Taurine – a cheap Autism intervention worth a trial

 

I did recently write a post all about Taurine and the many effects it has on the body, some of which really should affect autism. 

Taurine for subgroups of Autism? Plus, vitamin B5 and L Carnitine for KAT6A syndrome?

 

Having read the literature, it looked to me that anyone over 50 years old is likely to benefit from a little extra Taurine, but it certainly was not clear whether it would make my 21 year old’s autism better or worse. I went ahead and ordered some to investigate.

In theory one of the many effects of Taurine is negative. Taurine does affect the KCC2 transporter that takes chloride out of neurons the “wrong” way. The other effects include on calcium homeostasis, which we know is disturbed in most autism.

 

N = 2 Trial

Subject #1 (Peter)

I took 2g a day for a month and noticed no effect at all, other than some mild GI irritation.

In adults the long-term effects are numerous and varied throughout the body. Even the cells that remodel your bones (osteoblasts and osteoclasts) have special taurine transporters, whose sole role is to let taurine inside – taurine makes the osteoblasts work harder, while encouraging osteoclasts to take a break. The net effect should be stronger bones.  As you get older your natural levels of taurine fall substantially. There are taurine-rich foods you can eat and if you engage in strenuous exercise your liver starts making more taurine.

 

Subject #2 (Monty)

There is a clear contradiction when it comes to Taurine and sleep. Many energy drinks contain Taurine to keep you alert, but in theory Taurine should be calming and many people take it add bedtime to improve sleep.

Monty, aged 21 with ASD, likes getting up early and going to bed early.

Adding 2g a day of Taurine at breakfast shifted his circadian rhythms, so that he now goes to bed at a time typical for a 21 year old, but still wants to get up at 7am. Monty even fell asleep on the sofa watching TV late one night, something big brother often does. Indeed, Monty received a nod of approval when big brother discovered him in the early hours. 

The most beneficial change has been on his spring and summertime aggression. This has been controlled for years using an L-type calcium channel blocker. This does not resolve the allergy at all, but it “switches off” the consequential anxiety/aggression. With the addition of allergy therapies and the immunomodulation of Pioglitazone (in peak allergy season) the problem behaviors are controlled.

It appears that Taurine has a similar anti-anxiety/aggression effect. Maybe its effect on calcium channels and broader calcium homeostasis is the reason why. Anyway, it works – simple, cheap, OTC and effective.  It has no effect on allergy, in case you are wondering.

  

Conclusion

Taurine can be bought as a bulk powder for very little money. It is not like those numerous expensive supplements that would cost you several hundred dollars/euros/pounds a year.

If you have your own “healthspan polytherapy”, to ward off high blood pressure, high cholesterol, type 2 diabetes, dementia, arthritis, osteoporosis etc, consider spending a few pennies more and add a scoop of taurine.

The people who write to me and tell me how Verapamil has transformed life at home, by banishing aggression and self-injurious behaviors, should seriously consider a trial of Taurine.

 

Pioglitazone for Autism and Specifically Summertime Raging and Verapamil-responsive Autism?

 

Adult-sized people with autism can cause property damage and much worse.

I am told that summertime raging is a common problem encountered by neurologists, but it remains poorly understood and usually remains untreated.

The most common worry for parents of toddlers diagnosed with severe autism is their lack of speech.

By the time these children reach adulthood, the biggest worry for parents is often aggression and self-injury. Often it is the mother who faces the worst episodes of aggression, which is a really cruel turn of events.

Aggression is usually not present in young children with autism, in some people it never develops, but in others it later becomes established as a learned behavior and then you are stuck with how to deal with it.

One of my own therapy targets has long been to improve cognitive function; this can indeed be achieved and then you can improve important daily living skills (adaptive function). Some steps that you can take to improve cognition, and indeed speech, have a downside in that they increase anxiety, which may lead to aggression. Calcium Folinate (Leucovorin) does cause aggression in a significant minority of people.  I think that low dose Roflumilast (60mcg) is cognitive enhancing, as proposed by the researchers at 100mcg, but it does seem to increase edginess/anxiety. DMF (Dimethyl fumarate) increases alertness, which is a good thing, but too much alertness will make you anxious.

When dealing with a full sized adult, which is more important, increased cognition/speech or avoiding explosive aggression?

Clearly there is a need for a compromise.

In adults with severe autism, living at home, entirely extinguishing aggressive behavior looks like the number one treatment goal.

For children in mainstream school, following the regular curriculum, cognitive function has to be a top priority.  Fortunately, this is our case, but only after starting Bumetanide therapy in 2012.

It looks like you can potentially have the best of both worlds - increased IQ and adaptive function, but without aggressive behavior. That is my own experience, but it was not simple.

