The rise and rise of CM-AT for autism

Today's post surrounds a poster presentation delivered at INSAR 2019, the (still) premier international autism conference, albeit not without its battles. The poster was delivered by Heil and colleagues [1] and talks about a compound / preparation that has been discussed a few years back on this blog: CM-AT (see here).

CM-AT is described as a "pancreatic enzyme preparation" with chymotrypsin - a digestive enzyme - seemingly placed quite prominently in its list of ingredients. CM-AT is, from what I understand, something that is still going through the research processes with regards to its use in the context of autism. Heil and colleagues presented data on part of that research agenda, specifically pertinent to ascertaining "whether or not behavior (e.g., symptoms of irritability, hyperactivity) in preschoolers with autism could be improved with CM-AT."

Bearing in mind a conference poster presentation is not necessarily the same as a published peer-reviewed research article, the Heil data was based on the use of a "randomized, placebo-controlled, 12-week clinical trial" methodology where 92 children, aged between 3-5 years, diagnosed with an autism spectrum disorder (ASD) received CM-AT "as granules sprinkled on food" and almost a hundred boys with ASD received a placebo "which consisted of visually identical inert sprinkles." The 'Irritability' scale of the Aberrant Behavior Checklist (ABC) was the primary outcome measure.

Results: "children receiving CM-AT (relative to those receiving placebo) demonstrated significant reductions in Irritability... Hyperactivity... Inappropriate Speech... over the 12 weeks of the trial." Researchers further reported that those children with higher levels of irritability at baseline tended to show a greater positive response than when the participant sample as a whole was analysed.

I think you can perhaps see why these results - preliminary as they are - are worthy blogging material. Irritability, perhaps listed as a 'challenging behaviour' in the context of autism is something that many, many people would love to be able to effectively tackle; if not just because of the impact it can have on those with autism and those around them who have to 'cope' with such behaviours. Indeed, given the other options for managing such behaviour such as the antipsychotic risperidone (see here) and the issues which that drug and its similars can bring (see here), the idea that there may be other, less side-effect heavy options (see here) is definitely something to consider.

I'm hopeful that soon, very soon, I can talk more about CM-AT in the context of irritability and beyond in relation to autism...

----------

[1] Heil MF. et al. Pancreatic Replacement Therapy with CM-at Is Associated with Reduction in Maladaptive Behaviors in Preschoolers with Autism. INSAR 2019.

----------

"Vitamin D and omega-3 reduced irritability symptoms in children with ASD"

The title heading this post - "Vitamin D and omega-3 reduced irritability symptoms in children with ASD [autism spectrum disorder]" - comes from the findings reported by Hajar Mazahery and colleagues [1] discussing the results of their clinical trial. I have already mentioned the Mazahery trial before on this blog (see here) as a 'study to watch' based on the publication of their study protocol [2]. It looks like the wait is finally over...

So, as researchers previously reported, there were four arms to this clinical trial: supplementation with vitamin D alone ("2000 IU/day, VID"), supplementation with an omega-3 fatty acid ("722 mg/day DHA, OM"), vitamin D plus fatty acid supplementation together ("2000 IU/day vitamin D + 722 mg/day DHA, VIDOM") and a placebo group (olive oil). Results are reported for over 70 children diagnosed with an autism spectrum disorder (ASD) - "VID = 19, OM = 23, VIDOM = 15, placebo = 16" - over a 12-month period, with the primary outcome being "the Aberrant Behaviour Checklist (ABC) domains of irritability and hyperactivity."

Aside from the main finding - "vitamin D and omega-3 LCPUFA [long chain polyunsaturated fatty acid] reduced irritability symptoms in children with ASD" (compared against placebo) - a few other observations are noteworthy: "Compared to placebo, children on VID [vitamin D] also had greater reduction in hyperactivity." All this bearing in mind that the biological testing to examine for vitamin D and fatty levels reported "a good compliance rate" indicating that supplements were routinely being taken as required by the study.

