Saturday, 17 February 2018

The 'oral microbiota' and autism: the power of a spit sample

Although not everyone's cup of tea there's a lot that can be learned from a humble spit (saliva) sample. Buccal epithelial cells from saliva samples provide a medium for the collection and analysis of DNA for example, and alongside, make for a much less invasive collection method than DNA capture from blood samples for example. Saliva also has it's own metabolome, meaning that one can potentially get quite a bit of information on quite an extensive library of small molecules linked to various genetic and biological processes.

Now add the oral microbiota to the list and, as per the findings reported by Yanan Qiao and colleagues [1], how the oral cavity (i.e. the mouth) is home to a complex network of bacteria and relations that might provide some important clues pertinent to various diagnoses.

Autism was the particular diagnosis in the research spotlight this time around, as authors "collected samples from two distinct intraoral habitats, including saliva and dental plaques, in children with and without ASD [autism spectrum disorder]." Analysing over 100 samples provided by 32 children with ASD and 27 not-autism controls, a few interesting things were noted in the results published by Qiao et al.

Bearing in mind this was a cross-sectional study which relied on a 'snapshot' sample over only one testing occasion, authors reported that: (a) data on bacterial richness and diversity showed no significant differences in salivary samples across the groups, but a difference was reported based on examination of those dental plaque samples; (b) "the phylum Proteobacteria was more abundant in ASD patients (both in salivary and dental samples) compared to controls" whilst other phyla predominated in controls; (c) "increased amounts of potential pathogens, including Haemophilus, Corynebacterium, Cardiobacterium, Kingella, Streptococcus and Rothia, were observed in ASD patients" some of which correlated with the measurement of the severity of autism (via parental report on the Aberrant Behavior Checklist (ABC) questionnaire); and (d) "diagnostic models based on key microbes were constructed, with 96.3% accuracy in saliva."

Of course, there is still some way to go in this research area, not least starting with independent replication of the Qiao results perhaps also relying on multiple samples provided across a range of times and situations. Y'know, assuming that medication for example, could be part and parcel of the profile with autism in mind and indeed remembering that autism as a stand-alone label is probably less like 'real-life autism' than many people realise (see here). I'm also a little unsure as to why the Aberrant Behavior Checklist (ABC) was employed "to preliminarily evaluate the severity of ASD" when both so many controls were employed for inclusion/exclusion on the study and so many other more 'autism-specific' instruments are quite freely available (see here for one example). There are things that could have been done differently for sure...

But, this is a good first attempt. It puts the oral microbiome on the research map with autism in mind, added to the more well-known relation: the gut microbiome (see here). It also provides us with a more generalised view of how the bacteria and various other miniature beasties around us, are probably more intricately involved in our lives than we ever previously thought possible...

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[1] Qiao Y. et al. Alterations of oral microbiota distinguish children with autism spectrum disorders from healthy controls. Scientific Reports; 8: 1597.

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Friday, 16 February 2018

Autism, mental health and 'sexual and gender minority' status

The findings reported by Rita George & Mark Stokes [1] piqued my interest recently, and their conclusion that various mental health issues over-represented in autism (see here and see here for examples) might not be just solely connected to the presence of a diagnosis of autism.

Yes, I know this sounds like common sense (see here), but as I've come to realise in relation to lots of diagnostic labels, assumptions very often precede actual (peer-reviewed) evidence.

Based on responses on the DASS-21 (which is fast becoming the go-to measure for the self-report of things like stress, depression and anxiety-like behaviours with autism in mind [2]), researchers compared depression, anxiety and stress scores for over 300 people with autism compared with over 250 "typically-developing individuals." Alongside, membership of a minority grouping in terms of sex and gender, e.g. non-heterosexual, was also thrown into the statistical mix. Results suggested that along with differences in DASS scores being more generally observed between the groups: "As membership to a minority group became more restrictive, mental health symptoms worsened... suggesting stressors added."

Such an investigation follows a scheme of work by this authorship group who, quite recently, also reported that within the same participant group(?), some 70% of those with autism "reported being non-heterosexual" [3]. I was quite taken aback by the high rate of non-heterosexuality reported in this study, bearing in mind that this data was derived from an on-line sample and may not be entirely representative of the full autism spectrum as a function of the use of self-report for example (see here). I might also add that focusing just on autism to the exclusion of some other potentially important comorbid labels [4] could be something that needs to be looked at in future investigations in light of other results on gender variance for example [5].

