The positive effects of 12 weeks of probiotics and vitamin D in chronic schizophrenia?

The findings reported by Amir Ghaderi and colleagues [1] (open-access) provide the blogging fodder today, and the results of a study looking at a "novel combination of vitamin D and probiotic on metabolic and clinical symptoms in chronic schizophrenia." Said probiotic formulation contained "Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum (each 2 × 109)" and was delivered over a period of 12 weeks alongside a vitamin D supplement - "50,000 IU vitamin D3 every 2 weeks" - utilising a "randomized, double-blind, placebo-controlled trial" design. We are also told that the trial protocol was "retrospectively registered."

The Ghaderi study wasn't solely focused on what their combined intervention might do for the 'clinical symptoms' of schizophrenia despite this being a prominent part of the results obtained. They also wanted to examine things like "biomarkers of oxidative stress and cardiometabolic risk in chronic schizophrenia." This was done via the measurement of marker compounds pertinent to establishing total antioxidant capacity, total glutathione levels and high-sensitivity C-reactive protein (hs-CRP) among other things.

Results: first things first, vitamin D supplementation raised vitamin D levels in those who received the vitamin D + probiotic supplement. Not exactly an unexpected result I grant you, but important from the point of view that any subsequent findings *could* be linked to those increasing vitamin D levels. Further: "Vitamin D and probiotic co-supplementation was associated with a significant improvement in the general... and total PANSS scores." PANSS stands for the Positive and Negative Syndrome Scale and has some important uses in the context of schizophrenia, and the presentation of positive and negative symptoms. That all being said, the authors also mention how their supplementation combination did not seemingly affect scores on another measure included in the study - the Brief Psychiatric Rating Scale (BPRS) - which kinda demonstrates that vitamin D + probiotics is not a panacea for every aspect of schizophrenia.

Researchers also report on how their combined supplement also *correlated* with a some changes in those oxidative stress and cardiometabolic risk measures included for study in line with other study results (see here). There's quite a bit of data so I won't provide details. Suffice to say that some of them might be 'positively' important to those health inequalities that seem to follow a diagnosis of schizophrenia (see here).

What else? Well, I can't seem to find too much in the way of side-effects details in the Ghaderi paper so I'm assuming that it wasn't a significant issue. The fact that participants in the study were "being hospitalized during the intervention" means that they were, I assume, being monitored with greater assiduity than for example if they were in the community, including looking for potential side-effects.

And with that, and the requirement for further study (see here and see here), I say no more...

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[1] Ghaderi A. et al. Clinical and metabolic response to vitamin D plus probiotic in schizophrenia patients. BMC Psychiatry. 2019; 19:77.

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Magnesium and ADHD meta-analysed

The study results published by Mohammad Effatpanah and colleagues [1] provided some food for thought recently on the topic of whether there may be an *association* between "serum magnesium levels and the diagnosis of attention deficit hyperactivity disorder (ADHD)."

The name of the research game was meta-analysis, that well used 'boiling down' of the published (hopefully peer-reviewed) science literature into something like a coherent 'conclusion'. The starting point for Effatpanah was that: "Current research suggests conflicting evidence surrounding the association between serum magnesium levels and the diagnosis of attention deficit hyperactivity disorder (ADHD)." It's interesting that this isn't the first time that magnesium and ADHD has been put under the meta-analysis microscope [2] and that particular meta-analysis didn't suggest such conflict.

Never mind. Seven studies made the grade for Effatpanah, together revealing that "subjects with ADHD had 0.105 mmol/l (95% CI: -0.188, -0.022; P < 0.013) lower serum magnesium levels compared with to their healthy controls." Researchers did also talk about 'high heterogeneity' across the studies analysed. This indicates that whilst there may well be "an inverse relationship between serum magnesium deficiency and ADHD" overall, the individual studies included in their meta-analysis weren't always in agreement with one and another.

So what conclusions can we take from the Effatpanah and other (meta-analysis) studies in this area? Well, more investigation is required on the suggestion of a *link* between magnesium and ADHD. We need to know more about the biology of why reduced biological levels of magnesium might be important to ADHD or ADHD-type behaviours [3] and whether something as simple as supplementing with magnesium *might* make a difference for some people [4] (minus any medical or clinical advice from me on this or any other topic). Indeed, on that last issue, I might refer you back to some other occasions where magnesium has been mentioned in the context of nutritional intervention for ADHD (see here). I'm also inclined to mention that there may be other 'labels' where magnesium might require a little more study (see here), some of which might 'overlap' with a diagnosis of ADHD. And of course, we should remember that magnesium 'issues' in the context of autism might not be the end of the story when it comes to trace metals and ADHD (see here)...

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[1] Effatpanah M. et al. Magnesium status and attention deficit hyperactivity disorder (ADHD): A meta-analysis. Psychiatry Res. 2019 Feb 19;274:228-234.

[2] Huang YH. et al. Significantly lower serum and hair magnesium levels in children with attention deficit hyperactivity disorder than controls: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 2;90:134-141.

[3] Black LJ. et al. Low dietary intake of magnesium is associated with increased externalising behaviours in adolescents. Public Health Nutr. 2015 Jul;18(10):1824-30.

[4] Ghanizadeh A. A systematic review of magnesium therapy for treating attention deficit hyperactivity disorder. Arch Iran Med. 2013 Jul;16(7):412-7.

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ADHD and a link with zinc?

"The present results indicated that there were alterations in blood levels of zinc, which was associated with the symptom scores of ADHD [attention-deficit hyperactivity disorder]."

So concluded the paper published by Rongwang Yang and colleagues [1] looking at blood levels of various trace elements including "zinc (Zn), copper (Cu), iron (Fe), magnesium (Mg), and lead (Pb)" in a group of children diagnosed with ADHD compared to a group of non-ADHD controls.

Based on their analysis of blood samples using atomic absorption spectrometry, researchers observed that many of the metals (trace elements) analysed were not greatly different between their groups. Lower levels of zinc however, and "the number out of normal ranges" in relation to zinc were noted. Further: "Zinc levels were negatively correlated with parent-rated scores of inattentive subscale of SNAP-IV (r = − 0.40) as well as with total score of SNAP-IV (r = − 0.24)" where the SNAP-IV refers to the Swanson, Nolan, and Pelham – IV questionnaire, a tool used to screen/assess for possible ADHD.

