A gluten-free diet for "schizophrenia positive for antigliadin antibodies (AGA IgG)"

Short post alert...

"This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder."

So said the findings reported by Deanna Kelly and colleagues [1] as the conference abstract [2] of their study finally hits the peer-reviewed science literature (see here).

As per my previous musings on this study, this was the "first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA [anti-gliadin antibodies] IgG." Results were interesting insofar as "participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale... and in negative symptoms." Net result: encouraging findings with the need for more study; also with a nice focus on effect sizes too...

'Nuff said.

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[1] Kelly DL. et al. Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study. J Psychiatry Neurosci. 2019 Mar 27;44(3):1-9.

[2] Kelly D. et al. Randomized double-blind feasibility study of a gluten-free diet in people with schizophrenia and elevated antigliadin antibodies (AGA IgG). Schizophrenia Bulletin. 2018; 44: S190.

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The positive effects of 12 weeks of probiotics and vitamin D in chronic schizophrenia?

The findings reported by Amir Ghaderi and colleagues [1] (open-access) provide the blogging fodder today, and the results of a study looking at a "novel combination of vitamin D and probiotic on metabolic and clinical symptoms in chronic schizophrenia." Said probiotic formulation contained "Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum (each 2 × 109)" and was delivered over a period of 12 weeks alongside a vitamin D supplement - "50,000 IU vitamin D3 every 2 weeks" - utilising a "randomized, double-blind, placebo-controlled trial" design. We are also told that the trial protocol was "retrospectively registered."

The Ghaderi study wasn't solely focused on what their combined intervention might do for the 'clinical symptoms' of schizophrenia despite this being a prominent part of the results obtained. They also wanted to examine things like "biomarkers of oxidative stress and cardiometabolic risk in chronic schizophrenia." This was done via the measurement of marker compounds pertinent to establishing total antioxidant capacity, total glutathione levels and high-sensitivity C-reactive protein (hs-CRP) among other things.

Results: first things first, vitamin D supplementation raised vitamin D levels in those who received the vitamin D + probiotic supplement. Not exactly an unexpected result I grant you, but important from the point of view that any subsequent findings *could* be linked to those increasing vitamin D levels. Further: "Vitamin D and probiotic co-supplementation was associated with a significant improvement in the general... and total PANSS scores." PANSS stands for the Positive and Negative Syndrome Scale and has some important uses in the context of schizophrenia, and the presentation of positive and negative symptoms. That all being said, the authors also mention how their supplementation combination did not seemingly affect scores on another measure included in the study - the Brief Psychiatric Rating Scale (BPRS) - which kinda demonstrates that vitamin D + probiotics is not a panacea for every aspect of schizophrenia.

Researchers also report on how their combined supplement also *correlated* with a some changes in those oxidative stress and cardiometabolic risk measures included for study in line with other study results (see here). There's quite a bit of data so I won't provide details. Suffice to say that some of them might be 'positively' important to those health inequalities that seem to follow a diagnosis of schizophrenia (see here).

What else? Well, I can't seem to find too much in the way of side-effects details in the Ghaderi paper so I'm assuming that it wasn't a significant issue. The fact that participants in the study were "being hospitalized during the intervention" means that they were, I assume, being monitored with greater assiduity than for example if they were in the community, including looking for potential side-effects.

And with that, and the requirement for further study (see here and see here), I say no more...

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[1] Ghaderi A. et al. Clinical and metabolic response to vitamin D plus probiotic in schizophrenia patients. BMC Psychiatry. 2019; 19:77.

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Post-Exertional Malaise (PEM) in ME/CFS: what do patients say about it?

"The findings of this survey suggest that there are key domains of this symptom, including triggers, symptom onset, and duration, which have often not been comprehensively assessed in a previous PEM [post-exertional malaise] instrument."

So said the findings reported by Carly Holtzman and colleagues [1] (open-access available here) examining (yet again and yet again) an important part of the clinical profile of the conditions known as myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): post-exertional malaise or PEM.

Although still the source of some debate (see here), PEM basically refers to "a worsening of ME/CFS symptoms after minimal physical or mental exertion." Some authors have used other words to describe PEM - "payback" is one of them - but the sentiments remain the same: a physiological (and psychological) 'cost' following exertion. And said exertion does not necessarily have to be over-exertion either.

In light of the 'confusion' around PEM, Holtzman et al decided on a rather sensible course of action: "to try to develop a comprehensive measure [of PEM] with active collaboration of the patient community." This follows other independent research that has reaped the rewards of asking patients suffering with ME/CFS (yes, suffering) about their experience of their illness (see here for example). To do this, one of the rather famous authors on the Holtzman paper - Leonard Jason - started some conversations with various other patients who were unhappy with some of the descriptions of PEM that were being bounced around. Joined by Holtzman, things took off with regards to a questionnaire that was developed with PEM in mind [2] as we are told that: "comments and items received helped shape each new revision of the questionnaire."

"A survey was ultimately developed and was subsequently completed by 1534 members of the patient community."

Findings? Well, first and foremost "94.4% reported being diagnosed by a medical doctor." Nearly three-quarters of participants reported 'symptom exacerbation' immediately following exertion. Nine out of ten participants "had experienced delayed onset after exertion." As to the triggers of PEM, well, "basic activities of daily living" was a big one, as was "emotional events (88.3%), noise (85.5%), and sensory overload (83.6%)." What sorts of symptoms were experienced? So: "reduced stamina and/or functional capacity (99.4%), physical fatigue (98.9%), cognitive exhaustion (97.4%), problems thinking (97.4%), unrefreshing sleep (95.0%), muscle pain (87.9%), insomnia (87.3%), muscle weakness/instability (87.3%), temperature dysregulation (86.9%), and flu-like symptoms (86.6%)." Quite a few. How long did PEM last for? An average of 3-6 days (that's days) and in some cases, an awful lot longer. Also: "67.1% of the sample had experienced a “crash” that never resolved." Most participants who answered the survey also felt that it pretty well reflected their experience of PEM.

There's quite a bit more to do in this area in terms of developing said questionnaire and hopefully putting more flesh on the descriptive bones of PEM. I'm also inclined to suggest that as well as describing PEM and how it is experienced by those diagnosed with ME/CFS, science needs to do a lot more on the biology of PEM and what could potentially help (yet again, minus the psychobabble). Still, 'asking patients' continues to be an important theme in ME/CFS research...

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[1] Holtzman CS. et al. Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): A Patient-Driven Survey. Diagnostics (Basel). 2019 Mar 2;9(1). pii: E26.

