Monday, 11 December 2017

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.


[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.


Sunday, 10 December 2017

From limp to scurvy in the context of autism

"A panel of nutritional markers was sent, and a presumptive diagnosis of scurvy was made."

So said the case report detailed by Adam Yan and colleagues [1] as, yet again (see here and see here), the topic of scurvy in the context of autism appears in the peer-reviewed science literature. Scurvy, a condition affecting various tissues of the body, comes about as a result of a lack of adequate vitamin C in the diet. It's thought of as a rare disease nowadays, following on from some 'limey' historical observations (see here).

I say that scurvy is a rare disease, but as per the other blogging occasions when it's received attention, for those diagnosed on the autism spectrum it's not as rare as it should be. Indeed, even Yan et al note that "scurvy is increasingly identified in children with ASD [autism spectrum disorder] and developmental delay who consume restrictive diets, often lacking in fruits and vegetables." Their case report highlights how clinicians need to be observant...

The subject of the Yan case report was a young boy diagnosed with autism who was described as non-verbal. He came to clinical attention following "a 2-week history of limp and oral mucosal bleeding." Unfortunately, his first contact with medical professionals resulted in less-than-revealing typical test results that meant he was discharged with "a referral to dentistry to address the oral mucosal changes." Things did not improve. He presented again to hospital, this time "with new onset of fevers for 1 week, ongoing limp that had progressed to complete refusal to weight bear, and persistent bleeding from his oral mucosa." This second time a few more investigations were ordered and a very (VERY) low level of vitamin C (ascorbic acid) was detected: "The low ascorbic acid level confirmed the diagnosis of scurvy with a concomitant diagnosis of anemia." Treatment in the form of vitamin C and an iron supplement (alongside a multivitamin) did the trick in terms of the limp/leg problem and bleeding gums.

What are the lessons from this case report? Well, yet again, the realisation that issues such as those related to feeding problems present quite widely in relation to autism (see here) and can very much impact on health is paramount. Indeed, it should really be part of standard medical care to monitor and keep monitoring children in particular, with a diagnosis of autism to ensure that their nutritional needs are being met in many areas (see here). If they're not, supplement (under appropriate medical guidance) and don't be afraid to do so, keeping in mind that each person/child is different (see here).

I'm also minded to mention that when medical and other allied healthcare practitioners are faced with a child/adult with autism that is non-verbal and presenting with 'symptoms', the onus really should be on medicine to turn investigator to find out 'hows-and-whys' rather than discharging with a 'we don't know' sentiment. I say this in the context that a diagnosis of autism is seemingly not protective against any other condition/label/disease occurring, and noting other, more catastrophic, examples where this has happened (see here). And minus any sweeping generalisations, a few correctly framed questions can sometimes be enlightening [2] for all-manner of different issues pertinent to autism...


[1] Yan A. et al. Limp in a Child With Autism Spectrum Disorder. Global Pediatric Health. 2017. Nov 30.

[2] Cohen S. et al. Sleep patterns predictive of daytime challenging behavior in individuals with low-functioning autism. Autism Res. 2017 Dec 1.


Saturday, 9 December 2017

Inflammatory bowel disease and autism (again)

"Children with ASD [autism spectrum disorder] were more likely to meet criteria for Crohn’s disease (CD) and Ulcerative colitis (UC) compared to controls."

So concluded Maunoo Lee and colleagues [1] following their "retrospective case-cohort study" of the US Military Health System database. Having previously published their findings as a conference abstract [2], authors gave their data the full peer-reviewed publication treatment covering nearly 300,000 people: ~48,000 children diagnosed with ASD and ~240,000 matched (not-autism) controls.

Alongside gathering data on the frequency of ICD-9 diagnostic codes for CD and UC - both defined as inflammatory bowel diseases (IBDs) - researchers also examined prescription data for treating/managing such bowel conditions. They observed differences in the prescription rate ratio (PRR) *potentially* reflective of either a more severe or more difficult to control form of IBD in children diagnosed with ASD. In short, and hopefully without making too many sweeping generalisations, IBDs are seemingly over-represented when it comes to a diagnosis of autism, and may be more likely to have an atypical pathological course.

Of course all of this is not new news. I've talked about other research that has reported similar things in relation to IBDs and autism (see here) alongside the 'now-not-questioned-so-much' data on the over-representation of functional bowel problems in relation to autism (see here). There's still a way to go in research and clinical terms to try and answer questions about how such bowel issues come about in relation to autism and whether one might consider some IBDs as being potentially 'novel' in relation to 'some' autism (see here). But the days of bowel problems in autism being some sort of fringe issue seem to well and truly gone, as perhaps 'suffering' as a result of such bowel issues can hopefully start to be addressed and other potential 'effects' (see here) investigated further minus hype, generalisation and/or fear...


[1] Lee M. et al. Association of Autism Spectrum Disorders and Inflammatory Bowel Disease. J Autism Dev Disorders. 2017. Nov 23.


Friday, 8 December 2017

Big data Taiwan on risk of "major psychiatric disorders" in kindreds of those with schizophrenia

'Big data' Taiwan listed in the title of this post refers to the wide range of findings emerging from the resource known as the National Health Insurance Research Database (NHIRD) based in Taiwan. Seriously people, this is population-wide science at it's very, very best (see here)...

Today I present yet another example of how the NHIRD is being put to good use and, as reported by Cheng and colleagues [1], how NHIRD derived data supports "the familial dose-dependent co-aggregation of schizophrenia, bipolar disorder, major depressive disorder, ASD [autism spectrum disorder] and ADHD [attention-deficit hyperactivity disorder]." In other words, how lots of seemingly individual and specific behavioural and psychiatric labels may well 'club' around each other in affected families.

So, the starting point: "A previous genetic study has suggested that schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) share common disease-associated genes." Yes, several studies have talked about possible genetic 'relationships' between these labels (see here); accepting that structural genetics may only be a part of the story. Researchers specifically examined "whether individuals with first-degree relatives (FDRs) with schizophrenia have a higher risk of these major psychiatric disorders" and the extent of any enhanced risk.

The NHIRD harboured details for some 150,000 people diagnosed with schizophrenia and some 225,000 people with FDRs diagnosed with schizophrenia. Authors crunched the data to come up with relative risks (RRs) statistics using schizophrenia as the diagnostic starting point.

