Monday, 22 October 2018

"Omega-3 polyunsaturated fatty acid treatment for anxiety might be effective in clinical settings"

Today I present the findings of yet another systematic review and meta-analysis as per the publication from Kuan-Pin Su and colleagues [1] that concluded: "omega-3 PUFAs [polyunsaturated fatty acids] might help to reduce the symptoms of clinical anxiety." A finding that may have some quite profound implications for lots and lots of different diagnoses/conditions/labels where anxiety seems to be particularly over-represented and life-draining (see here and see here for examples).

So, the starting hypothesis was that "omega-3 PUFAs might have anxiolytic effects in patients with significant anxiety- and fear-related symptoms." Various studies, both in animals and humans, have implicated fatty acids in 'emotional states', particularly the so-called 'good fatty acids' including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The authors reported that "there have been no systematic reviews of this topic to date" so decided to remedy the situation.

Trawling through various repositories and databases of peer-reviewed science, they searched for relevant science on the topic of fatty acid supplementation and anxiety measurement. From little over a hundred possible science articles, they whittled the numbers down to 19 studies including over 1200 participants "with omega-3 PUFA treatment (mean age, 43.7 years; mean female proportion, 55.0%; mean omega-3 PUFA dosage, 1605.7 mg/d)" and "1037 participants without omega-3 PUFA treatment (mean age, 40.6 years; mean female proportion, 55.0%)." Taking into account that some studies (most) included a placebo element to their design, different dosages and formulations of PUFAs were used and that various different tools and schedules were used to 'measure anxiety', there were some boiled-down messages to emerge.

First: "The overall findings revealed modest anxiolytic effects of omega-3 PUFAs in individuals with various neuropsychiatric or major physical illnesses." That's not to say that every study was 'positive' in terms of PUFA effects on anxiety, but generally speaking the evidence tended to side more with an effect rather than no effect. Second, dose and formulation seemed to matter: "Participants treated with a daily dose of 2000 mg or more of omega-3 PUFAs showed a significantly greater association of treatment with reduced anxiety symptoms." Third: "the association of omega-3 PUFA treatment with reduced anxiety symptoms was significantly stronger in subgroups with specific clinical diagnoses than in subgroups without specific clinical conditions." So the effect of PUFA supplementation was stronger in those with a clinical diagnosis of something like anxiety than those who didn't have one.

Downsides? Well, there are of course limitations to the data included in the Su study; for example, "the significant heterogeneity among the included studies... with potential influence by some outlier studies" and these should not be underestimated. I'm also minded to bring in the [still emerging] issue that meta-analyses are only as good as the data that they are based on (see here and see here for examples). And I'd also mention that side-effects are something not discussed too heavily in the Su study but one shouldn't assume that just because we're talking about a fish oil so this is somehow side-effect free for everyone...

Given the low cost of fatty acid supplements and their wide, very wide, availability, the Su results provide some pretty good support to suggest that 'giving it a go' could be an option for at least some people diagnosed with an anxiety disorder. Please don't however take that as me giving anyone medical or clinical advice; I'm merely following what the results say and the media coverage that has followed (see here).

And since we're on the topic of food and mood, I note the recent meta-analysis from Camille Lassale and colleagues [2] suggesting that "adhering to a healthy diet, in particular a traditional Mediterranean diet, or avoiding a pro-inflammatory diet appears to confer some protection against depression in observational studies" has been garnering news headlines (see here). These studies combined suggest that diet might have an important effect of mood and well being. Now, where have I heard that before (see here)...?

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[1] Su K-P. et al. Association of Use of Omega-3 Polyunsaturated Fatty Acids With Changes in Severity of Anxiety Symptoms. JAMA Network Open. 2018;1(5):e182327.

[2] Lassale C. et al. Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. Molecular Psychiatry. 2018. Sept 26.

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Friday, 19 October 2018

Helminthic Trichuris Suis Ova vs. placebo for repetitive behaviours in adult autism

The trial results published by Eric Hollander and colleagues [1] were not entirely unexpected. I had previously mentioned their study on the "use of the immunomodulator Trichuris Suis Ova (TSO)" with autism in mind in another post (see here) but, at that time, still awaited the peer-reviewed publication version to appear. I wait no longer.

OK, Trichuris suis (T. suis) is a parasite. It makes its home in the deepest, darkest recesses of other creatures, apparently also having the rather important evolutionary advantage of being able to stay in egg form for quite a long time 'awaiting ingestion'. But just before you turn away John Hurt style (no, I'm not going to link to the 'chest-buster' scene), this particular parasite might not be 'all bad'. I'm specifically talking about some preliminary data suggesting that T. suis *might* have some important immunological effects [2] when ingested in a controlled manner under certain clinical circumstances.

Hollander et al took things one stage further by their insinuation of a link between use of an "immunomodulator" such as T. suis and their study to determine "the effect sizes for TSO vs. placebo on repetitive behaviors, irritability and global functioning in adults with ASD [autism spectrum disorder]." And just before you question the idea that immune function might be something important to some overt behaviour(s), there is other research out there discussing the possibility of such an effect (see here and see here) specifically with autism in mind.

"A 28-week double-blind, randomized two-period crossover study of TSO vs. placebo in 10 ASD adults, ages 17 to 35, was completed, with a 4-week washout between each 12-week period." This was a 'gold-standard' trial design albeit with a very, very small participant group who represented only a specific 'part' of the autism spectrum [3]. The trial was also registered for all to see the proposed hows-and-whys (see here) including the detail: "Have a personal or family history of allergies" as part of the inclusion criteria.

Results: "Differences between treatment groups did not reach statistical significance." This is an important point highlighting how use of T. suis ("the eggs of intestinal helminthes (trichuris suis ova) administered as 2500 ova doses every two weeks") did not translate into statistically significant group differences across measures looking at the social communication aspects of autism for example. I say this bearing in mind that the Hollander study was a cross-over trial too.

But... "Large effect sizes for improvement in repetitive behaviors (d = 1.0), restricted interests (d = 0.82), rigidity (d = 0.79), and irritability (d = 0.78) were observed after 12 weeks of treatment." What this means is that when comparing participants using T. suis vs. their baseline measurements, they seemed to do better on the T. suis portion of the trial across various different types of behaviour. Importantly too we are told that "TSO had only minimal, non-serious side effects" bearing in mind this included various gastrointestinal (GI) side-effects (and knowing that GI issues are already 'a thing' when it comes to autism).

So, there we have it. The results of the first (small scale) clinical trial using Trichuris Suis Ova (TSO) helminthic style with autism in mind. Obviously a lot more research is required before this type of intervention goes anything like 'mainstream'. Alongside there is also the 'acceptability' factor to consider: how many people would actually want to ingest a parasite such as T. suis? Indeed, one of the next courses of study is perhaps to see 'why' such helminthic therapy has the effect that it has on behaviour, and whether such an effect can be replicated in a medicine or other formulation rather than ingesting a parasite?

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[1] Hollander E. et al. Randomized Crossover Feasibility Trial of Helminthic Trichuris Suis Ova vs. Placebo for Repetitive Behaviors in Adult Autism Spectrum Disorder. World J Biol Psychiatry. 2018 Sep 19:1-25.

