Depression and autism: same message(s) as before

Today I'm bringing a couple of recently published studies to the blogging table pertinent to to the idea that depression or clinically-relevant depressive symptoms are over-represented when it comes to autism. Not a new topic by any means (see here) but an important one...

First up are the findings reported by Michelle Menezes and colleagues [1] who observed that: "depression is more common in youth with autism spectrum disorders than in typically developing youth and is associated with a multitude of other medical and psychiatric conditions."

The results, based on a systematic review of the peer-reviewed research literature, draw on data from over 40 studies published between 2012 and 2016 and add a further voice to the observation that depression is over-represented alongside a diagnosis of autism. The 'associated with a multitude of other medical and psychiatric conditions' is also not a new thing (see here for example). This in the context that autism rarely appears in some sort of diagnostic vacuum (see here), be that in relation to the psychiatric or physical domains.

"Unfortunately, few intervention studies have been conducted despite evidence of need and preliminary efficacy for some psychosocial and pharmacological treatments." This is another important point made by the authors. It stresses how screening (and not just screening at one point) should be more widespread as and when autism is diagnosed. And where present, those with depression should be able to access recognised treatment/intervention strategies for the condition(s) (including but not limited to [2] pharmacotherapy and other evidence-based therapeutic options). It also stresses how, just as facets of depression may present 'atypically' in relation to autism (see here), so there may be a potential need to adjust intervention strategies accordingly.

The second study [3] comes from a researcher who is no stranger to the research use of the words 'depression' and 'autism' (see here) from various different perspectives (see here). Indeed, I'm fast becoming a bit of a fan of the collected works being published by Dheeraj Rai and various colleagues.

On this particular research occasion, Rai et al report results based on the utilisation of one of those fabulous Scandinavian population registries - this time based in Sweden - including well over 200,000 participants. The research question posed was another interesting one: "Are individuals with autism spectrum disorders more likely to have depression in adulthood than the general population, and do these risks have a familial basis and differ by coexisting intellectual disability?"

The answer: well, again not exactly unexpectedly: "depression is overrepresented in autism spectrum disorders." More than that however, the authors talk about how: "The risk of a depression diagnosis was higher in ASD [autism spectrum disorder] without intellectual disability (adjusted RR, 4.28; 95% CI, 4.00-4.58) than in ASD with intellectual disability." They also mention how both non-autistic full and half siblings "appeared to have a greater risk of depression than the general population" which was "more apparent for siblings of children with ASD without intellectual disability."

I was also intrigued to read some of the important potential explanations put forward by authors to account for their results. So: "It was clear that individuals with ASD had a greater risk of depression than their nonautistic siblings, suggesting a mechanism other than shared familial characteristics" was linked to other recent findings from Rai et al [4] observing that some of the core features of autism ("social communication impairments") might be important in the context of bullying victimisation for example. Added to this, they suggest that: "receiving a diagnosis of ASD could partially buffer against an even greater risk of depression by helping individuals understand their difficulties and seek relevant support from educational, health, or social services." This is something that needs further testing as does their observation that: "Approximately half of the individuals with ASD with depression in our sample received a diagnosis of ASD after first being diagnosed as having depression"...

Based on these and the myriad of other studies that have discussed this topic, I'm minded to yet again stress how important further investigations are to discern the hows-and-whys of depression or depressive symptoms being over-represented in relation to autism and what can be done to intervene. I say this in the specific context that depression, as well as being quality-of-life-draining, is probably an important 'link' to those statistics on suicide risk and autism (see here and see here). If you're able to intervene with the depression side of things, I'd wager that at least for some, the risk of suicidality would decrease quite a bit...

Finally, I'm also minded to mention, yet again, that to talk about something like depression as being just 'comorbid' to autism may not do justice to how closely linked such behaviours/diagnosis may be to the autism spectrum (see here and see here). Indeed another recent paper on the topic of depression in young people diagnosed with autism [5] provides more evidence in this area: "The lack of evidence supporting various treatment approaches will be highlighted, including challenges specific to the treatment of depression in ASD [autism spectrum disorder], which are not addressed in the current treatment studies in typically developing youth with depression."

Yet again (see here) a question emerges: does intervening on the core symptoms of autism change the risk profile in relation to various quality-of-life-draining issues? Y'know, as per what we are continuing to learn from some of those so-called 'optimal outcomers' (see here)?

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[1] Menezes M. et al. Depression in Youth with Autism Spectrum Disorders: a Systematic Review of Studies Published Between 2012 and 2016. Review Journal of Autism and Developmental Disorders. 2018. Aug 14.

[2] Rahman MS. et al. Cardiorespiratory fitness and response to exercise treatment in depression. BJPsych Open. 2018. 4: 436-351.

[3] Rai D. et al. Association Between Autism Spectrum Disorders With or Without Intellectual Disability and Depression in Young Adulthood. JAMA Network Open. 2018; 1: e181465.

[4] Rai D. et al. Association of Autistic Traits With Depression From Childhood to Age 18 Years. JAMA Psychiatry. 2018; 75: 835-843.

[5] DeFilippis M. Depression in Children and Adolescents with Autism Spectrum Disorder. Children (Basel). 2018 Aug 21;5(9). pii: E112.

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"Bowel perforation in chronic idiopathic megarectum and megacolon" and autism: 15 years on...

There was something all-too familiar about the case report detailed by Chukwuebuka Anyaegbuna and colleagues [1]. The description of a young man in his mid-twenties "with autism spectrum disorder" and a "history of chronic constipation" (going back years with "multiple previous admissions") eventually being admitted to intensive care on the basis of a potentially life-threatening bowel state is, unfortunately, nothing new to science and clinical practice (see here).