Results: "The individuals with FDRs with schizophrenia exhibited higher RRs (95% confidence interval) of major psychiatric disorders, namely schizophrenia (4.76, 4.65-4.88), bipolar disorder (3.23, 3.12-3.35), major depressive disorder (2.05, 2.00-2.10), ASD (2.55, 2.35-2.77) and ADHD (1.31, 1.25-1.37) than were found in the total population." You'll notice the sliding scale of RRs, where an index case of schizophrenia most significantly raises the RR of schizophrenia being diagnosed in first-degree relatives, down to a slightly lower RR in relation to something like ADHD among FDRs. It's probably to be expected that a diagnosis of schizophrenia might raise the risk of schizophrenia in FDRs too. Indeed, this is precisely what other NHIRD derived data has previously suggested (see here).

The range (and risks) of other diagnoses present in FDRs of someone diagnosed with schizophrenia is probably of little surprise to anyone who's surveyed the peer-reviewed literature in this area (see here) or indeed works in psychiatric circles. Although contemporary psychiatric science goes to some lengths to 'compartmentalise' specific diagnoses/labels, there's always been a strong undercurrent that labels are likely to be linked or at the very least, overlap. I've talked quite a lot for example, about the links between autism and schizophrenia on this blog (see here and see here). How, minus the [important] societal implications and politics, people such as Mildred Creak and colleagues [2] probably reached a closer 'definition' of some modern-day autism than we have now with their inclusion of "distortion in motility patterns" and "acute, excessive and seemingly illogical anxiety." Yes, they headed it "schizophrenic syndrome in childhood" and autism has been moved away from this description. But with all the emphasis on gait and motility patterns coming back into fashion together with increasing recognition of the truly disabling effect that anxiety can have in the context of autism, I think they were closer that many people thought to hitting the diagnostic mark.

Other implications from the Cheng results? Screening, enhanced screening. So when schizophrenia is diagnosed in the family, greater resources are put into preferential screening of first-degree relatives also for schizophrenia and the range of other labels mentioned in the current study. I'd also add that given the ever-growing relationship between the behavioural/psychiatric and the somatic, a greater consideration of some other health-related conditions (see here and see here for examples) might also be useful...


[1] Cheng CM. et al. Co-aggregation of major psychiatric disorders in individuals with first-degree relatives with schizophrenia: a nationwide population-based study. Mol Psychiatry. 2017 Nov 7.

[2] Evans B. How autism became autism: The radical transformation of a central concept of child development in Britain. History of the human sciences. 2013;26(3):3-31.


Thursday, 7 December 2017

Cytokines and chemokines in depression point to immune system involvement: meta-analysed

Two papers are presented for your reading pleasure today, both covering a topic of growing importance on how at least some types of depression very much seem to show some immune system involvement whether causative or as part of the illness/condition course.

The first paper is by Leighton and colleagues [1] and provides results based on a systematic review and meta-analysis of the literature pertinent to the role of inflammation or chemicals involved in inflammatory processes ("chemotactic cytokines (chemokines)") in relation to depression. The authors begin their paper abstract with the words "Inflammatory illness is associated with depression" and concluded that their collected results "finds evidence linking abnormalities of blood chemokines with depression in humans."

The second paper is by Köhler and colleagues [2] and, although published slightly earlier this year (2017), similarly set about examining "measured cytokine and chemokine levels in individuals with major depressive disorder (MDD) compared to healthy controls (HCs)" also using a systematic review and meta-analysis. Their results similarly concluded that "a cytokine/chemokine profile [was] associated with MDD."

Combined these two review papers (and other research) provide a compelling case for immune system involvement in at least some cases or classes of cases of depression. Alongside other research [3] asking where the inflammation comes from in potential cases of 'inflammatory depression', there is still much to do in this promising area of interface between immune system/function and psychiatric/behavioural presentation (see here). Then also comes another potentially important implication from such studies: attend to the cytokine/chemokine profile and treat the depression? (see here). I say this with no medical advice given or intended and also acknowledging that the immune system is a mighty, mighty complex thing (see here)...


[1] Leighton SP. et al. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis. Molecular Psychiatry. 2017. Nov 14.

[2] Köhler CA. et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017 May;135(5):373-387.

[3] Berk M. et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Medicine. 2013;11:200.


Wednesday, 6 December 2017

'Physical signs' to aid the diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)?

I have to say that I wasn't completely au fait with the Perrin technique mentioned in the article by Lucy Hives and colleagues [1] or the exploration of whether "the five physical signs of the Perrin technique can assist in the screening of patients with CFS/ME, which could then subsequently lead to quicker treatment" but I was interested.

Interested because CFS/ME remains a condition diagnosed on the basis of observable symptoms. As a result, it is still subject to quite a few 'debates' on what the best fitting criteria might be (see here). Anything that might potentially help that diagnostic position is therefore welcomed. Indeed, anything that might provide something approaching an objective diagnosis could potentially open up a whole new world of treatment and intervention...

Accepting that talk of 'Perrin's point' "lymphatic drainage" and "the principle that toxins within fluid in the brain or spine column do not drain away as they should" are probably not everyone's cup of 'science' tea, the authors set about testing the Perrin technique for potentially diagnosing CFS/ME. Also whether "newly trained allied health professional (AHP) with no prior experience of CFS/ME" had the same diagnostic accuracy as more expert AHP. I'm not actually sure what specific disciplines those AHPs were actually following, but looking at the text - "One had 10 years of experience of using the Perrin technique and working with patients with CFS/ME (experienced AHP)" - and the affiliations of the authorship list (see here) - it looks to me like something between physiotherapy and osteopathy as a rough guess.

Approaching 100 participants were recruited for study - "52 patients with CFS/ME and 42 non-CFS/ME controls" - all adults and for those diagnosed with CFS/ME, all with "a prior formal diagnosis of CFS/ME at a National Health Service (NHS) hospital specialised clinic" and displaying various core features of CFS/ME (i.e. persistent fatigue and "the fatigue should feel worse after physical activity"). I note that they also required "a clear starting point to the fatigue." Assessments - "standard clinical neurological and rheumatological" - were also carried out and CFS/ME diagnosis was pitted (blind) against the Perrin technique. Indeed: "A priori, the Perrin technique required all five symptoms to be present for a patient to be diagnosed as CFS/ME." Not to copy too much text from the Hives paper, the five symptoms were: "(1) postural/mechanical disturbances of the thoracic spine... ; (2) breast varicosities... ; (3) tender Perrin’s point... ; (4) tender coeliac plexus... ; and (5) dampened cranial flow."

How did the Perrin technique do? Well, not bad at all: "Results show that, on average, the experienced AHP was most accurate (86%) at correctly diagnosing participants. This was followed by the newly trained who correctly diagnosed 77% and the physician who correctly diagnosed 69% of participants." I reiterate that the clinical team were "blinded to the groupings" (whether or not they were seeing a patient with CFS/ME or not).

