Vitamin D deficiency in adult patients admitted to a psychiatric ward: same as before

The 'same as before' part of the title of this post refers to the observation that vitamin D deficiency is not an uncommon feature for those admitted to psychiatric hospitals (see here and see here).

This time around I present the results published by Dipen Patel & Manjunath Minajagi [1] who reported that: "49% (N = 51) of participants were vitamin D deficient (serum 25(OH)D <30 nmol/L), and a further 42% (N = 44) were vitamin D insufficient (<50 nmol/L); 8.7% (N = 9) of participants were vitamin D sufficient (>50 nmol/L)."

'Participants' mentioned by Patel & Minajagi, referred to 104 adults (average age of 40) admitted to a psychiatric hospital who provided written consent to participate in their study and were diagnosed with a range of psychiatric disorders including "depressive episode", "bipolar affective disorder", "schizophrenia" and/or "personality disorder". We are told that: "Vitamin D levels were requested alongside standard admission blood tests on serum samples collected by venepuncture." Sounds like a good call by all accounts.

Alongside noting those quite important numbers/percentages of vitamin D deficiency and insufficiency (see here for more information about the distinction), authors also reported that: "There were no statistically significant differences noted in mean serum 25(OH)D associated with gender, age or primary diagnosis." They did however mention that: "Mean serum 25(OH)D was higher in participants of White British ethnicity compared with those of other ethnic backgrounds" indicating that skin colour probably plays a role in vitamin D production/levels. A shocker indeed [2].

"At the current time, there is insufficient evidence to draw any firm conclusions regarding an association between vitamin D deficiency and non-musculoskeletal health outcomes, including mental illness. More research in the form of larger epidemiological and intervention studies are needed to investigate the association between vitamin D and mental health outcomes; indeed, randomised controlled trials are planned that will hopefully shed more light on this intriguing area in the future." Sorry about the large text grab noted in that last sentence, but the authors said it better than I ever could in terms of (a) being cautious about making any specific connections between vitamin D deficiency/insufficiency and 'mental illness' and (b) the value of supplementation (see here and see here) outside of just restoring vitamin D levels to where they should be.

That being said, there is a further scheme of work to look at drawing on data from other labels (see here for example). Remembering also that, minus too many sweeping generalisations, some of the other health issues that seem to follow a psychiatric label *might* also show some involvement with vitamin D [3] too...

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[1] Patel D. & Minajagi M. Prevalence of vitamin D deficiency in adult patients admitted to a psychiatric hospital. BJPsych Bull. 2018 May 2:1-4.

[2] Bonilla C. et al. Skin pigmentation, sun exposure and vitamin D levels in children of the Avon Longitudinal Study of Parents and Children. BMC Public Health. 2014;14:597.

[3] Lu L. et al. Association of vitamin D with risk of type 2 diabetes: A Mendelian randomisation study in European and Chinese adults. PLoS Med. 2018 May 2;15(5):e1002566.

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Allergic disease and ADHD yet again...

Although words like 'first' and 'largest' were used in the paper by Chia-Feng Yang and colleagues [1] (open-access available here) observing that "AD [atopic dermatitis] and asthma with allergic sensitization are associated with ADHD [attention-deficit hyperactivity disorder] in children", I'm minded to be a little cautious with such 'we're the first/best' assertions.

Cautious because, on quite a few peer-reviewed research occasions (see here for example), a possible *link* between various allergic disease and ADHD has already been noted; even potentially extending to studies talking about how treatment for allergic disease might on some occasions also impact on presented ADHD symptoms (see here) (with no medical advice given or intended).

Yang et al relied on data from a research favourite country, Taiwan, derived from an initiative called the Childhood Environment and Allergic diseases Study (CEAS). The clue is in the name of the initiative in terms of what they were looking for/at, as per other publications derived from the initiative [2]. From the 3200-odd participants eligible for participation, researchers relied on data from over 2700 children. Questions about allergic disease history were asked to parents of said participants, alongside other 'environmental' factors such as family income, tobacco exposure and breastfeeding history. I note also a question about 'incensing at home' is also included relating to the use of burning incense typically linked to religious practices in certain cultures.

When it came to a diagnosis of ADHD, it's not entirely clear about how this was ascertained but it looks like diagnosis was given by a clinician: "The conditions of disease in children were confirmed by board-certified child psychiatrists or pediatric neurologists, according to the clinical evaluation." I should also mention that participants also received skin prick tests (SPTs) covering a range of potential allergens: "house dust mites (HDMs mix, including Der p, Der f, Der m, and Blot allergens), cockroaches, dog dander, milk, egg, and crab allergens" as way of defining allergic sensitisation.

Results: there was a "strong positive association between ADHD and allergic sensitization as diagnosed by positive SPTs." In other words, despite finding a fairly low level of ADHD in their sample (1%), those who 'reacted' to one or more of the allergens tested for via the skin prick test seemed to be at some increased risk of ADHD. Such an enhanced risk spanned both those presenting with "AD with allergic sensitization and asthma with allergic sensitization."