The Yang results have to be treated with some caution as the old 'correlation is not necessarily the same as causation' rule is observed. It's not beyond the realms of possibility that any suggested *association* between zinc and ADHD is purely epiphenomenal. But...

This is not the first time that zinc and ADHD have been talked about in the same breath (see here). Outside of linking levels of zinc to ADHD - or diagnostic facets of ADHD - one is also presented with other research suggestive that supplementation 'for ADHD' including zinc *might* show some effect (see here). There is the other question of whether zinc alone or in conjunction with other elements and/or biological factors might be important to the presentation of ADHD [2] but this is perhaps another reason why this area is deserving of further investigation. Indeed, further study of the possible processes through which zinc might influence the presentation of ADHD is also required.

And given that ADHD is something not exactly under-represented when it comes to other labels (see here), one has to question what role this fact might play in a more complicated clinical picture with zinc in mind (see here)?

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[1] Yang R. et al. Blood Levels of Trace Elements in Children with Attention-Deficit Hyperactivity Disorder: Results from a Case-Control Study. Biological Trace Element Research. 2019; 187: 376-382.

[2] Villagomez A. & Ramtekkar U. Iron, Magnesium, Vitamin D, and Zinc Deficiencies in Children Presenting with Symptoms of Attention-Deficit/Hyperactivity Disorder. Children (Basel). 2014 Sep 29;1(3):261-79.

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Carnitine supplementation and autism: "side-effects and behavioral outcomes"

'Favourable outcomes' is a term mentioned in amongst the various findings reported by Robin Goin-Kochel and colleagues [1] following their examination of "dose compliance, attrition, and potential side effects of short-term, high-dose carnitine supplementation" in a small group of boys diagnosed with an autism spectrum disorder (ASD). Understanding that the Goin-Kochel study was primarily directed at looking at safety, on the basis of 'high-dose' carnitine supplementation, it appears that an elevation of plasma carnitine and related metabolites was not the only effect noted in their small cohort (N=10).

Tracking back slightly, carnitine is an important compound. Not quite an amino acid, carnitine plays an important role in energy production; as per use of the word 'mitochondria' and it's transporting duties of long-chain fatty acids to the cell powerhouse for energy conversion. You probably won't be surprised to hear that carnitine has a *connection* to some autism (see here and see here). Indeed, Goin-Kochel et al mention the findings reported by Patrician Celestino-Soper and colleagues [2] and their identification of a genetic issue that impacts on 'carnitine biosynthesis' in some people diagnosed with ASD. At least one of the authors on the Goin-Kochel paper has some pretty important knowledge about that finding of trimethyllysine hydroxylase epsilon (TMLHE) gene issues in the context of autism...

Alongside looking for reports of any side-effects from the use of carnitine - "oral suspension or tablets of levocarnitine in 3 divided doses, starting at 200 mg/kg/day and increasing to 400 mg/kg/day, with a maximum daily dose of 6 g" - various behavioural schedules were included in the study protocol. Some were objective measures of autism symptomatology; others were parent-report measures. The use of the Clinical Global Impression Scale (CGIS) also provided a helpful 'clinicians' overview' of before and after supplementation in this open-trial.

Results: a few side-effects coinciding with carnitine use were reported. These included: "heavy odor (4 parents), diarrhea (4 parents), and sporadic vomiting (1 parent)." Such reported side-effects meant that three children remained at the lower dose of carnitine over the experimental period (8 weeks).

Alongside, a few other 'favourable outcomes' were also reported: "calmer behavior (2 parents), more energy (2 parents), increased prosocial behaviors (4 parents), greater awareness (2 parents), better eye contact (2 parents), and improved language skills (2 parents)." These parental reports were accompanied by some 'changes' noted on the various schedules included in the study protocol, including those CGIS ratings. The authors used the study results produced by Geier and colleagues [3] as their comparator; highlighting how both studies had picked up "improvements in overall ASD symptoms... and some language ratings." Importantly too, Goin-Kochel et al talk about how none of their cohort were rated as "worse at post treatment."

Where next? More research please. Bigger participant numbers, more methodologically sound study designs and perhaps also, investigation of the potential pros-and-cons of carnitine supplementation over a longer period of time. By all means keep an eye on those side-effects and perhaps look to the biochemistry as to why such side-effects might appear; indeed look to the biochemistry for potential best-responders to this type of intervention too ("One child had documented TMLHE deficiency and 3 had low carnitine levels" in the Goin-Kochel cohort). But more study is definitely indicated...

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[1] Goin-Kochel RP. et al. Side Effects and Behavioral Outcomes Following High-Dose Carnitine Supplementation Among Young Males With Autism Spectrum Disorder: A Pilot Study. Global Pediatric Health. 2019; 6: 1-8.

[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] Geier DA. et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med Sci Monit. 2011 Jun;17(6):PI15-23.

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Maternal prenatal vitamin use and reduced risk of offspring autism recurrence

Question: "Is maternal use of prenatal vitamins associated with decreased risk for autism recurrence in siblings of children with autism spectrum disorder?" Answer: "Maternal prenatal vitamin intake during the first month of pregnancy may reduce ASD [autism spectrum disorder] recurrence in siblings of children with ASD in high-risk families." So that looks like a 'very possibly' then.

That was the long-and-short of the findings reported by Rebecca Schmidt and colleagues [1]. Some notable names are included on the authorship list of the Schmidt paper who are no strangers to the idea that maternal prenatal vitamin use may very well impact on offspring risk of autism or ASD (see here and see here for examples).

The Schmidt study on this occasion relied on data from the MARBLES (Markers of Autism Risk in Babies: Learning Early Signs) study, an important longitudinal initiative originally designed to investigate "possible pre-natal and post-partum biological and environmental exposures and risk factors that may contribute to the development of autism." Yes, you read that right, that's 'biological and environmental' exposures and risk factors (see here)...

In this "prospective cohort study" younger brothers and sisters deemed to be at high-risk of autism (N=241) by virtue of their older sibling having been diagnosed with autism were the target participant group. Said group were followed from 6 months to around about their third birthday and developmentally assessed. Mums of the children were also asked about their vitamin use during pregnancy via interview. All the collected data was crunched and results presented.

