complaint to the tga: neurofolin - a food for special ... · good sources of folate include green...

Complaint to the TGA: Neurofolin - a food for special medical purposes for the dietary support of depression management

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Summary: This complaint is another example of regulatory double standards at the Food-Medicine Interface. It concerns Neurofolin® (containing 15 mg of L-methylfolate calcium) - a self-declared food for special medical purposes promoted for dietary support of depression management.

There are listed medicines solely containing the same ingredient, such as L-5MTHF (ARTG no: 270098), whose TGA indication requirement states: “Product presentation must not imply or refer to mental illnesses, disorders or conditions”.

Mental illnesses such as depression are regarded as restricted representations by the Therapeutic Goods Act 1989. Advertisements for therapeutic goods may only refer to such a representation if prior approval has been obtained.

Yet Neurofolin® is self-declared and promoted as, “a food for special medical purposes for the dietary support of depression management” and this claim does not need prior approval (according to FSANZ Standard 2.6.5).

I argue there is insufficient evidence to support the use of L-methylfolate calcium for depression, either as adjunctive, or especially as sole therapy. Medically diagnosed depression does NOT have special medically determined nutrient requirements for 15 mg of L-methylfolate calcium daily and there is no good evidence that the dietary management of patients with depression cannot be completely achieved without the use of this "food”. In my opinion, Neurofolin® does not meet the requirements of FSANZ Standard 2.6.5.

In addition, I allege the advertising claims made breach Australian Consumer Law (and would breach many sections of the Therapeutic Goods Advertising Code if this product was classified as a complementary medicine). Furthermore, the regulatory double standard involved is misleading for consumers and unfair to the complementary medicine industry.

I have sent this complaint to the TGA, with a copy to FSANZ, because it is yet another example of problems at the Food-Medicine interface which both the TGA and FSANZ have so-far failed to deal with. I presume the TGA will hand-ball the complaint to the Victorian Health Department because the company involved is based in Victoria. Regardless of who deals with this complaint, I request a written determination as to whether Neurofolin® meets the requirements of FSANZ Standard 2.6.5.

Furthermore, this case, and others such as Souvanaid®, Ceretain® and Neurothrive®, raise important questions regarding the ability of product sponsors to self-declare under FSANZ Standard 2.6.5 that their products are beneficial for serious conditions such as depression and Alzheimer’s disease without any independent assessment of all the available evidence. I argue that sponsor self-determination of Standard 2.6.5 is inappropriate and an independent assessment of evidence should be required before a product can be promoted as a “food for special medicinal purposes”.

I ask that the appropriateness of “food” sponsors to self-declare “food for special medicinal purposes” without independent assessment be addressed by both FSANZ and the TGA.

Complaint detail: Product name: Neurofolin®

Sponsor: Grunbiotics Pty Ltd (In partnership with Mylan) Level M2, West Podium, Rialto, 525 Collins St, Melbourne, VIC 3000 AUSTRALIA

Telephone +613 8692-0006 E: [email protected] W: http://www.grunbiotics.com/

Ingredient: L-methylfolate calcium 15 mg

Advertisement type: Internet

mailto:[email protected]

http://www.grunbiotics.com/


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Where did it appear (screen shots appended):

http://www.grunbiotics.com/neurofolin-for-depression https://www.neurofolin.com.au/ https://www.neurofolin.com.au/neurofolin-in-the-news

https://www.goodpricepharmacy.com.au/neurofolin-powder-30-sachets https://www.yourdiscountchemist.com.au/blog/neurofolin/ https://www.chemistdirect.com.au/neurofolin-powder-15g-sachets-x-30 https://www.chemistwarehouse.com.au/buy/87829/neurofolin-15g-powder-30-sachets https://www.royyoungchemist.com.au/neurofolin-powder-15g-x-30-sachets-1.html Etc.

Date seen: 9/05/2019

Claims (taken from appended screen shots):

• “NEUROFOLIN (DEPRESSION) For dietary support of depression management”. http://www.grunbiotics.com/neurofolin-for-depression

• “Neurofolin is a food for special medical purposes for the dietary support of depression management. It contains 15 mg of L-methylfolate, an active form of folate known to be deficient in individuals with depressive disorders and helps nutritionally support mood regulation”. http://www.grunbiotics.com/neurofolin-for-depression

• “There is certainly a trend globally in depression treatment towards augmenting medications with specialised nutritional support to improve the number of people who benefit. The data from the conference certainly shows how promising that approach is likely to be,” said Dr Bassett”. Screen shots of the video that follow in this link are appended. https://www.neurofolin.com.au/neurofolin-in-the-news

http://www.grunbiotics.com/neurofolin-for-depression

https://www.neurofolin.com.au/

https://www.neurofolin.com.au/neurofolin-in-the-news

https://www.goodpricepharmacy.com.au/neurofolin-powder-30-sachets

https://www.yourdiscountchemist.com.au/blog/neurofolin/

https://www.chemistdirect.com.au/neurofolin-powder-15g-sachets-x-30

https://www.chemistwarehouse.com.au/buy/87829/neurofolin-15g-powder-30-sachets

https://www.royyoungchemist.com.au/neurofolin-powder-15g-x-30-sachets-1.html






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• “Neurofolin is a food for special medical purposes for the dietary support of depression management. It contains 15 mg of L-methylfolate, an active form of folate known to be deficient in individuals with depressive disorders and helps nutritionally support mood regulation”. https://www.neurofolin.com.au/buy

• “Neurofolin contains L-methylfolate, an active form of folate that addresses part of a complex deficiency found in people with depression”. https://www.chemistdirect.com.au/neurofolin-powder-15g-sachets-x-30

• “It may be used alone or with antidepressants under the supervision of a healthcare professional”. https://www.chemistdirect.com.au/neurofolin-powder-15g-sachets-x-30

• “However, there is a new promising over the counter treatment that is showing positive signs when used in conjunction or alone with an antidepressant - L-methylfolate. L-methylfolate is marketed in Australia under the brand name Neurofolin”. https://www.yourdiscountchemist.com.au/blog/neurofolin/

Discussion: Restricted representations for therapeutic goods

Mental illness such as depression are regarded as restricted representations by the Therapeutic Goods Act 1989. Advertisements for therapeutic goods may only refer, expressly or by implication, to such conditions if prior approval is obtained from the Delegate of the Secretary. Approval involves assessing whether the representation is accurate and balanced, not misleading or likely to be misleading, and fulfils public interest criteria.1

FSANZ Standard 2.9.5: Food for special medical purposes

Definition: A food for special medical purposes means a food that is: (a) specially formulated for the dietary management of individuals: (i) by way of exclusive or partial feeding, who have special medically determined nutrient requirements or whose capacity is limited or impaired to take, digest, absorb, metabolise or excrete ordinary food or certain nutrients in ordinary food; and (ii) whose dietary management cannot be completely achieved without the use of the food.2 A product sponsor can self-assess whether the above conditions are met and there is no independent assessment of whether the claims for the product are accurate, balanced and not misleading.

Background on folate

Folate is a generic term for naturally occurring forms of a water-soluble B vitamin in food, dietary supplements and fortified foods, including synthetic folic acid. It is essential for cell development; for the metabolism of specific biochemical reactions in the body and for the metabolism of specific anticonvulsant drugs.

Sources of folate in food

Good sources of folate include green leafy vegetables, fruit (citrus, berries and bananas), legumes and some cereals. Voluntary fortification of several foods with folate has been permitted in Australia since June 1995 and many breakfast cereals now have added folate. Mandatory folic acid fortification of all flour used for making bread (except organic bread) came into effect in September 2009.

