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...

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

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Baclofen is back: "Baclofen as an adjuvant therapy for autism"

"Our data support [the] safety and efficacy of baclofen as an adjuvant to risperidone for improvement of hyperactivity symptoms in children with ASD [autism spectrum disorder]."

So said the findings reported by Seyedeh-Mahsa Mahdavinasab and colleagues [1] talking about the use of baclofen as an add-on medicine in the context of risperidone use in relation to autism. Baclofen by the way, is typically known as "a gamma-aminobutyric acid (GABA) agonist" (binds to the GABA receptors and activates them) which accounts for its use as "a skeletal muscle relaxant" given the inhibitory function of GABA and GABA receptors.

Why the 'baclofen is back' sentiment expressed in the title of this post? Well, a few years back there was some excitement about a compound called STX209 otherwise known as arbaclofen in the context of a genetic condition manifesting autistic signs and symptoms (see here) and autism itself. Arbaclofen is an enantiomer (mirror image in a chemical sense) of baclofen, but unfortunately fell by the wayside after some less than impressive results emerged from clinical trials (see here). Arbaclofen might have been kicked into the long grass for now but baclofen it seems, is still on the autism research agenda...

Researchers report results based on a "10-week randomized-controlled study aimed at evaluating the potential of baclofen as an adjuvant therapy to enhance the effect of risperidone in children with ASD." Risperidone is an antipsychotic which is indicated for selective use with children with autism (see here) specifically to treat/manage aggressive and challenging behaviours. They reported that several outcome measures saw a change - a positive change - specifically in relation to hyperactivity behaviours which can often accompany aggression. Importantly, they also noted that during and after 10 weeks of add-on baclofen use, adverse events were reported to be at a minimum.

There is more to do in this area before any sweeping generalisations are made. I personally would like to see more data on potential best- and non-responders in the context that GABA is still a topic of interest to autism research (see here). I know also that some people might be a little put-out by the idea that more medication is added to the lives of young children with autism and worries about how this might impact them in later years. We need a lot more data.

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[1] Mahdavinasab SM. et al. Baclofen as an adjuvant therapy for autism: a randomized, double-blind, placebo-controlled trial. Eur Child Adolesc Psychiatry. 2019 Apr 12.

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"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'...

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[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.

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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.

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[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.

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Risperidone administration affects homocysteine levels in first episode schizophrenia

Of the many themes that seem to quite consistently surface on this blog looking at the peer-reviewed science in relation to various behavioural/psychiatric labels, the idea that various pharmacological interventions might do quite a bit more than 'what they say on the tin' is a recurring one. Take one case in point (see here)...

Today's offering adds to that theme as the results reported by Ning Fan and colleagues [1] are presented for your reading pleasure and the particular finding that: "Serum Hcy [homocysteine] levels were significantly decreased in schizophrenia patients after risperidone treatment."

OK, a few points need explaining first. Homocysteine is a compound that has also received considerable attention on this blog as per it's involvement in a particular group of intersecting biological cycles with relevance to various diagnostic labels including schizophrenia (see here for example). Alongside other independent pieces of research (see here), the diagnosis of schizophrenia seems to have some important connections to homocysteine although the precise details still need to be properly elucidated.

High levels of homocysteine are generally not thought to be a good thing for quite a few reasons [2] and that goes as much for persons diagnosed with schizophrenia as it does for everyone else. So when elevated plasma levels of homocysteine are recorded, medicine really does need to do something to (a) identify why and (b) try and bring levels back to within a more typical range.

Fan et al reported a few important things in their study of 56 participants "first-episode and drug-naïve inpatients with schizophrenia" compared with a similar number of sex- and age-matched asymptomatic controls. First, plasma homocysteine levels were elevated in those with schizophrenia. Nothing new there. They also reported on some potentially interesting *associations* between elevated homocysteine levels and specific symptoms relevant to schizophrenia: "a significant positive correlation between Hcy levels and PANSS negative sub-score was observed." Finally, they reported that risperidone use seemed to affect homocysteine levels in their clinical group. Interesting.

