Intranasal Insulin for Improved Mood and Cognition

  

This post follows on the previous one that raised the issue of brain-specific insulin sensitivity being a common feature of neurological diseases/disorders.

It appears to be much more than just a rare possibility.   There have been numerous studies and even more are ongoing.

Intranasal insulin has even been tried one single-gene type of autism (Phelan-McDermid Syndrome) and in autism’s big brothers, bipolar and schizophrenia.

I did look for trials in children with Down Syndrome, since here is a direct link to Alzheimer’s, but there is just a trial in adults in progress.

There was an early trial in typical adults which is interesting since it found not only a cognitive improvement but also improved mood, so perhaps it should be trialed in adults with depression.  In the US, interestingly, T3 thyroid hormone is sometimes given off-label for depression and some antidepressants increase the conversion of the pro-hormone T4 to T3 in the brain.  I think central hypothyroidism is likely a feature of some neurological disorders, as I proposed in an earlier post.

I think it would be well worth trialing intranasal insulin in idiopathic Autism and, separately, idiopathic Asperger’s.  I am surprised nobody has done it. I really think Autism and Asperger’s  should be separated, since while we sometimes see the same therapy helps in both, sometimes there are Asperger-specific therapies, like Baclofen.

A small number of readers of this blog do follow the science and engage in some experimentation at home.  I think given what some people have already tried, intranasal insulin is not at all far fetched, you just need a metered dose nasal spray, insulin and the correct amount of dilutant/diluent, as in the trials.

Insulin and IGF-1 (insulin-like growth factor 1)

There are autism trials underway using subcutaneous injections of IGF-1 and also oral IGF-1 analogs.

IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body,

Insulin levels affect levels of growth hormone (GH) and IGF-1.

We know that various growth factors (NGF, BDNF, IGF-1 etc.) in people with autism can be disturbed, but there is both hypo and hyper.

We also know that the level of hormones measured in the blood can be very different to those in the brain/CNS.  This means that having blood tests indicating  high serotonin, thyroid T3, IGF-1 etc. does not tell you anything about the level within the brain.  Quite possibly they may be the opposite.

It would seem to be hugely preferable to target the brain directly, rather than the whole body.

The lack of side effects in the numerous studies of intranasal insulin is very encouraging.

Healthy Neurotypical Adults

Intranasal insulin improves memory in humans

Declarative memory in humans without causing systemic side effects like hypoglycaemia. The improvement of memory in the eighth week of treatment corroborates previous findings of improved memory function following acute intravenous administration of the peptide both in healthy subjects (Kern et al., 2001) and in patients with Alzheimer’s disease (Craft et al., 1999). In addition, intranasal insulin positively affected mood in our subjects. The improving effect of subchronic intranasal insulin administration appeared to be specific for hippocampus dependent declarative memory.

Our subjects in the insulin group also expressed enhanced mood. Acute intranasal intake of insulin enhanced the feelings of well-being and self-confidence, which is in accordance with previous results (Kern et al., 1999).

In summary our data indicate that prolonged intranasal intake of insulin improves both consolidation of words and general mood. These beneficial findings suggest intranasal administration of insulin as a potential treatment in patients showing memory deficits in conjunction with a lack of insulin, such as in Alzheimer’s disease

Adults with Schizophrenia

No effect of adjunctive, repeated-dose intranasal insulin treatment on psychopathology and cognition in patients with schizophrenia.

Abstract

OBJECTIVE:

This study examined the effect of adjunctive intranasal insulin therapy on psychopathology and cognition in patients with schizophrenia.

METHODS:

Each subject had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizoaffective disorder and been on stable antipsychotics for at least 1 month. In an 8-week randomized, double-blind, placebo-controlled study, subjects received either intranasal insulin (40 IU 4 times per day) or placebo. Psychopathology was assessed using the Positive and Negative Syndrome Scale and the Scale for Assessment of Negative Symptoms. A neuropsychological battery was used to assess cognitive performance. The assessment for psychopathology and cognition was conducted at baseline, week 4, and week 8.

RESULTS:

A total of 45 subjects were enrolled in the study (21 in the insulin group and 24 in the placebo group). The mixed model analysis showed that there were no significant differences between the 2 groups at week 8 on various psychopathology and cognitive measures (P > 0.1).

CONCLUSIONS:

Adjunctive therapy with intranasal insulin did not seem to be beneficial in improving schizophrenia symptoms or cognition in the present study. The implications for future studies were discussed.

Adults with Bipolar

A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder.

