Autoimmune thyroiditis and depressive disorder

"Our study demonstrates a strong association between anti-TPO levels, which are considered to be of diagnostic value for autoimmune thyroiditis... with uni- or bipolar depression."

"Beware the bad cat bearing a grudge"

So said the study published by Detlef Degner and colleagues [1]. Anti-TPO antibodies by the way, refers to anti-thyroid peroxidase antibodies which, as the name suggests, are antibodies against thyroid peroxidase, an important step in the production of thyroid hormones. Said thyroid hormones have some pretty far-reaching effects on our physiology. Anti-TPO antibodies are also diagnostic for autoimmune related conditions affecting the thyroid such as Hashimoto's thyroiditis.

The Degner paper looked at a small group of participants diagnosed with depression (n=52) and analysed various thyroid related measures compared with a smaller control group made up of 19 participants diagnosed with schizophrenia. Authors reported a "pathologically increased" frequency of anti-TPO antibodies in those with depression compared with those with schizophrenia (32% vs 5% respectively). With something of a rather large confidence interval (CI) and hence the need for quite a bit more investigation, they also reported "the odds ratio of uni- or bipolar patients with depression for an autoimmune thyroiditis was ten times higher...  when compared with schizophrenia patients".

Reiterating again the quite small participant numbers, one needs to be rather careful with this particular study before too many firm conclusions are reached. Added to the fact that there was no asymptomatic control group included for study, I'd like to see quite a bit more done in this area before pinning my colours to any particular mast. That being said, this is certainly not the first time that (a) thyroid function has been correlated with depressive symptoms or depressive disorder [2] and/or (b) elevated levels of anti-TPO antibodies have been linked to depression [3] also crossing different geographies [4]. The paper by Carta and colleagues [5] (open-access) further extends the anti-TPO antibody link to "mood and anxiety disorders". This, complete with some discussion about how a "sub-clinical dysfunction of axis Thyrotropin Releasing Hormone (TRH) – Thyroid Stimulating Hormone (TSH) with consequent alteration of circadian rhythms of TSH" might be involved, linking an "aberrancy in the immuno-endocrine system" as a bridge between autoimmunity and psychiatry.

Autoimmune conditions have been previously discussed on this blog as potentially being a risk factor for mood disorder (see here). Under this banner, I'm minded to bring in another paper by Carta and colleagues [6] discussing how "Anti-TPO prevalence was significantly higher in celiac patients than in the control group" and further: "A higher frequency of PD [panic disorder] and MDD [major depressive disorder] was found in celiac patients with positive anti-TPO when compared to negative anti-TPO patients". This assumes that there may be some elevated risk of autoimmune issues impacting on the thyroid extending into other autoimmune conditions such as celiac (coeliac) disease as per other work. I could start going on about how this research might impact on other peripheral work e.g gluten exposure and feelings of depression but don't want to get too speculative at this point on any correlation with something like gluten or gut permeability.

Suffice to say that outside of just looking at thyroid-stimulating hormone (TSH) levels, the Degner results and other research suggest a whole other ballgame of autoimmune involvement affecting thyroid function and potentially impacting on psychiatry...

Music to close: I Will Wait by Mumford and Sons.

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[1] Degner D. et al. Association between autoimmune thyroiditis and depressive disorder in psychiatric outpatients. Eur Arch Psychiatry Clin Neurosci. 2014 Sep 6.

[2] Demartini B. et al. Depressive Symptoms and Major Depressive Disorder in Patients Affected by Subclinical Hypothyroidism: A Cross-sectional Study. J Nerv Ment Dis. 2014 Aug;202(8):603-7.

[3] Pop VJ. et al. Are autoimmune thyroid dysfunction and depression related? J Clin Endocrinol Metab. 1998 Sep;83(9):3194-7.

[4] Muñoz-Cruzado Poce MJ. et al. Prevalence of thyroid disorders in patients diagnosed with depression. Aten Primaria. 2000 Jul-Aug;26(3):176-9.

[5] Carta MG. et al. The link between thyroid autoimmunity (antithyroid peroxidase autoantibodies) with anxiety and mood disorders in the community: a field of interest for public health in the future. BMC Psychiatry. 2004 Aug 18;4:25.

[6] Carta MG. et al. Association between panic disorder, major depressive disorder and celiac disease: a possible role of thyroid autoimmunity. J Psychosom Res. 2002 Sep;53(3):789-93.

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Degner D, Haust M, Meller J, Rüther E, & Reulbach U (2014). Association between autoimmune thyroiditis and depressive disorder in psychiatric outpatients. European archives of psychiatry and clinical neuroscience PMID: 25193677

Term vs. preterm birth and the presentation of autism

The paper by Katherine Bowers and colleagues [1] continues the interest in the concept of 'the autisms' with their observations on the presentation of autism (and its comorbidities) when looking at those "born preterm versus those born at term".

We'd better get back, 'cause it'll be dark soon,
and they mostly come at night... mostly

Based on an analysis of quite a healthy participant number heading up to 900 "males and females with autism spectrum disorder", authors reported on several phenotypic differences between the 13% born preterm compared to the majority born following a full-term pregnancy. These differences, also influenced by gender, were in core areas such as language skills and the presence of comorbidities such as sleep apnea and attention-deficit hyperactivity disorder (ADHD). The authors conclude that their results "may have implications for understanding the underpinnings of a subset of individuals with autism spectrum disorder and contribute to the development of focused treatments for autism spectrum disorder among children born preterm".

