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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Treating ADHD: better school results, less risk of crime and better sleep?

I

I had already written and scheduled in this blog post before an important - very important - headline appeared on the BBC News website: "ADHD [attention-deficit hyperactivity disorder] testing after 'impulsive crime' arrests should be mandatory, MPs say." The news piece covered, amongst other things, some of the peer-reviewed research findings suggesting that a diagnosis of ADHD appears to place someone at various enhanced risk for adverse life outcomes. And that potentially includes offending behaviour and prison time.

So...

Today's post is a bit of a mash-up insofar as bringing together three pieces of independent peer-reviewed research pertinent to the important idea of managing or 'treating' ADHD when it arises. I appreciate that not many people would want their nearest-and-dearest 'medicated' for example in the long-term. But when it comes to something like ADHD the case is indeed growing strong for how pharmacological intervention in particular, could literally be a life-saver for some (see here)...

The papers: first there are the findings reported by Andreas Jangmo and colleagues [1] who "analyzed school performance in students with ADHD compared to students without ADHD, and the association between pharmacological treatment of ADHD and school performance." This continues a research theme (see here). The second paper is that from Christina Mohr-Jensen and colleagues [2] which looked at "the risk of long-term conviction and incarceration associated with childhood attention-deficit/hyperactivity disorder (ADHD), and to identify risk and protective factors including associations with active treatment with ADHD medication." Again, this is a topic that has previously received quite a bit of study before (see here). Finally, I'd like to bring the paper by Stephen Becker and colleagues [3] to the blogging table, investigating whether "sleep duration is causally linked to sleepiness, inattention, and behavioral functioning in adolescents with ADHD." The answer: yes, yes it was, in line with other independent research (see here). And that potentially opens the door to intervention (see here).

Minus any sweeping generalisations from me or anyone else, the net result of these studies suggest that intervention for ADHD - primarily pharmacotherapy along the lines of what is currently indicated for ADHD - seems to have an important positive effect for many people diagnosed with ADHD. Some examples of this in action:

• School performance and ADHD: "ADHD was associated with substantially lower school performance independent of socioeconomic background factors." But the good news: "Treatment with ADHD medication for 3 months was positively associated with all primary outcomes" including higher grades and improving access to education. Such data was derived from a total sample size in the hundreds of thousands.
• Crime and ADHD: "Out of n=4,231 individuals with ADHD, n=1,355 (32.0%) had received at least one conviction compared to n=3,059 (15.6%) of the n=19,595 participants without ADHD." But... "The crime rates increased with the number of associated risks but were reduced during periods of taking ADHD medication."
• Sleep and ADHD: "Compared to the extended sleep week, parents reported more inattentive and oppositional symptoms during the restricted sleep week." The Becker study did not specifically talk about the use of intervention for sleep issues in the context of ADHD but it wouldn't be a giant leap to look at 'options' for improving sleep parameters in that context (and what knock-on effects this might have for behaviour).

Caveats? Well, correlation is not the same as causation, so even despite the 'strong' connections noted across these various studies mentioning ADHD, one cannot rule out other confounding variables playing a role. There's also the issue of balancing efficacy and safety to consider as and when any form of pharmacotherapy is introduced, something that is still being looked at with for example, methylphenidate and ADHD (paediatric ADHD) in mind [4]. I'm also minded to suggest that more fundamental work on the basis for ADHD should continue, alongside examination of the hows-and-whys of certain medicines *working* in the context of the biology of ADHD too. That, and an acceptance that medication might be but one tool in the arsenal (see here and see here and see here) to help prevent ADHD from negatively affecting a person's life and/or life chances.

But still the combined results are important. And they may well be important to those who don't quite reach all the thresholds for ADHD as a diagnosis [5] too... 

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[1] Jangmo A. et al. Attention-Deficit/Hyperactivity Disorder, School Performance, and Effect of Medication. J Am Acad Child Adolesc Psychiatry. 2019 Feb 1. pii: S0890-8567(19)30059-0.

[2] Mohr-Jensen C. et al. Attention-Deficit/Hyperactivity Disorder in Childhood and Adolescence and the Risk of Crime in Young Adulthood in a Danish Nationwide Study. J Am Acad Child Adolesc Psychiatry. 2019 Feb 11. pii: S0890-8567(19)30105-4.

[3] Becker SP. et al. Shortened Sleep Duration Causes Sleepiness, Inattention, and Oppositionality in Adolescents With ADHD: Findings From a Crossover Sleep Restriction/Extension Study. J Am Acad Child Adolesc Psychiatry. 2018 Nov 1. pii: S0890-8567(18)31914-2.

[4] Inglis SK. et al. Prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD: the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study. BMJ Open. 2016;6(4):e010433.

[5] Kirova AM. et al. Are subsyndromal manifestations of attention deficit hyperactivity disorder morbid in children? A systematic qualitative review of the literature with meta-analysis. Psychiatry Res. 2019 Feb 3;274:75-90.

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

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

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

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

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

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

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

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

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"ADHD was a risk factor for suicide attempt"

The findings reported by Kai-Lin Huang and colleagues [1] continue an important research theme (see here) on how a diagnosis of attention-deficit hyperactivity disorder (ADHD) may increase the risk of suicidal behaviours (see here). Further, that timely management of the symptoms of ADHD via indicated pharmacological means in particular, may provide some important risk-reduction from such behaviours; again substantiating previous investigations in this area (see here).

Based, yet again, on the fabulous but now sadly non-functional resource that is/was the National Health Insurance Research Database (NHIRD) in Taiwan, researchers undertook a "longitudinal cohort study [that] enrolled 20 574 adolescents and young adults with ADHD and 61 722 age- and gender-matched controls between 2001 and 2009." This is yet another example of Taiwanese 'big data' in action on the important topic of suicide (see here and see here). Alongside detailing any psychiatric comorbidities accompanying the diagnosis of ADHD, Huang and colleagues looked for diagnostic codes indicating suicide attempt(s) and whether or not medication(s) clinically indicated for ADHD were prescribed.

