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.  

Autism and the Police – challenging behaviors leading to restraint

 

Today’s post is about an issue that seems to cause a problem in some countries far more than others. While some people with mild autism (Asperger’s) may feel anxiety when dealing with the police, the big problem occurs when the police are called in to restrain someone with severe autism and particularly someone who is also non-verbal with MR/ID.  Most people with untreated severe autism actually have MR/ID, even if it was never diagnosed.

It would never occur to me to call the police to restrain my own son, but in North America this is a regular occurrence.  It sometimes does not end well, often it was the parents who called the police, when it is not the parents it is likely to be the school. The research shows that most often the police in the US do successfully resolve the incident.

I did ask my son’s assistant what she knows about the police dealing with aggressive autistic people. She knows lots of people with autism and parents. She initially did not understand my question, because where we live nobody would think to call the police to deal with their autistic son/daughter. You would just deal with it yourself, as best as you could.  Even if you did call the police, there is nowhere for them to take an aggressive person with autism.

Schools have a difficult job dealing with people with autism who exhibit challenging behaviors.  They have a range of options that do include restraint and indeed seclusion.  Monty, now aged 17 with autism, used to have a male 1:1 assistant for a couple of years.  The assistant was training to be a speech therapist and also worked at a special school. Because he was a male in his mid-twenties and athletic, he was the first option when a child in the school got aggressive and needed restraining. In some schools this restraint involves several staff and it is not without risks to all involved.

 

A Dreaded Part Of Teachers' Jobs: Restraining And Secluding Students

Earlier this year, an NPR investigation with WAMU and Oregon Public Broadcasting found deep problems in how school districts report restraint and seclusion. Following that investigation, NPR reached out to educators about their experiences with these practices. 

The view of some unhappy UK parents:-

Disabled children ‘constantly’ physically restrained and left with bruises and trauma, parents say

Small children are sometimes placed in a supposedly safe room and left alone to calm down. 

Our son was always in school with his own 1:1 assistant and never required any intervention from the school’s staff, even when he had extremely “challenging” behaviors as an 8 year old. At that time he only went to school in the morning and his assistant at that time, though female, was very tall, young and sporty and so well able to take care of physical behaviors, so keeping the peace in the classroom.

 

Challenging Behaviors as Children get Bigger

Young children with autism do have meltdowns for numerous reasons, but these are not usually difficult to deal with.  As children get bigger and stronger, challenging behaviors can become so severe that parents struggle to cope.

When Monty had his 9 months of raging, he was only eight years old; I could easily pick him up and hold him upside down, which was his “reset button”. At his current age of 17 years old, I could still do this …  but I might drop him if he wriggled.

Hopefully, parents figure out and treat challenging behaviors in childhood and so are not left with an aggressive autistic adult to deal with.  It is these adult-sized people with challenging behavior who are at risk if they encounter the police. Given the difficulty special schools have dealing with aggressive autistic kids; it is hardly surprising that many police officers lack the skills to safely restrain an aggressive adult-sized person with autism. In my opinion an untrained police officer is entirely the wrong people to be involved.

One piece of advice I was given shortly after Monty was diagnosed with autism, was from my doctor mother, “make sure he does not get aggressive, as he gets older”.  This is very wise advice, perhaps rather easier said than done, but was based on her seeing what actually happens to adults with a psychiatric diagnosis.

Here is a study from Canada exploring families living with a child with autism and challenging behaviors.

 

Home Sweet Home? Families’ Experiences With Aggression in Children With Autism Spectrum Disorders

Although not inherent to the diagnosis, many individuals with autism spectrum disorders (ASD) display aggressive behavior. This study examined the experiences of families living with individuals with ASD who also demonstrate aggressive behaviors. Using a qualitative approach, semi structured interviews were conducted with parents of nine males with autism and aggression. Eight families’ homes also were observed. Through constant-comparison analysis of interview data, triangulated with home observations, three central processes were identified: deleterious impact on daily routines and well-being of family members, limited supports and services, and financial strain. Emergent themes included isolation, exhaustion, safety concerns, home expenses, respite needs, and limited professional supports and alternative housing. Examination of families’ experiences living with someone with ASD who is aggressive, and the impact of aggression on the supports and services that families receive, constitutes an important step in tailoring resources to best meet families’ needs.

