"Suicidal spectrum behaviors" and ADHD meta-analysed

"Awareness of the association between ADHD [attention-deficit hyperactivity disorder] and SSBs [suicidal spectrum behaviors] should contribute to more effectively prevent SSBs."

That was the conclusion reached in the study published by Mathilde Septier and colleagues [1] and the results of their "first meta-analysis on the association between ADHD and SSBs taking possible confounders into account." Their systematic review and meta-analysis was preregistered (see here) so we knew it would be coming.

Starting with nearly 3000 references, the available data was whittled down to just over 50 studies. The data were analysed and boiled down to reveal "a significant association between ADHD and suicidal attempts..., suicidal ideations..., suicidal plans..., and completed suicide."

What's more to say? Well such results although stark are not completely unexpected given what has already been discussed on this blog on this topic (see here and see here and see here). They serve to confirm that a diagnosis of ADHD (or even the presentation of subclinical ADHD symptoms?) should really set in motion some preferential screening for suicidal spectrum behaviours and appropriate support offered as and when detected. Minus any sweeping generalisations, such results also invite further inquiry into how certain intervention options indicated for ADHD *might* also affect risk of suicidality in the context of ADHD (see here).

If you need someone to talk to, there are organisations out there...

----------

[1] Septier M. et al. Association between suicidal spectrum behaviors and Attention-Deficit/Hyperactivity Disorder: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2019 May 23. pii: S0149-7634(18)30941-2.

----------

Maternal polycystic ovary syndrome (PCOS) and autism yet again

Another mash-up post for you today as I bring two papers to the blogging table discussing a topic which has already had quite a bit of airtime on this blog: maternal diagnosis of polycystic ovary syndrome (PCOS) and risk of offspring diagnosis of autism (see here and see here). The papers in question are from Maria Katsigianni and colleagues [1] and Carolyn Cesta and colleagues [2] and, via different experimental means, both papers suggest that women with PCOS have a significantly greater risk of having a child diagnosed with autism or autism spectrum disorder (ASD).

PCOS, in case you didn't know, is a fairly common condition according to the NHS entry. It's characterised by three main features: irregular periods, the presence of high levels of androgens (male hormones) and polycystic ovaries ("ovaries become enlarged and contain many fluid-filled sacs (follicles) that surround the eggs"). Mention of (male) sex hormones in relation to PCOS have led quite a few researchers to suspect a connection between PCOS and autism but another important angle to the diagnosis is a link between PCOS and insulin (the hormone involved in blood sugar control)...

Anyhow, the Katsigianni paper first. This was a systematic review and meta-analysis of the existing peer-reviewed science on the topic of "whether women with PCOS have increased odds of having a child with ASD, while, secondarily, if these women themselves are at high risk of having the disease." Now just before anyone gets shirty with the use of the word 'disease', those are the authors words not mine. I fully go with the idea that autism is not a disease. Their 'boiling down the research literature' efforts yielded 10 studies which included over 30,000 children with autism and some 320,000 "non-ASD children." The results: "Diagnosed PCOS was associated with a 1.66 times increase in the odds of ASD in the offspring" and: "Women with PCOS were 1.78 times more likely to be diagnosed with ASD." Most data on which those findings were based were deemed to be of 'good quality'.

Then to the Cesta study. The primary aim was to "measure, in the general population, the association between maternal PCOS and offspring neuropsychiatric disorders where prenatal androgen levels and/or altered androgen function have been implicated in their etiology." That population was the Sweden, and yet another example of those fantastic Scandinavian population registries being put to good research use. Autism, by the way, wasn't the only label looked at by Cesta et al: "offspring attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and Tourette's disorder and chronic tic disorders (TD/CTD)."

Results: based on detecting some 20,000 PCOS-exposed offspring and 200,000 "unrelated PCOS-unexposed offspring" authors concluded that: "PCOS-exposed offspring had increased risk of being diagnosed with ADHD, ASD, and TD/CTD compared with unrelated PCOS-unexposed offspring." Interestingly Cesta observed that the association between maternal PCOS and autism and ADHD was stronger in girl offspring than boy offspring. They then go on to talk about prenatal androgen exposure "leading to ‘hyper-masculine’ behavioral and cognitive traits" in offspring as being one potential biological mechanism.

What's more to say? Well, despite the whole 'male sex hormone' *link* to autism I'd like to see a lot more investigation looking at biological mechanisms. Going back to the insulin link with PCOS, there is a requirement for further study in light of other findings (see here and see here). Insofar as implications for policy, well, preferential screening for autism in offspring when mum has a diagnosis of PCOS could be indicated. This adds to the growing number of other circumstances where such preferential screening seems to be indicated.

Oh, and there could be other areas of potential investigation to consider too (see here)...

----------

[1] Katsigianni M. et al. Maternal polycystic ovarian syndrome in autism spectrum disorder: a systematic review and meta-analysis. Molecular Psychiatry. 2019. March 13.

[2] Cesta CE. et al. Maternal polycystic ovary syndrome and risk of neuropsychiatric disorders in offspring: prenatal androgen exposure or genetic confounding? Psychol Med. 2019 Mar 12:1-9.

----------

Roger Moore's eyebrows, ADHD and coeliac disease part 2

Consider this post an extension of some previous blogging chatter (see here) about how behaviourally defined diagnostic labels such as attention-deficit hyperactivity disorder (ADHD) seem to rarely exist in some sort of clinical vacuum. Part of that vacuum also potentially encompasses a range of somatic symptoms and/or diagnostic labels.

The findings reported by Vendel Kristensen and colleagues [1] set out to "assess self-reported symptoms of impaired concentration in coeliac disease before and after treatment with gluten-free diet, compared with healthy controls and patient controls." Coeliac (celiac) disease, in case you didn't know, refers to the archetypal 'gluten can affect biology' condition, where a certain genetic predisposition (or two) adds to gluten exposure to start a whole cascade of biological actions that impact on physical health and well being. Alongside things like bowel symptoms, there is an increasing recognition that coeliac disease (CD) also potentially brings with it certain psychological symptoms, particularly when it is not properly treated/managed (see here).

Kristensen et al asked some 30 people - "newly diagnosed coeliac patients" - to complete various questionnaires pertinent to the presentation of ADHD type symptoms, depression and anxiety and gut issues. These were compared with responses from those diagnosed with an inflammatory bowel disease (IBD) and controls (healthcare professionals).

They reported that those diagnosed with CD before implementation of a gluten-free diet had "significantly higher scores than healthy controls" in relation to the presence of self-reported ADHD and depression/anxiety symptoms. Further: "After a gluten-free diet, their scores improved and were not significantly different from healthy controls." That gluten-free diet by the way, was in place for a minimum of 12 months.

