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In a study of erythrocyte folate concentrations, Carney and colleagues (1990) observed that among patients admitted to a psychiatric unit with endogenous depression, 20 percent had erythrocyte folate concentrations below 327 nmol/L (150 ng/mL), a prevalence markedly higher than that observed in euthymic, manic, schizophrenic, or alcoholic patients. A recent study involving plasma folate determinations suggests that the prevalence of folate deficiency may not be this high (Fava et al., 1997). Nevertheless, patients with low plasma folate levels responded less well to standard antidepressant (fluoxetine) therapy than did those with normal folate values. In these studies, there appears to be no uniform definition of folate deficiency (as indexed via the plasma or erythrocyte folate determination); moreover, folate assays (and absolute folate values) differed among laboratories (and within studies, e.g., Coppen et al. [1986]), making any blood deficiency threshold difficult to standardize (Young and Ghadirian, 1989).

Two double-blind studies (Coppen et al., 1986; Godfrey et al., 1990) evaluated the efficacy of folate supplementation in the recovery from psychiatric illness, but the use of nutrients for treatment is not relevant to this report and will not be discussed here.

Although the connection between folate and mental function has been most strongly made for depression and affective state, intake of the vitamin has also been linked (though less convincingly at present) to other psychiatric conditions and to deficits in learning and memory, particularly in the elderly (Joyal et al., 1993; Riggs et al., 1996; Wahlin et al., 1996).

The mechanism by which folate modifies brain functions has been sought for more than two decades and is generally hypothesized to be related to its role in single-carbon metabolism (Alpert and Fava, 1997). In particular, methylene tetrahydrofolate is the methyl donor in methionine synthesis from homocysteine and is postulated to be important in maintaining adequate methionine pools for S-adenosylmethionine (SAM) biosynthesis (Bottiglieri et al., 1994). SAM is the cofactor in key methylation reactions in catecholamine synthesis and metabolism in brain (Turner, 1977); catecholamines are transmitters known to be important in maintaining affective state, and exogenous SAM has been shown by some to elevate mood (Bell et al., 1988). Folate has also been linked to the maintenance of adequate brain levels of tetrahydropterin (Hamon et al., 1986), a key cofactor in the hydroxylation reactions leading to the synthesis of transmitters such as serotonin and the catecholamines (Turner, 1977). Methylation reactions involving folate may be important in maintaining neuronal and glial membrane lipids (Hirata and Axelrod,



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