Folate levels in the Australian population

The National Health Measures Survey (NHMS) showed that less than 1% of women aged 16–44 years had red cell folate levels in the at-risk range for NTDs (less than 906 nmol/L). Almost all males met their requirements for folate (2% with inadequate intakes).3

1 https://www.tga.gov.au/restricted-representations 2 https://www.legislation.gov.au/Details/F2017C00337 3 http://www.abs.gov.au/ausstats/[email protected]/Lookup/4364.0.55.006Chapter1002011-12

https://www.neurofolin.com.au/buy





https://www.tga.gov.au/restricted-representations

https://www.legislation.gov.au/Details/F2017C00337

http://www.abs.gov.au/ausstats/[email protected]/Lookup/4364.0.55.006Chapter1002011-12


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Sources of folate permitted for use by the TGA in listed medicines.

Folic acid, calcium folinate and levomefolate salts (glucosamine and calcium) are permitted ingredients in listed.4 Examples of products solely containing levomefolate salts include ARTG no: 270098 L-5MTHF and ARTG 310089 Activated Folate 500. These products have a TGA indication requirement: Product presentation must not imply or refer to mental illnesses, disorders or conditions (appended).

Metabolism of folic acid with respect to the central nervous system

The methylenetetrahydrofolate reductase (MTHFR) gene is responsible for the production of the enzyme MTHFR enzyme which metabolises folic acid into l-5-methyltetrahydrofolate (l-5-MTHF), also known as l-methylfolate (Levomefolic acid). L-methylfolate is the primary form of circulating folate in the blood and crosses the blood-brain barrier.5

A deficiency of folate in pregnancy increases the risk of foetal neural tube defects. L-methylfolate is also a cofactor in the production of monoamines serotonin, dopamine, and norepinephrine, which are involved in the regulation of mood and the mechanisms of actions of antidepressants. It has been suggested that up to 70% of depressed patients have a variants (polymorphisms) of the MTHFR gene that may compromise their ability to convert dietary folate or synthetic folic acid to l-methylfolate.6 This is said to be the rationale for augmenting conventional antidepressants with l-methylfolate supplementation, especially in non-responders.

However, 60–70% of the general population (not just depressed patients) have common variants of the MTHFR gene. Also, there is no statistically significant evidence that genetic polymorphisms have a clinically important impact on this pathway.5 The Academy of Nutrition and Dietetics states that no dietary interventions are needed for patients with MTHFR gene polymorphisms.7

Official recommendations

To prevent neural tube defects (NTDs) in babies it is recommended that women planning pregnancy should consume additional folic acid as a supplement at a level of 400-500 µg/day folic acid for at least one month before and three months after conception, in addition to consuming food folate from a varied diet. For high-risk patients (e.g. previous NTDs) 5 mg daily is recommended, timing as above.8

Post-mandatory folic acid fortification in Australia, there has been a statistically significant 14.4% decrease in the rate of NTDs in the total study population. The decrease in NTDs was most substantial for Aboriginal and Torres Strait Islander women and teenagers.9

The upper level of intake (ULI) of dietary folate equivalents is adult men and women is 1000 mcg per day.10 There are no official recommendations for patients with depression to consume additional folate.

Adverse effects

No adverse effects have been associated with consumption of the amounts of dietary folate equivalents normally found in foods or fortified foods. High supplemental intakes of folic acid have related to adverse neurological effects in people with B12 deficiency as they can precipitate or exacerbate the B12 deficiency.4

Concern has been expressed that voluntary fortification of food, high availability of low-cost folic acid supplements and mandatory addition of folic acid to grain may be adding excessive amounts to a person’s 4 https://www.tga.gov.au/folate-and-folic-acid-use-listed-medicines 5 https://www.racgp.org.au/afp/2016/april/mthfr-genetic-testing-controversy-and-clinical-implications/ 6 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616/ 7 https://jandonline.org/article/S2212-2672(13)01783-8/fulltext 8 https://www1.racgp.org.au/ajgp/2018/july/preconception-care/ 9 https://www.aihw.gov.au/reports/food-nutrition/monitoring-health-impacts-of-mandatory-folic-acid/contents/summary 10 https://www.nrv.gov.au/nutrients/folate

https://www.tga.gov.au/folate-and-folic-acid-use-listed-medicines

https://www.racgp.org.au/afp/2016/april/mthfr-genetic-testing-controversy-and-clinical-implications/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616/

https://jandonline.org/article/S2212-2672(13)01783-8/fulltext

https://www1.racgp.org.au/ajgp/2018/july/preconception-care/

https://www.aihw.gov.au/reports/food-nutrition/monitoring-health-impacts-of-mandatory-folic-acid/contents/summary

https://www.aihw.gov.au/reports/food-nutrition/monitoring-health-impacts-of-mandatory-folic-acid/contents/summary

https://www.nrv.gov.au/nutrients/folate


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diet. It has been suggested that under certain conditions, this may promote cancer, interact with medications and impair foetal development.11

Studies on folic acid, L-methylfolate and depression

Several studies have investigated the effect of nutritional supplements on depression, including folic acid.12,13,14 The findings do not support the use of folic acid for the treatment or prevention of depression. Also, there is no consistency in the association of serum folate levels and depression.15

There are two multicentre randomised controlled trials, Papakostas G, et al. (2012) that have investigated the effectiveness of l-methylfolate as adjunctive therapy to non-responders of standard anti-depressant therapy (SSRIs), appended.16

Trial 1 involved 148 adults and trial 2, 75 adults. Assessments Ire carried out every 10 days for each of the two, 30-day phases of treatment. Both trials Ire funded by Pamlab and 11 of 19 authors disclosed financial or other links with Pamlab (a producer of l-methylfolate).

In the first trial 7.5 mg/day adjunctive L-methylfolate did not improve Hamilton Depression Scale (HAM-D) response or degree of improvement compared with placebo in either phase of the trial. Participants who increased to 15 mg/day for the second phase of the trial did demonstrate improved response compared with placebo, though this fell short of clinical significance (24% vs 9%; p=0.1).

In the second trial 15 mg L-methylfolate improved HAM-D response rates compared with placebo (32.3% vs 14.6%; p=0.04) and gave greater improvement in HAM-D (−5.58 vs −3.04; p=0.05). In the second trial 15 mg L-methylfolate also improved the secondary outcomes of score change on Clinical Global Impression Scale (CGI) severity scale (−0.92 vs −0.34; p=0.01) and quick inventory of depressive symptomology-self-rated (QIDS-SR)(−4.7 vs −2.62; p=0.04) compared with placebo.

L-Methylfolate was Ill tolerated, with rates of adverse events no different from those reported with placebo.

A 2013 commentary (appended)17 noted there were methodological limitations to these studies, including a relatively small sample size, short treatment period and short duration of follow-up. Use of high doses of folate was also noteworthy given concerns that exposure to high doses accelerates tumour growth in people with a history of colorectal cancer. A strength of this study is the use of L-methylfolate instead of synthetic folic acid.

The commentary stated one must be cautious in recommending adjunctive antidepressant treatment with folate as they have yet to be fully established: (a) any long-term risks and benefits of exposure to high doses, (b) a dose-response relationship, or (c) the optimal duration of treatment required. The evidence base needs large, pragmatic clinical trials to replicate promising results from small-sized and medium-sized studies. These must also measure the important individual differences in folate metabolism to determine if there are clinical subgroups who respond to folate augmentation and how to identify them. There is still much research to be carried out before I can safely recommend widespread adjuvant prescribing for depression.

