Childhood ADHD and vitamin D meta-analysed

The results of the systematic review and meta-analysis published by Yadollah Khoshbakht and colleagues [1] (open-access available here) make for interesting, if not totally unexpected, reading.

Covering the existing peer-reviewed research literature (up to June 2017) on the topic of vitamin D status and attention-deficit hyperactivity disorder (ADHD), researchers concluded that: "The present review provides evidence supporting the relation between vitamin D deficiency and ADHD."

Vitamin D and ADHD is a topic already covered on this blog (see here). The general direction of findings so far have kinda mirrored that seen in other developmental diagnoses such as autism, insofar as vitamin D deficiency / insufficiency as measured by concentrations of 25-hydroxyvitamin D, tending to be pretty over-represented alongside the label (see here). It's perhaps also pertinent to mention that the diagnostic combination of autism and ADHD seems to be quite widespread (see here); particularly in these days of ESSENCE or autism plus (see here). This could very well have a bearing on any observations obtained as per other examples in other areas (see here).

Anyhow...

Khoshbakht et al looked at various studies and aspects of studies as part of their analyses. They also pre-registered their intention to undertake some research on vitamin D and ADHD as per a PROSPERO entry (see here) containing some details on hows-and-whys.

From various 'retrieved articles' numbering in the thousands, authors eventually settled on 13 studies ("9 case-control or cross-sectional studies and 4 prospective studies") that examined "the association between vitamin D concentration and the risk of ADHD." The final cumulative study participant number was not bad at all: "3484 patients with ADHD (2183 from the case-control and cross-sectional studies, 1301 from the prospective studies) and 11,837 healthy children (8151 from the case-control and cross-sectional studies, 3686 from the prospective studies) aged between 5 and 18 y were included." Authors also noted that various methods were used to measure 25-hydroxyvitamin D - 25(OH)D - ranging from the gold-standard that is liquid chromatography tandem mass spectrometry (LC-MS/MS) to something perhaps a little less accurate e.g. high-performance liquid chromatography (HPLC) minus the mass spec bit. All-in-all however, most studies were judged to be of moderate or high quality.

Results: "we found modest but significant lower serum vitamin D concentrations in children and adolescents with ADHD compared with healthy control subjects." Based on 9 studies where "the mean ± SD vitamin D concentrations in subjects with and without ADHD" was reported, authors concluded that "children with ADHD had 6.93 ng/mL lower serum vitamin D concentrations compared with healthy controls." And that wasn't all, as authors also looked at prospective studies where for example, vitamin D was measured in maternal serum or umbilical cord blood and then mapped onto risk of ADHD in offspring. With this type of study in mind, they observed that: "lower maternal or cord serum vitamin D concentrations increase the risk of developing ADHD in childhood or adolescence by 40%" albeit with some statistical caveats.

Khoshbakht and colleagues provide some possible pointers about how vitamin D *might* influence the pathophysiology of ADHD. They for example, mention an enzyme that I've been pretty interested in down the years - tryptophan hydroxylase 2 (TPH2) - and how the starting gene for this enzyme has been both linked to ADHD [2] in some studies (but not others). Further: "The TPH2 gene is activated by vitamin D hormone through its vitamin D response element." Personally, I find this interesting but not intellectually satisfying enough to provide an authoritative explanation for any effects of vitamin D deficiency on ADHD. Going also back to the vitamin D story with autism in mind, I'd like to think lessons could be learned about more particular vitamin D genetics (see here) and what role they might also play with regards to ADHD too. There are no doubt other pertinent mechanisms too.

There is still more research to do when it comes to vitamin D and ADHD of that there is no doubt. Again, going back to the relationship between ADHD and autism, I'm wondering whether more focus needs to be on this diagnostic combination (and perhaps other overlaps too) to ascertain whether one condition / label over another shows any stronger relationship with vitamin D levels. In light also of other meta-analysis work talking about lower vitamin D levels being linked to 'poorer cognition' (see here) for example, one might also reasonably suggest that an even broader research agenda might need to be followed.

And then there's the question of supplementation (see here) to consider and whether it may / may not do more than just raise vitamin D levels [3]? Oh wait, and there's more [4]...

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[1] Khoshbakht Y. et al. Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies. Adv Nutr. 2018 Jan 1;9(1):9-20.

[2] Park TW. et al. Association between TPH2 gene polymorphisms and attention deficit hyperactivity disorder in Korean children. Genet Test Mol Biomarkers. 2013 Apr;17(4):301-6.

