Thursday, 22 March 2018

PACE trial for chronic fatigue syndrome (still) being put through its paces

'Chronic fatigue trial results 'not robust', new study says' went the BBC headline reporting on the findings published by Carolyn Wilshire and colleagues [1].

Authors reports peer-reviewed results following their re-examining various aspects of the PACE trial - "pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation" - with regards to chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME).

This latest research and accompanying media attention continues a quite long-running saga (see here) known in some quarters as 'PACE-gate' (see here) where questions have been raised about a premier study that was "designed to examine the effectiveness of graded exercise therapy (GET) and cognitive behavioural therapy (CBT)" in relation to CFS/ME. Quite a few of those interventions are set within the still unfortunately believed idea that CFS/ME represents a 'biopsychosocial' illness (see here) and that 'changing mindsets and/or behaviour' will magically transform peoples lives. I say 'still unfortunately believed' because patient experiences do not seemingly match some of the peer-reviewed science in this area (see here).

The various twists-and-turns (see here and see here) around the PACE trial have involved bigger discussions about trial design, outcome threshold 'issues' and even the accessibility of research study data. Indeed, the Information Commissioner here in Blighty has even played a hand in the PACE saga (see here) leading to some rather messy and very public arguments.

The paper by Wilshire et al continues a theme from this research group re-examining the PACE trial protocols and findings. It encompasses various elements in terms of definitions of 'overall improvement' and even 'recovery' (see here) between 'specified in trial protocol' and 'used in published reports'. Wilshire and colleagues report: "Our findings suggest that, had the investigators stuck to their original primary outcome measure, the outcomes would have appeared much less impressive."

Insofar as recovery rates - other work [2] related to the original PACE trial paper had indicated some impressive recovery rates following CBT and/or GET - Wilshire has more things to say here too. So: "when recovery rates were calculated using the definition specified in the published protocol, these were extremely low across the board, and not significantly greater in the CBT or GET groups than in the Control group." It might seem like common-sense to know what recovery should look like when it comes to CFS/ME, but again, the waters have been continually muddied (see here).

"Some notable strengths of the PACE study included the large sample size..., the random allocation of patients to treatment arms, the use of a well-formulated protocol to minimise drop-outs, and the reporting of the full CONSORT trial profile (including detailed information about missing data)." Wilshire et al illustrate how the PACE trial was, initially, a good piece of science from a methodological point of view, but: "the design, analysis and reporting of the results introduced some significant biases."

And now it may be time to move on: "The time has come to look elsewhere for effective treatments." CBT and/or GET are still the topics of study when it comes to ME/CFS (see here and see here) but are seemingly finding it more and more difficult to find acceptance. The recent news that NICE are looking to update their guidance on CFS/ME in light of 'changes' made by other official bodies (see here) and some significant patient (and political) power, reflect an increasingly changing mood. An increasing realisation that talking and exercise therapies might not be the best treatment options for a somatic condition that has the propensity to *significantly* drain both health and other aspects of quality of life (see here).


[1] Wilshire CE. et al. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology. 2018; 6: 6.

[2] White PD. et al. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35.


On mitochondrial DNA (mtDNA) changes and autism

Mitochondrial issues accompanying some diagnoses of autism have quite a bit of peer-reviewed research backing (see here for example). Not for everyone, but for some people diagnosed with an autism spectrum disorder (ASD), there seems to be something afoot with regards to these 'powerhouses of the cell' that could well impact on various aspects of their lives [1]. Indeed, keep that paper from Poling et al [1] in mind...

Although by no means an expert on mitochondrial issues in any context, I believe that there are a few ways in which mitochondrial dysfunction can manifest. It can present as a secondary disorder for example (see here), where some acquired biochemistry (non-genetic) provides some of the 'answers'. Or it can present as a primary mitochondrial disorder, a genetic condition "confirmed by a known or indisputably pathogenic mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutation" [2], where issues in the genetic code of mitochondria are present.

