Caveat emptor: Folate in unipolar depressive illness, a systematic review and meta-analysis

J Psychopharmacol. 2018 Apr;32(4):377-384. doi: 10.1177/0269881118756060. Epub 2018 Feb 14.


Background: International guideline recommendations for the use of folate and its derivatives in the treatment of unipolar depressive disorders are confused and contradictory, perhaps reflecting wide variations in the underpinning evidence base.

Introduction: We discuss differing methods of evidence synthesis in the formulation of international guideline recommendations. As an example we evaluated the efficacy of folate and its derivatives in unipolar depression via systematic review and meta-analysis.

Methods: We searched Medline, EMBASE, PsychInfo and CENTRAL from database inception until 1 May 2017 for randomised controlled trials. We included trials that evaluated folate or its derivatives as monotherapy or to augment antidepressant therapy compared with placebo in patients with unipolar depressive illness. Standardised mean differences were used and studies were introduced as subgroups to explain the heterogeneity. Quality was assessed using the Grading of Recommendations Assessment, Development and Evaluation.

Results: No trials report on folate or methylfolate versus placebo as a monotherapeutic option. Only when the evidence was restricted to folate at a dose of <5 mg/day or methylfolate at a dose of 15 mg once daily as an adjunct to selective serotonin reuptake inhibitor therapy was there a significant benefit compared with placebo. All evidence was graded as low or very low quality for each outcome.

Discussion: Whilst previous guidelines on the treatment of unipolar depression have either avoided this topic entirely, or made recommendations on the basis of cherry-picked evidence, this review is the first to attempt to provide clinically useful recommendations based on comprehensive, current randomised placebo-controlled data. We invite discussion of the review and its recommendations, which are based on the limited evidence regarding folate formulation delivered and appropriate dosage.

Keywords: Depression; evidence; folate; meta-analysis.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Antidepressive Agents / therapeutic use*
  • Depression / drug therapy*
  • Depressive Disorder, Major / drug therapy*
  • Folic Acid / therapeutic use*
  • Humans
  • Randomized Controlled Trials as Topic


  • Antidepressive Agents
  • Folic Acid