 

The families who participated in this study demonstrated great resiliency in the face of adverse living situations. Many families of individuals with ASD become more optimistic and accepting of their children’s diagnoses over time, relying less on formal supports and services. Unfortunately, this optimism was not expressed by the families who participated in this study because aggression presented significant and pervasive challenges to their families, for which adequate knowledge, supports, and services were not in place. Many of the families in this study received ASD specific medical, home- and community-based services in a geographic location known to have a relatively high level of service for individuals with ASD; however, parents perceived that none of these services were equipped to deal with aggression

 

Canada is one of the better countries when it comes to dealing with severe autism.

In the United Kingdom, when it comes to autism and the police, it appears that neither party is satisfied.

Experiences of Autism Spectrum Disorder and Policing in England and Wales: Surveying Police and the Autism Community 

An online survey gathered the experiences and views of 394 police officers (from England and Wales) regarding autism spectrum disorder (ASD). Just 42 % of officers were satisfied with how they had worked with individuals with ASD and reasons for this varied. Although officers acknowledged the need for adjustments, organisational/time constraints were cited as barriers. Whilst 37 % of officers had received training on ASD, a need for training tailored to policing roles (e.g., frontline officers, detectives) was identified. Police responses are discussed with respect to the experiences of the ASD community (31 adults with ASD, 49 parents), who were largely dissatisfied with their experience of the police and echoed the need for police training on ASD.

 

I came across a very detailed study from the US, with very many links to other papers, for those interested in this topic. In the US it seems that most parents are satisfied with encounters with the police.  Given the bad impression of the American police given by much of the media, this is very noteworthy and encouraging. 

Correlates of Police Involvement Among Adolescents and Adults with Autism Spectrum Disorder

This study aimed to describe police interactions, satisfaction with police engagement, as well as examine correlates of police involvement among 284 adolescents and adults with autism spectrum disorder (ASD) followed over a 12- to 18-month period. Approximately 16% of individuals were reported to have some form of police involvement during the study period. Aggressive behaviors were the primary concern necessitating police involvement. Individuals with police involvement were more likely to be older, have a history of aggression, live outside the family home, and have parents with higher rates of caregiver strain and financial difficulty at baseline. Most parents reported being satisfied to very satisfied with their children's police encounters. Areas for future research are discussed in relation to prevention planning.

 

Similar to past studies concerning emergency service use among individuals with ASD (e.g., emergency department and psychiatric in-patient services; Kalb et al. 2012; Lunsky et al. 2015; Mandell 2008), aggression was the primary presenting concern resulting in police contact in the current study. A significant proportion of police resources are expended on resolving mental health crises in the community (de Tribolet-Hardy et al. 2015; Short et al. 2014). The appropriateness of such police involvement has been questioned due to the time, cost, and lack of adequate mental health training provided to police (Clifford 2010; Fry et al. 2002). Research concerning more effective solutions to responding to psychiatric crises, such as the use of crisis intervention teams (Franz and Borum 2011; Compton et al. 2008), is promising and should be extended to include individuals with ASD. A history of aggression differentiated individuals who did and who did not interact with police in the observation period. Aggressive behaviors commonly occur in ASD (Kanne and Mazurek 2011; Matson and Rivet 2008; Mazurek et  al. 2013), with rates reported to occur in up to 68% of affected individuals at some point in their lives (Lecavalier 2006). These behaviors can result in negative physical, emotional, and financial consequences for family members (Hartley et  al. 2012; Hodgetts et  al. 2013). Despite a high need and the recognized existence of effective empirically based interventions, there is often a lack of professional knowledge and community-based resources to assist individuals with ASD and their families deal with aggressive behaviors (Hodgetts et  al. 2013; White et  al. 2012). In the current study, an individual’s history of aggressive behavior, caregiver strain and police contact were associated with each other, further highlighting the need for appropriate community-based family supports. Police contact in the observation period was more likely among older individuals with ASD, those living outside of the family home, and individuals without structured day activities at baseline. Age, family involvement, service use and/or community involvement have similarly been shown to predict involvement with police and the greater criminal justice system among typically developing youth (Greenberg and Lippold 2013; Ryan and Yang 2005; Williams et al. 2007). There is a recognized decline in service availability in the adult service sector for individuals with ASD; a phenomenon referred to as a “service cliff” in past ASD research (Shattuck et al. 2011; Turcotte et al. 2016). Findings from the current study emphasize the importance of developing supports and service models to meet the needs of this population. Autism spectrum disorder symptom severity and ID status were not associated with police contact in this convenience sample. Similarly, Rava et al. (2017) found no association between individuals’ conversation ability and police contact. The diversity of individuals’ presentations emphasizes the broad training police may need to properly understand and interact with all individuals with ASD. To this effect, ASD support and advocacy organizations have initiated various tools to assist individuals with ASD disclose their diagnosis and individualized communication needs to law enforcement officers (e.g., information cards; Debbaudt 2006). The efficacy of these tools from the perspectives of the individual with ASD and law enforcement officials is an area for future research. Most police interactions did not result in criminal charges being brought against the individual with ASD. This replicates Rava et al.’s (2017) increased rate of police contact compared to convictions. In the current study, police contact resulted in a variety of outcomes, including crisis resolution, transportation to the emergency department, and/or physical restraint. Additionally, parents reported that police involvement had a calming effect in nearly half of all incidents and reported, on average, being somewhat satisfied with their children’s interactions with police. This is in contrast with a recent U.K. based study where almost three-quarters of surveyed parents of adults with ASD reported unsatisfactory ratings of their interactions with police officers (Crane et  al. 2016). In addition to being from a different jurisdiction, that study included only retrospective reports from caregivers who had police involvement, whereas our study followed a larger group of families forward, some of whom had police involvement in the observation period.

