Thursday, 27 July 2017

Early pregnancy vitamin D levels and later offspring 'behavioral difficulties'?

Drawing on data derived from the Rhea mother-child cohort based in Crete, Greece, the findings reported by Vasiliki Daraki and colleagues [1] provide some food for thought; specifically the observation that "high maternal vitamin D levels in early pregnancy may protect against [offspring] behavioral difficulties, especially ADHD [attention-deficit hyperactivity disorder]-like symptoms at preschool age."

Including nearly 500 mother-child pairs, researchers set about looking at whether pregnancy levels of vitamin D - "serum 25(OH) D concentrations were measured at the first prenatal visit (13 ± 2.4 weeks)" - correlated with cognitive functions and/or behavioural 'difficulties' in offspring at 4 years of age.

Results: as per the headline titling this post, there did seem to be some potentially important *associations* between maternal pregnancy levels of vitamin D and offspring outcomes. So: "children of women in the high 25(OH) D tertile (>50.7 nmol/l) had 37% decreased number of hyperactivity-impulsivity symptoms... and 40% decreased number of total ADHD-like symptoms... at 4 years of age, compared to children of women in the low 25(OH) D tertile (<38.4 nmol/l), after adjustment for several confounders." Investigations looking at pregnancy vitamin D levels and various cognitive functions of offspring children revealed nothing too significant.

Of course you would be right to point out that this was a study pitting one variable - pregnancy vitamin D levels - against a multitude of different offspring cognitive/behavioural outcomes some four years later. It's not entirely inconceivable that despite 'adjustment for several confounders' the authors might be in error in linking vitamin D to offspring outcomes and that some (more than one?) other variable(s) might account for the results. I should also point out that Greece is not exactly sunshine deficient; sunshine being a primary pathway pertinent to the biological synthesis of vitamin D.

But this is not the first time that pregnancy vitamin D levels have been *associated* with offspring ADHD or ADHD-like behaviours (see here) and I doubt it will be the last. Added to work looking at the possibility of an *association* between pregnancy vitamin D levels and offspring risk of autism (see here for example), bearing in mind autism and ADHD are not totally unconnected, there is an interesting theme developing on this topic. Perhaps Government (English at least) policy on recommending vitamin D supplementation for large swathes of the population (see here) may have a multitude of onward effects outside of just reducing the risk of bone manifestations of vitamin D deficiency/insufficiency?

And just before you go, even ALSPAC has something further to say on this matter [2]...

To close, 'Are you Tony Stank?'


[1] Daraki V. et al. High maternal vitamin D levels in early pregnancy may protect against behavioral difficulties at preschool age: the Rhea mother-child cohort, Crete, Greece. Eur Child Adolesc Psychiatry. 2017 Jul 6.

[2] Darling AL. et al. Association between maternal vitamin D status in pregnancy and neurodevelopmental outcomes in childhood: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Br J Nutr. 2017 Jul 12:1-11.


Wednesday, 26 July 2017

Open label study of probiotics and autism

"We concluded that probiotics have beneficial effects on both behavioral and GI [gastrointestinal] manifestations of ASD [autism spectrum disorder]."

So said the study results published by Sanaa Shaaban and colleagues [1] detailing observations from their "prospective, open-label study" following some 30 children diagnosed with an autism spectrum disorder (ASD) before and after 3 months of probiotic usage. The study details were posted in a clinical trials repository (see here) and note how various measurements were taken as participants took a preparation containing "100 × 106 colony forming units of three probiotic strains; Lactobacillus acidophilus, Lactobacillus rhamnosus and Bifidobacteria longum."

Including some notable authors on the paper who are seemingly not adverse to [scientifically] examining some of the more non-traditional interventions put forward with autism in mind (see here and see here), researchers caution about their latest findings. So: "this study is a single center with a small number of patients and a great deal of additional wide-scale randomized controlled trials are needed to critically confirm the efficacy of probiotics in ASD." Yes, indeed; blinding for example, is a rather important part of the scientific process and other studies 'in progress' have adopted such factors (see here). Set against a growing tide of research suggesting that those trillions of wee beasties that inhabit our deepest, darkest recesses (the gut microbiome) might have more than a passing connection to some autism - some aspects of autism - this area of study is crying out for quite a bit more attention (see here also) not least on hows-and-whys (see here). The way that someone might potentially 'impact' on the gut microbiome in a probiotic sense is also potentially important (see here).

