"Low parental melatonin levels could be one of the contributors to ASD and possibly ID etiology"

The title heading this post - "Low parental melatonin levels could be one of the contributors to ASD and possibly ID etiology" - comes from the findings reported by Wiebe Braam and colleagues [1]. It continues a research theme on the topic of melatonin and autism or autism spectrum disorder (ASD) (and intellectual disability, ID) (see here).

Perhaps most famously known for its links to circadian rhythms, melatonin is quite an important topic in many areas of autism research and practice. The use of melatonin to influence various sleep issues that seem to be quite regularly present in relation to autism (see here) takes the lion's share of the limelight (see here) but this is a compound potentially doing sooo much more. I've for example, talked about melatonin in relation to intestinal permeability issues (see here) on this blog, as this molecular handyperson [2] offers several possible links/effects with other biological systems. Indeed, Braam et al start from a position where melatonin "is important for normal neurodevelopment and is highly effective in protecting DNA from oxidative damage" continuing an interest for members of the authorship group.

The current findings have, I believe, been seen before on the preprint server bioRxiv [3] so we knew this peer-reviewed publication was coming. Including urine samples from 60 mothers of children diagnosed with autism and a somewhat smaller number from control mothers (with no children diagnosed with autism), researchers submitted said urine samples to analysis for a compound called 6-sulfatoxymelatonin, a primary urinary metabolite of melatonin. I understand that the gold-standard analytical method that is mass spectrometry was the chosen way to determine urinary 6-sulfatoxymelatonin, so one has some confidence that researchers were detecting/measuring this metabolite pretty accurately.

Researchers reported that levels of urinary 6-sulfatoxymelatonin were lower in mums of children diagnosed with autism compared to controls. This finding mirrors that reported in young people with autism [4] and, on more than one research occasion [5]. It looks like there may be a familial element to some of the issues with melatonin which quite neatly fits into other work suggesting similar things with other biological systems including that intestinal permeability [6] that I just mentioned.

Insofar as the implications and 'where next?' questions arising from such work, they are potentially numerous. The relationship with sleep and circadian rhythms is an obvious starting point. Further exploration of whether maternal melatonin biochemistry could be a *risk* factor for similarly altered biochemistry in relation to offspring with autism is also indicated. I'd also like to see some data on paternal and sibling levels of compounds such as 6-sulfatoxymelatonin too (and their related compounds) and how that might correlate with issues such as sleep in those populations.

The inclusion of the word 'sulfate' in 6-sulfatoxymelatonin might also lead to another area of possible research inspection with autism in mind. I hark back to work conducted seemingly aeons ago talking about how sulfate/sulphate chemistry might show some connection to some autism (see here). Sulfation is an important part of the reaction forming 6-sulfatoxymelatonin: 6-hydroxylation --> 6-hydroxymelatonin --> 6-sulfatoxymelatonin (I think), which would be reliant on there being enough sulphate to successfully produce such a reaction on a suitably large scale.

And finally, minus scaremongering or any sweeping generalisations, I do wonder whether further research needs to be done in a wider context of low urinary 6-sulfatoxymelatonin levels. I speak for example of research such as that by Devore and colleagues [7] talking about "Higher urinary melatonin levels... suggestively associated with a lower overall risk of breast cancer." This, in the context that such health issues have been reported with autism mentioned (see here); something which also requires a lot more scientific investigation...

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[1] Braam W. et al. Low maternal melatonin level increases autism spectrum disorder risk in children. Research in Developmental Disabilities. 2018. March 1.

[2] Boga JA. et al. Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? Rev Med Virol. 2012 Sep;22(5):323-38.

[3] Braam W. et al. Low parental melatonin levels increases autism spectrum disorder risk in children. bioRvix. 2016. April 2.

[4] Tordjman S. et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology. 2012 Dec;37(12):1990-7.

[5] Tordjman S. et al. Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder. Biol Psychiatry. 2005 Jan 15;57(2):134-8

[6] de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

[7] Devore EE. et al. Urinary Melatonin in Relation to Postmenopausal Breast Cancer Risk According to Melatonin 1 Receptor Status. Cancer Epidemiol Biomarkers Prev. 2017 Mar;26(3):413-419.

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Fatty acid supplementation and autism (again)

The findings reported by Sarah Keim and colleagues [1] (open-access available here) provide the discussion fodder today, on a topic that has graced this blog a few times: fatty acid supplementation in the context of autism (see here).

Indeed, it was coincidental that at the same time as the Keim findings appeared on PubMed, so I also stumbled upon news headlines suggesting that maternal use of fish oil supplements (i.e. fatty acids) *might* reduce offspring risk of allergies (see here). This is also an interesting finding; particularly in light of some observations that, appearing alongside the presence of certain childhood allergies, risk(s) of certain neurodevelopmental disorders might be heightened (see here and see here). I might just be adding 2 and 2 together and coming up with 5, but it strikes me that there could be some potentially important connections to be further explored between fish oils, allergy and offspring behavioural diagnoses...

Anyhow, detailing some quite small-scale results - N=31 children "aged 18–38 mo born at ≤29 wk of gestation" - garnered as part of something called The Preemie Tots Trial, Keim et al observed results that "suggested improvements in core ASD [autism spectrum disorder] symptoms as measured by the BITSEA ASD [Brief Infant Toddler Social and Emotional Assessment] scale." I might add that other data from this trial has, I think, already seen the peer-reviewed science publication light of day [2] and on more than one occasion [3].

The actual aim of the Keim study was to "confirm the feasibility of a full-scale trial in toddlers born very preterm and exhibiting ASD symptoms." This is probably why the participant numbers were quite small on this occasion, and why the autism-related findings don't yet need to be trumpeted out loud too much.

To accomplish their research goals, authors conducted a 90-day trial employing the gold-standard research method - "randomized, fully blinded, placebo-controlled trial" - where preterm born children received either "Omega-3-6-9 Junior (Nordic Naturals, Inc.) treatment (including 338 mg eicosapentaenoic acid, 225 mg DHA, and 83 mg GLA)" or a placebo: "canola oil (124 mg palmitic acid, 39 mg stearic acid, 513 mg linoleic acid, 225 mg α-linolenic acid, and 1346 mg oleic acid)".

Outside of the results obtained suggesting some potential positive effect(s) for the fatty acid supplement on autistic signs and symptoms, researchers also confirmed that within the confines of their study period: "No safety concerns were noted." Given that such fatty acid supplements are widespread in their availability, and often sold as a food supplement rather than a preparation with some medicinal claims, I probably wouldn't have expected anything else. That being said, I have heard isolated reports of some children taking fatty acid supplements and things not necessarily being wholly positive in terms of behaviour, bearing in mind anecdote is not the singular of data. This might however also tally with other data reporting no effect from fatty acid supplementation in some instances of autism (see here).