 

In the study below from Australia, it concludes that more training and awareness is needed by the local police when called in to deal with autistic people being violent at home. Not surprisingly, it is the parents who usually get attacked by the autistic person – so better keep in shape! 

Domestic violence events involving autism: a text mining study of police records in New South Wales, 2005-2016

Highlights

·      Text mining was applied to domestic violence police records in Australia.

·      Domestic violence involving autism most commonly involves parent-child relationships.

·      Autistic domestic violence more commonly involves intellectual disability.

Background

Recent research and high-profile media cases have suggested an association between autism spectrum disorder and violent behaviour. Whilst certain characteristics of autism may make individuals vulnerable to increased involvement with the police, either as a victim or person of interest, evidence regarding this is scant. The present study used a population-based dataset to describe the characteristics of domestic violence events involving autistic and non-autistic adults.

Methods

Text mining and descriptive statistics were applied to police-recorded data for 1,601 domestic violence events involving autism and 414,840 events not involving autism in the state of New South Wales, Australia from January 2005 to December 2016.

Results

The relationship between autistic victims and perpetrators was predominantly familial or carer whereas events not involving autism were predominantly involved intimate partners. Abuse types and injuries sustained were similar for both autistic and non-autistic events. The most common mental conditions present in autistic perpetrators were developmental conditions and intellectual disability, whilst non-autistic perpetrators most commonly reported psychoactive substance use or schizophrenia.

Conclusions

These results highlight the need to further understand the risk factors for strain and violence in relationships between autistic adults and their family members or carers, especially for those with comorbid behavioural developmental conditions. Given the uniqueness of domestic violence involving autism found in this study and the potentially unique nature of the circumstances surrounding these events, appropriate police awareness and training in relation to autism is needed.

Unfortunately, calling for help, whether from the police or a psychiatric hospital can lead to a quick downward spiral of events, from which there may be no return. 

In the US there are residential places at Kennedy Krieger where they try and treat children with extremely challenging behaviour – good luck to them!  The idea is that after a few weeks the child gets sent home. There are very limited places and I wonder who pays for them.

Where we live, there still are some residential mental institutions.  One boy we know of got very aggressive towards his mother and he was sent to live in such a facility, surrounded by adults with schizophrenia and other conditions.  This boy actually likes living there, it is very structured and there are activities, so he is not trying to escape home.

 

France and Belgium

I did meet a French former classmate of mine a few years ago and she told me all about her nephew with severe autism. Life got so bad with his aggression at home that, as a young boy, he was sent to live in an institution in Belgium.

I always remember this because I thought it extremely odd that a large country like France would send its disabled children across the border to live in little Belgium. I also wondered who paid for this.

The family were in no rush for the boy to come home and in fact feared the day when he would age out of the Belgian facility for children.

Across the world mental hospitals for adults have been shut down and they have not really been adequately replaced with alternatives. So there may be nowhere to go.

The French sending kids with autism to Belgium has actually been going on for years, as you can read below.