[3] Elshorbagy HH. et al. The Impact of Vitamin D Supplementation on Attention-Deficit Hyperactivity Disorder in Children. Ann Pharmacother. 2018 Feb 1:1060028018759471.

[4] Sahin N. et al. Vitamin D and vitamin D receptor levels in children with attention-deficit/hyperactivity disorder. Neuropsychiatr Dis Treat. 2018 Feb 19;14:581-585.

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The hyposerotonemic mouse and autism

Dear readers, please don't be put of this post by the title. All it refers to is a mouse described by Kane and colleagues* (open-access) which was engineered with a null mutation in the TPH2 gene governing the production of tryptophan hydroxylase, a required step in the synthesis of the aromatic amino acid tryptophan to everyone's favourite neurotransmitter, serotonin (or as we Brits like to call it 5-HT). Said mouse was unable to produce serotonin and hence lacked it - hyposerotonemia - despite having all the necessary receptors et al.

Meeces to pieces... @ Wikipedia  

Kane and colleagues set about looking at mice "derived from matings of heterozygous (TPH2+/−) males and heterozygous (TPH2+/−) females on a mixed C57BL/6-Sv129 background".

This selective breeding produced offspring who were homozygous for the null mutation, basically carrying the null mutation on both chromosome pairs (TPH2-/-). They then set about testing the TPH2-/- mice on various measures across various ages corresponding to human years (infancy, juvenile, adulthood) and compared results with wild-type pups who were not serotonin deficient.

Their findings? Well, the TPH2-/- mice presented with some interesting developmental features. A delay in hitting certain developmental milestones, transient early brain overgrowth normalising into the equivalent teen years and adulthood, among other things.

When put to various tasks equivalent to looking at some of the core and peripheral features associated with human autism spectrum disorders - a kind of mouse ADOS if you will - the TPH2-/- mice showed some significant differences in their behaviours compared with wild-type mice. So less preference for mother mouse's scent interpreted as the "early signs of a social communication deficit", alongside other socialisation issues and lots of repetitive, compulsive behaviours persisting into mouse adulthood. I'm not going to get to heavily into each individual finding because it's all there in the full-text paper.

The authors conclude: "these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism" and certainly I am not going to disagree with them. Yes, you could again use the argument that this was a mouse and not a human being, and the fact us humans are very, very, very complicated creatures by comparison. You could also argue that quite a few of the behaviours described by Kane and colleagues are also associated with other behavioural and psychiatrically-defined conditions and need not be just necessarily construed as autism; depression for example, bearing in mind the timing of presentation. It's a complicated picture of inference and 'ifs and buts' not helped by the mixed bag of research on serotonin and autism.

I remain however interested in these findings and indeed in the whole area of mouse models and autism given previous discussions on the BTBR dangermouse and also how mouse models might be able to translate autism hypotheses into viable murine-based findings. Er, should I mention sulphation and leaky gut here too, or is that old news now? Bearing in mind that those TPH2-/- mice might also carry other mutations and indeed epigenetic differences too, I'll be keeping an eye on the hyposerotonemic mouse research and just how useful it might be to autism research.

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* Kane MJ. et al. Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PLoS ONE. 2012; 7: e48975.

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Kane MJ, Angoa-Peréz M, Briggs DI, Sykes CE, Francescutti DM, Rosenberg DR, & Kuhn DM (2012). Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PloS one, 7 (11) PMID: 23139830

What's with 5-hydroxytryptophan (5-HTP)?

I might have said it before so please do excuse the repetition, but the aromatic amino acid tryptophan has been of some interest to me down the years. Like most people who have heard or know about tryptophan, the connection with serotonin (5-hydroxytryptamine or 5-HT) seems to be the big attraction when it comes to this very important amino acid and its pretty important effects on biology and daily life.

Putting serotonin slightly to one side for this post, I instead want to talk about another player along the tryptophan - serotonin pathway, 5-hydroxytryptophan (5-HTP) and various lines of study to this important intermediary compound in what is admittedly, a slightly disjointed post.

I was brought to this post by two factors:

• An interesting comment in a LinkedIn discussion about how issues with the production of melatonin observed in some cases of autism might tie into other findings in autism in relation to issues with tetrahydrobiopterin (BH4) for example. Without trying to make connections where there may not be any, it got me thinking about the whole tryptophan - serotonin - melatonin pathway in a little more detail.
• A curious paper which I stumbled upon a while back by Emanuele and colleagues* suggesting that the symptoms of romantic stress defined as "... a recent romantic break-up or reported recent romantic problems" might benefit from a brief dose of 5-HTP both behaviourally and biologically. Curious I know, and not necessarily relevant to this blog; but nevertheless it brought me back to 5-HTP.