One has to be careful not to make too many sweeping generalisations from the Kristensen data. The data do not, for example, mean that all cases of ADHD are somehow the product of undiagnosed coeliac disease. Not even close. What do they do (cautiously) suggest, is that preferential screening for something like coeliac disease *might* be a good idea as and when ADHD is diagnosed or significant ADHD-like symptoms present. Such findings also resonate with the idea that certain dietary interventions to manage *some* ADHD could be a research area to consider (see here) and bring into play an interesting concept: the gut-brain axis.

Oh, and in case you were wondering about the 'Roger Moore's eyebrows' bit, well, he was the best James Bond wasn't he?

----------

[1] Kristensen VA. et al. Attention deficit and hyperactivity disorder symptoms respond to gluten-free diet in patients with coeliac disease. Scand J Gastroenterol. 2019 May 3:1-6.

----------

ADHD and "criminogenic cognitions": is inattention a key issue?

"These results indicate that in community-recruited adults, inattention rather than hyperactivity is related to criminogenic cognitions."

That was a key conclusion reached in the paper by Paul Engelhardt and colleagues [1] who set out to put some further scientific flesh on the bones of the finding of a "strong link between ADHD [attention-deficit hyperactivity disorder] and criminal behaviour." They were specifically interested in some of the cognitive processes behind such a correlation, and whether specific facets of ADHD might be more strongly related to criminal behaviour.

OK, first things first, although there is more than a passing connection between ADHD and risk of incarceration for example (see here and see here) I do need to point out that not every person diagnosed with ADHD is a criminal or would-be criminal. Sweeping generalisations about the effects of behavioural and/or psychiatric labels have done more than enough damage down the years, and I don't want to add to any stigma. That being said, I don't think it's unfair to point out that there is a body of peer-reviewed research evidence out there observing that ADHD certainly seems to increase the risk of contact with law-makers and law enforcers alongside a host of other events (see here).

Engelhardt et al provided a sample of adults (N=198) aged between 18-65 years with a package of questionnaires designed to assess 'criminal thinking styles' and ADHD-related traits. Questionnaires were of the self-report kind. The results suggested that various variables/items on the ADHD questionnaire and more general demographic information *correlated* with criminogenic cognitions. So: "higher age and being female were negatively related to criminogenic cognitions" indicating that such variables were associated with lower criminogenic cognitions. Further, and as mentioned at the start of this post: "inattention/memory problems were more strongly associated with criminogenic cognitions than was impulsivity/emotional lability." In total, age, sex/gender and ADHD symptoms accounted for "between half and two-thirds of the variance in criminogenic cognitions."

The authors mention how their results differ from other data talking about hyperactivity as being linked to criminality, and whether their use of a non-criminal participant group and focus on criminogenic cognitions rather than criminality might be important. I'd agree that the Engelhardt results are important but require further investigations to be carried out to assess their validity. Having said that, the results as they stand do perhaps offer another avenue for intervention, based on the the idea that managing inattention (if that is possible) *could* be have some really important effects.

----------

[1] Engelhardt PE. et al. The Relationship between Adult Symptoms of Attention-Deficit/Hyperactivity Disorder and Criminogenic Cognitions. Brain Sci. 2019 Jun 2;9(6). pii: E128.

----------

Mindfulness for ADHD systematically reviewed

"According to presented descriptive results, all the studies (100%) showed improvement of ADHD [attention-deficit hyperactivity disorder] symptoms."

That was the standout sentence derived from the findings reported by Hélène Poissant and colleagues [1] who looked at "the available literature concerning MBIs [mindfulness-based interventions] in adult participants with ADHD." Mindfulness by the way, is described as a way of "reconnecting with our bodies and the sensations they experience" with a specific focus on "an awareness of our thoughts and feelings as they happen moment to moment." I'm no expert on mindfulness or mindfulness-based interventions but, from what I gather, the core of such intervention(s) is based around "somatically focused meditative techniques (body scan, sitting meditation, and mindful yoga) that are thought to help participants cultivate nonjudgmental, mindful awareness of present-moment experience." 'Focusing in on the present' seems to be the phrase that springs to mind.

Poissant et al examined the relevant peer-reviewed science on the application of the MBIs to ADHD upto June 2018. They specifically focused on adults with ADHD, and were able to track down "13 studies conducted with 753 adults (mean age of 35.1 years)" for inclusion in their systematic review. They observed that: "All the studies (100%) showed improvement of ADHD symptoms following an MBI." They also mentioned that: "mindfulness meditation training improves some aspects of executive function and emotion dysregulation" as per the findings of some of those studies.

Despite the '100% of studies showing improvement in ADHD symptoms' sentiments, I'm not falling hook, line and sinker for the value of MBIs in relation to ADHD. The main reason is the high risk of bias identified in quite a few of the studies reviewed by Poissant, related to things like performance bias ("blinding of participants and of personnel") and selection bias ("allocation concealment" and "selection bias"). One could argue that the examination of something like MBIs under research conditions is never going to be perfect. Unlike scientific investigation of a medicine, where a placebo can be formulated to look, smell and taste the same, it would be difficult to come up with something to approximate MBI and indeed, approximate what the 'active ingredient' of mindfulness actually is. Similar issues have been talked about on other occasions on this blog (see here).

That all being said, there is something appealing about MBIs both in terms of effect and also the fact that it can be learned by pretty much anyone, is cost-free and probably about as side-effect free as one could get. If such a simple technique helps with any one of the symptoms of ADHD and improves quality of life for those with ADHD, it's got to be something to be considered alongside the myriad of other possible interventions (see here and see here and see here) that *might* offset the risks that follow a diagnosis of ADHD (see here).

Oh, and it appears that mindfulness and ADHD is a topic in the ascendancy [2]...

----------

[1] Poissant H. et al. Behavioral and Cognitive Impacts of Mindfulness-Based Interventions on Adults with Attention-Deficit Hyperactivity Disorder: A Systematic Review. Behav Neurol. 2019;2019:5682050.

[2] Xue J. et al. A meta-analytic investigation of the impact of mindfulness-based interventions on ADHD symptoms. Medicine (Baltimore). 2019 Jun;98(23):e15957.

----------

Following ADHD long-term: "a persistence rate of 27.8%"

Studies such as the one published by Michel Lecendreux and colleagues [1] always catch my attention. Research that follows a group of people over a period of years makes for interesting reading; not least because one gets a flavour for what *could* happen when such findings are applied to a larger population.

The Lecendreux findings focused on a few important issues pertinent to a diagnosis of attention-deficit hyperactivity disorder (ADHD) specifically related to (a) the persistence of ADHD, and (b) the idea that signs and symptoms of ADHD not meeting the thresholds for a diagnosis of ADHD might be rather important. Indeed, that they may merit "a subthreshold diagnostic category" of their own.

