(Subclinical) mania symptoms in kids with autism

Although published a few years ago, PubMed recently brought the paper by Yu Okada and colleagues [1] to my attention and the finding that: "school-aged ASD [autism spectrum disorder] children frequently present subclinical BP [bipolar disorder] symptoms."

As per the authors' idea that "there has been increasing interest in bipolar disorder (BP) in children" and specifically that bipolar disorder might be important to at least some autism (see here and see here), a study idea emerged. That idea merged into a hypothesis: "to identify [the] reliable prevalence of BP and to evaluate a variety of subclinical BP symptoms in children with ASD."

Okada report case-control study results based on "110 referred children aged 6-15 years: 46 with ASD (the case group), 64 without ASD (the control group)" who were first time outpatients at a clinic in Osaka in Japan. As well as the use of a quite comprehensive "diagnostic approach for ASD", researchers also measured various types of cognitive functioning, also looking for the possible presence of the signs and symptoms of a diagnosis of bipolar disorder (via something called the K-SADS-PL-J). Results were collated.

"None of the children were diagnosed with BP in the case [autism] group, although two children were diagnosed with BP in the control group." Various other diagnoses were also recorded in the control (not-autism) group including anxiety disorder (n=28) and depressive disorder (n=16). When however researchers looked at subclinical mania symptoms - "elation/expansive mood, increased goal-directed activity, racing thoughts" - there was something to see for the autism group: "Based on the subclinical BP symptoms, the prevalence of elation/expansive mood and racing thoughts was significantly higher in the case group than in the control group: 26.1% versus 3.1% (p<.001) and 32.6% versus 9.4% (p=0.002), respectively."

There are a couple of ways to take the Okada findings. You could say that bipolar disorder in children with autism, with an average age of about 12 years, is low to non-existent. That's a good thing. But you could also argue that the increased frequency of subclinical mania symptoms noted in those with autism compared to not-autism controls might not be such a good thing. Indeed it could foretell a future greater risk of bipolar disorder in that group or even more pronounced mania in times to come (see here). With specific regard to the possible future diagnosis of bipolar disorder, I'm thinking specifically of the word 'prodrome' to mean early signs and symptoms indicating the onset of future 'disease' (psychopathology). I'll leave you to make the decision as to which option is more important but perhaps further investigation [2] may be indicated...

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[1] Okada Y. et al. Subclinical Manic Symptoms in Children with Autism Spectrum Disorder. Osaka City Med J. 2016 Dec;62(2):103-110.

[2] Van Meter A. et al. Bipolar Prodrome Symptom Scale - Abbreviated Screen for Patients: Description and validation. J Affect Disord. 2019 Feb 12;249:357-365.

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On C-reactive protein and bipolar disorder

"CRP [C-reactive protein] concentrations are increased in bipolar disorder regardless of mood state, but are higher during mania than in depression and euthymia, suggesting an increased inflammatory burden in mania."

So said the systematic review and meta-analysis published by Brisa Fernandes and colleagues [1] who surveyed the peer-reviewed literature on the topic of "measured serum and plasma CRP concentrations in adult patients with bipolar disorder (as defined by DSM-IV-TR) and healthy controls" and arrived at their conclusions based on an analysis of some 2000 people diagnosed with bipolar disorder (BD). CRP by the way, a member of the pentraxin family, is the molecule of choice when it comes to looking at response to inflammation. BD, previously known as manic depression, is a condition characterised by periods of depression and mania.

Continuing an important theme in psychiatry - that the immune system or expression of the immune system whether in terms of genetics or biology, seems to show some important associations with behaviour (see here for example) - the Fernandes paper represents important work. Of course it's not the first time that CRP levels and bipolar disorder have been mentioned on this blog (see here) but the 'collecting' of results based on the use of systematic review and meta-analysis this time around strengthens the association between these variables.

Where next I hear you ask? Well, the idea that CRP levels might be linked to cases of BD needs further research not least to ensure that certain over-represented medical comorbidity linked to BD are not an interfering variable when it comes to CRP levels (see here). The findings should also perhaps be seen in a larger context where CRP levels have been reported in other psychiatric / behavioural labels (see here). The non-specificity of CRP (i.e. not tied to just one label) also has implications for the idea that many different psychiatric / behavioural labels might show overlapping features (see here) for example.