The recent findings reported by Noémi Ágnes Varga and colleagues [3] focused on that latter route looking at issues with mtDNA in the context of autism. They turned up some rather interesting results...

So: "The aim of the present study was to investigate the presence of the most common pathogenic mtDNA alterations in patients with ASD." Researchers screened 60 children with autism and 60 not-autism controls. One detail stuck out when it came to those controls: "Our control group for mtDNA screening consisted of 60 European adults (26 females and 34 males, median age = 28 years, IQR = 13.75) selected from our biobank." Compared with those participants diagnosed with autism, they were quite a bit older (median age = 7 years vs. median age  = 28 years) and indeed, the gender ratios were a little bit more balanced.

Anyhow: "Mitochondrial deletions were identified in 16.6% (10/60) of our patients with ASD." OK, 'patients' is not exactly the word I would use for participation in such a research project but that shouldn't distract from the findings. Varga et al also provide some further insights into those 10 'participants' with a diagnosis of autism and mtDNA deletion(s) which turned up some other interesting details, such as the finding that various other symptoms presented alongside autism. Quite a few of them were connected to muscle and movement functions (limb and truncal ataxia, hypotonia, dyspraxia) which ties into other independent findings [4]. I also noted the words 'gluten sensitivity' were mentioned in one case, which is guaranteed to perk my professional interest (see here) although I'm still a little unsure of whether this connected to mtDNA issues or not.

Another set of potentially important details were also observed by researchers when comparing those with autism with and without mtDNA deletion(s). Keeping in mind the small numbers falling into that autism with mtDNA deletion(s) category, developmental regression seemed to be an important facet of the clinical profile of this group. Regression of previously acquired skills is something else I've talked about quite a bit on this blog with regards to autism (see here and see here for examples). Going back to that paper by Jon Poling and colleagues [1] that I told you to keep in mind, it's interesting to note the overlap of regression reported by them and also reported by Varga in the context of mitochondrial disorder. And this isn't the only occasion that regression and mitochondrial issues have been talked about in the same breath as autism [5] and even with other potentially important clinical indicators [6]. Correlation is not necessarily causation but...

There are quite a few other details listed in the Varga paper that I'd encourage readers to pursue but I think I've gone on enough about this topic for now. It, yet again, appears that a diagnosis of autism is protective of nothing when it comes to other conditions/diseases/symptoms/labels appearing and perhaps implies that preferential screening for mitochondrial disorder should be more commonplace than it is as and when autism is diagnosed. I'm also inclined to draw your attention to other clinical labels where mitochondrial issues might be relevant for some (see here) albeit not always with genetics in mind (see here). How perhaps investigations need to be carried out looking at any possible intersection between *some* autism and something like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (see here) for example, also in light of other important data (see here). Indeed, I'll be coming to the findings reported by Bilevicute-Ljunger and colleagues [7] on this topic quite soon in a separate post...


[1] Poling JS. et al. Developmental Regression and Mitochondrial Dysfunction in a Child With Autism. J Child Neurology. 2006;21(2):170-172.

[2] Niyazov DM. et al. Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment. Mol Syndromol. 2016 Jul;7(3):122-37.

[3] Varga NA. et al. Mitochondrial dysfunction and autism: comprehensive genetic analyses of children with autism and mtDNA deletion. Behavioral and Brain Functions. 2018. 14: 4.

[4] Ghaoui R. & Sue CM. Movement disorders in mitochondrial disease. J Neurology. 2018. Jan 6.

[5] Rossignol DA. & Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012 Mar;17(3):290-314.

[6] Shoffner J. et al. Fever plus mitochondrial disease could be risk factors for autistic regression. J Child Neurol. 2010 Apr;25(4):429-34.

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


Wednesday, 21 March 2018

Autistic traits + borderline personality disorder traits = enhanced risk of suicide ideation?

