"the first nationwide population-based study to investigate the risk of CFS in patients with IBD"

The quote titling this post - "the first nationwide population-based study to investigate the risk of CFS [chronic fatigue syndrome] in patients with IBD [inflammatory bowel disease]" - comes from the research published by Shin-Yi Tsai and colleagues [1].

Inflammatory bowel disease (IBD) covers quite a bit of diagnostic ground, but typically refers to ulcerative colitis (UC) or Crohn's disease (CD). There are many similarities between the conditions, but also some important differences too (see here). Both conditions manifest in the bowel (inflammation) and have pathological effects; both also typically show functional bowel symptoms too.

Utilising that fabulous (but sadly now defunct) research resource that was the National Health Insurance Research Database (NHIRD) in Taiwan, researchers set out to "evaluate the subsequent risk of CFS in patients with IBD" on the basis of "possible common pathophysiology between IBD and CFS" among other things. One of those 'pathophysiological' mechanisms quite prominently featuring in the Tsai article is "a similarity to the impaired intestinal mucosa of IBD." Interesting (see here).

So, from a starting population of a million people (or medical insurance records of a million people), authors whittled the figures down to the thousands in two groups: an IBD group (n=2163) and a non-IBD group (n=8652). All were "newly diagnosed" with IBD apparently; and none had a previous diagnosis of CFS "before the index date." Then: "Both groups were followed from the index date until the diagnosis of CFS, withdrawal from the NHI program, or December 31, 2011" with said CFS diagnosis following the Fukuda/CDC criteria.

Results: before heading into the CFS frequency figures according to group, there was another important observation made, potentially pertinent to a gut-brain connection: "The prevalence of depression, anxiety, [and] sleep disorder... was higher in the IBD group than in the non-IBD group." Indeed, the increased frequency of sleep disorder in the IBD group *might* have some important 'connection' with another diagnosis where sleep and 'gut issues' has been mentioned (see here and see here). And I might as well also mention depression and anxiety in that context too (see here).

Continuing: "After adjustment for age, and comorbidities, the risk of CFS was higher in the IBD group than in the non-IBD group (adjusted HR, 2.25; confidence interval [CI], 1.70–2.99)." There was also a possible sex-linked relationship too: "we identified male sex, advanced age, absence of comorbidities, and CD as the predictors of increased CFS risk." There's a pretty little diagram to accompany the Tsai findings (see here) outlining what *could* be going on with regards to IBD and CFS. Terms like 'bacterial translocation' and 'immunoinflammatory pathways' are used, in line with some other research in this area [2]. There's no mention of any psychobabble 'biopsychosocial' or the like in the Tsai paper which is always a good thing.

What else is there to say? Well authors go on to mention about the possibility of "intrinsic defects in IBD patients that precipitates CFS" which could have some quite profound implications for at least some cases of CFS. They added that future work might want to have a look at what certain immunotherapies indicated for some IBDs * might* mean for CFS and it's potential *treatment* too. We'll have to wait and see.

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[1] Tsai S-Y. et al. Increased risk of chronic fatigue syndrome in patients with inflammatory bowel disease: a population-based retrospective cohort study. Journal of Translational Medicine. 2019; 17:55.

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Big data Taiwan on risk of "major psychiatric disorders" in kindreds of those with schizophrenia

'Big data' Taiwan listed in the title of this post refers to the wide range of findings emerging from the resource known as the National Health Insurance Research Database (NHIRD) based in Taiwan. Seriously people, this is population-wide science at it's very, very best (see here)...

Today I present yet another example of how the NHIRD is being put to good use and, as reported by Cheng and colleagues [1], how NHIRD derived data supports "the familial dose-dependent co-aggregation of schizophrenia, bipolar disorder, major depressive disorder, ASD [autism spectrum disorder] and ADHD [attention-deficit hyperactivity disorder]." In other words, how lots of seemingly individual and specific behavioural and psychiatric labels may well 'club' around each other in affected families.

So, the starting point: "A previous genetic study has suggested that schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) share common disease-associated genes." Yes, several studies have talked about possible genetic 'relationships' between these labels (see here); accepting that structural genetics may only be a part of the story. Researchers specifically examined "whether individuals with first-degree relatives (FDRs) with schizophrenia have a higher risk of these major psychiatric disorders" and the extent of any enhanced risk.

The NHIRD harboured details for some 150,000 people diagnosed with schizophrenia and some 225,000 people with FDRs diagnosed with schizophrenia. Authors crunched the data to come up with relative risks (RRs) statistics using schizophrenia as the diagnostic starting point.

Results: "The individuals with FDRs with schizophrenia exhibited higher RRs (95% confidence interval) of major psychiatric disorders, namely schizophrenia (4.76, 4.65-4.88), bipolar disorder (3.23, 3.12-3.35), major depressive disorder (2.05, 2.00-2.10), ASD (2.55, 2.35-2.77) and ADHD (1.31, 1.25-1.37) than were found in the total population." You'll notice the sliding scale of RRs, where an index case of schizophrenia most significantly raises the RR of schizophrenia being diagnosed in first-degree relatives, down to a slightly lower RR in relation to something like ADHD among FDRs. It's probably to be expected that a diagnosis of schizophrenia might raise the risk of schizophrenia in FDRs too. Indeed, this is precisely what other NHIRD derived data has previously suggested (see here).

