperactivity disorder were removed from the analysis. The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT. These preliminary findings suggest that a neurochemical marker of ASD may be present very early in life, and if replicated in a larger, prospective study, this approach could transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.
  
Easy to read version: -

Cerebrospinal fluid levels of a hormone called vasopressin were lower in babies who went on to develop autism than in those who did not, a study found. 

Cerebrospinal Fluid Vasopressin and Symptom Severity in Children with Autism

 








Cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration differs between children with and without autism (AUT), predicts AUT diagnosis, and predicts symptom severity. (A) CSF AVP concentration is lower in children with AUT (n = 36) compared to control children (n = 36), whereas (B) CSF oxytocin (OXT) concentration does not differ between groups. 
(C) The effect of CSF AVP concentration on predicted (line) and observed (symbols) group is plotted, corrected for the other variables in the analysis. Children with AUT plotted above, and control children plotted beneath, the dashed line (which represents 50% probability) are correctly classified. Specifically, across the range of observed CSF AVP concentrations, the likelihood of AUT increased over 1,000-fold, corresponding to nearly a 500-fold increase in risk with each 10-fold decrease in CSF AVP concentration (range odds ratio = 1,080, unit odds ratio = 494, β1 ± SE = −6.202 ± 1.898). (D) CSF AVP concentration predicts Autism Diagnostic Observation Schedule (ADOS)–Calibrated Severity Score (CSS) in male but not in female children with AUT.

I think many hormones are likely disturbed in autism and that modifying them is one potential method of treating autism.

At Stanford they have already had success by squirting vasopressin up kids’ noses:-



In a Stanford study of 30 children with autism, intranasal vasopressin improved social skills more than a placebo, suggesting that the hormone may treat core features of the disorder.



A RANDOMIZED CONTROLLED TRIAL OF INTRANASAL VASOPRESSIN TREATMENT FOR SOCIAL DEFICITS IN CHILDREN WITH AUTISM

Stanford University, Department of Comparative Medicine, Stanford Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments and restricted, repetitive behaviors. Despite ASD’s prevalence, there are currently no medications that effectively treat its core features. Accumulating preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in mammalian social functioning, may be a possible treatment for ASD. Objective: The goal of this investigation is to examine the safety and efficacy of AVP in the treatment of social deficits in children with ASD. Material and Methods: Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-week intranasal AVP treatment in a sample of N=30 children with ASD aged 6-12 years. Results: AVP compared to Placebo treatment significantly enhanced social abilities in children with ASD as measured by change from baseline in the trial’s primary outcome measure, the Social Responsiveness Scale (a parent-report measure). AVP-related social improvements were likewise evident on clinician impression and child performance-based measures. AVP treatment also diminished anxiety symptoms and some restricted/repetitive behaviors. An endogenous blood AVP concentration by treatment group interaction was also observed, such that participants with the highest pre-treatment blood AVP concentrations benefitted the most from AVP (but not Placebo) treatment. AVP was well tolerated with minimal side-effects. No AVP-treated participant dropped out of the trial, and there were no differences in adverse event rates reported between the AVP and Placebo groups. Finally, no significant changes from baseline were observed in electrocardiogram, vital signs, height and weight, or clinical chemistry measurements after 4-week AVP treatment. Conclusions: These findings suggest that intranasally administered AVP is a well-tolerated and promising medication for the treatment of social impairments in children with ASD.

Using a double-blind, randomized, placebo-controlled, parallel clinical trial design, we found that the 4-week intranasal AVP treatment enhanced social abilities in children with ASD as assessed by the trial’s primary outcome measure, the SRS-2 T score. The robustness of this parent-reported social improvement score was corroborated by convergent evidence from clinician evaluation of the social communication abilities of trial participants and by performance of trial participants on laboratory tests of social cognition. These preliminary findings suggest that intranasally administered AVP may be a promising medication for treatment of core social impairments in children with ASD.


We also sought to investigate whether pretreatment neuropeptide concentrations in blood could predict AVP treatment response. We found that participants with the highest pretreatment AVP concentrations in blood benefitted the most from intranasal AVP treatment. This finding may seem counterintuitive, particularly in light of our recent studies showing that low AVP concentrations in CSF could be used to differentiate ASD cases from non-ASD control individuals (1314). One might therefore expect that it would be those children with the lowest endogenous AVP concentrations that stood to benefit the most from intranasal AVP treatment. However, being mindful of safety in this pediatric population, our pilot study used a conservative dose escalation regimen in which children were treated with fairly low doses of AVP throughout much of the trial. Assuming that blood AVP concentrations are related, in some manner, to brain AVP activity—a notion about which there is debate (142225)—it is possible that participants with lower endogenous AVP concentrations at the trial’s outset were “underdosed” in terms of drug amount or duration of treatment and, therefore, would not benefit as fully from AVP administration as those with higher endogenous AVP concentrations. This interpretation is consistent with our finding that AVP treatment enhanced simple social perceptual abilities independent of pretreatment AVP concentrations in blood, whereas it was only those AVP-treated individuals with higher pretreatment blood AVP concentrations who showed gains in complex social behaviors and a reduction in repetitive behaviors.