Following some quite recent discussions on this blog about how autism-related dimensions are not necessarily always autism-specific dimensions (see here) in the context of Borderline Personality Disorder (BPD), I'm talking today about the findings reported by Henri Chabrol & Patrick Raynal [1].

They detail some still emerging evidence that, alongside "significant comorbidity between ASD [autism spectrum disorder] and BPD", there could be some rather important outcomes arising from possessing both significant autistic traits and borderline personality disorder traits in the more general population when it comes to risk of suicide ideation. Further, that such data could also cast some light on that important issue for both clinical conditions and contribute to the pressing need to reduce any excess risk(s).

I've covered the issue of suicide - ideation, attempted and completion - on this blog a few times (see here). It's a topic that requires careful handling (see here) and something that, in respect of the core blogging material here, requires important continued attention (see here and see here).

Chabrol & Raynal detail results following the self-report of several parameters: autistic and BPD traits, thoughts of suicide and "depressive symptomatology" in a cohort of college students (N=474). They reported that, whilst BPD traits and autistic traits were only "weakly correlated", those participants who presented with both high BPD and high autistic traits (approaching 20% of their total sample) were the ones who expressed "the highest level of suicidal ideation."

Bearing in mind that this was research carried out with a 'non-clinical' population and a population that might not be necessarily completely representative of everyone else, additional investigations are warranted. Whether for example, the clinical combination of autism and BPD might elevate the risk of suicide ideation or beyond is one issue to be explored, particularly given research observing that suicide risk is not unknown to the diagnosis of BPD. I might also add that given the possibility of even greater complexity in behavioural/psychiatric presentation [2] coinciding with other observations in relation to some autism (see here), quite a wide research view might need to be taken. This coinciding with more and more evidence to suggest that autism is not typically a stand-alone diagnosis (see here).

And if anyone needs to talk to someone, organisations like the Samaritans are only an email or phone call away...


[1] Chabrol H. & Raynal P. The co-occurrence of autistic traits and borderline personality disorder traits is associated to increased suicidal ideation in nonclinical young adults. Comprehensive Psychiatry. 2018. Feb 15.

[2] Fan AH. & Hassell J. Bipolar disorder and comorbid personality psychopathology: a review of the literature. J Clin Psychiatry. 2008 Nov;69(11):1794-803.


Tuesday, 20 March 2018

"given that 81.6% of the children diagnosed with ASD had IQs below 40"

The quote titling this post - "given that 81.6% of the children diagnosed with ASD [autism spectrum disorder] had IQs below 40" - was part and parcel of the findings published by Zhijuan Jin and colleagues [1] who set about estimating the prevalence of autism or ASD among children resident in Shanghai, China.

This is not the first time that research groups have set out to determine the estimated prevalence of autism at a city / region / countrywide level in China [2], but does, I think, mark the first time that said prevalence estimates have been based on the DSM-5 description of autism (well, almost the first time [3]).

Looking at a population of some 75,000 children resident in Shanghai and aged between 3-12 years old, details of a two-stage project are described this time around. Parents and teachers completed the Social Communication Questionnaire to identify those children who might be 'at-risk' for autism/ASD. Those who were picked up as being 'at risk', were then subject to some rather more comprehensive assessment based on the use of DSM-5, of which just over 200 children were "identified as ASD cases." The estimated prevalence figure arrived at was 8.3 per 10,000 although the authors suspect that this is an underestimate...

But then back to that opening quote, and a quite a notable percentage of children diagnosed with autism who also presented with a low IQ classification. Bearing in mind the fact that there are differences in IQ ranges across different instruments, an IQ rating of 40 or below (age-adjusted) typically indicates quite a significant cognitive impairment or delay and is one facet of the diagnosis of learning (intellectual) disability. The observation from Jin et al that over 80% of their cohort could potentially be defined as such provides some important data on the combination of autism and learning disability (LD).