That last point is rather intriguing. Risperidone is a treatment of choice as per its second generation antipsychotic label and accompanying properties. Despite quite a lot of focus on the side-effects associated with such a medicine (see here for example) it does serve an important purpose for many people. It's mode of action is still under debate but it is generally thought to have some action in relation to effects on one or more neurotransmitter receptors. But... other potential effects have also been noted in the peer-reviewed research literature pertinent to mode of action including some in relation to immune function (see here) and how schizophrenia (some schizophrenia?) *might* have a significant immune component attached to it (see here for example). The Fan results add another potential mode of action to risperidone use and why it may impact on symptom presentation for some diagnosed with schizophrenia and related conditions. I'm not by any means saying that homocysteine is 'causative' of schizophrenia but the Fan results do suggest that quite a few more investigations may be warranted on the connection between schizophrenia, homocysteine and risperidone. Indeed, whether also other homocysteine-lowering compounds may provide some novel intervention options for some diagnosed with schizophrenia (see here) (with no medical or clinical advice given or intended).

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[1] Fan N. et al. Effect of Risperidone on Serum Homocysteine Levels in First-episode, Drug-naïve Patients with Schizophrenia. Neurosci Lett. 2017 Apr 15. pii: S0304-3940(17)30326-9.

[2] Zhang D. et al. Elevated Homocysteine Level and Folate Deficiency Associated with Increased Overall Risk of Carcinogenesis: Meta-Analysis of 83 Case-Control Studies Involving 35,758 Individuals. PLoS ONE. 2015; 10(5): e0123423. 

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Fan N, Tan Y, Yang F, Tian L, Chen S, Li J, Wang Z, & Zhang X (2017). Effect of Risperidone on Serum Homocysteine Levels in First-episode, Drug-naïve Patients with Schizophrenia. Neuroscience letters PMID: 28419824

Hyperuricemia present in both medicated and unmedicated kids with autism

I was intrigued to read the findings reported by Natchaya Vanwong and colleagues [1] talking about the presence of hyperuricemia - an excess of uric acid in the blood - in their cohort of children and young adults diagnosed with an autism spectrum disorder (ASD). Intrigued not only because the authors discuss how the use of the atypical antipsychotic risperidone might *correlate* with elevations of uric acid but also how: "Hyperuricemia was present in 44.70% of risperidone-naïve patients with ASD."

Uric acid, more readily associated with the condition gout, has been mentioned before on this blog in the context of autism (see here) and other conditions/states (see here) not totally unfamiliar to autism. It's therefore not necessarily new news that elevations of the stuff might have been found again. The Vanwong study looked at uric acid levels in "127 children and adolescents with ASD treated with risperidone and 76 age-matched risperidone-naïve patients with ASD" alongside a few other biological parameters. They concluded that yes, quite a few participants in their cohort presented with hyperuricemia "defined as the level of uric acid concentration in the blood >5.5 mg/dL" bearing in mind no 'not-autism' control group was included for direct study (including those not diagnosed with autism but in receipt of risperidone).

Implications following the Vanwong study? Well, bearing in mind that gout is traditionally seen as a disease of middle-to-older age, the first thing would be to screen for gout in those with high uric acid levels and keep monitoring just in case gout develops. Next up would be to perhaps also look at some of the "rare inherited genetic disorders that cause hyperuricemia" and whether they might 'overlap' with the presentation of autism; y'know in the context that 'autism genes are probably not just genes for autism' and all that. At this point, I'm also minded to remind readers of the important (but often forgotten work) by Mary Coleman and Ted Page [2] on the topic of autism and uric acid, bringing in purine metabolism 'issues' as something potentially important to some autism (uric acid comes about as a consequence of the metabolism of purines). This, in the context of the autisms (plural)...

Insofar as the potential correlation posed between uric acid and risperidone usage, a word of caution is perhaps warranted but big words about 'risperidone causing hyperuricemia' are not required at this point in time without further study. Remember: "Hyperuricemia was present in 44.70% of risperidone-naïve patients with ASD and 57.50% of ASD patients treated with risperidone." I say this mindful that there are biological parameters that do need careful inspection when such antipsychotic therapy is put in place (see here) but the data is not yet so convincing when it comes to uric acid elevations and risperidone use.

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[1] Vanwong N. et al. Hyperuricemia in Children and Adolescents with Autism Spectrum Disorder Treated with Risperidone: The Risk Factors for Metabolic Adverse Effects. Front. Pharmacol. 2017. 5 Jan.