 

Abstract

BACKGROUND:

Neurocognitive deficits are prevalent, persistent, and implicated as mediators of functional impairment in adults with bipolar disorder. Notwithstanding progress in the development of pharmacological treatments for various phases of bipolar disorder, no available treatment has been proven to be reliably efficacious in treating neurocognitive deficits. Emerging evidence indicates that insulin dysregulation may be pertinent to neurocognitive function. In keeping with this view, we tested the hypothesis that intranasal insulin administration would improve measures of neurocognitive performance in euthymic adults with bipolar disorder.

METHODS:

Sixty-two adults with bipolar I/II disorder (based on the Mini International Neuropsychiatric Interview 5.0) were randomized to adjunctive intranasal insulin 40 IU q.i.d. (n = 34) or placebo (n = 28) for eight weeks. All subjects were prospectively verified to be euthymic on the basis of a total score of ≤ 3 on the seven-item Hamilton Depression Rating Scale (HAMD-7) and ≤ 7 on the 11-item Young Mania Rating Scale (YMRS) for a minimum of 28 consecutive days. Neurocognitive function and outcome was assessed with a neurocognitive battery.

RESULTS:

There were no significant between-group differences in mean age of the subjects {i.e., mean age 40 [standard deviation (SD) = 10.15] years in the insulin and 39 [SD = 10.41] in the placebo groups, respectively}. In the insulin group, n = 27 (79.4%) had bipolar I disorder, while n = 7 (21.6%) had bipolar II disorder. In the placebo group, n = 25 (89.3%) had bipolar I disorder, while n = 3 (10.7%) had bipolar II disorder. All subjects received concomitant medications; medications remained stable during study enrollment. A significant improvement versus placebo was noted with intranasal insulin therapy on executive function (i.e., Trail Making Test-Part B). Time effects were significant for most California Verbal Learning Test indices and the Process Dissociation Task-Habit Estimate, suggesting an improved performance from baseline to endpoint with no between-group differences. Intranasal insulin was well tolerated; no subject exhibited hypoglycemia or other safety concerns.

CONCLUSIONS:

Adjunctive intranasal insulin administration significantly improved a single measure of executive function in bipolar disorder. We were unable to detect between-group differences on other neurocognitive measures, with improvement noted in both groups. Subject phenotyping on the basis of pre-existing neurocognitive deficits and/or genotype [e.g., apolipoprotein E (ApoE)] may possibly identify a more responsive subgroup

Children with Phelan-McDermid Syndrome 

22q13 deletion syndrome is a genetic disorder caused by deletions or rearrangements on the q terminal end (long arm) of chromosome 22. Any abnormal genetic variation in the q13 region that presents with significant manifestations typical of a terminal deletion should be diagnosed as 22q13 deletion syndrome. 22q13 deletion syndrome is often placed in the more general category of Phelan-McDermid Syndrome (abbreviated PMS), which includes some mutations and microdeletions. 

Physical

·         Absent to severely delayed speech: 99%

·         Normal to accelerated growth: 95%

·         High tolerance to pain: 77%

·         Hypotonia (poor muscle tone): 75%

·         Dysplastic toenails: 73%

·         Long eyelashes: 73%

·         Poor thermoregulation: 68%

·         Prominent, poorly formed ears: 65%

·         Large or fleshy hands: 63%

·         Pointed chin: 62%

·         Dolichocephaly (elongated head): 57%

·         Ptosis (eyelid) (droopy eyelids): 57%

·         Gastroesophageal reflux: 42%

·         Epileptic seizures: 27%

·         Kidney problems: 26%

·         Delayed ability to walk: 18%

Behavioral

·         Chewing on non food items: 85%

·         Delayed or unreliable toileting: 76%

·         Impulsive behaviors: 47%

·         Biting (self or others): 46%

·         Problems sleeping: 46%

·         Hair pulling: 41%

·         Autistic behaviors: 31%

·         Episodes of non-stop crying before age 5: 30%

·         Teeth grinding: (unknown) %

Intranasal insulin to improve developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial.

 

BACKGROUND:

The 22q13 deletion syndrome (Phelan-McDermid syndrome) is characterised by a global developmental delay, absent or delayed speech, generalised hypotonia, autistic behaviour and characteristic phenotypic features. Intranasal insulin has been shown to improve declarative memory in healthy adult subjects and in patients with Alzheimer disease.

AIMS:

To assess if intranasal insulin is also able to improve the developmental delay in children with 22q13 deletion syndrome.

METHODS:

We performed exploratory clinical trials in six children with 22q13 deletion syndrome who received intranasal insulin over a period of 1 year. Short-term (during the first 6 weeks) and long-term effects (after 12 months of treatment) on motor skills, cognitive functions, or autonomous functions, speech and communication, emotional state, social behaviour, behavioural disorders, independence in daily living and education were assessed.