[2] Jouvin MH. & Kinet JP. Trichuris suis ova: testing a helminth-based therapy as an extension of the hygiene hypothesis. J Allergy Clin Immunol. 2012 Jul;130(1):3-10.

[3] Hollander E. et al. Trichuris Suis Ova (TSO) as an immune-inflammatory treatment for repetitive behaviors in ASD. European Neuropsychopharmacology. 2016; 26: 891.

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Thursday, 18 October 2018

"contrary to its findings, there is no evidence that graded exercise therapy is effective" for myalgic encephalomyelitis / chronic fatigue syndrome


Things can sometimes move pretty fast in the world of peer-reviewed science. I had originally scheduled this post to appear in November (2018) but there's been some recent 'movement' in this area (see here) so I've decided to publish it now.

The original post is shown below. And below that are a few extra thoughts in light of the reported decision to remove the Larun article (at least for now)...

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The re-analysis paper published by Mark Vink & Alexandra Vink-Niese [1] makes for some really interesting reading. Not only because it adds to other voices in the peer-reviewed domain (see here) questioning the usefulness and safety of the intervention known as graded exercise therapy (GET) 'for' myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but also because it kinda fits in with a narrative suggesting that 'trusted evidence' is almost always open to interpretation (see here).

So, graded exercise therapy (GET) and ME/CFS. I have to say that out of all the interventions / treatments that I've come across down the years that have been indicated for various diagnostic labels, GET is probably one of the most reviled by the population it is supposed to be aimed at. The reasons for such a scenario are multiple and complex, but one of the more vocal arguments seems to be the lack of regard for harm caused by the use of a stepped physical activity schedule on a population whose illness is defined by boom-bust symptom profiles caused by physical exertion. Of particular importance to this line of thinking is the idea that post-exertional malaise (PEM) needs to have a lot more prominence attached to it when it comes to ME/CFS, minus any psychobabble 'deconditioning' chatter or related explanations.

The Vink-Vink-Niese paper is based on a Cochrane review paper of GET published by Lillebeth Larun and colleagues [2]. Yes, the same Cochrane that is going through a bit of turmoil at the moment. The Larun paper concluded a few things such as: "Exercise therapy did not worsen symptoms for people with CFS" and "Moderate‐quality evidence showed exercise therapy was more effective at reducing fatigue compared to ‘passive’ treatment or no treatment." This based on the examination of "eight randomised controlled studies" with "reported data from 1518 participants." To be fair to the Larun review paper, the authors did also mention that: "Serious side effects were rare in all groups, but limited information makes it difficult to draw firm conclusions about the safety of exercise therapy" and "further studies should be carried out to discover what type of exercise is most beneficial for people affected by CFS, which intensity is best, the optimal length, as well as the most beneficial delivery method." This, on the basis that CFS/ME is best described as a heterogeneous condition and accepting that exercise can come in various different forms, some of which might be more applicable than others when it comes to individuals with fatigue-related labels (see here for example) minus any sweeping generalisations.

Some familiar themes crop up in the Vink re-review paper - "Entry score requirements were not sufficiently strict" and "The review used subjective fatigue measured by questionnaires as the primary outcome" - which have quite notably hindered the research in this area. I note also that authors mention about attrition (dropout) rates in the reviewed studies and how, in some studies, over a third of participants placed in exercise conditions withdrew from such investigations. Such statistics will no doubt have an important influence on any final results, as well as providing an important clue that such an intervention might not be sufficiently well tolerated by quite a few [3].

Vink concludes by saying that: "The GET trials reviewed here are inherently biased: use of exercise may attract only the mildly affected and may deter the more disabled patients from participating" and that: "The flaws in the review and the trials... all created a bias in favour of the exercise intervention."

On the basis of their interpretation of the scientific data, I'm in agreement with Vink & Vink-Niese that the evidence base for the universal application of GET to ME/CFS is by no means indicated. You might well say that GET is not universally rolled out for everyone with ME/CFS but, as things currently stand at the time of writing, it is still part of the clinical guidance for the condition(s) here in Blighty (for now) and hence potentially something that can be suggested for anyone diagnosed with ME/CFS. The ethos behind GET also being tied into another biopsychosocial (BPS) favourite - CBT - also makes for a good reason why psychology really shouldn't be let anywhere near such clinical issues, particularly when the evidence against such 'interventions' is seemingly mounting (see here). Indeed, although little comfort to those currently living with ME/CFS, I'm sure one day we'll look back at the whole BPS 'involvement' with ME/CFS and truly say WTF?

And finally, whilst on the topic of 'not listening to your target population' I would also draw your attention to the recent findings from McManimen and colleagues [4] highlighting what could happen when those with ME/CFS face stigma (and dogma). Oh, and because the Cochrane name is part-and-parcel of today's post, I'll also draw your attention to an important message concerning some of their other advice pertinent to CFS...

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What else to add to this post? Well, a quote appearing in that Reuters report on the decision to temporarily withdraw the Larun review suggesting that "the withdrawal decision set a worrying precedent for scientific evidence being over-ridden by the opinions of activists" is, to my mind, inappropriate. Aside from the feedback received regarding the Larun article (see here) the Vink paper for example, is peer-reviewed science and published peer-reviewed science at that. It's not some activist randomly throwing around allegations and the like on social media or blogs(!). It's published peer-reviewed-science that calmly calls into question the conclusions of the original Larun analysis. Indeed, it's part of a trend for serious scientific conversations being held in the peer-reviewed science domain concerning some of the science and clinical practice around ME/CFS (see here). Nothing vexatious.

As I mentioned, given that other Cochrane reviews covering the topic of CFS have also been recently withdrawn [5] (see here for more on the withdrawal notice) it strikes me that Cochrane is perhaps also wisely ensuring that it's previous high standards are maintained and confidence restored in its 'evidence-based' name particularly when it comes to research into ME/CFS. Given also the turbulent few weeks that have just passed (see here) and seemingly, are still continuing (see here) for the 'collaboration', it's also a timely reappraisal that fits the important narrative that ME/CFS is a long-term physical health condition (see here) and not a mental disorder or worse. And intervention options need to recognise this fact...

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[1] Vink M. & Vink-Niese A. Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review. Health Psychology Open. 2018;5(2):2055102918805187.

[2] Larun L. et al. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2016 Jun 24;(6):CD003200.

[3] Cheshire A. et al. Guided graded Exercise Self-help for chronic fatigue syndrome: patient experiences and perceptions. Disabil Rehabil. 2018 Oct 16:1-10.

[4] McManimen SL. et al. Effects of unsupportive social interactions, stigma, and symptoms on patients with myalgic encephalomyelitis and chronic fatigue syndrome. J Community Psychol. 2018 Nov;46(8):959-971.

[5] Adams D. et al. WITHDRAWN: Traditional Chinese medicinal herbs for the treatment of idiopathic chronic fatigue and chronic fatigue syndrome. Cochrane Database Syst Rev. 2018 Oct 15;10:CD006348.