The range (and risks) of other diagnoses present in FDRs of someone diagnosed with schizophrenia is probably of little surprise to anyone who's surveyed the peer-reviewed literature in this area (see here) or indeed works in psychiatric circles. Although contemporary psychiatric science goes to some lengths to 'compartmentalise' specific diagnoses/labels, there's always been a strong undercurrent that labels are likely to be linked or at the very least, overlap. I've talked quite a lot for example, about the links between autism and schizophrenia on this blog (see here and see here). How, minus the [important] societal implications and politics, people such as Mildred Creak and colleagues [2] probably reached a closer 'definition' of some modern-day autism than we have now with their inclusion of "distortion in motility patterns" and "acute, excessive and seemingly illogical anxiety." Yes, they headed it "schizophrenic syndrome in childhood" and autism has been moved away from this description. But with all the emphasis on gait and motility patterns coming back into fashion together with increasing recognition of the truly disabling effect that anxiety can have in the context of autism, I think they were closer that many people thought to hitting the diagnostic mark.

Other implications from the Cheng results? Screening, enhanced screening. So when schizophrenia is diagnosed in the family, greater resources are put into preferential screening of first-degree relatives also for schizophrenia and the range of other labels mentioned in the current study. I'd also add that given the ever-growing relationship between the behavioural/psychiatric and the somatic, a greater consideration of some other health-related conditions (see here and see here for examples) might also be useful...

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[1] Cheng CM. et al. Co-aggregation of major psychiatric disorders in individuals with first-degree relatives with schizophrenia: a nationwide population-based study. Mol Psychiatry. 2017 Nov 7.

[2] Evans B. How autism became autism: The radical transformation of a central concept of child development in Britain. History of the human sciences. 2013;26(3):3-31.

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Methylphenidate as a 'suicide risk reducing agent' in ADHD: implications for other labels?

Don't get me wrong, I'm not falling hook, line and sinker for the findings reported by Sophie Hsin-Yi Liang and colleagues [1] observing that "among ADHD [attention-deficit hyperactivity disorder] youths, reduction of suicide risk was observed in patients prescribed MPH [methylphenidate] for duration 90 days and longer."

I've read too much on how complex something like suicide - ideation, attempts and completion - is to ever believe that there is some single magical answer to universally reducing or eliminating suicidal behaviours and the wide-ranging effects they have. Yes, there are some compounds that have a pretty good evidence base for being an 'anti-suicidal agent' (see here) but even with something like lithium, further investigations are required on their universal applicability and important details like their cost-benefit ratio.

Having said all that, I am drawn to the findings reported by Liang et al for a few very good reasons. First, is the continued reliance on 'big data' Taiwan and the use of the National Health Insurance Research Database (NHIRD) as a research resource. Second, is the continued focus on suicide and possible factors/predictors of suicide based on examination of NHIRD data [2]. Third, is the idea that "rates of suicide ideation, self-injury and suicide attempts are significantly increased in untreated ADHD populations" and how something like MPH use potentially (positively) affecting ADHD symptoms might have other effects. Finally, there is also the tantalising prospect that other conditions/labels where ADHD might be over-represented where also alongside there is a growing focus on suicidal behaviours, the Liang findings might also be relevant...

So what did Liang and colleagues do and find? Well looking at the records of some 85,000 children and young people where ADHD was diagnosed, researchers looked for evidence of recorded suicide attempts as a function of whether MPH was being used or not (where "MPH is the only stimulant approved for the treatment of ADHD in Taiwan"). They found that "100 (0.1%) youths met the criteria for suicide attempts during the surveillance period" and perhaps a little contrary: "37 (0.2%) in the group without any MPH use and 63 (0.1%) in the group with MPH use."

But the devil is in the detail, as authors then factored in a few pertinent, potentially confounding variables (gender, age, other diagnoses, other medication) and length of time of taking MPH (1-90 days, 91-180 days, over 180 days) into models of risk. They concluded that there was actually a 'risk reducing effect' from MPH use following such analyses: "We observed a 59% suicide attempt risk reduction among ADHD youths prescribed between 90 and 180 days and a 72% risk reduction in those prescribed more than 180 days of MPH."

This is not the first time that MPH use for ADHD and suicide risk has been discussed in the peer-reviewed science literature. The paper by Man and colleagues [3] talked about how the incidence of suicide went up before and at the beginning of MPH initiation in their cohort of around 25,000 children and young adults, but importantly risk "returned to baseline levels during continuation of methylphenidate treatment." They account for their findings by suggesting that: "The observed higher risk of suicide attempts before treatment may reflect emerging psychiatric symptoms that trigger medical consultations that result in a decision to begin ADHD treatment." I put this in the context that ADHD does seem to be a risk factor for various other psychiatric diagnoses (see here and see here). Other independent data [4] has also talked about "a potential protective effect of drugs for ADHD on suicidal behaviour, particularly for stimulant drugs." There seems to be a case for MPH as potentially affecting [some] suicide risk in relation to [some] ADHD...

I want to now take you back to the title of this post, and specifically the 'implications for other labels?' bit. How ADHD and specifically, MPH use for ADHD symptoms, might offer some important 'lessons' for conditions where for example ADHD is over-represented as a comorbidity. Of course I speak of autism and autism spectrum disorder (ASD) where it is fast becoming accepted that the risk of receiving a diagnosis of ADHD is pretty significantly heightened (see here). Alongside, quite a lot of attention is also being paid to the issue of suicide risk and autism (see here) and specifically, what factors might predispose to an elevated risk of suicide in cases of autism (see here) (hint: it's probably not all just down to depression or indeed, any one factor in isolation). Adding in the Liang findings to autism is, I think, quite a sensible thing to do. No, it's not about shifting 'blame' for suicidal behaviours from one label to the next, but instead realising that for some people on the autism spectrum, ADHD does present an additional 'feature' and such a feature might very well carry with it some increased risk for suicidal behaviours. The other strand of evidence that is probably relevant to this is the idea that the risk of various psychiatric diagnoses seem also to be elevated alongside a diagnosis of autism. The prospect therefore that MPH used to manage ADHD occurring alongside autism might reduce any risk of suicidal behaviours is something that requires quite a bit more investigation.

