"This study provides important information about psychiatric comorbidity in adult ASD" (again)

The quote titling this post - "This study provides important information about psychiatric comorbidity in adult ASD [autism spectrum disorder]" - comes from the findings published by Jack Underwood and colleagues [1] (open-access available here).

The Underwood study is a bit of a mash-up paper because, alongside examining things like psychiatric comorbidity and other features accompanying or allied to 'adult autism', it also ventures into the possible genetics of autism. Unfortunately, the relatively small sample size - "105 eligible individuals were matched to 76 healthy controls" (authors words not mine) - means that the genetic results in particular need to be treated with some caution. With this in mind, I'm not going to go further into this side of the Underwood report.

So: "105 individuals were all confirmed to have an ASD diagnosis consistent with ICD-10 criteria by case-note review" were the cohort included for study, all derived from the National Centre for Mental Health institution based in Wales. Interviews and questionnaires were disseminated, covering topics like marriage and employment status alongside questions on 'biological offspring' (children, to you and me). Participants were questioned about psychiatric comorbidity (as in, did they have any diagnoses) as well as medication use and substance use/abuse. We are told that: "By definition, control participants did not have psychiatric morbidity and were not using any psychotropic medication."

"Comorbid psychiatric diagnosis was reported by 89.5% (n = 94) of individuals with ASD." If you would have told me that statistic about 10 or 15 years ago I might have been shocked. These days such figures, high figures, on psychiatric comorbidity accompanying autism seem to be reported on almost a weekly basis. I don't say that to downplay the effects of such high comorbidity; just that there is little novelty in their discovery (see here and see here) particularly the high rates of depression and anxiety that were picked up (see here). Oh, and once again I'll question whether the word 'comorbidity' is entirely accurate in the context of various issues appearing alongside autism (see here).

Medication use? Yes, as probably expected, there was quite a bit of that, particularly antidepressants, anxiolitics (for anxiety) and antipsychotics in the autistic group. Again, there's little novelty in those findings (see here) but they do reiterate the need for regular monitoring and good medicines management (see here).

Onward: "Adults with ASD were significantly less likely to be currently working..., to be married or cohabiting..., to be currently off work because of sickness or disablement... and to have alcohol-related problem." Yes, there was more overlap with other independent findings in some of those areas (see here and see here for examples) but also some quite important details. Take for example the category termed 'problems due to alcohol use' which was reported by 36% of the autistic group compared with 8% of controls. Although not exactly great PR for the label of autism, there is an emerging understanding that alcohol use and abuse does seem to be over-represented alongside a diagnosis of autism (see here). The authors opine that this "could be usage to self-medicate for the aforementioned anxiety as suggested by other authors, or to facilitate social interactions" but really we need lots more data about this and the long-term effects of such 'self-medication' if that's what it truly is.

Another details also stuck out for me: "Forty-one (42.7%) individuals with ASD reported lifetime history of migraine headaches compared with 15 (20.5%) control participants." Migraine headaches (or even just headaches) have been talked about before on this blog in the context of autism (see here). With such a large percentage of participants with autism talking about this issue, I'm minded to suggest that a lot more investigation is needed in this area.

There is little in the way of new, novel findings in the Underwood paper but I don't want readers to think that this is a not a valuable addition to the peer-reviewed science literature. It is, simply because it continues important conversations about (a) the presentation of autism into adulthood (see here), (b) the idea that autism rarely appears in some sort of diagnostic vacuum (see here), and (c) the various inequalities - health and social - faced by those on the autism spectrum. What however I would like to see more of is research on 'what helps' to iron out some of these important issues and how services can be effectively delivered. Alongside we need some debates about funding too.

And just before I go, the focus on autism "and no self-report comorbid intellectual disability" in the Underwood paper did not go unnoticed. Autism science also needs to make sure that all voices on the autism spectrum are equally heard (see here). Indeed, another recent paper [2] makes the point very eloquently: "We found selection bias against ID [intellectual disability] throughout all fields of autism research. We recommend transparent reporting about ID and strategies for inclusion for this much marginalised group." I wouldn't disagree...

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[1] Underwood JFG. et al. Autism spectrum disorder diagnosis in adults: phenotype and genotype findings from a clinically derived cohort. Br J Psychiatry. 2019 Feb 26:1-7.

[2] Russell G. et al. Selection bias on intellectual ability in autism research: a cross-sectional review and meta-analysis. Molecular Autism. 2019; 10: 9.

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Risk of breast cancer in women with schizophrenia: meta-analysed

"In this meta-analysis of 12 cohort studies that included 125 760 women and in which conventional methods of meta-analysis had been used, schizophrenia in women was associated with an increased breast cancer incidence compared with the general population."

