Tuesday, 24 April 2018

Suicide risk in ADHD (based on a selective review)

The paper by Giancarlo Giupponi and colleagues [1] makes for pretty sombre reading in relation to the question of suicide risk in attention-deficit hyperactivity disorder (ADHD). Accepting that there were methodological differences among the various peer-reviewed studies included for [selective] review, authors' findings were along similar lines to what has previously been reported: "many studies indicate an association between ADHD and suicidal behavior."

I'm not going to say too much about the Giupponi findings on this blogging occasion, because they kinda speak for themselves. As well as covering quite a bit of research talking about suicidal behaviour in the context of child/adolescent and adult ADHD and the issue of "whether there is a direct relationship or whether the association depends on the increased prevalence of pre-existing comorbid conditions and individual and family dysfunctional factors", authors also mention the important role played by various medicines clinically indicated for ADHD as potentially being protective against suicidal behaviour(s) (see here). From a methodological perspective, I would have liked to have seen a table or something illustrating all the studies included in the Giupponi 'selective review' but oh-um...

The authors conclude by recommending that "patients with ADHD should be routinely screened for suicidal behavior, and early intervention protocols should be established in order to detect and reduce suicidal ideation and behavior and to improve the quality of life." I don't think anyone would disagree with such sentiments, added to what is already becoming known about suicidal behaviour in a more general context (see here). Given also the increasingly close proximity of ADHD to another label / conditions / diagnosis frequently discussed on this blog (see here) also including some enhanced suicide risk too (see here), I daresay that routine screening might extend much further than some might realise...

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[1] Giupponi G. et al. Suicide risk in attention-deficit/hyperactivity disorder. Psychiatr Danub. 2018 Mar;30(1):2-10.

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Monday, 23 April 2018

Anxiety symptoms are frequent in relation to childhood autism

The findings reported by Lieke Wijnhoven and colleagues [1] observing that "children with ASD [autism spectrum disorder] have a high risk to have co-occurring anxiety symptoms" are not likely to win any awards in relation to novelty. Most people, I assume, with some knowledge about autism will know that anxiety seems to be a quite consistent 'partner' to the label both in children and adults, and can for some, be absolutely disabling (see here).

But that's not to say that the Wijnhoven findings aren't important; as authors describe results both giving "an overview of the prevalence of anxiety symptoms in a clinical Dutch sample of children with ASD" and also examining "age, gender, ASD subtype, and IQ as potential risk factors for anxiety" in their sample of over 170 children diagnosed with an ASD.

Using a participant group already signed up for a "randomized controlled trial (RCT) testing the effect of an anxiety intervention for children with an ASD" [2], researchers analysed their responses to the Spence Children’s Anxiety Scale for Children and Spence Children’s Anxiety Scale for Parents (translated into Dutch). They also relied on data from cognitive testing, and just for good measure, added in data on the various comorbid diagnoses held by their participant group: "attention deficit hyperactivity disorder (45.3%), (persistent) depressive disorder (7.0%), oppositional defiant disorder (3.5%), obsessive–compulsive disorder (1.7%), reactive attachment disorder (1.7%), and posttraumatic stress disorder (1.2%)." Yes, those figures do put attention-deficit hyperactivity disorder (ADHD) at being present in over 45% of participant cases (see here).

Results: "In total, 66.3% of the participating children with ASD had child-rated subclinical or clinical anxiety symptoms on the total scale and/or on at least one subscale and 81.4% of the participating children with ASD had parent-rated subclinical or clinical anxiety symptoms on the total scale and/or on at least one subscale." Yep, just as you and I suspected, anxiety symptoms whether clinical or sub-clinical, are pretty rife in relation to autism. Additionally, girls seemed to present with more anxiety symptoms than boys; particularly when it came to "separation anxiety symptoms..., social phobia symptoms..., panic disorder/agoraphobia symptoms..., and generalized anxiety symptoms."

Age was and wasn't an issue, insofar as total anxiety symptoms being more 'intensely' reported for younger children than older children but: "Age was not a significant predictor of social phobia symptoms, specific phobia symptoms, panic disorder/agoraphobia symptoms, and generalized anxiety symptoms" based on child ratings. A similar pattern was also seen for parent-reports too.

What's more to say? Well, very little really. Anxiety once again, turns up as a frequent 'comorbidity' (if I can still - Mildred Creak - call it just comorbidity) and the challenges remain as to what can be done to minimise it and its effects (see here). Here's to hoping...

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[1] Wijnhoven LAMW. et al. Prevalence and Risk Factors of Anxiety in a Clinical Dutch Sample of Children with an Autism Spectrum Disorder. Front. Psychiatry. 2018; March 2; 9: 50.

[2] Wijnhoven LAMW. et al. The effect of the video game Mindlight on anxiety symptoms in children with an Autism Spectrum Disorder. BMC Psychiatry. 2015 Jul 1;15:138.

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Saturday, 21 April 2018

"a subset of patients with ME/CFS who have sensitivity to wheat and related cereals in the absence of coeliac disease"

The findings reported by Melanie Uhde and colleagues [1] make for some interesting conversation today, with their observation that: "there may be a subset of patients with ME/CFS [myalgic encephalomyelitis/chronic fatigue syndromewho have sensitivity to wheat and related cereals in the absence of coeliac disease, with potential relevance to some of their symptoms."

OK, first things first. Coeliac disease (CD) in case you don't know, is the archetypal 'gluten is the baddie' autoimmune condition. I don't want to dwell too much on the genetic and biological details of CD but it basically involves a certain type of genetics linked to a certain type of immune response being 'activated' and 'super-charged' by ingestion of gluten. Treatment/management is currently via a lifelong gluten-free diet (currently!) Outside of CD, there is growing recognition of a suite of other gluten-related conditions that are not quite CD but something similar. Indeed, Uhde and colleagues have been quite involved in looking at this so-called non-coeliac gluten/wheat sensitivity (see here) previously.

ME/CFS represents a diagnosis characterised by fatigue and in particular, persistent and unrelenting fatigue that does not disappear with rest. Post-exertional malaise (PEM) is also an important part of the condition too (see here). ME/CFS is a condition just starting to move out from the 'biopsychosocial' shadows (see here) with much greater recognition that this is an organic condition (set of conditions) and not something that typically appears or is perpetuated by 'having the wrong mindset' as some people have historically opined.

Uhde et al on this most recent research occasion considered "whether a subset of patients with ME/CFS may exhibit serologic markers associated with NCWS [non-coeliac wheat sensitivity], which might explain some of the corresponding symptoms." They report results based on the screening of some "131 patients with ME/CFS and 86 healthy controls" using the panel of serological markers discussed in their previous study [2]. Alongside: "Questionnaires were used to assess GI [gastrointestinal] symptoms within the past 6 months, including abdominal pain, bloating and nausea" onwards to a summed score of GI issues.

Results: using data from their previous study as a sort of control/comparison, a few notable observations were made. First: "one (0.76%) patient with ME/CFS and two (2.3%) control subjects as belonging to the coeliac disease group." Second: "20 (15.3%) patients with ME/CFS and 4 (4.6%) control subjects were categorised in the NCWS group" when taking into account their statistics aiming to categorise participants as "NCWS, coeliac disease.. [or] healthy control." Finally: "There was also a significant correlation between the calculated NCWS probability and the GI symptom severity total score in patients with ME/CFS" although I'm minded to suggest that the stats related to this finding weren't exactly 'up there' with the best.