Pharmacological intervention

Commercially available injectable sterile AVP was used in this study. It was initially purchased from JHP Pharmaceuticals (Rochester, MI), which was subsequently acquired by Par Sterile Products (Chestnut Ridge, NY) in 2014. The placebo solution was prepared by Koshland Pharm (San Francisco, CA) and consisted of ingredients used in the active solution except for the AVP compound. A pharmacist transferred 25 ml of AVP (20 International Units (IU)/ml) or placebo solutions into standard sterile amber glass bottles with metered (0.1 ml per puff) nasal spray applicators to ensure that the AVP and placebo applicators were visually indistinguishable to the research team. These applicators were coded and given to the Stanford Health Care’s Investigational Drug Service for refrigerated storage (2°C to 8°C) and subsequent dispensing. After the first AVP dose (see below), the dose-escalation regimen at home for all participants involved administration of 4 IU twice daily (or BID) of AVP during week 1 and 8 IU BID of AVP during week 2. Participants aged 6 to 9.5 years then received 12 IU BID of AVP during weeks 3 and 4, whereas participants aged 9.6 to 12.9 years received 16 IU BID of AVP during weeks 3 and 4. A range of possible AVP doses was identified by review of the published literature; the final study doses were then determined in close consultation with the FDA.


A few years ago I did write about the hormone TRH as a potential means of improving autism.  TRH can also be squirted up your nose, although I favoured an oral TRH super-agonist called Taltirelin/Ceredist.

I also suggested that DHED, an orally active, centrally selective prodrug of estradiol, could well be a therapeutic in autism. DHED should give all the benefits of the female hormone estradiol, without any side-effects outside the CNS.  Many of the benefits are via ROR alpha.

Without having samples of spinal fluid, identifying, let alone treating, central hormonal dysfunction is rather a matter of guesswork.

Hormones are very much interrelated and perform different functions in different parts of the body, so it would be easy to get unwanted effects, as with estradiol, if taken orally.
  
Bumetanide for TSC (Tuberous Sclerosis Complex)

A small trial in children with TSC (Tuberous sclerosis complex) has shown that bumetanide improved their features of autism (social behavior, irritability and hyperactivity) but did not reduce seizures.


Conclusion

This pilot study indicates the potential efficacy of bumetanide on behavioral problems in young patients with TSC. Bumetanide improved irritable, explosive, and social behavior in the majority of patients in this sample and treatment was well tolerated.


Folinic Acid for Autism, but at a lower dose than Dr Frye

I did recently complete my trial of generic Calcium Folinate at something like Dr Frye’s Leucovorin dose.

I found that it did indeed have a positive effect on the use of expressive language.  It prompted the use of more complex sentences.

The downside was that it did also cause aggressive/violent outbursts, so I put it in my “rejected” pile of therapies.  

I was interested to see that in France a trial has been carried out using a lower dose than that proposed by Dr Frye.  Is it possible to get benefits without the side effects? 

Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial  


Highlights 

Folinic acid treatment is well tolerated in children with Autism spectrum disorders.
Folinic acid treatment shows improvement in Autism Diagnostic Observation Schedule score.
Effect of 10 mg/d folinic acid should be confirmed by a larger a multi-center trial.
Autism spectrum disorders (ASD) are influenced by interacting maternal and environmental risk factors. High-dose folinic acid has shown improvement in verbal communication in ASD children. The EFFET randomized placebo-controlled trial (NCT02551380) aimed to evaluate the efficacy of folinic acid (FOLINORAL®) at a lower dose of 5 mg twice daily.
Nineteen children were included in the EFFET trial. The primary efficacy outcome was improvement of Autism Diagnostic Observation Schedule (ADOS) score. The secondary outcomes were the improvement in ADOS sub scores communication, social interactions, Social Responsiveness Score (SRS) and treatment safety.
The global ADOS score and social interaction and communication sub scores were significantly improved at week 12 compared to baseline in the folinic acid group (P = 0.003, P = 0.004 and P = 0.022, respectively), but not in the placebo group (P = 0.574, P = 0.780, P = 0.269, respectively). We observed a greater change of ADOS global score (−2.78 vs. −0.4 points) and (−1.78 vs. 0.20 points) in the folinic acid group, compared to the placebo group. No serious adverse events were observed.
This pilot study showed significant efficacy of folinic acid with an oral formulation that is readily available. It opens a perspective of therapeutic intervention with folinic acid but needs to be confirmed by a multi-center trial on a larger number of children.
  

Covid-19

There was concern that people with severe autism might be at increased risk during the current pandemic and indeed the death rate among people with intellectual disability/learning disability/mental retardation did double from 240 a month to 480 a month in the UK.  The real scandal though was deaths in care homes for the elderly, in countries with advanced healthcare systems, where tens of thousands of extra deaths have occurred.

In “advanced” healthcare systems like the UK, early in the epidemic, elderly people caught Covid-19 in hospital and when they returned to their care home, they infected others.  Care workers who are allowed/forced to work in multiple care homes then caught the virus in one home and transmitted it to the others.  Nobody was tested until care homes had already become breeding grounds for the virus.

In Hong Kong they report zero covid-19 deaths in care homes.  Elderly people could not return to their care home from hospital without testing negative for the virus, and procedures were in place to release elderly patients from hospital first to repurposed hotels, where they stayed until negative for the virus. Due to their grim experience with the 2003 SARS epidemic, Hong Kong already had very strict measures in place to limit infections and they even had regular rehearsals in care homes of the procedures to implement in future pandemics.

Where we live there was an outbreak in a care home and the authorities’ reaction was to arrest the boss of the care home.  I suppose that is one way to get other care homes to take matters seriously. We even had soldiers posted outside care homes to stop people entering.  In New York, Cuomo’s threat to care homes was that you might eventually lose your license to operate if you flout the rules. If most care homes are flouting the rules, they cannot all lose their licenses.

Some rich Western countries apparently implemented their much-vaunted flu pandemic procedures.  It looks like they have much to learn from other places, from Hong Kong to Greece, who did very much better.  Greece implemented a draconian lock down, very early, and has had a tiny number of cases and just 166 deaths. When Greece re-opens in July to tourists from high risk countries (UK, France, Italy, Spain etc) we will see what happens.