With no medical or clinical advice given or intended, there is also the intriguing idea that interventions targeting specific immune function findings may also have behavioural implications (see here for example). This alongside the idea that some medicines intended for the treatment or management of aspects of BD may already have some 'immune-modulating' actions (see here) potentially tied into their potential efficacy (or not). Again, further research is very much implied.

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[1] Fernandes BS. et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016 Nov 9. pii: S2215-0366(16)30370-4.

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Fernandes BS, Steiner J, Molendijk ML, Dodd S, Nardin P, Gonçalves CA, Jacka F, Köhler CA, Karmakar C, Carvalho AF, & Berk M (2016). C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. The lancet. Psychiatry PMID: 27838212

Bipolar disorder and the autism spectrum continued

In a previous post on this blog I talked about an important paper by Vannucchi and colleagues [1] summarising the state of the peer-reviewed research (up to 2014) on bipolar disorder and Asperger syndrome (AS). Today, I'm adding to the conversation on this important topic by introducing two papers to the discussions: the first by Xenia Borue and colleagues [2] and the second by Ahmad Abu-Akel and colleagues [3] covering the longitudinal course of bipolar disorder (BD) in relation to autism and the appearance of autistic and other traits in relation to cases of BD respectively.

Bipolar disorder (BD) previously known as manic depression is a condition affecting mood and specifically how it can 'swing' between extremes of depression and mania. There are a couple of different 'types' of BD reflective of how such mood swings can sometimes centre more on one aspect of BD over the other. As per the Vannucchi findings, the experience of BD may not be uncommon to the autism spectrum - "BD prevalence in adults with AS ranges from 6% to 21.4% of the cases" - but importantly: "is often characterized by atypical presentation, making its correct identification particularly difficult." Keep that in mind for now.

The papers by Borue and Abu-Akel put a little more scientific flesh on to the discussions about autism and BD. Specifically, how in these days of increasing recognition that autism rarely appears in some sort of diagnostic vacuum (see here), comorbidity might have some pretty important effects on clinical presentation.

To discuss the Borue findings first... well, based on a cohort of some 360 youths diagnosed with various types of BD who were followed for around 9 years, authors "compared youth with and without ASD [autism spectrum disorder] on clinical presentation, percentage of time with mood symptomatology, and psychosocial functioning." Approximately 8% of their cohort "met DSM-IV criteria for Asperger disorder or pervasive developmental disorder-NOS (referred to here as ASD)" which is an important detail. Further: "Compared to youth with BD, the clinical presentation of youth with BD+ASD more frequently involved distractibility, racing thoughts, depressed mood, social withdrawal, and low reactivity of negative mood states." The 'distractibility' side of things tallies with the observation that comorbid "attention-deficit/hyperactivity" (akin to ADHD) was more frequent in this group too and might be important [4]. Insofar as longitudinal course (at least over about 9 years), authors note: "Significant amelioration of clinical symptoms occurred over time, suggesting that early recognition and treatment of mood disorders in youth with ASD may improve clinical outcomes."

The Abu-Akel group set out to "determine the expression of autistic and positive schizotypal traits in a large sample of adults with bipolar I disorder (BD-I), and the effect of co-occurring autistic and positive schizotypal traits on global functioning in BD-I." BD-I focuses more on the manic side of clinical presentation. Bearing in mind autistic and schizotypal traits were self-assessed, authors reported that nearly 50% of their BD cohort (~800 people recruited via the Bipolar Disorder Research Network) "showed clinically significant levels of autistic traits." Around a quarter of their group also showed potentially important schizotypal traits too. Interestingly: "In the worst episode of mania, the high autistic, high positive schizotypal group had better global functioning compared to the other groups" with the requirement for quite a bit more study in this area.

What could these collective results mean?

Well, first and foremost all the chatter about traits and behaviours 'overlapping' shines through in these results. ESSENCE may indeed extend quite a bit further than just in childhood (see here) and this has some important implications for preferential screening services when an autism diagnosis is suspected or given. Second, I'm struck by how important traits outside of the autism spectrum might be to the presentation of something like BD in those reaching clinical thresholds for autism. I'm yet more convinced that the increasingly important association being made between autism and ADHD for example (see here) is really, really important. Third, the idea that autistic and certain schizotypal traits might actually be useful when it comes to 'global functioning' in cases of BD-I is an eye-opener. This needs further investigation. Finally, treatment for BD exists and with no medical or clinical advice given or intended, should not be withheld on the basis of a comorbid autism diagnosis.

