"Ruminative thinking is the autistic dimension more strongly associated with suicidality"

The quote titling this post - "Ruminative thinking is the autistic dimension more strongly associated with suicidality" - comes from the findings published by Liliana Dell'Osso and colleagues [1] and provides something of an extension of previous work from authors on this paper (see here).

The important topic under investigation by Dell'Osso et al was suicidality; something that crops up time and time again in connection to the autism spectrum (see here). No, such a topic doesn't make for great PR 'about autism'. But if you want to talk about research/clinical priorities when it comes to the autism spectrum, I can't think of many topics that would be more pressing...

The hypothesis: those with subthreshold autistic traits (AT) and autism spectrum disorder (ASD) "will both show a higher prevalence of suicidal ideation and behaviors" when compared with asymptomatic controls. Further: "to clarify if AT do actually imply a risk factor for suicidality similar to full-blown ASD, hypothesizing that suicidal thoughts and behaviors will not differ between subjects with subthreshold autism and full-blown ASD." Similar sentiments have been previously expressed in other research results (see here and see here and see here).

I won't bore you with all the details of the hows-and-whys of Dell'Osso study (it is open-access) but do want to focus in on a few important observations made. First authors reported that they "found no differences in suicidality scores between ASD and AT groups, while both showed a higher score than HC [healthy controls]." I might add that 'HC' is a term used by the authors and wouldn't be my choice for describing a control group. This finding is important not just for autism but potentially for lots of other labels that manifest autistic traits (see here and see here) on the basis that autistic traits are not necessarily exclusive to a diagnosis of autism.

Second: "the ASD group reported significantly higher MOODS-SR total score and MOODS-SR depressive component score than the AT group, and the AT group in turn scored significantly higher than the HC." I don't think anyone should be really surprised by the finding that the symptoms of mood disorders such as depression seem to be 'over-represented' alongside a diagnosis of autism given other data on this issue (see here). Indeed, one might even say that depression could, for some autistic people, be considered a core issue over and above just being described as a comorbidity (see here).

Finally I head back to the title of this post, and how something like ruminative thinking - "a pattern of repetitive thinking, usually associated to and exacerbating anxiety and depression, often affecting problem-solving and the processing of negative feelings and leading to social isolation" - might be a particular dimension *associated* with suicidality in the context of autism or the presentation of subthreshold autistic traits. I've talked a few times about rumination in the context of autism on this blog (see here and see here). Rumination has also been talked about in the context of autism and suicide before too (see here). If research continues to point to rumination as something important, one might potentially envisage the development of interventions that could ameliorate such an issue and possibly onward *affect* the risk of something like suicidality?

I don't want anyone to get the impression that the Dell'Osso findings have *solved* the issue of suicidality in the context of autism because they haven't. As I've said many times before on this blog, suicide is a very, very complicated and deeply personal issue (see here) with no one-size-fits-all answer to the questions it raises. As part of a larger picture however, the Dell'Osso results are however important. If their application in a clinical context saves even one life, I would consider that to be infinitely worthwhile.

If anyone needs someone to talk to, there are people who will listen (see here and see here)...

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[1] Dell'Osso L. et al. Mood symptoms and suicidality across the autism spectrum. Comprehensive Psychiatry. 2019. April 3.

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"Childhood seizures and risk of psychiatric disorders in adolescence and early adulthood"

I want to bring the findings reported by Julie Dreier and colleagues [1] to your attention today and their observation that: "Children with epilepsy and febrile seizures-with and without concomitant epilepsy-are at increased risk of developing a broad range of psychiatric disorders in later life."

Researchers report results based on the examination of one of those ever-so-impressive Scandinavian population registries that have moved science forward in many, many different areas (see here for example). This time around it was the Danish National Patient Register and the inclusion of data from "1 291 679 individuals... born in Denmark and followed up in our population cohort (approximately 15 million person-years)." Over 43,000 individuals showed a history of febrile seizure - "fits that can happen when a child has a fever" - and over 10,000 had epilepsy. Likewise: "83 735 (6%) cohort members were identified with at least one of the psychiatric disorders of interest" including substance abuse disorders, schizophrenia, mood disorder, anxiety, and personality disorder.

Results: "The risk of any psychiatric disorder was raised in individuals with a history of febrile seizures..., epilepsy..., or both disorders." The magnitude of the risk was categorised as statistically significant in terms of elevation but ranged from between a 10-50% increased risk. Further: "Excess risk of psychiatric illness associated with childhood seizures was present across a range of different disorders, most notably schizophrenia but also anxiety and mood disorders." Authors also opine that further research is needed on this topic with regards to mechanisms pertinent to identifying "potential options for prevention."

Although some caution is always required when one variable (epilepsy) is solely correlated with another (history of recorded psychiatric diagnosis), I am interested in the Dreier findings. I'm interested not only because of the *association* being made between a condition that often has life-changing effects on other often life-changing diagnoses but also because this *association* complements other links being made with epilepsy. I speak of the various studies linking epilepsy to diagnostic labels such as autism and attention-deficit hyperactivity disorder (ADHD) of course (see here and see here for examples) whilst pointing out that ADHD and autism are not to be categorised as mental health conditions. Such links between epilepsy and neurodevelopmental diagnoses are all the more interesting because the presence of labels such as autism and ADHD are also known to manifest elevations in other psychiatric diagnoses such as mood disorder, anxiety and schizophrenia (see here and see here and see here for examples). It's not therefore unreasonable to suspect that there may be some 'over-arching' themes when it comes to epilepsy/febrile seizures 'linking' with various developmental and psychiatric diagnoses.