[2] Page T. & Coleman M. Purine metabolism abnormalities in a hyperuricosuric subclass of autism. Biochim Biophys Acta. 2000 Mar 17;1500(3):291-6.

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Vanwong N, Srisawasdi P, Ngamsamut N, Nuntamool N, Puangpetch A, Chamkrachangpada B, Hongkaew Y, Limsila P, Kittitharaphan W, & Sukasem C (2017). Hyperuricemia in Children and Adolescents with Autism Spectrum Disorder Treated with Risperidone: The Risk Factors for Metabolic Adverse Effects. Frontiers in pharmacology, 7 PMID: 28105014

On the use of risperidone and young children with autism

Without trying to scaremonger, it is already well known that certain anti-psychotics potentially indicated for some of the more 'challenging behaviours' associated with conditions like autism for example, carry their own important side-effects. Risperidone, one of the more commonly used medicines, has quite an extensive list of possible side-effects, some of which have been previously mentioned on this blog (see here). Increased appetite and weight gain are some of the more commonly observed side-effects.

The paper by Lawrence Scahill and colleagues [1] indeed concluded that weight gain and increased appetite also seemed to be present in their cohort of children with autism (mean age 6.9 years) who were in receipt of risperidone for approximately 30 weeks. Worryingly, the authors reported that there was an average of about 5 kg weight gain among 97 of their cohort with "risperidone exposure" and: "At baseline, 7 patients met conventional criteria for metabolic syndrome; by Week 16, 12 additional patients were so classified." The authors suggested that: "Rapid weight gain with risperidone treatment may promote the cascade of biochemical indices associated with insulin resistance and metabolic syndrome. Appetite, weight, waist circumference, liver function tests, blood lipids, and glucose warrant monitoring."

As per other posts on this blog, I'm not adverse to the selective use of medication to manage certain 'challenging behaviours' with autism in mind (see here) bearing in mind appropriate screening and 'detective work' before immediately reaching for such meds (see here). With appropriate medicines management and monitoring procedures in place, medicines such as antipsychotics (even with appropriate adjuvant therapy) can play an important role in managing symptoms and onwards positively affecting quality of life.

But it is important to note that there are risks attached to such medication use and the possible benefits to the presentation of certain behaviours have to be balanced with the those risks and specifically the potential role of side-effects. The additional important focus on children  - "mean age 6.9 + 2.35 years" - highlighted in the Scahill study also invites quite a lot more scrutiny. I know some people might be a little shocked that young children on the autism spectrum are being medicated in such a fashion, but other evidence has reported on the potential value of such an approach [2] particularly when quite extreme behaviours are present and are able to be so utterly disruptive. To tie in those findings on the presence of something like metabolic syndrome and the young age of medication recipients however, suggests that moves should continue (at a pace) towards the discovery of new methods and means of managing such behaviours without potentially setting recipients up for a lifetime of possible future health complaints.

Indeed, I'll be blogging about the related results from Chen et al [3] soon enough.

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[1] Scahill L. et al. Weight Gain and Metabolic Consequences of Risperidone in Young Children With Autism Spectrum Disorder. Journal of the American Academy of Child & Adolescent Psychiatry. 2016. March 7.

[2] Fung LK. et al. Pharmacologic Treatment of Severe Irritability and Problem Behaviors in Autism: A Systematic Review and Meta-analysis. Pediatrics. 2016 Feb;137 Suppl 2:S124-35.

[3] Chen MH. et al. Risk of Developing Type 2 Diabetes in Adolescents and Young Adults With Autism Spectrum Disorder: A Nationwide Longitudinal Study. Diabetes Care. 2016 Mar 22. pii: dc151807.

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Scahill, L., Jeon, S., Boorin, S., McDougle, C., Aman, M., Dziura, J., McCracken, J., Caprio, S., Arnold, L., Nicol, G., Deng, Y., Challa, S., & Vitiello, B. (2016). Weight Gain and Metabolic Consequences of Risperidone in Young Children With Autism Spectrum Disorder Journal of the American Academy of Child & Adolescent Psychiatry DOI: 10.1016/j.jaac.2016.02.016

The genetics of self-injurious behaviour accompanying autism? Not quite...