No mind, this is interesting data and cries out for larger, more controlled studies. It potentially adds some 'serological' flesh on to the bones of at least some observations of dietary and nutritional interventions being useful for some with ME/CFS (see here) and indeed, some related protocols for intervention (see here). More than that, if it is shown that dietary intervention such as the implementation of a gluten-free diet might *treat' some ME/CFS, it provides further evidence for that all-important shift in moving ME/CFS away from more psychosomatic explanations. Whether however such dietary intervention will be funded by the State is another question...

Oh, and the focus on 'subsets of patients with ME/CFS' kinda taps into a growing realisation that ME/CFS might not be just 'one thing' in identity or severity [3]...

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[1] Uhde M. et al. Markers of non-coeliac wheat sensitivity in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Gut. 2018. March 17.

[2] Uhde M. et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016. 65: 1930-1937.

[3] Richardson AM. et al. Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection. J Transl Med. 2018 Apr 12;16(1):97.

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Friday, 20 April 2018

ALSPAC examines... pregnancy risk factors and oppositional-defiant disorder (ODD) and conduct disorder

ALSPAC mentioned in the title of this post refers to the Avon Longitudinal Study of Parent and Children, something of quite a regular feature on this blog by all accounts (see here and see here for examples). On this blogging occasion, I'm talking about ALSPAC in relation to the research paper published by I. Hyun Ruisch and colleagues [1] who reported that: "Common and potentially preventable pregnancy risk factors were independently related to both offspring ODD [oppositional-defiant disorderand CD [conduct disorder] symptomatology in children from the general population."

ODD and CD represent a couple of the most prevalent 'disruptive behavioural' conditions seen nowadays. Whilst subtly different from one and another both in scope and severity, both represent conditions where control and in particular, self-control in accordance with cultural rules and norms, is perhaps not as it should be. I've mentioned one or other of these conditions in previous posts on this blog (see here for example) and the heightened risk of future adverse outcomes seemingly associated with them.

As with many (nay, all) behavioural and psychiatric conditions, science is still at a bit of a loss as to how they come about, accepting that they all probably [variably] include genetic and non-genetic factors working differently in different people. Ruisch et al set about utilising data from ALSPAC to ascertain if and whether "a broad range of pregnancy factors" might play some [statistically significant] role. Their results are quite revealing...

So: "Higher ODD symptom scores were linked to paracetamol use... and life events stress... during pregnancy." Further: "Higher CD symptom scores were linked to maternal smoking..., life events stress... and depressive symptoms... during pregnancy."

It should be noted that ODD and CD symptoms scores were gathered via the Development and Well-Being Assessment (DAWBA) as per other ALSPAC research occasions (see here). Researchers also quizzed both mothers and teachers of their children; thus providing two potentially different snapshots of functioning and their related factors.

In relation to that sentence on "Common and potentially preventable pregnancy risk factors were independently related to both offspring ODD and CD symptomatology in children" my eye was immediately drawn to two variables reported as being connected to said diagnoses: pregnancy paracetamol use and maternal smoking; both of which have appeared with increasing regularity in relation to adverse offspring developmental outcomes.

First, paracetamol also known as acetaminophen to our cousins across the Pond and other parts of the world. What can I say? It seems to be going from bad to worse for this go-to over-the-counter medicine with regards to pregnancy use *associations* and offspring developmental factors (see here). Yes, I appreciate that more studies need to be done on the possible pregnancy effects of this medicine, but the emerging peer-reviewed science is starting to look quite consistent. And many of the studies pointing the finger at paracetamol, like ALSPAC, are not to be under-estimated in size or power...

Second, maternal tobacco smoking during pregnancy. Again, something that has been talked about before on this blog (see here) in the context of related clinical labels. We can't yet say that 'pregnancy smoking causes offspring CD' because proof of cause-and-effect are rarely established by such observational studies. But much like the paracetamol story, the data is becoming more and more consistent for a possible effect of pregnancy smoking on child development. And for various other reasons, smoking during pregnancy is generally not thought of being a great thing for the developing child.

More investigations are indicated but clues are starting to emerge.

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[1] Ruisch IH. et al. Pregnancy risk factors in relation to oppositional-defiant and conduct disorder symptoms in the Avon Longitudinal Study of Parents and Children. J Psychiatr Res. 2018 Feb 23;101:63-71.

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Thursday, 19 April 2018

Hans Asperger "was actively involved in the Nazi regime's euthanasia programme in Austria"

Credit: The BBC News website 19 April 2018
Many people will already have seen the headlines (see here for example) covering the paper by Herwig Czech [1] that concluded that: "The narrative of [Hans] Asperger as a principled opponent of National Socialism and a courageous defender of his patients against Nazi ‘euthanasia’ and other race hygiene measures does not hold up in the face of the historical evidence."

It makes for particularly difficult reading insofar as dispelling other highly-cited accounts of Asperger as being some sort of 'hero' - "the narrative of Asperger as an Oskar Schindler-like protector of children with autism" - who claimed "to have shielded his patients from the Nazi regime." Instead, as also acknowledged in an accompanying editorial on the Czech findings [2], the evidence uncovered seems to point to something rather more approaching: "that Asperger was not just doing his best to survive in intolerable conditions but was also complicit with his Nazi superiors in targeting society’s most vulnerable people." The main assertions seem to be around Asperger "referring children both directly and indirectly to Am Spiegelgrund", a notorious clinic that summed up the utter disdain that the Nazi regime had for the beautiful heterogeneity of life.

I don't really want to say too much more on this topic because I'm sure that discussions will go on with regards to the Czech findings and their implications. I do want to raise two points that may be pertinent however.

First, the question of 'does it matter?' that Asperger had such a past is bound to be raised. Yes, it does matter. As a previous opinion piece published just before the Czech article (see here) mentions: "To medical ethics, it does. Naming a disorder after someone is meant to credit and commend, and Asperger merited neither." That author, who also has a book coming out on this topic, went as far as suggesting that: "We should stop saying “Asperger.” It’s one way to honor the children killed in his name as well as those still labeled with it."

Second, and related to the first point, is the 'flack' that has been taken by the most recent Diagnostic and Statistical Manual (DSM) (version 5) when it dropped the term 'Asperger syndrome'. Instead, the authors of this 'diagnostic bible' chose to go down the more generic 'autism' route; something that also looks likely in the context of the ICD-11 proposals too (see here). In view of the Czech findings and bearing in mind that issue of 'medical ethics' it looks like this was a correct decision. I appreciate that this may have knock-on effects for those diagnosed and identifying as having Asperger syndrome - ""No-one with a diagnosis of Asperger syndrome should feel in any way tainted by this very troubling history," Carol Povey, director at the Centre of Autism for the UK's National Autistic Society, said in a statement to the BBC" - but with these new revelations must come some sort of change in thinking.

The Czech findings matter because lives matter. They matter because they paint a picture of a man who lived and worked in very difficult times but a man "that the Nazi authorities saw... in an increasingly positive light, including as someone willing to go along with their ideas of race hygiene."

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[1] Czech H. Hans Asperger, National Socialism, and “race hygiene” in Nazi-era Vienna. Molecular Autism. 2018; 9: 29.

[2] Baron-Cohen S. et al. Did Hans Asperger actively assist the Nazi euthanasia program? Molecular Autism. 2018; 9: 28.

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"adult patients with CFS report few autistic traits in the self-report instrument, the AQ"

The findings reported by Indre Bilevicute-Ljunger and colleagues [1] tap into something of a developing interest I have on this blog: whether there is 'clinical overlap' between the diagnosis of chronic fatigue syndrome (CFS) (also known as ME or myalgic encephalomyelitis) and the diagnosis of autism or autism spectrum disorder (ASD) (see here).