I understand that there is more to come from Keim and colleagues now that this pilot data has been published. I'd like to think if the results are confirmed and some biochemistry added to the mix (i.e. measuring functional fatty acid levels before and after supplementation), this intervention approach could be rolled out much further, as well as things like potential best-responders (and non-responders) being more accurately identified...

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[1] Keim SA. et al. ω-3 and ω-6 Fatty Acid Supplementation May Reduce Autism Symptoms Based on Parent Report in Preterm Toddlers. J Nutr. 2018 Feb 1;148(2):227-235.

[2] Boone KM. et al. Omega-3 and -6 fatty acid supplementation and sensory processing in toddlers with ASD symptomology born preterm: A randomized controlled trial. Early Hum Dev. 2017 Dec;115:64-70.

[3] Sheppard KW. et al. Effect of Omega-3 and -6 Supplementation on Language in Preterm Toddlers Exhibiting Autism Spectrum Disorder Symptoms. J Autism Dev Disord. 2017 Nov;47(11):3358-3369.

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Propranolol and autism?

"This review indicates that propranolol holds promise for EBAD [emotional, behavioural and autonomic dysregulation] and cognitive performance in ASD [autism spectrum disorder]."

So said the findings reported by Ilyas Sagar-Ouriaghli and colleagues [1] looking at the existing peer-reviewed (and conference) literature mentioning the use of the beta-blocker called propranolol in the context of autism. Beta-blockers, as I mentioned in a post some years back (see here), seem to have found quite an off-label following for a variety of diagnoses/conditions/states outside of their intended indications. Autism or autism spectrum disorder (ASD) seems to rank as one such following.

Analysing some 16 reports including "single-dose clinical trials" and more "case series and single case reports" with mention of autism, authors concluded that - so far - the research and clinical future for propranolol looks quite bright. Certainly bright enough for them to recommend further "good quality clinical trials, randomised controlled trials" to look at effectiveness and also important issues such as side-effects. I might add that included in the long list of potential drug interactions mentioned alongside propranolol, several medicines that tend to turn up with some regularity with 'some' autism in mind - the antipsychotics - need to be kept in mind and particularly the risk of hypotension from combined use.

I want to bring to your attention a few of the studies that currently populate the 'propranolol and autism' literature. The name Rachel Zamzow appears quite a bit in light of studies such as this one [2] and this one [3]. These and other results suggest that 'effects' might be quite widespread and the focus should perhaps be wide when it comes to further investigations of this particular medicine or possibly, some of its relations.

'Promising' is a word to springs to mind at the moment. We'll have to see if it endures. Oh, and then there is the questions of 'how and why' propranolol 'works' for some autism...

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[1] Sagar-Ouriaghli I. et al. Propranolol for treating emotional, behavioural, autonomic dysregulation in children and adolescents with autism spectrum disorders. J Psychopharmacol. 2018 Feb 1:269881118756245.

[2] Zamzow RM. et al. Effects of propranolol on conversational reciprocity in autism spectrum disorder: a pilot, double-blind, single-dose psychopharmacological challenge study. Psychopharmacology (Berl). 2016 Apr;233(7):1171-8.

[3] Zamzow RM. et al. Effects of acute beta-adrenergic antagonism on verbal problem solving in autism spectrum disorder and exploration of treatment response markers. J Clin Exp Neuropsychol. 2017 Aug;39(6):596-606.

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Vaccination rates and patterns among kids with autism and their siblings (again)

The publication of the paper by Ousseny Zerbo and colleagues [1] garnered some media headlines insofar as their conclusion that: "Children with ASD [autism spectrum disorder] and their younger siblings were undervaccinated compared with the general population."

Drawing on data from "6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink" researchers looked at immunisation status for over 3700 children diagnosed with ASD and over half a million kids not diagnosed with autism alongside their respective younger siblings. They were specifically looking at the proportion of children who "received all of their vaccine doses according to ACIP [Advisory Committee on Immunization Practices] recommendations."

Results: "For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD." Vaccination rates were also significantly lower for younger siblings of those with autism too. Further discussion of the details of the Zerbo results can be seen here.

Although headline grabbing, this research topic - vaccination rates among children with autism and their siblings - is by no means a new one (see here and see here for examples). The Gena Glickman findings [2] published last year (2017) for example, did not attract the same degree of media attention but highlighted how (a) parents of children diagnosed with autism were extremely vaccine compliant when it came to their earlier born children, and (b) "Families with children who had autism spectrum disorder were less likely to vaccinate subsequent children." To quote from some of the media on the latest Zerbo paper: ""We did not look at vaccination rates before the children were diagnosed with autism," Zerbo noted"; a pretty important omission by all accounts.

What's then also missing from the current data in this area? Well, the question of why - why are children with autism and their siblings less likely to be vaccinated - is a rather glaring omission, and one that stretches into other age ranges [3] too. Yes, it's easy to say that 'fear of the autism-vaccine link' is a primary reason for the undervaccination statistics, particularly with the data on age being a factor in the Zerbo findings and despite the 'too many too soon' argument having some strong evidence against it (see here). But... as per the Glickman and other data, many parents are/were extremely vaccine compliant when it came to earlier born children. If they were going to have long-standing fears about vaccination and indeed, act upon those fears, I would have thought that they would have influenced vaccination behaviour across all their children and not just as and when autism was diagnosed in a family member. Neither do I give much [research-based] credence to the idea that parents of children with autism are somehow over-represented among the so-called 'anti-vaxxer' groups (see here); not that is, as being a long-standing issue.

Glickman et al do provide another possible explanation in their study results that: "changes in vaccination behavior may relate to adverse reactions to vaccine" in their cohort. A sort of once bitten, twice shy sentiment if you like *might* potentially be in action, which kinda makes more sense. I know this takes us down a rather uncomfortable path in that, whilst acknowledging that vaccines represent an important cornerstone of modern healthcare (yes, they do), they are not somehow magically without side-effects for some. Hackles are bound to be raised by such utterances; despite some potentially important clues already appearing in the peer-reviewed research literature [4] relevant to this topic. But without even attempting to try and answer such 'why' questions, we are left with a fairly large number of children who "are at increased risk of vaccine-preventable diseases" with no real solutions in sight for protecting their health and/or the health of the wider population.

