Plasma Methylmalonic Acid Concentration in Folic Acid-Supplemented Depressed Patients with Low or Marginal Vitamin B-12: A Randomized Trial.

Abstract

BACKGROUND\nIndividuals with low serum vitamin B-12 and high serum folate have higher plasma concentrations of methylmalonic acid (MMA). Whether folic acid (FA) causes an increase in MMA is not known.\n\n\nOBJECTIVES\nWe aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12.\n\n\nMETHODS\nWe conducted a multicenter double-blind placebo-controlled randomized trial of oral FA (5\xa0mg/d for 12 wk) in middle-aged patients treated with antidepressant medication participating in the FoLATED (Folate Augmentation of Treatment-Evaluation for Depression) trial. Participants defined as having low serum vitamin B-12 (vitamin B-12\xa0≥150 and <220\xa0ng/L) or marginal serum vitamin B-12 (vitamin B-12\xa0≥\xa0220 and <280\xa0ng/L) were included. The primary outcome of this substudy was MMA at week 12. A mixed-effects linear regression was fitted and reported using the adjusted mean difference (aMD).\n\n\nRESULTS\nA total of 177 participants were included (85 randomly assigned to placebo and 92 to FA); the mean\xa0±\xa0SD age was 46.2\xa0±\xa011.8 y, and 112 (63.3%) were female. The MMA analysis included 135 participants and the aMD was -0.01 (95% CI: -0.06, 0.04; P\xa0=\xa00.71). Serum folate was measured on 166 participants and increased in the supplementation group; the aMD was 21.6\xa0μg/L (95% CI: 8.13, 25.02\xa0μg/L; P\xa0<\xa00.001). A total of 117 participants were assessed for RBC folate, which also increased in the supplementation group; the aMD was 461\xa0μg/L (95% CI: 387, 535\xa0μg/L; P\xa0<\xa00.001).\n\n\nCONCLUSIONS\nSupplementation of FA leads to an increase of serum and RBC folate, but does not change plasma MMA concentration in individuals with serum vitamin B-12 between 150 and 280\xa0ng/L. We cannot exclude effects in older people or those with serum vitamin B-12 <150\xa0ng/L. Previously reported associations may arise from effects of impaired vitamin B-12 status on folate metabolism.This trial was registered at www.isrctn.com as ISRCTN37558856.