Timely and accurate diagnosis of BD when co-occurring alongside autism (or the presence of autistic traits) continues to be a priority. Not least because of the potentially far-reaching and sometimes extreme effects that BD can have (see here for example) potentially overlapping with some distressing figures noted alongside autism (see here). Yes, the presentation of BD might be slightly different when autism/autistic traits are included in the diagnostic mix, but clinicians and other health professionals need to be sensitive to such subtleties. Once again, screening is the first step of the process...

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[1] Vannucchi G. et al. Bipolar disorder in adults with Asperger׳s Syndrome: a systematic review. J Affect Disord. 2014 Oct;168:151-60.

[2] Borue X. et al. Longitudinal Course of Bipolar Disorder in Youth With High-Functioning Autism Spectrum Disorder. Journal of the American Academy of Child & Adolescent Psychiatry. 2016. Oct 4.

[3] Abu-Akel A. et al. Autistic and Schizotypal Traits and Global Functioning in Bipolar I Disorder. Journal of Affective Disorders. 2016. Oct 3.

[4] Wang HR. et al. Prevalence and correlates of bipolar spectrum disorder comorbid with ADHD features in nonclinical young adults. J Affect Disord. 2016 Sep 28;207:175-180.

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Borue, X., Mazefsky, C., Rooks, B., Strober, M., Keller, M., Hower, H., Yen, S., Gill, M., Diler, R., Axelson, D., Goldstein, B., Goldstein, T., Ryan, N., Liao, F., Hunt, J., Dickstein, D., & Birmaher, B. (2016). Longitudinal Course of Bipolar Disorder in Youth With High-Functioning Autism Spectrum Disorder Journal of the American Academy of Child & Adolescent Psychiatry DOI: 10.1016/j.jaac.2016.08.011



Abu-Akel, A., Clark, J., Perry, A., Wood, S., Forty, L., Craddock, N., Jones, I., Gordon-Smith, K., & Jones, L. (2016). Autistic and Schizotypal Traits and Global Functioning in Bipolar I Disorder Journal of Affective Disorders DOI: 10.1016/j.jad.2016.09.059

Hospitalisation for mania following antibiotic exposure?

"Individuals hospitalized with acute mania have a markedly increased rate of bacterial infections, as evidenced by the recent prescription of antimicrobial agents. The prevention and effective treatment of bacterial infections may be important interventions for the management of individuals with mania."

That was the research bottom-line reported by Robert Yolken and colleagues [1] (yes, that Robert Yolken) who continued a theme of how immune function/response might be something pretty important when it comes to all-things psychiatry and in particular, when it comes to diagnoses like mania (see here). Some media interest in this work can be seen here.

On this occasion, the name of the game was to investigate "whether individuals hospitalized with acute mania have evidence of bacterial infections as determined by the prescription of systemic antimicrobial agents." Antimicrobial agents normally means antibiotics; evidence of their use was searched for in over 230 people "hospitalized for acute mania in either an inpatient unit or a day hospital" compared with some 550 controls.

Researchers reported that among their cohort there was "a substantially increased rate of recent antimicrobial prescription, defined as exposure within three days of ascertainment." 'Substantial' in this respect meant 18 of 234 hospitalised people (~7%) compared with 7 of 555 controls (~1%). Interestingly, authors also reported that the site of bacterial infection for which antimicrobials were given was most commonly urinary tract infection for women "while the respiratory tract and mucosal surfaces were the most common sites in men." Mention of the the urinary tract as a source of infection brought me back to another post a while back (see here) and some intriguing data about urinary tract infection and risk of acute psychosis.

This latest Yolken data further add to the growing body of research suggesting that either cause or effect, the immune system does seem to be associated with various behavioural and psychiatric labels. My reading of this work suggests that the authors favour the idea that the infection itself (or response to infection) might be the more important aspect to any relationship but I'm not so sure that things are so straight-forward. Indeed, on the other occasions where I've talked about infection and psychiatry, the use of antibiotics - particularly recurrent prescriptions of antibiotics - might not be without possible side-effects (see here) in certain contexts.

There is more to do in this area, not least with regards to possible mechanisms of effect and whether the "prevention and effective treatment of bacterial infections may be important interventions for the management of individuals with mania." I would also hope that given the 'when you swallow a grenade' sentiments associated with antimicrobial use, the trillions of wee beasties that call us home (the gut microbiota) might also figure in any future research strategy.

