Folate Augmentation of Treatment – Evaluation for Depression: a randomised controlled trial NWORTH open day, May 2012 Yvonne Sylvestre & Richard Tranter HTA Project 04/35/08 ISRCTN

Depression Predicted to be the second leading cause of disability by in 5 experience depression & only half will respond to antidepressants 2 Folate status in patients with depression 1/3 of patients with depression have decreased folate levels 3 Patients with low folate respond less well to antidepressants 4 Folate & antidepressant response Antidepressants work via effects on synaptic neurotransmitter activity Folate is a methyl-donor in many methylation reactions in the brain involving these neurotransmitters 5 Fluoxetine (20mg) & folic acid (10mg) or placebo for 6 weeks. N=27. Clinically significant improvement on HAM-D for the folic acid group compared to placebo. 25 Non-systematic reviews:  Augmenting antidepressants with folate 6, 7, 8, 9, 10, 11  Low folate levels and depression 12  L-methylfolate and depression 13 Background

PRIMARY OBJECTIVE To estimate the clinical- and cost-effectiveness of folate augmentation in antidepressant treatment of moderate to severe depression. SECONDARY OBJECTIVES To evaluate whether: response to antidepressants depends on genetic polymorphisms baseline folate status predicts treatment response folate augmentation decreases homocysteine levels and increases MethylMalonic Acid levels Research questions

and is supported by … FolATED is a collaboration between …

Overview: Design Randomisation (Visit 2 week 0) Blood results Randomisation (Folic acid/placebo) Repeat assessments Screening Interview (Visit 1 week -2) First follow up (Visit 3 week 4) Second follow up (Visit 4 week 12) Third follow up (Visit 5 month 6) HTA funded £1.5 million Large, multi-centred, double-blind, placebo-controlled trial Recruited from primary and secondary care from the three centres in Wales (North East Wales, North West Wales and Swansea) Randomised to 5mg folic acid or matching placebo for 12 weeks

To assess the cost-effectiveness of folic acid augmentation of antidepressant response Objectives: – to estimate benefits in terms of quality-adjusted life- years – to estimate total costs from the perspective of the NHS and PSS – to estimate the incremental cost utility ratio – to assess decision uncertainty (probability of cost- effectiveness) Health economics aims

Interpreting health economics findings Incremental QALYs Incremental Costs More effective, more costly Less effective, more costly Dominated Less effective, less costly More effective, less costly Dominant £30k/QALY 

Dietary protein Homocysteine Cystathionine Cysteine Methionine 5-Methyl-THF THF 5,10-Methylene THF Remethylation Transulphuration B6B6 B 12 MS MTHFR CßS Metabolism of folate and homocysteine BHMT Betaine CH 3 Folic acid FAD SAM SAH DHF (dietary) DHFR

Patients to receive either Placebo or 5mg FA/day for 12 weeks Plasma Hcy, Folate & B12 to be measured baseline, 12 weeks & 6 months Sub-study: Low B 12 subgroup ( < 260ng/L), ↑folate ↔ ↑MMA FOLATED – Biochemistry Protocol

Dan Carr & Andrea Jorgensen, Wolfson Centre for Personalised Medicine University of Liverpool Variation of one-carbon folate and methionine synthesis pathway genes influences efficacy of folic acid as an adjuvant to antidepressant therapy. 25 candidate genes selected based on functionality associated with either the one carbon folate or methionine pathways Are these variants predictive of efficacy? Genetics Hypothesis

Candidate Gene Selection Carr DF, et al Pharmacogenomics J. Oct;9(5):

Referred 1488 Screened 863 Consented 636 Randomised 475 Consort pre randomisation

Consort post randomisation

Who participated? 280 women 64% 160 men 36% Aged between 19 and 81 years (mean 45) Recruitment centres Bangor (51%), Wrexham (25%), Swansea (24%)

Who participated? 28% in full time work 28% part time work, students or retired 43% unemployed, at home or sick 23% single, 21% previously had partner, 55% currently had a partner or spouse

Entry criteria - moderate to severe depression Becks Depression Inventory, BDI > 18 (mean 33.7 s.d. 9.6) 25% new antidepressant treatment at recruitment, 75% continuing treatment 19% of men and 12% of women drank at unsafe levels Other sample characteristics

Pre-specified analysis plan written prior to analysis, which evolved to cover challenges in the data Data reported to CONSORT standards Primary analysis by “Treatment as Allocated” Missing data imputed by rigorous algorithm to minimise bias. Following best practice, we used 2 semi-independent analysis teams. Statistical and economic analyses techniques aligned Principles of Analysis

Primary Statistical Analysis Step 1:Unadjusted results Primary and secondary endpoints analysis on all variables of interest extended over every time-point Step 2:Adjusted analysis As for step 1 with the addition of adjustments for stratification co- variables and baseline measures Step 3:Exploratory A full structured analysis of all significant factors and interactions designed to further explore and explain results from stage 2.

Results Definitive RCT of folic acid augmentation of antidepressant treatment. Unequivocal results that will inform future treatment guidelines. 1 st draft of report submitted to HTA and awaiting review.

But does Folic Acid work? Watch this space ……………………………. The Folated team thanks you for listening.