Answers are therefore required and required quickly. The simplest and perhaps most logical solution I can see would be to go and ask parents/primary caregivers, under scientifically controlled study, why their children are undervaccinated; perhaps building on important work such as that by Hilton and colleagues [5]. There is the issue of recall to overcome (see here) and I'm sure the range of answers is going to be long and complicated in relation to undervaccination. Armed however, with such answers or at least clues from the parents/caregivers themselves and not just 'speculation', science and policy can perhaps then start to move things forward to further protect the health of all concerned. Hopefully also, such knowledge can be used to chip away at yet another important health inequality that seems to follow a diagnosis of autism throughout the lifespan (see here)...

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[1] Zerbo O. et al. Vaccination Patterns in Children After Autism Spectrum Disorder Diagnosis and in Their Younger Siblings. JAMA Pediatrics. 2018. Mar 26.

[2] Glickman G. et al. Vaccination Rates among Younger Siblings of Children with Autism. N Engl J Med. 2017 Sep 14;377(11):1099-1101.

[3] Filliter JH. et al. The next vaccine-autism question: Are school-aged youth with autism spectrum disorder undervaccinated and, if so, why? Paediatr Child Health. 2017 Aug;22(5):285-287.

[4] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[5] Hilton S. et al. MMR: marginalised, misrepresented and rejected? Autism: a focus group study. Archives of Disease in Childhood. 2007;92(4):322-327.

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Is early adolescent physical activity protective against later "chronic disabling fatigue"?

TIE fighter crossing the moon?

One particular detail in the recent paper by Simon Collin and colleagues [1] (open-access available here) talking about higher physical activity potentially being *protective* against subsequent adolescent 'fatigue', immediately caught my attention: "CDF [chronic disabling fatigue], a proxy for clinically diagnosed CFS/ME [chronic fatigue syndrome/myalgic encephalomyelitis]."

This is not the first time that this authorship group have used the term CDF and seen it's use 'merging' into meaning something close to or like CFS/ME (see here) and I doubt that it will be the last. Far be it from me to put myself forward as some sort of expert on diagnosing CFS/ME - I'm not - but CDF as representing a proxy for CFS/ME does not mean that CDF is the same as CFS/ME. And that's also bearing in mind that the issue of diagnosis of CFS/ME is still the topic of lots and lots of (continuing) discussion (see here)...

Keeping all that in mind, I do want to briefly talk about the new paper from Collin et al. The Avon Longitudinal Study of Parents and Children (ALSPAC) was, once again, the data source for their findings, and yet again, this was a study looking at adolescent and young adults. The aim of the study was to: "investigate whether levels and patterns of physical activity at age 11 years are associated with ‘chronic disabling fatigue’... at ages 13 and 16 years."

A strength of the Collin research is that authors looked at more than just subjective 'how much exercise did you do' questionnaire via their use of actigraphy. So: "All ALSPAC children who attended research clinics at age 11 years... were asked to wear an Actigraph AM7164 2.2 accelerometer (Actigraph LLC, Fort Walton Beach, Florida, USA) for 7 days." Further: "Data from children who had worn the accelerometer for at least 10 hours a day for at least 3 days were considered valid" and from such data various calculations were made in terms of sedentary time, total physical activity and the proportion of "moderate-to-vigorous physical activity." Such data was analysed in the context of CDF measurements at ages 13 and 16 using methods previously described in their other research [2].

Results: "Children who had CDF at age 13 years had lower levels of physical activity at age 11 years." The authors translated this into various stats including: "For each additional 1% of monitored time spent in moderate-to-vigorous activity, the odds of CDF were reduced by 16%" and "Each additional hour of sedentary time per day was associated with 35% higher odds of CDF."

But just before anyone thinks that pushing children off the sofa and into some moderate-to-vigorous exercise in early adolescence is some kind of magical shield protecting against CDF, a few words of caution from the authors might also be important. Namely: "the lower levels of physical activity at age 11 years [may be] a consequence of chronic fatigue which is already present or developing and which persists until the child is 13 years old." In other words, there could be an alternative explanation for the lower physical activity (PA) levels *causing* chronic disabling fatigue; those who didn't do much PA were already developing and manifesting CDF...

"The main limitation of our study is that children were not assessed by a doctor, which is why we describe our outcome as ‘chronic disabling fatigue’, a proxy for CFS/ME." Yup, no arguments there; also reiterating why one needs to be quite careful about the terminology used around CFS/ME. The suggestions that lower physical activity might show a *correlation* with CDF also needs to be carefully handled given some continuing conversations about 'exercise therapy' in the context of CFS/ME (see here) and in particular, what various patients have been reporting from interventions in this area (see here)...

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[1] Collin SM. et al. Physical activity at age 11 years and chronic disabling fatigue at ages 13 and 16 years in a UK birth cohort. Arch Dis Child. 2018 Jan 30. pii: archdischild-2017-314138.

[2] Norris T. et al. Natural course of chronic fatigue syndrome/myalgic encephalomyelitis in adolescents. Arch Dis Child. 2017 Jun;102(6):522-528.

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"not consistent with the hypothesis that ADHD medication increases risk of seizures"

ADHD mentioned in the title of this post - "not consistent with the hypothesis that ADHD medication increases risk of seizures" - refers to attention-deficit hyperactivity disorder; said quote coming from the paper by Kelsey Wiggs and colleagues [1].

Wiggs et al report findings based on the premise that: "Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of seizures" (see here) and specifically the question of whether or not "ADHD medication treatment increases risk among patients with and without preexisting seizures."

To try and answer their research question, authors relied on data from a sample including over 800,000 people diagnosed with ADHD "who had prescribed drug claims from the Truven Health MarketScan Commercial Claims and Encounters databases." I have talked about other research utilising these databases before on this blog (see here), once again looking at ADHD medicines and also including some of the authors listed on the Wiggs paper.

Wiggs reports results that were primarily two-fold: (a) assessing "overall risk of seizures among patients with ADHD" and (b) "odds of seizure events during months when a patient with ADHD received ADHD medication compared with when the same individual did not, while adjusting for antiepileptic medications."

Result: yes, yet again a diagnosis of ADHD did seem to *correlate* with a higher odds for seizure episodes when compared with (non-ADHD) controls. Similarly, use of ADHD medicines seemed to *correlate* with a lower odds of seizures, both in those with a history of seizures and those without.

With the requirement for further investigation, this are interesting findings. I note there has been previous peer-reviewed discussion on the potential risk(s) of seizure attached to certain medicines indicated for ADHD [2]. It's been a bit of a mixed bag in terms of any possible association or not, but allowing for individual medicines, the research has generally observed no significant effect of such medicines on seizure risk in cases of ADHD. Generally-speaking. Wiggs and colleagues seem to go one stage further on from suggesting no effect to observing something of a potential protective effect from such medicines in relation to seizure risk in cases of ADHD. If replicated, such findings could be rather important...