That was a primary findings reported by Chuanjun Zhuo & Patrick Triplett [1] following their survey of the peer-reviewed research literature on the topic of breast cancer risk and schizophrenia up to August 2017. The authors caution however that their review of this topic might not be the last word on it - "it is possible that a future study will show a decreased breast cancer risk in women with schizophrenia compared with the general population" - given "substantial between-study variance" among the research literature they examined. Another very good example of how the currency of science is probability and big sweeping generalisations may not necessarily stand the test of time.

"The status of physical health in patients with schizophrenia has become an important topic in health care management research" introduced the the Zhuo/Triplett paper, and with it, important recognition that diagnoses like schizophrenia can lead to an over-emphasis on the psychiatric often to the detriment of the somatic (see here). This, allied to other findings that have suggested that risk of premature mortality from various somatic complaints / diagnoses / issues is potentially heightened in relation to schizophrenia (see here).

Authors located studies fulfilling their study entry criteria, including "schizophrenia identified as exposure at baseline" and "documented incidence of breast cancer on follow-up" and applied their statistical analyses to results. Importantly: "Studies reporting breast cancer–related mortality rather than incidence were also excluded because the mortality outcome may be affected by many factors other than breast cancer incidence, such as comorbidities and treatments." Most of the included studies/data were found to be methodologically sound based on scores on the Newcastle-Ottawa Scale.

Alongside their finding that women with schizophrenia seemed to be at an elevated risk of breast cancer, authors also suggested that "intensive prevention and treatment against breast cancer are warranted for women with schizophrenia." So yes, this means discussing about potentially modifiable risk factors for breast cancer such as alcohol use and obesity (obesity, at the time of writing, being something of a focus for one large cancer charity here in Blighty). But this also means looking at how schizophrenia and its management might also place someone at elevated risk of something like breast cancer as a result of it sometimes being a "hormone-dependent cancer" and, as the authors note, "a significant positive association between plasma prolactin levels and the risk of breast cancer, has been observed." Minus any scaremongering, prolactin elevations have been noted following the use of certain antipsychotic medicines typically indicated for schizophrenia [2] and other conditions (see here). Any additional risk needs to be managed, and managed well.

I don't think anyone should be unduly alarmed by the Zhuo/Triplett results, but rather more mindful of the fact that a psychiatric diagnosis does not disqualify someone from other risks of more somatic conditions / complaints. The key, yet again, is screening and keeping an open mind...

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[1] Zhou C. & Triplett PT. Association of Schizophrenia With the Risk of Breast Cancer Incidence: A Meta-analysis. JAMA Psychiatry. 2018. March 7.

[2] Wu Chou AI. et al. Female schizophrenia patients and risk of breast cancer: A population-based cohort study. Schizophr Res. 2017 Oct;188:165-171.

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Psychiatric disorders among male juvenile detainees in South Korea

"Juvenile detainees evidence high rates of psychiatric disorders and comorbidities. Assessment of and intervention in psychiatric disorders, especially alcohol use disorder and comorbid alcohol use disorder with disruptive behavior disorders, may help prevent further offenses."

So concluded Johanna Inhyang Kim and colleagues [1] (open-access) following their investigation into the prevalence of DSM-IV psychiatric criteria in a sample of 173 male juvenile detainees aged between 15-19 years old held at a "male juvenile detention center in Seoul, South Korea, during the period of December 2015 to January 2016." Most of the detainees were held in relation to crimes against property (49%) but violent crimes (39%), traffic offences (24%) and sexual offences (19%) also featured in offending patterns.

The presence of a psychiatric diagnosis was made using the Mini International Neuropsychiatric Interview (MINI) screening for various groups of disorders: disruptive behavioural disorders (DBDs), substance use disorder (SUD) and "any anxiety disorder." Researchers also looked for the presence of psychotic disorder and major depression too, alongside collecting various demographic data and information about recidivism (repeat offending).

Results: "In total, 157 (90.8%) participants had at least one psychiatric diagnosis" is the standout figure from the paper compared with other independent data from this part of the world "of 15–38% among the general adolescent population." Alcohol use disorder was the most frequently mentioned label mentioned in the study, but 'comorbidity seems to be the rule' as we are told that: "Alcohol use disorder with DBDs was the most common combination, accounting for 46.2% of the detainees, followed by DBDs with anxiety disorders (22.5%)."

When it came to the important issue of repeat offending, researchers also report some interesting patterns. Dropping out of school, present in about a quarter of the total cohort, was reported to be a factor in relation to recidivism (present in about 90% of detainees). The presence of two psychiatric disorders also showed a notable connection to repeat offending particularly where an alcohol use disorder was one of them. The message seems to be that keeping kids/young adults in school and away from alcohol might be an important combination in relation to affecting repeat offending rates.

