Autism and altered levels of essential fatty acids

Brigandi et al. 2015. Int. J. Mol. Sci. 16: 10061-10076.

A quote to begin this post is taken from the paper by Sarah Brigandi and colleagues [1] (open-access available here): "Our study demonstrates an alteration in the PUFA [polyunsaturated fatty acids] profile and increased production of a PUFA-derived metabolite in autistic patients, supporting the hypothesis that abnormal lipid metabolism is implicated in autism."

The Brigandi results were based on the analysis of blood samples for fatty acid content for "121 autistic patients and 110 non-autistic, non-developmentally delayed controls, aged 3-17." Participants with autism met DSM-IV criteria and CARS scores for autism although did not include those "on the broader autism spectrum" diagnosed with Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) for example.

Using various analytical techniques including gas chromatography and liquid chromatography-mass spectrometry (LC-MS), authors assayed for various fatty acids (saturates, monosaturates and polyunstaurates) and also levels of that "PUFA-derived metabolite" prostaglandin E2 (PGE2) a "pro-inflammatory AA [arachidonic acid] metabolite" that "increases the risk of neuroinflammation which can lead to excessive production of reactive oxygen species (ROS)." For some further background you might wish to have a look at a previous occasion that PGE2 has been discussed on this blog (see here) and another occasion covering ROS (see here).

Results: "a number of PUFA, mainly AA and DHA [docosahexaenoic acid], were significantly lower in autistic individuals than controls." DHA, by the way, is known as an omega-3 fatty acid, so called because of the specific positioning of a chemical double bond in its chemical arrangement. Alongside another omega-3 fatty acid called eicosapentaenoic acid (EPA), this is the stuff that is usually listed as the active ingredient in the various fish oil supplements that you find dotted around these days.

When it came to levels of PGE2, Brigandi et al report some really quite interesting results albeit based on the analysis of considerably smaller participant groups (autism n=20 and controls n=20). So: "All control samples were under the detection limit for PGE2 detection of <0.71 ng/mL." The same however could not be said for the autism group where "PGE2 levels were detected in 9 of the 20 plasma samples from autistic individuals, ranging from 1.21 to 3.91 ng/mL." This was translated as a "marked difference" between the groups.

Just before I head into what these results *might* mean, it's worthwhile pointing out a few caveats surrounding the Brigandi study. As the authors report: "we did not conduct an age-matched nor gender-matched analysis between the autistic and control groups." Fair enough, so we can't rule out those factors impacting on the results obtained. Further: "Fasting was not a requirement prior to blood draws" and authors "did not collect dietary information from study participants." This last point in particular combines with a perhaps a too sweeping generalisation from the authors that they "do not expect dietary differences between the groups to be a primary explanation" for some of their results. Diets can and do differ when it comes to autism [2] and sometime in the most serious ways (see here). One needs to be very mindful of that fact more so when it comes to actual fat intake in cases of autism [3].

That all being said, I do think that these results invite much further study of fatty acids and autism (some autism) on top of quite a bit of other research in this area [4]. As per my previous posts in this area, the collected data so far on supplementing fatty acids in cases of autism is not exactly 'concrete' in terms of effectiveness (see here). Whereas an important comorbidity noted in quite a few cases of autism, ADHD (attention-deficit hyperactivity disorder) in whole or in part, is enjoying some rather more positive findings (see here and see here) indeed, even more generally [5], core autism does not seem to be benefiting as much from the supplementation side of things. It could be worthwhile focusing less on syndromes and more on symptoms [6] when it comes to supplementation as per the idea that fatty acids might be [partially] linked to things like reading ability (see here) or even with critical periods of requirement [7] in mind but I'd like to see a lot more science done on this first. That also includes looking at other potential biological correlates too [8]...

Maybe the VIDOMA study will provide a little more insight?

Music: Sheppard - Geronimo.

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[1] Brigandi SA. et al. Autistic Children Exhibit Decreased Levels of Essential Fatty Acids in Red Blood Cells. Int J Mol Sci. 2015 May 4;16(5):10061-10076.

[2] Kuschner ES. et al. A preliminary study of self-reported food selectivity in adolescents and young adults with autism spectrum disorder. Research in Autism Spectrum Disorders. 2015; 15-16: 53-59.

[3] Marí-Bauset S. et al. Fat intake in children with autism spectrum disorder in the Mediterranean region (Valencia, Spain). Nutr Neurosci. 2015 May 28.

[4] Bell JG. et al. Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders? Prostaglandins Leukot Essent Fatty Acids. 2000 Jul-Aug;63(1-2):21-5.

[5] Raine A. et al. Reduction in behavior problems with omega-3 supplementation in children aged 8–16 years: a randomized, double-blind, placebo-controlled, stratified, parallel-group trial. Journal of Child Psychology & Psychiatry. 2015; 56: 509-520.

[6] Bent S. et al. Internet-based, randomized, controlled trial of omega-3 fatty acids for hyperactivity in autism. J Am Acad Child Adolesc Psychiatry. 2014 Jun;53(6):658-66.

[7] van Elst K. et al. Food for thought: dietary changes in essential fatty acid ratios and the increase in autism spectrum disorders. Neurosci Biobehav Rev. 2014 Sep;45:369-78.

[8] Mostafa GA. et al. A possible association between elevated serum levels of brain-specific auto-antibodies and reduced plasma levels of docosahexaenoic acid in autistic children. J Neuroimmunol. 2015 Mar 15;280:16-20.

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Brigandi SA, Shao H, Qian SY, Shen Y, Wu BL, & Kang JX (2015). Autistic Children Exhibit Decreased Levels of Essential Fatty Acids in Red Blood Cells. International journal of molecular sciences, 16 (5), 10061-10076 PMID: 25946342

Reduced rumination and aggressive thoughts from a probiotic?

