title: Folate supplementation in schizophrenia: a possible role for MTHFR genotype.
abstract: BACKGROUND
  Folate deficiency and the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism have been linked to negative symptoms in schizophrenia both independently and synergistically. This study examined the effect of folate supplementation on negative symptoms overall and in relation to MTHFR 677C>T genotype.
  
  
  METHODS
  Forty-six stable adult schizophrenia outpatients were enrolled and 32 were randomised, double-blind, in a parallel-group, twelve week add-on trial of folate 2mg/d or matching placebo. The primary outcome measure was change from baseline to week 12 on the modified SANS total score using a mixed-model analysis. In addition, we measured the effect of MTHFR genotype on treatment effects and on changes in serum folate by grouping participants with T/T genotype together with C/T genotype and comparing their interactions to patients with C/C genotype.
  
  
  RESULTS
  Twenty-eight participants completed the trial. Folate supplementation did not significantly affect negative symptoms compared to placebo across the entire cohort. However, there was a significant genotype×treatment effect on negative symptoms (F=7.13, df=1,39, p=0.01). In addition, MTHFR status significantly moderated the relationship between change in serum folate and change in negative symptoms: among participants with at least one copy of the T allele negative symptoms were more likely to improve with increased serum folate (p=0.03).
  
  
  CONCLUSIONS
  We did not detect a therapeutic benefit of folate supplementation in a sample of patients with residual negative symptoms. However, a possible association between genotypes associated with reduced MTHFR activity and benefit from folate supplementation should be investigated further.
authors.affiliation: Schizophrenia Program, Massachusetts General Hospital, Harvard Medical School, United States. michelehill1@gmail.com
authors.forename: Michele
authors.initials: M
authors.lastname: Hill
authors.forename: Kelsey
authors.initials: K
authors.lastname: Shannahan
authors.forename: Sarah
authors.initials: S
authors.lastname: Jasinski
authors.forename: Eric A
authors.initials: EA
authors.lastname: Macklin
authors.forename: Lisa
authors.initials: L
authors.lastname: Raeke
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Roffman
authors.forename: Donald C
authors.initials: DC
authors.lastname: Goff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003072:Cognition Disorders / Q000178:diet therapy / Q000209:etiology; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D010045:Outpatients; D011110:Polymorphism, Genetic / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000150:complications / Q000178:diet therapy* / Q000235:genetics*; D014803:Vitamin B Complex / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D014803:Vitamin B Complex; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)