Minus however, any 'I told you so' sentiments, I have previously mentioned about how gender and sexual identity in relation to autism is both a research-rising area and can often have some quite profound implications for the person concerned (see here). We can um-and-ah about whether there is a 'connection' between autistic traits and sexual orientation (see here) or whether something like gender dysphoria is more or less likely in the context of autism (see here), but there is no denying that gender and sexual identity are variables that can and do potentially impact on mental health. In support of the George/Stokes findings, one need only look to the non-autistic focused research literature to see how various aspects of health-related quality of life for example, are seemingly influenced by variables such as sexual orientation [6] and how this potentially plays out over both childhood and into adulthood [7].

So when George & Stokes talk about: "Specialized care is recommended for this vulnerable cohort" there could be some pretty profound implications associated with timely and appropriate education and support taking into account sexual and gender identity in the context of autism...

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[1] George R. & Stokes MA. A Quantitative Analysis of Mental Health Among Sexual and Gender Minority Groups in ASD. J Autism Dev Disord. 2018 Jan 23.

[2] Nah YH. et al. Brief Report: Screening Adults with Autism Spectrum Disorder for Anxiety and Depression. J Autism Dev Disord. 2017 Dec 2.

[3] George R. & Stokes MA. Sexual Orientation in Autism Spectrum Disorder. Autism Res. 2018 Jan;11(1):133-141.

[4] May T. et al. Trends in the Overlap of Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder: Prevalence, Clinical Management, Language and Genetics. Current Developmental Disorders Reports. 2018. Jan 17.

[5] Strang JF. et al. Increased gender variance in autism spectrum disorders and attention deficit hyperactivity disorder. Arch Sex Behav. 2014 Nov;43(8):1525-33.

[6] Marti-Pastor M. et al. Health-related quality of life inequalities by sexual orientation: Results from the Barcelona Health Interview Survey. PLoS One. 2018 Jan 24;13(1):e0191334.

[7] Petterson LJ. et al. Sex, Sexual Orientation, Gender Atypicality, and Indicators of Depression and Anxiety in Childhood and Adulthood. Arch Sex Behav. 2017 Jul;46(5):1383-1392.

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Thursday, 15 February 2018

Walking as an intervention for good psychological health: number of steps or just enjoyment?

I'm once again returning to the topic of walking for health on this blog (see here) and some rather intriguing findings reported by Karen Hallam and colleagues [1] suggesting that adoption of a 100-day 10,000 steps a day program might have some bearing on aspects of mental and psychological health and wellbeing. But there's a bit of a twist...

The activity program in question was something called Stepathlon which, from what I gather, is a corporate initiative to promote health and fitness among employees. I might add that some employees in some occupations probably don't need such initiatives (see here). Various steps (pardon the pun!) are listed on the Stepathlon website including 'forming a team of 5 with your colleagues', getting yourself a pedometer or other fitness tracker that measures steps and then uploading your daily data on to their platform where it is compared with other groups across the world.

Hallam et al report results for nearly 2000 participants based on 'de-identified' data; also including participant reports based on the completion of the "short form of the Depression, Anxiety Stress Scales (DASS)" and the "Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS)." The various strands of data were analysed, correlated and the like.

Results: "The results of this study highlight some psychological and wellbeing benefits of being engaged in work based 10,000 step programs." The authors talk about observing a nearly 9% reduction in stress levels, 8% reduction in 'signs of depression' and a 5% reduction in anxiety when comparing pre-program with post-program data. They add: "This reinforces the benefits of this type of exercise regimen as playing a small yet significant role in improving mental as well as physical health."

But...

Things were not however completely straight-forward as the authors also talk about a "lack of a dose response" in terms of the number of steps completed and those psychological health and well being parameters being assessed. This could denote a few things: (a) participation in a program that encourages walking - walking in a group setting - may be beneficial irrespective of the number of steps that are actually taken, and/or (b) the wide variability in the number of daily steps taken over the course of the program - remember it lasted 100 days - scuppers any chance of getting meaningful correlation data between walking and psychological health. Indeed on that last point, authors mention that future work should really take into account things like the self-report nature of uploading daily activity levels and also the fact that within the sample there were "clearly individuals who were more active before commencing the program" and for whom such an intervention might not be all that effective given their already raised starting activity levels.