RESULTS:

The children showed marked short-term improvements in gross and fine motor activities, cognitive functions and educational level. Positive long-term effects were found for fine and gross motor activities, nonverbal communication, cognitive functions and autonomy. Possible side effects were found in one patient who displayed changes in balance, extreme sensitivity to touch and general loss of interest. One patient complained of intermittent nose bleeding.

CONCLUSIONS:

We conclude that long-term administration of intranasal insulin may benefit motor development, cognitive functions and spontaneous activity in children with 22q13 deletion syndrome.

For intranasal administration, insulin (40 IU/ml; Actrapid, Novo Nordisk, Mainz, Germany) was diluted with 0.9% saline solution to a concentration of 20 IU/ml so that each 0.1 ml puff with the nasal atomizer (Aero Pump, Hochheim, Germany) contained a dose of 2 IU insulin. Subjects received one dose of 2 IU insulin per day during the first 3 days according to the standard subcutaneous insulin therapy in children with type 1 diabetes mellitus. In three-day intervals, administration was increased gradually, until the final dosage of about 0.5-1.5 IU/kg/d (TID)

As with idiopathic autism there is interest in using the related IGF-1 as a therapy.

A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome

Background

Autism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors.

Methods

Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period.

Results

Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants.

Conclusions

This study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.

Drug administration

IGF-1 (Increlex; Ipsen Biopharmaceuticals, Inc) is an aqueous solution for injection containing human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNA technology. Placebo consisted of saline prepared in identical bottles by the research pharmacy at Mount Sinai. We received an Investigational New Drug exemption from the Food and Drug Administration (#113031) to conduct this trial in children with PMS. Based on the package insert for Increlex, dose titration was initiated at 0.04 mg/kg twice daily by subcutaneous injection, and increased, as tolerated, every week by 0.04 mg/kg per dose to a maximum of 0.12 mg/kg twice daily. This titration was justified based on our preclinical data, which indicated that 0.24 mg/kg/day is effective in reversing electrophysiological deficits whereas 0.12 mg/kg/day was not as effective[21]. We aimed to reach the therapeutic dose as quickly as is safe and tolerated in order to allow maximum time for clinical improvement. Doses could be decreased according to tolerability by 0.04 mg/kg per dose. Medication was administered twice daily with meals, and preprandial glucose monitoring was performed by parents prior to each injection throughout the treatment period. Parents were carefully trained in finger stick monitoring, symptoms of hypoglycemia, and medication administration.

Down Syndrome

The ongoing Down Syndrome trial is in adults.  As mentioned earlier, a feature of the syndrome is the likely early onset of Alzheimer’s, so not surprisingly if intranasal insulin helps people with Alzheimer’s it makes sense to trial it on people with Down Syndrome.

I think it makes sense to trial it on young people with Down Syndrome, prior to the onset of Alzheimer’s.

Investigation of the Safety of Intranasal Glulisine in Down Syndrome

This study is a single center, randomized, double-blind, placebo-controlled, cross-over pilot study designed to assess the safety of intranasally (IN) delivered glulisine versus placebo in patients with DS. Subjects will be randomized into this cross-over study and within subject comparisons conducted between single treatment of intranasal insulin glulisine and single treatment of intranasal placebo

The SNIFF (Study of Nasal Insulin in the Fight against Forgetfulness) Trials

The large clinical trials all relate to Alzheimer’s.  The big trial, SNIFF INI, will last for 18 months, but they are also making shorter trials using different types of insulin.  There is  SNIFF Quick to test fast acting insulin and SNIFF long to test the long acting type.

SNIFF Quick

SNIFF Long

SNIFF INI

The big 18 month study.

Conclusion

I think in a couple of decade’s time, it will be widely recognized that various physiological states exist in many complex diseases and while it may not be possible to cure those conditions, you can treat those altered physiological states.

In the case of autism those states might include:-

·        Oxidative stress

·        Mitochondrial stress

·        Microglial activation

·        Central hormonal dysfunction

·        Reduced brain insulin sensitivity

·        Impaired remyelination

·        Faulty GABA switch

These altered states are in addition to the specific channelopathies and other dysfunctions a particular person might have.

By applying what is learnt from other diseases we can then better treat the autism variants.  So what eventually develops from MS research in regard to remyelination can be translated to some autism variants, quite possibly that of Hannah Poling (mitochondrial disease, triggered by vaccination).

Reduced brain insulin sensitivity, where present, appears very treatable today.  I suspect some variants of autism do indeed feature reduced brain insulin sensitivity, but others will not.  There is no clever way to predict this, but it looks simple to test.

Autism Biology, Comorbidity, Mortality and Better use of Existing Research

Karolinska Institutet, the Medical University of Stockholm, viewed from garden next door

It is sometimes disappointing how the level of understanding of Autism, even among supposed experts, is so very low.

