Physician Letter

From the Desk of:

Irwin H. Rosenberg, MD

Senior Scientist and Director
Nutrition and Neurocognition Laboratory
Jean Mayer USDA HNRCA at Tufts University
Boston, MA

irwin_photo_homeMajor depressive disorders may affect as many as 6.7% of adults in the United States and along with less severe depression, this condition represents a major disease burden in this country.1 Despite major efforts and hundreds of trials over the past 25 years, the remission success rate, especially with single drug therapy, is disappointing. Also, in the last 25 years, there has been recognition that interaction of nutritional factors and brain function deserve increasing attention as a relatively cost-efficient way of approaching not only depressive disorders, but also disorders characterized by cognitive decline with aging. Certainly the population that might benefit from the successful use of nutritional therapy as adjunctive with drugs or even as direct therapy may be very large, especially with the aging of the US population.2

Depression and cognitive decline and dementia, which may be related in older individuals, represent a major opportunity for both treatment and prevention with nutrients in addition to drugs.2 I have been engaged for more than 3 decades in research on folic acid and the relationship of folate and related nutrients to healthy development and brain function. For much of my own career in medicine, I have been involved in studies utilizing the major breakthrough in the 1940s of the synthesis of vitamin B9 as folic acid or pteroylglutamic acid and the isolation and synthesis of other forms of folate or vitamin B9 for use in disorders ranging from hematologic to gastrointestinal to neurologic conditions.

The synthesis of folic acid and its identification made it the second to last of the vitamin discoveries, with the most recent being vitamin B12. The synthetic form of folate, usually referred to as folic acid, is the simplest form of the vitamin and represents the chemical basis for other forms, which are more representative of the way folate or vitamin B9 appear in nature. Those forms include methyltetrahydrofolate, which is the major circulating form of folate in man, and folinic acid,3,4 which is a reduced and formyl substituted form of the folic acid molecule.

Because of folic acid’s wide availability after its synthesis in the 1940s,5 there has been a heavy preponderance of studies with the unreduced and unsubstituted folic acid, but in recent decades, the availability of methyltetrahydrofolate and folinic acid have allowed some extensive exploration of the therapeutic abilities of these forms of folate.6,7

All 3 forms of folic acid can be absorbed across the intestine and into the blood stream, even if there are slightly different efficiencies and mechanisms of absorption. The 3 forms of folate differ in the way in which they are taken up and utilized by the brain and central nervous system, with the unmetabolized form of folic acid requiring some additional stages of metabolism in order to be in the form for ready uptake into the brain.3 However, the clinical and physiologic studies that have been done indicate that despite somewhat different mechanisms of absorption and uptake into the brain, all 3 of these forms of folate have been reported to contribute successfully to adjunctive therapy of depressive disorders. While there may be some theoretical arguments for why one or the other of these forms of folic acid might be more efficient in acting as adjunctive therapy in depressive disorders, there is no decisive evidence that one form or another is preferred in the clinical setting, especially when administered in adequate amounts. So, it is reassuring that all 3 forms have been shown in careful trials to contribute to the effectiveness of treatment of depression6-8 and one might make theoretical arguments that the use of all 3 forms of folate may offer some therapeutic advantage. Therefore, a product, such as EnLyte®, which contains 3.83 mg of L-methylfolate, 2.4 mg of folinic acid, and 2.5 mg of folic acid, may be an effective way of delivering folic acid or folate in the treatment of depressive disorders, especially in the presence of resistant depression or depression resistant to single-drug therapy.

There is much still to be learned about how folic acid or any of its forms may affect brain function with respect to the synthesis or metabolism of neurotransmitters or the methylation of active substances in the brain and those studies need to go on, even as we utilize the different forms of folate in clinical practice.

It is my hope that this example of successful nutrient-brain interaction in the case of resistant depression can also lead the way to increasing use of nutrients, such as folate, for the prevention of age-related cognitive decline and dementia. This could represent a major clinical and therapeutic breakthrough.

Irwin H. Rosenberg, MD
Senior Scientist and Director
Nutrition and Neurocognition Laboratory
Jean Mayer USDA HNRCA at Tufts University
Boston, Massachusetts

  1. National Alliance on Mental Illness. Mental illness: facts and numbers. Section=About_Mental_Illness&Template=/ContentManagement/ContentDisplay.cfm&ContentID=53155. Accessed October 11, 2011.
  2. Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000;71:614S-620S.
  3. Fava M, Mischoulon D. Evidence for folate in combination with antidepressants at initiation of therapy. J Clin Psychiatry. 2010;71:e31.
  4. Farah A. The role of L-methylfolate in depressive disorders. CNS Spectr. 2009;14(Suppl 2):2-7.
  5. Brody JE. Folic acid emerges as a nutritional star. folic-acid-emerges-as-a-nutritional-star.html?pagewanted=all&src=pm. Accessed October 11, 2011.
  6. Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336:392-395.
  7. Alpert JE, Mischoulon D, Rubenstein GE, Bottonari K, Nierenberg AA, Fava M. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry. 2002;14:33-38.
  8. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60:121-130.