title: Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation.
abstract: 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.
  
  
  OBJECTIVE
  (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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN37558856.
  
  
  BACKGROUND
  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.
authors: Clinical Trials Research Centre, University of Liverpool, Liverpool, UK.
authors: Emma
authors: E
authors: Bedson
authors: Ysbyty Gwynedd, Betsi Cadwalladr University Health Board, Bangor, UK.
authors: Diana
authors: D
authors: Bell
authors: Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK.
authors: Daniel
authors: D
authors: Carr
authors: School of Medicine, Cardiff University, Cardiff, UK.
authors: Ben
authors: B
authors: Carter
authors: Centre for Economics and Policy in Health, Bangor University, Bangor, UK.
authors: Dyfrig
authors: D
authors: Hughes
authors: Department of Biostatistics, University of Liverpool, Liverpool, UK.
authors: Andrea
authors: A
authors: Jorgensen
authors: Department of Health Sciences, University of York, York, UK.
authors: Helen
authors: H
authors: Lewis
authors: College of Medicine, Swansea University, Swansea, UK.
authors: Keith
authors: K
authors: Lloyd
authors: North Wales Centre for Primary Care Research, Bangor University, Bangor, UK.
authors: Andrew
authors: A
authors: McCaddon
authors: Medical Biochemistry & Immunology, University Hospital of Wales, Cardiff, UK.
authors: Stuart
authors: S
authors: Moat
authors: Centre for Economics and Policy in Health, Bangor University, Bangor, UK.
authors: Joshua
authors: J
authors: Pink
authors: Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK.
authors: Munir
authors: M
authors: Pirmohamed
authors: Centre for Mental Health & Society, Bangor University, Bangor, UK.
authors: Seren
authors: S
authors: Roberts
authors: College of Medicine, Swansea University, Swansea, UK.
authors: Ian
authors: I
authors: Russell
authors: Clinical Trials Unit, University College London, London, UK.
authors: Yvonne
authors: Y
authors: Sylvestre
authors: Department of Psychological Medicine, University of Otago, Christchurch, NZ.
authors: Richard
authors: R
authors: Tranter
authors: North Wales Organisation for Randomised Trials in Health, Bangor University, Bangor, UK.
authors: Rhiannon
authors: R
authors: Whitaker
authors: North Wales Centre for Primary Care Research, Bangor University, Bangor, UK.
authors: Clare
authors: C
authors: Wilkinson
authors: North Wales Centre for Primary Care Research, Bangor University, Bangor, UK.
authors: Nefyn
authors: N
authors: Williams
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003362:Cost-Benefit Analysis; D003863:Depression / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005492:Folic Acid / Q000191:economics* / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D012307:Risk Factors; D016896:Treatment Outcome; D014852:Wales
chemical_list: D000928:Antidepressive Agents; D005492:Folic Acid