The authors provide some further results and details on the possible hows-and-whys of their results. Obviously the immune system figures quite strongly given what for example, they were testing for with the SPT and their focus on AD and asthma. The word 'inflammation' also figures quite heavily. I note too that the authors reiterate previous suggestions that: "Control of allergens exposure might be a critical factor influencing the development of ADHD."

There is a further scheme of work to follow in this area, not just dealing with mechanisms but also in relation to 'treating' allergies also potentially 'treating' [some] ADHD. I say this on the basis that other independent research has observed that before reaching for the antihistamine as a potential ADHD-modifier, there may actually be a connection between early antihistamine exposure and the development of ADHD [3] (albeit with potential confounders) to keep in mind. Other work also supporting a link between ADHD and atopic disease [4] provides some other 'clues' that may require further investigation; not least "cow's milk intolerance", which ties into similar findings (see here) and could also be one route from which ADHD heightens the risk of subsequent future psychiatric disorder (see here) in light of other 'milk' associations (see here).

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[1] Yang CF. et al. Association between allergic diseases, allergic sensitization and attention-deficit/hyperactivity disorder in children: A large-scale, population-based study. J Chin Med Assoc. 2017 Nov 24. pii: S1726-4901(17)30304-0.

[2] Wang IJ. et al. Allergens, air pollutants, and childhood allergic diseases. Int J Hyg Environ Health. 2016 Jan;219(1):66-71.

[3] Schmitt J. et al. Increased attention-deficit/hyperactivity symptoms in atopic dermatitis are associated with history of antihistamine use. Allergy. 2017 Oct 4.

[4] Hak E. et al. Association of childhood attention-deficit/hyperactivity disorder with atopic diseases and skin infections? A matched case-control study using the General Practice Research Database. Ann Allergy Asthma Immunol. 2013 Aug;111(2):102-106.e2.

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Oral vitamin D and the inflammatory effects of sunburn

In something of a departure from the typical content of this blog, I want to briefly introduce the paper by Jeffrey Scott and colleagues [1] and specifically the findings that: "Compared to placebo, participants receiving vitamin D3 (200,000 IU) demonstrated reduced expression of pro-inflammatory mediators TNF-α... and iNOS... in skin biopsy specimens 48 hours after experimental sunburn."

Based on a small number of participants who either received a high dose of vitamin D - "vitamin D3 (cholecalciferol)" - or a placebo one hour after experimental sunburn, authors describe how there seemed to be some merit in supplementing with vitamin D (oral dosage form) to help mitigate some of the more damaging, inflammatory effects of sunburn based on their observations. They further noted: "increased skin expression of the anti-inflammatory mediator arginase-1, and a sustained reduction in skin redness, correlating with significant expression of genes related to skin barrier repair" in their supplemented group.

It is perhaps timely that this research is discussed today given the current heatwave that has settled over most of Blighty. If like me, you are sometimes prone to the odd bout of sunburn (8 hours at Flamingo Land has quite a lot to answer for!) such findings could eventually prove to be quite useful. Obviously there is the strong advice not to get sunburn in the first place but added to the various creams and lotions to soothe the skin after sunburn, the possibility that vitamin D supplementation might also come in handy is worthwhile experimentally investigating further. The fact that vitamin D is produced in the skin (albeit in a quite complicated series of biological processes) suggests that Mother Nature knew what she was doing when it came to skin exposure to (excess) sunlight.

On one last point - that related to "the immunotherapeutic properties of vitamin D" - I'd also like to think that other areas of science and medicine could benefit from further research in this area. I've discussed research before on this blog talking about how vitamin D supplementation might be important to certain labels under certain conditions with an immune system/inflammatory component attached to them (see here). Assuming that what goes on in the skin under inflammatory conditions following sunburn is not necessarily a hundred million miles away from what happens to other parts of the body under similar inflammatory conditions, there is perhaps quite a bit we can learn from the sunshine vitamin/hormone and it's multi-faceted effects...

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[1] Scott JF. et al. Oral vitamin D rapidly attenuates inflammation from sunburn: an interventional study. J Invest Dermatol. 2017 May 30. pii: S0022-202X(17)31558-0.

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Vitamin D deficiency is rife in an in-patient psychiatric unit for young people

"Adolescents within tier 4 adolescent mental health services may be at higher risk of vitamin D deficiency and so assessment of vitamin D levels should be considered as part of a standard physical health review for this group of young people."

So said the results reported by Neil Stewart & Simon Lewis [1] (open-access) who surveyed blood test results of patients admitted to a tier 4 psychiatric unit for vitamin D levels. Such a study was conducted on the basis that "it is plausible that vitamin D and/or vitamin D deficiency have a role in the pathogenesis of mental illness." Yes, indeed I might agree (see here and see here for examples).

Authors identified some 27 individuals who were tested for vitamin D deficiency between 2012 and 2014 from a population of 56. Over 80% (22/27) had vitamin D levels falling into the deficient or severely deficient range, and none of them had vitamin D levels reaching the bottom end of the typical range (75–250 nmol/L). A few other points are worthwhile noting: "In individuals from BME [black and minority ethnic] groups, who were potentially at higher risk of vitamin D deficiency due to increased skin pigmentation, 52.9% (9/17) were tested for vitamin D levels and 100% were deficient or severely deficient."