Results: "ADHD was an independent and direct risk factor for any suicide attempt, and an even stronger risk factor for repeated suicide attempts." As per my previous blogging forays into this topic, such news is by no means novel. The use of "long-term methylphenidate treatment" being associated with "a significantly decreased risk of repeated suicide attempts in men with ADHD" is also not new news, but does once more, provide yet more evidence for the use of such strategies and their seeming effects well beyond just symptom reduction/management.

What's more to say? Well, one might need to delve a little more into what it is about ADHD that *might* predispose to such extremes of behaviour. Whether this be a heightened risk of other comorbidity occurring as a function of ADHD (see here) impacting on suicidal behaviour(s) or something rather more directly linked to ADHD (see here), there is a schedule of further research to continue. I'm also minded to direct your attention to the findings reported by Mars and colleagues [2] and how general population 'risk factors' might also provide some clues. Minus any medical or clinical advice given or intended, I'll reiterate how the use of something like lithium seems to be quite useful in the context of potentially reducing suicide risk (see here) and how further work perhaps needs to be done on this compound with specific focus on suicide risk and ADHD. I say this, bearing in mind that lithium has a risk profile of its own.

Oh, and need I remind you that ADHD as being an 'over-represented' feature of autism for quite a few people (see here) might also imply some 'association' in the very serious statistics talking about suicide risk in the context of autism (see here)...

Again, if anyone needs to talk to someone, there are organisations out there willing to listen.

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[1] Huang KL. et al. Risk of suicide attempts in adolescents and young adults with attention-deficit hyperactivity disorder: a nationwide longitudinal study. Br J Psychiatry. 2018 Mar 4:1-5.

[2] Mars B. et al. What distinguishes adolescents with suicidal thoughts from those who have attempted suicide? A population-based birth cohort study. J Child Psychol Psychiatry. 2018 Mar 1.

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KPAX002 for Chronic Fatigue Syndrome part 2: controlled study says no

KPAX002 mentioned in the title of this post refers to "a mitochondrial modulator technology platform" according to the manufacturer that includes a low dose of methylphenidate combined with various nutrients designed to impact on mitochondrial function. Within the context of chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME) (but not necessarily accurately so!), there is some preliminary research history suggesting that KPAX002 might be something to look at for intervening in some of the disabling characteristics of CFS/ME (see here). This, on the basis that mitochondria in particular, might be something quite important to at least some cases (see here and see here).

The fly in the scientific ointment?

Well the results of the "phase 2 randomized, double-blinded, placebo-controlled trial" on KPAX002 published by Jose Montoya and colleagues [1] that, from an intention-to-treat point of view, reported no significant statistical difference in self-reported group scores of fatigue and other measures between active treatment and a placebo. In keeping with the phase 2 label attached to the trial - looking at both initial clinical results and also any side- or adverse effects - authors reported no statistically significant difference in the frequency of reported adverse effects between KPAX002 and a placebo over the 12 weeks of study. First, do no harm and all that.

The Montoya paper is open-access so readers can see for themselves how things were done and the details of the results. I however, want to highlight a few points that I thought were important:

First, the authors acknowledge the "unexpectedly positive results" observed the last time around [2] that led to this more rigorous trial. Personally, I don't think there was anything too unexpected about those pilot study results, given the methodological issues typically associated with a pilot study. Y'know, a small un-blinded participant group taking part in a trial using a preparation that they probably will have been told *might* affect various symptoms they experience or themselves possibly 'exposed' to other anecdotal reports of good effects. That and no control group, no placebo included and importantly, no objective measure of fatigue (a real issue when it comes to quite a bit ME/CFS research) and well, I'd be surprised if something significant didn't come up during the initial findings. And just in case you think I'm being all 'high-and-mighty' about this, I've published using the same type of pilot study methodology before, including some of the same inherent issues (see here).

Second, I'm a little bit disappointed that the authors weren't more forthright in how the results weren't statistically significant on any and all measures included for study. I say this on the basis of both the commercial take on the results (see here) and also sentences like: "The two groups demonstrating the most robust response to KPAX002 were subjects with more severe ME/CFS symptoms at baseline (P=0.086) and subjects suffering from both fatigue and pain (P=0.057)." Both those p-values (p being a measure of statistical significance) are above the [currently] recognised threshold for p equal to or less than 0.05, yet are listed as a 'robust response'. Even more, throughout the paper I note the words 'trend in favor of' being used, which some people might translate as being 'well, they were nearly statistically significant results'. I say this also bearing in mind that the final participant numbers - KPAX002 use = 48 and placebo = 57 - are not exactly facets of what one would call an under-powered study. I'm probably being a nit-picker here but like it or not, the [current] rules of science are the [current] rules of science.

Finally, once again, I note that under the heading 'Disclosure of conflict of interest', the word 'none' appears as per the last research occasion [2]. Personally, and with no malice intended, I would have listed the detail that at least one of the authors is an employee of the manufacturer of KPXA002 given the affiliation details and email address for further correspondence provided on the paper. Again, it's a small detail but one that should nevertheless be acknowledged. I would have also like to have seen a little more on who funded the trial too and especially who funded the provision of the KPAX002 supplement for trial purposes. I reiterate that there is no malice is intended in saying that, but readers require such details.

I don't want to come down too hard on these results because it's obvious that quite a bit of work has gone into their production. I'm also not closing the door on the idea that future research with a more targeted group with ME/CFS might not produce something a little more statistically significant with regards to KPAX002. But for now, the answer must be that controlled study of the formulation did not meet clinical endpoints in a statistical sense, and hence KPAX002 cannot be said to be superior to placebo for CFS/ME. With all the setbacks that the label(s) ME/CFS has had to endure down the years with regards to the 'psychobabble' explanations (see here) and other 'eureka' moments (see here), the Montoya findings are bad news for patients yet again. But, they also should represent a further call to re-double research efforts; particularly when it comes to the biology of the condition(s) and onward the acceleration of research for interventions for this quality of life draining condition (see here).