As readers of this blog are aware there is already a vast wealth of research in autism, highlighting many biological differences and comorbid medical conditions.  Not surprisingly this is reflected in life expectancy.

Autistica, a UK Autism charity, is trying to raise $15 million to fund five years of research into why there is premature death in autism.

This would be a complete waste of money, since the answers already exist in the literature if this “Autism Research” charity employed people who actually could/did read the research.

This subject dates back to a Swedish study from last year that is languishing behind a pay wall, so no open access to it.


The rather skimpy abstract:

Premature mortality in autism spectrum disorder.

  
The rather underwhelming press release from the Karolinska Institute:-

People with autism run a higher risk of premature death

Courtesy of SFARI we have this graphic and highlights.

Large Swedish study ties autism to early death

·        Autistic adults with a learning disability were found to die more than 30 years before non-autistic people.

·        The study found that on average people with autism died over 18 years earlier than non-autistic people.

·        Autistic adults with a learning disability are 40 times more likely to die prematurely due to a neurological condition, with epilepsy the leading cause of death

·        Autistic adults without a learning disability are 9 times more likely to die from suicide

 Autistica did produce a report that is based on the Swedish study:-

Personal tragedies, public crisis - The urgent need for a national response to early death in autism

Is there anything new here?

Epilepsy

People might rather not discuss it, but there are numerous examples of well-known people who had a child with severe autism, MR/ID and epilepsy, and it all ended pretty much as suggested in the Swedish Study.  A fatal seizure (SUDEP), or an accident like drowning following a seizure.

The logical thing to do is to prevent epilepsy developing in the first place, which some readers of this blog are already endeavoring to do.   This is not fantasy, just hard to prove it worked.

Suicide

We have seen that anxiety can be a key problem for people with Asperger’s. 

We heard from a UK pediatrician who found an off-label treatment, Baclofen, which was effective in most cases.  We also were told why he/she did not want to continue prescribing it do to the lack of any clinical trials supporting its use.

We saw how Prozac, the anti-anxiety pill frequently prescribed in autism has the known side effect of increasing suicidal thoughts.

We saw a long time ago in my hypothesis on TRH, that the US military is developing a TRH nasal spray to reduce the suicide rate in soldiers returning from combat.  A homemade version of this nasal spray was used for years by a US doctor/author to treat various neurological disorders.

We do not need to worry about suicide and people with Strict Definition Autism (SDA), but they are highly prone to accidents like drowning, caused by a combination of being allowed to wander off unsupervised and not knowing how to swim confidently.

Medical Comorbidities

Autism has a long list of known medical comorbidities and not surprisingly they will show up as a cause of death.

By accurately treating a person’s autism, you will at the same time be treating some of their comorbid conditions.

For example, if you have a problem with calcium channels (like Cav1.2) in your brain, you should not be surprised to have problems in other parts of the body where they are heavily expressed, so the heart and pancreas for Cav1.2.

The medical comorbidities are indeed a valuable tool to identify the possible biological dysfunctions underlying a person’s autism.  Then you can treat them at the same time, with the same drug.

Bipolar and Schizophrenia

In the case of autism’s adult-onset big brothers, namely bipolar and schizophrenia, there is a reduction in life expectancy of 10-20 years.

By comparison, type 1 diabetes on average reduces life expectancy by 20 years.  But you do not have to be Mr/Ms Average; if you control your condition well and also improve insulin sensitivity (ALA, NAC, Cinnamon, Sulforaphane, Cocoa flavanols etc.) the future can be bright.

People with Bipolar or Schizophrenia have a high suicide risk, in common with Asperger’s, but they also have high levels of substance abuse, starting with smoking and alcohol and going up the scale.

The core biological dysfunctions in both Bipolar and Schizophrenia are studied and some evidence-based therapies exist, lying forgotten in the literature.


Sweden as a Model

The autism mortality statistics in this post are based on Swedish data.  Sweden is not typical.  Sweden is possibly the best country in the world to live in if you have a physical or mental disability.  It is remarkable inclusive and the less able are well looked after.  So if the data existed for other countries, it would very likely look even worse. 

Conclusion

I think quasi-science organizations, like Autistica, are not helping and just add to the public misunderstanding of autism.  It is highly complex, but a great deal is already understood.  

Better use should be made of what is already known. It cannot be adequately explained in tabloid TV, or a few sound bites.

Why don’t researchers/Institutes like the Karolinska Institute, Stockholm, pay up a couple of thousand dollars and make their excellent research open access? 

As we saw when we looked at Down Syndrome, life expectancy is a case of out of sight is out of mind.