I was rather happy to see that authors have very much stuck to their findings minus too much speculation about their meaning. They, for example, suggest that all patients entering their particular service should "be considered at high risk of vitamin D deficiency" for whatever reason(s). They emphasise that vitamin D testing should be part and parcel of the routine physical examination normally provided to patients. They even talk about correcting any deficiency/insufficiency whilst monitoring vitamin D levels for any adverse effects or toxicity. In short, treat the physical health of their patients/service users despite the focus of their service being psychiatric. Lessons I'm sure that could be applied to many different labels/diagnoses with a behavioural or psychiatric element to them.

Going back to the idea that vitamin D deficiency might play a role in various conditions/states outside of those linked to bone health, the authors add to other voices suggesting that more investigation is needed to confirm/refute links between vitamin D status and behavioural or psychiatric issues. They note: "If an association between depression and vitamin D deficiency were to be confirmed through future study, vitamin D supplementation could potentially be a cost-effective treatment adjunct with minimal adverse effects." Again, I can't argue with the logic.

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[1] Stewart NF. & Lewis SN. Vitamin D deficiency in adolescents in a tier 4 psychiatric unit. BJPsych Bull. 2017 Jun;41(3):133-136.

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Does eczema increase the risk of childhood speech disorder?

Nativity Kylo?

The question posed in the title of this post reflects some interesting data published by Mark Strom & Jonathan Silverberg [1] who reported that: "Pediatric eczema may be associated with increased risk of speech disorder" on the basis of their analysis of data for some 350,000 children "from 19 US [United States] population-based cohorts."

Taking into account various variables such as "sociodemographics and comorbid allergic disease" authors determined that among the 19 cohorts, the majority (12) showed some kind of connection between eczema and elevated odds of speech disorder. Further, when pooled together, the prevalence of speech disorder among those children with eczema was 4.7% compared with a figure of 2.2% for those children without eczema.

One other detail to impart from the Strom/Silverberg study was how eczema plus other labels was also linked to risk of speech disorder as per the sentence: "children with both eczema and attention deficit disorder with or without hyperactivity or sleep disturbance had vastly increased risk of speech disorders than either by itself."

Allowing for the fact that correlation is not necessarily the same as causation and that as the authors admit: "Further, prospective studies are needed to characterize the exact nature of this association" these are interesting data strengthened by the large number of participants included for study. A quick trawl of the research literature in this area suggests that childhood speech disorders may very well be associated with additional health problems [2] although not necessarily just rooted in something like eczema.

The possibility that a physical ailment like eczema might have implications for a developmental condition like childhood speech disorder is a tantalising one. I've covered the preliminary idea of a 'skin-brain axis' before on this blog (see here) on the basis of data like that reported by Yaghmaie and colleagues [3] talking about atopic dermatitis and various developmental/psychiatric labels. More generally, allergic disease in infancy has been linked to various neurodevelopmental outcomes (see here) with again, the requirement for quite a bit more investigation of this possible association. Indeed, even the 'big data' of Taiwan has something to say on this topic (see here).

As to any mechanism, well, outside of the suggestion of shared genetic risk between something like eczema and speech (and language) issues, the idea that the immune function (a cardinal mechanism of eczema) might play a much greater role in our health and wellbeing than merely the somatic is becoming more mainstream in these days of immune system and psychiatry intersecting (see here). The more general idea that immune features such as inflammation might be able to 'interact' with psychology is a whole new frontier of medicine (see here) and one that should be incorporated into any future research strategy. The other potentially important question outside of any aetiological association is whether or not early treatment of eczema including attending to some of the possible triggers [3] might also have important implications for the risk of developing speech disorders?

Music: Blur - Trimm Trabb.

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[1] Strom MA. & Silverberg JI. Eczema Is Associated with Childhood Speech Disorder: A Retrospective Analysis from the National Survey of Children's Health and the National Health Interview Survey. J Pediatr. 2015 Oct 28. pii: S0022-3476(15)01140-3.

[2] Keating D. et al. Childhood speech disorders: reported prevalence, comorbidity and socioeconomic profile. J Paediatr Child Health. 2001 Oct;37(5):431-6.

[3] Yaghmaie P. et al. Mental health comorbidity in patients with atopic dermatitis. J Allergy Clin Immunol. 2013 Feb;131(2):428-33.

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Strom MA, & Silverberg JI (2015). Eczema Is Associated with Childhood Speech Disorder: A Retrospective Analysis from the National Survey of Children's Health and the National Health Interview Survey. The Journal of pediatrics PMID: 26520915

Introducing 'cutaneous gluten sensitivity'

I'm always amazed that despite our many advances in science and medicine, new diagnoses and clinical entities still manage to pop up from time to time. Today I'm introducing one such occasion as detailed in the paper by Veronica Bonciolini and colleagues [1] (open-access available here) and the idea that 'cutaneous gluten sensitivity' (CGS) might be part and parcel of at least some presentation of non-coeliac gluten sensitivity (NCGS).