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[1] Montoya JG. et al. KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial. Int J Clin Exp Med 2018;11(3):2890-2900

[2] Kaiser JD. A prospective, proof-of-concept investigation of KPAX002 in chronic fatigue syndrome. Int J Clin Exp Med. 2015 Jul 15;8(7):11064-74.

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Methylphenidate affecting academic performance meta-analysed

When first tweeting about the paper by Anne Fleur Kortekaas-Rijlaarsdam and colleagues [1] I kinda made a mistake. The text of the tweet read something like: "Does methylphenidate improve academic performance? A systematic review and meta-analysis... Pretty much so, but only in relatively small amounts."

Reading that tweet back to myself I realised that by saying 'but only in relatively small amounts' it's highly likely that any readers might have thought that I was talking about the dose of methylphenidate (MPH) rather than the [intended] effect on things like "math productivity (7.8% increase, p < .001); math accuracy (3.0% increase, p = .001); [and] increased reading speed (SMD .47, p < .001)." I apologise, and once again reiterate my blogging (and social media) caveat about not giving anything that looks, sounds or smells like medical or clinical advice.

I did think it worthwhile to write a short post about the Kortekaas-Rijlaarsdam findings given that (a) ADHD (attention-deficit hyperactivity disorder) is something that turns up quite a bit on this blog (see here for example), and (b) pharmacotherapy 'for ADHD' is an important intervention area which has also, unfortunately under some circumstances, been 'hijacked' for other purposes (see here). On that last point, I specifically refer to the idea that for some people, striving for a diagnosis of ADHD is merely a route to either better academic accommodations or perhaps more worryingly, to gain access to a class of medicines with some potentially significant 'cognitive-enhancing' qualities...

What sets the Kortekaas-Rijlaarsdam findings apart from other reviews of the potential nootropic (cognitive enhancing) abilities of something like MPH is their focus on resolving the issue of "whether there are improvements in core academic skills or just improvements in academic productivity" in the context of "the mediating or moderating effects of symptom improvements, demographic-, design- and disorder-related variables."

From a starting number of 148 full-text research articles, the collected texts were screened for eligibility and some 34 were eventually included for meta-analysis ("quantitative synthesis"). These articles were included because they "provided information about either accuracy or productivity scores for math, reading or spelling, or a combination of these" or could at least be calculated on the basis of their included data. Various mediating and moderating variables were also thrown into the statistical mix - "age, gender, percent diagnosed with ADHD-inattentive subtype, and study characteristics: release system, trial duration, and titration method" - and results reported.

As per previous sentences, various aspects of maths performance showed an improvement that correlated with MPH use, and reading speed but not accuracy also came out as potentially showing a relationship with medicine usage. Important too was the information that: "None of our mediators or moderators influenced MPH effects on math and reading accuracy or productivity."

So, following meta-analytic scrutiny of some 1700 children, it looks like there is a small but potentially relevant effect from MPH use of some academic abilities, at least in the short-term ("between 1 and 7 days"). The authors do well not to stray too much into speculating mode when it comes to the cause of any nootropic effect but instead to include the need for more research "to isolate groups of patients who may benefit more or less from MPH and to reveal its mechanism of action." Can't argue with that.

And going back to the topic of cognitive enahncers, an interesting article from a few years back on what they may or may not be doing to elements of our University student body...

Music to close... Sia and Chandelier. Seemingly always playing outside my dojo....

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[1] Kortekaas-Rijlaarsdam AF. et al. Does methylphenidate improve academic performance? A systematic review and meta-analysis. Eur Child Adolesc Psychiatry. 2018 Jan 20.

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ADHD and risk of injuries meta-analysed (again)

"ADHD [attention-deficit hyperactivity disorder] is significantly associated with an increased risk of unintentional injuries and ADHD medications have a protective effect, at least in the short term, as indicated by self-controlled studies."

So concluded the "systematic review with meta-analyses" conducted by Maite Ruiz-Goikoetxea and colleagues [1] pertinent to "the association between ADHD and risk of unintentional physical injuries in children/adolescents." The '(again)' mentioned in the title of this post references the findings reported by Amiri and colleagues [2] that were discussed earlier this year on this blog (see here).

Ruiz-Goikoetxea et al do make mention of the Amiri meta-analysis and how post-2014 (the point at which the Amiri systematic review and meta-analysis halted) "several methodological sound studies have been published." They also mention how the Amiri analysis "did not control for gender effects, which are a crucial confounder due to the association of both risk of UPIs [unintentional physical injuries] and ADHD to male gender" nor how they looked at the impact of medications for ADHD on the risk(s) of such injuries.

Splitting their analyses in two (a) a risk analysis looking at the risk of UPIs with ADHD in mind and (b) a medication analysis looking at the role (or not) of medication in terms of UPIs in the context of ADHD, authors report results based on their already published protocols [3]. They reported on "odds ratios (ORs) or hazard ratios (HRs) estimating the association between ADHD and injuries" and cumulatively included participant numbers in the tens of thousands.

Results: "a significantly higher risk of injuries in ADHD compared to children or adolescents without ADHD" was observed. Nothing particularly novel there. Also, based on the finding that: "Methylphenidate was the most frequent drug among children and adolescents with ADHD", researchers reported on "a significant protective effect of the medication" on injury risk. The size of the risk reduction for UPI when medication was used was estimated at about 10%.

Once again, I can't argue with the associations made in terms of how a diagnosis of ADHD does 'up' the risk of physical injury and how medication might be one option out of several to reduce the risk of UPIs in the context of ADHD. Added to other work talking about how medication might also positively affect specific risk of motor vehicle accidents in the context of adult ADHD (see here) for example, it's becoming clearer that intervention helps. I appreciate that there may be some consumer resistance to the idea of 'medicating children' but the data so far on the cost-benefit profile of something like methylphenidate for ADHD is pretty favourable (see here). Certainly, one has to be careful about making too many negative sweeping statements about such medication (see here for example) just for the sake of it.

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[1] Ruiz-Goikoetxea M. et al. Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: a systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews. 2017. Nov 21.