What do Autistica think the age at death of someone with autism+MR/ID +epilepsy was in 1960?

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445685/figure/F2/

In the Down Syndrome chart above, you just had to stop locking them up in institutions as babies, for them to have a better prognosis.

Since the 1970s, society no longer locks up toddlers with autism either, so now they live longer.  To live as long as other people, they need some help from science.

If you treat the underlying dysfunctions in people with autism, bingo they will live longer.  You do not need $15 million to figure that out.  You do need an open mind.

Cardiazol, a failed Schizophrenia treatment from the 1930s, repurposed at low doses as a Cognitive Enhancer in Down Syndrome and likely some Autism

Italy has many attractions, one being Lake Como (Villa Clooney). 

It is also the only western country still using Cardiazol, where it is used in a cough medicine

Varanasi and the Ganges, not a place you could forget, particularly the smell.

India is the only other country using Cardiazol

Today’s post draws on clever things going on in Down Syndrome research to improve cognitive function, but puts them in the perspective of the faulty GABA switch. 

In the United States it is estimated that 250,000 families are affected by Down Syndrome.  It is caused by a third copy of chromosome 21, resulting in up-regulation of around 300 genes.  A key feature is low IQ, this is partly caused by a physically smaller cerebellum and it appears partly by the GABA switch.  Research has shown that the cerebellum growth could be normalized, but this post is all about the GABA switch. 

In an earlier very science heavy post we saw how a faulty GABA switch would degrade cognitive function in many people with autism, schizophrenia or Down Syndrome. Basmisanil is a drug in Roche’s development pipeline.

The GABA Switch, Altered GABAa Receptor subunit expression in Autism and Basmisanil

   

More evidence to show the GABA switch affects schizophrenia was provided by our reader Natasa.

Gain-of-function missense variant in SLC12A2, encoding thebumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia

Perturbations of γ-aminobutyric acid (GABA) neurotransmission in the human prefrontal cortex have been implicated in the pathogenesis of schizophrenia (SCZ), but the mechanisms are unclear. NKCC1 (SLC12A2) is a Cl^--importing cation-Cl^- cotransporter that contributes to the maintenance of depolarizing GABA activity in immature neurons, and variation in SLC12A2 has been shown to increase the risk for schizophrenia via alterations of NKCC1 mRNA expression. However, no disease-causing mutations or functional variants in NKCC1 have been identified in human patients with SCZ. Here, by sequencing three large French-Canadian (FC) patient cohorts of SCZ, autism spectrum disorders (ASD), and intellectual disability (ID), we identified a novel heterozygous NKCC1 missense variant (p.Y199C) in SCZ. This variant is located in an evolutionarily conserved residue in the critical N-terminal regulatory domain and exhibits high predicted pathogenicity. No NKCC1 variants were detected in ASD or ID, and no KCC3 variants were identified in any of the three neurodevelopmental disorder cohorts. Functional experiments show Y199C is a gain-of-function variant, increasing Cl^--dependent and bumetanide-sensitive NKCC1 activity even in conditions in which the transporter is normally functionally silent (hypotonicity). These data are the first to describe a functional missense variant in SLC12A2 in human SCZ, and suggest that genetically encoded dysregulation of NKCC1 may be a risk factor for, or contribute to the pathogenesis of, human SCZ.

This study showed that some with schizophrenia will likely benefit from Bumetanide, but that the underlying reason for excessive NKCC1 activity in schizophrenia is not the same as in ASD.  Different cause but the same end result and the same likely therapy, repurposing an old existing drug.

α3 and α5 sub-units of GABA_A

The science is rather patchy, but it seems that the α3 sub-unit of GABA_A receptors is under-expressed in some autism and there is a fair chance that the α5 sub-unit is correspondingly over-expressed.

We know that over-expression of α5 is associated with cognitive impairment.

Down regulating α5 is currently a hot topic in Down Syndrome and at least two drugs are in development.

Reading the Down Syndrome research suggests that those involved have not really understood what is going on.  They do seek to modify GABA signaling, but have not realized that likely problem is the miss-expression of GABA_A subunits in the first place, exactly as in autism.  As in autism, this faulty “GABA switch” has more than one dimension.  An incremental benefit can be expected from correcting each one.


Further support for the use of low dose Clonazepam in some Autism

In previous posts we saw how Professor Catterall's idea to use low dose clonazepam to treat some autism does translate from mice to humans.  This was based on up-regulating the α3 sub-unit of GABA_A receptors.

There is some new research on this subject and Japanese research is very often of the highest quality.

In the paper below, highlighted by our reader Tyler, they use low dose clonazepam to reduce autistic behavior in a rare condition called Jacobsen syndrome.  While Professor Catterall and several readers of this blog are using low dose clonazepam to upregulate the α3 sub unit of GABA_A receptors, the Japanese attribute the benefit to the γ2 subunit.