Still, I do think that this is a good piece of research that should encourage further investigation. Aside from the significant physical health benefits associated with getting more active, I'd also like to think that such a program could be further adapted for various groups, particularly when things like stress, depression and anxiety are considered a part of the clinical picture. Autism springs to mind as one such avenue for further study, based on various evidence [2] including result similarly using the DASS-21 tool. Indeed, on another blogging occasion where I critically discussed the suggestion that "
autism acceptance could contribute to mental health in autism" (see here) again based on DASS scores, I wonder if a group walking 'intervention' (although I'm not so sure about medicalising such an activity) could also be the topic of more study too, added to other research?

And finally... bearing in mind that exercise might have some nootropic value for some (see here and see this recent study [3]), it seems that much of the chatter about sitting around video game playing fostering "a broad range of cognitive abilities such as visual processing, attention, spatial ability, and cognitive control" is not readily supported by the current peer-reviewed evidence...

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[1] Hallam K. et al. “Happy feet”: evaluating the benefits of a 100-day 10,000 step challenge on mental health and wellbeing. BMC Psychiatry. 2018; 18: 19.

[2] Nah YH. et al. Brief Report: Screening Adults with Autism Spectrum Disorder for Anxiety and Depression. J Autism Dev Disord. 2017 Dec 2.

[3] Gmiąt A. et al. Improvement of cognitive functions in response to a regular Nordic walking training in elderly women - A change dependent on the training experience. Exp Gerontol. 2018 Feb 9. pii: S0531-5565(17)30663-0.

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Wednesday, 14 February 2018

Low grade intestinal inflammation and autism

The suggestion that low grade intestinal inflammation might be related to some autism comes from the findings reported by Katarina Babinská and colleagues [1] (open-access available here).

Researchers set out to "assess the concentrations of fecal calprotectin in a sample of children with ASD [autism spectrum disorder] and to investigate the correlations of this inflammatory marker with the core behavioral symptoms of ASD."

Faecal calprotectin (FC) is a measure of the amount of calprotectin in a stool (poo) sample. It's typically released in response to the presence of inflammation and, here in Blighty at least, is indicated as "an option to support clinicians with the differential diagnosis of inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) in adults with recent onset lower gastrointestinal symptoms for whom specialist assessment is being considered." 

In terms of research history looking at autism and FC, there is some peer-reviewed science on the topic; also having been included as a parameter in the important paper by Laura de Magistris and colleagues [2] talking about 'leaky gut' in the context of some autism (see here) and how "FC was elevated in 24.4% of patients with autism and in 11.6% of their relatives." Such research is set in the more general context that bowel or gastrointestinal (GI) issues are absolutely no stranger to a diagnosis of autism (see here).

This time around Babinská et al measured FC (via ELISA) in some 87 children diagnosed with an autism spectrum disorder (ASD) aged between 2 and 17 years of age. The authors use the term 'low functioning' to describe this portion of their participant group but I'm rather less enamoured with such labels (see here) despite the well-deserved focus on a group very much under-represented in autism research and other areas. Alongside, over 50 age-matched controls (not-autism) and 29 siblings of children with ASD also provided samples for analysis and comparisons.

Results were not exactly as cut-and-dried as one might have expected. So: "In non-relatives significantly lower values of fecal calprotectin were observed than in both subjects with ASD and their siblings." What this means is that based on group results, those with autism and the siblings of those with autism seemed to manifest higher levels of FC than non-related controls. Based on individual results, where elevated levels of fecal calprotectin was set at 50 µg/g of feces or higher according to test producers guidance as being a level of concern, the frequency of such a finding was greater in those with autism (22%) and their siblings (20%) than in non-related controls (9%) but this difference was reported as 'non-significant'.

