Thursday, 18 April 2019

Saffron for ADHD?

I'm very partial to a bit of 'left field' research on this blog. By 'left field' I mean research that is slightly unusual or atypical. I'd place the study findings by Sara Baziar and colleagues [1] in that 'left field' category because they reported results - randomised double-blind study results - suggesting that: "Short-term therapy with saffron capsule showed the same efficacy compared with methylphenidate" when it came to managing some of the symptoms of attention-deficit hyperactivity disorder (ADHD).

Saffron a.k.a Crocus sativus L is a herb commonly cultivated in places like India and Greece. As with many herbs/spices, cooking represents but one potential use of saffron. It contains a myriad of different chemical compounds, some of which seem to have a variety of potential medicinal uses. Real pharmacognosy in action.

The starting point for the Baziar study was that although methlyphenidate (ritalin) is indicated for treating / managing many cases of ADHD, not everyone is suited to such a medicine or the side-effects that it can sometimes produce. So "alternative medication, like herbal medicine, should be considered." Enter then saffron, and some evidence that it might be a useful herb for various psychiatric complaints [2], to be pitted against methylphenidate in a sort of scientific head-to-head contest with ADHD symptoms in mind.

For 6 weeks, fifty or so children and young adults with "a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD" were randomly allocated to receive methylphenidate (MPH) "20-30 mg/d (20 mg/d for <30 kg and 30 mg/d for >30 kg)" or saffron capsules "20-30 mg/d saffron capsules depending on weight (20 mg/d for <30 kg and 30 mg/d for >30 kg)." At baseline, 3 weeks and 6 weeks researchers measured ADHD-related symptoms.

The results were unsurprisingly surprising. By that, I mean that there were no statistically significant differences between the two groups, bearing in mind the clinical effectiveness profile that methylphenidate use for ADHD has already established (see here). So: "General linear model repeated measures showed no significant difference between the two groups on Parent and Teacher Rating Scale scores." Importantly too we are told that: "The frequency of adverse effects was similar between saffron and MPH groups."

The Baziar results don't immediately open the floodgates to saffron being used to 'manage ADHD' instead of a clinically-proven molecule like methylphenidate. It doesn't work like that. As far as I can see this seems to be the first time that saffron has been put under the scientific spotlight with ADHD mind (taking into account other 'herbal medicines' have been explored with ADHD in mind). We therefore need more data and some all-important replication. We need more data comparing saffron against methylphenidate and other intervention options for ADHD. And we also need more data on why? Why might saffron be a useful therapeutic option for some ADHD? What are the pertinent biological mechanisms at work?

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[1] Baziar S. et al. Crocus sativus L. Versus Methylphenidate in Treatment of Children with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Pilot Study. J Child Adolesc Psychopharmacol. 2019 Feb 11.

[2] Shafiee M. et al. Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. J Affect Disord. 2018 Feb;227:330-337.

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Wednesday, 17 April 2019

Autistic traits in schizophrenia: meta-analysed

"Current findings support that individuals with schizophrenia spectrum disorders have higher autistic symptoms than healthy controls."

So said the meta-analysis findings reported by Franco De Crescenzo and colleagues [1] and their study which "systematically reviews and quantitatively synthetizes the current evidence on the presence of autistic symptoms in individuals with schizophrenia spectrum disorders." I might quibble (again) with the use of the term 'healthy controls' but the findings reiterate something quite important: autistic signs and symptoms are not necessarily exclusively linked to a diagnosis of autism (see here and see here).

The De Crescenzo paper represents a 'let's boil down the existing peer-reviewed science literature into a coherent statement' kinda study; as 13 studies including nearly 2000 participants were included for review and meta-analysis. The primary outcome "was the Autism Spectrum Quotient (AQ)" and its use on those diagnosed with schizophrenia or schizophrenia spectrum disorder (SSD) vs. those with autism or vs. those asymptomatic controls as a total score or scores on the various sub-domains. The results went something along the lines of "individuals with SSDs have significantly higher autistic symptoms than healthy controls and lower autistic symptoms than individuals with autism." That finding followed for the total AQ score and most of the sub-domain scores.

What else is there to say? Well, the De Crescenzo results relied on the AQ for their measurement of autistic signs and symptoms. I've mentioned more than once on this blog how the AQ might show an important connection to autism but is not necessarily the premier (exclusive) autism screener (see here and see here). Applying such logic to the current meta-analysis findings and one has to be a little bit careful about what is being measured by such a scale and whether such overlap is there on the basis of just autistic signs and symptoms.