"The prevalence of ASD was 14.1% (18) in children whose mothers took prenatal vitamins in the first month of pregnancy compared with 32.7% (37) in children whose mothers did not take prenatal vitamins during that time." As you can see, that is quite a stark [statistically significant] difference between the groups bearing in mind that around 25% of the total cohort were eventually diagnosed with autism (or at least met thresholds for a diagnosis based on the use of a gold-standard instrument). Authors also add that prenatal vitamin use did not seemingly impact on "other nontypical development" which included various other developmental 'outcomes'. They also reported that: "Children in the former maternal prenatal vitamin group also had statistically significantly lower autism symptom severity... and higher cognitive scores." This implies that even if such vitamin use did not 'halt' a/the pathway to an autism diagnosis in some, it might well have affected the presentation of their autism in terms of symptoms and intellectual functions (see here).

So an important question: what were the nutrients being supplemented that seemed to show such an effect? Well, as per that other previous research from Schmidt et al folic acid popped up again, as well as another important nutrient, iron (Fe) which she's also been previously interested in (see here).

As per some 'expert reaction' to the study (see here) there is a need for further research in this area before any sweeping generalisations are made. Ideally, I'd like to see Schmidt or others go further into the whole folate metabolism bit applied to autism (see here and see here) and what that means for supplementation levels in mums-to-be where offspring autism recurrence risk is potentially high. Indeed, whether folic acid is actually the ideal supplement for some pregnant mums (see here) is another potential route of investigation on the basis of what has previously turned up in 'some autism' (see here). By saying all that, I want to make it clear that I'm not giving anything that looks, sounds or smells like medical or clinical advice on this or any topic. The Schmidt findings also potentially tie into another area of autism research looking at the inter-pregnancy interval (IPI) with autism in mind (see here and see here). This, on the basis that words like 'depletion of micronutrients' have been banded around as being one possible explanation for the elevated risk of offspring autism correlating with a short IPI. Again, more study is indicated.

I try not to get too excited about new findings when it comes to autism because, inevitably, many end up falling by the wayside or being over-hyped. Given however the history of peer-reviewed science on the topic of pregnancy nutrition and risk of offspring autism, I'm inclined to think that there may be something quite special in the Schmidt findings and what directions they could eventually take with regards to both research and policy. Certainly when I read another study talking about siblings at 'high-risk' for autism, I'll be looking to see whether pregnancy nutrition has been considered as a potentially modifying variable...

28 February 2019: An addition. So, here I am talking about prenatal vitamin use and offspring autism risk and lo-and-behold, someone has just published a meta-analysis and systematic review of this topic [2]. The conclusion: "the likelihood of ASD in offspring whose mothers used multivitamin supplements during the prenatal period was significantly reduced compared with that in offspring of mothers without such supplementation."

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[1] Schmidt RJ. et al. Association of Maternal Prenatal Vitamin Use With Risk for Autism Spectrum Disorder Recurrence in Young Siblings. JAMA Psychiatry. 2019. Feb 27.

[2] Guo B-Q. et al. Maternal multivitamin supplementation is associated with a reduced risk of autism spectrum disorder in children: A systematic review and meta-analysis. Nutrition Research. 2019. Feb 24.

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Lactobacillus (L.) reuteri and mouse-modelled autism: spotlight on the vagus nerve?

I am a little late getting to the findings reported by Martina Sgritta and colleagues [1] but I eventually arrived at them. As per the title of this post - "Lactobacillus (L.) reuteri and mouse model autism: spotlight on the vagus nerve?" - there were a number of important elements to this research covering mouse-modelled autism, the "gut-microbiota-brain axis", and something called the vagus nerve. Pretty good fodder for this blog by all accounts, given some past discussions (see here) including mention of previous research from some of the Sgritta paper co-authors (see here).

So, continuing a theme from this research group suggesting that, in mice at least, some pregnancy 'risk factors' for autism might have a microbial connection [2], authors set out to examine whether the inclusion of a specific bacterial species called Lactobacillus reuteri or L. reuteri for short might have some important effect on the social behaviour of a mouse model of autism. L. reuteri has been the source of quite a bit of study down the years [3] as a function of it's antimicrobial activity and connection to inflammatory conditions. Outside of the Baylor College group research, this bacterial species has also been talked about with autism in mind [4] in other studies, as per conclusions like: "This study identifies bacterial species that are sensitive to an autism-related mutation." I'll say no more on that study for now aside from offering a viewpoint from elsewhere on the web.

Alongside their observation that "treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD [autism spectrum disorder] models" Sgritta et al also put a little scientific flesh on what underlying mechanism(s) might be pertinent to such 'rescuing' of social issues. You might think it was something to do with the contribution of L. reuteri to the gut microbiome of the [mouse] host? Well, yes and no, as authors highlighted how "L. reuteri acts in a vagus nerve-dependent manner" so bringing in the notion that bacteria in the gut *talk to* the brain (or the wider central nervous system) via the vagus nerve. The paper by Bruno Bonaz and colleagues [5] provides as good an explanation as any of how bacteria talk to the brain and what this means for the "gut-microbiota-brain axis." Interestingly too, authors mention how when the vagus nerve was 'disrupted' in said mouse-modelled autism, so the the gut-microbiota-brain link was also disrupted, and onward that L. reuteri didn't seemingly work as well at rescuing those social issues. They also talk about a role for oxytocin receptors in their findings similar to their last research occasion, but I'm going to leave that for now. All I will say is that oxytocin has also been mentioned in other autism research circles (see here).

Obviously, there are caveats to the Sgritta findings; not least that mouse-modelled autism is just mouse-modelled autism and probably not totally representative of real-life human autism (see here). Generalisations of the social behaviour of mice raised and living under laboratory conditions to people (children and adults) traversing the big, wide real world always require a degree of caution.

But I am interested in this area and would like to see more study done on the "gut-microbiota-brain axis" with autism in mind. Given that L. reuteri is freely available to anyone and everyone and seems to have quite a good safety record, I'd perhaps suggest that a clinical trial could be something that a young, upcoming researcher or research group might possibly want to consider exploring...

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[1] Sgritta M. et al. Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder. Neuron. 2018 Dec 3. pii: S0896-6273(18)31009-2.

