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
ISRCTN37558856
Background
Depression
• Predicted to be the second leading cause of disability by 2020 1
• 1 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
Research questions
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
FolATED is a collaboration between …
and is supported by …
Overview: Design
Screening Interview (Visit 1 week -2)
HTA funded £1.5 million
Randomisation (Visit 2 week 0)
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
Blood results
Randomisation (Folic acid/placebo)
Repeat assessments
First follow up (Visit 3 week 4)
Second follow up (Visit 4 week 12)
Third follow up (Visit 5 month 6)
Health economics aims
• To assess the cost-effectiveness of folic acid
augmentation of antidepressant response
• Objectives:
– to estimate benefits in terms of quality-adjusted lifeyears
– 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 costeffectiveness)
Interpreting health economics findings
Incremental Costs
Less effective,
more costly
Dominated

£30k/QALY
More effective,
more costly

Incremental QALYs
Less effective,
less costly
More effective,
less costly
Dominant
Metabolism of folate and homocysteine
Folic acid
DHFR
Dietary protein
DHF (dietary)
DHFR
Methionine
THF
5,10-Methylene
THF
FAD
MTHFR
BHMT
MS
B12
5-Methyl-THF
Remethylation
SAM
Betaine
Homocysteine
SAH
CH3
B6
CßS
Cystathionine
Transulphuration
Cysteine
FOLATED – Biochemistry Protocol
• 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 B12 subgroup (< 260ng/L),
↑folate ↔ ↑MMA
Genetics Hypothesis
• 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?
Candidate Gene Selection
DIET
Thymidylate synthesis
THF-polyglutamate
Folic Acid
5-methyl-THFpolyglutmate
dUMP
FPGS
dTMP
DHFR
TYMS
FOLH1
5,10methylene-THF
FOLR1
DHFR
GGH
FPGS
B6
GART
5,10-methenylTHF
B2
THFglutamate
SHMT
MTHFD1
MTHFR
SLC19A1
DHF
FTCD
5-formiminoTHF
AMT
MTHFS
5-formyl-THF
5-methylTHF
THF
FTCD
FTCD
MTHFD1
MTHFD1
10-formyl-THF
GART
Purine synthesis
MTRR
Homocysteine
MTR
B12
Betaine
Methionine
Glycine
AHCY
Cysteine
CTH
ATIC
TCN2
BHMT
Serine
CBS
ALDH1L1 MTFMT
MAT1A
S-adenosyl
homocysteine
DNMT1
S-adenosyl
methionine
AMD1
Cystathione
DNA Methylation
S-adenosyl
methionineamine
Carr DF, et al. 2009. Pharmacogenomics J. Oct;9(5):291-305.
Consort pre randomisation
Referred 1488
Screened 863
Consented 636
Randomised
475
Consort post randomisation
475
Randomised
Group A
237
Group B
238
Lost to
follow up
14
Lost to
follow up
21
223
217
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
Other sample characteristics
• 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
Principles of Analysis
• 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
Primary Statistical Analysis
Step 1:Unadjusted results
Step 2:Adjusted analysis
Primary and secondary
Step 3:Exploratory
endpoints analysis on
all variables of interest
extended over every
time-point
As for step 1 with the
addition of adjustments
for stratification covariables and baseline
measures
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.
• 1st draft of report submitted to HTA and
awaiting review.
But does Folic Acid work?
Watch this space …………………………….
The Folated team thanks you for listening.