Folic-ing around in schizophrenia

I seem to have been focusing a lot on folic acid (vitamin B9) and vitamin B12 these days. It's not that I'm in anyway choosing the direction taken, it just happens that the published papers are appearing that way.

And as if to prove my point, enter the paper by Joshua Roffman and colleagues* (open-access) reporting results from a gold-standard, randomised, double-blind, placebo-controlled study on the addition of folic acid and vitamin B12 supplement to antipsychotic medication for a group of adults with chronic schizophrenia.

MTHFR, FOLH = word score @ Wikipedia  

The paper is open-access but a few summary points are worth mentioning bearing in mind Dr Emily Deans has already discussed this research:

• One hundred and forty participants diagnosed with schizophrenia but psychiatrically stable were included for initial study. They were all taking an antipsychotic for 6 months "but displayed persistent symptoms despite antipsychotic treatment".
• As per the study protocol, participants were randomly split into folate-vitamin B12 supplementation or placebo. Actually whilst it was random, it was stratified random, meaning that randomisation took into account serum folate levels which were measured at baseline and formed an important part of the study outcomes. Indeed, the split was also not 50:50 in each group; instead weighted towards the supplementing group. 
• On most other variables the groups showed no significant difference (age, gender splits, medications, SES). That is aside from serum vitamin B12 levels, where the experimental group showed a significantly higher mean level at baseline compared to the placebo group (631 pg/ml vs. 511 pg/ml respectively).
• The primary outcome measure was the change in negative symptoms as judged by the SANS. Not being an expert on schizophrenia, I was interested to read about the characterisation of positive and negative symptoms in schizophrenia and, as the authors put it, "considerable disability is associated with negative symptoms and cognitive deficits, for which effective treatment is not available".
• Results: after 16 weeks of study, there were lots and they were mixed in with some DNA genotyping data pertinent to genes involved in the folate metabolism cycle. So our old Scrabble friend MTHFR (see here) got a look in, as did MTR (methionine synthase) - as per my previous post. 
• One gene in particular seemed to get quite well caught up in the study results: FOLH1 - which among other things is involved in folate transfer and absorption. Mention of the words 'glutamate excitotoxicity' alongside FOLH1 also stirs up some interesting thoughts. 
• So, yadda, yadda, "folate and vitamin B12 improves negative symptoms of schizophrenia" but only modestly given the "15% difference in SANS scores" between the experimental and placebo groups. Importantly in these days of personalised medicine, the FOLH1 gene was the focus, in that FOLH1 484C>T variant seemed to tie into treatment response. This was slightly at odds with what had been noted on another occasions**.
• So, if a participants was homozygous - as in identical copies of the same allele - for FOLH1 484T,  they were more likely to show greater benefit from the supplements. I'll come back to this shortly.
• That's not also to say that there weren't other gene related findings tied into intervention response. As the authors note about MTHFR 677C>T "only T allele carriers exhibited a significant benefit for active treatment over placebo for negative symptoms". Thankfully in line with what has previously been discussed***.

Every paper covered on this blog is a learning journey for me and this one is no exception. Likewise, it is always interesting to see when results don't exactly pan out as they are predicted to. In the case of the Roffman paper, it was the FOLH1 gene findings which didn't go to plan, and how contrary to the expected role of the 484C variant, the so-called low-functioning variant which one would expect to have reduced folate absorption - as was demonstrated in a separate asymptomatic cohort - it was actually the presence of the high-functioning variant (484T) which governed a positive treatment response.

In light of these findings, and the fact that red blood cell (RBC) levels of folate grew and grew in the experimental group over the course of the trial (although not significantly related to the change in negative symptoms), one starts to ponder other explanations to account for the results.

I've gone over MTHFR so won't say much more on that. The authors touch upon one potentially pertinent issue - DNA methylation - which is where I always seem to end up back to when talking about folate and MTHFR and the like. That for example, the supplementation of folic acid and vitamin B12 might, just might, impact on important reactions such as the recycling of homocysteine back to methionine onward to the production of SAMe is one possible effect. Indeed, it is a shame that elements of the methionine cycle were not measured over the course of the current trial.

I could go on. I could ask what kind of vitamin B12 was used as a supplement, whether the oral dosage form is the ideal way to get vitamin B12 into the body, whether outside of the reported symptoms, there may have been other variables affected by the results and whether despite increasing levels of folate, there were corresponding increases to levels of the active form of folic acid, 5-methyltetrahydrofolate? Indeed on that last point apparently there are plans afoot to look at the use of 5-methyltetrahydrofolate (or as the authors call it 1-methylfolate)...

Please stop now... and so I shall.

----------

* Roffman JL. et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. March 2013.

** Roffman JL. et al. Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia. Schizophr Bull. 2013; 39: 330-338.

*** Hill M. et al. Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophr Res. 2011; 127: 41-45.

----------

Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, Silverstein NJ, Smoller JW, Hill M, & Goff DC (2013). Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia. JAMA psychiatry (Chicago, Ill.), 1-9 PMID: 23467813