Disabled French Alone – or Sent to Belgium

For years France has been sending disabled citizens to Belgium. This kind of “forced exile”, denounced by the paper Libération, applies especially to adults. Problems are a bit different for children: certain parents are themselves addressing Belgium because it proposes education methods, especially for autistic children, which still do not exist in France. 

In his latest report, the EU Commissioner for Human Rights reproached the French government for depriving an estimated 20 000 disabled children of school education. 

 

Conclusion

The research suggests that 2 in 3 people with autism will engage in aggressive behaviors at some point in their life. These tend to be learned behaviors, meaning once they develop they are likely to reoccur.  Once the "beast within" has been discovered, it is really a case of controlling it, rather than banishing it forever; it is likely both biological and behavioral.

For children with challenging aggressive behavior, there should be an urgency to resolve the issue as much as possible, otherwise the future will not be bright.  Psychiatric drugs are unlikely to be the answer, they are just a band-aid with troubling side effects.

Calling the police to deal with an aggressive adult-sized person with autism does seem to be asking for even more trouble. In the US, it may work well for some people, some of the time, if they happen to have extremely understanding and well-trained first responders, but I think their luck will eventually run out.

Without aggressive behavior there would be no need for institutionalization, in a strict setting.

The medical literature and parent reports are scattered with many clues and ideas of how to resolve challenging aggressive behavior in autism; you just have to look and the sooner the better. It may well take time to find the optimal solution, but the sooner you start looking, the sooner you will find it.  Verapamil is an effective solution in my case, but yours is very likely to be different.  Nobody keeps a comprehensive list to refer to.

Based on the studies I reviewed, the police in the US are doing a better job dealing with autism than the police in some other countries. This is not the impression you get from media reporting, which makes it seem that the cops will just shoot you, or suffocate you, if you are autistic and aggressive. So a pat on the back is deserved.

When is an SSRI not an SSRI? Low dose SSRIs as Selective Brain Steroidogenic Stimulants (SBSSs) via Allopregnanolone modifying GABAa receptors and neonatal KCC2 expression

Today’s post might seem to have a very complicated tittle, but to regular readers it is really just another take on what we have seen time and time again.

Today we see how another steroid imbalance in autism – low levels of allopregnenolone in this case – affects the neurotransmitter GABA and indeed the chloride transporter KCC2.

Putting Prozac/Zoloft to a better use?

I did report previously on a trial in adults with autism where pregnenolone was used.

Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder.

Pregnenolone - an effective OTC anti-inflammatory therapy for autism?

Why Low Doses can work differently, or “Biphasic, U-shaped actions at the GABAa receptor”

Recall that disturbed hormonal homeostasis is a key feature of autism. What matters is the level of each hormone inside the brain (i.e. centrally), not in your blood. The only way to get a reliable idea of what is going on would be to take a sample of spinal fluid.

Today we look at boosting allopregnenolone not with a steroid hormone, but with a 1/10^th dose of Prozac (Fluoxetine) or indeed Zoloft (Sertraline). Prozac is a selective serotonin reuptake inhibitor (SSRI) when given at the usual dose of 20-80mg, but at 2.5mg it does not function as an SSRI.

At regular doses selective serotonin reuptake inhibitors (SSRI) drugs like Prozac are well known to cause problems, as do benzodiazepines like Clonazepam.

Thanks to Professor Catterall we saw in earlier posts how tiny doses of Clonazepam have an effect on one particular sub-unit of GABA_A receptors. By fine tuning the response of this receptor we saw how a cognitive improvement can be achieved, in some people. The dose is so low there appear to be no long term side effects. At least one other professor of medicine, I am in contact with, has been treating his son with autism with low dose clonazepam for years.

Many adults and children with autism are prescribed Prozac for anxiety. Even Temple Grandin has said she takes Prozac.

At low, non-serotonergic doses, some drugs like Prozac show a different mode of action, they potently, positively, and allosterically modulate GABA action at GABA_A receptors. These drugs achieve this by increasing the amount of the steroid hormone allopregnanolone.

Neurosteroid biosynthesis down‐regulation and changes in GABA_A receptor subunit composition are a feature of several neurological conditions, including some autism.

Stimulating allopregnenalone biosynthesis will have multiple effects including on TSPO and endocannabinoid receptors.

SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake

Brain principal glutamatergic neurons synthesize 3α-hydroxy-5α-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABA_A receptors. Cerebrospinal fluid (CSF) Allo levels are decreased in patients with posttraumatic stress disorder (PTSD) and major depression. This decrease is corrected by fluoxetine in doses that improve depressive symptoms. Emotional-like behavioral dysfunctions (aggression, fear, and anxiety) associated with a decrease of cortico-limbic Allo content can be induced in mice by social isolation. In socially isolated mice, fluoxetine and analogs stereospecifically normalize the decrease of Allo biosynthesis and improve behavioral dysfunctions by a mechanism independent from 5-HT reuptake inhibition. Thus, fluoxetine and related congeners facilitate GABA_A receptor neurotransmission and effectively ameliorate emotional and anxiety disorders and depression by acting as selective brain steroidogenic stimulants (SBSSs).                               

When the results of these in vitro studies are compared to those of our in vivo studies, it becomes evident that in mice the doses of fluoxetine and norfluoxetine that cause a rapid increase in brain Allo levels do not exceed brain concentrations in the low nanomolar range, whereas the fluoxetine concentrations that directly activate 3a-HSD in vitro are in the micromolar range. Moreover, the high potency and stereospecificity of fluoxetine and norfluoxetine in decreasing aggressive behavior and normalizing brain Allo content during social isolation (see Table 1, and Figure 3) support the notion that these compounds facilitate the action of 5a-R type I or 3a-HSD by an unidentified indirect mechanism, which is most probably perturbed by protracted social isolation.

Thus, these drugs, which were originally termed ‘SSRI’ antidepressants, may be beneficial in psychiatric disorders because in doses that are inactive on 5-HT reuptake mechanisms, they increase the bioavailability of neuroactive GABAergic steroids. On the basis of these considerations, we now propose that the term ‘SSRIs’ should be changed to the more appropriate term ‘selective brain steroidogenic stimulants’ (SBSSs), which more accurately defines the pharmacological mechanisms expressed by fluoxetine and its congeners.

Conclusions

The pharmacology of the S stereoisomers of fluoxetine and norfluoxetine appears to be prototypic for molecules that possess specific neurosteroidogenic activity. The doses of S-fluoxetine and S-norfluoxetine required to normalize brain Allo content downregulation, pentobarbital action, aggressiveness, and anxiety in socially isolated mice are between 10-fold to 50-fold lower than those required to induce SSRI activity. However, the precise mechanisms of action by which S-fluoxetine and S-norfluoxetine increase neurosteroids remain to be investigated.

Derivatives of S-fluoxetine and S-norfluoxetine, acting with high potency and specificity on brain neurosteroid expression at doses devoid of significant action on brain 5-HT reuptake mechanisms, may represent a new class of pharmacological tools important for the management of anxiety, related mood disorders, dysphoria, fear, and impulsive aggression.

On the basis of these data, new drugs devoid of SSRI activity but that are potent neurosteroidogenic agents should be developed for the treatment of psychiatric disorders that result from the downregulation of neurosteroid expression, including major depression, and in the prevention of PTSD.

France often gets very negative comments about how it treats people with autism, but in the case studies below it looks like some innovative work is going on in some of their day hospitals, where boys and girls with severe autism are sent to pass their time. 

The system in England has recently been highlighted as being pretty appalling, where over 2,000 people with autism are currently detained in Assessment and Treatment Units (ATUs), privately run secure residential "hospitals", at great cost paid for by the State. Those inside might enter with the approval of their family to stay for 3 weeks for respite care, but end up being detained for 3 years, or even longer. The State assumes their guardianship and the individual and parents are powerless. The individuals are kept in prison-like conditions and not surprisingly get worse not better, the worse they get, the harder it is ever to be released. Hard to believe this is still happening.  If you live in England, best not to hand your child over to the State. Someone has even written a book about escaping from such a unit. This is no better than the old State Hospitals in the US, that finally were closed down in the 1970s, that warehoused mentally disabled people, until their premature death.

Low-Dose Fluoxetine in Four Children with Autistic Spectrum Disorder Improves Self-Injurious Behavior, ADHD-Like Symptoms, and Irritability

Autism Spectrum Disorder (ASD) is defined by the copresence of two core symptoms: alteration in social communication and repetitive behaviors and/or restricted interests. In ASD children and adults, irritability, self-injurious behavior (SIB), and Attention Deficit and Hyperactivity Disorders- (ADHD-) like symptoms are regularly observed. In these situations, pharmacological treatments are sometimes used. Selective Serotonin Reuptake Inhibitors- (SSRI-) based treatments have been the subject of several publications: case reports and controlled studies, both of which demonstrate efficacy on the symptoms mentioned above, even if no consensus has been reached concerning their usage. In this article four clinical cases of children diagnosed with ASD and who also present ADHD-like symptoms and/or SIB and/or other heteroaggressive behaviors or irritability and impulsivity treated with low doses of fluoxetine are presented.

