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Wednesday, 10 February 2016

More Failed Autism Trials and (28 million) thoughts as to why



Two autism therapies mentioned in this blog have recently failed in their clinical trials.

The selective mGluR5 antagonist mavoglurant failed in two trials funded by Roche and Coronado Biosciences threw in the towel with its Trichuris suis ova (“TSO”) program.  TSO are parasites that are introduced to the gut to modify the immune response, they are thought to help conditions like ulcerative colitis and some autism.



"Coronado Biosciences (NASDAQ: CNDO) has decided to no longer pursue the development of its Trichuris suis ova (“TSO”) program. The Company is terminating all on-going TSO trials, including the Company’s Phase 2A clinical trial of TSO in pediatric patients with autism spectrum disorder. A preliminary analysis of data from this trial failed to demonstrate any signal of activity."


The original user of TSO in autism documented his case here:-

http://autismtso.com/

It has been a long time since the father updated his site. Does he still give TSO to his son?

This adds to a growing list of very expensive failures.

The good news is that people are beginning to wonder why these, and all the previous trials, "failed".  Perhaps some were not failures, rather narrowly selective successes.  A new initiative is underway called Autism Biomarkers Consortium for Clinical Trials to try to develop more objective measures both for diagnosing autism in young children and for tracking changes.


"The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multicenter research study based at Yale that spans Duke University, Boston Children’s Hospital, the University of Washington/Seattle Children’s Research Institute and the University of California, Los Angeles. The aim of the consortium is to develop reliable and objective measurements of social function and communication in people with autism."
  

NIH provides $28M to study autism biomarkers via its Biomarkers Consortium


That is a lot of money.



I wish them well.

I do not think they fully realize the task facing them.  There are hundreds of “autisms” and many are dynamic, so changing over time.  Even if you find a responder to a therapy, if you tested the same person six months later he might not respond positively. 

It is highly unlikely that any single therapy can target all the symptoms in any case of autism.  So multiple therapies will be needed.

For many people, autism is a moving target, any kind of allergy, tooth issue or other inflammation could cause a false negative.



Single Gene vs Idiopathic Autism

It should be much easier to develop treatment for single gene autisms, like Fragile X, than for the idiopathic (“we have no clue what causes it”) autisms.  The above trials by Roche were in Fragile-X, where at least you know that all the subjects in the trial started with the same single gene dysfunction. 

But do they have other genetic/epigenetic dysfunctions?  Do they all have the same downstream dysfunctions? 

Fragile X is caused by a lack of the FRMP protein, perhaps the only time to correct this is very early in life.  Thereafter you have the downstream consequences, some of which overlap with ideopathic autism, some of these may well be treatable. 


 Autism Case Reports and Anecdotal Evidence

A good source of information remains published case reports.  These are documented pieces of anecdotal evidence showing what appeared to help a particular person. Here is one highlighted recently by Agnieszka, a reader of this blog.

Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism, A Case Report and Review of Literature



The index patient is a 9 year old boy with autism spectrum disorder diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). He suffered from generalized tonic-clonic epilepsy from age 4. He had taken multiple different medications such as phenobarbital, sodium valporate, and carbamazepine with sufficient dosages and durations without favorable control of his epilepsy. According to his parents’ reports, the patient took cefixime 200mg/day to control diarrhea about 2 years ago. The seizure episodes were dramatically decreased 3 days after starting the medication while the there was no change in his anti-epileptic medication regime. The seizure episodes were controlled for about 5 months, after which the number of seizure episodes again increased. His highly educated parents administered cefixime 200mg/day to control seizure again. They reported that seizure attacks were controlled markedly after taking cefixime for three days. The patient was not febrile while the medication trials were administered. Both parents reported that they repeated this trial for several times to control the seizure episodes in the recent years. The epilepsy was controlled in all of the trials after taking cefixime for 3 to 5 days. Then, they discontinued cefixime after 7 days. They reported that there was a marked decreased in the number of seizure attacks as well as aggressive behaviors.


You cannot read too much into any one case report, other than to note how many totally unrelated interventions seem to benefit unique cases of autism.  This only goes to show that totally unrelated dysfunctions can manifest themselves as “autism”.

If you grouped all the anecdotal evidence together you would have some interesting reading.  If someone actually followed up on these anecdotes and did some additional investigation on each case we might learn very much more.