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Wednesday, 17 October 2018

"maternal pre-pregnancy obesity is associated with autism-like behaviors in offspring"

The results reported by Kandice Varcin and colleagues [1] concluding that "maternal pre-pregnancy obesity is associated with autism-like behaviors in offspring" continue and extend a research theme (see here and see here). A research theme that highlights a potentially important relationship between maternal weight (and/or related parameters) and offspring development across various, potentially intertwined, variables (see here).

Including the notable name of Andrew Whitehouse on the authorship team (see here and see here for some examples of his other research), researchers set about to explore whether "pre-pregnancy weight was related to autistic-like traits among offspring not diagnosed with ASD [autism spectrum disorder]." I added the bold highlight to the word 'not' to emphasise how this work was set slightly apart from the other research that has observed an *association* between maternal weight before or during pregnancy and a risk of a formal diagnosis of autism in offspring. Pregnant women in their second trimester of pregnancy were recruited and "had their height measured." They also "reported their pre-pregnancy weight" which combined with the height measurements to give the measure known as the body mass index (BMI). And also: "At 19-20 years of age, 1238 offspring of these women completed a measure of autistic-like traits, the Autism-Spectrum Quotient (AQ)." Keep those issues in mind for now.

Results: "Regression analyses identified a positive association between increasing maternal pre-pregnancy BMI and increasing AQ Total Score amongst offspring; this association was maintained even after controlling for a range of variables including maternal/obstetric factors (age at conception, education, smoking, alcohol consumption, hypertensive diseases, diabetes, threatened abortion), paternal BMI at pregnancy, and child factors (parity, sex)." Sorry for the large quote, but the authors said it better than I ever could. Authors also reported that those women defined as being obese before pregnancy, according to their BMI measurement, were quite a bit more likely to "have offspring with high scores (≥26) on the AQ." This then lead them to conclude that "maternal pre-pregnancy obesity is associated with autism-like behaviors in offspring."

Caveats? Well, yes, a few. Height measured in the second trimester but participants "reported their pre-pregnancy weight"? I can see a few complications there in terms of accuracy of recall and perhaps the possibility of some bias creeping in. Having said that, many mums-to-be do have records of their weight during that 'special time' and some probably before as part of their regular clinical care or just as a result of how health conscious everyone is being these days. That and the fact that most people roughly know their typical weight (outside of pregnancy).

But also the AQ... the AQ. Regular readers probably already know that I have some qualms about the AQ and it's 'specificity' when it comes to autism and autistic traits (see here and see here). I know it's often seen as one of the internet's premier 'are you autistic?' instruments, but sometimes I think it's done more harm than good by way of it's probable link to the rise and rise of the 'self diagnosis' (see here) for example. I could go on about this, but I won't. Instead I'll just mention that 'autism-like' behaviours as judged by the AQ is probably the correct phrase to use in the context of the Varcin paper. Indeed, one might easily suggest that in a non-clinical population, AQ might also be tapping into other labels and traits [2]: "Higher AQ scores were associated with higher scores of loneliness, social anxiety, depression, and anxiety, as well as with lower scores of quality of life (QoL)." So unless one accepts that depression and/or anxiety might potentially be core features of autism (see here and see here), AQ might be picking up other things other than autism.

Still, I can't argue with the *association* talked about by Varcin et al, and what it might mean for the quite spectacular rise and rise in the numbers of people being diagnosed with an autism spectrum disorder (see here). No, not by any means the only factor to account for the increase in diagnoses, but potentially an important part of the story...

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[1] Varcin KJ. et al. Maternal pre-pregnancy weight and autistic-like traits among offspring in the general population. Autism Res. 2018 Sep 19.

[2] Reed P. et al. Loneliness and Social Anxiety Mediate the Relationship between Autism Quotient and Quality of Life in University Students. Journal of Developmental and Physical Disabilities. 2016; 28: 723-733.

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Tuesday, 16 October 2018

Prevalence of autism in preterm infants meta-analysed

"The prevalence of ASD [autism spectrum disorder] is significantly high in the preterm population. Adequate resources are needed to improve the outcomes of these children."

So said the findings reported by Sachin Agrawal and colleagues [1] who present the results of yet another meta-analysis with autism in mind; yet again on a topic that has filled quite a few peer-reviewed science column inches (see here and see here for examples).

'Preterm' typically refers to babies who are born alive but before completing the usual 37 weeks of gestation. It is further sub-categorised into extremely (less than 28 weeks), very (born between 28 and 32 weeks gestation) and moderate-to-late (born between 32 and 37 weeks gestation) preterm. The risk of a wide variety of 'adverse' outcomes seems to be significantly heightened following preterm birth, covering both physical (somatic) and psychological/developmental domains. Outside of the very final outcome that is early mortality, longer-term issues, particularly associated with brain development occurring outside of the womb, have been a feature of several results. Autism has also been mentioned in this context (see here).

Agrawal et al set about analysing the data pertinent to autism risk and preterm birth. They talk about the scenario of a 'perfect storm' whereby "whatever initiates the preterm birth process might also initiate abnormal pathways of brain development" as being potentially pertinent to autism. Covering the research literature up to May 2017, some 18 studies including over 3300 preterm infants were included for analysis. They specifically included studies that utilised known diagnostic tests for autism or ASD (ADOS, ADI, DAWBA) rather than those that used only "ASD screening tools" and looked up the cumulative prevalence rate for autism.

Results: 7%. That was the overall autism prevalence rate among preterm infants included in the various studies analysed. There was quite a bit of variation across the studies and the prevalence figure fluctuated to some degree as and when children with disabilities were included or not, but the 7% figure seemed to be an accurate one. Authors also put the 7% figure into some 'real world' perspective too: "This equates to ∼900 000 additional children each year who will develop ASD given that globally ∼15 million infants are born preterm (before 37 weeks’ gestation), of whom 13 million survive." Kinda takes your breath away doesn't it?

A couple of other important details are worthwhile mentioning too. So: "Our meta-regression analysis revealed no significant association between gestational age, birth weight, and prevalence of ASD in preterm infants." This doesn't totally rule out such factors as exerting an effect, but...

What else to say? Well preferential screening for autism or ASD in cases of preterm birth could be indicated. The allocation of further research resources into how and why preterm birth occurs could also be useful, focusing on how and why the infant brain seems to be so sensitive to maturation outside of mum's body. And then in relation to all those 'we don't know what causes autism' sentiments that continue to be expressed, well, add prematurity to the growing list of strong possibilities (see here and see here for other examples).

Oh and minus any medical or clinical advice being given or intended, it appears that nutrition, particularly omega-3 fatty acid levels, *might* play 'some' role in some preterm births [2] with some intriguing possibilities for supplementation (minus sweeping generalisations)...

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[1] Agrawal S. et al. Prevalence of Autism Spectrum Disorder in Preterm Infants: A Meta-analysis. Pediatrics. 2018 Aug 3. pii: e20180134.

[2] Olsen SF. et al. Plasma Concentrations of Long Chain N-3 Fatty Acids in Early and Mid-Pregnancy and Risk of Early Preterm Birth. EBioMedicine. 2018 Aug 2. pii: S2352-3964(18)30252-4.