On previous blogging occasions when the topic of autism and LD has been discussed, the question of how prevalent is LD in autism has been a difficult one. On some occasions, the data has suggested that around 35% of children with autism have LD on the basis of IQ scores (see here). On other occasions, a figure nearer 70% has been implied (see here). The Jin data suggest that in their cohort, 70% may actually be quite a conservative estimate.

I would like to see more study on this topic. I'd like to know whether, seemingly like other ethnic groups, learning disability + autism is the more typical presentation when it comes to autism in Chinese children and how this plays out as children age into adulthood. I'd like to know whether the distinction between autism and social (pragmatic) communication disorder (SCD) noted in the DSM-5 exerted any effect on the Jin data. I'd like to know quite a bit more on this rather interesting area of investigation...


[1] Jin Z. et al. Prevalence of DSM-5 Autism Spectrum Disorder Among School-Based Children Aged 3-12 Years in Shanghai, China. J Autism Dev Disord. 2018 Feb 16.

[2] Sun X. et al. Prevalence of autism in mainland China, Hong Kong and Taiwan: a systematic review and meta-analysis. Mol Autism. 2013 Apr 9;4(1):7.

[3] Jiang L. et al. Epidemiological investigation on autism spectrum disorders among preschool children in Shanghai. Zhonghua Liu Xing Bing Xue Za Zhi. 2015 Dec;36(12):1365-8.


Monday, 19 March 2018

One more time... ADHD is over-represented in cases of epilepsy

"Among the 73 children with epilepsy, 23% (n = 17) had comorbid ADHD [attention-deficit hyperactivity disorder], of whom 59% (n = 10) had predominantly inattentive type, 35% (n = 6) combined type, and 6% (n = 1) predominantly hyperactive-impulsive type."

So said the findings reported by Anita Choudhary and colleagues [1] adding to an ever growing body of peer-reviewed research literature suggesting that a diagnosis of epilepsy may, for whatever reason(s), elevate the risk of ADHD being diagnosed or, at the very least, the symptoms of ADHD occurring (see here).

This time around, Choudhary et al focused on data derived from a children's neurology service where epilepsy was "defined as two or more unprovoked seizures occurring 24 hours apart after four weeks of age, with at least one epileptic seizure in the previous five years, regardless of AED [anti epileptic drugtreatment, based on International League Against Epilepsy definitions."

As per the opening sentence, some 73 children aged 6-12 years old met their study eligibility criteria; being part of a larger trial where data on behavioural comorbidity in the context of epilepsy had already been published [2]. Importantly for this latest study, the authors excluded those who "had an intellectual disability or comorbid chronic systemic disease" which seems to be rather relevant to the clinical picture emerging with regards to epilepsy in the context of a condition 'over-represented' in ADHD, autism (see here). Alongside a behavioural/psychiatric evaluation based first on parent/caregiver ratings and if required, followed up with a more professional consultation, researchers also carried out assessments related to cognitive functions and reviewed health records.

Aside from noting that ADHD seemed to be over-represented among their cohort with epilepsy, authors also talked about a couple of variables that also seemed to be important to the presentation of ADHD in those with epilepsy. So: "Children with both epilepsy and ADHD had lower IQ scores and were significantly less likely to be attending school, with epilepsy being the primary reason." That point about the presence of epilepsy *correlating* with lower IQ scores is not necessarily something prevalent across the research in this area, but some authors have talked about a "subgroup of about 10–25% of children that shows a clinically significant intellectual decline" [3] which could potentially be relevant.

Pertinent biological mechanisms crossing both epilepsy and ADHD? Well similar to the last blogging occasion, one has to mention that epilepsy does affect various brain functions (see here) so that is something to consider as also impacting the likelihood of ADHD. Whether this means affecting something structural or something like connectivity, we just don't know at present. I'm also minded to highlight the possibility of genetic overlaps too; drawing on work in autism where autism genes are not just genes for autism (see here) so one might consider a similar scenario pertained for at least some with the epilepsy-ADHD diagnostic combination...