Bowel issues - both functional and more pathological - are over-represented when it comes to a diagnosis of autism (see here and see here for examples). The specific diagnosis of 'megarectum' detailed in the Anyaegbuna paper in relation to autism had also been noted some 15 years previously [2] in the peer-reviewed science literature. Indeed, the paper by Nadeem Afazal and colleagues [2] looking at over 100 children with autism "who were referred for gastroenterological assessment" showed that constipation was not an infrequent finding for this group. They also reported that many autistic children in their cohort "had moderate/severe loading or acquired megarectum." Their observation that "consumption of milk [was found] to be the strongest predictor of constipation in the autistic group" also chimed with me, as an interested researcher of diet as being a potentially important variable for 'some autism' [3]. And indeed, such an observation also seemingly intersects with other more recent dietary-bowel findings too (see here)...

The Anyaegbuna findings represent the continued failure of autism research and practice to take seriously the issue of bowel problems associated with autism. Stretching back over a period of about twenty years or so, I've noted the various comments from various (typically ill-informed) people protesting that various gastrointestinal (GI) investigations are 'not medically indicated' when it comes to some cases of autism. Some even made jokes about it. It's probably not unreasonable for me to say that set within this atmosphere, there has been a general reluctance to look at such issues for fear of castigation or shaming. There have been some brave research souls (see here and see here) who've kept on looking at bowel issues and autism, but not half as many as there should be. And it is those suffering with such bowel problems who have been let down: please do make sure that you take a good look at the X-rays accompanying the Anyaegbuna report to see what I mean.

Having said all that, I would like to think that things are slowly changing. It's no longer taboo to talk about bowel issues being over-represented in relation to autism. Indeed, we've had study after study all pointing in the same direction: bowel issues are seemingly related to autism, covering both childhood and adulthood. And such bowel issues might have some important effects on behaviour (see here). What we are sadly lacking at the current time however, is a concerted research effort asking 'why'? and 'what can we do to prevent (yes, prevent) such bowel issues occurring rather than just treating them when they occur?'

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[1] Anyaegbuna C. et al. Bowel perforation in chronic idiopathic megarectum and megacolon. BMJ Case Rep. 2018 Aug 20;2018. pii: bcr-2018-225406.

[2] Afzal N. et al. Constipation with acquired megarectum in children with autism. Pediatrics. 2003 Oct;112(4):939-42.

[3] Whiteley P. et al. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

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

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

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

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

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

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

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

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The inflammatory effects of unemployment?

"Our study demonstrates that systemic inflammation is associated with an important but little-studied aspect of the social environment, as it is elevated in unemployed compared to employed survey participants."

So said the results of the meta-analysis produced by Amanda Hughes and colleagues [1] (open-access) including data from "12 national studies, incorporating data collected between 1998 and 2012 from all countries in Great Britain" looking at two markers of systemtic inflammation: C-reactive protein (CRP) and fibrinogen. The numbers of participants available for study complete with biological data were "30,037 for CRP analyses and 28,661 for fibrinogen analyses" aged between 22-64 years old.

Alongside the biological information on CRP and/or fibrinogen, researchers also importantly analysed for employment status including "unemployment as commonly understood – the state of being in the labour force and available for work, but currently without it" as distinct from "non-employment categories such as retirement, homemaking or sickness/disability." Data from various other potentially confounding variables were also collected and included in the statistic mix including: age, gender, "socioeconomic position", tobacco smoking status and body mass index (BMI).

Bearing in mind the correlative nature of this research, various potentially important results emerged, not least that "markers of systemic inflammation were elevated for unemployed compared to employed participants." Authors undertook 'robustness checks' to see whether the various potentially confounding variables might have exerted a significant effect on their results and concluded that: "Associations were robust to adjustment for age, gender, education, long term illness, smoking classified using both heaviness and duration, adiposity specified using three BMI-based measures, and mental health, indicating these factors did not explain differences."

What does this research mean then? Well, based on the idea that something like elevations in CRP might be a risk factor for cardiovascular mortality in the general population [2] authors suggest that unemployment might be of 'clinical significance' when it comes to adverse health conditions associated with such an employment status.

There are a few other key points to emerge from the Hughes findings, not least that they may have turned up evidence for "a stronger inflammation-unemployment association in higher-unemployment areas." Their data for example, suggested that unemployment rates were lower in England than in Wales or Scotland over the study period, and that this may have been reflected in their combined data analysis. Different age groups also seemed to show some differences as per the observation that "associations were stronger in the 45–54 group than for younger participants or those approaching retirement."

Stressing again the correlational nature of this meta-analysis, these are potentially informative results. They suggest that, for whatever reasons, the state of being unemployed may not just have social and psychological effects on a person (and their families) but also a somatic element too. I assume one further stage of any research in this area would be to see whether a switch from unemployment to employment has any effects on those inflammatory measures and what element of employment might produce any reductions [3]. Another area of interest might be to see whether factors such as socio-economic status (SES) might also be an important correlate to inflammatory measures [4]. Alongside implications for the general population, I might also advance the idea that where specific groups are 'under-employed', similar inflammatory effects and onward elevated risks for various inflammatory-derived conditions could be something in need of investigation and intervention.

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[1] Hughes A. et al. Unemployment and inflammatory markers in England, Wales and Scotland, 1998–2012: Meta-analysis of results from 12 studies. Brain, Behavior, and Immunity. 2017. March 30.

[2] Li Y. et al. Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: A meta-analysis. Atherosclerosis. 2017 Apr;259:75-82.

[3] Kim S. & Ferraro KF. Do productive activities reduce inflammation in later life? Multiple roles, frequency of activities, and C-reactive protein. Gerontologist. 2014 Oct;54(5):830-9.

[4] Liu RS. et al. Socioeconomic status in childhood and C reactive protein in adulthood: a systematic review and meta-analysis. J Epidemiol Community Health. 2017. 10 May.

