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

Ben Carter; Zohra Zenasni; Stuart J Moat; Peter R Hudson; Ian T Russell; Andrew McCaddon; Rhiannon Whitaker; Joshua Pink; Seren Roberts; Clare Wilkinson; Dyfrig Hughes; Emma Betson; Diana Carr; Andrea Jorgenson; Munir Pirmohamed; Nevyn Williams; Helen Lewis; Keith Lloyd; Yvonne Sylvesture; Richard Tranter

doi:10.1093/jn/nxab280

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

Ben Carter, Zohra Zenasni, Stuart J Moat, Peter R Hudson, Ian T Russell, Andrew McCaddon, Rhiannon Whitaker, Joshua Pink, Seren Roberts, Clare Wilkinson, Dyfrig Hughes, Emma Betson, Diana Carr, Andrea Jorgenson, Munir Pirmohamed, Nevyn Williams, Helen Lewis, Keith Lloyd, Yvonne Sylvesture, Richard Tranter

School of Health Sciences

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Abstract

BACKGROUND: Individuals 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.

OBJECTIVES: We aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12.

METHODS: We conducted a multicenter double-blind placebo-controlled randomized trial of oral FA (5 mg/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 ≥150 and <220 ng/L) or "marginal" serum vitamin B-12 (vitamin B-12 ≥ 220 and <280 ng/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).

RESULTS: A total of 177 participants were included (85 randomly assigned to placebo and 92 to FA); the mean ± SD age was 46.2 ± 11.8 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 = 0.71). Serum folate was measured on 166 participants and increased in the supplementation group; the aMD was 21.6 μg/L (95% CI: 8.13, 25.02 μg/L; P < 0.001). A total of 117 participants were assessed for RBC folate, which also increased in the supplementation group; the aMD was 461 μg/L (95% CI: 387, 535 μg/L; P < 0.001).

CONCLUSIONS: Supplementation 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 ng/L. We cannot exclude effects in older people or those with serum vitamin B-12 <150 ng/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.

Original language	English
Pages (from-to)	3738-3745
Number of pages	8
Journal	Journal of Nutrition
Volume	151
Issue number	12
Early online date	11 Sept 2021
DOIs	https://doi.org/10.1093/jn/nxab280
Publication status	Published - Dec 2021

Keywords

Nutrition and Dietetics
Medicine (miscellaneous)

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10.1093/jn/nxab280

2021 Plasma MethylmalonicFinal published version, 604 KBLicence: CC BY

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Carter, B., Zenasni, Z., Moat, S. J., Hudson, P. R., Russell, I. T., McCaddon, A., Whitaker, R., Pink, J., Roberts, S., Wilkinson, C., Hughes, D., Betson, E., Carr, D., Jorgenson, A., Pirmohamed, M., Williams, N., Lewis, H., Lloyd, K., Sylvesture, Y., & Tranter, R. (2021). Plasma Methylmalonic Acid Concentration in Folic Acid–Supplemented Depressed Patients with Low or Marginal Vitamin B-12: A Randomized Trial. Journal of Nutrition, 151(12), 3738-3745. https://doi.org/10.1093/jn/nxab280

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title = "Plasma Methylmalonic Acid Concentration in Folic Acid–Supplemented Depressed Patients with Low or Marginal Vitamin B-12: A Randomized Trial",

abstract = "BACKGROUND: Individuals 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.OBJECTIVES: We aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12.METHODS: We conducted a multicenter double-blind placebo-controlled randomized trial of oral FA (5 mg/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 ≥150 and <220 ng/L) or {"}marginal{"} serum vitamin B-12 (vitamin B-12 ≥ 220 and <280 ng/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).RESULTS: A total of 177 participants were included (85 randomly assigned to placebo and 92 to FA); the mean ± SD age was 46.2 ± 11.8 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 = 0.71). Serum folate was measured on 166 participants and increased in the supplementation group; the aMD was 21.6 μg/L (95\% CI: 8.13, 25.02 μg/L; P < 0.001). A total of 117 participants were assessed for RBC folate, which also increased in the supplementation group; the aMD was 461 μg/L (95\% CI: 387, 535 μg/L; P < 0.001).CONCLUSIONS: Supplementation 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 ng/L. We cannot exclude effects in older people or those with serum vitamin B-12 <150 ng/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.",

