"Suicidal spectrum behaviors" and ADHD meta-analysed

"Awareness of the association between ADHD [attention-deficit hyperactivity disorder] and SSBs [suicidal spectrum behaviors] should contribute to more effectively prevent SSBs."

That was the conclusion reached in the study published by Mathilde Septier and colleagues [1] and the results of their "first meta-analysis on the association between ADHD and SSBs taking possible confounders into account." Their systematic review and meta-analysis was preregistered (see here) so we knew it would be coming.

Starting with nearly 3000 references, the available data was whittled down to just over 50 studies. The data were analysed and boiled down to reveal "a significant association between ADHD and suicidal attempts..., suicidal ideations..., suicidal plans..., and completed suicide."

What's more to say? Well such results although stark are not completely unexpected given what has already been discussed on this blog on this topic (see here and see here and see here). They serve to confirm that a diagnosis of ADHD (or even the presentation of subclinical ADHD symptoms?) should really set in motion some preferential screening for suicidal spectrum behaviours and appropriate support offered as and when detected. Minus any sweeping generalisations, such results also invite further inquiry into how certain intervention options indicated for ADHD *might* also affect risk of suicidality in the context of ADHD (see here).

If you need someone to talk to, there are organisations out there...

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[1] Septier M. et al. Association between suicidal spectrum behaviors and Attention-Deficit/Hyperactivity Disorder: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2019 May 23. pii: S0149-7634(18)30941-2.

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Mindfulness for ADHD systematically reviewed

"According to presented descriptive results, all the studies (100%) showed improvement of ADHD [attention-deficit hyperactivity disorder] symptoms."

That was the standout sentence derived from the findings reported by Hélène Poissant and colleagues [1] who looked at "the available literature concerning MBIs [mindfulness-based interventions] in adult participants with ADHD." Mindfulness by the way, is described as a way of "reconnecting with our bodies and the sensations they experience" with a specific focus on "an awareness of our thoughts and feelings as they happen moment to moment." I'm no expert on mindfulness or mindfulness-based interventions but, from what I gather, the core of such intervention(s) is based around "somatically focused meditative techniques (body scan, sitting meditation, and mindful yoga) that are thought to help participants cultivate nonjudgmental, mindful awareness of present-moment experience." 'Focusing in on the present' seems to be the phrase that springs to mind.

Poissant et al examined the relevant peer-reviewed science on the application of the MBIs to ADHD upto June 2018. They specifically focused on adults with ADHD, and were able to track down "13 studies conducted with 753 adults (mean age of 35.1 years)" for inclusion in their systematic review. They observed that: "All the studies (100%) showed improvement of ADHD symptoms following an MBI." They also mentioned that: "mindfulness meditation training improves some aspects of executive function and emotion dysregulation" as per the findings of some of those studies.

Despite the '100% of studies showing improvement in ADHD symptoms' sentiments, I'm not falling hook, line and sinker for the value of MBIs in relation to ADHD. The main reason is the high risk of bias identified in quite a few of the studies reviewed by Poissant, related to things like performance bias ("blinding of participants and of personnel") and selection bias ("allocation concealment" and "selection bias"). One could argue that the examination of something like MBIs under research conditions is never going to be perfect. Unlike scientific investigation of a medicine, where a placebo can be formulated to look, smell and taste the same, it would be difficult to come up with something to approximate MBI and indeed, approximate what the 'active ingredient' of mindfulness actually is. Similar issues have been talked about on other occasions on this blog (see here).

That all being said, there is something appealing about MBIs both in terms of effect and also the fact that it can be learned by pretty much anyone, is cost-free and probably about as side-effect free as one could get. If such a simple technique helps with any one of the symptoms of ADHD and improves quality of life for those with ADHD, it's got to be something to be considered alongside the myriad of other possible interventions (see here and see here and see here) that *might* offset the risks that follow a diagnosis of ADHD (see here).

Oh, and it appears that mindfulness and ADHD is a topic in the ascendancy [2]...

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[1] Poissant H. et al. Behavioral and Cognitive Impacts of Mindfulness-Based Interventions on Adults with Attention-Deficit Hyperactivity Disorder: A Systematic Review. Behav Neurol. 2019;2019:5682050.

[2] Xue J. et al. A meta-analytic investigation of the impact of mindfulness-based interventions on ADHD symptoms. Medicine (Baltimore). 2019 Jun;98(23):e15957.

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Probiotics for autism systematically reviewed

"Our review includes two randomized controlled trials, which showed improvement of ASD [autism spectrum disorder] behaviors, and three open trials, all which exhibited a trend of improvement."

So said the findings reported by Jun Liu and colleagues [1] and the results of their "updated systematic review" on the topic of probiotic 'therapy' in the context of behaviour and gastrointestinal (GI) functioning in autism.

The current scientific outlook for probiotic use in the context of autism looked to be pretty good on the basis of the Liu findings. They corroborate quite a few individual study results that have been fodder for this blog (see here and see here) and fit in well with an emerging pattern of research suggesting that the trillions of wee beasties that inhabit the gastrointestinal (GI) tract might be doing a lot more than just helping us digest food (see here and see here).

What else is required? Well Liu et al talk about more "rigorous trials" to answer questions like who on the autism spectrum might be a best responder to this type of intervention and what bacterial species might be most important. I'd also like to see a little more research on the hows-and-whys of such intervention (see here for example) and whether probiotics are as harmless as many have made them out to be.

Still...

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[1] Liu J. et al. Probiotic Therapy for Treating Behavioral and Gastrointestinal Symptoms in Autism Spectrum Disorder: A Systematic Review of Clinical Trials. Curr Med Sci. 2019 Apr;39(2):173-184.

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"Neurodevelopmental effects of prenatal vitamin D in humans"

The results of the systematic review and meta-analysis published by Azahara García-Serna & Eva Morales [1] provide the blogging fodder today.