The 68% significant improvement in 500 patients given l-methylfolate after 12 weeks from the video illustrated above appear to have come (without attribution) from a 2013 published, uncontrolled, “naturalistic” study in which most patients (91%) also received a conventional anti-depressant.18 It was reported that Pamlab funded the study writing and editing of the manuscript; had a role in the design of the

11 https://www.nature.com/articles/ejcn2016194 12 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133130/ 13 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381191/ 14 https://jamanetwork.com/journals/jama/article-abstract/2726983 15 https://www.nature.com/articles/ejcn201797 16 https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2012.11071114. 17 https://www.ncbi.nlm.nih.gov/pubmed/23625145. 18 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616/

https://www.nature.com/articles/ejcn2016194



https://jamanetwork.com/journals/jama/article-abstract/2726983

https://www.nature.com/articles/ejcn201797

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2012.11071114

https://www.ncbi.nlm.nih.gov/pubmed/23625145



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study, the interpretation of the data, and the review and approval of the manuscript for submission. In addition, all authors disclosed financial or other links with Pamlab.

A 2016 follow-up of patients in both trials (n=223) was reported by Zajecka JM, et al.19 No serious adverse event requiring early termination occurred in 68 subjects who met criteria for the 12-month open-label phase. Potential benefits of adjunctive l-methylfolate therapy Ire supported by high rates of response, remission and recovery. This study was also funded by Phamlab and several authors also disclosed financial or other links with Phamlab.

A 2017 systematic review by Schefft C, et al, of the efficacy of adding nutritional supplements in unipolar depression found no more controlled clinical trials involving l-methylfolate therapy than those described above. They stated there was too little data to draw firm conclusions. They suggested that in future RCTs on nutritive agents it would be desirable to adjust sample sizes accordingly and to operationalize both treatment-resistance and states of nutrient deficiency more precisely.

Comment on the claims made Considering the above studies, I argue there is insufficient evidence to support the use of L-methylfolate calcium for depression, either as adjunctive, or especially as sole therapy. Medically diagnosed depression does NOT have special medically determined nutrient requirements for 15 mg of L-methylfolate calcium daily and there is no good evidence that the dietary management of patients with depression cannot be completely achieved without the use of this "food”. In my opinion, Neurofolin® does not meet the requirements of FSANZ Standard 2.6.5.

In addition, I allege the advertising claims made breach Australian Consumer Law (and would breach many sections of the Therapeutic Goods Advertising Code if this product was classified as a complementary medicine). Furthermore, the regulatory double standard involved is misleading for consumers and unfair to the complementary medicine industry.

I allege the following claims are misleading and deceptive:

• “NEUROFOLIN (DEPRESSION) For dietary support of depression management”. http://www.grunbiotics.com/neurofolin-for-depression The evidence above does not support these claims.

• “It contains 15 mg of L-methylfolate, an active form of folate known to be deficient in individuals with depressive disorders and helps nutritionally support mood regulation”. http://www.grunbiotics.com/neurofolin-for-depression I could not find evidence that showed L-methylfolate is “deficient in individuals with depressive disorders” nor that it “helps nutritionally support mood regulation”.

• “The data from the conference certainly shows how promising that approach is likely to be,” said Dr Bassett. Screen shots of the video show 68% significant improvement in 500 patients given l-methylfolate after 12 weeks”. https://www.neurofolin.com.au/neurofolin-in-the-news These figures appear to have come (without attribution) from an uncontrolled, “naturalistic” open-label study in which in which most patients (91%) also received a conventional anti-depressant. The figures are deceptive and misleading. In addition, it was not disclosed that Dr Bassett has been involved in the Neurofolin Advisory Board and has attended meetings hosted by Grunbiotics.20

• “Neurofolin contains L-methylfolate, an active form of folate that addresses part of a complex deficiency found in people with depression”. https://www.chemistdirect.com.au/neurofolin-powder-15g-sachets-x-30

19 http://www.psychiatrist.com/jcp/article/pages/2016/v77n05/v77n0521.aspx 20 https://www.medianet.com.au/releases/143713/






http://www.psychiatrist.com/jcp/article/pages/2016/v77n05/v77n0521.aspx

https://www.medianet.com.au/releases/143713/


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I could not find evidence that showed L-methylfolate “addresses part of a complex deficiency found in people with depression”.

• “It may be used alone or with antidepressants under the supervision of a healthcare professional”. https://www.chemistdirect.com.au/neurofolin-powder-15g-sachets-x-30 I could not find evidence that showed L-methylfolate could be used alone for the management of depression and Ire not convinced by the studies reviewed above that it was a useful addition to conventical anti-depressant therapy.

• “However, there is a new promising over the counter treatment that is showing positive signs when used in conjunction or alone with an antidepressant - L-methylfolate. L-methylfolate is marketed in Australia under the brand name Neurofolin”. https://www.yourdiscountchemist.com.au/blog/neurofolin/ The statement, “a new promising over the counter treatment that is showing positive signs when used in conjunction or alone with an antidepressant” is not in accord with the scientific evidence above and is deceptive and misleading.

Conclusion: I ask the TGA &/or the Victorian Health Department to investigate the advertised claims made for Neurofolin® and provide a written determination as to whether Neurofolin® meets the requirements of FSANZ Standard 2.6.5.

In addition, this case, and others such as Souvanaid®, Ceretain® and Neurothrive®, raise important questions regarding the ability of product sponsors to self-declare under FSANZ Standard 2.6.5 that their products are beneficial for serious conditions such as depression and Alzheimer’s disease without any independent assessment of all the available evidence.

I argue that sponsor self-determination of Standard 2.6.5 is inappropriate and an independent assessment of evidence should be required before a product can be promoted as a “food for special medicinal purposes”.

I ask that the appropriateness of “food” sponsors to self-declare “food for special medicinal purposes” without independent assessment be addressed by both FSANZ and the TGA.

Sincerely, Dr Ken Harvey MB BS, FRCPA, AM Associate Professor Public Health and Preventive Medicine Monash University Level 1, 553 St Kilda Rd Melbourne VIC 3004 M: +61 419181910 E: [email protected] W: monash.edu President, Friends of Science in Medicine W: scienceinmedicine.org.au Director, Medreach Pty Ltd W: medreach.com.au 14 May 2019




http://monash.edu/

http://www.scienceinmedicine.org.au/

http://www.medreach.com.au/


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Screen shots (taken 09/05/2019):






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Public Summary Summary for ARTG Entry: 270098 L-5MTHF

ARTG entry for Medicine Listed

Sponsor Research Nutrition Pty Ltd

Postal Address 18 / 93 Rivergate Place,MURARRIE, QLD, 4172 Australia

ARTG Start Date 15/02/2016

Product category Medicine

Status Active

Approval area Listed Medicines

Conditions

Colouring agents used in listed medicine for ingestion, other than those listed for export only under section 25 of the Act, shall be only those included in the list of 'Colourings permitted in medicines for oral use'.

The sponsor shall keep records relating to this listed medicine as are necessary to: (a) Expedite recall if necessary of any batch of the listed medicine, (b) Identify the manufacturer(s) of each batch of the listed medicine. Where any part of or step in manufacture in Australia of the listed medicine is sub-contracted to a third party who is not the sponsor, copies of relevant Good Manufacturing Practice agreements relation to such manufacture shall be kept.