So, based on a starting participant sample of just over a thousand families including a child in the "6-12 years age range", interviews were conducted covering various aspects of ADHD and beyond: "symptoms of ADHD, conduct disorder, and oppositional defiant disorder as well as family living situation, school performance, sleep disturbance, eating habits, use of supplemental iron, and history of ADHD treatment." Approaching half of the original sample (492 / 1012) were followed up some 9 years later where "the persistence of ADHD and its impairments and the emergence of new conditions were assessed."

Results: "At follow-up, 16.7% of the children diagnosed with ADHD at baseline met full criteria for ADHD and 11.1% met criteria for subthreshold ADHD, yielding a persistence rate of 27.8%." Diagnosis of ADHD was, by the way, based on DSM-5 criteria (see here). That figure of 27.8% in terms of ADHD persistence from childhood to early adulthood is potentially an important one. It tells us that for a majority of children diagnosed with ADHD in childhood, their symptoms of inattention, hyperactivity and impulsivity will reduce to such a degree that they are no longer considered clinically significant or at least not reaching thresholds for a diagnosis of ADHD. Whether such a reduction in symptoms is through processes such as maturation or the timely implementation of intervention/management strategies needs quite a bit more work. Whether also ADHD potentially 'morphs' into something else as people age also needs further exploration (see here).

Another important detail was also mentioned by Lecendreux et al: "Among children not diagnosed with ADHD at baseline, 1.1% met criteria for ADHD at follow-up." Such a figure is important in relation to the concept of adult-onset ADHD [2] and the question of whether ADHD is a diagnosis with foundations always rooted in infancy. The Lecendreux findings suggest that for some people, this might not be the case and opens the door to possible talk about acquired ADHD for examples. This also sounds very familiar (see here).

Insofar as the issue of a possible 'subthreshold diagnostic category' for ADHD, I find myself agreeing with the "dimensional conceptualization" mentioned by the authors. Several other conditions / states / diagnoses have recognised 'lite versions' of the label. In autism for example, one might see this as social communication disorder (SCD) or mention of the broader autism phenotype (BAP). I'm even minded to place the label known as pathological demand avoidance (PDA) in a similar bracket given recent opinions (see here). Such chatter about 'lite' does not and should not downplay the effects of such sub-threshold labels. It merely acknowledges that there may be a wider spectrum of issues / difficulties experienced outside of the receipt of a core diagnosis.

So it should perhaps be the same with ADHD too, given what is beginning to emerge on the long-term 'effects' that a diagnosis of ADHD and subthreshold ADHD might bring (see here and see here).

----------

[1] Lecendreux M. et al. A 9-Year Follow-Up of Attention-Deficit/Hyperactivity Disorder in a Population Sample. J Clin Psychiatry. 2019 May 7;80(3). pii: 18m12642.

[2] Cooper M. et al. Investigating late-onset ADHD: a population cohort investigation. J Child Psychol Psychiatry. 2018 Oct;59(10):1105-1113.

----------

Nighttime body movements and autism

I was rather interested in the findings reported by Nobushige Naito and colleagues [1] talking about how atypical body movements during the night seemed to be more frequently observed in children diagnosed with an autism spectrum disorder (ASD) compared to not-autism controls. Interested because, sleep is a long-running 'issue' in relation to autism (see here) and because, researchers relied on the use of actigraphy in their study: "a movement-based index measured by an accelerometer" rather than just second-hand observational questioning.

So: "Seventeen TD [typically developing] children and 17 children with ASD participated in this study (5 to 8 years old)." Importantly (see here) we are told that: "Considering the frequent co-occurrence of ASD and ADHD [attention-deficit hyperactivity disorder] symptoms, we did not exclude ASD patients with ADHD symptoms." Authors relied on data from a waistband accelerometer worn by participants over at least 3 nights. Using a waistband was seen as preferable to the more typical wristband. Data was collected and analysed. It included something called a movement index (MI): "the ratio of the body movement period in 20 minutes was calculated continuously for 9 hours using the sliding window method."

Results: "a higher rate of body movement 2 to 3 hours after the first onset of body stillness was more prominent in children with ASD than in TD children." Importantly authors also mention how the objective data provided by the waistband accelerometer showed a different "time course of body movements during night in young children with ASD" despite parents/carers reporting no "apparent" problems with sleeping. They also talk some of the differences in body movements seen in those children with ASD potentially *related* to some awake behaviours - "a lower social ability and more frequent maladaptive behaviour."

The Naito results represent a good start at looking at these important behaviours. I'm a little bit hesitant to go all-in with the suggestion from the authors that "atypical nocturnal body movement could be an ASD state and trait marker in young children with ASD" but can see the importance of further investigations in this area.

----------

[1] Naito N. et al. Atypical body movements during night in young children with autism spectrum disorder: a pilot study. Sci Rep. 2019 May 6;9(1):6999.

----------

Childhood dietary patterns and ADHD?

The findings of the systematic review and meta-analysis published by Bianca Del-Ponte and colleagues [1] provide the blogging fodder today, and the suggestion that: "a diet high in refined sugar and saturated fat can increase the risk, whereas a healthy diet, characterized by high consumption of fruits and vegetables, would protect against ADHD [attention-deficit hyperactivity disorder] or hyperactivity."

The starting point: "The diet during childhood has been investigated as a factor potentially involved in the ADHD etiology." Yes it has, and Del-Ponte et al managed to find 14 studies looking at this issue published in the peer-reviewed literature. The data were boiled down and results obtained suggesting that "healthy dietary patterns were protective against ADHD (OR: 0.65; 95% CI: 044 – 0.97), while unhealthy dietary patterns were found as risk to ADHD (OR: 1.41; 95% CI: 1.15–1.74)."

The authors admit that the science upon which they made their observation is "weak" insofar as cause and effect not being proved. This is an important point (see here) that follows other research in this area too (see here and see here) together with an understanding that many different variables *might* influence the risk of something like ADHD as a diagnosis or in behaviour (see here and see here for examples).

Still, if there is even the remotest possibility that diet might be something to consider in respect of ADHD, adding it to the intervention arsenal that already exists (see here) can only be a good thing...

----------

[1] Del-Ponte B. et al. Dietary patterns and attention deficit/hyperactivity disorder (ADHD): A systematic review and meta-analysis. Journal of Affective Disorders. 2019; 252: 160-173.

----------

"Neurodevelopmental effects of prenatal vitamin D in humans"

The results of the systematic review and meta-analysis published by Azahara García-Serna & Eva Morales [1] provide the blogging fodder today.

Their aim was to summarise the collected peer-reviewed research evidence pertinent to "the association between 25-hydroxyvitamin D [25(OH)D] levels in maternal blood in pregnancy or newborn blood at birth and neurodevelopmental outcomes, including cognition, psychomotor performance, language development, behavioral difficulties, attention deficit and hyperactivity disorder (ADHD), and autistic traits." This coming from authors who already have some research 'form' in this area (see here).