[2] Buffington SA. et al. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring. Cell. 2016 Jun 16;165(7):1762-1775.

[3] Mu Q. et al. Role of Lactobacillus reuteri in Human Health and Diseases. Front Microbiol. 2018;9:757. 

[4] Tabouy L. et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav Immun. 2018 Oct;73:310-319.

[5] Bonaz B. et al. The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis. Front Neurosci. 2018;12:49. 

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"Vitamin D and omega-3 reduced irritability symptoms in children with ASD"

The title heading this post - "Vitamin D and omega-3 reduced irritability symptoms in children with ASD [autism spectrum disorder]" - comes from the findings reported by Hajar Mazahery and colleagues [1] discussing the results of their clinical trial. I have already mentioned the Mazahery trial before on this blog (see here) as a 'study to watch' based on the publication of their study protocol [2]. It looks like the wait is finally over...

So, as researchers previously reported, there were four arms to this clinical trial: supplementation with vitamin D alone ("2000 IU/day, VID"), supplementation with an omega-3 fatty acid ("722 mg/day DHA, OM"), vitamin D plus fatty acid supplementation together ("2000 IU/day vitamin D + 722 mg/day DHA, VIDOM") and a placebo group (olive oil). Results are reported for over 70 children diagnosed with an autism spectrum disorder (ASD) - "VID = 19, OM = 23, VIDOM = 15, placebo = 16" - over a 12-month period, with the primary outcome being "the Aberrant Behaviour Checklist (ABC) domains of irritability and hyperactivity."

Aside from the main finding - "vitamin D and omega-3 LCPUFA [long chain polyunsaturated fatty acid] reduced irritability symptoms in children with ASD" (compared against placebo) - a few other observations are noteworthy: "Compared to placebo, children on VID [vitamin D] also had greater reduction in hyperactivity." All this bearing in mind that the biological testing to examine for vitamin D and fatty levels reported "a good compliance rate" indicating that supplements were routinely being taken as required by the study.

Implications? Well, strike up more peer-reviewed evidence that nutrition is important not just for physiological health but also for psychological/behavioural health and wellbeing too (see here). Add this research also to other peer-reviewed science that suggests that at least 'some autism' might be particularly 'sensitive' to elements of such nutritional medicine (see here).

I could go on about how vitamin D in particular seems to be something important to autism (see here and see here for examples). I could also go on about how fatty acids have some important evidence-based history with autism in mind (see here). But do I really need to? Minus any medical or clinical advice given or intended, the Mazahery results really speak for themselves.

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[1] Mazahery H. et al. A randomised controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of irritability and hyperactivity among children with Autism Spectrum Disorder. The Journal of Steroid Biochemistry and Molecular Biology. 2018. Oct 26.

[2] Mazahery H. et al. Vitamin D and omega-3 fatty acid supplements in children with autism spectrum disorder: a study protocol for a factorial randomised, double-blind, placebo-controlled trial. Trials 2016; 17:295.

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Childhood ADHD and vitamin D meta-analysed again

Consider this short post about the findings reported by Evangelia Kotsi and colleagues [1] an extension of some previous discussions on the topic of vitamin D levels and attention-deficit hyperactivity disorder (ADHD) (see here and see here).

The conclusion reached by Kotsi et al - "The systematic review and meta-analysis of observational studies demonstrated an inverse association between serum 25(OH)D and young patients with ADHD" - was not entirely unexpected given the results of other independent meta-analyses [2]. They do however reiterate that in amongst the tons of research linking vitamin D deficiency / insufficiency to various labels (see here and see here for other examples), ADHD should perhaps be part of any future research strategy. Specifically, as the authors mention, the question is: "whether vitamin D-deficient infants are more likely to develop ADHD in the future?" (Perhaps.)

A couple of next research steps should also include: (a) a focus on the reason(s) for vitamin D deficiency / insufficiency in relation to ADHD (including the genetics angle) and (b) whether supplementation *might* be something that 'affects' the behavioural presentation of ADHD [3] as well as just physiological levels of the sunshine vitamin/hormone and hence should be considered an intervention? We'll see what happens.

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[1] Kotsi E. et al. Vitamin D levels in children and adolescents with attention-deficit hyperactivity disorder (ADHD): a meta-analysis. Atten Defic Hyperact Disord. 2018 Oct 26.

[2] Khoshbakht Y. et al. Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies. Adv Nutr. 2018 Jan 1;9(1):9-20.

[3] Dehbokri N. et al. Effect of vitamin D treatment in children with attention-deficit hyperactivity disorder. World J Pediatr. 2018 Nov 19.

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"no evidence of any beneficial effect of monthly vitamin D3 supplementation on mood-related outcomes"

The quote titling this post - "no evidence of any beneficial effect of monthly vitamin D3 supplementation on mood-related outcomes" - comes from the paper published by Maria Choukri and colleagues [1] (open-access available here). Their study represents an important continuation of research looking at whether supplementing with vitamin D (the sunshine vitamin/hormone) may affect depression or depressive symptoms (see here). The authors in this case observed that their study "did not provide evidence for the benefit of single monthly dose of vitamin D3 supplementation over autumn and winter on depression and other mood outcomes in healthy pre-menopausal women."

Just before heading further into the Choukri findings, it's worthwhile mentioning some of the history in this area. So, vitamin D is an essential part of maintaining good bone integrity as per the connection between deficiency of the stuff and conditions like rickets (see here). More recently, scientific and clinical eyes have turned to other possible roles for vitamin D in light, for example, of 'deficiency' connections to various developmental and/or behaviourally-defined labels such as autism, schizophrenia and depression (see here and see here and see here respectively). When deficiency (or insufficiency) is detected, people supplement with vitamin D to correct the deficiency, following Government guidance (see here). Speculation then turned to whether supplementation might also 'impact' on the presentation of some of those developmental/clinical labels as well as just correcting any biological deficiency. The results have tended to be mixed so far (see here and see here) with some important biological caveats (see here)...