Their aim was to summarise the collected peer-reviewed research evidence pertinent to "the association between 25-hydroxyvitamin D [25(OH)D] levels in maternal blood in pregnancy or newborn blood at birth and neurodevelopmental outcomes, including cognition, psychomotor performance, language development, behavioral difficulties, attention deficit and hyperactivity disorder (ADHD), and autistic traits." This coming from authors who already have some research 'form' in this area (see here).

Twenty-five studies ("articles") were included in their boiling-down-of-the-relevant-research-literature published up to May 2018. From the combined data, a few *associations* were detected: "Comparing the highest vs. the lowest category of prenatal 25(OH)D levels, the pooled beta coefficients were 0.95... for cognition, and 0.88... for psychomotor development. The pooled relative risk for ADHD was 0.72..., and the pooled odds ratio for autism-related traits was 0.42." What this meant is that measured higher levels of vitamin D in pregnant mums-to-be or in offspring newborn blood correlated with "improved cognitive development and reduced risk of ADHD and autism-related traits later in life" for offspring.

Of course one has to be careful with such data whether it comes from a meta-analysis or not. We're still talking about observational studies where one variable (vitamin D) is being analysed in the context of one or a few others (related to offspring development). Yes, researchers can control for this potential confounder or that potential confounder, but there remains a 101 other variables that likely affect the likelihood of ADHD or 'autism-related traits' appearing, not least biology and genetics.

That being said, the García-Serna / Morales are potentially important. They point to the need for further research into various possibly interlinked areas when it comes to vitamin D levels and their intake. This follows Government guidance (at least here in Blighty) suggesting that many people should be taking a vitamin D supplement already (see here). I'm also minded to suggest that future investigations should also be looking at other related areas around vitamin D such as the various genetic processes that seem to be important to vitamin D levels and the metabolism of the sunshine vitamin (see here).

And if you're still not convinced by the potential effects of vitamin D and offspring outcomes, perhaps the findings - systematic review findings - published by Janet Janbek and colleagues [2] might help sway you a little...

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[1] García-Serna A. & Morales E. Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis. Molecular Psychiatry. 2019. Jan 25.

[2] Janbek J. et al. Associations between vitamin D status in pregnancy and offspring neurodevelopment: a systematic literature review.  Nutr Rev. 2019 Feb 26. pii: nuy071.

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"In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis"

The title heading this post - "In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis" - comes from the findings published by Annemette Halvorsen and colleagues [1] on a topic that has been of some research interest for quite a few years (see here and see here for example).

SSRIs denote a class of medicines called the selective serotonin reuptake inhibitors, principally used to treat/manage various types of depression. Although in quite a few cases a lifesaver, such medicines also come with a risk-benefit profile (same as all medicines), a risk-benefit profile that also extends to their use during important times such as pregnancy. Minus any scaremongering sentiments, for quite a while now, there has been some interest in whether SSRI use during pregnancy *might* have some important implications for offspring health and development [2]. Such *associations* whilst potentially important, need of course to be balanced with the reasons why SSRIs are used, and how for example, depression is not typically something that magically disappears as and when a woman becomes pregnant...

The Halvorsen paper represents a "systematic review and meta-analysis" of the pertinent research literature examining whether "in utero exposure to selective serotonin reuptake inhibitors (SSRIs) is associated with increased risk of developing mental- or behavioral disorders." Such a 'boiling down'  of the research literature was, we are told, "conducted in adherence with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline" and specifically covered in connection to various childhood developmental labels such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

Based on their analysis of the available data - "20 studies were included in the review and results from 18 of these were meta-analyzed" - researchers observed "a statistically significant positive association between in utero exposure to SSRIs and mental- or behavioral disorders such as autism spectrum disorder..., attention-deficit/hyperactivity disorder... and mental retardation." I say that with the suggestion that intellectual (learning) disability might be a more appropriate description for that last label mentioned. The authors caution however that their results do not necessarily mean that prenatal SSRI exposure *causes* something like autism or ADHD: "these associations do not necessarily reflect a causal relationship since the results included in this meta-analysis are likely affected by residual confounding by indication, which is likely to account for some (or all) of the positive association."

So what to make of this research? Well 'it's complicated' is the long-and-short of it. Minus any sweeping generalisations I'll take you back to some other research (see here) that did try and disentangle the 'causality' side of this area of study (whether underlying maternal depression or antidepressant use was the most important variable). The findings reported by Rai et al [3] did [cautiously] talk about how "children exposed to antidepressants during pregnancy seemed to be at a higher risk of autism, particularly autism without intellectual disability, than children of mothers with psychiatric disorders who were not treated with antidepressants during pregnancy." Other research however has observed something rather different (see here). Y'see, it's complicated.

So all I can really say is that more research is required, and if in doubt, talk to your prescribing physician.

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[1] Halvorsen A. et al. In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis. Acta Psychiatr Scand. 2019 Apr 2.

[2] Pedersen LH. et al. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ. 2009;339:b3569.

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

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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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"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 gut microbiome and autism... so far (continued)

Building on other reviews of the peer-reviewed science literature looking at the intestinal microbiota in relation to autism (see here), the paper published by Feitong Liu and colleagues [1] provides an updated 'where we're at' position in relation to the "potential evidence for the characteristic dysbiosis of gut microbiota in ASD [autism spectrum disorder] patients compared with healthy controls (HCs)." Just before you say anything, those are the authors words not mine; I'm not a fan of the word 'patients' nor use of the term 'healthy control' to denote not autism - not autistic, but there you go.

Language use aside, the Liu paper covers quite a lot of the peer-reviewed science talking about gut bacteria and autism up to March 2018. Their systematic review took in data from 16 studies - human studies "that compared the composition of gut microbiota in ASD patients and HCs using culture-independent techniques." Researchers had also previously registered their intention to conduct this review as per their PROSPERO entry (see here).