That all being said I have talked about overlap between scores on the AQ in autism and schizophrenia before on this blog (see here) and the notion of potential 'fuzzy boundaries' between the two labels. Indeed, it makes you wonder whether science and clinical practice were too quick to dismiss the important findings from Mildred Creak and colleagues [2] and the seeming desire to move autism as far away from schizophrenia as possible...

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[1] De Crescenzo F. et al. Autistic Symptoms in Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis. Front Psychiatry. 2019;10:78.

[2] Evans B. How autism became autism: The radical transformation of a central concept of child development in Britain. Hist Human Sci. 2013;26(3):3-31.

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Tuesday, 16 April 2019

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 malaiseinstrument."

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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Monday, 15 April 2019

Early Autism and Developmental Disabilities Monitoring says autism prevalence is still rising...

"The overall ASD [autism spectrum disorder] prevalence was 13.4 per 1,000 children aged 4 years in 2010, 15.3 in 2012, and 17.0 in 2014 for Early ADDM [Autism and Developmental Disabilities Monitoring] sites with data for the specific years."

So said the surveillance summary published by Deborah Christensen and colleagues [1]. Those of you who follow the US ADDM initiative (see here) will already know about the aims of this "group of programs funded by the CDC" looking at the (estimated) autism numbers, changes to the numbers and the impact of the numbers on various communities. Through initiatives like the ADDM, we already know that the estimated prevalence of autism in 8-year olds living in the United States is round about 1 in 59 (see here) and that the estimate continues to grow for pretty much every surveillance year examined. We are also starting to find out about how the change to DSM-5 from DSM-IV is likely to/not to impact on future figures (see here). And hopefully, at some point, we might have some further data on what happens to autism past childhood (see here) from such an initiative.

The Christensen paper adds another tier to the knowledge being acquired as per their analysis of the (estimated) prevalence rate of autism in 4 year olds "whose parents or guardians lived within designated sites." Those sites were: Arizona, Colorado, Missouri, New Jersey, North Carolina, Utah, and Wisconsin. The Early ADDM initiative does not cover the same area as its big brother/sister ADDM but "is conducted in two phases using the same methods and project staff members as the ADDM Network." Those phases include first "reviewing and abstracting data from children’s records, including comprehensive evaluations performed by community professionals" and then a second phase involving "a review of the abstracted evaluations by trained clinicians using a standardized case definition and method." DSM-IV criteria covers most of the time points examined but: "For 2014 only, prevalence estimates based on surveillance case definitions according to DSM-IV-TR and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) were compared."

Results: as per the opening sentence of this post, the overall (estimated) autism prevalence across all sites for autism in 4 year olds was on the increase between 2010 and 2014. That's not to say that there weren't differences between the various sites - New Jersey, a favourite autism prevalence site (see here) showed the highest prevalence: 19.7, 22.1, and 28.4 per 1,000 for 2010, 2012 and 2014 respectively - but overall the prevalence rate was increasing not decreasing.

There were a number of other important points raised in the Christensen findings. So: "Among four sites with ≥60% data on cognitive test scores (Arizona, New Jersey, North Carolina, and Utah), the frequency of co-occurring intellectual disabilities was significantly higher among children aged 4 years than among those aged 8 years for each site in each surveillance year except Arizona in 2010." I don't think I need to say much more about that. Also: "The overall prevalence estimate using a DSM-IV-TR case definition was approximately 20% higher than the prevalence estimate based on DSM-5 criteria." Again, I don't think too much more discussion is needed on this point aside from saying that for 4-year olds, the switch to DSM-5 might have made more of a difference than for 8-year olds. Indeed in comparison to the Wiggins data [2] based on 8-year olds where "46.0% children met both DSM-IV-TR and DSM-5 surveillance status, 44.0% met neither the DSM-IV-TR nor DSM-5 surveillance status, 4.0% met DSM-IV-TR status, but not DSM-5 status, and 6.0% met DSM-5 status, but not DSM-IV-TR status of ASD" the Christensen data showed something a little different: "Among 1,237 children who met the surveillance case definition for either DSM-IV-TR or DSM-5, 974 (78.7%) met both case definitions, 234 (18.9%) met the DSM-IV-TR but not the DSM-5 case definition, and 29 (2.3%) met the DSM-5 but not the DSM-IV-TR case definition." Perhaps more study is required on the diagnostic changes?

What's more to say? Well, one of the authors - Walter Zahorodny - kinda said it all in a media comment: "There’s no letup. I really don’t understand why the rate is going up in this way." So maybe the next question, a question that really should have been examined a long, long time ago, needs to be 'Why?' rather than just a continual chain of studies saying autism prevalence is increasing...