I've taken my time to come to discussing the findings from Laura Steenbergen and colleagues [1] (open-access) providing "the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood." It's not that I didn't find such results to be really interesting and having potential for quite a few different areas of psychiatry, but rather that other blogging topics have popped up in the meantime. No mind, we're here now.

Based on a growing evidence base suggesting that those trillions of wee beasties which call our gastrointestinal (GI) tract home might be doing so much more than helping us to digest our food and produce the odd vitamin or two [2], Steenbergen et al set about looking at whether probiotic supplementation "may reduce cognitive reactivity in non-depressed individuals." Just in case you need further explanation about what was being tested, we are told that: "Cognitive reactivity refers to the activation of dysfunctional patterns of thinking that are triggered by subtle changes in mood, such as ruminative (e.g., recurrent thoughts about possible causes and consequences of one’s distress), aggressive (e.g., to think about hurting others or oneself), hopelessness (e.g., loss of motivation and expectations about the future), and/or suicidal thoughts (e.g., to think that one’s death is the only way to end the suffering)." The probiotic under examination was a mixture called 'Ecologic®Barrier' - "a multispecies probiotic containing Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, and Lactococcus lactis (W19 and W58)." This is also not the first time that this preparation has been looked at by some authors on the Steenbergen paper either [3].

Using a "triple-blind, placebo-controlled, randomized, pre- and post-intervention assessment design" - triple blind meaning that group allocator, participants and outcome assessor were all blinded as to whether participants were given Ecologic®Barrier or a placebo (maize starch and maltodextrins) - researchers examined data for two groups of young adults (approximately 20 years of age) allocated to either probiotic (n=20) or placebo (n=20) over 4 weeks. All participants were described as 'healthy' with "no reported cardiac, renal, or hepatic conditions, no allergies or intolerance to lactose or gluten, no prescribed medication or drug use, and who reported to consume no more than 3–5 alcohol units per week participated in the study." They were also all non-smokers. Also: "No information was provided about the different types of intervention (probiotics vs. placebo) or about the hypotheses concerning the outcome of the experiment." Mood and "dysfunctional thoughts" were assessed pre- and post intervention/placebo using the Leiden Index of Depression Sensitivity (LEIDS-r), the Beck Depression Inventory II (BDI-II) and the Beck Anxiety Inventory (BAI) and off they went.

Results: bearing in mind that "cognitive reactivity is an important vulnerability marker of depression", authors reported that "a 4-week multispecies probiotic intervention reduced self-reported cognitive reactivity to sad mood, as indexed by the LEIDS-r." Specifically, scores on the rumination and aggression scales seemed to be most positively affected "indicating that in the probiotics supplementation condition participants perceived themselves to be less distracted by aggressive and ruminative thoughts when in a sad mood." Various other parameters also seemed to be affected by probiotic administration but these did not reach statistical significance.

Just before however you rush out to buy a probiotic with the hope that your mood might be lifted and your ruminating somehow quashed, there are a few important caveats to note about the Steenbergen findings. First and foremost is their quite small participant group who were self-reporting. Self-report is a good tool when it comes to analysing a person's psychology, thoughts and feelings but is very dependent on the schedule used and how it 'grades' something like rumination or aggression. Normally, these are done in the form of statements and a Likert scale. The Steenbergen study did not rely on other 'objective' measurements.

Second: "we did not include dietary measures and did not control for consumption of other probiotic products or fermented foods (e.g., yogurt)." From that point of view, we don't know whether simple dietary changes might also have exerted some effect on the results obtained. Indeed, whether illness or even natural biology - "Female participants were not controlled for the menstrual cycle" - might also have affected results bearing in mind that most participants were female.

Finally is the issue of compliance and the lack of objective data on who actually stuck to the 4-week regime and how rigidly. By saying all this, I'm not trying to poo-poo the results, just highlighting limitations.

Still with those caveats in mind, the Steenbergen results are a potentially important addition to the idea that gut bacteria might have some interesting effect on psychology (psychobacteriomics as I like to call it) as per the recent JAMA review [4]. Whether there may be wider implications for the current results, perhaps overlapping with other research suggestions about probiotic administration and psychology/behaviour (see here) remains to be seen. Further inspection of the potential mechanisms of effect including the gut microbiota as part of the triad of gut barrier function and gut immunity are also indicated bearing in mind previous data on something like depression and the inner workings of the gut (see here).

Oh, and I'll be coming to the paper by Lisa Christian et al [5] on gut bacteria and toddler temperament quite soon...

Music: LunchMoney Lewis - Bills.

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[1] Steenbergen L. et al. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain, Behavior, and Immunity. 2015. April 7.

[2] Magnúsdóttir S. et al. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Front Genet. 2015 Apr 20;6:148.

[3] Van Hemert S. & Ormel G. Influence of the Multispecies Probiotic Ecologic® BARRIER on Parameters of Intestinal Barrier Function. FNS. 2014; 5: 1739-1745.

[4] Friedrich MJ. Unraveling the Influence of Gut Microbes on the Mind. JAMA. 2015; 313: 1699-1701.

[5] Christian LM. et al. Gut microbiome composition is associated with temperament during early childhood. Brain, Behavior, and Immunity. 2015; 45: 118-127.

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Steenbergen L, Sellaro R, van Hemert S, Bosch JA, & Colzato LS (2015). A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain, behavior, and immunity PMID: 25862297

The autisms, case reports and two 'intervention' options

I'm looking at two papers today which I'd like to think cover the title of this post pretty well dealing with the plurality of autism - the autisms - and the idea that intervention or management-wise, there is no 'one size fits all' when it comes to the autisms.