Pioglitazone has been covered quite extensively in this blog and it is again featuring in the research. Pioglitazone is an interesting old drug used to treat people with type 2 diabetes; the phase 2 trial for autism has been completed.  I doubt there will be a phase 3 trial due to the high costs. Pioglitazone is broadly anti-inflammatory; it reduces the pro-inflammatory cytokine IL-6 and increases the anti-inflammatory cytokine IL-10.

We have seen in early posts how important is IL-6 and that it plays a key role in both allergy and even how milk teeth roots “dissolve” and then permanent teeth erupt. This transition to permanent teeth is another common cause of raging in autism, in our case it was mostly wintertime raging. 

IL-6, either directly or indirectly, seems to negatively affect behavior.

 

PPAR gamma

In earlier posts there was a lot about the various PPARs. These are used in medicine as targets to treat conditions like high cholesterol and type 2 diabetes.

Resveratrol and Pterostilbene are the OTC supplements that some readers are using. Sytrinol is another such supplement, but its cognitive benefit unfortunately just lasts a few days.

Here is a relatively recent paper on the subject, for those seeking the details. 

 

Nuclear Peroxisome Proliferator-Activated Receptors (PPARs) as Therapeutic Targets of Resveratrol for Autism Spectrum Disorder

 

Or just look up the old posts in this blog:- 

https://epiphanyasd.blogspot.com/search/label/PPAR%CE%B3

PPARs are rather complicated, but do seem to be very relevant.  For example, the master regulator of mitochondrial biogenesis, something called PGC-1 alpha, is activated by PPAR gamma. If you have mitochondrial dysfunction that included a reduced number of mitochondria, you might want to make more mitochondria. A PPAR gamma agonist might be beneficial.

Dysregulation of PGC-1 alpha is associated with neurodegenerative and metabolic disorders including Parkinson's, Alzheimer's and Huntington's.

Outside this blog, there is some interest in PGC-1 alpha and autism, particularly in connection with oxidative stress and mitochondrial dysfunction.

 

“In conclusion, we demonstrated mitochondrial oxidative stress may affect a significant subgroup of ASD children and that the SIRT1/PGC-1α signaling pathway may be a promising medical treatment for ASD.”

Source: Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder

It does look like PPARs can be targeted and provide a benefit for at least some types of autism. My choice is Pioglitazone.

 

Dumber in the Summer

In parallel with summertime raging comes the phenomenon I called “Dumber in the Summer”, where cognitive function regresses.

Monty’s assistant told me recently there is no “Dumber in the Summer” this year, and I opened my medicine cupboard and explained why this is indeed the case.

At least in our case, when you resolve summertime raging, you also protect against cognitive regression. That therapy involves Verapamil, Pioglitazone and allergy therapies, Dymista spray (azelastine + fluticasone) plus Ceterizine and Clemastine. Clemastine also has the pro-myelination effect and stabilizes microglia.

 

Pioglitazone Side effects

In the stage 2 trials for autism doses of 0.25 mg/kg, 0.5 mg/kg and 0.75 mg/kg were all found to be safe and well tolerated.

As a summertime add-on therapy it appears very well tolerated.

In adults with type 2 diabetes, who will tend to be overweight and not so healthy, there are common side effects.  At one point, it was thought that there was an association between this drug and bladder cancer. Now this is thought not to be the case.

For adults with severe untreated autism, who are aggressive and self-injure, these behaviors very much limit where they can live and what they can do during the day. Life expectancy is also severely reduced. If Pioglitazone can help control these behaviors, some side effects are likely a price worth paying. 

 

Conclusion

Pioglitazone, by the standards of autism drugs, has plenty of evidence in the literature, regarding both mouse models and humans, to support an n=1 trial.  It addresses neuro-inflammation, one key feature of autism and it has beneficial effects on mitochondria.

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway

In a small cohort of autistic children, daily treatment with pioglitazone eased some autistic behaviors, such as irritability, lethargy, stereotypy, and hyperactivity, without significant side effects

 pioglitazone treatment inhibits the secretion of proinflammatory factors, such as nitric oxide and IL-6, and enhances the levels of the secretion of anti-inflammatory factors IL-4 and IL-10. Therefore, considering the results of Qiu and Li and our present findings, pioglitazone acted to benefit autistic-like behaviors possibly via the inhibition of IL-6 secretion in astrocytes stimulated by LPS, which inhibited the neuroinflammatory response.

 

I think for people whose child with autism has a behavioural or cognitive regression in summer, there is good reason to expect a benefit.  They very likely have allergies or other autoimmune conditions.

For people who deal with aggression and self-injury in a person who responds partially, but not 100%, to Verapamil, they may find that Pioglitazone helps to complete their anti-aggression therapy.