Previous Autism Clinical Trials

When I read the original clinical trials of NAC and Bumetanide in Autism, the results seemed good enough to me to warrant my own trial.

I do not see why there has not yet been a follow up of Stanford’s trial of NAC.  There was a patent (below) and then nothing.  It clearly works in many people, but most clinicians will not prescribe it until it is “evidence based”.  Those granted the patent should then go and collect some more evidence.



Bumetanide has also been patented for autism and the next stage of trials will follow, we are informed.

I will be interested to see whether the phase 3 trials are solid enough to convince mainstream clinicians to actually prescribe it.  "A diuretic for autism, come on, be serious!"

Nothing would surprise me.


Funding for Future Trials

It would be a bold person who invested any profit-seeking capital in autism trials, but they keep coming forward.  Here is another new one, OV101 from start-up Ovid.

The only reliable source is public money and philanthropy.

It looks like the US NIH (National Institutes of Health) still has deep pockets and Jim Simons keeps backing his Foundation.



mGLuR5

Roche may not have succeeded with their mGLuR5 drug, mavoglurant, but mGluR5 remains a target for treating schizophrenia and autism



Receptors in brain linked to schizophrenia, autism



Disruption of mGluR5 in parvalbumin-positive interneurons induces corefeatures of neurodevelopmental disorders





What would a successful Autism Trial look like?

Given the heterogeneous nature of autism, even a really effective drug might not look so good in the data.  Very specific drugs that counter the disorders where there can be both hypo and hyper, will come out with some good responders, some with no effect and a sizable number with a bad effect; so on average not so good.

Drugs that affect the most common down stream effect, oxidative stress, would come out best.  So I the results Hardan obtained in his Stanford trial of NAC will be as good as it gets.  Those results were enough for me, but not so impressive to many.

Now reconsider a long forgotten trial of an anti-depressant drug, developed from a first generation antihistamine.

This trial has a rather eclectic mix of 26 subjects, but 36% were responders, either much improved or very much improved in a wide variety of symptoms including aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia. However the authors judge the trial drug as: 


  "Mirtazapine was well tolerated but showed only modest effectiveness for treating the associated symptoms of autistic disorder" 


What were they hoping for ?






Abstract

OBJECTIVE:

The aim of this study was to conduct a naturalistic, open-label examination of the efficacy and tolerability of mirtazapine (a medication with both serotonergic and noradrenergic properties) in the treatment of associated symptoms of autism and other pervasive developmental disorders (PDDs).
METHODS:

Twenty-six subjects (5 females, 21 males; ages 3.8 to 23.5 years; mean age 10.1 +/- 4.8 years) with PDDs (20 with autistic disorder, 1 with Asperger's disorder, 1 with Rett's disorder, and 4 with PDDs not otherwise specified were treated with open-label mirtazapine (dose range, 7.5-45 mg daily; mean 30.3 +/- 12.6 mg daily). Twenty had comorbid mental retardation, and 17 were taking concomitant psychotropic medications. At endpoint, subjects' primary caregivers were interviewed using the Clinical Global Impressions (CGI) scale, the Aberrant Behavior Checklist, and a side-effect checklist.

RESULTS:

Twenty-five of 26 subjects completed at least 4 weeks of treatment (mean 150 +/- 103 days). Nine of 26 subjects (34.6%) were judged responders ("much improved" or "very much improved" on the CGI) based on improvement in a variety of symptoms including aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia. Mirtazapine did not improve core symptoms of social or communication impairment. Adverse effects were minimal and included increased appetite, irritability, and transient sedation.

CONCLUSIONS:


Mirtazapine was well tolerated but showed only modest effectiveness for treating the associated symptoms of autistic disorder and other PDDs.



I think that was a successful trial that should have been followed up, rather then being forgotten.








41 comments:

  1. http://journal.frontiersin.org/article/10.3389/fnins.2016.00016/abstract

    This paper basically concludes that for autism that just about every brain cell type is likely affected. The paper looked at a variety of neurological disorders and this just happened to be their conclusion for autism.

    In other words, unless you treat everything that is wrong in the brain and perhaps even the body, you are still going to have dysregulated systems that lead to a poor outcome. Furthermore, expecting silver bullet success from any drug is unrealistic as for example impaired glutaminergic signaling is going to have effects on gabaergic signalling and vice versa since they play off of each other. Fixing one system won't get you a good outcome if both systems are broken. This is a lesson you learn the hard way when doing concurrent programming (which I used to do), but seems to be lost with regards to efforts at coming up with useful comprehensive therapies for autism.