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[1] Christensen DL. et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 4 Years - Early Autism and Developmental Disabilities Monitoring Network, Seven Sites, United States, 2010, 2012, and 2014. MMWR Surveill Summ. 2019 Apr 12;68(2):1-19.

[2] Wiggins L. et al. Comparison of autism spectrum disorder surveillance status based on two different diagnostic schemes: Findings from the Metropolitan Atlanta Developmental Disabilities Surveillance Program, 2012. PLoS ONE. 2018; 13(11): e0208079.

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Friday, 12 April 2019

A poo(p) transplant for [some] autism? 2 years on with caveats...

The results published by Dae-Wook Kang and colleagues [1] provide some important follow-up work to a study already discussed on this blog (see here) which suggested that: "MTT is safe and well-tolerated in children with ASD ages 7–16 years" and also "led to significant improvements in both GI- and ASD [autism spectrum disorder] -related symptoms" [2]. MTT by the way, refers to Microbiota Transfer Therapy, or in other words a poo(p) transplant. A press release accompanying the recent Kang paper is also available (see here).

The original Kang study included quite a bit more than just a poo(p) transplant as per their use of a 4-stage protocol: "(1) oral vancomycin, (2) MoviPrep, (3) SHGM [Standardized Human Gut Microbiota], and (4) Prilosec" with 18 participants diagnosed with an autism spectrum disorder (ASD). The results on that last occasion were promising insofar as (a) adverse effects being small and fairly limited and (b) some improvements noted in relation to behaviour and gastrointestinal (GI) symptoms. That all being said, one needs to remember that the previous study was an open trial and results were therefore preliminary.

On this latest research occasion, Kang et al followed up their 18 participants "two years after treatment was completed." The follow-up involved "the same GI and behavior tests that we employed previously" which involved the use of various parent- and professional-report questionnaires on behaviour, questionnaire analysis of GI issues and analysis of poo(p) samples: "16 out of 18 original ASD participants provided an additional fecal sample two years after the open-label trial."

Researchers reported that "most improvements in GI symptoms were maintained, and autism-related symptoms improved even more after the end of treatment." They observed something of a possible *relationship* between bowel and behavioural signs and symptoms whereby "GI relief provided by MTT may ameliorate behavioral severity in children with ASD, or vice versa, or that both may be similarly impacted by another factor" which is interesting (see here). They also noted that the bacterial composition of stools analysed at follow-up showed evidence of sustained change "including significant increases in bacterial diversity and relative abundances of Bifidobacteria and Prevotella." In short, things were still looking pretty good after 2 years.

"Despite steady and continuous improvement in behaviors over two years, we must underscore that the original clinical trial and current follow-up study are open-label trials without a control for placebo effect." The authors are frank about the limitations of their studies, and how behavioural and GI symptoms in particular can potentially be influenced by all-manner of different variables. Indeed, they noted that "12 of 18 participants made some changes to their medication, diet, or nutritional supplements" which allied to the waxing and waning of symptoms typically associated with autism (see here), means that one has to be careful about making too many sweeping statements about cause-and-effect.

But in the context that for these 18 participants, a poo(p) transplant was seemingly not associated with too many adverse side-effects and that their behavioural and GI data typically followed a course of improvement, one cannot easily discount the Kang results. The call for further research "with a placebo-control arm" made by the authors should echo throughout the autism research landscape. And with it, further focus on how gut bacterial make-up and the all-important metabolites that specific bacterial species produce seem to be something quite important to at least some autism (see here)...

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[1] Kang D-W. et al. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Scientific Reports. 2019; 9: 5821.

[2] Kang D-W. et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017; 5: 10.

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Thursday, 11 April 2019

Psychiatric symptoms in minimally verbal kids with autism: filling a gap

The findings reported by Daniela Plesa Skwerer and colleagues [1] (open-access available here) provide the blogging fodder today. They include some important information on an under-studied group on the autism spectrum (see here) with regards to the "overall burden of psychiatric comorbidities and emotion dysregulation" in those diagnosed with an autism spectrum disorder (ASD) "who had limited verbal abilities (i.e., few to no words used spontaneously)." Such work follows the recent publication of a paper by Ginny Russell and colleagues [2] who observed that those diagnosed with autism + intellectual (learning) disability were not exactly well-represented in the peer-reviewed autism research arena.

