2017 autism research review on Questioning Answers

All hail The Onion

So, it comes around again. The annual 'what was hot in autism research this year' review for 2017.

I'm a bit pressed for time as you probably are too, so I'll make it short this year and pull together a sort of top 5 research areas that emerged/continued in 2017 based on the 300-odd entries made on this here Questioning Answers blog this year. So, in no particular order...

1. Physical activity and autism received a whole lotta research attention this year (see here). Guess what? Exercise is kinda good for lots of different reasons (see here and see here for examples), some of which may well tie into various aspects of a diagnosis of autism too (see here).

2. Psychosis and/or schizophrenia can manifest alongside autism and vice-versa (see here and see here). And such symptom combinations may have important implications for management too (see here). I know this area of research potentially carries a lot of 'baggage' with it, but burying heads in the sand isn't gonna help. It also reiterates the ideas that (a) there is no substitute for a thorough professional assessment when autism is suspected (see here) and (b) overlaps with a bigger question on whether quite a lot of the 'comorbidity' discussed with reference to autism, might in some cases be something so much more 'core'...

3. We should all be listening a lot more to autistic people / people with autism (see here and see here, and yes, it should be 'who speaks for whom'!). This doesn't mean that important parent/carer voices are somehow silenced given the important role(s) they can and do play (see here). Just that we can learn a lot more when voices are combined. I'm also minded to suggest disposing of the term 'neurotypical' or NT in 2018 and beyond (see here) given the absurdity of assuming that anyone is at all 'neurotypical' or indeed, assuming that everyone on the autism spectrum are somehow 'neurodiverse'. Oh, and going back to the representation of autism in the media, don't assume that fictional portrayals are always going to please everyone all of the time (see here)...

4. Sexual identity and preference(s) in relation to autism is rising in research terms (see here and see here). Granted, some of the associations that have been reported on need quite a bit more study (see here) but alongside talk about gender dysphoria rates in autism (see here), important questions need asking and answering. I know some people might see this research area as a bit 'so what?' but one shouldn't underestimate how important gender and sexual identity can be to a person for lots of different reasons.

5. The continued rise and rise of the systematic review and/or meta-analysis in relation to autism research. Not everyone is (or should be) completely enamoured with such collected analyses, particularly in light of the term 'if you've met on person with autism, you've met one autistic person'. But such data are casting a little more 'generalised' light on many areas of autism research and practice and providing some nice general directions for further study. A few this year included: fatty acid use and autism (see here and see here), anxiety and autism (see here), visual issues and impairments and autism (see here) and breastfeeding and autism (see here). For the most part, such analyses have added to the ideas that (a) autism does not normally reside in some sort of diagnostic vacuum; and (b) receipt of a diagnosis of autism should represent a 'starting point' for further investigations not the finishing line.

So there you have it.

I'm also going to make a prediction about one important direction that autism research (and practice) will continue on in 2018: even more recognition that the diagnosis of autism rarely exists in a diagnostic vacuum...

I'll hopefully catch you all in 2018. Happy New Year!

Music to close the year, and I'm going for the Eye of the Tiger yet again. C'mon, get up and practice your punching arms (or Sanbon tsuki if you prefer) to the beat. You know you want to*.

* No medical advice is given or intended. Please consult your medical professional in you have an existing health condition before beginning any new exercise regime. I mean it...

Amyotrophic Lateral Sclerosis (ALS) and neuropsychiatric symptoms in kindreds

"Neuropsychiatric symptoms in addition to schizophrenia, including obsessive-compulsive disorder, autism, and alcoholism, occur more frequently in ALS [amyotrophic lateral sclerosis] kindreds than in controls."

So said the findings reported by Margaret O’Brien and colleagues [1] observing something of a curious *association* between ALS (also called Lou Gehrig's disease after the American baseball player and/or motor neuron disease) and behavioural/psychiatric presentation(s) among first- and second-degree relatives.

I have actually talked about ALS before on this blog, with reference to ALS and the finger length ratio (see here) and also how a diagnosis of autism is seemingly not protective against the development of ALS (see here) (and what happens when 'it's their autism' sentiments perhaps interfere with sound medical investigation). But this is the first time I've covered the possibility of a familial link between ALS and autism (and other labels), even if not being the first time that it has been seen in the peer-reviewed domain [2]...

O'Brien et al identified patients diagnosed with ALS from the Irish Register of ALS and included some 130 people into their study. Alongside a roughly equal number of sex- and age-matched non-ALS controls, the frequency of various neuropsychiatric disorders was determined among their first- and second degree relatives.

Results: "A total of 77 patients with ALS (61.4%) and 51 control participants (38.6%) reported at least 1 first-degree or second-degree relative with a history of schizophrenia, psychosis, suicide, depression, alcoholism, or autism." The authors mention that risk was not however uniform across participants with ALS, as two subgroups emerged "based on the number of family members with a neuropsychiatric condition: expected (0-2) and high (≥3)." They also noted that issues with the gene C9orf72 (chromosome 9 open reading frame 72) linked to quite a few cases of ALS did not seemingly explain their findings: "A total of 5 of 29 probands (17.2%) with a strong family history of neuropsychiatric conditions (≥3 first-degree or second-degree relatives) carried the C9orf72 repeat expansion."

There are potentially important points raised by the data from O'Brien and colleagues but one of the first things we need is replication, and replication across different populations given for example, some [seeming] disparity in the prevalence of ALS world-wide [3] and what that could mean for kindred psychopathology. I am also drawn to some comments made by authors on the O'Brien paper in relation to other work on ALS and schizophrenia [4] for example, stressing how "the divide between psychiatry and neurology is a false one." This is perhaps important when one looks at the relationship between autism and epilepsy (see here) for example, and whether one should see epilepsy in such cases as a comorbidity or indeed, something rather more 'integral' to that particular 'type of autism'. I'm favouring the latter in light of the evidence being produced (see here) which could have some important implications for many areas of autism research and practice (see here for one example).

Mechanisms? I don't think we're even able to think about possible mechanisms just yet but...

No-one really knows what causes ALS despite the link being made with the genetics of C9orf72 and some cases. I note that the current CDC information on ALS talks about some studies suggesting "a possible link with exposure to heavy metals (e.g., lead and mercury)" or other environmental stressors. This could be rather interesting to look at from the point of view of exposure not necessarily being the key issue but rather genetic and biological differences in how the body stores/gets rid of such compounds as being important; bearing in mind what seems to be appearing in the autism literature on this topic (see here) for example. Just one thought...