There is quite a lot of other data included in the Kim study and I would encourage interested parties to take a more detailed look. One thing that struck me about the Kim data was the apparent lack of results when it came to attention-deficit hyperactivity disorder (ADHD) in relation to offending and repeat offending outcomes. Minus any sweeping generalisations, I've talked before on this blog about how a diagnosis of ADHD might elevate the risk of contact with law enforcement agencies (see here) for whatever reason(s) and how a combination of ADHD and conduct disorder in particular, might be tied into a range of long-term adverse outcomes including 'risk of criminality' (see here). Kim and colleagues paint a slightly different clinical picture whereby a different combination of psychiatric factors might be specifically related to this group of people in this part of the world.

More investigations are implied including reference to what potential nutritional changes might do to [some] behaviour in this population (see here).

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[1] Kim JI. et al. Prevalence of psychiatric disorders, comorbidity patterns, and repeat offending among male juvenile detainees in South Korea: a cross-sectional study. Child Adolesc Psychiatry Ment Health. 2017 Jan 18;11:6.

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Kim JI, Kim B, Kim BN, Hong SB, Lee DW, Chung JY, Choi JY, Choi BS, Oh YR, & Youn M (2017). Prevalence of psychiatric disorders, comorbidity patterns, and repeat offending among male juvenile detainees in South Korea: a cross-sectional study. Child and adolescent psychiatry and mental health, 11 PMID: 28115987

"Increased risk for substance use-related problems in autism"

"We aimed to investigate the risk of substance use-related problems in ASD [autism spectrum disorder]."

Findings: "The risk of substance use-related problems was the highest among individuals with ASD and ADHD [attention-deficit hyperactivity disorder]."

So said the findings reported by Agnieszka Butwicka and colleagues [1] (open-access) looking again at an important but slightly uncomfortable topic: substance use-related problems or substance use disorder (SUD) with autism in mind. Covering various issues including those related to alcohol, drugs, tobacco, crime, somatic disease and death, authors "identified 26,986 probands with an autism spectrum disorders (ASD) among all individuals born in Sweden between January 1, 1973 and December 31, 2009" (yes, yet again it was one of those Scandinavian population registries that provided the data). Data from those diagnosed with autism or ASD were cross-referenced with information on substance-use related problems and compared with "unaffected (without an ASD diagnosis) full siblings (N = 30,456), half-siblings (N = 15,946), and parents (N = 50,155) of probands with ASD." Researchers also took into account issues such as comorbidity - "stratified on probands’ psychiatric comorbidity with ADHD" - and disposable family income and parental education. The examination of ADHD + autism continues an important research direction in recent times (see here).

Results: "Probands had a substantially increased risk of any substance-related problem..., such as substance use disorder..., somatic disease linked to alcohol misuse..., substance-related crime... and death." The sorts of statistics being produced with regards to 'risk' were not unimportant and indeed, were quite contrary to the 'stereotyped' view that "ASD patients are somehow protected from substance use-related problems" (authors words not mine). Further: "Within the substance use disorder category, the highest risk was found for drug use disorder..., followed by tobacco... and alcohol use disorder." The risk figures remained similar even when parental age, region of birth, education and family income were taken into account.

Insofar as one of the opening sentences of this post suggesting that autism + ADHD might be a particularly 'sensitive' combination when it comes to substance-use related problems, the data is pretty stark: "comorbid ADHD or ADHD with ID [intellectual disability] entailed a substantially higher risk, especially for substance use disorder." Autism + ID (without ADHD) however "was not associated with an increased risk of any substance use-related problems..., when all outcomes where regarded as one group."

I don't really want to go too far into the 'hows and whys' of the Butwicka data because this important area of investigation is still in it's infancy. I do appreciate the authors' discussions on how "substance use-related problems in individuals with ASD were indeed less common in the past, but that some factor(s) caused an increase over time" as being potentially important. They for example, talk about how "prior more narrow diagnostic practice may have [previously] excluded ASD patients with substance use-related issues or assigned other diagnoses to them." In other words, taking also into account how autism +ID did not seem to substantially increase the risk of substance use-related issues, the widening of the autism spectrum to potentially include more people might have had some effect on the relationship examined [2]. Obviously, if true, this might have some important implications particularly when it comes to screening and also questioning what role substance use serves for this group in terms of reason(s) for starting and maintaining such behaviour(s).

The important autism + ADHD relationship also picked out by the authors is noteworthy. On several occasions on this blog I've discussed the cold, hard science that suggests that long-term outcome following a diagnosis of ADHD is not exactly brilliant when it comes to various individual and social variables (see here and see here for example). Without trying to generalise/stigmatise nor shift 'blame' from label to label, it's not outside the realms of possibility that comorbid ADHD diagnosis or even features of ADHD, might exert a significant influence on substance use behaviours [3] and the related problems stemming from their use. The implication is therefore, that efforts to minimise such adverse effects linked to a label of ADHD perhaps need to be stepped up.