I do wonder why so many people are living in care homes. In Sweden, I saw on TV, one lady complaining that her fit and healthy father, capable of walking a few miles/km had caught covid-19 in his care home, was refused transfer to hospital and later died.  Why was he sent to live a care home in the first place?

Milan has an old care home called Pio Albergio Trivulzia ("Baggina"), it had over a thousand residents and media reports 200+ covid deaths.

There are horrific cases in the UK of young adults being sent to live in small mental hospitals by their parents; they subsequently deteriorate and some have even died.  Why did the parents hand their children over in the first place?  They thought they could not cope at home, but clearly some dedicated institutions have even less capacity to care. 


Conclusion

Re-purposing existing cheap drugs to treat a different medical condition makes a lot of sense, but it is not going to make the inventor or the drug firm much money.  It is not popular with drug producers.

Developing new drugs to treat any neurological condition looks great in the early stages of research and then they all seem to fade way, wasting many tens of millions of dollars.  Don’t raise your hopes.

Is intranasal vasopressin the smartest hormone to choose to modify?  It is possible today, using existing products and appears to be safe, which are the most important issues. I think there is more potential beyond this single hormone.

Treat autism and intellectual disability/mental retardation medically, so those people can live more normally, be more fulfilled and do not later need such expensive care home provision. It is a win-win strategy.









Saturday, 29 February 2020

Clinical Trials – Bumetanide and Memantine & Making Sense of it all in a Single Book





This week I received a message: -

“Your Bumetanide treatment is on trial among 25 teenagers here and parents are loving it”

My reply, brief as usual (unlike my blog posts)

“Great!”

I did not mention that in the first phase of the trial 50% of the teenagers are going to be on the placebo.  It is Dr Ben-Ari’s treatment.

A clinician told me that all the parents of children, to whom she has prescribed bumetanide, think their children are responders and is wondering how to deal with the parental placebo effect.

I had another clinician telling me, “I guess from your experience with the blog, most people are not responders to Bumetanide”.  Then came an analysis of the recent tiny study in China that showed on average there was a measurable improvement on the CARS scale (Childhood Autism Rating Scale), but the question arose was “is this response large enough for parents to notice?”

Memantine (Namenda)

A few years ago, Memantine was also trialled at the University Hospital where we live, the same one that is part of the current Bumetanide study.

Memantine was subject to a rigorous multi-center study of nearly one thousand children a few years ago.  The FDA did not like all the off-label prescribing of Memantine for autism and asked the producer to carry out a serious clinical trial.

The first phase of the trial was to identify the responders, those responders then were to be enrolled to two follow-on trials to collect additional useful data.  The trial was terminated after the first phase was completed because in the subsequent trials the placebo produced as good results as Memantine.

So, we should assume memantine is no good for autism?

Or

In spite of spending millions of dollars and liaising with the FDA on the detailed structure of the trial, the producer did not know how to organize an autism trial properly?

I was just writing a part of my autism book that reviews all the drugs trialed to date in autism and I noted that Antonio Hardan (for me, Dr NAC from Stanford) has published a review of data from those expensive Memantine trials.


… the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

I think that is Hardan-speak for “I think Memantine can be a useful therapy, for some people”.  I am not totally sure and I can see why Barney Rubble might be left scratching his head. 

Hardan is about to become Stanford's Dr Nexium, as he runs a clinical trial of the acid lowering drug esomeprazole (Nexium).  I am not sure why he thinks this will improve autism.  I think it will make some people's autism worse, because over time it will cause intestinal dysbiosis.

https://stanfordhealthcare.org/trials/a/NCT03866668.html

Intestinal Dysbiosis Secondary to Proton-Pump Inhibitor Use



Autism for Dummies?

Writing a comprehensive book about autism is quite a task.  If it is too complicated nobody will read it, but if you do not go into the how and why of autism, you have not contributed very much.

My elder son has suggested calling it “Autism for Dummies”; but that was not helpful suggestion.  We probably all count as Dummies, when it comes to autism, even Dr Naviaux, who I think knows the most.

I like the book written by a US Academic who treated his "untreatable" brain cancer (Gioblastoma, life expectancy 14 months), by reading the research and applying off-label therapies, using cheap generic drugs.  He has lived long enough to publish a second edition.  The first edition has a cover that looks like a medical textbook; he learned his lesson and the second edition looks more like a cookery book.

Before using pharmaceuticals to treat autism, we used a Peter-created, ABA-inspired, home therapy program.  Amongst many resources, we had two old, but excellent books - they were published nearly 40 years ago.  One was blue and one was yellow (code named by me and therapists as the yellow and blue books), one was about increasing good behaviors and the other was about reducing bad behaviors.  I could not leave them lying around at home, because in the tittle of these use cute looking books was in large print “SEVERE RETARDATION”.  The books are great and of course they should have been combined into a single book. 




I am not a fan of giving a nice name to somethings that is bad.

To me, intellectual disability sounds like not being very good at playing chess.

Accept bad news and move on.


Peter’s Book

I decided to have three sections in my book and have a nice cookery book style cheerful cover, so nobody can be embarrassed.  I will not be citing endless complicated research papers. 

I start with all the general issues that are relevant to understanding autism, that do not relate to complicated science.  I finish with a section on how autism can be treated based on applying the research findings to date, what ideas I came up with myself and other people’s ideas shared on this blog. 

Sandwiched in between easy reading section 1 and practical section 3, is a more heavy-going section 2; it is a simplified review of the biology and chemistry that is relevant to autism.  These are things you need to know to make any sense of those tens of thousands of published autism papers, that most people do not know exist.