Whichever way you look at it, another reason to support trial of low dose clonazepam in autism.  When I say low, I mean a dose 100 to 1,000 times lower than the standard doses.

PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking 

Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood.

ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABA_AR agonist (Clonazepam)

   

A curative effect of clonazepam on autistic-like behaviour

 These results demonstrate that ASD-like behaviour in PX-RICS^−/− mice is caused by impaired postsynaptic GABA signalling and that GABA_AR agonists have the potential to treat ASD-like behaviour in JBS patients and possibly non-syndromic ASD individuals.

“Correcting GABA” in Down Syndrome

I expect there may be four different methods, all relating to GABA_A, to improve cognition in Down Syndrome just as there appear to be in autism:-

·        Reduce intracellular Cl- by blocking NKCC1 with bumetanide

 ·        Down regulate α5 sub-units of GABA_A

 ·        Damp down GABAA receptors with an antagonist

 ·        Upregulate α3 sub-units of GABA_A

Two of the above are being pursued in Down Syndrome research, but two do not seem to be.

Enhancing Cognitive Function in Down Syndrome

These are the sort of headlines that appeal to me:-

IQ-Boosting Drugs Aim to Help Down Syndrome Kids Learn

Cognitive-enhancing drugs may have a significant impact, doctors say. An IQ boost of just 10 to 15 points could greatly increase the chance that someone with the syndrome would be able to live independently as an adult, said Brian Skotko, co-director of the Down syndrome program at Massachusetts General Hospital in Boston, who has a sister with the condition.

In 2004, Stanford University neurobiologist Craig Garner and a student of his at the time, Fabian Fernandez, realized scientists might be able to counteract the Down Syndrome with drugs…

Researchers did a test in mice using an old GABA-blocking drug called PTZ. After 17 days, the treatment normalized the rodents’ performance on mazes and certain object recognition and memory tasks for as long as two months, according to results published in 2007 in Nature Neuroscience….

“It was bloody amazing,” Garner said by telephone. “It was shocking how well it worked.”

  

Inhibiting Inhibition to Treat Down Syndrome Symptoms

In their work, Hernandez, who is at Roche AG, and colleagues both at Roche and in academia chronically treated mice that have an animal version of Down syndrome with RO4938581, a drug that targets GABA receptors containing an alpha5 subunit. GABA is the major inhibitory transmitter in the brain, and in Down syndrome, there appears to be too much inhibitory signaling in the hippocampus – where, it so happens, GABA receptors with the alpha5 subunit are concentrated.

Treatment with RO4938581 improved the animals' memory abilities in a maze, decreased hyperactivity and reversed their long-term potentiation deficit. In the hippocampus, which is an important brain structure for memory and cognition, it also increased the birth rate of neurons back to the levels seen in normal animals, and led to a decrease in the number of inhibitory connections between cells.

  

In short there are two methods being developed, both potentially applicable to some autism:-

METHOD 1.   Dampen GABA_A receptors with an antagonist

METHOD 2.   Dampen GABA with an inverse agonist of α5 sub-unit  

Initially it was thought method 1 could not be used because of the risk of seizure/epilepsy.

“these drugs (GABA_A antagonists) are convulsant at high doses, precluding their use as cognition enhancers in humans, particularly considering that DS patients are more prone to convulsions”

From:-

Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice

  

However this seems to have been overly conservative.

In the 2007 Stanford study they make a big point of their dosing being far lower than that used to induce seizures.

While you may need for a decade to get hold of Basmisanil (method 2), Cardiazol/PZT (method 1) is available in some pharmacies today.  The only complication is that it is in a cough medicine that also contains Dihydrocodeine.

In some countries Dihydrocodeine is used in OTC painkillers along with paracetamol or ibuprofen, while in other countries it is a banned substance.

In Italy and India Cardiazol, with Dihydrocodeine, is given to toddlers as a cough medicine.

  

METHOD 1.   Dampen GABA_A receptors with an antagonist

  

As seems to be the case quite often, you can sometimes repurpose an old drug rather than spend decades developing a new one.  This is the case with Cardiazol/ Pentylenetetrazol that was used in the Stanford trial.

Confusing Medical Jargon, (again)

Cardiazol, the name an elderly psychiatrist would recognize, is also called:-

·        Pentylenetetrazol
·        Pentylenetetrazole
·        Metrazol
·        Pentetrazol
·        Pentamethylenetetrazol
·        PTZ
·        BTD-001 

·        DS-102

Other than to confuse us, why do they need so many names for the same drug?