Just before anyone gets the wrong end of the stick here, I'm not at all insinuating that CFS/ME and autism are one and the same. They are not. As per a previous research foray into the diagnostic borderlands of CFS/ME [2] I have however long been struck by how there may be some 'shared' symptoms relevant to both labels; particularly with reference to the presence of perceptual and motor issues ("auditory hyperacuity", "problems of balance", "walking problems"). Added also to a number of anecdotal reports suggesting that a diagnosis of autism is seemingly not protective against receipt of a diagnosis of CFS/ME, and it strikes me that there could be more investigations required in this area. At the time of writing however, there is very little in the peer-reviewed research domain examining any such 'overlap'.

Bilevicute-Ljunger et al - including the notable name of Susanne Bejerot on the authorship list (see here) - set out to examine any potential 'relationship' between autism and CFS by means of assessing three participant groups with everyone's favourite 'are you autistic?' self-report measure, the Autism-Spectrum Quotient (AQ). Said groups included those diagnosed with CFS (n=59) , those diagnosed with autism (n=50) and a group headed under the rather uninformative label of 'healthy controls' (HC) (n=53). The presented results showed that those diagnosed with ASD "scored significantly higher on the AQ than the CFS group and the HC group" and that: "No differences in AQ scores were found between the CFS and HC groups." Authors therefore concluded that: "Despite clinical observations of symptom overlap between ASD and CFS, adult patients with CFS report few autistic traits in the self-report instrument, the AQ."

Sounds pretty straight-forward eh? Well, hold on just a moment...

"The choice of instrument to assess autistic traits may influence the results." That was another line included in the Bilevicute-Ljunger paper, in conjunction with the idea that the AQ may very well be 'testing for' something in the context of autism, but that doesn't mean it is without issues in terms of things like specificity for autism (see here and see here). Indeed, I'll also take you back to a recent blog post (see here) which kinda said everything that needed to be said in terms of the [general] current state of adult questionnaires and screening measures for autism [3] including the AQ: "Evidence suggests some utility of diagnostic measures in identifying autism spectrum disorder among clinic referrals, although specificity for diagnosis was relatively low." Ergo, it is not completely unlikely that scoring high on the AQ and various other instruments *might* not necessarily mean just autism is present. I'll be coming back to the issue of AQ yet again on this blog quite soon.

Without trying to sound like someone who has a bee in their bonnet about the AQ not being a particularly great 'autism-specific' measure, I would like to see some further work done looking at any overlap between symptom presentation in CFS/ME and the same with regards to autism. I'd perhaps be minded to suggest that science starts to look at CFS/ME symptoms in autism rather than the other way around first and foremost. This would provide a baseline to see how prevalent CFS/ME in diagnosis or traits might be when an autism diagnosis is in the frame, particularly extending into adulthood. It might also provide some 'clues' as to whether shared or overlapping genetics / biology / physiology could be further investigated (hint: immune functions such as autoimmunity, oxidative stress, gut microbiota, etc. might be places to look) minus the psychobabble that both conditions have had to endure over the years. I'd similarly be interested in the idea that the sex ratios are seemingly opposing when it comes to ME/CFS and autism, and what that might mean for ensuring that screening for autism or autistic traits in relation to ME/CFS takes account of the chatter about sex/gender *potentially* influencing symptoms profiles (see here) and things like the female camouflage effect (see here)...

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[1] Bilevicute-Ljunger, I. et al. Patients with chronic fatigue syndrome do not score higher on the Autism-apectrum quotient than healthy controls: comparison with autism spectrum disorder. Scandinavian Journal of Psychology. 2018.

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Wednesday, 18 April 2018

"Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder"

It's been a while coming but the paper by Jim Adams and colleagues [1] detailing the effects of a "comprehensive nutritional and dietary intervention for autism spectrum disorder" has finally seen the peer-reviewed light of day. I say 'a while coming' because as per the ClinicalTrials.gov entry for this research (see here), it was seemingly scheduled to start back in 2011 and be completed by 2013, I assume, without taking 5 years to write up and be published. But better late than never I suppose.

Anyhow, the nutritional and dietary intervention scheduled adopted by Adams et al was rather a complicated affair as per the study description. So: "Day 0: Vitamin/Mineral supplementation begins. Day 30: Essential Fatty Acid supplementation begins. Day 60: Epsom salt baths begin. Day 90: Carnitine Supplementation begins. Day 180: Digestive Enzyme supplementation begins. Day 210: Healthy, casein-free, gluten-free diet [HGCSF] begins." Quite a few of those individual intervention elements have been fodder for this blog before (see here and see here for examples); also reflecting other research interests from Adams and colleagues (see here). Talk about a gluten- and casein-free diet is also music to my [research] ears (see here), as is the welcome inclusion of sulfate / sulphate back into autism research proceedings (see here).

Results of that nutritional and dietary schedule are reported for a starting pool of 67 children diagnosed with an autism spectrum disorder (ASD), where 28 participants completed the 'treatment' arm and some 27 participants completed a non-treatment arm (where no new intervention(s) were reported for the 12 months of the study). Additional findings for 50 not-autism controls (I don't like the word 'neurotypical' and its rather sweeping connotations) are also reported. The study duration was a year, and the sorts of measures examined over the course of the intervention were quite comprehensive, covering both behaviour and cognition and also physiological parameters.

Results: it's always refreshing to see a study first and foremost reports any adverse effects based on the tenet 'first, do no harm'. Authors note that: "A few adverse effects were reported for some treatments" and go on to list what happened over the course of each element of the intervention. They talk for example, how: "One parent reported that implementation of the diet [healthy, gluten- and casein-free diet] in a strict manner resulted in increased aggression towards peers, inability to problem solve, and increased spinning behavior, probably due to frustration in regards to removal of favorite foods." Thankfully, most of the adverse effects noted over the study period were relatively minor and certainly not life threatening. Once again, first, do no harm.

With levels of compliance regarding the various study elements also reported as being quite high, the authors report that across the various behavioural assessments - including the CARS, SRS, VABS, and ATEC - significant effects in favour of intervention were found. Based on blinded evaluations using something called the Reynolds Intellectual Assessment Scales (RIAS), authors reported "a significant improvement in nonverbal intellectual ability in the treatment group compared to the non-treatment group." By contrast, blinded use of the gold-standard assessment instrument known as ADOS revealed "no significant change on the ADOS scores for either treatment or non-treatment group." Interestingly, when parents were asked to rate the effectiveness of each part of the intervention, results revealed that: "The highest rated treatments were the vitamin/mineral supplement and the essential fatty acids, followed by the Healthy HGCSF diets, followed by the carnitine, digestive enzymes, and Epsom salt baths."

Adams and colleagues also provide further details on "3 exceptional cases of improvement during the study, all of which occurred in the treatment group." For one participant it appears that the introduction of a carnitine supplement was associated with some quite remarkable improvements in relation to strength and energy levels in particular. The authors note that: "low carnitine seems likely to have contributed to her challenges, and carnitine supplementation seems to have helped." There could be some interesting tie-ups there with regards to previous peer-reviewed results too (see here for example). For another participant it seemed that the introduction of a HGCSF diet *correlated* with the resolution of urination problems, where a dairy-free diet removed the need for "intermittent catheterization" and resolution of associated problems. OK, these examples don't so much focus on the core issues associated with autism, but I'm pretty sure that they were factors that would have influenced quality of life.