[1] Choudhary A. et al. Childhood epilepsy and ADHD comorbidity in an Indian tertiary medical center outpatient population. Sci Rep. 2018 Feb 8;8(1):2670.

[2] Choudhary A. et al. Behavioral comorbidity in children and adolescents with epilepsy. J Clin Neurosci. 2014 Aug;21(8):1337-40.

[3] Vingerhoets G. Cognitive effects of seizures. Seizure. 2006; 15: 221-226.


Saturday, 17 March 2018

"specificity for diagnosis was relatively low": the psychometric properties of autism diagnostic measures

The quote accompanying this fairly brief post - "specificity for diagnosis was relatively low" - comes from the findings reported by Sarah Wigham and colleagues [1] who undertook a systematic review of various "structured questionnaires and diagnostic measures" used in the assessment of autism in adults.

Their conclusions, based on some 20 studies identified in the current peer-reviewed literature, suggest that 'could do better' is a phrase best suited to various measures currently used to identify adults with autism, particularly in the context of an often complicated clinical picture (see here).

Similar things have already been discussed on this blog (see here for one example). In particular, how individual self-report 'are you autistic?' screening instruments whilst making good 'pop psychology' (see here) are absolutely no match for a thorough professional clinical assessment, save other important diagnoses/conditions being overlooked and going unmanaged (see here and see here). I know this puts the concept of 'self-diagnosis' as a result of the use of such instruments in some hot water, but as in many other branches of medicine and psychiatry, professionals and the assessments they conduct are there for a very good reason. Whether you can access such assessments in a timely fashion is an entirely different issue...

When I first tweeted about this paper being published, I emphasised one author on the Wigham paper in particular: Dr Tom Berney. The reasoning behind this was because of his involvement/link to research that has looked at how we identify adults with autism here in Blighty on the back of some headlines a few years back on estimating how many adults have autism here (see here). He, alongside some other notable authors who highlighted that '1% of adults with autism' figure, also talked about how some of the screening/assessment instruments used in that study weren't really cutting the epidemiological mustard [2]. It appears they might have been right.

So what lessons can be learned from this recent review? Well first, that whilst autism-related behavioural dimensions are vitally important to a diagnosis of autism, they are not universally specific to a diagnosis of autism, is important. Second is the need to perhaps move away from often very brief autism screening instruments that seem to provide a 'quick snapshot' to something rather more far-reaching and comprehensive. I know we all want a 'quick answer' that uses as few finite resources as possible, but sometimes, to get something right, you need to spend time and resources looking at it carefully. And diagnosing professionals also need to be mindful of notions of 'frank autism' too (see here). Finally, I'd like to re-emphasise that autism plus [3] does seem to be more typical these days, over autism appearing in some sort of diagnostic vacuum. As Wigham et al opine: "Robust autism spectrum disorder assessment tools specifically for use in adult diagnostic health services in the presence of co-occurring mental health and neurodevelopmental disorders are a research priority." Indeed they are.


[1] Wigham S. et al. Psychometric properties of questionnaires and diagnostic measures for autism spectrum disorders in adults: A systematic review. Autism. 2018 Feb 1:1362361317748245.

[2] Brugha TS. et al. Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community. Psychol Med. 2012 Mar;42(3):647-56.


Friday, 16 March 2018

Carefully: effect of SSRI use on "rating-scale-assessed suicidality in adults with depression"

I stress the word 'carefully' in the title of this post discussing the findings reported by Jakob Näslund and colleagues [1] because it covers the very sensitive idea that "selective serotonin reuptake inhibitors (SSRIs) have been claimed to elicit or aggravate suicidal ideation."