The Plesa Skwerer paper started with the observation that various psychiatric symptoms and conditions seem to be over-represented when it comes to a diagnosis of autism (see here for example). They noted that much of the research on this topic tended look at those who could be considered to be at the 'more able end' of the autism spectrum based on skills like self-report ability. They noted that "the population most severely affected, the ~30% of individuals with ASD who remain non- or minimally verbal beyond school-age" are not particularly well-represented in such comorbidity studies. The specific words they use are the "neglected “severe end of the spectrum”."

So: "Sixty-five participants diagnosed with ASD who had limited verbal abilities" were invited to participate in their study. They were already part of a larger research initiative. When I say 'invited' what I really meant is that: "Informed consent was obtained from the parents." All were diagnosed with an autism spectrum disorder (ASD) and the group was fairly equally split between children (5-11 years old) and young adults (12-18 years old). Parents/caregivers had a big role to play in the Plesa Skwerer study as we told that they were asked to complete various questionnaires about their children, including the Child and Adolescent Symptom Inventory (CASI-5) to "examine the frequency and severity of comorbid psychiatric symptoms." Completing the CASI-5 is no mean feat as per it having "173 items, which rate behaviors as occurring never, sometimes, often and very often."

Results: "All participants met cutoff criteria for at least one CASI-5 classification, and the number of categorical classifications parents endorsed ranged from 1 to 15, with a mode and a median of 6 classifications." This is an important detail. It tells us that, based on proxy reporting, every participant, child or young adult, presented with potentially clinically significant symptoms for one or more psychiatric/behavioural disorder. Some of the most popular labels that featured were things like vocal tics, phobia and the various types of attention-deficit hyperactivity disorder (ADHD). Further: "except oppositional defiant disorder and conduct disorder, more participants showed clinically concerning severity scores than expected based on general population norms." Authors concluded that: "The overall picture to emerge from this study is that minimally verbal children and adolescents present with extremely heterogeneous profiles of co-morbid psychopathology that are not easily predicted by autism symptom severity, intellectual disability, or limitations in communication."

There are some important caveats to the Plesa Skwerer findings, not least that proxy-reporting was the method used to ascertain the presence of not of such psychiatric comorbidity. This point tells us that a lot more needs to be done to help those who are minimally-verbal to be able to communicate much more readily. Yes, it's a tall order but where there's a will, there's a way. Also, researchers admit that they "excluded those with the most severe behavior problems including aggression, self-injury or non-compliance, and therefore our findings must be viewed in the context of whom our participants represent." Personally I see this is being a pretty issue across quite a lot of research on autism. Indeed, in light of legal rulings here in the UK (see here) talking about aggression 'not being a choice for children with autism' I daresay that by excluding those who present with such issues means that many, many children and adults on the autism spectrum are under-represented in autism research as it stands.

Still, the important message from Plesa Skwerer et al stands: those with autism who are described (defined?) as minimally-verbal seem to show a similar profile of psychiatric comorbidity and a "high degree of maladaptive behavior" as that identified in other parts/regions of the autism spectrum. Screening is implied and, so as to ensure that health inequalities are minimised, access to intervention is also indicated.

Bravo to the researchers who look at the under-studied parts of the autism spectrum.

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[1] Plesa Skwerer D. et al. Prevalence and Correlates of Psychiatric Symptoms in Minimally Verbal Children and Adolescents With ASD. Front Psychiatry. 2019 Feb 18;10:43.

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

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Wednesday, 10 April 2019

"Autism prevalence in China is comparable to Western prevalence" But is it really?

I was intrigued by the findings reported by Xiang Sun and colleagues [1] whose paper is the source material for the quote heading this brief post: "Autism prevalence in China is comparable to Western prevalence."

Intrigued because the idea that the prevalence of autism - in school-aged children - hovers around 1 in 100 (1%) in the Western world is still being banded around, even when data is being produced suggesting that rates are actually increasing well beyond the 1% mark in recent times (see here and see here).

Don't get me wrong, I am impressed with the Sun paper and the significant efforts and work that went into their study to look at "autism prevalence (mainstream and special schools) in Jilin City, and mainstream school autism prevalence in Jiamusi and Shenzhen cities" in China. Impressed because of the numbers involved, the 3-stage process undertaken (screening, clinical assessment, research diagnostic assessment) as part of the study and also because the data adds to a growing volume of other studies looking at autism in China (see here and see here for examples) and nearby areas (see here).

I'm not going to bore you with any more of my musings on this paper and issue. Suffice to say that the 1% statistic is old and increasingly out of touch with the current reality of autism in many, many different nations...

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[1] Sun X. et al. Autism prevalence in China is comparable to Western prevalence. Molecular Autism. 2019; 10: 7.

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