Minus any sweeping generalisations and being careful how I phrase this, one area that requires a lot more investigation is the neurological effect that epilepsy in particular can have. I speak of the idea that seizures can, in some cases, affect the physical nature of the brain [2] and the question of whether such 'damage' might also then affect the presentation of behaviour akin to the signs and symptoms of a neurodevelopmental or psychiatric diagnosis. I know this is not a particularly palatable line of thinking but it does require further scientific exploration. This is also pertinent to the Dreier study focusing in on childhood seizures and by inference, possible effects on the developing brain. Another area of further investigation is whether the presentation of epilepsy or seizures *might* be part-and-parcel of various syndromes also presenting with neurodevelopmental and/or psychiatric features? We do have some examples of this already (see here) and, given that various genetic syndromes are quite regularly being identified day-by-day, it's another area that could yield some important data.

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[1] Dreier JW. et al. Childhood seizures and risk of psychiatric disorders in adolescence and early adulthood: a Danish nationwide cohort study. Lancet Child Adolesc Health. 2018 Dec 6. pii: S2352-4642(18)30351-1.

[2] Bronen RA. et al. The Status of Status: Seizures Are Bad for Your Brain's Health. American Journal of Neuroradiology. 2000; 21: 1782-1783.

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"little evidence for the involvement of Mg2+ in the mood disorders"?

Mg2+ described in the title of this post refers to magnesium, a mineral that participates in quite a few important biological reactions in the human body. Outside of its proposed involvement in a variety of somatic conditions and diagnoses, a deficiency in magnesium has also been *linked* to various psychiatric and behavioural issues too (see here). The findings reported by Danny Phelan and colleagues [1] however, stress caution in making too many sweeping generalisations on the basis of the currently available peer-reviewed data, albeit with hints that magnesium might have some role to play for some...

The name of the research game for Phelan et al was 'systematic review and meta-analysis', which basically means identifying, collating and 'boiling down' the [currently available] relevant research into some sort of coherent whole. Some 58 research articles including over 45,000 participants were used for 'quantitative synthesis' across a variety of different effects: the prevalence/incidence of depression as a function of magnesium intake, magnesium levels as a function of mood disorder status, magnesium concentration according to mood disorder severity and mood disorder status as a function of magnesium treatment. The results were interesting...

"Adherence to a diet high in Mg2+ was associated with a lower prevalence of depression in cross-sectional studies... but not in longitudinal cohorts that assessed the incidence of new-onset depression." Taking into account the difference in study design, this finding translates as a suggestion that "dietary Mg2+ intake may play a part in the pathology of depression" with the caveat that cause-and-effect was not proven. Accepting also that 'depression' as an umbrella term covers quite a bit of diagnostic ground, authors observed that: "There were no studies which reported on the effects of dietary Mg2+ on symptoms of bipolar disorder" so no conclusions can be currently formed either way.

Next: "Against expectations, we found higher Mg2+ levels in bodily fluids in patients with a mood disorder relative to healthy control subjects." This is a peculiar finding and one that needs further explanation beyond possibly just reflecting "the hypothesis that an increase in Mg2+ may underlie the clinical efficacy of (fast-acting) antidepressants" or dehydration *caused by* the use of pharmacotherapy indicated for mood disorders. I might add that such a findings could just be indicative of magnesium showing a epiphenomenal relationship with mood disorder too.

Finally: "In line with expectations, we found that treatment with Mg2+ supplements was associated with a decline in depressive symptoms." The authors yet again mention that study design/type may have something to do with the results observed; in particular, that a such an effect seemed to be confined to those studies with no placebo condition.

I was initially a little unsure about the 'cautiousness' expressed by Phelan et al on a possible role for magnesium in [some] mood disorders. Statements like: "Our results provide little evidence for the involvement of Mg2+ in the mood disorders" didn't seemingly really reflect the findings being reported on, but with a bit of further critical thinking I've changed my tune a bit. I would still perhaps argue that it would have been more accurate to say something along the lines of 'there is evidence out there for an effect on dietary magnesium potentially being associated with a lower instance of depression but that evidence is not as methodologically strong as one would hope'. But oh-um. Certainly I think we can conclude that there is an additional scheme of research to follow to aid in future position statements on this topic.

And then there is the question of 'why?'. Why should magnesium affect mental health? And what about any effects from various 'different types' of magnesium available?

To close, I've linked to this before but here it is again: possibly the best opening to a film ever...

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[1] Phelan D. et al. Magnesium and mood disorders: systematic review and meta-analysis. BJPsych Open. 2018 Jul;4(4):167-179.

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Low grade inflammation in acute psychiatric inpatients

I was interested to read the findings reported by Emanuele Osimo and colleagues [1] (open-access available here) recently, and their observation that: "Evidence of low-grade inflammation was present in all major diagnostic groups, with prevalences ranging from 12 to 40% depending on the measure."

'Major diagnostic groups' included in the Osimo paper, included "acutely unwell psychiatric inpatients from all major ICD-10 diagnostic groups" covering labels such as psychotic disorder, schizophrenia, mood disorders, personality disorders and organic mental disorders.

Authors - including the notable name of Golam Khandaker who has published work previously covered on this blog (see here and see here for examples) - conducted an "anonymised search of the electronic patient records" for those hospitalised in a specialist mental health department for the treatment of a mental health / psychiatric condition between 2013 and 2016. Alongside, they had to have "a blood test result for CRP [C-reactive protein] or for WBC [total white cell count] [that] had been recorded on the electronic medical notes system within 14 days of admission" yielding almost 600 participants. In effect, a blood test pertinent to the measurement of compounds reflective of immune system processes such as inflammation.

As per the opening sentences to this post, and using CRP and/or WBC as a measure of inflammation, authors identified some quite notable prevalences of low-grade inflammation in their patient group. So: "The prevalence of inflammation in the major ICD-10 diagnostic groups of psychotic disorders (F20–29), mood disorders (F30–39), neurotic disorders (F40–48) and personality disorders (F60–69) was 32%, 21%, 22% and 42%, respectively." Various other variables also seemed to be *associated* with the presence of such inflammation too. Authors note for example that: "Patients with medical comorbidities were more likely to be inflamed" alongside various other factors also potentially exerting an effect: "older age, black ethnicity, being single, self-harm, diagnoses of schizophrenia, bipolar disorder, current treatments with antidepressants, [and] benzodiazepines" were all associated with low-grade inflammation.

