Childhood inflammation and hypomanic symptoms in young adulthood?

"Higher levels of systemic inflammatory marker IL-6 in childhood were associated with hypomanic symptoms in young adulthood, suggesting that inflammation may play a role in the pathophysiology of mania."

That was the conclusion reached by Joseph Hayes and colleagues [1] (open-access available here) who drew on data derived from the excellent resource that is ALSPAC ("Charting the health of 14,500 families in the Bristol area to improve the health of future generations"). I'll be talking about other ALSPAC-derived data in upcoming posts too.

Based on a cohort of some 4600 children who provided blood samples (analysable blood samples no less) at aged 9 years old and "who completed the Hypomania Checklist (HCL-32)" at aged 22 years, researchers looked at how blood levels of C-reactive protein (CRP) and IL-6 might link in with later self-reported hypomanic symptoms.

Bearing in mind the focus on "immune activity in healthy individuals" (quite a few participants were excluded from the study as a result of reporting an infection in the week before samples were taken), researchers reported some interesting associations. As per the opening sentence: "Higher IL-6 levels in childhood were associated with adult hypomania features in a dose-response fashion." That being said: "Higher serum IL-6 levels at age 9 years were associated with female sex, non-white British ethnicity, lower SES, higher past psychological and behavioural problems and higher BMI" too. When it comes to BMI (body mass index), the observation that various immune system markers might be elevated is not necessarily a new idea.

Although childhood IL-6 levels were associated with later hypomanic symptoms (even when adjusted for the various potentially confounding variables), blood levels of CRP did not seem to show the same kind of relationship: "There was no evidence of an association between CRP levels and hypomanic symptoms." Similarly, when authors looked at the possibility of an association between the presence of atopic disease and hypomanic symptoms based on the inclusion of a parent-response question when their child participant was 10 years old - "Has a doctor ever actually said that your study child has asthma or eczema?" - the authors reported little indication of any connection.

At least one of the co-authors on the Hayes paper has some prior interest in the possible psychiatric manifestations of childhood inflammation as per other entries on this blog (see here). As much as I am intrigued by this area of research, you don't have to be a rocket scientist to understand the potential flaws in such a study where one or two biological variables are mapped on to a self-report questionnaire quite a few years later potentially excluding a myriad of factors not readily taken into account in a study like this. It would for example, be preferable to have seen multiple measures of CRP and/or IL-6 during childhood (say, every year) to see if any potential association between childhood inflammation and hypomanic symptoms holds. That also only IL-6 seemed to show some sort of connection maybe also implies that the generalised idea that 'inflammation' might tie into later psychiatric symptoms is perhaps a little bit too generalised. I could go on i.e. CRP is not the only pentraxin, IL-6 is not necessarily just a pro-inflammatory cytokine, etc.

In short, some interesting observations and yes "immunological understanding of major mental illness could potentially lead to novel approaches to diagnosis, prevention and treatment" but I think we need a lot more quality data on this topic.

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[1] Hayes JF. et al. Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study. Psychol Med. 2016 Aug 1:1-11.

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Hayes JF, Khandaker GM, Anderson J, Mackay D, Zammit S, Lewis G, Smith DJ, & Osborn DP (2016). Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study. Psychological medicine, 1-11 PMID: 27476619

Mercury and autism: where the science currently stands

Yes, I know that on the 'hot potato' scale, to talk about mercury and autism still moves the needle up to somewhere approaching furnace level for some people despite discussions on this heavy metal still figuring in several quarters. This is however a blog based on peer-reviewed science (for the most part) and so with mucho, mucho caveats included I want to draw your attention to the review paper by Janet Kern and colleagues [1] (open-access available here) and the observation that: "The preponderance of the evidence indicates that mercury exposure is causal and/or contributory in ASD [autism spectrum disorder]." I might add that this authorship group are no strangers to this particular topic (see here).

As per the 'review' heading accompanying the Kern paper, this was an analysis (inventory) of the up-to-date - "1999 to February 2016" - peer-reviewed studies done around the topic of mercury and autism. The authors present the data based on tissue type, ASD vs. not-ASD and various other parameters detailing the back-and-forth of relationship and no relationship that seems to percolate through the autism research scene. They conclude that "the vast majority (74%) of those studies suggest that mercury is a risk factor for ASD" and that any effect is likely to consist of "both direct and indirect effects of mercury exposure." This direct and indirect effects explanation is accompanied by a graphic highlighting the many and varied ways that mercury exposure might be linked to cases of autism. They also direct readers to a similar paper on this topic [2] that "also found that 74% of studies support a link between mercury exposure and ASD."