[2] Amiri S. et al. Attention deficit/hyperactivity disorder and risk of injuries: a systematic review and meta-analysis. J Inj Violence Res. 2017 Jun 1;9(2).

[3] Ruiz-Goikoetxea M. et al. Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: protocol for a systematic review and meta-analysis. BMJ Open. 2017 Sep 25;7(9):e018027.

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Methylphenidate as a 'suicide risk reducing agent' in ADHD: implications for other labels?

Don't get me wrong, I'm not falling hook, line and sinker for the findings reported by Sophie Hsin-Yi Liang and colleagues [1] observing that "among ADHD [attention-deficit hyperactivity disorder] youths, reduction of suicide risk was observed in patients prescribed MPH [methylphenidate] for duration 90 days and longer."

I've read too much on how complex something like suicide - ideation, attempts and completion - is to ever believe that there is some single magical answer to universally reducing or eliminating suicidal behaviours and the wide-ranging effects they have. Yes, there are some compounds that have a pretty good evidence base for being an 'anti-suicidal agent' (see here) but even with something like lithium, further investigations are required on their universal applicability and important details like their cost-benefit ratio.

Having said all that, I am drawn to the findings reported by Liang et al for a few very good reasons. First, is the continued reliance on 'big data' Taiwan and the use of the National Health Insurance Research Database (NHIRD) as a research resource. Second, is the continued focus on suicide and possible factors/predictors of suicide based on examination of NHIRD data [2]. Third, is the idea that "rates of suicide ideation, self-injury and suicide attempts are significantly increased in untreated ADHD populations" and how something like MPH use potentially (positively) affecting ADHD symptoms might have other effects. Finally, there is also the tantalising prospect that other conditions/labels where ADHD might be over-represented where also alongside there is a growing focus on suicidal behaviours, the Liang findings might also be relevant...

So what did Liang and colleagues do and find? Well looking at the records of some 85,000 children and young people where ADHD was diagnosed, researchers looked for evidence of recorded suicide attempts as a function of whether MPH was being used or not (where "MPH is the only stimulant approved for the treatment of ADHD in Taiwan"). They found that "100 (0.1%) youths met the criteria for suicide attempts during the surveillance period" and perhaps a little contrary: "37 (0.2%) in the group without any MPH use and 63 (0.1%) in the group with MPH use."

But the devil is in the detail, as authors then factored in a few pertinent, potentially confounding variables (gender, age, other diagnoses, other medication) and length of time of taking MPH (1-90 days, 91-180 days, over 180 days) into models of risk. They concluded that there was actually a 'risk reducing effect' from MPH use following such analyses: "We observed a 59% suicide attempt risk reduction among ADHD youths prescribed between 90 and 180 days and a 72% risk reduction in those prescribed more than 180 days of MPH."

This is not the first time that MPH use for ADHD and suicide risk has been discussed in the peer-reviewed science literature. The paper by Man and colleagues [3] talked about how the incidence of suicide went up before and at the beginning of MPH initiation in their cohort of around 25,000 children and young adults, but importantly risk "returned to baseline levels during continuation of methylphenidate treatment." They account for their findings by suggesting that: "The observed higher risk of suicide attempts before treatment may reflect emerging psychiatric symptoms that trigger medical consultations that result in a decision to begin ADHD treatment." I put this in the context that ADHD does seem to be a risk factor for various other psychiatric diagnoses (see here and see here). Other independent data [4] has also talked about "a potential protective effect of drugs for ADHD on suicidal behaviour, particularly for stimulant drugs." There seems to be a case for MPH as potentially affecting [some] suicide risk in relation to [some] ADHD...

I want to now take you back to the title of this post, and specifically the 'implications for other labels?' bit. How ADHD and specifically, MPH use for ADHD symptoms, might offer some important 'lessons' for conditions where for example ADHD is over-represented as a comorbidity. Of course I speak of autism and autism spectrum disorder (ASD) where it is fast becoming accepted that the risk of receiving a diagnosis of ADHD is pretty significantly heightened (see here). Alongside, quite a lot of attention is also being paid to the issue of suicide risk and autism (see here) and specifically, what factors might predispose to an elevated risk of suicide in cases of autism (see here) (hint: it's probably not all just down to depression or indeed, any one factor in isolation). Adding in the Liang findings to autism is, I think, quite a sensible thing to do. No, it's not about shifting 'blame' for suicidal behaviours from one label to the next, but instead realising that for some people on the autism spectrum, ADHD does present an additional 'feature' and such a feature might very well carry with it some increased risk for suicidal behaviours. The other strand of evidence that is probably relevant to this is the idea that the risk of various psychiatric diagnoses seem also to be elevated alongside a diagnosis of autism. The prospect therefore that MPH used to manage ADHD occurring alongside autism might reduce any risk of suicidal behaviours is something that requires quite a bit more investigation.

And while I'm mentioning MPH in the context of [some] autism, the recent Ccohrane review of MPH for kids and young people diagnosed with autism [5] suggests something quite positive when it comes to issues such as "symptoms of hyperactivity and possibly inattention" (albeit with more research required)...

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[1] Liang SHY. et al. Suicide risk reduction in youths with attention-deficit/hyperactivity disorder prescribed methylphenidate: A Taiwan nationwide population-based cohort study. Research in Developmental Disabilities. 2018; 72: 96-105.

[2] Lin YW. et al. Influential Factors for and Outcomes of Hospitalized Patients with Suicide-Related Behaviors: A National Record Study in Taiwan from 1997-2010. PLoS One. 2016 Feb 22;11(2):e0149559.

[3] Man KKC. et al. Association of Risk of Suicide Attempts With Methylphenidate Treatment. JAMA Psychiatry. 2017 Oct 1;74(10):1048-1055.

[4] Chen Q. et al. Drug treatment for attention-deficit/hyperactivity disorder and suicidal behaviour: register based study. BMJ. 2014 Jun 18;348:g3769.

[5] Sturman N. et al. Methylphenidate for children and adolescents with autism spectrum disorder. Cochrane Database Syst Rev. 2017 Nov 21;11:CD011144.