I'd like to start by making one thing abundantly clear about today's post: I am not insinuating that self-injurious behaviour (SIB) accompanying autism is solely under genetic (or epigenetic) control.

As I've discussed before on this blog, there are potentially many, many reasons why SIB under the umbrella of the so-called 'challenging behaviours' occurs (see here). As and when it does happen, the onus is on those significant others to turn detective before anyone immediately reaches for something like the anti-challenging behaviour meds (see here) or indeed makes any sweeping generalisations about it 'just being part of their autism'. I say this mindful that sometimes it can seemingly be the smallest things that can trigger such episodes...

The findings reported by Matthew Shirley and colleagues [1] (open-access) do however require some attention with the idea that certain genetic issues *might* "contribute to the etiology of SIB." The specific genetic issues under the research spotlight were copy number variants (CNVs) and authors were looking at quite a precise cohort of children/young adults diagnosed with "autism and intellectual disability with self-injurious behavior (SIB) resulting in tissue damage" (N=14). I might add that CNVs with autism and learning disability in mind have some history (see here).

Based on quite a thorough work-up (including a functional behavioural assessment), researchers zoomed in on 4 children (29%) where they identified "a CNV likely to have a causal role" in SIB. I'm afraid my very limited knowledge of genetics precludes any critical discussion about the nature or role of any individual genetic issues reported but I might backtrack slightly based on something the authors write regarding 'causality': "the present findings are not able to indicate definitively that any of these variants is causal." Apparently we need to wait for more data from additional patients with the same/similar clinical phenotype before much more can be said on this issue. Indeed: "it is likely that exome or genome sequencing will greatly increase the diagnostic yield of the cohort we are studying."

Perhaps just as important as the question of whether genetics plays a role in a complex behaviour pattern like SIB are the authors' observations of what might have triggered SIB in their participants. The authors talk about the results of the very important functional behaviour assessments as revealing some common themes: "SIB was multiply maintained by escape from demands and access to preferred toys... SIB was multiply maintained by access to preferred foods and access to attention... Head-banging was found to be maintained by access to preferred foods... Head-hitting, self-biting, and head-banging against hard surfaces were observed to be maintained by automatic reinforcement." What these excerpts tell me is that SIB could potentially be a communicative act, bearing in mind details of language and communication 'level' of participants are fairly scant in the Shirley paper. As I've talked about previously (see here), issues such as fatigue and setting event are also potentially important parameters when getting to the bottom of SIB and other challenging behaviours.

The final question, and perhaps an important one when one realises just how extreme an effect SIB can exert (see here), is 'what can be done about reducing levels of SIB' when they present.  Well, working out the hows and whys of such behaviour should be the first strategy, and can sometimes yield impressive results. Although I suggested at the beginning of this post that the 'anti-challenging behaviour meds' should be a further-down-the-list resort, there is evidence that they can be helpful for some people in some situations assuming appropriate medicines management and monitoring for potential side-effects (see here). With no medical or clinical advice given or intended, I'd also be minded to direct readers to some research looking at adjuvant therapies such as the use of N-acetylcysteine (NAC) where issues like irritability might show some connection to SIB (see here and see here) or even something of particular interest to me, the use of naltrexone (see here). More research is indicated and indeed, quite a lot more with much greater participant numbers before anyone starts on about having identified the genetics of SIB in autism...

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[1] Shirley MD. et al. Copy Number Variants Associated with 14 Cases of Self-Injurious Behavior. PLoS ONE. 2016; 11: e0149646.

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Shirley, M., Frelin, L., López, J., Jedlicka, A., Dziedzic, A., Frank-Crawford, M., Silverman, W., Hagopian, L., & Pevsner, J. (2016). Copy Number Variants Associated with 14 Cases of Self-Injurious Behavior PLOS ONE, 11 (3) DOI: 10.1371/journal.pone.0149646

Psychopharmacologic intervention for adults with autism: systematically reviewed

"The results indicate that only two medications, fluoxetine and risperidone, can be considered as promising evidence-based practices for adults with ASD [autism spectrum disorder]."

So said Lauren Taylor [1] and her (systematic) review of what might work, pharmaceutically speaking, when it comes to managing "behavioural disturbance in adults with ASD." Including over 40 studies examining psychopharmacology in adults diagnosed with ASD, Taylor concluded that many medicines/formulations did not cut the scientific mustard in this area. Further: "The subsequent establishment of clinical guidelines for medication use in this population is essential."

