Ordinary Gifted or Gifted with Asperger’s Syndrome? And Treatment options for Aspies

Asperger with his Little Professors

This blog is focused more on severe autism, but today it is turn for the Aspies.  The post does rather ramble, because I included some old unused material on micro-dose LSD that may be Aspie-relevant.

Most people diagnosed with autism these days do not have severe autism and so their ideal medical therapy may be very different to the Polypill, I developed for my son.

For a young Aspie he might just need a single intervention like Sertraline (Zoloft) and nothing else, or perhaps Amantadine.

There is more than twenty years of experience medically treating people with Asperger’s, but it very much remains a case of trial and error to find what works.

It does look like most translational research in autism is now focused on those without problems with speech or cognition. That is good news for people with Asperger’s, not so good for the other end of the spectrum.

The paper below is 20 years old, but the medical treatment has not become out of date.

Gifted children with Asperger's Syndrome

Behavior Problems. Children with AS usually have some behavior problems. They may be compulsive or hyperactive. They may be prone to tantrums or aggressive outbursts. They may routinely hit other children without provocation or touch people in inappropriate ways. Some AS children suffer from anxiety attacks or specific phobias. They may be sensitive to teasing, but consistently demonstrate provocative behaviors that invite teasing. Some AS children will engage adults in endless arguments if given the opportunity. Parents especially may find themselves trapped in repeated discussions about the same events or disagreements. Adults should not attempt to reason for more than a minute with such children (Barron & Barron, 1992; Dewey, 1991; Klin & Volkmar, 1995). Brief, concrete directives are most effective. Visual supports like pictograms can be posted on a child's notebook, desk, or on the wall to visually cue the child regarding expected behaviors. The addition of visual supports can be remarkably effective in helping AS students organize their behavior. Teachers and parents should consult with an augmentative communication specialist to learn more about visual supports.

In addition to behavioral and educational approaches, medications may be helpful in treating specific problematic behaviors. Medications can significantly improve the quality of life of AS children when they exhibit compulsive or aggressive behaviors that interfere with school adjustment or family life. Medication may also be needed to alleviate symptoms of depression, thought disorder, or anxiety attacks. Tofranil and Prozac have been recommended (Grandin, 1992). Beta blockers have been helpful for some aggressive AS children, and Anafranil, Luvox, or one of the SSRIs (e.g., Zoloft) can be useful in reducing obsessive-compulsive tendencies (Gragg & Francis, 1997; Rapoport, 1989).

If you now look at what is recommend today, two decades later it is pretty much the same.

From the Kennedy Krieger Institute:

What Anxiety Treatments Work for People with Autism?

  

For core anxiety symptoms, her group listed four possible SSRI antidepressants, sertraline (Zoloft), Prozac, Celexa, or escitalopram (Lexapro). That listing was based upon data on children and teenagers who do not have a developmental disorder. The researchers noted that youth with autism often report one particular side effect with SSRI drugs: "behavioral activation," which may appear as hyperactivity, impulsiveness, or trouble sleeping.¹⁴ Other possible side effects, which are not unique to autism, are suicidal thoughts in adolescents, or worsening of mood problems in people with bipolar disorder. So these drugs "should be prescribed cautiously in youth with ASD, with close monitoring," the researchers advised. Their article, in the journal Pediatrics, includes starting and maximum doses for doctors to consider. (See Additional Resources below for a link to the article, to share with your health care provider.)

Over at the MIND Institute at UC Davis:-

Specifying and Treating Anxiety in Autism Research (STAAR) Study

At least 50 percent of children with autism spectrum disorder (ASD) exhibit clinically significant anxiety symptoms. These are associated with increased social deficits, depression, irritability, and stereotyped and self-injurious behaviors. While it is clear that anxiety represents a substantial problem for those with ASD, there are important issues that need to be clarified before effective treatment becomes widespread. This project of the ACE will explore better ways to detect anxiety in children with ASD and determine whether cognitive behavioral therapy or medication can better alleviate their symptoms

  

Studies often appear to show no benefit, but it depends what you choose to measure (the primary outcome) and how large the sample is.

Prozac proves no better than a placebo in treating kids with autism

At first, the fluoxetine group appeared to show a slight but significant easing of obsessive-compulsive symptoms after four months compared with the placebo. But after the researchers controlled for factors including age, sex and the severity of symptoms at the start of the trial, the difference vanished. Fluoxetine did no better than the placebo.

The relatively small sample size could have limited the researchers’ ability to detect a benefit from the drug, Neumeyer says. “It’s possible that, with higher numbers, they would’ve found subgroups who benefit from SSRIs,” she says. “That’s the painful part of this [kind of] research though; you’re left wondering.”

Interesting to see low dose Prozac (fluoxetine) used successfully in severe French autism:-

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

In this article, the authors present four clinical cases of ASD-diagnosed children with ADHD-like symptoms and/or SIB and/or other heteroaggressive behaviors and/or irritability and impulsivity. Each was treated with low doses of fluoxetine, specified as follows: 2.5 mg/d (liquid formulation) in the morning for the first week, followed by a flexible titration schedule based on weight and tolerability. The Hollander et al. protocol [3] is reproduced here, in which children with ASD were given low doses of fluoxetine. Patients were assessed using the Clinical Global Impression Scales (CGI) [12] during the time of fluoxetine introduction and observation. None had tried an SSRI treatment before the reported trial.