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Hughes A, Kumari M, McMunn A, & Bartley M (2017). Unemployment and inflammatory markers in England, Wales and Scotland, 1998-2012: Meta-analysis of results from 12 studies. Brain, behavior, and immunity PMID: 28365380

"Medical Conditions in the First Years of Life Associated with Future Diagnosis of ASD"

I rank the paper by Stacey Alexeeff and colleagues [1] (open-access available here) as being in the 'pretty important' category when it comes to hierarchy in autism research. Not only because of their use of data derived from Kaiser Permanente (KP) (quite a large US healthcare provider that has some autism research history) including some "3911 ASD [autism spectrum disorder] cases and 38,609 controls" but also because some of the findings reiterate what is already 'known' about in relation to autism and how various medical conditions might be quite important to at least some 'types' of autism. These results are also being presented at IMFAR 2017 (see here) which will be opening its doors very soon...

The Alexeeff paper is open-access but a few choice details are worthwhile pulling out:

• As per those participant numbers, the authors confirmed that "ASD cases were defined as children with either (a) an ASD diagnosis from an ASD specialist or (b) two or more ASD diagnoses from non-specialists, separated in time." This contrasted with controls who "were required to never have had an ASD diagnosis as of June 2012" (the period of study covered those born between 2000 and 2009).
• The medical conditions screened for in participant records were quite wide-ranging: "Over 1000 ICD-9 codes were grouped into 79 medical conditions (e.g., constipation) within 19 domains (e.g., gastrointestinal)" and importantly, relied on physician/clinician input. Researchers ascertained how frequently said medical conditions occurred in each of the groups: "whether certain medical conditions occurring in early childhood were associated with a higher risk of future ASD diagnosis."
• Results: "38 of the 79 medical conditions had statistically significant associations with ASD risk after multiple testing adjustment." These conditions ranged from various types/forms of developmental delay (language, learning, motor) to more somatic conditions: "nutrition, genetic, ear nose and throat, and sleep conditions." It's also worth noting that some types of diagnosis/conditions displayed only a weak association with subsequent risk of ASD including that related to asthma (previously discussed quite a bit on this blog).
• Researchers also looked at what clusters of medical conditions might be associated with lower or higher likelihood of an ASD diagnosis being given. They concluded that: "Developmental delay and mental health condition clusters were associated with the highest relative risks of ASD." They further suggest that "combinations of medical comorbidities could aid in risk stratification for ASD prior to ASD diagnosis using a supervised clustering analysis based on machine-learning methods." Machine learning yet again, applied to autism research eh?

There's little more for me to discuss about this work other than to say that much more targeted research is needed to build on these latest findings from Alexeeff and colleagues. Coinciding with the ideas that (i) autism rarely exists in some sort of diagnostic vacuum (see here) and that (ii) autism genes are not necessarily just genes for autism (see here) (indeed a topic rising in research importance [2]) the lessons to be learned are becoming a little clearer. I might also focus a little more on those somatic diagnoses discussed in the Alexeeff paper as being quite important to the clinical picture when it comes to autism. Y'know how various medical comorbidities are indeed over-represented when it comes to autism and how appropriate screening and management/treatment [3] should be offered when and where they are identified (see here) save any further healthcare inequalities arising...

To close, I appreciate that there are quite a lot of opinions out there about a certain US autism organisation, but a recent document of theirs talking about the various conditions/comorbidities that can follow a diagnosis of autism (see here) deserves an airing. Not that they were however the first group to talk about this important part of the autism spectrum (see here) but better late than never...

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[1] Alexeeff SE. et al. Medical Conditions in the First Years of Life Associated with Future Diagnosis of ASD in Children. J Autism Dev Disord. 2017 Apr 22.

[2] Diaz-Beltran L. et al. Cross-disorder comparative analysis of comorbid conditions reveals novel autism candidate genes. BMC Genomics 2017. 18: 315.

[3] Flor J. et al. Developmental functioning and medical Co-morbidity profile of children with complex and essential autism. Autism Res. 2017 May 5.

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Alexeeff SE, Yau V, Qian Y, Davignon M, Lynch F, Crawford P, Davis R, & Croen LA (2017). Medical Conditions in the First Years of Life Associated with Future Diagnosis of ASD in Children. Journal of autism and developmental disorders PMID: 28434058

Autistic adults as critical autism experts (with research caveats)

"Findings suggest that autistic adults should be considered autism experts and involved as partners in autism research."

That was the conclusion reached in the paper by Kristen Gillespie-Lynch and colleagues [1] (open-access) reporting on the results of an online survey assessing "autism knowledge and stigma among 636 adults with varied relationships to autism, including autistic people and nuclear family members." Among the various groups of people who contributed to the survey, several viewpoints emerged. The message primarily however was that: "autistic people are autism experts through their lived experiences." I don't think many people would quibble with such findings.

A few other details emerged from the Gillespie-Lynch study that merit discussion. Many participants showed a "reduced tendency to view autism through a deficit-defined medical model compared with non-autistic people." This is perhaps not an unexpected finding given the history of applying the medical model to autism and the rise and rise of the neurodiversity movement that "challenges the medical model" in particular respect over the question of deficit vs. difference and implications thereof. Although the medical model provides the means to identify and diagnose autism or autism spectrum disorder (ASD) (on the basis of deficits), it's not unexpected that for some, once those tasks have been completed, the 'treatment' side of the model is not necessarily a top priority; or at least not as important as addressing the various inequalities that seem to stem from a diagnosis. That being said, I do agree with the authors sentiments that: "the neurodiversity movement and the medical model overlap in recognizing that supports are needed to ameliorate challenges associated with autism." Those challenges are variable and person-dependent but include the effects of both core and peripheral signs and symptoms and the various over-represented comorbidities that seem to follow a diagnosis of autism (see here). I would, at this point, also caution on using the words 'biopsychosocial model' in the context of autism as the authors have included in their discussions, given what it has meant for other labels (see here) and the potential 'psychologising' of some important medical symptoms.