Hives et al also provide some data on the specificity and sensitivity of the Perrin technique in relation to CFS/ME diagnosis, as well as some initial chatter about whether all the five symptoms together represent the most efficient grouping. They concluded that: "accuracy for both AHPs, overall, is highest when using only tests of tender coeliac plexus and postural/mechanical disturbance of the thoracic spine" potentially suggesting that "not all of the five physical signs may be necessary."

Whilst pretty interesting results, there is a need for further independent replication before anyone gets too excited about a possible objective test for CFS/ME. The authors similarly note that this was a straight 'yes you're diagnosed with ME/CFS' vs 'no diagnosis of CFS/ME' but also in future need to take into account other conditions potentially overlapping with CFS/ME such as fibromyalgia (FM) and whether the diagnostic waters are still so clear with such comparisons in mind. As I've mentioned in other posts (see here), the tendency in some quarters to conflate CFS/ME with 'chronic fatigue' also perhaps needs some further investigation too.

Still, there are reasons to be optimistic about the Hives findings. How, even alongside more traditional ways and means of diagnosing CFS/ME, the Perrin technique (in whatever form) *might* serve as a useful accompaniment to aiding the diagnostic process and perhaps even further distancing CFS/ME from the whole biopsychosocial model of disease (see here)...


[1] Hives L. et al. Can physical assessment techniques aid diagnosis in people with chronic fatigue syndrome/myalgic encephalomyelitis? A diagnostic accuracy study. BMJ Open. 2017; 7: e017521.


Tuesday, 5 December 2017

Methylphenidate as a 'suicide risk reducing agent' in ADHD: implications for other labels?

Don't get me wrong, I'm not falling hook, line and sinker for the findings reported by Sophie Hsin-Yi Liang and colleagues [1] observing that "among ADHD [attention-deficit hyperactivity disorder] youths, reduction of suicide risk was observed in patients prescribed MPH [methylphenidate] for duration 90 days and longer."

I've read too much on how complex something like suicide - ideation, attempts and completion - is to ever believe that there is some single magical answer to universally reducing or eliminating suicidal behaviours and the wide-ranging effects they have. Yes, there are some compounds that have a pretty good evidence base for being an 'anti-suicidal agent' (see here) but even with something like lithium, further investigations are required on their universal applicability and important details like their cost-benefit ratio.

Having said all that, I am drawn to the findings reported by Liang et al for a few very good reasons. First, is the continued reliance on 'big data' Taiwan and the use of the National Health Insurance Research Database (NHIRD) as a research resource. Second, is the continued focus on suicide and possible factors/predictors of suicide based on examination of NHIRD data [2]. Third, is the idea that "rates of suicide ideation, self-injury and suicide attempts are significantly increased in untreated ADHD populations" and how something like MPH use potentially (positively) affecting ADHD symptoms might have other effects. Finally, there is also the tantalising prospect that other conditions/labels where ADHD might be over-represented where also alongside there is a growing focus on suicidal behaviours, the Liang findings might also be relevant...

So what did Liang and colleagues do and find? Well looking at the records of some 85,000 children and young people where ADHD was diagnosed, researchers looked for evidence of recorded suicide attempts as a function of whether MPH was being used or not (where "MPH is the only stimulant approved for the treatment of ADHD in Taiwan"). They found that "100 (0.1%) youths met the criteria for suicide attempts during the surveillance period" and perhaps a little contrary: "37 (0.2%) in the group without any MPH use and 63 (0.1%) in the group with MPH use."

But the devil is in the detail, as authors then factored in a few pertinent, potentially confounding variables (gender, age, other diagnoses, other medication) and length of time of taking MPH (1-90 days, 91-180 days, over 180 days) into models of risk. They concluded that there was actually a 'risk reducing effect' from MPH use following such analyses: "We observed a 59% suicide attempt risk reduction among ADHD youths prescribed between 90 and 180 days and a 72% risk reduction in those prescribed more than 180 days of MPH."

This is not the first time that MPH use for ADHD and suicide risk has been discussed in the peer-reviewed science literature. The paper by Man and colleagues [3] talked about how the incidence of suicide went up before and at the beginning of MPH initiation in their cohort of around 25,000 children and young adults, but importantly risk "returned to baseline levels during continuation of methylphenidate treatment." They account for their findings by suggesting that: "The observed higher risk of suicide attempts before treatment may reflect emerging psychiatric symptoms that trigger medical consultations that result in a decision to begin ADHD treatment." I put this in the context that ADHD does seem to be a risk factor for various other psychiatric diagnoses (see here and see here). Other independent data [4] has also talked about "a potential protective effect of drugs for ADHD on suicidal behaviour, particularly for stimulant drugs." There seems to be a case for MPH as potentially affecting [some] suicide risk in relation to [some] ADHD...

I want to now take you back to the title of this post, and specifically the 'implications for other labels?' bit. How ADHD and specifically, MPH use for ADHD symptoms, might offer some important 'lessons' for conditions where for example ADHD is over-represented as a comorbidity. Of course I speak of autism and autism spectrum disorder (ASD) where it is fast becoming accepted that the risk of receiving a diagnosis of ADHD is pretty significantly heightened (see here). Alongside, quite a lot of attention is also being paid to the issue of suicide risk and autism (see here) and specifically, what factors might predispose to an elevated risk of suicide in cases of autism (see here) (hint: it's probably not all just down to depression or indeed, any one factor in isolation). Adding in the Liang findings to autism is, I think, quite a sensible thing to do. No, it's not about shifting 'blame' for suicidal behaviours from one label to the next, but instead realising that for some people on the autism spectrum, ADHD does present an additional 'feature' and such a feature might very well carry with it some increased risk for suicidal behaviours. The other strand of evidence that is probably relevant to this is the idea that the risk of various psychiatric diagnoses seem also to be elevated alongside a diagnosis of autism. The prospect therefore that MPH used to manage ADHD occurring alongside autism might reduce any risk of suicidal behaviours is something that requires quite a bit more investigation.

And while I'm mentioning MPH in the context of [some] autism, the recent Ccohrane review of MPH for kids and young people diagnosed with autism [5] suggests something quite positive when it comes to issues such as "symptoms of hyperactivity and possibly inattention" (albeit with more research required)...


[1] Liang SHY. et al. Suicide risk reduction in youths with attention-deficit/hyperactivity disorder prescribed methylphenidate: A Taiwan nationwide population-based cohort study. Research in Developmental Disabilities. 2018; 72: 96-105.