In conclusion, in these case reports, we found that the prescription of fluoxetine, in addition to valproate and cyamemazine (Case 1) or to risperidone (Cases 2, 3 and 4), could be effective on severe behavioral symptoms associated with ASD in children. It is important to inform child psychiatrists about this therapeutic possibility even if it would be difficult to predict the rate of responders on the basis of this cases and the literature. The role of comedication remains unanswered as none of our cases was on fluoxetine monotherapy.

  

Recall this old post:- 

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

Micro-dosing LSD for Aspies?

Since we are on the subject of Aspies, I will insert a post that I never finished.  It is very much for the genuine Aspie, the one with a high IQ, the type working over at Google HQ. Usually male, does not strictly need any medical treatment, but may seek some out nonetheless.

Even though LSD was used at high doses in people with severe autism in the 1960s at UCLA, current interest involves micro-doses taken by people without any severe disability. 

A trial is about to start at Imperial College in London that may particularly interest Californian and Dutch Aspies.

First ever trials on the effects of microdosing LSD set to begin

Silicon Valley geeks say it sharpens their thinking and enhances creativity. Other people say it lifts the fog of depression. A novel experiment launching 3 September 2018 will investigate whether microdosing with LSD really does have benefits – or whether it’s all in the mind.

Microdosing using psychedelic drugs – either LSD or magic mushrooms – is said to have become very popular, especially with people working in the Californian digital tech world, some of whom are said to take a tiny amount one or more days a week as part of their routine before heading to work. It’s not for a psychedelic high, though – it’s to make them more focused.

Microdosers tend to use either tiny amounts of LSD – as little as one-fifteenth of a tab – or of psilocybin, the active ingredient in magic mushrooms. The study is recruiting just those who use LSD, because of the difficulty in disguising even ground-up mushrooms in a capsule.

But it’s illegal. So how many people are microdosing is unknown and there is only anecdotal evidence of the effects and any downsides. In a bid to learn more, the Beckley Foundation, which was set up to pioneer research into mind-altering substances, and the unit it funds at Imperial College London, will launch the first ever placebo-controlled trial of microdosing on Monday, 3 September 2018.

It will be unique, says Balázs Szigeti, the study leader. The cost and the illegality of LSD would make a conventional study prohibitively expensive. So he has hit on a way of running it by inviting those who already microdose to join a “self-blinded” study. They will take either what they usually use in a capsule or an identical dummy capsule instead, without knowing which is which. They will complete questionnaires and tests and play cognitive games online, and only at the end will they learn whether they were happy and focused because of LSD or because they thought they were using LSD.

The trial itself:-

https://selfblinding-microdose.org/

Conclusion

The big difference between treating mild autism (Asperger’s) and severe autism is whether cognitive function is a target.  For severe autism raising cognitive function is the most important target, because it has the potential to improve all other behavioral issues. 

Aspies have been self-treating for decades and in some countries have a helpful psychiatrist happy to prescribe off-label (SSRIs, bet-blockers etc).  They often seem to like 5HT2A agonists.

The effective drugs for mild autism (Asperger’s) may have only limited value to those with severe autism.  Unless you resolve cognitive impairment, you will not transform the developmental trajectory.

It would be helpful if during the initial observational autism diagnosis, the doctor made clear to parents, what kind of autism the child has.   This often is not the case.

It is clear that most people diagnosing autism in very young children do not attempt to measure IQ, or even use an autism ratings scale, like CARS.  There are understandable reasons for this, but it still looks lazy to me.  Nowadays people struggle less hearing the word “autism”, but nobody wants to hear about MR/ID in their 3 year old.  So better to keep silent and avoid parents bursting into tears.

You really do need to be told where you are on the scale from Aspie to the other extreme of Autistic disorder/ Kanner’s/Classic/SDA.  You might think this would be obvious, but it is not.  If you have a 4 year old Aspie, start with Aspie therapies, not therapies for severe autism.

We saw in Catherine Lord’s study that all of those in her 20 year longitudinal study of children with an autism diagnosis, also had an IQ , when measured, indicating MR/ID.  Her study group was a random selection of those diagnosed with autism where she worked.  Back then autism meant autism.  Her “top performing” 40% have normal IQ as adults, but even in that group their measured IQ at age 3 or 4 was less than 70.  This group are not Aspies, they would have had normal/high IQ when tested at the age of 3 or 4.

The meaning of the diagnosis has changed so much in 20 years that the research now talks of autism with a developmental disorder and autism without a developmental disorder.

Actually, “autism” is supposed to be a developmental disorder; that was the whole point. But never mind.

Aspies have had a wide range of treatment options for more than 20 years and they also stand to benefit for the new generation of “autism” drugs, which are actually mainly for mild autism.

As with severe autism, treating an Aspie will also require personalized medicine, or just call it trial and error.  Prozac might be hopeless, but Zoloft work wonders.  ADHD meds might help, or just make things worse.  Oxytocin might improve empathy, or do absolutely nothing.  Perhaps the study at Imperial will show micro-dose LSD does have a benefit.  Since you are fully verbal and have a high IQ it is not hard to establish whether there is a benefit or not, move on and perfect your personal therapy.

It is the other end of the spectrum, where there is a big problem.  You may need to look at the new drugs being developed for Down Syndrome, Fragile-X and the numerous rare single gene autisms. Those drugs will not be cheap.

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.