First up are the findings reported by Ziats and colleagues [1] who presented results for a child - "A 4-year-old male with autism and two episodes of neurodevelopmental regression" - who was also found to have a "mutation in the TMLHE gene, which encodes the first enzyme in the carnitine biosynthesis pathway, and concurrent carnitine deficiency." Supplementation with carnitine (see here) seemed to lead to some interesting changes in the developmental profile for this boy such that: "the patient's regression ended, and the boy started gaining developmental milestones."

Accepting that this was another example of the N=1 and autism (see here) I was rather interested in these results having previously blogged about issues with the TMLHE (trimethyllysine hydroxylase) gene in relation to autism (see here). The source of that previous post was the paper from Patricia Celestino-Soper and colleagues [2] (open-access) who concluded that: "TMLHE deficiency is a risk factor for autism" and quite a bit more should be done to screen for such issues. I wouldn't disagree with those sentiments (see here).

Next up are the results reported by Serret and colleagues [3] (open-access) who presented findings based on two participants "diagnosed with autism spectrum disorders in childhood and presented regression with catatonia features and behavioural disorders after a stressful event during adolescence." Further: "both patients presented mutation/microdeletion of the SHANK3 gene, inducing a premature stop codon in exon 21." Issues with SHANK3 have been reported in relation to autism previously.

Authors reported that: "lithium therapy reversed clinical regression, stabilized behavioural symptoms and allowed patients to recover their pre-catatonia level of functioning, without significant side effects." Further: "These cases support the hypothesis of a specific SHANK3 phenotype" and that lithium might hold some favour in improving clinical presentation in those cases.

Again, I was interested in the Serret findings with the caveat about their also using the case study approach in their paper. Lithium is an interesting compound that has graced this blog a few times in relation to its potential 'anti-suicide' correlating properties (see here) and as a possible management tool when it comes to the presentation of mood disorders comorbid to a diagnosis of autism (see here). Accepting that lithium has its own potential side-effects profile, the idea that cost-benefits might be calculated and if so deemed more benefit and less cost subsequently applied to 'some' autism, is an interesting prospect.

Reiterating my opening paragraph, what the Ziats and Serret papers serve to tell us is that within 'the autisms' there may be many different roads to a diagnosis of autism and that under the diagnostic label of 'autism', genetics, biochemistry and subsequent intervention/management strategies may vary from person to person. As I've said before, receipt of a diagnosis of autism (when it is eventually received) should be a starting point for further inquiry not the 'finishing line'.

That comorbidity - if I can still call it that - might also be a 'target' for analysis and investigation is also an important point raised and further asks more questions about the value of intervening on said comorbidity and the possible knock-on effects on the presentation of more core autism symptoms (see here). Y'know something like what is emerging in the body of research looking at anxiety and autism (see here).

With the body of work linking this, that and t'other to autism I'm starting to think that some further resources might be needed to pull all the available peer-reviewed information together in terms of what factors have been linked to those 'autisms'. I've always been very partial to autism research looking at inborn errors of metabolism (IEMs) as a starting point for investigations (see here) given both the data on overlap and even the idea that some of the various interventions for specific IEMs might hold promise for 'some' autism (see here). Analysis of things like rare genetic variations also being linked to the appearance of autism (see here) ties into the IEM investigations and perhaps represents the next tier of evaluation, bearing in mind the reduced costs of things like whole genome sequencing these days set within the perspective of personalised medicine (see here). Environment, bearing in mind the range of factors this might cover, should also be included in any diagnostic work-up based on the evolving science connecting something like infection to autism onset for some (see here and see here). There are various tests that could be performed covering a whole slew of potential infective agents (see here).

This is just a rough-and-ready idea of where autism research and practice could go with this but much like the pathways to diagnosing and managing bowel issues when comorbid to autism for example (see here), a general diagnostic roadmap is perhaps indicated...

Music: Years & Years - King.

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[1] Ziats MN. et al. Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation. Am J Med Genet A. 2015 May 5.

[2] Celestino-Soper PB. et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci U S A. 2012 May 22;109(21):7974-81.

[3] Serret S. et al. Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports. BMC Psychiatry 2015, 15:107.

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Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, & Schaaf CP (2015). Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation. American journal of medical genetics. Part A PMID: 25943046




Serret, S., Thümmler, S., Dor, E., Vesperini, S., Santos, A., & Askenazy, F. (2015). Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports BMC Psychiatry, 15 (1) DOI: 10.1186/s12888-015-0490-1

Predicting the onset of schizophrenia?

"A lower level of inflammatory response indicated by PTX3 [pentraxin-3] might be implicated in developing schizophrenia."

That was the primary conclusion reported by Natalya Weber and colleagues [1] (open-access here) who "tested preonset serum specimens from 160 US military service members who were later diagnosed with schizophrenia or bipolar disorder and 160 matched controls without psychiatric disorders."

PTX-3 by the way, is a compound of some note when it comes to the concept of inflammation, residing in the same family as a better known inflammatory-related compound, C-reactive protein (CRP) (see here). The difference between CRP and PTX-3 seems to be down to CRP being a 'short' pentraxin and PTX-3 being a 'long' one.

Weber et al assessed levels of PTX-3 in "first available serum specimens" of 160 military personnel who were "later diagnosed with schizophrenia or bipolar disorder" (n=80 respectively) and compared them with 160 matched controls. As per other work by authors on the Weber paper [2], using military cohorts has some significant advantages when it comes to potential biomarker work in this area (see here). They reported that: "PTX3 levels among subjects with schizophrenia were significantly lower... than the levels among their paired controls" thus indicating that prior to the onset of schizophrenia, PTX-3 levels might be something to watch for risk of developing the condition. The authors even went as far as to say that: "a level of PTX3 below the median (0.6 ng/ml) was associated with an OR [odds ratio] of 3.0 (CI, 1.6–5.7)" when it came to risk of subsequent schizophrenia.