[2] Lin YW. et al. Influential Factors for and Outcomes of Hospitalized Patients with Suicide-Related Behaviors: A National Record Study in Taiwan from 1997-2010. PLoS One. 2016 Feb 22;11(2):e0149559.

[3] Man KKC. et al. Association of Risk of Suicide Attempts With Methylphenidate Treatment. JAMA Psychiatry. 2017 Oct 1;74(10):1048-1055.

[4] Chen Q. et al. Drug treatment for attention-deficit/hyperactivity disorder and suicidal behaviour: register based study. BMJ. 2014 Jun 18;348:g3769.

[5] Sturman N. et al. Methylphenidate for children and adolescents with autism spectrum disorder. Cochrane Database Syst Rev. 2017 Nov 21;11:CD011144.


Monday, 4 December 2017

Is the word 'comorbid' accurate when describing emotional and behavioural issues occurring alongside autism?

The findings reported by Per Normann Andersen and colleagues [1] observing that: "The amount of autism symptoms and degree of attention problems at baseline significantly predicted EBP [emotional and behavioral problems] at follow-up" potentially taps into a wider discussion in the context of autism.

EBP refers to feeling "anxious/depressed, withdrawn/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behavior, and aggressive behavior." The wider discussion is framed around a question on whether use of the term 'comorbid' - comorbid EBP for example - is accurate when it comes to such 'issues' appearing alongside the core features of autism? Should instead we be thinking and talking about comorbid issues/symptoms such as depression and anxiety as being something rather more central to at least 'some' autism? Y'know, is there a lot more than just the the triad/dyad of core features for some at least?

It's a discussion that has emerged before on this blog (see here and see here) and continues in the peer-reviewed science arena [2]. It has some potentially profound implications for things like autistic identity, the distinction between autism as a developmental condition as opposed to a psychiatric disorder, talk about the 'disabling aspects' of autism (and 'where they potentially come from') and the often polarised topic of intervention specifically 'for autism'...

Andersen et al report results based on analysis of children and adolescent diagnosed with autism - 'high-functioning' autism (HFA) (their term not mine) - where "levels of EBP, autism symptoms, inattention problems, and verbal IQ" were assessed at baseline and 2 years later.  The aim was to see whether symptoms such as autism "can predict EBP 2 years later."

Interestingly, the authors opted for the use of the Autism Spectrum Screening Questionnaire (ASSQ) as one of their study instruments, [partly] devised by a researcher who I have a lot of time for on this blog (see here) and his equally pertinent concept of ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations). This was complemented by "the Schedule for Affective Disorders and Schizophrenia for School Age Children/Present and Lifetime version-2009 (K-SADS-PL)" covering questions on possible "affective disorders, psychotic disorders, anxiety disorders, behavioral disorders (ADHD), substance abuse disorders, eating disorders, tic disorders and ASD [autism spectrum disorder]" and the ADHD rating scale IV among others research tools.

Results: "the level of autism symptoms at baseline were the best predictor of EBP in our group of children with HFA." The authors also observed that "attention problems had an independent impact on EBP" but noted that whilst autism and attention issues correlated at baseline, the role of attentional issues on EBP was "considerably less compared to the level of autism symptoms." Authors also stated that verbal IQ did not seemingly predict EBP, which is perhaps at odds with other independent research on a similar topic (see here). They conclude by suggesting that "interventions aimed at improving ASD symptoms may positively affect the prevalence of EBP in children with HFA."

Of course the Andersen study was not perfect and one has to be careful not to extrapolate too much. As the authors note, their study: "focused on symptoms of autism and attention, and we cannot generalize these findings to those with ASD and clinical diagnoses of ADHD" representing one important limitation. They add that their focus on those with an IQ above 70 and their investigating a very 'male-orientated' sample group also limited the generalisability of their findings to the entire autism spectrum; particularly some of the 'under-studied' people of the autism spectrum (see here). And before you mention it, yes, IQ still needs quite a bit more research work done on it when it comes to autism...

Nevertheless, I believe that these findings do add to an increasingly vocal peer-reviewed research evidence base suggesting that the term 'comorbidity' might not be the most 'useful' description when it comes to chatter about a range of labels/conditions/symptoms that are seemingly over-represented in relation to autism. Indeed, as per more historical mentions - yes, Mildred Creak yet again - set within the context of the plural 'autisms' (see here), many issues described today as 'comorbid' may eventually turn out to be rather more central to [some] autism...

The idea also discussed by Andersen et al about 'intervening' in/on the traditional 'core symptoms' of autism as potentially 'offsetting' some of the effects of those EBP is, no doubt, going to be a bit of a hot potato. We do have a few other examples showing how a reduction/dissipation of core autism symptoms does seem to impact on 'comorbid' signs and symptoms as per some of the discussions on the term 'optimal outcome' (see here). In the example recorded by Gillberg et al [3] observing that "The minority of the AS [Asperger syndrome] group who no longer met criteria for a full diagnosis of an autism spectrum disorder were usually free of current psychiatric comorbidity", we see how there could be quite a bit more to a diagnosis of autism (AS) than has traditionally been recognised. Other research from Andersen and colleagues [4] talking about the same cohort as being discussed today with depression and autism presentation again in mind likewise adds to such 'intervening' sentiments.

I have one final point to make just in case the idea of intervening does not sit well with some: if one assumes that something like depression is in fact, a core part of some autism and could be 'modified' by intervention(s) targeting core autism symptoms, there is a potentially important impact to be made on one of the primary issues affecting the autistic population: risk of suicide. I say that on the basis that depression or related psychiatric disorder (see here) is an all-too-frequent companion when it comes to suicidal behaviour(s) and therefore represents a potentially modifiable variable. Exactly how and where intervention on core autism symptoms is done is another question for another day; also bearing in mind that 'current' core autism symptoms themselves, might be an important risk factors when it comes to suicidal thoughts/behaviours (see here).

Lots more research is indicated, minus hype and minus too much politics...


[1] Andersen PN. et al. Severity of Autism Symptoms and Degree of Attentional Difficulties Predicts Emotional and Behavioral Problems in Children with High-Functioning Autism; a Two-Year Follow-up Study. Frontiers in Psychology. 2017; 8: 2004.

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

[3] Gillberg IC. et al. Boys with Asperger Syndrome Grow Up: Psychiatric and Neurodevelopmental Disorders 20 Years After Initial Diagnosis. J Autism Dev Disord. 2016 Jan;46(1):74-82.