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[1] O'Brien M. et al. Clustering of Neuropsychiatric Disease in First-Degree and Second-Degree Relatives of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurology. 2017. Oct 16.

[2] Goodman AB. et al. A family history study of schizophrenia spectrum disorders suggests new candidate genes in schizophrenia and autism. Psychiatr Q. 1994 Winter;65(4):287-97.

[3] Chiò A. et al. Global Epidemiology of Amyotrophic Lateral Sclerosis: a Systematic Review of the Published Literature. Neuroepidemiology. 2013;41(2):118-130.

[4] McLaughlin RL. et al. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nat Commun. 2017 Mar 21;8:14774.

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Congenital cytomegalovirus (CMV) infection and autism continued and meta-analysed

The findings - based on systematic review and meta-analysis - reported by Kaori Maeyama and colleagues [1] make for important reading on the topic of an "association of congenital cytomegalovirus (CMV) infection with autism spectral disorder (ASD)." CMV by the way, is a herpesvirus that can be potentially transmitted during pregnancy from mother to developing child and can, in some instances, lead to various adverse developmental and neurodevelopmental outcomes.

I've talked about CMV and autism a few times already on this blog (see here and see here) including the idea that, outside of any possible *link* with some autism, there may [eventually] be ways and means of protecting against some of the adverse effects of such viral exposure during such a critical period (see here) (with lots more research required).

Maeyama et al concluded that a "high prevalence of congenital CMV infection in ASD cases (OR 11.31, 95% CI 3.07-41.66) was indicated" on the basis of their analysis of the collected research literature published so far. They caution however, that quite a bit more research is required. Not least on how much of a contribution CMV infection might make to the very broad autism spectrum.

As I've said before on this topic, the data so far produced suggest that 'CMV-related autism' (if I can call it that) is likely to be quite a rare occurrence but we don't know for sure. Part of that stems from the fact that I don't think CMV is routinely screened for during pregnancy (at least here in Blighty) and I'm pretty sure that most autism assessments/diagnostic procedures probably won't also ask about or include a screen for CMV exposure either. It's therefore highly likely that we don't yet know the true extent to which CMV infection may/may not be linked to autism.

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[1] Maeyama K. et al. Congenital Cytomegalovirus Infection in Children with Autism Spectrum Disorder: Systematic Review and Meta-Analysis. J Autism Dev Disord. 2017 Nov 28.

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Music therapy for social skills in autism: RCT says not...

"Adding IMT [improvisational music therapy] to the treatment received by children with ASD [autism spectrum disorder] did not improve social affect or parent-assessed social responsiveness."

So said the report published by Crawford and colleagues [1] commenting on recent research [2] observing that IMT might be 'music to the ears' but seemingly not so when it comes to altering symptom severity in the social affect domain of autism.

I'm no expert on IMT in any context so approach this topic with some caution. I remember quite a few years back watching and hearing about sessions where IMT was used as part of a schedule of interventions in the context of autism (see here) and thinking at the time, that it's inclusion seemed like quite a good idea. The data from Bieleninik and colleagues [2] perhaps urge caution that 'sounding good' might not necessarily translate into better outcomes when put under the scientific microscope.

So, 360 or so children diagnosed with ASD were randomised to receive either 'enhanced standard care' (ESC) or ESC + IMT (IMT delivered at high- and low-frequency among this group). I have to say that whilst ESC initially sounded pretty good, I was a little disappointed to hear that it meant "usual care as locally available plus parent counseling to discuss parents' concerns and provide information about ASD." Parent counselling? Remind me what year we're in if this is all we've got under the label of ESC.

After 5 months of ESC and ESC+IMT the scores on the Autism Diagnostic Observation Schedule (ADOS) social affect domain showed... no significant difference between the groups. Even most of the secondary outcomes (17 of 20) showed no significant difference. In short, IMT added to that ESC failed to significantly impact on social affect compared to ESC alone.

An accompanying editorial on the Bieleninik findings [3] talked about the implications of the trial results particularly in light of a previous Cochrane review [4] which suggested that "music therapy may help children with ASD to improve their skills in primary outcome areas that constitute the core of the condition including social interaction, verbal communication, initiating behaviour, and social-emotional reciprocity." The authors urge caution that the previous Cochrane review examined various different types of music therapies for example and whilst coming out on the side of music therapy for autism, determined the scientific quality of available research at that time to be "as either moderate or low quality."

Where next for IMT? Well, I'm going to be a bit more up-beat about this intervention that usual. I say that on the basis that music therapy is probably going to be one of the more 'risk-averse' interventions put forward for autism (first, do no harm and all that). Whilst social affect was not seemingly 'statistically' affected by its inclusion as an intervention option, this does not mean that other facets of autism - whether core or peripheral - might not benefit from its use with some people on the autism spectrum. On this note, I'll refer you to the paper by Pavlicevic and colleagues [5] and the suggestion that "long-term shared therapeutic musicking provides young adults with ongoing opportunities for experiencing confidence and self-esteem, with feelings of shared acceptance and success." Music to the ears eh?

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[1] Crawford MJ. et al. International multicentre randomised controlled trial of improvisational music therapy for children with autism spectrum disorder: TIME-A study. Health Technol Assess. 2017 Oct;21(59):1-40.

[2] Bieleninik L. et al. Effects of Improvisational Music Therapy vs Enhanced Standard Care on Symptom Severity Among Children With Autism Spectrum Disorder: The TIME-A Randomized Clinical Trial. JAMA. 2017 Aug 8;318(6):525-535.

[3] Broder-Fingert S. et al. Music Therapy for Children With Autism Spectrum Disorder. JAMA. 2017; 318(6): 523-524.

[4] Geretsegger M. et al. Music therapy for people with autism spectrum disorder. Cochrane Database Syst Rev. 2014 Jun 17;(6):CD004381.

[5] Pavlicevic M. et al. Making music, making friends: Long-term music therapy with young adults with severe learning disabilities. J Intellect Disabil. 2014 Mar;18(1):5-19.

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Various symptoms cluster around psychosis but...

The findings reported by Abigail Livny and colleagues [1] provide some [brief] blogging fodder today. Looking to "characterize the symptoms of patients later hospitalized for psychotic disorders in primary mental health outpatient settings" researchers found several variables seemed to be *correlated* in their target population (N=1092).

So: "thought disorder, perceptual abnormalities, poor orientation, and suicidality was associated with an increased risk for hospitalization for nonaffective psychotic disorder" as a function of various time periods. The hazard ratios (HRs) produced were not to be sniffed at. The authors concluded however that: "Despite the increased risk, the positive predictive values of this symptom cluster were low" suggesting that looking for such a symptom cluster does not necessarily guarantee prediction of "later hospitalization for nonaffective psychotic disorder."