It's always going to be difficult to talk about substance use disorder and the problems stemming from such behaviours with any specific diagnostic label in mind. There is a particular stigma attached to substance-use behaviours and certainly with autism in mind, more adverse sweeping generalisations are not required (see here for example). But this should not mean that discussions are buried and reality somehow airbrushed for the sake of political correctness or positive public relations. The reality as demonstrated by the Butwicka and other peer-reviewed data [4] is that substance use is / can be a destructive behaviour not least for the person and the people around them. Certainly in the context of autism and the quite large health and social disparities that seem to continually surround the diagnosis (see here for example), a failure to screen for and tackle substance use behaviours further adds to the adverse risks/inequalities that can potentially accompany a diagnosis.

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[1] Butwicka A. et al. Increased Risk for Substance Use-Related Problems in Autism Spectrum Disorders: A Population-Based Cohort Study. J Autism Dev Disorder. 2016. Oct 12.

[2] Clarke T. et al. Substance use disorder in Asperger syndrome: An investigation into the development and maintenance of substance use disorder by individuals with a diagnosis of Asperger syndrome. Int J Drug Policy. 2016 Jan;27:154-63.

[3] Connolly RD. et al. Probabilities of ADD/ADHD and Related Substance Use Among Canadian Adults. J Atten Disord. 2016 May 14. pii: 1087054716647474.

[4] Arnevik EA. & Helverschou SB. Autism Spectrum Disorder and Co-occurring Substance Use Disorder - A Systematic Review. Subst Abuse. 2016 Aug 17;10:69-75.

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Butwicka, A., Långström, N., Larsson, H., Lundström, S., Serlachius, E., Almqvist, C., Frisén, L., & Lichtenstein, P. (2016). Increased Risk for Substance Use-Related Problems in Autism Spectrum Disorders: A Population-Based Cohort Study Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-016-2914-2

Substance use disorder and autism: a case report

Minus any sweeping generalisations, I want to bring your attention to the recent paper by Ashy Rengit and colleagues [1] today, continuing a theme of case reports discussing autism co-occurring with a substance use disorder (SUD). A SUD is generally defined as where the use of one or more substances (drugs) with psychoactive properties leads to significant impairment or distress for a person. Although some people might envisage the use of illicit drugs as being the only way to receiving a diagnosis like SUD, the label also covers more 'everyday' drugs such as problematic alcohol use for example. Indeed, alcohol use disorder (AUD) has its very own category in DSM-5.

I appreciate that this topic is generally neither good dinner-table conversation nor particularly great when it comes to the public image of autism, but as per other discussions overlapping with this topic (see here) it would be folly to ignore it. That some of the characteristics accompanying the diagnosis of autism *might* play a hand in increasing the risk of developing a SUD [2] provides an important message on the value of screening for risk of SUD and where appropriate, educating and intervening early.

Rengit et al provide some useful discussions on the "risk factors which predispose individuals with ASD [autism spectrum disorder] to developing SUD" but I hasten to reiterate that sweeping generalisations are to be avoided, including the ideas of "a positive family history for substance misuse" and the suggestion that autism might be one 'phenotype' "previously reported to be associated with cannabis use" [3] for example.

"It is relaxing in general and provides an amount of happiness" is the explanation offered by Mr. A, the participant under inspection, when it came to explaining his history of alcohol use and abuse. His relationship with alcohol, we are told, began after he graduated from high school and thereafter escalated from "one or two beers per week in solitude" to "hard liquor and wine on a daily basis." There is a familiar theme included in the Rengit paper on how a 'vicious cycle' of anxiety and depression are "perpetuated by his psychosocial limitations" and how combined with chronic worry, a pattern related to his alcohol use may be emerging in conjunction with social circumstances "eliminating his motivation to leave the house." That some of the traditional strategies for overcoming depression and anxiety only previously "showed limited benefit" also provides a rationale for how alcohol might be part and parcel of a self-medication strategy in this case. Similar sentiments have been noted in other research on this topic [4]. I might also bring to your attention the history of suicide attempt(s) reported by the authors as a consequence of "feeling overwhelmed by the new environment and social challenges" that college life brought and how it may also be relevant to discussions on the pathway to SUD in relation to autism. This is particularly relevant to some important discussions recently.