Implications? Well, strike up more peer-reviewed evidence that nutrition is important not just for physiological health but also for psychological/behavioural health and wellbeing too (see here). Add this research also to other peer-reviewed science that suggests that at least 'some autism' might be particularly 'sensitive' to elements of such nutritional medicine (see here).

I could go on about how vitamin D in particular seems to be something important to autism (see here and see here for examples). I could also go on about how fatty acids have some important evidence-based history with autism in mind (see here). But do I really need to? Minus any medical or clinical advice given or intended, the Mazahery results really speak for themselves.

----------

[1] Mazahery H. et al. A randomised controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of irritability and hyperactivity among children with Autism Spectrum Disorder. The Journal of Steroid Biochemistry and Molecular Biology. 2018. Oct 26.

[2] Mazahery H. et al. Vitamin D and omega-3 fatty acid supplements in children with autism spectrum disorder: a study protocol for a factorial randomised, double-blind, placebo-controlled trial. Trials 2016; 17:295.

----------

Helminthic Trichuris Suis Ova vs. placebo for repetitive behaviours in adult autism

The trial results published by Eric Hollander and colleagues [1] were not entirely unexpected. I had previously mentioned their study on the "use of the immunomodulator Trichuris Suis Ova (TSO)" with autism in mind in another post (see here) but, at that time, still awaited the peer-reviewed publication version to appear. I wait no longer.

OK, Trichuris suis (T. suis) is a parasite. It makes its home in the deepest, darkest recesses of other creatures, apparently also having the rather important evolutionary advantage of being able to stay in egg form for quite a long time 'awaiting ingestion'. But just before you turn away John Hurt style (no, I'm not going to link to the 'chest-buster' scene), this particular parasite might not be 'all bad'. I'm specifically talking about some preliminary data suggesting that T. suis *might* have some important immunological effects [2] when ingested in a controlled manner under certain clinical circumstances.

Hollander et al took things one stage further by their insinuation of a link between use of an "immunomodulator" such as T. suis and their study to determine "the effect sizes for TSO vs. placebo on repetitive behaviors, irritability and global functioning in adults with ASD [autism spectrum disorder]." And just before you question the idea that immune function might be something important to some overt behaviour(s), there is other research out there discussing the possibility of such an effect (see here and see here) specifically with autism in mind.

"A 28-week double-blind, randomized two-period crossover study of TSO vs. placebo in 10 ASD adults, ages 17 to 35, was completed, with a 4-week washout between each 12-week period." This was a 'gold-standard' trial design albeit with a very, very small participant group who represented only a specific 'part' of the autism spectrum [3]. The trial was also registered for all to see the proposed hows-and-whys (see here) including the detail: "Have a personal or family history of allergies" as part of the inclusion criteria.

Results: "Differences between treatment groups did not reach statistical significance." This is an important point highlighting how use of T. suis ("the eggs of intestinal helminthes (trichuris suis ova) administered as 2500 ova doses every two weeks") did not translate into statistically significant group differences across measures looking at the social communication aspects of autism for example. I say this bearing in mind that the Hollander study was a cross-over trial too.

But... "Large effect sizes for improvement in repetitive behaviors (d = 1.0), restricted interests (d = 0.82), rigidity (d = 0.79), and irritability (d = 0.78) were observed after 12 weeks of treatment." What this means is that when comparing participants using T. suis vs. their baseline measurements, they seemed to do better on the T. suis portion of the trial across various different types of behaviour. Importantly too we are told that "TSO had only minimal, non-serious side effects" bearing in mind this included various gastrointestinal (GI) side-effects (and knowing that GI issues are already 'a thing' when it comes to autism).

So, there we have it. The results of the first (small scale) clinical trial using Trichuris Suis Ova (TSO) helminthic style with autism in mind. Obviously a lot more research is required before this type of intervention goes anything like 'mainstream'. Alongside there is also the 'acceptability' factor to consider: how many people would actually want to ingest a parasite such as T. suis? Indeed, one of the next courses of study is perhaps to see 'why' such helminthic therapy has the effect that it has on behaviour, and whether such an effect can be replicated in a medicine or other formulation rather than ingesting a parasite?

