Add-on nutraceuticals for depression?

It came as no surprise to me that the systematic review and meta-analysis article by Jerome Sarris and colleagues [1] found what it did in relation to the use of [certain] adjunctive (add-on) nutraceuticals alongside antidepressants to reduce depressive symptoms: some of them might actually be clinically useful.

With no medical or clinical advice given or intended, the authors report that "adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants" might be something to consider "for improving inadequate response to antidepressants." Dr Sarris was one among many authors who contributed to the 'personal view' paper titled: 'Nutritional medicine as mainstream in psychiatry' [2] which was also covered a while back on this blog (see here). This latest addition to that and other opinions [3] which covered the peer-reviewed literature on a variety of nutrients also found something of a mixed bag of results for various other compounds including the aromatic amino acid tryptophan, zinc, folic acid and vitamin C.

Quite a bit more science needs to be done in this area, not least around the hows and whys that the various preparations might exert some effect. Vitamin D has of course been covered quite a bit on this blog in relation to something like depression (see here for example) so that particular nutraceutical might already have a research head start compared to others. I'm also minded to suggest that the involvement of something like SAMe (S-adenosylmethionine) as an add-on treatment might also imply a role for epigenetic variables in relation to at least some depression [4]. And then there is the question of who might be best responders to such nutraceutical use which implies heterogeneity and possible plural depressions...

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[1] Sarris J. et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. American Journal of Psychiatry. 2016. April 26.

[2] Sarris J. et al. Nutritional medicine as mainstream in psychiatry. Lancet Psychiatry. 2015 Mar;2(3):271-4.

[3] Sarris J. et al. International Society for Nutritional Psychiatry Research consensus position statement: nutritional medicine in modern psychiatry. World Psychiatry. 2015 Oct;14(3):370-1.

[4] McGowan PO. & Kato T. Epigenetics in mood disorders. Environ Health Prev Med. 2008 Jan;13(1):16-24.

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Sarris J, Murphy J, Mischoulon D, Papakostas GI, Fava M, Berk M, & Ng CH (2016). Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. The American journal of psychiatry PMID: 27113121

Decreased brain levels of vitamin B12 in autism

I have to thank Dr Malav Trivedi for bringing my attention to some recent findings reported by Yiting Zhang and colleagues (including Malav) [1] (open-access) suggesting that: "levels of vitamin B12, especially its MeCbl [methylcobalamin] form, decrease with age in frontal cortex of control human subjects."

Further, researchers reported: "abnormally lower total Cbl [cobalamin] and MeCbl levels in subjects with autism and schizophrenia, as compared to age-matched controls." Some media on the findings can also be read here.

Working from the lab of Dr Richard Deth (quite a familiar name to this blog), researchers initially analysed a most precious sample medium (postmortem brain samples) obtained from various biobanks and including various patient groups. So alongside samples from 12 children with autism were samples from 9 people diagnosed with schizophrenia and some 43 'controls' with ages ranging between 19 weeks old and 80 years old. "Changes in Cbl species were compared with the status of methylation and antioxidant pathway metabolites" accompanied by data derived from a knock-out mouse model: "the influence of decreased GSH [glutathione] production on brain Cbl levels was evaluated in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice in which GSH synthesis was impaired, leading to a brain GSH level decrease of 60–70%."

Looking at postmortem frontal cortex brain samples, researchers reported that finding on levels of vitamin B12 - particularly the MeCbl vitamer -  decreasing with age. Bearing in mind the relatively small participant numbers included, the idea that lower brain tissue levels of total cobalamin and methylcobalamin were also present (almost unanimously) in the autism and schizophrenia groups could be important. I might at this point direct readers to previous discussions on vitamin B12 and autism on this blog (see here) including the research idea of supplementing (see here) with no medical advice given or intended.

There are a few other details worth pointing out from the Zhang findings. Analysis of thiols in brain samples across the autism vs control group revealed some potentially interesting data. So, methionine levels were quite a bit lower in the autism group [significantly lower] as were levels of "the methyl donor S-adenosylmethionine (SAM)." Both these compounds form an important part of the whole 'methylation of DNA' process (see here) among other things.