There is quite a bit more to see in the Adams paper and I would encourage readers to take the time to read it in its entirety. Despite the fact that not every measure showed significant effects from such an intervention regime, I like the idea that authors didn't just focus on one intervention but rather, in a systematic way, looked at a whole suite of interventions focused on nutritional and dietary factors. I believe this is more 'naturalistic' in terms of what parents/caregivers tend to report. Indeed the authors themselves discuss how: "A limitation of this study is that all participants received all treatments, whereas probably only a subset are likely to benefit from any single intervention (for example, only participants with low carnitine are likely to benefit from carnitine supplementation)." Yup.

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[1] Adams JB. et al. Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder—A Randomized, Controlled 12-Month Trial. Nutrients. 2018; 10(3): 369.

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Tuesday, 17 April 2018

Low grade inflammation in acute psychiatric inpatients

I was interested to read the findings reported by Emanuele Osimo and colleagues [1] (open-access available here) recently, and their observation that: "Evidence of low-grade inflammation was present in all major diagnostic groups, with prevalences ranging from 12 to 40% depending on the measure."

'Major diagnostic groups' included in the Osimo paper, included "acutely unwell psychiatric inpatients from all major ICD-10 diagnostic groups" covering labels such as psychotic disorder, schizophrenia, mood disorders, personality disorders and organic mental disorders.

Authors - including the notable name of Golam Khandaker who has published work previously covered on this blog (see here and see here for examples) - conducted an "anonymised search of the electronic patient records" for those hospitalised in a specialist mental health department for the treatment of a mental health / psychiatric condition between 2013 and 2016. Alongside, they had to have "a blood test result for CRP [C-reactive proteinor for WBC [total white cell count] [that] had been recorded on the electronic medical notes system within 14 days of admission" yielding almost 600 participants. In effect, a blood test pertinent to the measurement of compounds reflective of immune system processes such as inflammation.

As per the opening sentences to this post, and using CRP and/or WBC as a measure of inflammation, authors identified some quite notable prevalences of low-grade inflammation in their patient group. So: "The prevalence of inflammation in the major ICD-10 diagnostic groups of psychotic disorders (F20–29), mood disorders (F30–39), neurotic disorders (F40–48) and personality disorders (F60–69) was 32%, 21%, 22% and 42%, respectively." Various other variables also seemed to be *associated* with the presence of such inflammation too. Authors note for example that: "Patients with medical comorbidities were more likely to be inflamed" alongside various other factors also potentially exerting an effect: "older age, black ethnicity, being single, self-harm, diagnoses of schizophrenia, bipolar disorder, current treatments with antidepressants, [and] benzodiazepines" were all associated with low-grade inflammation.

Such findings add to the ever-growing amount of research that suggests a role for the immune system in relation to various psychiatric / behavioural diagnoses (see here). Further, that with a little more focus on the somatic as well as the psychiatric (see here) when it comes to such conditions, potentially relevant clues may emerge pertinent to treatment options. I might finally also draw your attention to some work previously discussed on this blog dealing with the idea that inflammation *might* have the ability to affect social cognitive processing (see here). Such a finding, focused on symptoms rather than labels, could offer a few alternative directions for intervention given the widespread nature of social cognitive issues across a wide variety of psychiatric conditions.

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[1] Osimo EF. et al. Prevalence and correlates of low-grade systemic inflammation in adult psychiatric inpatients: An electronic health record-based study. Psychoneuroendocrinology. 2018 Mar 1. pii: S0306-4530(17)31581-0.

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Monday, 16 April 2018

Immunoadsorption and ME/CFS: observations from a small proof of concept study

Immunoadsorption refers to "an alternative blood purification technique... used to eliminate pathogenic antibodies." I'll freely admit that I don't know an awful lot about this procedure, so approach the findings reported by Carmen Scheibenbogen and colleagues [1] with a degree of naivety with regards to 'usefulness' and also important issues such as safety.

Authors report preliminary findings from their 'proof of concept' study, using immunoadsorption (IA) on a small group of adults (N=10) diagnosed with Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS / ME) who also presented with "infection-triggered disease onset, disease severity according to the Bell scale of ≤ 50 of 100, and elevated levels of ß2 antibodies." The Bell scale by the way, seems to refer to a scale developed by David Bell with scores ranging from 0 to 100 to denote fatigue symptoms, post-exertional malaise (PEM) and 'ability to work full-time'. A lower score denotes more severe symptoms. The description "elevated levels of ß2 antibodies" refers to antibodies against ß2 adrenergic receptors; receptors which are found throughout the body and are involved in various biological tasks including smooth muscle relaxation and regulating certain cardiac functions. As the authors note: "Antibodies to ß2... receptors had been reported in various other diseases including dilatative cardiomyopathy, postural tachycardia, regional pain syndrome, Alzheimer, Sjögren’s syndrome, asthma and others." The 'antibodies' bit implies that the body is failing to recognise these receptors as 'self' and instead wrongly mounts an immune response against them.

Scheibenbogen et al mention that during their other studies on ME/CFS [2] they noted "a sustained decline of pretreatment elevated ß2 antibody levels in clinical responders to rituximab treatment." The rituximab bit refers to some initially encouraging results [3] from the use of this treatment that, unfortunately, do not seem to have weathered more rigorous scientific scrutiny (see here). Authors further hypothesised that IA might be a route to "removing autoantibodies" and specifically those "elevated antibodies against β2."

Results: "Prior to IA all patients had elevated antibodies against β2, in addition 7 patients against ß1 adrenergic receptors and 6 patients against both M3 and M4 acetylcholine receptors." Autoantibodies in many of the participants included for study went beyond just those against β2.

Following quite a few cycles of IA - "IA was conducted in 5 cycles on days 1–3 and 6–7 with 2 to 2.5-fold plasma volume filtered" - authors reported that: "Levels of ß2 adrenergic antibodies were low to undetectable in 9 of 10 patients." This is kinda what would be expected following IA (bearing also in mind that: "After the 5th IA cycle all patients received 25 g IgG i.v." also known as IVIG).

Insofar as the clinical course of participants' presented symptoms, well, it was a bit of a mixed bag. So: "A rapid improvement of several symptoms was reported by 7 of these 9 patients during IA. However, none of the patients completely recovered and 5 patients had worsening of fatigue towards the end of treatment despite improvement of other symptoms." I'm happy to report that the authors did utilise the wonderful technology headed under the term actigraphy (activity monitoring) as per their assessing participants step counts "by a Vivofit activity tracker." Such objective activity monitoring is sadly lacking from many other studies on ME/CFS (see here for example). Again however, the step counts reflect an initial 'good start' for IA followed by a not-so-good finish...

"Taken together, this pilot study provides evidence that IA can effectively remove ß2 and M3/M4 autoantibodies in CFS/ME and can result in rapid moderate to marked symptom improvement." I wouldn't disagree with the authors' conclusions but would perhaps suggest that the current results as they stand don't yet provide authoritative evidence for a beneficial effect of IM in the longer term. More [controlled] study is required.

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[1] Scheibenbogen C. et al. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLoS One. 2018 Mar 15;13(3):e0193672.

[2] Loebel M. et al. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain, Behavior, and Immunity. 2016; 52: 32-39.

[3] Fluge Ø. et al. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS One. 2015 Jul 1;10(7):e0129898.

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Saturday, 14 April 2018

Autistic traits and risk of suicidality: ALSPAC opines...