Such findings add to the ever-growing amount of research that suggests a role for the immune system in relation to various psychiatric / behavioural diagnoses (see here). Further, that with a little more focus on the somatic as well as the psychiatric (see here) when it comes to such conditions, potentially relevant clues may emerge pertinent to treatment options. I might finally also draw your attention to some work previously discussed on this blog dealing with the idea that inflammation *might* have the ability to affect social cognitive processing (see here). Such a finding, focused on symptoms rather than labels, could offer a few alternative directions for intervention given the widespread nature of social cognitive issues across a wide variety of psychiatric conditions.

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[1] Osimo EF. et al. Prevalence and correlates of low-grade systemic inflammation in adult psychiatric inpatients: An electronic health record-based study. Psychoneuroendocrinology. 2018 Mar 1. pii: S0306-4530(17)31581-0.

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

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

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

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

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

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

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

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

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

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

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Pregnancy antidepressant use and offspring outcomes beyond autism?

I'll say one thing for the British Medical Journal (BMJ), they don't seem to be afraid to cover important issues relating to the *possible* "reproductive safety of drugs" [1] as per their publication of yet another paper looking at antidepressant use during pregnancy and offspring outcomes published by Xiaoqin Liu and colleagues [2]. This follows another paper published in the BMJ and covered on this blog a few weeks back (see here).

The specific class of drugs being examined again are, as I mentioned, the antidepressants and based, yet again, on data from one or more of those wonderful Scandinavian population registries in relation to how pregnancy use of antidepressants *might* impact on risk of risk of various psychiatric disorders in offspring. A diagnosis of autism spectrum disorder (AD) has been a primary focus of previous research in this area; particularly the question of whether the medicines themselves or the condition(s) that the medicines are used for (i.e. maternal psychopathology) might be the more important variables related to enhanced offspring risk of autism. The last paper covered on this blog by Rai and colleagues [3] very cautiously suggested that: "The results of all these analyses, which used different assumptions, seemed to be consistent with each other, suggesting that the association between in utero exposure to antidepressants and autism might not be fully explained by confounding." Cautiously...

This time around the net was widened from just looking at autism as an offspring outcome to "overall risk of psychiatric disorders" including: "autism spectrum disorder... mood disorder... neurotic, stress related, and somatoform disorder... behavioural and emotional disorder... and mental retardation." I might add that these are the authors words not mine and diagnoses were based on ICD-10 criteria and codings.

Looking and following some 900,000 children born between 1998 and 2012 in Denmark until 2014, researchers categorised participants according to their pregnancy antidepressant exposure(s): "unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy)" and looked at the frequency of those conditions included for study.

Results: some 2% of children were born to mums who used an antidepressant during pregnancy (n=21,063). Various types of antidepressants were used but the majority were prescribed SSRIs (Selective Serotonin Reuptake Inhibitors) either alone (monotherapy) or in conjunction with other non-SSRI medication.

"We observed increased risks of psychiatric disorders in all three groups of antidepressant users (discontinuation, continuation, and new user groups), compared with the unexposed group." This itself is an important finding but does not yet disentangle whether medicine use or the reason(s) for medicine use might be the more important variable. Then: "we observed an increased risk of psychiatric disorders in children whose mothers continued antidepressant use during pregnancy, compared with mothers who discontinued." Such a statement potentially edges a little closer to some influence of pregnancy antidepressant use on offspring outcomes but, and it is an important but: "These associations could be attributable to the severity of the underlying maternal disorders in combination with in utero antidepressant exposure." In other words, those mums who needed to continue antidepressant use throughout pregnancy probably had to do so because their symptoms either returned or were not controlled properly when medication is not in place. This might imply that more serious maternal psychiatric disorder could be a variable in any enhanced risk of offspring psychiatric disorder.

When it came to looking at specific diagnostic labels for offspring, all but "mental retardation" (I prefer the term learning disability) seemed to be elevated alongside "in utero exposure to antidepressants." The conditions with the highest risk were the mood disorders including diagnoses such as clinical depression and bipolar disorder. Given that antidepressants are typically (but not exclusively) used to treat/manage mood disorders, such a finding of maternal mood disorder potentially transmitting down into offspring mood disorder receives further credence from such results.

The Liu paper and accompanying editorial grapple with the question of whether the *possible* risks from pregnancy use of antidepressants on offspring merit a change to guidance on their use at such a critical time. As I've mentioned on other occasions discussing this topic, antidepressants are not typically just dispensed willy-nilly without appropriate clinical indication. They provide an important service in controlling various types of symptoms; pertinent to the idea that uncontrolled depression during pregnancy for example, can have all-manner of negative outcomes. As all medicines do, yes they may have side-effects but these need to be weighed up against perceived benefits, taking into account any important influence on the developing child. Indeed, the authors note: "any final decision on antidepressant continuation should be individualised and made jointly by health professionals and patients."

And whilst I've mentioned pregnancy antidepressant use and offspring autism risk, yet another review paper enters the scientific fray [4]...

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[1] Nordeng H. et al. Prenatal exposure to antidepressants and increased risk of psychiatric disorders. BMJ. 2017; 358: j3950.

[2] Liu X. et al. Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study. BMJ. 2017; 358: j3668.

[3] Rai. D. et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017; 358: j2811.

[4] Andalib S. et al. Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review. Eur Psychiatry. 2017 Jun 20;45:161-166.

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Vitamin D supplementation did not affect depression scores in bipolar disorder

The paper by Wendy Marsh and colleagues [1] is the offered up for discussion today and the finding that: "despite a greater rise in Vitamin D levels in the VitD supplementation group, there was no significant difference reduction in depressive symptoms" in their small cohort of adults diagnosed with "DSM IV bipolar depression and Vitamin D deficiency (<30 ng/ml)."