And while I'm mentioning MPH in the context of [some] autism, the recent Ccohrane review of MPH for kids and young people diagnosed with autism [5] suggests something quite positive when it comes to issues such as "symptoms of hyperactivity and possibly inattention" (albeit with more research required)...

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[1] Liang SHY. et al. Suicide risk reduction in youths with attention-deficit/hyperactivity disorder prescribed methylphenidate: A Taiwan nationwide population-based cohort study. Research in Developmental Disabilities. 2018; 72: 96-105.

[2] Lin YW. et al. Influential Factors for and Outcomes of Hospitalized Patients with Suicide-Related Behaviors: A National Record Study in Taiwan from 1997-2010. PLoS One. 2016 Feb 22;11(2):e0149559.

[3] Man KKC. et al. Association of Risk of Suicide Attempts With Methylphenidate Treatment. JAMA Psychiatry. 2017 Oct 1;74(10):1048-1055.

[4] Chen Q. et al. Drug treatment for attention-deficit/hyperactivity disorder and suicidal behaviour: register based study. BMJ. 2014 Jun 18;348:g3769.

[5] Sturman N. et al. Methylphenidate for children and adolescents with autism spectrum disorder. Cochrane Database Syst Rev. 2017 Nov 21;11:CD011144.

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Dementia risk in adult ADHD

"Adults with ADHD [attention-deficit hyperactivity disorder] have a 3.4-fold risk of developing dementia."

That was the conclusion reached by Nian-Sheng Tzeng and colleagues [1] who applied the 'big data' power of the Taiwanese National Health Insurance Research Database (NHIRD) to the question of whether yet more enhanced risk of adversity might be associated with a diagnosis of ADHD. Dementia by the way, reflects various symptoms/conditions pertinent to the decline of cognitive and other abilities.

Drawing on participant numbers in the hundreds, researchers determined that the risk of receipt of a dementia diagnosis in cases of adult ADHD was marginally higher compared with an asymptomatic (asymptomatic for ADHD) control group (5.4% vs. 4%). An association between ADHD diagnosis and risk of subsequent dementia remained after various, potentially interfering variables, were also taken into consideration ("age, gender, comorbidities, geographical area of residence, urbanization level of residence, and monthly income").

This is not the first time that enhanced risk of dementia in ADHD has been discussed in the peer-reviewed domain [2]. As per that previous report from Golimstok and colleagues - "there is no clear explanation for the association found" - science still does not have many clues as to why ADHD might preferentially predispose to certain types of dementia. I say this on the basis that we don't really know that much about the biology of either condition/diagnosis. That's not however to say that science is not getting closer to some important clues, as the report from Zhang and colleagues [3] talking about an animal model of Alzheimer's disease that also had "a high frequency of antecedent ADHD symptoms" is detailed. More studies are indicated.

To close, a link to an article marking the recent passing of the father of the ADHD diagnosis: Keith Conners together with a warning...

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[1] Tzeng NS. et al. Risk of Dementia in Adults With ADHD: A Nationwide, Population-Based Cohort Study in Taiwan. J Atten Disord. 2017 Jun 1:1087054717714057.

[2] Golimstok A. et al. Previous adult attention-deficit and hyperactivity disorder symptoms and risk of dementia with Lewy bodies: a case-control study. Eur J Neurol. 2011 Jan;18(1):78-84.

[3] Zhang Q. et al. Alzheimer's Model Develops Early ADHD Syndrome. J Neurol Neurophysiol. 2015;6(6):1-6.

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Injury risk and ADHD: part 2

Consider this short post a sort of follow-on to a previous entry on this blog concerning the elevated risk of injury following a diagnosis of attention-deficit hyperactivity disorder (ADHD). The paper in question today is that by Wu-Chien Chien and colleagues [1] who yet again [2], brought the quite significant scientific weight of the "National Health Insurance Research Database in Taiwan" to bear on this topic.

In this latest paper, Chien et al relied on data from a 'subset' of the main insurance research database and found some not unexpected things: "The patients with ADHD had a 143% increased risk of overall injuries than the controls after considering all the confounding factors" and "the use of methylphenidate was associated with a 22.6% decrease in the risk of injuries in the patients with ADHD."

What's more to say? Well, yet again risk of adverse issues *correlating* with a diagnosis of ADHD comes to the forefront (see here for another example). Yet again the idea that 'tackling' ADHD is a worthy goal (for many reasons) if not only to mitigate such elevated risks being presented, bearing in mind that medication "approved solely for ADHD treatment" is not some sort of magic bullet [3]. There are also other potentially important intervention options to look at (see here for example). I'm minded at this point to also bring in the recent findings reported by Borschuk and colleagues [4] talking about how comorbid asthma accompanying ADHD (yes, there is a surprisingly strong relationship between the two diagnoses) might play a role in the expression of ADHD and onwards provide some 'interesting' directions when it comes to tackling ADHD and it's elevated risk for various adverse outcomes...

To close, appreciating a talent...

