Editorial
Folic acid and the treatment of depression

https://doi.org/10.1016/j.jpsychores.2006.07.007Get rights and content

Abstract

Reduced plasma, serum, or red blood cell folate is commonly found in major depressive illnesses. Supplementing antidepressant medication with folic acid enhances the therapeutic effect. Although more work is required to confirm these beneficial results, it is suggested that, meanwhile, 2 mg of folic acid should be given during the acute, continuation, and maintenance treatment of depression.

Introduction

Numerous studies have reported that patients with major depression have low plasma, serum, or red blood cell folate concentration [1]. We have previously found that both plasma and red blood cell folate concentrations were on average about 24% lower in drug-free, acutely ill depressed patients than in normal control subjects and that lower serum folate concentrations were associated with greater severity of depression [2]. An earlier study by Reynolds et al. [3] showed that the therapeutic outcome following antidepressant or electroconvulsive therapy was inferior if the plasma folate was low. High plasma folate levels are also important for the continuation treatment of depression. Papakostas et al. [4] followed up 71 outpatients with remitted major depression for 28 weeks who were treated with fluoxetine and found that the relapse rate of patients with low folate was 42.9% compared with the 3.2% relapse rate of patients with higher folate levels. Coppen and Abou-Saleh [5] reported that patients with higher plasma folate attending a lithium clinic had significantly lower affective morbidity over 2 years than patients with lower plasma folate. Papakostas et al. [6] have also reported that, in patients who failed to respond to fluoxetine and who received augmentation therapy with lithium or desipramine, low folate was associated with a lower response rate (7.1%) than in those with normal folate levels (44.7%).

Community studies have also shown a link between low serum folate and depressive symptoms. Sachdev et al. [7] examined the relationship between folic acid and depression in a community sample of 412 persons between 60 and 64 years of age and found that low serum folate and high homocysteine were associated with depressive symptoms.

A further important finding is the association between coronary artery disease (CAD) and depression [8]. Surveys have shown that patients who develop depression have an increased risk of CAD and that patients with CAD who are depressed have a worse outlook than nondepressed patients. CAD and depression show a common pathology in the form of low serum folate [9].

Folate is a major determinant of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of folate deficiency, and increased homocysteine levels are found in depressive patients [10]. In a large-population study from Norway, increased plasma homocysteine was associated with increased risk of depression but not of anxiety [11]. Furthermore, the MTHFR C677T polymorphism that impairs homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association [12]. In folate-deficient depressed patients, CSF amine metabolites were significantly reduced in a subgroup of patients with high plasma homocysteine who also had the lowest levels of red blood cell and CSF folate and CSF SAM [13].

Section snippets

Implications for treatment

It is important that the treatment of major depression, ranked by the WHO as the fourth most important cause of premature mortality and disability [14], is improved. Antidepressants are weak therapeutic agents and have not improved in efficacy since their introduction in the 1950s. Fifty percent of the patients responded to treatment using the active drug, whereas only 32% responded to placebo [15]. It is therefore crucial that we devise better treatments for this serious and lethal condition.

Augmentation of antidepressants by folic acid

Coppen and Bailey [15] reported a study of patients attending their general practitioners (GPs) with a major depressive disorder (DSM-III-R) and who scored at least 20 on the Hamilton Rating Scale (HRS). All GPs attended training sessions on the use of the DSM and the HRS. Among the eligible 127 patients, 109 completed the trial after random allocation to receive either 20 mg of fluoxetine plus 500 μg of folic acid or fluoxetine with the placebo capsule. The trial was designed to last 10 weeks.

Dosage of folic acid to augment antidepressants

The study of Coppen and Bailey [15] showed that the dose of folic acid is important. For men, the 500-μg dose of folic acid was insufficient to lower their plasma and homocysteine levels and to cause an improved response rate. We suggest the use of 2 mg of folic acid, which would be expected to increase plasma folate to more than 20 ng/ml in both sexes.

Trials of antidepressant treatments take a long time to carry out, and continuation and maintenance studies take even longer. Adding 2 mg of

References (18)

There are more references available in the full text version of this article.

Cited by (60)

View all citing articles on Scopus

Declaration of interest: Alec Coppen possesses a patent for medication, including that for an antidepressant and folic acid, whereas Mohammed T. Abou-Saleh has none.

View full text