"This study was a double-blind, placebo-controlled, randomised clinical trial conducted from February 2013 to October 2013 in Dunedin, New Zealand (45° 52′0 S, similar to the latitude of Montreal, Canada; or Lyon, France in the northern hemisphere)." The latitude information is important to various studies mentioning vitamin D because geography influences sun exposure which then influences vitamin D production (see here). Importantly too, the Choukri study was focused on 'healthy' women who were not currently diagnosed with a variety of exclusionary conditions/labels. "A total of 152 healthy women (18–40 years) in Dunedin, New Zealand were randomly assigned to receive 50 000 IU [international units] (1·25 mg) of oral vitamin D3 or placebo once per month for 6 months" we are told, and measures covering anxiety, depression, 'flourishing' and positive and negative mood were utilised before and after.

Results: first and foremost measured vitamin D levels did what they were expected to do as a function of vitamin D or placebo receipt. There was for example, no significant baseline difference in vitamin D levels between the groups (vitamin D vs placebo). At the end of the study, those in the placebo group showed "the expected seasonal pattern in terms of a decline in absolute level and change over the seasonal periods" in vitamin D levels, whilst the supplemented group did not.

But alongside... "There were no statistically significant differences between the vitamin D and placebo groups in any of the outcome measures – depression, anxiety, flourishing, or positive and negative mood, controlling for the baseline measures and the covariates." Indeed, across the various measures, there wasn't even anything close to a statistically significant difference reported between the groups. Ergo, in healthy women "over the winter period", vitamin D supplementation did not seemingly impact on mood-related outcomes despite altering biological vitamin D levels.

I could mention about some possible caveats attached to this study such as the fact that this was a study carried out on an already healthy population "with no vitamin D deficiency or high depressive symptoms." But this is not the first time that vitamin supplementation has 'failed' to show a demonstrable connection to improving mood and probably won't be the last either...

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[1] Choukri MA. et al. Effect of vitamin D supplementation on depressive symptoms and psychological wellbeing in healthy adult women: a double-blind randomised controlled clinical trial. J Nutr Sci. 2018 Aug 23;7:e23.

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Effects of pregnancy vitamin D deficiency on social behaviours of offspring rats

I note the findings reported by Nathanael Yates and colleagues [1] have garnered a few lay and science media headlines recently (see here) as authors concluded that "early life levels of vitamin D are an important consideration for maternal behavioural adaptations as well as offspring neuropsychiatry." Further coverage of their findings is provided in a helpful article for The Conversation (see here), where some authors - including the autism research powerhouse that is Andrew Whitehouse - provide a little more interpretation of their findings. I might also add that Whitehouse is no stranger to the vitamin D - autism research story (see here).

So, what's all the current discussion about?

Well, vitamin D - the 'sunshine' vitamin/hormone - is front and centre of this latest research, and some investigation into "how early life vitamin D deficiency during rat pregnancy and lactation alters maternal care and influences neurodevelopment and affective, cognitive and social behaviours in male adult offspring." This is set within the context that vitamin D seems to be doing a lot more than just contributing to bone health (see here). You'll of course note the use of the word 'rat' in the above text, and in particular what happened to offspring baby rats in terms of "offspring neurodevelopmental markers, ultrasonic vocalisations and adult behavioural outcomes including social, cognitive and affective-like behaviours" when mummy rat diets are loaded up with enough vitamin D as opposed to those mummy rats who were provided with a vitamin D deficient diet. The theory behind those vitamin D loaded vs. vitamin D deficient mummy rat diets is that: "In both humans and rats, a baby developing in the womb is completely reliant on the mother’s vitamin D stores." Probably something to do with the lack of sunlight exposure in the womb(!)...

Results: there did seem to be some difference across various 'test a rat / test an offspring rat' measures as a function of vitamin D status, looking across behaviour, brain scans (yes, rats did meet some MRI equipment) and also "plasma corticosterone levels and neural expression of genes associated with language, dopamine and glucocorticoid exposure." So for example, authors describe how "males that had been exposed to vitamin D deficiency in early life exhibited decreased social behaviour, impaired learning and memory outcomes and increased grooming behaviour, but unaltered affective behaviours." It's not difficult to see the 'decreased social behaviour' links that *could* be made with a condition / label / diagnosis like autism; particularly when vitamin D has quite the peer-reviewed research history with autism in mind (see here).

Interestingly too, but not made too much of in the chatter about this study for obvious reasons, were the observations made around maternal care as a function of vitamin D status, bearing in mind that vitamin D deficiency will probably impact both mummy rat and baby rat. So: "the quality of maternal care was decreased in dams consuming a vitamin D-deficient diet." Mmm...

Whilst this is important work, and adds to our understanding that appropriate nutrition throughout the lifespan is important to various aspects of functioning, I'll reiterate that this was research using rats. Rats not humans. It is perhaps timely that at around the same time that the Yates paper was published, I also chanced upon some discussion over at Spectrum on how we all need to be a little bit careful when talking about modelling autism in various animals (see here) and their relevance to real, often much more complicated, people (see here) and their [multiple] labels (see here).

I note that in their piece for the The Conversation, authors caution that their findings don't mean everyone who is pregnant (or could become pregnant) should rush out and load up on vitamin D so as to potentially influence offspring developmental course. I would second that view; but would also direct your attention to some Government advice quite recently (at least here in Blighty) that we should perhaps all be thinking about vitamin D supplementation (see here) and the many and varied ways that this vitamin/hormone *might* impact on our physiology and beyond (see here).

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[1] Yates NJ. et al. Vitamin D is crucial for maternal care and offspring social behaviour in rats. J Endocrinol. 2018 May;237(2):73-85.

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"Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder"

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

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

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

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

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

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

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

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

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Childhood ADHD and vitamin D meta-analysed

The results of the systematic review and meta-analysis published by Yadollah Khoshbakht and colleagues [1] (open-access available here) make for interesting, if not totally unexpected, reading.

Covering the existing peer-reviewed research literature (up to June 2017) on the topic of vitamin D status and attention-deficit hyperactivity disorder (ADHD), researchers concluded that: "The present review provides evidence supporting the relation between vitamin D deficiency and ADHD."

Vitamin D and ADHD is a topic already covered on this blog (see here). The general direction of findings so far have kinda mirrored that seen in other developmental diagnoses such as autism, insofar as vitamin D deficiency / insufficiency as measured by concentrations of 25-hydroxyvitamin D, tending to be pretty over-represented alongside the label (see here). It's perhaps also pertinent to mention that the diagnostic combination of autism and ADHD seems to be quite widespread (see here); particularly in these days of ESSENCE or autism plus (see here). This could very well have a bearing on any observations obtained as per other examples in other areas (see here).