[2] Jason LA. et al. The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome. J Health Psychol. 2018 Oct 24:1359105318805819.

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ADHD and a link with zinc?

"The present results indicated that there were alterations in blood levels of zinc, which was associated with the symptom scores of ADHD [attention-deficit hyperactivity disorder]."

So concluded the paper published by Rongwang Yang and colleagues [1] looking at blood levels of various trace elements including "zinc (Zn), copper (Cu), iron (Fe), magnesium (Mg), and lead (Pb)" in a group of children diagnosed with ADHD compared to a group of non-ADHD controls.

Based on their analysis of blood samples using atomic absorption spectrometry, researchers observed that many of the metals (trace elements) analysed were not greatly different between their groups. Lower levels of zinc however, and "the number out of normal ranges" in relation to zinc were noted. Further: "Zinc levels were negatively correlated with parent-rated scores of inattentive subscale of SNAP-IV (r = − 0.40) as well as with total score of SNAP-IV (r = − 0.24)" where the SNAP-IV refers to the Swanson, Nolan, and Pelham – IV questionnaire, a tool used to screen/assess for possible ADHD.

The Yang results have to be treated with some caution as the old 'correlation is not necessarily the same as causation' rule is observed. It's not beyond the realms of possibility that any suggested *association* between zinc and ADHD is purely epiphenomenal. But...

This is not the first time that zinc and ADHD have been talked about in the same breath (see here). Outside of linking levels of zinc to ADHD - or diagnostic facets of ADHD - one is also presented with other research suggestive that supplementation 'for ADHD' including zinc *might* show some effect (see here). There is the other question of whether zinc alone or in conjunction with other elements and/or biological factors might be important to the presentation of ADHD [2] but this is perhaps another reason why this area is deserving of further investigation. Indeed, further study of the possible processes through which zinc might influence the presentation of ADHD is also required.

And given that ADHD is something not exactly under-represented when it comes to other labels (see here), one has to question what role this fact might play in a more complicated clinical picture with zinc in mind (see here)?

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[1] Yang R. et al. Blood Levels of Trace Elements in Children with Attention-Deficit Hyperactivity Disorder: Results from a Case-Control Study. Biological Trace Element Research. 2019; 187: 376-382.

[2] Villagomez A. & Ramtekkar U. Iron, Magnesium, Vitamin D, and Zinc Deficiencies in Children Presenting with Symptoms of Attention-Deficit/Hyperactivity Disorder. Children (Basel). 2014 Sep 29;1(3):261-79.

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"NMDAR-antibody encephalitis might best be described as a mixed mood-psychosis syndrome"

Every once in a while a paper comes along with the potential to 'really shift opinions'. I'm gonna place the publication by Adam Al-Diwani and colleagues [1] in that category, and their (pre-registered) systematic review around the topic of N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis.

NMDAR-antibody encephalitis reflects a condition characterised by the immune system failing to identify self as self. For whatever reason, the immune system starts treating specific cells of the body as 'enemy' and mounts an immune attack against them. This results in the formation of specific antibodies - "against the NR1 subunit of the NMDA receptor" [2] - also typically resulting in "psychiatric features before progressing to seizures, a complex movement disorder, autonomic dysfunction, and hypoventilation." The book and film 'Brain on Fire' is about as good an education as you might need on the personal costs and effects of NMDAR-antibody encephalitis.

As Al-Diwani et al mention, things are getting rather interesting for NMDAR-antibody encephalitis in psychiatric circles. Awareness of the condition is growing, albeit with further 'flesh on the bones' required in terms of clinical features to look out for which could accompany the biological testing for the condition. Researchers sought to do just that: "the psychopathology of NMDAR-antibody encephalitis needs to be clearly defined to encourage accurate clinical identification and prompt treatment."

They trawled the peer-reviewed scientific literature looking for mention of NMDAR-antibody encephalitis, and eventually settled on over 300 records describing 1100 people in total. Over 460 of those people were identified with "definite NMDAR-antibody encephalitis according to consensus criteria" and their psychiatric features were examined. "The authors extracted 50 lower-level psychiatric features reported in these 464 patients, defined their frequency, and grouped them into eight higher-level features." Further comparisons were made leading to them assessing "whether individual patients were best described by one or by several psychiatric diagnoses" used as comparators.

Various features were potentially important: "The most common higher-level features were behaviour (316 [68%]), psychosis (310 [67%]), mood (219 [47%]), catatonia (137 [30%]), and sleep disturbance (97 [21%]), and these features frequently coexisted in individual patients." Various interesting graphs and figures are presented by the authors to illustrate their findings. The end result was the description of NMDAR-antibody encephalitis as "polymorphic and not to respect traditional psychiatric classifications." That being said, the notion of a "mixed mood-psychosis syndrome" represents as good a description as any based on the Al-Diwani findings.

Other details? "Overall, the age and sex distribution centred around young women, and the frequency of cases was greatly reduced after 40 years of age." Important information there about a potentially vulnerable group. Also: "139 (30%) of 464 cases were associated with ovarian teratoma, seven (2%) with previous herpes simplex virus encephalitis, and 24 (5%) with pregnancy." Ovarian teratoma is described as a rare cancer categorised as a 'germ cell tumour'. The *link* between ovarian teratoma and NMDAR-antibody encephalitis is something that has been of interest for a few years [3] and perhaps provides a clue for further investigation.

I do stand by my 'game-changer' type comment of the Al-Diwani paper. There is of course more to do in this area (including examining a curious link between NMDAR-antibody encephalitis and 'an autistic-like regression' in some children which is becoming all the more prominent in the research literature [4]). Putting all the various features identified by the authors into a useful set of diagnostic criteria is also a next step...

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[1] Al-Diwani A. et al. he psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. The Lancet Psychiatry. 2019. Feb 11.

[2] Finke C. A transdiagnostic pattern of psychiatric symptoms in autoimmune encephalitis. The Lancet Psychiatry. 2019. Feb 11.

[3] Acién P. et al. Ovarian teratoma-associated anti-NMDAR encephalitis: a systematic review of reported cases. Orphanet J Rare Dis. 2014;9:157.

[4] Khundakji Y. et al. Anti-NMDA receptor encephalitis in a toddler: A diagnostic challenge. International Journal of Pediatrics and Adolescent Medicine. 2018; 5: 75-77.

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"The most common peri-onset events reported by subjects were infection-related episodes (64%)"

The quote titling this post - "The most common peri-onset events reported by subjects were infection-related episodes (64%)" - comes from the (open-access) findings reported by Lily Chu and colleagues [1] continuing something of a research theme from this authorship group examining myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) (see here).