    Unfortunately, combinatorial intervention studies are complex and totally non-existent when it comes to autism research. Furthermore, sometimes some drugs or interventions will fix one problem but cause a side effect or else intensify another problem that needs fixed, which requires addressing these side effects. Coming up with experiments that control this complexity often is not practical and in the end the research never gets done.

    So far to date I have employed interventions directly targeting the serotonergic system, the glutaminergic system, the opioid system, and the gabaergic system (I am using the word system loosely here), as all appear to be big players in idiopathic autism and as yet there have not yet been good candidates for a dysregulated system that rules them all (there may never be), though at the moment I think the opioid system and its relation to the immune system would be where I would bet money on if I was forced to do so. Even then, it is possible that targeting those systems may be just the tip of the iceberg as correcting those deficits may not deal with the neurological system dysfunctions stemming from how the autistic brain is wired together. Fixing this problem may require non-drug/diet interventions in the realm of TMS, TDCS, or related artificial brain stimulation therapies. Perhaps monotherapy drug solutions may rescue autism at a very early stage in development (perhaps even prenatally) but in the case of my family I think the challenge is that of putting Humpty Dumpty back together again.

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    1. That is an interesting paper.

      The paper on autism genes discussed here is also interesting.

      http://psych.ucsf.edu/news/new-autism-genes-are-revealed-largest-ever-study

      Interesting that girls with ASD have far more mutations than boys.

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    2. Hi Peter,
      If you do end up finding a genetic issue, are there any targeted medications being developed.
      We did genetic exome sequencing for my son as suggested by geneticist, came back normal.
      There seem to be more tests that could be done to identify high risk autism genes (aroun 50) as mentioned in the paper. But I was told was except methyl folate genetic issue, others dont really have any drugs in development.
      Thanks
      BK

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    3. Hi BK,

      I think most people will have a number of genetic variations on whole exome sequencing. I think they will generally only tell you the ones they think are relevant to the condition (ie autism). The problem is that they do not always seem to know which are the autism genes, there are 700+.

      If you know which gene(s) are affected you could look for ways to compensate for this. There may not be specific published drug therapies, but that does not mean there is not an off-label therapy that achieves what you want.

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    4. More food for thought from a paper I read yesterday:

      Teaching neurons to respond to placebos

      http://onlinelibrary.wiley.com/doi/10.1113/JP271322/abstract

      Essentially, this is relevant because this suggests that with some types of drugs that are not good to be given chronically, that you can significantly reduce the dosage using the placebo response.

      Another recent article I read a little less than a week ago covers the same topic:

      http://mosaicscience.com/story/medicine-without-the-medicine-how-to-train-your-immune-system-placebo

      Delete
  2. Tyler, I am with you when you say "Even then, it is possible that targeting those systems may be just the tip of the iceberg as correcting those deficits may not deal with the neurological system dysfunctions stemming from how the autistic brain is wired together. Fixing this problem may require non-drug/diet interventions in the realm of TMS, TDCS, or related artificial brain stimulation therapies." I am looking into low-level (cold) laser therapy, only because it is easier to access and cheaper than TMS. Quite a bit of research in humans has accumulated in the past several years, including using it for traumatic brain injury and post-stroke recovery... all very promising.

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    1. Anonymous, I actually have several years of experience with this stuff, though not cold lasers specifically (which are unnecessary and expensive and require protective eyegear for both the administrator and recipient).

      In fact, I have done this for several years with my oldest son using infrared CCTV LED's. This is specifically what I use right now:

      http://www.amazon.com/gp/product/B00QNC2ICM/ref=s9_hps_bw_g421_i5

      This is another guys review of LLLT that is pretty decent even though I don't agree with everything he says:

      http://selfhacked.com/2013/11/14/my-review-of-lllt/

      I could send you tons of other info, but in lieu of me explaining everything my entire experience and my opinions about LLLT from my point of view, I think the above link should suffice if you have not stumbled upon it already.