I added the words 'with research caveats' to the title of this post to ensure that such a positive message about autism and the autism spectrum is not just given a 'free pass' when it comes to scrutiny of the scientific method, the way the study was carried out and the applicability of the results to the entire autism spectrum. This was an online survey not a face-to-face piece of research (other related research has similarly used such a method and on more than one occasion) and the authors acknowledge that they: "did not verify diagnosis of participants who self-identified as autistic" for example. Given what we are beginning to see when it comes to some of the 'self-screening' instruments out there regarding possible autism or not (see here), I'm always a little cautious that self-diagnosis / self-identification does not necessarily mean [eventual] clinician-diagnosed autism and how important this is when it comes to correctly ascertaining the wants and wishes of those diagnosed as being on the spectrum.

On the point about the representativeness of this research, the authors also note: "Findings may not generalize to autistic participants who lack the verbal and computer skills needed to complete the survey." Yet another example it seems of this important issue.

I have to say that I'm also a little disheartened that yet again an important group that was once very firmly on the autism spectrum aren't really given the credit they deserve according to the Gillespie-Lynch findings: "Autistic participants were more likely to recognize that most children cannot outgrow autism." The 'optimal outcome' children and adults it seems, still represent one of the most maligned groups associated with the autism spectrum (assuming that optimal outcome occurring in up to 9% of the autism population is not an insignificant figure). This despite the fact that even the diagnostic stability of the most 'high-functioning' cases of autism can wobble it seems (see here) even into adulthood. One of the premier experts on autism also seems to agree according to some recent media (see here). I often wonder if the seeming lack of acceptance of this group/feature might have something to do with the 'identity' side of autism and the idea that within the vast heterogeneity of autism (or the plural autisms if you prefer) the use of 'them and us descriptions' like 'neurotypical' are perhaps not as binary or long-lasting as many would believe or want to believe?

Within the context of [approximate] phrases such as 'if you've met one person with autism, you've met one autistic person' there is caution in over-generalising these latest results but they are nonetheless important. I think it would be rather fitting to end with a few choice phrases from the Gillespe-Lynch paper: "As many of our survey respondents indicated, each person, regardless of whether or not they are autistic, is unique" and: "Some autistic people seek out factual knowledge about autism while others believe that they can only be experts in their own particular form of autism." Either way, the insights provided by people on the autism spectrum (all parts of the autism spectrum and indeed, across the age ranges) should be valued, and where possible, incorporated into research and practice.

And one voice from the autism spectrum carries some rather sensible messages...

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[1] Gillespie-Lynch K. et al. Whose Expertise Is It? Evidence for Autistic Adults as Critical Autism Experts. Front. Psychol. 2017. March 28.

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Gillespie-Lynch, K., Kapp, S., Brooks, P., Pickens, J., & Schwartzman, B. (2017). Whose Expertise Is It? Evidence for Autistic Adults as Critical Autism Experts Frontiers in Psychology, 8 DOI: 10.3389/fpsyg.2017.00438

"early medical events are associated with clinical ASD phenotypes"

The paper by Charlotte Willfors and colleagues [1] (open-access) provides some food for thought today and the observation that various individual and cumulative medical events - "early medical events likely to be caused by environmental factors" - may be important to at least some autism.

Researchers "scrutinized the early medical histories of a rare and informative sample of 13 MZ [monozygotic] twin pairs discordant for clinical ASD [autism spectrum disorder]" also including "13 MZ typically developing (TD) control pairs (n=52) matched for sex" as an 'exploratory step. Discordant for autism means that one twin had autism and the other did not.

This research first step looked at medical events (likely to be caused by environmental factors!) included things like delivery and neonatal variables (e.g. foetal distress, hypoxia), minor and frequent infections (e.g. ear infections), allergy and epilepsy to name a few. Data was acquired from a few sources including medical records and medical history "assessed from a parent reported questionnaire." They examined exposure to the medical events "in relation to either quantitative or qualitative discordance for ASD." Qualitative discordance referred to when "only one twin within a pair meeting the diagnostic criteria of ASD." A 'confirmatory' study was also carried out whereby a larger, independent cohort of 100 twin pairs "quantitatively discordant for autistic traits" were also quizzed and findings cross-validated.

Results: a few non-shared environmental (NSE) events seemed to be important based on their analysis. So: "Single early medical factors, likely to be caused by NSE, that discriminated between twins in qualitative ASD discordant pairs were dysregulation during the first year of life (comprising feeding and sleeping problems, excessive crying and worrying) and birth weight." Authors also reported that cumulatively, the appearance of early medical events were significantly different in MZ twins with autism compared with their non-ASD co-twin. It's worth mentioning that some of those 'dysregulation' events have been talked about in the earliest descriptions of autism (see here). Birth weight too has something of a long-standing connection to [some] autism (see here). When it came to analysis based on autistic traits (the confirmatory study) it seemed that "early dysregulation and the cumulative load of a variety of early adverse medical events" continued to be important variables (although birth weight linked to ASD traits lost its significance).

These are important findings. The focus on MZ twins (who share a common structural genetic blueprint) means that the genetics side of things is to a large extent 'controlled for' and the results are more likely to reflect some environmental or, more accurately, non-genetic influence. There is a caveat to this though, as per the authors recognition: "with the exception of putative post-twinning de novo mutations." I might also add that MZ twins are also not necessarily epigenetically the same too so gene expression can (and does) differ. What causes these epigenetic differences is still the source of some debate but I might chime in with one idea (see here) out of many possibilities.