The sponsor shall retain records of the distribution of the listed medicine for a period of five years and shall provide the records or copies of the records to the Complementary Medicines Branch, Therapeutic Goods Administration, upon request.

The sponsor of the listed medicine must not, by any means, intentionally or recklessly advertise the medicine for an indication other than those accepted in relation to the inclusion of the medicine in the Register.

All reports of adverse reactions or similar experiences associated with the use or administration of the listed medicine shall be notified to the Head, Officeof Product Review, Therapeutic Goods Administration, as soon as practicable after the sponsor of the goods becomes aware of those reports. Sponsors of listed medicines must retain records of such reports for a period of not less than 18 months from the day the Head, Office of Product Review is notifiedof the report or reports.

The sponsor shall not supply the listed medicine after the expiry date of the goods.

Where a listed medicine is distributed overseas as well as in Australia, product recall or any other regulatory action taken in relation to the medicine outside Australia which has or may have relevance to the quality, safety or efficacy of the goods distributed in Australia, must be notified to the National Manager Therapeutic Goods Administration, immediately the action or information is known to the sponsor.

Products

1. L-5MTHF

Product Type Single Medicine Product Effective date 14/11/2018

Permitted Indications

Helps enhance/promote general health and wellbeing

Aid/assist healthy red blood cell production

Maintain/support blood health

Maintain/support healthy cardiovascular system function

Helps enhance/promote healthy liver function

Helps prevent dietary (state vitamin/mineral/nutrient) deficiency

Maintain/support (state vitamin/mineral) within normal range

Support healthy stress response in the body

Aid/assist/helps synthesis of neurotransmitters

Maintain/support nervous system function

Indication Requirements

Product presentation must not imply or refer to serious cardiovascular conditions.

Product presentation must not imply or refer to mental illnesses, disorders or conditions.

Label statement: Vitamins and minerals can only be of assistance if dietary intake is inadequate OR Vitamin and/or mineral supplements should not replace a balanced diet.

Product presentation must not imply or refer to liver disease, such as cirrhosis, hepatitis.

Standard Indications

No Standard Indications included on Record

Specific Indications

Public Summ

ary

Page 1 of 2 Produced at 09.05.2019 at 11:32:30 AESTThis is not an ARTG Certificate document.The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown. Visit www.tga.gov.au for contact information

Warnings

No Warnings included on Record

Additional Product information

Pack Size/Poison information

Pack Size Poison Schedule

Components

1. Formulation 1

Dosage Form Capsule, hard

Route of Administration Oral Visual Identification

Active Ingredients

levomefolate calcium 550 microgram

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm. Public Summ

ary


http://www.tga.gov.au/about/website-copyright.htm

Public Summary Summary for ARTG Entry: 310089 Activated Folate 500

ARTG entry for Medicine Listed

Sponsor Herbs of Gold Pty Ltd

Postal Address PO Box 3143,KIRRAWEE, NSW, 2232 Australia

ARTG Start Date 4/10/2018

Product category Medicine

Status Active

Approval area Listed Medicines

Conditions

Colouring agents used in listed medicine for ingestion, other than those listed for export only under section 25 of the Act, shall be only those included in the list of 'Colourings permitted in medicines for oral use'.

The sponsor shall keep records relating to this listed medicine as are necessary to: (a) Expedite recall if necessary of any batch of the listed medicine, (b) Identify the manufacturer(s) of each batch of the listed medicine. Where any part of or step in manufacture in Australia of the listed medicine is sub-contracted to a third party who is not the sponsor, copies of relevant Good Manufacturing Practice agreements relation to such manufacture shall be kept.

The sponsor shall retain records of the distribution of the listed medicine for a period of five years and shall provide the records or copies of the records to the Complementary Medicines Branch, Therapeutic Goods Administration, upon request.

The sponsor of the listed medicine must not, by any means, intentionally or recklessly advertise the medicine for an indication other than those accepted in relation to the inclusion of the medicine in the Register.

All reports of adverse reactions or similar experiences associated with the use or administration of the listed medicine shall be notified to the Head, Officeof Product Review, Therapeutic Goods Administration, as soon as practicable after the sponsor of the goods becomes aware of those reports. Sponsors of listed medicines must retain records of such reports for a period of not less than 18 months from the day the Head, Office of Product Review is notifiedof the report or reports.

The sponsor shall not supply the listed medicine after the expiry date of the goods.

Where a listed medicine is distributed overseas as well as in Australia, product recall or any other regulatory action taken in relation to the medicine outside Australia which has or may have relevance to the quality, safety or efficacy of the goods distributed in Australia, must be notified to the National Manager Therapeutic Goods Administration, immediately the action or information is known to the sponsor.

Products

1. Activated Folate 500

Product Type Single Medicine Product Effective date 4/10/2018

Permitted Indications

Maintain/support general health and wellbeing

Aid/assist healthy red blood cell production

Maintain/support blood health

Maintain/support cardiovascular system health

Helps decrease/reduce homocysteine levels

Helps prevent dietary (state vitamin/mineral/nutrient) deficiency

Help maintain/support emotional wellbeing

Maintain/support cognitive function/mental function

Maintain/support memory/mental recall

Maintain/support brain function

Maintain/support brain health

Maintains/support healthy foetal development

Indication Requirements

Product presentation must not imply or refer to mental illnesses, disorders or conditions.

Product presentation must not imply or refer to serious cardiovascular conditions.

Label statement: Advise your doctor of any medicine you take during pregnancy, particularly in your first trimester.

Label statement: Vitamins and minerals can only be of assistance if dietary intake is inadequate OR Vitamin and/or mineral supplements should not replace a balanced diet.

Standard Indications

Public Summ

ary


No Standard Indications included on Record

Specific Indications

Warnings

Vitamins and minerals can only be of assistance if dietary intake is inadequate OR Vitamin and/or mineral supplements should not replace a balanced diet.

Additional Product information

Pack Size/Poison information

Pack Size Poison Schedule

Components

1. Formulation 1

Dosage Form Capsule, hard

Route of Administration Oral Visual Identification

Active Ingredients

levomefolate glucosamine 1.052 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summ

ary


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Article

L-Methylfolate as Adjunctive Therapy for SSRI-ResistantMajor Depression: Results of Two Randomized,

Double-Blind, Parallel-Sequential Trials

George I. Papakostas, M.D.

Richard C. Shelton, M.D.

John M. Zajecka, M.D.

Bijan Etemad, M.D.

Karl Rickels, M.D.

Alisabet Clain, M.S.

Lee Baer, Ph.D.

Elizabeth D. Dalton, B.A.

Garret R. Sacco, B.A.

David Schoenfeld, Ph.D.

Michael Pencina, Ph.D.

Allison Meisner, M.A.

Teodoro Bottiglieri, Ph.D.

Erik Nelson, M.D.

David Mischoulon, M.D., Ph.D.

Jonathan E. Alpert, M.D., Ph.D.

James G. Barbee, M.D.

Sidney Zisook, M.D.

Maurizio Fava, M.D.

Objective: The authors conducted twomulticenter sequential parallel compari-son design trials to investigate the effect ofL-methylfolate augmentation in the treat-ment of major depressive disorder inpatients who had a partial response or noresponse to selective serotonin reuptakeinhibitors (SSRIs).