Section 2 is not going to be a favourite for Roger, but I think he will like sections 1 and 3.  To really judge what to do in the therapy part (section 3), understanding at least part of section 2 is advisable and that is why it has to be there.

It is just like fixing your car, it does help to know a little bit about how it works, before you start tinkering with it.  Even the mechanic at the dealership does not know everything about how it works, but hopefully he knows enough.

If the mechanic cannot fix your car, you just sell it. You may feel a pain in your wallet, but no long-term guilt.

The autism is equivalent is putting your child into an institution, or group home.  You either feel guilty at this point, or later on when something goes terribly wrong. 

I am forever having to fix things - from cars to computers, to solar panels, air conditioners, blocked drains, a leaking swimming pool etc.  Once you realize the "experts" are often not so expert, you engage yourself to solve the problems; or at least tell the expert what you want him to do, like “I found the leak, here it is, now fix it like this”.

Don’t skip section 2, invest time to learn some biology.



Friday, 14 February 2020

Thirst – Too much or too little (Polydipsia and Hypodipsia) Vasopressin and Angiotensin

Today’s post is about both drinking too much water and drinking too little water.

Polydipsia (drinking too much water) is a known cause of death in autism and schizophrenia.  A big part of the reason we talk about autism being a spectrum, is the pioneering work of an English Psychiatrist called Dr Lorna Wing.  Wing outlived her daughter with severe autism, because her daughter Susie developed Polydipsia around the menopause and this caused the sodium level in her blood to fall to the point where her heart stopped beating and she died.  Even though Mum was a (retired) doctor, the condition was not resolved; but Susie’s death should have been avoidable.  Polydipsia is treatable and people should not be dying from it.

Hypodipsia (drinking too little water) can occur in older people, who are neglected in care homes and for a wide range of other reasons.  People with autism treated by the diuretic Bumetanide are at risk of Hypodipsia and indeed this accounts for some of the side effects some people experience.  The other possible side effects of Bumetanide are caused by low levels of potassium in blood. Hypodipsia is also called Adipsia.

Hypodipsia/Adipsia is treatable and much more easily so than Polydipsia; drink more water. Drugs are not used to treat Hypodipsia/Adipsia, therapy relies on modifying behavior.  Drinks can be made more available and more interesting, some kids love drinking from a water fountain or water dispenser. Use a large glass rather than a small glass.  Many people prefer cold water.

Cold water can increase interest in water, but in people who binge drink, cold water is likely to temper their thirst, through a mechanism explained in the paper below called "Thirst".


The Biology of Thirst

There are multiple pathways involved in thirst and so multiple therapies are needed to treat Polydipsia.  The most likely problem relates to Vasopressin, a hormone produced the hypothalamus, a tiny part in the middle of your brain. Vasopressin release is triggered by a hormone called Angiotensin II.

To understand how complex the biology is there are two excellent papers suggested below.


Our bodies are mostly water, and this water is constantly being lost through evaporative and other means. Thus the evolution of robust mechanisms for finding and consuming water has been critical for the survival of most animals. In this Primer, we discuss how the brain monitors the water content of the body and then transforms that physical information into the motivation to drink.


Angiotensin II, or ANG II, is the key hormone driving thirst because it triggers the release of the hormone Vasopressin.

ANP (Atrial natriuretic peptide) hormone should tell you to stop drinking, because your volume of blood is excessive.  This signal must be too weak in people with Polydipsia.

Polydipsia is also a tell-tale sign of the onset of diabetes. Blood sugar rises, your kidneys cannot process the glucose, so the glucose and fluids are excreted as urine making you dehydrated.  You then drink like a fish; hopefully someone notices, otherwise you lose weight, feel tired and finally end up in hospital.

You see in the chart below that eating should activate certain hormones to make you thirsty.







(A) The most potent hormonal stimulus for thirst is angiotensin II (AngII), which is generated when the rate-limiting enzyme renin is secreted by the kidneys in response to hypovolemia or hypotension. Other hormonal stimuli for thirst are secreted by the stomach and pancreas during eating, as well as by the ovaries during pregnancy. Atrial natriuretic peptide, a potent inhibitor of thirst, is secreted by the heart in response to hypertension.
(B) The physiological stimuli that induce secretion of thirst-related hormones include changes in plasma volume and pressure, as well as eating and pregnancy. Decreases in blood volume and pressure increase levels of the dipsogenic hormone AngII, whereas increases in blood volume increase levels of the thirst-inhibiting hormone ANP.

This paper is interesting for those who like details.



Plasma Osmolality

Plasma osmolality measures the body's electrolyte-water balance

Serious electrolyte disturbances, like dehydration (hypodipsia) and overhydration (polydipsia), may lead to cardiac and neurological complications and result in a medical emergency.

Sodium is the main electrolyte found in extracellular fluid and potassium is the main intracellular electrolyte; both are involved in fluid balance and blood pressure control.

The most serious risk to life is from Hyponatremia, low sodium concentration in the blood.

Hyponatremia is the most common type of electrolyte imbalance. It occurs in about 20% of those admitted to hospital and 10% of people during or after an endurance sporting event.

Hypokalemia is the risk to those with autism taking Bumetanide.  The level of potassium circulating in your blood falls below a safe level and blood pressure may rise and abnormal heart rhythm may be experienced. The person will feel lethargic and may experience constipation.






Vasopressin

The hormone Vasopressin has functions within the brain, mediated by 2 types of receptor (Vasopressin receptor 1A and 1B) which relate to behavior (social bonding, aggressive behavior etc).

There is another type of receptor (Vasopressin receptor 2) which is in your kidneys and relates to diuresis and thirst.

The vasopressin system is well known to be dysfunctional in schizophrenia, so we should expect behavioral effects and effects relating to thirst.   There are even measurable irregularities in vasopressin levels in people with schizophrenia.