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[1] Wiggs KK. et al. Attention-deficit/hyperactivity disorder medication and seizures. Neurology. 2018 Feb 23. pii: 10.1212/WNL.0000000000005213.

[2] McAfee AT. et al. A cohort study of the risk of seizures in a pediatric population treated with atomoxetine or stimulant medications. Pharmacoepidemiol Drug Saf. 2013 Apr;22(4):386-93.

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ATEC (Autism Treatment Evaluation Checklist) still rising

The paper by Shreyas Mahapatra and colleagues [1] (open-access available here) provides the blogging fodder today and some important data relating to an important instrument in autism research circles: the Autism Treatment Evaluation Checklist (ATEC).

I'm a fan of the ATEC. Not only because it was one of the first instruments specifically devised to look at measuring changes to autistic symptom severity but also because it's freely available to use. No royalty payments required; free and open for anyone and everyone to use.

Devised by the late Bernard Rimland and Stephen Edelson of the Autism Research Institute (ARI), the ATEC was born out of the need for researchers and non-researchers alike to measure how autism / autistic features can, on some occasions, fluctuate, specifically in response to intervention. It's perhaps no coincidence that the ARI also holds some important data on parent ratings of how useful certain interventions were reported to be when it comes to autism (see here). Although probably not loved by all, such ratings - derived from those who probably know their children best - provide an important rough-and-ready measure of what intervention options perhaps need a little more investigation and which should probably be avoided. The fact that they're based on the reports of over 27,000 parents also helps matters too...

Anyhow, one thing that did seem to be missing from the increasing interest (see here and see here) in the ATEC is data on "the norms on the longitudinal changes in ATEC in the “treatment as usual population." The Mahapatra paper sought to partially remedy that situation based on an "observational cohort who voluntarily completed ATEC evaluations over the period of four years from 2013 to 2017."

Based on observations for some 2600-odd children (mostly males) all of whom scored 20 or above on the ATEC total score, researchers provided some important baseline data. They for example, show how total ATEC scores, a measure of autism severity, seem to change / fluctuate as children age (see Table 1). They also show how subscale scores - Speech / Language / Communication, Sociability, Sensory / Cognitive awareness, Health / Physical / Behavior - move around as a function of 'starting position' and age too. In short, it provides researchers and non-researchers alike some data on what might be expected to happen to the presentation of autism based on ATEC scoring.

But it's not by any means a perfect start. As the authors point out: "In the selection of participants for inclusion in this study, a baseline of ASD [autism spectrum disorder] diagnosis could not be established as child’s diagnosis is not part of ATEC questionnaire" indicating that not every child who participated might have had a diagnosis of autism or ASD. There were other methodological 'issues' too that need to be kept in mind.

I'm still however happy to talk about the ATEC and its potential usefulness to lots more autism studies aside from that already discussed in the peer-reviewed literature. Assuming also that ATEC has some overlap with other more standardised measures used in autism research [2] I think the future continues to look rather rosy for this rather important instrument.

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[1] Mahapatra S. et al. Autism Treatment Evaluation Checklist (ATEC) Norms: A "Growth Chart" for ATEC Score Changes as a Function of Age. Children (Basel). 2018 Feb 16;5(2). pii: E25.

[2] Geier DA. et al. A Comparison of the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS) for the Quantitative Evaluation of Autism. J Ment Health Res Intellect Disabil. 2013 Oct;6(4):255-267.

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What do parents/caregivers want from medication for ADHD among offspring?

I know the title of this post - "What do parents/caregivers want from medication for ADHD among offspring?" - might seem a little obvious but I don't see such research as meaningless. Indeed, I was drawn to blogging about the paper from Melissa Ross and colleagues [1] precisely because it is obvious that parents/caregivers have a vested interest in the management of offspring issues with attention-deficit hyperactivity disorder (ADHD) and as such, their views should and do count.

Medicines indicated for treating/managing ADHD have cropped up on this blog before (see here for example). Allowing for the fact that such medicines are like all medicines insofar as having a cost-benefit ratio to consider, the medicines typically indicated for ADHD can literally be life-changing (see here) and indeed on occasion, life-saving (see here). The key I always think is good medicines management and regular clinical input in terms of monitoring for efficacy and any unwanted side-effects.

Ross et al talked to approaching 200 parents/caregivers of children and young adults diagnosed with ADHD, asking them to consider various issues including "desired improvements in their child's ADHD" in light of quite a bit of ADHD medication use. We are told that: "A validated Best-Worst Scaling instrument assessed priorities among 16 concerns when considering ADHD medication."

Results: white mothers of children with ADHD formed the majority voice among participants, and they listed some important priorities for their children. "Overall, the most important ADHD medication concerns were the child becoming a successful adult..., school behavior improvements..., and better grades." I also cast a 'good for you' smile over another observation: "Others thinking badly of the child was a significantly less important concern" as I hark back to other work on another label where 'negative judgements' have been mentioned (see here).

'Nuff said.

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[1] Ross M. et al. Caregivers' Priorities and Observed Outcomes of Attention-Deficit Hyperactivity Disorder Medication for Their Children. J Dev Behav Pediatr. 2018 Feb/Mar;39(2):93-100.

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PACE trial for chronic fatigue syndrome (still) being put through its paces

'Chronic fatigue trial results 'not robust', new study says' went the BBC headline reporting on the findings published by Carolyn Wilshire and colleagues [1].

Authors report peer-reviewed results following their re-examining various aspects of the PACE trial - "pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation" - with regards to chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME).

This latest research and accompanying media attention continues a quite long-running saga (see here) known in some quarters as 'PACE-gate' (see here) where questions have been raised about a premier study that was "designed to examine the effectiveness of graded exercise therapy (GET) and cognitive behavioural therapy (CBT)" in relation to CFS/ME. Quite a few of those interventions are set within the still unfortunately believed idea that CFS/ME represents a 'biopsychosocial' illness (see here) and that 'changing mindsets and/or behaviour' will magically transform peoples lives. I say 'still unfortunately believed' because patient experiences do not seemingly match some of the peer-reviewed science in this area (see here).

The various twists-and-turns (see here and see here) around the PACE trial have involved bigger discussions about trial design, outcome threshold 'issues' and even the accessibility of research study data. Indeed, the Information Commissioner here in Blighty has even played a hand in the PACE saga (see here) leading to some rather messy and very public arguments.

The paper by Wilshire et al continues a theme from this research group re-examining the PACE trial protocols and findings. It encompasses various elements in terms of definitions of 'overall improvement' and even 'recovery' (see here) between 'specified in trial protocol' and 'used in published reports'. Wilshire and colleagues report: "Our findings suggest that, had the investigators stuck to their original primary outcome measure, the outcomes would have appeared much less impressive."