      Now, since my son does not have a shaved or balding head, I only use it on the forehead and sides of the head (i.e. where there is no hair) for 10 minutes per spot which is the amount of time used most recently in a study on USA veterans with TBI from combat. 10 minutes with 25 milliwatt LED's is 15joules/cm^2 which is a lot more than the standard 3joules/cm^2 you use on other areas of the body (such as a swollen knee or ankle or else for hair growth), but really only about 3% of the photons make it through the scalp and skull and hit the cortex, so I am not sure why the researchers in the study I am referencing used only 10 minutes (because 3% of 15j is less than half a joule of energy at 0.45j), but that is what I am going with because they must have their reasons and they got good benefits with this amount of exposure to the brain (or maybe they determined more than 3% of the photos made it through the skull or whatever their reasoning was).

      Now how do you apply this to a severely autistic child who doesn't like things on their head. Well, the trick is to do it in their first stage II session of sleep when children under age 10 are very hard to agitate out of sleep. This happens about 10 minutes after they fall asleep and you can do just about anything short of pooring cold water on them and they won't wake up. If your child is swatting at their face or wakes up 10 minutes or so after they fall asleep it means they are either taking longer to get into stage II sleep, or else they are not getting into stage II sleep which means melatonin might help in this situation. If you miss the first cycle of stage II sleep, then you are likely to agitate your child and wake them up which is going to probably do more harm than good in that situation.

      The CCTV LED's light I linked above is 15 watts, but has 96 LED's over 600 square centimeters (60x10) for a total of 25milliwatts per cm/^2. So a joule is 1 watt per second so for 25 milliwatts you need 40 seconds of exposure to get 1 joule of output per cm/^2. So 3 joules would be 3x40 seconds = 2 minutes. Going a little bit over 2 minutes is OK, just you don't want less than 2 minutes if you are trying to rapid heal injured tissue.

      Now there are people who use cold lasers for this stuff, but all the research I am aware of (the most modern research) suggests that what matters is wavelength and exposure, not intensity or frequency of exposure (i.e. lasers that oscillate on and off at some frequency say 10hz). The mechanism of action is thought to be on complex IV of the mitochondrion via a hormetic response of upregulating the cells' stress response.

      Holding these LED's lights up to your child's head for 10 minutes at a time while they are asleep is cumbersome, but that is the most practical way to do this that I know of.

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  3. Thanks Tyler, we have a similar LED, that is helpful to know about milliwatts to joule conversion, since all studies talk in joules! Ours has a paddle with two sides, NIR (880) and Red (660 I think), and also several frequency settings. We use a minute or so each on continuous and two others (70 and 120 Hz), alternating between NIR and Red.

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    1. NIR penetrates tissue better than RED which is why you may want to use RED on peripheral injuries (skin, muscle, etc.) but it won't do much to get in the brain. And oscillation frequency or waveform (square, sine, etc.) is irrelevant. All that an oscillating frequency will do is generally ensure you need twice as much time delivering the light or laser to get the amount of energy you need for therapeutic use.

      Delete
    2. Hi Tyler & Anonymous, hope you both might be willing to expand a little on this therapy. I have been using it for two weeks on my son Morgan, & having very high hopes & expectations in it am impatient to see results! I am using a unit that is round, with an internal diameter of 6cm and an alleged output of 3 watts at 850nm. I figure this gives me an output of 1007 milliwatts over 9.5 seconds, or 12.72 joules over 2 minutes, which is the length of time I have applied it to each spot on Morgan’s head to date. (Part of the reason for my high expectations arises from self-experimentation: the first couple of times I applied it to my own head, for 3 minutes per spot, I experienced greater daily mental stamina with reduced need for sleep on the two days following application. However that buzz seems to have disappeared …)

      Tyler, I have been wondering about why you limit the application to just three spots, rather than the range described in case report 1 in “Improved Cognitive Function After Transcranial, Light-Emitting Diode Treatments in Chronic, Traumatic Brain Injury: Two Case Reports” at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104287/. Is it just because your son would otherwise wake up, or is there a specific risk in applying the LEDs to the base of the occiput of which I am unaware? Also Tyler, if I may ask, I have been wondering why you have been using on your son for so long? Is it, again as in case report 1, that he regresses without it being used regularly?

      Please don’t rush to answer; I know it is a busy time of year! Alexandria

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    3. Hi Alexandria,

      I am really curious about the so called brain stimulation techniques but responses to these as far as I know have been mixed according to parents. It seems that if not done correctly, there is even the possibility of potential harm.

      Could you give me a reference or reliable source where I could get basic information about this if I decide to do it myself.. Provided it can be done by a non expert. Is it safe..I can't wait to show off about this stuff straight from Matrix series in front of my niece and nephews. But on a more serious note please guide me, where to begin regarding reading up about the principles and the implementation part.. I would be really grateful.