This is interesting data which, as the authors point out, is strengthened by "including the follow-up of an initially disease-free population with subsequent complete and reliable case/control ascertainment" alongside the collection of biological samples "years before disease onset". Military personnel are screened and screened over their time serving, thus making this population about as valuable to research as all those archived newborn bloodspot cards that I'm so interested in (see here). The authors do caution that their results may not be entirely generalisable to the population at large as a result of their 'captive audience' (how many civvies spend their days like military personnel?) but the strengths of the study perhaps outweigh the limitations.

The idea that the immune system and the orchestration of its arsenal of compounds might be perturbed when it comes to a behavioural/psychiatric condition like schizophrenia is by no means a new idea (see here for example). That being said, science is still fumbling around trying to make sense of the idea that immune function / inflammation might impact on something like schizophrenia and the specific hows and whys of the relationship. Weber et al do speculate on what their results might mean as per comments that: "Long-lasting or temporal lack of PTX3 could potentially impact pathogen recognition, activation, and orientation of the adaptive immune response and/or antibody production." Further: "Impairment of any of these functions, particularly those where PTX3 plays its unique role, could lead to a vulnerability to the neurotropic pathogens associated with schizophrenia and bipolar disorder." Part of those 'neurotropic pathogens' must surely include the body of work referring to a possible role for Toxoplasma gondii in relation to some schizophrenia (see here).

Interestingly also the authors talk about how their findings might relate to the issue of autoimmunity and how their findings might be contributory to immune system "derailment into a dysregulated state of autoimmune activation and damage." As per my discussions on autism and autoimmunity (see here for example) I do think there is a lot more to see in this particular area with schizophrenia also in mind (see here), perhaps also mediated by some interesting connections to the human endogenous retroviruses (HERVs) among other things. And yes, before you ask, HERVs have been implicated in cases of schizophrenia and perhaps even with the words 'molecularly mimicry' and 'superantigen' in mind [3].

More research in this area please.

Music: Björk - Hyperballad.

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[1] Weber NS. et al. Predictors of the Onset of Schizophrenia in US Military Personnel. J Nerv Ment Dis. 2015 May;203(5):319-24.

[2] Niebuhr DW. et al. Association between bovine casein antibody and new onset schizophrenia among US military personnel. Schizophr Res. 2011 May;128(1-3):51-5.

[3] Brodziak A. et al. The role of human endogenous retroviruses in the pathogenesis of autoimmune diseases. Med Sci Monit. 2012 Jun;18(6):RA80-8.

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Weber NS, Larsen RA, Yolken RH, Cowan DN, Boivin MR, & Niebuhr DW (2015). Predictors of the Onset of Schizophrenia in US Military Personnel. The Journal of nervous and mental disease, 203 (5), 319-24 PMID: 25919381

Health and adults on the autism spectrum

"Nearly all medical conditions were significantly more common in adults with autism, including immune conditions, gastrointestinal and sleep disorders, seizure, obesity, dyslipidemia, hypertension, and diabetes."

So said the study results from Lisa Croen and colleagues [1] who set out to "describe the frequency of psychiatric and medical conditions among a large, diverse, insured population of adults with autism in the United States." Said participant group was derived from the interrogation of data from Kaiser Permanente Northern California and included over 1500 adults with autism compared against 15,000 non-autistic controls. Diagnosis of autism, by the way, was via ICD-9 codes - "299.0, 299.8, 299.9" - that had to be mentioned at least twice in participants' medical records.

Alongside the over-representation of various medical conditions in participants diagnosed with autism, researchers also reported that: "Adults with autism had significantly increased rates of all major psychiatric disorders including depression, anxiety, bipolar disorder, obsessive-compulsive disorder, schizophrenia, and suicide attempts." They concluded: "Future research is needed to understand the social, healthcare access, and biological factors underlying these observations."

For many people either on the autism spectrum or interested in autism these data are not likely to be new news. That a diagnosis of autism might place someone at some heightened risk of both medical and psychiatric / behavioural comorbidity has been covered extensively on this blog (see here) with more data being published almost daily [2]. If there is some novelty allied to the Croen results, it is the shift to focusing on adult presentation and not just the descriptions of children on the autism spectrum. The additional idea that 'healthcare access' for example, might be something requiring a little more thought as a function of such results is something that has also been recently explored (see here).

As per other discussions about how 'optimal outcome' might not necessarily mean 'symptom-free' (see here) and the realisation that various comorbidity might be profoundly 'disabling' for quite a few people on the autism spectrum (see here), so the pace picks up on the notion that 'the label of autism does not appear in a diagnostic vacuum'...

Music: The Disposable Heroes of Hiphoprisy - Television, the Drug of the Nation.

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[1] Croen LA. et al. The health status of adults on the autism spectrum. Autism. 2015 Apr 24. pii: 1362361315577517.

[2] de Vinck-Baroody O. et al. Overweight and Obesity in a Sample of Children With Autism Spectrum Disorder. Acad Pediatr. 2015 Apr 30. pii: S1876-2859(15)00079-0.

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Croen LA, Zerbo O, Qian Y, Massolo ML, Rich S, Sidney S, & Kripke C (2015). The health status of adults on the autism spectrum. Autism : the international journal of research and practice PMID: 25911091

Ginkgo biloba for ADHD?

