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

NWORTH open day, May 2012Yvonne Sylvestre & Richard Tranter

HTA Project 04/35/08 ISRCTN37558856

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

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 costlyDominated

Less effective,less costly

More effective,less costlyDominant

£30k/QALY

Dietary protein

Homocysteine

Cystathionine

Cysteine

Methionine

5-Methyl-THF

THF

5,10-Methylene THF

Remethylation

Transulphuration

B6

B12

MS

MTHFR

CßS

Metabolism of folate and homocysteine

BHMTBetaine CH3

Folic acid

FAD

SAM

SAH

DHF (dietary)DHFR

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 B12 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. 2009. Pharmacogenomics J. Oct;9(5):291-305.

5-methyl-THF

THF

Betaine Glycine

MTRR B12

Cystathione

MTHFD1

S-adenosyl homocysteine

S-adenosyl methionineDNMT1

5-formimino-THF

10-formyl-THF

Homocysteine Methionine

dUMP dTMP

AHCYSerine

Cysteine

CTH

MAT1A

S-adenosyl methionineamine

AMD1

DHFR

CBS

B6

GART ATIC

MTHFD1

MTHFD1

AMT

MTHFS

FTCDFTCD

SHMT

GART

TYMS

THF-polyglutamate

THF-glutamate

GGH

FPGS

DHF DHFR

FPGS

5,10-methylene-THF

MTHFRB2

5-methyl-THF-polyglutmate

FOLH1

SLC19A1

DIET

Folic Acid

MTR

TCN2

FTCD5-formyl-THF

DNA Methylation

Thymidylate synthesis

ALDH1L1 MTFMT

Purine synthesis

FOLR1

5,10-methenyl-THF

BHMT

Referred

1488

Screened

863

Consented

636

Randomised 475

Consort pre randomisation

Consort post randomisation

217

Group A 237

Group B 238

223

475 Randomised

Lost to follow up

14

Lost to follow up

21

Who participated?

280 women64%

160 men36%

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 retired43% 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.

• 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.