It remains the holy grail of psychiatry to be able to 'predict' who might go on to develop something like a clinical diagnosis of psychosis or other related condition and onward, target those vulnerable groups/people with appropriate screening and other required services. Whilst there is seemingly no end of potential 'behaviours to watch for' (indeed, conditions/labels to watch for too), the fact of the matter is that we still don't [reliably] know who will or won't go to develop psychosis. And I doubt that position will change very much without some greater focus on biological 'risk' markers also added to the mix (see here and see here for examples)...

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[1] Livny A. et al. A Population-Based Longitudinal Study of Symptoms and Signs Before the Onset of Psychosis. Am J Psychiatry. 2017 Nov 28: appiajp201716121384.

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"people with a diagnosis of schizophrenia have an increased hazard of being obese"

Warm but not hot on the heels of a previous post potentially turning upside-down our understanding of inflammatory markers in the context of schizophrenia (see here) I'm bringing the paper by Isobel Cameron and colleagues [1] to the blogging table.

What's the link you may ask?

Well, if one assumes that the Hartwig findings [2] on inflammatory markers in schizophrenia could be 'influenced' by the presence of increasing body mass index (BMI) talked about in other research [3] one should, most definitely, be looking at how weight and/or BMI issues manifest in relation to schizophrenia as Cameron et al did.

So with the aim of estimating levels of obesity "in a national population sample by comparing patients with schizophrenia with matched controls" nearly 5000 adult cases of schizophrenia and "19 752 controls matched by age, gender and practice" were initially identified from a database covering Scotland. Further: "Patients with a recorded BMI were classified as obese (BMI ≥30 kg/m2) or not obese (BMI <30 kg/m2)."

Results: bearing in mind that other population statistics point to obesity not being an unfamiliar health issue in Scotland (see here) as in many other parts of the world, authors reported that: "people with a diagnosis of schizophrenia have an increased hazard of being obese when compared with adults matched by age, gender and practice attended." Taking into account occasions where "no BMI, height and weight were recorded in the 3 years before entry into the PCCIU database" researchers presented two different statistics. One where missing data were treated "as not obese following the logic that as there was no weight or BMI recorded the GP saw no clinical need to obtain these measures" and the other where records were excluded when BMI was not recorded. Both ways were associated with "an increased obesity hazard" to a similar sort of degree.

"Our analyses show that even within a nation with a substantial obesity prevalence, patients with schizophrenia are significantly more likely to be obese." This isn't of course the first time that issues with weight (or BMI) have been noted in the peer-reviewed science domain with schizophrenia in mind [3] and I doubt it will be the last.

The question should then be: what can be done about overweight and obesity in the specific context of schizophrenia? For potential answers to that, I'll refer you to some of the collected works of Dr Brendon Stubbs and colleagues (see here) and their very thorough reviews and meta-analyses on all-manner of topics that potentially tie into such a weighty issue...

This is my last post before Christmas, and so includes a traditional(?) song to send best wishes to all (hopefully not from the drunk tank)...

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[1] Cameron IM. et al. Obesity in individuals with schizophrenia: a case controlled study in Scotland. British Journal of Psychiatry Open. 2017; 3: 254-256;

[2] Hartwig FP. et al. Inflammatory Biomarkers and Risk of Schizophrenia: A 2-Sample Mendelian Randomization Study. JAMA Psychiatry. 2017 Nov 1.

[3] Annamalai A. et al. Prevalence of obesity and diabetes in patients with schizophrenia. World J Diabetes. 2017 Aug 15;8(8):390-396.

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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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Maternal obesity and offspring autism meta-analysed (yet again)

I think the findings reported by Sanchez and colleagues [1] make it at least the third time (see here and see here) that a meta-analysis has been conducted on the collected peer-reviewed research asking the question: does maternal weight before and/or during pregnancy affect offspring risk of being diagnosed with autism spectrum disorder (ASD)?

Granted the emphasis this time around was on "the association between maternal pre-pregnancy overweight/obesity status and child neurodevelopmental outcomes" (bold added by me), but the general question is similar to that looking at pregnancy overweight/obesity status, and whether such anthropometric variables might show an effect. The answer: according to the existing literature (see here for example) is yes; for whatever reason(s) "compared with children of normal weight mothers, children whose mothers were overweight or obese prior to pregnancy were at increased risk for compromised neurodevelopmental outcomes." A diagnosis of autism was but one outcome highlighted by the Sanchez results, as attention-deficit hyperactivity disorder (ADHD) also showed a potential *correlation* (see here).

"Of 1483 identified papers, 41 were included in the systematic review, and 32 articles representing 36 cohorts were included in the meta-analysis" indicating that there is some degree of confidence in a possible *correlation* between maternal weight and offspring outcomes.

What do the results mean? Well, being cautious that correlation is not necessarily the same as causation, and understanding that there may be a multitude of variables 'under' the issue of maternal obesity before and during pregnancy, there are a couple of potentially important implications arising from such findings. Pregnant mothers and potential mothers-to-be are already bombarded with quite a lot of information aimed at keeping themselves and their [potential] offspring 'healthy'. Part of that advice talks about how watching what you eat and maintaining a good physical activity schedule are key elements. Evidence like this from Sanchez et al perhaps add another dimension to any advice given; bearing in mind that pregnancy weight is probably not going to be an important factor for all autism or all ADHD. Indeed, the chances are that such findings are probably going to be part of a 'bigger picture' when it comes to risk profiles.

Mechanism(s) of effect? Potentially lots. Once again I'm going to zoom in on the idea that inflammation potentially generated by something like obesity [2] could be an important issue given all the previous chatter about maternal immune activation (MIA) and 'some' autism (see here). I don't doubt that there could be other factors to consider, but that's all I can [reliably] provide at the moment [3].

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[1] Sanchez CE. et al. (2017) Maternal pre-pregnancy obesity and child neurodevelopmental outcomes: a meta-analysis. Obesity Reviews. 2017. Nov 22.

[2] Lumeng CN. & Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011 Jun;121(6):2111-7.

[3] van der Burg JW. et al. The role of systemic inflammation linking maternal BMI to neurodevelopment in children. Pediatr Res. 2016 Jan;79(1-1):3-12.

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MoBa does... maternal pregnancy iodine intake and offspring ADHD symptoms and diagnosis

Yet another 'MoBa does...' post today, reflecting data derived from the Norwegian Mother and Child Cohort Study and the findings reported by Marianne Hope Abel and colleagues [1] (open-access available here).