Regular readers of this blog might know that I'm not adverse to talking about a possible relationship between the very nebulous term 'depression' and the so-called sunshine vitamin/hormone that is vitamin D (see here and see here for examples) on the basis of measured vitamin D levels typically being lower in this population. In the specific context of bipolar disorder - where moods can swing between the extremes of depression and mania - there is also some evidence that the diagnosis is by no means protective against vitamin D insufficiency/deficiency [2] and hence supplementation might be indicated where deficiency/insufficiency is detected. Could supplementation to correct a vitamin D deficiency also impact on depressive symptoms? Well, it may not be as simple as that as per other recent examples...

Marsh et al utilised the gold standard in scientific trial design (double-blind, placebo-controlled) where "5000IU [international units] Vitamin D3 po qday supplementation" was pitted against placebo for 12 weeks. As well as looking at whether vitamin D levels improved, researchers examined scores on various schedules looking at aspects of mood (depression, anxiety, mania).

Results: when it came to those mood scores, there wasn't a great deal of difference between the groups ("16 VitD vs 17 placebo subjects") after 12 weeks. The authors note that: "MADRS [Montgomery-Åsberg Depression Rating Scale] score decreased significantly in both placebo... and VitD groups... but there were no differences between treatment groups." So, it seems that vitamin D supplementation is not some sort of cure-all for aspects of bipolar depression; bearing in mind the relatively small participant group numbers included for study.

There was also another quite intriguing observation raised by the authors: "At 12wks, the placebo group VitD levels remained unchanged, while the VitD group levels increased to 28 ng/ml." Further: "both groups’ VitD levels remained deficient." Even after 12 weeks of supplementing 5000IU daily of vitamin D3 (total dose = 420,000IU?), the supplemented group as a whole were still in the insufficient range? Of course it could be that there were issues with compliance; researchers were asking participants to take tablets daily for 12 weeks - even the most observant participants might not have completed the entire regime (particularly if they did not feel/see any effects during the trial). But I also wonder if there may other important variables affecting vitamin D levels [3] that might also account for the findings?

This is not the first time [4] that vitamin D supplementation 'for depression' has fallen under controlled conditions. I do still think that science needs to do more in this area; not least on how other confounding variables might affect efficacy and specifically how genetics might show some interplay (see here for example). We currently seemed to be faced with a picture suggestive of vitamin D inadequacy being *associated* with depression but correcting said levels (as least with oral supplementation) does not seem to be all that useful when it comes to affecting presented psychological symptoms. Well, in some cases anyway [5]...

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[1] Marsh WK. et al. Vitamin D supplementation in bipolar depression: A double blind placebo controlled trial. J Psychiatric Res. 2017. July 22.

[2] Boerman R. et al. Prevalence of Vitamin D Deficiency in Adult Outpatients With Bipolar Disorder or Schizophrenia. J Clin Psychopharmacol. 2016 Dec;36(6):588-592.

[3] Mazahery H. & von Hurst PR. Factors Affecting 25-Hydroxyvitamin D Concentration in Response to Vitamin D Supplementation. Nutrients. 2015;7(7):5111-5142.

[4] Kjærgaard M. et al. Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial. Br J Psychiatry. 2012 Nov;201(5):360-8.

[5] Bahrami A. et al. High Dose Vitamin D Supplementation Is Associated With a Reduction in Depression Score Among Adolescent Girls: A Nine-Week Follow-Up Study. J Diet Suppl. 2017 Jul 31:1-10.

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Suicidality in children and young adults with 'high-functioning' autism

"Consistent with the previous findings, [the] rate of suicidality is higher in individuals with ASD [autism spectrum disorder]."

That was one of the conclusions reported in the paper by Sevcan Karakoç Demirkaya and colleagues [1] (open-access) yet again touching on a most important topic when it comes to autism, particularly the part of the autism spectrum labelled as 'high-functioning'. Personally, I'm not a great fan of the 'functioning' description typically added to autism to somehow denote can from can't do. As science is starting to realise, high-functioning does not automatically imply 'can function' across the board just as the even worse description 'low-functioning' does not necessarily generalise to mean 'can't function'. I know it's the best we have at the moment but...

Anyhow, Karakoç Demirkaya et al report results following a review of medical charts for some 55 adolescents (mostly boys) aged between 7 and 20 years of age. All were diagnosed with an ASD and all had "capability of reading, writing and speaking" and were deemed to have cognitive abilities in the typical range (i.e. no learning disability). Included in the data examined were responses to the Eskin’s Suicide Screening Questionnaire; specifically answers to 5 questions on thoughts of (suicidality) and actual attempts at suicide.

Results: "Suicidality was observed in 16 individuals in our group which accounts for a rate of suicide of 29%. Among the suicidal ones, seven individuals had the diagnosis of AD [autistic disorder], eight had AS [Asperger syndrome], and an individual had PDD-NOS [pervasive developmental disorders - not otherwise specified]." Because no 'not autism' control group was included in this specific study, authors draw attention to how their figure compared with "the result of previous studies implemented on a typically developing adolescent population in our country" (Turkey) and suggest that their figure was slightly higher (29% vs 25%). I have to say that I'm pretty shocked by the suicidality figures reported in both the autism and not-autism groups.

On the issue of actual suicide attempts, Karakoç Demirkaya and colleagues report that about 12% of their small-ish cohort had some history of this type of behaviour. Again, this contrasted with data from other independent studies where around 4-5% of adolescents were reporting such a history. Worrying figures again.

Further: "Rates of comorbid psychiatric disorders such as mood disorders, anxiety disorders and disruptive behaviors were 23.6%, 43.6% and 65.4% respectively. Groups with the psychotic features, positive family history for suicidal behaviors and completed suicide showed more suicidality than the non-suicidal group." This is an important part of the results obtained. It implies that when we say suicidality (thoughts and/or behaviours) is 'elevated' when it comes to the autism spectrum, we can't at the present time, tease autism apart from other comorbidities that may also have an important bearing on this type of behaviour. It's a point that has been raised in relation to suicidality accompanying other labels too (see here).

