Do folate supplementation benefit negative symptoms? JAMAPsy.May.2013


Folate deficiency is a risk factor for schizophrenia.Reduced folate intake ( during famines in China and Netherlands ) is shown to have increased schizophrenia incidence two decades after. High levels of serum homocysteine (low levels of folate) during the third trimester of pregnancy  is associated with  2-fold increased risk for schizophrenia in offspring.Low folate levels are seen in individuals with schizophrenia.This might be more associated with negative symptoms.Polymorphisms of genes that regulate folate metabolism ( e.g.  Methylene tetrahydro folate reductase (MTFR) gene) that reduce the enzyme activity is overrepresented among patients with schizophrenia.Patients with Schizophrenia and low folate levels were symptomatically better when treated with folate.

Joshua L. Roffman  and colleagues report the results of a large multisite ,randomized, double-blind, placebo-controlled, parallel-group, 16-week trial of supplementation with folate and vitamin B12  vs placebo in adult out- patients with schizophrenia on stable antipsychotics with PANSS score of 60 or more .Vitamin B12 was combined with folate  to potentiate down- stream effects of folate on methylation reactions and reduce the risk of masked pernicious anemia.

140 patients were randomized to folate plus vitamin B12 (n = 94) or placebo (n = 46).Both groups were similar in baseline demographic and clinical characteristics,   medication use patterns and dietary folate and vitamin B12 intake.


Patients who received folate plus vitamin B12 exhibited a significant decline in negative symptoms.However the difference between the folate and placebo groups did not reach statistical significance.Both the active and placebo groups improved significantly over time in PANSS total score,  again, there was no difference in improvement between treatment groups.There was no significant overall correlation between change in folate levels and change in negative symptom ratings at any treatment visit. Interestingly the  active treatment group did better significantly  when genotype was taken into account. Patients homozygous for the 484T allele FOLH1 (FOLH1 is a glutamate carboxypeptidase on the intestinal brush border that facilitates transfer of dietary folate into the body) ie a high functioning variant, demonstrated significantly greater benefit with active treatment . Folate and vitamin B12 supplementation did not confer a benefit for positive symptoms or depression scores, regardless of genotype.


Individual differences in folate metabolism related to the presence of common functional genetic variants may have a bearing on treatment outcomes in those with negative symptoms of schizophrenia.

Summary of the article:

Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, Silverstein NJ, Smoller JW, Hill M, Goff DC.JAMA Psychiatry. 2013 May 1;70(5):481-9

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