Nutrition and Depression: The Role of Folate

Authors and Disclosures

Dr. Alpert is Instructor and Dr. Fava is Associate Professor, Department of Psychiatry, Harvard Medical School, Boston, Mass.

Sidebar: Folate and Metabolism

The biochemical mechanisms through which folate exerts an influence on neuropsychiatric status are likely to involve the 1-carbon cycle, a pathway essential to many transmethylation reactions within the CNS, including the metabolism of neuroactive substances such as the monoamine neurotransmitters and melatonin; the formation of membrane phospholipids; and the synthesis, repair, and recombination of nucleic acids.

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Folate plays an integral role in the 1-carbon cycle (Fig. A). It is first converted to 5-methyltetrahydrofolate (MTHF) and then combines with homocysteine, in a reaction catalyzed by vitamin B12-dependent methionine synthetase, to produce L-methionine. Methionine produced through this cycle, and also furnished directly but in insufficient amounts as a dietary amino acid, is combined with adenosine triphosphate (ATP) in a reaction catalyzed by methionine adenosine transferase (MAT) to form S-adenosyl-methionine (SAMe, or ademetionine). SAMe, in turn, is widely distributed throughout the CNS as an intermediary of over 35 transmethylation reactions.

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In 1963, Smythies

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hypothesized a defect in the mechanism of the 1-carbon cycle as an underlying factor in some psychotic and mood disorders. Although the "transmethylation hypothesis" of schizophrenia as outlined by Smythies has not been well supported by subsequent research, evidence for a role of the 1-carbon cycle in processes relevant to the expression of affective disorders continues to accrue. This includes the work of Tolbert and colleagues,

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who observed that the RBCs of unipolar depressives had lower levels of activity of MAT compared with erythrocytes from controls. Moreover, following antidepressant treatment, a significant increase in the Vmax of the MAT activity of patients with major depression was observed.

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Similarly, low cerebrospinal fluid levels of SAMe have been reported among a sample of depressed adults,

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and parenteral doses of SAMe and some oral formulations of the compound have been associated with antidepressant efficacy greater than placebo and comparable to standard antidepressants, though, quite interestingly, with a more rapid onset.

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As would be predicted from the utilization of folate in 1-carbon metabolism, reduction in brain levels of SAMe has been reported in rats maintained on a folate-deficient diet,^[10] and lowered levels of SAMe have been reported in animal studies following treatment with the antifolate agent methotrexate and in children with inborn errors of folate metabolism.^[11] Thus, at least some of the important neuropsychiatric effects of folate and methylfolate are likely to be mediated through their direct impact on synthesis of this principal methyl donor.

Among the myriad transmethylation reactions involving the 1-carbon cycle, which are most relevant to the relationship between folate and depressive disorders remains a matter of speculation. Both folates and SAMe appear to influence the rate of synthesis of tetrahydrobiopterin (BH4), the cofactor in the hydroxylation of phenylalanine and tryptophan.^[11,12,13] Since this is the rate-limiting step in the biosynthesis of dopamine, norepinephrine, and serotonin--neurotransmitter systems that are thought to be involved in the pathophysiology and treatment of depressive disorders--alterations in the rate of synthesis of this important cofactor may be relevant to depression.^[14]

In support of this hypothesis, BH4 synthesis in brain preparations from depressed patients has been reported to be lower than in preparations from controls,^[15] and exogenous BH4 may have antidepressant properties.^[16,17] Given the diversity of neural processes influenced by alterations in 1-carbon metabolism--from gene transcription to membrane fluidity--these observations point to one of many potential mechanisms underlying the observed relationships between folate and depression, an intriguing area that requires further study.

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16. Curtius H, Niederwieser A, Levine R, et al: Successful treatment of depression with tetrahydrobiopterin. Lancet i:657-658, 1983.

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