----------

[1] Hollander E. et al. Randomized Crossover Feasibility Trial of Helminthic Trichuris Suis Ova vs. Placebo for Repetitive Behaviors in Adult Autism Spectrum Disorder. World J Biol Psychiatry. 2018 Sep 19:1-25.

[2] Jouvin MH. & Kinet JP. Trichuris suis ova: testing a helminth-based therapy as an extension of the hygiene hypothesis. J Allergy Clin Immunol. 2012 Jul;130(1):3-10.

[3] Hollander E. et al. Trichuris Suis Ova (TSO) as an immune-inflammatory treatment for repetitive behaviors in ASD. European Neuropsychopharmacology. 2016; 26: 891.

----------

"risperidone is efficacious in the treatment of symptoms in children and adolescents with ASD"

The heading titling this post - "risperidone is efficacious in the treatment of symptoms in children and adolescents with ASD [autism spectrum disorder]" - comes from the systematic review published by Narong Maneeton and colleagues [1]. These researchers scoured the existing peer-reviewed research literature - "from January 1988 to February 2017" - to "systematically review the efficacy, acceptability and tolerability of risperidone in children and adolescents with ASD." They concluded that, on balance, around "one in every three ASD children and adolescents has benefits from treatment with risperidone." They also cautioned that there is a further scheme of work to follow, looking at the use of risperidone in this particular patient group as per the findings of previous reviews. The continued examination of potential adverse side-effects associated with risperidone use is one such important area to be investigated (see here and see here for examples).

Risperidone is categorised as an antipsychotic medicine. It's typically used to treat psychosis and mania. It's also sometimes used in the context of certain 'challenging behaviours' being presented as a function of a diagnosis of autism or autism spectrum disorder (ASD): "explosive and aggressive behavior" according to one source. Importantly however, the use of risperidone as a tool to intervene on the 'core features' of autism is not, at the time of writing, currently indicated.

Maneeton et al looked specifically for studies classified as a randomised controlled trials (RCTs) in the context of risperidone use with children and adolescents aged up to 18 years of age and diagnosed with autism or ASD. They found seven RCTs including some 370 participants. All of the trials relied on the DSM-IV description of autism or ASD and, aside from two trials, most lasted for between 6 and 8 weeks. The Aberrant Behaviour Checklist (ABC) was a commonly used tool in the studies included for review, with response criteria on such an instrument anticipating between a 25% and 50% reduction in scores (specifically on the irritability subscale) as a result of risperidone use.

Results: as per the opening sentence of this post, a positive behavioural response typically favoured risperidone use over the placebo used as a comparator when it came to certain challenging behaviours. This was noted across those short-term studies ("acute response") and also longer-term intervention (6 months). The authors also reported that a variety of side-effects - adverse side-effects - were noted alongside the use of risperidone. These included things like an increase in appetite, "drowsiness, somnolence, fatigue, anxiety, hypersalivation and elevation of prolactin level." The prolactin bit has been discussed before on this blog (see here) specifically in the context that: "There is no known normal function for prolactin in men."

Bearing in mind that Maneeton and colleagues were discussing risperidone use in 'children and adolescents' with autism, and the requirement for particular caution when using such a powerful medicine on the [still] developing body and brain, these are useful findings. Of course in an ideal world, no-one would want children and young people to have to take risperidone. But like other medicines indicated for other behavioural labels (see here), with regular and appropriate monitoring and medicines management, such pharmacotherapy can be transformative in its effects for some.