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Methylphenidate + fatty acids for ADHD? Erm, we need more science...

I don't mind telling you that I was left a bit baffled by the results published by Mahbobeh Firouzkouhi Moghaddam and colleagues [1] (open-access available here) talking about the use of specific polyunsaturated fatty acids (PUFAs) as a sort of add-on to more traditional pharmacotherapy indicated for cases of attention-deficit hyperactivity disorder (ADHD). Baffled because science is supposed to be presented in such a way that methods and results are easy to read and intepret and hence replicate, and appropriate conclusions are supposed to be based on those results. Read on and I hope you'll see what I mean...

Based on the use of a randomised, placebo-controlled trial design, some 40 children (6-12 years of age) who obtained "the least score in an ADHD rating scale questionnaire, responding to the treatment based on least reduction of 25% of symptoms relative to the base state in ADHD scaling" were allocated to either a methylphenidate (MPH) + PUFA ("capsules containing 180mg EPA and 120 mg DHA") group or a MPH + placebo group. Participants were monitored quite regularly over 8 weeks of intervention via the ADHD rating scale adopted and "filled by the resident of psychiatry for patients of both groups." I say all that bearing in mind that I'm not exactly sure what specific ADHD rating scale was actually used during the study.

No mind, the results: "mean severity of symptoms before treatment in both groups of methylphenidate plus PUFA and placebo was the same, and severity of symptoms after treatment in the group under methylphenidate plus PUFA treatment had reduced much more compared to the placebo group, and major changes were observed in the subscale of predominantly attention deficit type." The authors were able to describe the types of symptom patterns presenting by participants in relation to ADHD type. Indeed, quite impressively: "Response to treatment (a reduction of at least 25% in the signs) in the group taking methylphenidate plus PUFA was 90% (18 patients) and in methylphenidate plus placebo group, it was 60% (12 patients)." They did also note side-effects in both groups; the most common in both groups (taking MPH) were sleep disorders and anorexia. For the PUFA group "just one case of burping" was recorded. Researchers concluded that further trials are needed to confirm/refute their findings.

Appreciating that these study results are presented in English but English is perhaps not the mother tongue of researchers, I can get past the slightly odd tone of the article text in places. I do still have an issue with not being able to find out which ADHD scale was used during the study; something that is important if someone wanted to try and independently replicate this study.

More than that, I have to say that I am also a little hesitant when it comes to the way the statistics and findings have been presented in this paper. My first reading of the results was that MPH + PUFA supplementation was superior to MPH + placebo based on the text presented in the article. A more detailed look at the findings revealed that this was not necessarily the case based on (a) looking at the comparisons across the various types of ADHD pre- and post-intervention groups (see Table 1 of the paper) and (b) comparing 'mean severity of symptoms after treatment' between the PUFA and placebo groups (Table 2). You will see that assuming a drop in ADHD scores denotes improvement in behaviour(s), Table 1 suggests that only those with the mixed/combined type of ADHD as a group showed a reduction in scores (9.4±8.39 vs. 0.6±1.20) between pre- and post-intervention with MPH + PUFAs. This was compared with two groups in the MPH + placebo arm of the trial: predominantly attention deficit and mixed type, where a reduction was noted. In all other scenarios, the group values actually increased. Bearing in mind the authors don't actually tell us how many people were included in those ADHD groups, I was a little surprised to see that the p-values remained highly significant for all ADHD types across both study arms. One can only deduce from these findings - those presented in Table 1 - that MPH + PUFA supplementation is at best, as good as MPH + placebo for a specific type of ADHD but at worst, potentially making MPH less effective in other types of ADHD.

Then to the data showing "comparison between the mean severity of symptoms in the intervention and control groups after the treatment" (Table 2). Here again, the picture is one of no real [statistical] difference between MPH alone and MPH + PUFA supplementation after 8 weeks of intervention based on the group scores and the p-values produced. Yes, you could say that MPH + PUFA seems to show some equivalence to MPH + placebo, but then the question 'why take a PUFA supplement?' comes to the surface. And please also, none of that 'almost significant' stuff based on a p-value of 0.18 for example particularly in light of other discussions...

"This study shows that PUFA is an efficient nutrient to treat ADHD and it can be used to treat patients." I'm not so sure that this sentence is completely compatible with the study findings as they are presented; both in the text of the results and the table data. Don't get me wrong, more than most I would love to see fatty acids finding their place with at least some people presenting either with a diagnosis of ADHD or significant features of ADHD (see here and see here for examples) also on the back of some very recent peer-reviewed findings [2]. The trouble is that I don't think these are necessarily the results to show that...

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[1] Moghaddam MF. et al. Effectiveness of methylphenidate and PUFA for the treatment of patients with ADHD: A double-blinded randomized clinical trial. Electron Physician. 2017 May 25;9(5):4412-4418.

[2] Chang JC. et al. Omega-3 Polyunsaturated Fatty Acids in Youths with Attention Deficit Hyperactivity Disorder (ADHD): A Systematic Review and Meta-Analysis of Clinical Trials and Biological Studies. Neuropsychopharmacology. 2017 Jul 25.

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On ADHD medication and motor vehicle crashes

"Among patients with ADHD [attention-deficit hyperactivity disorder], rates of MVCs [motor vehicle crashes] were lower during periods when they received ADHD medication."

That was the research bottom-line discussed by Zheng Chang and colleagues [1] who continue a theme on how managing/treating the symptoms of ADHD can often have some profound effects on those diagnosed with ADHD and also the wider population.

The outcome measure on this occasion was MVCs; in particular: "Emergency department visits for MVCs" as assessed from data from the "Truven Health Analytics MarketScan Commercial Claims and Encounters databases." I've talked about the application of this resource in a research context before on this blog (see here). Such Emergency Room (ER) (also known as Accident & Emergency (A&E) here in Blighty) visits were assessed for those with and without a diagnosis of ADHD or those in receipt of  "ADHD medication between January 1, 2005, and December 31, 2014." Authors compared the "risk of at least one MVC between patients with ADHD and matched controls."