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Monday, 15 October 2018

Autism research really needs to study the prevalence and treatment of scurvy in autism

The results published by Melinda Saavedra and colleagues [1] describing another case report where scurvy was [eventually] diagnosed as appearing alongside autism represents yet another 'call to action' on this topic.

I've covered this issue quite a few times before on this blog (see here and see here and see here), and quite frankly it's reached the point where autism research really needs to step up and formally study the prevalence of scurvy in relation to autism. Indeed given the almost universal reports of medical science not initially recognising that scurvy can be no stranger to autism, the time has also come to "announce [to] the pediatrician and other professionals dedicated to primary health care about scurvy as a potential consequence of restrictive diets in children with autism spectrum disorders."

This time around the clinical focus was on a 4 year old boy who was brought to clinical attention as a result of "hip pain and refusal to walk, associated with petechiae and bruising of the lower limbs." The clues were all there that scurvy could be a cause of such symptoms, but it was only when it was revealed that the child had "selective feeding habit" that the penny seemed to finally drop. Indeed: "Levels of Vitamin C in blood were measured and without waiting for results he started treatment with 300 mg per day of ascorbic acid." Lo and behold, his vitamin C results were found to be low, and vitamin C supplementation eventually did the trick. Of vital importance, the pain associated with scurvy also showed improvement and he was discharged from clinical care with a maintenance dose of vitamin C and some nutritional advice.

'Selective feeding patterns', 'picky eating' or whatever you want to call it, is an issue that is not stranger to autism (see here). It's reasonable to assume that where such feeding issues continue into the longer-term, and dependent on what foods are consumed as part of such a restrictive pattern, there are likely to be biological consequences for the person concerned as a function of what nutritional inadequacies follow. Indeed, I daresay that such a pattern follows what is being noticed in connection with other food-related conditions in the longer term (see here). Set in this context, a lot more research and importantly, clinical practice, needs to focus on the hows-and-whys of such behaviours and their remediation. There is no longer any excuse for allowing diseases of the past such as scurvy and also others like rickets, to plague the children of today, vulnerable children of today, where healthy food in most parts of the world, is not in short supply.

Oh, and bear in mind that 'picky eating' might not be the only reason why scurvy might appear alongside autism [2]. We need lots more data.

And also, as I write this [3]...

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[1] Saavedra MJ. et al. Scurvy due to restrictive diet in a child with autism spectrum disorder: case report. Arch Argent Pediatr. 2018 Oct 1;116(5):e684-e687

[2] Hasan Al-Breiki S. et al. Scurvy as the tip of the iceberg. Journal of Dermatology & Dermatologic Surgery. 2014; 18: 46-48.

[3] Caldwell KJ. et al. Child With Autism and a Limp. Ann Emerg Med. 2018 Oct;72(4):493-495.

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Saturday, 13 October 2018

Regressive vs. non-regressive autism: limited chemical differences noted

The paper published by Antonio Gomez-Fernandez and colleagues [1] examining whether or not there may be some potentially important biological differences as a function of reported regression vs. no regression in autism provides the blogging fodder today. Not for the first time has the immune system and 'regressive autism' been mentioned in the peer-reviewed science literature (see here and see here), but the current work focuses on the examination of various immune system and other related compounds: in a seemingly well-defined cohort: "Analyses of plasma molecules, such as cathepsin, IL1β, IL6, IL8, MPO, RANTES, MCP, BDNF, PAI NCAM, sICAM, sVCAM and NGF."

"Fifty-four children (45 males and nine females) aged 2-6, who were diagnosed with ASD [autism spectrum disorder], and a control group of 54 typically-developing children of similar ages were selected." Authors relied on quite an extensive battery of assessments looking at behaviour, alongside their use of the DSM-5 diagnostic criteria for autism (see here). Also accompanying physical examination "with a special emphasis on neurological and nutritional status", authors garnered blood samples from participants (overnight fasting) for their immune system and related functioning evaluations.

"The group of ASD children was further divided into two subgroups based on the presence or absence of neurodevelopmental regression during the first two years of life, which was assessed using a five-item questionnaire following the guidelines used by the Autism Diagnostic Interview-Revised (ADI-R) for the evaluation of this process." The ADI-R has been previously discussed on this blog in relation to regression in autism (see here). And just in case you might not be totally convinced that regression can be part of a pathway to autism, here's some more evidence for you (see here)...

Results: "there were 20 children included in the AMR [neurodevelopmental regression] subgroup and 32 in the ANMR [without neurodevelopmental regression] subgroup; two children could not be classified in these subgroups because they were adoptees, allocated by a national adoption agency." Bearing in mind that we cannot rule out any recruitment bias that might have leaned towards including those with regressive autism on the Gomez-Fernandez study, the figure of approaching 40% of their cohort showing such a regressive profile is notable. I'd also draw your attention to the finding that the behavioural profile for the regressive group (AMR) was also significantly different from the non-regressive group (ANMR) insofar as perhaps painting a picture of greater [group] autism severity...

Interestingly, the study did not show too many immune system and other compound differences between those diagnosed with autism and the asymptomatic (for autism) control group. So: "No differences were found between the two groups in terms of the cytokine and adhesion molecule levels studied, except for NGF [nerve growth factor], in which the group of ASD children was found to have twice the plasma levels compared to the control group." NGF is no stranger to autism research, and other studies have come to a similar conclusion [2].

When it came to examining results based on comparing the regressive (AMR) and non-regressive (ANMR) groupings, things got slightly more interesting but again no complicated pattern of difference was noted. So, for the ANMR (non regression) grouping: "lower plasma levels of the NCAM adhesion molecule were detected compared to the levels in the AMR subgroup and the control group. This ANMR group also exhibited higher NGF levels than the typically-developing children, which could indicate an alteration in neuronal development." Again, adhesion molecules have been mentioned in other autism research (see here).

"In conclusion, the results of this study show that there is not a typical profile for the expression of relevant plasma cytokines, adhesion molecules or growth factors in children with ASD compared with that in typically-developing children." OK, there are caveats to the phrasing used by the authors; not least that the participant numbers were quite small in the Gomez-Fernandez study and the idea that within the very heterogeneous autism spectrum, there may be smaller groupings (phenotypes) that perhaps show a tendency to greater immune system and related 'issues' (see here). But there are also some strengths attached to the Gomez-Fernandez study; not least the study "benefits from a careful selection of children of similar ages, as well as the complete diagnosis of ASD with multiple tests, clinical follow-up and associated complementary tests."

Questions still remain. Perhaps an important one is the question around why some children show a regressive pattern of behaviour as part of their path to a diagnosis of autism? Yes, issues such as infection do seem to be part-and-parcel of the clinical profile for some (see here and see here for examples) and perhaps more detailed focus is required in such areas. But much like a group showing the opposite of regressive autism - those who seemed to 'grow out' of autism - currently thought to include as many as one in ten (see here), a wider range of biological as well as psychometric measures are required to help pick out potentially important mechanisms pertinent to the idea that autism is not necessarily 'hard-wired' for all...