I'm gonna leave it at that with the Karakoç Demirkaya findings save any charges of 'going beyond the data'. As I seem to do quite a lot these days, the primary message is that screening - preferential screening - should be an important part of the continued 'management' of autism (see here). Alongside other media headlines illustrating how for example, psychosis can be (a) present and (b) can sometimes exert a powerful effect on some people on the autism spectrum, further investigation(s) on the role of such issues (minus any stigma) in relation to suicidality and autism is also indicated.

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[1] Karakoç Demirkaya S. et al. Assessment of suicidality in children and adolescents with diagnosis of high functioning autism spectrum disorder in a Turkish clinical sample. Neuropsychiatr Dis Treat. 2016 Nov 11;12:2921-2926.

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Karakoç Demirkaya, S., Tutkunkardaş, M., & Mukaddes, N. (2016). Assessment of suicidality in children and adolescents with diagnosis of high functioning autism spectrum disorder in a Turkish clinical sample Neuropsychiatric Disease and Treatment, Volume 12, 2921-2926 DOI: 10.2147/NDT.S118304

Infections treated with anti-infective agents linked to schizophrenia?

Identify everyone born in Denmark between 1985-2002. Identify those treated "in the primary care setting" for an infection. Identify those diagnosed with schizophrenia and affective disorders. Look-see whether there is an overlap between infection or treated infection and schizophrenia / affective disorders. Report results.

That's basically the study published by Köhler and colleagues [1] (a name that has appeared on this blog before) who concluded that: "Infections treated with anti-infective agents and particularly infections requiring hospitalizations were associated with increased risks of schizophrenia and affective disorders, which may be mediated by effects of infections/inflammation on the brain, alterations of the microbiome, genetics, or other environmental factors."

Mention of Denmark as being the source material for such a discovery means, yet again, that those various Scandinavian population registries are proving their 'big data' scientific worth. Indeed, such resources really do put countries such as Blighty to shame insofar as tracking the health of the Nation and at the same, providing science with lots and lots of research nuggets.

Taking into account various "confounders", authors report that alongside a possible connection between infection or treatment for infection being 'associated' with schizophrenia / affective disorders there was "a dose-response and temporal relationship" further substantiating their findings. Indeed, those who had to be hospitalised for infection (a serious infection then) were at much greater risk of subsequently being diagnosed with schizophrenia or affective disorders. This tallies with other research on this topic (see here).

One more thing: "The excess risk was primarily driven by infections treated with antibiotics, whereas infections treated with antivirals, antimycotics, and antiparasitic agents were not significant after mutual adjustment." Interesting. This suggests that bacterial infections or their treatments, e.g. antibiotics seem to be important factors in relation to the subsequent risk of schizophrenia and/or affective disorders. Again, this is not the first time that this point has been raised (see here and see here) and provides some corroborative evidence as to why the microbiome was mentioned by authors in relation to possible mechanisms to account for their findings.

I could start talking about how this research is further evidence for a role for the immune system and/or inflammatory processes in relation to psychiatric labels (see here for example) but you've probably heard it all before I'm sure. What we are also starting to understand with some confidence, is that infection and the effects of it's treatment might go way beyond just the somatic...

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[1] Köhler O. et al. Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. Acta Psychiatr Scand. 2016 Nov 21.

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Köhler O, Petersen L, Mors O, Mortensen PB, Yolken RH, Gasse C, & Benros ME (2016). Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. Acta psychiatrica Scandinavica PMID: 27870529

Atopy increases vulnerability to affective and anxiety issues?

In a year of impossible things...

I was rather interested to read the recent paper by Renee Goodwin and colleagues [1] observing that: "Atopy appears to be associated with increased vulnerability to affective and anxiety problems, compared to youth without atopy."

Atopy, referring to a predisposition to developing allergic diseases such as eczema, asthma and/or hayfever, is something on the 'up' in research terms when it comes to aspects of psychiatry and/or developmental outcomes (see here for example). Goodwin et al set about further testing the possibility of a link based on data "drawn from the Raine Study (N = 2868) [a favourite initiative on this blog], a population-based birth cohort study in Western Australia."

Looking at signs of atopy - "using parent report and objective biological confirmation (sera IgE)" - at ages 1-5 years and "the range of internalizing and externalizing mental health problems at ages 5-17 years" authors reported on some interesting patterns/correlations in relation to affective and anxiety problems potentially being linked. Authors also described how their results held strong even "after adjusting for a range of potential confounders."

Whilst there are always going to be issues associated with studies linking one or two variables across various years, the Goodwin paper represents yet another example of how further research resources need to be ploughed into the area of immune function and behaviour. Yes, I appreciate that we are entering the era of immunopsychiatry (if I can call it that) and that there is some good science emerging in this area (see here) but questions about the [various] hows and whys still need answering [2].

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[1] Goodwin RD. et al. Childhood atopy and mental health: a prospective, longitudinal investigation. Psychol Med. 2016 Oct 20:1-9.

[2] Hatfield SJ. et al. What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 1. Epidemiology, risk factors and outcomes. Clin Exp Dermatol. 2016 Nov 2.

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Goodwin RD, Robinson M, Sly PD, & Holt PG (2016). Childhood atopy and mental health: a prospective, longitudinal investigation. Psychological medicine, 1-9 PMID: 27762174

Anxiety spreads across various psychiatric labels

"Comorbid anxiety symptoms are ubiquitous among psychiatric patients with mood or schizophrenia spectrum disorders, and in almost half of them, reportedly severe."

So said the findings reported by Karpov and colleagues [1] who sought to put some further research flesh on to the bones of the idea that clinically relevant anxiety symptoms might not be unstrange bedfellows with a variety of other psychiatric labels.

