Individualised medicine and autism: a brave new world

Pharmacogenetics: "the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects."

Having recently watched a rather interesting documentary on the BBC titled 'Can you cure my cancer?' illustrating how the era of personalised medicine is here and now (see here) in at least one aspect of medicine, I was really quite interested in the science of how our genes might affect our response (or not) to things like medication. Pharmacogenetics is not necessarily a new concept (see here) but only in recent years with the increasingly inexpensive ways and means that the genome can be mapped, have we seen something of a translation of the idea from laboratory to bedside on a broader scale.

Now it seems that autism research and practice might also be benefiting from this brave new world as per the paper from Teri Smith and colleagues [1] (open-access available here). This is a case report of an adolescent diagnosed with an autism spectrum disorder (ASD) among other things, who presented with several genetic 'issues' that may well have impacted on the metabolism of certain types of medicines used to manage specific symptoms. The genetic issues identified included some pertinent to the workings of cytochrome p450 enzymes which may have had important effects on the metabolism of certain pharmaceutics. Interestingly too was the finding that this young man also "showed a MTHFR C/T gene variation that suggested reduced enzymatic activity associated with a reduced conversion of folic acid to methylfolate." MTHFR controlling the production of methylenetetrahydrofolate reductase has something of a history with autism in mind (see here) as it might have in a few other diagnoses too (see here).

"It is clear in this clinical case that certain recommendations for care could be made due to
pharmacogenetic findings." That was one of the concluding sentiments from the authors, alongside how said genomic testing was all done via a spit sample (so being a pretty non-invasive method of collecting DNA).

I'm impressed with this paper and the precedent it may well set. As per my other musings on the use of pharmaceutics when it comes to autism (see here for example) I would firmly place myself in the 'buyer beware' category when it comes to medicating in cases of autism but do understand that there is a place for some pharmaceutics to tackle certain issues associated with autism under certain circumstances. That is, alongside good medicines management. If the science of pharmacogenetics can aid the process of medicating when it comes to the label of autism, I'm sure most people would be happy to see it as an addition particularly when talking about the more plural 'autisms'.

If I had to quibble at all with the idea of pharmacogenetics it might however be to say two things:

• (i) the structural genome represents only one part of what we call gene function. As per the rise and rise of the science of epigenomics (see the Nature special on this), it is becoming more and more apparent that there are lots of issues potentially impacting on the how the genome 'works' not necessarily just tied down to structural mutation(s). Looking for genetic mutations is all well and good but might not necessarily give you all the data on specific gene functions. And speaking of gene expression, I'll draw your attention to the paper from Carolyn Ch'ng and colleagues [2] noting that following their meta-analysis of gene expression in cases of autism: "A subset of the highly ranked genes is suggestive of effects on mitochondrial function." Mitochondrial function and autism eh?
• (ii) The name Jeremy Nicholson has appeared a few times on this blog (see here for example) based on some research looking at potential biomarkers for autism [3]. Aside from such research forays, Prof. Nicholson can perhaps also be credited with "the principle of pharmacometabonomics" [4], that is that those trillions of wee beasties which inhabit our gastrointestinal (GI) tract - the gut microbiome - might also have the ability to influence our response to certain types of medicines. I've talked about this issue elsewhere (see here). That and the fact that certain GI issues might also potentially affect things like drug absorption (see here) and the recipe starts to get a little more complicated.

Still, I'll keep my eye open for more on this topic, and also when some brave soul decides that genomic / epigenomic / microbiomic analysis might even help with gauging response to other interventions put forward for some on the autism spectrum...

To close: The Ballad of Bilbo Baggins by the great, late Leonard Nimoy.

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[1] Smith T. et al. Pharmacogenetics Informed Decision Making in Adolescent Psychiatric Treatment: A Clinical Case Report. Int J Mol Sci. 2015 Feb 20;16(3):4416-4428.

[2] Ch'ng C. et al. Meta-Analysis of Gene Expression in Autism Spectrum Disorder. Autism Res. 2015; Feb 26.

[4] Yap IK. et al. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 2010 Jun 4;9(6):2996-3004.

[5] Clayton TA. et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14728-33.

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Smith T, Sharp S, Manzardo AM, & Butler MG (2015). Pharmacogenetics Informed Decision Making in Adolescent Psychiatric Treatment: A Clinical Case Report. International journal of molecular sciences, 16 (3), 4416-4428 PMID: 25710722

Gut issues in autism impacting on drug availability and absorption

As indicated in a recent post, I was really rather pleased to see the paper by Andrew Heitzer and colleagues [1] (open-access) asking the important question: Should clinical trial research of psychotropic medication in autism control for gastrointestinal symptoms? Some media about the study can also be found here.