Authors also did a little work on another important area in relation to bowel symptoms/pathology and autism: how *might* something like intestinal inflammation 'interact' with the behavioural signs and symptoms of autism? Well, we are told that those diagnosed with autism "had to meet criteria for ASD" on two gold-standard diagnostic tools: the Autism Diagnostic Observation Schedule – second edition and the Autism Diagnostic Interview-Revised (ADI-R). Data from the ADI was examined in the context of the FC findings and lo and behold: "In the group with ASD significant correlations of fecal calprotectin with all domains of the ADI-R diagnostic tool were found: qualitative abnormalities in reciprocal social interaction and communication, restrictive and repetitive patterns of behavior." I say this bearing in mind that similar analyses between FC values and ADOS ratings do not seem to have been either done or reported on for some reason.

When the authors talk about low grade intestinal inflammation as potentially being relevant to some autism, they seem to be accurate insofar as the measured levels of FC in some participants and the *correlation* with autism scores on one of the gold-standard assessment instruments. That being said, there is quite a bit more to do in this area before anyone gets too carried away with the results as they stand. So for example, all that chatter about inflammatory bowel disease (IBD) being related to some autism (see here and see here) did not seem to register in this particular study insofar as the guidance on FC being a marker for possible IBD, albeit based on higher levels of FC being detected: "Active, symptomatic inflammatory bowel disease 200 – 40,000 mg/kg."

I also note that the authors report an important limitation when it came to their research: "Additional factors that might have been a cause of elevated FC levels, such as nutritional or gastrointestinal factors were not analysed." Nutritional factors eh? Y'mean like milk type for example [3] or other dietary and/or environmental factors such as the implementation of a gluten-free diet [4] positively affecting FC levels? Indeed, there are lots of potential factors that could cause a 'false-positive' when it comes to elevated FC such as infections like C. diff or gastrointestinal conditions such as coeliac disease, many of which have shown some important connections to autism (see here for example).

It looks like there is still much more research to do in this area but investigations should definitely continue.

To close, my brood have just discovered the brilliant film 'The Great Escape'. As well as setting up many, many discussions about war, bravery and captivity, they've also commented on the theme tune...

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[1] Babinská K. et al. Fecal calprotectin levels correlate with main domains of the autism diagnostic interview-revised (ADI-R) in a sample of individuals with autism spectrum disorders from Slovakia. Physiol Res. 2017 Dec 30;66(Supplementum 4):S517-S522.

[2] de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

[3] Ho S. et al. Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study. Eur J Clin Nutr. 2014 Sep;68(9):994-1000.

[4] Balamtekın N. et al. Fecal calprotectin concentration is increased in children with celiac disease: relation with histopathological findings. Turk J Gastroenterol. 2012;23(5):503-8.

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Tuesday, 13 February 2018

Once more... listen to parents: on the identification of the early behavioural signs of autism

"The results suggest that parents may detect some clinically informative behaviors based on their day-to-day observations more readily than do clinicians during brief clinical assessments."

So said the findings reported by Lori-Ann Sacrey and colleagues [1] who compared the views of parents "of children at high-risk of autism spectrum disorder (ASD; have an older sibling with ASD)" with clinicians opinions when it came to reporting on around 20 clinical signs that could indicate the presence of autism.

Clinicians relied on the Autism Observational Scale for Infants (AOSI) to make their judgements and parents used the Autism Parent Screen for Infants (APSI) (a sort of parent-version of the AOSI) for theirs when infants were between 12 and 18 months of age. Infants being 'observed' subsequently underwent "a blind independent diagnostic assessment for ASD at 36 months of age" to see how accurate those earlier parent and clinician observations were.

The old adage that 'parents generally know their children best' shines through in the Sacrey results with "parent-reported symptoms being better able to differentiate between children with and without ASD at both 12 and 18 months of age compared to clinician observations during a brief office visit." No, most parents aren't experts when it comes to child development and no, typically they aren't seeing lots of children on a day-to-day basis who may present with various developmental issues including autism. But... compared with an often "brief clinical assessment", all those day-in day-out observations that are made - particularly when autism is 'already a part of the family' - do seem to count for quite a bit. Once again, we would all do well to listen to parents (see here) and any concerns they have about their child's development. I might add that combined with the recording technology available to most people these days and the tendency for many parents to document their child's every developmental move, there is potentially plenty of data available for further analysis (see here).