My first thoughts when I came across the Taylor paper was the guidance provided here in Blighty with regards to medication and autism (see here). To quote from the NICE document as it currently stands: "Do not use antipsychotic medication for the management of core symptoms of autism in adults. Do not use antidepressant medication for the routine management of core symptoms of autism in adults." One might argue that the review detailed by Taylor does not just focus on 'core symptoms' but rather a wider recognition of "psychiatric and behavioural disorder in adults with autism" in light of what is known about comorbidity (see here for example). Based on this assumption, there are indeed various levels of evidence to suggest that for some at least, time-sensitive trials of psychopharmacology might be useful where autism is mentioned.

But just before the floodgates are opened to widespread use of preparations such as fluoxetine and risperidone 'for autism', a word or two of caution. First and foremost are a few questions that everyone should be asking when confronted with so-called challenging behaviours (behavioural disturbances?) when it comes to autism: 'Is the behaviour something new?' and 'What might the triggers be?' I say this because I've covered this topic before, and sometimes one needs to turn detective before reaching for the medicines cabinet (see here). Second, the advantages of such medicines use has to be always balanced against potential side-effects from medication. Not to come down to hard on something like risperidone for example, there is a volume of research suggesting a possible link between this medicine use and elevated prolactin levels for example (see here). Monitoring is key. Finally, the idea that there is increased recognition of 'psychiatric comorbidity' being potentially over-represented alongside a diagnosis of autism is an important one for preferential screening (see here). When emphasizing the possibility of a heightened risk of schizophrenia or psychotic disorder when it comes to the autism spectrum (see here), one might look to the wider literature for clues about how one might mitigate such risk (see here and see here for example). I say that last point with the knowledge that within the massive heterogeneity that is autism, not every person is going to transition to schizophrenia or other psychotic disorder and not every experience of this phenomenon when it does happen, will be the same.

And like buses, yet more on the issue of psychopharmacological intervention for autism [2]. Conclusion: "Overall, randomized, placebo-controlled studies of medications for the treatment of ASD are scarce."

Indeed.

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[1] Taylor LJ. Psychopharmacologic intervention for adults with autism spectrum disorder: A systematic literature review. Research in Autism Spectrum Disorders. 2016; 25: 58-75.

[2] Accordino RE. et al. Psychopharmacological Interventions in Autism Spectrum Disorder. Expert Opin Pharmacother. 2016 Feb 18.

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Taylor, L. (2016). Psychopharmacologic intervention for adults with autism spectrum disorder: A systematic literature review Research in Autism Spectrum Disorders, 25, 58-75 DOI: 10.1016/j.rasd.2016.01.011

Hyperprolactinemia and risperidone use in autism

The findings reported by Yaowaluck Hongkaew and colleagues [1] (open-access) on prolactin levels being "positively and significantly associated with risperidone dose" in cases of children and adolescents diagnosed with an autism spectrum disorder (ASD) is the point of discussion today.

Prolactin by the way, is the hormone most commonly associated with stimulating breast development and milk production in women. To quote from the US National Institute of Health (NIH) entry on prolactin: "There is no known normal function for prolactin in men." Risperidone is a neuroleptic (antipsychotic) which has quite a few clinical indications including for the management of irritability in (some) autism [2]. Indeed, risperidone is one of the few (only?) drugs to be specifically approved for pediatric autism and dealing with irritability.

It's been known for a while that risperidone use is associated with elevations in prolactin levels [3]. More recently, the research base has expanded to suggest that various factors might impact on the elevations in prolactin correlated with risperidone use [4] including "sex, pubertal stage, psychiatric disease, and associated autoimmune disorders."

So, then to the Hongkaew study which is open-access but...