Anyhow...

Khoshbakht et al looked at various studies and aspects of studies as part of their analyses. They also pre-registered their intention to undertake some research on vitamin D and ADHD as per a PROSPERO entry (see here) containing some details on hows-and-whys.

From various 'retrieved articles' numbering in the thousands, authors eventually settled on 13 studies ("9 case-control or cross-sectional studies and 4 prospective studies") that examined "the association between vitamin D concentration and the risk of ADHD." The final cumulative study participant number was not bad at all: "3484 patients with ADHD (2183 from the case-control and cross-sectional studies, 1301 from the prospective studies) and 11,837 healthy children (8151 from the case-control and cross-sectional studies, 3686 from the prospective studies) aged between 5 and 18 y were included." Authors also noted that various methods were used to measure 25-hydroxyvitamin D - 25(OH)D - ranging from the gold-standard that is liquid chromatography tandem mass spectrometry (LC-MS/MS) to something perhaps a little less accurate e.g. high-performance liquid chromatography (HPLC) minus the mass spec bit. All-in-all however, most studies were judged to be of moderate or high quality.

Results: "we found modest but significant lower serum vitamin D concentrations in children and adolescents with ADHD compared with healthy control subjects." Based on 9 studies where "the mean ± SD vitamin D concentrations in subjects with and without ADHD" was reported, authors concluded that "children with ADHD had 6.93 ng/mL lower serum vitamin D concentrations compared with healthy controls." And that wasn't all, as authors also looked at prospective studies where for example, vitamin D was measured in maternal serum or umbilical cord blood and then mapped onto risk of ADHD in offspring. With this type of study in mind, they observed that: "lower maternal or cord serum vitamin D concentrations increase the risk of developing ADHD in childhood or adolescence by 40%" albeit with some statistical caveats.

Khoshbakht and colleagues provide some possible pointers about how vitamin D *might* influence the pathophysiology of ADHD. They for example, mention an enzyme that I've been pretty interested in down the years - tryptophan hydroxylase 2 (TPH2) - and how the starting gene for this enzyme has been both linked to ADHD [2] in some studies (but not others). Further: "The TPH2 gene is activated by vitamin D hormone through its vitamin D response element." Personally, I find this interesting but not intellectually satisfying enough to provide an authoritative explanation for any effects of vitamin D deficiency on ADHD. Going also back to the vitamin D story with autism in mind, I'd like to think lessons could be learned about more particular vitamin D genetics (see here) and what role they might also play with regards to ADHD too. There are no doubt other pertinent mechanisms too.

There is still more research to do when it comes to vitamin D and ADHD of that there is no doubt. Again, going back to the relationship between ADHD and autism, I'm wondering whether more focus needs to be on this diagnostic combination (and perhaps other overlaps too) to ascertain whether one condition / label over another shows any stronger relationship with vitamin D levels. In light also of other meta-analysis work talking about lower vitamin D levels being linked to 'poorer cognition' (see here) for example, one might also reasonably suggest that an even broader research agenda might need to be followed.

And then there's the question of supplementation (see here) to consider and whether it may / may not do more than just raise vitamin D levels [3]? Oh wait, and there's more [4]...

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[1] Khoshbakht Y. et al. Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies. Adv Nutr. 2018 Jan 1;9(1):9-20.

[2] Park TW. et al. Association between TPH2 gene polymorphisms and attention deficit hyperactivity disorder in Korean children. Genet Test Mol Biomarkers. 2013 Apr;17(4):301-6.

[3] Elshorbagy HH. et al. The Impact of Vitamin D Supplementation on Attention-Deficit Hyperactivity Disorder in Children. Ann Pharmacother. 2018 Feb 1:1060028018759471.

[4] Sahin N. et al. Vitamin D and vitamin D receptor levels in children with attention-deficit/hyperactivity disorder. Neuropsychiatr Dis Treat. 2018 Feb 19;14:581-585.

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On biotin and 'some autism'

Although I've mentioned biotin (vitamin B7) in the context of autism before on this blog (see here), due credit needs to be given to Peter over at the Epiphany blog for more extensive coverage (peer-reviewed based) of this nutrient (see here). Discussing how, within the increasingly large range of conditions that manifest autism or autistic behaviour(s), there may be one or two 'types' of autism that manifest biotin deficiency, there is a pretty obvious course of intervention as and when deficiency is found: supplementation.

And supplementation is exactly what was discussed in the paper by Paul Benke and colleagues [1] reporting on a case report of a young female who presented with "features of autism spectrum disorder, isolated headaches, and episodes of headaches and limb shaking." Alongside those symptoms, authors also discussed a fairly unusual part of her clinical history where "hair and nails did not grow."

Although there are various reasons why hair and nails might not grow - indeed, just about every nutritional deficiency seems to affect something like nail health and growth - biotin was noted as a point of concern in this young lady's clinical picture. Indeed authors noted that: "Administration of biotin restored her nail and hair growth and improved intellectual ability and school performance." They added that use of acetazolamide, more typically indicated for glaucoma and/or epilepsy, seemed to provide some relief from other symptoms: "episodes of headaches, single limb shaking, and loss of consciousness." And before you say it, yes, autism is no protection against the development of headaches (see here).

Bearing in mind this was a single case report yet also acknowledging the tenet: 'if you've met one person, you've met one autistic person', I find descriptions such as this to often be revealing. Other case reports talking about biotinidase deficiency associated with autism [2], where biotinidase is the enzyme responsible for freeing up biotin bound to food (see here), add to the interest in this area. Specifically how some other symptoms - "seizures, weak muscle tone (hypotonia), breathing problems, hearing and vision loss, problems with movement and balance (ataxia), skin rashes, hair loss (alopecia), and a fungal infection called candidiasis" - associated with biotinidase deficiency are not a million miles away from what has been talked about in some autism literature too (see also the comments section of another post here).