For those who might not know, NCGS describes part of a proposed spectrum of gluten-related conditions that lies outside of the classical 'gluten can affect health' autoimmune condition that is coeliac disease (CD). There is still some debate about the boundaries of NCGS and the precise diagnostic criteria (see here) but I'm of the opinion that there is something to see in this area and that, on occasion, there also may be psychological/behavioural issues associated with the label (see here) albeit with more research required.

Insofar as the relationship between cutaneous (skin) issues potentially associated with NCGS, well we have a precedent here with the link between dermatitis herpetiformis (DH) and CD, a skin condition manifesting as red raised patches of blisters often accompanied by severe itching. Treatment of DH normally involves a gluten-free diet (GFD) similar to the management of CD, although other preparations can also help soothe the itching and blistering.

The Bonciolini paper details the authors' efforts to document various cutaneous manifestations seemingly linked to NCGS and "to characterize the new pathologic entities known as CGS." To do this: "17 consecutive patients affected by NCGS after having considered gastroenterology and allergy in order to exclude other forms of gluten sensitivity such as CD and WA [wheat allergy]" were examined. The authors did a pretty good job of excluding conditions such as CD in their participant group as per their use of "serological assay with specific antibodies (anti-tissue transglutaminase antibodies (tTG) IgA and IgG, anti-endomysial antibodies (EMA), anti-gliadin antibodies (AGA), deamidated gliadin peptide (DGP) and total IgA) and esophagogastroduodenoscopy with multiple biopsies." Further researchers: "enrolled NCGS patients only after dietary elimination of gluten followed by DBPC [double-blind, placebo-controlled]" challenge. Skin samples were taken and various inspections of skin lesions carried out.

Results: "The common clinical feature of all the patients involved in this study, as well as the one detached from our clinical experience, was the severe itching." Researchers reported that the itching was difficult to treat with standard medications but "it showed prompt resolution when GFD was introduced" and "the reaction was faster than in DH patients." In terms of the skin lesions themselves, the authors describe them as "polymorphic" (I assume meaning that they took on various different shapes and sizes) and perhaps due to some pretty continual itching also took on a "psoriatic-like" appearance (as in similar to the plaques seen in psoriasis).

"The histological and immunopathological assays performed on skin samples exclude specific skin diseases of CD and the allergy skin tests exclude sensitization to gluten. Therefore, it is reasonable to assume that there may also appear skin manifestations among the extraintestinal manifestations of NCGS or that “cutaneous gluten sensitivity” (CGS) exists and needs to be characterized."

We await further investigations...

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[1] Bonciolini V. et al. Cutaneous Manifestations of Non-Celiac Gluten Sensitivity: Clinical Histological and Immunopathological Features. Nutrients. 2015 Sep 15;7(9):7798-7805.

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Bonciolini V, Bianchi B, Del Bianco E, Verdelli A, & Caproni M (2015). Cutaneous Manifestations of Non-Celiac Gluten Sensitivity: Clinical Histological and Immunopathological Features. Nutrients, 7 (9), 7798-7805 PMID: 26389946

Atopic dermatitis and autism: systematically reviewed

I briefly want to bring the paper from Lucia Billeci and colleagues [1] to your attention today and the suggestion that following their systematic review of the current peer-reviewed literature, there seemed to be something of "an association between ASD [autism spectrum disorder] and AD [atopic dermatitis]."

Atopic, by the way, refers to sensitivity to allergens, and in the case of AD, how such sensitivity manifests on the skin causing itchiness, redness and the skin to become sore potentially also making it more prone to other infections.

Looking at 18 studies covering the topic of AD and other atopic diseases in relation to autism using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, authors concluded that "the frequencies of AD in ASD compared with a control group ranged from 7 to 64.2 %." Accepting such variability, they concluded that there may be quite a bit more to see in terms of an 'association' between the diagnostic entities.

I've covered the idea of a connection between autism and atopy quite a few times on this blog (see here and see here). Although to some extent confused by a possible relationship with other comorbidity that quite regularly feature alongside autism (attention-deficit hyperactivity disorder, ADHD), the idea of a sort of skin-brain axis with autism in mind (see here) does seem to be gaining some scientific traction on the basis of such data. That and the idea that immune function (a driver of conditions such as atopy) might be closely linked to at least some autism (see here for example) and one gets further peer-reviewed evidence that research efforts might need to be increased.

Oh, and that atopy and psychiatry might also extend further than just autism and/or ADHD is potentially important [2]...

Music: Foxes - Body Talk.

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[1] Billeci L. et al. Association Between Atopic Dermatitis and Autism Spectrum Disorders: A Systematic Review. Am J Clin Dermatol. 2015 Aug 8.

[2] Catal F. et al. Psychiatric disorders and symptoms severity in preschool children with atopic eczema. Allergol Immunopathol (Madr). 2015 Aug 3. pii: S0301-0546(15)00092-0.

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Billeci L, Tonacci A, Tartarisco G, Ruta L, Pioggia G, & Gangemi S (2015). Association Between Atopic Dermatitis and Autism Spectrum Disorders: A Systematic Review. American journal of clinical dermatology PMID: 26254000

Atopic disease and adolescent psychotic experiences

I was intrigued to read the paper by Khandaker and colleagues [1] (open-access here) reporting results based on a longitudinal study that suggested: "Childhood atopic disorders increase the risk of psychotic experiences in adolescence".

