Nutrition and Depression: The Role of Folate

Jonathan E. Alpert, MD, PhD, Maurizio Fava, MD

Medscape Psychiatry & Mental Health eJournal. 1997;2(1)

The Basis for Folate Deficiency in Depression

How folate interrelates with depression is unclear. A wide variety of factors and conditions are associated with folate deficiency states, including drugs (particularly certain anticonvulsants, antibiotics, oral contraceptives, and antifolate cancer chemotherapeutics); malabsorption syndromes; chronic diseases (including autoimmune disorders such as rheumatoid arthritis); inborn errors of folate metabolism such as 5,10-methylene tetrahydrofolate reductase deficiency; alcoholism; increased utilization states such as pregnancy; and dietary folate deficiency.^[1,23] Does a primary folate deficiency produce depression and its symptoms, or does poor nutrition as a symptom of depression cause a decrease in folate level?

Consistent with the latter hypothesis--that poor nutrition in depression leads to low folate levels--is the finding that when measured across depressive subtypes, low folate appears to predominate in melancholic depression, and anorexia and weight loss are common features of this type.^[10] Nevertheless, efforts to prove that low folate in depression is the result of poor diet have so far been inconclusive.^[8,11] Mixed results may, in part, reflect the difficulty of obtaining an accurate dietary record among depressed patients. In addition, they may suggest a multifactorial etiology. Abou-Saleh and Coppen^[23] hypothesized that it is a combination of decreased appetite, decreased absorption, and increased utilization of folate that results in folate depletion and eventually produces a CNS effect. In addition, as appears to be true of depression itself, the etiology of folate deficiency in depressive disorders and the temporal relationship between low folate levels and depression are likely to reflect considerable heterogeneity across patient populations. Among medical and alcohol-dependent populations, in particular, it is plausible to suggest that folate deficiency may be a predisposing factor to the development of depression. For other individuals with persistent depression, loss of appetite or poor food selection may contribute to the secondary development of low folate levels, which then seems likely to exacerbate the depression and produce greater refractoriness to standard antidepressant therapies.

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Cite this: Nutrition and Depression: The Role of Folate - Medscape - Jan 30, 1997.

Abstract & Introduction
Folate Deficiency and Depression
Folate and the Prediction of Antidepressant Response
Folate in the Treatment of Depression
The Basis for Folate Deficiency in Depression
Conclusion
References
Sidebar: Folate and Metabolism

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.

^[1,2,3]

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.

^[3,4]

In 1963, Smythies

^[5]

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,

^[6]

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.

^[7]

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

^[8]

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.

^[9]

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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Bottiglieri T, Hyland K, Reynolds EH: The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 48:137-152, 1994.
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Nutrition and Depression: The Role of Folate

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