As per my discussions on various other nutrients that seem to be 'deficient' in at least some people on the autism spectrum (see here and see here), the defining message seems to be that post-diagnosis of autism, a screening program needs to be put into place looking at various nutrients in the context of something like eating patterns and behaviours. This could be part of a broader range of screening for something like inborn errors of metabolism that can and do show a connection to some autism (see here) and often (always?) involve nutrients (see here for example). Or could just mirror what is happening in other parts of psychiatry, where physiological parameters are starting to gain some parity with behavioural/developmental/psychiatric ones (see here) mindful of what correcting any deficiency might bring to various aspects of health (see here)...

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[1] Benke PJ. et al. Biotin and Acetazolamide for Treatment of an Unusual Child With Autism Plus Lack of Nail and Hair Growth. Pediatr Neurol. 2018 Feb;79:61-64.

[2] Zaffanello M. et al. A case of partial biotinidase deficiency associated with autism. Child Neuropsychol. 2003 Sep;9(3):184-8.

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Considerable vitamin D deficiency in a specialist secure unit for those with intellectual and developmental disability

The results published by Ian McKinnon and colleagues [1] (open-access available here) reporting that over 80% of patients in "secure care facilities for people with intellectual and developmental disabilities (IDD) who offend, as well as providing specialised services for people with severe autism spectrum disorders" presented with "suboptimal vitamin D levels" came as little surprise to me.

Having already discussed other research on vitamin D levels in another in-patient unit here in Blighty (see here) and more generally how autism seems to be particularly interesting to vitamin D research (see here), the messages seem to be that: (a) those presenting with a behavioural / developmental / psychiatric diagnosis are, in the most part, lacking in vitamin D biologically-speaking for whatever reason(s), and (b) screening for vitamin D levels should be commonplace in such facilities. Current guidance from the UK Government on population vitamin D supplementation also come into play (see here).

McKinnon et al discuss their findings based on a facility not a million miles away from where I currently write this post. They begin: "It is estimated that approximately 50% of the population of Northern England have insufficient or deficient vitamin D levels" which is something that I can vouch for in terms of our sunlight exposure 'ere up North. Further: "It was hypothesised that patients in secure services would have suboptimal levels of 25OHD due to less exposure to sunlight, and as a possible consequence of medications prescribed for mental disorders."

So, looking at two cohorts - existing patients who regularly provided blood samples "as part of their annual health checks" and new admissions to the facility - conveniently adding up to 100 participants, vitamin D was assayed for. Unfortunately, I can't actually find the technique used to test for vitamin D in the McKinnon paper so I can't really comment on whether the gold-standard technique that is mass spectrometry was used. I would assume so but...

Results: taking into account season of testing and various medication use history - "regression analysis demonstrated no effect of season or level of security on the vitamin D status of the patient at baseline" - the results are quite stark. At baseline, only 17 patients (17%!) had results that fell into the 'sufficient' or 'optimal' groupings (above 50 and 70 nmol/L respectively). Forty-two participants had results in the 'insufficient' grouping and even worse, forty-one were deficient.

Based on such results, and with guidance from the National Health Service Specialist Pharmacy Service, a supplementation protocol was put in place for those found to be lacking in vitamin D. Lo and behold, a year later at retesting things looked rather better from a vitamin D perspective: "The numbers of patients with sufficient and optimal 25OHD had improved substantially."

"We recommend further research in this area, including prospective studies of the longer-term health sequelae." I'd second that call from the authors for more research in this area. Not only on vitamin D status and any somatic health-related parameters, but also on what supplementation may or may not mean for some in terms of behavioural presentation too (see here and see here)...

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[1] McKinnon I. et al. Vitamin D in patients with intellectual and developmental disability in secure in-patient services in the North of England, UK. BJPsych Bull. 2018 Feb;42(1):24-29.

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Scurvy and autism yet again...

"Here, we report a case of pediatric scurvy in an 11-year-old autistic child with a restricted diet who presented with refusal to walk, fatigue, a purpuric rash, and gingival bleeding."

Yep, the topic is scurvy and autism surfaces again on this blog (see here and see here and see here for other blogging entries), and yet another case report [1] illustrating how a disease that should really have been banished at least a century ago very much remains a part of modern medicine in some circumstances.

In case you didn't already know, scurvy is a disease of nutrition. A chronic lack of vitamin C (ascorbic acid), pretty vital for the synthesis and upkeep of collagen for example, leads to a variety of symptoms including weakness, fatigue, joint pain and perhaps most famously, bleeding gums (gingival bleeding). Vitamin C is present in many fruits and vegetables or can even be delivered as a supplement. Indeed, some pretty famous people have extolled the virtues of regular vitamin C consumption (see here) albeit with varying degrees of successful results outside of scurvy prevention or treatment.

As I mentioned, scurvy appearing alongside autism is not a novel finding. Restricted feeding patterns exemplified by the inclusion of a small repertoire of foods seems to be THE primary risk factor when it comes to scurvy following a diagnosis of autism. As far as I am aware, once the hurdle of actually diagnosing scurvy has been overcome, treatment with vitamin C supplementation seems to be able to resolve many symptoms pretty quickly both inside and outside the context of autism.

What's more to do in this area? Well, as I've mentioned before, screening for scurvy should perhaps be a lot more commonplace following a diagnosis of autism. Given that restricted feeding patterns - not necessarily including any special diets that are put in place for clinical reasons - are pretty frequent in relation to autism, there's a big case for further examinations for scurvy to be more widespread. Minus any clinical or medical advice being given or intended, use of nutritional supplements in the context of restricted feeding habits and autism might also be a sensible option given potential issues outside of just those linked to vitamin C (see here). Obviously this requires some clinical input to ensure that the right dose and preparation is given, but given the quite painful effects of something like scurvy, the question is: why should a diagnosis of autism be a barrier to sound health and wellbeing?

And as I write, there is yet more [2] appearing on this topic, and yet again treatment with vitamin C led to "rapid improvement"...

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[1] Burhop J. et al. Do You C What I C: Emergency Department Evaluation and Diagnosis of Pediatric Scurvy in an Autistic Child With a Restricted Diet. Pediatr Emerg Care. 2018 Jan 23.

[2] Kinlin LM. et al. Scurvy as a mimicker of osteomyelitis in a child with autism spectrum disorder. International Journal of Infectious Diseases. 2018. Feb 6.

