UA-45667900-1
Showing posts with label Fragile X. Show all posts
Showing posts with label Fragile X. Show all posts

Wednesday, 6 November 2019

Metformin to raise Cognition in Fragile X and some other Autisms?




I started to write this post a long time ago, when Agnieszka first highlighted an interview with Dr Hagerman from UC Davis.  Hagerman is experimenting in using Metformin to treat Fragile-X.

Having again be reminded about Metformin, I realized that I never finished my post on this subject. With some extras about autophagy and a nice graphic courtesy of Ling’s excellent paper, here it is. 

Metformin has already been covered in 5 previous posts.


One interesting point is that the researchers at UC Davis are using the measurement of IQ as one of the outcome measures in their trial of Metformin.  I have been suggesting the French Bumetanide researchers do this for a long time.

It is my opinion that simple medical interventions can have a profound impact on the IQ of some people with severe autism. I mean raising IQ not by 5-10 points as at UC Davis, but by 20-50 points.  IQ can be measured using standardized tools and is far less subjective than any autism rating scale.

The big-time potential IQ enhancers we have seen in this blog include: -

·        Bumetanide/Azosemide
·        Statins (Atorvastatin, Lovastatin, Simvastatin, but they are not equivalent and the effect has nothing to do with lowering cholesterol)
·        Micro-dose Clonazepam
·        Clemastine
·        It seems DMF, in n=2 trial

The good news is that these drugs are all off-patent cheap generics (except DMF), as is metformin.  No need for drugs costing $50,000 a year.

For those that do not know, metformin is the first line medication for type-2 diabetes. It was introduced as a medication in France in 1957 and the United States in 1995.  In many countries Metformin is extremely cheap, with 30 x 500 mg tablets costing about $2 or Eur 2. In the US it costs about $10 for generic, so not expensive. 

There are sound reasons why Metformin could increase IQ in someone with autism or Fragile-X. In the case of idiopathic autism is there a likely biomarker to identify a likely responder? One has not yet been identified.

Clearly Metformin will not work for all people with autism and MR/ID, but even if it only works for 10% that would be great.

Are all parents going to notice an increase in IQ of 5-10 points?  You might think so, but I doubt it.  I would hope therapists, teachers and assistants would notice.

I think basic mental maths is the best way to notice improved cognitive function in people with IQ less than 70.  You can easily establish a baseline and then you can notice/measure improvements.

Improved cognitive function does not just help with maths, it helps with learning basic skills like tying shoe laces, brushing teeth and later shaving.  This does also involve many other types of skill.





In the study, researchers from the UC Davis Medical Investigation of Neurodevelopmental Disorders Institute in California tested the long-term effects of metformin, delivered at 1,000 milligrams (mg) twice a day, for one year in two male patients, 25 and 30 years old. Genetic analysis confirmed that both patients had mutations in the FMR1 gene, confirming their fragile X syndrome diagnoses.

The younger patient had autism and was also diagnosed with generalized anxiety disorder. First prescribed metformin at 22, he is currently taking 500 mg of metformin twice a day and 10 mg per day of simvastatin — used to lower the level of cholesterol in the blood.
The second patient was also diagnosed with anxiety and exhibited socially nervous behaviors, including panic attacks. He had severe limitations in language use, and communicated in short sentences and by mumbling. He had been on an extended-release formulation of metformin, taking 1,000 mg once a day for one year.

Both patients showed significant cognitive and behavioral improvements. After one year of treatment with metformin, test results revealed an increase in the patients’ IQ scores, from 53 to 57 in the younger patient and from 50 to 58 in the second patient.

Verbal and nonverbal IQ — the ability to analyze information and solve problems using visual or hands-on reasoning — were also improved in both patients. Non-verbal IQ increased from 50 to 52 in the younger patient and from 47 to 51 in the other. Verbal IQ went from 61 to 66 in the first patient, and from 58 to 68 in the second.