• Data on 147 children and young adults diagnosed with an autism spectrum disorder (ASD) were included for study. "All participants receiving a risperidone-based regimen for at least 4 weeks were enrolled in this study." Researchers also made sure that (a) medication was taken before the donation of a blood sample, and (b) participants were not taking other medications "that could potentially affect risperidone metabolism and prolactin elevation." This did not however exclude all other medicines.
• Said blood draws was analysed for serum prolactin concentration using a chemiluminescence immunoassay system.
• Results: "mean risperidone dose of the subjects was 1 mg/day or 0.03 mg/kg/day" and "mean duration of therapy was 46.06 months". Sixty-six participants (44%) presented with hyperprolactinemia - elevated levels of serum prolactin - most of whom were male. 
• Dosage of risperidone also seemed to have an effect on prolactin results: "The median prolactin level at the high dose was significantly higher than at the recommended dose and low dose" based on categorisations of dose higher or lower than the FDA recommended amount taking into account body weight.
• Duration of treatment, age, weight and other variables did not show any statistical correlation with prolactin levels.
• The authors conclude: "This information will be helpful to clinicians by providing significantly important clinical information to properly inform therapeutic practice and prevent sexual dysfunction consequently in autistic children treated with risperidone."

I don't mean to come down too hard on risperidone with this post but this is not the first time that prolactin levels have been reported as elevated when it comes to autism [5] following the use of this pharmaceutic. Aside from the aesthetic changes potentially associated with higher prolactin levels and in particular, their potential effects on males (the subject of litigation), there is some suggestion in the literature that elevations in prolactin over the longer term might elevate risk of certain other issues [6] albeit correlation not necessarily being the same as causation and reiterating the duration of treatment measured by Hongkaew et al. As an aside, I'm going to be coming to the paper by Stubbs and colleagues [7] in the near future in light of other work on the potential effects of elevated prolactin.

Insofar as the use of risperidone for managing irritability in cases of autism, I've talked before about it's usefulness in this area and how certain adjuvant therapies might also help (see here). Accepting that irritability under the heading of 'challenging behaviours' is a mighty complicated issue (see here) and potentially tied into many different factors, there remains a place for risperidone under certain circumstances (assuming good medicines management accompanies such use). 

Still, the collected literature on prolactin and risperidone use with autism in mind adds a cautionary note to this medicine and other relations allied to other important side-effects such as weight gain. Use and monitor with care is perhaps the important message from the Hongkaew and other data...

Music: the quite controversial Disarm from the Smashing Pumpkins.

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[1] Hongkaew Y. et al. Hyperprolactinemia in Thai children and adolescents with autism spectrum disorder treated with risperidone. Neuropsychiatr Dis Treat. 2015 Jan 22;11:191-6.

[2] 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.

[3] Aboraya A. et al. Hyperprolactinemia associated with risperidone: a case report and review of literature. Psychiatry (Edgmont). 2004 Nov;1(3):29-31.

[4] Margari L. et al. Prolactin variations during risperidone therapy in a sample of drug-naive children and adolescents. Int Clin Psychopharmacol. 2015 Mar;30(2):103-8.

[5] Anderson GM. et al. Effects of short- and long-term risperidone treatment on prolactin levels in children with autism. Biol Psychiatry. 2007 Feb 15;61(4):545-50.

[6] Tworoger SS. et al. A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development. Cancer Res. 2013 Aug 1;73(15):4810-9.

[7] Stubbs B. et al. Schizophrenia and the risk of fractures: a systematic review and comparative meta-analysis. Gen Hosp Psychiatry. 2015 Jan 15. pii: S0163-8343(15)00005-5.

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Hongkaew Y, Ngamsamut N, Puangpetch A, Vanwong N, Srisawasdi P, Chamnanphon M, Chamkrachchangpada B, Tan-Kam T, Limsila P, & Sukasem C (2015). Hyperprolactinemia in Thai children and adolescents with autism spectrum disorder treated with risperidone. Neuropsychiatric disease and treatment, 11, 191-6 PMID: 25653528

Immunological effects from risperidone treatment in autism

The findings from Jai Eun Choi and colleagues [1] suggesting that use of the antipsychotic risperidone may impact on levels of certain cytokines - messenger cells of the immune system - in some cases of autism spectrum disorder (ASD) grabbed my attention recently. I've always been pretty interested in the complexity of the immune system when it comes to something like autism (see here) as well as the various examples of how many of the medications used to 'manage' aspects of autism appear to have quite a few more biological effects over and above those listed on the patient information leaflet. Think melatonin for example, and what a molecular handyperson this pharmaceutic has turned out to be (see here).