Our doctor reader Agnieszka did her best to collect case studies of people with autism responsive to Verapamil, but not enough parents wanted to participate.

Based on the comments section in this blog, it would look like our reader George in Romania has a son whose son’s aggression is reduced by Verapamil.  If some aggression persists in summer, I think there is a very good chance that Pioglitazone will help reduce it.  George did recently share with us the the anti-inflammatory Probiotic Lactobacillus Plantarum 299v, from the previous post and widely used for irritable bowel syndrome (IBS), improved his son's speech.  

Note that the research clearly shows that most autism has an "inflammatory" element, but the exact nature varies (for details read the work of Paul Ashwood at the MIND Institute).  There are very many different anti-inflammatory therapies that are reported to benefit specific people, but there are no unifying therapies that work for all. Some will inevitably make non-responders worse and potentially dramatically so, like L.reuteri ATCC PTA 6475, found in Biogaia Gastrus. Trial and error seems unavoidable if you want to find an effective therapy.

The research proposes Pioglitazone as a year round therapy for idiopathic autism.  In the phase 2 trial almost half of the children were deemed to be responders to the treatment; not a bad result. I think it also has potential as just a summertime add-on therapy. We used it last summer and now again this summer.

People with a diagnosis of mitochondrial disease, who also present with lethargy, might be another target group because of PGC-1 alpha.

Self-Injurious Behavior (SIB) in Autism– if all else fails, why not ECT?

 

I did mention Electroconvulsive Therapy (ECT) in a recent post as a therapy for Self-Injurious Behavior (SIB) in autism and since there has been a review paper published very recently, it is the topic of today’s post.

There was a previous post on this subject:-

Electro Convulsive Therapy (ECT) and Cannabidiol (CBD) in Autism

By coincidence, Mr Electric, Elon Musk, has just revealed that he has Asperger's Syndrome. I don't think he will be fitting ECT to his Tesla vehicles anytime soon.  ECT is likely only going to be used by those at the other extreme end of the autism spectrum, the ones who do not know was money is, let alone cryptocurrencies.

There are many possible ways to treat someone who self-injures or indeed is aggressive towards others. From a psychiatric unit you might get various psychiatric drugs (antipsychotics etc), protective and restraining devices and in some cases Electroconvulsive Therapy (ECT).

Some literature on ECT suggests that it is effective in almost all cases of SIB.

This blog is mainly about novel personalized medicine and in the case of SIB there are multiple choices, which may, or may not be effective in any one case. In my son’s case the SIB was driven by an ion channel dysfunction which is fully treatable with a cheap little yellow pill, Verapamil.

  

Electroconvulsive Therapy (ECT)

ECT is a psychiatric treatment where seizures in the brain are electrically induced in patients to provide relief from mental disorders.  There are no muscular convulsions.  ECT involves multiple administrations, typically given two or three times per week until the patient is no longer suffering symptoms. ECT is administered under anesthesia with a muscle relaxant.

ECT is often used with informed consent as an intervention for major depressive disorder, mania, and catatonia.

Unfortunately, in autism, maintenance ECT therapy is required.  It is a treatment, not a cure.

The study below refers to catatonia, which you may not be familiar with.

Catatonia is a group of symptoms that usually involve a lack of movement and communication, and also can include agitation, confusion, and restlessness. Until recently, it was thought of as a type of schizophrenia.

Source: https://www.verywellmind.com/what-is-catatonic-schizophrenia-2794979

 

  

Electroconvulsive Therapy (ECT) for Autism Spectrum Disorder Associated with Catatonia and Self-Injury: A Clinical Review 

 

Objectives

We reviewed published clinical reports that evaluated treatment effects of electroconvulsive therapy (ECT) with children, adolescents, and adults who had autism spectrum disorder (ASD), catatonia, and self-injury.

Methods

Published reports were identified from an internet search and summarized according to seven review criteria: (a) participant description, (b) clinical presentation, (c) previous treatments, (d) course of ECT, (e) treatment outcome, (f) side effects, and (g) evaluation methodology.

Results

ECT was associated with clinical improvement in all participants. Most notable benefits included decreased self-injury, acquisition or recovery of functional life skills, elimination of catatonic symptoms, and return to baseline functioning. Maintenance ECT was typically required to sustain improved clinical status in the months and years following acute ECT.

Conclusions

There appears to be sufficient evidence that supports therapeutic benefits from ECT in persons with ASD, catatonia, and self-injury. However, measurement methods and evaluation design vary greatly among reports, there may be a publication bias towards cases with positive findings, and more rigorous clinical research is necessary particularly concerning optimization of maintenance ECT to maximize benefit and monitor for any adverse response.

