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Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation

Emma Bedson, Diana Bell, Daniel Carr, Ben Carter, Dyfrig Hughes, Andrea Jorgensen, Helen Lewis, Keith Lloyd Orcid Logo, Andrew McCaddon, Stuart Moat, Joshua Pink, Munir Pirmohamed, Seren Roberts, Ian Russell, Yvonne Sylvestre, Richard Tranter, Rhiannon Whitaker, Clare Wilkinson, Nefyn Williams

Health Technology Assessment, Volume: 18, Issue: 48, Pages: 1 - 160

Swansea University Author: Keith Lloyd Orcid Logo

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DOI (Published version): 10.3310/hta18480

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AbstractBackgroundFolate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak.Objectives(1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to anti...

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Published in: Health Technology Assessment
ISSN: 1366-5278 2046-4924
Published: 2014
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2018-05-29T15:18:04.7400307</datestamp><bib-version>v2</bib-version><id>39943</id><entry>2018-05-03</entry><title>Folate Augmentation of Treatment &#x2013; Evaluation for Depression (FolATED): randomised trial and economic evaluation</title><swanseaauthors><author><sid>a13aaa0df9045c205e82ed3b95d18c10</sid><ORCID>0000-0002-1440-4124</ORCID><firstname>Keith</firstname><surname>Lloyd</surname><name>Keith Lloyd</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2018-05-03</date><deptcode>FGMHL</deptcode><abstract>AbstractBackgroundFolate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak.Objectives(1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism.DesignFolATED (Folate Augmentation of Treatment &#x2013; Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost&#x2013;utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a &#x2018;small&#x2019; effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453.SettingsClinical &#x2013; Three centres in Wales &#x2013; North East Wales, North West Wales and Swansea. Trial management &#x2013; North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis &#x2013; University Hospital of Wales, Cardiff. Genetic analysis &#x2013; University of Liverpool.ParticipantsFour hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research.InterventionsOnce a day for 12 weeks experimental participants added 5&#x2009;mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners.Main outcome measuresAssessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by &#x2018;area under curve&#x2019; (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health &#x2013; BDI-II (primary), Clinical Global Impression (CGI), Montgomery&#x2013;&#xC5;sberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health &#x2013; UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale &#x2013; 5 Dimensions (EQ-5D); Biochemistry &#x2013; serum folate, B12, homocysteine; Adherence &#x2013; Morisky Questionnaire; Economics &#x2013; resource use.ResultsFolic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from &#x2013;12.7 to 7.0 days] and saved a mean of just &#xA3;48 (95% CI from &#x2013;&#xA3;292 to &#xA3;389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from &#x2013;5.2% to &#x2013;0.8%).ConclusionsThe FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM.Trial registrationCurrent Controlled Trials ISRCTN37558856.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information.</abstract><type>Journal Article</type><journal>Health Technology Assessment</journal><volume>18</volume><journalNumber>48</journalNumber><paginationStart>1</paginationStart><paginationEnd>160</paginationEnd><publisher/><issnPrint>1366-5278</issnPrint><issnElectronic>2046-4924</issnElectronic><keywords>Clinical trial, depression folic acid</keywords><publishedDay>31</publishedDay><publishedMonth>7</publishedMonth><publishedYear>2014</publishedYear><publishedDate>2014-07-31</publishedDate><doi>10.3310/hta18480</doi><url/><notes/><college>COLLEGE NANME</college><department>Medicine, Health and Life Science - Faculty</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>FGMHL</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2018-05-29T15:18:04.7400307</lastEdited><Created>2018-05-03T15:44:07.5278358</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Emma</firstname><surname>Bedson</surname><order>1</order></author><author><firstname>Diana</firstname><surname>Bell</surname><order>2</order></author><author><firstname>Daniel</firstname><surname>Carr</surname><order>3</order></author><author><firstname>Ben</firstname><surname>Carter</surname><order>4</order></author><author><firstname>Dyfrig</firstname><surname>Hughes</surname><order>5</order></author><author><firstname>Andrea</firstname><surname>Jorgensen</surname><order>6</order></author><author><firstname>Helen</firstname><surname>Lewis</surname><order>7</order></author><author><firstname>Keith</firstname><surname>Lloyd</surname><orcid>0000-0002-1440-4124</orcid><order>8</order></author><author><firstname>Andrew</firstname><surname>McCaddon</surname><order>9</order></author><author><firstname>Stuart</firstname><surname>Moat</surname><order>10</order></author><author><firstname>Joshua</firstname><surname>Pink</surname><order>11</order></author><author><firstname>Munir</firstname><surname>Pirmohamed</surname><order>12</order></author><author><firstname>Seren</firstname><surname>Roberts</surname><order>13</order></author><author><firstname>Ian</firstname><surname>Russell</surname><order>14</order></author><author><firstname>Yvonne</firstname><surname>Sylvestre</surname><order>15</order></author><author><firstname>Richard</firstname><surname>Tranter</surname><order>16</order></author><author><firstname>Rhiannon</firstname><surname>Whitaker</surname><order>17</order></author><author><firstname>Clare</firstname><surname>Wilkinson</surname><order>18</order></author><author><firstname>Nefyn</firstname><surname>Williams</surname><order>19</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling 2018-05-29T15:18:04.7400307 v2 39943 2018-05-03 Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation a13aaa0df9045c205e82ed3b95d18c10 0000-0002-1440-4124 Keith Lloyd Keith Lloyd true false 2018-05-03 FGMHL AbstractBackgroundFolate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak.Objectives(1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism.DesignFolATED (Folate Augmentation of Treatment – Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost–utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a ‘small’ effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453.SettingsClinical – Three centres in Wales – North East Wales, North West Wales and Swansea. Trial management – North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis – University Hospital of Wales, Cardiff. Genetic analysis – University of Liverpool.ParticipantsFour hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research.InterventionsOnce a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners.Main outcome measuresAssessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by ‘area under curve’ (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health – BDI-II (primary), Clinical Global Impression (CGI), Montgomery–Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health – UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale – 5 Dimensions (EQ-5D); Biochemistry – serum folate, B12, homocysteine; Adherence – Morisky Questionnaire; Economics – resource use.ResultsFolic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from –12.7 to 7.0 days] and saved a mean of just £48 (95% CI from –£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from –5.2% to –0.8%).ConclusionsThe FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM.Trial registrationCurrent Controlled Trials ISRCTN37558856.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information. Journal Article Health Technology Assessment 18 48 1 160 1366-5278 2046-4924 Clinical trial, depression folic acid 31 7 2014 2014-07-31 10.3310/hta18480 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University 2018-05-29T15:18:04.7400307 2018-05-03T15:44:07.5278358 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Emma Bedson 1 Diana Bell 2 Daniel Carr 3 Ben Carter 4 Dyfrig Hughes 5 Andrea Jorgensen 6 Helen Lewis 7 Keith Lloyd 0000-0002-1440-4124 8 Andrew McCaddon 9 Stuart Moat 10 Joshua Pink 11 Munir Pirmohamed 12 Seren Roberts 13 Ian Russell 14 Yvonne Sylvestre 15 Richard Tranter 16 Rhiannon Whitaker 17 Clare Wilkinson 18 Nefyn Williams 19
title Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation
spellingShingle Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation
Keith Lloyd
title_short Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation
title_full Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation
title_fullStr Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation
title_full_unstemmed Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation
title_sort Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation
author_id_str_mv a13aaa0df9045c205e82ed3b95d18c10
author_id_fullname_str_mv a13aaa0df9045c205e82ed3b95d18c10_***_Keith Lloyd
author Keith Lloyd
author2 Emma Bedson
Diana Bell
Daniel Carr
Ben Carter
Dyfrig Hughes
Andrea Jorgensen
Helen Lewis
Keith Lloyd
Andrew McCaddon
Stuart Moat
Joshua Pink
Munir Pirmohamed
Seren Roberts
Ian Russell
Yvonne Sylvestre
Richard Tranter
Rhiannon Whitaker
Clare Wilkinson
Nefyn Williams
format Journal article
container_title Health Technology Assessment
container_volume 18
container_issue 48
container_start_page 1
publishDate 2014
institution Swansea University
issn 1366-5278
2046-4924
doi_str_mv 10.3310/hta18480
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 0
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description AbstractBackgroundFolate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak.Objectives(1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism.DesignFolATED (Folate Augmentation of Treatment – Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost–utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a ‘small’ effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453.SettingsClinical – Three centres in Wales – North East Wales, North West Wales and Swansea. Trial management – North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis – University Hospital of Wales, Cardiff. Genetic analysis – University of Liverpool.ParticipantsFour hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research.InterventionsOnce a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners.Main outcome measuresAssessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by ‘area under curve’ (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health – BDI-II (primary), Clinical Global Impression (CGI), Montgomery–Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health – UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale – 5 Dimensions (EQ-5D); Biochemistry – serum folate, B12, homocysteine; Adherence – Morisky Questionnaire; Economics – resource use.ResultsFolic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from –12.7 to 7.0 days] and saved a mean of just £48 (95% CI from –£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from –5.2% to –0.8%).ConclusionsThe FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM.Trial registrationCurrent Controlled Trials ISRCTN37558856.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information.
published_date 2014-07-31T03:50:48Z
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