The findings reported by Iryna Culpin and colleagues [1] observing that: "Social communication impairments are an important autistic trait in relation to suicidality" return me back to a topic that features much too frequently on this blog: suicide risk and autism.

Drawing on data from the Avon Longitudinal Study of Parents and Children (ALSPAC) initiative, that continues to provide some important insights on labels like autism (see here for example), researchers sought to answer a couple of important research questions: "1. Is an autism diagnosis and/or autistic traits associated with suicidal ideation (suicidal thoughts and plans) and suicidal behaviour (self-harm with and without suicidal intent) by age 16 years? 2. Are any of the observed associations explained by depressive symptoms in early adolescence?"

The question of whether autism or autistic traits are *associated* with suicide (ideation and/or behaviour) is something that has entered the peer-reviewed research psyche quite a bit in recent times. I've talked for example, about data from 'big data' Taiwan on this topic (see here) who concluded that: "ASD [autism spectrum disorder] was an independent risk factor of attempted suicide" [2] based on the analysis of over 5000 young people diagnosed with autism and some 22, 000 not-autism controls.

The numbers included in the Culpin study were a little less impressive - "5,031 members of the UK-based birth cohort study-the Avon Longitudinal Study of Parents and Children" - but ALSPAC does have the advantages of "long-term follow-up, the availability of data on several outcomes, as well as rich data on confounders, and longitudinal design that enables to examine mediating pathways." Indeed, as well as focusing on a diagnosis of autism, Culpin et al also had some 'rich data' on the presence of "four dichotomised ASD traits (social communication, pragmatic language, repetitive behaviour, sociability)." This enabled them to both observe any findings based on a diagnosis / label of autism or ASD and also traits pertinent to a diagnosis of autism or ASD. Issues such as self-harm and/or suicidal thoughts or plans were similarly sought from participants at age 16 years based on answers to questions such as "Have you ever hurt yourself on purpose in any way (e.g., by taking an overdose of pills or by cutting yourself?)" and "On any of the occasions when you have hurt yourself on purpose, have you ever seriously wanted to kill yourself?"

Results: as per the opening sentence, authors observed that "social communication difficulties may be important in relation to suicidality." They interpret this by suggesting that their results tally with others where "social impairments and difficulties in establishing interpersonal relationships are triggers for suicidal behaviour."

But... when it came to examining the diagnosis of autism or ASD in relation to suicidality, they reported that there was: "no evidence of an association between ASD diagnosis and any of the outcomes." They caution however that the numbers of those with a diagnosis were "very low and confidence intervals wide." I also note that data on the numbers of those with a diagnosis of ASD with self-harm with or without suicidal intent are shown as 'censored' to "prevent disclosure due to small cell counts."

Finally, it's worthwhile noting another part of the Culpin study analysis looking at a role for depressive symptoms on the observations made. We are told that "data from the Short Mood and Feelings Questionnaire (SMFQ), a 13-item instrument used to evaluate core depressive symptomatology in children aged 8 to 18 years" was also analysed. Authors report on "evidence of an indirect pathway from impaired social cognition to self-harm via depressive symptoms" but such depressive symptoms only accounted for about a third of the "total estimated association between impaired social cognition and self-harm." Enough however for them to conclude that "addressing the mental health needs of children with autism" *might* offset some risk in this area. Who would argue with that?

There are issues with the Culpin study insofar as the focus on self-report over clinical diagnosis for something like depression or depressive symptoms and "limitations in establishing suicidal intent accompanying self-harm, particularly using self-reports which could be influenced by fluctuations in mood or change over time." I will, once again, reiterate that the report of no evidence of of an association between a diagnosis of autism or ASD and suicidality is also likely to be "imprecise due to small numbers."

A final question: by tackling and hopefully influencing "impairments in social communication" alongside other interventions, is it possible that the risk of suicidality in relation to autism can be reduced? I say this bearing in mind that future studies in this area might want to take a larger view of autism (see here) on the basis that a diagnosis of autism rarely exists in a diagnostic vacuum (see here). How also, issues such as depression like various other quality-of-life-draining facets that seem to be over-represented in relation to autism (see here), may very well be a lot more 'core' over 'comorbidity' (see here) at least for some.

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[1] Culpin I. et al. Autistic Traits and Suicidal Thoughts, Plans and Self-Harm in Late Adolescence: Population-Based Cohort Study. J Am Acad Child Adolescent Psychiatry. 2018. March 14.

[2] Chen MH. et al. Risk of Suicide Attempts Among Adolescents and Young Adults With Autism Spectrum Disorder: A Nationwide Longitudinal Follow-Up Study. J Clin Psychiatry. 2017 Nov/Dec;78(9):e1174-e1179.

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Friday, 13 April 2018

Violent ideation and behavior in relation to serious mental illness: substance abuse counts

I approach the findings reported by Matthew Roché and colleagues [1] in the same way as I would any other peer-reviewed science results covering the topic of violence in relation to a diagnosis / label / condition: cautiously and minus the need for sweeping generalisations (see here), but without shying away from potentially important findings.

Roché et al discuss results based on their analysis of "intake records of 63,572 patients diagnosed with SMIs [serious mental illness] (i.e., schizoaffective disorder, schizophrenia, bipolar disorder, and unipolar depression), substance use disorders, and non-SMI psychiatric disorders" in relation to the risk of violent ideation and behavior (VIB). As well as looking at the frequency of VIB among their cohort, they also looked for other variables outside of a diagnosis of SMI that may impact on VIB.

Results: "patients with SMI conditions had higher rates of VIB than both patients with non-SMI psychopathology and those with substance use disorders only." No, this does not make for great PR for SMIs but is a reality of their observations. Further: "patients with SMI and comorbid substance use pathology were responsible for the majority of VIB within each SMI condition." This equation - SMI plus substance abuse equals greater risk of violence - is something that is becoming rather important based on the peer-reviewed science literature. It follows other independent findings [2] too and might even link into other areas.

Appreciating that those diagnosed with a SMI are also at greater risk of being a victim of crime (see here) including crime with a violent element attached to it, there are some important lessons to be learned from the Roché data. Not least is the potential focus on reducing comorbid substance abuse in the context of a diagnosis of serious mental illness so as to potentially modify the heightened risk of VIB and also, other less than desirable outcomes [3]. This is not something that can be done easily (see here) but does not mean it cannot be attempted at all.

I might also add that violence, as and when it does occur in the context of SMI, is likely to be related to other social and situational factors as well as being influenced by something like substance abuse (disorder). Indeed, in the context that various aspects of life can very much be *altered* by the experience of an SMI (diet, physical activity, etc) I'm minded to direct your attention to other variables potentially important to VIB such as nutritional factors for example (see here and see here). Science might also perhaps look to other diagnoses that potentially complicate the clinical picture in SMI as perhaps also exerting any effect on the risk of VIB (see here) and the [developmental] importance of transitioning risk from one label to another (see here) again, minus any sweeping generalisations. Finally, and minus passing the buck, the findings reported by Patel and colleagues [4] further complicate the clinical picture...

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[1] Roché MW. et al. Prevalence and Risk of Violent Ideation and Behavior in Serious Mental Illnesses: An Analysis of 63,572 Patient Records. J Interpers Violence. 2018 Mar 1:886260518759976.

[2] Fazel S. et al. Schizophrenia, substance abuse, and violent crime. JAMA. 2009 May 20;301(19):2016-23.

[3] Skalisky J. et al. Prevalence and Correlates of Cannabis Use in Outpatients with Serious Mental Illness Receiving Treatment for Alcohol Use Disorders. Cannabis Cannabinoid Res. 2017 Jun 1;2(1):133-138.