Accepting that different people have different ways and means bringing them to something like a diagnosis of SUD, the Rengit paper brings to light a potentially important but difficult issue linked to some autism. Given the increasing numbers of people being diagnosed with autism (some of them quite late in life) and how in these times of continued austerity many are being left to fend for themselves, one might appreciate that cases of SUD linked to autism are only likely to increase further. This is on top of the idea that certain comorbidity that is over-represented in cases of autism might also increase the chances of something like SUD [5]. That a SUD may further disadvantage people on the autism spectrum not just in terms of health but also in relation to obtaining and sustaining employment for example - "He was also fired from his job for being suspected of being intoxicated" - requires further study and action on both screening vulnerable populations and also managing/treating such issues quickly as and when they occur [6]. Oh, and don't forget the burden of such additional issues on caregivers too [7]...

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[1] Rengit AC. et al. Brief Report: Autism Spectrum Disorder and Substance Use Disorder: A Review and Case Study. J Autism Dev Disord. 2016 Mar 5.

[2] Tabata K. et al. Three cases of alcoholism with autism spectrum disorder. Alcohol Alcoholism. 2014 Sep;49 Suppl 1:i54.

[3] Stringer S. et al. Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium. Transl Psychiatry. 2016 Mar 29;6:e769.

[4] Clarke T. et al. Substance use disorder in Asperger syndrome: An investigation into the development and maintenance of substance use disorder by individuals with a diagnosis of Asperger syndrome. Int J Drug Policy. 2016 Jan;27:154-63.

[5] Pedersen SL. et al. The Indirect Effects of Childhood ADHD on Alcohol Problems in Adulthood through Unique Facets of Impulsivity. Addiction. 2016 Mar 21.

[6] Kronenberg LM. et al. Personal recovery in individuals diagnosed with substance use disorder (SUD) and co-occurring attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). Arch Psychiatr Nurs. 2015 Aug;29(4):242-8.

[7] Kronenberg LM. et al. Burden and Expressed Emotion of Caregivers in Cases of Adult Substance Use Disorder with and Without Attention Deficit/Hyperactivity Disorder or Autism Spectrum Disorder. Int J Ment Health Addict. 2016;14:49-63.

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Rengit AC, McKowen JW, O'Brien J, Howe YJ, & McDougle CJ (2016). Brief Report: Autism Spectrum Disorder and Substance Use Disorder: A Review and Case Study. Journal of autism and developmental disorders PMID: 26944591

Melatonin and leaky gut continued

The paper from Garth Swanson and colleagues [1] reporting findings suggesting that "suppression of melatonin in AD [alcohol use disorder] may promote gut leakiness and endotoxemia" make for the discussion point today.

Continuing a theme from previous times on this blog that "melatonin may serve important gastrointestinal barrier functions" [2] and specifically those related to the concept of intestinal permeability and the so-called 'leaky gut' (see here), these are potentially important findings outside of the more traditional sleep-melatonin link. Swanson et al measured plasma melatonin levels and intestinal permeability via a urine sample in their small participant group of people (as opposed to the previous studies looking at rats). Participants included "20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers)."

Authors reported less total sleep time in participants with AD and "and increased fragmentation of sleep." They also suggested that those with AD had lower levels of melatonin and said lower levels "correlated with increased intestinal permeability and a marker of endotoxemia" (i.e. lipopolysaccharide binding protein). Ergo, there may be quite a bit more to see when it comes to melatonin outside of just sleep with the gut in mind.

Wearing my autism research blogging hat and without wishing to equate alcohol use disorder with autism (bearing in mind a diagnosis of autism is in no way protective of such issues developing) I'd like to think that there may be some important science to do in this area on the back of the very preliminary results from Swanson et al. Melatonin as a management agent for sleeping problems in autism [3] is in the ascendancy these days albeit not necessarily working by "simply replacing melatonin" [4]. The various 'molecular handyperson' abilities of melatonin [5] kinda hint that, as one metabolite of the wonderful tryptophan cascade (see here), melatonin might be doing so very much more when taken.

Gastrointestinal or bowel issues being 'over-represented' when it comes to autism is a topic that is becoming less and less argued about these days as a result of the volumes of data being produced on this issue (see here for example). Part of the research question that still needs answering about functional bowel issues and autism is whether or not they are reflective of more 'pathological' states with the gut and in particular, their association (or not) with underlying problems that may well impact on gut barrier function and integrity (see here). The implication being that where present, alterations to gut permeability (leaky gut) may have the ability to do various 'things' to a person including potentially impacting on behaviour and development.

If we assume that melatonin might have some 'gut healing' properties [6] as part of it's repertoire of proposed actions [7] and considering it's growing use with autism in mind, the intriguing prospect that leaky gut is already being 'treated' in cases of autism is opened up. I say this with the understanding that science has yet to fully understand leaky gut or fully corroborate the idea that leaky gut can be treated where present in relation to autism (outside of the data from de Magistris et al [8] suggesting that those with autism "on a reported gluten-casein-free diet had significantly lower IPT [intestinal permeability] values compared with those who were on an unrestricted diet and controls").