[4] Andersen PN. et al. Associations Among Symptoms of Autism, Symptoms of Depression and Executive Functions in Children with High-Functioning Autism: A 2 Year Follow-Up Study. J Autism Dev Disord. 2015 Aug;45(8):2497-507.


Sunday, 3 December 2017

Vitamin D for schizophrenia? No but...

The results published by Amir Krivoy and colleagues [1] talking about "no significant effect of vitamin D on psychotic, depressive or metabolic parameters" in a cohort of people diagnosed with schizophrenia, make for interesting reading.

Interesting, not only because authors reported very little effect of supplementation on the symptoms of schizophrenia, but also because such 'negative' findings kinda follow a theme in vitamin D - psychiatric research circles: low levels of vitamin D (insufficiency and/or deficiency) being associated with a condition (see here) yet little [experimental] evidence that supplementation does anything more than correct the vitamin D availability issues (see here for another example). Certainly the quite significant speculation that vitamin D might have lots and lots of 'extra-bone' related actions do not yet seem to have been borne out by the currently available experimental data in this area...

Krivoy et al describe the methodology and results of their "eight-week, randomized, double-blind, placebo-controlled clinical trial" focused on some 47 patients "age between 18 and 65 years old, diagnosis of schizophrenia according to DSM-IV-TR criteria confirmed by two senior psychiatrists, treated with clozapine for at least 18 weeks and being on a stable clozapine dose for at least four weeks prior to enrollment, serum 25(OH) vitamin D level below 75 nmol/L (30 ng/ml) and total severity of psychopathology score, as measured by the Positive and Negative Symptom Scale (PANSS) total score above 70." Vitamin D supplementation - 14,000 IU [international units] per week - was pitted against a placebo formulation, although I can't seem to find what exactly the placebo contained (N=24 vs. N=23 respectively). Various outcome measures were used to determine any effect or not.

Results: as per the opening line of this post, there was little to see between the vitamin D and placebo receiving groups when compared on the basis of PANSS scores. Both groups showed a trend towards a decreasing total and sub-scale psychopathology scores over the course of the experimental period indicative of some modest improvement in psychiatric symptoms. At the same time, authors report that vitamin D levels did change amongst those in receipt of the vitamin D supplement: "The 25(OH) vitamin D serum levels increased significantly in the drug group... while essentially unchanged in the placebo group" so we can be pretty sure that there was both compliance with the experimental regime and that vitamin levels were increasing in the supplemented group as expected.

There was one small 'ray of hope' when it came to supplementation that has been hinted at in the research literature previously: "A beneficial effect of vitamin D supplementation was noted on cognitive performance, as reflected in an increase in MoCA [Montreal Cognitive Assessmenttotal score." I say 'hinted at' because although it is a little premature to talk about vitamin D as a nootropic (cognitive enhancer), there is evidence that low levels of the stuff *might* under certain circumstances, negatively affect certain cognitive abilities (see here for example). Whether supplementation with vitamin D is a more general cognitive 'affector' remains to be seen but the Krivoy results suggest further inspection is indicated.

There is more to do in this area before the vitamin D - schizophrenia link is branded completely spurious. The authors mention the relatively small sample sizes included for study and how the nature of schizophrenia as a condition potentially means that "patients with extreme presentation are less likely to consent to participate in a randomized controlled trial due to their paranoid and suspicious attitudes" as being something important. It's also interesting that at least one of the supplemented participants seemed to show little response to vitamin D in a physiological levels sense: "This patient, despite attending all assessments and dosing visits, showed vitamin D level of 22 nmol/L at baseline and 17 nmol/L at endpoint due to unclear reasons." Assuming that vitamin D testing was accurate i.e. using something like mass spectrometric methods over older, potentially less reliable assays (see here) I wonder if there could be other components required in future studies in this area, such as also looking at the genetics of vitamin D metabolism as per other, unrelated research (see here).


[1] Krivoy A. et al. Vitamin D Supplementation in Chronic Schizophrenia Patients Treated with Clozapine: A Randomized, Double-Blind, Placebo-controlled Clinical Trial. EBioMedicine. 2017. Nov 29.


Saturday, 2 December 2017

US National Health Interview Survey (NHIS) on autism rates and beyond

The US National Center for Health Statistics (NCHS) has recently released a data brief [1] covering the topic of diagnosed developmental disabilities and specifically: "the latest prevalence estimates for diagnosed autism spectrum disorder, intellectual disability, and other developmental delay among children aged 3–17 years from the 2014–2016 National Health Interview Survey (NHIS)."

The figures show a number of trends in relation to various diagnoses; not least that the prevalence of autism spectrum disorder (ASD) rose year on year between 2014 and 2016, albeit not significantly. In 2014, the percentage of positive responses to the question: "Has a doctor or health professional ever told you that [sample child] had Autism, Asperger’s disorder, pervasive developmental disorder, or autism spectrum disorder?" was 2.24%; in 2015 it was 2.41% and in 2016 it was 2.76%. I might add that we already knew what the 2014 data showed given other publications (see here).

When it came to the categorisation of developmental disability - "A composite measure of children with a diagnosis of autism spectrum disorder, intellectual disability, or any other developmental delay" - the figures were rather more significant. So: "During 2014–2016, the prevalence of children aged 3–17 years who had ever been diagnosed with a developmental disability increased from 5.76% to 6.99%." The categorisation 'other developmental delay' seemed to be the main driver of the [statistically significant] increase in that composite measure (2014: 3.57%; 2015: 3.56%; 2016: 4.55%).

There are a few additional details to mention about the report by Benjamin Zablotsky and colleagues. Boys, yet again, were the over-represented group when it came to all and total categories and race/ethnicity seemed to show some important differences such as a typically lower percentage estimate being present for most diagnoses in Hispanic children compared to other groups.

What can we make of these recent statistics? Well, it's pretty evident that, for whatever reason(s), there is still an upward trend when it comes to a diagnosis of autism and various other developmental labels. It's worthwhile pointing out that the current report used "a more restrictive definition for a developmental disability that does not include conditions such as attention-deficit/hyperactivity disorder or learning disabilities" so the figures might also not be entirely reflective of the 2014-2016 situation. I also had a question in mind about what the difference was between 'intellectual disability' (shown) and 'learning disability' (not shown) given their interchangeable meaning at least here in Blighty (see here).


[1] Zablotsky B. et al. Estimated prevalence of children with diagnosed developmental disabilities in the United States, 2014–2016. NCHS Data Brief, no 291. Hyattsville, MD: National
Center for Health Statistics. 2017


Friday, 1 December 2017

"a pooled ASD prevalence of 6.3% in individuals with epilepsy"

The quote heading this short-ish post came from the findings reported by Lauren Strasser and colleagues [1] who systematically reviewed and meta-analysed the collected data pertinent to "the prevalence and risk factors for autism spectrum disorder (ASD) in epilepsy."