So what did their systematic review reveal? Well, they talked about how most studies looked at the intestinal microbiota via the examination of stool samples, although a couple relied on gut biopsy samples instead. Coincidentally, I spotted a bit of an error in the Liu paper in relation to their study reference numbering in one of the results sections, and how the Luna study (see here) and Williams study (see here) which relied on biopsy samples were replaced by other 'stool as a sample media' studies in the Liu write-up. It's only a small point and doesn't detract from the paper overall. The included studies also covered various different populations in a geographic sense as well as taking into account a mix of participants (with autism) in terms of the presence of gastrointestinal (GI) issues and the use of 'special' diets. Indeed, we are told that: "As restricted diet is very common in ASD patients, we tried to extract the information of eating habit in ASD and control group." Yes it is common, and yes it can have sometimes very negative effects (see here). Finally, all the studies included for review were "identified and assessed as medium (6–7) to high (8) quality" suggesting that the data were pretty reliable in a methodological sense.

Some key points emerged: "Overall, the changed structure of gut bacterial community in terms of β-diversity was observed coherently in ASD patients compared with HCs." Beta-diversity basically translates into 'between samples diversity' and in this case represents autism vs. not-autism controls. Out of the 16 studies included in their systematic review, Liu et al reported that "ten studies analyzed β-diversity (unweighted UniFrac distance, weighted UniFrac distances, and Bray-Curtis)." Six of those 10 studies "consistently reported that the microbiota of ASD patients clustered significantly apart from that of HCs." Ergo, there is evidence - some evidence - that the gut microbiome is significantly 'different' in autism compared with not-autism in a group sense. Some evidence at least.

Also: "Consistently, ASD patients had elevated abundance of Proteobacteria rather than HCs. In addition, Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter were consistently decreased, while Lactobacillus, Bacteroides, Desulfovibrio, and Clostridium were increased in ASD patients relative to HCs."  Bear also in mind that Liu et al talked about various other bacterial species that were, in individual studies, elevated or depressed in the groups with autism, and how important such information might be. Such bacterial changes in terms of diversity or individual species predominating might also have knock-on effects as a result of the different chemical messages that different bacteria produce. One example: "Bacteroides is an abundant genus at all ages, from infants to adults. It is the main producer of propionate in the gut, and the abundance of propionate in feces correlates strongly with the abundance of Bacteroides." It probably won't surprise you to hear that propionic acid (propionate) has also got some research history when it comes to autism (see here) and indeed, with caveats, continues to do so [2]. Other examples are included in the Liu paper, including the 'chemical of the moment', butyrate (butyric acid) (see here). This complements other recently published research [3] too. And let's not forget how such bacteria and their chemical messaging also has some important 'effects' on things like gut barrier function and gut immune function, as part of the 'new triad' when it comes to autism and the gut (see here).

"Microbiome reconstitution could be a potential therapy to ASD patients in future." That's another topic raised in the Liu study on how "remodeling gut microbiota with diet, antibiotics, prebiotics, probiotics, and FMT [fecal microbiota transplant]" could be an option. Actually the future is now, as a quick scour of the autism research literature shows that some of these options are already being / have been investigated (see here and see here for examples). We do need a lot more information on the hows-and-whys of such therapeutic options; importantly covering safety, effectiveness and maybe highlighting the possible mechanisms involved, but there is already existing literature in this area.

As well as highlighting some of the shortcomings of the current research literature discussing the intestinal microbiota and autism, the Liu study provides a nice overview of this topic as things currently (up to March 2018) stand. Whether such information can eventually be 'manipulated' to improve things like quality of life in the context of autism remains to be seen...

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[1] Liu F. et al. Altered composition and function of intestinal microbiota in autism spectrum disorders: a systematic review. Translational Psychiatry. 2019; 43.

[2] Shams S. et al. Systemic treatment with the enteric bacterial metabolic product propionic acid results in reduction of social behavior in juvenile rats: Contribution to a rodent model of autism spectrum disorder. Dev Psychobiol. 2019 Jan 28.

[3] Wang M. et al. Alterations in Gut Glutamate Metabolism Associated with Changes in Gut Microbiota Composition in Children with Autism Spectrum Disorder. mSystems. 2019 Jan 29;4(1). pii: e00321-18.

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"no good evidence that time in front of a screen is "toxic" to health"

BBC News January 4 2019

Quite a few days back the BBC here in Blighty ran the headline "Worry less about children's screen use, parents told" as part of their coverage of the paper by Neza Stiglic & Russell Viner [1]. This paper - "a systematic review of reviews" no less - set out to "systematically examine the evidence of harms and benefits relating to time spent on screens for children and young people’s (CYP) health and well-being, to inform policy."

Informing policy is just what the Stiglic/Viner paper did (see here), as the Royal College of Paediatrics & Child Health (RCPCH) concluded that: "Many of the apparent connections between screen time and adverse effects may be mediated by lost opportunities for positive activities (socialising, exercise, sleep) that are displaced by screen time" but parents shouldn't necessarily get too stressed if their offspring find some enjoyment in their computer/tablet and/or phone in amongst their busy lives. Indeed it was refreshing to see that children and young peoples' voices were being heard on the potential benefits of screen time, with comments such as: "Gives you knowledge" and "Provides you with more opportunities to reach a wider community." All those hours of watching You Tubers fooling around or building whatever on Roblox or similar platforms can actually be intermixed with something approaching gaining knowledge; i.e. learning. Who knew!

The Stiglic/Viner review paper drew on data from 13 reviews reporting "associations between time on screens (screentime; any type) and any health/well-being outcome in CYP [children and young people]." All was not however completely rosy when the reviews were boiled down to a consensus, as we are told that authors found "moderately strong evidence for associations between screentime and greater obesity/adiposity and higher depressive symptoms" and "moderate evidence for an association between screentime and higher energy intake, less healthy diet quality and poorer quality of life." I don't think anyone should really be surprised that more screen time *might* mean an increased tendency towards being overweight or obese. If one subscribes to the idea that energy in - energy out is at least partially related to being overweight or being obese [2] it stands to reason that unless people are running around whilst using their tablets or phones, there is likely to be less 'energy out'.