So, once again the research gauntlet is thrown down: who will be first to apply some science to this area and measure melatonin vs. placebo in terms of sleep and gut barrier function when it comes to outcome in relation to autism?

Music: The Streets - Dry your eyes.

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[1] Swanson GR. et al. Decreased Melatonin Secretion is Associated with Increased Intestinal Permeability and Marker of Endotoxemia in Alcoholics. Am J Physiol Gastrointest Liver Physiol. 2015 Apr 23: ajpgi.00002.2015.

[2] Sommansson A. et al. Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo. Am J Physiol Gastrointest Liver Physiol. 2013 Jul 1;305(1):G95-G105.

[3] Veatch OJ. et al. Sleep in Autism Spectrum Disorders. Current Sleep Medicine Reports. 2015. April 24.

[4] Goldman SE. et al. Melatonin in children with autism spectrum disorders: endogenous and pharmacokinetic profiles in relation to sleep. J Autism Dev Disord. 2014 Oct;44(10):2525-35.

[5] Boga JA. et al. Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? Rev Med Virol. 2012 Sep;22(5):323-38.

[6] Eliasson L. Melatonin heals the gut. Acta Physiol (Oxf). 2014 Oct;212(2):120-1.

[7] Romo-Nava F. et al. Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord. 2014 Jun;16(4):410-21.

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

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Swanson GR, Gorenz A, Shaikh M, Desai V, Forsyth CB, Fogg L, Burgess HJ, & Keshavarzian A (2015). Decreased Melatonin Secretion is Associated with Increased Intestinal Permeability and Marker of Endotoxemia in Alcoholics. American journal of physiology. Gastrointestinal and liver physiology PMID: 25907689

Alcohol and autism

I tread very carefully with this post today looking at some of the peer-reviewed research on the topic of alcohol use (and abuse) and autism without wishing to stigmatise nor generalise.

I was brought to this important topic as a result of the recent paper by Tabata and colleagues [1] who discussed three case reports of alcoholism associated with a diagnosis of autism. For each person described in that report, a common theme describing alcohol being used as a means to "reduce anxiety" related to "the stress of interpersonal communication" is inferred as per other mentions in the literature. I don't however doubt that the ways and means that one arrives at alcohol as being a problem issue is going to be far more individual and complicated than just drinking to relieve stress and anxiety.

As indicated, science has talked about alcohol and autism quite a bit before the Tabata paper. Outside of the body of work looking at a 'possible' overlap between something like foetal alcohol syndrome / foetal alcohol spectrum disorder and autism (see here) or certain medicines examined with both autism and alcoholism in mind (see here which might also tie into some recent guidance), there are other papers to consider.

The paper by Miles and colleagues [2] titled: 'Autism families with a high incidence of alcoholism' was seemingly one of the first reports looking at whether there may be a familial relationship between autism and behaviours associated with alcoholism. I know this kind of reading might be quite difficult for some and so again, I reiterate my initial comment about not wanting to generalise or stigmatise with this entry. Miles et al looked at patterns of familial alcoholism and whether such behaviour may be "consistent with transmission of a genetic trait". Their results suggested that there may be something more to see in this area, and in particular, under certain circumstances where parental alcoholism might impact on symptom presentation as per their finding: "suggesting an association between maternal alcoholism and regressive onset autism". I hasten to add that given the continued delicacy of the topic of regression and autism (see here) I don't say this as being a stick used to beat those parents who talk about their child's autism presentation in such regressive terms. The paper by Schumann and colleagues [3] kinda adds to the Miles' results with their observation that a mutation in something called the autism susceptibility candidate 2 gene (AUTS2) might show some connection to alcohol drinking behaviour. That and other work [4] looking at this gene in relation to other dependencies might also be important but that's all I'm gonna say on this issue for now.

The findings reported by Palmqvist and colleagues [5] on potential under-diagnosis of substance use disorders (SUD) in cases of autism (and ADHD) highlighted how, certainly in Sweden, something like possible alcohol abuse is not routinely assessed. As per research by De Alwis and colleagues [6] one of reasons why alcohol misuse might not be so preferentially indicated where an autism diagnosis is present are the "social underpinnings of drinking"; something the authors seem to imply may be protective - "those with high autistic traits scores were less likely to report drinking to intoxication". But, and it is an important point, De Alwis et al also reported that: "upon engagement in drinking, their [those with elevated autistic traits] vulnerability to alcohol dependence is elevated". This hints that some issue may be present, accepting the authors' focus on autistic traits over and above a specific autism diagnosis.