Bish, bash, Bosch @ Wikipedia 

I've talked about the issue of atopic disease and it's potential overlap with something like neurodevelopment before on this blog (see here) based on the possibility of a neuro-immune interaction (i.e. that our immune system might be involved in many more processes than just fighting infection as per the microglia work) as suggested by Meldrum and colleagues [2]. The recent paper from Chang and colleagues [3] reporting a possible connection between allergic disease and behavioural issues in preschoolers adds to that debate. I very much consider the Khandaker findings to be of a similar ilk in terms of potential mechanisms of effect (accepting though that correlation does not necessarily mean causation).

In brief, Khandaker et al followed several thousand children over the course of their trial (data from the ALSPAC cohort which has just received some good news), detailing the presence of atopic diseases such as asthma and eczema of participants at age 10 and any subsequent psychotic experiences at age 13. Various markers linked to inflammation (C-reactive protein and IL-6) were also assessed at age 9. It was then a case of comparing those with atopic disease, whether present singularly or combinatorially, with those without atopic disease on whether the risk of a psychotic episode (PE) was more or less likely. And it was more likely in the atopic group; although strangely enough those markers of inflammatory processes did not seem to "mediate association between atopy and PEs" bearing in mind that inflammatory markers were not seemingly assessed at the time of the PE.

As per the authors findings, I'm not yet able to provide a specific hypothesis to explain the Khandaker findings. I do hark back to my previous chatter about the 'skin-brain axis' for example (see here) as potentially being important although not specifically related to the psychosis findings. The accompanying literature on psychocutaneous disorders [4] "conditions that are characterized by psychiatric and skin manifestations" may very well be something of a research focus to account for at least the proposed eczema - PE link.

With regards to asthma, well there is the suggestion from Moreno and colleagues [5] that asthma was one of a number of conditions "more frequent in individuals with psychotic symptoms but no psychosis diagnosis" but again, comparatively little to suggest a mechanism of connection outside of individual case reports on steroid medication for example (used for some cases of asthma) being linked to the presence of psychotic episodes [6]. I could be really speculative and talk about physiological mechanisms other than atopy potentially linked to such somatic and psychiatric symptoms such as that encompassed by the body of work looking at dietary elements [7] (and this paper by Faith Dickerson and colleagues [8]) but don't want to get ahead of myself given the lack of testing for such parameters in the Khandaker paper.

What however we can take from the Khandaker results is that a possible connection between somatic and psychiatric symptoms should remain an important area of research particularly with regards to shared genetics, epigenetics or biological markers. Perhaps also that more emphasis should be placed on screening for psychotic episodes and related conditions in cases where atopy is present. The tantalising question of whether treating somatic symptoms might have a potential knock-on effect on psychiatric symptoms or vice-versa also remains, as for example, per the recent update on the use of anti-inflammatory agents for schizophrenia by Sommer and colleagues [9]. There doesn't at the moment appear to be an awful lot of research on the potential usefulness of antihistamines (H1-receptor antagonists) commonly used to treat allergic disorders, in cases of psychosis or conditions manifesting psychosis. When however it comes to H2-receptor antagonists and accepting that these medicines are not generally viewed as antihistamines, I am drawn to the chatter about famotidine and schizophrenia [10] for example, something which I think was also mentioned with regards to autism at one point [11] and seemingly never heard of again. So, with no medical advice given or intended, there's still quite a bit more research to do in this area.

To close, having watched the recent BBC4 documentary about The Doors and really appreciating the musical talent they were, a classic: Riders on the Storm... sit back and enjoy.

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[1] Khandaker GM. et al. A population-based study of atopic disorders and inflammatory markers in childhood before psychotic experiences in adolescence. Schizophr Res. 2013 Nov 21. pii: S0920-9964(13)00520-3. doi: 10.1016/j.schres.2013.09.021.

[2] Meldrum SJ. et al. Allergic disease in the first year of life is associated with differences in subsequent neurodevelopment and behaviour. Early Hum Dev. 2012 Jul;88(7):567-73. doi: 10.1016/j.earlhumdev.2011.12.032.

[3] Chang HY. et al. Allergic diseases in preschoolers are associated with psychological and behavioural problems. Allergy Asthma Immunol Res. 2013 Sep;5(5):315-21.

[4] Al Hawsawi K. & Pope E. Pediatric psychocutaneous disorders: a review of primary psychiatric disorders with dermatologic manifestations. Am J Clin Dermatol. 2011 Aug 1;12(4):247-57.

[5] Moreno C. et al. Psychotic symptoms are associated with physical health problems independently of a mental disorder diagnosis: results from the WHO World Health Survey. World Psychiatry. 2013 Oct;12(3):251-7.

[6] Lee KM. et al. Steroid-induced acute psychosis in a child with asthma: report of one case. Acta Paediatr Taiwan. 2001 May-Jun;42(3):169-71.

[7] Karlsson H. et al. Maternal antibodies to dietary antigens and risk for nonaffective psychosis in offspring. Am J Psychiatry. 2012 Jun;169(6):625-32.