Case 1 

An 8-year-old girl (19 kg) had an ASD diagnosis according to the DSM-5 and ADI-R criteria based on information provided by parents. She also had significant mental retardation, with severe SIB (banging her head against objects and biting her hands), forcing her entourage to maintain a daily and permanent physical restraint. She spends most of her time in a day hospital. She received the following pharmacological treatment: risperidone 2 mg/d and cyamemazine 80 mg/d without modifications to her SIB and at the price of a major slowing down and a manifestation of a tendency toward blunting. The CGI severity of illness score was at five (markedly ill). We decreased and stopped risperidone and started valproic acid. After four weeks of valproic acid 400 mg/d in combination with cyamemazine (60 mg/day), SIBs did not improve. Then, we added fluoxetine 2.5 mg/d and increased it after one week to 5 mg/d and to 10 mg/d in the third week. After one week, the CGI improvement scale (CGI-I) was at two; after three weeks, it lowered to 1 (very much improved). We also observed a significant decrease in anxiety as well as the disappearance of SIB (disappearance of the behavior consisting of the banging and rubbing her head against objects). However, it should be noted that the entourage kept the bandages on her hands because she continued to bite them, even if she did it with less intensity than before. There were no side effects. After three months of fluoxetine, her clinical state remains stable.

Case 2 

A 12-year-old boy (70 kg), with DSM-5 criteria for an ASD and ADI-R confirming this diagnosis, exhibited extreme irritability, violence, and impulsiveness as well as SIB (he had thrown seven television sets out of the window). The CGI severity illness scoring was at six (severely ill). In the day hospital where he spent most of his time, it was difficult for staff to manage his impulsivity and unpredictability. His treatment included risperidone 4 mg/d as well as loxapine 80 mg/d. Despite this pharmacological treatment, episodes of aggression and SIBs continued. This treatment induced a significant weight gain (8 kg in 5 months). Treatment with fluoxetine 2.5mg/d was introduced and increased to5mg/d after one week and to 10 mg/d at the beginning of the third week. After one week, there was a CGI-I score of three, which decreased to two after two weeks of treatment and to one after three weeks. Such a positive clinical response allowed for a reduction in risperidone to 2mg/d and in loxapine to 60 mg/d. The treatment was tolerated well by the patient, and he began to lose weight (4 kg). After two months off luoxetine, his clinical state remains stable.

Case 3

 A 6-year-old male child (30 kg) with DSM-5 criteria and ADI-R for an ASD exhibited problems of SIB and repetitive behaviors (washing his hands for more than 30 minutes at least two to three times per day), severe irritability, frequent crying, social withdrawal, and inappropriate speech. Treatment with risperidone 2mg/d had improved irritability and partially the SIB, but it had also produced significant weight gain (four kg in three months). A decrease in the risperidone dosage seemed necessary. Treatment with fluoxetine2.5mg/d was begun, which quickly led to a reduction in inappropriate behavior (for example, impulsive crawling on the ground in the classroom). After one week, the CGI-I scoring was at two. The dosage was gradually increased to 5 mg/d the second week and to 7.5mg/d the third week. The repetitive behaviors gradually subsided. After three weeks the CGI-I score was at one, and it remained stable for nine weeks. The risperidone dosage could be decreased to 0,5 mg/day and the patient’s weight remained the same.

Case 4 

A 12-year-old boy (62kg) withDSM-5 and ADI-R criteria for a severe case of ASD, including severe ADHD-like symptoms, often required physical restraint and did not improve despite a long-term treatment of risperidone 3 mg/d as well as melaton in 4mg at bedtime. The CGI severity illness scoring was at 6 (severely ill). The behavioral pattern included irritability, marked agitation, crying, severe hyperactivity, and other behaviors typical of this disorder. He was also anxious, rendering the situation at his day hospital where he spent most of his time all the more difficult. A prescription of fluoxetine 2.5mg/d was initiated with an immediate and complete improvement of ADHD-like symptoms:CGI-I at one week of treatment was at a one, making this case the most remarkable of the four presented here. Treatment with fluoxetine was continued with a dosage increase up to 5 mg/d to allow for a decrease in the risperidone dose to 1 mg/d. CGI-I score remained stable at one for the duration of the nine weeks.

