|1||Schizophr Bull 2013 Mar 39: 330-8|
|Title||Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia.|
|Abstract||Low serum folate levels previously have been associated with negative symptom risk in schizophrenia, as has the hypofunctional 677C>T variant of the MTHFR gene. This study examined whether other missense polymorphisms in folate-regulating enzymes, in concert with MTHFR, influence negative symptoms in schizophrenia, and whether total risk allele load interacts with serum folate status to further stratify negative symptom risk. Medicated outpatients with schizophrenia (n = 219), all of European origin and some included in a previous report, were rated with the Positive and Negative Syndrome Scale. A subset of 82 patients also underwent nonfasting serum folate testing. Patients were genotyped for the MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTR 2756A>G (rs1805087), MTRR 203A>G (rs1801394), FOLH1 484T>C (rs202676), RFC 80A>G (rs1051266), and COMT 675G>A (rs4680) polymorphisms. All genotypes were entered into a linear regression model to determine significant predictors of negative symptoms, and risk scores were calculated based on total risk allele dose. Four variants, MTHFR 677T, MTR 2756A, FOLH1 484C, and COMT 675A, emerged as significant independent predictors of negative symptom severity, accounting for significantly greater variance in negative symptoms than MTHFR 677C>T alone. Total allele dose across the 4 variants predicted negative symptom severity only among patients with low folate levels. These findings indicate that multiple genetic variants within the folate metabolic pathway contribute to negative symptoms of schizophrenia. A relationship between folate level and negative symptom severity among patients with greater genetic vulnerability is biologically plausible and suggests the utility of folate supplementation in these patients.|
|2||JAMA Psychiatry 2013 May 70: 481-9|
|Title||Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia.|
|Abstract||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.|
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.
Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg of folic acid and 400 ?g of vitamin B12.
Three community mental health centers affiliated with academic medical centers in the United States.
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.
One hundred forty subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo.
Change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale).
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.
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.
clinicaltrials.gov Identifier: NCT00611806.