Indeed, it's probably no coincidence that the Chu cohort of "150 subjects fitting Fukuda 1994 CFS criteria" is the same as that used in their other research [2] when discussing another important issue: "post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome."

On this most recent publishing occasion, Chu et al set out to: "Describe ME/CFS onset and course in one United States-based cohort." They did this via the use of "a detailed survey" that asked various questions about the first stages of participants' illness and what this eventually led to. The results obtained weren't exactly unexpected, but yet again stress how lots of things 'assumed' about ME/CFS really need to be properly verbalised in the peer-reviewed science literature (see here and see here for other examples). Of particular note in the Chu findings pertinent to inquiry on the 'course' of ME/CFS is this important snippet of information: "Based on available data, the median age of illness onset was 36.6 ± 12.3 years and median duration of illness was 12.5 ± 10.1 years." That's 'median duration of illness was 12.5± 10.1 years'.

Results: "The most common peri-onset events reported by subjects were infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%)." Infection or rather 'infection-related episodes' came out top of the pops with regards to possible onset events. I've said 'possible onset events' in that last sentence not to be belittle the first-hand reports obtained, but rather to emphasise how we're still in a bit of a 'not knowing' state when it comes to definite causative infective agents and ME/CFS onset. Yes, there is some quite strong evidence that infections caused as a result of Epstein–Barr virus (EBV) seem to be involved in some cases of ME/CFS (see here) but more often that not, people aren't screened for every possible viral or bacterial agent. At this point, I'd also hark back to the viral 'hit-and-run' hypothesis that has been talked about in some ME/CFS circles recently (see here and see here) and what this also means.

Onward: "For the overwhelming majority of patients (96%, n = 141), their illness did not improve with time although different patterns of illness were seen." That last sentence really speaks for itself in terms of what ME/CFS means in the long-term. That's not to say that symptoms did not 'fluctuate' - "59%, fluctuating (symptoms could change in severity but were always present)" - but participants on the whole did not 'shake off' their disability. And when it came to some details about how symptoms ebbed and flowed over the course of time, Chu et al have some data on that too: "Over time, flu-like symptoms, fatigue, unrefreshing sleep, and exertion-related items decreased the most, by between 12 and 25%... Cognitive symptoms present at the beginning of the illness tended to persist, declining by only 4–10%." Further focus on 'cognitive symptoms' is perhaps important [3].

Further: "Ninety-seven percent suffered from at least one other illness: anxiety (48%), depression (43%), fibromyalgia (39%), irritable bowel syndrome (38%), and migraine headaches (37%) were the most diagnosed conditions." The authors phrase this in the context that "patients with co-morbid medical or psychiatric conditions are the rule rather than the exception" when it comes to ME/CFS. But just before anyone starts making noises that anxiety and depression are so significantly present in this cohort and probably beyond, such findings does not open the door to any psychobabble 'biopsychosocial' (BPS) explanations about the cause/perpetuation of ME/CFS. I think many patients (and researchers) have had quite enough of all that (see here).

The Chu paper is a comprehensive one and adds to our knowledge about ME/CFS. It has its limitations - "reliance on subject self-report, recall bias, and relative superficiality of some survey items" - but no more or less than lots of other ME/CFS research. It hopefully will open the door to a lot more similar study; perhaps also including the odd biological measure also.

And just before you go, I'll draw your attention to the findings reported by Katherine Rowe [4] who also asked a cohort of participants with ME/CFS about their illness experiences. There's a few important matching details included in the paper - "Eighty percent reported a defined onset following an infection" - but also some other noteworthy information. One such observation was that: "Many indicated the need to be sensitive about when psychological assistance is offered... They were sensitive as to whether this was implying that psychological issues were the “cause.”." It's not difficult to see why patients with ME/CFS would think such [BPS] things.

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[1] Chu L. et al. Onset patterns and course of myalgic encephalomyelitis/ chronic fatigue syndrome. Front. Pediatr. 2019. Jan 16.

[2] Chu L. et al. Deconstructing post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: A patient-centered, cross-sectional survey. PLoS One. 2018;13(6):e0197811.

[3] Robinson LJ. et al. Impairments in cognitive performance in chronic fatigue syndrome are common, not related to co-morbid depression but do associate with autonomic dysfunction. PLoS One. 2019 Feb 5;14(2):e0210394.

[4] Rowe KS. Long Term Follow up of Young People With Chronic Fatigue Syndrome Attending a Pediatric Outpatient Service. Front Pediatr. 2019 Feb 21;7:21.

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Psychiatric and seizure medicines for autism: what 'works' best

The paper by Devon Coleman and colleagues [1] represents pretty good scientific value for money by my reckoning. Describing the results of a 'survey' called the "National Survey on Treatment Effectiveness for Autism" created by the researchers, the aim was to provide "separated... scales for overall benefits and overall AEs [adverse effects]" for a wide range of interventions used in the context of autism.

The focus this time around was on "Psychiatric and Seizure medications data" but it looks like there may be quite a bit more to see from this group in future with regards to data on "supplements, diets, therapies, and educational interventions" also collected during this initiative. Before continuing on with this paper I have to hat-tip the authors for mentioning a great and much under-valued resource in autism circles: "the Parent Ratings of Behavioral Effects of Biomedical Interventions Survey,... conducted by the Autism Research Institute (ARI) and published in 2008." Indeed, in other posts talking about the medicines cabinet and autism (see here) I've expressed my positive views of the ARI resource albeit with caveats.

Anyhow: "we report ratings of 26 psychiatric and seizure medications by 505 participants." Researchers actually noted that nearly 900 people completed their survey; most of whom were described as the "Primary caregiver of an individual with autism." Some people might um-and-ah about the lack of 'authentic autistic representation' in this study, but one needs to bear in mind that most participants - about three-quarters - were under 18 years of age, most diagnosed with autism and not autism spectrum disorder (described as "less severe than a diagnosis of autism") and most were currently described as having mild, moderate or severe autism. I know this won't be enough for some people, but there you have it.

