Therapeutic Folate Benefit May Be Explained by Genes
Functional variants in genes that regulate folate absorption significantly influence treatment response in patients given folate plus vitamin B12 supplementation to improve negative symptoms of schizophrenia, according to a study published online March 6 in JAMA Psychiatry. These findings, the authors say, support a personalized medicine approach for the treatment of negative symptoms in schizophrenia, […]
Functional variants in genes that regulate folate absorption significantly influence treatment response in patients given folate plus vitamin B12 supplementation to improve negative symptoms of schizophrenia, according to a study published online March 6 in JAMA Psychiatry. These findings, the authors say, support a personalized medicine approach for the treatment of negative symptoms in schizophrenia, and possibly other folate interventions in additional clinical areas. Negative symptoms in schizophrenia (apathy, social withdrawal, and loss of emotional expressiveness) are not improved with anti-psychotics and have previously been tied to reduced blood folate levels. Given mandatory folate fortification of grain products in the United States, the authors explain that the benefits of folate supplementation may be less readily detected and clinical response may depend on genotype. In a multicenter clinical trial, 140 stable patients with schizophrenia who chronically displayed symptoms despite anti-psychotic treatment were randomized (2:1) to receive daily, oral supplementation with 2 mg of folic acid and 400 μg of vitamin B12 (n=94) or placebo (n=46). DNA extracted from whole blood samples in 120 consenting participants was genotyped for four variants previously associated with negative symptom severity (FOLH1 484C>T, MTHFR 677C>T, MTR 1298G>A, and COMT 675G>A). The researchers found that in the study cohort, baseline red blood cell folate levels correlated significantly with FOLH1 T and MTHFR T allele loads, despite equivalent dietary folate intake in the genotype groups. During validation of these results in a separate cohort of 89 healthy individuals, there was only a significant inverse relationship between red blood cell folate concentration at baseline and FOLH1 C allele load. The researchers found that improvements in patients’ negative symptoms with supplementation were only significant when considering genotype. Specifically, only patients homozygous for the 484T allele, the high-functioning variant of folate hydrolase 1 (FOLH1), showed significantly greater benefit with active treatment. While the treatment effects seen when considering genotype were “modest,” the authors say they could still be clinically meaningful. “The present results have direct treatment implications not only for schizophrenia but also for folate-related interventions in other areas of medicine,” write the authors, led by Joshua L. Roffman, M.D., from Massachusetts General Hospital in Boston. “Well-replicated associations of reduced folate and elevated homocysteine concentrations as risk factors for stroke, cardiovascular disorders, and dementia have been tempered by large, prospective studies that have failed to find a benefit of folate supplementation on disease progression. The current results suggest that individual differences in folate metabolism related to the presence of common functional genetic variants may have a bearing on treatment outcomes in these other disorders, as well as negative symptoms of schizophrenia.” Roffman tells DTTR that the findings provide “general support for the idea of personalized genotype-based interventions” but that the evidence in not yet sufficient to recommend routine genetic testing.