The situation however does need improving; particularly in the context of those side-effects and the worry they carry especially into the longer-term. I'm also minded to suggest that science needs to delve a little further into the proposed mechanism of effect when using medicines like risperidone in terms of immune system effects (see here) and other important biological pathways (see here) outside of the known "dopamine D2, 5-HT2A, alpha1-adrenoceptor, and histamine-1 receptor antagonist" biological action. By doing so, one *could* perhaps foresee future medicines with the 'anti-irritability' action but perhaps minus the considerable risk of side-effects?

And without any comment or opinion from me, the recent ruling here in Blighty that 'aggressive behaviour is not a choice for children with autism' (see here for my take) needs to be very carefully managed from a pharmacotherapy point of view. I say this so as not to make medicines such as risperidone, the first line of intervention or worse still, a 'chemical cosh'...

----------

[1] Maneeton N. et al. Risperidone for children and adolescents with autism spectrum disorder: a systematic review. Neuropsychiatr Dis Treat. 2018 Jul 11;14:1811-1820.

----------

Simvastatin + risperidone for autism?

"This study provides preliminary evidence for potential therapeutic effects of simvastatin in the treatment of autism that warrants further investigations."

So said the results of the trial published by Ehsan Moazen-Zadeh and colleagues [1] looking at whether adding simvastatin - a lipid-lowering medicine - (20-40 mg/day) or placebo to a daily regime of risperidone - an antipsychotic medicine - to a cohort of "70 drug-free children aged 4 to 12 years old with diagnosis of autistic disorder" would have any effect on the primary outcome of irritability as measured by the "Aberrant Behavior Checklist-Community (ABC-C) scale irritability subscale score." A trial entry for this study can be found here (including reference "to evaluate the efficacy of L-carnosine in the treatment of autism" in the translated version for some reason?).

Anyhow, under "randomized, double-blind, placebo-controlled" conditions, researchers noted something of a potential effect from the addition of simvastatin to risperidone when compared with risperidone + placebo on the group irritability subscale scores over 10 weeks of use. They conclude that further study is required in this area.

There is very little other peer-reviewed science literature in this area of the autism research landscape. I note that Peter over at Epiphany has talked about statins and autism on a couple of occasions (see here for example) and how useful they have seemed to be for his son. Albeit based on an N=1, Peter speculated that the effect of statin use for his son (Atorvastatin) was not necessarily due to its effect on lipid lowering but rather other actions. Noting that simvastatin has specifically been linked to 'cognitive dysfunction' in some isolated cases [2] I understand that other studies have talked about a more protective 'pro-cognitive' effect from such statin use under other circumstances [3]. I do wonder if there could be something more to see in this area pertinent to at least some on the autism spectrum.

----------

[1] Moazen-Zadeh E. et al. Simvastatin as an Adjunctive Therapy to Risperidone in Treatment of Autism: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Child Adolesc Psychopharmacol. 2017 Jul 18.

[2] Suraweera C. et al. Simvastatin-induced cognitive dysfunction: two case reports. J Med Case Rep. 2016 Apr 5;10:83.

[3] Ling Q. & Tejada-Simon MV. Statins and the brain: New perspective for old drugs. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Apr 3;66:80-6.

----------

NAC + risperidone = decreased irritability in autism?

It's been a while since I talked about NAC - N-acetylcysteine - on this blog with either autism or schizophrenia in mind (see here and see here respectively). Today I'm going to remedy that situation by bringing the paper by Nikoo and colleagues [1] to your attention, and their observation: "N-acetylcysteine can be considered as an adjuvant therapy for ADs [autistic disorders] with beneficial therapeutic outcomes." Adjuvant therapy by the way, refers to a sort of add-on therapy.

We have to call him, Havok. That's his name now.

Just in case you don't know, NAC among other things is the treatment of choice when it comes to paracetamol (acetaminophen) overdose through it's very important role in the formation of the glutathione (the big 'G' as I should start to call it). Glutathione already has something of a research interest when it comes to autism (see here); more recently increased following papers such as the one by Rahbar and colleagues [2] taking about some of the genetics of the glutathione system with [some] autism in mind, touched upon in a recent post.