      Delete
  4. Peter, I posted on another thread about mitrazipine's effect on mu opiod receptors, which may well be behind its observed effects in autism (in addition to or instead of its effects on histamine or serotonin receptos).

    That small naltrexone trial for autism, as well as numerous reports from parents who have tried Low Dose Naltrexone reported improvements in those very same areas, notably irritability, aggression, low moods. Naltrexone acts primarily on mu opioid receptors.

    Now what is REALLY interesting about this study on ‘autistic' mice who lacked mu opioid receptors is that these mice had lowered activity of quite a few genes implicated in autism. Although the genes themselves were intact, something something linked to the lack of mu receptor activity made all these genes go quiet.

    "Inactivation of the mu opioid receptor gene, therefore, alters expression of several candidate genes for ASD"

    Look at the list of the things they found (my bolding and spacing):

    "We detected changes in the expression of genes coding for the adhesion and scaffold proteins
    ------ neuroligins (Nlgn1 and Nlgn2) and SHANK3 (Shank3).

    Transcriptional levels were also modified for the genes coding transporters of
    ------ norepinephrine (NE, Slc6a2)
    ------ dopamine (DA, slc6a3)
    ------ and serotonin (5HT, slc6a4),
    ------ as well as several receptors, including beta3 subunit of GABAA receptors (Gababrb3)
    ------ and 5HT2a serotonin
    ------ and D2 dopamine receptors.

    The most dramatic changes in expression were observed for the genes coding the
    ------ neuropeptides CRH and OXYTOCIN.

    Expression of Grm5, coding these receptors, was not modified in Oprm1−/− mice; HOWEVER expression of
    Homer3, coding a key molecular interactor of mGluR5 receptors, was significantly downregulated…"

    They conclude that "Stereotyped and perseverative behaviors detected in Oprm1−/− mice further complete autistic-like core symptoms in these animals. In addition, mutant mice show multiple comorbid symptoms of ASD, including aggressiveness, exacerbated anxiety, motor clumsiness, and increased susceptibility to seizures. …”

    The researchers then go on to test treating two of the affected pathways simultaneously, with some really interesting results, concluding that "facilitation of mGluR4 signaling was able to restore social reward in these animals."


    Apart from mirtazapine and obviously naltrexone, are there any other agents capable of modulating mu receptors that you think could/should be trialed for autism?



    (that mice study can be accessed in full via
    http://www.nature.com/npp/journal/v39/n9/full/npp201459a.html

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    1. Nat, all very interesting. There are various drugs related to addiction that seem to help autism, which does appear odd; Baclofen is one example.

      There is a class of drug called Peripherally-Acting Mu-Opioid Receptor Antagonists (PAMORA).

      I supposed you would want a Centrally-acting Mu-Opioid Receptors Antagonist which should be called CAMORA.

      Naltrexone is an antagonist of the μ-opioid receptor (MOR), the κ-opioid receptor (KOR) to a lesser extent, and to a far lesser extent, at the δ-opioid receptor (DOR)


      I did find this one, which just blocks MOR :-

      Cyprodime is an opioid antagonist from the morphinan family of drugs.

      Cyprodime is a selective opioid antagonist which blocks the μ-opioid receptor, but without affecting the δ-opioid or κ-opioid receptors. This makes it useful for scientific research as it allows the μ-opioid receptor to be selectively deactivated so that the actions of the δ and κ receptors can be studied separately, in contrast to better known opioid antagonists such as naloxone which block all three opioid receptor subtypes

      I think mirtazapine should be trialed again. It clearly might have multiple benefits.

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    2. This of course crosses paths with the good old opioid theory of autism, which originally came about to explain effects of gluten and similar.

      Interesting also that many 'novel' proposed treatments for autism such as CBD and even ketamine also affect MORs.