There are a few other issues that could come into play as a result of the Sacrey and other, related but independent findings. I tend to go on quite a bit on this blog about how various 'comorbidities' (if I can still call them that) seem to be over-represented when it comes to a diagnosis of autism. One of the more prevalent ones is that of bowel / gastrointestinal (GI) issues (see here) which is becoming more readily accepted in various circles as being a part of the clinical picture for quite a few people on the autism spectrum. I've talked before about how parents were/are typically the first ones to pick up the bowel-side of things and how, their observations of their own child's bowel symptoms, can on many occasions, provide some important 'pointers' to the professionals (see here). I see the Sacrey work as an extension of this other research, as the message 'listen to parents' continues to be a consistent theme.

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[1] Sacrey LR. et al. Parent and clinician agreement regarding early behavioral signs in 12- and 18-month-old infants at-risk of autism spectrum disorder. Autism Res. 2018 Jan 22.

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Monday, 12 February 2018

Methylphenidate affecting academic performance meta-analysed

When first tweeting about the paper by Anne Fleur Kortekaas-Rijlaarsdam and colleagues [1] I kinda made a mistake. The text of the tweet read something like: "Does methylphenidate improve academic performance? A systematic review and meta-analysis... Pretty much so, but only in relatively small amounts."

Reading that tweet back to myself I realised that by saying 'but only in relatively small amounts' it's highly likely that any readers might have thought that I was talking about the dose of methylphenidate (MPH) rather than the [intended] effect on things like "math productivity (7.8% increase, p < .001); math accuracy (3.0% increase, p = .001); [and] increased reading speed (SMD .47, p < .001)." I apologise, and once again reiterate my blogging (and social media) caveat about not giving anything that looks, sounds or smells like medical or clinical advice.

I did think it worthwhile to write a short post about the Kortekaas-Rijlaarsdam findings given that (a) ADHD (attention-deficit hyperactivity disorder) is something that turns up quite a bit on this blog (see here for example), and (b) pharmacotherapy 'for ADHD' is an important intervention area which has also, unfortunately under some circumstances, been 'hijacked' for other purposes (see here). On that last point, I specifically refer to the idea that for some people, striving for a diagnosis of ADHD is merely a route to either better academic accommodations or perhaps more worryingly, to gain access to a class of medicines with some potentially significant 'cognitive-enhancing' qualities...

What sets the Kortekaas-Rijlaarsdam findings apart from other reviews of the potential nootropic (cognitive enhancing) abilities of something like MPH is their focus on resolving the issue of "whether there are improvements in core academic skills or just improvements in academic productivity" in the context of "the mediating or moderating effects of symptom improvements, demographic-, design- and disorder-related variables."

From a starting number of 148 full-text research articles, the collected texts were screened for eligibility and some 34 were eventually included for meta-analysis ("quantitative synthesis"). These articles were included because they "provided information about either accuracy or productivity scores for math, reading or spelling, or a combination of these" or could at least be calculated on the basis of their included data. Various mediating and moderating variables were also thrown into the statistical mix - "age, gender, percent diagnosed with ADHD-inattentive subtype, and study characteristics: release system, trial duration, and titration method" - and results reported.

As per previous sentences, various aspects of maths performance showed an improvement that correlated with MPH use, and reading speed but not accuracy also came out as potentially showing a relationship with medicine usage. Important too was the information that: "None of our mediators or moderators influenced MPH effects on math and reading accuracy or productivity."

So, following meta-analytic scrutiny of some 1700 children, it looks like there is a small but potentially relevant effect from MPH use of some academic abilities, at least in the short-term ("between 1 and 7 days"). The authors do well not to stray too much into speculating mode when it comes to the cause of any nootropic effect but instead to include the need for more research "to isolate groups of patients who may benefit more or less from MPH and to reveal its mechanism of action." Can't argue with that.

And going back to the topic of cognitive enahncers, an interesting article from a few years back on what they may or may not be doing to elements of our University student body...

Music to close... Sia and Chandelier. Seemingly always playing outside my dojo....

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[1] Kortekaas-Rijlaarsdam AF. et al. Does methylphenidate improve academic performance? A systematic review and meta-analysis. Eur Child Adolesc Psychiatry. 2018 Jan 20.