I approach the paper by Fereshteh Shakibaei and colleagues [1] with some degree of caution save any suggestions that I am somehow 'promoting' the herb Ginkgo biloba for attention-deficit hyperactivity disorder (ADHD) or anything else. I'm not, but I am interested in the results of their placebo-controlled trial suggesting that "The G. biloba is an effective complementary treatment for ADHD" and their subsequent calls for further research into this potentially promising intervention.

As per the Medline Plus entry for Ginko biloba, irrespective of your views on herbal remedies and health (have you never heard of pharmacognosy?), there is a growing evidence base suggesting that such a preparation might have a place in the management of quite a few conditions/diagnoses. The caveat being that (a) quite a bit more research is needed, and (b) much like more mainstream pharmaceutics, such herbs are not without their contraindications when it comes to their use alongside other medicines. Treat your herbs et al like you would your typical medicines is the best advice, bearing in mind I don't give medical or clinical advice on this blog.

Shakibaei et al reported results looking at a group of children/adolescents over 6 weeks already in receipt of pharmacotherapy for their ADHD symptoms - "methylphenidate (20-30 mg/day" - to which either G. biloba was added - "80-120 mg/day" - or a placebo. They report that based on responses to the "Parent and teacher forms of the ADHD Rating Scale-IV (ADHD-RS-IV)" (something I've come across in my own research) compared with the placebo group "more reduction was observed with G. biloba" illustrative of potential positive changes to symptoms. The specific area of 'inattention' seemed to be positively affected by the use of G. biloba. The commonplace 'further studies are required' sentence completes the Shakibaei results.

This is not the first times that G. biloba has been discussed in the peer-reviewed domain with ADHD in mind (see here). As per the 2009 review from Rucklidge and colleagues [2] (someone who knows a thing or two about supplements and ADHD) the jury is still out about G. biloba and it's possible effect with ADHD mind. Certainly, there are quite a few other candidate 'nutrient supplements' which seem to be performing quite a bit better than this herb (see here and see here for example).

That being said, I'd be interested to see what future research has to say about the usefulness of G. biloba with ADHD in mind, specifically from the angle of an adjuvant (add-on) treatment alongside more traditional pharmacotherapy. Again, I say this without in any way, shape or form 'promoting' such use at the current time and with the understanding that management of ADHD is likely to require quite a holistic approach.

Music: The Foo Fighters (who should be at the SoL anytime.... now).

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[1] Shakibaei F. et al. Ginkgo biloba in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. A randomized, placebo-controlled, trial. Complement Ther Clin Pract. 2015 Apr 18. pii: S1744-3881(15)00029-8.

[2] Rucklidge JJ. et al. Nutrient supplementation approaches in the treatment of ADHD. Expert Rev Neurother. 2009 Apr;9(4):461-76.

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Shakibaei F, Radmanesh M, Salari E, & Mahaki B (2015). Ginkgo biloba in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. A randomized, placebo-controlled, trial. Complementary therapies in clinical practice PMID: 25925875

Psychological morbidity of coeliac disease

"Anxiety, depression and fatigue are common complaints in patients with untreated celiac disease and contribute to lower quality of life."

That was one of the conclusions reached in the paper by Fabiana Zingone and colleagues [1] (open-access available here) following their review of the research literature "on psychological morbidity of celiac disease." Celiac (coeliac) disease (CD), by the way, is the autoimmune condition classically treated via the use of a gluten-free diet (GFD). Readers might wish to peruse my training post on the condition for some further background information about some of the known 'hows and whys' (see here) as well as other posts on what we don't know about CD (see here) (hint: quite a bit).

The Zingone paper is open-access so it doesn't require any grand discussions from me at this point. "Our search of the available literature suggests that CD has a considerable psychological impact" is another way the authors discuss their findings and I for one, would not argue with such sentiments on potential extraintestinal manifestations of the condition. Importantly, they make a distinction between whether such 'psychological impact' may directly derive from having the disease itself or other reasons potentially relating "to the patient’s subjective perception of the disorder and of the GFD used to treat it."

I was also taken by some of the 'clinical implications' listed by the authors when it comes to the 'considerable psychological impact' including that: (1) "GFD improves quality of life (QoL) in symptomatic patients, but not always in asymptomatic patients", (2) "Anxiety and depression may affect dietary adherence and QoL" and (3) "Fatigue is sometimes the unique symptom at CD presentation."

Point (1) taps into the idea of a better cost-benefit profile from the use of a GFD when people actually see such a diet improving their health and wellbeing. As per other rumblings on this blog, I might also suggest that this effect extends into some of the asymptomatic group too (see here). Point (2) raises an important issue that potential psychological effects associated with CD might have important implications for things like sticking to the diet. I wonder if that also includes those slightly outside of the classical presentation of CD too? Point (3) on fatigue as a possible 'unique' symptom of CD takes me back to a distant post titled 'gluten relations' and the idea that screening for CD or even the broader non-coeliac gluten sensitivity (NCGS) might be indicated in a few 'fatigue-linked' conditions including cases of chronic fatigue syndrome / myalgic encephalomyelitis (CFS / ME) (sorry, SEID). By saying that I'm not making any value judgements about SEID simply being CD or vice-versa, merely that within the spectrum of fatigue-manifesting conditions, one might find one or two surprising results [2] as you might in other conditions too [3].

Yet after all that, mass screening for CD is still not indicated? [4]

Music: Muse - Plug In Baby.

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[1] Zingone F. et al. Psychological morbidity of celiac disease: A review of the literature. United European Gastroenterol J. 2015 Apr;3(2):136-45.