                                                              

Researcher Randi Hagerman is a big proponent of metformin — a diabetes drug that helps people manage their weight. In fact, Hagerman takes the drug herself as a preventive measure against cancer.
Metformin has also unexpectedly shown promise for improving cognition in people with fragile X syndrome, a leading genetic cause of autism characterized by severe intellectual disability.

A study published in 2017 linked impaired insulin signalling in the brain to cognitive and social deficits in a fruit fly model of fragile X, and the flies improved on metformin. A second paper that year showed that metformin reverses abnormalities in a mouse model of the syndrome, including the number of branches the mice’s neurons form. It also improved seizures and hyperactivity in the mice — issues we also see in people with fragile X.
I began prescribing metformin to people with fragile X syndrome to help curb overeating. Many of the people I treat are overweight because of this habit — it’s one of the symptoms of a subtype of fragile X called the Prader-Willi phenotype, not to be confused with Prader-Willi syndrome.
I was surprised when the families of these individuals told me they could talk better and carry out conversations, where they couldn’t before. That really gave us impetus to conduct a controlled clinical trial.
It’s not a cure-all, but we do see some positive changes. It doesn’t resolve intellectual disability, but we have seen IQ improvements of up to 10 points in two boys who have been treated with metformin. We are very excited about that.

Individuals on metformin tend to start eating less, and often lose weight as a result. I could kick myself, because metformin has been approved to treat obesity for many years, but I never thought to use it in fragile X syndrome. Oftentimes children with fragile X syndrome have so many problems that you aren’t thinking about obesity as the top priority.
We’ve also seen a gradual effect on language, which we can detect after two to three months. Sometimes there are improvements in other behaviors too; I’ve seen mood-stabilizing effects. Many people with fragile X syndrome have issues with aggression, and it’s possible these could be moderated with metformin too. 

Individuals with fragile X syndrome (FXS) have both behavioral and medical comorbidities and the latter include obesity in approximately 30% and the Prader‐Willi Phenotype (PWP) characterized by severe hyperphagia and morbid obesity in less than 10%. Metformin is a drug used in individuals with type 2 diabetes, obesity or impaired glucose tolerance and it has a strong safety profile in children and adults. Recently published studies in the Drosophila model and the knock out mouse model of FXS treated with metformin demonstrate the rescue of multiple phenotypes of FXS.

Materials and Methods

We present 7 cases of individuals with FXS who have been treated with metformin clinically. One case with type 2 diabetes, 3 cases with the PWP, 2 adults with obesity and/or behavioral problems and, a young child with FXS. These individuals were clinically treated with metformin and monitored for behavioral changes with the Aberrant Behavior Checklist and metabolic changes with a fasting glucose and HgbA1c.

Results

We found consistent improvements in irritability, social responsiveness, hyperactivity, and social avoidance, in addition to comments from the family regarding improvements in language and conversational skills. No significant side‐effects were noted and most patients with obesity lost weight.

Conclusion

We recommend a controlled trial of metformin in those with FXS. Metformin appears to be an effective treatment of obesity including those with the PWP in FXS. Our study suggests that metformin may also be a targeted treatment for improving behavior and language in children and adults with FXS.

Recruiting: Clinical Trial of Metformin for Fragile X Syndrome


While a growing number of families are trying metformin and reporting mixed results, metformin has not yet been systematically studied in patients with Fragile X syndrome. This open-label trial is designed to better understand the safety and efficacy of this medicine on behavior and cognition, and to find the best dosages for children and adults.

20 children and adults with Fragile X syndrome will take metformin 250mg twice a day for the first week, followed by metformin 500mg twice a day for the next 8 weeks.
The study will measure changes in the total score on the Aberrant Behavior Checklist-Community (ABC-C) after 9 weeks of metformin treatment. The ABC-C is a 58-item behavior scale which is filled out by a caregiver. In addition, Transcranial Magnetic Stimulation (TMS) will be used to look for changes in cortical excitability and Electroencephalography (EEG) will assess levels of synaptic plasticity.
Participants in this study must be Canadian residents and be able to travel to the University of Sherbrooke in Quebec, Canada, for several visits. If you are interested in metformin but this trial is not convenient, there are two alternatives. FRAXA is funding a new trial of metformin in New Jersey, and Dr. Randi Hagerman is currently recruiting for metformin trial at the University of California at Davis MIND Institute.



