In the May issue of JAMA Psychiatry Joshua Roffman and colleagues from Massachusetts General Hospital in Boston report the interesting results of their multicenter study on the effects of supplementation with folic acid and vitamin B12 in patients with a schizophrenic disorder (Roffman et al., JAMA Psychiatry 2013;70:481-489). Several findings indicate that reduced folate concentrations increase the risk of developing schizophrenia. For example, a mutation in the gene for methylenetetrahydrofolate reductase (MTHFR) is observed significantly more frequently in patients with schizophrenia than in the general population. In this mutation, a cytosine at position 677 is replaced by a thymine (677C>T). Each copy of the 677T variant reduces the enzyme activity by 35%. Famine in the Netherlands and China led to a doubling of the incidence of schizophrenia about two decades later, which suggests the conjecture that the reduced intake of folic acid during early development of the CNS increases the risk for schizophrenia.
Folic acid is a B vitamin that provides methyl groups for methylation reactions (e.g., synthesis of neurotransmitters and DNA). Vitamin B12 is a cofactor of methionine synthase. It remethylates homocysteine to methionine, which is in turn converted to the methyl group donor S-adenosyl-methionine. Although folic acid plays a decisive role in methylation reactions, vitamin B12 was also supplemented in the study in order not to limit the effects of folic acid supplementation by a potential vitamin B12 deficiency.
Roffmann et al. now treated in a randomized, double-blind study 139 patients over 16 weeks with either 2 mg of folic acid and 400 μg of vitamin B12 (n = 93) daily or placebo (n = 46). 121 patients were treated over the entire study period. Inclusion criteria were an antipsychotic treatment for at least six months in duration with a stable dose for at least six weeks and a PANSS score (PANSS = Positive and Negative Syndrome Scale) of at least 60 points. The primary hypothesis of the study was that supplementation with folic acid and vitamin B12 leads to a significantly greater improvement of negative symptoms than placebo, and that the treatment effect depends on the genotype. In addition to the genotype of the MTHFR the genotypes of three additional enzymes that regulate the metabolism of methyl groups were investigated: folate hydrolase 1 (FOLH1), methionine synthase (MTR) and catechol-O-methyltransferase (COMT).
When examining the entire group, regardless of their genotype, the SANS score decreased (SANS = Scale for the Assessment of Negative Symptoms) in the group of patients who were actively treated, statistically significantly by 0.19 points per week, but not in the group of patients treated with placebo (0.02 points per week). However, the group difference was not statistically significant (group difference was 0.21 points / week, p = 0.15).
When all four studied genotypes were included together in the analysis, negative symptoms (measured with the SANS) in the actively treated group were significantly better influenced than in the placebo group (folic acid/vitamin B12: -0.17/week, p = 0.04; placebo: +0.16/week, p = 0.18; group difference: 0.33/week, p = 0.02). When individual genotypes were assessed separately, only the genotype for FOLH1 predicted the change in negative symptoms. Carriers of the T/T genotype benefited significantly from the treatment (reduction of SANS scores by 0.59 points/week, p = 0.005), but not carriers of a C allele (+0.09/week, p = 0.64). This difference was statistically significant (p = 0.02). Also carriers of a MTHFR 677T allele benefited from the active treatment greater than placebo, but this difference was not statistically significant. MTR and COMT genotypes did not influence the response to treatment.
Folate Hydrolase 1 is localized in the intestinal epithelium. It facilitates the transport of folic acid from the intestinal lumen into the body. A mutation with a base substitution from thymine to cytosine at position 484 (484T>C) results in a reduction of the activity of the enzyme, which in turn leads to reduced folate concentrations. The low active variant 484C was associated with increased negative symptoms in a study of patients with a schizophrenic disorder. Counter-intuitively, however, in the present study only patients that were homozygous for the variant encoding the active enzyme could benefit from treatment with folic acid. Possibly a longer treatment duration is necessary for the treatment of carriers of the 484C allele in order to achieve similar effects. Nevertheless, the treatment with folate and vitamin B12 is an interesting approach as long as other effective treatments for negative symptoms in schizophrenic disorders are absent.
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