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[1] Yolken R. et al. Individuals hospitalized with acute mania have increased exposure to antimicrobial medications. Bipolar Disorders. 2016. 17 July.

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Yolken R, Adamos M, Katsafanas E, Khushalani S, Origoni A, Savage C, Schweinfurth L, Stallings C, Sweeney K, & Dickerson F (2016). Individuals hospitalized with acute mania have increased exposure to antimicrobial medications. Bipolar disorders PMID: 27425597

Acute bipolar depression and immune alterations

"Individuals with acute bipolar depression show immune alterations. Some of the alterations are similar to those found in acute mania."

That was the bottom line reported by Faith Dickerson and colleagues [1] following their analysis of blood samples provided by "82 individuals with acute bipolar depression, 147 with acute mania, and 280 controls." Looking for the presence of various antibodies to "human herpesviruses, gliadin, Toxoplasma gondii, and endogenous retroviruses as well as for C-reactive protein (CRP) and pentraxin-3" in said samples, researchers reported a few potentially important findings.

So: "The levels of CRP and IgG antibodies to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were significantly elevated in the bipolar depressed group." Further: "Levels of pentraxin-3 were reduced in both psychiatric groups." Researchers also reported that for 32 individuals who were hospitalised (and I assume treated) for bipolar depression, they "showed a significant decrease in the levels of MPMV antibodies, but not a change in the other markers."

Looking through the list of antigens included for analysis, without looking at the authorship list, I could have told you that the authors Faith Dickerson and/or Robert Yolken were involved in this study based on what has been discussed before on this blog (see here and see here for example). The work coming out of Johns Hopkins has been particularly interesting with their focus on "the role of infectious and inflammatory processes in complex psychiatric disease such as schizophrenia, bipolar disorder, and autism." Their most recent work on pentraxin-3 looks very interesting indeed (see here) and complements their most recent results.

The finding of elevations in the levels of CRP in the "bipolar depressed group" fits in well with the idea of inflammation being somehow involved in psychiatry (see here) and seemingly crossing diagnostic labels (see here). One might reasonable ask whether the research voices are indeed getting stronger for the potential usefulness of 'treating inflammation' when it comes to something like depression (see here) bearing in mind no clinical or medical advice is given or intended.

Finally, is that "endogenous retrovirus" finding reported by Dickerson et al. Regular readers of this blog might already know that I'm an avid [amateur] follower of the idea that all those fossil viruses that lurk in our genomes might be some much more than just junk DNA. With schizophrenia in mind (see here), with attention-deficit hyperactivity disorder (ADHD) in mind (see here), with autism in mind (see here), even with chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) in mind (see here), I've covered the topic a few times on this blog. Although never coming across MPMV before, this is not the first time that antibodies to non-human primate viruses have been talked about with psychiatric / behavioural conditions in mind [2]. Indeed a previous paper from Dickerson and colleagues [3] even went as far as suggesting that as part of suite of inflammatory markers, the presence and elevation of MPMV antibodies is likely derived "from the activation of homologous endogenous retroviruses and to be a reflection of immune activation." Similar sentiments seem to carry over to the most recent results too.

Music: Doves - There Goes The Fear.

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[1] Dickerson F. et al. Immune alterations in acute bipolar depression. Acta Psychiatr Scand. 2015 Jun 9.

[2] Lillehoj EP. et al. Serum antibodies reactive with non-human primate retroviruses identified in acute onset schizophrenia. J Neurovirol. 2000 Dec;6(6):492-7.

[3] Dickerson F. et al. A combined marker of inflammation in individuals with mania. PLoS One. 2013 Sep 3;8(9):e73520.

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Dickerson F, Katsafanas E, Schweinfurth LA, Savage CL, Stallings C, Origoni A, Khushalani S, Lillehoj E, & Yolken R (2015). Immune alterations in acute bipolar depression. Acta psychiatrica Scandinavica PMID: 26061032

Bipolar disorder is frequent in adult Asperger syndrome

"BD [bipolar disorder] in AS [Asperger syndrome] patients is frequent, usually it onsets during adolescence and is often characterized by atypical presentation, making its correct identification particularly difficult".