Insofar as recovery rates - other work [2] related to the original PACE trial paper had indicated some impressive recovery rates following CBT and/or GET - Wilshire has more things to say here too. So: "when recovery rates were calculated using the definition specified in the published protocol, these were extremely low across the board, and not significantly greater in the CBT or GET groups than in the Control group." It might seem like common-sense to know what recovery should look like when it comes to CFS/ME, but again, the waters have been continually muddied (see here).

"Some notable strengths of the PACE study included the large sample size..., the random allocation of patients to treatment arms, the use of a well-formulated protocol to minimise drop-outs, and the reporting of the full CONSORT trial profile (including detailed information about missing data)." Wilshire et al illustrate how the PACE trial was, initially, a good piece of science from a methodological point of view, but: "the design, analysis and reporting of the results introduced some significant biases."

And now it may be time to move on: "The time has come to look elsewhere for effective treatments." CBT and/or GET are still the topics of study when it comes to ME/CFS (see here and see here) but are seemingly finding it more and more difficult to find acceptance. The recent news that NICE are looking to update their guidance on CFS/ME in light of 'changes' made by other official bodies (see here) and some significant patient (and political) power, reflect an increasingly changing mood. An increasing realisation that talking and exercise therapies might not be the best treatment options for a somatic condition that has the propensity to *significantly* drain both health and other aspects of quality of life (see here).

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[1] Wilshire CE. et al. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology. 2018; 6: 6.

[2] White PD. et al. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35.

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On mitochondrial DNA (mtDNA) changes and autism

Mitochondrial issues accompanying some diagnoses of autism have quite a bit of peer-reviewed research backing (see here for example). Not for everyone, but for some people diagnosed with an autism spectrum disorder (ASD), there seems to be something afoot with regards to these 'powerhouses of the cell' that could well impact on various aspects of their lives [1]. Indeed, keep that paper from Poling et al [1] in mind...

Although by no means an expert on mitochondrial issues in any context, I believe that there are a few ways in which mitochondrial dysfunction can manifest. It can present as a secondary disorder for example (see here), where some acquired biochemistry (non-genetic) provides some of the 'answers'. Or it can present as a primary mitochondrial disorder, a genetic condition "confirmed by a known or indisputably pathogenic mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutation" [2], where issues in the genetic code of mitochondria are present.

The recent findings reported by Noémi Ágnes Varga and colleagues [3] focused on that latter route looking at issues with mtDNA in the context of autism. They turned up some rather interesting results...

So: "The aim of the present study was to investigate the presence of the most common pathogenic mtDNA alterations in patients with ASD." Researchers screened 60 children with autism and 60 not-autism controls. One detail stuck out when it came to those controls: "Our control group for mtDNA screening consisted of 60 European adults (26 females and 34 males, median age = 28 years, IQR = 13.75) selected from our biobank." Compared with those participants diagnosed with autism, they were quite a bit older (median age = 7 years vs. median age  = 28 years) and indeed, the gender ratios were a little bit more balanced.

Anyhow: "Mitochondrial deletions were identified in 16.6% (10/60) of our patients with ASD." OK, 'patients' is not exactly the word I would use for participation in such a research project but that shouldn't distract from the findings. Varga et al also provide some further insights into those 10 'participants' with a diagnosis of autism and mtDNA deletion(s) which turned up some other interesting details, such as the finding that various other symptoms presented alongside autism. Quite a few of them were connected to muscle and movement functions (limb and truncal ataxia, hypotonia, dyspraxia) which ties into other independent findings [4]. I also noted the words 'gluten sensitivity' were mentioned in one case, which is guaranteed to perk my professional interest (see here) although I'm still a little unsure of whether this connected to mtDNA issues or not.

Another set of potentially important details were also observed by researchers when comparing those with autism with and without mtDNA deletion(s). Keeping in mind the small numbers falling into that autism with mtDNA deletion(s) category, developmental regression seemed to be an important facet of the clinical profile of this group. Regression of previously acquired skills is something else I've talked about quite a bit on this blog with regards to autism (see here and see here for examples). Going back to that paper by Jon Poling and colleagues [1] that I told you to keep in mind, it's interesting to note the overlap of regression reported by them and also reported by Varga in the context of mitochondrial disorder. And this isn't the only occasion that regression and mitochondrial issues have been talked about in the same breath as autism [5] and even with other potentially important clinical indicators [6]. Correlation is not necessarily causation but...

There are quite a few other details listed in the Varga paper that I'd encourage readers to pursue but I think I've gone on enough about this topic for now. It, yet again, appears that a diagnosis of autism is protective of nothing when it comes to other conditions/diseases/symptoms/labels appearing and perhaps implies that preferential screening for mitochondrial disorder should be more commonplace than it is as and when autism is diagnosed. I'm also inclined to draw your attention to other clinical labels where mitochondrial issues might be relevant for some (see here) albeit not always with genetics in mind (see here). How perhaps investigations need to be carried out looking at any possible intersection between *some* autism and something like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (see here) for example, also in light of other important data (see here). Indeed, I'll be coming to the findings reported by Bilevicute-Ljunger and colleagues [7] on this topic quite soon in a separate post...

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[1] Poling JS. et al. Developmental Regression and Mitochondrial Dysfunction in a Child With Autism. J Child Neurology. 2006;21(2):170-172.

[2] Niyazov DM. et al. Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment. Mol Syndromol. 2016 Jul;7(3):122-37.

[3] Varga NA. et al. Mitochondrial dysfunction and autism: comprehensive genetic analyses of children with autism and mtDNA deletion. Behavioral and Brain Functions. 2018. 14: 4.

[4] Ghaoui R. & Sue CM. Movement disorders in mitochondrial disease. J Neurology. 2018. Jan 6.

[5] Rossignol DA. & Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012 Mar;17(3):290-314.

[6] Shoffner J. et al. Fever plus mitochondrial disease could be risk factors for autistic regression. J Child Neurol. 2010 Apr;25(4):429-34.

[7] Bilevicute-Ljunger. I. et al. Patients with chronic fatigue syndrome do not score higher on the Autism-apectrum quotient than healthy controls: comparison with autism spectrum disorder. Scandinavian Journal of Psychology. 2018.

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Autistic traits + borderline personality disorder traits = enhanced risk of suicide ideation?

Following some quite recent discussions on this blog about how autism-related dimensions are not necessarily always autism-specific dimensions (see here) in the context of Borderline Personality Disorder (BPD), I'm talking today about the findings reported by Henri Chabrol & Patrick Raynal [1].