"Our data indicate that taking into account the cumulative load of early medical factors might strengthen or discourage a suspicion of ASD, at least in a minority of cases." This is an interesting thought provided by the authors based on their findings. It ties in well with the idea that although behavioural presentation is core to autism presentation and diagnosis, behaviour might not be the only important feature present in relation to autism. I do have to express a degree of caution however with such an approach based on the idea that various types of regression have been noted in the peer-reviewed literature to accompany some autism (see here) and with it, the concept of 'acquired autism' should really be properly recognised (see here for example) in these days of the plural 'autisms'. Indeed, there's a research study idea for anyone out there: looking at MZ twins discordant for autism with onset of said autism tied into a regression of skills?

Scientific replication is the name of the [future] game in this area of study, drawing on larger cohorts and perhaps based in other geographical areas outside of Sweden. We also need to find out what mechanisms might be potentially associating something like 'early dysregulation' with the onset of autism, taking into account how factors such as early feeding practices/issues for example, might provide at least one avenue for future study (see here).

To close, in light of some recent media headlines about the 'myth' that autism rates are on the up (and quite significantly so over past two decades), I offer some past posts suggesting that the word 'myth' should be reserved for other [non-peer-reviewed] matters (see here and see here and see here) and not this particular branch of epidemiological science. As to what may be 'causing' the upswing in numbers of diagnosed cases, well, it's likely to be very, very, very complicated (and without any need for sweeping generalisations please)...

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[1] Willfors C. et al. Medical history of discordant twins and environmental etiologies of autism. Transl Psychiatry. 2017 Jan 31;7(1):e1014.

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Willfors C, Carlsson T, Anderlid BM, Nordgren A, Kostrzewa E, Berggren S, Ronald A, Kuja-Halkola R, Tammimies K, & Bölte S (2017). Medical history of discordant twins and environmental etiologies of autism. Translational psychiatry, 7 (1) PMID: 28140403

Prescription medication use and autism: good medicines management required

"Prescription drug use and polypharmacy rates among adults with ASD [autism spectrum disorder] are substantially higher than those in an age-, sex-, and race-matched cohort of adults without ASD."

That sentence taken from the paper by Rini Vohra and colleagues [1] (open-access available here) is probably not likely to win any 'novel findings of the year' awards given the already quite voluminous data published on the medication use and autism (see here for example). What gives the Vohra data a bit of an edge is that: (a) they included data for some 1700 adults with autism "matched 1:3 with adults without autism", (b) data were derived from administrative health insurance claims databases in the United States ("Medicaid programs"), and (c) they examined "the rates of prescription drug use, general polypharmacy, and psychotropic polypharmacy among adults" thus were able to detail not just psychotropic medication use but also that for other, more general conditions too.

Their findings were stark. Accompanying that opening sentence on medication use and autism, authors reported that: "Annually, almost 75% of adults with ASD had >20 prescription drug claims compared with 33% of adults without ASD." That's more than 20 prescription medication claims per year.

Further: "Other than psychotropics, many adults with ASD used medical prescription drugs such as antimicrobials (47%), dermatologic agents (48%), respiratory agents (38%), gastrointestinal agents (31%), alternative medications (25%), antiparkinsonian agents (22.6%), antihyperlipidemics/statins (7.3%), and immunologics (2.0%)." So when we start talking about the label of autism not appearing in some sort of diagnostic vacuum, and particularly that various medical comorbidity seem to be 'over-represented' when it comes to autism (see here), this is reflected in the large burden of medication being dispensed. If readers trawl through the adjusted odds ratios (AORs) generated when those with autism were compared with controls (Table 1), you'll note that many classes of medicine were more frequently prescribed to those with autism.  And where medicines were less frequently prescribed to the autism group, there were some potentially telling signs too: analgesics (used for pain relief), antidiabetics and antimicrobials. One could argue that maybe those diagnosed with autism have less need of things like pain relief or antibiotics or less likely to need antidiabetic medicines. One might however similarly argue that their medical and healthcare screening services could perhaps be 'less rigorous' than those not diagnosed with autism too, potentially as a result of various factors (see here).

Onwards: "Adults with ASD and a psychiatric comorbidity such as an adjustment disorder (26%), mood disorder (31%), or schizophrenia (32%) had significantly high rates of psychotropic polypharmacy." I probably don't need to say much more about this sentence aside from the fact that mood disorder including things like depression are not uncommon diagnoses alongside autism (see here). The links with the schizophrenia spectrum are also not to be underestimated (see here).

Finally: "Older age, female gender, White race, and presence of three or more comorbid conditions among adults with ASD is significantly associated with using six or more prescription drug classes per year." This sentence is not a roadmap to predicting who will need what medicines when it comes to autism but does provide some important information. There is for example, a woeful lack of research on autism in a longitudinal sense (see here) despite the topic of ageing and autism being debated time and time again. Inevitably as people age, their medication requirements are likely to change (increase?); this is as true for autism as it is for the not-autism population.

I included the words 'good medicines management required' in the title of this post because, as you can see, the level of prescription medicines use when it comes to autism can be high and one needs to be careful that medicines are appropriate, monitored regularly and don't interact with one and another. Given what is also known about psychotropic medicines in particular in terms of potential side-effects (see here and see here for examples), the onus is surely on prescribers to keep an even closer eye on those with autism who are being medicated under their care.