Bearing in mind that epilepsy is quite a comprehensive term, authors estimated that some 6-7% of those diagnosed with epilepsy or a condition manifesting epilepsy will also present with an ASD. Further that specific types of epilepsy might confer a specific risk for ASD: "When divided by type, the risks of ASD for general epilepsy, infantile spasms, focal seizures, and Dravet syndrome were 4.7%, 19.9%, 41.9%, and 47.4% respectively."

The relationship between autism and epilepsy has been known about for many years (see here). We know for example, that age and intellectual functioning level play a role in the risk of developing epilepsy in the context of autism but are careful with sweeping generalisations (see here). We also know that a growing number of genetic conditions manifest both as autism or autistic traits and epilepsy (see here for example). We even have 'colliding' research areas talking about options for treating some 'difficult to treat' cases of epilepsy as perhaps also impacting on some of the features of autism too (see here) (with no medical or clinical advice given or intended).

What's also being recognised a little more in the peer-reviewed research literature and beyond is that being diagnosed with certain types of epilepsy also potentially impacts on the risk of autism or ASD also being diagnosed or presenting with 'significant' autistic traits (see here and see here). This to me has quite a few important implications, not least that this data "may help clinicians in early screening and diagnosis of ASD in this population." It also cements the relationship between autism and epilepsy / epilepsy and autism and further asks whether for some people at least, 'comorbidity' in relation to the presence of both terms should be replaced with something rather more core and fundamental?


[1] Strasser L. et al. Prevalence and risk factors for autism spectrum disorder in epilepsy: a systematic review and meta-analysis. Dev Med Child Neurol. 2017 Nov 9.


Thursday, 30 November 2017

"psychiatric comorbidity may be the earliest manifestation of the onset of IMID in some individuals"

IMID shown in the title of this post refers to immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) and formed quite an important part of the findings reported by Ruth Ann Marrie and colleagues [1] (open-access available here). This work adds to an area of increasing importance on how the physical and psychological/psychiatric might very well be linked by the immunological (see here for discussions on other recent work from this authorship group).

Similar to their last publication [2] Marrie et al relied on data out of the "the Canadian province of Manitoba" and included some 12,000 diagnosed cases of IMID. The aim of their study this time around was "to estimate the incidence of several psychiatric disorders, including depression, anxiety, bipolar disorder and schizophrenia, in the 5-year periods pre- and post-IMID diagnosis." Further: "We hypothesised that the incidence of psychiatric comorbidity would be higher in the incident IMID than in the matched general population cohorts pre- and post-IMID diagnosis."

Results: "the incidence of psychiatric comorbidity was increased in the IMID cohorts in the 5–10 years before IMID diagnosis." Minus too many sweeping generalisations, there is something potentially rather 'stunning' about such findings and the idea that for some at least, psychiatric findings might be a prelude to something rather more somatic a few years down the line. Authors also noted that post-IMID diagnosis, there was also a possible *connection* to receipt of a psychiatric label too.

Explanations? Well, with the requirement for quite a bit more independent analysis in this area of science, there are a few possibilities to consider. Authors talk about a possible "prodromal period for the IMID in which inflammation has developed sufficiently to increase the risk of psychiatric disorders but not to precipitate typical clinical manifestations of IMID." You'll note the use of the word 'inflammation' in that last sentence pertinent to the idea that inflammation as a component of immune function might well be doing lots and lots of different things (see here).

They also mention the possibility that "psychiatric disorders and IMID may share common aetiologic factors." So, drawing on a little autism research here, and how autism genes might not necessarily be just genes for autism (see here) and how such genetic overlap may include some of the genetics of immune function (see here), the feeling is that such sentiments could be pertinent to other labels too. Of course it's also important to note that outside of just structural genetics, there may be other non-genetic factors that could exert a possible effect such as the availability of certain nutrients for example (see here).

And there is another important point raised by Marrie and colleagues: "the occurrence of psychiatric disorders pre-diagnosis of IMID could potentially be conceptualised as early symptoms of IMID rather than as distinct comorbid conditions." This is something rather appealing to me following my reading of the research literature in this area down the years. Yet again drawing on research in autism, I've often thought that at least of the 'comorbidity' that is over-represented alongside a diagnosis of autism might actually be a lot more 'central' to some presentations. Take for example all the chatter about gastrointestinal (GI) issues being present alongside [some] autism (see here). Minus all the fluffy psychological explanations for the presence of various bowel issues alongside a diagnosis of autism, there is evidence that the bowel might be quite a bit more central to quite a few cases of autism under specific circumstances (see here). Further extending such work I note that bowel issues also might carry relevance to other behavioural/psychiatric diagnoses too (see here). If also proven in the context of 'psychiatric IMID' (if I can call it that), such a move away from notions of comorbidity towards more core issues has implications not just for screening and assessment but also management and treatment too...

Reiterating that quite a bit more work needs to be done on the whole 'immune system doing more than just traditional immune system things', I continue to find this area of research absolutely fascinating.


[1] Marrie RA. et al. Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease. Epidemiol Psychiatr Sci. 2017 Nov 3:1-10.

[2] Marrie RA. et al. Increased incidence of psychiatric disorders in immune-mediated inflammatory disease. J Psychosom Res. 2017 Oct;101:17-23.


Wednesday, 29 November 2017

Aluminium in brain tissue in autism: a first?

"These are some of the highest values for aluminium in human brain tissue yet recorded and one has to question why, for example, the aluminium content of the occipital lobe of a 15 year old boy would be 8.74 (11.59) μg/g dry wt.?"

That was one of the statements/questions posed in the paper by Matthew Mold and colleagues [1] covering yet another potential 'hot potato' topic in the area of autism research and science (see here). Indeed, the idea mentioned by Mold et al that: "Animal models of ASD [autism spectrum disorder] continue to support a connection with aluminium and to aluminium adjuvants used in human vaccinations in particular" is likely to met with furrowed brows in quite a few quarters given the recent goings-on with regards to some of the 'mouse' work in this area (see here).

But as far as I can see, the Mold data is a stand-alone piece of work that sought to cover a 'missing piece' in relation to how "no previous reports of aluminium in brain tissue from donors who died with a diagnosis of ASD" have been published in the peer-reviewed domain. In that respect, I'm covering it on this blog, hypothesis-free in terms of the possible wheres-and-hows...