Nikoo et al reported results based on a gold-standard randomised, double-blind trial whereby one group of children/adolescents with autism received the antipsychotic risperidone plus NAC and another group received risperidone plus placebo over the course of 10 weeks. Risperidone, as I just mentioned is an antipsychotic medicine which has some interesting history when it comes to [some] autism (see here). Irritability was the focus of the study, and what happened to scores on the "Aberrant Behavior Checklist-Community (ABC-C) Irritability subscale" at baseline (start), 5 weeks and 10 weeks. 

The results suggested that NAC may well have some value as an add-on treatment when it came to scores of irritability in cases of autism as per the authors findings: "By week 10, the NAC group showed significantly more reduction in irritability (P = 0.02) and hyperactivity/noncompliance (P = 0.01) subscales scores."

This is not the first time that NAC + risperidone has been mentioned in the peer-reviewed autism research literature. The paper by Ghanizadeh & Moghimi-Sarani [3] (open-access) also reported significant positive effects albeit alongside a few adverse events such as: "constipation (16.1%), increased appetite (16.1%), fatigue (12.9%), nervousness (12.9%), and daytime drowsiness (12.9%)." This follows other research out of Iran looking at NAC + risperidone in relation to some of the negative symptoms of schizophrenia [4]. On all these research occasions, the experimental period of observation was relatively short (8-10 weeks).

Like many others, I'm always a tad reserved when it comes to the use of antipsychotics for cases/behaviours of/associated with autism. As per my recent discussions on weight gain and such pharmaceutics (see here), one always needs to be a little cautious about the use of such medicines and the application of good medicines management including continual health monitoring as a priority when used. The guidance from NICE here in Blighty advising that such medicines should not be used to manage the core symptoms of autism (see here) is testament to the research base on their effectiveness and their limited place in any management plan. That being said, such pharmaceutics do have a role for some people on the autism spectrum [5] even only if as a 'last resort' in the short-term.

I end by harking back to the paper by Hardan and colleagues [6] talked about in a previous post, which suggested that NAC on it's own might have something to add when it comes to irritability in relation to some autism.  I don't necessarily endorse NAC as being a cure-all for irritability in relation to autism - irritability as part of the so-called challenging behaviours is a very multi-faceted thing with lots of potential precursors [7] - but one might give some consideration to NAC as an intervention for some on the autism spectrum. The next question needs to be: how precisely does it work, and does it have any link back to 'the big G' findings with autism in mind?

Music then. Marvin Gaye and Heard it Through The Grapevine (and something funky is going down apparently).

----------

[1] Nikoo M. et al. N-Acetylcysteine as an Adjunctive Therapy to Risperidone for Treatment of Irritability in Autism: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Efficacy and Safety. Clin Neuropharmacol. 2015 Jan 9.

[2] Rahbar MH. et al. Interaction between GSTT1 and GSTP1 allele variants as a risk modulating-factor for autism spectrum disorders. Research in Autism Spectrum Disorders. 2015; 12: 1-9.

[3] Ghanizadeh A. & Moghimi-Sarani E. A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders. BMC Psychiatry. 2013 Jul 25;13:196.

[4] Farokhnia M. et al. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol. 2013 Nov-Dec;36(6):185-92.

[5] Dinnissen M. et al. Clinical and pharmacokinetic evaluation of risperidone for the management of autism spectrum disorder. Expert Opin Drug Metab Toxicol. 2015 Jan;11(1):111-24.

[6] Hardan AY. et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012 Jun 1;71(11):956-61.

[7] Guinchat V. et al. Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement. Research in Developmental Disabilities. 2015; 38: 242–255.

----------

Nikoo M, Radnia H, Farokhnia M, Mohammadi MR, & Akhondzadeh S (2015). N-Acetylcysteine as an Adjunctive Therapy to Risperidone for Treatment of Irritability in Autism: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Efficacy and Safety. Clinical neuropharmacology PMID: 25580916