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[1] Gomez-Fernandez A. et al. Children With Autism Spectrum Disorder With Regression Exhibit a Different Profile in Plasma Cytokines and Adhesion Molecules Compared to Children Without Such Regression. Front. Pediatr. 2018. September 26.

[2] Dinçel N. et al. Serum nerve growth factor levels in autistic children in Turkish population: a preliminary study. Indian J Med Res. 2013 Dec;138(6):900-3.

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Friday, 12 October 2018

Pervasive refusal syndrome and autism: autistic traits 'speeding up the recovery process'?

Before reading the case report paper by Emily Bond & Rosalind Oliphant [1], I have to admit that I knew next to nothing about the label known as pervasive refusal syndrome (PRS). PRS, a condition manifesting as 'refusal to eat, weight loss, social withdrawal and school refusal', is not currently recognised in any of the major diagnostic manuals (DSM, ICD) but does seem to have a following in certain circles [2].

Bond & Oliphant detail a case report of a 9-year old boy who came to clinical attention "due to concerns regarding minimal dietary intake." He had previously been diagnosed with an autism spectrum disorder (ASD) as well as attention-deficit hyperactivity disorder (ADHD) following a trend these days (see here). He was subsequently detained under the Mental Health Act as a consequence of "his resistance of treatment in the community" and also him "lacking Gillick competence." The authors detail his clinical journey, and how, with the right support and accommodations, he was eventually discharged from hospital care with the expectation for him to "make a full recovery to his premorbid functioning with support in the community."

Among the various issues raised in the Bond/Oliphant paper, one of the most striking points made by the authors was in the sentence: "It is possible that the ASD [autism spectrum disorder] symptoms such as literal thinking and concrete processing have actually aided in speeding up the recovery process." The idea that certain autistic traits might actually have had a positive benefit to getting someone through treatment for PRS...

I'm slightly careful here not to go off on the 'autism is a superpower' tangent that some people have previously spoken about (particularly on social media). For this young man, autism for him included communication issues ("His sole method of communication was typing on an iPad to his mother")  and various other traits (e.g. "struggling with understanding abstract questions, complex reasoning, and problem solving skills") which probably didn't impart any superpower for him. He did have an interest in superheros and dressing up in costumes however...

Authors mention how his recovery from PRS - he was discharged after 4 months - was significantly quicker than is typically expected (around 12 months "from previous literature"). They noted that: "The clinical team working with our case quickly found that he responded very well to rules, boundaries, and clear consequences of behaviour." This is perhaps even more notable in the context of his autism-ADHD diagnostic combination.

It did get me wondering whether further research might be revealing into how autism or specific autistic traits might positively impact on other treatment/management scenarios. I'm specifically thinking about more psychologically-inclined interventions, for example, dealing with something like anxiety (see here) where talking therapy is something that is being particularly pushed forward. Whether or not I agree that such therapy is going to be all that useful in the longer-term if for example, one considers that anxiety might be intricately related to some core functions in relation to autism (see here) is irrelevant. Whether certain autistic traits might be a critical variable in intervention success however requires much further study...

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[1] Bond EC. & Oliphant RYK. Pervasive Refusal Syndrome in Autistic Spectrum Disorder. Case Rep Psychiatry. 2018 Jun 7;2018:5049818.

[2] Nunn KP. et al. Pervasive refusal syndrome (PRS) 21 years on: a re-conceptualisation and a renaming. Eur Child Adolesc Psychiatry. 2014 Mar;23(3):163-72.

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Thursday, 11 October 2018

Depressive symptoms in ADHD: "comparing child and parent reports"

I was drawn to blogging about the results published by Annie Fraser and colleagues [1] for a few reasons. Their observation that: "Young people with ADHD [attention-deficit hyperactivity disorder] are at high risk of experiencing symptoms of depression but may under‐report the severity of their symptoms" was interesting. It potentially ties into some other important observations about 'happiness' in the context of ADHD (see here) and also how there is an elevated risk of suicidality when ADHD is part of the clinical picture (see here). Similarly, it fits the narrative that various developmental and/or behavioural labels/conditions/disorders are typically never really stand-alone diagnoses...

So: "This study used a subsample of children originally recruited as part of the Cardiff University Study of ADHD Genes and Environment (SAGE)." As per the 'comparing child and parent reports' part of the Fraser paper, both parents and children completed the Mood and Feelings Questionnaire (MFQ) to measures depressive signs and symptoms in participating children/young adults ("mean age was 14.6 years (range 8–20 years)"). The MFQ "is a widely used depression screening instrument" according to the authors, and has some pretty good backing. Results from the MFQ were compared with a non-ADHD (I assume?) general population sample from a similar part of the United Kingdom (UK) and statistics were applied.

Having already alluded to the observation that depression scores on the MFQ were higher (indicative of more depressive symptoms) in the ADHD group than the population control group (N=1460), there are some further details to mention. Both parent- and child-rated MFQs showed the trend of more depressive symptoms in participants with ADHD. And when it came to clinical cut-off points for suspected depression, quite a few more of those diagnosed with ADHD reached them compared with controls (parent‐report 54.5% vs. 10.6%... child‐report 32.4% vs. 10.5%).

"Amongst the most common depression symptoms found in our ADHD sample were difficulty concentrating, restlessness and feeling grumpy with parents. These symptoms overlap with those of ADHD, so it is unsurprising that they were common in our sample." Think of those last sentences in one particular context: the rise and rise of the term 'ESSENCE' (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) and all the chatter about how behavioural symptoms across various different labels seem to 'overlap' with one and another. How also, developmental and behavioural labels rarely exist alone or in some sort of diagnostic vacuum (see here for example). And add them to another sentence from the authors: "This could suggest that depression scores in this sample are artificially elevated by symptoms which overlap with ADHD symptoms." Indeed.

"Suicidal thoughts and symptoms of psychomotor and cognitive retardation (i.e. talking more slowly than usual, moving and walking more slowly than usual, and sleeping more than usual) were the lowest scoring symptoms on both parent‐ and child‐report." Having already mentioned those quite worrying statistics on how a diagnosis of ADHD seems to elevate the risk of suicidality, this might initially seem like better news from the Fraser paper. Items such as "S/he thought about death or dying.... S/he thought his/her family would be better off without him/her... S/he thought about killing him/herself" were not, in the majority, reported on with great fervour. But one needs to be cautious. I say that because the authors also added: "symptoms of suicidality (‘I thought about killing myself’) were present in 20%–25% of the ADHD sample, according to both parent‐report and child‐report, compared to 2%–7% of the population sample." This is a more worrying way of looking at the findings.

So to conclude: depression or depressive symptoms are no stranger to ADHD, the symptoms of ADHD probably overlap with some of the symptoms of depression (at least according to the MFQ), and an enhanced risk of suicidality seems to be confirmed as and when ADHD is diagnosed. There's more than enough further investigations to be done on those topics; perhaps also drawing on a few other important observations too (see here and see here and see here).

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[1] Fraser A. et al. The presentation of depression symptoms in attention‐deficit/hyperactivity disorder: comparing child and parent reports. Child and Adolescent Mental Health. 2018;23(3):243-250.