Having made mention of the topic of attention-deficit hyperactivity disorder (ADHD) in this post, and acknowledging that a diagnosis of autism might elevate the risk of something like ADHD (see here), one might also look to such comorbidity as potentially affecting the risk of alcohol abuse. I'm not trying to shift any 'blame' here on to ADHD but there is quite a bank of research suggesting that ADHD itself might be associated with an increased likelihood of alcohol issues [7]. I can't readily provide any detailed explanation of why this should be (high genetic liability, risk-taking behaviours, societal issues?) but one might entertain the thought that where ADHD is present alongside autism, factors might align which both instigate and perpetuate problematic behaviours with alcohol. Santosh & Mijovich hinted as much in their paper [8]. Similar processes may also pertain to other comorbidity [9] which have been mentioned with the autism spectrum in mind (see here).

I do believe that more research resources need to be put into further investigating the important topic of autism and alcohol use and abuse not only for the health effects which may manifest but also in light of where such behaviours can in the extreme lead [10]. Such research might also include animal models too (see here). Alcohol is all around us and if the latest estimates are to be believed issues with alcohol are probably not restricted to any one group. Early identification of potential alcohol issues, assessing the hows and whys of such behaviour and putting in place effective strategies to offset behaviours or health effects when linked to cases of autism sound like reasonable steps to take. Some further, more general, guidance can be found here.

Now, would it be too outlandish if I was to start talking about "a gut–brain axis in alcohol dependence" [11] given what has been suggested with [some] autism in mind down the years?

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[1] Tabata K. et al. Three cases of alcoholism with autism spectrum disorder. Alcohol Alcoholism. 2014 Sep;49 Suppl 1:i54.

[2] Miles JH. et al. Autism families with a high incidence of alcoholism. J Autism Dev Disord. 2003 Aug;33(4):403-15.

[3] Schumann G. et al. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7119-24.

[4] Chen YH. et al. Genetic analysis of AUTS2 as a susceptibility gene of heroin dependence. Drug Alcohol Depend. 2013 Mar 1;128(3):238-42.

[5] Palmqvist M. et al. Screening for substance use disorders in neurodevelopmental disorders: a clinical routine? Eur Child Adolesc Psychiatry. 2014 May;23(5):365-8.

[6] De Alwis D. et al. ADHD symptoms, autistic traits, and substance use and misuse in adult Australian twins. J Stud Alcohol Drugs. 2014 Mar;75(2):211-21.

[7] Levy S. et al. Childhood ADHD and risk for substance dependence in adulthood: a longitudinal, population-based study. PLoS One. 2014 Aug 27;9(8):e105640.

[8] Santosh PJ. & Mijovic A. Does pervasive developmental disorder protect children and adolescents against drug and alcohol use? Eur Child Adolesc Psychiatry. 2006 Jun;15(4):183-8.

[9] Frye MA. et al. Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder. Am J Psychiatry. 2003 May;160(5):883-9.

[10] Sher L. Risk and protective factors for suicide in patients with alcoholism. ScientificWorldJournal. 2006 Oct 31;6:1405-11.

[11] Leclercq S. et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. PNAS. 2014. 6 October.

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Tabata K, Yoshida T, & Naoe J (2014). Three cases of alcoholism with autism spectrum disorder. Alcohol and alcoholism (Oxford, Oxfordshire), 49 Suppl 1 PMID: 25221235

Sensitizing to gluten?

Actually the title to this post should really read 'sensitising' rather than 'sensitizing' as a function of my Limey status. No mind, today I'd like to introduce you to two pretty unusual papers which I stumbled across in recent times which have the common denominators of (a) both being about gluten and the possible induction of problems with gluten, and (b) both carrying Marios Hadjivassiliou as part of the authorship team. They're both open-access too.

The first paper is by Currie and colleagues* who concluded that: "Alcohol related cerebellar degeneration may, in genetically susceptible individuals, induce sensitization to gluten". The second paper by Ludvigsson & Hadjivassiliou** in a similar vein suggested that there was a: "very small excess risk for future CD [coeliac disease] in individuals with an earlier head trauma".

Why am I talking about these papers you might ask? Well, outside of any autism-gluten research obsession I might have, I was interested to read about how an issue with gluten might come about as a function of an environmental insult; in these cases, alcohol abuse and head injury. Just however before I stray away from the autism-gluten science, the keen reader might have already spotted the name Ludvigsson, Jonas Ludvigsson, as being one and the same lead author on that 'not coeliac disease but something gluten related' paper in relation to cases of autism (see here for some discussion).

I'm not going too heavily into these papers but it strikes me that there are a few possible connections to be made from the cumulative data. Autoimmunity is the source of some speculation in both papers. The Currie paper speculates that: "autoimmunity may have a role to play in the development of ataxia in patients that drink excessively". Ataxia by the way, refers to a group of conditions which affect motor skills. Similarly, L & H (because they both have particularly long surnames) talk about "an autoimmune response against transglutaminases triggered by the brain injury". The transglutaminases (plural) or at least one of them (tTG) have already been talked about on this blog with reference to the process of coeliac (celiac) disease (see here).