Glutathione, a compound that has seen its fair share of speculation with autism in mind (see here), was also on the research menu in the Zhang study. Interestingly and again bearing mind the small participant numbers, brain levels of this stuff were lower in the autism group as a whole but not significantly so when compared to controls. This finding might map on to other brain studies with autism in mind (see here). Likewise, cysteine (another potentially relevant compound to some autism) produced a similar finding.

I would encourage readers to take some time looking at the Zhang paper. In conjunction with other results reporting on some important elements to the emerging story (see here) I believe there are further studies to be done applicable to the notion that: "impaired methylation may be a critical pathological component" for at least some autism (see here). Indeed, other research papers have also discussed this issue [2]. The idea that studies about human ageing may likewise be informative to autism (and schizophrenia) research also carries quite a lot of traction too.

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[1] Zhang Y. et al. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PLoS One. 2016 Jan 22;11(1):e0146797.

[2] Keil KP. & Lein PJ. DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? Environmental Epigenetics. 2016; 1-15.

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Zhang Y, Hodgson NW, Trivedi MS, Abdolmaleky HM, Fournier M, Cuenod M, Do KQ, & Deth RC (2016). Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PloS one, 11 (1) PMID: 26799654

The big H and schizophrenia

Frankly I am more than a little interested in all-things homocysteine when it comes to behaviour and psychiatry. Perhaps more readily finding discussion and argument with regards to more physical health complaints as per the literature on homocysteine and cardiovascular disease risk*, the 'big H' ties into quite a lot of other interesting areas such as folic acid and the link with another important amino acid, methionine and all that methylation mumbo-jumbo.

Islands in the CpG stream @ Wikipedia 

With autism in mind, the various investigations looking at homocysteine have been pretty much all one direction: elevated levels detected in various biological fluids** (open-access). I hate to make generalisations about the autisms, but homocysteine does appear to be something in need of more detailed consideration as per another potential elephant in the room.

Today however my interest turns to a paper by Makoto Kinoshita and colleagues*** (open-access version here) who report that their cohort of participants with schizophrenia (n=42) not only presented with significantly elevated levels of plasma total homocysteine but also that this homocysteine load might also affect DNA methylation.

OK, a recap. Homocysteine and methionine take part in a merry dance together which crosses one-carbon metabolism (folic acid) and should eventually result in methionine being converted to SAM which then donates a methyl group for the process of DNA methylation. I've kinda covered this process on a previous post with autism in mind complete with hand drawn diagram by yours truly.

Kinoshita et al used some nifty technology (quantitative high-resolution DNA methylation array) to look at the methylation status of CpG islands (see here) located across whole gene regions based on the analysis of peripheral leukocytes. They concluded that alongside those elevations in homocysteine "plasma total homocysteine might affect DNA methylation across whole gene regions" and when talking about genes which have been linked to schizophrenia, one might be minded to look at methylation outside of more structural changes to the genome.

Outside of what I've already discussed about the big 'H' and methylation, there is another potentially important implication from all this talk about epigenetics and schizophrenia: intervention. I'm taken back for example to some interesting work about folic acid and SNPs in schizophrenia which was discussed on this blog (see here). The question being whether any intervention strategy designed to bring the homocysteine-methionine relationship back into planetary alignment would impact on gene methylation and then on presented symptoms? (Bearing in mind my caveat about not giving medical advice on this blog).

To finish, I can't talk about (CpG) islands without linking to an interpretation of a famous song about islands.... (what's occurring?)

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* Wald DS. et al. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002 Nov 23;325(7374):1202.

** Kałużna-Czaplińska J. et al. A focus on homocysteine in autism. Acta Biochim Pol. 2013 Jun 6.

*** Kinoshita M. et al. Plasma total homocysteine is associated with DNA methylation in patients with schizophrenia. Epigenetics. 2013 Apr 26;8(6).

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Kinoshita M, Numata S, Tajima A, Shimodera S, Imoto I, & Ohmori T (2013). Plasma total homocysteine is associated with DNA methylation in patients with schizophrenia. Epigenetics : official journal of the DNA Methylation Society, 8 (6) PMID: 23774737

Methionine synthase and autism

The paper by Christina Muratore and colleagues* (open-access) including Dick Deth and Antonio Persico in the authorship line-up, is the source of today's post. Concerned with quite an important enzyme, methionine synthase (MS), and in particular MS mRNA status in post-mortem frontal cortex samples, the authors report lower levels of MS mRNA in cases of autism. I should add that quite a good overview of this paper can also be found here.