Then to the medicines that were 'graded', which fell into "five general categories: stimulants (four medications), SSRIs [selective serotonin reuptake inhibitors] (five medications), antipsychotics (four medications), seizure (nine medications), and other (four medications)." There's a lot of data included in the Coleman paper which really is too much for a blog post. I'll direct you to Figure 8 of the Coleman paper which provides a handy 'net benefit score' taking into account an 'overall benefit score' and an 'overall adverse score' for each medicine. When it came to SSRI medicines - typically indicated for treating depression - sertraline came top. When it came to antiepileptic medicines - primarily used to manage epilepsy and/or seizures - lamotrigine came top. When it came to antipsychotic medicines, aripiprazole came top. I was also interested to see that buspirone, a medicine typically indicated for anxiety, also did pretty well according to the Coleman results, which kinda ties in with some continuing research interest in this medicine with autism in mind (see here). Researchers also provide a handy 'medications for symptoms' overview as a consequence of their results (see Table 7) covering various symptoms from aggression/agitation to tics/abnormal movements. I can see this being particularly useful when it comes to physicians having to make big medication decisions (which should never be entered into lightly).

There's a couple of other details that are also mentioned in the Coleman paper outside of those 'how was medicine rated?' sentiments. Some details are not likely to make many friends in some quarters. So, around 2% of participants were described as follows: "No current diagnosis, but he/she was on the autism spectrum previously." Yes folks, such data once again harks back to the idea that for some people at least, autism is not a lifelong diagnosis (see here and see here). And also: "Thirty-four percent of participants had early onset of symptoms, but 56% had normal development followed by a plateau or regression." Regression accompanying autism is not the 'dirty' concept that it used to be (see here). Indeed, in the few years that I've been blogging about autism research, I've seen it become a lot more commonplace to talk about regression and autism (see here) even to the point that some now talk about it being 'the rule rather than the exception' (see here). Interesting.

And then there's something even more controversial in the Coleman paper: "The perceptions of possible causes of the regression are listed in Table 2." So we have things like high fever, illness, seizure and then... vaccination. I know this takes us into some uncomfortable territory, but the authors report that 51% of respondents to their survey who cited regression as part of the clinical picture mentioned vaccination as the 'perceived cause' whether singly or in conjunction with other factors. Of course I'm going to provide a link to what the population-based science says on this matter (see here) with the caveat that such 'perceived cause' data perhaps needs objective and dispassionate follow-up (see here and see here).

The Coleman results are not without their limitations as per author comments such as: "The survey is retrospective and based on respondent memory which reduces the accuracy" and "The results are subject to “placebo effect” since it represents clinical data without a placebo control, so the real benefit is likely less than the perceived benefit." But let's not take too much away from the findings and how they may, as well as informing clinical practice, also hopefully lead to further inquiry to make medicines safer and more reliable for those on the autism spectrum who access them.

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[1] Coleman DM. et al. Rating of the Effectiveness of 26 Psychiatric and Seizure Medications for Autism Spectrum Disorder: Results of a National Survey. J Child Adolesc Psychopharmacol. 2019 Feb 6.

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The DePaul Symptom Questionnaire for chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME)

It's another short descriptive post today as I bring the paper by Len Jason & Madison Sunnquist [1] to your attention charting "the development of the DePaul Symptom Questionnaire (DSQ) to assess symptoms of the major chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) case definitions."

I say this is a descriptive post because the Jason/Sunnquist paper provides some important technical details about the DSQ and its evolution; all from a research group who seem to be pretty clued into ME/CFS and its very wide range of clinical presentation (see here).

There are some important aspects included in the paper; not least a focus on the issue of post-exertional malaise (PEM), something which has been a real focus to these researchers (see here). The other very welcomed side to the Jason/Sunnquist paper are the various links to the DSQ derivatives all provided free of charge.

'Nuff said.

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[1] Jason LA. & Sunnquist M. The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions. Front Pediatr. 2018;6:330.

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"A fast reduction in HERV-H activity in ADHD patients undergoing MPH therapy"

Just in case the title of this post is not readily translatable, here's a key to help. HERV-H refers to human endogenous retrovirus H. ADHD means attention-deficit hyperactivity disorder. MPH therapy refers to the therapeutic use of methylphenidate, "widely used in the treatment of attention deficit hyperactivity disorder."

Putting all these concepts together are the findings reported by Cipriani Chiara and colleagues [1] following a research trend in recent years (see here). The general idea is that those fossil viruses, that we all carry in our genome as a result of our ancestral exposure to various viruses down the ages, might not be as dormant or 'junk' as many would believe. Being 'transcriptionally active', meaning that they could code for viral proteins, such HERVs have been *associated* with quite a few conditions and labels (see here and see here for examples). ADHD has also been mentioned with HERVs in mind (see here).

The Chiara results observing a "fast reduction in HERV-H activity in ADHD patients undergoing MPH therapy" were based on the examination of HERV-H expression in peripheral blood mononuclear cells (PBMCs) from those diagnosed with ADHD (N=7) first under drug-naïve conditions (without use of MPH) and then at intervals of 1 week, 8 weeks and 24 weeks of MPH use. Results were also compared with a small cohort of not-ADHD controls (I hate the use of the term 'healthy controls' (HC) despite the fact that: "None of them had a history of neurological or psychiatric disorders, learning disability, or infectious diseases"). Researchers observed a rapidly decreasing HERV-H 'relative' expression at all intervals of MPH use in their participant group with ADHD. The concluded that: "after 24 weeks of MPH therapy, HERV-H levels were comparable to those found in PBMCs from HC."

Alongside, although quite notably not reported in the study abstract, authors also looked at some of the clinical signs and symptoms of their participants with ADHD over the course of the study. Based on the use of the "long version of the Conners’ Parents Rating Scale-Revised questionnaire (CPRS-R)" they observed a corresponding trend of a reduction in scores (indicative of improvement) specifically focused on "the Conners’ parent oppositional (CP-O), the Conners’ parent inattention (CP-I), the parent hyperactivity/impulsivity (CP-H), and the Conners’ parent ADHD-Index (CP-AI)."

Putting the two findings together, the authors conclude that methylphenidate use *might* be something important to HERV-H expression in ADHD and *could* potentially explain part of the therapeutic action of the drug on ADHD.

Obviously one has to bear in mind issues such as correlation not being the same as causation alongside the relatively small participant numbers and the lack of any comparative data (say, from other interventions being used in the context of ADHD or following the use of MPH in non-ADHD populations). But the Chiara findings are interesting, and suggest some follow-up studies could be equally enlightening...

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[1] Chiara C. et al. The Decrease in Human Endogenous Retrovirus-H Activity Runs in Parallel with Improvement in ADHD Symptoms in Patients Undergoing Methylphenidate Therapy. Int J Mol Sci. 2018 Oct 23;19(11). pii: E3286.