Maternal pregnancy iodine intake (both calculated from food sources and also as a supplement) was the starting variable, where responses to "a food frequency questionnaire (FFQ)" provided researchers with enough data to categorise mums-to-be in terms of their iodine intake. Iodine, by the way, is something of an important nutrient from many biological reasons; not least for optimal thyroid function. During pregnancy, suitable iodine levels are also seemingly required to ensure that the developing child is able to reach their full potential (see here).. seemingly.

Alongside, researchers also looked at both children diagnosed with attention-deficit hyperactivity disorder (ADHD) and "maternal report of child ADHD symptoms at eight years of age" on the basis of other data talking about "a negative impact on child behavior problems when mothers had inadequate iodine intake from food and initiated use of supplemental iodine in the first trimester of pregnancy." Keep in mind that last part about supplemental use during early pregnancy...

So, including some 77,000 mother-child pairs where "for 27,945 there were data on maternally reported ADHD scores when the child was aged eight years", what did the researchers find?

"Iodine from food was significantly associated with maternally reported child ADHD symptoms at eight years of age... but not with risk of child ADHD diagnosis." Authors expanded on this observing that the 'inattention' side of ADHD symptoms, derived from a questionnaire covered in independent research [2], was the driving force behind the connection being made, not the hyperactivity subscale. They also noted that "maternal iodine intake of less than ~200 µg/day" seemed to be the crucial cut-off point when it came to those maternal reports of ADHD symptoms.

But... I'm sure it can't have escaped your attention that although maternal reports of offspring ADHD symptoms - indeed, inattention - *correlated* with maternal iodine intake, there was little to see when it came to "risk of specialist-diagnosed ADHD in the child." Indeed, the authors also note that they found "no evidence of any beneficial effect of supplemental iodine in pregnancy" and even that "initiating iodine supplement use within the first trimester in mothers with inadequate iodine intake from food (<EAR) was associated with both an increased risk of ADHD diagnosis and higher ADHD symptom score at eight years of age."

Science is [almost] never clear-cut in the conclusions it arrives at and the Abel results just add to that sentiment. Given that this authorship group seemingly having a considerable research interest in all-things iodine and health, I'm assuming that these latest results were quite the talking point. Certainly, just a little bit different from their other recent publication on this topic [3] that concluded: "Maternal iodine intake below the Estimated Average Requirement during pregnancy was associated with symptoms of child language delay, behavior problems, and reduced fine motor skills at 3 y of age" but perhaps not with the supplementation angle in mind: "results showed no evidence of a protective effect of iodine supplementation during pregnancy."

I don't know what and how much to make of the findings as they stand, aside from suggesting that other recent findings [4] also questioning the value of daily iodine supplementation "in mildly iodine-deficient pregnant women" perhaps add to the discussions in this area. MoBA represents a great resource in these days of population science, so one can't blame the findings on a lack of "large sample size, prospective design, extensive collection of data, and the possibility of linking the cohort to national registries." It could, therefore, well be that talk on iodine supplementation during early pregnancy perhaps needs a lot more science behind it before anyone makes any grand, sweeping claims about its usefulness...

To close, in case you're wondering about the photo included in this post, it's all part of the Public Health England 'celebrations' for 100 years of public health marketing (see here).

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[1] Abel MH. et al. Maternal Iodine Intake and Offspring Attention-Deficit/Hyperactivity Disorder: Results from a Large Prospective Cohort Study. Nutrients. 2017 Nov 13;9(11). pii: E1239.

[2] Silva RR. et al. A rating scale for disruptive behavior disorders, based on the DSM-IV item pool. Psychiatr Q. 2005 Winter;76(4):327-39.

[3] Abel MH. et al. Suboptimal Maternal Iodine Intake Is Associated with Impaired Child Neurodevelopment at 3 Years of Age in the Norwegian Mother and Child Cohort Study. J Nutr. 2017 Jul;147(7):1314-1324.

[4] Gowachirapant S. et al. Effect of iodine supplementation in pregnant women on child neurodevelopment: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Nov;5(11):853-863.

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The art of the gut microbiome: 'Excretory Wipings' across 45+ years

Excretory Wipings May 18-October 21, 1970 is a piece of art composed by the artist Billy Apple (more accurately known as Billy Apple®). Due to possible copyright issues et al I don't want to show the actual piece on this blog but will describe to you what it comprises: a conceptual art work including toilet paper with erm, traces of a bowel movement provided during that particular period of 1970.

It's probably not everyone's cup of tea when it comes to art, but believe it or not, it might potentially be a rather important research starting point if say you wanted to characterise the gut microbiome past and present. Indeed, that is exactly what the paper by Thilini Jayasinghe and colleagues [1] describes, as they compared the bacterial colonies present in the 1970 sample(s) with a more up-to-date set of samples provided by the same artist in 2016.

Some media interest in the Jayasinghe results can be seen here. In short, three archived samples sourced from the 1970 art piece were compared with three more recent samples sourced exactly 46 years later (2016). Researchers performed 16SrRNA sequencing to "study bacterial phylogeny and taxonomy" [2] and try and find out whether there were similarities/differences in the types of bacteria present and indeed, whether overall bacterial diversity had reduced/stayed the same/increased between the testing periods.

Following this N=1 study, a few details emerged. So: "We observed that 45% of the microbial species were retained over the 45 year interval." Such a finding has to bear in mind that the artist "was suffering from diverticular disease in 2016" and that such a condition may well impact on the type of gut bacteria that is present and/or predominating. Indeed, the authors talk quite a bit about how "the 2016 microbiomes contained significantly higher level of genus Prevotella... which may be related to the observed diverticular disease by having a negative impact on gut immune system." Interestingly too, the word 'butyrate' appears in the Jayasinghe text, as in lower levels of butyrate-producing bacteria being present in the more recent sample. Butyrate is currently going through a period of bacterial 'sainthood' [3] at the moment...

Next: "The diversity of the microbial species from samples taken when Apple was 80 years of age was lower than that from samples when he was 35." Bacterial diversity is something of real interest these days, as more and more people start talking about gut bacterial diversity (and the loss of it) as potentially being related to all-manner of life-enhancing and life-not-so-enhancing correlations. The recent results are framed by the authors in the context of being "consistent with the idea of a drift towards a core microbiome" where ageing seems to play a role in diversity.

Of course, one shouldn't forget that this was a N=1 study and that gut bacterial populations are subject to all-manner of influences pushing and pulling on what bacteria may or may not be present in a longitudinal sense. These latest results say very little outside of what happened to the bacterial profile of Billy Apple® between the testing occasions.

