Folate augmentation of treatment evaluation for depression a randomised controlled trial
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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

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Folate augmentation of treatment evaluation for depression a randomised controlled trial

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
Background Depression: a randomised controlled trial

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 folate6, 7, 8, 9, 10, 11

    • Low folate levels and depression 12

    • L-methylfolate and depression 13


Research questions
Research questions Depression: a randomised controlled trial

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
FolATED is a collaboration between … Depression: a randomised controlled trial

and is supported by …


Overview design
Overview: Design Depression: a randomised controlled trial

  • 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

Screening Interview (Visit 1 week -2)

Randomisation (Visit 2 week 0)

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
Health economics aims Depression: a randomised controlled trial

  • 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)


Interpreting health economics findings
Interpreting health economics findings Depression: a randomised controlled trial

Incremental Costs

£30k/QALY

Less effective,

more costly

Dominated

More effective,

more costly

Incremental QALYs

Less effective,

less costly

More effective,

less costly

Dominant


Metabolism of folate and homocysteine Depression: a randomised controlled trial

Folic acid

Dietary protein

DHFR

DHF (dietary)

DHFR

Methionine

THF

BHMT

SAM

5,10-Methylene THF

CH3

Betaine

MS

SAH

FAD

B12

Homocysteine

5-Methyl-THF

MTHFR

B6

CßS

Remethylation

Cystathionine

Transulphuration

Cysteine


Folated biochemistry protocol
FOLATED – Biochemistry Protocol Depression: a randomised controlled trial

  • 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
Genetics Hypothesis Depression: a randomised controlled trial

  • 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
Candidate Gene Selection Depression: a randomised controlled trial

Carr DF, et al. 2009. Pharmacogenomics J. Oct;9(5):291-305.


Consort pre randomisation
Consort pre randomisation Depression: a randomised controlled trial


Consort post randomisation
Consort post randomisation Depression: a randomised controlled trial


Who participated
Who participated? Depression: a randomised controlled trial

280

women

64%

160

men

36%

Aged between 19 and 81 years (mean 45)

Recruitment centres

Bangor (51%), Wrexham (25%), Swansea (24%)


Who participated1
Who participated? Depression: a randomised controlled trial

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
Other sample characteristics Depression: a randomised controlled trial

  • 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
Principles of Analysis Depression: a randomised controlled trial

  • 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
Primary Statistical Analysis Depression: a randomised controlled trial


Results
Results Depression: a randomised controlled trial

  • 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
But does Folic Acid work? Depression: a randomised controlled trial

Watch this space …………………………….

The Folated team thanks you for listening.


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