Whilst one should always be a little cautious about making too much of any specific link with something like preterm birth (see here to illustrate the many and varied outcomes following this variable) I was interested in the Bowers' results. I think back to similar research into autism subgroups from Unwin and colleagues [2] (talked about in a previous post) describing how low birth weight was "associated with greater sleep disturbances".

Although many variables can affect foetal growth measures, preterm birth can adversely impact on birth weight and with that, one might see a possible common feature appearing in relation to issues at birth. That being said, the strength of any association between preterm birth and something like the comorbid presence of ADHD in cases of autism is likely to be a complex issue as per the findings from Harris and colleagues [3] who concluded that in the general population: "former late preterm infants have similar rates of LD [learning disabilities] and ADHD as term infants".

Bowers et al also took into account a role for gender in their results, reporting that there may be more to see here. Although quite an obvious variable to look at when it comes to autism (see here), there is perhaps not as much appreciation of how sex might link into autism phenotypes as one might imagine. Recently, Reinhardt and colleagues [4] did venture into this area, concluding that whilst they did not see any "significant effects of sex or a diagnostic group by sex interaction" when it came to autism presentation, further research is indicated in this area. I might add that such investigations might also wish to look further at comorbidity too, or autism plus [5] if you like.

Music to close and Bulletproof by La Roux.

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[1] Bowers K. et al. Phenotypic differences in individuals with autism spectrum disorder born preterm and at term gestation. Autism. 2014 Sep 5. pii: 1362361314547366.

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

[3] Harris MN. et al. ADHD and learning disabilities in former late preterm infants: a population-based birth cohort. Pediatrics. 2013 Sep;132(3):e630-6.

[4] Reinhardt VP. et al. Examination of Sex Differences in a Large Sample of Young Children with Autism Spectrum Disorder and Typical Development. J Autism Dev Disord. 2014 Sep 5.

[5] Gillberg C. & Fernell E. Autism Plus Versus Autism Pure. J Autism Dev Disord. 2014 Jun 24.

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Bowers K, Wink LK, Pottenger A, McDougle CJ, & Erickson C (2014). Phenotypic differences in individuals with autism spectrum disorder born preterm and at term gestation. Autism : the international journal of research and practice PMID: 25192860

Autism across DSM-IV and DSM-5 descriptions

The paper/poster(?) by Harker & Stone [1] kinda says it all when it comes to the question: what changed in the description of autism between the DSM-IV-TR and DSM-5? The added bonus of comparing the US IDEA (Individuals with Disabilities Education Act) description of autism with DSM-5 will, I assume, also be important to quite a few people not least when it comes to any further research which uses the datasets on numbers of cases for example (see here).

I have little more to say aside from reiterating what already appears to be happening when it comes to the use of the revised descriptions of autism - autism spectrum disorder - in DSM-5 on numbers being diagnosed (see here). That and the requirement for quite a bit more investigation on the social communication disorder (SCD) category [2] including what a diagnosis of SCD actually translates into in terms of services and provisions offered compared to a DSM-5 diagnosis of ASD...

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[1] Harker CM. & Stone WL. Comparison of the Diagnostic Criteria for Autism Spectrum Disorder Across DSM-5, DSM-IV-TR, and the Individuals with Disabilities Act (IDEA)3 Definition of Autism.

[2] Norbury CF. Practitioner review: Social (pragmatic) communication disorder conceptualization, evidence and clinical implications. J Child Psychol Psychiatry. 2014 Mar;55(3):204-16.

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Yes, people with autism do have headaches

I don't mean to be haughty but a sentence included in the paper by Victorio [1] led to the title of today's very quick post. Based on a chart review of patients diagnosed with an autism spectrum disorder (ASD) attending a neurology clinic, the author concluded that "ASD patients, despite being known to have indifference to pain, can experience headaches".

Pain is something which has cropped up quite a bit in the autism research arena and has appeared more than once on this blog (see here and see here). The suggestion of an 'indifference' to pain being potentially over-represented in relation to autism I think stretches back to some older work which I have to say, has been pretty widely disputed in more recent years [2].

The focus on migraine as "the most frequent headache type" reported by Victorio might also be quite interesting in light of other research linking migraine headaches to some of the sensory issues reported in cases of autism [3]. Moving migraine away from just the head was also a suggestion put forward by another author [4] which opens up a whole new world of possibilities...

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[1] Victorio M. Headaches in patients with autism spectrum disorder. The Journal of Headache and Pain 2014, 15(Suppl 1):B37.

[2] Nader R. et al. Expression of pain in children with autism. Clin J Pain. 2004 Mar-Apr;20(2):88-97.

[3] Sullivan JC. et al. The presence of migraines and its association with sensory hyperreactivity and anxiety symptomatology in children with autism spectrum disorder. Autism. 2013 Sep 26;18(6):743-747.

[4] Casanova MF. The minicolumnopathy of autism: A link between migraine and gastrointestinal symptoms. Med Hypotheses. 2008;70(1):73-80.

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Victorio, M. (2014). EHMTI-0290. Headaches in patients with autism spectrum disorder The Journal of Headache and Pain, 15 (Suppl 1) DOI: 10.1186/1129-2377-15-S1-B37

Schizophrenia after child and adolescent psychiatric disorders

More of a 'bring to your attention' post today, as I bring to your attention(!) the paper by Cecilie Frejstrup Maibing and colleagues [1] who concluded: "The risk of being diagnosed with schizophrenia spectrum disorders [SSD] after a child and adolescent psychiatric disorder was significantly increased particularly in the short term but also in the long-term period".