Medication is a part of life when it comes to autism. I base that last sentence on the wealth of data, peer-reviewed and otherwise, that has been published on this topic. I'm sure nobody particularly likes the idea of medication particularly when it comes to autism and certainly nobody should like the idea that some people on the autism spectrum are receiving quite a lot of prescription medicine concurrently and over quite long periods of time. But here's the thing, medication (generally) serves an important purpose. In the case of the antiepileptics/anticonvulsants it can be life-saving. Where mood disorders such as depression are being pharmacologically treated, it can be life-saving. Until, science is able to get a better idea of why some many conditions/labels seem to be over-represented when it comes to autism, medication is often all that it can offer at the moment...

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[1] Vohra R. et al. Prescription Drug Use and Polypharmacy Among Medicaid-Enrolled Adults with Autism: A Retrospective Cross-Sectional Analysis. Drugs Real World Outcomes. 2016 Nov 21.

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Vohra R, Madhavan S, Sambamoorthi U, StPeter C, Poe S, Dwibedi N, & Ajmera M (2016). Prescription Drug Use and Polypharmacy Among Medicaid-Enrolled Adults with Autism: A Retrospective Cross-Sectional Analysis. Drugs - real world outcomes PMID: 27873285

"While you're here, I just want to talk about your weight"

The important Doctor-Patient relationship

In a slight departure from the typical material discussed on this blog, I want to briefly direct readers to the paper by (Prof) Paul Aveyard and colleagues [1] and results suggesting that: "A behaviourally-informed, very brief, physician-delivered opportunistic intervention is acceptable to patients and an effective way to reduce population mean weight."

The title of this post comes from some of the media coverage of the Aveyard study summarising how general practitioners (GPs) in particular, might be ideally placed to bring up the topic of 'weight issues' when seeing some of their patients for other health matters.

Minus any charges of plagiarism, I'd like to particularly draw readers attention to the example given in the Aveyard paper of a 'typical physician intervention'. So:

"Physician: While you're here, I just wanted to talk about your weight. You know the best way to lose weight is to go to [Slimming World or Rosemary Conley] and that's available free on the NHS?
Patient: Oh?
Physician: Yes, and I can refer you now if you are willing to give that a try?
Patient: Yes, ok.
Physician: Ok, what you need to do is take this envelope back outside to the person who weighed you and they will book you into the weight loss course now.
Patient: Ok.
Physician: Good, but I'd like to see how you're getting on, so come and see me again in 4 weeks, please. Ok?
Patient: Ok, see you then."

In these days of the 10-minute consultation combined with something of an 'epidemic' of obesity and overweightedness I like the idea that a 30-second chat from an authority figure like a GP with a patient can potentially transform lives, even if only a proportion of the intended market. Despite the fact that only 40% of those offered weight reduction classes actually attended, there are some pretty decent statistics included in the paper to suggest that for this group, weight change was better than for those who weren't offered any additional support ("mean weight change at 12 months was 2·43 kg with the support intervention and 1·04 kg with the advice intervention, giving an adjusted difference of 1·43 kg"). And with decreasing weight, so the risk of various other health complaints also decreases accepting the old/new adage of 'not out-running a bad diet' [2].

In these days of the soundbite and 140-characters or less, it makes me wonder what other health promotion advice might be amenable to a very brief chat from someone like a GP?

To close, lest we forget...

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[1] Aveyard P. et al. Screening and brief intervention for obesity in primary care: a parallel, two-arm, randomised trial. Lancet. 2016. Oct 24.

[2] Malhotra A. et al. It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet. Br J Sports Med. 2015 Aug;49(15):967-8.

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Aveyard, P., Lewis, A., Tearne, S., Hood, K., Christian-Brown, A., Adab, P., Begh, R., Jolly, K., Daley, A., Farley, A., Lycett, D., Nickless, A., Yu, L., Retat, L., Webber, L., Pimpin, L., & Jebb, S. (2016). Screening and brief intervention for obesity in primary care: a parallel, two-arm, randomised trial The Lancet DOI: 10.1016/S0140-6736(16)31893-1

Parkinsonism in adults with autism

"We find a high frequency of parkinsonism among ASD [autism spectrum disorder] individuals older than 39 years."

So said the paper by Sergio Starkstein and colleagues [1] (open-access) and Q & A with authors who, during a "a hypothesis-generating, pilot study" with extras looked for parkinsonism motor signs in a small group of adults diagnosed with an autism spectrum disorder.

Parkinsonism is an umbrella term that refers to any condition that leads to a combination of symptoms noted in Parkinson's disease including tremor, slow movement (bradykinesia) speech issues and/or muscle stiffness. Parkinsonism does not necessarily mean just Parkinson's disease (PD) as per the number of conditions that have been mentioned under this umbrella (see here).

Starkstein and colleagues describe their results within the context of a research initiative looking to examine ASD in older individuals. They report: "As the project progressed, we observed what appeared to be high rates of parkinsonian signs in our ASD subjects" (n=19) that was then extended into a more systematic assessment of parkinsonian signs in a different cohort (n=37). In that latter group: "The frequency of occurrence of the cardinal signs for parkinsonism were 46 % (N = 17) with bradykinesia, 19 % (N = 7) with resting tremor, 19 % (N = 7) with rigidity, and 19 % (N = 7) with postural instability." Assessment by the way, was via the Movement Disorders Society-Unified Parkinson’s disease Rating Scale (MDS-UPDRS) with a slight modification whereby "final clinical judgment on the presence of bradykinesia was based on scores rating limb bradykinesia... and/or scores rating global spontaneity of movement."

Because medication, particularly certain neuroleptic pharmacotherapy, can impact on parkinsonism, researchers also looked at the 20 participants from both cohorts combined who were not currently on neuroleptics. So: "After excluding subjects currently on neuroleptic medications, the frequency of occurrence of parkinsonism was 20 % in the combined sample and 17 and 25 %, in each sample, respectively." Oh, and 4 participants (7% of the combined sample) were "diagnosed with PD by community neurologists."

