MTHFR

Vitamins, Monoamines, and Depression.

http://primarypsychiatry.com/vitamins-monoamines-and-depression/ [174]

Synthesis of the three monoamine neurotransmitters, serotonin, dopamine, and norpepinephrine, is regulated by L-methylfolate. “There are several mechanisms by which folate may affect central nervous

system (CNS) pathways implicated in the depressive disorders. Biopterin, which is dependent on Lmethylfolate for synthesis, serves as an essential co-factor for converting phenylalanine to tyrosine, and for hydroxylation of tyrosine and tryptophan to yield dopamine, norepinephrine, and serotonin.”[174]

Association between MTHFR C677T polymorphism and depression: An updated meta-analysis of 26 studies.

http://www.ncbi.nlm.nih.gov/pubmed/23831680 [175]

“Previous studies concerning the association between the 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and depression have provided inconclusive findings…This metaanalysis recruited 26 published studies which were selected by a search of electronic databases up to January 2013, including 4992 depression cases and 17,082 controls. Meta-analyses results suggested that MTHFR C677T polymorphism contributed to the increased depression risk in overall populations (for T vs. C: OR=1.19, 95%CI=1.07-1.32; for TT+CT vs. CC: OR=1.15, 95%CI=1.01-1.31; for TT vs. CC: OR=1.42, 95%CI=1.16-1.75; for TT vs. CT+CC: OR=1.38, 95%CI=1.16-1.63).” [175]

Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatricdisorders: a HuGE review.

http://www.ncbi.nlm.nih.gov/pubmed/17074966 [176]

“The authors performed a meta-analysis of studies examining the association between polymorphisms in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene, including MTHFR C677T and

A1298C, and common psychiatric disorders, including unipolar depression, anxiety disorders, bipolar disorder, and schizophrenia. The primary comparison was between homozygote variants and the wild type for MTHFR C677T and A1298C… This meta-analysis demonstrates an association between the MTHFR C677T variant and depression, schizophrenia, and bipolar disorder, raising the possibility of the

use of folate in treatment and prevention.” [176]

Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability?

http://www.ncbi.nlm.nih.gov/pubmed/21185933 [177]

“We conducted a meta-analysis of all published case-control studies investigating associations between two common MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T (sample size 29,502)

and A1298C (sample size 7934), and the major psychiatric disorders (i) schizophrenia (SZ), (ii) bipolar disorder (BPD), and (iii) unipolar depressive disorder (UDD)… MTHFR C677T was significantly

associated with all of the combined psychiatric disorders (SZ, BPD and UDD); random effects odds ratio (OR) =1.26 for TT versus CC genotype carriers; confidence interval (CI) 1.09-1.46); meta-regression did not suggest moderating effects of psychiatric diagnosis, sex, ethnic group or year of publication. Although MTHFR A1298C was not significantly associated with the combination of major psychiatric

disorders, nor with SZ, there was evidence for diagnostic moderation indicating a significant association with BPD (random effects OR=2.03 for AA versus CC genotype carriers, CI: 1.07-3.86). Meta-analysis

on UDD was not possible due to the small number of studies available. This study provides evidence for shared genetic vulnerability for SZ, BPD and UDD mediated by MTHFR 677TT genotype, which is in

line with epigenetic involvement in the pathophysiology of these psychiatric disorders.” [177]

Role of MTHFR C677T gene polymorphism in the susceptibility of schizophrenia: An updated metaanalysis.

http://www.ncbi.nlm.nih.gov/pubmed/27025471 [178]

“Total 38 studies with 10,069 cases and 13,372 controls were included in the present meta-analysis. Results of meta-analysis showed significant associated between C677T polymorphism and risk of

schizophrenia (OR T vs C=1.18, 95%CI=1.10-1.27, p=<0.001; OR CT vs CC=1.10, 95%CI=1.04-1.17, p=<0.001; OR TT vs CC=1.40, 95%CI=1.20-1.64, p=<0.001; OR TT + CT vs CC=1.19, 95%CI=1.09- 1.30, p=<0.001). We also performed subgroup and sensitivity analyses. Subgroup analysis was done according to ethnicity and significant association was found between C677T polymorphism and risk of

schizophrenia in all three ethnic populations-African (OR=2.51; 95%CI=1.86-3.40; p=<0.001), Asian (OR=1.21; 95%CI=1.10-1.33; p=<0.001) and Caucasian (OR=1.07; 95%CI=1.01-1.14; p=0.01). In

conclusion the results of the present meta-analysis suggested that the MTHFR C677T polymorphism is a risk factor for schizophrenia.” [178]