As for the 'higher depressive symptoms', well let's just say that this is something else that is no stranger to the debate about screen time, as other recent research has similarly observed (see here). Whether it is the actual use of tablets, phones and/or television or the type of material being accessed [3] *correlating* with depression is a question that needs further investigation. I might add that the scenario of when screen time turns into an addiction also needs to be discussed in this context (see here), bearing in mind the limitations of observational studies in relation to discerning cause-and-effect.

Also: "There is weak evidence for association of screentime with behaviour problems, anxiety, hyperactivity and inattention, poorer self-esteem and poorer psychosocial health in young children." Bearing in mind that 'weak evidence' does not mean 'no evidence', this part of the Stiglic/Viner review paper is also important. It means that sweeping conclusions that screen time is somehow playing a major role in the rise of behaviour problems in children (young and old) are not yet necessarily backed up by the scientific evidence. Indeed, as per other topics on this blog, I'd advance the position that certain facets of screen time may actually be advantageous to quite a few children and young people (see here) who are perhaps not for example, the social butterflies that other children are.

The Stiglic/Viner review and subsequent RCPCH advice does not say that screen time for children is risk-free. It does not say that parents shouldn't be continually asking questions about how long their children spend using screens and/or what material they are accessing. It does however mean that, on the basis of the currently available evidence, parents shouldn't get too stressed about moderate screen use in their offspring. Balance things out with the odd physically active inclined hobby or two (avoiding any tiger parenting notions) by all means, but don't stress too much about their swiping. See the potential positives as well as the potential negatives of screen use, and remember that screen time is an inevitable part of growing up these days...

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[1] Stiglic N. & Viner RM. Effects of screentime on the health and well-being of children and adolescents: a systematic review of reviews. BMJ Open. 2019;9:e023191.

[2] Malhotra A. et al. It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet. Br J Sports Med 2015;49:967-968.

[3] Kelly Y. et al. Social Media Use and Adolescent Mental Health: Findings From the UK Millennium Cohort Study. EClinical Med. 2019. Jan 4.

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"maternal obesity and overweight were significantly associated with [offspring] increased ASD risk"

The title heading up this brief post - "maternal obesity and overweight were significantly associated with [offspring] increased ASD [autism spectrum disorder] risk" - comes from the results published by Xian-Yang Lei and colleagues [1].

Under systematic review and meta-analysis conditions, researchers basically found what many people had suspected for quite a while, insofar as maternal weight, before or during pregnancy, being a 'risk factor' for an offspring diagnosis of autism or ASD. They arrived at their conclusion based on "13 eligible studies for meta-analysis (involving 943,293 children and 30,337 cases)" which collectively found that "both maternal obesity... and maternal overweight... were significantly associated with ASD, while maternal underweight was not associated with ASD." Researchers also looked at paternal weight as a possible risk factor for offspring autism but found no statistical association between paternal obesity, overweight or underweight based on the available data (limited to only three studies).

Mindful of the potential for 'stigma' to set in with such investigation, and likewise being careful not to generalise too much from such findings, the Lei results point to both the requirement for more research in this area and a possible 'intervention' route towards reducing the risk of offspring autism: "pre-pregnancy weight control is suggested." I've covered this topic numerous times on this blog (see here and see here and see here for examples) and have concluded that whilst correlation is not the same as causation and that pre- and peri-pregnancy weight is often intricately tied into other features of the condition known as metabolic syndrome, immune function and in particular inflammation, are perhaps important areas for further assessment. Research should perhaps head in that direction, and see what further crops up...

And as if to further prove the point [2]...

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[1] Lei XY. et al. Association between parental body mass index and autism spectrum disorder: a systematic review and meta-analysis. Eur Child Adolesc Psychiatry. 2018 Nov 23.

[2] Windham GC. et al. Maternal Pre-pregnancy Body Mass Index and Gestational Weight Gain in Relation to Autism Spectrum Disorder and other Developmental Disorders in Offspring. Autism Res. 2018 Dec 21.

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"Psychotic experiences are important clinical markers of risk for future suicidal behavior"

The quote titling this post - "Psychotic experiences are important clinical markers of risk for future suicidal behavior" - comes from the systematic review and meta-analysis findings reported by Kathryn Yates and colleagues [1].

Authors posed the research question: "Are psychotic experiences associated with an increased risk of later suicidal ideation, suicide attempt, and/or suicide death?" and looked to the existing peer-reviewed research literature to try and answer it. Based on the combined results from ten studies that "reported on 84 285 participants from 12 different samples and 23 countries" and met the inclusion criteria of their review, Yates et al made some important conclusions.

"Individuals who reported psychotic experiences had an increase in the odds of future suicidal ideation (5 articles; n = 56 191; odds ratio [OR], 2.39 [95% CI,1.62-3.51]), future suicide attempt (8 articles; n = 66 967; OR, 3.15 [95% CI, 2.23-4.45]), and future suicide death (1 article; n = 15 049; OR, 4.39 [95% CI, 1.63-11.78])." These are important statistics. They translate into some important details insofar as "individuals who reported PEs [psychotic experiences] had 2-fold increased odds of subsequent suicidal ideation, 3-fold increased odds of subsequent suicide attempt, and 4-fold increased odds of subsequent suicide death." Some further nifty statistical analysis from the authors looking into something called the population-attributable fraction (PAF), defined as "the proportion of incidents in the population that are attributable to the risk factor", suggested that the percentage figure for "PEs for suicide attempts and suicide deaths combined was 24.7%." That is also something rather important.