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[1] Chien WC. et al. The risk of injury in adults with attention-deficit hyperactivity disorder: A nationwide, matched-cohort, population-based study in Taiwan. Res Dev Disabil. 2017 Apr 27;65:57-73.

[2] Kang JH. et al. Attention-deficit/hyperactivity disorder increased the risk of injury: a population-based follow-up study. Acta Paediatr. 2013 Jun;102(6):640-3.

[3] Fleming M. et al. Educational and Health Outcomes of Children Treated for Attention-Deficit/Hyperactivity Disorder. JAMA Pediatr. 2017. May 1.

[4] Borschuk AP. et al. The influence of comorbid asthma on the severity of symptoms in children with attention-deficit hyperactivity disorder. J Asthma. 2017 May 1:1-7.

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Chien WC, Chung CH, Lin FH, Yeh CB, Huang SY, Lu RB, Chang HA, Kao YC, Chiang WS, Chou YC, Tsao CH, Wu YF, & Tzeng NS (2017). The risk of injury in adults with attention-deficit hyperactivity disorder: A nationwide, matched-cohort, population-based study in Taiwan. Research in developmental disabilities, 65, 57-73 PMID: 28458048

"Asthma was associated with increased risk for schizophrenia"

'Big data' Taiwan is once again the topic of a post on this blog as the results published by Wei-Chen Wang and colleagues [1] (open-access available here) receive an airing, specifically that: "Asthma was associated with increased risk for schizophrenia."

There are some common themes attached to these findings. Taiwan is already a research-favourite place on this blog as a result of their use of the National Health Insurance Research Database (NHIRD) for various research purposes. I can't name all the occasions I've talked about research from Taiwan based on the NHIRD but a few of them can be seen here and here. Another commonality of this latest research from Wang et al is the idea that physical illness with a substantial immune system component to it *might* show an important connection to a behavioural/psychiatric disorder. Asthma and related atopic diseases has been mentioned on a few other occasions (see here and see here). Hold those thoughts for now...

This time around Wang and colleagues "aimed to investigate the association between asthma, corticosteroid use, and schizophrenia." Comparing 'measures of schizophrenia' in some 25,000 participants diagnosed with asthma and 50,000 without asthma over 7 years, and adjusting for various potentially confounding variables - "sex, age, residence, socioeconomic status, corticosteroid use, outpatient and emergency room visit frequency, Charlson comorbidity index, and total length of hospital stays days for any disorder" - the results were interesting. Not least that "asthma was associated with significantly greater hazard ratio for incident schizophrenia." Researchers also noted that various other confounding variables also showed a relationship with schizophrenia such as rural residence, poor general health and lower economic status. "Corticosteroid use was not associated with increased risk for schizophrenia" we are also told.

Whilst interesting, the results do not say that everyone with asthma is at risk of developing schizophrenia. Not even close. The rates of schizophrenia identified in the Wang study were also quite low overall despite the large starting populations studied: "Of the total 75,069 subjects, 238 were diagnosed with schizophrenia during the study period: 100 (0.40%) of subjects were in the asthma cohort and 138 (0.28%) in the non-asthma cohort."

But, set within the context of other independent datasets [2] observing "the existence of an association between atopic disorders in general and asthma in particular and the risk of developing schizophrenia" there is cause for further investigation into any association. Not least that Wang et al describe their results in the context that: "a convergent disturbance in the immune-inflammatory system may contribute to the pathoetiology of asthma and schizophrenia." Y'know, all that talk that among the [plural] schizophrenias, one or two phenotypes might, to some quite large extent, be linked to immune function or dysfunction. Well, it's not as if we haven't got some quite reliable research clues already (see here). There may also be some subsequent discussions on the requirement for enhanced screening for something like schizophrenia as and when a diagnosis of asthma (or other atopic disease) is diagnosed as per other data (see here).

Finally, going back to the previous research occasions when asthma has been *correlated* with labels such as attention-deficit hyperactivity disorder (ADHD) and even autism, I'm wondering whether there could be wider links present when it comes to immune-related conditions and behavioural presentations. It's pretty well known that various behavioural/developmental/psychiatric labels tend to 'club together' (see here and see here for examples). There is also a growing realisation that alongside overlapping genetics and biology when it comes to such labels, the days of autism genes for example, just being genes for autism are beginning to drift off (see here); something probably relevant to conditions such as ADHD and schizophrenia too. So, could it be that immune system related conditions such as asthma and atopic disease, might have lots and lots of implications in relation to many developmental/behavioural/psychiatric labels? Even more intriguing, are there clues to possible intervention avenues too? (with no medical or clinical advice given or intended).

We await further investigations...

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[1] Wang WC. et al. Asthma, corticosteroid use and schizophrenia: A nationwide population-based study in Taiwan. PLoS One. 2017 Mar 28;12(3):e0173063.

[2] Pedersen MS. et al. Schizophrenia in patients with atopic disorders with particular emphasis on asthma: a Danish population-based study. Schizophr Res. 2012 Jun;138(1):58-62.

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Wang WC, Lu ML, Chen VC, Ng MH, Huang KY, Hsieh MH, Hsieh MJ, McIntyre RS, Lee Y, & Lee CT (2017). Asthma, corticosteroid use and schizophrenia: A nationwide population-based study in Taiwan. PloS one, 12 (3) PMID: 28350822

Relative age and ADHD medication

"Youngest children in class 'more likely to be given ADHD drugs'" went the NHS Choices headline that led me to the short report produced by Martin Whitely and colleagues [1] (open-access).

ADHD - attention-deficit hyperactivity disorder - is something of interest to this blog; not least the idea that relative age (age relative to peers in the same school year group) might be an important variable when it comes to at least some diagnoses of the condition (see here).