That 'development of autoimmunity' suggestion also leads into another potential commonality across these papers: the cerebellum. Part of the brain long thought to be involved in motor control (as well as other cognitive functions), the suggestion is that "antigliadin antibodies may arise after a cerebellar insult rather than being the cause of it per se" in the alcohol study. The head injury paper provides an equally interesting commentary, if a little less 'proven' by results: "head trauma resulting in cerebral and cerebellar insults may trigger autoimmunity against TG6 which in turn may lead in some genetically susceptible individuals, to the development of CD".

If I've got all my factoids correct, there is a rather interesting hypothesis to test from these collected results. Take an immune system which genetically looks a little like that seen in coeliac disease with regards to those HLA-DQ2 and DQ8 heterodimers. Add an environmental insult which in particular, targets the cerebellum or indeed some other part of the brain. For whatever reason, the exposure to that insult starts to do odd things to "normally shielded" self epitopes such as TG6 which "may result in the immune system reacting to self-antigens in the central nervous system ultimately leading to autoimmunity". Gluten just happens to be one of the external agents to which antibodies also start being produced against as self and other start to become mixed up, and hey presto, you're gluten sensitive.

OK, I know there is still much to do in this area of research and by no means should anyone take such a hypothesis as fact at this point in time. Marios Hadjivassiliou has done a lot of work in the area of extra-intestinal presentation of gluten issues (see here for example***) but we're not yet in a position to start definitively linking all the pieces together just yet. That and the differences between the two papers discussed in this post in terms of what was looked at (antigliadin antibodies vs. patient register details for head injury and/or small intestinal biopsy reports) and how participants were examined, means I am to a large extent comparing apples and oranges.

Still, I do find this line of inquiry to be quite fascinating. I'm also thinking back to the paper by Emily Severance and colleagues**** on how infection with the gondii (that's Toxoplasma gondii) in a mouse model might also be able to invoke an immune reaction to gluten (see here for my take of the study). There's more to come on this blog from Dr Severance, but again, speculations on immune activation through the slightly different environmental process of infection translating into a immunological effect against gluten.

But still the possibility of an acquired sensitivity to dietary gluten...

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* Currie S. et al. Alcohol induces sensitization to gluten in genetically susceptible individuals: a case control study. PLoS One. 2013 Oct 15;8(10):e77638.

** Ludvigsson JF. & Hadjivassiliou M. Can head trauma trigger celiac disease? Nation-wide case-control study. BMC Neurol. 2013 Aug 9;13:105.

*** Hadjivassiliou M. et al. Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry 2002;72:560-563.

**** Severance EG. et al. Anti-gluten immune response following Toxoplasma gondii infection in mice. PLoS One. 2012;7(11):e50991.

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Currie S, Hoggard N, Clark MJ, Sanders DS, Wilkinson ID, Griffiths PD, & Hadjivassiliou M (2013). Alcohol induces sensitization to gluten in genetically susceptible individuals: a case control study. PloS one, 8 (10) PMID: 24204900




Ludvigsson JF, & Hadjivassiliou M (2013). Can head trauma trigger celiac disease? Nation-wide case-control study. BMC neurology, 13 PMID: 23927742

Diet determines gut bacteria

Continuing my interest/borderline obsession with all things gut bacterial, I offer this short post. It is a short post because this link to an entry in Science by Martin Enserink says just about everything I might want to say and probably better than I would say it. For those who want the slimmed down version.. for your consumption:

Enterotypes, that is categorised types of gut bacteria, seem to occur as a consequence of what form your diet takes according to this study by Gary Wu and colleagues*. So eat lots of meat and saturated fat and Bacteroides is the predominant species. If alcohol and polyunsaturated fats are among your primary dietary selections then Ruminococcus is your man/woman. Love your carbs? Then Prevotella predominates. Important also that whilst changes to fat and fibre content of your diet in the short term produce some detectable changes to gut bacteria, your enterotype seems to be a little more stable from meal to meal (at least in the 10 participants included in the trial over a period of 10 days).

There are so many more questions to be asked about this area of study. With my autism research hat on, I wonder what the bacterial consequences are when diets like a gluten- and casein-free diet are adopted, or when a specific carbohydrate diet (SCD) is followed over a course of months or years? Do the gut bacterial populations stay the same, or if not, could this conceivably tie into any behavioural effects noted from such dietary intervention the same way as happens when you 'shock and awe' gut bacteria with strong antimicrobials?

* Wu G. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. September 2011. DOI: 10.1126/science.1208344