Our reader Mira, whose son has FXS, recently referred to Dr Hagerman’s trial of low dose Sertaline/Zoloft in Fragile X. GABA_A malfunction appears to be a feature of Fragile X, but it is not necessarily the identical malfunction to those with idiopathic autism who respond to bumetanide.

A Randomized, Double-Blind, Placebo-Controlled Trial of Low-Dose Sertraline in Young Children with Fragile X Syndrome

Objective

Observational studies and anecdotal reports suggest sertraline, a selective serotonin reuptake inhibitor (SSRI), may improve language development in young children with fragile X syndrome (FXS). We evaluated the efficacy of six months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 52 children with FXS ages 2–6 years.

Results

Eighty-one subjects were screened for eligibility and 57 were randomized to sertraline (27) or placebo (30). Two subjects from the sertraline arm and three from the placebo arm discontinued. Intent-to-treat analysis showed no difference from placebo on the primary outcomes: the Mullen Scales of Early Learning (MSEL) expressive language age equivalent and Clinical Global Impression-Improvement (CGI-I). However, analyses of secondary measures showed significant improvements, particularly in motor and visual perceptual abilities and social participation. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events occurred.

Conclusion

This randomized controlled trial of six-months of sertraline treatment showed no primary benefit with respect to early expressive language development and global clinical improvement. However, in secondary, exploratory analyses there were significant improvements seen on motor and visual perceptual subtests, the Cognitive T score sum on the MSEL, and on one measure of Social Participation on the Sensory Processing Measure–Preschool. Further, post hoc analysis found significant improvement in early expressive language development as measured by the MSEL among children with ASD on sertraline. Treatment appears safe for this 6-month period in young children with FXS, but we do not know the long-term side effects of this treatment. These results warrant further studies of sertraline in young children with FXS using refined outcome measures, as well as longer term follow-up studies to address long-term side effects of low-dose sertraline in early childhood.

Allopregnanolone Elevations Following Pregnenolone Administration are Associated with Enhanced Activation of Emotion Regulation Neurocircuits

Neurosteroid biosynthesis down‐regulation and changes in GABA_A receptor subunit composition: a biomarker axis in stress‐induced cognitive and emotional impairment

By rapidly modulating neuronal excitability, neurosteroids regulate physiological processes, such as responses to stress and development. Excessive stress affects their biosynthesis and causes an imbalance in cognition and emotions. The progesterone derivative, allopregnanolone (Allo) enhances extrasynaptic and postsynaptic inhibition by directly binding at GABA_A receptors, and thus, positively and allosterically modulates the function of GABA. Allo levels are decreased in stress-induced psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), and elevating Allo levels may be a valid therapeutic approach to counteract behavioural dysfunction. While benzodiazepines are inefficient, selective serotonin reuptake inhibitors (SSRIs) represent the first choice treatment for depression and PTSD. Their mechanisms to improve behaviour in preclinical studies include neurosteroidogenic effects at low non-serotonergic doses. Unfortunately, half of PTSD and depressed patients are resistant to current prescribed 'high' dosage of these drugs that engage serotonergic mechanisms. Unveiling novel biomarkers to develop more efficient treatment strategies is in high demand. Stress-induced down-regulation of neurosteroid biosynthesis and changes in GABA_A receptor subunit expression offer a putative biomarker axis to develop new PTSD treatments. The advantage of stimulating Allo biosynthesis relies on the variety of neurosteroidogenic receptors to be targeted, including TSPO and endocannabinoid receptors. Furthermore, stress favours a GABA_A receptor subunit composition with higher sensitivity for Allo. The use of synthetic analogues of Allo is a valuable alternative. Pregnenolone or drugs that stimulate its levels increase Allo but also sulphated steroids, including pregnanolone sulphate which, by inhibiting NMDA tonic neurotransmission, provides neuroprotection and cognitive benefits. In this review, we describe current knowledge on the effects of stress on neurosteroid biosynthesis and GABA_A receptor neurotransmission and summarize available pharmacological strategies that by enhancing neurosteroidogenesis are relevant for the treatment of SSRI-resistant patients. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.

Too little allopregnanalone can induce autism.