"The possibility that individuals with autism are at increased risk for Parkinson’s disease as adults has important implications for detection and assessment, clinical practice, systems of care, training, and public policy." That's an important sentence from the authors about their findings and the implications for screening and care of adults on the autism spectrum. Added to the idea that various other medical comorbidity might be 'over-represented' when it comes to autism (adult autism) (see here and see here and more recently in the paper by Fortuna and colleagues [2]) and how the symptoms of autism can sometimes affect the delivery of appropriate screening and healthcare (see here), and quite a research agenda continues to emerge.

As to the mechanism(s) potentially pertinent to parkinsonism being associated with autism... well, all I can really say is that it is likely to be a complicated relationship insofar as the plurality of autism and all that elevated risk of other comorbidity allied to the label. To single out one area where the possibility of overlap might occur, I'll draw your attention to the findings reported by Cheng and colleagues [3] who, based on that ever-so useful resource called the Taiwan National Health Insurance Research Database (see here), reported that: "Patients with asthma had an elevated risk of developing Parkinson's disease later in life." Given something of an emerging connection between asthma and autism (see here) one might speculate that this could be just one avenue for further investigation.

Music: Florence + The Machine - Rabbit Heart (Raise it Up).

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[1] Starkstein S. et al. High rates of parkinsonism in adults with autism. Journal of Neurodevelopmental Disorders 2015, 7:29.

[2] Fortuna RJ. et al. Health Conditions and Functional Status in Adults with Autism: A Cross-Sectional Evaluation. J Gen Intern Med. 2015 Sep 11.

[3] Cheng CM. et al. Risk of developing Parkinson's disease among patients with asthma: a nationwide longitudinal study. Allergy. 2015 Aug 27.

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Starkstein, S., Gellar, S., Parlier, M., Payne, L., & Piven, J. (2015). High rates of parkinsonism in adults with autism Journal of Neurodevelopmental Disorders, 7 (1) DOI: 10.1186/s11689-015-9125-6

More medical illness associated with bipolar disorder

In a previous post on this blog I covered the idea that a diagnosis of bipolar disorder (previously called manic depression) might 'set someone up' for an elevated risk of various other medical illnesses when compared with data from asymptomatic controls (see here).

Today I'm continuing that theme based on the findings reported by Hsu and colleagues [1] and the suggestion that: "BDs [bipolar disorders] were an independent risk factor for PUDs [peptic ulcer diseases]." With a starting point once again centred on the examination of data from the Taiwan National Health Insurance Research Database, perhaps one of the premier population-wide databases producing data at the present time (see here), researchers analysed the medical insurance records of over 21,000 people diagnosed with BDs compared with over 84,000 "frequency-matched patients without BDs" for the presence of PUDs.

They reported that the incidence of PUDs was higher in those with bipolar disorders compared with asymptomatic controls. The hazard ratio came in at 1.51 with 95% confidence intervals 1.43-1.59. The authors also concluded that: "BDs were an independent risk factor for PUDs" when taking into account other potentially interfering comorbidities. As usual, further research is called for surrounding any possible connection(s) and that when a diagnosis of BD is received "practitioners could notice the occurrence of PUD." I might add that this is not the first time that peptic ulcer disease has been linked to bipolar disorder as per research accounts such as the one from Goodwin and colleagues [2].

I'm no expert on peptic ulcer disease so cannot readily offer any explanation as to why it should be more frequently reported when bipolar disorder is present than not. One could speculate that some of the known triggers of PUD might be more readily present in cases of BD as in the link between PUD and stress for example [3] in light of what stress can do to trigger some of the features of BD.

I am also intrigued by the Helicobacter pylori (H. pylori) link to BD in light of what this bacterium does to the stomach lining. Appreciating the very stark way that H. pylori was shown to be connected to PUD and that questions still remain about the exact hows and whys, I do wonder if this gastrointestinal microbiota link might extend much further into the how gut and brain might be connected. With my speculating hat on, I might suggest that concepts such as leaky membranes and inflammation might also figure in some sort of way...

Music: Jason Derulo - Want To Want Me.

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[1] Hsu YC. et al. Increased Subsequent Risk of Peptic Ulcer Diseases in Patients With Bipolar Disorders. Medicine (Baltimore). 2015 Jul;94(29):e1203.

[2] Goodwin RD. et al. Peptic ulcer and mental disorders among adults in the community: the role of nicotine and alcohol use disorders. Psychosom Med. 2009 May;71(4):463-8.

[3] Levenstein S. et al. Psychological stress increases risk for peptic ulcer, regardless of Helicobacter pylori infection or use of nonsteroidal anti-inflammatory drugs. Clin Gastroenterol Hepatol. 2015 Mar;13(3):498-506.e1.

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Hsu YC, Hsu CC, Chang KH, Lee CY, Chong LW, Wang YC, & Kao CH (2015). Increased Subsequent Risk of Peptic Ulcer Diseases in Patients With Bipolar Disorders. Medicine, 94 (29) PMID: 26200637

Medical comorbidity and adult autism (again)

Regular readers are probably tired of reading blog titles like the one for today on this site. It's not as if the idea that a diagnosis of autism might predispose someone to quite a few more comorbid conditions (see here and see here) hasn't been discussed on quite a few occasions.

But just in case the message hasn't got through, I draw your attention to the paper by Kyle Jones and colleagues [1] concluding that: "Adults in this cohort of autism spectrum disorder first ascertained in the 1980s experience a high number of chronic medical conditions, regardless of intellectual ability."

The cohort in question was part of the 1980s Utah/UCLA autism epidemiologic study and some further follow-up of some of the people who participated in this quite early research foray into the epidemiology of autism. I say 'some' of the cohort because, as has been discussed previously on this blog (see here), sadly not everyone has survived over the years. Part and parcel of that 'excess mortality' in this cohort discussed by Bilder and colleagues [2] was thought due to "the presence of comorbid medical conditions" among other things.