Twenty-five studies ("articles") were included in their boiling-down-of-the-relevant-research-literature published up to May 2018. From the combined data, a few *associations* were detected: "Comparing the highest vs. the lowest category of prenatal 25(OH)D levels, the pooled beta coefficients were 0.95... for cognition, and 0.88... for psychomotor development. The pooled relative risk for ADHD was 0.72..., and the pooled odds ratio for autism-related traits was 0.42." What this meant is that measured higher levels of vitamin D in pregnant mums-to-be or in offspring newborn blood correlated with "improved cognitive development and reduced risk of ADHD and autism-related traits later in life" for offspring.

Of course one has to be careful with such data whether it comes from a meta-analysis or not. We're still talking about observational studies where one variable (vitamin D) is being analysed in the context of one or a few others (related to offspring development). Yes, researchers can control for this potential confounder or that potential confounder, but there remains a 101 other variables that likely affect the likelihood of ADHD or 'autism-related traits' appearing, not least biology and genetics.

That being said, the García-Serna / Morales are potentially important. They point to the need for further research into various possibly interlinked areas when it comes to vitamin D levels and their intake. This follows Government guidance (at least here in Blighty) suggesting that many people should be taking a vitamin D supplement already (see here). I'm also minded to suggest that future investigations should also be looking at other related areas around vitamin D such as the various genetic processes that seem to be important to vitamin D levels and the metabolism of the sunshine vitamin (see here).

And if you're still not convinced by the potential effects of vitamin D and offspring outcomes, perhaps the findings - systematic review findings - published by Janet Janbek and colleagues [2] might help sway you a little...

----------

[1] García-Serna A. & Morales E. Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis. Molecular Psychiatry. 2019. Jan 25.

[2] Janbek J. et al. Associations between vitamin D status in pregnancy and offspring neurodevelopment: a systematic literature review.  Nutr Rev. 2019 Feb 26. pii: nuy071.

----------

"Physical and mental health issues were highly prevalent among children with obesity..."

The quote titling this post - "Physical and mental health issues were highly prevalent among children with obesity" - comes from the findings reported by Stasia Hadjiyannakis and colleagues [1].

Researchers set out to "examine the association between BMI [body mass index] class and EOSS-P [Edmonton Obesity Staging System for Pediatrics] stage" on the basis that measures such as BMI "do not always accurately and reliably identify children and youth with obesity-related health risks or comorbidities" [2] and issues like obesity don't typically appear in a "metabolic, mechanical, mental health and social milieu" vacuum.

As you might have already noted, Hadjiyannakis and colleagues have some 'research form' in this area. This time around data on nearly 850 children "with obesity aged 5-17 years" attending one of a number of weight management clinics were the source material. They observed that most of their cohort - about two-thirds of them - were described as having severe obesity according to their BMI score. When it came to their EOSS-P staging scores, 80% fell into the categories of a 2 or 3 denoting moderate to severe issues with regards to health issues such as metabolic complications either requiring pharmacotherapy or being described as "uncontrolled".

Of particular note to this blog and the focus on the intersection between physical and mental health parameters, researchers describe how "mental health concerns were most common" among their participant group. By 'mental health concerns' they specifically talk about anxiety and attention-deficit hyperactivity disorder (ADHD) as being present and "equally distributed across BMI classes." I was particularly intrigued with the ADHD bit because despite the focus on hyperkinetic behaviours in ADHD, the emerging research picture is suggesting that ADHD and obesity *might* actually be connected (see here) under quite a few different circumstances (see here).

What's more to say? Well, the Hadjiyannakis results perhaps imply that preferential screening for various physical and mental / behavioural are indicated when obesity is present. Specifically, and bearing in mind that "mental health risks were high across BMI classes" the results suggest that the possibility of an elevated risk of mental / behavioural diagnoses is not something confined to those with more or less severe obesity but rather, potentially, a universal issue.

----------

[1] Hadjiyannakis S. et al. Obesity class versus the Edmonton Obesity Staging System for Pediatrics to define health risk in childhood obesity: results from the CANPWR cross-sectional study. Lancet Child Adolesc Health. 2019 Apr 2. pii: S2352-4642(19)30056-2.

[2] Hadjiyannakis S. et al. The Edmonton Obesity Staging System for Pediatrics: A proposed clinical staging system for paediatric obesity. Paediatr Child Health. 2016;21(1):21–26.

----------

Managing ADHD: pharmacotherapy use and quality of life

"The QoL [quality of life] of the children with ADHD [attention-deficit hyperactivity disorder] and the subjective well-being of the parents improved significantly after introducing pharmacotherapy."

That was the research 'bottom line' described by Hanife Temizsoy and colleagues [1] following the publication of their study results designed to "investigate the changes of QoL of children with ADHD and their parents' subjective well-being before and after starting pharmacotherapy." Pharmacotherapy is the fancy word for medication; and the Temizsoy findings add to quite a large bank of peer-reviewed research suggesting that some medicines 'for ADHD' have a pretty good benefit-risk profile (see here). Indeed, the use of indicated medicines for ADHD seems to have some good potential for decreasing various future risks that seem to follow a diagnosis of ADHD (see here and see here).

"We assessed the QoL and the parental well-being in 60 children and adolescents with ADHD between the ages of 6 and 12 years." Various questionnaires were utilised, including the KINDL designed to assess "Health-Related Quality of Life in children and adolescents aged 3 years and older" and "the World Health Organization (WHO) Big Five Questionnaire", a short questionnaire on (current) well being. The results obtained were encouraging.

Bearing in mind that the Temizsoy was a straightforward 'before and after' study lacking important methodological features such as blinding and objective measures from physicians or other objective viewers for example, the results are important. I'm also minded to add that whilst certain medicines indicated for ADHD do seem to have quite a good track record for improving features of the condition, they are not without potential side-effects as per just about every other medicine in existence.

But... if children with ADHD and their parents/carers are reporting that their quality of life is getting better with medication compared to times without medication, surely this counts for something. With regular monitoring, good medicines management and possibly alongside the use of other potential intervention options (see here and see here for examples), ADHD for many people, is a condition that can be managed and managed well.

----------

[1] Temizsoy H. et al. Influence of Psychopharmacotherapy on the Quality of Life of Children with Attention-Deficit/Hyperactivity Disorder. J Child Adolesc Psychopharmacol. 2019 Mar 29.

----------

"Maternal diabetes, especially GDM, is probably a risk factor for ADHD"

It's coincidental that as I write this post about the findings reported by Lifeng Zhao and colleagues [1] talking about how "Maternal diabetes, especially GDM [gestational diabetes mellitus], is probably a risk factor for ADHD [attention-deficit hyperactivity disorder]" so the BBC news website highlights how screening for gestational diabetes here in Blighty is still a bit of a hit-and-miss affair (see here).

