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Thursday, 31 March 2016

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



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





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.




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.







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.









14 comments:

  1. Peter, I think this is a very interesting research and I'm sure intranasal insulin is worth a trial.
    I know a few young people with autism, also suffering from diabets and even one of them has lost his eye sight at the age of 16. I can only talk through experience and these incidents led me to believe that there must be a connection between insulin resistance and autism.
    I often wonder if the kind of Aspergers my son is suffering from may be the onset of schizophrenia as he had a few psychotic episodes and psychosis has been established. In this case insulin trial results can't be good but I'm afraid I'll have to risk it.
    Baclofen is really helpful and we saw countable results. My son admitted that brain fog has lifted by third week and can go back to his " independent research on mathematics".
    Peter, I suppose you have read about branched chain amino acids and Dr. Evangeliou research. Leucine is considered helping insulin resistance. I have been advised on trialling BCAA but I don't know details/dosage yet. If you have any ideas, please let me know.

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    1. BCAAs (branch chained amino acids) are known to be deficient in some autism, including a rare single-gene type. So if you are deficient, then supplementing might help. In addition, there may be people who are not deficient, but benefit from more, as you found with vitamin E. I have not used BCAAs.

      I think that quite often Asperger's overlaps with Schizophrenia, these are just words not biological diagnoses. In the same way some people with autism are given the bipolar label.

      There are many ideas for treating schizophrenia, one of which was D-serine, that I mentioned before.

      I would not get too carried away and just use a small number of therapies that really are effective in your case and do not produce side effects. (baclofen, NAC etc)

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  2. If you want to do BCAA's and you have a difficult child who does not like yucky stuff (most BCAA powders taste bad) I would go with Scivation XTEND. It also has glutamine, B6, citrulline, and some potassium and this is what I settled on after a lot of trial and error in terms of the best tasting/affordable options for a BCAA powder. Though, I don't do BCAA's for the reasons you suggest (I use them to block peripheral kynurenine/tryptophan access to the blood brain barrier), I would go with this brand as all of the different flavors I have bought all taste pretty good (watermelon is what I use at the moment).

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  3. Thank you Peter, Tyler for your advice.
    Just for your information, Dr. Evangeliou claims that before going to other amino acids like glycine or serine you first give BCAA for some reason I can't follow.

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  4. Petra, this is for you. Are you Greek or live in Greece? If yes, please send a message at jimfayo806@gmail.com Thanks!!

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  5. A little off topic but Peter I think this paper might interest you:

    http://journals.lww.com/pain/pages/articleviewer.aspx?year=9000&issue=00000&article=99591&type=abstract

    Basically, it talks about a mechanism for inducing chronic pain whereby GABergic plasticity may be modulated to an excitatory state via a mechanism not via chloride accumulation in interneurons. The alternative mechanism is via a protein called neuroligin-2. I think you may have covered neuroligins in a previous blog post, but I am sure you know what they are by now anyways.

    Now, I don't really know if this directly applies to autism, since it is about chronic pain research which seems to be a bigger deal now than autism in the USA at the moment thanks to a sweeping opioid/heroin epidemic almost exclusively created by out wonderful doctors who are just fine in prescribing Oxycontin to any random Joe, but won't even remotely consider off-label treatments for autism.

    Nevertheless, this might be an avenue to explore with regards to maybe possibly a complimentary adjunct to Bumetanide if there are indeed drugs/interventions that can deal with neuroligin problems via neurologin analogs or interventions that upregulate neuroligin production since in autism deletions or mutations of neuroligin genes (there are several) can push inhibitory interneurons into a permanent state of excess excitation. It is definitely something to think about.

    ReplyDelete
  6. I had posted this a couple days ago, but it must not have went through to blogger for some reason. I'll give it another go.
    -----------------------------------------------------------

    Hi Peter,
    I appreciate this post, and while I’m still trying to wrap my head around a lot of the neurochemistry gracing these pages, this is one small corner of the subject matter where I have something resembling expertise. From 2009 to 2013, I was involved with a group doing a pilot study on intranasal insulin as a treatment for mild to moderate Alzheimer’s (I did most of the work with the study design and statistics). We wanted to do something bigger, but it’s hard to get funding for something like this – it’s generic everywhere and all of the suppliers we approached wouldn’t bite. Neither did the NIH for that matter. Eventually, we put together a small study on 12 individuals and the published work is here: https://www.researchgate.net/publication/267871555_A_Single-Dose_Pilot_Trial_of_Intranasal_Rapid-Acting_Insulin_in_Apolipoprotein_E4_Carriers_with_Mild-Moderate_Alzheimer%27s_Disease

    The punchline is that 2 of the 30 cognitive measures we looked at showed statistical improvement, but that could just be a multiple testing artifact. We were somewhat less optimistic after seeing the data than we were before. But I definitely don’t mean to take the wind out of anyone’s sails on this, I still think it holds a lot of promise as a concept. Also, this has a couple differences in the context of ASD - the subjects we were looking at were all APOE4 positive senior citizens, who may have a diminished response. Also, we used glulisine, which is an analog of insulin but not exactly insulin, so there’s that.

    Not being a lawyer, I don’t know what it would mean to outright recommend trying this at home, so I won’t. But I will say had a great safety profile in our subjects (i.e. zero adverse events). We found that peripheral insulin was always acutely *reduced* by intranasal insulin administration, which we thought was kind of weird, so I guess in the right circumstances that could cause problems. The effects for better and for worse appear to be transient, but who knows what would happen in either direction if it was applied several times per day.

    Cheers,
    Christopher Anderson

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    1. This comment has been removed by the author.

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    2. Thanks for this Christopher and a big thanks for not being "Anonymous".

      A transient improvement is still worthwhile and of course the long acting insulin might be best.

      As you highlight, there is no big money to be made here, so insulin nasal sprays may not be appearing anytime soon at the local pharmacy.

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    3. Peter, I was speaking to my pharmacist yesterday about this, and he said there was one other person who had contacted him for the same. He was going to look into into the device and cost and get back to me next week. So, it maybe that compounding pharmacies could do it.

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  7. The human body does create HGH in the body naturally. It is a product of the pituitary gland. When you are young, this substance is released into the blood stream and helps you grow.

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  8. Here is a guy who has compiled about as much research as he could find on intranasal insulin (his stated goal is general cognitive enhancement which is questionable in an already healthy person) and looks like a good source of information for farming for ideas with respect to intranasal insulin and autism:

    http://www.lostfalco.com/intranasal-insulin-studies-on-cognitive-enhancement-alzheimers-traumatic-brain-injury-etc/

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    Replies
    1. Hey Tyler, Lostfalco here. Thanks for the shout out!

      I've also written about how to buy intranasal insulin legally over the counter and make it at home for $25 here: http://www.lostfalco.com/intranasal-insulin/

      It's one of the best cognitive enhancers I've tried and it has significant potential to help a lot of people with Alzheimer's, age related cognitive decline, mood issues, memory problems, etc.

      Pretty exciting stuff.

      Delete

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