They detail some still emerging evidence that, alongside "significant comorbidity between ASD [autism spectrum disorder] and BPD", there could be some rather important outcomes arising from possessing both significant autistic traits and borderline personality disorder traits in the more general population when it comes to risk of suicide ideation. Further, that such data could also cast some light on that important issue for both clinical conditions and contribute to the pressing need to reduce any excess risk(s).

I've covered the issue of suicide - ideation, attempted and completion - on this blog a few times (see here). It's a topic that requires careful handling (see here) and something that, in respect of the core blogging material here, requires important continued attention (see here and see here).

Chabrol & Raynal detail results following the self-report of several parameters: autistic and BPD traits, thoughts of suicide and "depressive symptomatology" in a cohort of college students (N=474). They reported that, whilst BPD traits and autistic traits were only "weakly correlated", those participants who presented with both high BPD and high autistic traits (approaching 20% of their total sample) were the ones who expressed "the highest level of suicidal ideation."

Bearing in mind that this was research carried out with a 'non-clinical' population and a population that might not be necessarily completely representative of everyone else, additional investigations are warranted. Whether for example, the clinical combination of autism and BPD might elevate the risk of suicide ideation or beyond is one issue to be explored, particularly given research observing that suicide risk is not unknown to the diagnosis of BPD. I might also add that given the possibility of even greater complexity in behavioural/psychiatric presentation [2] coinciding with other observations in relation to some autism (see here), quite a wide research view might need to be taken. This coinciding with more and more evidence to suggest that autism is not typically a stand-alone diagnosis (see here).

And if anyone needs to talk to someone, organisations like the Samaritans are only an email or phone call away...

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[1] Chabrol H. & Raynal P. The co-occurrence of autistic traits and borderline personality disorder traits is associated to increased suicidal ideation in nonclinical young adults. Comprehensive Psychiatry. 2018. Feb 15.

[2] Fan AH. & Hassell J. Bipolar disorder and comorbid personality psychopathology: a review of the literature. J Clin Psychiatry. 2008 Nov;69(11):1794-803.

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"given that 81.6% of the children diagnosed with ASD had IQs below 40"

The quote titling this post - "given that 81.6% of the children diagnosed with ASD [autism spectrum disorder] had IQs below 40" - was part and parcel of the findings published by Zhijuan Jin and colleagues [1] who set about estimating the prevalence of autism or ASD among children resident in Shanghai, China.

This is not the first time that research groups have set out to determine the estimated prevalence of autism at a city / region / countrywide level in China [2], but does, I think, mark the first time that said prevalence estimates have been based on the DSM-5 description of autism (well, almost the first time [3]).

Looking at a population of some 75,000 children resident in Shanghai and aged between 3-12 years old, details of a two-stage project are described this time around. Parents and teachers completed the Social Communication Questionnaire to identify those children who might be 'at-risk' for autism/ASD. Those who were picked up as being 'at risk', were then subject to some rather more comprehensive assessment based on the use of DSM-5, of which just over 200 children were "identified as ASD cases." The estimated prevalence figure arrived at was 8.3 per 10,000 although the authors suspect that this is an underestimate...

But then back to that opening quote, and a quite a notable percentage of children diagnosed with autism who also presented with a low IQ classification. Bearing in mind the fact that there are differences in IQ ranges across different instruments, an IQ rating of 40 or below (age-adjusted) typically indicates quite a significant cognitive impairment or delay and is one facet of the diagnosis of learning (intellectual) disability. The observation from Jin et al that over 80% of their cohort could potentially be defined as such provides some important data on the combination of autism and learning disability (LD).

On previous blogging occasions when the topic of autism and LD has been discussed, the question of how prevalent is LD in autism has been a difficult one. On some occasions, the data has suggested that around 35% of children with autism have LD on the basis of IQ scores (see here). On other occasions, a figure nearer 70% has been implied (see here). The Jin data suggest that in their cohort, 70% may actually be quite a conservative estimate.

I would like to see more study on this topic. I'd like to know whether, seemingly like other ethnic groups, learning disability + autism is the more typical presentation when it comes to autism in Chinese children and how this plays out as children age into adulthood. I'd like to know whether the distinction between autism and social (pragmatic) communication disorder (SCD) noted in the DSM-5 exerted any effect on the Jin data. I'd like to know quite a bit more on this rather interesting area of investigation...

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[1] Jin Z. et al. Prevalence of DSM-5 Autism Spectrum Disorder Among School-Based Children Aged 3-12 Years in Shanghai, China. J Autism Dev Disord. 2018 Feb 16.

[2] Sun X. et al. Prevalence of autism in mainland China, Hong Kong and Taiwan: a systematic review and meta-analysis. Mol Autism. 2013 Apr 9;4(1):7.

[3] Jiang L. et al. Epidemiological investigation on autism spectrum disorders among preschool children in Shanghai. Zhonghua Liu Xing Bing Xue Za Zhi. 2015 Dec;36(12):1365-8.

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One more time... ADHD is over-represented in cases of epilepsy

"Among the 73 children with epilepsy, 23% (n = 17) had comorbid ADHD [attention-deficit hyperactivity disorder], of whom 59% (n = 10) had predominantly inattentive type, 35% (n = 6) combined type, and 6% (n = 1) predominantly hyperactive-impulsive type."

So said the findings reported by Anita Choudhary and colleagues [1] adding to an ever growing body of peer-reviewed research literature suggesting that a diagnosis of epilepsy may, for whatever reason(s), elevate the risk of ADHD being diagnosed or, at the very least, the symptoms of ADHD occurring (see here).

This time around, Choudhary et al focused on data derived from a children's neurology service where epilepsy was "defined as two or more unprovoked seizures occurring 24 hours apart after four weeks of age, with at least one epileptic seizure in the previous five years, regardless of AED [anti epileptic drug] treatment, based on International League Against Epilepsy definitions."

As per the opening sentence, some 73 children aged 6-12 years old met their study eligibility criteria; being part of a larger trial where data on behavioural comorbidity in the context of epilepsy had already been published [2]. Importantly for this latest study, the authors excluded those who "had an intellectual disability or comorbid chronic systemic disease" which seems to be rather relevant to the clinical picture emerging with regards to epilepsy in the context of a condition 'over-represented' in ADHD, autism (see here). Alongside a behavioural/psychiatric evaluation based first on parent/caregiver ratings and if required, followed up with a more professional consultation, researchers also carried out assessments related to cognitive functions and reviewed health records.