 

The reports and summarized results are presented in Table 1. Among the participants (N=14), 28.5% were female and 71.4% were male ranging in age from 8 to 33 years old. From this sample, 35.7% were children, 28.5% were adolescents, and 35.7% were adults. Beyond the primary diagnoses of ASD and catatonia, the participants had comorbid conditions of intellectual disability, attention-deficit hyperactivity disorder, bipolar disorder, major depressive disorder, Tourette’s disorder, Addison’s disease, and neuroleptic malignant syndrome. The clinical presentation of participants at the time of referral for ECT was uniformly debilitating. Many participants refused to feed themselves, were significantly underweight and malnourished, and required nasogastric or gastrostomy tube feeling. Their general level of adaptive functioning was typically compromised, described as “needing assistance with feeding, getting dressed, brushing his teeth, and combing his hair”, displaying “significant mood instability characterized by irritability, tantrumming, alternating laughing and crying episodes as well as intermittent insomnia and anorexia”, and exhibiting “spontaneous episodes of punching, kicking, and biting, often requiring her to be restrained by several adults”. Self-injury was severe and long-standing, for example, a child, adolescent, and adult who had a “five year history of self-injury” that “included slapping and punching his head as well as banging his head or his knees and shoulders”, performed “hand-to-head, knee-to-head, and hand-to-body self-injury”, and “struck knees against his head, hit his head against a fixed surface or object, punched his face and head with hands, pressed fingers against his eyes, and bit any part of his body”. The seriousness of cases was reflected in participants who required inpatient hospitalization and were no longer able to attend school, live at home, or participate in the community. Use of protective equipment such as hard and soft helmets, padded gloves, arm and body guards, and rigid arm restraints restricting flexion at the elbow was uniform across reports.

Access to ECT in the USA varies greatly among states based on the presence or absence of procedural restrictions, practice regulations, administrative requirements, and stipulations regarding consent. This variability from state-to-state impacts patient care and evaluation of effectiveness of ECT when procedures and protocols are not uniform and administered consistently.

Maintenance ECT in which the number of treatment sessions was gradually decreased during the hospital stay preceding and then following discharge was indicated in nearly all clinical reports. Haq and Ghaziuddin  wrote that “withdrawal of maintenance-ECT in patients with autism and catatonia often precipitates relapse of symptoms, perhaps more rapidly and predictably than in the treatment of mood disorders”. They advised that m-ECT be continued as long as clear evidence shows it benefits the patient. Similarly, Wachtel, Hermida, and Dhossche proposed that ECT should be considered a “treatment rather than a cure” and that patient relapse remains a concern even with m-ECT in place. Indeed, many of the reports we reviewed found that participants relapsed quickly when ECT was discontinued or treatment frequency reduced, requiring a readjusted m-ECT schedule and/or concomitant pharmacotherapy to confer therapeutic benefit, While our review demonstrates that there are presently no precise parameters and guidelines for administering m-ECT to persons with ASD, the demonstration that ECT regimens must be tailored to unique patient circumstances is in line with m-ECT paradigms among neurotypical individuals.

 

 

Conclusion

Self-injury and aggression in autism can become overwhelming and, one way or another, have to be treated.  Electroconvulsive Therapy (ECT) clearly is one option that may be available, depending on where you live.

If you stop the maintenance therapy, the behaviors will return.  Ideally you live near the hospital. 

In terms of what it is actually doing, I think we can compare it to an old computer whose screen keeps freezing, you just restart it and hope for the best.  Then you know it is time to look around for a new computer, before you lose whatever is on the hard drive.  ECT is like a system reset, without knowing what the underlying problem is. 

In the absence of an effective alternative, why not ECT?

Is there a pharmacological "reset button" for at least some aspects of some autism? A short course of steroids does something along these lines; you can even have a single dose, as in therapy for an asthma attack/exacerbation.  Suramin is not really a monthly "reset", because the drug has a very long half-life and so it is there all month long, just at a slowly reducing level.  

Vasopressin, Oxytocin, the Lateral Septum, Aggression and Social Bonding, Autism gene NLGN3 and MNK inhibitors for reversing Fragile-X and likely more Autism

 

The Lateral Septum, in green, turns the volume

 up or down in aggression

Today’s post started by me checking for anything new in the research about the hormone Vasopressin and autism. I was surprised by just how much research continues to be published on the subject – no smoke without fire, perhaps.

We also get another insight into how aggressive raging develops in the brain; we even have a photo.

A novel therapy for Fragile-X is also thrown into the mix, due to a link to oxytocin.

So, what is cooking in the research?

The first thing to note is that you really do have to look at both Oxytocin and Vasopressin, because these two hormones are very closely related.

We have previously looked at the autism gene NLGN3, this gene encodes the cute sounding neuroligin-3.

 

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

 

The reason people with Fragile-X have autism is because they lack the protein FMRP (Fragile X mental retardation protein).