But I'm still intrigued by such findings and the idea that there may be other resources to 'tap into' when it comes to looking either long-term at gut bacterial profiles or indeed, comparing gut bacterial patterns as a function of time and various ages. Y'know, comparing bacterial profiles of various ages in years gone by with similarly aged participants in more modern times, and trying to determine what various factors linked to modern life might have done (or not) to gut bacterial profiles. I don't doubt that some results might be rather interesting and discussion-provoking...

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[1] Jayasinghe TN. et al. Long-term stability in the gut microbiome over 46 years in the life of Billy Apple®. Human Microbiome Journal. 2017; 5-6: 7-10.

[2] Janda JM. & Abbott SL. 16S rRNA Gene Sequencing for Bacterial Identification in the Diagnostic Laboratory: Pluses, Perils, and Pitfalls . Journal of Clinical Microbiology. 2007;45(9):2761-2764.

[3] Canani RB. et al. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World Journal of Gastroenterology : WJG. 2011;17(12):1519-1528.

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The 'hard' martial arts and health benefits systematically reviewed

Shotokan karate is a hobby of mine. I say 'hobby' but for me it's become so much more than that. It's not just that I find myself practising my age-uke (pronounced 'aggey-uki') or various favourite kata whenever I have some space free around me; it's more in relation to how it's been a route for me to live a lot more healthier [active] lifestyle more generally. I am indeed at one with myself...

A recent paper by Sandra Origua Rios and colleagues [1] provides some good evidence that practising the martial arts - the 'hard martial arts such as karate, taekwondo or kung fu - carries quite a few health benefits for adults. Based on their searching the collected peer-reviewed research literature and use of the Effective Public Health Practice Project tool, authors concluded that most studies on such training carried positive effects "showing some improvement and maintenance of balance, cognitive function and psychological health" when practised by adults. Studies like this one from Witte and colleagues [2] tell you quite a lot about what you need to know. All this is good news indeed to the many, many practitioners of such martial arts. Also an added boost to the masses that will undoubtedly take up one or more of the arts when they watch the very best demonstrate their skills at the 2020 Olympics...

Of course it's not necessarily all 'positive' when it comes to the use of martial arts and health and wellbeing. The authors note that 'risk of injury' is always going to be a concern when engaging in disciplines that rely on strikes, blocks and throws and 'confrontation of force by force'. In the context that risk of injury is a risk carried by most, if not all sporting activities, the authors add that the majority of injuries sustained in the hard martial arts tend to be minor; particularly when practising at less than elite competitive level (as most people do). Indeed, on the specific point of injury risk, I can add a few things: (a) developing 'control' when sparring (we call it 'kumite') is a key point that comes from practice and more practice, and (b) protective equipment such as mitts and on occasion, gum shields and various, ahem, parts-of-body protectors, are available and sometimes used. Other injuries such as bruising, blistering and some occasional joint pain/stiffness are typically short-lived and clear up after a few days of rest. I might also mention that actually facing an opponent and 'not fearing getting hit' is something else important that comes from such training, given that most people aren't used to being in such an atypical situation and tend to panic (and that's when injuries can happen).

Origua Rios et al also suggest that more research is required on the risk-benefit profile of the hard martial arts including evidence based on randomised controlled trials (RCTs) tracking "morbidity and mortality in the long term." I would agree; but with the proviso that looking at hard martial arts vs. no martial arts training is not necessarily going to be the only methodological way forward in light of other, more general evidence talking about sedentary behaviour and health-related quality of life for example. Indeed, when one talks about 'cognitive functions' potentially being positively affected by martial arts training, it would be useful to see comparisons with the more 'soft' martial arts such as Tai Chi for example, to see how and why such as effect might originate and perhaps generalise. I have my ideas about where any maintenance/improvement to cognitive abilities may originate from in karate terms (try learning and retaining knowledge of all those kata!) but more scientifically-derived information is required.

I know that the hard martial arts probably won't be everyone's cup of tea. I know some people might think it's a bit too rough or challenging or something for those with sprightly athleticism who can 'do a really good high kick'. I would however caution against such preconceptions. As my instructor(s) often say: quality of movement is better than speed or height of said movement (or words to that effect).

And with physical activity (PA) and cognitive functions in mind, it's perhaps also timely that a recent meta-analysis from Celia Álvarez-Bueno and colleagues [3] has also been published talking about how: "PA, especially physical education, improves classroom behaviors and benefits several aspects of academic achievement, especially mathematics-related skills, reading, and composite scores in youth." I daresay that getting more children and young people involved in the martial arts might have a similar effect; although ensuring that due care and attention is paid to 'enjoyment' as being a big part of why someone does or does not stick to a particular sport (see here).

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[1] Origua Rios S. et al. Health benefits of hard martial arts in adults: a systematic review. J Sports Sci. 2017 Nov 21:1-9.

[2] Witte K. et al. Comparing the effectiveness of karate and fitness training on cognitive functioning in older adults—A randomized controlled trial. Journal of Sport and Health Science. 2016; 5: 484-490.

[3] Álvarez-Bueno C. et al. Academic Achievement and Physical Activity: A Meta-analysis. Pediatrics. 2017. Nov 22.

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ADHD and risk of injuries meta-analysed (again)

"ADHD [attention-deficit hyperactivity disorder] is significantly associated with an increased risk of unintentional injuries and ADHD medications have a protective effect, at least in the short term, as indicated by self-controlled studies."

So concluded the "systematic review with meta-analyses" conducted by Maite Ruiz-Goikoetxea and colleagues [1] pertinent to "the association between ADHD and risk of unintentional physical injuries in children/adolescents." The '(again)' mentioned in the title of this post references the findings reported by Amiri and colleagues [2] that were discussed earlier this year on this blog (see here).

Ruiz-Goikoetxea et al do make mention of the Amiri meta-analysis and how post-2014 (the point at which the Amiri systematic review and meta-analysis halted) "several methodological sound studies have been published." They also mention how the Amiri analysis "did not control for gender effects, which are a crucial confounder due to the association of both risk of UPIs [unintentional physical injuries] and ADHD to male gender" nor how they looked at the impact of medications for ADHD on the risk(s) of such injuries.

Splitting their analyses in two (a) a risk analysis looking at the risk of UPIs with ADHD in mind and (b) a medication analysis looking at the role (or not) of medication in terms of UPIs in the context of ADHD, authors report results based on their already published protocols [3]. They reported on "odds ratios (ORs) or hazard ratios (HRs) estimating the association between ADHD and injuries" and cumulatively included participant numbers in the tens of thousands.