I have only one further point to make about the Shaaban results in relation to the observations that behavioural signs and symptoms (as assessed by the ATEC) seemed to show a relationship with GI symptoms following probiotic use. I'm wondering whether this potential tie-up might learn something from work looking at probiotic use in something like irritable bowel syndrome (IBS) (see here) and onward what happens to psychiatric issues that are seemingly over-represented in cases of IBS (see here). I say that on the basis that bowel issues seem to be most definitely over-represented when it comes to a diagnosis of autism (see here) and the whole 'gut-brain axis' thing continues -across decades - to persist with autism in mind (see here)...


[1] Shaaban SY. et al. The role of probiotics in children with autism spectrum disorder: A prospective, open-label study. Nutr Neurosci. 2017 Jul 7:1-6.


Tuesday, 25 July 2017

"a leaky gut may play a critical role in the development of age-related inflammation and frailty"

The quote heading this post is taken from the findings reported by Yanfei Qi and colleagues [1] who set out to investigate whether "an aging-associated leaky gut is linked to the age-related inflammation and frailty."

'Leaky gut' is still something of a contentious claim in medical and scientific circles despite some increasing evidence to say that it is a real phenomenon and potentially relevant to several conditions (see here) including some parts of the autism spectrum (see here). Although leaky gut is perhaps a slight misnomer - we all have leaky guts to some degree - the more accurate term 'intestinal hyperpermeability' suggests that for several different reasons, parts of the gastrointestinal (GI) tract may, at times or more chronically, be slightly more permeable that they typically should be. This in turn means that the contents of the GI tract - food derivatives, gut bacteria, etc - might be more readily exposed to parts of the body that they really shouldn't be and onward, potentially pathogenic.

Qi et al carried out some important analysis on two cohorts of differing ages (18-30 years old vs. 70 years and over) with regards to serum samples provided by participants. Markers of immune function, specifically inflammatory related compounds (e.g. tumour necrosis factor (TNF)-α and interleukin (IL)-6)) were assayed for, alongside levels of zonulin "a marker for leaky gut". Zonulin is something that I've covered quite recently on this blog in relation to autism research (see here). This biological data gathered by Qi and colleagues was also complemented by physiological measures such as "strength of plantar flexor muscles and number of steps taken per day."

Results: serum concentrations of zonulin were quite a bit - 22% - higher in the older participants compared to younger ones. Researchers also reported that levels of "high-mobility group box protein (HMGB1, a nuclear protein triggering inflammation)" were elevated in the older participants group too. They observed that zonulin levels also seemed to tie into concentrations of TNF-α and IL-6 (albeit not necessarily impressively). Zonulin levels also showed a potentially important *relationship* with "habitual physical activity" (those 'steps per day' data that was collected). The conclusion: "Serum zonulin was associated with both systemic inflammation and 2 key indices of physical frailty. These data suggest that a leaky gut may play a critical role in the development of age-related inflammation and frailty."

This is interesting stuff. It kinda accords with other independent data suggesting that generally speaking, gut barrier function does not necessarily have to deteriorate with age, but under certain circumstances such as age + inflammation, there might be effects to had [2]. Certain classes of medication might also show some involvement in this process too [3]. Although by no means a universal connection, I was interested in these results in the context of autism. Specifically how those Esnafoglu et al findings [4] reporting on 'significantly higher' serum zonulin levels in their cohort with autism, might also tie into reports of inflammatory markers being elevated in at least a subgroup of those on the autism spectrum (see here for example). I'd like to see the Qi study replicated with quite a few different labels and subgroups within labels...