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Pre- and peri-pregnancy use of folic acid and multivitamins and risk of offspring autism

The findings reported by Stephen Levine and colleagues [1] observing that: "Maternal exposure to folic acid and multivitamin supplements before and during pregnancy is associated with a reduced risk of ASD [autism spectrum disorder] in the offspring compared with the offspring of mothers without such exposure" provides the blogging fodder today.

Accompanied by media headlines such as 'Taking vitamins before and during pregnancy slashes autism risk by 75%, new study shows' the Levine paper adds to the growing research literature suggesting that certain nutrients taken during critical periods of pregnancy *might* be important when it comes to offspring development (see here).

"Epidemiologic studies report inconsistent associations between maternal supplementation with multivitamins or FA [folic acid] before and during pregnancy and the risk of ASD in offspring." I'm glad the authors have mentioned that the peer-reviewed literature on folic acid in relation to offspring autism risk is not all one-way. It's something that I've been particularly interested in on this blog for some time (see here and see here for examples) in terms of countering the often simplistic view that mothers-to-be should all be loading up on folic acid for example, to offset any enhanced risk of offspring autism. Yes, folic acid is a required supplement during pregnancy when it comes to something like reducing the risk of  neural tube defects (NTDs) in offspring, but with autism in mind, the evidence is not yet so clear-cut.

Levine et al report results based on Israeli children born between 2003 and 2007 and followed-up until early 2015. Their cohort included "all children with ASD and a randomly selected one-third of all children" born during their index dates including some 45,000 participants in total. When it came to exposure patterns (exposure to folic acid and/or multi-vitamins during pregnancy), the authors relied on a prescription register that included "drug names, prescription and dispensation dates, number of pills dispensed, and ATC codes." Importantly, this meant that researchers were able to classify some important details: "vitamin supplements were classified as FA and/or multivitamin supplements, an FA supplement, and a multivitamin supplement" and the timing of their dispensation: "before pregnancy (540-271 days before childbirth) and during pregnancy (270 days before childbirth up to the date of childbirth)." This is something rather different from some other previous research attempts that have for example, tended to rely on maternal recall of pregnancy supplements.

Results: "This study of 45 300 children revealed a decreased risk of ASD in children born to mothers who used FA and/or multivitamin supplements before and/or during pregnancy compared with those who had not." Among all supplement combinations - FA and/or Multivitamin Supplements, FA Supplements, Multivitamin Supplements - there was a reduced relative risk (RR) of offspring autism compared with 'unexposed' children that was present both before pregnancy and during pregnancy supplementation and took into account various covariates such as "sex, birth year, socioeconomic status (high vs low),17 a maternal and paternal psychiatric diagnosis by childbirth (present or absent), maternal and paternal age at childbirth, and parity." The sorts of risk reduction statistics being talked about - above 50% and even approaching that 75% risk reduction - are not to be sniffed at.

Although quite a good study design, the Levine results are to be treated with some caution. Not least that the authors noted: "causality cannot be inferred from observational epidemiologic studies such as this one" so one has to be careful.

But... yet again, this is further research talking about pregnancy folic acid and offspring autism. This is an area that requires further investigation in relation to possible mechanisms (or combinations of mechanisms) [2] potentially involved. Also, whether specific groups of women taking other important medicines during pregnancy, might benefit from something like folic acid supplementation in the context of enhanced offspring risk of autism [3].

To close, a musical choice to mark the passing of Mark E Smith: Mr Pharmacist (my favourite) or the more widely known, Hit the North?

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[1] Levine SZ. et al. Association of Maternal Use of Folic Acid and Multivitamin Supplements in the Periods Before and During Pregnancy With the Risk of Autism Spectrum Disorder in Offspring. JAMA Psychiatry. 2018. Jan 3.

[2] Goodrich AJ. et al. Joint effects of prenatal air pollutant exposure and maternal folic acid supplementation on risk of autism spectrum disorder. Autism Res. 2017 Nov 9.

[3] Bjørk M. et al. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. JAMA Neurol. 2017 Dec 26.

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"Mitochondrial Modifying Nutrients" and chronic fatigue syndrome: a pilot study

"Recent evidence suggests that mitochondrial dysfunction may play a role in the pathophysiology of chronic fatigue syndrome (CFS)" was the starting point for the study results reported by Ranjit Menon and colleagues [1].

Detailing findings -  "open-label trial" findings - following use of a 'nutraceutical combination' in a small number of participants with CFS, researchers produced evidence that further investigations might be needed. The trial protocol for their investigation can be viewed here. The 'combination' under inspection included "primary nutrients: Coenzyme Q10, Alpha lipoic acid, Acetyl-l-carnitine, N-acetyl cysteine, B Vitamins"; many of which have been shown to act on various "mitochondrial targets" in the context that mitochondria might play a role in at least some cases of CFS (see here for example), but not necessarily all (see here). Indeed, I'll draw your attention when other groups have talked about nutraceutical 'intervention' (see here) in the context of mitochondria and CFS previously (see here and see here).

Over the 16 weeks of the trial period, researchers quite regularly assessed various parameters relating to the core feature of fatigue (based on use of the Chalder Fatigue Scale) and various mood, sleep and general health variables. They observed that alongside "a significant improvement in fatigue symptoms across [the] treatment period on the Chalder Fatigue Scale" there were also some potentially important differences noted in other measures too. Not least with "clinician-reported symptom-improvement" in mind.

Obviously the emphasis on the Menon results being an open trial (i.e. not blinded/masked, not randomised, with no control group), and very much, a small open trial, mean that these are preliminary findings and shouldn't yet be informing any research or clinical opinions. The additional fact that no objective 'actigraphic' measure of physical functioning was included for study is something else to bear in mind. Such results *should* support further research; indeed, one would hope that in this new era of interest and 'changing perspectives' with CFS in mind (see here), many more investigations in this thread would be forthcoming.

And whilst on the topic of clinical trials for CFS, the news out of Norway when it comes to the use of Rituximab is not looking too good despite a previously promising start [2]. No-one said it was going to be easy...

To close, I've nabbed a screenshot of a picture from the film Unrest that I think is starting to take on an almost iconic status...

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[1] Menon R. et al. Mitochondrial Modifying Nutrients in Treating Chronic Fatigue Syndrome: A 16-week Open-Label Pilot Study. Advances in Integrative Medicine. 2017. Nov 15.

[2] Fluge Ø. et al. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358.

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