Recycle @ Wikipedia  

OK, let's start from the beginning here. Methionine synthase (MS) is an important enzyme concerned with the regeneration of methionine from homocysteine.

Homocysteine or the 'big H' has been mentioned on more than one occasion on this blog with autism in mind (see here and quite recently here). Indeed, the relationship between methionine and homocysteine intersects a number of other important cycles including those related to folate metabolism and the important methyl-giving properties of SAMe (see this post to see what I'm talking about) and further down the line, that all-important glutathione link (see this post). Oh and it's vitamin B12 dependent.

Anyhow...

• In this study, levels of messenger RNA (mRNA) - an important part of the translation of DNA to proteins - for MS were studied in post-mortem brain samples from deceased person who were diagnosed with autism (n=10) and control, not-autism persons (n=41). Ages at death ranged from 4-30 years for the autism group and 28 weeks - 83 years for the control group.
• Based on the application of qRT-PCR, MS mRNA status across the lifespan of samples included suggested a "striking age-dependent decrease in mRNA levels". In other words, the older the person at time of their death, the less MS mRNA levels were detected in the frontal cortex samples. That being said, they didn't observe corresponding alterations to the level of MS protein despite this age-related change. 
• With the autism group specifically in mind and depending on the primers used to detect specific domains of MS, mRNA levels were reduced compared to controls. The caveat being that again, levels of MS protein were not different when comparing autism vs. controls. That and the suggestion of a lack of an age-dependent decrease in MS mRNA in autism compared to that observed across control samples. 
• Oh and the fact that addition of the pro-inflammatory cytokine TNF-α also seemed to affect levels of MS mRNA.
• There were also some additional findings reported which warrant further attention. So when looking at some of the main players related to that methionine cycle (including methionine, homocysteine, glutathione, etc) in frontal cortex samples (via HPLC) in autism (n=10) and control (n=8) samples, only two parameters came up different: lower, yes lower, homocysteine levels in the autism group alongside lower cystathione levels. Immediately I'm taken back to the recent paper by Jill James discussed quite recently (see here) and their cautions on the use of peripheral markers to denote what might be happening in the brain, albeit with the caveat that the Muratone group was quite a small group.

There are some other details included in this paper regarding "alternative splicing of MS mRNA" but I wouldn't pretend to know all the ins-and-outs of these findings. Suffice to say that there is a suggestion that oxidative stress might have some role to play in what happens to MS both over the course of normal ageing and potentially also in cases of autism.

There's not a great deal more to add about this paper. Yes, again research with a reliance on post-mortem brain samples and all the caveats that go alongside their use (cause of death, comorbidity, etc.). Again however we are presented with some tantalising data about the processes around an important enzyme which has quite a bit of research around it with autism in mind. That alongside some interesting differences found between measures in brain compared with other peripheral tissues which starts to ask some interesting questions about the application of such secondary measures.

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* Muratore CR. et al. Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an accelerated decrease in autism. PLoS ONE. 2013; 8: e56927.

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Muratore, C., Hodgson, N., Trivedi, M., Abdolmaleky, H., Persico, A., Lintas, C., De La Monte, S., & Deth, R. (2013). Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism PLoS ONE, 8 (2) DOI: 10.1371/journal.pone.0056927

MTHFR and autism reloaded

MTHFR @ Paul Whiteley

I've talked before about the enzyme methylenetetrahydrofolate reductase, or MTHFR to its friends, and the suggested link with autism.

A few points are worth remembering:

• MTHFR serves a primary function in reducing the compound 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 
• On a grander scale, 5-methyltetrahydrofolate, the reduced and methylated form of folic acid, is an important methyl group donor for the recycling of homocysteine back to methionine utilising vitamin B12 along the way. 

'What's the big deal?' you might be thinking to yourself, as hopefully you are still reading this post. Well, there may be a few consequences of disruption along this pathway: elevated levels of homocysteine (discussed in this post), reduced levels of S-adenosylmethionine (SAMe), etc.