[2] Isasi C. et al. Fibromyalgia and chronic fatigue syndrome caused by non-celiac gluten sensitivity. Reumatol Clin. 2015 Jan-Feb;11(1):56-7.

[3] Gadoth A. et al. Transglutaminase 6 Antibodies in the Serum of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2015. April 13.

[4] Ludvigsson JF. et al. Screening for celiac disease in the general population and in high-risk groups. United European Gastroenterol J. 2015 Apr;3(2):106-20.

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Zingone F, Swift GL, Card TR, Sanders DS, Ludvigsson JF, & Bai JC (2015). Psychological morbidity of celiac disease: A review of the literature. United European gastroenterology journal, 3 (2), 136-45 PMID: 25922673

Early Start Denver Model (ESDM) and autism: 2 year outcomes

"These results provide evidence that gains from early intensive intervention are maintained 2 years later. Notably, core autism symptoms improved in the ESDM [Early Start Denver Model] group over the follow-up period relative to the COM [community-intervention-as-usual] group."

Those were some of the conclusions reported in amongst the potentially very important results from Annette Estes and colleagues [1] looking at "the sustained effects of early intervention" following previous studies [2] specifically looking at the ESDM for children with an autism spectrum disorder (ASD). ESDM by the way, is a behavioural intervention model that draws on elements of Applied Behaviour Analysis (ABA) and is based on 'a relationship-focused developmental model'.

Authors reported that when examining follow-up data for some 39 children aged 6 previously included in a trial of ESDM, those that received intervention (compared to those in receipt of 'treatment as usual') "demonstrated improved core autism symptoms and adaptive behavior." These findings were present despite no significant group differences in intellectual functioning between ESDM and COM participants. Perhaps also important were the discussions that: "The two groups received equivalent intervention hours during the original study, but the ESDM group received fewer hours during the follow-up period."

As I've hinted before on this blog, parent-led interventions when it comes to autism have historically been met with varying degrees of success when experimentally tested (see here). By saying this, I'm not trying to poo-poo such efforts; merely that discussions about how early intervention for autism is the gold standard are all well and good, but exactly what form that early intervention takes has yet to be authoritatively decided bearing in mind the pluralisation of the label (see here). In more recent times, we have seen some slightly more optimistic results appearing with specific interventions in mind, as per previous preliminary results based on very, very early implementation of something like ESDM (see here) and the use of ABA possibly linked to those 'optimal outcomers' (see here). But there is still a lot more to do in this area of research before any big promises are made.

Insofar as the idea that intensive efforts in the early years might pay more cost-effective dividends as time goes on, I'm sure that a few eyes and ears will have been grabbed [3] by such a sentiment in these times of continued austerity and resources being squeezed. As I suggested in a previous post (see here) on the idea that parent training might be superior over parent education [4] when it comes to facets of autism, such squeezes to finances/resources might not necessarily translate great experimental results into great real-world outcomes without some blue-sky thinking about how such programmes can be delivered mindful of costs. Estes et al seem to suggest that 'early and intensive' might be eventually able to give way to 'less and sustained'.

One last thing: I'm minded to take readers back to the post I wrote concerning the paper by Barnevik Olsson and colleagues [5] and the idea that 'tackling' core autism symptoms is a noble cause but that one has to be mindful of all of the other comorbidity that can follow a diagnosis and can seriously impact on behaviour and development. What perhaps I would like to see a lot more of in lots of areas of intervention with autism in mind, is how said program/tool/schedule also impacts on comorbid features and whether those variables should be the more important factors related to outcome. Sort of like what has been talked about the dietary intervention and autism in mind...

Music: Paul McCartney & Wings - Live And Let Die.

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[1] Estes A. et al. Long-Term Outcomes of Early Intervention in 6-Year-Old Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2015. April 28.

[2] Dawson G. et al. Randomized, controlled trial of an intervention for toddlers with autism: the Early Start Denver Model. Pediatrics. 2010 Jan;125(1):e17-23.

[3] Penner M. et al. Cost-Effectiveness Analysis Comparing Pre-diagnosis Autism Spectrum Disorder (ASD)-Targeted Intervention with Ontario's Autism Intervention Program. J Autism Dev Disord. 2015 May 5.

[4] Bearss K. et al. Effect of parent training vs parent education on behavioral problems in children with autism spectrum disorder: a randomized clinical trial. JAMA. 2015 Apr 21;313(15):1524-33.

[5] Barnevik Olsson M. et al. “Recovery” from the diagnosis of autism – and then?  Neuropsychiatric Disease and Treatment. 2015. 11: 999-1005.

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Annette Estes, Jeffrey Munson, Sally J. Rogers, Jessica Greenson, Jamie Winter, & Geraldine Dawson (2015). Long-Term Outcomes of Early Intervention in 6-Year-Old Children With Autism Spectrum Disorder J Am Acad Child Adolesc Psychiatry : 10.1016/j.jaac.2015.04.005

Respiratory illness and schizophrenia

"Schizophrenia is associated with impaired lung function and increased risk for pneumonia, COPD [Chronic obstructive pulmonary disease] and chronic bronchitis."

That was the primary conclusion reached in the paper by Krista Partti and colleagues [1] who aimed to "compare the respiratory health of people with psychosis with that of the general population." Their findings, based on data from "a nationally representative sample of 8028 adult Finns" (Finns as in inhabitants of Finland) involved collected data on the frequency of respiratory disease/symptoms as well as measuring lung function via the technique known as spirometry. Tobacco smoking or exposure to smoking, one of the primary causes of respiratory illness in the general population, was "quantified with serum cotinine levels."

