Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials

J Psychopharmacol. 2004 Jun;18(2):251-6. doi: 10.1177/0269881104042630.


The objective of this review was to determine the effectiveness, adverse effects and acceptability of folate in the treatment of depression. Electronic databases (Cochrane Controlled Trials Register and the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register) and reference lists were searched, and authors, experts and pharmaceutical companies contacted to identify randomized controlled trials that compared treatment with folic acid or 5'-methyltetrahydrofolic acid to an alternative treatment, for patients with a diagnosis of depressive disorder. Three randomized trials (247 participants) were included. Two studies assessed the use of folate in addition to other treatment, and found that adding folate reduced Hamilton Depression Rating Scale (HDRS) scores on average by a further 2.65 points [95% confidence interval (CI) 0.38-4.93]. Fewer patients treated with folate experienced a reduction in their HDRS score of less than 50% at 10 weeks (relative risk 0.47, 95% CI 0.24-0.92). The remaining study found no statistically significant difference when folate alone was compared with trazodone. The identified trials did not find evidence of any problems with the acceptability or safety of folate. The limited available evidence suggests folate may have a potential role as a supplement to other treatment for depression. It is currently unclear if this is the case both for people with normal folate levels, and for those with folate deficiency.

Publication types

  • Clinical Trial
  • Comparative Study
  • Meta-Analysis
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Administration, Oral
  • Aged
  • Antidepressive Agents / therapeutic use
  • Depressive Disorder / diagnosis
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / epidemiology
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • Fluoxetine / administration & dosage
  • Fluoxetine / therapeutic use
  • Humans
  • Male
  • Meta-Analysis as Topic*
  • Psychiatric Status Rating Scales
  • Sex Characteristics
  • Tetrahydrofolates / administration & dosage
  • Tetrahydrofolates / blood
  • Tetrahydrofolates / therapeutic use*
  • Trazodone / administration & dosage
  • Trazodone / therapeutic use
  • Treatment Outcome


  • Antidepressive Agents
  • Tetrahydrofolates
  • Fluoxetine
  • Trazodone