Based on the analysis of various patient groups included in the "Helsinki University Psychiatric Consortium Study" for the presence of anxiety symptoms (as measured by the Overall Anxiety Severity and Impairment Scale (OASIS)) researchers reported that approaching half of their cohort variously diagnosed with "schizophrenia or schizoaffective disorder (SSA, n=113), bipolar disorder (BD, n=99), or depressive disorder (DD, n=188)" reported as 'severe or extreme' their anxiety. Drilling down further into their data, authors concluded that said anxiety symptoms correlated with "high neuroticism, symptoms of depression and borderline personality disorder and low self-efficacy in all patients, and with early trauma in patients with mood disorders."

Accepting that it is not necessarily new news that clinically relevant psychiatric signs and symptoms might extend beyond the handy diagnostic boxes that we currently use as part of our labelling system, I'd like to think there is another important feature of this 'interconnectedness'. The idea for example, that 'tackling' seemingly secondary issues such as anxiety might impact on more primary diagnosis is something that I'm keen to see extended in the research literature. There are various example of this being suggested/done with regards to other labels (see here for example) and indeed, how from a quality of life aspect, dealing with the very obvious disruption that chronic anxiety would bring, might be a target over and above intervention for other, more primary diagnoses...

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[1] Karpov B. et al. Anxiety symptoms in a major mood and schizophrenia spectrum disorders. Eur Psychiatry. 2016 Jul 19;37:1-7.

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Karpov, B., Joffe, G., Aaltonen, K., Suvisaari, J., Baryshnikov, I., Näätänen, P., Koivisto, M., Melartin, T., Oksanen, J., Suominen, K., Heikkinen, M., Paunio, T., & Isometsä, E. (2016). Anxiety symptoms in a major mood and schizophrenia spectrum disorders European Psychiatry, 37, 1-7 DOI: 10.1016/j.eurpsy.2016.04.007

Rates of medical illnesses in bipolar disorder

I've mentioned a few times on this blog that a diagnosis of autism or autism spectrum disorder (ASD) is by no means protective against any other diagnosis being received, be it based on a somatic illness or condition, or something more behaviourally defined.

Reading through the paper by Liz Forty and colleagues [1] (open-access) it appears that a similar scenario might also pertain to other behaviourally-defined conditions as per the example of bipolar disorder (BD) and their conclusion: "Bipolar disorder is associated with high rates of medical illness."

If I had a world of my own, everything would be nonsense

I was drawn to discuss this paper for a few reasons. First and foremost is the idea that a psychiatric diagnosis may actually place a person 'at risk' of a few important comorbidities above and beyond the presentation of their behavioural symptoms. We seem to be in an unfortunate situation these days that receipt of a psychiatric diagnosis seems to lead to a severe lack of appreciation that other symptoms or ailments of a more physical nature can also be present. Take for example the health inequalities which seem to be springing up as and when a diagnosis of schizophrenia is received (see here) and coincidentally in the same journal as the Forty paper, the study results from Mike Crawford and colleagues [2] concluding: "Assessment and treatment of common physical health problems in people with schizophrenia falls well below acceptable standards." Another reason I want to talk about the Forty paper is the fact that bipolar disorder (previously referred to as manic depression) has been described as occurring 'quite frequently' with regards to at least one part of the autism spectrum (see here). What this might suggest is that a co-occurrence of BD and something like Asperger syndrome might mean that said medical illness/conditions reported to be raised in BD would also be raised in BP + Asperger syndrome.

The Forty paper is open-access but a few pointers might be useful...

• Based on quite an impressive participant number (N=1720) diagnosed with bipolar disorder, lifetime rates of self-reported medical illnesses were compared with data derived from participants diagnosed with unipolar depression (N=1737) and asymptomatic controls (N=1340) (both previously described in other work from some of the authors [3]).
• Participants were quizzed - yes, no or uncertain - over whether any of 20 health conditions had been diagnosed by a health professional including: "asthma, cancer, diabetes type 1, diabetes type 2, elevated lipids/high cholesterol, epilepsy, gastric ulcers, heart disease, hypertension, kidney disease, liver disease, memory loss/dementia, migraine headaches, multiple sclerosis, osteoarthritis, osteoporosis, Parkinson’s disease, rheumatoid arthritis, stroke, thyroid disease." All the 'uncertain' codings were "excluded from analyses for that medical illness".
• Results: "The most prevalent medical conditions in the bipolar sample were migraine headache (23.7%), asthma (19.2%), elevated lipids (19.2%), hypertension (15%), thyroid disease (12.9%) and osteoarthritis (10.8%)." Quite a few of these conditions were significantly more frequently reported in cases of BD over control groups (see Figure 1 here). I'll in particular highlight the findings for asthma and thyroid disease as being more commonly reported in the BD group.
• Authors also divided the BD group up into subgroups (BD1 and BD2) based on the severity of manic episodes, and reported that: "The rates of gastric ulcers, heart disease, Parkinson’s disease and rheumatoid arthritis were significantly higher in the bipolar II group." They also found that several variables seemed to be linked to an increased medical illness burden including: "a longer illness duration, a typically acute onset of mood episodes, a greater number of psychiatric in-patient admissions, deterioration in functioning, increased rates of anxiety disorder, suicide attempt, rapid cycling, and treatment with anxiolytics, mood stabilisers and electroconvulsive therapy (ECT)." Some of these variables also predicted the high medical illness burden group too.

Reiterating the authors' sentiments about the need for such medical comorbidity to be taken into account by healthcare professionals "in order to improve outcomes for patients with bipolar disorder" these are important results. Assuming that there may be shared/overlapping genetic or biological mechanisms at work which influence risk of BD and also such medical comorbidity, one might think that future work would take this into account when looking at the possible underlying aetiology of BD. Such work might also accept the heterogeneity noted in BD as per similar sentiments when it comes to conditions like 'the autisms' (see here) and 'the schizophrenias' (see here).