"I coulda been a contender"

The findings were based on an analysis of one of those very informative Scandinavian registries - based in Denmark - which initially identified over 25,000 people born between 1990-2000 diagnosed "with child and adolescent psychiatric disorders". Some 1200 of these people were subsequently diagnosed with schizophrenia spectrum disorders leading to the various conclusions and statistics being produced including: "The risk of schizophrenia spectrum disorders was highly elevated, particularly within the first year after onset of the child and adolescent psychiatric disorder, and remained significantly elevated >5 years with an incidence rate ratio of 4.93". Further: "among persons diagnosed with a child and adolescent psychiatric disorder between the ages 0-13 years and 14-17 years, 1.68% and 8.74 %, respectively, will be diagnosed with a schizophrenia spectrum disorder <8 years after onset of the child and adolescent psychiatric disorder".

With my autism research blogging hat on, and without hopefully making too many sweeping generalisations, I found the Maibing research to be rather interesting. I've previously talked about spectrums colliding on this blog (see here) with specific reference to the work of Kenneth Gadow [2] for example, on "an interrelation between ASD [autism spectrum disorder] and SSD symptoms". That and a post on 'labels and lumping' (see here) affirms that there may indeed be common ground between some of the spectrums, which I might add, are probably plural spectrums [3] (see my take here). As per other research on the possibility of Asperger syndrome in first-episode psychosis (see here), diagnostic vigilance seems to be a key point to take from the Maibing work, and that appears to extend well beyond just what happens after a diagnosis of autism is received...

So, Golden Touch by Razorlight.

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[1] Maibing CF. et al. Risk of Schizophrenia Increases After All Child and Adolescent Psychiatric Disorders: A Nationwide Study. Schizophr Bull. 2014 Sep 5. pii: sbu119.

[2] Gadow KD. Schizophrenia spectrum and attention-deficit/hyperactivity disorder symptoms in autism spectrum disorder and controls. J Am Acad Child Adolesc Psychiatry. 2012 Oct;51(10):1076-84.

[3] Arnedo J. et al. Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies. Am J Psychiatry. 2014. September 15.

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Maibing CF, Pedersen CB, Benros ME, Mortensen PB, Dalsgaard S, & Nordentoft M (2014). Risk of Schizophrenia Increases After All Child and Adolescent Psychiatric Disorders: A Nationwide Study. Schizophrenia bulletin PMID: 25193974

Temporal trends in US autism prevalence: mainly real increase

"Diagnosed autism prevalence has risen dramatically in the U.S over the last several decades 
and continued to trend upward as of birth year 2005. The increase is mainly real and has occurred mostly since the late 1980s".

"They call me Cha Cha because I'm the
best dancer at St. Bernadette's"

That was the conclusion reached in the paper by Cynthia Nevison [1] (open-access) following her analysis of temporal trends in autism diagnosis for birth years between 1970 and 2005. Based on an analysis of datasets derived from IDEA (Individuals with Disabilities Education Act) and the CDDS (California Department of Developmental Services), the author suggested that between 75-80% "of the tracked increase in autism since 1988 is due to an actual increase in the disorder rather than to changing diagnostic criteria". The question of what environmental factors might have been driving such an increase in cases is also discussed in the Nevison paper, with the author concluding "children’s exposure to most of the top ten toxic compounds has remained flat or decreased over this same time frame". That top 10 list by the way, seems to come at least partly from the Landrigan paper talked about a couple of years back (see here).

There is quite a bit of information included in the Nevison paper which I'm reluctant to write a mega-blog entry on at this time. This includes various caveats about the use of IDEA and CDDS databases and their constraints on for example, what ASDs (autism spectrum disorders) are included in the datasets. I will however summarise some of the main findings in relation to the environmental factors probed by the author bearing in mind that autism research does not appear to be her main area of scientific interest (with all due respect).

So:

• Air pollution... something which has cropped up with ever-increasing frequency in the peer-reviewed research on autism (see here and see here for example). Nevison concludes: "there is no obvious evidence to suggest that trends in estimated vehicular emissions or directly measured air pollution are consistent with the sharp temporal increase in U.S. autism". So no smoking tailpipe (exhaust) there then as per other recent research findings [2].
• Mercury in vaccines... a topic guaranteed to furrow brows and raise blood pressure in some quarters (see here and see here for example). Nevison discusses the phaseout of thimerosal (thiomersal) from paediatric vaccines used in the US concluding that "the expansion of thimerosal exposure in the late 1980s and early 1990s coincides closely with the rise in autism around that time". But... "the temporal trends in autism and thimerosal following the childhood vaccine thimerosal phaseout are incompatible". Other sources of mercury exposure get a similarly 'unlikely' mark from Nevison.
• Organophosphate (OP) pesticide exposure... an interesting area which again has been covered previously on this blog (see here and see here). Nevison points out the declining use of such pesticides in the US following "the adoption of crops genetically modified to produce Bt toxin, which repels targeted insect pests, thus reducing the need for external insecticides". Recognising that pesticides are not to be trifled with (see here) I've always been a little confused about the mechanism(s) through which OP exposure could theoretically impact on the presentation of autism. I know people have talked about PON1 and autism [3] (some autism) but I do feel as though the primary effect of OPs - acting on acetlycholinesterase -  is something in need of a lot more research with autism in mind before anyone gets too carried away. 
• There is however a caveat to the pesticides-autism conclusion by the author following some mention of "the rapidly increasing application of glyphosate, the active ingredient in the herbicide Roundup®". She continues: "it appears that glyphosate cannot be responsible for the first autism cases in the 1930s and is unlikely to have caused the late 1980s uptick, but could be interacting in recent years with other toxins to drive up the prevalence of U.S. autism". Depending on where you look, you'll get various different messages about the pros and cons of glyphosate. I remember reading a report a few years back (see here) authored by one of the researchers involved in that 'organic food might be better for you' paper recently (see here) which painted a rather disturbing picture of the product. For balance, I'm going to also refer you to the various documents provided by Monsanto (the producer of Roundup) for their response to safety concerns. When it comes to a search of PubMed with the terms 'autism and glyphosate' the current result is zero although it has been mentioned elsewhere in the peer-reviewed domain [4]. 
• Maternal obesity... I'm being quite careful here accepting the previous discussions in this area of autism research (see here). Nevison reports that: "the time trend in obesity among U.S. women correlates well to that of autism, suggesting maternal obesity may be a direct influence or a comorbid consequence of the dietary factors contributing to autism, or both". 