Results: "a significantly higher risk of injuries in ADHD compared to children or adolescents without ADHD" was observed. Nothing particularly novel there. Also, based on the finding that: "Methylphenidate was the most frequent drug among children and adolescents with ADHD", researchers reported on "a significant protective effect of the medication" on injury risk. The size of the risk reduction for UPI when medication was used was estimated at about 10%.

Once again, I can't argue with the associations made in terms of how a diagnosis of ADHD does 'up' the risk of physical injury and how medication might be one option out of several to reduce the risk of UPIs in the context of ADHD. Added to other work talking about how medication might also positively affect specific risk of motor vehicle accidents in the context of adult ADHD (see here) for example, it's becoming clearer that intervention helps. I appreciate that there may be some consumer resistance to the idea of 'medicating children' but the data so far on the cost-benefit profile of something like methylphenidate for ADHD is pretty favourable (see here). Certainly, one has to be careful about making too many negative sweeping statements about such medication (see here for example) just for the sake of it.

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[1] Ruiz-Goikoetxea M. et al. Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: a systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews. 2017. Nov 21.

[2] Amiri S. et al. Attention deficit/hyperactivity disorder and risk of injuries: a systematic review and meta-analysis. J Inj Violence Res. 2017 Jun 1;9(2).

[3] Ruiz-Goikoetxea M. et al. Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: protocol for a systematic review and meta-analysis. BMJ Open. 2017 Sep 25;7(9):e018027.

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Mortality patterns in older adults with learning disability

"Older adults with ID [intellectual disability] in Sweden carry a higher mortality risk compared with the general population, mainly attributable to respiratory, nervous and circulatory diseases."

So said the findings reported by Nawi Ng and colleagues [1] (open-access) looking at the records of some 15,000 individuals diagnosed with an intellectual (learning) disability compared with a similar number of control participants with respect to "patterns and risk of mortality." Researchers observed "a 4-fold higher mortality rate and a shorter median survival time among older adults with ID compared with the general older adult population." Such findings add to a growing body of research literature (see here and see here) suggesting that behavioural, cognitive and/or psychiatric diagnoses seem to be accompanied by some significant health inequalities too.

I could go into the details about the Ng study and the various ins-and-outs of how they arrived at their conclusions but to be honest, I'm just not minded to. I say that on the basis that the figures speak for themselves: "the mortality rate among individuals with ID was three times higher than in the control population" and: "Individuals with DS [Down's syndrome] had an 11-fold higher mortality risk than the control population." Sombre reading, perhaps partially reflecting how modern-day society treats some of its most vulnerable citizens.

The ultimate question should be: is there anything that can be done to improve this situation for those with a learning disability? Yes, is the answer; taking into account how a diagnosis of ID for example, means that some might be "more prone to cardiovascular disease risk factors, morbidity and mortality than the general population." The authors add that: "Cardiovascular disease health promotion and prevention programmes should be tailored for individuals with ID, to prevent or delay cardiovascular diseases and premature mortality in this vulnerable group." Corresponding action in relation to deaths resulting from epilepsy for example, should also (and always) be a priority.

"How a society treats its most vulnerable is always the measure of its humanity" is a phrase attributed to many speakers. On the basis of the research from Ng and other study results, society is seemingly failing many of those diagnosed with a learning disability as it is other vulnerable sections of society (see here).

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[1] Ng N. et al. Mortality patterns and risk among older men and women with intellectual disability: a Swedish national retrospective cohort study. BMC Geriatrics. 2017; 17: 269.

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"patients with CFS/ME do not exhibit insufficient concentrations of circulating total 25(OH)D"

The title heading this post comes from the findings reported by Kate Earl and colleagues [1] (open-access available here), where '25(OH)D' refers to calcifediol, a compound typically used to estimate how much vitamin D is present in the body and CFS/ME refers to Chronic Fatigue Syndrome / Myalgic Encephalomyelitis.

After assaying some 92 people with CFS/ME and an almost equal number of 'age-matched healthy controls' (HCs) for plasma total 25(OH)D and individual vitamin D metabolites - "25(OH)D2 and 25(OH)D3" - researchers concluded that vitamin D deficiency was not rife in their cohort. Indeed we are told that: "total 25(OH)D was significantly higher (p=0.001) in serum of patients with CFS/ME compared with HCs (60.2 and 47.3 nmol/L, respectively)." The authors were also able to report that vitamin D supplementation by the CFS/ME group seemed to be a primary reason for their findings.

There are a few important strengths to the Earl results that are worth mentioning. Not least that vitamin D metabolites were measured by mass spectrometric methods similar to other independent research occasions (see here for example). Mass spectrometry seems to have quite a few advantages over other methods of vitamin D analysis; now labelled as a gold-standard technique. Added to their use of a deuterated standard ("hexadeuterated (OH)D3") and one has some degree of confidence in the analytical results; albeit, as the authors acknowledge: "that only the main marker of vitamin D status, that is, 25(OH)D, was measured" and how "there is a need to assess all of the vitamin D metabolites" of which there are quite a few [2].

At first glance, the Earl findings seem pretty unremarkable. Supplementation with vitamin D, as everyone is being encouraged to do these days (see here), means higher levels of circulating vitamin D. I would be surprised if they didn't. This is also not the first time that vitamin D levels in relation to CFS/ME have been talked about in the peer-reviewed domain either (see here) albeit not always with the same results but again with that caveat about supplementation in mind.

Given however that a measure of fatigue - "the Chalder Fatigue Questionnaire" - was also included for all participants in the Earl study, and how nothing very much seemed to be present when looking at any connection between fatigue scores and vitamin D status, this provides a possible clue that vitamin D is probably not a big player specifically in relation to the presentation of fatigue in most cases of CFS/ME. Such a questionnaire does not rule out other potential associations (e.g. post-exertional malaise, PEM) nor that other, potential comorbidity appearing alongside CFS/ME might not have a stronger vitamin D link (see here for example). But for now, it adds to the literature (see here) casting doubt on any direct role for vitamin D in relation to CFS/ME.

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[1] Earl KE. et al. Vitamin D status in chronic fatigue syndrome/myalgic encephalomyelitis: a cohort study from the North-West of England. BMJ Open. 2017 Nov 8;7(11):e015296.

[2] Abu Kassim NS. et al. Simultaneous determination of 12 vitamin D compounds in human serum using online sample preparation and liquid chromatography-tandem mass spectrometry. J Chromatogr A. 2017 Dec 6. pii: S0021-9673(17)31772-7.