[8] Dickerson F. et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry. 2010 Jul 1;68(1):100-4.

[9] Sommer IE. et al. Efficacy of Anti-inflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update. Schizophr Bull 2014; 40: 181-191.

[10] Martinez MC. Famotidine in the management of schizophrenia. Ann Pharmacother. 1999 Jun;33(6):742-7.

[11] Linday LA. et al. Famotidine treatment of children with autistic spectrum disorders: pilot research using single subject research design. J Neural Transm. 2001;108(5):593-611.

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Khandaker GM, Zammit S, Lewis G, & Jones PB (2013). A population-based study of atopic disorders and inflammatory markers in childhood before psychotic experiences in adolescence. Schizophrenia research PMID: 24268471

Neurofibromatosis and autism

An article a few weeks back on the SFARI site alerted me to the fact that the paper by Shruti Garg and colleagues* looking at the prevalence of autism spectrum disorder (ASD) in cases of neurofibromatosis type 1 (NF1) here in Blighty was on its way. The SFARI entry talked about NF1 in the context of "higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings" as per the findings by Adviento and colleagues**.

Café au lait spots @ Wikipedia 

I'm not going to claim to be an expert on the RASopathies because I'm not. From what I gather from the accumulated literature on these developmental syndromes is that we are dealing with a group of conditions which are marked by "mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes" which is involved in cell signalling. Quite a good overview of the Ras/MAPK pathway can be found in this article by Jarell and colleagues*** (open-access) with melanoma in mind, hinting at the connection with cancer (see here).

Neurofibromatosis type 1 (NF1), one of the RASopathy family of conditions, is a genetic condition characterised by the presence of coffee coloured patches on the skin called café au lait spots. There are certain criteria for the minimum number of such spots to be present on the skin as part of the diagnosis of NF1. Neurofibromas (little bumps under the skin) are also generally noted in later development, alongside other potential symptoms such as scoliosis and tumours on the optic nerve (optic nerve glioma) among other things.

There is also a connection between NF1 and cognitive and behavioural functions. Although not a universal connection, NF1 is associated with some degree of learning disability for some; as per the paper by Lorenzo and colleagues**** "young children with NF1 have significantly poorer intellectual functioning, expressive language, and visual perception". Other research has detailed an overlap in cases of NF1 with the symptoms of conditions such as ADHD*****.

OK so after all that, what was found?

The paper by Garg et al reports a "high prevalence of ASD in NF1" based on a survey of an NF1 registry based on first a screen for possible autistic traits (using the SRS) and then further assessment of a random sample of the group screening positive for a potential ASD. Indeed: "The population prevalence estimate is 24.9% ASD (95% confidence interval 13.1%–42.1%) and 20.8% broad ASD (95% confidence interval 10.0%–38.1%); a total of 45.7% showing some ASD spectrum phenotype". These figures are pretty astounding in terms of the presentation of autism in cases of NF1.

This is not the first time that neurofibromatosis has been linked to autism. I note that Prof. Gillberg (he of the ESSENCE suggestion) discussed "the simultaneous occurrence of neurofibromatosis and childhood psychosis" back in the early 1980s******. For those slightly mystified as to why I'm referencing a paper on childhood psychosis, I might point you to some of the history of autism research and times perhaps less scientifically enlightened.  The paper by Mbarek and colleagues******* carries an even more startling revelation in that "Neurofibromatosis type 1 (NF1) is increased about 150-fold in autistic patients" and their linking back to the severity of presentation in autism.

Right up to date, there is also another paper by Garg and colleagues******** from earlier this year (2013) including Prof. Jonathan Green on the authorship list, noting "a high prevalence of ASD symptoms associated with NF1 as well as substantial co-occurrence with ADHD symptoms". That also NF1 was "a potentially important single-gene cause for autism symptoms" brings us full circle as to the latest paper by Garg and colleagues. I should also tip my hat to the paper by Walsh and colleagues which very much supported the previous Garg findings (see here*********).

This is an interesting area of autism research, of that there is no doubt. I'm minded to suggest that the results pointing towards an association between NF1 and autism not only offer some potentially interesting insights into how genes and biochemical pathways might intersect across the conditions, but also provide further evidence that our use of the singular term 'autism' is becoming more and more outdated as time goes on, to eventually be replaced by the 'autisms'. As part of those autisms, the NF1 connection might eventually offer new targets for intervention for some (yes, even a potential role for things like mTOR inhibitors as per some connection**********) and given that skin connection, might even fit into that emerging skin-brain axis that I've talked about on a previous post (see here).

In short, some really quite interesting findings.

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* Garg S. et al. Neurofibromatosis Type 1 and Autism Spectrum Disorder. Pediatrics. November 2013.

** Adviento B. et al. Autism traits in the RASopathies. J Med Genet. 2013 Oct 7. doi: 10.1136/jmedgenet-2013-101951.

*** Jarell AD. et al. The RAS/mitogen activated protein (MAP) kinase pathway in melanoma biology and therapeutics. Biologics. 2007 December; 1(4): 407–414.