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Wednesday, 10 October 2018

"the friendships and social experiences of autistic girls are similar to those of neurotypical girls"

The quote heading this post - "the friendships and social experiences of autistic girls are similar to those of neurotypical girls" - comes from the findings reported by Felicity Sedgewick and colleagues [1] (open-access available here) continuing a growing research theme looking at the presentation of autism across the sexes/genders. The results however perhaps challenge the idea that "being autistic ‘overrides’ being female in some way."

OK, first things first, by mentioning the word 'neurotypical' the authors refer to a not-autistic control group. As I've said on many, many occasions, the word 'neurotypical' from a research/clinical point of view is however meaningless (see here): there is no way for a living brain, with all its complex structures, connections and functions, some of which are changing second to second, to ever be described as 'typical'. And autism research in particular really shouldn't be using such a misnomer, no matter how [social media] fashionable it might seem.

Rant over. Despite using the term, the Sedgewick paper covers an important real-world part of the whole 'gender differences in autism' area looking at "gender differences in the friendships and conflict experiences of autistic girls and boys relative to their neurotypical [non-autistic] peers." Over 100 adolescents (aged 11-18 years) were included for study; about half diagnosed with autism with an "independent clinical diagnosis of an autism spectrum condition." Said autism diagnoses were also complemented by assessment via the gold-standard ADOS which actually revealed that: "Two boys and four girls failed to meet the ADOS-2 threshold (score = 7) for autism." Data from these children were still included in the study given the "pre-existing clinical diagnosis" and other supporting information. I'm wondering however if perhaps some of these children were examples that an autism diagnosis (or reaching the cut-off points on one of the gold standard autism assessment instruments) is not necessarily for life (see here)? Further, all participants "completed the Friendship Qualities Scale, the Revised Peer Experiences Questionnaire and were interviewed about their friendships" and results were analysed...

Results: "Autistic and non-autistic girls’ conflict and friendships were more like each other than autistic and non-autistic boys, and vice versa." The authors frame this in the context that their findings "provide compelling support for the possibility that gender may be more important than diagnosis in determining young autistic people’s social experiences." That's not to say that there weren't some important group differences in relation to social challenges, conflict and conflict resolution - "autistic girls described an ‘all-or-nothing’ approach, either taking sole responsibility for what had happened... or ending the friendship entirely, seeing the other person as the wrong-doer..., or feeling it could not be resolved" - just that there was more to align girls than to divide them when it came to comparisons with non-autistic peers.

Authors also report results from their interviews with adolescents which again revealed that gender over a diagnosis of autism seemed to a key aspect. So: "Having a few good friends was key, with all girls talking about having a small number of close friends that they considered to be ‘best’ friends. These close friends were those who they spent the most time with and talked to most." Also: "Both autistic and neurotypical girls emphasised that friends supported them." And finally: "Both autistic and neurotypical girls alluded to wanting to fit in, but in different ways." It should also be noted that Sedgewick et al mention how 'camouflaging' (a term being increasingly used in autism circles) is not a specific strategy reserved for autism: "Few girls reporting having boyfriends, but most said people dated to fit in with the popular crowd. These behaviours could be seen as a form of ‘camouflaging’, as teenagers described seeking peer acceptance, even if they were not personally motivated to date."

As to the boys of this particular cohort, well again, there didn't appear to be any really prominent stand-out separation points between autism and not-autism. As the authors report: "autistic and non-autistic adolescent boys reported their friendship and conflict experiences as highly similar – activity-focused, practically supportive friendships combined with a laissez-faire attitude to conflict. The exception to this pattern was that neurotypical boys described more intimate friendship experiences than their autistic male counterparts."

Cumulatively the Sedgewick findings reinforce the idea that there may be some subtle but important differences between boys and girls, women and men diagnosed with autism (see here). In this light, the suggestion that "autistic girls (and possibly women) need different strategies and supports to understand and effectively navigate the social expectations placed upon them" is correct when compared to males diagnosed with autism. The results suggesting however, little significant differences in friendships and social experiences between autistic girls and non-autistic girls (and autistic boys and non-autistic boys) kinda grates against some of the narratives that have emerged in recent years. It implies that rather than viewing someone as an 'autistic girl' one should perhaps first focus on that person as a girl when it comes to social experiences and friendships rather than subscribing to the idea that autism is wholly 'behind' any issues as some 'identity' discussions have intimated. The findings also imply that camouflaging and masking are not necessarily exclusive features of autism but, perhaps in some contexts, are rather more representative of a general effect specifically across gender.

I would like to see a lot more research done in this area. I'd like to see more longitudinal work done looking at friendships and social experiences into adulthood with autism in mind, where other environments replace the school playground (including the online and social media environments). I'd like to know about how friendships develop, persist or 'fall to one side' and whether other 'comorbidity' (see here), that more likely than not will 'follow' a diagnosis of autism (see here), play any role in such social experiences. I'd also like to see further work on societal inclusion (see here) in the context of the Sedgewick research too. There is a scheme of work to do.

And let us also not forget that learning the intricacies of things like friendships and social experiences or challenges such as conflict are also influenced by other important variables, such as a role for siblings [2] (for better or for worse)...

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[1] Sedgewick F. et al. 'It's different for girls': Gender differences in the friendships and conflict of autistic and neurotypical adolescents. Autism. 2018 Oct 3:1362361318794930.

[2] Ben-Itzchak E. et al. Having Siblings is Associated with Better Social Functioning in Autism Spectrum Disorder. J Abnorm Child Psychol. 2018 Oct 3.

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Tuesday, 9 October 2018

MDMA-assisted psychotherapy for the "reduction of social fear and avoidance that are common in the autistic population"

I approach the findings reported by Alicia Danforth and colleagues [1] (open-access available here) very, very carefully. Their preliminary observations on the use of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in the context of adult autism, specifically "to reduce social anxiety" require a lot more follow-up work before anyone gets too carried away. Not least because MDMA or "chemical entities represented as containing MDMA" is categorised as a drug of abuse.

OK, first things first: what is "MDMA-assisted psychotherapy for reduction of social fear and avoidance"? Well, MDMA is  more commonly known as Ecstasy or Molly/Mandy in drug circles. Its effects include "producing feelings of increased energy, pleasure, emotional warmth, and distorted sensory and time perception" thought to be due to its chemical activity on various neurotransmitters (and related biology) such as dopamine and serotonin. Here in Blighty it's currently listed as a Class A drug of abuse alongside things like cocaine and heroin.

MDMA-assisted psychotherapy aims to utilise some of those, and other, behavioural effects associated with recreational MDMA drug use to help further the aims of psychotherapy (talking therapy). Danforth et al have previously published on some of the background behind such a notion [2] specifically in the context of 'treating' social anxiety comorbid to autism. And just before you say/think anything, anxiety and autism is most definitively a 'happening topic' at the moment (see here and see here for examples).