Aside from noting that ADHD seemed to be over-represented among their cohort with epilepsy, authors also talked about a couple of variables that also seemed to be important to the presentation of ADHD in those with epilepsy. So: "Children with both epilepsy and ADHD had lower IQ scores and were significantly less likely to be attending school, with epilepsy being the primary reason." That point about the presence of epilepsy *correlating* with lower IQ scores is not necessarily something prevalent across the research in this area, but some authors have talked about a "subgroup of about 10–25% of children that shows a clinically significant intellectual decline" [3] which could potentially be relevant.

Pertinent biological mechanisms crossing both epilepsy and ADHD? Well similar to the last blogging occasion, one has to mention that epilepsy does affect various brain functions (see here) so that is something to consider as also impacting the likelihood of ADHD. Whether this means affecting something structural or something like connectivity, we just don't know at present. I'm also minded to highlight the possibility of genetic overlaps too; drawing on work in autism where autism genes are not just genes for autism (see here) so one might consider a similar scenario pertained for at least some with the epilepsy-ADHD diagnostic combination...

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[1] Choudhary A. et al. Childhood epilepsy and ADHD comorbidity in an Indian tertiary medical center outpatient population. Sci Rep. 2018 Feb 8;8(1):2670.

[2] Choudhary A. et al. Behavioral comorbidity in children and adolescents with epilepsy. J Clin Neurosci. 2014 Aug;21(8):1337-40.

[3] Vingerhoets G. Cognitive effects of seizures. Seizure. 2006; 15: 221-226.

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"specificity for diagnosis was relatively low": the psychometric properties of autism diagnostic measures

The quote accompanying this fairly brief post - "specificity for diagnosis was relatively low" - comes from the findings reported by Sarah Wigham and colleagues [1] who undertook a systematic review of various "structured questionnaires and diagnostic measures" used in the assessment of autism in adults.

Their conclusions, based on some 20 studies identified in the current peer-reviewed literature, suggest that 'could do better' is a phrase best suited to various measures currently used to identify adults with autism, particularly in the context of an often complicated clinical picture (see here).

Similar things have already been discussed on this blog (see here for one example). In particular, how individual self-report 'are you autistic?' screening instruments whilst making good 'pop psychology' (see here) are absolutely no match for a thorough professional clinical assessment, save other important diagnoses/conditions being overlooked and going unmanaged (see here and see here). I know this puts the concept of 'self-diagnosis' as a result of the use of such instruments in some hot water, but as in many other branches of medicine and psychiatry, professionals and the assessments they conduct are there for a very good reason. Whether you can access such assessments in a timely fashion is an entirely different issue...

When I first tweeted about this paper being published, I emphasised one author on the Wigham paper in particular: Dr Tom Berney. The reasoning behind this was because of his involvement/link to research that has looked at how we identify adults with autism here in Blighty on the back of some headlines a few years back on estimating how many adults have autism here (see here). He, alongside some other notable authors who highlighted that '1% of adults with autism' figure, also talked about how some of the screening/assessment instruments used in that study weren't really cutting the epidemiological mustard [2]. It appears they might have been right.

So what lessons can be learned from this recent review? Well first, that whilst autism-related behavioural dimensions are vitally important to a diagnosis of autism, they are not universally specific to a diagnosis of autism, is important. Second is the need to perhaps move away from often very brief autism screening instruments that seem to provide a 'quick snapshot' to something rather more far-reaching and comprehensive. I know we all want a 'quick answer' that uses as few finite resources as possible, but sometimes, to get something right, you need to spend time and resources looking at it carefully. And diagnosing professionals also need to be mindful of notions of 'frank autism' too (see here). Finally, I'd like to re-emphasise that autism plus [3] does seem to be more typical these days, over autism appearing in some sort of diagnostic vacuum. As Wigham et al opine: "Robust autism spectrum disorder assessment tools specifically for use in adult diagnostic health services in the presence of co-occurring mental health and neurodevelopmental disorders are a research priority." Indeed they are.

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[1] Wigham S. et al. Psychometric properties of questionnaires and diagnostic measures for autism spectrum disorders in adults: A systematic review. Autism. 2018 Feb 1:1362361317748245.

[2] Brugha TS. et al. Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community. Psychol Med. 2012 Mar;42(3):647-56.

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Carefully: effect of SSRI use on "rating-scale-assessed suicidality in adults with depression"

I stress the word 'carefully' in the title of this post discussing the findings reported by Jakob Näslund and colleagues [1] because it covers the very sensitive idea that "selective serotonin reuptake inhibitors (SSRIs) have been claimed to elicit or aggravate suicidal ideation."

I think it's sensible to begin this post by stressing that (a) NO medical or clinical advice is given or intended on this blog, and (b) anyone with concerns about their taking this class of medicines really needs to speak to their physician BEFORE making any changes to their prescribed medication routine. I know that point (b) sounds like me giving medical / clinical advice but it's common sense to talk to your medical professional first who's spent years studying and probably years practising medicine, rather than tinker around yourself...

There is always a balancing act to consider when discussing research such as this. A medicine indicated for various clinical conditions, that is taken by many, many people, and quite successfully treating / treated (nay, very successfully [2]) a condition that can, without treatment, have life-limiting consequences. No-one wants to rock the boat and scare or deter people from accessing such a treatment. At the same time however, one needs to know everything about that medicine; not least whether for some, there may be side-effects to possibly consider...

It's been a quite a long running saga talking about the possible additional effects of SSRI use for some (see here). It's drawn heavily on often harrowing individual stories and perspectives and not also been helped by the seeming (in)actions of some of the manufacturers of such medicines (see here). Näslund et al decided to approach this delicate topic from the point of view of analysing "the effect of [SSRI] treatment on rating-scale-assessed suicidal ideation in individual patients." This is distinct from other work that has focused on actual suicides or "suicide-related adverse events" that have been carried out before. The authors suggested that their approach might have the advantages of measuring the "net influence of treatment on suicidality at a group level" as well as the ability to "detect individual cases of emergence or aggravation of suicidal ideation." To this end, scores on the Hamilton Rating Scale for Depression (HRSD) particularly focused on "item 3 of the HRSD" covering suicidal ideation/attempts, was a core feature of their study covering "young adults (18–24) (n = 537) and adults (≥25) (n = 7725)." Said participants were derived from "all industry-sponsored, HRSD-based, FDA-registered placebo-controlled studies undertaken to explore the effects of citalopram, paroxetine or sertraline in major depression in adults."