Could it be magic... @ Wikipedia 

The Choi paper worked on the assumption that use of risperidone and other antipsychotics have previously been shown to correlate with changes to serum levels of certain cytokines as per examples of work in the area of schizophrenia [2] and here [3]. Some of this research even hinted that part of the reason why antipsychotics might 'work' in some cases of schizophrenia was to do with their potential effect on "the inflammatory-like situation" present [4]. Certainly it's been noted before on this blog how inflammation may very well play some role when it comes to psychiatry (see here) particularly in light of some of the research on the various inflammatory markers (see here) accepting the chicken-and-egg question of what comes first: inflammation or symptoms?

Anyhow, based on a small-ish sample (n=45), Choi et al looked at plasma levels of "27 different cytokines" both before risperidone treatment was introduced and after 8 weeks on the drug. Interestingly the words 'responders' and 'nonresponders' were included in the analyses undertaken to look for any changes/trends following antipsychotic use (something which I think more studies should head towards). As it happens, "2 of the 27 plasma cytokines showed statistically significant decreases in median levels" - eotaxin and monocyte chemoattractant protein-1 (MCP-1). Further, when those responders and non-responders were separated out "the median values of interleukin (IL)-5 were significantly higher (p=0.005) in the overall responder group than in nonresponders".

Obviously one has to be a little bit guarded about the conclusions reached from this fairly small and fairly short study. Whilst risperidone does have a place in the medicines cabinet for some people with autism (see here), paediatric use (as was the case in the Choi study) is not without risks as per a recent entry on the SFARI website (see here). The guidance from NICE here in the UK (well, England at least) also mentioned how cautious physicians must be when using antipsychotics "for behaviour that challenges" with autism in mind.

I was quite interested in the Choi findings particularly that of the elevations in IL-5 in the responder group. I'm no expert on IL-5 but some light reading around the topic (see here) seems to imply that elevations of this cytokine are probably not going to be a great thing from the point of view of their involvement in the activation of eosinophils [5]. I've talked before on this blog about some of the work looking at eosinophils and autism (see here) and some potentially interesting correlations with other research (see here). I'd perhaps like to see more about this correlation in future studies particularly building on other findings in relation to IL-5 and autism [6] (open-access here) including as part of being a risk factor for offspring autism [7] (open-access here).

Insofar as the eotaxin and MCP-1 findings, well, again there is probably a lot more work to do on these compounds as a function of their mention in other autism research [8] (open-access here). The paper by Paul Ashwood [9] (who incidentally was an author on the Choi paper) looking at Fragile X syndrome (FXS) with and without autism also caught my eye: "significant differences were observed between the FXS group with autism and the FXS without autism for IL-6, eotaxin, MCP-1" as another avenue for further study.

So then... somewhere the drinks are free (or should that be all-inclusive).

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[1] Choi JE. et al. Change in Plasma Cytokine Levels During Risperidone Treatment in Children with Autism. J Child Adolesc Psychopharmacol. 2014 May 14.

[2] Zhang XY. et al. Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J Clin Psychiatry. 2004 Jul;65(7):940-7.

[3] Kim DJ. et al. Effect of risperidone on serum cytokines. Int J Neurosci. 2001;111(1-2):11-9.

[4] Cazzullo CL. et al. Cytokine profiles in schizophrenic patients treated with risperidone: a 3-month follow-up study. Prog Neuropsychopharmacol Biol Psychiatry. 2002 Jan;26(1):33-9.

[5] Takatsu K. & Nakajima H. IL-5 and eosinophilia. Curr Opin Immunol. 2008 Jun;20(3):288-94.

[6] Suzuki K. et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS One. 2011;6(5):e20470.

[7] Goines PE. et al. Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: A case-control study. Mol Autism. 2011 Aug 2;2:13.

[8] Ashwood P. et al. Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J Neuroimmunol. 2011 Mar;232(1-2):196-9.

[9] Ashwood P. et al. Plasma cytokine profiles in Fragile X subjects: is there a role for cytokines in the pathogenesis? Brain Behav Immun. 2010 Aug;24(6):898-902.

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Choi JE, Widjaja F, Careaga M, Bent S, Ashwood P, & Hendren RL (2014). Change in Plasma Cytokine Levels During Risperidone Treatment in Children with Autism. Journal of child and adolescent psychopharmacology PMID: 24828014