Cardiazol/ Pentylenetetrazol is a drug that was widely used in the 1930s in Mental Hospitals to trigger seizures that were supposed to treat people with Schizophrenia.  At much lower doses, it found a new purpose decades ago as an ingredient in cough medicine.

Electroconvulsive therapy later took the place of Cardiazol, as psychiatrists sought to treat people by terrifying them.  It was later concluded that the only benefit in giving people Cardiazol was the fear associated with it. Electroconvulsive therapy is still used today in autism.

  

For a background into Cardiazol as a schizophrenia therapy, the following is not very pleasant reading:-

  

‘A violent thunderstorm’: Cardiazol treatment in British mental hospitals

  

The 2007 Stanford trial of Cardiazol (there called PTZ) also trialed another GABA_A antagonist called picrotoxin (PTX).  Picrotoxin is, not surprisingly, a toxin, it is therefore a research drug but it has been given to horses to make them run faster.

Pharmacotherapy for Cognitive Impairment in a Mouse Model of Down Syndrome

  

Recent neuroanatomical and electrophysiological findings from a

mouse model of Down syndrome (DS), Ts65Dn, suggest that there is

excessive inhibition in the dentate gyrus, a brain region important for

learning and memory. This circuit abnormality is predicted to compromise normal mechanisms of synaptic plasticity, and perhaps mnemonic processing. Here, we show that chronic systemic administration of noncompetitive GABAA antagonists, at non – epileptic doses, leads to a persistent, post drug, recovery of cognition in Ts65Dn mice, as well as recovery of deficits in long – term potentiation (LTP). These data suggest that excessive GABAergic inhibition of specific brain circuits is a potential cause of mental retardation in DS, and that GABAA antagonists may be useful therapeutic tools to facilitate functional changes that can ameliorate cognitive impairment in children and young adults with the disorder.

One important things is that this cognitive enhancing effect persisted for a couple of months.

As you will see in the human clinical trial at the end of this post, they are comparing single doses with daily doses to understand the pharmokinetics.

The lead author, Craig Garner went on to start his own company because nobody seemed interested in his findings.

http://balance-therapeutics.com/

“Balance is now testing a GABA-blocking drug, BTD-001, on 90 adolescents and adults with Down syndrome in Australia, with results expected by early next year, said Lien, chief executive officer of the company.”

GABA_A agonists and antagonists

The jargon does get confusing, if you want to stimulate GABA_A receptors, you would use an agonist like GABA itself, or something that mimics it.

If you want to damp down the effect of GABA_A receptors you would need an antagonist.

So if GABA_A receptors are “malfunctioning”, you could either fix the malfunction or turn them down to reduce their effect.

If you cannot entirely repair the malfunction you could always do both.  The overall effect might be better, or might not be, and it might well vary from person to person depending on the degree and nature of malfunction.

We saw in a previous post the idea of using drugs like bumetanide, diamox, and potassium bromide to restore E/I balance and then give GABA a little boost with a GABA agonist like Picamillon.  This is very easy to test.  In our case that little boost, did not help.

In those people who do not respond well, we can take the idea developed by Stanford for Down Syndrome and do the opposite, use a tiny amount of an antagonist, to see if that fine tuning has any beneficial effect.  We now see this is both simple and safe.

METHOD 2.   Inverse agonists of α5 sub-unit GABA_A

I do like method 2, but would prefer not to wait another decade.

Method 2 sets out to improve cognitive function by dampening the activity of α5 sub-unit GABA_A.

The Downs Syndrome researchers at Roche are developing Basmisanil/RG-1662 for this purpose.  It will be a long while till it appears on the shelf of your local pharmacy.

I did look to see if there any clever ways to down regulate the α5 sub-unit of GABA_A , other than those drugs being developed for Down Syndrome. 

Inverse agonists of of α5 sub-unit GABA_A

• α₅IA
• Basmisanil (RG-1662, RO5186582): derivative of Ro4938581, negative allosteric modulator at GABA_A α₅, in human trials for treating cognitive deficit in Down syndrome.^[3]
• L-655,708
• MRK-016
• PWZ-029: moderate inverse agonist^[4]
• Pyridazines^[5]
• Ro4938581^[6]
• TB-21007^[7][8]

The only option today would be the Pyridazines, which include cefozopran (a 4^th generation antibiotic), cadralazine (reduces blood pressure), minaprine (withdrawn antidepressant), pipofezine (a Russian a tricyclic antidepressant), hydralazine (reduces blood pressure, but has problems), and cilazapril (ACE inhibitor).

Pipofezine looks interesting.

Now we can compare Pipofezine with Mirtazapine.   They are both this tricyclic antidepressants, so both closely related to H1 antihistamine drugs.  We saw in earlier posts that Mirtazapine helps some people with autism in quite unexpected ways.