“It has been found that 69 – 83% of psychiatric polydipsic patients have a diagnosis of schizophrenia, and that 6 –17% of chronic psychiatric patients are polydipsic”

Vasopressin is released within the brain by the action of the hormone Angiotensin II.
Angiotensin II has multiple physiologic effects, including acting in the brain to promote drinking and salt consumption and acting in the periphery to constrict blood vessels and promote water reuptake by the kidneys.

Angiotensin II plays a key role in blood pressure and so there are numerous drugs that reduce Angiotensin II levels.  They are called ACE inhibitors and ARBs.

I did suggest a few years ago that Angiotensin could be an interesting target to treat schizophrenia and some autism.  The reason I was initially interested was the potential immuno-modulatory effect, but Telmisartan in particular has numerous potentially useful effects in autism. 

There are those two old posts:-

Targeting Angiotensin in Schizophrenia and Some Autism


I think it is likely that some sub-types of autism would likely benefit from an ACE inhibitor. As a secondary benefit, it will also reduce any troubling high levels of leptin.

There are other ways to modulate Th1, Th2 and Th17, but if you have elevated Angiotensin Converting Enzyme (ACE), then an ACE inhibitor would appear the logical choice.

How about a clinical trial in adults with Asperger's?


Angiotensin II in the Brain & Therapeutic Considerations


Telmisartan seems to have numerous potentially useful additional effects:


·        Acts as a PPAR gamma agonist, like the glitazone drugs shown effective in autism trials


·        Acts as a PPAR delta agonist, which should activate the impaired PPARδ  PGC-1α signaling pathway, and enhance mitochondrial biogenesis. This should help people with mitochondrial disease and should be evident by increased exercise endurance and, in theory, improved cognitive function.

·        Telmisartan regulates the Bcl-2 cancer gene, implicated in autism


While the effect in autism is complex, Telmisartan is already seen as a potent target for prevention and treatment in human prostate cancer


·        Telmisartan and other ARBs appear to give protection from Alzheimer’s Disease (suggested to be via its effect on PPAR gamma). Perhaps useful for young adults with Down Syndrome, where early onset Alzheimer’s is expected?

·       Telmisartan and other ARBs have a tendency to increase the level of potassium in blood. Up to 10% of people would experience mild hyperkalemia.  For people with autism taking bumetanide, this effect on potassium might actually be helpful. They would need to reduce their potassium supplementation, or might need none at all.


Vasopressin as a behavioral Therapy?

Vasopressin is a target of therapy in both autism and schizophrenia.

The vasopressin system is thought to be dysfunctional in schizophrenia and indeed that life-threatening water intoxication in schizophrenic patients only occurs if it is associated with a concurrent increase in vasopressin secretion.

It is bizarre that the same hormone that controls diuresis also influences social bonding and impulsive and aggressive behavior.  It does explain why in some people all these processes are all disrupted.

It looks like some people need less vasopressin and that can be achieved with an ACE inhibitor. Some people need to tamp down just Vasopressin receptor 1A, encoded by a gene known as the "daring/ruthlessness gene" AVPR1A, which you can with a new drug called Balovaptan.  Some people might want to tamp down just Vasopressin receptor 1B, which may reduce aggressive behaviors.

The research shows that another group of people actually respond to more Vasopressin, this can be achieved with a vasopressin nasal spray.

In the case of our reader Tanya’s son with Polydipsia, I would think an ACE inhibitor may help not only with reducing thirst, but give the Balovaptan effect to his behavior.  My guess is the vasopressin nasal spray from Stanford would have a negative effect on him.

ACE inhibitors are cheap generics with very known safety profiles.  You can achieve the same effect with another class of drugs called angiotensin receptor blockers (ARBs).  It is more a question of which drug produces the least side effects in the specific person. ACE inhibitor and ARBs are use to lower blood pressure.

We will see later that bother ARBs and ACE inhibitors are used in clinical practise to treat Polydipsia.

The recent Vasopressin trials in autism:-

Can manipulating a ‘social’ hormone’s activity treat autism?

Many people with autism have trouble making eye contact, reading the emotions in other faces, and sharing affection. And no drugs are approved to treat such social impairments. Now, results from a small academic clinical trial suggest boosting levels of vasopressin—a hormone active in the brain that’s known to promote bonding in many animals—can improve social deficits in children with autism. But in a confusing twist, a larger, company-sponsored trial that took the reverse approach, tamping down vasopressin’s effects, also found some improvements in adults with autism.
                                                                                                                               
Oxytocin is very similar to Vasopressin, in modifying behavior.



Whereas OT plays a key role both in prosocial behavior and in the central nervous control of stress and anxiety, AVP has primarily  been implicated in male-typical social behaviors, including aggression and pair-bond formation, and in stress-responsiveness.  Although most of the studies conducted thus far on human social behavior have focused on OT, few studies on AVP suggest behavioral effects similar to those found in animal research.  Coccaro and colleagues [33] examined the relationship between cerebrospinal fluid (CSF) AVP and indices of aggression in personality-disordered subjects. The authors found a positive correlation between levels of CSF AVP and life histories of general aggression and aggression against other persons, suggesting an enhancing effect of central AVP in individuals with impulsive aggressive  behavior. Two recent studies examined the effect of intranasal AVP administration on human facial responses related to social  communication. In a first study, Thompson and colleagues [144] examined the effects of 20 IU intranasal AVP on cognitive, autonomic, and somatic responses to emotionally expressive facial stimuli in healthy male students using a placebo-controlled, double-blind design. Whereas AVP did not affect attention toward, or autonomic arousal in response to, emotional facial expressions with different valence (neutral, happy, and angry), the authors did observe selective enhancements of the corrugator supercilii electromyogram (EMG) responses evoked by emotionally neutral facial expressions. Interestingly, subjects of the AVP group yielded magnitudes in response to neutral facial expressions that were similar to the magnitudes of placebo subjects in response to angry facial expressions [144]. In view to the crucial role of this muscle group for species specific agonistic social communication [86], these results suggest that AVP may influence aggression by biasing individuals to respond to emotionally ambiguous social stimuli as if they were threatening or aggressive.