[4] Patel RS. et al. Is Cannabis Use Associated With the Worst Inpatient Outcomes in Attention Deficit Hyperactivity Disorder Adolescents? Cureus. 2018 Jan 7;10(1):e2033.

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Thursday, 12 April 2018

On recognising "the disabling effects of ME/CFS"

The findings reported by Caroline Kingdon and colleagues [1] observing that "Using SF-36v2™ scores as a proxy, people with ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome] were measurably more disabled than PWMS [people with multiple sclerosis] or HCs [healthy controls] in this study population" didn't really surprise me.

Although I'm always a little cautious about making sweeping 'who's the more disabled' comparisons when it comes to various diseases / conditions / labels, I've previously talked about how truly quality-of-life-sapping a diagnosis of ME/CFS can be (see here). Indeed, from previous results published by Falk Hvidberg and colleagues [2] for example, the message was pretty clear: "The ME/CFS study population is more disabled and socially marginalized than the average population with regards to the subjects of long-term illness, number of illnesses, proportion of disability pensioners and relationships." Indeed on that research occasion, ME/CFS beat the likes of lung cancer, depression and schizophrenia in terms of measured severity of health-related quality of life.

The Kingdon results add to such sentiments; on this occasion comparing the "impact of disability" associated with ME/CFS with reports from PWMS and asymptomatic (so-called 'healthy') controls. Multiple sclerosis (MS) by the way, refers to an autoimmune condition that affects many different parts of the body "including problems with vision, arm or leg movement, sensation or balance."

The results, based on data "collected as part of the UK ME/CFS Biobank" included reports from over 50 people diagnosed with ME/CFS and similar numbers diagnosed with MS or asymptomatic. We are told that the SF-36v2™ is an instrument that "uses 36 questions to collect information about functional status and well-being from respondents" and covers various domains.

One figure in particular (see here) provides a good visual representation of how disabling ME/CFS was on this [group] study occasion. Median scores from participants with ME/CFS were 'consistently below' scores from the other groups on every domain, indicative of greater disability. I should also note that despite median [group] scores on the mental health domain also being lower for the ME/CFS group than the comparators, they were at least 'nearer' to the other groups than scores on the other domains examined. I say this in the context that mental health is almost certain to be affected by a diagnosis of ME/CFS, but does not need any psychobabble (i.e. psychosomatic / biopsychosocial) explanations thank you very much (see here).

There are a couple of other important trends noted in the Kingdon data worth noting. So: "Disease onset had a greater impact on employment among people with ME/CFS than among PWMS" and "Post disease onset, 83% of people with ME/CFS earned below £20,000, compared with 59% of PWMS and 54% of HCs." ME/CFS it seems, is not only a condition that hits people hard in a physical sense, it also represents an important route to financial hardship too. Further: "Unemployment costs are borne by both the individual and society." So not only does it make good sense to cure ME/CFS (yes, that's cure as in complete recovery) for the people concerned, but society also benefits. I'm also minded to suggest that when and where people with ME/CFS are disabled to such an extent by their symptoms, we (society) owe it to them to ensure that they are properly supported both medically and also, financially (see here).

Any questions?

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[1] Kingdon CC. et al. Functional Status and Well-Being in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Compared with People with Multiple Sclerosis and Healthy Controls. PharmacoEconomics. 2018. March 13.

[2] Falk Hvidberg M. et al. The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). PLoS One. 2015 Jul 6;10(7):e0132421.

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Wednesday, 11 April 2018

Plasma anandamide concentrations are lower in children with autism

The findings reported by Debra Karhson and colleagues [1] piqued my interest for two primary reasons. First, they detail "the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD [autism spectrum disorder]." Second, authors also report on the use of a gold-standard technique when it came to their analyses: the development and use of "a LC-MS/MS [liquid chromatography-tandem mass spectrometrymethod to quantitatively analyze AEA [anandamide] concentrations in small volumes of banked plasma with short sample preparation time and high sample repeatability."

OK, the basis for the Karhson study was the 'increasing interest for ASD' examining the endogenous cannabinoid or endocannabinoid system. This is a system, an internal system, that comprises of quite a few compounds, enzymes and receptors that play "important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults" [2]. Yes, as the name suggests, there is an 'overlap' between some of the workings of the endocannabinoid system (ECS) and components of a certain drug of abuse but that doesn't insinuate anything at the present time.

Anandamide (AEA) is a sort of messenger molecule that is part of the ECS. It shares some chemical characteristics with the active compound found in cannabis, leading quite a few commentators to talk about AEA in terms of being a 'pleasure' or 'bliss' molecule. It does not however, have the 'staying power' of its molecular companion; chemically-speaking being fairly readily degraded in the body. Indeed, of the many biological roles and functions linked to AEA and the ECS more generally, I'd in particular, like to direct your attention to some of the science-so-far literature in relation to pregnancy (see here). And, no, that does NOT mean that smoking marijuana during pregnancy is a good thing...

The authors highlight how the ECS is a research area rising in relation to autism (and associated diagnoses) based, quite extensively, on animal models of autism and all the associated 'issues' that this carries (see here). So: "despite the promise of these preclinical data, no studies to date have investigated AEA concentrations in humans with ASD." They sought to remedy that situation.

Results are reported based on the LC-MS/MS analysis of plasma samples provided by some 59 children with autism and 53 not-autism controls. As per my continued interest in all-things mass spec when specifically applied to autism research, I was encouraged by the use of a "commercially available stable isotope-labeled AEA-d8" being used as an internal standard, and the fact that the lower limit of detection for AEA was in the femtogram range. In short, authors were able to train their system to specifically look for AEA and were able to get down to some really quite low levels of detection.

"Two significant findings were observed: (1) plasma AEA concentrations significantly differentiated ASD cases from controls, such that children with lower AEA concentrations were more likely to have ASD, and (2) AEA concentrations were significantly lower in ASD compared to control children." I don't really need to say much more than that, aside from adding in another quote: "These results, although preliminary, corroborate preclinical evidence that AEA signaling may be impaired in patients with ASD."

The question of what these findings actually mean is still unanswered. It should for example, be noted that the Karhson results in real people were based on the analysis of plasma samples, where previous animal work has tended to be a little more 'invasive' in terms of the tissue types looked at (e.g. in the brain). The authors also mention that further investigations need to give due credit to the idea that autism rarely exists in some sort of diagnostic vacuum (see here), and some of these 'comorbidities' could very well influence the results obtained [3].

Further studies on this topic are very much required.

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[1] Karhson DS. et al. Plasma anandamide concentrations are lower in children with autism spectrum disorder. Molecular Autism. 2018; 9: 18.

[2] Lu H-C. & Mackie K. An introduction to the endogenous cannabinoid system. Biological Psychiatry. 2016;79(7):516-525.

[3] Romigi A. et al. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy. Epilepsia. 2010 May;51(5):768-72.

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Tuesday, 10 April 2018

"results suggest that maternal CMV infections may influence ASD symptoms"

CMV infections mentioned in the title of this post - "results suggest that maternal CMV infections may influence ASD [autism spectrum disorder] symptoms" - refers to cytomegalovirus, a beta-herpes virus, that infects quite a percentage of the population, but is typically kept in check by a healthy immune system.