Without courting controversy as to the sources of and relative role that mercury might have on cases of autism I was drawn to a particular conclusion made by the authors that "children with ASD are more susceptible to mercury than typically developing children." I've seen and blogged about enough autism research down the years to understand that for some people on the autism spectrum, behavioural 'symptoms' can be accompanied by various genetic and biological 'issues' linked to the handling of various toxicants and other environmental agents. I'm not yet convinced with the argument that universally people diagnosed with autism are somehow preferentially exposed to greater levels of mercury than the rest of the population but I am warming to the idea that their 'handling' of such a heavy metal (and others) might to some extent be 'impaired' and that this could have some impact on body burden levels as well as clinical presentation.

Obviously, more research is implied.

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[1] Kern JK. et al. The relationship between mercury and autism: A comprehensive review and discussion. J Trace Elem Med Biol. 2016 Sep;37:8-24.

[2] Desoto MC. & Hitlan RT. Sorting out the spinning of autism: heavy metals and the question of incidence. Acta Neurobiol Exp (Wars). 2010;70(2):165-76.

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Kern JK, Geier DA, Sykes LK, Haley BE, & Geier MR (2016). The relationship between mercury and autism: A comprehensive review and discussion. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 37, 8-24 PMID: 27473827

76% of youths with autism meet ADHD diagnostic criteria? No, more like 59%

"In a population of children diagnosed with ASD [autism spectrum disorder], the rate of ADHD [attention-deficit hyperactivity disorder] + ASD was 42% and the rate of ADHD + ASD + ID [intellectual disability] was 17%, resulting in a 59% total comorbidity rate of ADHD and ASD."

That was one of the important findings reported by Tara Stevens and colleagues [1] who using data from the Survey of Pathways to Diagnosis and Services (Pathways), a US initiative that has previously been discussed on this blog (see here), threw their research hat into an increasingly important part of the autism research and practice landscape.

I mentioned the percentage figure of 76% in the title of this post with reference to other, smaller scale, findings previously talked about on this blog (see here) based on the work published by Joshi and colleagues [2] and their observation of a: "high rate of comorbidity with ADHD... in psychiatrically referred youth with ASD, with a clinical presentation typical of the disorder."

The Stevens data is based on a larger sample cohort and whilst not necessarily carrying the same sort of diagnostic clout as the Joshi data ("Diagnostic interviews were administered by highly trained and closely supervised psychometricians with bachelor’s or master’s degrees in psychology or a related field") does benefit from those larger numbers included and indeed, the more naturalistic setting of data collection. That Stevens et al report that: "Average age at diagnosis was over 6 years for children with ASD + ADHD but close to 2.5 years for children with ASD only" also provides some welcome information about the experiences of a dual diagnosis of autism plus ADHD.

In these days of autism plus [3] (ESSENCE even) further focus on the idea that the label of autism rarely exists in some sort of diagnostic vacuum (see here) represents an important step towards offering appropriate - preferential - screening when autism is mentioned and also focusing minds on how comorbidity can in some cases be even more disabling than the core diagnosis of autism (see here). Although one has to be quite careful not to 'big up' the relationship between autism and ADHD, particularly in these days where a very vocal group of people talk about over-diagnosis of ADHD, I'd be minded to suggest that as per the example with other comorbidity over-represented when it comes to autism, tackling something like ADHD when it is present/diagnosed might have some important repercussions for the presentation of core autism itself and its impact on quality of life...

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[1] Stevens T. et al. The comorbidity of ADHD in children diagnosed with autism spectrum disorder. Research in Autism Spectrum Disorders. 2016; 31: 11–18.

[2] Joshi G. et al. Symptom Profile of ADHD in Youth With High-Functioning Autism Spectrum Disorder: A Comparative Study in Psychiatrically Referred Populations. J Atten Disord. 2014 Aug 1. pii: 1087054714543368.

[3] Gillberg C. & Fernell E. Autism plus versus autism pure. J Autism Dev Disord. 2014 Dec;44(12):3274-6.

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Stevens, T., Peng, L., & Barnard-Brak, L. (2016). The comorbidity of ADHD in children diagnosed with autism spectrum disorder Research in Autism Spectrum Disorders, 31, 11-18 DOI: 10.1016/j.rasd.2016.07.003

Group A Streptococcal infections and paediatric neuropsychiatric disorders: Taiwan style

There they go again. Taiwan and their 'big data' publishing, yet again, some rather interesting population-based research trends derived from data from the National Health Insurance Research Database (NHIRD).

This time around it is the paper by Han-Cheng Wang and colleagues [1] and the hypothesis to evaluate the "association between group A streptococcal (GAS) infections and the risks of developing tic disorders, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD)." For those in the know, the relationship between Strep infection and those neuropsychiatric labels brings us into the realm of PANDAS and PANS (and no, not the fluffy black-and-white kind of panda either).