L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.

http://www.ncbi.nlm.nih.gov/pubmed/23212058 [179]

L-methylfolate Plus SSRI or SNRI from Treatment Initiation Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3036555/ [180]

Several studies have demonstrated l-methylfolate as an effective augmentation strategy with SSRI/SNRIs. [179, 180]

Comparative assessment of adherence measures and resource use in SSRI/SNRI-treated patients with depression using second-generation antipsychotics or L-methylfolate as adjunctive therapy.

http://www.ncbi.nlm.nih.gov/pubmed/24372461 [181]

“Patients who augmented SSRI/SNRI therapy with [second-generation atypical antipsychotics] (SGA) or L-methylfolate achieved [modified application of the HEDIS] (mHEDIS) acute medication management

(AMM) acute phase and continuation phase adherence scores of 69%-79% and 50%-62%, respectively. These modified scores exceeded the 2012 national median benchmarks for unmodified HEDIS AMM

measures for commercial health plans. In this study, augmentation with L-methylfolate was associated with significantly higher adherence measures compared with augmentation with SGA. In addition, health care utilization and total health care costs, as well as depression-related costs, were significantly lower in the L-methylfolate augmentation group compared with augmentation with SGA.” [181]

Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial.

http://www.ncbi.nlm.nih.gov/pubmed/24813065 [182]

“The objective of the current post hoc analysis was to evaluate the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive L-methylfolate 15 mg versus placebo from

a trial of inadequate responders to selective serotonin reuptake inhibitors (SSRIs)… Biomarkers associated with inflammation or metabolism and genomic markers associated with L-methylfolate

synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with L-methylfolate 15 mg. Confirmatory studies are needed.” [182]

Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism: a randomized, doubleblind, placebo-controlled study.

http://www.ncbi.nlm.nih.gov/pubmed/27035272 [183]

“159 of 170 vitamin-treated patients and 123 of 160 placebo-treated patients were completers. Of the active treatment group, 131 (82.4%) showed a reduction in homocysteine (for a mean in this subgroup

of 25%, p < .001), while 28 (17.6%) showed no significant change. Placebo patients demonstrated a small elevation in homocysteine. Active-treatment patients demonstrated, on average, a 12-point

reduction on the MADRS by week 8, and 42% achieved full remission (p < .001). No side effect was significantly different between groups. No patients experienced mania.” [183]

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases.

http://www.ncbi.nlm.nih.gov/pubmed/25449138 [184]

“The Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with various diseases (vascular, cancers, neurology, diabetes, psoriasis, etc.) with the epidemiology of the

polymorphism of the C677T that varies dependent on the geography and ethnicity. The 5, 10- Methylenetetrahydrofolate reductase (MTHFR) locus is mapped on chromosome 1 at the end of the

short arm (1p36.6). This enzyme is important for the folate metabolism which is an integral process for cell metabolism in the DNA, RNA and protein methylation. The mutation of the MTHFR gene which

causes the C677T polymorphism is located at exon 4 which results in the conversion of valine to alanine at codon 222, a common polymorphism that reduces the activity of this enzyme. The homozygous

mutated subjects have higher homocysteine levels while the heterozygous mutated subjects have mildly raised homocysteine levels compared with the normal, non-mutated controls. Hyperhomocysteinemia is an emerging risk factor for various cardiovascular diseases and with the increasing significance of this polymorphism in view of the morbidity and mortality impact on the patients, further prevention strategies and nutritional recommendations with the supplementation of vitamin B12 and folic acid which reduces plasma homocysteine level would be necessary as part of future health education. This literature review therefore focuses on the recent evidence-based reports on the associations of the MTHFR C677T polymorphism and the various diseases globally.” [184]

Methylfolate meta-analysis for depression

https://www.ncbi.nlm.nih.gov/pubmed/29442609 [185]

No trials report on folate or methylfolate versus placebo as a monotherapeutic option. Only when the evidence was restricted to folate at a dose of <5 mg/day or methylfolate at a dose of 15 mg once daily

as an adjunct to selective serotonin reuptake inhibitor therapy was there a significant benefit compared with placebo. [185]