Metformin has emerged as a candidate drug for the targeted treatment of FXS based on animal studies showing rescue of multiple phenotypes in the FXS model. Metformin may contribute to normalizing signalling pathways in FXS in the central nervous system, which may include activities of mTOR and PI3K, both of which have shown to be pathogenically overactive in FXS. In addition, metformin inhibits phosphodiesterase, which would lead to correction of cAMP levels, and MMP9 production, which is also elevated in FXS. Looking at the potential signalling pathways, metformin appears to be a good candidate for targeting several of the intracellular functions in neurons disrupted in FXS and, therefore, has potential to rescue several types of symptoms in individuals with FXS. The researchers have utilized metformin in the clinical treatment of over 20 individuals with FXS between the ages of 4 and 58 years and have found the medication to be well tolerated and to provide benefits not only in lowering weight gain and normalizing appetite but also in language and behavior. In this controlled trial, the researchers hope to further assess metformin's safety and benefits in the areas of language and cognition, eating and weight loss, and overall behavior.


mTOR and P13K

Hagerman highlights Metformin’s effects on mTOR and P13K pathways.

This is a highly complex subject and the graphic below from an early post shows how interconnected everything is.  If mTOR is not working correctly you can expect many things not to work as nature intended.

Numerous things can cause an imbalance in mTOR and so there are numerous ways to re-balance it.

Not surprisingly much of this pathway plays a role in many types of cancer.

Hagerman herself is taking Metformin to reduce her chances of developing cancer. I think that is a good choice, particularly if you are overweight.  My anticancer choice, not being overweight, is Atorvastatin which targets inhibition of PI3K signalling through Akt and increases PTEN.

Hagerman is 70 years old and I think many cancers actual initiate years before they are large enough to get noticed and to be effective any preventative therapy needs to be started before that initiation has occurred. Hopefully she started her Metformin long ago. 

Given that 50% of people are likely to develop one cancer or another, I am with Dr Hagerman on the value of prevention, rather than treatment/cure.







The Wrong Statin for Fragile-X?

In the first article highlighted in this post, there is a case history of a man with FX being treated by a Statin, it looks to me that he has the wrong prescription (Simvastatin). Perhaps Dr Hagerman should read this old post from this blog:-


Choose your Statin with Care in FXS, NF1 and idiopathic Autism







   Simvastatin does not reduce ERK1/2 or mTORC1 activation in the Fmr1-/y hippocampus.
So  ? = Does NOT inhibit

The key is to reduce Ras. In the above graphic it questions does Simvastatin inhibit RAS and Rheb.
                                                                                                     

For anyone really interested, the following graphic from a previous post shows the fragile X mental retardation protein, FMRP.  Lack of FMRP goes on increase neuroligins (NLFNS) this then creates an excitatory/inhibitory imbalance which cause mental retardation and features of autism.





This all suggests that the 25 year-old young man with Fragile X treated at UC Davis (case study above) should switch from Simvastatin to Lovastatin.




Metformin and Autophagy

I also think Dr Hagerman is less likely to get dementia now that she is talking metformin.  If she takes vigorous exercise at least once a week, I think that is also going to keep her grey cells ticking over nicely. Like Dr Ben Ari, Hr Hagerman is working way past normal retirement.  If you love your job, then why not?  As with many things, in the case of neurons, “use them or lose them”.

Autophagy in Dementias


Dementias are a varied group of disorders typically associated with memory loss, impaired judgment and/or language and by symptoms affecting other cognitive and social abilities to a degree that interferes with daily functioning. Alzheimer’s disease (AD) is the most common cause of a progressive dementia, followed by dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia (VaD) and HIV associated neurocognitive disorders (HAND).
The pathogenesis of this group of disorders has been linked to the abnormal accumulation of proteins in the brains of affected individuals, which in turn has been related to deficits in protein clearance. Autophagy is a key cellular protein clearance pathway with proteolytic cleavage and degradation via the ubiquitin-proteasome pathway representing another important clearance mechanism. Alterations in the levels of autophagy and the proteins associated with the autophagocytic pathway have been reported in various types of dementias. This review will examine recent literature across these disorders and highlight a common theme of altered autophagy across the spectrum of the dementias.