Method: In the first trial, 148 outpatientswith SSRI-resistant major depressive disor-derwere enrolled in a 60-day study dividedinto two 30-day periods. Patients wererandomly assigned, in a 2:3:3 ratio, toreceive L-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for30 days), placebo for 30 days followed by

L-methylfolate (7.5mg/day) for 30 days, orplacebo for 60 days. SSRI dosages werekept constant throughout the study. In thesecond trial, with 75 patients, the designwas identical to the first, except that theL-methylfolate dosage was 15 mg/day dur-ing both 30-day periods.

Results: In the first trial, no significant dif-ferencewas observed in outcomes betweenthe treatment groups. In the second trial,adjunctive L-methylfolate at 15 mg/dayshowed significantly greater efficacy com-pared with continued SSRI therapy plusplacebo on both primary outcome mea-sures (response rate and degree of changein depression symptom score) and twosecondary outcome measures of symptomseverity. The number needed to treat forresponse was approximately six in favorof adjunctive L-methylfolate at 15 mg/day.L-Methylfolate waswell tolerated, with ratesof adverse events no different from thosereported with placebo.

Conclusions: Adjunctive L-methylfolateat 15 mg/day may constitute an effective,safe, and relatively well tolerated treatmentstrategy for patients with major depressivedisorder who have a partial response or noresponse to SSRIs.

(Am J Psychiatry 2012; 169:1267–1274)

Evidence began to accumulate for an associationbetween folate-deficiency states and depression soon afterclinically reliable assays for folate became widely availablein the 1960s (1–9). In addition to studies suggesting arelationship between low folate levels and an elevated riskfor major depressive disorder, there is also accumulatingevidence to suggest that low folate levels in patients withmajor depression may predict poorer prognosis duringtreatment (3, 10–15). These studies have in turn attractedthe interest of the research community regarding the useof folate as a potential treatment for major depression. Todate, several clinical studies have examined the use of folicacid or various folic acid metabolites (16–23) as mono-therapy or as adjunctive therapy for major depression.

Despite the progressive development of dozens of anti-depressant agents, more than half of all patients treatedwith antidepressant monotherapy will fail to experiencea remission of their major depressive episode (24). Thus,developing safe, well-tolerated, and effective treatmentsthat would help bring about remission in patients withantidepressant-resistant major depression is of paramountimportance. In light of studies suggesting the potentialefficacy, safety, and tolerability of l-methylfolate as anadjunct to standard antidepressants (19, 20), it mayrepresent a unique opportunity for novel treatment de-velopment in major depression. l-Methylfolate is thebiologically active form of folate and the only form of folatethat crosses the blood-brain barrier. l-Methylfolate also

This article is featured in this month’s AJP Audio, is an article that provides Clinical Guidance (p. 1274),and is discussed in an Editorial by Dr. Nelson (p. 1223)

Am J Psychiatry 169:12, December 2012 ajp.psychiatryonline.org 1267

http://ajp.psychiatryonline.org

regulates the formation of a critical cofactor for neuro-transmitter synthesis, tetrahydrobiopterin (BH4). BH4 inturn activates tryptophan hydroxylase and tyrosine hydrox-ylase, which are necessary and rate-limiting enzymes forthe synthesis of three monoamines: serotonin, dopa-mine, and norepinephrine. Because l-methylfolate indirectlyregulatesmonoamine levels, lowCNS levels of l-methylfolatecould lead to monoamine deficiency. Until recently, ran-domized, double-blind, placebo-controlled trials focusing onthe use of l-methylfolate as adjunctive therapy for antide-pressant-resistant major depression were lacking. Here wereport on the outcome of two separate trials of l-methylfolateas an adjunct to a selective serotonin reuptake inhibitor(SSRI), identical in design except for differences in dosing. Inorder to enhance our study’s statistical power to detecta difference in antidepressant effect between drug andplacebo, the sequential parallel comparison design (25) wasselected as the study design for our clinical trials.

Method

Trial 1

Study design. The first trial was a 60-day, multicenter (11clinical sites in the United States), randomized, double-blind,sequential parallel comparison trial of adjunctive l-methylfo-late for SSRI-resistant major depressive disorder. Institutionalreview board-approved written informed consent was obtainedfrom all study patients before any study procedures wereconducted. Eligibility was assessed primarily during the screen-ing visit and secondarily during the baseline visit, whichoccurred 14 days after the screening visit. Patient inclusion andexclusion criteria were as follows: being 18–65 years of age;meeting DSM-IV criteria for current major depressive disorderduring the screening and baseline visit, as assessed by theStructured Clinical Interview for DSM-IV Axis I Disorders (26);having a score $12 on the Quick Inventory of DepressiveSymptomatology–Self-Rated (QIDS-SR) (24) at both screeningand baseline visits; having received treatment with an SSRI atadequate dosages (defined as $20 mg/day of fluoxetine,citalopram, or paroxetine; $10 mg/day of escitalopram; or $50mg/day of sertraline) during the current episode for at least 8weeks, as assessed historically using the Massachusetts GeneralHospital Antidepressant Treatment Response Questionnaire(which measures historical, not prospective antidepressantuse); and having been on a stable dose of SSRI for the past 4weeks at the baseline visit. Exclusion criteria were breastfeed-ing, pregnancy, or being of child-bearing age and not usinga medically accepted means of contraception; demonstrating.25% decrease in depressive symptom severity as reflected bythe QIDS-SR total score between screening and baseline; havinga serious suicide or homicide risk or an unstable medical illnessas assessed by the evaluating clinician; having an active substanceuse disorder within the past 6 months; having a history of mania,hypomania (including antidepressant-induced), psychotic symp-toms, or seizure disorder; showing clinical evidence of untreatedhypothyroidism; having failed to experience sufficient symptomimprovement after more than two antidepressant trials during thecurrent major depressive episode; and taking vitamins or dietarysupplements containing.400 mg of folate or.6 mg of vitamin B12.

Study procedures. Patients who were found eligible during thebaseline visit were enrolled in the study according to a formatof the sequential parallel comparison design (25), and eligible

patients were randomized to one of three treatment groups in a 2:3:3 ratio. The study was divided into two 30-day phases (phases 1and 2). One group of patients (randomization probability 3:8)received two dummy pills identical to l-methylfolate in appear-ance during phases 1 and 2 (placebo-placebo group). The secondgroup (randomization probability 3:8) received two dummypills during phase 1 and one dummy pill and one 7.5-mgl-methylfolate pill during phase 2 (placebo-drug group). Thethird group (randomization probability 2:8) received one dummypill and one 7.5-mg l-methylfolate pill during phase 1 and two7.5-mg l-methylfolate pills during phase 2 (drug-drug group).This format of the sequential parallel comparison design wasselected instead of the one (25) involving a randomization todrug and placebo in phase 1 and a re-randomization of placebononresponders to drug or placebo in phase 2.

Postbaseline study visits occurred every 10 days. SSRI dosagesremained constant during phases 1 and 2 of the study. Partic-ipants unable to tolerate the study medications as per protocolwere withdrawn from the study.

The 17-item Hamilton Depression Rating Scale (HAM-D) (27),QIDS-SR, and Clinical Global Impressions (CGI) severity andimprovement scales (28) were administered during all postscreenvisits.

