Contribution of methylenetetrahydrofolate reductase (MTHFR) polymorphisms to negative symptoms in schizophrenia.
ABSTRACT Folate deficiency may contribute to negative symptoms in schizophrenia, but the underlying mechanism remains uncertain. We examined whether the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C functional polymorphisms contribute to negative symptoms.
Outpatients with schizophrenia (n = 200) were evaluated with the Positive and Negative Syndrome Scale (PANSS). Subjects also provided a blood sample for MTHFR genotype and serum chemistries. Comparisons of PANSS symptoms, folate, and homocysteine status were conducted based on genotype.
The 677T allele load was associated with negative symptom severity. Contrary to our expectations, the T allele was also found to be protective against positive symptoms. The A1298C polymorphism did not contribute to negative symptoms, and only weakly to positive symptoms. The specific effects of the C677T polymorphism were confirmed with haplotype analysis. Among patients homozygous for the 667T allele, serum folate levels correlated with negative symptom severity.
Increased MTHFR 677T allele load confers risk for negative symptoms in schizophrenia, while reducing severity of positive symptoms. Further, the biochemical interaction of low serum folate with 677T-variant MTHFR may induce downstream effects salient to the expression of negative symptoms.
SourceAvailable from: Ellen Siobhan Mitchell[Show abstract] [Hide abstract]
ABSTRACT: The B vitamins folic acid, vitamin B12 and B6 are essential for neuronal function, and severe deficiencies have been linked to increased risk of neurodevelopmental disorders, psychiatric disease and dementia. Polymorphisms of genes involved in B vitamin absorption, metabolism and function, such as methylene tetrahydrofolate reductase (MTHFR), cystathionine β synthase (CβS), transcobalamin 2 receptor (TCN2) and methionine synthase reductase (MTRR), have also been linked to increased incidence of psychiatric and cognitive disorders. However, the effects of these polymorphisms are often quite small and many studies failed to show any meaningful or consistent associations. This review discusses previous findings from clinical studies and highlights gaps in knowledge. Future studies assessing B vitamin-associated polymorphisms must take into account not just traditional demographics, but subjects’ overall diet, relevant biomarkers of nutritional status and also analyze related genetic factors that may exacerbate behavioral effects or nutritional status.Neuroscience & Biobehavioral Reviews 11/2014; 47. DOI:10.1016/j.neubiorev.2014.08.006 · 10.28 Impact Factor
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ABSTRACT: Objective The present study was to examine serum levels of brain-derived neurotrophic factor (BDNF), folate, homocysteine (Hcy), and their relationships with hippocampal volume and psychopathology in drug naïve, first episode schizophrenia. Method Drug naïve, first episode schizophrenia patients and healthy controls were enrolled in the study. Serum levels of BDNF, folate and Hcy were measured using enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence immunoassay (ECLIA), and enzymatic cycling method respectively. Hippocampus was parcellated and bilateral hippocampal volumes were measured using FreeSurfer. Results Forty-six patients with drug naïve, first episode schizophrenia (SZ group) and 30 healthy controls (control group) were enrolled. The SZ group had significantly lower serum levels of BDNF and folate, and significantly higher serum levels of Hcy compared with the control group (p = 0.013, p < 0.001, p = 0.003 respectively). There were no significant differences in hippocampal volumes between the two groups (ps > 0.2). Within the SZ group, there were significant positive relationships between serum levels of BDNF and both left and right hippocampal volumes (r = 0.327, p = 0.026; r = 0.338, p = 0.022 respectively). In contrast, such relationships did not exist in the control group. Within the SZ group, there were significant negative relationships between serum levels of folate and PANSS-total scores and PANSS-negative symptom scores (r = 0.319, p = 0.031; r = 0.321, p = 0.030 respectively); and there was a positive relationship between serum levels of Hcy and PANSS-total scores (r = 0.312, p = 0.035). Controlling for potential confounding variables resulted in similar findings. Conclusions Drug naïve, first episode schizophrenia presents decreased serum levels of BDNF, folate and increased serum levels of Hcy, which may play an important role in the neurodevelopmental process and clinical manifestation of schizophrenia.Schizophrenia Research 10/2014; 159(1). DOI:10.1016/j.schres.2014.07.033 · 4.43 Impact Factor
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ABSTRACT: Purpose Alterations in one-carbon metabolism (OCM) have been repeatedly reported in schizophrenia. However, there is a scarcity of studies addressing the effects of antipsychotics on selected OCM markers in schizophrenia and provided results are inconsistent. Methods We recruited 39 first-episode schizophrenia (FES) patients and determined serum profile of total homocysteine (tHcy), folate, vitamin B12, lipoproteins and glucose at base-line and after 12 weeks of treatment with second-generation antipsychotics (SGA) including olanzapine and risperidone in monotherapy. Results After 12 weeks of treatment, all patients had signifi-cantly higher body mass index (BMI), serum levels of total cholesterol (TC), low-density lipoproteins (LDL), triglycer-ides (TG) and tHcy together with significantly lower levels of folate and vitamin B12. The analysis of differences between SGA revealed the same biochemical alterations in patients treated with olanzapine as in the whole group, while those receiving risperidone had no statistically significant changes in serum folate, vitamin B12 and TG. There was a significant-ly higher increase in BMI and TC in patients treated with olanzapine in comparison with those treated with risperidone. Patients receiving olanzapine had a higher decrease in vitamin B12 than those assigned to the treatment with risperidone. Changes in folate, vitamin B12, tHcy and TC levels were significant only in males, even after Bonferroni correction. Multiple regression analysis revealed that changes in tHcy levels are associated with gender and baseline metabolic pa-rameters (BMI, glucose, TC, LDL and HDL) but not with selected SGA. Conclusions These results indicate that SGA may influence OCM, especially in first-episode schizophrenia (FES) males.European Journal of Clinical Pharmacology 10/2014; 70(12). DOI:10.1007/s00228-014-1762-2 · 2.70 Impact Factor