Vasopressin receptor 1A  (encoded by the AVPR1A gene)

The genetic variants of the AVPR1A gene might be related to narcissism and gentle behavior. NatureNews has referred to AVPR1A as the "daring gene". The term "ruthlessness gene" has also been coined by Nature.com

Balovaptan  is a selective small molecule antagonist of the vasopressin receptor 1A, which is under development by Roche for the treatment of autism.  On 29 January 2018, Roche announced that the US Food and Drug Administration (FDA) had granted Breakthrough Therapy Designation for balovaptan in individuals with autism. The FDA granted this based on the results of the adult phase II clinical trial called VANILLA (Vasopressin ANtagonist to Improve sociaL communication in Autism) study.

So, Roche hope that blocking the rector encoded by the “ruthlessness gene” will improve social behavior.  This is reducing the effect of Vasopressin selectively, so not affecting diuresis.

I think you would expect the people who respond well to Balovaptan to also respond well to an ACE inhibitor or ARB, and vice versa.

In my son, an ARB made him want to sing, so I expect Balovaptan would likely have a similar effect.

In my son, increasing oxytocin in the blood, via increasing oxytocin produced in the gut, using the bacteria Lreuteri DSM 17938 did make him more emotional.

Neither of the above two effects were that significant to bother with.


Vasopressin V1b receptor 

 

“Inactivation of the Avpr1b gene in mice (knockout) produces mice with greatly reduced aggression and a reduced ability to recognize recently investigated mice.[13] Defensive behaviour and predatory behaviours appear normal in these knockout mice,[14] but there is evidence that social motivation or awareness is reduced.[15] The AVPR1B antagonist, SSR149415, has been shown to have anti-aggressive actions in hamsters[16] and anti-depressant- and anxiety (anxiolytic)-like behaviors in rats.[17] A single nucleotide polymorphism (SNP) has been associated with susceptibility to depression in humans.[6]

                              

Vasopressin, social cognition and schizophrenia

Introduction: vasopressin, also known as arginine-vasopressin (AVP) or antidiuretic hormone, is mainly synthesized on hypothalamus. It acts on three receptors, of which the centrally expressed V1A and V1B are known to mediate a variety of mental and behavioural effects. In recent years, research on social attachment and cognition in both animal models and humans has also revealed the involvement of vasopressin. Social dysfunction is a key feature of schizophrenia, and in the late 1970’s there were reports associating endogenous vasopressin and psychotic disorders. Indeed, studying the brains of untreated individuals with schizophrenia revealed heightened vasopressin levels, findings which were replicated in plasma levels; the latter were found to normalize after antipsychotic treatment. Methods: searches were undertaken in PubMed and other databases using keywords such as ‘vasopressin’, ‘social cognition’, ‘schizophrenia’ and ‘psychosis’. Results: recent data in human studies suggest that peripheral vasopressin relates to severity of acute psychosis in women with acutely-ill untreated first-episode psychosis, and that the administration of AVP may alter the valence of social stimuli in a sex-dependent manner. In fact, polymorphisms in genes in the AVP pathway have been associated with schizophrenia. The role of the V1A and V1B receptors in the neural regulation of social behaviour has also been studied with several genetic animal models of schizophrenia that reproduce certain aspects of the human disease phenotype. These findings add further evidence that the central vasopressin system may have therapeutics effects on positive and negative symptoms of schizophrenia, probably due to interactions with the glutamatergic and dopaminergic systems. Conclusions: vasopressin plays a significant role in the regulation of social recognition, social communication, and aggression, in integration with the “social behaviour” neural network. Vasopressin regulation is altered in schizophrenia and it has been hypothesized that this might relate to some clinical symptoms and cognition dysfunction. However, other putative factors (e.g., polydipsia, antipsychotics) could account for the results, and the published literature does not yet support a cohesive perspective regarding vasopressin and schizophrenia. Future studies should consider variations in AVP and its receptor genes as potential moderators of the relationship between hormone levels, clinical symptoms, and social cognition.



Psychogenic Polydipsia (PPD) and Hyponatremia in the research

The first thing to note is that the same condition gets called different things.  The fanciest sounding term is Psychogenic polydipsia (PPD), the simplest is Excessive water drinking behavior.  Take your pick, but Google them all.  The best research is the schizophrenia research, as is often the case.


The aim of this study was to determine the incidence of polydipsia in 49 autistic children, and also the influence of psychotropic drugs and residential factors on water drinking behavior, as compared with in 89 mentally retarded children, in schools for mentally handicapped children in Fukui prefecture. Questionnaires were used to detect polydipsia and to assess the severity of the water drinking behavior in the autistic children and mentally retarded children. The incidence of polydipsia in the autistic children tended to be higher (P = 0.074) than that in the retarded children. The severity of water drinking behavior was significantly higher in autism (P = 0.022) than in mental retardation. The majority of the autistic children with polydipsia had been taking no psychotropic drugs. The incidence of polydipsia showed no significant difference between two residential situations, i.e. 'not at home' and 'at home'. The present study suggests that polydipsia or excessive water drinking behavior occurs more often in autism than in mental retardation, possibly due to some intrinsic factor in autism itself.