In relation to the suggestion that serum zonulin levels negatively correlated with habitual physical activity (steps per day), again, there is a whole other research agenda to be [cautiously] followed. It's already known that certain patterns of exercise can affect (increase) intestinal permeability [5] although the specifics still require quite a bit more investigation (hint: exercising for 2 hours plus at a time is probably not great for gut function). As with everything in life, there is a balance to be struck between too little and too much of a good thing...


[1] Qi Y. et al. Intestinal Permeability Biomarker Zonulin is Elevated in Healthy Aging. J Am Med Dir Assoc. 2017 Jul 1. pii: S1525-8610(17)30297-9.

[2] Valentini L. et al. Small intestinal permeability in older adults. Physiol Rep. 2014 Apr 22;2(4):e00281.

[3] Meier J. & Sturm A. The intestinal epithelial barrier: does it become impaired with age? Dig Dis. 2009;27(3):240-5.

[4] Esnafoglu E. et al. Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects. J Pediatr. 2017 May 11. pii: S0022-3476(17)30487-0.

[5] Costa RJS. et al. Systematic review: exercise-induced gastrointestinal syndrome-implications for health and intestinal disease. Aliment Pharmacol Ther. 2017 Aug;46(3):246-265.


Monday, 24 July 2017

On DSM-5, Asperger syndrome and 'level of support'

It wasn't so much the findings reported by Garrido and colleagues [1] that took my attention, but rather their use of a particular sentence: "We have equated diagnosis of Asperger syndrome with ASD-level 1 of support" in the context of the DSM-5 guidance for diagnosing an autism spectrum disorder.

For those who might not know, the two main documents for diagnosing autism or autism spectrum disorder (ASD) are the ICD and DSM schedules. Both are currently under/have recently been the subject of revision (ICD-11 and DSM-5 respectively) and both have played a significant role in relation to various aspects around autism (see here for example).

The quite recently revised DSM-5 description of autism (see here) has been the source of quite a lot of discussion. Not only that the latest description might have some quite important effects on the numbers of people potentially being diagnosed with autism or ASD (see here) but also that this revision did away with the diagnostic sub-categories included in previous DSM versions; notably the diagnosis of Asperger syndrome. There were mechanisms built into the DSM-5 such that those already diagnosed with Asperger syndrome (AS) would not lose out in terms of 'identity' but as the DSM-5 becomes more readily used (and also assuming ICD-11 allies with DSM-5 as anticipated), the specific diagnosis of AS is likely to be consumed by the broader ASD label in the longer term. Other authors have talked about the hows-and-whys of this issue in more informed detail than I ever could (see here although I think the authors needs to spellcheck 'Asperger' in some places).

With that rather long introduction in mind, I want to go back to that 'ASD-level 1 support' labelling of AS in the Garrido paper. DSM-5 criteria for autism, sorry ASD, does provide the diagnosing team with an option to place the recipient of a diagnosis on a scale of severity ranging from 'requiring support' to 'requiring very substantial support' shown as levels 1-3 respectively. The assumption is that money and resources will be attached at varying degrees based on the support level indicated. The level 1 support option applied to AS presumes that the dyad of symptoms - social affect and restricted, repetitive behaviours - does impact on day-to-day functioning but issues such as the consistent and complex use of language as a communicative strategy for example, puts their support requirements below say those with 'marked' or 'severe' deficits in verbal and nonverbal social communication skills. Fair enough. When however it comes to the repetitive behaviour side of things in terms of severity, level 1 support basically acknowledges that inflexible behaviour "causes significant interference with functioning in one or more contexts" but importantly, does not use words like 'distress' as it does in level 2 and 3 descriptions.

I may just be focusing too much on details here, but it strikes me that the sweeping assumption made by Garrido et al reveals a broader issue with level of support shown in DSM-5. Although there is not a great deal of peer-reviewed research out there on the severity/support level components to the DSM-5 ASD diagnosis, the work that is there tends to suggest a degree of 'fuzziness' both in the pattern of skills/deficits displayed in relation to autism and onward how clinicians might define decisions on support level [2]. What seems to be inferred with the level of support criteria offered in DSM-5 is that those with a current diagnosis of AS as a group - this diagnosis then changing to ASD - will seemingly never hit criteria for levels 2 or 3 on the basis of the language and communicative skills they possess. I say this with the understanding that I'm not precisely sure whether the individual components of the dyad - social affect and restricted, repetitive behaviours - are separately graded in terms of level of support needed in DSM-5 or just condensed into one severity level for all the diagnostic components combined. Garrido and colleagues imply that one severity level is likely going to be the rule.