Although not usually a 'problem-causer', CMV infection under certain circumstances can have various unwanted adverse effects. One such circumstance is that of congenital CMV infection, where some infants acquire CMV during the nine months that makes us, and in some cases, it leads to an array of adverse physical and developmental outcomes. You probably won't be surprised to hear that congenital CMV infection has also been *linked* to some instances of autism (see here) and indeed, on more than one peer-reviewed research occasion (see here).

The findings reported by Brooke Slawinski and colleagues [1] add to this important area of autism science with their suggestion of a potentially important *correlation* between the presence of CMV infection and scores on one of the premier autism assessment tool, the Social Responsiveness Scale version 2 (SRS-2).

Authors looked for "CMV IgG and HSV2 [herpes simplex virus 2IgG in serum from the mothers of 82 children whose ASD symptoms were assessed at 3-6 years of age using the Social Responsiveness Scale version 2 (SRS-2)." The presence of IgG antibodies typically indicates past and/or recent exposure to a pathogen (in this case, CMV) with results expressed as seropositivity or seronegativity. Authors observed that those children whose mothers were seropositive for CMV IgG antibodies scored marginally higher on the SRS than those who were seronegative for CMV IgG antibodies. They did not find a similar relationship / correlation when looking at past / recent exposure to HSV2. Ergo, children *potentially exposed* to CMV infection during pregnancy showed a more severe autism presentation than those that weren't, at least in relation to the SRS measured social aspects of autism.

Of course you can see the issues with this work as it stands. Two variables (albeit "robust to several statistical adjustments") have been brought together and a possible 'connection' made. Not for the first time I might add, where one needs to be slightly cautious about making too much of any relationship given the wide array of potentially influencing variables / confounders. There is also an inference in the Slawinski work that a positive results means that maternal CMV infection during pregnancy was present and that "prenatal exposure to maternal infections" plays a role with [some] autism in mind. That is of course, if you assume that infections post-pregnancy might not also play a role in some autism (see here for example)...

The authors sensibly announce that their findings are "being further evaluated in ongoing prospective studies with larger population samples" so there should be more to see on this topic. For now however, I think it's important to stay mindful of the fact that exposure to various infective agents - viral, bacterial and otherwise - seem very much able to influence both physiology and behaviour in a wide variety of contexts including autism. Oh, and response to infection *might* also play a role in behaviour too (see here).

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[1] Slawinski BL. et al. Maternal cytomegalovirus sero-positivity and autism symptoms in children. Am J Reprod Immunol. 2018 Mar 9.

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Monday, 9 April 2018

Mood cognition, fatigue, musculoskeletal, gastrointestinal and dermatological symptoms make up Gulf War Syndrome

The results of the meta-analysis by Alexis Maule and colleagues [1] provide an important addition to the peer-reviewed literature on Gulf War Syndrome / Illness (GWS). Their detailing and combining of results from various studies looking at self-reported health symptoms among deployed troops during the Persian Gulf War of 1990 adds further credence to the range of symptoms reported by returning troops. Also, they provide further clues as to where science should continue to look and intervene to help our veterans.

I've talked about the Persian Gulf War and GWS a few times before on this blog (see here and see here and see here for examples). Described in some quarters as one of the most toxic wars in history, there are still many questions that require answering about why so many veterans returned from theatre in such poor health. Much like another quite nebulous condition very often confused with other diagnoses under the heading 'medically unexplained symptoms' (see here), the relative lack of knowledge about GWS has made the condition / constellation of symptoms fertile ground for various 'psychosomatic explanations'. This, I believe, has done, and continues to do, a real disservice to the veterans of this conflict and their loved ones.

Maule et al settled on some 21 published studies, including nearly 130,000 participants and covering almost 30 years of research (the war itself started in late 1990) where self-reported symptoms were compared "in GW-deployed veterans and GW-era control veterans." GW-deployed veterans were defined as "veterans who deployed to the Gulf area in support of the 1990–1991 GW." Their comparators were described as "non-deployed veterans or veterans serving in the military during the 1990–1991 GW period who deployed to areas other than the Gulf (eg, Germany, Bosnia)." Reported health symptoms were searched for and responses boiled down across the studies.

Results: "A total of 56 distinct health symptoms were reported in three or more studies and included in the meta-analysis." Of the various health symptoms reported, 'lacking energy' topped the frequency chart for deployed veterans, fairly closely followed by related issues such as 'fatigue' and 'unrefreshing sleep'. When classifying reported health symptoms together, the following categories emerged: mood-cognition, fatigue, musculoskeletal, gastrointestinal and dermatological symptoms. Further: "Results of the meta-analysis showed GW-deployed veterans had increased odds of reporting all of the analysed symptoms compared with GW-era controls, indicating that the health problems associated with GW deployment include widespread, multiple body symptoms."

The authors do caution that it is not possible to say that all of these symptoms are cardinal features of GWS insofar as their inability "to assess the effect of some covariates relevant to health symptom reporting (eg, post-traumatic stress disorder and specific deployment exposures)." They also talk about how their meta-analysis approach, similar to other occasions across various different topics, may also be liable to publication bias ("when studies with positive findings are more likely to be published than studies with null and/or negative findings"). They did try and 'correct' for this possible bias and still reported that "42 out of the 56 summary ORs [odds ratios] remained significant." That included all those 'fatigue-related' health items previously reported on.

The work from Maule and colleagues adds to a significant research base observing that poorer health outcomes seem to be an important part of deployment to the Persian Gulf during Operation Desert Storm [2]. It again reminds us that we owe a debt to those veterans and their families, to continue to pursue a research agenda that takes their health issues seriously, and provides them with answers and the relief that many still sorely need.

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[1] Maule AL. et al. Meta-analysis of self-reported health symptoms in 1990–1991 Gulf War and Gulf War-era veterans. BMJ Open. 2018; 8: e016086.

[2] Porter B. et al. Health Status of Gulf War and Era Veterans Serving in the US Military in 2000. J Occup Environ Med. 2018 Jan 24.

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Saturday, 7 April 2018

Risk of breast cancer in women with schizophrenia: meta-analysed

"In this meta-analysis of 12 cohort studies that included 125 760 women and in which conventional methods of meta-analysis had been used, schizophrenia in women was associated with an increased breast cancer incidence compared with the general population."

That was a primary findings reported by Chuanjun Zhuo & Patrick Triplett [1] following their survey of the peer-reviewed research literature on the topic of breast cancer risk and schizophrenia up to August 2017. The authors caution however that their review of this topic might not be the last word on it - "it is possible that a future study will show a decreased breast cancer risk in women with schizophrenia compared with the general population" - given "substantial between-study variance" among the research literature they examined. Another very good example of how the currency of science is probability and big sweeping generalisations may not necessarily stand the test of time.

"The status of physical health in patients with schizophrenia has become an important topic in health care management research" introduced the the Zhuo/Triplett paper, and with it, important recognition that diagnoses like schizophrenia can lead to an over-emphasis on the psychiatric often to the detriment of the somatic (see here). This, allied to other findings that have suggested that risk of premature mortality from various somatic complaints / diagnoses / issues is potentially heightened in relation to schizophrenia (see here).

Authors located studies fulfilling their study entry criteria, including "schizophrenia identified as exposure at baseline" and "documented incidence of breast cancer on follow-up" and applied their statistical analyses to results. Importantly: "Studies reporting breast cancer–related mortality rather than incidence were also excluded because the mortality outcome may be affected by many factors other than breast cancer incidence, such as comorbidities and treatments." Most of the included studies/data were found to be methodologically sound based on scores on the Newcastle-Ottawa Scale.