The recent Jones paper "queried medical symptoms, disorders, hospitalizations, surgeries, and medication use" for 92 participants from the original cohort, mostly aged in their mid-30s. The found that: "The most common medical conditions were seizures, obesity, insomnia, and constipation." Further: "The median number of medical conditions per person was 11." Interestingly, researchers suggested that various factors might further increase the risk of such medical comorbidity including gender (females over males) and the presence of obesity. I say that bearing in mind the relatively small participant numbers included for study (69 of the 92 participants were male).

What's more to say on the basis of these and other findings? Well, the need for greater appreciation that autism seems to go much further than the presentation of core symptoms might be one thing (see here). As per my various ramblings on physical health and activity with the autism spectrum in mind (see here) tackling issues such as obesity might be another thing (see here) bearing in mind how various eating/feeding issues for example, might complicate matters when it comes to autism and obesity (see here). The same also goes for sleep (see here).

In the words of Jones et al: "Understanding of these conditions commonly experienced should direct community-based and medical primary care for this population." Once again, I cannot disagree with such sentiments.

Music: Glen Campbell - Wichita Lineman.

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[1] Jones KB. et al. A description of medical conditions in adults with autism spectrum disorder: A follow-up of the 1980s Utah/UCLA Autism Epidemiologic Study. Autism. 2015. July 10.

[2] Bilder D. et al. Excess mortality and causes of death in autism spectrum disorders: a follow up of the 1980s Utah/UCLA autism epidemiologic study. J Autism Dev Disord. 2013 May;43(5):1196-204.

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Jones, K., Cottle, K., Bakian, A., Farley, M., Bilder, D., Coon, H., & McMahon, W. (2015). A description of medical conditions in adults with autism spectrum disorder: A follow-up of the 1980s Utah/UCLA Autism Epidemiologic Study Autism DOI: 10.1177/1362361315594798

Seeking out autism medical comorbidity clusters

I was rather interested in the findings reported by Kimberly Aldinger and colleagues [1] (open-access here) recently and an intriguing attempt to find out whether "there are predictive patterns of medical conditions that co-occur with ASD [autism spectrum disorder], which could inform medical evaluation and treatment in ASD, as well as potentially identify etiologically meaningful subgroups."

Comorbidity (if I can still call it that) is of great interest to this blog and the idea that autism rarely exists in some sort of diagnostic vacuum. Comorbidity clusters have also been previously mentioned here (see here) following the work of people such as Isaac Kohane and colleagues [2] with the emphasis on medical/somatic comorbidity over psychological/behavioural features or diagnoses.

In their recent paper, Aldinger et al reported results based on "hierarchical clustering and multivariate analyses" based on two well-known autism research datasets, the Autism Genetic Resource Exchange (AGRE) and the Simons Simplex Collection (SSC) forward to the idea of picking out subgroups on the autism spectrum as a function of co-occurring medial comorbidites such as "GID [gastrointestinal disturbances], seizure disorders, allergies, and sleep problems."

After quite a bit of statistical analysis, authors reported a few potentially important results. First and foremost was the finding that: "the prevalence of certain medical conditions was consistent in two genetically distinct ASD family cohorts (multiplex and simplex), specifically allergies, GID and seizures." Quite surprisingly, the prevalence of GID in children with ASD in both datasets hovered around the 42-43% mark (AGRE = 42.4%; SSC = 43.1%). It strikes me that 40% might be a good round estimate for how frequent bowel issues might be accompanying a diagnosis of autism...

Next were the findings that: "the proband data in both AGRE and SSC cohorts revealed predictive relations among GID, seizures and sleep problems, three commonly reported and clinically challenging medical conditions for children with ASD." Further: "clinical diagnosis of GID or sleep disturbances increases the risk for the presence of the other condition, as well as for seizures." This is important data suggesting that there may be clinical interplay between medical comorbidity occurring alongside a diagnosis of autism. That being said, this is not the first time that such connections have been potentially made (see here) assuming that bowel issues might have the ability to provoke pain and discomfort for example.

Finally: "The presence of GID, seizures and sleep problems together predicted more severe adaptive behavioral symptoms relevant to their ASD diagnosis, consistent with studies of children in which a functional GID was the medical focus." The implication here being that the presence of comorbidity may have some important bearing on the manifestation of behavioural signs and symptoms in cases of autism bearing in mind "familial loading for ASD". Again, not exactly a new finding (see here) but important nonetheless.

I'm impressed with this research (bearing in mind it's limitations) and how autism research in general is embracing the idea that medical comorbidity might play an important role for quite a few people diagnosed as being on the autism spectrum. Not only does it offer some additional ways and means that one might potentially 'intervene' but also provides something of a primer / roadmap for what to look for when autism presents in the doctor's lounge.

Even the gut microbiome gets a mention in the Aldinger paper: "Moreover, there is recent recognition that the gut microbiome, in addition to impacting gut physiology by immune or autonomic dysfunction, can affect both brain and behavior." Interesting...

Music: Led Zeppelin - Whole Lotta Love.

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[1] Aldinger KA. et al. Patterns of Risk for Multiple Co-Occurring Medical Conditions Replicate Across Distinct Cohorts of Children with Autism Spectrum Disorder. Autism Res. 2015 May 24.

[2] Kohane IS. et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One. 2012;7(4):e33224.

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Aldinger KA, Lane CJ, Veenstra-VanderWeele J, & Levitt P (2015). Patterns of Risk for Multiple Co-Occurring Medical Conditions Replicate Across Distinct Cohorts of Children with Autism Spectrum Disorder. Autism research : official journal of the International Society for Autism Research PMID: 26011086