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Study: Gene variations contributing to low folate, B12, causing "schizophrenia" symptoms


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Big surprise -- low B12 and folate can contribute to neuropsychiatric symptoms. Psychiatry has resolutely ignored this for decades, preferring instead to go the high-profit route hand in hand with pharma.




Genes Dictate Folate Benefit in Schizophrenia

By Nancy Walsh, Staff Writer, MedPage Today

Published: March 08, 2013

  • Patients with schizophrenia saw symptom improvement with folate supplements, but response was predicted by variants in genes that regulate the folate metabolism.
  • Among patients receiving folate supplements, the greatest improvements were seen for those who had the lowest baseline levels of red blood cell folate.
Patients with schizophrenia saw symptom improvement with folate and vitamin B12 supplements, but response was predicted by variants in genes that regulate the folate metabolism, a randomized clinical trial showed.


When four missense single nucleotide polymorphisms were included in an analysis of the effects of folate use on negative schizophrenia symptoms, there was a significant difference in scores between the treatment and placebo groups of −0.33 each week (95% CI −0.62 to −0.05, P=0.02), according to Joshua L. Roffman, MD, of Harvard Medical School, and colleagues.


Specifically, carriers of the T/T variant in the FOLH1 gene had a significant weekly improvement in negative symptom scores of −0.59 (95% CI −0.99 to −0.18, P=0.005), the researchers reported online in JAMA Psychiatry.


Available treatments for schizophrenia primarily target the positive symptoms of the disorder, such as hallucinations, but are less useful for controlling the negative symptoms of withdrawal and apathy.


Previous research has shown folate deficiency to be a risk factor for schizophrenia, and small studies conducted in populations with folate deficiency found symptomatic improvements with supplementation.


Several specific polymorphisms in genes involved in the regulation and absorption of folate -- MTHFR, FOLH1, MTR, and COMT -- also have been linked with the negative symptom phenotype, and a small study by Roffman's group found benefits in negative symptoms among patients with a low-functioning variant in MTHFR.


To more fully explore the influence of these genetic polymorphisms, they conducted a three-center study that included 140 patients who had scores of 60 or higher on a symptom scale for both positive and negative symptoms.


"We hypothesized that folate plus vitamin B12 supplementation would improve negative symptoms but that treatment response would depend on the presence of hypofunctional genetic variants in the folate metabolic pathway," Roffman and colleagues wrote.


Participants' mean age was 45, and almost three-quarters were men.


They were randomized to receive 2 mg of folate plus 400 µg of vitamin B12 per day or placebo for 4 months, and were stratified at baseline according to serum folate levels.


The vitamin B12 was included to avoid the possibility that pernicious anemia could go unrecognized.



Only when the genetic variants were entered into the model was statistical significance reached, the investigators reported.


When they examined the effects of the individual polymorphisms, they found a slight, though not significant, benefit for folate use in the T allele carriers of MTHFR, and no effect for MTR and COMT variants.


Among patients receiving folate supplements, the greatest improvements were seen for those who had the lowest baseline levels of red blood cell folate (r = 0.43, P=0.04).


In a previous cross-sectional study, it appeared that the variants associated with the hypofunctional C allele were associated with a greater benefit from supplementation, but in this study the high-functioning homozygous T-allele variant was needed for symptomatic improvements to occur.


This finding suggested that the C allele may interfere with the absorption of folate, they explained.


But it's also possible, they noted, that with longer treatment, C allele carriers might have begun to show improvements as downstream effects of gene expression become more apparent.


The study had certain limitations, such as the inclusion of multiple outcomes and a heterogeneous population.


In addition, the effects of the folate treatment were modest.


"Even small effects of folate and vitamin B12 supplementation could be clinically meaningful, though, given the disability associated with negative symptoms, the lack of available treatments, and the minimal apparent adverse effects of vitamin supplementation," the researchers observed.


Their findings may be relevant not only for schizophrenia, but also for other conditions such as cardiovascular disease and dementia, where low folate levels appeared to be a risk factor but no benefits were seen with supplementation in large intervention studies.


"The current results suggest that individual differences in folate metabolism related to the presence of common functional genetic variants may have a bearing on treatment outcomes in these other disorders, as well as negative symptoms of schizophrenia," they commented.



The study was supported by the National Institute of Mental Health and the Howard Hughes Medical Institute.


The authors reported receiving support and consulting for a variety of companies, including Eli Lilly, Novartis, Janssen, Otsuka, Hoffman-La Roche, Bristol-Myers Squibb, Abbott, Merck, and Pfizer.


The lead author and one co-author have applied for a patent related to treatment response in schizophrenia according to folate genes.



Primary source: JAMA Psychiatry

Source reference:

Roffman, J et al "Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia" JAMA Psychiatry 2013; DOI: 10.1001/jamapsychiatry.2013.900.

This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

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