The present study indicates that polydipsia tends to occur somewhat more often in autism than in mental retardation, and is significantly more severe in autism. Bremner et al. studied 877 mentally handicapped inpatients. In their study, the prevalence of polydipsia in autism was 27.2% (six of 22 cases), compared with 16.3% in the present study. Furthermore, they described a case of autism with fatal water intoxication, who was taking fluvoxamine and chlorpromazine, but did not discuss the role of the drugs as a cause of polydipsia. Autism has been stated to be associated with a hypothalamic-pituitary dysfunction indicated by a blunted-plasma growth-hormone response following the oral administration of l-dopa, an abnormal plasma growth hormone response to insulin-induced hypoglycemia, and a premature or delayed response of growth hormone to clonidine and l-dopa. The blunted growth hormone response exhibited by at least 30% of autistic children to a provocative challenge with l-dopa suggests an alternation of hypothalamic dopamine receptor sensitivity (subsensitivity) in autistic children. The premature response of growth hormone to clonidine and delayed response to l-dopa suggest possible abnormalities of both dopaminergic and noradrenergic neurotransmission in subjects with autism. Furthermore, Hiratani et al. described a case of autism with water intoxication and the episodic release of antidiuretic hormone. The thirst center is said to be located in the hypothalamus. Therefore, a possible factor causing polydipsia in autism may be a hypothalamic–pituitary dysfunction. In 1988, the male case described by Hiratani et al. , who was 19-years old at that time, exhibited a remarkable daily body weight change that was probably due to excessive water drinking. After mild water restriction and intermittent forced water restriction according to the setting of a body weight limit, the daily change became smaller in 1994. We have often observed that autistic children sometimes fiddle with water, or only drink from a single faucet, presumably one manifestation of the restricted interest characteristic of autism. Therefore, preservative tendencies may contribute to compulsive water drinking. In conclusion, in view of the present results, it is possible that the principal cause of polydipsia is some intrinsic factor in autism itself (e.g. a hypothalamic–pituitary dysfunction, restricted interest and activity)


Note in this paper,   Vasopressin  = ADH (antidiuretic hormone)

Psychogenic polydipsia (PPD), a clinical disorder characterized by polyuria and polydipsia, is a common occurrence in inpatients with psychiatric disorders. The underlying pathophysiology of this syndrome is unclear, and multiple factors have been implicated, including a hypothalamic defect and adverse medication effects. Hyponatremia in PPD can progress to water intoxication and is characterized by symptoms of confusion, lethargy, and psychosis, and seizures or death. Evaluation of psychiatric patients with polydipsia warrants a comprehensive evaluation for other medical causes of polydipsia, polyuria, hyponatremia, and the syndrome of inappropriate secretion of antidiuretic hormone. The management strategy in psychiatric patients should include fluid restriction and behavioral and pharmacologic modalities.

In addition to high water intake, risk of hyponatremia is further compounded by impaired water excretion. Impairment in excretion can be due to coexisting ADH increases secondary to stress, nausea, or a syndrome of inappropriate secretion of ADH (SIADH)


Most psychiatric patients with hyponatremia will fit into the final category and will have low plasma osmolality. They will have normovolemia and will lack clinical indicators of altered volume status. PPD and SIADH fit into this category. Most cases of PPD severe enough to cause hyponatremia have a very high volume of intake. These cases have very low levels of ADH and have urine osmolality that is very low (< 100). SIADH by definition has high ADH levels and high urine osmolality (> 500). SIADH, as opposed to the other conditions listed (except salt wasting), has high urine sodium (> 20). High urine sodium occurs in SIADH due to low activation of the RAA system.




Investigation

A comprehensive work-up needs to include a thorough history, physical examination, and routine laboratory tests. Low-cost and high-yield tests for determining diagnosis include the plasma and urine osmolality and plasma and urine sodium. Other tests that may be of benefit include a complete metabolic panel, urinalysis, urea, chest x-ray, and CT head.

Whereas history, serum sodium, and osmolality produce some diagnostic certainty, a water restriction test is the gold standard for diagnosis. A valid test achieves plasma osmolarity greater than 295 mOsm/kg, producing a maximal renal response of ADH in normal individuals. Plasma ADH can be drawn before and after water restriction and then sent if other results are equivocal. With the diagnosis of PPD alone, urine is very dilute prior to water restriction (< 100 mOsm/kg), and plasma ADH is low. The picture can be clouded if there is a corresponding central defect of SIADH and PPD. Then ADH will be elevated (due to SIADH), and the urine will not be maximally dilute. If the defect is renal hypersensitivity to ADH and PPD, the urine still will not be maximally dilute. However, in this setting, ADH could be low or normal (but its increased effect on the kidney would produce an SIADH-like picture). With both comorbid conditions, the added problem of increased renal retention of water will produce hyponatremia more often than the increased intake of PPD alone. In DI, as with PPD, urine would be dilute prior to a water restriction test. ADH levels would depend on whether the defect is central DI (low ADH secretion) or renal DI (low renal response to ADH). Hence, prior to a water restriction test, central DI and PPD can appear similar (low ADH and dilute urine). Although PPD can have low sodium, whereas DI can have high sodium, both can coexist, as exemplified in a case study. After water restriction, PPD alone shows very concentrated urine (> 600 mOsm/L) and high ADH. On the other hand, DI shows urine concentration that rises little even after fluid restriction (< 600 mOsm/L). (Urine concentration can rise somewhat if DI is only a partial defect.) As with PPD, ADH will be elevated in renal DI, but ADH will be low in the case of central DI. Exogenous ADH can be administered immediately following a nondiagnostic water restriction test. In PPD, no increase in urinary concentration occurs after exogenous ADH is administered. Yet in central DI, in which this hormone is lacking, a dramatic increase in urinary concentration will occur. Some impairment in concentrating ability often is present in chronic PPD due to medullary gradient washout and down-regulation of ADH release. These factors can cloud the picture even more. Chronic PPD patients can have maximal urine concentrations closer to 600 mOsm/L instead of the normal range, greater than 800 mOsm/L. (Note: Raising osmolarity with hypertonic saline is best completed by nephrology [0.5 mL/kg for up to 2 hours] if needed due to poor compliance. Raising plasma osmolarity should be avoided in patients strongly suspected of having nephrogenic DI, as it could induce hypernatremia [eg, long-term lithium use]. Drugs listed under “Contributing factors” could interfere with an accurate test.)