Based on a not insignificant participant number - "2,596 patients and 25,960 controls" - researchers set about looking at under-18 year olds newly diagnosed with a GAS infection and their subsequent risk of receiving one or more of those neuropsychiatric labels.

Compared to controls, the incidence of neuropsychiatric disorder in the GAS group was higher (60.42 per 10,000 person-years vs. 49.32 per 10,000 person-years) particularly when it came to the presentation of a tic disorder. If said GAS infection was serious enough to put someone in hospital, the risk of neuropsychiatric disorder was even higher compared with than those who did not have a GAS infection. The authors conclude: "Our results confirmed an association between previous group A streptococcal infection and neuropsychiatric disorders."

Set within the growing research base suggesting that various infections can very much lead to behavioural outcomes (see here for another example) as well as physical ones, there is some interesting science still to be done on the hows and whys. Whether said infection meets us during the nine months that made us (see here) or some time after provides some intriguing insights on how timing and infection type might show differential effects for a person. The question of whether (a) we can prevent certain infections or (b) offset their primary effects via the use of agents affecting immune function or immune response perhaps represent some of the more important avenues for further investigations in this area.

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[1] Wang HC. et al. Group A Streptococcal Infections Are Associated With Increased Risk of Pediatric Neuropsychiatric Disorders: A Taiwanese Population-Based Cohort Study. J Clin Psychiatry. 2016 Jul;77(7):e848-54.

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Wang, H., Lau, C., Lin, C., Chang, A., & Kao, C. (2016). Group A Streptococcal Infections Are Associated With Increased Risk of Pediatric Neuropsychiatric Disorders The Journal of Clinical Psychiatry DOI: 10.4088/JCP.14m09728

Offending behaviour and ADHD

"Although some associations between ADHD [attention-deficit hyperactivity disorder] and offending may be accounted for by co-morbidity with substance use disorders, early onset of offending and repeated violent offending appear to be directly related to ADHD."

That was the conclusion reached by Jan Román-Ithier and colleagues [1] reporting on their study designed to "examine correlates of childhood ADHD symptoms among prisoners." Based on a sample adult prison population (N=1179) where self-reported "retrospective measures of ADHD and a diagnostic interview for substance use disorders" were coupled with data on offending behaviour(s), researchers reported that there may be more to see when it comes to self-reported ADHD and offending behaviour not necessarily just due to substance abuse. Indeed: "Self-reported ADHD was associated with age of first arrest, a number of violent and non-violent offences and re-offending."

Of course you'd be right if you highlighted a few methodological issues with the current data insofar as the use of self-report and indeed, retrospective self-report when it comes to ADHD or ADHD-type symptoms. I might even throw in the idea that feigning ADHD is not something unheard of in the peer-reviewed literature either (see here) bearing in mind one might expect some special treatment or accommodation for prisoners who might meet diagnostic thresholds. There is more [controlled] research to be done in this area for sure.

But set within the idea that there may be something of an over-representation of ADHD in the prison population (see here), the Román-Ithier results add further weight to the idea that screening (including preferential screening for some) and treating ADHD early in life might be something to seriously think about from a population health and wellbeing perspective. Yes, one has to be careful about sweeping generalisations when it comes to ADHD and 'adverse outcomes' (see here) including the idea that ADHD persistence might not be uniform [2] and I don't doubt that some might be slightly adverse to the idea of some of the currently indicated treatment measure for ADHD when it comes to medication for example (see here). But as with many things in life, the pros and cons of tackling such issues need to be weighed up on an individual basis assuming for example, that a life of offending and re-offending is probably not to be helpful to anyone. I might also throw the findings by Chorniya & Kitashimab [3] into this post and how substance abuse disorder and other 'risky behaviours' might also decline as and when ADHD is appropriately managed.

And outside of just pharmacotherapy for ADHD, there are other management options to potentially consider (see here and see here and see here for example)...

To close, fair-dos to Gary Lineker...

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[1] Román-Ithier JC. et al. Attention deficit hyperactivity disorder symptoms, type of offending and recidivism in a prison population: The role of substance dependence. Crim Behav Ment Health. 2016 Jul 26.

[2] McAuley T. et al. Clinical, Sociobiological, and Cognitive Predictors of ADHD Persistence in Children Followed Prospectively Over Time. J Abnorm Child Psychol. 2016 Jul 29.

[3] Chorniya A. & Kitashimab L. Sex, drugs, and ADHD: The effects of ADHD pharmacological treatment on teens' risky behaviors. Labour Economics. 2016. July 5.