Asthma has been highlighted from the Forty results on the basis of the condition already showing something of an interesting 'link' with conditions like autism and attention-deficit hyperactivity disorder, ADHD (see here). Indeed, data from Taiwan (yes, further interrogation of the Taiwan National Health Insurance Research Database) concluded that a diagnosis of asthma might increase the risk of subsequent mood disorders (including BD) later in life [4]. Forty et al suggested that of the possible reasons why asthma might be more frequently present in BD "carbon dioxide hypersensitivity and corticosteroid therapy may partly explain this association." I'd be perhaps inclined to add that other [speculative] work looking at the link between autism and asthma for example, might also offer another potential explanation [5].

Thyroid disease was also plucked out from the Forty data. The reason: some interesting data previously covered on this blog talking about autoimmune thyroiditis and various types of depression (see here). I'm not by the way saying that every case of thyroid disease in BD is due to such an autoimmune pathology, but as per other discussions, there might be quite a bit more to see when it comes to immune system function and behavioural and/or psychiatric diagnoses. At the very least, testing for said autoimmune issues might be considered for some.

There is little more for me to say on this subject matter. This is by no means the first time that medical comorbidity has been linked to BD [6] and even more widely depression [7] and I very much doubt it will be the last. If there are lessons to be learned from this area of investigation, the primary one must be to look at mind and body when it comes to diagnosing and managing psychiatric issues such as bipolar disorder as per other examples.

Oh, and I wonder if this would be a good time to introduce the findings from Almeida and colleagues [8] again published in the same journal as Forty and colleagues, concluding: "B vitamins did not increase the 12-week efficacy of antidepressant treatment, but enhanced and sustained antidepressant response over 1 year." Food for thought?

Music: Janis Joplin and Piece of my heart.

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[1] Forty L. et al. Comorbid medical illness in bipolar disorder. Br J Psychiatry. 2014. October 30.

[2] Crawford MJ. et al. Assessment and treatment of physical health problems among people with schizophrenia: national cross-sectional study. Br J Psychiatry. 2014. October 16.

[3] Farmer A. et al. Medical disorders in people with recurrent depression. Br J Psychiatry. 2008 May;192(5):351-5.

[4] Chen MH. et al. Higher risk of developing major depression and bipolar disorder in later life among adolescents with asthma: a nationwide prospective study. J Psychiatr Res. 2014 Feb;49:25-30.

[5] Becker KG. Autism, asthma, inflammation, and the hygiene hypothesis. Med Hypotheses. 2007;69(4):731-40.

[6] Sylvia LG. et al. Medical burden in bipolar disorder: findings from the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE). Bipolar Disord. 2014 Aug 16. doi: 10.1111/bdi.12243.

[7] Smith DJ. et al. Depression and multimorbidity: a cross-sectional study of 1,751,841 patients in primary care. J Clin Psychiatry. 2014 Nov;75(11):1202-1208.

[8] Almedia OP. et al. B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: results from the B-VITAGE randomised, double-blind, placebo-controlled trial. Br J Psychiatry. 2014. September 25.

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Forty L, Ulanova A, Jones L, Jones I, Gordon-Smith K, Fraser C, Farmer A, McGuffin P, Lewis CM, Hosang GM, Rivera M, & Craddock N (2014). Comorbid medical illness in bipolar disorder. The British journal of psychiatry : the journal of mental science PMID: 25359927

Autoimmune thyroiditis and depressive disorder

"Our study demonstrates a strong association between anti-TPO levels, which are considered to be of diagnostic value for autoimmune thyroiditis... with uni- or bipolar depression."

"Beware the bad cat bearing a grudge"

So said the study published by Detlef Degner and colleagues [1]. Anti-TPO antibodies by the way, refers to anti-thyroid peroxidase antibodies which, as the name suggests, are antibodies against thyroid peroxidase, an important step in the production of thyroid hormones. Said thyroid hormones have some pretty far-reaching effects on our physiology. Anti-TPO antibodies are also diagnostic for autoimmune related conditions affecting the thyroid such as Hashimoto's thyroiditis.

The Degner paper looked at a small group of participants diagnosed with depression (n=52) and analysed various thyroid related measures compared with a smaller control group made up of 19 participants diagnosed with schizophrenia. Authors reported a "pathologically increased" frequency of anti-TPO antibodies in those with depression compared with those with schizophrenia (32% vs 5% respectively). With something of a rather large confidence interval (CI) and hence the need for quite a bit more investigation, they also reported "the odds ratio of uni- or bipolar patients with depression for an autoimmune thyroiditis was ten times higher...  when compared with schizophrenia patients".

Reiterating again the quite small participant numbers, one needs to be rather careful with this particular study before too many firm conclusions are reached. Added to the fact that there was no asymptomatic control group included for study, I'd like to see quite a bit more done in this area before pinning my colours to any particular mast. That being said, this is certainly not the first time that (a) thyroid function has been correlated with depressive symptoms or depressive disorder [2] and/or (b) elevated levels of anti-TPO antibodies have been linked to depression [3] also crossing different geographies [4]. The paper by Carta and colleagues [5] (open-access) further extends the anti-TPO antibody link to "mood and anxiety disorders". This, complete with some discussion about how a "sub-clinical dysfunction of axis Thyrotropin Releasing Hormone (TRH) – Thyroid Stimulating Hormone (TSH) with consequent alteration of circadian rhythms of TSH" might be involved, linking an "aberrancy in the immuno-endocrine system" as a bridge between autoimmunity and psychiatry.

Autoimmune conditions have been previously discussed on this blog as potentially being a risk factor for mood disorder (see here). Under this banner, I'm minded to bring in another paper by Carta and colleagues [6] discussing how "Anti-TPO prevalence was significantly higher in celiac patients than in the control group" and further: "A higher frequency of PD [panic disorder] and MDD [major depressive disorder] was found in celiac patients with positive anti-TPO when compared to negative anti-TPO patients". This assumes that there may be some elevated risk of autoimmune issues impacting on the thyroid extending into other autoimmune conditions such as celiac (coeliac) disease as per other work. I could start going on about how this research might impact on other peripheral work e.g gluten exposure and feelings of depression but don't want to get too speculative at this point on any correlation with something like gluten or gut permeability.