That news report mentions how about a quarter of those mums-to-be who are most at risk of developing pregnancy diabetes - "having a high BMI [body mass index] or being of South Asian or Black Caribbean ethnicity" - did not get screened at all. Left untreated, gestational or pregnancy diabetes can increase the risk of various adverse events including "a baby that grows larger than usual, leading to problems in labour; premature birth; pre-eclampsia and stillbirth."

The Zhao findings - a meta-analysis - continue a theme suggesting that exposure to maternal diabetes, including pregnancy diabetes, seems to increase the risk of various other developmental and behavioural diagnoses also being present in offspring. The primary source material of this blog - autism - has been talked about on various occasions as being one of those developmental/behavioural diagnoses (see here and see here). That ADHD is quite often mentioned in the diagnostic mix when it comes to autism (see here) is another point to make.

The basics of the Zhao paper: a search of the peer-reviewed science literature was undertaken revealing nine studies that fitted the inclusion criteria including "7,218,903 participants." The quality of most studies was ranked as high. The results were interesting in that researchers "did not find significant association between maternal diabetes and ADHD risk (OR: 1.20, 95% CI: 0.96–1.49)." This observation is slightly at odds with the quote titling this post, which Zhao et al put down to the "high heterogeneity" detected among the included studies and their subgroup analysis of case-control studies (n=3).

Also... when it came to looking at another type of study - a cohort study (n=6) - "the meta-analysis demonstrated that maternal diabetes increased the risk of ADHD in offspring by 40%." Further, and bearing in mind the description 'diabetes' covers quite a bit of diagnostic ground, authors zoomed in on one particular 'type of diabetes', that called gestational diabetes (GDM) and looked at any effect. This is where things got a little more interesting as their results, based on four studies, indicated that "GDM exposure increased the risk of ADHD for children by 164%" in Caucasian children. Ergo, although a little mixed, the existing research literature at the time of analysis indicated that maternal diabetes during pregnancy, particularly GDM, *might* have some important effect on risk of offspring ADHD.

I'm not going to say much more at this point in time in terms of potential mechanisms that *might* elevate the risk of ADHD in offspring exposed to pregnancy diabetes. It's likely to be pretty complicated. Given also that GDM appears more often than not alongside other conditions (see here), it's not going to be easy to tease apart what might be the more important issues. Is it inflammation? Is something to do with blood sugar or insulin? At the moment, we just don't know enough...

----------

[1] Zhao L. et al. The association of maternal diabetes with attention deficit and hyperactivity disorder in offspring: a meta-analysis. Neuropsychiatr Dis Treat. 2019;15:675–684.
----------

Saffron for ADHD?

I'm very partial to a bit of 'left field' research on this blog. By 'left field' I mean research that is slightly unusual or atypical. I'd place the study findings by Sara Baziar and colleagues [1] in that 'left field' category because they reported results - randomised double-blind study results - suggesting that: "Short-term therapy with saffron capsule showed the same efficacy compared with methylphenidate" when it came to managing some of the symptoms of attention-deficit hyperactivity disorder (ADHD).

Saffron a.k.a Crocus sativus L is a herb commonly cultivated in places like India and Greece. As with many herbs/spices, cooking represents but one potential use of saffron. It contains a myriad of different chemical compounds, some of which seem to have a variety of potential medicinal uses. Real pharmacognosy in action.

The starting point for the Baziar study was that although methlyphenidate (ritalin) is indicated for treating / managing many cases of ADHD, not everyone is suited to such a medicine or the side-effects that it can sometimes produce. So "alternative medication, like herbal medicine, should be considered." Enter then saffron, and some evidence that it might be a useful herb for various psychiatric complaints [2], to be pitted against methylphenidate in a sort of scientific head-to-head contest with ADHD symptoms in mind.

For 6 weeks, fifty or so children and young adults with "a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD" were randomly allocated to receive methylphenidate (MPH) "20-30 mg/d (20 mg/d for <30 kg and 30 mg/d for >30 kg)" or saffron capsules "20-30 mg/d saffron capsules depending on weight (20 mg/d for <30 kg and 30 mg/d for >30 kg)." At baseline, 3 weeks and 6 weeks researchers measured ADHD-related symptoms.

The results were unsurprisingly surprising. By that, I mean that there were no statistically significant differences between the two groups, bearing in mind the clinical effectiveness profile that methylphenidate use for ADHD has already established (see here). So: "General linear model repeated measures showed no significant difference between the two groups on Parent and Teacher Rating Scale scores." Importantly too we are told that: "The frequency of adverse effects was similar between saffron and MPH groups."

The Baziar results don't immediately open the floodgates to saffron being used to 'manage ADHD' instead of a clinically-proven molecule like methylphenidate. It doesn't work like that. As far as I can see this seems to be the first time that saffron has been put under the scientific spotlight with ADHD mind (taking into account other 'herbal medicines' have been explored with ADHD in mind). We therefore need more data and some all-important replication. We need more data comparing saffron against methylphenidate and other intervention options for ADHD. And we also need more data on why? Why might saffron be a useful therapeutic option for some ADHD? What are the pertinent biological mechanisms at work?

----------

[1] Baziar S. et al. Crocus sativus L. Versus Methylphenidate in Treatment of Children with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Pilot Study. J Child Adolesc Psychopharmacol. 2019 Feb 11.

[2] Shafiee M. et al. Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. J Affect Disord. 2018 Feb;227:330-337.

----------

Magnesium and ADHD meta-analysed

The study results published by Mohammad Effatpanah and colleagues [1] provided some food for thought recently on the topic of whether there may be an *association* between "serum magnesium levels and the diagnosis of attention deficit hyperactivity disorder (ADHD)."

The name of the research game was meta-analysis, that well used 'boiling down' of the published (hopefully peer-reviewed) science literature into something like a coherent 'conclusion'. The starting point for Effatpanah was that: "Current research suggests conflicting evidence surrounding the association between serum magnesium levels and the diagnosis of attention deficit hyperactivity disorder (ADHD)." It's interesting that this isn't the first time that magnesium and ADHD has been put under the meta-analysis microscope [2] and that particular meta-analysis didn't suggest such conflict.

Never mind. Seven studies made the grade for Effatpanah, together revealing that "subjects with ADHD had 0.105 mmol/l (95% CI: -0.188, -0.022; P < 0.013) lower serum magnesium levels compared with to their healthy controls." Researchers did also talk about 'high heterogeneity' across the studies analysed. This indicates that whilst there may well be "an inverse relationship between serum magnesium deficiency and ADHD" overall, the individual studies included in their meta-analysis weren't always in agreement with one and another.