One needs to bear in mind that the United States was the focus on these findings and as such the conclusions may not pertain to other parts of the globe. I probably don't need to say it but one should also bear in mind the saying 'correlation is not the same as causation' too. There are also other issues which have been discounted by Nevison as being related to the autism prevalence. Lead (Pb) is one of them; something which I personally would not be so keen to disregard given the more recent evidence on even trace amounts of this stuff not being great for the developing child (see here). This on top of what has been talked about with autism in mind (see here). 

I have a few other points to make which were perhaps not readily implied in the Nevison paper: first is the assumption that autism is some kind of universal condition. What I think many people have come to realise over the past few years is that within the significant behavioural and developmental heterogeneity grouped under the label autism, also compounded by the increased frequency of various comorbid conditions, a more plural description - the autisms - might be more pertinent. What this implies is that different weightings for concepts like genetics or environment (or epigenetics!) are likely acting across risk of different types of autism. 

Second, and related to point one, is the concept of synergy across different 'causative' factors. In the same way that autism science has started to accept that there is no one gene linked to all cases of autism, so environmental examinations can't really expect there to be one environmental factor working alone pertinent to all autism. If one is to assume that various environmental factors (see here and see here for example) may be linked to autism onset, it is more likely that combinations of factors are playing a role or possibly specific environmental factors acting on specific types of autism. Take for example the early work on air pollution and genotype being potentially associated with autism risk [5] as one example.

At the risk of being too speculative, I'm also minded to bring to your attention an emerging idea which might also be relevant: transgenerational epigenetics. The idea is that what happened in previous generations might have an influence on subsequent generations without structurally altering DNA in terms of the physical language of the genome. There has been some media interest in this concept in recent times (see here). With autism in mind, we've seen hints of this idea in the peer-reviewed research literature as per discussions on how advancing grandparental age might be linked to an increased risk of autism (see here). Jill Escher also talked about past chemical exposures potentially impacting on "vulnerable fetal germline epigenetics" (see here for her presentation). The implication being that correlating current exposure patterns with current autism diagnosis prevalence might not necessarily be the best way of looking at whether (and which) environmental factors might have a bearing on autism prevalence...

The primary message from the Nevison report is that the numbers of cases of autism do appear to be on the rise in the United States, and as per other reports from geographical neighbours (see here) the debates are not yet over about the reasons for that increase. Something another study has also talked about recently [6]...

So then, Only Love Can Break Your Heart by Saint Etienne.

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[1] Nevison CD. A comparison of temporal trends in United States autism prevalence to trends in suspected environmental factors. Environmental Health 2014, 13:73

[2] Gong T. et al. Exposure to Air Pollution From Traffic and Neurodevelopmental Disorders in Swedish Twins. Twin Res Hum Genet. 2014 Sep 17:1-10.

[3] D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Nov;10(11):1006-16.

[4] Seneff S. et al. Is Encephalopathy a Mechanism to Renew Sulfate in Autism? Entropy 2013. 15; 372-406.

[5] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

[6] Dave DM. & Fernandez JM. Rising autism prevalence: real or displacing other mental disorders? Evidence from demand for auxiliary healthcare workers in California. Economic Inquiry. 2014. 25 August.

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Nevison, C. (2014). A comparison of temporal trends in United States autism prevalence to trends in suspected environmental factors Environmental Health, 13 (1) DOI: 10.1186/1476-069X-13-73

Psychiatric effects of childhood inflammation?

"Higher levels of the systemic inflammatory marker IL-6 [interleukin 6] in childhood are associated with an increased risk of developing depression and psychosis in young adulthood". So said the paper by Golam Khandaker and colleagues [1] looking at the growing link between inflammation and psychiatry.

The bright light of Autumn @ Wikipedia 

The name Khandaker has appeared before on this blog (see here and see here), most recently with research looking at a possible link between the presence of a neurodevelopmental disorder and subsequent reports of psychotic experiences [2]. It's all rather fascinating research.

With the most recent investigation in mind...

• Two inflammatory markers, IL-6 and C-Reactive Protein (CRP), were the variables of choice as per their inflammatory link (see here and see here). Said inflammatory markers were analysed in blood samples from quite a nice cohort (~4500) of 9-year olds who took part in the ALSPAC initiative. 
• When their cohort were 18 years old, their mental health was assessed for things like depression and psychotic experiences (PEs) using various questionnaires and semi-structured interviews.
• Results: depending on whether participants fell into groups suggestive of low, medium or high inflammation on the basis of inflammatory markers seemed to have some effect on their mental health almost a decade later. So: "participants in the top third of IL-6 values compared with the bottom third at age 9 years were more likely to be depressed... at age 18 years". This finding was reported after correction for various potentially interfering variables.
• Additionally: "Risks of PEs and of psychotic disorder at age 18 years were also increased with higher IL-6 levels at baseline".
• The authors conclude: "Higher IL-6 levels in childhood were associated with subsequent risks of depression and PEs in a dose-dependent manner".

