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The Folate Factor

Among the busiest of B vitamins, folate has a special role in depression treatment.

Although they number from 1 (thiamine) to 12 (cobalamin), there are eight B vitamins—don't bother seeking numbers 4, 8, 10, or 11. The rest are all facilitators of the nervous system and tend to work in concert. Some are also strong soloists. Folate, B9, is one.

Folate actually encompasses a group of related compounds. Folic acid is the form most often used in supplements and to fortify foods. Methylfolate is the version naturally found in foods. Able to cross the blood-brain barrier, it is the form required by the central nervous system.

Folate is responsible for the very development of the nervous system, which starts early in embryogenesis—often before women know they are pregnant. As a precaution, in the U.S. and a number of other countries, grain products are fortified with folate to prevent birth defects of the brain and spinal cord. Folate also contributes to the formation of myelin, the protective sheath of neurons that speeds conduction of nerve signals. The vitamin plays a continuing role in brain function throughout the lifespan.

Production of the neurotransmitters serotonin, dopamine, and norepinephrine all depend on folate. So does production of melatonin, the hormone that regulates sleep.

Folate is a cofactor in the synthesis of nucleic acids and is needed to maintain the integrity of DNA. Additionally, through "donation" of its methyl component, it regulates gene expression, turning genes on and off.

DNA repair is especially important in the brain, since neurons do not replicate. As a result, they accumulate DNA dings over time. The gradual erosion of DNA integrity and efficiency is a passport to pathology.

Even among healthy people, as the brain ages, it is particularly susceptible to accumulated DNA damage and defective DNA repair as well as lagging cellular housekeeping and inefficiencies of mitochondrial operations. "Without folate," says Massachusetts psychiatrist Emily Deans, "you can't send the signals for regeneration and repair in the brain, which is why one symptom of low folate is depression, and long-term lack of folate can cause dementia."

As if folate didn't have enough to do, it is critical for dismembering homocysteine, an amino acid produced in the course of protein metabolism. In high concentrations, homocysteine damages the lining of blood vessels and leads to vascular inflammation, contributing to the risk of heart attack and stroke as well as to anxiety, depression, and other psychiatric disorders. High homocysteine levels almost always correlate with low folate levels.

People differ widely in the efficiency with which they convert folate to usable methylfolate. Low levels are most common among the elderly. They may consume few folate-rich foods and take medications that interfere with folate metabolism.

A deficiency of folate can not only lead to depression but also hinder recovery from it. Recent studies pinpoint folate deficiency, especially stemming from genetic variability in folate metabolism, as a cause of resistance to antidepressant treatment.

Nevertheless, adjunctive folate can radically boost the effectiveness of medication for major depression. Methylfolate in particular circumvents the metabolic chink that leads to cerebral folate deficiency.

In one multicenter study, when given long term at a dose of 15 milligrams—35 times the recommended daily intake of 400 micrograms—along with an SSRI, folate induced remission or full recovery for the vast majority of patients who had failed to respond to an SSRI alone. Most patients responded in the first three to six months of the yearlong trial. Among the "most notable findings" of the study, the researchers report in the Journal of Clinical Psychiatry, "were the high rates of sustained remission and no reported recurrence in those who recovered."

How Folate Minds the Brain

  • Ensures development of the brain and spinal cord early in embryogenesis
  • Contributes to synthesis of monoamine neurotransmitters (serotonin, dopamine, norepinephrine)
  • Enables synthesis of brain-derived neurotrophic factor, essential for neural plasticity
  • Slows senescence by protecting telomere length
  • Through methyl "donation," maintains epigenetic code that turns genes on and off
  • Maintains cognitive function
  • Stabilizes and repairs DNA, particularly important for neurons, as most are not replaceable
  • Beefs up number and function of brain mitochondria, the high-output energy factories of neurons
  • Converts homocysteine, which is toxic to brain cells and vasculature

Folate Facts

  • Since 1998, folic acid has been added to grain products in the U.S. to prevent spina bifida and other neural tube defects.
  • Foods naturally rich in folate include beef liver, spinach, asparagus, Brussels sprouts, romaine lettuce, avocado, orange juice, and broccoli.
  • Due to genetic variability in folate metabolism, many people are partially or completely unable to convert folic acid to methylfolate, needed by the brain.
  • Folate acts with vitamins B6 (pyridoxine) and B12 to detoxify homocysteine, converting it into the amino acid methionine, a protein building block.
  • Because folate deficiency impairs DNA synthesis, it severely disrupts red blood cell formation, leading to megaloblastic anemia.
  • At the opposite end of the spectrum, excess folate may abet cell proliferation and cancer. (Folate underwrites DNA synthesis, which helps cells divide.)
  • Folate insufficiency during gestation or early life may set the genome up for early senescence.
  • Besides inefficiencies of folate metabolism, folate deficiency can stem from poor diet; use of drugs that interrupt folate absorption or metabolism, including stomach-acid blockers; and heavy alcohol use.
  • Severe folate deficiency is now rare in the general population, but subclinical deficiency is common; most at risk are women of childbearing age and persons over age 65.