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The inter-pregnancy interval and risk of offspring autism yet again

I'm gonna try and keep this post quite brief starting with the observation that: "ASD [autism spectrum disorder] was increased in second and later-born children who were conceived less than 18 months or 60 or more months after the mother's previous birth."

So said the findings reported by Laura Schieve and colleagues [1] adding to quite a consistent research theme (see here and see here and see here). Based on "data from the Study to Explore Early Development [SEED]" initiative, with "rigorous case-finding and case-classification methods and detailed data collection on maternal reproductive history" researchers were quite confident in their observations. SEED, I might add, is developing quite a good peer-reviewed autism research reputation (see here).

Implications? Well, based on the current collected peer-reviewed research literature in this area it appears that there may be a specific time frame when it comes to potentially modifying the risk of offspring autism. Please don't take this as gospel but an interpregnancy interval (IPI) of somewhere between 12-18 and 60-72 months 'seems' to be emerging as an 'optimal' period based on the collected data currently to hand. I say this bearing in mind that multiple factors associated with pregnancy and birth *seem* to be associated with offspring outcomes (indeed, Schieve and colleagues have examined others too). This probably also includes what happens after birth (see here for example) and factors like parental age at conception/birth too (see here).

Possible mechanisms of effect? Yet again, it is more than likely that multiple factors are going to be influencing risk (or not) of offspring autism. I am drawn to the idea that a depletion of micronutrients associated with pregnancy might be an area for further investigation in relation to the IPI effect on offspring autism risk. This set in the context that pregnancy places some significant physical and biological demands on a mother's body; demands probably not immediately resolved as soon as baby enters the big, wide world. As to which micronutrients might be the more important to replenish, well, take yer pick (see here and see here for examples). Bearing, that is, in mind that no medical or clinical advice is given or intended...

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[1] Schieve LA. et al. Autism spectrum disorder and birth spacing: Findings from the study to explore early development (SEED). Autism Research. 2017. Nov 22.

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"A Blood Based Diagnostic Test for Coeliac Disease" (minus dietary gluten?)

The findings reported by Vikas Sarna and colleagues [1] have the potential to excite. Excite because, as the authors note: "A diagnosis of celiac disease based on serologic and histologic evidence and duodenal histology requires patients to be on gluten-containing diets" but a "growing number of individuals adhering to a gluten-free diet (GFD) without exclusion of celiac disease complicates its detection." A diagnostic test therefore, that could confirm/reject a diagnosis of coeliac disease (CD) without someone having to have gluten in their diet for some weeks, might be a rather exciting prospect.

Having previously posted their study aims and objectives on the ClinicalTrials.gov website (see here), authors tested the idea that "multimerized HLA bound to different gliadin-peptides (tetramer) and with the help of a flow-cytometer identify (along with other relevant T-cell-markers) gluten specific T-cells."

If all that sounds a little 'science-y' the long-and-short of it is the suggestion that the specific gene variants linked to CD - HLA-DQ2 and HLA-DQ8 variants - produce molecules -  HLA-DQ8 and HLA-DQ2 molecules - that bind to 'super-charged' gluten peptides to form a more complex molecule (tetramer) that has some rather important effects on components of the immune system, specifically on CD4+ T cells. Looking for such 'gluten specific T-cells' could be done by adding HLA-DQ-gluten tetramers to blood samples from patients with suspected/diagnosed CD. I think...

Anyhow, examining blood samples from a range of people - "62 subjects with celiac disease on a GFD, 19 subjects without celiac disease on a GFD [due to self-reported gluten-sensitivity], 10 subjects with celiac disease on a gluten-containing diet, and 52 presumed healthy individuals [controls]" - researchers put their test to the test. Most samples were analysed blind: "except for samples from subjects with celiac disease on a gluten-containing diet" and results were compared.

"An HLA-DQ-gluten tetramer-based assays that detects gluten-reactive T cells identifies patients with and without celiac disease with a high level of accuracy, regardless of whether the individuals are on a GFD." The sensitivity and specificity figures reported by Sarna are pretty good when authors managed to 'optimise' their results based on the values obtained. Indeed: "The values identified subjects with celiac disease on a gluten-containing diet with 100% sensitivity (95% CI, 1.00-1.00]) and 90% specificity (95% CI, 0.83-0.98) vs controls." Even a couple of the control participants - 'presumed healthy individuals' - were actually found to have unrecognised CD.

More science needs to be done before this potential diagnostic test is rolled out further and potentially across many, many groups. Larger participant numbers and a greater diversity of participants in terms of ethnicity, sex/gender and age need to included for study. I'm also wondering whether those with other autoimmune conditions/diagnoses could also be included in future research plans too, on the basis that birds of an autoimmune feather tend to flock together (see here and see here).

Things do seem to be getting rather interesting when it comes to CD these days. Alongside this rather exciting work, there is also the prospect of preparations that degrade gluten peptides also coming into the mainstream (see here) and how nutrients like vitamin D might also show some potentially important gastrointestinal effects [2] (see here also) pertinent to CD and beyond. No, it's not quite the end of the 'lifelong gluten-free diet' (yet!), but science is seemingly moving just a little bit closer...

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[1] Sarna VK. et al. HLA-DQ-Gluten Tetramer Blood Test Accurately Identifies Patients With and Without Celiac Disease in Absence of Gluten Consumption. Gastroenterology. 2017 Nov 13. pii: S0016-5085(17)36352-7.

[2] Scricciolo A. et al. Vitamin D3 Versus Gliadin: A Battle to the Last Tight Junction. Dig Dis Sci. 2017 Nov 20.

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Low birth weight and autism: rise of the population attributable risk

RIP Cheggers.

"LBW [low birth weight] accounted for 6.0% of all ASD [autism spectrum disorder] cases, 2.4% of BCD [behaviour and conduct disorder], and 6.8% of LD [learning disability] among the study population."

Those were the observations made by Sandie Ha and colleagues [1] and with it, another example of the use of the population attributable risk/fraction in the context of autism (see here for another occasion). Published in 2014 but only recently appearing on PubMed, Ha et al report results based on data from the 2011 (US) National Survey of Children’s Health, (NSCH) - a "random-digit-dial phone survey conducted between February 2011 and June 2012" - where data on birth weight and receipt or not of a diagnosis of "attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), behavior and conduct disorder (BCD) and learning disability (LD)" were available. As an aside, I've talked about the other studies arising from the NSCH program before on this blog (see here and see here for examples).

