title: 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, double-blind, placebo-controlled study.
abstract: OBJECTIVE
  This study was designed to evaluate the efficacy and safety of reduced B vitamins as monotherapy in adults with major depressive disorder (MDD) who were also positive for at least 1 methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with depression and further test the hypothesis that reduced (metabolized) B vitamins will lower homocysteine in a majority of clinically responding patients.
  
  
  METHODS
  330 adult patients with MDD (DSM-5) and positive for either MTHFR C677T or A1298C polymorphism were enrolled in a trial conducted between August 1, 2014, and April 3, 2015. 160 patients received placebo, while 170 received a capsule containing a combination of reduced B vitamins. Plasma homocysteine levels were measured at baseline and week 8. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate efficacy for MDD.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  A combination of reduced B vitamins and micronutrients, when used in the treatment of MDD in patients with MTHFR polymorphism, resulted in a separation from placebo by week 2, and 42% of the treatment arm achieved remission by week 8. Further, clinical improvement correlated with a significant reduction in homocysteine levels in a majority of responders. These results support the homocysteine theory of depression and the safety and therapeutic benefit of reduced B vitamins as monotherapy for MDD, particularly in patients with MTHFR polymorphism.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT02709668.
authors.affiliation: The Mech Center: Outpatient and Research Clinic, Plano, Texas.
authors.forename: Arnold W
authors.initials: AW
authors.lastname: Mech
authors.forename: Andrew
authors.initials: A
authors.lastname: Farah
mesh_terms: D000293:Adolescent; D000328:Adult; D003865:Major Depressive Disorder / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D018977:Micronutrients / Q000627:therapeutic use; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D013223:Statistics as Topic; D014803:Vitamin B Complex / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D018977:Micronutrients; D006710:Homocysteine; D014803:Vitamin B Complex; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)