Results: "In patients above the age of 24, SSRIs were found to reduce the mean rating of the HRSD suicidality item from week 1 until study end-point and also to reduce the risk for aggravation of suicidal ideation and emergent suicidal behaviour." This is very good news. It provides "strong support for the view that the net effect of SSRI treatment is beneficial rather than harmful" when it comes to suicide ideation/contemplation bearing in mind the specific focus on on item on the HRSD. I will again link to the recent findings by Cipriani and colleagues [2] reporting that: "All antidepressants were more efficacious than placebo in adults with major depressive disorder." It doesn't, as Näslund et al suggest, rule out rare cases of 'adverse effects', but does suggest that any such extreme side-effects are not likely to be encountered by most people who take such medicines.

When however it came to those younger adults (aged 18-24 years), the results were a little less straight-forward. So: "In young adults, those given an SSRI were at enhanced risk for worsening of suicidal ideation (in the unadjusted analysis) or emergent suicidality (loose but not strict definition) during the late (weeks 3–6) but not the early phase (weeks 1–2) of treatment." You'll see from the number of brackets used in that last quote that the authors provide some caveats to such findings; but this shouldn't take away from the trends observed. Indeed, bearing in mind such findings and also that "both SSRIs and placebo resulted in an end-point rating of suicidality equal to that observed in adults given an SSRI and lower than that observed in adults given placebo" you kinda get the impression that further investigations are needed to ascertain for example, whether depression and/or suicidality in the 25 and overs is somehow 'different' from depression in the younger age group. At least, different insofar as what treatment choices might be primarily made available. No, I'm not saying that this is evidence enough that SSRIs should have some sort of age restriction, just that cost/benefit ratios might perhaps have to be a little more 'age-sensitive' as well as individual-sensitive.

And, if anyone needs someone to talk to, there are resources available.

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[1] Näslund J. et al. Effects of selective serotonin reuptake inhibitors on rating-scale-assessed suicidality in adults with depression. Br J Psychiatry. 2018 Feb 5:1-7.

[2] Cipriani A. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018. Feb 21.

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Childhood ADHD and vitamin D meta-analysed

The results of the systematic review and meta-analysis published by Yadollah Khoshbakht and colleagues [1] (open-access available here) make for interesting, if not totally unexpected, reading.

Covering the existing peer-reviewed research literature (up to June 2017) on the topic of vitamin D status and attention-deficit hyperactivity disorder (ADHD), researchers concluded that: "The present review provides evidence supporting the relation between vitamin D deficiency and ADHD."

Vitamin D and ADHD is a topic already covered on this blog (see here). The general direction of findings so far have kinda mirrored that seen in other developmental diagnoses such as autism, insofar as vitamin D deficiency / insufficiency as measured by concentrations of 25-hydroxyvitamin D, tending to be pretty over-represented alongside the label (see here). It's perhaps also pertinent to mention that the diagnostic combination of autism and ADHD seems to be quite widespread (see here); particularly in these days of ESSENCE or autism plus (see here). This could very well have a bearing on any observations obtained as per other examples in other areas (see here).

Anyhow...

Khoshbakht et al looked at various studies and aspects of studies as part of their analyses. They also pre-registered their intention to undertake some research on vitamin D and ADHD as per a PROSPERO entry (see here) containing some details on hows-and-whys.

From various 'retrieved articles' numbering in the thousands, authors eventually settled on 13 studies ("9 case-control or cross-sectional studies and 4 prospective studies") that examined "the association between vitamin D concentration and the risk of ADHD." The final cumulative study participant number was not bad at all: "3484 patients with ADHD (2183 from the case-control and cross-sectional studies, 1301 from the prospective studies) and 11,837 healthy children (8151 from the case-control and cross-sectional studies, 3686 from the prospective studies) aged between 5 and 18 y were included." Authors also noted that various methods were used to measure 25-hydroxyvitamin D - 25(OH)D - ranging from the gold-standard that is liquid chromatography tandem mass spectrometry (LC-MS/MS) to something perhaps a little less accurate e.g. high-performance liquid chromatography (HPLC) minus the mass spec bit. All-in-all however, most studies were judged to be of moderate or high quality.

Results: "we found modest but significant lower serum vitamin D concentrations in children and adolescents with ADHD compared with healthy control subjects." Based on 9 studies where "the mean ± SD vitamin D concentrations in subjects with and without ADHD" was reported, authors concluded that "children with ADHD had 6.93 ng/mL lower serum vitamin D concentrations compared with healthy controls." And that wasn't all, as authors also looked at prospective studies where for example, vitamin D was measured in maternal serum or umbilical cord blood and then mapped onto risk of ADHD in offspring. With this type of study in mind, they observed that: "lower maternal or cord serum vitamin D concentrations increase the risk of developing ADHD in childhood or adolescence by 40%" albeit with some statistical caveats.

Khoshbakht and colleagues provide some possible pointers about how vitamin D *might* influence the pathophysiology of ADHD. They for example, mention an enzyme that I've been pretty interested in down the years - tryptophan hydroxylase 2 (TPH2) - and how the starting gene for this enzyme has been both linked to ADHD [2] in some studies (but not others). Further: "The TPH2 gene is activated by vitamin D hormone through its vitamin D response element." Personally, I find this interesting but not intellectually satisfying enough to provide an authoritative explanation for any effects of vitamin D deficiency on ADHD. Going also back to the vitamin D story with autism in mind, I'd like to think lessons could be learned about more particular vitamin D genetics (see here) and what role they might also play with regards to ADHD too. There are no doubt other pertinent mechanisms too.

There is still more research to do when it comes to vitamin D and ADHD of that there is no doubt. Again, going back to the relationship between ADHD and autism, I'm wondering whether more focus needs to be on this diagnostic combination (and perhaps other overlaps too) to ascertain whether one condition / label over another shows any stronger relationship with vitamin D levels. In light also of other meta-analysis work talking about lower vitamin D levels being linked to 'poorer cognition' (see here) for example, one might also reasonably suggest that an even broader research agenda might need to be followed.

And then there's the question of supplementation (see here) to consider and whether it may / may not do more than just raise vitamin D levels [3]? Oh wait, and there's more [4]...

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[1] Khoshbakht Y. et al. Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies. Adv Nutr. 2018 Jan 1;9(1):9-20.

[2] Park TW. et al. Association between TPH2 gene polymorphisms and attention deficit hyperactivity disorder in Korean children. Genet Test Mol Biomarkers. 2013 Apr;17(4):301-6.

[3] Elshorbagy HH. et al. The Impact of Vitamin D Supplementation on Attention-Deficit Hyperactivity Disorder in Children. Ann Pharmacother. 2018 Feb 1:1060028018759471.

[4] Sahin N. et al. Vitamin D and vitamin D receptor levels in children with attention-deficit/hyperactivity disorder. Neuropsychiatr Dis Treat. 2018 Feb 19;14:581-585.

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