Below is an excellent graphic from a paper highlighted by Ling. Note metformin, above AMPK.


Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity









I would highlight the presence of IP3R, the calcium channel proposed by Gargus as being a nexus in autism, for where multiple types of autism meet up, to do damage.

Verapamil, in Monty’s Polypill, increases autophagy independently of mTOR in a complicated mechanism  involving IP3R and likley calpain.  It is proposed as a therapy for Huntington’s Disease via this mechanism. At the lower right of the chart below we see calpain, a group of calcium dependent enzymes, not well understood.  ROS can activate calpains via L-type calcium channels.





I would not worry about the details.  The take home point is that if you have autism, dementia or many other neurological conditions, you might well benefit from increasing autophagy.  There are very many ways to do this.      
                                                           
Conclusion

Fortunately, I am not a doctor.  I do recall when my doctor father was out visiting his sick patients at their homes, he did have not only his medical bag, but also some useful gadgets always kept in his car, that might come in handy.

The autism equivalent is the personalized Polypill therapy for daily use and the autism toolbox to delve into to treat flare-ups in autism as and when they arise.

I do think some people should have metformin in their daily Polypill therapy.

I think we can safely call Fragile-X a type of autism, so we already know it works for at least some autism.  Metformin is a very safe old drug, with minimal side effects and it is cheap.  It ticks all the boxes for a potential autism therapy.  Will it work for your case?  I can tell you with certainty that it does not work for everyone.

Metformin has been trialled to treat people with obesity and autism, since it can reduce appetite.

Metformin forTreatment of Overweight Induced by Atypical Antipsychotic Medication in YoungPeople With Autism Spectrum Disorder: A Randomized Clinical Trial.


INTERVENTIONS:

Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years.

MAIN OUTCOMES AND MEASURES:

The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication.

RESULTS:

Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005).

CONCLUSIONS AND RELEVANCE:

Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD.

My guess is that a minority will be responders, the benefit will manifest itself in different ways and so it will be a useful part of polytherapy for some people, but it will not be a silver bullet.  Other than via an IQ test, I think the benefit will be hard to measure, even when it is very evident. 

In the end there will be a clever way to predict who will respond to which therapy.  Today’s post actually replaces one that will look into genetic testing and DEGs (differentially expressed genes). Most likely testing for DEGs will be the best predictor of what drugs work for whom.

Intelligent, cautious trial and error using safe drugs is an alternative strategy.  It is available today; it is cheap and it does work.

I have not tried Metformin yet, in recent years I have had most success with my own ideas. I have some of Dr Frye's calcium folinate sitting at home waiting for a trial.  Both Metformin and calcium folinate should be trialled.  The other obvious thing to trial is that Japanese PDE4 inhibitor Ibudilast (Ketas).  Thanks to Rene we now know you can acquire this is via any international pharmacy in Germany, with a prescription. It also reappeared on the website of a Japanese online pharmacy. The Western PDE4 inhibitors, like Daxas/Roflumilast are not selective enough and so are emetic (they make you want to vomit). Low dose Roflumilast has been patented as a cognitive enhancer, but you may need to have a bucket with you at all times.




     






Tuesday, 6 November 2018

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.


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 1/10th 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 GABAA 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 GABAA receptors. These drugs achieve this by increasing the amount of the steroid hormone allopregnanolone.
Neurosteroid biosynthesis down‐regulation and changes in GABAA 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.


Brain principal glutamatergic neurons synthesize 3α-hydroxy-5α-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABAA 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 GABAA 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.


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. GABAA 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.

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.


Neurosteroid biosynthesis down‐regulation and changes in GABAA 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 GABAA 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 GABAA 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 GABAA 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 GABAA 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.


Results
Autism 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 GABAA 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 GABAA 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.



Results
Some 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.




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.