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Román-Ithier, J., González, R., Vélez-Pastrana, M., González-Tejera, G., & Albizu-García, C. (2016). Attention deficit hyperactivity disorder symptoms, type of offending and recidivism in a prison population: The role of substance dependence Criminal Behaviour and Mental Health DOI: 10.1002/cbm.2009

Inflammation is part of Gulf War Syndrome

Although mostly trying to avoid any politics-talk on this blog I am going to make some reference to it in this post set in the context of the Persian Gulf War otherwise known at the First Iraq War.

The recent publication of the Chilcot report describing the case for the UK's involvement in the 2003 Iraq War (the second Iraq War) has further lit up an already illuminating year in British politics, by perhaps adding fuel to the notion that 'finishing the job' might have been an important link between the two conflicts...

Operation Desert Storm - the combat phase of the First Gulf War (1991) - described by some as 'the most toxic war in history' left a mark not just on the region where it was fought and its people but also on many of the returning service personnel, some of whom came back in a pretty poor state of health. Their various symptoms known collectively as Gulf War Syndrome or Illness, are still the topic of discussions and debate to this day despite increasing evidence that they are 'real' symptoms (see here) and not just some psychosomatic manifestation of combat stress for example, as advocated by some quite prominent figures. The possible reasons for illness are varied (see here) but when one uses the words 'sarin' in the context of potential exposures for example you get a flavour for what might have been involved [1] and their potential contributions to health or rather ill-health.

The paper by Gerhard Johnson and colleagues [2] (open-access) adds further credence to the idea that Gulf War Illness (GWI) is indeed a real phenomenon and specifically: "that inflammation is a component of the pathobiology of GWI." Based on the examination of a relatively small number of veterans (85 out of 500 deployed veterans who were invited to participate), researchers undertook a "structured interview" that "assessed their health status, and blood samples were obtained." They managed to divide veterans up into GWI+ (n=57) and GWI- (n=28) groupings dependent on whether or not they reached the Fukuda criteria [3] for a "a chronic multisymptom condition" linked to deployment to the Gulf War.

Results: over 80 specific analytes were assayed for from the blood samples provided by participants. Many compounds had an immunological slant in terms of being cytokines or being other markers of immune system (specifically inflammatory) 'activation'. "The results of the current study provide evidence of alterations in a number of blood parameters that are readily measurable in routine clinical laboratories" was the headline as six specific compounds, all with inflammation in mind, were ripe for further independent study: plasma C-reactive protein (CRP), leptin, brain-derived neurotrophic factor (BDNF), and matrix metalloproteinase-9 (MMP-9)  = higher in the GWI+ group. Heart-type fatty acid binding protein (H-FABP) and matrix metalloproteinase-2 (MMP-2) = lower in the blood of GWI+ subjects. Alongside "the distributions of peripheral blood lymphocyte, monocyte, neutrophil, and platelet counts were higher in GWI+ subjects" compared with GWI- participant data leading researchers to observe that "a model utilizing three readily measurable biomarkers [lymphocytes, monocytes, and C reactive protein]... appears to significantly augment the symptom-based case definition of GWI."

"The limitations of the study include small sample size, restricted geographic, ethnic, and sex composition of the study subjects, assay of blood parameters only once, some plasma protein assays, including cytokines, considered inevaluable due to a high percentage of assays below the level of detection, overlap of biomarker distributions within the normal range, absence of correction for multiple comparisons, a limited number of blood proteins found to be positively related to GWI+ status, and the absence of a confirmation cohort study." Apologies for just grafting a large chunk of text from the Johnson paper into this post, but when it comes to the limitations of their work, the authors do a pretty good job of cautioning against any over-hype and providing a roadmap to 'where next?'

And as part of that 'where next?' it appears that we might be talking quite soon about some findings if an associated ClinicalTrials.gov entry is anything to go by (see here) on the use of 'delayed-release prednisone' with this group. I say this without making any value judgements or providing anything that looks, sounds or smells like medical or clinical advice.

We wait and see.

And to close: "all is as the Force wills it" apparently...

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[1] Proctor SP. et al. Effects of sarin and cyclosarin exposure during the 1991 Gulf War on neurobehavioral functioning in US army veterans. Neurotoxicology. 2006 Dec;27(6):931-9.

[2] Johnson GJ. et al. Blood Biomarkers of Chronic Inflammation in Gulf War Illness. PLoS ONE 11(6): e0157855.

[3] Fukuda K. et al. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA. 1998 Sep 16;280(11):981-8.

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Johnson GJ, Slater BC, Leis LA, Rector TS, & Bach RR (2016). Blood Biomarkers of Chronic Inflammation in Gulf War Illness. PloS one, 11 (6) PMID: 27352030