Should anyone be surprised by these results? Well, yes and no. Yes, because the magnitude of the association between PEs and suicidal behaviours was probably a lot more pronounced than many would have perhaps expected. No, because other literature has talked about psychosis in depression for example, as being potentially important to the development and presentation of suicidal behaviour (see here). Having said all that, I will reiterate that suicidal behaviours are very complicated.

Aside from the important issue of potentially expanding screening for suicidal behaviours when PEs are present, there are other factors to consider. Not least that: "The mechanisms explaining the association between PEs and suicidal behavior are potentially manifold." I was particularly interested in one theory put forward by the authors, suggesting that: "In the context of high stress and poorer communication skills, this might adversely affect the individual’s ability to formulate logical plans to manage perceived challenges and instead increase the likelihood of turning to suicide." Such an idea is based on other findings observing that there may be cognitive 'challenges' accompanying PEs that may impair problem-solving skills. Y'know, not having the skills to stop molehills from turning into mountains? Perhaps further research in this area might also turn to looking at some of the underlying biology behind such issues as well as the psychology. How, for example, inflammatory processes and the immune system *might* show some important involvement (see here and see here) for at least some people? One future avenue of research attention at least.

The data from Yates and colleagues is particularly poignant at the time of writing this post as the US CDC release figures suggesting that suicide mortality in the United States has climbed and climbed and climbed over the past few decades (see here). Again, the reasons are probably going to be complicated but that shouldn't stop people from continually asking 'why?' and 'what can we do about them?'

I close this post with some important contact details should anyone need someone to talk to (see here)...

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[1] Yates K. et al. Association of Psychotic Experiences With Subsequent Risk of Suicidal Ideation, Suicide Attempts, and Suicide Deaths. JAMA Psychiatry. 2018. Nov 28.

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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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Relative age and ADHD: more data and a meta-analysis

So, relative age and ADHD. The observation that in amongst the various pathways that might lead someone to a diagnosis of attention-deficit hyperactivity disorder (ADHD), "the youngest children within a school class are at a disadvantage in many aspects compared with their older classmates" including increasing "the probability of having ADHD-related symptoms... or other psychopathology..., of receiving a diagnosis of ADHD... or being treated with stimulant medications."

I've talked about this issue a few times on this blog (see here and see here) and am blogging today about a couple of other studies that add to the literature in this area. The first investigation was undertaken by Janine Wendt and colleagues [1] and concluded that: "Using a prospective study design and comprehensive adjustment for confounding and baseline symptoms, we confirmed prior evidence of the association between young ASE [age at school entry] and teacher-reported ADHD symptoms in primary school." The second study was published by Josephine Holland & Kapil Sayal [2] who, following a systematic review of the peer-reviewed science literature on this topic, concluded that "the majority of studies show evidence of a relative age effect influencing both the diagnosis of and receipt of medication for ADHD."

Both studies are open-access so really don't require too much explanation from me. The Wendt study relied on data collected from over 120 "Rudolf Steiner Schools (Waldorf Schools) located within Germany" (Waldorf schools are based on the philosophy of producing "free, morally responsible, and integrated individuals equipped with a high degree of social competence") covering over 3000 children. We are told that this prospective study gathered data via parent- and teacher- reports: "ADHD-related symptoms were assessed at school entry and second and fourth grades by parent-reported and teacher-reported versions of the Strengths and Difficulties Questionnaire (Hyperactivity-Inattention Subscale)." Their results found a possible *association* between age and school entry (ASE) and teacher-reported ADHD symptoms using the SDQ: "ASE was negatively associated with ADHD-related symptoms in the second grade... and fourth grade. Associations remained after adjusting for potential confounders and pre-existing symptoms at baseline." Those 'potential confounders' included "gender, time of observation and source of information." I'm also inclined to point out that the prevalence of possible ADHD overall in the Wendt study was pretty high in some scenarios: "The frequency of ADHD indications ranged from 3.7% (girls, second grade, parent reports) to 25.0% (boys, second grade, teacher reports)."

Then to the Holland-Sayal study. This was a systematic review of the existing research literature pertinent to the questions: "Is there an association between younger relative age, defined as being in the second half of the academic year, and: (1) the presence of high levels of ADHD symptoms, (2) receiving a clinical diagnosis of ADHD and (3) receiving medication for ADHD?" Based on an examination of the literature "published from the 1st of January 2000 to the search date of the 7th September 2017" and including 20 papers for review, the answer: yes, generally-speaking, there is more evidence for a relative age effect in relation to ADHD symptoms, diagnosis or receipt of medication for ADHD than against it.

Holland & Sayal do caution that their findings were not totally unambiguous. They discuss how differences across the various studies included for analysis might be important to the final outcome determined. So: "studies differed by sample size, years studied, ages studied and methods of reporting and recording ADHD diagnosis and medication." They also noted that: "The culture of diagnostic practice within a country’s health system may have an influence on the relative age effects found" implying that the willingness to diagnose ADHD in a particular country or region could very well have had an effect on the main findings.

Overall however, these studies add to the existing research-based message observing that age and maturation may be important 'influencers' of reported ADHD symptoms, diagnosis and/or receipt of ADHD medicines.

The big question now is 'what is science and clinical practice going to do about it? bearing in mind that there may be 'redshirting' models to follow [3]...

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[1] Wendt J. et al. Young age at school entry and attention-deficit hyperactivity disorder-related symptoms during primary school: results of a prospective cohort study conducted at German Rudolf Steiner Schools. BMJ Open. 2018;8:e020820.

[2] Holland J. & Sayal K. Relative age and ADHD symptoms, diagnosis and medication: a systematic review. European Child & Adolescent Psychiatry. 2018. Oct 6.

[3] Whitely M. et al. Attention deficit hyperactivity disorder late birthdate effect common in both high and low prescribing international jurisdictions: systematic review. J Child Psychol Psychiatry. 2018 Oct 14.