**** Lorenzo J. et al. Cognitive Features that Distinguish Preschool-Age Children with Neurofibromatosis Type 1 from Their Peers: A Matched Case-Control Study. J Pediatr. 2013 Aug 1. pii: S0022-3476(13)00797-X.

***** Mautner VF. et al. Treatment of ADHD in neurofibromatosis type 1. Dev Med Child Neurol. 2002 Mar;44(3):164-70.

****** Gillberg C. & Forsell C. Childhood psychosis and neurofibromatosis--more than a coincidence? J Autism Dev Disord. 1984 Mar;14(1):1-8.

******* Mbarek O. et al. Association study of the NF1 gene and autistic disorder. Am J Med Genet. 1999 Dec 15;88(6):729-32.

******** Garg S. et al. Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study. Dev Med Child Neurol. 2013 Feb;55(2):139-45.

********* Walsh KS. et al. Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1. Dev Med Child Neurol. 2013 Feb;55(2):131-8.

********** Liu N. et al. Mammalian target of rapamycin inhibitor abrogates abnormal osteoclastogenesis in neurofibromatosis type 1. Chin Med J (Engl). 2013 Jan;126(1):101-7.

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Shruti Garg, Jonathan Green, Kathy Leadbitter, Richard Emsley, Annukka Lehtonen, D. Gareth Evans, MD, Susan M. Huson, MD, FRCP (2013). Neurofibromatosis Type 1 and Autism Spectrum Disorder Pediatrics

Autoimmune disease as a risk factor for mood disorder?

Autoimmunity, the process by which the immune system fails to recognise self as self and subsequently targets those self tissues and cells, is something talked about quite a lot on this blog with autism specifically in mind. Part of the very wide and diverse immune-related features which have been discussed with at least some of the autisms in mind, it's not yet altogether clear exactly how and why autoimmunity is linked to behaviour but the association is an interesting one.

Sally? @ Wikipedia  

The paper by Michael Benros and colleagues* expands that autoimmune - behaviour interest and their observations suggesting: "Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis". Their conclusion is based on the analysis of a huge patient set from which nearly 100,000 people had a hospital contact for mood disorder. Mood disorder by the way, is an overarching term for quite a few conditions (see here) which as the name suggests, affect mood; be it an unusual 'high' or an unusual 'low'.

"A prior hospital contact because of autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 45%". To me this is a really interesting association. OK I know correlation does not equal causation, but added to the association they made between hospitalisation for infection and subsequent mood disorder (62% increase) and the large participant numbers, there is lots to ponder here.

I've gone on a few times on this blog about the bi-directional link between our physiology and the presentation of more psychiatric or behavioural 'symptoms'. Be it C.diff infection and depression or the skin-brain axis (see here), the connections are starting to be formed and examined. I'm just remembering back to some interesting research on allergic disease and neurodevelopment as also potentially being relevant to this post (see here) with the focus on allergy and its potential developmental effects and indeed the implication of some interesting potential interventions too.

So what could be the mode of action for this autoimmune-infection-mood disorder link? Well, we have some contenders but at the moment nothing concrete. That the immune system might be doing so much more than protecting against disease is already pretty well known about as for example with the rise and rise of research into microglia (see here) and some other areas of interest** particularly with a focus on a very nebulous term: inflammation.

Regular readers might know about my views and opinions on the role of food and the gut to behaviour - no really -  and certainly when it comes to certain autoimmune conditions like coeliac (celiac) disease, we have a body of research suggesting how food, certain elements of food, under the right circumstances might be able to affect behaviour. Think Marios Hadjivassilliou for example.

Even more outlandish, how about some role for those HERVs - human endogenous retroviruses - which seem to be cropping up with lots of conditions in mind (see here) and in particular autoimmune conditions***? Too speculative? Whether any of these areas overlap with the Benros paper is something as yet unknown. But the association posited between autoimmune conditions / infections and subsequent mood disorders is really, really interesting.

To close, with the new Stone Roses inspired movie on the horizon, how about a song about Sally Cinnamon?

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* Benros ME. et al. Autoimmune Diseases and Severe Infections as Risk Factors for Mood Disorders. JAMA Psychiatry. 2013;():1-9. doi:10.1001/jamapsychiatry.2013.1111.

** del Rey A. et al. A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning. Brain, Behavior, and Immunity. 6 June 2013. http://dx.doi.org/10.1016/j.bbi.2013.05.011

*** Dreyfus DH. Autoimmune disease: A role for new anti-viral therapies? Autoimmun Rev. 2011 Dec;11(2):88-97. doi: 10.1016/j.autrev.2011.08.005.

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Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, & Mortensen PB (2013). Autoimmune Diseases and Severe Infections as Risk Factors for Mood Disorders: A Nationwide Study. JAMA psychiatry (Chicago, Ill.), 1-9 PMID: 23760347

The skin-brain axis and autism?

I'm sure that many people with an eye on the autism research scene will have come across the term 'gut-brain axis' at some point in their reading. Denoting the suggestion of a possible relationship between what goes on in our deepest, darkest recesses and brain function (and onwards observed behaviour), the gut-brain axis has seemingly found a home particularly when looking at autism spectrum disorders.

