Folate and depression--a neglected problem.

Researchers are not immune to fashion. A wealth of data going back several decades relating serotonin function to the regulation of mood and the current emphasis on genetics in biological psychiatry research have resulted in an increasing number of studies relating various polymorphisms of serotonin-related genes to various types of psychopathology. The assumption behind these studies is that the polymorphisms may alter serotonin function and therefore alter susceptibility to depressed mood or other symptoms. This line of research is important from a theoretical perspective but has fewer practical implications (except possibly in predicting response to drugs); practical methods to alter genes in depression patients are a long way in the future. The current explosion of work on serotonin-related polymorphisms is in sharp contrast to the much smaller number of recent studies on an entirely reversible environmental factor known to lower serotonin synthesis—folate deficiency. The purpose of this editorial is to draw attention to what is known about the epidemiology and biochemical and clinical effects of folate deficiency, to point out what studies are needed and to consider the recent recommendation that patients with depression should be treated with 2 mg of folic acid. 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. 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. There is an important need for additional studies on folate and depression, the most pressing of which is larger studies on the ability of folate to potentiate the action of standard antidepressant therapies. Additional issues that need to be addressed are the dosage of folate needed to get the maximum effect and the possibility that the response may differ in different subgroups, such as those with and without overt folate deficiency. Meanwhile, how should clinicians act, considering what we currently know? In particular, should all depression patients be given folate supplements, and if so, how much? Is there no need for supplements in countries with mandatory or voluntary fortification of foods with