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Colliding spectrums again: autism and schizophrenia meta-analysed (again)

"The systematic review and meta-analysis showed a significant association between schizophrenia and ASD [autism spectrum disorder]."

That was the conclusion made by Zhen Zheng and colleagues [1] following their trawl through the peer-reviewed science literature with a view to examining "the association between schizophrenia and ASD."

This is not the first time that Zheng et al have featured in the autism meta-analysis arena (see here and see here and see here) so one could perhaps see them as seasoned professionals when it comes to this type of science. It's also not the first time that the relationship between autism and schizophrenia has been subjected to such analyses either (see here) continuing quite a long relationship between the labels and/or spectrums [2] (see here also).

So: "The meta-analysis of the prevalence of schizophrenia in individuals with ASD encompassed 1,950,113 participants and 14,945 individuals with ASD." From such numbers/data, authors were quite confidently able to determine that schizophrenia was more frequent in cases of autism than in control participants. Indeed, this was described as a 'robust' finding and the magnitude of the risk was not to be sniffed at: "odds ratio = 3.55, 95% confidence interval: 2.08-6.05, P < .001."

In relation to the "prevalence of ASD in individuals with schizophrenia", the authors relied on a smaller number of participants but concluded that: "The prevalence of ASD in individuals with schizophrenia ranged from 3.4 to 52%." Ergo, schizophrenia occurring alongside autism and autism occurring alongside schizophrenia both show over-representation.

As I mentioned on a previous blogging occasion when these labels were discussed in an overlapping sense, there are many implications from such findings. There are implications related to the preferential screening for schizophrenia and/or autism (also including other related issues too) when one or other label is diagnosed and for timely and appropriate intervention for such issues when detected (see here). There are implications for the idea that, biologically-speaking, there may be some shared mechanisms at work covering both (heterogeneous) labels (see here and see here for examples). There are also implications in relation to the social impact of such an association; bearing in mind the often very negative image portrayed of schizophrenia in certain quarters of the media and the rise and rise of 'autistic identity' in other circles. There is lots to think about.

And finally and quite timely, the paper from Giacomo Deste and colleagues [3] talking about the PANSS Autism Severity Score (PAUSS) as a "simple, fast and reliable tool for the identification of autistic features in adult patients with schizophrenia" looks rather interesting...

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[1] Zheng Z. et al. Association Between Schizophrenia and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Autism Res. 2018 Oct 3.

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

[3] Deste G. et al. Looking through autistic features in schizophrenia using the PANSS autism severity score (PAUSS). Psychiatry Research. 2018. Oct 29.

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"Omega-3 polyunsaturated fatty acid treatment for anxiety might be effective in clinical settings"

Today I present the findings of yet another systematic review and meta-analysis as per the publication from Kuan-Pin Su and colleagues [1] that concluded: "omega-3 PUFAs [polyunsaturated fatty acids] might help to reduce the symptoms of clinical anxiety." A finding that may have some quite profound implications for lots and lots of different diagnoses/conditions/labels where anxiety seems to be particularly over-represented and life-draining (see here and see here for examples).

So, the starting hypothesis was that "omega-3 PUFAs might have anxiolytic effects in patients with significant anxiety- and fear-related symptoms." Various studies, both in animals and humans, have implicated fatty acids in 'emotional states', particularly the so-called 'good fatty acids' including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The authors reported that "there have been no systematic reviews of this topic to date" so decided to remedy the situation.

Trawling through various repositories and databases of peer-reviewed science, they searched for relevant science on the topic of fatty acid supplementation and anxiety measurement. From little over a hundred possible science articles, they whittled the numbers down to 19 studies including over 1200 participants "with omega-3 PUFA treatment (mean age, 43.7 years; mean female proportion, 55.0%; mean omega-3 PUFA dosage, 1605.7 mg/d)" and "1037 participants without omega-3 PUFA treatment (mean age, 40.6 years; mean female proportion, 55.0%)." Taking into account that some studies (most) included a placebo element to their design, different dosages and formulations of PUFAs were used and that various different tools and schedules were used to 'measure anxiety', there were some boiled-down messages to emerge.

First: "The overall findings revealed modest anxiolytic effects of omega-3 PUFAs in individuals with various neuropsychiatric or major physical illnesses." That's not to say that every study was 'positive' in terms of PUFA effects on anxiety, but generally speaking the evidence tended to side more with an effect rather than no effect. Second, dose and formulation seemed to matter: "Participants treated with a daily dose of 2000 mg or more of omega-3 PUFAs showed a significantly greater association of treatment with reduced anxiety symptoms." Third: "the association of omega-3 PUFA treatment with reduced anxiety symptoms was significantly stronger in subgroups with specific clinical diagnoses than in subgroups without specific clinical conditions." So the effect of PUFA supplementation was stronger in those with a clinical diagnosis of something like anxiety than those who didn't have one.

Downsides? Well, there are of course limitations to the data included in the Su study; for example, "the significant heterogeneity among the included studies... with potential influence by some outlier studies" and these should not be underestimated. I'm also minded to bring in the [still emerging] issue that meta-analyses are only as good as the data that they are based on (see here and see here for examples). And I'd also mention that side-effects are something not discussed too heavily in the Su study but one shouldn't assume that just because we're talking about a fish oil so this is somehow side-effect free for everyone...

Given the low cost of fatty acid supplements and their wide, very wide, availability, the Su results provide some pretty good support to suggest that 'giving it a go' could be an option for at least some people diagnosed with an anxiety disorder. Please don't however take that as me giving anyone medical or clinical advice; I'm merely following what the results say and the media coverage that has followed (see here).

And since we're on the topic of food and mood, I note the recent meta-analysis from Camille Lassale and colleagues [2] suggesting that "adhering to a healthy diet, in particular a traditional Mediterranean diet, or avoiding a pro-inflammatory diet appears to confer some protection against depression in observational studies" has been garnering news headlines (see here). These studies combined suggest that diet might have an important effect of mood and well being. Now, where have I heard that before (see here)...?