If I had to boil it down to a single important effect, it would probably be that reductions in the levels of SAMe might have some profound effects on methylation patterns in DNA (see here). Indeed with autism in mind, methlylation capability has been questioned in both people with autism (here) and their parents (here) bearing in mind the need for a lot more investigation in this area and my continued fixation on methylation (see a previous post). So then the MTHFR enzyme serves an important function. 

In my first post about MTHFR and autism, I talked about point mutations, SNPs, of the MTHFR gene (which control production of the enzyme) and how one particular SNP, C677T (whether homozygous or heterozygous) might show some link to cases of autism and onwards to the production of MTHFR (see this example study by Goin-Kochel and colleagues*). That and the recent suggestion that increasing doses of folic acid might affect the 'risk' of offspring autism as a function of maternal C677 status (see here), makes for some interesting observations on this very interesting SNP.

A recent paper by Guo and colleagues** extends the interest in the MTHFR C677T SNP in relation to autism, with their suggestion, quote: "MTHFR C677T is a risk factor of autism in Chinese Han children". 

Guo et al reported the presence of the C677T SNP in 16% of their cohort of children with autism, compared with 8.6% of their asymptomatic controls. This contrast between the groups is pretty similar to that reported by Mohammad and colleagues*** (16.3% autism vs. 6.5% controls) in a different ethnic population. Perhaps also just as interesting was the suggestion by Guo that 'overactivity' based on selected ADI-R scores seemed to be related to the presence of the SNP. A pretty similar finding to that presented by Goin-Kochel* bearing in mind the ins and outs of the ADI-R.

Taken cumulatively, it does appear as though there might be some connection between the C677T SNP, MTHFR and autism, albeit in a relatively small proportion of cases. Before however we get carried away, bear in mind that the same SNP has been linked to lots and lots of other different conditions including type-2 diabetes (here) and hypertension (here) in specific populations. There is even the suggestion that this SNP might be a risk allele for decreased kidney function too (see here full-text). The specificity of the finding is therefore something that requires quite a bit more research and whether such findings might actually indicate a subset of people with autism at potentially greater risk of such conditions either currently or in later life.

Indeed with that 'overactivity' finding in mind - I assume to be related to something like hyperactivity - the results looking at the C677T SNP in relation to conditions exemplified by hyperactivity such as ADHD, are less than impressive at the current time as per this paper by Ergul and colleagues****. That being said, other psychiatric diagnoses looked at by Ergul et al have shown some possible relationship (here) but I'm going to leave that for another day.

I admit to being slightly less than impressed with the whole area of genetic markers related to autism given the genetic complexity that surrounds the condition and all the additional issues relating to heterogeneity and comorbidity. This despite the recent gene pathway analysis paper from Skafidas and colleagues which, as several people have pointed out, didn't seem to talk too much about false-positives and the like. That's not to say however that genetics may not be an important part of autism but rather as we are starting to realise from the whole epigenetics revolution for example, that genomic changes might not the 'be all and end all'. There's so much more to DNA.

Bearing this in mind however, I'm intrigued by the suggestion that a SNP in MTHFR, most probably with other SNPs in other genes too, might have the capacity to trigger a cascade of biochemical actions which potentially ends up with reduced DNA methylation, and likely more issues with the function of DNA in cases of autism as in other conditions. A sort of 'genes causing an epigenetic effect' model if you like, which itself raises quite a lot of important questions about how we are the way we are.

To finish, it's been a while since I offered some musical accompaniment to my posts. To correct this I link to a song which I've been hearing a lot on the radio recently Razorlight and In the Morning.

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* Goin-Kochel RP. et al. The MTHFR 677C-->T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations. Autism Research. 2009; 2: 98-108.

** Guo T. et al. Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population. Genetic Testing & Molecular Markers. July 2012.

*** Mohammad NS. et al. Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatric Genetics. 2009; 19: 171-176.

**** Ergul E. et al. Methylenetetrahydrofolate reductase gene polymorphisms in Turkish children with attention-deficit/hyperactivity disorder. Genetic Testing & Molecular Biomarkers. 2012; 16: 67-69.

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Guo T, Chen H, Liu B, Ji W, & Yang C (2012). Methylenetetrahydrofolate Reductase Polymorphisms C677T and Risk of Autism in the Chinese Han Population. Genetic Testing and Molecular Biomarkers PMID: 22775456