title: Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia.
abstract: OBJECTIVE
  More effective treatments are needed for negative symptoms of schizophrenia, which are typically chronic, disabling, and costly. Negative symptoms have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism, suggesting the potential utility of folate supplementation.
  
  
  OBJECTIVE
  To determine whether folic acid plus vitamin B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response.
  
  
  METHODS
  Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg of folic acid and 400 μg of vitamin B12.
  
  
  METHODS
  Three community mental health centers affiliated with academic medical centers in the United States.
  
  
  METHODS
  Outpatients with chronic schizophrenia who were psychiatrically stable but displayed persistent symptoms despite antipsychotic treatment. Eligible patients were 18 to 68 years old, were treated with an antipsychotic agent for 6 months or more at a stable dose for 6 weeks or more, and scored 60 or more on the Positive and Negative Syndrome Scale.
  
  
  METHODS
  One hundred forty subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo.
  
  
  METHODS
  Change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale).
  
  
  RESULTS
  Folate plus vitamin B12 improved negative symptoms significantly compared with placebo (group difference, -0.33 change in SANS score per week; 95% CI, -0.62 to -0.05) when genotype was taken into account but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P = .02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS score per week; 95% CI, -0.99 to -0.18). In parallel, we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (P = .03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups.
  
  
  CONCLUSIONS
  Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00611806.
authors: Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA 02129, USA. jroffman@partners.org
authors: Joshua L
authors: JL
authors: Roffman
authors: J Steven
authors: JS
authors: Lamberti
authors: Eric
authors: E
authors: Achtyes
authors: Eric A
authors: EA
authors: Macklin
authors: Gail C
authors: GC
authors: Galendez
authors: Lisa H
authors: LH
authors: Raeke
authors: Noah J
authors: NJ
authors: Silverstein
authors: Jordan W
authors: JW
authors: Smoller
authors: Michele
authors: M
authors: Hill
authors: Donald C
authors: DC
authors: Goff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D043425:Glutamate Carboxypeptidase II / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics; D016896:Treatment Outcome; D014805:Vitamin B 12 / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D005492:Folic Acid; D043425:Glutamate Carboxypeptidase II; D014805:Vitamin B 12