Before your eyes start to glaze over and you reach for the 'click away' button, it is probably best if I start at the beginning and briefly show you how things usually go with regards to tryptophan, serotonin and melatonin. So in my very best handwriting (yes, you can perhaps see why I didn't ace certain school exams) and with no expense spared... see figure 1.

Figure 1: Bless you tryptophan.

In short:


L-Tryptophan is converted to 5-HTP via the enzyme tryptophan hydroxylase, TPH which relies on the cofactors of iron and BH4 for optimal functioning. Keep this cofactor thing in mind.

5-HTP is then converted to serotonin (5-HT) and onwards to various other compounds including 5-hydroxyindoleaceticacid (5-HIAA).

The conversion of 5-HT to melatonin is via the intermediate compound, N-Acetlyserotonin (NAS).

Just before anyone mentions, I have only included the TPH enzyme in my schematic and not the other enzymes involved in the various other reactions so as to keep it simple.

Hopefully you can see from my scribbles the central role tryptophan plays in this important metabolic process and how little issues with components in the pathway can potentially have knock-on effects for downstream metabolites.

So to the title of this post: "What's with 5-hydroxytryptophan?". Well, potentially quite a bit.

The first time I heard about 5-HTP was with reference to the collected data on the potential therapeutic use of the compound in cases of depression as per the Cochrane Review by Shaw and colleagues** (full-text). As per nearly every Cochrane Review I've ever read, the text reads something like, a few trials showing possible effects from [5-HTP] supplementation on depressive symptoms but not enough rigorous study to be able to form a suitable opinion. Don't believe me... well, see the Cochrane Review for GFCF diets for autism (here). Anyway, mention also of the fact that antidepressants already exist to 'treat' depression probably accounts for the drop in research interest in this area in recent years. That and possibly 'peak X' (see here for more details).

Where next?

Sleeping aid. Looking again at the magnificent figure offered to accompany this post, one could perhaps see how sleep could be affected by 5-HTP purely based on melatonin featuring some way down the pathway. The evidence.. well let's just say it needs improving despite some initial attempts (here and here). Additional evidence on any direct effect from 5-HTP administration on melatonin levels is even more scant.

Fibromyalgia. Heading into some pretty interesting territory here with again a dearth of recent investigations on this topic. Caruso and colleagues*** reported some interesting results from a double-blind, placebo-controlled trial of 5-HTP in fibromyalgia (FM) suggestive of positive effects to be had. Other, less controlled trials, also seemed to indicate some improvements in FM symptoms although with side-effects reported. Other than that, reviews and sprinklings of speculation.

Finally autism. Not much more to say aside from the very limited research on 5-HTP supplementation does not (so far) support any resounding changes to presented symptoms as per the paper by Sverd and colleagues****. Evidence has been presented to suggested that 5-HTP administration seemed to do a very good job at raising blood serotonin concentrations in males with autism (here). Whether this finding is (a) transferable to the majority and (b) might relate to issues with the availability of tryptophan as a starting material (in plasma and urine) or indeed the function of TPH (cofactor availability?) are still matters of speculation.

The Red Hot Chili Peppers @ Paul Whiteley

I'm just about done with 5-HTP for now. As per previous posts, the main caveat is that no medical advice or endorsement of anything is given or intended. Hopefully knowing a little bit more about 5-HTP after this post and how we should perhaps not be closing the research door on it just yet, would you be interested to learn that the gut microbiota might very well have an important effect on the serotonergic system*****? Accepting that bacteria and 'the microbiome' is a research area on the rise, one wonders whether 5-HTP might also have a hand in this process.

To finish, the Red Hot Chili Peppers rocked the SoL yesterday evening and so here is one of their finest... Higher Ground. And to the woman sat behind me who told me to sit down... it's a rock concert.

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* Emanuele E. et al. An open-label trial of L-5-hydroxytryptophan in subjects with romantic stress.
Neuro Endocrinol Lett. 2010; 31: 663-666.

** Shaw KA. et al. Tryptophan and 5-Hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002: CD003198

*** Caruso I. et al. Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. The Journal of International Medical Research. 1990; 18: 201-209.

**** Sverd J. et al. Effects of L-5-hydroxytryptophan in autistic children. J Autism Child Schizophr. 1978;8: 171-180.

***** Clarke G. et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manne. Molecular Psychiatry. June 2012.
DOI: 10.1038/mp.2012.77