Does folic acid supplementation relieve depression symptoms?

A2017 systematic review and meta-analysis, which included 30 publications (N51,569 adults) evaluated the addition of different nutritional supplements including folic acid to current antidepressants in the treatment of unipolar depression based on DSM III criteria. Any studies that had patients with a neurological or medical comorbidity were excluded. Pooled data from three randomized controlled trials (RCTs) (N5567) compared 0.5, 5, and 10 mg a day of folic acid supplementation to placebo for 10, six, and 12 weeks, respectively. The depression rating scales used in these trials were Hamilton depression rating scale (HDRS) and Beck depression inventory (BDI). Score range was not included in any studies except one where HDRS ,9 was considered a positive response. The pooled standardized mean difference (SMD) in response to treatment with SSRI plus folic acid versus SSRI plus placebo was –0.26 (95% CI, –0.67 to 0.15; P5 .05). Two RCTs (N5127) were also included in the 2015 meta-analysis described below. The remaining RCT (N5440) demonstrated SMD –0.02 (95% CI, –0.17 to 0.21). Limitations of the meta-analysis come from the data requiring larger sample sizes and moderate heterogeneity across studies. A 2015 systematic review and meta-analysis of 11 RCTs (N51,747) examined whether the use of folate or vitamin B12 reduces depression scale scores by at least 50% when compared with placebo treatment. Five hundred five of the patients were taking antidepressants. Depression diagnoses were based on DSM IV criteria, and depression scales used included the Major Depression Inventory, BDI, HDRS, and Patient Health Questionnaire. Studies included were RCTs of folate, B12, or both with minimum of four weeks treatment duration and availability of valid depression measures at the time of initiation and study exit. Studies with dementia patients or taking additional micronutrients were excluded. Only five of the 11 RCTs (N5 505) included participants who had a current depressive episode and found no significant reduction in depression scale scores by adding folate (0.5–10 mg) or methylfolate (7.5–15 mg) compared with placebo to the current antidepressant regimen over a fourto 52-week period (SMD –0.12; 95% CI, –0.45 to 0.22, P5.5). Authors reported moderate heterogeneity across studies: A 2016 RCT (N5219, not included in the above meta-analyses because of study design) evaluated the effect vitamin B12 and folic acid supplementation had on depressive symptoms in older adults ($65 years) with elevated homocysteine concentrations (12–50 Umol/L) who were not on antidepressants. Exclusion criteria included cancer diagnosis within five years, being bedridden, serum creatinine concentration of . 150 mmol/L, current or recent intramuscular injection of B12, use of folic acid supplement, or participation in other studies. Participants received either 500 mg vitamin B12 and 400 mg folic acid daily or placebo for two years. Depressive symptoms were measured using the geriatric depression scale-15 (GDS-15), with a score of five or higher indicating the presence of clinically relevant depressive symptoms. Two-year changes in score were calculated for participants who scored GDS-15 $5 at baseline (N5161). No difference was observed between the intervention group and placebo group (mean change 1.46 vs 1.76, P5.55). A limitation of this study was that D3, which has been shown to reduce depressive symptoms, was added to both the B-vitamin and placebo tablets.