The Whitely paper draws on data from a research favourite place - Western Australia (WA) - and focused on "the proportions of WA children born in the early and late months of a recommended school-year intake who received at least one Pharmaceutical Benefits Scheme [PBS] prescription for an ADHD medication in 2013."

The results: from a starting population of some 300,000 children, about 6,000 of them (~2%) were in receipt of a state-recognised prescription of an ADHD medication. The article does not actually mention which ADHD medication was given but methylphenidate (a.k.a Ritalin) is listed in the PBS directory and is the typically indicated medication used for ADHD (see here). Boys, we are told, were more likely to be prescribed ADHD medication than girls (2.9% vs. 0.8% respectively).

Then to the headline: when splitting the children into two age groups - 6-10 year olds and 11-15 year olds - researchers noted that those born in June (the last birth month influencing year of school intake) were more likely to be prescribed ADHD medication than those born in July. This trend was noted in both age groups. The conclusion being that the youngest children in a year group at school were more likely to be in receipt of prescribed medication for ADHD compared to older children in the year group.

Alongside the caveats linked to the Whitely report made by NHS Choices, there is a need for further investigation in this area and in particular, whether the results generalise to places outside of just WA. I've already linked to my previous discussion about relative age and ADHD diagnosis/medication (see here again) and from comparisons with the Taiwanese data [2] on this topic, including the fact that Taiwan have a different cut-off month for school entry (August 31). On that basis, yes the trend appears to generalise across geographies...

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[1] Whitely M. et al. Influence of birth month on the probability of Western Australian children being treated for ADHD. MJA. 2017; 206: Feb 6.

[2] Chen MH. et al. Influence of Relative Age on Diagnosis and Treatment of Attention-Deficit Hyperactivity Disorder in Taiwanese Children. J Pediatr. 2016 May;172:162-167.e1.

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Martin Whitely, Leanne Lester, John Phillimore, & Suzanne Robinson (2017). Influence of birth month on the probability of Western Australian children being treated for ADHD The Medical Journal of Australia

'Big data' Taiwan and schizophrenia risk

Today I bring the findings reported by Chou and colleagues [1] (open-access available here) to the blogging table and how the research might of the Taiwan National Health Insurance Database (NHIRD) brought it's 'big data' ("n = 23 422 955") to bear on the question: what is the risk of developing schizophrenia where one or more first-degree or other relatives are affected?

The answer: "Having an affected co-twin, first-degree relative, second-degree relative, or spouse was associated with an adjusted RR [relative risk] (95% CI) of 37.86 (30.55-46.92), 6.30 (6.09-6.53), 2.44 (1.91-3.12), and 1.88 (1.64-2.15), respectively. Compared with the general population, individuals with one affected first-degree relative had a RR (95% CI) of 6.00 (5.79-6.22) and those with 2 or more had a RR (95% CI) of 14.66 (13.00-16.53) for schizophrenia."

To translate the science-talk: if one twin is diagnosed with schizophrenia, there is a hugely increased risk of the other twin also being affected. If a mother or father, sister or brother, or your child(ren) are diagnosed with schizophrenia, there is an enhanced risk but nothing like the risk to twins. As you move outwards to other outlying family members (uncles, aunts, grandparents, etc) affected, your risk continues to diminish albeit still noticeable. Interestingly, when it comes to spouses (husband or wife), there is a small but increased risk that if they are diagnosed with schizophrenia so the other partner is at some small, enhanced risk. This tallies with the concept of assortative mating [2] but does not necessarily rule out other shared non-genetic factors either.

The final sentence in that quote provides some evidence for a cumulative effect too. So if one of your close family members is diagnosed with schizophrenia, so the risk to yourself might be heightened. If two or more close family members are diagnosed, the relative risk to yourself jumps quite a bit more.

"A family history of schizophrenia is therefore associated with a higher risk of developing schizophrenia, mood disorders, and delusional disorders. Heritability and environmental factors each account for half of the phenotypic variance of schizophrenia."

To close, Yoda don't like seagulls...

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[1] Chou IJ. et al. Familial Aggregation and Heritability of Schizophrenia and Co-aggregation of Psychiatric Illnesses in Affected Families. Schizophr Bull. 2016 Nov 21. pii: sbw159.

[2] Parnas J. Assortative mating in schizophrenia: results from the Copenhagen High-Risk Study. Psychiatry. 1988 Feb;51(1):58-64.

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Chou IJ, Kuo CF, Huang YS, Grainge MJ, Valdes AM, See LC, Yu KH, Luo SF, Huang LS, Tseng WY, Zhang W, & Doherty M (2016). Familial Aggregation and Heritability of Schizophrenia and Co-aggregation of Psychiatric Illnesses in Affected Families. Schizophrenia bulletin PMID: 27872260

Atopic dermatitis and the "increased risk of developing ADHD and ASD later in life"

I'm not gonna dwell too much on the findings reported by Lee and colleagues [1] talking about how "toddlers who suffer from AD [atopic dermatitis] at the age younger than 3 years are at a higher risk of developing ADHD [attention-deficit hyperactivity disorder] and ASD [autism spectrum disorder] during later childhood" because science already seems to understand that there may be an important connection between early allergic disease and later offspring behavioural/developmental outcomes (see here for example).

That the Lee data is derived once again from the 'big data' powerhouse that is Taiwan - specifically the National Health Insurance Research Database (NHIRD) - makes the findings that little bit more 'believable' given the numbers and processes involved in collecting said information.