Decrease in endogenous brain allopregnanolone induces autism spectrum disorder (ASD)-like behavior in mice: A novel animal model of ASD.

ResultsAutism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABA_A receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1mg/kg, i.p.) and methylphenidate (MPH: 2.5mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABA_A receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD.

Marked elevation of adrenal steroids, especially androgens, in saliva of prepubertal autistic children

ResultsSome steroids, whose levels are raised in autism (allopregnanolone, androsterone, pregnenolone, dehydroepiandrosterone and their sulfate conjugates) are neuroactive and modulate GABA, glutamate, and opioid neurotransmission, affecting brain development and functioning. These steroids may contribute to autism pathobiology and symptoms such as elevated anxiety, sleep disturbances, sensory deficits, and stereotypies among others.

Tuning the Brain

I did write a post a while back to show the effect of tuning GABAa receptors.

Why Low Doses can work differently, or “Biphasic, U-shaped actions at the GABAa receptor”

The effect of allopregnanolone of KCC2 expression and hence the level of chloride within neurons.

Neonatal allopregnanolone or finasteride administration modifies hippocampal K(+) Cl(-) co-transporter expression during early development in male rats.

Abstract

The maintenance of levels of endogenous neurosteroids (NS) across early postnatal development of the brain, particularly to the hippocampus, is crucial for their maturation. Allopregnanolone (Allop) is a NS that exerts its effect mainly through the modulation of the GABAA receptor (GABAAR). During early development, GABA, acting through GABAAR, that predominantly produces depolarization shifts to hyperpolarization in mature neurons, around the second postnatal week in rats. Several factors contribute to this change including the progressive increase of the neuron-specific K(+)/Cl(-) co-transporter 2 (KCC2) (a chloride exporter) levels. Thus, we aimed to analyze whether a different profile of NS levels during development is critical and can alter this natural progression of KCC2 stages. We administrated sustained Allop (20mg/kg) or Finasteride (5α-reductase inhibitor, 50mg/kg) from the 5th postnatal day (PD5) to PD9 and assessed changes in the hippocampal expression of KCC2 at transcript and protein levels as well as its active phosphorylated state in male rats. Taken together data indicated that manipulation of NS levels during early development influence KCC2 levels and point out the importance of neonatal NS levels for the hippocampal development.                                                                                                                           

Conclusion

Add very low dose Prozac to the long list of possible SIB therapies, more practical than electroconvulsive therapy (ECT), that is for sure!

This post was long waiting in my “to-complete” pile. I thought it would be a short one, but it kept growing.  It does draw together several interesting issues and shows there is a pattern developing in all these blog posts.

The majority of psychiatric drugs have such severe drawbacks that the great majority of children are better off without them.  However, there are many existing drugs that have little known neurological effects that can be highly beneficial and are known to be safe to use long term.

Psychiatric drugs that can be repurposed at lower dosages for different purposes may indeed be free of the major drawbacks encountered at higher doses.

It looks like humans with Fragile X Syndrome (FXS) are leading the way with low dose SSRI therapy to modulate GABA.  It would seem highly plausible that other idiopathic autism might also benefit and the French case studies in this post are examples of those who did benefit.

I think this is another example of fine-tuning the brain to optimize its functioning. It probably will not produce miracles, but the science shows that allopregnenalone can be tuned to vary mood in humans.  Low levels of allopregnenalone can produce autistic-like behaviours in mouse models.

The effect of allopregnenalone on KCC2 expression may only be present in tiny babies, if it continues into childhood that would be another reason to consider it as a target for modulation.  If that were the case, then Finasteride the cheap generic drug for prostate enlargement, should be investigated.

As is always the case in autism, both extremes are likely to exist; some people will likely benefit from low dose SSRIs but it will make some others worse (anxiety, SIB etc). If you start with elevated allopregnenalone, you would want less, not more.

Repurposing existing drugs has huge unrealized potential.

The OTC antihistamine Clemastine, which I highlighted in an earlier post as being a Positive Allosteric Modulator (PAM) of P2X7, and so helps remyelination, is yet another example of repurposing a safe drug.  Reportedly, it has this effect even below the regular dosage for allergy; at the high dosage usage in MS trials it will send you to sleep and risk some other side effects. As MS is not a singular condition, it seems that some people respond much more so than others. It also seems to have a benefit is some psychiatric disorders; not bad for a cheap OTC antihistamine.