The methylation, neurotransmitter, and antioxidant connections between folate and depression

Abstract

Depression is common--one-fourth of the U.S. population will have a depressive episode sometime in life. Folate deficiency is also relatively common in depressed people, with approximately one-third of depressed individuals having an outright deficiency. Folate is a water-soluble B-vitamin necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, epinephrine, and dopamine. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), participates in re-methylation of the amino acid metabolite homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters.Without the participation of 5-MTHF in this process, SAMe and neurotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression. SAMe supplementation was shown to improve depressive symptoms. 5-MTHF also appears to stabilize, enhance production of, or possibly act as a substitute for, tetrahydrobiopterin (BH4), an essential cofactor in monoamine neurotransmitter biosynthesis. There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment for depression related to folate deficiency; however, the studies that have been conducted are promising. Depressed individuals with low serum folate also tend to not respond well to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Correcting the insufficiency by dosing folate along with the SSRI results in a significantly better antidepressant response. (Altern Med Rev 2008; 13:216-226)

Introduction

Clinical depression is common; one in four people will experience depression in their lifetime. It can be debilitating, but is treatable; however, many people do not respond to antidepressant medications. As many as 60 percent of individuals treated with a selective serotonin reuptake inhibitor (SSRI) drug, the standard of depression care, do not achieve remission of depression. Others discontinue drug therapy due to side effects or cost. The causes of depression are manifold, and can include socioeconomic, situational, genetic, and biochemical mechanisms. Because successful drug treatment of depression is uncertain at best, the alternative practitioner has an opportunity to treat the person with efficacious, non-toxic methods. However, the cause of the depressive symptoms must be addressed. One biochemical mechanism that appears to be involved is one-carbon metabolism--a simple biochemical process that appears to be perturbed in a significant number of individuals. One-carbon donation, also called methyl donation, may be at the root of many biochemical disturbances seen in depression and may be improved by providing the cofactors, such as folate, necessary for its optimal metabolism.

Folate is a B-vitamin that, as per the definition of a vitamin, cannot be synthesized de novo; it must be derived from diet or supplementation. Dietary folate is found in leafy green vegetables, legumes, beans, liver, citrus fruits, and yeast. Multiple biochemical conversions are required for dietary folate to become the metabolically active, tissue-usable forms. Folic acid is the term for the synthetic molecule, which is highly absorbed (85-95%) compared to the dietary form (50%). In either case, genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) enzyme (present in approximately 60 percent of the U.S. population), which catalyzes the conversion of methylenetetrahydrofolate to the active form of...