Treatment for hyponatremia

See the full paper


Treatment for PPD

Behavioral treatments

Therapeutic fluid restriction is an inexpensive form of treatment; given the higher rates of noncompliance, it may take several days for an effect to be seen in patients with mental illness. Patient weights often are used to determine water intake diurnally. Differences in weight in PPD patients (2.2%) can be much greater than in controls (0.6%) [33]. Reinforcement schedules using tokens to get rewards, as well as removal of these tokens for nonadherence have been used with some success. Most behavioral intervention studies are in inpatients, as they often require close monitoring and substantial time commitment from staff. In extreme cases of nonadherence, patients may require a locked unit away from all water sources. Another novel behavioral outpatient treatment that may suit higher-functioning patients addresses several areas of behavioral change. Therapists used cognitive techniques to address thoughts leading to drinking behavior and then implemented a behavioral program to restrict water intake. They implemented a stimulus control device that included positive reinforcement and coping skills. They followed the patient with weekly visits for 12 weeks and addressed delusions and fears related to drinking excessively. The patient used a record book for time, fluid amount, and situation for each beverage consumed. The patient was given a 500-mL water jug as a stimulus control device and instructed to fill it only six times daily to achieve a goal of less than 3 L for water restriction. The patient used coping skills (substituting ice cubes for drinks, taking small sips, distracting activities). Positive feedback from the therapist and improvement of urinary frequency reinforced fluid restriction.

Drug treatments

Atypical antipsychotic agents have been shown in case reports to have some success in alleviating symptoms of PPD. Clozapine has had effects in the literature in management of PPD but remains unproven in large trials. Low-dose risperidone and olanzapine improved polydipsia in a case report. Their effect potentially stemmed from dopamine receptor regeneration after chronic, typical neuroleptic administration. Kruse et al.  theorized that this reduction in dopamine supersensitivity decreased thirst stimulation. Beta blockers such as propranolol have been found to be effective. Another method of treatment for patients with chronic hyponatremia is demeclocycline, 600 to 1200 mg/d, which directly inhibits ADH action at the level of the distal renal tubules and reduces urine concentration. Demeclocycline is expensive and is associated with nephrotoxicity [15], and it has not been found to be efficacious in double-blind, placebo-controlled trials. Lithium, which works as a direct competitive antagonist of ADH action by inducing nephrogenic DI, is rarely used because its own adverse effects are potentially nephrotoxic and thyrotoxic. A double-blind, placebo-controlled pharmacologic study (crossover design) looked at the use of clonidine, an B-adrenergic blocking agent, and enalapril, an ACE inhibitor, in 14 chronically psychotic, institutionalized patients who suffered from PPD. These medications were administered separately and individually at a dose of clonidine, 0.2 mg orally twice daily, and enalapril, 10 mg orally twice daily. The study found improvement in fluid consumption (determined by calculated urine output and urine osmolality) in approximately 60% of the test subjects who were on either drug, although no behavioral improvement was demonstrated. The study concluded that medications known to affect body water balance might decrease excess fluid intake in some patients with histories of water abuse. ACE inhibitors in other trials as PPD treatment have produced equivocal results. Irbesartan, an angiotensin receptor blocker, was found to be an effective adjunct in the treatment of PPD in a case report of a schizophrenic patient due to a proposed effect of blocking the thirstinducing effect of angiotensin. Recently, newer agents called “aquaretics” that antagonize ADH receptors were developed. These agents have been found to increase free water clearance without directly affecting the handling of tubular sodium. Conivaptan is an aquaretic that recently has been approved by the US Food and Drug Administration for the treatment of euvolemic hyponatremia in hospitalized patients.


Conclusion

I have rather gone into the details in today’s post, because for some people with autism, and more with schizophrenia, it will literally be a matter of life or death.

People do not usually die the first time they binge drink water.

The first medical emergency should set alarm bells ringing, because drinking water to excess is known to be habit forming.  One day your luck may run out.

In today’s post there were a whole range of therapies (ACE Inhibitor, ARB, Propranolol, Clozapine etc) and a list of medical investigations that can be carried out. 



As Agnieszka pointed out to Tanya in the comments recently, a treatable tumor of the Pituitary gland was the cause of death for a well-known Greek girl with autism; the symptom she presented with was Polydipsia. Had the patient had a CT scan of the head, as suggested in the above paper by Dundas, Harris and Narasimhanm, she might be alive today. A tumor there is likely going to affect function of the hypothalamus, where Vasopressin is produced.

I do wonder whether, somewhat paradoxically, treating a person with Polydispsia, with a diuretic might not be a very clever solution.

If you take Bumetanide (or a non-sulfonamide diuretic, for those, like Tanya’s son, with an allergy), you actually get to drink a lot of water, without a problem with low sodium levels (hyponatremia); you just need to eat bananas to maintain potassium levels.  You also might be so preoccupied about dashing urgently for the toilet, you lose all interest in binge drinking water.