      Have a look at this on ketamine and its actions http://www.sciencedirect.com/science/article/pii/S2210844014200062

      That one case study on ketamine for autism is behind a paywall so we have to trust the second-hand reports and the fact that the outcome led to a Phase II trial https://www.clinicaltrials.gov/ct2/show/NCT02611921


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    3. PS another clue that intranasal ketamine is showing promising results is that they've moved on from this (unpublished) pilot study to phase II now

      http://www.cureswithinreach.org/research/search-complete-research/research-projects/225-ketamine-for-autism

      Again all the discussion revolves around ketamine's NMDA action, whereas what we are seeing could easily be down to its MOR-modulating effects


      "... Wink et al34 reported a 29-year-old woman with autism who was treated with intranasal ketamine (20–60 mg) on 12 dosing occasions across 6 weeks. She showed improvements in mood, social interactions, flexibility, tolerance of changes in routine, motivation, and concentration. Adverse events were mostly mild; the most prominent was headache, which lasted for up to 10 hours after a treatment. A case report also showed benefits with intranasal ketamine in depression..." From http://www.psychiatrist.com/jcp/article/Pages/2015/v76n05/v76n0514.aspx


      Another case report on (a one-off?) administration of ketamine improving CORE symptoms of autism

      http://www.degruyter.com/dg/viewarticle/j$002fijdhd.2016.15.issue-1$002fijdhd-2015-0003$002fijdhd-2015-0003.xml

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    4. More on that original Wink et al. case report that initiated the current trial:

      "In a recent report, intranasal ketamine was used in an adult ASD patient with co morbid psychiatric conditions.

      Despite extensive treatment, at presentation she suffered from social impairment, repetitive behaviors, sensory sensitivity, contamination fears, low weight, absent menstrual cycles, chronic
      purging, depressed mood, anhedonia, low energy, poor concentration, and chronic suicidality.”
      In August 2013, the patient consented to begin clinical treatment with intranasal ketamine. Within 24 hours following each self-administered intranasal dose of ketamine, the patient reported significant improvement in mood, increased
      ease of interacting with others, more flexibility and tolerance of routine
      change,increased motivation, improved concentration, decreased suicidal thoughts, and feeling more connected to others"

      Delete
    5. Ketamine has numerous properties including being a L-type calcium channel blocker. Intranasal ketamine has been used off-label in the US for all sorts of neurological things. The big drawback is that ketamine is widely abused as a "recreational" drug all over the world.

      Delete
    6. Another case study, treatment started with mirtazapine then added galantamine

      http://www.omicsgroup.org/journals/mirtazapinegalantamine-combo-tackles-behavioral-facets-in-autism-2165-7890-1000145.php?aid=59073

      and Massachusetts General Hospital is running a phase 3 trial on mirtazapine, to be concluded in 2017 and still recruiting.
      https://clinicaltrials.gov/ct2/show/NCT01302964

      J.

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    7. J, well spotted.


      It looks like Autism Speaks are funding the idea of David Posey who did the 2001 Mirtazapine study, that I mentioned. Things move that fast !!!

      https://www.autismspeaks.org/about-us/press-releases/autism-speaks-awards-16-new-research-grants-funding-more-5-million-over-next

      "Another trial will focus on treating anxiety, which affects 1 in 4 affected individuals with ASD. Anxiety can be extremely debilitating for individuals with ASD, and can even hinder their responsiveness to behavioral interventions. Few medications have been tested to treat anxiety. One funded study will examine the ability of the medication Mirtazapine to treat anxiety symptoms in a randomized, placebo-controlled trial in children and adolescents with ASD (Mirtazapine Treatment of Anxiety in Children and Adolescents with Pervasive Developmental Disorders, David Posey, M.D., Indiana University School of Medicine)."

      Delete
    8. Well, this CT for sure has a long time frame.

      Hopefully it will come up with something better than the usual "X% awesome responders, don't bother with it" that seems to be the norm regarding autism treatment publications.

      J.

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  5. The list of things abused as "recreational" drugs that may well be helpful in (some cases of) autism is getting longer and longer. Don't forget cannabinoids and MDMA too http://www.mdma-autism.org/

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    1. Don't forget what Ivar Lovaas was doing at UCLA in the 1960s.

      Modification of Autistic Behavior with LSD-25
      http://neurodiversity.com/library_simmons_1966.html

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    2. Interesting, I didn’t know about Lovaas. Just wonder how it all would look like today if he had stuck more to this area of research instead of doing what some claim now to be the only evidence based help for autism, at least where I live (I don’t mind ABA as an effective way of teaching skills).