Their most recent publication discusses the results of a small clinical trial of MDMA-assisted psychotherapy with 12 adults with autism. The study details were held on ClinicalTrials.gov (see here) albeit with the published paper listing the wrong trial entry. Authors used a "randomized, placebo-controlled, double-blind methodology for this exploratory phase 2 single-site study conducted from February 2014 through April 2017." MDMA was 'synthesised' and compounded into capsules alongside placebo (dummy) capsules containing lactose (I'm assuming that none of the participants were lactose intolerant given the emerging data on lactose issues and autism [3]). Then: "After three 60- to 90-min non-drug preparatory psychotherapy sessions, participants received two blinded experimental sessions with MDMA or placebo, spaced approximately 1 month apart." Said psychotherapy sessions were described as "standardized mindfulness-based therapy adapted from dialectical behavioral therapy (DBT)." Various assessments of behaviour and physiology were used during the study to ascertain any effect. Importantly too, authors describe their use of various instruments to pick up any adverse side-effects including that related to suicidality.

Results: this was a small study. Although 12 participants were enrolled and entered the study, only data for 11 were available as the authors remarked that a participant "enrolled with hypertension and pre-study substance use disorder within exclusion window for enrollment." Researchers reported however that scores on their primary outcome measure - The Liebowitz Social Anxiety Scale (LSAS) - showed evidence of "rapid and durable improvement in social anxiety symptoms in autistic adults following MDMA-assisted psychotherapy." They also commented that: "Reductions were retained for the MDMA group at 6-month follow-up compared to primary endpoint, supporting durability of improvements." And participants themselves in their subjective reporting also communicated similar sentiments regarding the use of MDMA-assisted psychotherapy as per accounts of "reduced barriers to successful social interactions and increased confidence in school, at work, in friendships, and in romantic relationships."

Then: "No SAEs [serious adverse events] were reported on this study." That's good but doesn't mean that no adverse events were reported following the use of MDMA-assisted psychotherapy, as anxiety and 'depressed mood' were listed as "treatment-emergent psychiatric adverse events" and not specifically seen in the placebo group. Also: "Suicidal ideation was the most commonly reported AE; however, prevalence was similar across groups (25.0% both groups) and was pre-existing in medical history." In other words, one needs to be a little cautious about using MDMA in this context as in other contexts.

Caveats? I've already mentioned the small participant group included for study, which kinda 'down-grades' the levels of positive effects noted by Danforth and colleagues. I was also drawn to another sentence in their paper - "Both groups in this study received the same type of psychotherapy with encouragement toward self-directed healing and meaning-making" - and a niggling question I have about how one is able to ensure that both experimental and control groups received the same type/magnitude/experience of psychotherapy. I say this in the context that DBT seems to have a lot of different 'elements' to it (see here) which are perhaps not easily tested/compared under controlled conditions. Perhaps next time authors could think about including a cross-over portion to their trial too?

That all being said, I'm still [cautiously] interested in the findings presented by Danforth and what research is yet to come on this topic. I've said it a few times on this blog about how anxiety is a real quality-of-life-drainer in many contexts but specifically with autism in mind, the evidence is pretty strong for an important effect. Anything that could safely and reliably help those who are confronted with such issues (and perhaps other issues too?) should be explored objectively and dispassionately.

And on the topic of MDMA, whoever thought it would be a good idea to give to an octopus in the name of science?

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[1] Danforth A. et al. "Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study". Psychopharmacology. 2018. Sept 8.

[2] Danforth AL. et al. MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2016; 64: 237-249.

[3] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

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Monday, 8 October 2018

On autism symptom trajectories and diagnosing autism late...

It's another one of my mash-up posts today, as two paper are brought to the blogging table. The first paper is from So Hyun Kim and colleagues [1] and looked at the rather interesting topic of differing symptom trajectories in the context of diagnosing autism. The second paper by Sally Ozonoff and colleagues [2] follows in a similar vein in terms of their analysis of children "who had undergone multiple comprehensive assessments in preschool and were determined to be ASD [autism spectrum disorder]-negative, only to meet criteria for ASD when tested in middle childhood."

Both these paper originate from well-respected autism research groups and appear in the same respected journal (Journal of the American Academy of Child & Adolescent Psychiatry). The common theme between them is that within the significant heterogeneity seen under the label of 'autism', there are various different developmental and presented symptoms trajectories, some of which (a) are not as stable as one might imagine, and (b) do not seemingly follow the oft-used assertion that 'autism is present and manifests from birth'. Indeed, on that last point, the implications are that autism is sometimes very much associated with regression (see here) and onward, that genetic and/or non-genetic post-natal factors may very well influence some children reaching clinical cut-off thresholds for a diagnosis of autism (see here for example).

So, to the Kim paper first: authors looked at over 900 "observations of the Autism Diagnostic Observation Schedule (ADOS)" from nearly 150 young children. They were specifically looking at symptoms trajectories based on those ADOS scores and whether or not 'clusters' of similar symptom trajectories were evident. The answer: yes, yes there were some different clusters of symptom trajectories noted. Not six developmental trajectories as per other research (see here) but four clusters: "Nonspectrum ∼25%; Worsening ∼27%; Moderately-Improving ∼25%; Severe-Persistent ∼23%)." Authors also report how: "Trajectory clusters varied significantly in the proportions of confirmatory ASD diagnosis, the level of baseline and final verbal/nonverbal abilities, and symptom severity."

Then to the Ozonoff paper: "Fourteen children met inclusion criteria for the Late Diagnosed group and were compared to a large sample of high- and low-risk siblings from the same sites who had ASD or typical development (TD) outcomes at age 3." Authors focused in on these 14 children and concluded that: "Seven showed very little evidence of ASD in preschool, while seven demonstrated subtle, subthreshold symptomatology." They also suggest that their results identifying a small but important group of children who seemingly first present with 'typical' behaviour but then 'grow into' the presentation of autism "shed light on reasons why the mean age of ASD diagnosis remains over 4 years." Indeed (see here).

I don't really need to say much more than I have already on these studies. Aside that is, from reiterating that the autism spectrum is truly wide and heterogeneous in both symptom presentation and also it seems, with regards to symptom onset and stability too. Alongside other research (see here) talking about how the presentation of autistic signs and symptoms wax and wane for some, I'm wondering when autism research is going to start looking beyond just presented behaviour, at whether for example, genetic and biological 'changes' might accompany such fluidity in behaviour and 'cluster' differences. Y'know, the same way that another group seemingly heading in the opposite direction - those who 'lose their diagnosis' (see here and see here) - also need to be closely investigated from a biological point of view too. It's only when we have such biological data that we can then start meaningfully probing the possible hows-and-whys...

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[1] Kim SH. et al. Variability in Autism Symptom Trajectories Using Repeated Observations from 14 to 36 Months of Age. Journal of the American Academy of Child & Adolescent Psychiatry. 2018. Sept 5.

[2] Ozonoff S. et al. Diagnosis of Autism Spectrum Disorder After Age 5 in Children Evaluated Longitudinally Since Infancy. Journal of the American Academy of Child & Adolescent Psychiatry. 2018. Sept 3.