"Participants with schizophrenia and other non-affective psychoses had significantly lower lung function values compared with the general population, and the association remained significant for schizophrenia after adjustment for smoking and other potential confounders." Indeed, as per the opening sentence to this post, authors reported some pretty elevated odds ratios (ORs) for various respiratory illnesses related to a diagnosis of schizophrenia compared with asymptomatic controls.

This is not the first time that respiratory diseases have been reported as potentially being more frequently diagnosed in cases of schizophrenia. Schoepf and colleagues [2] reported that in their cohort of those diagnosed with schizophrenia, various physical comorbidity were detected including COPD. As a predictor of "general hospital mortality" both COPD and bronchitis were included in the list of diseases. Other studies have arrived at similar conclusions [3] including data derived from the 'big data' producer that is Taiwan as per the findings from Hsu and colleagues [4].

As per the NHS Choices entry on COPD: "The main cause of COPD is smoking." Tobacco smoking is reported to be more frequently present in cases of schizophrenia [5] albeit with the need for some caution when it comes to making sweeping statements about the overlap [6]. It's therefore not beyond the realms of possibility that smoking habits may very well have a primary role in the association reported by Partti et al particularly in light of their findings on cotinine levels.

That being said, and acknowledging that smoking cessation programmes may be lifesavers for people with schizophrenia as they are for the rest of the population, I'm interested in whether there may be other factors at work when it comes to lung function and schizophrenia. Airway physiology, for example, might be something to consider, particularly in light of other findings when it comes to autism covered previously on this blog (see here). I'm not trying to downplay lifestyle factors [7], just sayin' that we need to cover all the potential bases including looking at whether familial transmission might also be a factor to consider [8].

Music: Song 2 by Blur.

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[1] Partti K. et al. Lung function and respiratory diseases in people with psychosis: population-based study. Br J Psychiatry. 2015 Apr 9.

[2] Schoepf D. et al. Physical comorbidity and its relevance on mortality in schizophrenia: a naturalistic 12-year follow-up in general hospital admissions. Eur Arch Psychiatry Clin Neurosci. 2014 Feb;264(1):3-28.

[3] Hendrie HC. et al. Health outcomes and cost of care among older adults with schizophrenia: a 10-year study using medical records across the continuum of care. Am J Geriatr Psychiatry. 2014 May;22(5):427-36.

[4] Hsu JH. et al. Increased risk of chronic obstructive pulmonary disease in patients with schizophrenia: a population-based study. Psychosomatics. 2013 Jul-Aug;54(4):345-51.

[5] Kelly C. & McCreadie R. Cigarette smoking and schizophrenia. BJPsych Advances. 2000; 6.

[6] Chapman S. et al. Citation bias in reported smoking prevalence in people with schizophrenia. Aust N Z J Psychiatry. 2009 Mar;43(3):277-82.

[7] Filik R. et al. The cardiovascular and respiratory health of people with schizophrenia. Acta Psychiatr Scand. 2006 Apr;113(4):298-305.

[8] Zöller  B. et al. Familial transmission of chronic obstructive pulmonary disease in adoptees: a Swedish nationwide family study. BMJ Open 2015;5:e007310 doi:10.1136/bmjopen-2014-007310

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Partti K, Vasankari T, Kanervisto M, Perälä J, Saarni SI, Jousilahti P, Lönnqvist J, & Suvisaari J (2015). Lung function and respiratory diseases in people with psychosis: population-based study. The British journal of psychiatry : the journal of mental science PMID: 25858177

Severe obesity pre-pregnancy and offspring developmental outcome

"Children whose mothers were severely obese before pregnancy had increased risk for adverse developmental outcomes."

That was the conclusion reached in the paper by Heejoo Jo and colleagues [1] based on results derived from the Infant Feeding Practices Study II (IFPS II) "a US nationally distributed longitudinal study of maternal health and infant health and feeding practices." Said data included information on "maternal prepregnancy BMI [body mass index] and child psychosocial development in 1311 mother–child pairs." Child development was measured in a number of ways including scores on the Strengths and Difficulties Questionnaire and other indications of diagnoses linked to child development.

Various results are presented including the suggestion that mothers with a prepregnancy BMI above 35 - classed as obese II and III - were potentially quite a bit more likely to have a child presenting with various "emotional symptoms" or "psychosocial difficulties" compared with those children of mothers with a more typical weight (BMI 18.5–24.9). When it came to specific developmental diagnoses, the children of obese mothers as a group were also at greater risk of receipt of a label of attention-deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) or developmental delay too. Importantly the authors note that: "Adjustment for potential causal pathway factors including pregnancy weight gain, gestational diabetes, breastfeeding duration, postpartum depression, and child’s birth weight did not substantially affect most estimates."

Without wishing to blame or stigmatise, the finding that maternal prepregnancy BMI might be a specific risk factor for offspring receipt of a diagnosis of ASD or developmental delay "(aOR [adjusted odds ratio] 3.13; 95% CI, 1.10–8.94)" is what grabbed my attention. Harking back to previous posts on this blog (see here) specifically discussing the paper by Paula Krakowiak and colleagues [2] (open-access), it is not necessarily new news that issues with maternal weight/BMI and it's association with various metabolic conditions, might place offspring at some increased risk of subsequent autism or ASD. This includes the increasingly strong evidence pointing towards gestational diabetes - an outcome associated with elevated maternal weight - as potentially increasing the risk of offspring autism (see here).

Allowing for the fact that there may be lots of interfering pregnancy variables influencing the risk of autism [3] (see here), some perhaps working synergistically, there are perhaps some important public health messages to take from the Jo paper and other peer-reviewed studies [4]. Weight loss is one modifiable option that might be considered following this body of data; although as per important recommendations: "If you are very overweight and pregnant, don't try to lose weight during your pregnancy, as this may not be safe." There is also still some debate about the best way to achieve weight loss (before pregnancy) as has been played out recently with headlines such as 'Exercise 'not key to obesity fight'' on the back of the editorial by Malhotra et al and not being able to 'outrun a bad diet'. I might add that the simple 'calories in - energy out' formula might also not be as useful as one might first think (see here).