keywords = "Nutrition and Dietetics, Medicine (miscellaneous)",

author = "Ben Carter and Zohra Zenasni and Moat, \{Stuart J\} and Hudson, \{Peter R\} and Russell, \{Ian T\} and Andrew McCaddon and Rhiannon Whitaker and Joshua Pink and Seren Roberts and Clare Wilkinson and Dyfrig Hughes and Emma Betson and Diana Carr and Andrea Jorgenson and Munir Pirmohamed and Nevyn Williams and Helen Lewis and Keith Lloyd and Yvonne Sylvesture and Richard Tranter",

note = "{\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.",

year = "2021",

month = dec,

doi = "10.1093/jn/nxab280",

language = "English",

volume = "151",

pages = "3738--3745",

journal = "Journal of Nutrition",

issn = "0022-3166",

publisher = "Elsevier BV",

number = "12",

}

Carter, B, Zenasni, Z, Moat, SJ, Hudson, PR, Russell, IT, McCaddon, A, Whitaker, R, Pink, J, Roberts, S , Wilkinson, C , Hughes, D, Betson, E, Carr, D, Jorgenson, A, Pirmohamed, M, Williams, N, Lewis, H, Lloyd, K, Sylvesture, Y & Tranter, R 2021, 'Plasma Methylmalonic Acid Concentration in Folic Acid–Supplemented Depressed Patients with Low or Marginal Vitamin B-12: A Randomized Trial', Journal of Nutrition, vol. 151, no. 12, pp. 3738-3745. https://doi.org/10.1093/jn/nxab280

TY - JOUR

T1 - Plasma Methylmalonic Acid Concentration in Folic Acid–Supplemented Depressed Patients with Low or Marginal Vitamin B-12: A Randomized Trial

AU - Carter, Ben

AU - Zenasni, Zohra

AU - Moat, Stuart J

AU - Hudson, Peter R

AU - Russell, Ian T

AU - McCaddon, Andrew

AU - Whitaker, Rhiannon

AU - Pink, Joshua

AU - Roberts, Seren

AU - Wilkinson, Clare

AU - Hughes, Dyfrig

AU - Betson, Emma

AU - Carr, Diana

AU - Jorgenson, Andrea

AU - Pirmohamed, Munir

AU - Williams, Nevyn

AU - Lewis, Helen

AU - Lloyd, Keith

AU - Sylvesture, Yvonne

AU - Tranter, Richard

PY - 2021/12

Y1 - 2021/12

N2 - BACKGROUND: Individuals 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.OBJECTIVES: We aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12.METHODS: We conducted a multicenter double-blind placebo-controlled randomized trial of oral FA (5 mg/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 ≥150 and <220 ng/L) or "marginal" serum vitamin B-12 (vitamin B-12 ≥ 220 and <280 ng/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).RESULTS: A total of 177 participants were included (85 randomly assigned to placebo and 92 to FA); the mean ± SD age was 46.2 ± 11.8 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 = 0.71). Serum folate was measured on 166 participants and increased in the supplementation group; the aMD was 21.6 μg/L (95% CI: 8.13, 25.02 μg/L; P < 0.001). A total of 117 participants were assessed for RBC folate, which also increased in the supplementation group; the aMD was 461 μg/L (95% CI: 387, 535 μg/L; P < 0.001).CONCLUSIONS: Supplementation 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 ng/L. We cannot exclude effects in older people or those with serum vitamin B-12 <150 ng/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.

AB - BACKGROUND: Individuals 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.OBJECTIVES: We aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12.METHODS: We conducted a multicenter double-blind placebo-controlled randomized trial of oral FA (5 mg/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 ≥150 and <220 ng/L) or "marginal" serum vitamin B-12 (vitamin B-12 ≥ 220 and <280 ng/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).RESULTS: A total of 177 participants were included (85 randomly assigned to placebo and 92 to FA); the mean ± SD age was 46.2 ± 11.8 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 = 0.71). Serum folate was measured on 166 participants and increased in the supplementation group; the aMD was 21.6 μg/L (95% CI: 8.13, 25.02 μg/L; P < 0.001). A total of 117 participants were assessed for RBC folate, which also increased in the supplementation group; the aMD was 461 μg/L (95% CI: 387, 535 μg/L; P < 0.001).CONCLUSIONS: Supplementation 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 ng/L. We cannot exclude effects in older people or those with serum vitamin B-12 <150 ng/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.

KW - Nutrition and Dietetics

KW - Medicine (miscellaneous)

U2 - 10.1093/jn/nxab280

DO - 10.1093/jn/nxab280

M3 - Article

C2 - 34510193

SN - 0022-3166

VL - 151

SP - 3738

EP - 3745

JO - Journal of Nutrition

JF - Journal of Nutrition

IS - 12

ER -

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

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