"Children from the AD group with 3 comorbidities together, namely, allergic rhinitis, allergic conjunctivitis, and asthma, had the greatest risk of developing ADHD and ASD." Within statements like that it is getting progressively more difficult to downplay the impact that immune function (or immune response?) might have to quite a few people diagnosed as on the autism spectrum or with ADHD (or both). Further, that for some the 'treatment' of certain allergic symptoms might also impact on behaviour/development (see here and see here for examples) provides an important roadmap for further investigations in this area and the identification of who might be 'best responders' for such intervention (with no medical advice given or intended).

"Pediatricians taking care of toddlers with AD should have knowledge of this increased risk of developing ADHD and ASD later in life, especially when children have certain comorbidities such as allergic rhinitis, allergic conjunctivitis, and asthma." Who would disagree, bearing in mind that the spectrum of potential correlates linked to early life allergy may be pretty wide?

To close, some words of wisdom: "there is no good reason for self-conscious farters to avoid fibre."

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[1] Lee CY. et al. Longitudinal association between early atopic dermatitis and subsequent attention-deficit or autistic disorder: A population-based case-control study. Medicine (Baltimore). 2016 Sep;95(39):e5005.

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Lee CY, Chen MH, Jeng MJ, Hsu JW, Tsai SJ, Bai YM, Hung GY, Yen HJ, Chen TJ, & Su TP (2016). Longitudinal association between early atopic dermatitis and subsequent attention-deficit or autistic disorder: A population-based case-control study. Medicine, 95 (39) PMID: 27684861

The (surprising) rate of ADHD in Taiwan

The idea that use of the diagnostic label called attention-deficit hyperactivity disorder (ADHD) is on the increase, and pretty significantly so, is quite common-place these days (see here). Appreciating that not everyone is convinced that the increase is necessarily genuine (see here) I would like to discuss some interesting data coming out of the 'big data' country that is Taiwan in the form of the findings reported by Wang and colleagues [1].

As regular readers might already know, Taiwan is the producer of quite a lot of big data findings in recent years as a function of the implementation of the National Health Insurance Research Database (NHIRD) some of which have been covered before on this blog (see here for example). This time around Wang et al set about exploring "trends in ADHD diagnosis in youths and the proportion of those receiving medication, with the aim of determining whether ADHD is overdiagnosed and overmedicated in Taiwan."

With a participant number approaching 150,000 diagnosed with ADHD between 2000 and 2011 - young people below 18 years of age - researchers calculated figures for ADHD each year between 2000 and 2011. They also looked at some details around medication history for cases during each year based on "those with at least one record of pharmacotherapy (immediate-release methylphenidate, osmotic controlled-release formulation of methylphenidate, and atomoxetine)."

Results: very interestingly the prevalence rates of ADHD for 2000 and in 2011 were not as dissimilar as you might first think (0.1% vs 1.2% respectively). The authors also point out that their prevalence rates are at odds with other work: "The rate of ADHD diagnosis was far lower than the prevalence rate (7.5%) identified in a previous community study using face-to-face interviews." They did observe some differences in rates of ADHD according to age where rates seemed to be higher as age increased - those aged between 7-12 years old or 13-18 years had a higher rate of ADHD compared with those 6 years and under. They also noted that medication use was 'more probable' as children got older and indeed, that medication use generally was on the rise.

These are important data. Yes, one could argue that the results might only be relevant to Taiwan and not necessarily generalisable to other parts of the world but you could say that about any piece of research based on one population. The NHIRD has strengths; many of them outside of just being rather large and including some 99% of the population and I've generally taken to believing findings from it as and when they emerge. So when the authors conclude that their findings are "not consistent with a systematic public opinion about overdiagnosis or overmedication of ADHD in Taiwan" I'm generally inclined to go with them.

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[1] Wang LJ. et al. Prevalence rates of youths diagnosed with and medicated for ADHD in a nationwide survey in Taiwan from 2000 to 2011. Epidemiol Psychiatr Sci. 2016 Jul 20:1-11.

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Wang, L., Lee, S., Yuan, S., Yang, C., Yang, K., Huang, T., Chou, W., Chou, M., Lee, M., Lee, T., & Shyu, Y. (2016). Prevalence rates of youths diagnosed with and medicated for ADHD in a nationwide survey in Taiwan from 2000 to 2011 Epidemiology and Psychiatric Sciences, 1-11 DOI: 10.1017/S2045796016000500

Risk of type 2 diabetes in autism

"Adolescents and young adults with ASD [autism spectrum disorder] were more likely to develop type 2 DM [type 2 diabetes mellitus] during the follow-up. In addition, those with ASD using atypical antipsychotics exhibited a high risk. Therefore, further research is necessary to investigate the common pathophysiology of ASD and type 2 DM."

So said the findings reported by Mu-Hong Chen and colleagues [1] as, yet again, Taiwan and their very useful National Health Insurance Research Database (NHIRD) continues to give to autism and related research.

Type 2 diabetes - the one where the pancreas don't produce enough insulin or the body's cells don't react to insulin - was the focus of NHIRD interrogation this time around, following in the scientific footsteps of previous research looking at both type 1 and type 2 diabetes in relation to autism (see here). Enrolling over 6,000 adolescents and young adults diagnosed with an autism spectrum disorder (ASD) and nearly 25,000 age and sex-matched controls "between 2002 and 2009", researchers followed participants until the end of 2011 watching for who and how many would be diagnosed with type 2 DM.