The results, based on quite a large number of people (2 million+) diagnosed with ADHD, suggested that: "Patients with ADHD had a significantly higher risk of an MVC than their matched controls." Medication for ADHD - of which over 80% of the cohort with ADHD were taking - seemed to affect the risk of MVCs as per the sentence introducing this post. Indeed authors noted: "months with ADHD medication were associated with a 12%... lower risk of MVCs in male patients with ADHD relative to unmedicated months and a 14%... lower risk of MVCs in female patients with ADHD." The figures actually got even better for risk reduction of MVCs when analysed at the "within-individual" level: "men with ADHD were 38% less likely to have MVC events during medicated months relative to unmedicated months" and for women, this figure went up to 42% less likely to have an MVC during medicated months. All-in-all, treating ADHD with medication meant less visits to the ER for motor vehicle crashes.

Accepting that the use of medication for ADHD (or anything else) is not something that should ever be entered into lightly, there is quite a large body of evidence emerging suggesting that specific preparations at least, are both safe and reliable in terms of tackling the symptoms of ADHD (see here). Indeed, clinicians are seemingly becoming a lot more comfortable with employing pharmacotherapeutic strategies for ADHD (see here) probably in part, due to the effectiveness of available medications and their pretty good safety profile. I say all that noting that medication is not necessarily the only tool in the arsenal (see here and see here for examples).

Of course there are caveats to this latest set of results; not least that this was a study looking at two variables (MVCs leading to ER attendance and ADHD medication(s)) and so might potentially have missed other data/factors (e.g. MVCs not requiring ER attendance). One also assumes that ADHD medication prescriptions were also being taken uniformly every day as indicated...

Still, there is good reason to think that ADHD medication might be 'doing what it says on the tin' in terms of tackling issues such as inattention and impulsivity and how this had knock-on effects for MVCs requiring hospitalisation. Indeed, thinking also about the safety of other motorists who might have potentially benefited from the behaviour of those drivers with ADHD under medication, one can only see the life-changing potential of these informative results...

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[1] Chang Z. et al. Association Between Medication Use for Attention-Deficit/Hyperactivity Disorder and Risk of Motor Vehicle Crashes. JAMA Psychiatry. 2017. May 10.

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Chang Z, Quinn PD, Hur K, Gibbons RD, Sjolander A, Larsson H, & D'Onofrio BM (2017). Association Between Medication Use for Attention-Deficit/Hyperactivity Disorder and Risk of Motor Vehicle Crashes. JAMA psychiatry PMID: 28492937

Injury risk and ADHD: part 2

Consider this short post a sort of follow-on to a previous entry on this blog concerning the elevated risk of injury following a diagnosis of attention-deficit hyperactivity disorder (ADHD). The paper in question today is that by Wu-Chien Chien and colleagues [1] who yet again [2], brought the quite significant scientific weight of the "National Health Insurance Research Database in Taiwan" to bear on this topic.

In this latest paper, Chien et al relied on data from a 'subset' of the main insurance research database and found some not unexpected things: "The patients with ADHD had a 143% increased risk of overall injuries than the controls after considering all the confounding factors" and "the use of methylphenidate was associated with a 22.6% decrease in the risk of injuries in the patients with ADHD."

What's more to say? Well, yet again risk of adverse issues *correlating* with a diagnosis of ADHD comes to the forefront (see here for another example). Yet again the idea that 'tackling' ADHD is a worthy goal (for many reasons) if not only to mitigate such elevated risks being presented, bearing in mind that medication "approved solely for ADHD treatment" is not some sort of magic bullet [3]. There are also other potentially important intervention options to look at (see here for example). I'm minded at this point to also bring in the recent findings reported by Borschuk and colleagues [4] talking about how comorbid asthma accompanying ADHD (yes, there is a surprisingly strong relationship between the two diagnoses) might play a role in the expression of ADHD and onwards provide some 'interesting' directions when it comes to tackling ADHD and it's elevated risk for various adverse outcomes...

To close, appreciating a talent...

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[1] Chien WC. et al. The risk of injury in adults with attention-deficit hyperactivity disorder: A nationwide, matched-cohort, population-based study in Taiwan. Res Dev Disabil. 2017 Apr 27;65:57-73.

[2] Kang JH. et al. Attention-deficit/hyperactivity disorder increased the risk of injury: a population-based follow-up study. Acta Paediatr. 2013 Jun;102(6):640-3.

[3] Fleming M. et al. Educational and Health Outcomes of Children Treated for Attention-Deficit/Hyperactivity Disorder. JAMA Pediatr. 2017. May 1.

[4] Borschuk AP. et al. The influence of comorbid asthma on the severity of symptoms in children with attention-deficit hyperactivity disorder. J Asthma. 2017 May 1:1-7.

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Chien WC, Chung CH, Lin FH, Yeh CB, Huang SY, Lu RB, Chang HA, Kao YC, Chiang WS, Chou YC, Tsao CH, Wu YF, & Tzeng NS (2017). The risk of injury in adults with attention-deficit hyperactivity disorder: A nationwide, matched-cohort, population-based study in Taiwan. Research in developmental disabilities, 65, 57-73 PMID: 28458048

Trends in ADHD medication use in the US and Europe: is this a bad thing?

I don't want to dwell too much on the findings reported by Christian Bachmann and colleagues [1] observing that in five Western countries - Denmark, Germany, the Netherlands, the United Kingdom (UK) and the United States (US) - ADHD (attention-deficit hyperactivity disorder) medication use between 2005/2006-2012 was on the increase. But I do think it is important to mention some of the implications from such figures and some of the positives and negatives associated with such generated data.

OK, first things first. The general consensus is that the prevalence of ADHD in many parts of the world is on the up compared with say a decade or two ago. We can um-and-ah about whether this is a true increase in cases or whether through changes to the way ADHD is diagnosed for example, the figures are artificially inflated (see here). Indeed, whether for some - not by any means all - a diagnosis of ADHD is merely a means to an end (see here). Suffice to say that many studies either looking directly at rates of ADHD or via analysis of medication prescribing patterns suggest that more cases are being diagnosed these days. And that includes the use of ADHD as a comorbid diagnosis in relation to labels such as autism for example (see here) on the back of the important discussions about autism not typically presenting in some sort of diagnostic vacuum (see here).