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Psychosis in depression linked to an increased risk of completed suicide

The results of the systematic review and meta-analysis published by Rossetos Gournellis and colleagues [1] provide the blogging fodder today, discussing an important topic on "whether psychotic features increase the risk of completed suicides in unipolar depression." The authors' conclusion was that yes: "The presence of psychosis in major depression should alert clinicians for the increased risk of completed suicide", something that may potentially have implications for various different 'scenarios' where psychosis (psychotic features), depression and suicide risk intersect. I'll come back to this shortly.

So, the name of the research games was systematic review and meta-analysis focused on both the peer-reviewed and 'gray' literature for studies "providing data on completed suicides in PMD [unipolar psychotic major depression] compared to non-PMD." Psychotic major depression by the way, is pretty much what the name suggests: depression or a depressive episode with the addition of psychotic symptoms such as hallucinations or delusions. Boiling down the pertinent research literature from thousands of articles to just nine articles covering "33,873 patients, among them 828 suicides", authors began their analyses.

Results: As already mentioned, the data pointed to the idea that psychosis might be an important part of suicide risk: "PMD patients manifest elevated risk of suicide even when they are compared with non-PMD patients who suffer from severe depression." Authors also concluded that: "This [suicide] risk is elevated in both the acute phase of the disorder and lifetime" and: "The data are inconclusive on the contribution of age, mood congruence, comorbidity, and suicide method on PMD’s suicide risk." The bottom line is that psychosis or the presence of symptoms of psychosis could be an important screening variable for risk of suicide in depression and also a target for intervention/prevention...

Before I go, I just want to head back to that previous sentence about these results perhaps having significance for 'different scenarios' where depression, psychosis and risk of suicide mix. I speak of course about the core topic of this blog - autism - and the on-going efforts to understand the complicated hows-and-whys of suicide risk in relation to autism (see here and see here). Acknowledging that the paths that take someone towards suicidality are often complex (see here), there is already some recognition in the peer-reviewed science domain that psychosis alongside autism might be a risk factor for suicide (see here). This, on the basis that psychosis and conditions manifesting psychosis might be 'over-represented' in relation to the autism spectrum (see here and see here) and depression is also not something unfamiliar (see here). It strikes me as eminently sensible that psychosis as well as depression could perhaps be screened more routinely as and when a diagnosis of autism is received. Both conditions/states are manageable...

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[1] Gournellis R. et al. Psychotic (delusional) depression and completed suicide: a systematic review and meta-analysis. Annals of General Psychiatry. 2018;17, 39.

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On autism symptom trajectories and diagnosing autism late...

It's another one of my mash-up posts today, as two paper are brought to the blogging table. The first paper is from So Hyun Kim and colleagues [1] and looked at the rather interesting topic of differing symptom trajectories in the context of diagnosing autism. The second paper by Sally Ozonoff and colleagues [2] follows in a similar vein in terms of their analysis of children "who had undergone multiple comprehensive assessments in preschool and were determined to be ASD [autism spectrum disorder]-negative, only to meet criteria for ASD when tested in middle childhood."

Both these paper originate from well-respected autism research groups and appear in the same respected journal (Journal of the American Academy of Child & Adolescent Psychiatry). The common theme between them is that within the significant heterogeneity seen under the label of 'autism', there are various different developmental and presented symptoms trajectories, some of which (a) are not as stable as one might imagine, and (b) do not seemingly follow the oft-used assertion that 'autism is present and manifests from birth'. Indeed, on that last point, the implications are that autism is sometimes very much associated with regression (see here) and onward, that genetic and/or non-genetic post-natal factors may very well influence some children reaching clinical cut-off thresholds for a diagnosis of autism (see here for example).

So, to the Kim paper first: authors looked at over 900 "observations of the Autism Diagnostic Observation Schedule (ADOS)" from nearly 150 young children. They were specifically looking at symptoms trajectories based on those ADOS scores and whether or not 'clusters' of similar symptom trajectories were evident. The answer: yes, yes there were some different clusters of symptom trajectories noted. Not six developmental trajectories as per other research (see here) but four clusters: "Nonspectrum ∼25%; Worsening ∼27%; Moderately-Improving ∼25%; Severe-Persistent ∼23%)." Authors also report how: "Trajectory clusters varied significantly in the proportions of confirmatory ASD diagnosis, the level of baseline and final verbal/nonverbal abilities, and symptom severity."

Then to the Ozonoff paper: "Fourteen children met inclusion criteria for the Late Diagnosed group and were compared to a large sample of high- and low-risk siblings from the same sites who had ASD or typical development (TD) outcomes at age 3." Authors focused in on these 14 children and concluded that: "Seven showed very little evidence of ASD in preschool, while seven demonstrated subtle, subthreshold symptomatology." They also suggest that their results identifying a small but important group of children who seemingly first present with 'typical' behaviour but then 'grow into' the presentation of autism "shed light on reasons why the mean age of ASD diagnosis remains over 4 years." Indeed (see here).

I don't really need to say much more than I have already on these studies. Aside that is, from reiterating that the autism spectrum is truly wide and heterogeneous in both symptom presentation and also it seems, with regards to symptom onset and stability too. Alongside other research (see here) talking about how the presentation of autistic signs and symptoms wax and wane for some, I'm wondering when autism research is going to start looking beyond just presented behaviour, at whether for example, genetic and biological 'changes' might accompany such fluidity in behaviour and 'cluster' differences. Y'know, the same way that another group seemingly heading in the opposite direction - those who 'lose their diagnosis' (see here and see here) - also need to be closely investigated from a biological point of view too. It's only when we have such biological data that we can then start meaningfully probing the possible hows-and-whys...

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[1] Kim SH. et al. Variability in Autism Symptom Trajectories Using Repeated Observations from 14 to 36 Months of Age. Journal of the American Academy of Child & Adolescent Psychiatry. 2018. Sept 5.

[2] Ozonoff S. et al. Diagnosis of Autism Spectrum Disorder After Age 5 in Children Evaluated Longitudinally Since Infancy. Journal of the American Academy of Child & Adolescent Psychiatry. 2018. Sept 3.

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"weak evidence that EIBI may be an effective behavioral treatment for some children with ASD"

Today I bring to your attention the 'Cochrane does...' findings reported by Brian Reichow and colleagues [1] which concluded that: "There is weak evidence that EIBI [early intensive behavioral intervention] may be an effective behavioral treatment for some children with ASD [autism spectrum disorder]."

The Cochrane in the term 'Cochrane does...' refers to the Cochrane Database of Systematic Reviews, an important resource that provides systematic reviews on various aspects of healthcare that help inform practice and policy. I've talked about them a few times previously on this blog (see here and see here). EIBI - "a treatment based on the principles of applied behavior analysis" - is something that has been part and parcel of the autism research scene for many years. It aims to 'target' the early presentation of autism in both severity and "functional behaviors and skills" among other things; in the context to 'modify' the presentation of autism and "lessen the impact of symptoms on children's functioning."

