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Many studies, going back to the 1960s, show an elevated incidence of folate deficiency in patients with depression. Studies vary depending on the criteria used to define folate deficiency, but often, about one-third of depression patients were deficient. Given that depression is often accompanied by decreased appetite and weight loss, the high incidence of folate deficiency in depression patients is not surprising. However, there is some evidence, though not conclusive, that folate deficiency may be involved in the etiology of depression in a minority of patients. Alternatively, depressed mood may decrease appetite, lower folate levels and thereby help to prevent recovery from depression. A recent review and metaanalysis looked at the results from the limited number of studies that investigated the effect of giving folate to depression patients and concluded that “there is some evidence that augmentation of antidepressant treatment with folate may improve patient outcome.” Whether the putative beneficial effect of folate is limited to those with folate deficiency is not clear.

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If folate deficiency can contribute to depressed mood and folate supplementation is beneficial in patients, a plausible mechanism implicates serotonin. In most,but not all studies on patients with neuropsychiatric disorders, folate deficiency was associated with low levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). In one study, supplementation with folate restored CSF 5-HIAA levels to normal. There is also a decrease in serotonin synthesis in patients with 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency, a disorder of folate metabolism.While the mechanism relating folate deficiency to low serotonin is not known, it may involve S-adenosylmethionine (SAMe). SAMe is a major methyl donor formed from methionine. Folate is involved in a cycle that regenerates methionine from homocysteine after SAMe is demethylated to S-adenosylhomocysteine, with subsequent conversion to homocysteine. Folate deficiency decreases SAMe in the rat brain.In humans, SAMe is an antidepressant and increases CSF 5-HIAA levels. Thus, there is some consistency in what is known about the interrelations of folate, SAMe and depression.