  

To be classed as a Pyridazines there has to be the benzene ring with two adjacent nitrogen atoms

So mirtazapine is not quite a Pyridazine, so may not directly affect the α5 sub-unit; but it does have potent effects elsewhere on the same receptor.  It is will increase the concentration of neuroactive steroids that act as positive allosteric modulators via the steroid binding site on GABA_A receptors.

  

We saw this in earlier posts that changes in progesterone levels affect not only the function of GABA_A but even the subunit composition and hence indirectly possibly α5 sub-unit expression.

I previously suggested both progesterone and pregnenalone as potential autism therapies.  Pregnenalone has since been trialed at Stanford.

The problem with these substances is that they are also female hormones and giving them in high doses to young boys is not a good idea.  Stanford used adults in their trial.

However, affecting the metabolites of progesterone rather than increasing the amount of progesterone itself may give the good, without the bad.  Also, perhaps there is a reason, oxidative stress perhaps, why progesterone metabolism might be disturbed in autism?

Anyway, it is yet another plausible reason why mirtazapine helps some people with autism.

Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3-hydroxysteroid dehydrogenase activity

Certain 3-reduced metabolites of progesterone such as 3,5-tetrahydroprogesterone (3,5-THP, 5-pregnan-3-ol-20-one, allopregnanolone) and 3,5-tetrahydroprogesterone (3,5-THP, 5-pregnan-3-ol-20-one, pregnanolone) are potent positive allosteric modulators of the -aminobutyric acid_A (GABA_A) receptor complex.^1, 2, 3

 Mirtazapine affects neuroactive steroid composition similarly as do SSRIs. The inhibition of the oxidative pathway catalyzed by the microsomal 3-HSD is compatible with an enhanced formation of 3-reduced neuroactive steroids. However, the changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of this antidepressant rather than clinical improvement in general.

So there may indeed be an effect on α5 sub-unit GABA_A, but there is also an effect on another α5 subunit, this time the nicotinic acetylcholine receptors (nAChR).  Those I looked at in earlier posts.  This is getting rather off-topic.

The gene that encode the α5 sub-unit of nAChR is called CHRNA5.  It is associated with nicotine dependence (and hence lung cancer), but is also linked to anxiety.  GABA sub-units expression also plays a key role in anxiety.  So a reason Mirtazapine should help reduce anxiety.

  

Progesterone modulation ofα5 nAChR subunits influences anxiety-related behavior during estrus cycle 

 It has already been shown that GABA_A receptor subunit expression and composition is modulated by progesterone both in vitro and in vivo(Biggio et al. 2001; Griffiths & Lovick 2005; Lovick 2006; Pierson et al. 2005; Weiland & Orchinik 1995) but this is the first report showing an effect of physiological concentrations of progesterone on nAChR subunit expression levels.

Pharmokinetics of Cardiazol

Since mouse experiments indicated an effect that continues after stopping using the drug, the clinical trials are particularly looking at the so called pharmokinetics.  What is best a small daily dose or occasional larger doses?

You would hope they will be keeping a watchful eye on seizures.

I do not know what doses was used in those mental hospitals in the 1930s, but it must be well documented somewhere.

Safety and Efficacy Study of Orally Administered DS102 in Healthy Subjects

Experimental doses in adults vary widely from a “one off” 100mg to a daily dose of 2000mg. Look how they treat the 7 cohorts in the trial.

The cough medicine has 100mg of Cardiazol per 1ml

The usual dose is one drop per year of age, so a 12 year old would have a 0.6ml  dose containing 60mg of Cardiazol.  That is dosage is give 2 to 4 times a day, so up to 240mg a day

This dose is well up there with the dosage used in the above clinical trial, which starts at a one off dose of just 100mg or daily doses of 500mg in adults.

The above trial has been completed but the results have not been published.

If the trial is positive at the lower dose range, the cough medicine is a very cheap alternative.

Conclusion

I wish a safe inverse agonist of the α5 sub-unit of GABA_A existed for use today.

I do not know anyone with Down Syndrome and this blog does not have many readers from Italy.  The standard pediatric dose of Cardiazol Paracodina  cough medicine might be well worth a try for both those with Down Syndrome and some autism with cognitive dysfunction. 

We actual have quite a few readers from India and that is the only other country using this drug.  In India the producer is Nicholas Piramal and the brand name is Cardiazol Dicodid, it cost 30 US cents for 10ml.  So for less than $1, or 70 rupees, you might have a few months of cognitive enhancement, that is less than some people pay for 1 minute of ABA therapy.

If a few drops of this children’s cough medicine improves cognition please lets us all know.