Dividing groups into adolescents and young adults, researchers reported that those diagnosed with autism were at "higher risk of developing type 2 DM than those without ASD" after adjusting for various potential forms of bias including "atypical antipsychotics use, and medical comorbidities." Further: "Short-term... and long-term... use of atypical antipsychotics were associated with a higher likelihood of subsequent type 2 DM." Ergo, yet another important, growing and potentially life-changing comorbidity appears to be 'over-represented' when it comes to the label of autism.

Accepting that it is not necessarily new news that certain pharmaceutical formulations can affect risk of type 2 diabetes [2], these are interesting and potentially important results. The focus on how maternal diabetes 'exposure' might modify risk of autism in offspring (see here) coupled to ideas about how autoimmunity inferred by type 1 diabetes history might link into some autism (see here) have tended to predominate in this area of the autism research landscape. The Chen results tap into a pretty under-appreciated idea that for one reason or another, a diagnosis of autism could potentially raise the risk of something like type 2 diabetes.

There is additional research to do on this topic. So, in these days of greater appreciation that 'autism genes' might not necessarily just be 'genes for autism' (pleiotropy), one could reasonably ask the question of whether there are subtle genetic (or epigenetic) issues influencing risk of type 2 diabetes. As per my use of the word 'epigenetic' in that last sentence, I'm also minded to bring in the work from people like the late David Barker, and the idea that birth weight might also 'program' for a greater risk for type 2 diabetes and related health issues (see here) given what's known about this area with autism in mind (see here).

That type 2 diabetes is not a wholly genetic issue is something else to bear in mind as issues such as weight and eating patterns come into the frame. Minus any sweeping generalisations, weight issues and particularly obesity are not uncommon research topics when it comes to autism (see here) and as for eating patterns and habits, well, let's just say there is some science there too (see here). Whether singularly or combined (and with potential added mention of exercise) one might already see how screening for type 2 diabetes should be added to the list of monitoring required when a diagnosis of autism is received. I might also mention some recent research chatter about leptin as being important to type 2 diabetes in kids and where that might go with regards to other autism research (see here). I'm sure there other factors too.

And, if and when type 2 diabetes in diagnosed, there are a number of positive changes that can be made to lifestyle including the idea that 'reversal' is not something totally unheard of...

So:  The Force Awakens and Dark Side of the Moon... synch or no synch?

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

[2] Galling B. et al. Type 2 Diabetes Mellitus in Youth Exposed to Antipsychotics: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2016 Mar 1;73(3):247-59.

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Chen, M., Lan, W., Hsu, J., Huang, K., Su, T., Li, C., Lin, W., Tsai, C., Tsai, S., Lee, Y., Chen, Y., Pan, T., Chang, W., Chen, T., & Bai, Y. (2016). Risk of Developing Type 2 Diabetes in Adolescents and Young Adults With Autism Spectrum Disorder: A Nationwide Longitudinal Study Diabetes Care DOI: 10.2337/dc15-1807

Relative age and ADHD

"ADHD children may just be immature, research suggests".

So went the recent BBC headline with reference to the findings reported by Mu-Hong Chen and colleagues [1] (open-access) and the idea that: "Relative age, as an indicator of neurocognitive maturity, is crucial in the risk of being diagnosed with ADHD [attention-deficit hyperactivity disorder] and receiving ADHD medication among children and adolescents."

Chen et al are not unfamiliar names discussed on this blog (see here for example) in light of the rise and rise of data emerging from the Taiwan National Health Insurance Research Database (NHIRD) covering all-manner of associations linked to diagnoses such as ADHD and autism. Indeed, not so long ago I was discussing the idea the atopic dermatitis *might* be implicated in one or other diagnosis (see here). This time around the NHIRD was used to test a different hypothesis: "those born in August are more likely to be diagnosed with ADHD and receive a prescription for ADHD treatment than those born in September."

An important detail first that many parents with a child born around late August / early September will probably have considered before their child starts school - "The cut-off birthdate for entry to school in Taiwan is August 31, and consequently, those born in August are typically the youngest in their grades." From a starting population of 1 million - "approximately 4.3% of the population of Taiwan" - who were randomly selected from the NHIRD, researchers whittled the numbers down to just under 400,000 aged 4-17 years who were "categorized on the basis of their birth month." The prevalence of ADHD and receipt of "a prescription for ADHD medication (methylphenidate or atomoxetine)" were examined by month, and various statistics were produced.

Results: an interesting pattern of diagnosis by birth month emerged. "The prevalence of subjects receiving ADHD diagnosis or medication increased with each birth month from September (1.8% and 1.2%) to August (2.9% and 2.1%)." In other words, those born in August were almost twice as likely to be diagnosed with ADHD as those born the previous September. This increased 'risk' mostly held true when analysis was also done on the basis of specific years starting 1997-1998 through to 2010-2011 and also crossed the genders.

The idea that relative immaturity compared to class peers might influence ADHD diagnosis is not a new one. Halldner and colleagues [2] reported on a smaller yet still pretty large cohort of children looking at ADHD diagnosis and medication treatment in Sweden. They reported that "ADHD diagnoses and medication treatment were both significantly more common in individuals born in November/December versus January/February" but also "no corresponding differences in parent- or self-reported ADHD symptoms by calendar birth month." Other authors [3] have arrived at similar conclusions including during recent research.

Some commentators have already cautioned about reading too much into the Chen results as a function of them being exclusively based on ADHD diagnosis and medication data without reference to important variables such as family history and environmental influences. I agree that further investigation is indicated before anyone heads down the 'it's all due to immaturity' route and perhaps over-simplifying what can often be a complicated diagnosis/presentation. This also perhaps ties into some important discussions on the increasing rate of ADHD being noted worldwide (see here).