Alongside their finding that women with schizophrenia seemed to be at an elevated risk of breast cancer, authors also suggested that "intensive prevention and treatment against breast cancer are warranted for women with schizophrenia." So yes, this means discussing about potentially modifiable risk factors for breast cancer such as alcohol use and obesity (obesity, at the time of writing, being something of a focus for one large cancer charity here in Blighty). But this also means looking at how schizophrenia and its management might also place someone at elevated risk of something like breast cancer as a result of it sometimes being a "hormone-dependent cancer" and, as the authors note, "a significant positive association between plasma prolactin levels and the risk of breast cancer, has been observed." Minus any scaremongering, prolactin elevations have been noted following the use of certain antipsychotic medicines typically indicated for schizophrenia [2] and other conditions (see here). Any additional risk needs to be managed, and managed well.

I don't think anyone should be unduly alarmed by the Zhuo/Triplett results, but rather more mindful of the fact that a psychiatric diagnosis does not disqualify someone from other risks of more somatic conditions / complaints. The key, yet again, is screening and keeping an open mind...

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[1] Zhou C. & Triplett PT. Association of Schizophrenia With the Risk of Breast Cancer Incidence: A Meta-analysis. JAMA Psychiatry. 2018. March 7.

[2] Wu Chou AI. et al. Female schizophrenia patients and risk of breast cancer: A population-based cohort study. Schizophr Res. 2017 Oct;188:165-171.

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Friday, 6 April 2018

"evidence does not support the validity of pathological demand avoidance as an independent syndrome"

Pathological Demand Avoidance (PDA) mentioned in the title of this post represents "a behaviour profile within the autism spectrum" according to one authoritative source.

As I mentioned in a blogpost a few years back discussing PDA (see here), the label encompasses quite a few characteristics that overlap with facets of autism. Importantly however, it also includes a few other elements, including 'resisting and avoiding the ordinary demands of life' and the 'active use of various strategies to resist demands via social manipulation', not readily associated with autism (see here for further information). The late Prof. Liz Newson talked quite a bit about PDA [1] and I was honoured to see her speak so passionately about this topic on a few occasions.

As per the UK National Autistic Society (NAS) entry on PDA, the label is "increasingly, but not universally, accepted as a behaviour profile that is seen in some individuals on the autism spectrum." Such a description sets the scene for how things stand at the moment with regards to PDA and it's current lack of formal acceptance in the various diagnostic manuals despite relatively common usage, at least here in Blighty. The viewpoint article published by Jonathan Green and colleagues [2] is likely to provoke reactions on both sides of the debate of whether PDA is an "independent syndrome" or merely reflects "an important known range of co-occurring difficulties for many children with autism spectrum disorder." Green et al suggest the latter.

This is a difficult topic to talk about. Not least because there are quite a few children and adults who have been diagnosed with PDA. The idea that these people may have been 'mis-diagnosed' or perhaps even given the label on the basis of a diagnostic 'fad' has the potential to cause quite a bit of distress both to them, their parents / caregivers and various other people who have an interest in their education and development. I make no value judgements on the Green paper aside from looking at the quality of the [current] peer-reviewed science upon which it is based.

On the topic of the peer-reviewed science on PDA, well, the term 'limited in quantity' probably best describes it so far, which is a bit surprising given the increasingly popularity of the label. I daresay that this point probably impacted on the conclusion reached by Green and colleagues, but there are some important things to highlight so far.

The paper by Elizabeth O'Nions and colleagues [3] talking about the possibility of identifying PDA via the use of the DISCO (Diagnostic Interview for Social and Communication Disorder) covered some important issues. First: "the sense that identifying PDA features in individuals within the autism spectrum may serve an important clinical function in providing tailored educational and support strategies" is mentioned. In these times when autism is increasingly being talked about in the plural sense ('the autisms') and rarely as a 'stand-alone' diagnosis (see here), PDA perhaps represents a first important step in categorising or sub-categorising part of the autism spectrum. It's perhaps no coincidence that the name Gillberg also appears on quite a bit of the literature talking about PDA, with his interest in the overlapping concept of ESSENCE including autism (see here). I might add that this is not the first time that efforts have been made with regard to formulating a diagnostic instrument for PDA [4].

Second, O'Nions and colleagues both in their adapting DISCO to diagnosis paper and other peer-reviewed publications [5] make reference to how data suggest that "a number of the traits characteristic of PDA are not very specific to the PDA phenotype and may be relatively common across the autism and problem behaviour phenotypes." They observed for example that: "Outrageous acts and lack of concern for their effects draw parallels with conduct problems and callous-unemotional traits" and even that: "The pathological demand avoidance group displayed comparable levels of autistic traits and peer problems to the autism spectrum disorders group and anti-social traits approaching those seen in the conduct problems and callous-unemotional traits group." This is important in any debate about whether PDA is deserving of a stand-alone diagnosis status or something more 'comorbid'. It should also be viewed alongside the idea that autistic traits are not seemingly just autism-specific (see here) but also occur across various different labels and diagnoses (see here). Going back to the idea for example, that callous-unemotional and anti-social traits seem to be part and parcel of some PDA, I'll draw your attention to a group of conditions where such issues are also seemingly 'over-represented' (see here) and how such conditions are themselves over-represented when it comes to the autism spectrum [6] (see here also). In short, it's [clinically] complicated.

Finally, although by no means a specific gender-linked diagnosis, I note that there are facets of the description of PDA that could 'overlap' with issues that are 'rising' when it comes to autism and in particular, female autism. So, again from the NAS description, the phrase "appears social at first and to be people-orientated" is mentioned in connection to PDA; complemented by observations on the use of 'role-play' with regard to obtaining needs and wants. I've specifically mentioned female autism in this context because of the growing interest in how the female presentation of autism might be subtly different (camouflaged) from the male presentation (see here), bearing in mind the need not to make too many sweeping generalisations (see here).

To reiterate, I remain neutral as to the current position of PDA as a distinct entity or something more 'co-occurring' symptom-wise. I do think the Green findings should be a 'call to action' for more research on this topic in terms of symptom comparisons and importantly, symptom presentation more longitudinally. With my interest in all-things 'comorbidity' in relation to autism (see here) I'd also like to see more investigations done on how the comorbidity profile may be similar/different in relation to more classical presentations of autism. And then there's biology to consider, and whether PDA notably 'differs' across any physiological measure(s) compared with other manifestations of the autism spectrum?

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[1] Newson E. et al. Pathological demand avoidance syndrome: a necessary distinction within the pervasive developmental disorders. Arch Dis Child. 2003 Jul;88(7):595-600.

[2] Green J. et al. Pathological Demand Avoidance: symptoms but not a syndrome. The Lancet Child & Adolescent Health. 2018. March 23.

[3] O'Nions E. et al. Identifying features of 'pathological demand avoidance' using the Diagnostic Interview for Social and Communication Disorders (DISCO). Eur Child Adolesc Psychiatry. 2016 Apr;25(4):407-19.

[4] O'Nions E. et al. Development of the 'Extreme Demand Avoidance Questionnaire' (EDA-Q): preliminary observations on a trait measure for Pathological Demand Avoidance. J Child Psychol Psychiatry. 2014 Jul;55(7):758-68.

[5] O'Nions E. et al. Pathological demand avoidance: exploring the behavioural profile. Autism. 2014 Jul;18(5):538-44.

[6] Gordon-Lipkin E. et al. Anxiety and Mood Disorder in Children With Autism Spectrum Disorder and ADHD. Pediatrics. 2018 Mar 30. pii: e20171377.

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