Recent reports suggest that people with lower folate levels are at higher risk of major depression or may experience more severe depressive symptoms.  Other studies indicate that in folate deficient patients, antidepressants may be less effective or may take longer to take effect.  In addition, some clinical trials have shown that folate may have a therapeutic effect on depression, either when taken alone or in combination with an antidepressant.

The link between folate deficiency and depression is further supported by genetic studies which indicate that a common polymorphism (C677T) of the enzyme methylene tetrahydrofolate reductase (MTHFR) is more common in patients with depression.  This enzyme is essential for the conversion of dietary folate to its active metabolite, MTHF or L-methylfolate.  It is believed that people with this variant of MTHFR have lower levels of L-methylfolate available for the synthesis of certain neurotransmitters, including serotonin.

What about folate and perinatal depression?

During pregnancy, the demand for folate is increased.  Without adequate supplementation, levels of maternal folate decrease gradually from the fifth month of pregnancy onwards and remain low for several months after childbirth.  This decline in folate levels is further accentuated in women with shorter inter-pregnancy intervals.

Given the evidence supporting a link between low folate levels and depression, a recent study has explored the association between depressive symptoms during and after pregnancy and self-reported use of folic acid supplements during pregnancy.  In this prospective study including 6809 pregnant women, depressive symptoms were measured with the Edinburgh Postnatal Depression Scale (EPDS) at 18 and 32 weeks of pregnancy and at 8 weeks, 8 months and 21 months postpartum.  Information on the use of folic acid supplements was collected using a questionnaire administered at 18 and 32 weeks gestation.

In this study, folic acid supplementation did not appear to reduce the risk of depression during pregnancy and up to 8 months after pregnancy. However, this study did find that folic acid supplements during pregnancy protected against depression at 21 months postpartum.  This effect was most pronounced in women with the MTHFR C677T TT genotype.  The authors speculated that in these women with C677T TT genotype produce lower levels of active L-methylfolate and thus may be more vulnerable to its depletion during pregnancy and the postpartum period.

In another study conducted during pregnancy, it was observed that women homozygous for the the MTHFR C677T genotype had higher levels of depressive symptoms during pregnancy.  The folate status of the women in this study was not evaluated; however, all the women were taking folic acid supplements and lived in a country with folic acid fortification of foods.  If we assume there is a link between low folate and risk for depression, this study suggests that standard levels of folate supplementation may not adequately compensate for the folate deficiency observed in women homozygous for the C677T genotype of the MTHFR enzyme.

Should Some Childbearing Women Take Even More Folic Acid?

Because women with low folate levels are at increased risk of having a child with a neural tube defect (NTD), the association between the C667T polymorphism of the MTHFR enzyme and this particular birth defect has been extensively studied. In a 2000 meta-analysis, Botto and Yang found that mothers homozygous for the C667T polymorphism were at a 2-fold increased risk of having a child with a NTD (odds ratio 2.0), while infants with this polymorphism had an 80% increased risk of having a NTD (odds ratio 1.8).

The U. S. Public Health Service and CDC recommend that all women of childbearing age consume 0.4 mg (400 micrograms) of folic acid daily to reduce the risk of serious birth defects.    All women of reproductive age should take folic acid daily because half of all pregnancies are unplanned and because these neural tube defects occur very early in pregnancy (3-4 weeks after conception); before many women know they are pregnant.

In addition, a recent article from the Motherisk program notes that there are some women who are clearly at greater risk for folate deficiency during pregnancy.  On this list, they include women with the polymorphism in the MTHFR C677T gene described above, as well as several other similar gene variants.  The list also includes women who:

  • Have diabetes
  • Are obese
  • Smoke
  • Take antiepileptic drugs (e.g., valproic acid, carbamazepine, barbiturates)
  • Take folate antagonists (e.g., methotrexate, sulfonamides)
  • Belong to high-risk ethnic groups (e.g., Sikh, Celtic, Northern Chinese)

Because women in these groups may not achieve protective levels of folic acid with standard prenatal vitamin supplements and therefore may be at higher risk of having a child with a neural tube defect, the authors recommend that clinicians should offer these women 5 mg per day of folic acid before conception and until the end of the first trimester (i.e., until after closure of the neural tube).

This article did not address the association between low folate levels and risk for depression.  However, extrapolating from the data generated in non-pregnant populations, one could argue that because childbearing women are at higher risk of folate deficiency, they may benefit from supplementation with even higher doses of folic acid (i.e., more than 400 mcg per day) and that this intervention may reduce the risk of depression during pregnancy and the postpartum period.  (Note:  The studies described in detail above used standard doses of folate, less than 400 mcg per day.)  This is a question for future research studies.

Ruta Nonacs, MD PhD

Devlin AM, Brain U, Austin J, Oberlander TF.  Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth. PLoS One. 2010 Aug 16;5(8):e12201.

Lewis SJ, Araya R, Leary S, et al.  Folic acid supplementation during pregnancy may protect against depression 21 months after pregnancy, an effect modified by MTHFR C677T genotype.  Eur J Clin Nutrition (2012) 66, 97–103.

Read more about L-methylfolate:

Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant-Augmenting Agent (CNS Spectrums)








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