The Reichow review found five studies that examined EIBI in the context of autism or autism spectrum disorder (ASD) and included over 200 children. They concluded that: (a) "No adverse effects were reported across studies" following the important tenet: first, do no harm, (b) there was "weak evidence that children receiving the EIBI treatment performed better than children in the comparison groups after about two years of treatment on scales of adaptive behavior, intelligence tests, expressive language (spoken language), and receptive language (the ability to understand what is said)", and (c) "Differences were not found for the severity of autism symptoms or a child's problem behavior."

Although the overall key message from authors was one that: "The evidence supports the use of EIBI for some children with ASD", the authors caution that the evidence base in this area remains weak. They mention that: "only a small number of children were involved in the studies, and only one study had an optimum design in which children were randomly assigned to treatment groups." There is a requirement for more [longitudinal] investigation following more 'rigourous' methodological designs.

I've always been in two minds about the usefulness of EIBI and autism, and indeed, early behavioural intervention in general. Yes, infants and young children are always going to be reactive to the behaviour of those around them, but the inference that the course of autism can be universally and significantly 'affected' by [various] structured programs of this type, has always been a challenge to me (see here). I've been particularly worried about headlines reporting that something like 'super-parenting' could potentially affect the presentation of autism (yes, someone did actually say that) and the connotations stemming from them. I also have concerns coming from a perspective that the behavioural presentation of autism probably comes about for various reasons in various people; some of them are likely linked to biology, as per the examples of various inborn errors of metabolism manifesting autism (see here) and autism presentation following viral or bacterial infection (see here and see here). In such cases, it strikes me that one perhaps needs to look at the biology first rather than the presented (secondary) symptoms in a sort of 'catch-up' manner. I know that last sentence is likely not to sit well with some people who follow the sweeping generalisation that autism is innate and immutable, but there are some good examples in the peer-reviewed research literature on well-controlled intervention studies of this type (see here and see here). And yes, there needs to be more longitudinal follow-up in these areas too...

I'm not totally poo-pooing the idea of EIBI in the context of autism, but rather, would wish to see greater long-term, controlled evidence before grand sweeping generalisations and big headlines are made. A better focus on 'sub-groups' might also be quite useful when it comes to possible best- and non-responders [2] to the various interventions put forward with autism in mind...

To close, a crow with a Yorkshire accent. This is what the internet was made for.

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[1] Reichow B. et al. Early intensive behavioral intervention (EIBI) for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2018 May 9;5:CD009260.

[2] Paynter J. et al. Differential outcome subgroups in children with autism spectrum disorder attending early intervention. J Intellect Disabil Res. 2018 May 23.

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Selective mutism and autism

The findings reported by Hanna Steffenburg and colleagues [1] make for potentially important reading reporting: "In this study of a clinical group of children who were diagnosed with SM [selective mutism] and assessed at a center for neurodevelopmental disorders, 63% also met criteria for ASD [autism spectrum disorder]."

Selective mutism (SM) refers to an anxiety disorder typically manifesting during early childhood that affects the use of spoken language in certain social situations such as at school. 'Literally being unable to speak' is a phrase that follows SM in certain contexts, where speech and language skills are not typically affected when and where family or close friends are around. It's not surprising that there is 'overlap' between SM and autism given the characterisation of SM in terms of being "nervous, uneasy or socially awkward" and "stiff, tense or poorly co-ordinated" (minus any sweeping generalisations). And just before you question it, 'poorly-coordinated' is perhaps an under-rated aspect for many people diagnosed as being on the autism spectrum (see here).

Steffenburg and colleagues - including the notable ESSENCE-related name of Christopher Gillberg - sought to examine the possible 'overlap' of SM and autism on the basis that various diagnoses/labels can occur alongside SM; quite a few of them also recognised in relation to autism (see here). Approaching 100 children/young adults diagnosed with selective mutism were assessed at the premier 'autism spectrum conditions' clinic in Gothenberg, Sweden. The clinical assessment undertaken of course covered the diagnosis of autism but also various cognitive functions too.

Almost two-thirds of those with SM who were assessed also met criteria for an autism spectrum disorder (ASD). Added to that: "A further 20% (n=19) had autistic features that were “subclinical”, but, nevertheless, sufficiently marked to have an impact on everyday life." Only 17% were described as having no ASD symptoms. Those are pretty interesting percentages.

Authors also mention how: "The level of cognitive function was average in more than half of the study group but more than one-third of the study group had a borderline IQ or an ID [intellectual disability]." They use such a finding in the context of the ESSENCE term - Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations - where overlapping diagnoses/labels is the rule not the exception.

The implications? Well, screen and keep a continual eye open for autism in cases of SM seems to be an important first implication. That also includes keeping in mind those 'subclinical' signs and symptoms, which could be relevant to discussions about the broader autism phenotype (BAP) (see here) and also that curious DSM-5 diagnostic category known as social communication disorder (SCD) (see here). The focus on 'anxiety' in relation to SM might also be important given the pretty well-established connection between autism and anxiety (see here for example) following in the footsteps of some often forgotten autism research history (take a bow Mildred Creak and colleagues for including the term "acute, excessive and seemingly illogical anxiety"). I'm also minded to mention that given the pretty high rate of autism described in SM by Steffenburg and other researchers, further investigations perhaps need to be directed towards shared biology/genetics as well as shared behavioural presentation? Y'know, along the lines of whether 'comorbidity' might be something more 'core' (see here)?

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[1] Steffenburg H. et al. Children with autism spectrum disorders and selective mutism. Neuropsychiatr Dis Treat. 2018 May 7;14:1163-1169.

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ALSPAC says... "Social communication impairments had the strongest association with a depression diagnosis at age 18 years"

ALSPAC mentioned in the title of this post refers to The Avon Longitudinal Study of Parents and Children, one of the premier research initiatives here in Blighty, that has provided all-manner of interesting and important research associations. With autism in mind, ALSPAC has opined on various different research questions (see here and see here for examples) including the issue of a possible 'real' increase in the numbers of children presenting with autistic traits (see here).

On this particular research occasion, ALSPAC was the source data for the findings reported by Dheeraj Rai and colleagues [1] who set out to "compare trajectories of depressive symptoms from ages 10 to 18 years for children with or without ASD [autism spectrum disorder] and autistic traits, to assess associations between ASD and autistic traits and an International Statistical Classification of Diseases, 10th Revision (ICD-10) depression diagnosis at age 18 years, and to explore the importance of genetic confounding and bullying." I might add that some of this authorship group are making some real research waves when it comes to investigations using population registries with autism in mind (see here).

