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.