Homocysteine metabolism and B-vitamins in schizophrenic patients: low plasma folate as a possible independent risk factor for schizophrenia.

Two apparently unrelated disorders, neural tube defects (NTD) and schizophrenia showed increased risks in birth cohorts exposed to famine during early gestation. NTD is associated with impaired folate metabolism. We investigated whether schizophrenia is also linked with a dysfunctional folate metabolism. In addition to the prevalence of the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, we compared plasma and red blood cell (RBC) folate, vitamin B6, vitamin B12, and homocysteine (Hcy) concentrations of 35 schizophrenic patients with those of 104 unrelated controls. Schizophrenic patients had significantly lower plasma folate concentrations after adjustment for Hcy levels, and elevated RBC folate levels compared to controls. Vitamin B6, vitamin B12, and Hcy levels did not differ from control values. Plasma folate levels below the 10th percentile of controls were associated with an approximate 4-7-fold (before and after adjustment of folate levels for Hcy, respectively) risk of having schizophrenia. In addition, a significant dose-response relation between plasma folate concentrations and risk for schizophrenia suggested a protective effect by high plasma folate concentrations. Elevated Hcy levels and, in line with this finding, homozygosity for the 677C-->T mutation in the MTHFR gene were not associated with an increased risk for schizophrenia. Evidence is presented suggesting that folate metabolism is disturbed in schizophrenic patients, independently of Hcy.