There is, as one might expect, some accompanying media interest in these results (see here). I was interested to see that Judy Van de Water commented on the Khandaker results. Regular readers of the autism research scene will probably already known about Dr Van de Water's interest in immune function (including inflammation) and autism previously talked about on this blog (see here for example). She is quoted talking about: "kids who get fevers more often and for longer periods of time may also have higher levels of inflammation". Mmm...

Whilst the Khandaker results are very interesting, as always, I do think there is more to do in this area. Aside from correlating spot analyses of inflammatory markers with events almost a decade later, IL-6 is portrayed as the bad guy in this scenario based on it's connection to systemic inflammation. But things are rarely so straight-forward as per the paper by Scheller and colleagues [3] (open-access) on the two faces of IL-6. To boil depression and PEs solely down to childhood inflammation also does little to say how complex such conditions are; something which Dr Khandaker's other research has also hinted at. I've also talked about other correlates and things like depression including vitamin D levels (see here), certain bacteria (see here) and possibly even something like dietary components (see here) showing potential involvement. It's complicated as I said.

Oh and headlines like 'Could aspirin and ibuprofen help fight depression?' are perhaps a little premature at this time... but at least they didn't suggest paracetamol.

Music to close. MAGIC! and Rude (Marry that Girl!).

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[1] Khandaker GM. et al. Association of Serum Interleukin 6 and C-Reactive Protein in Childhood With Depression and Psychosis in Young Adult Life. JAMA Psychiatry. 2014. August 13.

[2] Khandaker GM. et al. A population-based longitudinal study of childhood neurodevelopmental disorders, IQ and subsequent risk of psychotic experiences in adolescence. Psychol Med. 2014 Apr 25:1-10.

[3] Scheller J. et al. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2011; 1813: 878-888.

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Golam M. Khandaker, Rebecca M. Pearson, Stanley Zammit, Glyn Lewis, & Peter B. Jones (2014). Association of Serum Interleukin 6 and C-Reactive Protein in Childhood With Depression and Psychosis in Young Adult Life JAMA Psychiatry : doi:10.1001/jamapsychiatry.2014.1332

Maternal iron intake and offspring autism risk

Much like the discussions around the paper by Rogers and colleagues (see here) on treating autism in the first year of life, the media scrum around the findings from Rebecca Schmidt and colleagues [1] talking about maternal iron supplements and offspring autism spectrum disorder (ASD) risk preceded the publication of the paper by a few days. It's getting to be a pet-hate of mine that big headlines are being generated sometimes days before your average Jane or Joe can see the data upon which they're based...

Grumbling aside, here are a few factoids from the now published Schmidt paper:

• CHARGE was the source initiative for participants, as it has been for various studies, and following on from other research on nutrition during pregnancy potentially affecting offspring autism risk from this group (see here), the idea was to look at pre- and pregnancy maternal iron intake in relation to autism risk.
• Data for mothers of children with autism (n=520) were compared against mothers with children who did not have autism (n=346) and "maternal daily iron intake was quantified on the basis of frequency, dose, and brands of supplements and cereals consumed each month from 3 months before pregnancy through the end of pregnancy and during breastfeeding (the index period), as reported in parental interviews". You'll note the words 'parental interviews' there.
• Results: well, the mothers of children with autism were less likely to report taking 'iron-specific supplements' than control mothers and overall, a "lower mean daily iron intake" in the order of 5-6 mg/day less than controls was observed.
• "Low iron intake significantly interacted with advanced maternal age and metabolic conditions; combined exposures were associated with a 5-fold increased ASD risk". Advanced maternal age by the way, refers to women who were 35 or older at the time of their child's birth, and metabolic conditions means obesity, diabetes or hypertension (in line with other evidence).

These are interesting findings which add to the growing literature on how maternal nutrition before and during the nine months that made us potentially impacts on offspring development and outcome. Certainly, there are hints of the foetal programming hypothesis in there, for which the late David Barker receives quite a bit of credit. I was also wondering whether other issues potentially affecting foetal nutrition such as the inter-pregnancy interval (see here) might also tie into these findings too?

But there are some obvious cautions to take on board when it comes to these findings. First is the continued reliance on self-report, which even under the most controlled of situations, is always going to be an estimate at best. Next, and I might be completely wrong about this, but even with the report of a mean daily intake of ~51 mg/day, the mothers with children with autism group were still quite a bit above the daily recommendations in the United States (see here) for pregnant or lactating women. Finally, I'm wondering whether the idea of "combined exposures" when it comes to maternal age and the presence of metabolic syndrome might actually be the more important issue raised in this paper...

Iron and autism is a topic which has been discussed a few times on this blog (see here). The data is slightly mixed when it comes to looking at iron levels in children with autism as per my discussions on the Reynolds paper [2] versus the Hergüner findings [3]. Dr Schmidt and colleagues did not directly assay for iron or ferritin levels in their current paper so we can't really say much more at this point on how actual maternal iron levels translated into offspring iron levels and what effect(s) this may have had on offspring autism or other risks. That and whether other factors might also have played some role as per the rodent findings from Harvey & Boksa [4] talking about an additive effect from iron deficiency and prenatal immune activation (a topic that has cropped up a few times with autism in mind). These are perhaps the next studies that need to be done alongside what biological effects supplementation may have [5].

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[1] Schmidt RJ. et al. Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder. Am J Epidemiol. 2014. 22 September.

[2] Reynolds A. et al. Iron status in children with autism spectrum disorder. Pediatrics. 2012; 130 Suppl 2:S154-S159.