In healthy neurons, FMRP modulates the local translation of numerous synaptic proteins. Synthesis of these proteins is required for the maintenance and regulation of long-lasting changes in synaptic strength. In this role as a translational inhibitor, FMRP exerts profound effects on synaptic plasticity.

When you look at the interactions of the FMRP protein you can find ways to compensate for this deficiency.  This is nicely illustrated in the graphic below. You just need to find another way to influence elF4E and elF4G.

Some people have told me they find these charts a bit overwhelming, but they precisely show what is going on.  You just have to look up all the terms, you do not know.  In the chart below there is NF1 autism, there is PTEN autism, problems with Ras are called RASopathies and cause MR/ID plus autism. We have at least one reader with TSC (Tuberous sclerosis) type autism. We have readers whose kids lack FMRP, because they have Fragile-X syndrome. 

Today we see that an inhibitor of MnK (in yellow in the chart below) is another via option to treat Fragile-X.

Beyond Fragile-X, we can see that numerous other upstream dysfunctions in the chart can result in miss-expression of neuroligins (NLGNs) in the chart below and then result in autism.

 

 One of the papers below goes further and suggests

“This work uncovers an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, oxytocinergic signalling, and social novelty responses”

“We propose that pharmacological inhibition of MNKs may provide a new therapeutic strategy for neurodevelopmental conditions with altered translation homeostasis”

“Our work not only highlights a new class of highly-specific, brain-penetrant MNK inhibitors but also expands their application from fragile X syndrome to a non-syndromic model of ASD”

 

Regarding Fragile X 

“Collectively, this work establishes eFT508 (an MNK inhibitor) as a potential means to reverse deficits associated with FXS.”

 

What is the connection to Oxytocin?

A problem with your neuroligins causes an impairment in oxytocin signalling.

 

The role of the Lateral Septum (LS) in both aggression and desirable social behavior 

If you scan through the research on vasopressin and oxytocin you will eventually come across references to the LS.  The LS is a part of your brain called the Lateral Septum.

In the picture below you see a mouse brain and the green part is the Lateral Septum (LS).

 

Source: https://neurosciencenews.com/rage-lateral-septum-3637/ 

“Our research provides what we believe is the first evidence that the lateral septum directly ‘turns the volume up or down’ in aggression in male mice, and it establishes the first ties between this region and the other key brain regions involved in violent behavior”

Both social bonding and offensive aggression involve vasopressin receptors in a part of the brain called the Lateral Septum (LS).  Activity in the Lateral Septum (LS) is regulated by inhibitory GABA, and excitatory glutamate.

There is a notable difference between males and females, at least in rats.  No sex differences were found in extracellular GABA concentrations during social playing; however, glutamate plays a major role in female social playing. When glutamate receptors are blocked in the LS pharmacologically, there is a significant decrease in female social playing, while males had no decrease in playing. This suggests that in the lateral septum, GABA neurotransmission is involved in social play behavior regulation in both sexes, while glutamate neurotransmission is sex-specific, involved in regulation of social play only in females.

 

Aggressive behavior in females 

Neural mechanisms of female aggression: Implications on the oxytocin and vasopressin systems

These models allowed me to investigate the role of the brain oxytocin (OXT) and vasopressin (AVP) systems on aggressive behavior. Both neuropeptides are known to regulate social including aggressive behaviors in males and lactating females.

Taken together this part of my thesis shows that the balance between OXT and AVP release within the LS regulates female aggression in a receptor and region-specific manner via modulating GABAergic neurotransmission.

Overall, this thesis shows that females are able to develop escalated as well as abnormal aggression just like males. In addition, the OXT and the AVP system seem to be main players in regulating aggressive behavior in female Wistar rats, especially, regarding their role in controlling aggression by acting on the LS.

 

The effect of Vasopressin as a therapy

 

Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model 

Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGE family member L2 (MAGEL2) gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin could alleviate the disabilities of social behavior. We used Magel2-knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and projections in the lateral septum were inappropriate for performing a social habituation/discrimination task. Mechanistically, the lack of vasopressin impeded the deactivation of somatostatin neurons in the lateral septum, which predicted social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identified vasopressin in the lateral septum as a key factor in the pathophysiology of Magel2-related neurodevelopmental syndromes.

 

In humans, intranasal administration of AVP increased activity in the LS and reciprocated social collaboration (47). Intranasal OXT administration enhances the suppression of oscillatory activity (8–25 Hz) during execution and observation of social actions (48). Altogether, OXT- and AVP-dependent modulation of neural activity in response to social stimuli directly affect EEG activity, which may have a predictive value for the impact of such treatment in ASD-associated disorders. Furthermore, an imbalance between inhibition and excitation is associated with ASD, and AVP treatment could reset the balance by altering the functions of SST neurons (49).