The use of medication prescribing patterns to track estimated ADHD prevalence is the preferred method employed by Bachmann et al who concluded that: "ADHD medication use prevalence increased from 1.8% to 3.9% in the Netherlands cohort (relative increase: +111.9%), from 3.3% to 3.7% in the US cohort (+10.7%), from 1.3% to 2.2% in the German cohort (+62.4%), from 0.4% to 1.5% in the Danish cohort (+302.7%), and from 0.3% to 0.5% in the UK cohort (+56.6%)."

So, the positives from the Bachmann data. Well, accepting that ADHD is a label that, in the longer term, has been associated with heightened risk for all-manner of adverse life events (see here and see here for examples) I don't think anyone would argue that with the availability of good, safe, reliable treatment options (see here) and that such management avenues should be properly utilised. I know some people might be a little reluctant to want to medicate children for example, but the data from the various collected studies on something like methylphenidate use (typically indicated for ADHD or the presentation of ADHD-type behaviours) generally regards the medicine as safe and well tolerated albeit with monitoring and good medicines management implied. And by saying that I'm not suggesting that medication is/should be the only management option when it comes to ADHD (see here and see here for other examples). My reading of the Bachmann data is that prescribing clinicians are doling out more prescriptions for managing ADHD but this is a reflection of (a) greater recognition of ADHD and ADHD behaviours and/or (b) the value of prescribing such medicines to things like quality of life of recipients and their families.

The negatives... well, it wouldn't be difficult to suggest that with the realisation that quite a few ADHD medications have a good overall safety/response profile, clinicians perhaps become a little more 'comfortable' with their prescription over a wider range of presenting behaviours without necessarily looking at other options first. The fact for example, that Bachmann et al observed: "ADHD medication use was highest in 10-14-year olds", a special time when quite a few biological changes are on-going, could be interpreted as such medication use being a pharmacological 'crutch' during such a period. I don't know enough about ADHD to comment on whether its presentation is 'enhanced' as and when puberty hits but if it's anything like other labels [2]...

Reiterating that medication is not the only intervention option when it comes to ADHD and that one still needs to be cautious about the use of psychoactive substances typically being part of ADHD pharmacotherapy, I am airing on the more positive implications of the Bachmann findings rather than the negatives. Like many other discussions about medication use under various different circumstances (see here for example) it's easy to say that such medicines use is growing because of inappropriate or over-zealous use and should be curbed. But such medications often afford a real increase in quality of life when it comes to ADHD and, bearing in mind those enhanced risks typically associated with the label of ADHD, I can't in all honesty say that greater medication use is specifically detrimental to individuals personally or in a wider context...

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[1] Bachmann CJ. et al. Trends in ADHD medication use in children and adolescents in five western countries, 2005-2012. Eur Neuropsychopharmacol. 2017 Mar 20. pii: S0924-977X(17)30184-0.

[2] Gillberg C. & Schaumann H. Infantile autism and puberty. J Autism Dev Disord. 1981 Dec;11(4):365-71.

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Bachmann CJ, Wijlaars LP, Kalverdijk LJ, Burcu M, Glaeske G, Schuiling-Veninga CC, Hoffmann F, Aagaard L, & Zito JM (2017). Trends in ADHD medication use in children and adolescents in five western countries, 2005-2012. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology PMID: 28336088

Relative age and ADHD medication

"Youngest children in class 'more likely to be given ADHD drugs'" went the NHS Choices headline that led me to the short report produced by Martin Whitely and colleagues [1] (open-access).

ADHD - attention-deficit hyperactivity disorder - is something of interest to this blog; not least the idea that relative age (age relative to peers in the same school year group) might be an important variable when it comes to at least some diagnoses of the condition (see here).

The Whitely paper draws on data from a research favourite place - Western Australia (WA) - and focused on "the proportions of WA children born in the early and late months of a recommended school-year intake who received at least one Pharmaceutical Benefits Scheme [PBS] prescription for an ADHD medication in 2013."

The results: from a starting population of some 300,000 children, about 6,000 of them (~2%) were in receipt of a state-recognised prescription of an ADHD medication. The article does not actually mention which ADHD medication was given but methylphenidate (a.k.a Ritalin) is listed in the PBS directory and is the typically indicated medication used for ADHD (see here). Boys, we are told, were more likely to be prescribed ADHD medication than girls (2.9% vs. 0.8% respectively).

Then to the headline: when splitting the children into two age groups - 6-10 year olds and 11-15 year olds - researchers noted that those born in June (the last birth month influencing year of school intake) were more likely to be prescribed ADHD medication than those born in July. This trend was noted in both age groups. The conclusion being that the youngest children in a year group at school were more likely to be in receipt of prescribed medication for ADHD compared to older children in the year group.

Alongside the caveats linked to the Whitely report made by NHS Choices, there is a need for further investigation in this area and in particular, whether the results generalise to places outside of just WA. I've already linked to my previous discussion about relative age and ADHD diagnosis/medication (see here again) and from comparisons with the Taiwanese data [2] on this topic, including the fact that Taiwan have a different cut-off month for school entry (August 31). On that basis, yes the trend appears to generalise across geographies...

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[1] Whitely M. et al. Influence of birth month on the probability of Western Australian children being treated for ADHD. MJA. 2017; 206: Feb 6.

[2] Chen MH. et al. Influence of Relative Age on Diagnosis and Treatment of Attention-Deficit Hyperactivity Disorder in Taiwanese Children. J Pediatr. 2016 May;172:162-167.e1.

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Martin Whitely, Leanne Lester, John Phillimore, & Suzanne Robinson (2017). Influence of birth month on the probability of Western Australian children being treated for ADHD The Medical Journal of Australia

ADHD symptoms and chronic fatigue syndrome?