[3] Hergüner S. et al. Ferritin and iron levels in children with autistic disorder. Eur J Pediatr. 2012; 171: 143-146.

[4] Harvey L. & Boksa P. Additive effects of maternal iron deficiency and prenatal immune activation on adult behaviors in rat offspring. Brain Behav Immun. 2014 Aug;40:27-37.

[5] Dosman CF. et al. Children with autism: effect of iron supplementation on sleep and ferritin. Pediatr Neurol. 2007 Mar;36(3):152-8.

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Rebecca J. Schmidt, Daniel J. Tancredi, Paula Krakowiak, Robin L. Hansen, & Sally Ozonoff (2014). Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder American Journal of Epidemiology : doi: 10.1093/aje/kwu208

Gut issues in autism impacting on drug availability and absorption

As indicated in a recent post, I was really rather pleased to see the paper by Andrew Heitzer and colleagues [1] (open-access) asking the important question: Should clinical trial research of psychotropic medication in autism control for gastrointestinal symptoms? Some media about the study can also be found here.

"You write "Born to Kill" on your helmet
and you wear a peace button".

The answer is of course, yes and not just when it comes to psychotropic medicines either, given that gastrointestinal (GI) symptoms both functional and more pathological, are by no means an uncommon event when a diagnosis of autism is received (see here).

As anyone with an interest in pharmcokinetics and pharmacodynamics should be able to tell you, various factors can affect a persons response to medication, particularly medication delivered orally (by mouth). Outside of medicines interactions, ageing is one of the more well-studied factors pertinent to drug response as per the review by Mangoni & Jackson [2] for example, but there are other suggestions on the horizon. Indeed, I might also take this opportunity to link to some of the work by Prof. Jeremy Nicholson and colleagues [3] talking about how gut bacteria may play a role in drug metabolism. This area may be particularly pertinent to autism given this research teams' previous forays into autism science (see here) and the growing interest in the gut microbiota and autism (see here).

There are various other factors which may also affect drug response in relation to autism such as stomach acid conditions (see here) and even drug transporter capability (see here). This outside of adherence to instructions like taking medication with water or avoiding food/certain foods when taking particular medicines, which one should never assume are just followed.

Of course there are other ways in which medication, when indicated, can potentially be reformulated to overcome some of these issues. I've talked before about some work our research group were involved with looking at making up the opiate antagonist naltrexone into a cream (see here). Although not necessarily a big fan of the sweeping statements made about oxytocin and autism (see here), I've likewise always been interested in the intra-nasal route of drug administration. There are other ways too (bearing in mind I'm making no value judgements on these).

So once again, yes, as part of good medicines management, clinicians and researchers need to be mindful that comorbid issues like GI symptoms can potentially affect the workings of various medicines if and when required by people with autism.

Music then. Bohemian Like You by The Dandy Warhols.

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[1] Heitzer AM. et al. Should clinical trial research of psychotropic medication in autism control for gastrointestinal symptoms? J Clinical Pharmacology. 2014. 6 May.

[2] Mangoni AA. & Jackson SHD. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. Jan 2004; 57(1): 6–14.

[3] Clayton TA. et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14728-33.

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Heitzer AM, Job MA, Pandit NK, & Valdovinos MG (2014). Should clinical trial research of psychotropic medication in autism control for gastrointestinal symptoms? Journal of clinical pharmacology PMID: 24788353

Omega-3 fatty acids and ADHD

With a title like that, this post could turn out to be quite a long winded blog entry. As it happens, I'm not going to subject you, dear reader, to such a literary onslaught but rather focus my attention on the paper by Elizabeth Hawkey & Joel Nigg [1] who undertook two meta-analyses and concluded that: "Omega-3 levels are reduced in children with ADHD [attention-deficit hyperactivity disorder]" and "Dietary supplementation appears to create modest improvements in symptoms".

"Maybe the 80s will be like radical or something"

Omega-3 fatty acids, including α-Linolenic acid (ALA), Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) sourced from things like fish have been the stuff of controversy and debate over the years, particularly focused on their potential link with various facets of child development. I don't want to get into all the nitty-gritty of discussions but suffice to say that this is an area which, for quite a few years, seemed to be cast into the scientific desert. In more recent times, science has started to more systematically examine the possibility of a link between omega-3 fatty acids and development and how supplementation might be indicated for some (see here).

Specifically with ADHD in mind, omega-3 fatty acids boasts quite a thriving research base. The one go-to article that many people have relied on in recent years was the Cochrane Review of PUFAs (polyunsaturated fatty acids) by Gillies and colleagues [2] that concluded: "Overall, there is little evidence that PUFA supplementation provides any benefit for the symptoms of ADHD in children and adolescents". Bearing in mind that review looked at research up to August 2011, the evidence base has moved on somewhat since then, with various controlled trials publishing results as per those from Milte and colleagues [3] and Richardson and colleagues [4] specifically based on analysis of the omega-3 fatty acids. Although not wholly positive [5], the combined results seem to imply that for some with ADHD, there may be certain benefits [6] to be had following certain supplementation.

There's little more for me to say on this topic aside from pointing out the need for further investigation on the hows and whys of fatty acid deficiency/supplementation with at least some diagnosed with ADHD and how this might also translate into other conditions where ADHD may be quite frequently comorbid (see here). As part of a wider body of peer-reviewed research suggestive that dietary variables may play some role for some with ADHD (see here and see here) I'm minded to suggest that food and nutrition should rank further up the research priorities hierarchy when it comes to intervention and ADHD.

So then, Urge Overkill? (if you don't recognise the band name, you'll probably recognise the song).