Suffice to say that outside of just looking at thyroid-stimulating hormone (TSH) levels, the Degner results and other research suggest a whole other ballgame of autoimmune involvement affecting thyroid function and potentially impacting on psychiatry...

Music to close: I Will Wait by Mumford and Sons.

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[1] Degner D. et al. Association between autoimmune thyroiditis and depressive disorder in psychiatric outpatients. Eur Arch Psychiatry Clin Neurosci. 2014 Sep 6.

[2] Demartini B. et al. Depressive Symptoms and Major Depressive Disorder in Patients Affected by Subclinical Hypothyroidism: A Cross-sectional Study. J Nerv Ment Dis. 2014 Aug;202(8):603-7.

[3] Pop VJ. et al. Are autoimmune thyroid dysfunction and depression related? J Clin Endocrinol Metab. 1998 Sep;83(9):3194-7.

[4] Muñoz-Cruzado Poce MJ. et al. Prevalence of thyroid disorders in patients diagnosed with depression. Aten Primaria. 2000 Jul-Aug;26(3):176-9.

[5] Carta MG. et al. The link between thyroid autoimmunity (antithyroid peroxidase autoantibodies) with anxiety and mood disorders in the community: a field of interest for public health in the future. BMC Psychiatry. 2004 Aug 18;4:25.

[6] Carta MG. et al. Association between panic disorder, major depressive disorder and celiac disease: a possible role of thyroid autoimmunity. J Psychosom Res. 2002 Sep;53(3):789-93.

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Degner D, Haust M, Meller J, Rüther E, & Reulbach U (2014). Association between autoimmune thyroiditis and depressive disorder in psychiatric outpatients. European archives of psychiatry and clinical neuroscience PMID: 25193677

Lithium for mood disorder symptoms in autism?

Modern classroom? @ Wikipedia 

The paper published by Matthew Siegel and colleagues [1] talking about some preliminary observations on the use of lithium where symptoms of mood disorder might be present in cases of autism spectrum disorder (ASD) caught my eye recently. Concluding that: "lithium may be a medication of interest for those who exhibit two or more mood disorder symptoms, particularly mania or euphoria/elevated mood" the sentiments of more research-to-do in this area presents some intriguing options. That all being said, side-effects of lithium supplementation may yet scupper any large-scale plans for using this medication option with this cohort as per the authors note that: "Forty-seven percent of patients were reported to have at least one side effect, most commonly vomiting (13%), tremor (10%), fatigue (10%), irritability (7%), and enuresis (7%)".

I had a few thoughts after reading the Siegel paper and their findings based on the use of Clinical Global Impressions - Improvement (CGI-I) ratings that "Forty-three percent of patients who received lithium were rated as "improved"". Mood disorders, or the symptoms of mood disorders, covers quite a bit of diagnostic ground. My recent discussions on bipolar disorder being fairly frequent in cases of Asperger syndrome (see here) coincide with the Siegel findings and particularly the case report by Frazier and colleagues [2] discussing a treatment regime which mentions the use of lithium. Other reports have similarly described the use of lithium as a possible management option where bipolar disorder and autism are comorbid [3]. What this tells me is that Siegel et al were not the first to look at lithium and autism (with comorbidity).

A quick glance at the other peer-reviewed literature in this area suggests that lithium is also finding some favour where less idiopathic types of autism are present. The paper by Luiz & Smith [4] talking about lithium as a promising treatment for Fragile X syndrome represents another potentially important area. The precise mode of action is still the subject of some conjecture but the overview provided by Chiu & Chuang [5] (open-access) gives some indication of what might be going on and could be similarly mapped on to potential biological mechanisms linked to autism and mood disorder if and when comorbid.

Finally, I have to make some mention about the important links being made between the use of lithium and the prevention of suicide in mood disorders [6]. I know it's not exactly a topic which makes great dinner party conversation but the emerging evidence base, alongside other important compounds, could potentially be life-saving for some people. Without trying to brush everyone on the autism spectrum as being at risk from suicide, the growing body of evidence suggesting that suicide ideation (see here) or suicide attempts (see here) might be more frequent for those on the autism spectrum [7] is something that needs to be taken seriously. This may imply that alongside appropriate societal support being provided, lithium might also have some important role to fulfil for some people...

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[1] Siegel M. et al. Preliminary Investigation of Lithium for Mood Disorder Symptoms in Children and Adolescents with Autism Spectrum Disorder. J Child Adolesc Psychopharmacol. 2014 August 5.

[2] Frazier JA. et al. Treating a child with Asperger's disorder and comorbid bipolar disorder. Am J Psychiatry. 2002 Jan;159(1):13-21

[3] Kerbeshian J. et al. Lithium carbonate in the treatment of two patients with infantile autism and atypical bipolar symptomatology. J Clin Psychopharmacol. 1987 Dec;7(6):401-5.

[4] Liu Z. & Smith CB. Lithium: A Promising Treatment for Fragile X Syndrome. ACS Chem Neurosci. 2014 May 15.

[5] Chiu CT. & Chuang DM. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther. 2010 Nov;128(2):281-304.

[6] Cipriani A. et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013 Jun 27;346:f3646.

[7] Paquette-Smith M. et al. History of Suicide Attempts in Adults With Asperger Syndrome. Crisis. 2014; 35: 273-277.

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Siegel M, Beresford CA, Bunker M, Verdi M, Vishnevetsky D, Karlsson C, Teer O, Stedman A, & Smith KA (2014). Preliminary Investigation of Lithium for Mood Disorder Symptoms in Children and Adolescents with Autism Spectrum Disorder. Journal of child and adolescent psychopharmacology PMID: 25093602

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