So what conclusions can we take from the Effatpanah and other (meta-analysis) studies in this area? Well, more investigation is required on the suggestion of a *link* between magnesium and ADHD. We need to know more about the biology of why reduced biological levels of magnesium might be important to ADHD or ADHD-type behaviours [3] and whether something as simple as supplementing with magnesium *might* make a difference for some people [4] (minus any medical or clinical advice from me on this or any other topic). Indeed, on that last issue, I might refer you back to some other occasions where magnesium has been mentioned in the context of nutritional intervention for ADHD (see here). I'm also inclined to mention that there may be other 'labels' where magnesium might require a little more study (see here), some of which might 'overlap' with a diagnosis of ADHD. And of course, we should remember that magnesium 'issues' in the context of autism might not be the end of the story when it comes to trace metals and ADHD (see here)...

----------

[1] Effatpanah M. et al. Magnesium status and attention deficit hyperactivity disorder (ADHD): A meta-analysis. Psychiatry Res. 2019 Feb 19;274:228-234.

[2] Huang YH. et al. Significantly lower serum and hair magnesium levels in children with attention deficit hyperactivity disorder than controls: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 2;90:134-141.

[3] Black LJ. et al. Low dietary intake of magnesium is associated with increased externalising behaviours in adolescents. Public Health Nutr. 2015 Jul;18(10):1824-30.

[4] Ghanizadeh A. A systematic review of magnesium therapy for treating attention deficit hyperactivity disorder. Arch Iran Med. 2013 Jul;16(7):412-7.

----------

ADHD and a link with zinc?

"The present results indicated that there were alterations in blood levels of zinc, which was associated with the symptom scores of ADHD [attention-deficit hyperactivity disorder]."

So concluded the paper published by Rongwang Yang and colleagues [1] looking at blood levels of various trace elements including "zinc (Zn), copper (Cu), iron (Fe), magnesium (Mg), and lead (Pb)" in a group of children diagnosed with ADHD compared to a group of non-ADHD controls.

Based on their analysis of blood samples using atomic absorption spectrometry, researchers observed that many of the metals (trace elements) analysed were not greatly different between their groups. Lower levels of zinc however, and "the number out of normal ranges" in relation to zinc were noted. Further: "Zinc levels were negatively correlated with parent-rated scores of inattentive subscale of SNAP-IV (r = − 0.40) as well as with total score of SNAP-IV (r = − 0.24)" where the SNAP-IV refers to the Swanson, Nolan, and Pelham – IV questionnaire, a tool used to screen/assess for possible ADHD.

The Yang results have to be treated with some caution as the old 'correlation is not necessarily the same as causation' rule is observed. It's not beyond the realms of possibility that any suggested *association* between zinc and ADHD is purely epiphenomenal. But...

This is not the first time that zinc and ADHD have been talked about in the same breath (see here). Outside of linking levels of zinc to ADHD - or diagnostic facets of ADHD - one is also presented with other research suggestive that supplementation 'for ADHD' including zinc *might* show some effect (see here). There is the other question of whether zinc alone or in conjunction with other elements and/or biological factors might be important to the presentation of ADHD [2] but this is perhaps another reason why this area is deserving of further investigation. Indeed, further study of the possible processes through which zinc might influence the presentation of ADHD is also required.

And given that ADHD is something not exactly under-represented when it comes to other labels (see here), one has to question what role this fact might play in a more complicated clinical picture with zinc in mind (see here)?

----------

[1] Yang R. et al. Blood Levels of Trace Elements in Children with Attention-Deficit Hyperactivity Disorder: Results from a Case-Control Study. Biological Trace Element Research. 2019; 187: 376-382.

[2] Villagomez A. & Ramtekkar U. Iron, Magnesium, Vitamin D, and Zinc Deficiencies in Children Presenting with Symptoms of Attention-Deficit/Hyperactivity Disorder. Children (Basel). 2014 Sep 29;1(3):261-79.

----------

Nicotine exposure and offspring ADHD (yet again)

The study findings reported by Andre Sourander and colleagues [1] talking about "an association with and a dose-response relationship between nicotine exposure during pregnancy and offspring ADHD [attention-deficit hyperactivity disorder]" continue an important research theme (see here and see here).

What was different about the Sourander results compared with some of the other studies in this area was their focus on the measurement of cotinine levels - cotinine being a biomarker for exposure to tobacco smoke - in mums-to-be as "measured by using quantitative immunoassays from maternal serum specimens collected during the first and second trimesters of pregnancy and archived in the national biobank." Indeed, such a biological marker measurement protocol mimics other research from members of this authorship group when looking at maternal nicotine exposure and offspring risk of schizophrenia for example (see here).

Based on the analyses of samples from over a thousand participants born in the late 1990s and diagnosed with ADHD compared with samples from a similar number of non-ADHD control participants, researchers came to their possible *link* observation. They mention how the relationship between maternal cotinine levels and offspring ADHD diagnosis was statistically significant even when other important, potentially confounding, variables were taken into account. When categorising their maternal cotinine results into bands approximating light to heavy nicotine exposure and the possibility of a link with offspring ADHD diagnosis, researchers also reported something that looked like a dose-response relationship. Ergo, a biomarker of nicotine exposure during pregnancy *looked* to be potentially linked to offspring risk of ADHD.

Although important work, my first thought when reading this research was about how these results are 'set' within the context that historically, smoking rates or tobacco exposure rates during pregnancy were so much larger decades ago than they are now (see here), but ADHD is seemingly showing only quite a recent rise in numbers (see here). Although no expert on pregnancy tobacco consumption during the 20th century, I'm assuming that all those adverts about smoking being 'healthy' in the 1940s and beyond (see here) probably meant that quite a few women smoked during their pregnancy in the belief that it was 'healthy'. At the very least, it probably meant that they were exposed to a lot more second-hand tobacco smoke as a result of smoking being allowed in various public places and also more likely to be observed in the home environment. Surely then we would have seen an explosion of ADHD diagnoses at that point in time if the link was so simple? That is, assuming that the tobacco of today is the same as the tobacco of yesteryear.

I'm also intrigued that within the various potentially confounding variables which Sourander and colleagues adjusted for - "maternal socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and child’s birth weight for gestational age" - there's another variable that could exert an effect on ADHD risk: relative age (see here and see here). Relative age refers to the observation that the youngest children in the school classroom compared to their older classmates, are more likely to be diagnosed with ADHD. It strikes me that alongside something like tobacco or nicotine exposure, so age and other effects could be important.

I'm not trying to poo-poo the link that Sourander and various other research teams have independently observed. I'm also not trying to downplay the harms that tobacco (nicotine) exposure can have for the unborn child. I merely suggest that with typically falling rates of (reported) tobacco exposure during pregnancy in many countries (see here) and increasing levels of childhood (and adulthood) ADHD being reported, there must be other factors at work in any such relationship (see here for example).

----------

[1] Sourander A. et al. Prenatal Cotinine Levels and ADHD Among Offspring. Pediatrics. 2019. Feb 25.