      5 mg Mirtazapaine in the evening got my son to sleep immediately which was ok, but all next day he was unusually irritable, unhappy and tired so I did not continue. I saw similar irritability in him before and thought it’s associated with drugs affecting serotonine receptors (e.g. cyproheptadine). In the case reports and study about Mirtazapine they used doses from 5 mg to 45, quite a wide range.I think that different mechanisms of action may be expected with such different dosing but I don’t know how this relates to opioid receptors. 5 mg Mirtazapine may euqal more for my son as he uses Diamox and Verapamil which both are CYP3A4 inhibitors and that may influence Mirtazapine metabolism.

      I cannot say I can explain all symptoms/behaviors of my son in terms of biological processes, but on that day on Mirtazapine I saw some that I suspect to be related to mitochondrial impairment, so I checked this and found that Mirtazapine was associated with the decrease of the complex I activity:
      http://www.ncbi.nlm.nih.gov/pubmed/20588251
      I don’t know if it is of any clinical relevance and if complex 1 inhibition could be seen so quickly, after the first dose?

      I wonder how was the child who improved on low dose of Remeron in the first days of treatment? What about drowsiness etc? I would appreciate if parents could tell more if they are reading this discussion.

      The mood and stamina got back to typical soon after, so at worst Mirtazapine is just not for my son.

      I appreciate these published case reports, which are often more helpful than studies, but I think it’s a pity that all what we know from them is behavioral description pre- and posttreatment. Some labs for mitochondrial dysfunction are so simple and cheap for example....

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    3. Agnieszka, a pity Mirtazapine did not help, but it was well worth checking and no harm done. In the new trial, now recruiting, the dose starts at 7.5mg and goes up to 45mg. These do seem to be very large doses that may invite side effects.

      Delete
  6. would love to hear from others using mortazapine. Giving it a try thanks to a tip from Agnieszka. Hoping it can help anxiety from pain (chronic pain flares from tumor). I see that it is also prescribed to treat nerve pain. We are using 7.5 . I noticed in the paper Agnieszka shared that lower doses is for depression and higher for anxiety - so I am wondering if going a little higher than 7.5 would be better?? But we are also using verapamil and I read caution advised when combining - just not sure at what dosage. Hoping to get some feedback here.

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    1. I don't think that it might be risky to give Verapamil + Mirtazapine. No interactions listed here:
      http://reference.medscape.com/drug-interactionchecker

      Verapamil might slow Mirtazapine metabolism very slightly, which probably has no impact when you use typical dose of the latter. I thought it might be important when using low dose, but I am not sure.

      Mirtazapine may act on many receptors so may have many effects and it's dose-dependent. Low dose seems to affect H1 histamine receptors mainly.

      RG can you share your experience with low dose Mirtazapine?

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    2. Hi Agnieszka, Tanya,

      Mirtazapine has been very good for us. We tried it primarily for sleep problems, both an inability to fall asleep and to sleep deeply. From the lastpyschiatrist blog and a few anecdotal reports on the internet, it seemed that 3.75mg was effective for sleep. I halved that to a little less than 2mg and it kicked in after two hours. It was the deepest I had seen my daughter sleep. I had her with me in my bed and noticed slow, deep breathing, something I had not seen before. She woke up after 10 hours well rested. I tried a range of doses upwards up to 7.5mg to see if the time to sleep could be shortened. It did not. Here's what happened:
      4mg: Sleep after two hours first night, deep sleep. Next morning slight traces of irritability, continuing through the day. Very mild. Second night at same dose, sleep onset pushed out to over four hours after taking, so have to assume no effect. Poor sleep quality, light napping, half awake through the night. More irritability during the day, extended crying jags. Going down to 2mg on the third night would allow her to sleep but not deeply, and continued irritability and crying the next day. The following day everything would normalize.

      6mg, 7.5mg: No effect on sleep, she kept awake and irritability similar to the 4mg dose. Three days for irritability and crying to fade away.

      For sleep only the 2mg is effective and without irritability. With higher doses it takes two to three days for the negative effects to wear off.

      It has been excellent for cognition. There are many things that she wants to do now, where she is initiating activities, such as texting her father for things she wanted him to bring her. Willing to try things such as sparkling water. Also tasting and eating unfamiliar foods such as chicken mole which was a chicken smothered in a plate of green sauce. Asked to go rollerblading, which she hasn't in years. Wants to do her lessons, especially reading, and asks for it at all hours. A few nights ago insisted on more lessons, and brought her book to the table. I was busy and her father told her to do it herself, and she was able to spend ten minutes on it without help, this is big for us since she will only work with supervision.