The issue of risk factors for autism is a complicated and often emotive topic when periods such as pregnancy are thrown into the mix. I've covered lots of research on them down the years of this blog and although I've tried to handle them as sensitively as possible, there is always the risk that correlation/association might be viewed as 'blame'. Blame is certainly something that I've not intended in summarising such research and hopefully not interpreted that way by readers. Wearing the objective goggles of science, I would champion continued research on the possible mechanisms behind obesity and specific issues such as gestational diabetes when it comes to offspring outcomes, simply because they may provide important clues as to the underlying nature of at least some autism as well as other conditions [5]. I'd also suggest that when it comes to the topic of parental weight and something like offspring autism, one also might need to take into account other potentially important correlations too (see here).

Music: David Bowie - Starman.

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[1] H Jo. et al. Maternal Prepregnancy Body Mass Index and Child Psychosocial Development at 6 Years of Age. Pediatrics. 2015. April 27.

[2] Krakowiak P. et al. Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders. Pediatrics. 2012;129(5):e1121-e1128.

[3] Walker CK. et al. Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay. JAMA Pediatr. 2015 Feb;169(2):154-62.

[4] Reynolds LC. et al. Maternal obesity and increased risk for autism and developmental delay among very preterm infants. J Perinatol. 2014 Sep;34(9):688-92.

[5] Hussen HI. et al. Maternal overweight and obesity are associated with increased risk of type 1 diabetes in offspring of parents without diabetes regardless of ethnicity. Diabetologia, April 2015.

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Jo, H., Schieve, L., Sharma, A., Hinkle, S., Li, R., & Lind, J. (2015). Maternal Prepregnancy Body Mass Index and Child Psychosocial Development at 6 Years of Age PEDIATRICS, 135 (5) DOI: 10.1542/peds.2014-3058

Social anxiety affecting autism intervention outcome?

"Anxiety is an unpleasant state of inner turmoil" according to one definition. In other descriptions, words such as 'worry' and 'dread' are used (see here) describing how beyond the typical feelings of apprehension about a new situation for example, anxiety can turn into something altogether more serious and life-disrupting for some.

There are various types of anxiety disorder (see here) to consider, but for the purposes of this post I'm going to focus on social anxiety disorder in the context of autism and how the results from Melanie Pellecchia and colleagues [1] suggest we should be dedicating quite a few more resources to studying and ameliorating this important issue.

"This study examined the extent to which clinical and demographic characteristics predicted outcome for children with autism spectrum disorder." That was the starting point for the Pellecchia study looking at how child characteristics including the presentation of autism and other comorbidities might affect outcome following a school-based behavioural intervention. Drawing on data from an initial sample of over 150 pupils with autism, authors concluded that: "age and the presence of symptoms associated with social anxiety, such as social avoidance and social fearfulness, as measured through the Child Symptom Inventory-4, were associated with differences in outcome." Further: "The findings regarding the role of social anxiety are new and have important implications for treatment."

I'll chime in here and say that social anxiety in relation to autism is by no means a 'new ' concept as per other mentions on this blog (see here and see here for example). Indeed, anxiety appearing in the context of autism or autistic traits (see here) is something that many people have recognised as being potentially central to the more disabling features for quite a few on those on the autism spectrum. That and an 'intolerance of uncertainty' to borrow an important phrase [2]. The novelty from the Pellecchia data comes from the idea that the presentation of social anxiety alongside paediatric autism might well have some important effects on intervention outcome.

It's an interesting idea that when it comes to intervention for autism, the presentation of core autism symptoms might not be the major hurdle to 'treatment' success or positive outcome. I'm not sure how relevant it might be to this discussion, but I have talked previously on this blog about how one or two intervention ideas put forward for autism are probably not affecting core symptoms but rather peripheral or comorbid presentations. It strikes me that a question requiring some answers is whether targeting issues like social or other forms of anxiety when comorbid, might similarly affect the core presentation of autism? How about targeting other potential manifestations of anxiety presenting as more somatic features too?

And just in case you needed telling, issues such as anxiety are not some 'flash in the pan' thing when it comes to quite a few cases of autism [3]. Indeed, the implication being that even into adulthood, moves to curb anxiety-related issues might potentially have some very positive effects on the presentation of autism and onwards improvements in quality of life. The flip-side to all that being that anxiety, when unremitting, might have some far-reaching implications [4]...

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[1] Pellecchia M. et al. Child characteristics associated with outcome for children with autism in a school-based behavioral intervention. Autism. 2015. April 24.

[2] Boulter C. et al. Intolerance of uncertainty as a framework for understanding anxiety in children and adolescents with autism spectrum disorders. J Autism Dev Disord. 2014 Jun;44(6):1391-402.

[3] Gotham K. et al. Depressive and anxiety symptom trajectories from school age through young adulthood in samples with autism spectrum disorder and developmental delay. J Am Acad Child Adolesc Psychiatry. 2015 May;54(5):369-376.e3.

[4] Verhoeven JE. et al. Anxiety disorders and accelerated cellular ageing. Br J Psychiatry. 2015. May 1.

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Pellecchia, M., Connell, J., Kerns, C., Xie, M., Marcus, S., & Mandell, D. (2015). Child characteristics associated with outcome for children with autism in a school-based behavioral intervention Autism DOI: 10.1177/1362361315577518