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Saturday, 6 October 2018

"C-Reactive Protein as a Peripheral Biomarker in Schizophrenia"

The results of the 'updated systematic review' published by Guillaume Fond and colleagues [1] looking at the "relationships between elevated blood C-reactive protein (CRP) levels and schizophrenia (SZ) onset risk, illness characteristics and treatments, cognition and physical health" provides the blogging fodder today.

Fond (a name not unfamiliar to all-things schizophrenia) et al dip into a topic with more than its fair share of research 'uncertainty' (see here and see here for examples) on whether or not C-reactive protein (CRP), a marker of systemic inflammation, shows a connection to schizophrenia. On this particular research occasion, no new data is added to the debate, but rather authors looked at the collected peer-reviewed data (up to November 2017) to see if any 'general opinions' could be discerned from the collected works.

Results: based on over 50 studies included in their review, authors concluded that it was 'reasonable' to assume that high-sensitivity CRP (hs-CRP) may be a marker for 'schizophrenia onset risk'. The caveat to that statement is that CRP is probably not something 'schizophrenia-specific' in terms of elevations of CRP being indicative of a inflammatory state. So increased hs-CRP may well be a risk factor for "increased positive symptoms, cognitive impairment, hypovitaminosis D, microbiota disturbances, cardiovascular and metabolic syndrome risk in SZ subjects, and increased nicotine dependence in SZ smokers."

I'm pretty happy with the Fond results and interpretation as they stand. They suggest that CRP probably does show some sort of connection to schizophrenia and onward, points to an immune system connection to at least some cases (see here and see here). At the same time, they also imply that certain other observations around schizophrenia - such as a link with certain physical health issues (see here) and/or vitamin D deficiency (see here) - probably also contribute to the elevations of CRP noted in relation to cases of schizophrenia. They also imply that moves to reduce levels of CRP in relation to schizophrenia may well have various other 'knock-on' effects on those other risk factors associated with the condition/diagnosis. This 'double hit' effect could be quite useful.

And with that last sentence in mind, and accepting that consistently high levels of CRP are probably good for no-one, the next question: what can we do about elevated CRP levels in relation to schizophrenia and further, the immune system issues also being co-expressed? Lots, is my impression; perhaps also learning from other labels where immune function (and dysfunction) has been noted [2] and intervention is similarly indicated.

And there's more to come from this authorship group on this blog soon...

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[1] Fond G. et al. C-Reactive Protein as a Peripheral Biomarker in Schizophrenia. An Updated Systematic Review. Front. Psychiatry. 2018. Aug 23.

[2] Marchezan J. et al. Immunological Dysfunction in Autism Spectrum Disorder: A Potential Target for Therapy. Neuroimmunomodulation. 2018 Sep 5:1-20.

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Friday, 5 October 2018

ALSPAC says... frequency of depression during pregnancy has increased over time

Yes, it's yet another 'ALSPAC [Avon Longitudinal Study of Parents and Children] says...' post today, and the findings reported by Rebecca Pearson and colleagues [1] observing that "prenatal depression is on average 51% more common among young mothers in the current generation of the ALSPAC cohort than during their mothers’ generation 25 years ago."

Having already attracted some media attention (see here), the aim of the current study was to "compare prenatal depression prevalence in young women across time." Because ALSPAC is a longitudinal study (following participants across some quite long periods of time) also involving several generations of the same families, it was ideally placed to compare depressive symptoms during pregnancy across different temporal cohorts.

And compare it did, as responses to the Edinburgh Postnatal Depression Scale (EPDS) were analysed from those in the original ALSPAC cohort participating in the early 1990s (N=2390) compared with those second-generation ALSPAC participants (G1: 2012-2016, N=180), including "66 mother-offspring pairs." All participants were aged between 19-24 years of age at the time of pregnancy assessment and, to reiterate, all "had the same measure of prenatal depression assessed at approximately the same time in pregnancy."

Results: well, alongside some potentially important differences between the two cohorts - "ALSPAC-G1 women were more likely to have achieved A-Levels and were less likely to smoke, but were more likely to take antidepressants" - the study suggested that reaching cut-off scores on the EPDS (≥13) was about 50% more likely in the G1 (younger) cohort. The strength of this 'association' actually increased when researchers took into account other variables potentially likely to affect the study results such as "age, BMI, smoking, parity, and education." They also noted that: "Restricting the analyses to the 66 mother-offspring pairs and accounting for clustering of pairs, we found a virtually identical association, but with wider a confidence interval."

Caveats? Well, one needs to remember that this was a study based on one self-report questionnaire which includes 10 questions answered on a scale from 'not at all' to 'most of the time' (or something similar). It's useful in the context of depression over the course of pregnancy but, as per the instructions for completion, only provides a snapshot (over the past 7 days), so please keep that in mind. The authors are also quite specific in their discussion about the applicability of their results, bearing in mind the age of their cohort(s) and the fact that: "The ALSPAC population largely consists of white European individuals."

That all being said, the findings are interesting and certainly worthy of further inspection and study. The authors go through the possible hows-and-whys of their findings; heading down the path that something(s) in the environment has changed over the decades and could be related to mechanisms. So: "This [younger] generation of young women has also experienced rapid change in technology, internet, and social media use, which has been associated with increased feelings of depression and social isolation and changes to social relationships." They also mention words like 'chronic stress' and 'sedentary lifestyle' as perhaps influencing the wider increase in depression that seems to be present these days. Whilst important (see here for example), I'm not totally convinced that the rise in depression or depressive symptoms is necessarily just a product of such modern living. Take 'chronic stress' for example; are we saying that young mothers-to-be are more stressed now than during the 1990s? I'm also minded to point out that the physical environment has also changed somewhat in the intervening years, as per the comment by the authors about G1 women being "more likely to take antidepressants." I don't doubt that there have been other 'chemical' changes too; some of which might be important.

Oh, there's another possibility too: I've talked about research using the EPDS before on this blog (see here). On that particular research occasion [2] an observation was made suggesting that "pregnant women with broader autism phenotype (BAP) showed an increased risk for developing postpartum depression (PPD)." Not to try and make connections where none may exist, but I'm wondering whether Pearson et al or someone else from ALSPAC might want to have a look-see whether this could be relevant to their current findings. Well, it's not as if ALSPAC don't have data on autistic traits for example (see here) and set against more recent ALSPAC research findings (see here), there's another hypothesis to be tested.

And as if to prove a point, the findings reported by Hirokawa and colleagues [3] observing that the BAP and postpartum depression might be *linked* should also be [carefully] introduced as part of the research conversation...

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[1] Pearson MR. et al. Prevalence of Prenatal Depression Symptoms Among 2 Generations of Pregnant Mothers. JAMA Network Open. 2018; 1: e180725.

[2] Asano R. et al. Broader autism phenotype as a risk factor for postpartum depression: Hamamatsu Birth Cohort (HBC) Study. Research in Autism Spectrum Disorders. 2014; 8: 1672-1678.

[3] Hirokawa K. et al. Associations between broader autism phenotype (BAP) and maternal attachment are moderated by maternal postpartum depression when infants are one month old: A prospective study of the Japan environment & children's study. J Affect Disord. 2018 Sep 19;243:485-493.

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