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[1] Hawkey E. & Nigg JT. Omega-3 fatty acid and ADHD: Blood level analysis and meta-analytic extension of supplementation trials. Clin Psychol Rev. 2014 Jun 2;34(6):496-505.

[2] Gillies D. et al. Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database Syst Rev. 2012 Jul 11;7:CD007986.

[3] Milte CM. et al. Eicosapentaenoic and docosahexaenoic acids, cognition, and behavior in children with attention-deficit/hyperactivity disorder: a randomized controlled trial. Nutrition. 2012 Jun;28(6):670-7.

[4] Richardson AJ. et al. Docosahexaenoic acid for reading, cognition and behavior in children aged 7-9 years: a randomized, controlled trial (the DOLAB Study). PLoS One. 2012;7(9):e43909.

[5] Dubnov-Raz G. The effect of alpha-linolenic acid supplementation on ADHD symptoms in children: a randomized controlled double-blind study. Front. Hum. Neurosci. 2014; 8:780.

[6] Widenhorn-Müller K. et al. Effect of supplementation with long-chain ω-3 polyunsaturated fatty acids on behavior and cognition in children with attention deficit/hyperactivity disorder (ADHD): a randomized placebo-controlled intervention trial. Prostaglandins Leukot Essent Fatty Acids. 2014 Jul-Aug;91(1-2):49-60.

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Hawkey E, & Nigg JT (2014). Omega-3 fatty acid and ADHD: Blood level analysis and meta-analytic extension of supplementation trials. Clinical psychology review, 34 (6), 496-505 PMID: 25181335

Antibiotics and risk of pediatric Crohn's disease

I couldn't let the meta-analysis from Ryan Ungaro and colleagues [1] pass without a brief mention. Concluding that: "Exposure to antibiotics appears to increase the odds of being newly diagnosed with CD [Crohn's disease] but not UC [ulcerative colitis]" and further: "This risk is most marked in children diagnosed with CD", the implications from this and other findings in this area may be far-reaching.

I've talked before on this blog about antibiotic exposure and risk of inflammatory bowel disease (IBD) (see here) and how, bearing in mind risk is risk, there may be quite a bit more to see in the whole gut bacteria - disease risk arena. Acknowledging that science is still feeling it's way around this area and in particular, whether the use of probiotics might offset any risk or mitigate symptoms [2], the meta-analytic contribution of Ungaro et al represent another important driver for further investigation into those trillions of beasties which call us home [3]. Oh and then there is the gut-brain axis too?

Music to close... Be Happy.

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[1] Ungaro R. et al. Antibiotics Associated With Increased Risk of New-Onset Crohn’s Disease But Not Ulcerative Colitis: A Meta-Analysis. The American Journal of Gastroenterology. 2014. 16 September.

[2] Orel R. & Trop TK. Intestinal microbiota, probiotics and prebiotics in inflammatory bowel disease. World J Gastroenterol. Sep 7, 2014; 20(33): 11505–11524.

[3] Wu GD. Diet, the Gut Microbiome and the Metabolome in IBD. Nestle Nutr Inst Workshop Ser. 2014;79:73-82.

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Ungaro R, Bernstein CN, Gearry R, Hviid A, Kolho KL, Kronman MP, Shaw S, Van Kruiningen H, Colombel JF, & Atreja A (2014). Antibiotics Associated With Increased Risk of New-Onset Crohn's Disease But Not Ulcerative Colitis: A Meta-Analysis. The American journal of gastroenterology PMID: 25223575

Increasing parental age and autism severity?

An interesting paper by David Geier and colleagues [1] (open-access here) caught my eye recently, concluding that there was a lack of support for the suggestion that: "increasing parental age was associated with increasing autism spectrum disorder phenotypic severity".

"the snozzberries taste like snozzberries".

Before progressing through the paper and its possible implications, the eagle-eyed out there might have already spotted the name Dr Brian Hooker on the authorship list of the Geier paper. Outside of his other peer-reviewed work [2], I probably only need to mention the letters 'CDC' and everything that has [so far] followed including (at the time of writing) a removal statement retraction statement (updated: 04/10/14) for another paper [3]...

Anyhow, the idea behind the Geier paper stems from the quite widely disseminated notion that there may be a connection between increasing parental age at conceiving and an increased risk of offspring autism. I've covered it a few times on this blog (see here and see here). The authors elaborate about a recent hypothesis suggesting that "there must be a linkage between increasing genetic load and increasing parental age in autism spectrum disorder pathogenesis" based on studies like the one from Kong and colleagues [4] (covered in a previous post) and Lampi and colleagues [5]. Further, that as a consequence of an increasing genetic load (all those SNPs et al), "there should be a significant relationship between increasing parental age and increasing autism spectrum disorder phenotypic severity of subjects diagnosed with an autism spectrum disorder".

The paper is open-access but maybe a few details are in order:

• Participants (N=351), diagnosed with DSM-IV autism, were drawn from "patients presenting for outpatient genetic consultations at the ASD Centers, LLC". Mean age was approximately 9 years of age, most male and most reporting developmental regression following birth. Details of age of parents at time of offspring birth were analysed alongside use of the ATEC (Autism Treatment Evaluation Checklist) at initial clinical presentation. These variables formed the crux of the study.
• Results: "Overall, it was observed that no significant relationships were observed between increasing autism spectrum disorder phenotypic severity and increasing maternal or paternal age". Except, that is, for something that seemed to suggest that older maternal age at birth of child seemed to correlates with "improved sociability" in offspring. The authors report that their observations: "provide important insights into the apparent lack of a relationship between increasing parental age and increasing autism spectrum disorder phenotypic severity".

