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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.











26 comments:

  1. hi all, this is not related to thirst, but I wonder ; is this research wrong? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955787/

    ReplyDelete
  2. The sample is far too small and they draw odd conclusions.

    The data shows that the inflammatory cytokine IL-6 was 8.34 in the group with GI issues and much lower at 4.7 in the non-GI kids.

    but the paper says

    "We did not find significant differences in the levels of plasmatic cytokines between GI and No-GI group except for resistin levels (p = 0.032)."

    So I think I would ignore this paper.

    ReplyDelete
  3. For anyone fighting not only autism but also GI problems like constipation I think this recent article on gut, brain and serotonin could be very relevant:
    https://journals.physiology.org/doi/full/10.1152/ajpgi.00173.2019

    /Ling

    ReplyDelete
  4. And for anyone further interested in the mentioned drug prucalopride for gut issues, here's another article:
    Prucalopride exerts neuroprotection in human enteric neurons
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243219/

    "Notably, the finding that prucalopride rescued the neuronal expression of nNOS as well as pChAT that was reduced by oxidative stress challenge suggests that damage of functionally distinct neuronal populations, i.e., nitrergic (inhibitory) and cholinergic (excitatory) neurons, can be prevented by 5-HT4 stimulation. The 5-HT4 activity is mediated by PKA/CREB signaling, a system crucial for neurogenesis
    [..]
    Ideally, 5-HT4-mediated PKA activation might be exploited to restore neuronal circuitry also in enteric neuropathies.
    [..]
    Prucalopride is currently used for treatment of chronic constipation and has an excellent safety and tolerance profile. These findings widen the role of this compound beyond its well-defined enterokinetic property and support that 5-HT4 activation can be a target for pharmacological intervention in neurodegenerative diseases of the gut."

    I have no idea if this drug is approved for kids though.

    /Ling

    ReplyDelete
    Replies
    1. Ling, you could just use 5-HTP.

      https://www.cuimc.columbia.edu/news/moody-gut-often-accompanies-depression-new-study-helps-explain-why

      Delete
    2. Thanks for the link Peter! :-)
      /Ling

      Delete
  5. Hi,

    My non verbal autistic adult son drinks excessive water. 3 years ago he drank an excessive amount that led to his first tonic clonic seizure. His sodium levels dropped. He is now epileptic. At home we can limit the amount but when we are out at a restaurant he can drink 10 glasses at a meal. I'm going to share your article with his doctor. Do you have any suggestions as to how to address this issue? Thank you.

    ReplyDelete
    Replies
    1. This article is very thorough. Read it slowly, two or three times and you will know all I know. You need some prescription meds from your doctor, as explained in the article.

      Delete
  6. Recently I posted about my son's 3AM rages. Adding BCAAs plus niagen continues be a game changer in terms of mood but then the rages began upon waking in the middle of the night. I added phosphorylated serine about a week ago and this has completely eliminated the night rages. Additionally, I think it's supporting the mood improvements at least in the morning with possibly some language improvements, though subtle.
    I feel like we are onto something with amino acids. What might I try next? I would love to regain some language and reduce the brain fog.
    Thanks for your help.
    Nancy

    ReplyDelete
    Replies
    1. What is the purpose of the serine. In other words, what gave you the idea to try it?

      Delete
    2. Nancy, you are doing well.

      There are very many studies using phosphatidylserine; many are 20 years old. There is even one showing it improves golf performance (it reduces stress).

      https://examine.com/supplements/phosphatidylserine/

      The research does show that it can blunt the increase in stress levels, measured by cortisol levels.

      You did ask about Doctors in the US. I think if you want to try medications I write about, you can find a MAPS doctor in the US who will listen to your requests. One reader finds that Dr Dan Rossignol, will prescribe off-label, if she brings him research evidence to support its use. It will not be cheap.

      Before trying more exotic solutions like Mildronate, I would check your son is not a bumetanide responder. You can get a prescription for this from a MAPS doctor like Rossignol.

      All autism doctors have their pet therapies and may pour scorn on other people's therapies. There is no one-stop shop.

      People who have good exercise endurance and like sport are unlikely to have mitochondrial disease. It is the "couch potatoes" we need to look out for. Mildronate might potentially enhance Complex 1 in mitochondria of people who lack it.

      Delete
    3. Nancy, phosphatidylserine can actually be replaced by buttermilk powder according to my previous trials and a paper that AJ once found. It's dirt cheap in comparison, and has the same effect on lucid dreaming.
      Look for posts with 'buttermilk' here.

      /Ling

      Delete
  7. My son's osteopath suggested it as perhaps my son's cortisol is elevated in the night.

    ReplyDelete
  8. Thanks, Ling. This is actually phosphorylated serine. I have no idea what the difference is, or if it matters. I will search buttermilk, though. These supplements are a small fortune but of course worth every penny when they give even small results.
    As for my son's energy status, he was a very energetic little guy even before diagnosed at 3. Even after the second regression, the high energy continued. But we committed ourselves to making sure he could participate in all the outdoor things we loved, so he skis, bikes, and kayaks. Also, these activities competed with the nonpurposeful arm, fist, lower jaw, and upper body tensing. More and more, at 26, he is less enthusiastic about the idea of activities that require work such as biking. He will do it, and can do it, but would always pick the couch potato if given the choice in recent years.
    I think I always assumed that mitochondria issues were part of his profile.
    Should I assume that is likely not true?
    Nancy

    ReplyDelete
  9. I am actually wondering, after writing about my son's movement stereotypies, if I should be thinking about inhibiting mGluR5. My son was a huge responder to Pantogam, the Russian version of arbaclofen. The improvements only lasted a couple months but his body calmed like I had never seen (except for the later trial of tVNS, again with a short period of improvement). Would this explain his positive response to the BCAAs?
    Nancy

    ReplyDelete
  10. Hi Peter,

    Hope all is well!