      There was one other big change very soon after, and this was in my daughter's face. Since puberty, her face changed and there's always been a bit of puffiness. This was something only we could tell, strangers just thought she had a slightly broad face. On some days the puffiness would increase and lower on others. It had come down quite a bit with low dose clonazepam and Diamox, and we assumed it had gone. Within two days after mirtazapine, we noticed that her face changed, her features sharper. My mother who didn't know about the medicine, said that her face was looking like it used to and was smaller.

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    3. very interesting, thanks for sharing! Do you mind if I ask how old is your daughter? I tried 3.75 the first night and the next morning he was lethargic. The next night I tried 7.5 and the next morning he jump out of bed and opened all the curtains ready for the day. But that only happened once. You've given me good ideas on how to experiment with the dose - and I will make sure to tweak his foods so as not to add to blood sugar crashes. We do avoid high protein due to high ammonia. Such a good report for your daughter and this medicine - so wonderful!

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  7. Thanks Agnieszka. RG, did you notice any effect on blood sugar? We have been trying it for nearly 2 weeks and finally realized I think it is causing some day time hypoglycemia. Took me a few days of not being at home and near the fridge to realize - or days of eating foods that exacerbate crashes... I did notice a side effect is increased appetite - my son eats well, and is very thin, yet good muscle tone. However since starting we have had a few moments of hypoglycemia type fits. Might have to shelve this one.

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    1. I have not tested her blood sugar as she dislikes the lances. I have noticed that she gets hungry a little earlier than before and also gets upset if not given food immediately. I have to assume this to be hypoglycemia. Manageable with things like cheese, yogurt and eggs on hand. My daughter is also on the Ketogenic diet, so this may stabilize things somewhat.

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    2. RG, What about drowsiness and mood next day? It helps anxiety and irritability? In our case even 1ml of periactin gave drowsiness, increased crankiness and irritability the whole next day. We tried for a week then stopped it. That's why didn't dare trying mirtazapine.

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    3. No drowsiness at all the following day, even if woken early, though she can sleep a good ten hours. Irritability only at doses of 4mg and up.

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    4. RG, are you using mirtazapine for anxiety? Or did you want to try it based on the reports of cognitive improvement?

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    5. I tried it primarily for a horrendous sleep disorder. The cognitive improvements have been a wonderful bonus. I had other interventions in the pipeline for cognition, mirtazapine sort of cut the line.

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    6. Question for you RG re: mirtazapine -
      When we first started it seemed he was experiencing some blood sugar crashes but that was easily remedied. My son has been on a very low dose, like your daughter (1/4 of 15mg tablet) for 6 weeks now and in the last week I have noticed his bowels are a bit sluggish. Have you noticed this with mirt.? I have had to give him senna tea three times in the last week and a half - trying to figure if this is due to mirt. or from boosting protein to off set blood sugar crashes (although it hasn't been that big of a boost). But otherwise things going really well with this verap and mirt combo.

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    7. Hi Tanya,

      That's great, that you found a successful combination.

      We have the opposite problem here, chronic diarrhea. Not due to mirtazapine though.

      The hypoglycemia seems to have resolved, I don't see it anymore.

      Btw, the dosage is still a work in progress. The 2mg dose works for a about 3 to 4 days and then does not. At that point I have to come in with a 7.5mg dose. But not for more than a day. Finding the right dose is quite tricky.

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  8. Thanks for the reply RG. Yes it seems to be going well - for now. Not to be negative but as with so many things we have tried I guess I am conditioned to expect things to take a nose dive

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  9. OH one more question RG: I ask because i've read a few of your replies on other topics and it seems our kids are a bit similar - do you give your daughter anything to support liver function? TMG? or even milk thistle? just to name a couple..

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    1. Hi Tanya,

      I have wanted to try DMG, but haven't. I give her 2 whole eggs plus 3 yolks every day. It makes a difference in speech.

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    2. Sorry Tanya, I seem to have lost the rest of my message. The choline in the eggs seem to be adequate. I run labs at least twice a year and liver function seems fine.

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  10. RG,

    I tried to follow your idea of providing choline in egg yolks, but my son, while will ostentatiously show inability to perform some sorting quests on the IQ tests required by eduaction system in my country, always picks yolk particles out of his meal with perfect precision.

    I wonder if you also tried any choline supplement to compare the effect. This small study on choline alfoscerate caught my attention:

    http://psychopharmacology.ru/index.php/PPBN/article/viewArticle/147

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