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[1] Su K-P. et al. Association of Use of Omega-3 Polyunsaturated Fatty Acids With Changes in Severity of Anxiety Symptoms. JAMA Network Open. 2018;1(5):e182327.

[2] Lassale C. et al. Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. Molecular Psychiatry. 2018. Sept 26.

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"C-Reactive Protein as a Peripheral Biomarker in Schizophrenia"

The results of the 'updated systematic review' published by Guillaume Fond and colleagues [1] looking at the "relationships between elevated blood C-reactive protein (CRP) levels and schizophrenia (SZ) onset risk, illness characteristics and treatments, cognition and physical health" provides the blogging fodder today.

Fond (a name not unfamiliar to all-things schizophrenia) et al dip into a topic with more than its fair share of research 'uncertainty' (see here and see here for examples) on whether or not C-reactive protein (CRP), a marker of systemic inflammation, shows a connection to schizophrenia. On this particular research occasion, no new data is added to the debate, but rather authors looked at the collected peer-reviewed data (up to November 2017) to see if any 'general opinions' could be discerned from the collected works.

Results: based on over 50 studies included in their review, authors concluded that it was 'reasonable' to assume that high-sensitivity CRP (hs-CRP) may be a marker for 'schizophrenia onset risk'. The caveat to that statement is that CRP is probably not something 'schizophrenia-specific' in terms of elevations of CRP being indicative of a inflammatory state. So increased hs-CRP may well be a risk factor for "increased positive symptoms, cognitive impairment, hypovitaminosis D, microbiota disturbances, cardiovascular and metabolic syndrome risk in SZ subjects, and increased nicotine dependence in SZ smokers."

I'm pretty happy with the Fond results and interpretation as they stand. They suggest that CRP probably does show some sort of connection to schizophrenia and onward, points to an immune system connection to at least some cases (see here and see here). At the same time, they also imply that certain other observations around schizophrenia - such as a link with certain physical health issues (see here) and/or vitamin D deficiency (see here) - probably also contribute to the elevations of CRP noted in relation to cases of schizophrenia. They also imply that moves to reduce levels of CRP in relation to schizophrenia may well have various other 'knock-on' effects on those other risk factors associated with the condition/diagnosis. This 'double hit' effect could be quite useful.

And with that last sentence in mind, and accepting that consistently high levels of CRP are probably good for no-one, the next question: what can we do about elevated CRP levels in relation to schizophrenia and further, the immune system issues also being co-expressed? Lots, is my impression; perhaps also learning from other labels where immune function (and dysfunction) has been noted [2] and intervention is similarly indicated.

And there's more to come from this authorship group on this blog soon...

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[1] Fond G. et al. C-Reactive Protein as a Peripheral Biomarker in Schizophrenia. An Updated Systematic Review. Front. Psychiatry. 2018. Aug 23.

[2] Marchezan J. et al. Immunological Dysfunction in Autism Spectrum Disorder: A Potential Target for Therapy. Neuroimmunomodulation. 2018 Sep 5:1-20.

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Bipolar disorder and "completed suicide"

"Suicide rates in BD [bipolar disorder] vary between studies but our analyses show that they are approximately 20-30-fold greater than in general population."

That rather sober sentence comes from the results of the systematic review published by Plans and colleagues [1] looking at "the existing literature of completed suicide in BD patients." As per the words 'completed suicide' this was a review article specifically focused on looking at studies examining the very final decision taken to end ones life and acting upon it. The authors did look at "suicide attempts and suicidal behaviour" during the course of their review but only in the context of completed suicide.

Then to the cold, objective science... over 60 articles met the authors inclusion criteria and allowed researchers to review "epidemiological data, genetic factors, risk factors and treatment of completed suicide in BD." Aside from the quite startling risk of completed suicide in relation to a diagnosis of bipolar disorder, authors were also able to note some important risk variables too: "early onset, family history of suicide among first-degree relatives, previous attempted suicides, comorbidities." Another important statement was also made pertinent to that 'treatment' analysis: "Lithium is the only treatment that has shown anti-suicide potential" in line with other observations (see here).

What's more to say? Well acknowledging that the paths towards suicide are various and numerous (see here) and, more often that not, influenced by both internal and external factors, the connection between bipolar disorder and suicide risk is cemented by the Plans review. I could talk about how bipolar disorder and other depression-related illnesses (yes, illnesses) are potentially *connected* to various other diagnostic labels (see here for example) and, within that context, may very well influence suicide risk there too (see here). But there's nothing particularly novel about such discussions.

The 'lithium' bit to the Plans paper is also important to reiterate, and how such medication is truly a life-saver for some. As with all medicines, it does have a 'risk profile' [2] but, with appropriate monitoring, any side-effects need to be balanced against the very real risk highlighted by Plans et al.

And then there is the need for lots more scientific investigation in this area to directly 'tackle' bipolar disorder in terms of aetiology and pathology and logically onward, to impact on suicide risk...

To close, there are people to talk to (or text) if needed...

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[1] Plans L. et al. Association between completed suicide and bipolar disorder: A systematic review of the literature. J Affect Disord. 2018 Aug 23;242:111-122.

[2] Albert U. et al. Lithium treatment and potential long-term side effects: a systematic review of the literature. Riv Psichiatr. 2014 Jan-Feb;49(1):12-21.

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"Anxiety and depression in adults with autism spectrum disorder" research reviewed and meta-analysed

I'm only making a fairly brief post today around the paper published by Matthew Hollocks and colleagues [1] titled: "Anxiety and depression in adults with autism spectrum disorder: a systematic review and meta-analysis."