The starting point this time around was the notion that a diagnosis of autism is in no way protective when it comes to a diagnosis of depression and/or the expression of depressive signs and symptoms. Again, it's a topic that has cropped up before on this blog (see here) and is perhaps one of the longer term associations that have been made down the years. The idea that depression or depressive symptoms *might* be something much more than just 'comorbid' in the context of at least 'some' autism is something else that has been banded around the peer-reviewed research literature before (see here) but the evidence base is not particularly big or strong in this area at the moment.

There were a few different research questions asked by Rai et al, including looking at children "with or without ASD or high scores on autistic trait measures" and any relationship(s) with depression and depressive traits. They report findings for over 6000 children ("maximum sample with complete data") where questionnaire items on bullying were also included ("Relational and overt bullying was assessed as separate yes or no items at ages 8, 10, and 13 years using the modified Bullying and Friendship Interview Schedule") alongside various other potentially confounding variables.

Results: "children with ASD and those with higher scores on all autistic trait measures had more depressive symptoms at age 10 years than the general population, and these remained elevated in an upward trajectory until age 18 years." I don't think there's anything too novel in such findings, aside from the observation that depression / depressive symptoms may start quite early on in childhood. I can remember when I started out in autism research a couple of decades ago hearing about depression being typically linked to the onset of adulthood in the context of autism. This current data suggests otherwise.

Next: "Social communication impairments had the strongest association with a depression diagnosis at age 18 years. Findings were robust to adjustment for a range of confounders, including maternal depression and anxiety and the child’s polygenic risk for autism." This is important. What it suggests is that there may something 'more than just comorbid' about depression or depressive symptoms appearing alongside autism or at least in connection to certain autistic traits. I know some people have already taken exception to this possibility alongside the use of the word 'impairment' by the authors. But much like other research on an important bedfellow to depression - anxiety - one may have to entertain the possibility that there may be some enhanced 'predisposition' to something like depression alongside the presentation of autistic traits (see here and see here) perhaps mediated by factors such as rumination and perseveration for example [2]. This doesn't mean that depression is solely a product of autistic traits; merely that certain traits may potentially form an important vulnerability factor. I'm similarly minded to bring in other work from the ALSPAC initiative [3] (including Rai and colleagues as authors) where related findings were mentioned: "Social communication impairments are an important autistic trait in relation to suicidality." This on the basis that depression and suicidality show an important association.

Also: "We found evidence of a substantial role of bullying in contributing to and explaining a higher risk of depression in individuals with ASD and autistic symptoms." Bullying in the context of autism is another long-standing topic (see here). Bullying covers a lot of ground in terms of behaviour and also source (see here). The authors opine that: "Previous work has shown strong links between the experience of bullying and later depression... although confounding could have a role, the association is considered to be at least partially causal." It's also important to note that social-communication 'issues' were reported to be potentially predictive of being bullied according to the authors. The model that then appears hints that the appearance of depression *might* be linked to "reduced self-esteem or social isolation after the bullying" accepting that causality is not established and also not accounting for other variables: "other relevant characteristics, including comorbidities with neurodevelopmental conditions (eg, attention-deficit/hyperactivity disorder) and classroom placement could be important in this association within or outside the context of bullying." That last point is important in the context that autism rarely exists in some sort of diagnostic vacuum (see here).

There are a few caveats attached to the Rai findings that need to be kept in mind outside of any 'correlation does not necessarily equal causation' sentiments. So: "atypical presentations of depression are common in ASD, and our study has the potential for outcome measurement error because we used scales... that have not been adapted for autism." Indeed. I've previously talked about how bipolar disorder for example, might not follow a typical pattern when present in the context of autism (see here). I daresay that this could also hold for other types/forms of depression too. I'm also minded to reiterate that depression, as well as being a heterogeneous condition, also seemingly has many pathways to it. Some of those pathways will include psychological and social variables such as bullying and perhaps even more extremes of 'trauma'; where a diagnosis of PTSD is for example, no stranger to autism (see here). 'Happiness' and perceived quality of life (see here) are also likely to exert an important effect too.

Other pathways to depression seem to be more biologically defined as per depression in the context of physical ailments (see here) that may have a *link* to some autism (see here) or following the use of seemingly common medicines according to recent news reports (see here). I'll also mention that things like physical activity and exercise *seem* to show an important relationship with depression (see here). This could also be pertinent to the data suggesting that physical activity levels are typically not optimal where and when autism is diagnosed (see here). Other factors (fatigue, sleep, etc) also need to be mentioned in the context of depression. In short, there are lots and lots of potential variables to consider [4].

Outside of the important messages from the Rai findings on how depression is over-represented in relation to autism and how social factors like bullying seem to be linked  to it and thus are subsequently 'modifiable', there is another important point to consider: depression is typically treatable. Minus any medical or clinical advice being given or intended, the first step in managing/treating depression is identifying it. Perhaps the Rai findings might serve as a further call to action for preferential screening in the context of autism...

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[1] Rai D. et al. Association of Autistic Traits With Depression From Childhood to Age 18 Years. JAMA Psychiatry. 2018 Jun 13.

[2] Patel S. et al. Association between anger rumination and autism symptom severity, depression symptoms, aggression, and general dysregulation in adolescents with autism spectrum disorder. Autism. 2017 Feb;21(2):181-189.

[3] Culpin I. et al. Autistic Traits and Suicidal Thoughts, Plans, and Self-Harm in Late Adolescence: Population-Based Cohort Study. J Am Acad Child Adolesc Psychiatry. 2018 May;57(5):313-320.e6.

[4] Köhler CA. et al. Mapping risk factors for depression across the lifespan: An umbrella review of evidence from meta-analyses and Mendelian randomization studies. J Psychiatr Res. 2018 May 25;103:189-207.

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Mood cognition, fatigue, musculoskeletal, gastrointestinal and dermatological symptoms make up Gulf War Syndrome

The results of the meta-analysis by Alexis Maule and colleagues [1] provide an important addition to the peer-reviewed literature on Gulf War Syndrome / Illness (GWS). Their detailing and combining of results from various studies looking at self-reported health symptoms among deployed troops during the Persian Gulf War of 1990 adds further credence to the range of symptoms reported by returning troops. Also, they provide further clues as to where science should continue to look and intervene to help our veterans.