  

Predicting Autism measuring Neonatal CSF vasopressin concentration 

We have yet another predictor of future autism.

Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder

The Russian paper below is very thorough. At least in the case of autism, I do not agree with the therapeutic implications.  The paper suggests Oxytocin agonists (like oxytocin itself) and Vasopressin antagonists.

I propose Oxytocin agonists and Vasopressin agonists, as a practical solution today.  It is not a perfect solution, but totally doable today.

  

The role of oxytocin and vasopressin dysfunction in cognitive impairment and mental disorders 

Oxytocin (OXT) and arginine-vasopressin (AVP) are structurally homologous peptide hormones synthesized in the hypothalamus. Nowadays, the role of OXT and AVP in the regulation of social behaviour and emotions is generally known. However, recent researches indicate that peptides also participate in cognitive functioning. This review presents the evidence that the OXT/AVP systems are involved in the formation of social, working, spatial and episodic memory, mediated by such brain structures as the hippocampal CA2 and CA3 regions, amygdala and prefrontal cortex. Some data have demonstrated that the OXT receptor's polymorphisms are associated with impaired memory in humans, and OXT knockout in mice is connected with memory deficit. Additionally, OXT and AVP are involved in mental disorders' progression. Stress-induced imbalance of the OXT/AVP systems leads to an increased risk of various mental disorders, including depression, schizophrenia, and autism. At the same time, cognitive deficits are observed in stress and mental disorders, and perhaps peptide hormones play a part in this. The final part of the review describes possible therapeutic strategies for the use of OXT and AVP for treatment of various mental disorders.

 

4.4. Autism

Autism spectrum disorder (ASD) is a group of disorders that are characterized by early disturbances of social communication and limited, repetitive behaviour. Individuals with autism have impaired social cognition and social perception, executive dysfunction, and atypical perceptual and information processing. Additionally, they exhibit atypical neural development at the systems level . Autism is characterized by a disturbance of social interaction first of all, but it is also characterized by cognitive dysfunctions, including working memory impairment. The OXT/AVP system plays a role in such deficits. In male mice with a mutation in the Magel2 gene, social behaviour and cognitive functions are disrupted in adulthood, which makes this model similar to ASD. The lack of Magel2 causes a change in the OXT system. Subcutaneous administration of OXT to mice with this mutation during the first week of life suffices to restore normal social behaviour and learning abilities in adult mice. Exogenous OXT stimulates the release of endogenous OXT and inhibits the accumulation of intermediate forms of OXT (this is observed in OXT neurons in mice with the Magel2 mutation). This was revealed by neuroimaging methods. Human ASD is associated with altered face processing and decreased activity in brain areas involved in this process. OXT enhances the importance of social stimulus in ASD, and probably can stimulate face processing and eye contact in people with ASD. Genetic polymorphisms of the OXT and AVP receptor genes are associated with ASD. Additionally, this review revealed a link between social cognition disorders in autism and some SNPs in the OXTR and V1a receptor genes. The most significant associations between SNPs in OXTR and social cognition were found for rs2254298, rs53576 and rs7632287. SNP rs2254298 has been associated with a diagnosis of ASD. SNP in the V1a receptor gene, rs7294536, is closely associated with a deficit in social interactions. In addition, OXTR rs237887 polymorphism affects facial recognition memory in families with autistic children.

 

 

 

 

Fig 1. The role of oxytocin and vasopressin systems in the pathogenesis of mental disorders. Stress activates the HPA axis and rises in plasma glucocorticoid levels, which leads to social through the cortisol release. HPA axis activation increases the risk of development of psychopathologies. OXT and AVP regulate emotional behaviours, multiple aspects of social behaviour and cognitive functions. Negative environment, including stress factor, causes an imbalance of the OXT/AVP system, which also leads to psychopathological behaviour: aggression, social impairment, anxiety, emotional and cognitive disorders. At the same time, the OXT/AVP system forms a reaction to stress oppositely. OXT inhibits the HPA axis stress induced activity (anxiolytic effect). AVP activates the HPA axis (anxiogenic effect). OXT and AVP can be used as the treatment of mental diseases associated with social and cognitive dysfunctions. OXT – oxytocin; AVP – arginine-vasopressin; iOXT – intranasal oxytocin; iAVP – intranasal arginine-vasopressin; ACTH - adrenocorticotropic hormone; CRH – corticotropin releasing hormone; HPA axis - hypothalamic-pituitary-adrenal axis.