"You write "Born to Kill" on your helmet
and you wear a peace button".

The answer is of course, yes and not just when it comes to psychotropic medicines either, given that gastrointestinal (GI) symptoms both functional and more pathological, are by no means an uncommon event when a diagnosis of autism is received (see here).

As anyone with an interest in pharmcokinetics and pharmacodynamics should be able to tell you, various factors can affect a persons response to medication, particularly medication delivered orally (by mouth). Outside of medicines interactions, ageing is one of the more well-studied factors pertinent to drug response as per the review by Mangoni & Jackson [2] for example, but there are other suggestions on the horizon. Indeed, I might also take this opportunity to link to some of the work by Prof. Jeremy Nicholson and colleagues [3] talking about how gut bacteria may play a role in drug metabolism. This area may be particularly pertinent to autism given this research teams' previous forays into autism science (see here) and the growing interest in the gut microbiota and autism (see here).

There are various other factors which may also affect drug response in relation to autism such as stomach acid conditions (see here) and even drug transporter capability (see here). This outside of adherence to instructions like taking medication with water or avoiding food/certain foods when taking particular medicines, which one should never assume are just followed.

Of course there are other ways in which medication, when indicated, can potentially be reformulated to overcome some of these issues. I've talked before about some work our research group were involved with looking at making up the opiate antagonist naltrexone into a cream (see here). Although not necessarily a big fan of the sweeping statements made about oxytocin and autism (see here), I've likewise always been interested in the intra-nasal route of drug administration. There are other ways too (bearing in mind I'm making no value judgements on these).

So once again, yes, as part of good medicines management, clinicians and researchers need to be mindful that comorbid issues like GI symptoms can potentially affect the workings of various medicines if and when required by people with autism.

Music then. Bohemian Like You by The Dandy Warhols.

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[1] Heitzer AM. et al. Should clinical trial research of psychotropic medication in autism control for gastrointestinal symptoms? J Clinical Pharmacology. 2014. 6 May.

[2] Mangoni AA. & Jackson SHD. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. Jan 2004; 57(1): 6–14.

[3] Clayton TA. et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14728-33.

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Heitzer AM, Job MA, Pandit NK, & Valdovinos MG (2014). Should clinical trial research of psychotropic medication in autism control for gastrointestinal symptoms? Journal of clinical pharmacology PMID: 24788353

Not all good news for fish oils

I'm sure that you've all seen the headlines and hype about the humble fish oil and those yummy omega-3 fatty acids down the years. Good for the heart, good for developing foetuses, good for mental health. There is even some suggestion that it might be a useful complementary therapy for some cases of autism. Blimey! Why don't they just add it to tap water.

Well, there might be a good reason for keeping an open mind about oily fish and fish oil supplements based on a new piece of research suggesting some potential drug interaction. The study in question is this one by Roodhart and colleagues* published in the journal Cancer Cell. The main message has been summarised by various news sources but the BBC carry as good as any description. Cancerous tumours generally don't like to be destroyed by the various chemotherapy drugs currently on offer. One of the ways in which they develop resistance to one drug, cisplatin, according to Prof. Emile Voest's team, is via the production of two fatty acids, an n-6 (omega-6), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and an n-3 (omega-3), hexadeca-4,7,10,13-tetraenoic acid (16:4), so-called platinum-induced polyunsaturated fatty acids, which start a chemical chain reaction leading to resistance. I should perhaps also point out that these fatty acids are made endogenously via mesenchymal stem cells. Such fatty acids are also apparently "abundantly present in commercially available fish oil products".

The point Voest and colleagues are making is that additional fish oil supplementation may not be the best course of action when such chemotherapeutics are being taken; at least until more investigations are carried out.

There are lots of interesting points to be made from research such as this. Of course there are lots of reasons for drug resistance, some genetic and some more environmental. Hippocrates (I think) was quoted as suggesting that we let food be thy medicine. I don't fundamentally disagree with this notion, but highlight the possibility that food might also be our poison as is the case of gluten in coeliac disease, or for certain food constituents as in this case, at least contra-treatment. Diet or dietary supplements and drug interactions is an important point. Grapefruit for example, has quite a few noted adverse drug interactions, which either limit the effectiveness of medications or sometimes potentially much worse. There are others being discovered regularly.

Human biochemistry is a complicated thing. Most of us try to keep the body machine in good working order through diet, exercise and the odd supplement here and there. What research like this tells us is that when taking our medicine for whatever ailment, treat your dietary supplements like the drugs they are and check with your physician about any possible interactions.

* Roodhart JML. et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids Cancer Cell. September 2011.