Folate augmentation of treatment evaluation for depression a randomised controlled trial
This presentation is the property of its rightful owner.
Sponsored Links
1 / 20

Folate Augmentation of Treatment – Evaluation for Depression: a randomised controlled trial PowerPoint PPT Presentation


  • 59 Views
  • Uploaded on
  • Presentation posted in: General

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

Download Presentation

Folate Augmentation of Treatment – Evaluation for Depression: a randomised controlled trial

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


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

  • 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

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 …

and is supported by …


Overview design

Overview: Design

  • 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

  • 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

Incremental Costs

£30k/QALY

Less effective,

more costly

Dominated

More effective,

more costly

Incremental QALYs

Less effective,

less costly

More effective,

less costly

Dominant


Folate augmentation of treatment evaluation for depression a randomised controlled trial

Metabolism of folate and homocysteine

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

  • 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

  • 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

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


Consort pre randomisation

Consort pre randomisation


Consort post randomisation

Consort post randomisation


Who participated

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 participated1

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

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

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

Primary Statistical Analysis


Results

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

But does Folic Acid work?

Watch this space …………………………….

The Folated team thanks you for listening.


  • Login