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Saturday, 10 February 2018

The latest CDC figures on ADHD medication trends among women aged 15-44

The report published by Kayla Anderson and colleagues [1] has made quite a few media headlines (see here for example) based on their observations that: "The percentage of privately insured reproductive-aged women who filled a prescription for an ADHD [attention-deficit hyperactivity disordermedication increased 344% from 2003 (0.9%) to 2015 (4.0%). Further: "ADHD medication prescriptions increased across all age groups and U.S. geographic regions, and the increase was confined to stimulant medications."

"The new report raises questions about the increasing use of a diagnosis that once was reserved for children and adolescents" was one of the issues discussed following the publication of the Anderson report. This continues a theme in psychiatric circles on whether the diagnosis of ADHD is being 'over-used' across many different age groups [2]. Another issue - that of the potential performance-enhancing abilities of certain medicines commonly indicated for managing ADHD (see here for a recent review [3]) - has also come into the media spotlight too as a result of these latest findings.

A further point of discussion has also been noted by Anderson et al: "ADHD medication prescriptions are increasingly common among privately insured, reproductive-aged women. Additional research on ADHD medication safety among this population, including safety before and during pregnancy, could help women and their health care providers make evidence-based decisions concerning the risks and benefits of pharmacologic and behavioral treatment options for common conditions, including ADHD." The question raised is whether use of something like "a prescription for mixed amphetamine salts... for lisdexamfetamine.. for methylphenidate" is 'safe' before and during pregnancy when it comes to offspring health, wellbeing and development?

The area of pregnancy medicine use is a particularly complicated issue. Not least because various medicines used before and during pregnancy have come under the spotlight in recent times, in terms of their potential effects on the unborn child. Ranging from the pretty convincing valproate story (and guidance) (see here) to the *possible* effects of various anti-depressants (see here) to that of over-the-counter pain relief medicines (see here), the research literature is quite 'lively' when it comes to pregnancy pharmacotherapy. Of course there are gaps in the literature as it stands, and one should never forget that many of the prescription medicines under the research spotlight are not typically prescribed and dispensed willy-nilly, but...

In relation to 'stimulant medication' indicated for ADHD and any effect(s) on the unborn child, we're not yet in any position to make any valued judgements just yet. There is some research out there [4] and it's not all positive [5] but a lot more investigations are indicated. I say that bearing in mind that: (a) ADHD might not be the only condition/label given to some mothers, which will likely affect their medication profile too (see here for example), and (b) much like other work looking at medicines and risk of 'adverse' childhood issues, there's always the possibility that the risk to offspring *might* be elevated as a result of the underlying condition being treated/managed (i.e. ADHD) or some related comorbidity irrespective of any medication influences.

I'm not coming out as any sort of 'champion' for ADHD medications (despite their quite impressive safety and efficacy profiles) but neither am I going to demonise a whole class of medicines based on a currently pretty scant evidence base. Understanding also how much of an effect a diagnosis of ADHD can have on a person (see here and see here for examples), further investigations are indicated before hype and sweeping generalisations take hold.

And this is not the first time that research has indicated that ADHD medication use is on the up (see here)...

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[1] Anderson KN. et al. Attention-Deficit/Hyperactivity Disorder Medication Prescription Claims Among Privately Insured Women Aged 15-44 Years - United States, 2003-2015. MMWR Morb Mortal Wkly Rep. 2018 Jan 19;67(2):66-7

[2] Danielson ML. et al. Prevalence of Parent-Reported ADHD Diagnosis and Associated Treatment Among U.S. Children and Adolescents, 2016. J Clin Child Adolesc Psychol. 2018 Jan 24:1-14.

[3] Kortekaas-Rijlaarsdam AF. et al. Does methylphenidate improve academic performance? A systematic review and meta-analysis. Eur Child Adolesc Psychiatry. 2018 Jan 20.

[4] Nörby U. et al. Perinatal Outcomes After Treatment With ADHD Medication During Pregnancy. Pediatrics. 2017 Dec;140(6). pii: e20170747.

[5] Bro SP. et al. Adverse pregnancy outcomes after exposure to methylphenidate or atomoxetine during pregnancy. Clin Epidemiol. 2015 Jan 29;7:139-47.

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