I think it's sensible to begin this post by stressing that (a) NO medical or clinical advice is given or intended on this blog, and (b) anyone with concerns about their taking this class of medicines really needs to speak to their physician BEFORE making any changes to their prescribed medication routine. I know that point (b) sounds like me giving medical / clinical advice but it's common sense to talk to your medical professional first who's spent years studying and probably years practising medicine, rather than tinker around yourself...

There is always a balancing act to consider when discussing research such as this. A medicine indicated for various clinical conditions, that is taken by many, many people, and quite successfully treating / treated (nay, very successfully [2]) a condition that can, without treatment, have life-limiting consequences. No-one wants to rock the boat and scare or deter people from accessing such a treatment. At the same time however, one needs to know everything about that medicine; not least whether for some, there may be side-effects to possibly consider...

It's been a quite a long running saga talking about the possible additional effects of SSRI use for some (see here). It's drawn heavily on often harrowing individual stories and perspectives and not also been helped by the seeming (in)actions of some of the manufacturers of such medicines (see here). Näslund et al decided to approach this delicate topic from the point of view of analysing "the effect of [SSRI] treatment on rating-scale-assessed suicidal ideation in individual patients." This is distinct from other work that has focused on actual suicides or "suicide-related adverse events" that have been carried out before. The authors suggested that their approach might have the advantages of measuring the "net influence of treatment on suicidality at a group level" as well as the ability to "detect individual cases of emergence or aggravation of suicidal ideation." To this end, scores on the Hamilton Rating Scale for Depression (HRSD) particularly focused on "item 3 of the HRSD" covering suicidal ideation/attempts, was a core feature of their study covering "young adults (18–24) (n = 537) and adults (≥25) (n = 7725)." Said participants were derived from "all industry-sponsored, HRSD-based, FDA-registered placebo-controlled studies undertaken to explore the effects of citalopram, paroxetine or sertraline in major depression in adults."

Results: "In patients above the age of 24, SSRIs were found to reduce the mean rating of the HRSD suicidality item from week 1 until study end-point and also to reduce the risk for aggravation of suicidal ideation and emergent suicidal behaviour." This is very good news. It provides "strong support for the view that the net effect of SSRI treatment is beneficial rather than harmful" when it comes to suicide ideation/contemplation bearing in mind the specific focus on on item on the HRSD. I will again link to the recent findings by Cipriani and colleagues [2] reporting that: "All antidepressants were more efficacious than placebo in adults with major depressive disorder." It doesn't, as Näslund et al suggest, rule out rare cases of 'adverse effects', but does suggest that any such extreme side-effects are not likely to be encountered by most people who take such medicines.

When however it came to those younger adults (aged 18-24 years), the results were a little less straight-forward. So: "In young adults, those given an SSRI were at enhanced risk for worsening of suicidal ideation (in the unadjusted analysis) or emergent suicidality (loose but not strict definition) during the late (weeks 3–6) but not the early phase (weeks 1–2) of treatment." You'll see from the number of brackets used in that last quote that the authors provide some caveats to such findings; but this shouldn't take away from the trends observed. Indeed, bearing in mind such findings and also that "both SSRIs and placebo resulted in an end-point rating of suicidality equal to that observed in adults given an SSRI and lower than that observed in adults given placebo" you kinda get the impression that further investigations are needed to ascertain for example, whether depression and/or suicidality in the 25 and overs is somehow 'different' from depression in the younger age group. At least, different insofar as what treatment choices might be primarily made available. No, I'm not saying that this is evidence enough that SSRIs should have some sort of age restriction, just that cost/benefit ratios might perhaps have to be a little more 'age-sensitive' as well as individual-sensitive.

And, if anyone needs someone to talk to, there are resources available.


[1] Näslund J. et al. Effects of selective serotonin reuptake inhibitors on rating-scale-assessed suicidality in adults with depression. Br J Psychiatry. 2018 Feb 5:1-7.

[2] Cipriani A. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018. Feb 21.


Thursday, 15 March 2018

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).


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]...


[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.