Including data pertinent to around 81,000 children aged between 2 and 17 years of age, researchers reported that around 9% of the cohort were "born with a LBW as reported by their parent" in response to the question: "What was [sampling child’s] birth weight?" There were some interesting correlates alongside those responses regarding LBW status: "children who were female, non-Hispanic black, had single mothers, had less educated mothers, were poorer, lacked insurance, were exposed to in-home smoking, or born prematurely were more likely to have LBW compared to those with normal BW."

Insofar as 'neurobehavioural disorders' (ND) also asked about: "The weighted prevalence of parent-reported ND among children ages 2 to 17 was approximately 9.9% for ADHD, 2.3% for ASD, 4.1% for BCD, and 10.6% for LD." Yes, this was a telephone-based survey where "both exposure and outcome are based on parental reporting, and thus the information may not represent actual diagnoses" but with the size of the participant numbers included, these prevalence/frequency figures still make for important reading.

Then to the main event - the population-attributable risk percentage (PAR%) and the finding headlining this post: "LBW [low birth weight] accounted for 6.0% of all ASD [autism spectrum disorder] cases, 2.4% of BCD [behaviour and conduct disorder], and 6.8% of LD [learning disability] among the study population." The authors caution that "maternal age at delivery, gestational age, and pregnancy complications could be important confounders" and were not taken into account in their analyses and could be "potential reasons for LBW" alongside undetected "congenital anomalies or genetic disorders." Caution is required.

It's not new news that birth weight might impact on something like autism risk (see here and see here). One also has to bear in mind that something like LBW may not necessarily appear in isolation to other pregnancy or birth events (see here) so a wider research agenda perhaps needs to be followed. But the size of the PAR% talked about by Ha and colleagues is not easily ignored. Taking into account that LBW for some may very well have some 'genetic' influences, one is left asking whether those more 'social' variables linked to LBW might be to some degree 'influenced' with a corresponding effect on neurodevelopmental 'consequences' reported. I say this in the context that poverty as a variable, has already been linked to some diagnoses included in the Ha study (see here)...

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[1] Ha SU. et al. Population attributable risks of neurobehavioral disorders due to low birth weight in US children. Adv Pediatr Res. 2014;1. pii: 2.

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On hormonal contraception and suicide risk

I'll freely admit that the material covered in the paper by Charlotte Wessel Skovlund and colleagues [1] suggesting that: "Use of hormonal contraception was positively associated with subsequent suicide attempt and suicide" is (a) slightly outside of the typical remit of this blog and (b) not something that I'm particularly qualified to talk about. I was however minded to discuss this paper in the context that previous work from this research group has *linked* hormonal contraception use with depression [2] (see here for some of the media on this past paper) and in the more general context of blogging occasions where depression and risk of suicide have been discussed here (see here).

Similar to their last research outing where hormonal contraception - 'birth control methods that act on the endocrine system' - was analysed, some of those rather important Scandinavian population registries were the source study material. Denmark was the country of choice and "a nationwide prospective cohort study of all women in Denmark who had no psychiatric diagnoses, antidepressant use, or hormonal contraceptive use before age 15 and who turned 15 during the study period, which extended from 1996 through 2013." You'll note the words 'no psychiatric diagnoses, antidepressant use' were included, illustrating how researchers were already mindful of the role that depression has in such extreme behaviour(s). Researchers collected information "about use of hormonal contraception" and also suicide attempts and completions. This, based on resources such as the Danish National Prescription Register, illustrating once again the long Scandinavian tradition of "creating nationwide administrative and health registries" [3].

Results: "Compared with women who never used hormonal contraceptives, the relative risk among current and recent users was 1.97 (95% CI=1.85–2.10) for suicide attempt and 3.08 (95% CI=1.34–7.08) for suicide." I should put that in some context in terms of hundreds of thousands of women - "nearly half a million women" - who were tracked over the course of the study, and how nearly 7000 first suicide attempts were recorded and 71 [completed] suicides registered. The numbers were comparatively small; bearing in mind that behind each figure is a person, a life and a family.

Taking into account the tenet 'correlation is not the same as causation' and indeed, appreciating how complex and individual suicidal thoughts and behaviour can be, these are potentially important data minus any scaremongering. Certainly these are findings worthy of quite a lot more study, particularly in light of the large population included for study mimicking the authors' previous chosen study design, alongside the prospective nature of their investigation.

Mechanisms of effect? I don't think anyone is quite there yet with regards to definitive hows-and-whys. I note that others have talked about a possible *correlation* between elevations in progesterone and suicide attempts [4] but such observations need to be treated cautiously at this point, again reiterating how complex and individual the processes leading someone to suicidal thoughts and behaviours are. Skovlund and colleagues did talk about suicide risk potentially differing according to different contraceptive formulations used: "Risk estimates for suicide attempt were 1.91... for oral combined products, 2.29... for oral progestin-only products, 2.58... for vaginal ring, and 3.28... for patch" potentially suggesting that specific products might have differing risk profiles. This is something else that could perhaps help isolate any pertinent mechanisms.

Questions remain, not least: Are there particular groups of women, based on genetics or other biology, that may be at increased risk of depression and/or suicide when taking such contraception? The answer: we don't yet know. Bearing in mind that in this, and their other work on hormonal contraception and depression, age seemed to be an important variable as per the observation: "Adolescent women experienced the highest relative risk" thus representing a good place to start. And on the topic of adolescent women perhaps having an elevated risk, I might also draw your attention to the findings reported by Jean Twenge and colleagues [5] who discussed another potentially important variable to consider: "Since 2010, adolescents spent more time on social media and electronic devices, activities positively correlated with depressive symptoms and suicide-related outcomes." I wonder if this is something that perhaps needs to be controlled for in future studies?

To close, there's always someone to talk to (see here) if needs be, and please, talk to your medical professional (not Dr Google) if you're at all concerned by these latest findings.

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[1] Skovlund CW. et al. Association of Hormonal Contraception With Suicide Attempts and Suicides. Am J Psychiatry. 2017 Nov 17:appiajp201717060616.

[2] Skovlund CW. et al. Association of Hormonal Contraception With Depression. JAMA Psychiatry. 2016 Nov 1;73(11):1154-1162.

[3] Pottegård A. et al. Data Resource Profile: The Danish National Prescription Registry. Int J Epidemiol. 2017 Jun 1;46(3):798-798f.

[4] Mousavi SG. et al. Recurrent suicide attempt and female hormones. Advanced Biomedical Research. 2014;3:201. doi:10.4103/2277-9175.142046

[5] Twenge J. et al. Increases in Depressive Symptoms, Suicide-Related Outcomes, and Suicide Rates Among U.S. Adolescents After 2010 and Links to Increased New Media Screen Time. Clinical Psychological Science. 2017. Nov 14.

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