That all being said, the idea that perceptions of classroom behaviour may not fully take into account age in comparison to peers perhaps suggests that further education and training should be offered to education providers in order to highlight this issue. That other more social factors such as level of economic deprivation (see here) may also influence decisions about using the label ADHD provides a timely reminder that psychiatric labels do not exist outside of social context.

Finally, readers might also entertain the idea that conception in the winter months leading to a late summer birth might also play a role in the results obtained and more than one environmental factor could play a role in the findings. That includes the continuing interest in the overlap between asthma and ADHD (see here). Science in this area might also learn a thing or two from some other recent research findings too...

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[1] Chen M-H. et al. Influence of Relative Age on Diagnosis and Treatment of Attention-Deficit Hyperactivity Disorder in Taiwanese Children. The Journal of Pediatrics. 2016. 10 March.

[2] Halldner L. et al. Relative immaturity and ADHD: findings from nationwide registers, parent- and self-reports. J Child Psychol Psychiatry. 2014 Aug;55(8):897-904.

[3] Elder TE. The importance of relative standards in ADHD diagnoses: evidence based on exact birth dates. J Health Econ. 2010 Sep;29(5):641-56.

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Chen, M., Lan, W., Bai, Y., Huang, K., Su, T., Tsai, S., Li, C., Lin, W., Chang, W., Pan, T., Chen, T., & Hsu, J. (2016). Influence of Relative Age on Diagnosis and Treatment of Attention-Deficit Hyperactivity Disorder in Taiwanese Children The Journal of Pediatrics DOI: 10.1016/j.jpeds.2016.02.012

ADHD primes for psychosis and/or schizophrenia?

My efforts turn once again to Taiwan today and the results reported by Yu-Chiau Shyu and colleagues [1] that: "Compared to the control group, the ADHD [attention-deficit hyperactivity disorder] group showed significantly increased risk of developing any psychotic disorder... and schizophrenia."

As per the multitude of other instances where Taiwan is mentioned as a research powerhouse, the source data for the Shyu findings was the Taiwan National Health Insurance Research Database and the analysis of data for over 73,000 people "newly diagnosed with ADHD" compared with a similar number of age- and sex-matched non-ADHD controls. "Having a diagnosis of any psychotic disorder and of schizophrenia were set as two different outcomes and were analyzed separately" we are told, as was the possible role (or not) of methylphenidate (MPH) treatment of ADHD on psychosis / schizophrenia outcomes.

In line with the opening paragraph, there was potentially something to see when it came to a previous diagnosis of ADHD priming someone for future psychotic disorder or schizophrenia. The adjusted hazard ratios (aHRs) - "5.20; 95% confidence interval [CI], 4.30-6.30 and 4.65; 95% CI, 3.59-6.04" - for psychotic disorder and schizophrenia respectively are not to be sniffed at. Shyu et al also noted that where MPH use was part of the the ADHD intervention regime, there was a suggestion that MPH use increased the risk of developing psychotic disorder but not schizophrenia. Such a finding is not unheard of in the peer-reviewed literature [2]. The authors also noted that: "Compared to ADHD patients without psychosis, patients with ADHD who developed psychosis had significantly older age at first diagnosis of ADHD (9.4±3.3years vs. 10.6±4.0years)."

This is not the first time that ADHD has been associated with psychosis and/or schizophrenia. The results reported by Dalteg and colleagues [3] are testament to the idea of a possible connection, even if moderated by variables such as substance abuse issues. Indeed, the idea that a diagnosis of ADHD might elevate the risk of substance abuse [4] is an important point given the various voices lending support to the idea that substance abuse might also be a risk factor for psychosis [5]. That being said, I don't want to stigmatise everyone with ADHD on the basis of this connection; there may be quite a few other 'shared pathways' also to consider (see here) and not just of the genetic variety as per nutritional issues for example (see here and see here).

The Shyu results do however reiterate that birds of a developmental / psychiatric feather may very well flock together as per other research findings in related areas (see here). That such a connection can so severely affect quality of life potentially provides further evidence that continued efforts to alleviate childhood psychiatric issues should represent an important goal of modern-day medicine (see here) particularly in respect to the rising numbers being discussed (see here)...

Music: Rush Hour - Jane Wiedlin.

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[1] Shyu YC. et al. Attention-deficit/hyperactivity disorder, methylphenidate use and the risk of developing schizophrenia spectrum disorders: A nationwide population-based study in Taiwan. Schizophr Res. 2015 Sep 9. pii: S0920-9964(15)00462-4.

[2] Kraemer M. et al. Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature. Clin Neuropharmacol. 2010 Jul;33(4):204-6.

[3] Dalteg A. et al. Psychosis in adulthood is associated with high rates of ADHD and CD problems during childhood. Nord J Psychiatry. 2014 Nov;68(8):560-6.

[4] Lee SS. et al. Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: a meta-analytic review. Clin Psychol Rev. 2011 Apr;31(3):328-41.

[5] Cantwell R. et al. Prevalence of substance misuse in first-episode psychosis. Br J Psychiatry. 1999 Feb;174:150-3.

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Shyu YC, Yuan SS, Lee SY, Yang CJ, Yang KC, Lee TL, & Wang LJ (2015). Attention-deficit/hyperactivity disorder, methylphenidate use and the risk of developing schizophrenia spectrum disorders: A nationwide population-based study in Taiwan. Schizophrenia research PMID: 26363968