Maybe I'm better suited as a brunette? @ Wikipedia

That was the primary finding reported by Vannucchi and colleagues [1] based on their systematic review of the relevant peer-reviewed research literature in this area. They found that the prevalence of BD ranged between 6 - 20% depending on the studies included for review. They also reported that "BD assumes peculiar features which might shape its under-recognition or misdiagnosis" in cases of AS. In short, this is an area which perhaps requires a little more investigation.

Bipolar disorder, previously called manic depression, is concerned with mood and how it can 'swing' between extremes of depression and mania. Although discussions about the 'causes' of BD parallel discussions on the causes of lots of conditions which manifest psychiatric symptoms, research like that from Faedda and colleagues [2] talking about "generalized anxiety disorders" as risk factors for BD might be important. I've mentioned BD a few times on this blog: be it in relation to the genetic 'common ground' of psychiatry (see here) or the interesting work coming out of Johns Hopkins on gastrointestinal (GI) inflammation and immune activation in cases of BD (see here). Suffice to say that there may be quite a bit more to BD [3] than what just goes on the old grey-pinkish matter.

Asperger syndrome probably needs little introduction to regular readers of this blog. In case you don't know, here is the UK National Autistic Society (NAS) description of the condition. As per the growing acceptance that comorbidity, some medical comorbidity, might be elevated when a diagnosis on the autism spectrum is received (see here), there is also a realisation that the presence of autism or AS might also elevate the risk of psychiatric comorbidity too. The paper by Rosenberg and colleagues [4] (open-access here) corroborates this view, and indeed highlights how BD represents one such comorbid psychiatric diagnosis. At the risk of going off at a tangent, I was also intrigued by the finding by Rosenberg et al that: "Autistic regression was associated with lower risk of any comorbidity" which might imply different factors or weightings (genetic, environment) being involved in different types of autism...

The comment in the Vannucchi review about "atypical presentation" of BD in cases of AS got me thinking quite a bit. The case report detailed by Frazier and colleagues [5] (open-access) offers some insight into how this atypical presentation might manifest; in particular: "Bipolar disorder should be entertained as a possible diagnosis when there is deterioration in cognition, language, behavior, or activity; when there is a clear pattern of fluctuation or cyclicity in activity, behavior, and interests (with "good times" and "bad times"); and when observed behavior indicates a mood problem". They go on to mention: "His affective [mood] disorder exacerbated the underlying symptoms of Asperger’s [syndrome]" and that: "Once comorbid bipolar disorder was diagnosed and appropriate treatment occurred, Abraham gradually began to recover and his self-injury, aggression, and intense pressured obsessiveness disappeared". Self-injury and aggression eh?

I'm not necessarily saying that everyone with AS who has BD will fit into the description provided by Frazier et al in terms of presentation or intervention (which, by the way, was made up of "oral clonazepam... lithium... and risperidone"). But this and other reports do offer some good starting points to looking at the issue of BD as comorbid to cases of AS or other autism spectrum diagnoses. Oh and if one is to assume that something like immune function might be related to cases of BD, maybe, just maybe, one might consider looking at some of the correlates of immune activation as per reports like the one from Emily Severance and colleagues [6] on food potentially being a factor. Food and psychiatry... now where have I heard about that before?

Music to close. When You Were Young by The Killers.

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[1] Vannucchi G. et al. Bipolar disorder in adults with Asperger׳s Syndrome: A systematic review. J Affect Disord. 2014 Jul 8;168C:151-160.

[2] Faedda GL. et al. Clinical risk factors for bipolar disorders: A systematic review of prospective studies. J Affect Disord. 2014. July 18.

[3] Rege S. & Hodgkinson SJ. Immune dysregulation and autoimmunity in bipolar disorder: Synthesis of the evidence and its clinical application. Aust N Z J Psychiatry. 2013 Dec;47(12):1136-51.

[4] Rosenberg RE. et al. Parent report of community psychiatric comorbid diagnoses in autism spectrum disorders. Autism Res Treat. 2011;2011:405849.

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

[6] Severance EG. et al. Immune activation by casein dietary antigens in bipolar disorder. Bipolar Disord. 2010 Dec;12(8):834-42.

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Vannucchi G, Masi G, Toni C, Dell׳Osso L, Erfurth A, & Perugi G (2014). Bipolar disorder in adults with Asperger׳s Syndrome: A systematic review. Journal of affective disorders, 168C, 151-160 PMID: 25046741