----------

"An estimated 7.7 million children in the United States (16.5 percent) have at least one mental health disorder"

The press release carrying the quote titling this post - "An estimated 7.7 million children in the United States (16.5 percent) have at least one mental health disorder" - concerns the findings reported by Daniel Whitney & Mark Peterson [1]. Their research letter discussed findings (from the United States) "providing recent national and state-level estimates of the prevalence of treatable mental health disorders and mental health care use in children."

Based on data derived from the 2016 National Survey of Children’s Health (NCSH), a "nationally representative, parent-proxy survey of US children younger than 18 years" that has been mentioned more than once on this blog (see here and see here), researchers present some important data. Including information from over 46 million children (now that's what I call a decent sample size) various trends were observed, notably that almost one in seven children and young adults were reported to have a mental health condition. Such conditions covered "depression, anxiety problems, or attention-deficit/hyperactivity disorder" and by present, I mean that parents responded in the positive to the question: "Has a doctor or other health care provider EVER told you that this child has” a mental health disorder?"

Another detail was also mentioned in the Whitney & Peterson paper: "half of the estimated 7.7 million US children with a treatable mental health disorder did not receive needed treatment from a mental health professional." This was based on responses to the question: "DURING THE PAST 12 MONTHS, has this child received any treatment or counseling from a mental health professional? Mental health professionals include psychiatrists, psychologists, psychiatric nurses, and clinical social workers." Other media on the Whitney / Peterson paper have picked up on this trend (see here) and the possible whys-and-wherefores.

The primary weakness of the NCSH - "parent-proxy survey" - is more than compensated for by the huge participant numbers included for study. The figures arrived at also follow a trend seemingly present across many nations (see here and see here and see here) suggesting that significant numbers of young people are experiencing mental health disorder. We can quibble about the reasons for the increase but there is no mistaking the fact that something is going on. And it's seemingly affecting millions of children and young people around the world...

And as if to prove the point further [2] the startling findings from Gräf et al: "School performance was available for 1462 children (51% boys, mean age 7.3 years). Of these, 41% had signs of at least one MHP [mental health problem]."

----------

[1] Whitney DG. & Peterson MD. US National and State-Level Prevalence of Mental Health Disorders and Disparities of Mental Health Care Use in Children. JAMA Pediatrics. 2019. Feb 11.

[2] Gräf C. et al. Mental health problems and school performance in first graders: results of the prospective cohort study ikidS. European Child & Adolescent Psychiatry. 2019. Feb 26.

----------

Treating ADHD: better school results, less risk of crime and better sleep?

I

I had already written and scheduled in this blog post before an important - very important - headline appeared on the BBC News website: "ADHD [attention-deficit hyperactivity disorder] testing after 'impulsive crime' arrests should be mandatory, MPs say." The news piece covered, amongst other things, some of the peer-reviewed research findings suggesting that a diagnosis of ADHD appears to place someone at various enhanced risk for adverse life outcomes. And that potentially includes offending behaviour and prison time.

So...

Today's post is a bit of a mash-up insofar as bringing together three pieces of independent peer-reviewed research pertinent to the important idea of managing or 'treating' ADHD when it arises. I appreciate that not many people would want their nearest-and-dearest 'medicated' for example in the long-term. But when it comes to something like ADHD the case is indeed growing strong for how pharmacological intervention in particular, could literally be a life-saver for some (see here)...

The papers: first there are the findings reported by Andreas Jangmo and colleagues [1] who "analyzed school performance in students with ADHD compared to students without ADHD, and the association between pharmacological treatment of ADHD and school performance." This continues a research theme (see here). The second paper is that from Christina Mohr-Jensen and colleagues [2] which looked at "the risk of long-term conviction and incarceration associated with childhood attention-deficit/hyperactivity disorder (ADHD), and to identify risk and protective factors including associations with active treatment with ADHD medication." Again, this is a topic that has previously received quite a bit of study before (see here). Finally, I'd like to bring the paper by Stephen Becker and colleagues [3] to the blogging table, investigating whether "sleep duration is causally linked to sleepiness, inattention, and behavioral functioning in adolescents with ADHD." The answer: yes, yes it was, in line with other independent research (see here). And that potentially opens the door to intervention (see here).

Minus any sweeping generalisations from me or anyone else, the net result of these studies suggest that intervention for ADHD - primarily pharmacotherapy along the lines of what is currently indicated for ADHD - seems to have an important positive effect for many people diagnosed with ADHD. Some examples of this in action:

• School performance and ADHD: "ADHD was associated with substantially lower school performance independent of socioeconomic background factors." But the good news: "Treatment with ADHD medication for 3 months was positively associated with all primary outcomes" including higher grades and improving access to education. Such data was derived from a total sample size in the hundreds of thousands.
• Crime and ADHD: "Out of n=4,231 individuals with ADHD, n=1,355 (32.0%) had received at least one conviction compared to n=3,059 (15.6%) of the n=19,595 participants without ADHD." But... "The crime rates increased with the number of associated risks but were reduced during periods of taking ADHD medication."
• Sleep and ADHD: "Compared to the extended sleep week, parents reported more inattentive and oppositional symptoms during the restricted sleep week." The Becker study did not specifically talk about the use of intervention for sleep issues in the context of ADHD but it wouldn't be a giant leap to look at 'options' for improving sleep parameters in that context (and what knock-on effects this might have for behaviour).

Caveats? Well, correlation is not the same as causation, so even despite the 'strong' connections noted across these various studies mentioning ADHD, one cannot rule out other confounding variables playing a role. There's also the issue of balancing efficacy and safety to consider as and when any form of pharmacotherapy is introduced, something that is still being looked at with for example, methylphenidate and ADHD (paediatric ADHD) in mind [4]. I'm also minded to suggest that more fundamental work on the basis for ADHD should continue, alongside examination of the hows-and-whys of certain medicines *working* in the context of the biology of ADHD too. That, and an acceptance that medication might be but one tool in the arsenal (see here and see here and see here) to help prevent ADHD from negatively affecting a person's life and/or life chances.

But still the combined results are important. And they may well be important to those who don't quite reach all the thresholds for ADHD as a diagnosis [5] too... 

----------

[1] Jangmo A. et al. Attention-Deficit/Hyperactivity Disorder, School Performance, and Effect of Medication. J Am Acad Child Adolesc Psychiatry. 2019 Feb 1. pii: S0890-8567(19)30059-0.

[2] Mohr-Jensen C. et al. Attention-Deficit/Hyperactivity Disorder in Childhood and Adolescence and the Risk of Crime in Young Adulthood in a Danish Nationwide Study. J Am Acad Child Adolesc Psychiatry. 2019 Feb 11. pii: S0890-8567(19)30105-4.

[3] Becker SP. et al. Shortened Sleep Duration Causes Sleepiness, Inattention, and Oppositionality in Adolescents With ADHD: Findings From a Crossover Sleep Restriction/Extension Study. J Am Acad Child Adolesc Psychiatry. 2018 Nov 1. pii: S0890-8567(18)31914-2.