 

 

5. OXT and AVP systems in mental disorder treatments in recent years, interest in the usage of OXT as the treatment of various psychiatric diseases is growing. OXT and AVP systems that exist in balance produce the contrary effect on emotional behaviour. Positive social stimuli and/or psychopharmacotherapy can shift this balance towards OXT and can help to stimulate emotional behaviour and restore mental health through this shifting. OXT produces an effect on several neurobiological systems, including the HPA axis, limbic system, neurotransmitters, and immune processes related to stress disorders. The exact effects of iOXT still remain unclear; nevertheless, it is known that iOXT action depends on individual sensitivity. Data from functional magnetic resonance imaging demonstrated that iOXT induces temporary activation of some cortex areas and prolonged activation of hippocampus and forebrain areas. These structures are characterized by a high density of OXT receptors. At the same time, iAVP causes stable deactivation in the parietal cortex, thalamus, and mesolimbic pathway. Importantly, the intravenous administration of OXT and AVP does not repeat activation patterns caused by intranasal administration of OXT and AVP. Nevertheless, it is possible that a small amount of OXT which crosses the blood-brain barrier may lead to an additional central OXT release since OXT is able to bind to brain OXT ergic neurons and cause its own release. Generally, OXT doses administered in studies vary from 15 IU to more than 7000 IU. As the table indicates, the results of these studies are very different. The most frequently used dose is 24 IU. Many studies are focused on the capability of OXT in the treatment of depressive disorders. It was demonstrated that iOXT reduces the time of concentration on aggressive facial expressions and increases the time of concentration on happy faces in men and women with chronic depression. Therefore, iOXT regulates emotion recognition in depression. iOXT can be used in combination with antidepressants, enhancing antidepressant efficiency. iOXT administration positively affects mother-child relationship in mothers with postpartum depression (PPD). iOXT activates the protective behaviour of mothers with PPD towards their children. Similar results were found in animal experiments. In rats, iOXT reduced the depressive-like behaviour in adult animals subjected to early maternal separation. Moreover, the research of specific neurogenesis markers Ki67 and BrdU demonstrated that iOXT promotes hippocampal neurogenesis, which is impaired in depressed rats. Many studies investigate the therapeutic properties of iOXT and iAVP for the treatment of schizophrenia and autism. It is known that schizophrenia disturbs social behaviour; and cognitive function. iOXT has the potential for usage as a therapeutic tool to restore impaired functions during schizophrenia. Some data suggest that iOXT reduces the negative symptoms of schizophrenia, improves working memory, verbal memory and cognitive function, and also improves social function in patients with schizophrenia and schizoaffective disorder. Although many studies indicate a positive effect of iOXT on cognitive function in people with schizophrenia, the neuropeptide has a very selective action on behaviour. The exact mechanism of iOXT action is also indefinite; therefore, its therapeutic potential requires further research. Eventually, iOXT can be used as an additional therapeutic agent in traditional schizophrenia treatment. iOXT can also be applied to ASD treatment. It was found that iOXT improves social abilities in children and emotionality in adult men with ASD. Moreover, the improvement of emotional state was observed in adults after an 8 IU dose, but not after 24 IU. The study of iOXT's therapeutic properties was also carried out using a mouse valproate autism model. iOXT improved social behaviour in that model, and reduced anxiety, depressive-like behaviour, and repetitive behaviour. iOXT has some positive effects in the ASD treatment. Despite this, studies of the potential therapeutic usage of iOXT are still at an early stage, and doctors have insufficient data to prescribe iOXT to patients. A few data indicate the therapeutic possibilities of AVP compared to OXT. It is known that iAVP was used in the treatment of the first episode of schizophrenia, in addition to the traditional benzodiazepine treatment. Cognitive functions (namely the memorization process, long-term and short-term memory) improved in patients. iAVP treatment ameliorated social ability in children with ASD. Additionally, iAVP treatment reduced anxiety and repetitive behaviors in these children. These data indicate the necessity of further investigation of AVP's treatment potential.

 

 

Rescue of oxytocin response and social behaviour in a mouse model of autism

A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases^1-3. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin^4-6, which regulate aspects of social behaviour in mammals⁷. However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3-knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor Nlgn3, regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions. 

Social recognition and communication are crucial elements in the establishment and maintenance of social relationships. Oxytocin and vasopressin are two evolutionarily conserved neuropeptides with important functions in the control of social behaviours, in particular pair-bonding and social recognition7,8 . In humans, genetic variation of the oxytocin receptor (OXTR) gene is linked to individual differences in social behaviour9 . Consequently, signalling modulators and biomarkers for the oxytocin or vasopressin system are being explored for conditions with altered social interactions such as autism spectrum disorders (ASDs)5,6 . In mice, mutation of the genes encoding oxytocin or its receptor results in a loss of social recognition and social reward signalling10–14. Mutation of Cntnap2, a gene linked to ASD in humans, resulted in reduced levels of oxytocin in mice, and the addition of oxytocin improved social behaviour in this model15. However, the vast majority of genetic risk factors for autism have no known links to oxytocinergic signalling. 