Be it when it comes to describing the potential hows and whys of things like a gluten- and casein-free diet (potentially) showing some effects, or those quite consistent findings of elevated rates of gastrointestinal (GI) issues reported in at least a proportion of cases of autism(s), the gut-brain axis seems to be quite an enduring concept as it might also be in other conditions such as schizophrenia.

Axis not axes @ Wikipedia  

The specifics of the gut-brain axis have not however yet been fully elucidated; although quite a lot of speculation has focused on things like gut bacteria and intestinal permeability as showing some involvement; concepts which have cropped up on this blog quite regularly.

In this post I want to talk about another axis potentially relevant to autism and quite a few other developmentally defined or mental health related conditions: the skin-brain axis following the appearance of a rather interesting paper by Yaghmaie and colleagues* on mental health comorbidity in patients with atopic dermatitis.

A few points are worth noting given that I'm not able to post a link to the full-text paper:

• This was a survey paper based on the US 2007 National Survey of Children's Health dataset (N=91,642). 
• In short, the parents of children aged 0-17 years (0 years denoting those under 1 year old) were contacted and asked quite a few questions about the health of their children. 
• For the purposes of this study, children with a history of atopic dermatitis (AD) as per the question: "during the past 12 months, have you been told by a doctor or other healthcare provider that XXX had eczema or any kind of skin allergy?" were asked about "provider-diagnosed mental health conditions" covering various diagnoses "previously been reported as associated with AD" and their results were compared with those without AD. Odds ratios (ORs) were calculated based on the risk derived from AD for various conditions.
• The 12-month prevalence of AD for 2007 was 12.9%; a rise from previous estimates from data in 2003 (10.6%). Interestingly when comparing AD estimates state-by-state, California turned out to have the lowest AD prevalence (8.5%). Regular readers will know that in autism research terms, California has always been a bit of a focus (see here for example).
• A diagnosis of AD was associated with an elevated risk of quite a few conditions: autism (OR: 3.04 CI: 2.13-4.34), ADHD (OR: 1.87 CI: 1.54-2.27) and conduct disorder (OR 1.87 CI: 1.46-2.39) among other things. All relationships were statistically significant when comparing AD and non-AD samples.
• The authors also report that the severity of AD was also related to the likelihood of a developmental/mental health condition, in that the more severe the AD, the more likely a diagnosis was to be received.

Bearing in mind the nature and sampling methods of the Yaghmaie study, I have to say that I was taken aback by the findings of this paper and the potential implications. It's not that skin conditions have not been talked about with autism for example in mind before, as per the research base on things like psoriasis for example (see this post) and the whole autoimmunity side of things. Indeed, the atopy and allergy field has been mentioned quite a few times in autism research; alongside issues such as mast cell activation also being a source of speculation. But the implication that a skin condition like AD might actually raise the risk of developing autism or ADHD or a conduct disorder is a whole new ballgame on the mind-body relationship stakes bearing in mind the question of correlation-and-causation.

The authors also go as far as to suggest: "Strategies to prevent AD or to aggressively treat early skin inflammation might modify the risk of mental health disorders in at-risk children". This sentence really got me thinking. Thinking about inflammation and how this topic has been looked at on more than one occasion in autism research circles. Thinking about how skin and brain/behaviour might be linked, bearing in mind the source embryological material. Thinking also about the genetic - environmental factors which are linked to AD, and indeed going back to that gut-brain axis, how food might also play a role as per the link between gluten and dermatitis herpetiformis for example. Lots of thinking indeed.

The final words about the paper by Yaghmaie and colleagues should I suppose be ones of caution insofar as science needs to (a) replicate these findings, both in the US (home to participants) and outside the US, and (b) start looking in more details as to what the shared biological mechanisms and pathways could be (at least one authorship group have asked similar questions recently**).

That being said, this is yet more potential evidence for the whole-body nature of quite a few developmental and mental health conditions - remember the airways and autism research - and how autism research needs to keep expanding its scientific boundaries outside of the view that the grey (or rather pinkish) matter floating inside our skull is working completely in isolation.

Oh and perhaps I should also mention the meta-analysis by Schmitt and colleagues*** as adding more fuel to the correlation fire? And while we are on the topic of atopy, how about the paper by Chou and colleagues**** on allergic rhinitis and ADHD?

Stop now... and I will.

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* Yaghmaie P. et al. Mental health comorbidity in patients with atopic dermatitis. J Allergy Clin Immunol. December 2012.

** Denda M. et al. How does epidermal pathology interact with mental state? Medical Hypotheses. 2013; 80: 194-196.

*** Schmitt J. et al. Association of atopic eczema and attention-deficit/hyperactivity disorder - meta-analysis of epidemiologic studies. Z Kinder Jugendpsychiatr Psychother. 2013; 41: 35-44.

**** Chou PH. et al. Prevalence of allergic rhinitis in patients with attention-deficit/hyperactivity disorder: a population-based study. Eur Child Adolesc Psychiatry. December 2012.

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Yaghmaie P, Koudelka CW, & Simpson EL (2012). Mental health comorbidity in patients with atopic dermatitis. The Journal of allergy and clinical immunology PMID: 23245818