[4] Inglis SK. et al. Prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD: the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study. BMJ Open. 2016;6(4):e010433.

[5] Kirova AM. et al. Are subsyndromal manifestations of attention deficit hyperactivity disorder morbid in children? A systematic qualitative review of the literature with meta-analysis. Psychiatry Res. 2019 Feb 3;274:75-90.

----------

Serum zonulin testing via ELISA: be very careful

I appreciate that the findings reported by Mary Ajamian and colleagues [1] probably aren't going to set many research hearts racing. Their observations that "current commercial zonulin assays are not detecting the actual protein as prehaptoglobin-2" is not exactly 'change the world' science, but that doesn't mean that they aren't important findings.

So, zonulin is the name of the research game. A protein described with properties "capable of reversible tight junction disassembly and, therefore, is implicated in the regulation of mucosal permeability" means that zonulin and dysregulation of the zonulin pathway has found a home in the science of 'gut permeability' a.k.a leaky gut. And it is with mention of the misnomer called 'leaky gut' and it's *association* with some autism (see here) that I gravitated towards the Ajamian findings. Indeed, zonulin has already made a mark in autism research too (see here). We'll come back to this shortly.

Researchers zoomed in on some of the commercially available methods currently available to 'test for zonulin' - "commercially-available ELISA assays" - and whether they are cutting the scientific mustard. And before I go on I should mention that Ajamian et al aren't the only ones who have looked at this issue [2]. Two ELISA assays were examined: "from CUSABIO (Wuhan, China) and Immundiagnostik AG (Bensheim, Germany)" and pitted against each other and various other analytical techniques to assess "whether the assays are reliably detecting zonulin as prehaptoglobin-2 and if not, what they may be detecting instead." I note the words 'mass spectrometric analysis' are also used in the Ajamian paper, which is music to my analytical ears.

Results: "Serum samples were collected from well-characterised patients and healthy individuals between the ages of 16 and 70 years living in Melbourne, Australia." Those 'well-characterised' participants included those diagnosed with non-coeliac wheat sensitivity (NCWS), coeliac disease, and ulcerative colitis (N=93) and their results were compared with nearly 50 asymptomatic controls. "The majority of study participants were zonulin-producers" as haptoglobin phenotype (see here) was also described in the Ajamian study.

Then to the serum [purported] zonulin levels as measured by those commercial assays: "Compared with the cohort of healthy individuals with a median (IQR) of 0.00 (0.00) ng/mL, patient median (IQR) values for purported zonulin were elevated (all p<0.0001) at levels of 0.032 (0.90) ng/mL in NCWS, 0.07 (1.27) ng/mL in coeliac disease, and 1.73 (2.17) ng/mL in ulcerative colitis" using the CUSABIO assay. Unfortunately, when compared with the other commercial assay (the Immundiagnostik assay), there was apparently little relationship observed between the two when it came to [purported] zonulin levels. And things didn't get any better when for example we are told that "2 of 19 participants who were zonulin non-producers had levels detected by CUSABIO assay."

Various other experiments were carried out and reported on in the Ajamian paper. These included attempts to find out what else might be being picked up by those ELISA assays. Unfortunately, even with the notable analytical prowess of something like mass spectrometry, no definitive compound(s) emerged. Something called complement C3 is discussed, as are other potential matches: "haptoglobin, and albumin." But again unfortunately: "neither complement C3 nor haptoglobin, despite both being candidate target proteins as determined by mass spectrometry, was detected by the CUSABIO assay." So we're not really any further forward when it comes to what might be being detected by such assays.

"In conclusion, the current commercial zonulin ELISA assays investigated in this study detect different proteins, neither of which was zonulin. Therefore, there can be no value of circulating concentrations in assessing intestinal mucosal barrier dysfunction and permeability until the target proteins are indeed identified." A harsh conclusion but faithful to the results observed. What this means is that the literature already published talking about zonulin levels in this, that and t'other label/diagnosis/condition (see here) need to be treated with some caution. And yes, that includes studies that have looked at zonulin levels in autism (see here) and related labels like attention-deficit hyperactivity disorder (ADHD) (see here).

----------

[1] Ajamian M. et al. Serum zonulin as a marker of intestinal mucosal barrier function: May not be what it seems. PLoS One. 2019;14(1):e0210728. Published 2019 Jan 14.

[2] Scheffler L. et al. Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family. Front Endocrinol (Lausanne). 2018;9:22.

----------

Maternal prenatal acetaminophen use and the risk of ADHD in offspring (again)

By discussing the findings - meta-analysis findings - published by Xiaoyun Gou and colleagues [1] I once again approach the topic of whether some medicines use during pregnancy might have some important implications for offspring development. And yet again we're talking about the use of acetaminophen a.k.a paracetamol, during pregnancy and how it *might* have some important implications when it comes to offspring development (see here and see here and see here for other blogging examples on this subject).

The Gou study focused on the risk of an offspring diagnosis of attention-deficit hyperactivity disorder (ADHD) following maternal exposure to paracetamol during pregnancy. And whether timing of said exposure and/or duration of exposure showed any *association* to risk of offspring ADHD.

As per the opening sentence to this post, the Gou study was a meta-analysis, meaning that it was a synthesis of the available peer-reviewed research literature. Indeed, authors identified 8 studies published up to November 2018 that included data on nearly a quarter of a million participants in total.

Given the quite consistent consensus already seen in the science on this topic (see here for example) it's probably not unexpected that that authors concluded that: "Maternal exposure to acetaminophen during pregnancy increased the risk of attention deficit/hyperactivity disorder in offspring with a pooled adjusted risk ratio of 1.25." Further: "Children exposed prenatally to acetaminophen in the third trimester seemed to have the greatest risk of developing attention deficit/hyperactivity disorder" and "a longer duration of maternal acetaminophen use during pregnancy was correlated with a higher risk ratio."

Of course such findings, even such meta-analysis findings, come with cautions about correlation not necessarily being the same as causation given the observational nature of the studies included for review. There are also a myriad of other potential factors that seemingly impact on offspring risk for ADHD (see here and see here for some other possible examples) which perhaps require consideration at the same time.

But... this is a topic that requires a lot more investigation. Investigations into whether (a) the association is indeed a real one and not just epiphenomenal, (b) the reasons leading to paracetamol use during pregnancy which may also exert an effect on offspring risk, and (c) which biological mechanisms may be pertinent to any connection (see here and see here), are all indicated. As for where medical opinion stands on this topic at the moment, well, minus any medical or clinical advice from me, I go with the research literature on this topic [2] and would suggest that if you're in doubt, talk to your medical professional...

----------

[1] Gou X. et al. Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis. Aust N Z J Psychiatry. 2019 Jan 17:4867418823276.

[2] Andrade C. et al. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016 Mar;77(3):e312-4.

----------