    Peter, I just found the following paper on the mechanism of action of Bumetanide in ASD and wanted to share with you and the community. I will be delving into it shortly, but wanted to make sure you've seen it:

    https://www.nature.com/articles/s41398-020-0692-2


    AJ

    ReplyDelete
    Replies
    1. Thanks AJ. This study confirms again that bumetanide is a safe intervention in young children and improves symptoms of autism.

      I think that in a larger clinical trial you would divide the group into non-responders, minor responders and super-responders.

      The point here is that some parents will not notice a drop in CARS score of 4, which is a minor responder. Should they be taking bumetanide every day, or not?

      Over a 10-20 year period, particularly starting in a 3 year old, a minor shift towards normal brain functioning may have a profound impact.

      Delete
    2. Good spotting AJ!
      /Ling

      Delete
  11. Dear Peter Lloyd-Thomas,

    My name is Bruno and I currently live in Brazil. In addition, I am the father of Eduardo who is currently three and a half years old. Last year, at two years and ten months (March 2019), my son was diagnosed with autism. His type of autism has the following characteristics: stereotype, speech repetition, echolalia and little dialogue.
    Since the diagnosis, Eduardo started ABA, which was intensified on September 2019, and he also started one treatment with a DAN supporter who works in Brazil and who was visited in November 2019.
    Since the treatments started, I really felt an evolution of my son, the only problem is that it is a weak evolution. In order to try to improve the situation, I ended up finding your blog and I was intrigued by the amount of good information presented. Therefore, in the light of your knowledge, I would like to ask for help to indicate which remedies I should give to my child, considering what is written in the polypill part of your blog.
    I want to highlight that, according to his medical prescription, my son is currently using PEA, Omega 3, Vitamin D, personalized probiotic, folinic acid and a multivitamin called spectrum needs. Despite all this arsenal, I believe that the result has been very poor.
    In your opinion, what remedies would be interesting to give my child? Bumetanide, NAC, Atorvastatin, Broccoli Sprout?
    I would be very grateful if you could help me where to start, that is, what substances to give to my son.

    Best regards,

    Bruno

    ReplyDelete
  12. Peter, thank you for this post. This is a valuable entry - as not many discuss, at length, this dangerous issue.
    Just wanted to share a follow up - after full work ups, clear scans, the nephrologist recommended we increase his dietary protein. His opinion is stress and/or pain affecting ADH, being the likely factors behind the polydipsia and to increase protein as treatment then we follow up in a month. Easy enough to do. So for now, that is the plan. other ideas waiting in wings if this fails. Thanks again
    ~Tanya

    ReplyDelete
  13. Review of Clinical Studies Targeting Inflammatory Pathways for Individuals With Autism.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886479/

    /Ling

    ReplyDelete
    Replies
    1. Ling, there are even more drugs they could have included in this review paper. The reality is that no amount of clinical trials, of the kind we have seen, will ever show any single drug helps most people in the trial.

      Within the list of drugs they reviewed are therapies that do work for many people. To find them, you would have to try them and that is not the way medicine works, it looks too "hit and miss".

      Two of those drugs are on my to do list, Pioglitazone and Celecoxib. I think Pioglitazone looks good, but for some people (I guess 20%) it will not be tolerated. I am testing it on myself at the moment. NSAIDs help many people with autism, but are not suitable for long term use. Celecoxib is the best suited to longer term use, because it is the most selective for COX-2.

      Delete
    2. I agree, the paper only mentions a few drugs, but I still find reviews like this one good because I can find many references at the same place. Some of the studies they referred to were actually from the 70's and 80's.

      I'm a bit intrigued by you planning a trial on Celecoxib. I have got the feeling that it is the NSAID that is always included as a comparison in studies and that always fails. I'd propose a lower dose of something else and a gut friendly adjuvant...

      /Ling

      Delete
    3. Ling, I have used Ibuprofen for years, but only rarely and for very short periods. Some people use it a lot; it is their main autism intervention.

      Many NSAIDS are also PPAR gamma agonists, like Pioglitazone.

      Sulindac, Celecoxib and Ibuprofen are Wnt inhibitors.

      Ponstan affects those sodium channels that Knut thinks are critical around 2-3 years of age.

      NSAIDS are cheap and available. The question is more about tolerance/side effects. Celecoxib should be the best tolerated.

      Delete
  14. my daughter responds very well to aspirin.....but it is not for long
    term use ... aspirin helps very much her mood swings
    carla marta (locked at home because of coronavirus...be careful!)

    ReplyDelete
    Replies
    1. Aspirin is another cheap Wnt inhibitor.

      Here is a paper listing many more common drugs that can be repurposed as Wnt inhibitors.

      A Second WNT for Old Drugs: Drug Repositioning against WNT-Dependent Cancers
      https://www.mdpi.com/2072-6694/8/7/66/pdf

      Delete

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