Trial 2

The results of the first trial were available to the investigatorsand sponsor prior to, and were informative in the developmentof the design of, the second trial. In the first trial, 7.5 mg/day ofadjunctive l-methylfolate did not appear to result in superiortreatment outcome (efficacy) than continued antidepressanttherapy plus placebo. However, among patients who did notrespond to 7.5 mg/day of l-methylfolate in phase 1 but whosedosage of l-methylfolate was increased to 15 mg/day in phase 2,the response rates in phase 2 were greater than in patients whocontinued on antidepressant monotherapy and adjunctiveplacebo (24.0% compared with 9%), although the difference fellshort of statistical significance (p=0.1). Given the possibility ofa better response with a longer trial of l-methylfolate, the targetdose for the second trial was set at 15 mg/day.

The design of the second trial was identical to the first exceptthat the dosing of l-methylfolate was 15 mg throughout the trialfor all patients receiving it (those assigned to the placebo-druggroup and to the drug-drug group). Six clinical sites participatedin the second trial, and all were selected from the 11 sites thatparticipated in the first trial based on their demonstrated abilityto enroll the target patients in a reasonable time frame during thefirst trial. Institutional review board-approved written informedconsent was obtained from all study patients before any studyprocedures were conducted.

General Statistical Considerations

The two primary outcome measures for both studies weredefined as the difference in response rates according to theHAM-D and in degree of improvement in HAM-D score betweenthe two treatment groups. Response according to the HAM-Dwas defined as a reduction of $50% in HAM-D score duringtreatment (or a final score of #7). The Hochberg-Benjaminiapproach (29) was used to control for multiple testing. Accordingto this approach, the trial can be declared a success if one of thetwo primary outcome measures is significant at the 0.025 level orif both are significant at the 0.05 level. The sample sizes of thetwo studies were selected based on power calculations withspecific assumptions about response rates in the two phases,according to the analytical method described in Fava et al. (25)for the sequential parallel comparison design. Secondary out-come measures included continuous change in scores on theQIDS-SR and CGI severity scale during treatment. Additional

1268 ajp.psychiatryonline.org Am J Psychiatry 169:12, December 2012

L-METHYLFOLATE AS ADJUNCTIVE THERAPY FOR SSRI-RESISTANT DEPRESSION


secondary outcome measures included the proportion of pa-tients who met response criteria according to the QIDS (areduction of $50% in QIDS score during treatment or a finalscore #5), remission status according to the QIDS (a final score#5), or remission status according to the HAM-D (a final score#7).

Sequential Parallel Comparison Design AnalyticModel

The traditional analytical approach for standard antidepressantclinical trials has been to compare the difference in symptomimprovement during treatment with a drug and with placebo forall patients randomized to treatment (intent-to-treat approach),defining endpoint symptom severity for patients who prematurelydiscontinue treatment as the last available depression severityscore (last observation carried forward).

The format of the sequential parallel comparison designapproach used in this study, however, was conducted as follows:

1. A standard intent-to-treat/last-observation-carried-forwardapproach was employed for patients treated with drug duringphase 1.

2. The phase 2 data set of interest was limited to patientstreated with placebo during phase 1 who completed phase 1without experiencing a clinical response according to the HAM-Dand entered phase 2.

3. The last-observation-carried-forward approach was appliedto the sequential parallel comparison design analysis data set forphase 2, with the final visit of phase 1/first visit of phase 2 servingas the new baseline visit. Drug was compared with placebo inphase 2 for this patient subset alone.

4. The intent-to-treat/last-observation-carried-forward datacomparing drug and placebo during phase 1 (see step 1 above)was combined with the data comparing drug and placeboaccording to the sequential parallel comparison design modelfor phase 2 (steps 2 and 3 above) and analyzed using thestatistical model described by Fava et al. (25) using a weightand a randomization fraction chosen to maximize the powerof the test. When calculating the pooled treatment effect fromtreatment effects obtained in phases 1 and 2, equal weightswere given for each phase.

In the first trial, only the 7.5-mg/day arms were designed to becomparable to placebo. Thus, the 15-mg/day arm was not pooledwith the 7.5-mg/day arms when conducting efficacy analyses.

Dichotomous measures were analyzed according to thesequential parallel comparison design method for dichotomousoutcomes as described by Fava et al. (25), while the “seeminglyunrelated regressions model,” controlling for baseline scores, wasemployed for the comparison of continuous outcomes accordingto the method of Tamura and Huang (30). Equal weights of 0.5 foreach phase were selected before the analyses were conductedto avoid more arbitrary or data-driven choices. For the com-parison of adverse events between groups, the chi-square testwas used. All tests were two-tailed, with alpha set at 0.05 (noadjustments for multiple comparisons). Safety and tolerabilityanalyses were conducted based on all data available (all patientsrandomized, all study visits).

Power Calculations

For the first trial, assuming a difference in response rates indrug versus placebo of 0.375 versus 0.20 in phase 1 and 0.25versus 0.10 in phase 2, 148 subjects with a phase 1 allocation of 3:3:2 to placebo:placebo:drug were required to attain 80% powerwith the two-sided test of the hypothesis at the 0.05 level.Participant retention between phases was assumed to be 85%.

For the second trial, assuming a difference of –2.0 in HAM-Dscore change between the treatment and placebo groups in bothphases and standard deviations of reductions equal to 4.0 in both

treatment arms and both phases (approximate pooled effect sizeof 0.35), 75 subjects with a phase 1 allocation of 3:3:2 to placebo:placebo:drug were required to attain 80% power with the two-sided test of the hypothesis at the 0.05 level. Placebo response inphase 1 was expected to be 25% and participant retentionbetween phases 85%.

Results

Trial 1

In thefirst trial, 148 patients (103 [69.5%] of themwomen)were randomly assigned to treatment. The participants’mean age was 47.9 years (SD=11.6). Their mean baselineHAM-D score was 19.7 (SD=4.7). A total of 36 patientswere assigned to the drug-drug sequence (7.5 mg/dayof l-methylfolate in phase 1 and 15 mg/day in phase 2),58 to the placebo-drug sequence (placebo in phase 1 and7.5 mg/day of l-methylfolate in phase 2), and 54 to theplacebo-placebo sequence (placebo in both phases 1 and2). A total of 119 patients (80.0%) completed the study. Allpatients were taking an SSRI at the time of randomizationand continued throughout the trial; 36 were on sertraline,35 on escitalopram, 35 on fluoxetine, 32 on citalopram,and 10 on paroxetine. Efficacy analyses of phases 1 and 2are reported inTable 1. Pooling of phases 1 and 2 for the twoprimary outcome measures is depicted in Figures 1 and 2.As noted above, 7.5 mg/day of adjunctive l-methylfolate

did not appear to result in a treatment outcome (efficacy)superior to continued SSRI therapy plus placebo in eitherphase of the study. However, patients who underwent anincrease in dosage to 15 mg/day in phase 2 had a greaterresponse rate than those who continued on SSRI therapyplus adjunctiveplacebo (24.0%comparedwith 9%), althoughthe difference fell short of statistical significance (p=0.1).Adverse events are reported in Table 2. There was no

statistically significant difference in the change in weight,supine and standing heart rate, or supine and standing dias-tolic and systolic blood pressure between the l-methylfolateand placebo groups in phase 1 or 2.