There is another issue that needs comment, on whether at least some cases of AS actually meet the operational criteria of DSM-5 ASD over and above the new categorisation of social (pragmatic) communication disorder (SCD) (see here). I can see this being a contentious point. SCD as the name suggests, focuses on 'the social use of verbal and nonverbal communication' and how 'deficits result in functional limitations in effective communication, social participation, social relationships, academic achievement, or occupational performance, individually or in combination'. Previous data has suggested that something approaching 10% of cases of AS - redefined as ASD in DSM-5 - might not actually meet DSM-5 criteria for ASD but might hit diagnostic thresholds for SCD [3]. As I've asked before on this blog, what level of support are those with SCD likely to get? and what are the implications for 'membership' of the autism spectrum for those diagnosed with SCD? are questions that still need answering.

I have been a little pedantic in this post but do want to convey the message that even with the redefinition of AS into ASD, the DSM-5 severity/level of support descriptions are in need of a lot more experimental study to see how they work in real-life [4]. Indeed, further longitudinal studies on how DSM-5 diagnosis and severity 'grading' translate into money, resources and services offered and received and onward outcomes for those diagnosed, should really be in the planning stages as we speak...


[1] Garrido D. et al. Communicative and social-adaptive profile in children with autism spectrum disorder: a new approach based on the DSM-5 criteria. Rev Neurol. 2017 Jul 16;65(2):49-56.

[2] Weitlauf AS. et al. Brief Report: DSM-5 “Levels of Support:” A Comment on Discrepant Conceptualizations of Severity in ASD. Journal of autism and developmental disorders. 2014;44(2):471-476.

[3] Kim YS. et al. A comparison of DSM-IV pervasive developmental disorder and DSM-5 autism spectrum disorder prevalence in an epidemiologic sample. J Am Acad Child Adolesc Psychiatry. 2014 May;53(5):500-8.

[4] Burns CO. & Matson JL. An evaluation of the clinical application of the DSM-5 for the diagnosis of Autism Spectrum Disorder. Expert Rev Neurother. 2017 Jul 5.


Saturday, 22 July 2017

"medical disorders in children with ASD and ADHD appear to be widespread"

The quote titling this brief post is taken from the results of the systematic review undertaken by Jet Muskens and colleagues [1] (open-access) who surveyed the peer-reviewed science literature "on medical comorbidity in the two major developmental disorders autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD)."

Continuing an important theme (see here), the authors concluded that various categories of conditions - "immunology, neurology and gastroenterology" - are over-represented in relation to autism and ADHD and that "future studies should not only focus on psychiatric symptoms, but provide a broader evaluation of medical disorders" when it comes to those labels.

Minus too much chatter, I was impressed to see that many of the research articles covered on this blog down the years had made it into the Muskens review. So, the likes of Harumi Jyonouchi gets a well-deserved mention (see here and see here) and the focus on how the immune system might be doing so much more than just protecting us from the odd pathogen or two. The authors also bring in some of the very convincing scientific evidence that various gastrointestinal (GI) issues are over-represented in relation to autism (see here). There's even mention of how useful that Taiwanese research database has been down the years to autism and ADHD research (see here).

What's more to say? Well, preferential screening for various medical conditions in the context of an autism diagnosis yet again, receives more support. As does the idea that when a medical diagnosis is received by a person diagnosed on the autism spectrum, that medical diagnosis deserves the same healthcare management and/or treatment as it does in the context of not-autism save any further health inequalities potentially appearing (see here). The days for example of 'blaming autism' for every single physical complaint are also to be consigned to the historical dustbin. And with it, recognition that concepts such as ESSENCE or 'autism plus' (see here and see here) really need to include the somatic as well as the behavioural/psychiatric...