Relying on one of the most personal and precious resources in autism research - brain tissue - "from the Oxford Brain Bank ", researchers examined brain tissue samples from various parts of the brain donated by families of "5 individuals with ADI-R confirmed (Autism Diagnostic Interview-Revised) ASD." As far as I can make out, we aren't told an awful lot about the 5 people studied aside from their diagnosis, sex/gender and age range. We don't for example, know about any comorbidities (autism rarely appears in some sort of diagnostic vacuum) or indeed, the reason(s) why they died.

Brain tissues were prepared and treated ready for analysis of aluminium content via "transversely heated graphite furnace atomic absorption spectrometry (TH GFAAS) using matrix-matched standards and an established analytical programme alongside previously validated quality assurance data." From what I gather, this is an accepted (albeit quite old) method for analysis of various trace metals in biological fluids including aluminium [2]. It's also worthwhile bearing in mind the publication record of some of the authors in the area of aluminium (see here) including research pertinent [3] to the Camelford 'incident'. Some people here in Blighty might remember Camelford, where the accidental addition of some 20 tonnes of aluminium sulphate into the local drinking water led to it being described as "Britain's worst mass poisoning event".

Alongside assaying for aluminium content in brain samples, researchers also examined brain sections to see where aluminium congregated in samples via the use of fluorescence microscopy. This involved the selective staining of cells for aluminium content and onward looking at where and what type of cell showed such staining.

Results: "The brains of all 5 individuals had at least one tissue with a pathologically-significant content of aluminium." Further: "The brains of 4 individuals had at least one tissue with an aluminium content ≥5.00 μg/g dry wt. while 3 of these had at least one tissue with an aluminium content 10.00 μg/g dry wt." I don't know enough about aluminium and what should or shouldn't be there, but I believe the authors hark back to some of their previous work to try and define "loose categories of brain aluminium content." In terms of the aluminium cell staining work, some interesting findings are reported pertinent to how "aluminium somehow had crossed the blood-brain barrier and was taken up by a native cell namely the microglial cell." Other authors had previously speculated on this scenario [4].

It's worthwhile mentioning/reiterating some of the limitations of this work before any grand sweeping judgements or generalisations are made. Not only was this a very, very small study with no specific control samples available during this particular investigation, but the amount of tissue available to researchers was limited. One cannot also rule out issues such as sample degradation being a factor (see here) given the lack of specific details on the samples being investigated. As I said, brain samples are one of the most precious resources available to autism research.

There is however a need for much more research in this area, particularly when going back to the opening statement/question of this post in terms of amount of aluminium detected and where it seemed to congregate in the brain samples analysed. Indeed, with all the chatter about microglia and inflammation in relation to [some] autism down the years (see here for example), it's looking increasingly *interesting* that aluminium might play some kind of role, for some at least. Added to independent findings suggesting that the blood-brain barrier should also be target for further study for some (see here) and observations that upwards of about 15% of individuals with an ASD might present with elevated levels of aluminium in other tissue types (see here) and future work is indicated on a larger scale minus hype and/or generalisations. I might also suggest that further research be directed on the basis of other organs potentially affected by aluminium concentrations such as the kidneys..

I'm also minded to point out that following other work on other metals in the context of autism (see here), I'm still siding with the idea that various genetic and biological mechanisms involved in the *removal* of metals may be 'atypical' in relation to at least some autism. If that is the case, there could be several different ways to potentially intervene [5]...


[1] Mold M. et al. Aluminium in brain tissue in autism. Journal of Trace Elements in Medicine and Biology. 2017. Nov 26.

[2] Bradley C. & Leung FY. Aluminum determined in plasma and urine by atomic absorption spectroscopy with a transversely heated graphite atomizer furnace. Clin Chem. 1994 Mar;40(3):431-4.

[3] King A. et al. Unusual neuropathological features and increased brain aluminium in a resident of Camelford, UK. Neuropathol Appl Neurobiol. 2017 Oct;43(6):537-541.

[4] Morris G. et al. The putative role of environmental aluminium in the development of chronic neuropathology in adults and children. How strong is the evidence and what could be the mechanisms involved? Metab Brain Dis. 2017 Oct;32(5):1335-1355.

[5] Yu L. et al. Lactobacillus plantarum CCFM639 can prevent aluminium-induced neural injuries and abnormal behaviour in mice. Journal of Functional Foods. 2017; 30: 142-150.


Tuesday, 28 November 2017

"findings suggest a protective effect of CRP" on schizophrenia risk?

Science is often a puzzling endeavour. Sometimes, just when you think that you've got something nailed down, scientific results appear that 'trash' long held, cherished beliefs. So it was with the publication of the results by Fernando Pires Hartwig and colleagues [1] who presented findings looking at "the effect of inflammatory markers on schizophrenia risk" based on the use of "a mendelian randomization (MR) design."

MR, by the way, is a interesting technique based on the principle that "genetic variants that either alter the level of, or mirror the biological effects of, a modifiable environmental exposure that itself alters disease risk should be related to disease risk to the extent predicted by their influence on exposure to the environmental risk factor." It's a technique that has already been applied to inflammatory markers in the context of schizophrenia on more than one occasion (see here and see here). Those inflammatory markers studied have included ones which were covered by the Hartwig paper. Specifically: "Genetically elevated circulating levels of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-6 receptor (sIL-6R)." I should also point out that Hartwig and colleagues have some research form in the area of applying MR to various aspects of medical science (see here).

As per an accompanying editorial on the Hartwig paper [2], the long-and-short of it was that researchers "used 2-sample MR to test for a potentially causal relationship between inflammation and schizophrenia and to improve inference for the association between genes, inflammatory biomarkers, and risk of developing schizophrenia." I can't claim any specific expertise in the use of MR (see here for a good overview [3]) but it appears that data on single-nucleotide polymorphisms (SNPs) in relation to those inflammatory markers was used to test whether said markers might be linked 'causally' to risk of schizophrenia. Their results were interesting: "we did not find strong evidence that lifelong exposure to increased action of these proinflammatory cytokines increases schizophrenia risk, as previously hypothesized" and indeed that: "blockade of IL-6 effects and low CRP levels might instead increase schizophrenia risk." This is contrary to quite a lot of other research in this area (see here for example).