Brief, because their results - "The pooled estimation of current and lifetime prevalence for adults with ASD [autism spectrum disorder] were 27% and 42% for any anxiety disorder, and 23% and 37% for depressive disorder" - were not entirely unexpected (see here and see here for examples) despite the 'gathered together' literature suffering from "a high degree of heterogeneity in study method and an overreliance on clinical samples."

I've said it before and I'll say it again, the [research] conversation now needs to move in a different direction to answer a couple of key questions in this area: (1) why are anxiety and depression so over-represented when it comes to autism? and (2) what are the most effective strategies to combat such issues in the context of a diagnosis of autism?

My opinion? I'm inclined to suggest that anxiety and depression are going to be present for a myriad of different reasons. I know people talk about life experiences as being important to their presentation of such symptoms and I'm not disagreeing at all. I'm inclined however to also suspect that the use of the word 'comorbidity' in respect of anxiety and depression in the context of autism is not altogether accurate. There is ample evidence in the peer-reviewed domain to suggest for example, that some of the core features of autism may actually 'heighten' the risk of depression and anxiety occurring (see here and see here). The nature of any relationship between core symptoms and things like depression and/or anxiety are likely to be complex and probably include aspects such as self-attention and brooding [2] and other related concepts such an intolerance of uncertainty (see here) and perhaps even something more pathological (see here). As unpalatable as this might be to some, the accompanying data from those who 'lost their diagnosis' (see here) supports the need for further investigations into this area...

And whilst on the topic of 'comorbidity', the paper by Eric Rubenstein  & Lauren Bishop‐Fitzpatrick [3] is definitely timely...

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[1] Hollocks MJ. et al. Anxiety and depression in adults with autism spectrum disorder: a systematic review and meta-analysis. Psychol Med. 2018 Sep 4:1-14.

[2] Burns A. et al. Self-Focused Attention and Depressive Symptoms in Adults with Autistic Spectrum Disorder (ASD). J Autism Dev Disord. 2018 Sep 14.

[3] Rubenstein E. & Bishop-Fitzpatrick L. A Matter of Time: The Necessity of Temporal Language in Research on Health Conditions that Present with Autism Spectrum Disorder. Autism Res. 2018 Sep 5.

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"risperidone is efficacious in the treatment of symptoms in children and adolescents with ASD"

The heading titling this post - "risperidone is efficacious in the treatment of symptoms in children and adolescents with ASD [autism spectrum disorder]" - comes from the systematic review published by Narong Maneeton and colleagues [1]. These researchers scoured the existing peer-reviewed research literature - "from January 1988 to February 2017" - to "systematically review the efficacy, acceptability and tolerability of risperidone in children and adolescents with ASD." They concluded that, on balance, around "one in every three ASD children and adolescents has benefits from treatment with risperidone." They also cautioned that there is a further scheme of work to follow, looking at the use of risperidone in this particular patient group as per the findings of previous reviews. The continued examination of potential adverse side-effects associated with risperidone use is one such important area to be investigated (see here and see here for examples).

Risperidone is categorised as an antipsychotic medicine. It's typically used to treat psychosis and mania. It's also sometimes used in the context of certain 'challenging behaviours' being presented as a function of a diagnosis of autism or autism spectrum disorder (ASD): "explosive and aggressive behavior" according to one source. Importantly however, the use of risperidone as a tool to intervene on the 'core features' of autism is not, at the time of writing, currently indicated.

Maneeton et al looked specifically for studies classified as a randomised controlled trials (RCTs) in the context of risperidone use with children and adolescents aged up to 18 years of age and diagnosed with autism or ASD. They found seven RCTs including some 370 participants. All of the trials relied on the DSM-IV description of autism or ASD and, aside from two trials, most lasted for between 6 and 8 weeks. The Aberrant Behaviour Checklist (ABC) was a commonly used tool in the studies included for review, with response criteria on such an instrument anticipating between a 25% and 50% reduction in scores (specifically on the irritability subscale) as a result of risperidone use.

Results: as per the opening sentence of this post, a positive behavioural response typically favoured risperidone use over the placebo used as a comparator when it came to certain challenging behaviours. This was noted across those short-term studies ("acute response") and also longer-term intervention (6 months). The authors also reported that a variety of side-effects - adverse side-effects - were noted alongside the use of risperidone. These included things like an increase in appetite, "drowsiness, somnolence, fatigue, anxiety, hypersalivation and elevation of prolactin level." The prolactin bit has been discussed before on this blog (see here) specifically in the context that: "There is no known normal function for prolactin in men."

Bearing in mind that Maneeton and colleagues were discussing risperidone use in 'children and adolescents' with autism, and the requirement for particular caution when using such a powerful medicine on the [still] developing body and brain, these are useful findings. Of course in an ideal world, no-one would want children and young people to have to take risperidone. But like other medicines indicated for other behavioural labels (see here), with regular and appropriate monitoring and medicines management, such pharmacotherapy can be transformative in its effects for some.

The situation however does need improving; particularly in the context of those side-effects and the worry they carry especially into the longer-term. I'm also minded to suggest that science needs to delve a little further into the proposed mechanism of effect when using medicines like risperidone in terms of immune system effects (see here) and other important biological pathways (see here) outside of the known "dopamine D2, 5-HT2A, alpha1-adrenoceptor, and histamine-1 receptor antagonist" biological action. By doing so, one *could* perhaps foresee future medicines with the 'anti-irritability' action but perhaps minus the considerable risk of side-effects?

And without any comment or opinion from me, the recent ruling here in Blighty that 'aggressive behaviour is not a choice for children with autism' (see here for my take) needs to be very carefully managed from a pharmacotherapy point of view. I say this so as not to make medicines such as risperidone, the first line of intervention or worse still, a 'chemical cosh'...

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[1] Maneeton N. et al. Risperidone for children and adolescents with autism spectrum disorder: a systematic review. Neuropsychiatr Dis Treat. 2018 Jul 11;14:1811-1820.

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