Whilst welcoming the Muskens review, it's important to note that others have already 'primed' for the importance of medical comorbidity in relation to a diagnosis of autism...


[1] Muskens JB. et al. Medical comorbidities in children and adolescents with autism spectrum disorders and attention deficit hyperactivity disorders: a systematic review. European Child & Adolescent Psychiatry. 2017. July 3.


Friday, 21 July 2017

Antidepressants during pregnancy and autism in offspring (with care)

There are a few topic areas in the quite vast autism research landscape that consistently seem to keep cropping up. The possibility of some kind of *association* between pregnancy antidepressant use and risk of offspring autism is one of those areas (see here) as the results published by Dheeraj Rai and colleagues [1] (open-access) are presented for your attention. I would also draw your attention to an accompanying editorial discussing the Rai findings (see here).

So: "To help to improve the understanding of the association between antidepressant use during pregnancy and autism in offspring, we applied a range of... causal analytical methods on data from a large total population cohort in Stockholm County" was the starting point, as once again one of those very useful Scandinavian registries provided the source study material (indeed, Rai et al are seemingly experts in their analysis of such resources). The added bonus to the Rai study was their attempt to 'unravel' any association between gestational antidepressant exposure and autism from the reason why such medication was being taken in the first place: maternal psychiatric health issues (and whether this variable may in fact account, at least in part, for any association that has previously been identified).

From a starting population approaching three-quarters of a million people, researchers eventually settled on looking at over 250,000 children under 17 years of age (but over 4 years of age "in whom a diagnosis of autism might be less reliable") who were born to over 150,000 mothers. The vast majority of children (239,943 of 254,610) had no history of exposure to antidepressants during pregnancy. The remaining participants were divided up into two groups: one where there was documentation leading to the assumption of exposure to pregnancy antidepressants (n=3342) and one where there was an indication for such exposure ("mothers with a psychiatric disorder") but no recorded use of antidepressants during pregnancy (n=12,325). Researchers summed up how many children were diagnosed with an autism spectrum disorder (ASD) in each group and applied some statistical modelling.

Results: I think it's important to first highlight a statistic that seems to have been missed by many covering the Rai findings: "Of the 238 943 cohort children for whom there was no record of maternal history of psychiatric disorder or antidepressant use during pregnancy, 4889 had autism (2.1%)." That's 2.1% with a diagnosis of autism or ASD; quite a far cry from the 1% [estimate] statistic from just a few years back (at least here in Blighty).

Then: "Exposure to antidepressants during pregnancy was associated with a higher odds of a diagnosis of autism in offspring than exposure to a maternal psychiatric disorder without antidepressants." The authors caution that: "the absolute risk was small, and 4.1% of children exposed to antidepressants in utero had autism compared with 2.9% of those with a maternal history of psychiatric disorder." Further when looking at those children diagnosed with ASD in the groups, authors observed that "autism without intellectual disability" seemed to be over-represented; something also picked up in previous findings from authors on this current paper [2].

Alongside various opinions on these findings (see here for example), the authors caution about the possible meaning of their results. One obviously has to be quite careful when discussing such data to ensure that an important class of medicines is not unduly vilified. No medicine is however without potential side-effects and appropriate clinical decisions and good medicines management [2] is key, particularly when pregnancy is included as variable. The authors talk, for example, about how "if a causal link were robustly established, and if no pregnant women took antidepressants during pregnancy, only 2% of autism cases in this population would be prevented." Alongside they [importantly] mention that antidepressant use during pregnancy is not typically just a 'choice' but rather being clinically indicated: depression does not simply disappear when a woman is pregnant. Interestingly too, they mention about how their data "suggest that there is an increased background risk of autism in children of women with psychiatric conditions, regardless of antidepressant treatment." This follows a trend in other areas of psychiatry (see here for example).

Yet again, the call is further research in this area and, quite a few more investigations into the possible hows-and-whys of any association (with medication use and/or maternal psychiatric presentation) is made. I might also suggest that taking into account other childhood conditions such as attention-deficit hyperactivity disorder (ADHD), potentially over-represented when it comes to a diagnosis of autism or ASD, could be another important step forward in light of other preliminary *associations* being made with pregnancy medication history in mind (see here). This also includes looking at any issues associated with timing of potential exposure and/or dose ("Because of small numbers, we were not able to assess trimester specific or dose response effects.").