I've talked about the Persian Gulf War and GWS a few times before on this blog (see here and see here and see here for examples). Described in some quarters as one of the most toxic wars in history, there are still many questions that require answering about why so many veterans returned from theatre in such poor health. Much like another quite nebulous condition very often confused with other diagnoses under the heading 'medically unexplained symptoms' (see here), the relative lack of knowledge about GWS has made the condition / constellation of symptoms fertile ground for various 'psychosomatic explanations'. This, I believe, has done, and continues to do, a real disservice to the veterans of this conflict and their loved ones.

Maule et al settled on some 21 published studies, including nearly 130,000 participants and covering almost 30 years of research (the war itself started in late 1990) where self-reported symptoms were compared "in GW-deployed veterans and GW-era control veterans." GW-deployed veterans were defined as "veterans who deployed to the Gulf area in support of the 1990–1991 GW." Their comparators were described as "non-deployed veterans or veterans serving in the military during the 1990–1991 GW period who deployed to areas other than the Gulf (eg, Germany, Bosnia)." Reported health symptoms were searched for and responses boiled down across the studies.

Results: "A total of 56 distinct health symptoms were reported in three or more studies and included in the meta-analysis." Of the various health symptoms reported, 'lacking energy' topped the frequency chart for deployed veterans, fairly closely followed by related issues such as 'fatigue' and 'unrefreshing sleep'. When classifying reported health symptoms together, the following categories emerged: mood-cognition, fatigue, musculoskeletal, gastrointestinal and dermatological symptoms. Further: "Results of the meta-analysis showed GW-deployed veterans had increased odds of reporting all of the analysed symptoms compared with GW-era controls, indicating that the health problems associated with GW deployment include widespread, multiple body symptoms."

The authors do caution that it is not possible to say that all of these symptoms are cardinal features of GWS insofar as their inability "to assess the effect of some covariates relevant to health symptom reporting (eg, post-traumatic stress disorder and specific deployment exposures)." They also talk about how their meta-analysis approach, similar to other occasions across various different topics, may also be liable to publication bias ("when studies with positive findings are more likely to be published than studies with null and/or negative findings"). They did try and 'correct' for this possible bias and still reported that "42 out of the 56 summary ORs [odds ratios] remained significant." That included all those 'fatigue-related' health items previously reported on.

The work from Maule and colleagues adds to a significant research base observing that poorer health outcomes seem to be an important part of deployment to the Persian Gulf during Operation Desert Storm [2]. It again reminds us that we owe a debt to those veterans and their families, to continue to pursue a research agenda that takes their health issues seriously, and provides them with answers and the relief that many still sorely need.

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[1] Maule AL. et al. Meta-analysis of self-reported health symptoms in 1990–1991 Gulf War and Gulf War-era veterans. BMJ Open. 2018; 8: e016086.

[2] Porter B. et al. Health Status of Gulf War and Era Veterans Serving in the US Military in 2000. J Occup Environ Med. 2018 Jan 24.

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One percent of Chinese middle school students "met the definition of CFS"

CFS mentioned in the title of this post refers to chronic fatigue syndrome otherwise known as myalgic encephalomyelitis (ME). The question of how prevalent CFS/ME might be in various groups - particularly young people - was tackled in the paper published by Jieyao Shi and colleagues [1] (open-access available here). This continues some previous research chatter on this topic (see here) including the important differentiation of chronic fatigue syndrome from just 'chronic fatigue' (see here)...

So, what was done? "This cross-sectional survey enrolled 18,420 middle-school students aged 10 to 18 years (mean 14.9 ± 1.68) who were selected randomly between September 2010 and January 2011 from 25 junior- and senior-middle schools in Suzhou, China at a ratio of 1:1 with respect to the gender and grade." That's quite a big starting participant group in anyone's book; although eventually whittled down ever so slightly to 18,190 after dropping those who did not complete the study instruments properly for example.

As to the question of defining CFS (a *real issue* down the years), we are told that two schedules were used: "the US CDC-94 definition of CFS" otherwise known as the Fukuda criteria, and the "Chaldea fatigue scale (CFQ)" which is an error;  it should read the Chalder Fatigue Scale. A diagnosis of CFS was decided on the basis of both schedules yielding a positive result and "at the same time the school health workers excluded the fatigue symptoms that may be associated with other medical conditions after reviewing their yearly routine physical examination records." Where CFS criteria were not fully met, a diagnosis of chronic fatigue (CF) was given.

Results: "The prevalence of CFS and CF in this study was 0.9% and 12.0%, respectively." Nothing particularly novel there given other data that has discussed similar CFS frequency figures present in similar age-groups (see here). The idea that chronic fatigue not CFS is present in around 1 in 10 young adults is rather startling...

I was also quite interested in another observation made by Shi et al: "Other than fatigue, muscle pain, joint pain, difficulty in concentration, headache, and sore throat as specified in the CDC-94, despondency, irritability and being afraid of going to school were the most important symptoms of CFS in the middle-school students investigated in this study." Despondency, irritability and being afraid to go to school are again, probably not unexpected when it comes to CFS/ME in this age-group. I'm minded to suggest that such characteristics are likely 'reactive' symptoms to the presence of CFS/ME over and above having any significant aetiological input. If for example, you've been bed-bound, struck down by months or years of not being able to do all the things that teenagers and young adults like and want to do, it's very possible that you probably wouldn't feel your best and could, in the longer-term, be prone to developing something approaching depressive symptoms. That doesn't mean that depressive symptoms or actual depression caused your CFS/ME or even that depression is a core part of your CFS/ME; merely that depression joins the clinical presentation as per other instances in medicine [2]. As for the observation about being afraid to go to school, well, one only needs to look at other conditions where school refusal has been noted (see here) to perhaps understand some important hows-and-whys.

"Our study shows that CFS is prevalent among Chinese teenagers, and requiring proper intervention and treatment." That was the conclusion reached by Shi and colleagues, and with it the next obstacle to face: what is 'proper intervention and treatment'? Importantly too, will this manage to leave out the psychobabble explanations that have pervaded Western ideas on CFS/ME? Will it instead concentrate on the idea that CFS/ME is a multi-faceted organic illness - with probably more than one aetiology [3] - displaying both physiological and psychological side-effects?

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[1] Shi J. et al. Chronic fatigue syndrome in Chinese middle-school students. Medicine (Baltimore). 2018 Jan;97(4):e9716

[2] Tang PL. et al. A Systematic Review and Meta-Analysis of Demoralization and Depression in Patients With Cancer. Psychosomatics. 2015 Nov-Dec;56(6):634-43.

[3] Mørch K. et al. Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course. BMC Gastroenterology. 2013;13:28.

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