With the pinnacle of the season of 'jolly' almost upon us, I'd like to make some brief discussion on the findings reported by Denise Rogers and colleagues [1] and specifically the observation that: "ADHD [attention-deficit hyperactivity disorder] symptoms were significantly greater in the CFS [chronic fatigue syndrome] group than in HC [healthy controls]."

With the aim of examining both the prevalence of fatigue in cases of ADHD and the prevalence of ADHD symptoms in adults with CFS (a term 'linked to' the condition called myalgic encephalomyelitis), researchers set about investigating several measures including self-reported (that's 'self-reported') fatigue "across groups of adults with ADHD (N = 243), CFS (N = 86), and healthy controls (HC) (N = 211)." The results were interesting insofar as that previous sentence on ADHD symptoms perhaps not being uncommon in cases of CFS vs. asymptomatic controls but also that: "Fatigue is a common clinical feature of attention deficit hyperactivity disorder (ADHD) in adulthood."

Accepting that there may be important implications from the notion that fatigue may be part and parcel of at least some ADHD (see here for example), the idea that ADHD signs and symptoms might be over-represented in cases of CFS is interesting, if not necessarily novel [2]. Minus any sweeping generalisations or psychobabble explanations of hows-and-whys (we've had quite enough of those in relation to CFS), I'd like to think that such an association could shed some light on the possible shared genetics, epigenetics and biochemistry of both conditions. Given also some initial data emerging on the potential usefulness of something like methylphenidate (indicated for cases of ADHD) for cases of CFS (see here) there are also avenues to explore in relation to shared drug targets across both conditions (see here for some discussion on oxidative stress for example). I'd like to see more study on this topic, bearing in mind how broad labels like CFS and ADHD can be. I'm also wondering whether researchers might also one day replace examination of ADHD traits with autistic traits so as to perhaps provide data on whether there may be other important associations to be had...

And with that I wish you all a very Merry Christmas and a happy and healthy New Year. I'm not done just yet with this years blogging adventures as my annual 'what was hot in autism research in 2016' post is scheduled sometime next week (if you're interested/bored of turkey/bored of watching Christmas films - delete as appropriate).

Music to close and as always at this time of year, it wouldn't be the same without Kirsty and Shane. And please, do try to stay out of the drunk tank this Christmas...

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[1] Rogers DC. et al. Fatigue in an adult attention deficit hyperactivity disorder population: A trans-diagnostic approach. Br J Clin Psychol. 2016 Dec 5.

[2] Sáez-Francàs N. et al. Attention-deficit hyperactivity disorder in chronic fatigue syndrome patients. Psychiatry Res. 2012 Dec 30;200(2-3):748-53.

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Rogers, D., Dittner, A., Rimes, K., & Chalder, T. (2016). Fatigue in an adult attention deficit hyperactivity disorder population: A trans-diagnostic approach British Journal of Clinical Psychology DOI: 10.1111/bjc.12119

ADHD symptoms not methylphenidate treatment might prime for psychotic events

"This study does not support the hypothesis that MPH [methylphenidate] increases risk of incident psychotic events. It does indicate an increased risk of psychotic events before the first prescription of MPH, which may be because of an association between psychotic events and the behavioural and attentional symptoms that led to psychiatric assessment and initiation of MPH treatment."

The results published by Man and colleagues [1] (open-access) sit right with me. I say that on the basis that previous research suggesting that attention-deficit hyperactivity disorder (ADHD) may 'prime' someone for an elevated risk of developing psychosis (see here) has potentially received some welcome substantiation. That MPH might not be the bogeyman that some people might think (see here too) is also an important part of the Man findings (minus any charges of me providing medical or clinical advice on this blog... I'm not).

The Man paper is open-access but a few choice details are worthwhile mentioning:

• Based on data from the "Clinical Data Analysis and Reporting System (CDARS)" an initiative based in Hong Kong, researchers set about identifying those "aged 6–19 years who received at least one prescription of MPH with at least one psychotic disorder and/or hallucination diagnostic code (psychotic events) during the study period (January 2001 to December 2014)." Given that only MPH and atomoxetine are seemingly licensed in the Hong Kong for "the treatment of ADHD", the authors were able to focus specifically on MPH quite easily.
• Although over 20,000 patients were in receipt of MPH prescriptions, only data for 103 participants were used in the study as a result of that diagnosis of a psychotic/hallucinatory condition. Most were male and 76 out of the 103 participants had "a clinical ADHD diagnosis."
• Researchers looked at MPH treatment and those psychotic/hallucinatory events taking into the account timing and including "a 90-day pre-exposure period" representing a period before MPH use (see here).
• Results: "The primary analysis indicated no statistically significant association between MPH treatment and occurrence of incident psychotic events." But, when compared with baseline data, there did seem to be something to see during that pre-exposure period (before MPH) and incident psychotic event(s). Ergo, something other than MPH use seemed to be linked to the experience of psychosis and we therefore head back to the idea that ADHD as one reason for MPH use might have some quite profound implications for future mental health.

There is still quite a bit more to do in this area as per more longitudinal research with greater participant numbers. I might also draw your attention to Table 2 of the Man paper (see here) examining other 'psychiatric comorbidities' when it came to those participants experiencing a psychotic episode. The list of potential correlates is interesting in light of other work (see here).

Whilst MPH comes out of such research with more than a whiff of roses, it is perhaps important to understand that medicines, all medicines come with potential side-effects and that includes MPH. Nevertheless, the idea that the benefits of controlled use of MPH might trump the risk of serious psychiatric side-effects such as psychosis is something that needs to be said and with it, a realisation that treating/managing the signs and symptoms of ADHD early, might have more profound repercussions for those diagnosed...

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[1] Man KKC. et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Translational Psychiatry. 2016; 6: e956.

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Man, K., Coghill, D., Chan, E., Lau, W., Hollis, C., Liddle, E., Banaschewski, T., McCarthy, S., Neubert, A., Sayal, K., Ip, P., & Wong, I. (2016). Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system Translational Psychiatry, 6 (11) DOI: 10.1038/tp.2016.216