Background:

Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak.

Objectives:

(1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism.

Design:

FolATED (Folate Augmentation of Treatment – Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost–utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a ‘small’ effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453.

Settings:

Clinical – Three centres in Wales – North East Wales, North West Wales and Swansea. Trial management – North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis – University Hospital of Wales, Cardiff. Genetic analysis – University of Liverpool.

Participants:

Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B₁₂ deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research.

Interventions:

Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners.

Main outcome measures:

Assessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by ‘area under curve’ (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health – BDI-II (primary), Clinical Global Impression (CGI), Montgomery–Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health – UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale – 5 Dimensions (EQ-5D); Biochemistry – serum folate, B₁₂, homocysteine; Adherence – Morisky Questionnaire; Economics – resource use.

Results:

Folic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from –12.7 to 7.0 days] and saved a mean of just £48 (95% CI from –£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from –5.2% to –0.8%).

Conclusions:

The FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM.

Trial registration:

Current Controlled Trials ISRCTN37558856.

Funding:

This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 04/35/08. The contractual start date was in October 2006. The draft report began editorial review in May 2012 and was accepted for publication in August 2013. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Andrew McCaddon is a scientific advisor and shareholder of COBALZ Ltd – a private limited company developing novel B vitamin and antioxidant supplements.