Trial 2

Given the results in trial 1, the second trial used only 15mg/day of l-methylfolate in the drug-drug and placebo-drug sequences. Seventy-five patients (53 [70.6%] of themwomen) were assigned to treatment as follows: 19 to thedrug-drug sequence (15 mg/day of l-methylfolate in bothphases 1 and 2), 28 to the placebo-drug sequence (placeboin phase 1 and 15 mg/day of l-methylfolate in phase 2),and 28 to the placebo-placebo sequence (placebo in bothphases 1 and 2). The participants’mean age was 48.4 years(SD=12.1), and their mean baseline HAM-D score was 21.2(SD=3.9). A total of 61 patients (81.3%) completed thestudy. Again, all participantswere taking an SSRI at baselineand continued throughout the trial. Efficacy analyses ofphases 1 and 2 are presented in Table 3. Pooling of phases 1and 2 on the two primary outcomemeasures is depicted inFigures 1 and 2.


PAPAKOSTAS, SHELTON, ZAJECKA, ET AL.


In the second trial, 15mg/day of adjunctive l-methylfolateappeared to result in a treatment outcome (efficacy) superiorto continued SSRI therapy plus placebo in both primaryoutcome measures, achieving statistical significance at the0.05 level both in the difference in response rates (32.3%

comparedwith 14.6%, p=0.04) and in the difference in degreeof improvement (–5.58 compared with –3.04, p=0.05) on theHAM-D. The results also suggested superior efficacy for l-methylfolate on two of the secondary outcome measures—change in score on the QIDS-SR (–4.7 compared with –2.62,p=0.04) and on the CGI severity scale (–0.92 compared with–0.34, p=0.01).Adverse events are reported in Table 4. There was

no statistically significant difference in the change inweight, supine and standing heart rate, or supine andstanding diastolic and systolic blood pressure between thel-methylfolate and placebo groups in phase 1 or 2. Onepatient in the l-methylfolate group was withdrawn fromthe trial because of the development of manic symptoms.

Discussion

This is the first report of randomized, double-blind,placebo-controlled trials involving the adjunctive use ofl-methylfolate (at 7.5 mg/day and 15 mg/day) for patientswithmajor depression who have responded only partially ornot at all to SSRIs. To enhance statistical power, both studiesused a novel sequential parallel comparison design (25).Results of both studies were informative about the use of l-methylfolate as adjunctive therapy in major depression. Inthe first trial, we found no difference between placebo andadjunctive l-methylfolate at 7.5 mg/day (administered for

TABLE 1. Efficacy Results of the First of Two Trials of L-Methylfolate (MTHF) Compared With Placebo as an Adjunct to SSRIs inPatients With SSRI-Resistant Depression

Phase 1 (30 Days) Phase 2 (30 days)b

MeasureaMTHF,

7.5 mg/day (N=36)Placebo(N=112)

MTHF, 7.5 or15 mg/day (N=35)

Placebo(N=33)

PooledMTHFc

PooledPlaceboc pd

N % N % N % N % % %Completed treatment 33 91.6 98 87.5 30 85.7 30 90.9HAM-D

Response 7 19.4 32 28.5 6 17.1 3 9.0 18.3 18.8 0.92Remission 4 11.1 20 17.8 5 14.2 2 6.0 12.7 11.9 0.15

Mean SD Mean SD Mean SD Mean SD Mean MeanBaseline score 18.8 4.2 19.9 4.8 16.2 3.4 16.8 4.7 17.5 18.4Score reduction 24.3 5.0 26.3 6.6 23.1 4.2 22.1 4.9 23.70 24.19 0.87

QIDS-SR N % N % N % N % % %Response 9 25.0 28 28.5 3 8.5 3 9.0 16.8 18.8 0.70Remission 0 0.0 10 8.9 3 8.5 1 3.0 4.3 6.0 0.58


CGI severity scaleBaseline score 4.1 0.5 4.2 0.6 3.8 0.7 3.9 0.7 4.0 4.1Score reduction 20.5 0.9 20.7 1.0 20.5 0.7 20.4 0.8 20.53 20.59 0.96

a HAM-D=Hamilton Depression Rating Scale; QIDS-SR=Quick Inventory of Depressive Symptomatology–Self-Rated; CGI=Clinical GlobalImpressions scale. Treatment response was defined as a reduction of $50% in HAM-D or QIDS-SR score during treatment (or a final score of#7 on the HAM-D or #5 on the QIDS-SR), and remission was defined as a final score of #7 on the HAM-D or #5 on the QIDS-SR.

b According to the format of the sequential parallel comparison design model used in this study, only patients who completed phase 1 and didnot achieve a treatment response (as indicated by the HAM-D) are analyzed in phase 2.

c Pooled results from phases 1 and 2.d Using the Fava et al. method (25) for dichotomous measures in sequential parallel comparison design analyses and the Tamura and Huangmethod (30) for continuous measures.

FIGURE 1. Pooled Response Rates in Two Trials of L-Methylfolate (MTHF) Compared With Placebo as an Adjunctto SSRIs in Patients With SSRI-Resistant Depressionª

14.6

32.3

18.3 18.8

Trial 1 (7.5 mg/day for 30 days)

(N=148)

Trial 2 (15 mg/day for 30 days)

(N=75)

Resp

on

se R

ate

(%

)

SSRI plus MTHF

SSRI monotherapy

a Response was defined as a reduction of $50% in HamiltonDepression Rating Scale score during treatment or a final score of#7. Significant difference between groups in trial 2 (p=0.04). Thepooled analysis was conducted as described in Fava et al. (25).




up to 30 days); however, among patients who experiencedno response with 7.5 mg/day, the response rate and changein depression symptom score were greater than amongthose who continued on SSRI therapy plus placebo,although the difference did not reach statistical significance.The latter finding informed our design of the second trial,which was identical to the first trial except that all patientstreated with adjunctive l-methylfolate received 15 mg/day.

The results of the second trial indicated greater efficacyfor 15 mg/day of adjunctive l-methylfolate (administeredfor up to 30 days) with continued SSRI therapy comparedwith continued SSRI therapy plus placebo on bothprimary outcome measures. These results suggest that15 mg/day of l-methylfolate can be a useful adjunctivetreatment strategy for patients with major depression whohave not responded to SSRIs. The number needed to treat

TABLE 2. Adverse Events Reported in the First of Two Trialsof L-Methylfolate (MTHF) Compared With Placebo as anAdjunct to SSRIs in Patients With SSRI-Resistant Depression

Placebo(N=112)a

MTHF,7.5 mg/day(N=94)a

MTHF,15 mg/day(N=30)a

Side Effect Category N % N % N % p

Gastrointestinal 23 20.1 9 9.6 3 10.0 0.06Sleep 12 10.7 3 3.2 2 6.7 0.11Psychological 12 10.7 2 2.1 2 6.7 0.05Somatic 22 19.6 9 9.6 3 10.0 0.09Infectious 13 11.6 6 6.4 2 6.7 0.38Cardiovascular 4 3.6 0 0.0 2 6.7 0.08Sexual 0 0.0 0 0.0 0 0.0 0.99Miscellaneous 3 2.7 1 1.1 2 6.7 0.24a Ns are based on the total numbers of participants who receivedplacebo, 7.5 mg of L-methylfolate, or 15 mg of L-methylfolate,respectively, at some point during the trial.

FIGURE 2. Pooled Mean Reduction in Hamilton DepressionRating Scale Score in Two Trials of L-Methylfolate (MTHF)Compared With Placebo as an Adjunct to SSRIs in PatientsWith SSRI-Resistant Depressionª

Trial 1 (7.5 mg/day for 30 days)

(N=148)

Trial 2 (15 mg/day for 30 days)

(N=75)

Mean

Ch

an

ge in

HA

M-D

Sco

re

SSRI plus MTHF

–3

–5.6

–3.7–4.2

SSRI monotherapy

a Significant difference between groups in trial 2 (p=0.05). Thepooled analysis was conducted as described in Tamura and Huang(30).