Insofar as the suggestion that autism without intellectual (learning) disability might be an important phenotype when it comes to any association, subsequent research in this area seemingly fits in well with increasingly vocal calls [4] to stop using the generic label of autism as a research starting point (see here). Allied to suggestions for more 'bottom-up' research with autism in mind (see here), also coincidentally mentioning "maternal SSRI use during pregnancy" in the context of autism [5], a future research agenda is seemingly emerging. I might also point out that certain sensitivities need to be kept in mind on the basis of suggestions that an 'environmental exposure' might, in whole or part, be *associated* with a particular type(s) of autism.

All such work - present and future - however needs to be done/presented with care, understanding and minus scaremongering, so as not to unduly alarm pregnant mothers, their families or indeed, the physicians providing their care at such a critical time...


[1] Rai D. et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017; 358: j2811.

[2] Rai D. et al. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ. 2013 Apr 19;346:f2059.

[3] Angelotta C. & Wisner KL. Treating Depression during Pregnancy: Are We Asking the Right Questions? Birth Defects Res. 2017 Jul 17;109(12):879-887.

[4] Waterhouse L. et al. The ASD diagnosis has blocked the discovery of valid biological variation in neurodevelopmental social impairment. Autism Res. 2017 Jul;10(7):1182.

[5] Unwin LM. et al. A "bottom-up" approach to aetiological research in autism spectrum disorders. Front Hum Neurosci. 2013 Sep 19;7:606.


Thursday, 20 July 2017

Is gluten avoidance linked to a lower risk for depression?

I've talked a few times on this blog about how avoiding dietary gluten both within (see here) and outside of (see here) the context of coeliac (celiac) disease, the archetypal 'gluten is baddie' autoimmune condition, might have some pretty interesting effects on some aspects of a person's psychology. Today's post reflects yet more peer-reviewed science suggesting that there may indeed be something to see in this potentially important area; particularly pertinent to the presentation of depression or depressive symptoms.

So, the findings reported by Haley Zylberberg and colleagues [1] based on data from some 22,000 participants taking part in the US 2009-2014 National Health and Nutrition Examination Survey are the source material today. Some background material related to this cohort can be found here. They specifically looked at the "prevalence of depression, insomnia, quality-of-life variables, and psychotropic medication use in CD [coeliac disease] participants and PWAGs [people who avoid gluten] to controls." People who avoid gluten - PWAG - represent a group who don't have a diagnosis of CD but nonetheless similar to those who were diagnosed with CD, reported avoiding dietary gluten.

Results: "Depression was present in 8.2% of controls compared with 3.9% of participants with CD... and 2.9% of PWAGs." Even after adjustment for various confounding variables ("age, sex, race, income, and access to healthcare") those gluten avoiders (without CD) less frequently presented with depression compared with data from controls.

Added to the previous occasions where gluten consumption seems either to be linked to [some] depression or removal of gluten seems to positively impact on depressive symptoms at least for some, this is interesting work. Yes, quite a few more controlled trials are required to examine such relationships between food and mood. Although we can speculate on possible mechanisms [2] we don't really know why there may be an effect from gluten removal, but this is an emerging area of science; particularly in the context of how disruptive/disabling/damaging depression can be to someone.

Bearing in mind the caveats of this blog - no medical or clinical advice is given or intended - please don't assume that I'm advocating gluten removal for anything (unless clinically indicated) on the basis of this or other posts. If in doubt, consult your medical physician.


[1] Zylberberg HM. et al. Depression and insomnia among individuals with celiac disease or on a gluten-free diet in the USA: results from a national survey. Eur J Gastroenterol Hepatol. 2017 Jun 27.

[2] Pruimboom L. & de Punder K. The opioid effects of gluten exorphins: asymptomatic celiac disease. J Health Popul Nutr. 2015 Nov 24;33:24.