There are a few words of caution to attach to the Hartwig results that need mentioning not least the primary tenet on which analyses are based: genetic variants (SNPs) affecting something like CRP are of primary importance to schizophrenia. I don't for example, see anything in the data looking at gene function/expression being affected as a result of non-structural changes to the genome via something like epigenetic 'alterations' for example (and there is such a thing as epigenetic Mendelian randomization y'know). I say this on the basis that other genes involved potentially involved in processes linked to DNA methylation have also been *associated* with cases of schizophrenia (see here). The authors also caution that their analyses are based on "lifelong exposure to elevated cytokine and CRP levels" and that exposure during 'critical windows' might be the important issue when it comes to any change in schizophrenia risk. Similarly they note that "it is possible that IL-6 and CRP effects on schizophrenia risk are related to a maternal effect (eg, maternal susceptibility to infections during pregnancy), so that our findings are explained by the correlation between maternal and offspring genotypes." This final point is based on the idea that maternal infection during pregnancy (or the biological consequences of) seems to be quite a big risk factor for at least some presentations of schizophrenia (see here) as well as [cautiously] other labels (see here). Here, the importance of a reprogrammed immune system during pregnancy might also come into play alongside any maternal 'susceptibility'.

Personally I'm not yet ready to totally trash the idea that the immune system, and specifically elevations in inflammatory markers such as CRP and other pentraxins, might not be important to some schizophrenia risk in a more detrimental way. I appreciate that one has to be careful when talking about immune system markers and their inflammatory direction (see here for some chatter on IL-6 and its pro- and anti-inflammatory natures) but the existing data is too evident to just discard on the basis of one new study, despite it's scientific prowess. I don't however doubt that there may be several confounding variables linked to increases in CRP in schizophrenia; not least the impact of something like increased body mass index (BMI) that seems to follow some cases of schizophrenia [4]. These variables need to be further explored, particularly in the context of what side-effects pharmacological management of schizophrenia might have (see here). And I also hat-tip the paper by Manu and colleagues [5] applying the Bradford Hill's guidelines on 'causation' to this area and concluding that (upto 2014) "there is insufficient evidence that the replicated, strong association between schizophrenia and elevated inflammatory markers has etiopathological relevance"...

For now however, the Hartwig findings reiterate that science is an ever-changing, ever-evolving process...


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

[2] Byrne E. et al. Inference in Psychiatry via 2-Sample Mendelian Randomization—From Association to Causal Pathway? JAMA Psychiatry. 2017. Nov 1.

[3] Sheehan N. et al. Mendelian Randomisation and Causal Inference in Observational Epidemiology. PLoS Med. 2008; 5(8): e177.

[4] Fernandes BS. et al. C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Mol Psychiatry. 2016 Apr;21(4):554-64.

[5] Manu P. et al. Markers of inflammation in schizophrenia: association vs. causation. World Psychiatry. 2014 Jun; 13(2): 189–192.


Monday, 27 November 2017

MoBa does... prenatal exposure to acetaminophen and offspring ADHD risk

MoBa mentioned in the title of this post refers to the Norwegian Mother and Child Cohort Study, an initiative that has figured quite a few times on this blog (see here and see here and see here for examples).

This time around [1] scientific attention turned to a question of growing research importance: does acetaminophen - paracetamol to us here in Blighty - use during pregnancy affect the risk of offspring being diagnosed with attention-deficit hyperactivity disorder (ADHD)? The data thus far on the issue of this pain-relieving, antipyretic medicine and offspring health has been discussion-provoking to say the least (see here and see here)...

The findings reported by Eivind Ystrøm and colleagues [1] are based on observations for over 100,000 offspring "including 2246 with ADHD." Both "maternal use of acetaminophen during pregnancy and... paternal use before pregnancy" were included in the statistical mix designed to estimate "hazard ratios (HRs) for an ADHD diagnosis."

The results were not exactly unexpected given what has gone on before in this area of investigation. Acetaminophen use was pretty widespread across all pregnancies; approximately 50% of mums had used it at some point. Short-term use during pregnancy - less than 8 days - actually correlated with a decreased risk of offspring ADHD according to the Ystrøm findings. More chronic use of the medicine however - "more than 29 days of maternal acetaminophen use" - showed an opposite relationship, yielding something like a 200% increase in offspring ADHD "even after adjusting for indications of use, familial risk of ADHD, and other potential confounders."

Alongside the suggestion that short-term paracetamol use was associated with a decreased risk for offspring ADHD was another 'make you think' finding: "Paternal and maternal use of acetaminophen were similarly associated with ADHD." Here, a father's use of paracetamol a month or so before conception seemed also to affect the risk for offspring ADHD too. In some media interest on this paper, the authors speculate "that "it could be that fathers who use a lot of acetaminophen have a higher genetic risk for ADHD" or that long-term use of the medicine might lead to changes in sperm." I might add that given the focus on paracetamol as a pain-relieving medicine, the topic of pain and ADHD is already something present in the peer-reviewed science domain (see here). Further research is called for in an accompanying editorial on the Ystrøm paper by Mark Wolraich [2] noting the benefits of using 'big data' from initiatives such as MoBA.

Accepting that the Ystrøm results suggest correlation and not necessarily causation, not everyone has been overwhelmed by the findings. I note in that lay media piece about the research, a few critical voices have suggested that "children diagnosed with ADHD by codes in their medical records" is no substitute for the real 'diagnostic' thing. Personally, I don't see this argument as being particularly valid as anyone that reads anything about MoBA would probably realise. Scandinavian countries and their population databases have some of the best collected and kept databases in the world in terms of reliability and applicability of population health data and statistics. A quick check on PubMed regarding the amount of peer-reviewed data that has been generated from MoBA for example, illustrates that point well.

Perhaps a more pertinent issue is the question of whether longer-term use of paracetamol during pregnancy could denote a more serious underlying maternal illness/injury which might have a more powerful effect on the risk of offspring ADHD than medicine use itself. This is a similar sort of argument to that put forward in relation to pregnancy antidepressant use and various offspring outcomes detailed in the research literature (see here) and similarly, is not something that can be answered by study designs such as those used by Ystrøm.

But then other the questions arise: 'Is paracetamol use during pregnancy safe?' 'How much is safe?' and 'What are the alternatives?' At this point I'm going to stand back and say little more given my blogging caveats of no medical and/or clinical advice given or intended. I will refer you to some current opinion on this topic provided in the peer-reviewed domain [3] alongside suggesting that more large and smaller-scale investigations are required, including that on 'adjacent' diagnoses in relation to pregnancy paracetamol use too (see here)...


[1] Ystrøm et al. Prenatal Exposure to Acetaminophen and Risk of ADHD. Pediatrics. 2017. Oct 30.

[2] Wolraich ML. An Association Between Prenatal Acetaminophen Use and ADHD: The Benefits of Large Data Sets. Pediatrics. 2017. Oct 30.

[3] Andrade C. et al. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016 Mar;77(3):e312-4.