Nutrition and Depression: The Role of Folate

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


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

In This Article

Folate Deficiency and Depression

In 1962, Herbert[4] reported evidence supporting an association between folate deficiency and depressive symptoms. Herbert developed insomnia, irritability, fatigue, and forgetfulness after 4 months of having been on a folate-deficient diet. These symptoms abated following folate replacement. Among patients with folate deficiency severe enough to produce megaloblastic anemia, depressive symptoms have been described as the most common neuropsychiatric complication, followed by dementia and peripheral neuropathy.[5] In several patient cohorts, low to deficient serum or RBC folate concentrations (generally defined as plasma values <=2.5ng/mL or RBC values <200ng/mL) were found in 15% to 38% of patients with depression.[6,7,8,9,10] Because anemia was rare among these patients with low folate, and fewer than one quarter had macrocytosis, folate deficiency would not have been detected in most of these individuals if laboratory hematologic indices had been used as a screen.[7,9]

Low serum B12 concentrations (<200pg/mL) were found less commonly (12% to 14%) than low folate levels among depressed patients.[8,10] Low B12 levels did not appear to distinguish depressed from nondepressed patients.[7] And, when associated with macrocytic anemia, low B12 concentrations were accompanied by mood disturbance in 20% of a heterogeneous patient sample compared with an incidence of 56% among patients with folate deficiency.[5]

Depressed patients have been found to have consistently lower serum or RBC folate concentrations[6,7,11] than other psychiatric patients or normal controls, and patients with very low folate levels generally have higher ratings for depression than patients with normal folate levels.[6,8,12] Lower serum levels of the folate derivative 5-methyltetrahydrofolate have also been reported among depressed subjects compared with controls; those levels were related to severity of depression prior to treatment.[13]

In a group of euthymic outpatients who were taking lithium (26 diagnosed with bipolar disorder and 81 with unipolar mood disorders), those with the highest plasma folate levels exhibited retrospectively over 2 years the lowest degree of "affective morbidity," a concept incorporating the severity and duration of mood disorder symptoms.[12] Additionally, a negative correlation has been reported between serum folate and duration of a current episode of depression in a sample of 44 depressed patients whose folate levels fell generally within the normal range.[14]

All of these findings seem to indicate that folate deficiency is associated with the emergence and, perhaps, severity of depressive illness in a subset of patients. Within a normal range of concentrations, lower folate values may be linked to greater persistence of depressive symptoms. However, it should be noted that these observations do not, of themselves, constitute proof of a causal association between folate and depression, nor do they clarify the direction of causality if such a relationship exists.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.