Of course one has to be careful with any study of correlation/association, particularly when it comes to something as simple as just looking at ATEC scores of severity of behaviours in the autism domains and parents age at time of birth of their children. I personally would also have liked to see some further discussion on whether the broader autism phenotype (BAP) for example, might have been an influencing variable too in light of studies like the one from Hasegawa and colleagues [6]. Also, the participant group is quite large - as the authors note - but even there I think back to the sort of sample numbers that those [big data] studies in Taiwan are including (see here) as to where we should be heading.

That all being said, I don't want to downplay the Geier results. Another quote might be useful here: "most observed de novo genetic events are unconnected to an autism spectrum disorder diagnosis, and those that do confer risk are distributed across many genes and are not necessarily sufficient for disease". This ties in rather nicely with the recent discussions on common variations and autism risk (see here) and how Gaugler and colleagues [7] questioned how much weight to give to de novo mutations in the grand scheme of autism 'causation'. This also might imply that non-genetic events, or at least non-structural genetic events headed under the general banner of environment might also play some contributory role to at least some cases of autism. Again, something which has cropped up on this blog before (see here).

Music to close. Given the recent vote near these parts, one of Scotland's most famous exports... Franz Ferdinand and Do You Want To.

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[1] Geier DA. et al. An Evaluation of the Effect of Increasing Parental Age on the Phenotypic Severity of Autism Spectrum Disorder. J Child Neurol. 2014 Aug 27. pii: 0883073814541478.

[2] Hooker B. et al. Methodological issues and evidence of malfeasance in research purporting to show thimerosal in vaccines is safe. Biomed Res Int. 2014;2014:247218.

[3] Hooker BS. Measles-mumps-rubella vaccination timing and autism among young african american boys: a reanalysis of CDC data. Transl Neurodegener. 2014; 3: 16.

[4] Kong A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012 Aug 23;488(7412):471-5.

[5] Lampi KM. et al. Parental age and risk of autism spectrum disorders in a Finnish national birth cohort. J Autism Dev Disord. 2013 Nov;43(11):2526-35.

[6] Hasegawa C. et al. Broader autism phenotype in mothers predicts social responsiveness in young children with autism spectrum disorders. Psychiatry Clin Neurosci. 2014 Jun 6. doi: 10.1111/pcn.12210.

[7] Gaugler T. et al. Most genetic risk for autism resides with common variation. Nature Genetics. 2014. July 20.

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Geier DA, Hooker BS, Kern JK, Sykes LK, & Geier MR (2014). An Evaluation of the Effect of Increasing Parental Age on the Phenotypic Severity of Autism Spectrum Disorder. Journal of child neurology PMID: 25163730

Anxiety and sensory over-responsivity linked to gut issues in autism

"The name's Lonnegan! Doyle Lonnegan!"

Consider this micropost an extension of some previous discussions on this blog about how gastrointestinal (GI) issues present in cases of autism might show some connection to the presence of anxiety and sensory issues (see here). Today I'm discussing further research by Micah Mazurek and colleagues [1] which follows a previous publication by this author [2] on this topic.

In the latest paper, Dr Mazurek and colleagues describe the course of abdominal pain in 225 children diagnosed with an autism spectrum disorder (ASD). Of the quarter of participants who presented with "chronic abdominal pain at baseline", the majority (over 80%) still had the same GI issue at 1-year follow-up. Indeed, a further 25% of those who did not present with abdominal pain at the start of the study finished the study with such an issue. The authors conclude: "Abdominal pain appears to be common and persistent among children with ASD". Further, anxiety and sensory over-responsivity also seemed to correlate with bowel features which is probably not unexpected.

Yes, you might indeed say that this study was based on "the parent-reported GI Symptom Inventory Questionnaire" among other things and so one has to be slightly cautious about inferring states. But as I've mentioned before on this blog, parents/primary caregivers tend to be pretty good at picking up when such issues are present in their children (see here) if not precise to all the technical details [3].

Perhaps the most important detail about the Mazurek study is their mention of the word 'pain' and how so many of their cohort seemed to be enduring quite a bit of it for such a long period of time. You wouldn't think that there was guidance on identifying and managing these issues [4] would you? And whilst we are on the topic of GI issues and autism, I might as well bring your attention to the potentially important question asked by Heitzer and colleagues [5]: Should clinical trial research of psychotropic medication in autism control for gastrointestinal symptoms? Answers on a postcard please (although I will blogging about this paper in times to come).

So then, how about William Shatner singing Pulp to close. Replacing a Sheffield accent with a Montreal one... mmm, maybe he needs a little Henderson's Relish with that cheese?

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[1] Mazurek MO. et al. One-year course and predictors of abdominal pain in children with autism spectrum disorders: The role of anxiety and sensory over-responsivity. Research in Autism Spectrum Disorders. 2014; 8: 1508-1515.

[2] Mazurek MO. et al. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol. 2013 Jan;41(1):165-76.

[3] Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

[4] Buie T. et al. Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report. Pediatrics. 2010; 125: S1-S18.

[5] Heitzer AM. et al. Should clinical trial research of psychotropic medication in autism control for gastrointestinal symptoms? J Clinical Pharmacology. 2014. 6 May.

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Mazurek, M., Keefer, A., Shui, A., & Vasa, R. (2014). One-year course and predictors of abdominal pain in children with autism spectrum disorders: The role of anxiety and sensory over-responsivity Research in Autism Spectrum Disorders, 8 (11), 1508-1515 DOI: 10.1016/j.rasd.2014.07.018