Thus, modification of translation homeostasis in Nlgn3KO mice by MNK inhibition restores oxytocin responses and social novelty responses. This work uncovers an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, oxytocinergic signalling, and social novelty responses. Although loss of Nlgn3 impairs oxytocin responses in VTA DA neurons, the behavioural phenotype does not fully phenocopy genetic loss of oxytocin. Oxytocin knockout mice exhibit impaired habituation in the social recognition task10, whereas Nlgn3KO mice habituate normally but exhibit a selective deficit in the response to a novel conspecific. This is probably due to differential roles of Nlgn3 and oxytocin across several neural circuits and over development. Moreover, Nlgn3 loss-of-function also affects signalling through additional GPCRs23. We propose that pharmacological inhibition of MNKs may provide a new therapeutic strategy for neurodevelopmental conditions with altered translation homeostasis. Notably, MNK loss-of-function appears to be overall well tolerated. MNK1/2 double-knockout mice are viable46 and several MNK inhibitors are entering clinical trials for cancer therapy47. Previously available MNK inhibitors were greatly limited by specificity and brain penetrance. Our work not only highlights a new class of highly-specific, brain-penetrant MNK inhibitors but also expands their application from fragile X syndrome41 to a non-syndromic model of ASD. The common disruption in translational machinery and phenotypic rescue in two very different genetic models indicate that genetic heterogeneity of ASD might be reduced to a smaller number of cellular core processes. This raises the possibility that pharmacological interventions targeting such core processes may benefit broader subsets of patient populations.

 

A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice 

Fragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans. FXS is caused by mutations that trigger epigenetic silencing of the Fmr1 gene. Loss of Fmr1 results in increased activity of the mitogen-activated protein kinase (MAPK) pathway. An important downstream consequence is activation of the mitogen-activated protein kinase interacting protein kinase (MNK). MNK phosphorylates the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). Excessive phosphorylation of eIF4E has been directly implicated in the cognitive and behavioral deficits associated with FXS. Pharmacological reduction of eIF4E phosphorylation is one potential strategy for FXS treatment. We demonstrate that systemic dosing of a highly specific, orally available MNK inhibitor, eFT508, attenuates numerous deficits associated with loss of Fmr1 in mice. eFT508 resolves a range of phenotypic abnormalities associated with FXS including macroorchidism, aberrant spinogenesis, and alterations in synaptic plasticity. Key behavioral deficits related to anxiety, social interaction, obsessive and repetitive activities, and object recognition are ameliorated by eFT508. Collectively, this work establishes eFT508 as a potential means to reverse deficits associated with FXS.

  

Conclusion

I think I have written enough about Oxytocin and Vasopressin.

The research is not entirely consistent regarding Vasopressin, but my assumption is that for my kind of autism I want an Oxytocin Agonist and a Vasopressin Agonist, some people might think it would be a Vasopressin Antagonist.

The good news is that there is significant research in humans, reported in previous posts, to support the use of both Oxytocin Agonist and a Vasopressin Agonist

I also think there will be both short-term, or immediate effects, from both treatments but also potentially different long-term effects from continued therapy, that is indeed suggested by the animal research models.  For example, neurite outgrowth is stimulated by oxytocin.  It is suggested that oxytocin may contribute to the regulation of scaffolding proteins expression.

Is it worth using oxytocin as a therapy to generate some extra hugs? You can argue both ways, but the longer-term benefits of correcting low oxytocin levels may be more profound.

The effects of vasopressin and oxytocin are somewhat overlapping. We know that low levels of vasopressin in spinal fluid are a good marker for autism, so putting a little extra vasopressin in the brain does not seem unreasonable.

As usual with the human body, the effects of oxytocin and vasopressin are different within the brain and in the rest of your body.  Also, the levels of these hormones in your blood are not a good predictor of their levels within the brain.  This is a reoccurring problem.  Because taking a spinal fluid sample is an invasive procedure, it is rarely taking place and then endless time and money is wasted on blood tests that may well send the doctor in the wrong direction, or just no direction.

It is highly likely that increasing Oxytocin and Vasopressin in the brain is going to affect aggressive behaviors, via actions in the Lateral Septum (LS).  Due to the role of GABA potentiating activity in the Lateral Septum (LS) you might expect a possible difference in bumetanide-responders and bumetanide non-responders (because GABA is acting as excitatory).

I would consider Oxytocin and Vasopressin as fine-tuning autistic behavior and you would have to personalize the dosage. In some people it might be a case of either or, rather than both.

Using MNK inhibitors to treat human Fragile-X looks a great idea and hopefully a commercialized therapy could then be trialed in broader autism.