TABLE 3. Efficacy Results of the Second of Two Trials of L-Methylfolate (MTHF) Compared With Placebo as an Adjunct to SSRIsin Patients With SSRI-Resistant Depression

Phase 1 (30 days) Phase 2 (30 days)b

MeasureaMTHF,

15 mg/day (N=19) Placebo (N=56)MTHF,

15 mg/day (N=18) Placebo (N=21)PooledMTHFc

PooledPlaceboc pd

N % N % N % N % % %Completed treatment 17 89.4 50 89.2 15 83.3 19 90.4HAM-DResponse 7 36.8 11 19.6 5 27.7 2 9.5 32.3 14.6 0.04Remission 3 15.7 7 12.5 2 11.1 1 4.7 13.4 8.6 0.45


QIDS-SR N % N % N % N % % %Response 7 36.8 12 21.4 2 11.1 1 4.7 23.9 13.1 0.15Remission 4 21.0 1 1.7 1 5.5 1 4.7 13.3 3.3 0.09


CGI severity scaleBaseline score 4.6 0.6 4.4 0.6 4.0 0.6 3.9 0.8 4.4 4.2Score reduction 21.3 0.9 20.6 1.0 20.5 1.0 20.1 0.6 20.92 20.34 0.01

a HAM-D=Hamilton Depression Rating Scale; QIDS-SR=Quick Inventory of Depressive Symptomatology–Self-Rated; CGI=Clinical GlobalImpressions scale. Treatment response was defined as a reduction of $50% in HAM-D or QIDS-SR score during treatment (or a final score of#7 on the HAM-D or #5 on the QIDS-SR), and remission was defined as a final score of #7 on the HAM-D or #5 on the QIDS-SR.

b According to the format of the sequential parallel comparison design model used in this study, only patients who completed phase 1 and didnot achieve a treatment response (as indicated by the HAM-D) are analyzed in phase 2.

c Pooled results from phases 1 and 2.d Using the Fava et al. method (25) for dichotomous measures in sequential parallel comparison design analyses and the Tamura and Huangmethod (30) for continuous measures.




for response in the second trial was approximately six infavor of adjunctive l-methylfolate compared with pla-cebo, which is comparable to results reported for otheraugmentation strategies in major depression, such as useof atypical antipsychotics (31) and lithium (32). In bothtrials, l-methylfolate appeared to be relatively well tol-erated, with approximately 80% of patients completing 60days of double-blind treatment. No statistically significantdifference was observed in physiological variables (supineand standing blood pressure and heart rate) between thetwo groups, and side effects reported for the adjunctivel-methylfolate group were comparable in type and fre-quency to those reported for the placebo group.

Although we observed no differences between groups inremission rates in this study, it must be kept in mind thatthe evaluable treatment segments in phases 1 and 2 wereat most 30 days in duration, which is quite brief fordetecting remission. In the first phase of the SequencedTreatment Alternatives for Depression study (STAR*D), forinstance, the overall remission rate following 14 weeks oftherapy with citalopram was approximately 33%, with thevast majority of remissions being achieved after week 4(33). In addition, further skewing toward late remissionwould be expected in our sample compared with that ofphase 1 of STAR*D given that the latter sample was ofpatients with less refractory depression than ours (espe-cially our phase 2 sample, since the STAR*D sampleconsisted of patients who were treatment-naive duringtheir current episode).

Several limitations should be taken into account wheninterpreting our findings. First, these trials exclusivelyinvolved the use of SSRIs as augmented agents. Whether15 mg/day of l-methylfolate would be an effective adjunc-tive therapy for other classes of antidepressants remainsto be determined. In addition, our studies examined theuse of 7.5 mg/day and 15 mg/day of l-methylfolate.Whether higher dosages of l-methylfolate would result in

similar or different outcomes than 15 mg/day is unclear.Furthermore, these trials excluded certain populations ofpatients (children and adolescents; patients with bipo-lar disorder, psychotic major depression, active substanceuse disorders, or unstable axis III comorbid illness; andwomen with perinatal depression). Further studies areneeded to examine whether 15 mg/day of l-methylfolatewould be efficacious in these patient populations as well. Afinal limitation concerns the fact that these trials did notutilize a standard parallel comparison design, but insteadused the sequential parallel comparison design, a novelstudy design that enhances statistical power in random-ized clinical trials (34, 35). However, the effects noted withthe sequential parallel comparison design are certainlyconsistent with those noted in phase 1 of the study andtherefore typical of a standard design.In summary, our results suggest that 15 mg/day, but not

7.5 mg/day, of adjunctive l-methylfolate may constitutean effective, safe, and relatively well tolerated augmenta-tion strategy for patients with major depression who havehad no response or a partial response to SSRIs. Replicationof these results in an independent cohort is needed, as wellas additional research to further clarify the antidepressantrole of l-methylfolate and other elements of the one-carbon cycle.

Received July 25, 2011; revisions received March 12 and July 2,2012; accepted July 16, 2012 (doi: 10.1176/appi.ajp.2012.11071114).From the Center for Treatment-Resistant Depression, DepressionClinical and Research Program, the Biostatistics Center, and theClinical Trials Network and Institute, Massachusetts General Hospital,Boston; Harvard Medical School, Boston; the Harvard Clinical Re-search Institute, Boston; the Department of Biostatistics, BostonUniversity, Boston; the Department of Psychiatry, Vanderbilt Univer-sity School of Medicine, Nashville; Rush University Medical Center,Chicago; the Department of Psychiatry, University of Pennsylvania,Philadelphia; Baylor Research Institute, Institute of Metabolic Dis-ease, Dallas; the Department of Psychiatry, University of CincinnatiAcademic Health Center, Cincinnati; the Louisiana State UniversityHealth Sciences Center, New Orleans; the Department of Psychiatry,University of California San Diego; and San Diego VA HealthcareService. Address correspondence to Dr. Papakostas ([email protected]).Dr. Papakostas has received research support from, served as

a consultant or speaker for, or received honoraria for CME activitiesfor Abbott, AstraZeneca, Brainsway, Bristol-Myers Squibb, Cephalon,Dey Pharma, Eli Lilly, Forest, GlaxoSmithKline, Lundbeck, NIMH,Otsuka, Pamlab, Ridge Diagnostics, Roche, Takeda, Theracos, andSunovion. Dr. Shelton has received research support or served asa consultant for Bristol-Myers Squibb, Eli Lilly, Cyberonics, Elan,Euthymics Bioscience, Forest, Janssen Pharmaceutica, Medtronic,Novartis, Otsuka, Pamlab, Pfizer, Repligen, Ridge Diagnostics, TakedaPharmaceuticals, and St. Jude Medical. Dr. Zajecka has receivedresearch support from or served as a consultant, adviser, or speakerfor Abbott, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb,Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Hoffman-LaRoche,McNeil, Novartis, Otsuka, Pamlab, Pfizer, Shire, and Takeda. Dr.Schoenfeld is a patent holder for the sequential parallel design usedin this study; the patent is owned by his employer, MassachusettsGeneral Hospital. Dr. Pencina has served as a consultant for Pamlaband RCT Logic. Ms. Meisner has served as a consultant for Mas-sachusetts General Hospital and Pamlab, has received a grant fromthe National Heart, Lung and Blood Institute, and has received funds

TABLE 4. Adverse Events Reported in the Second of TwoTrials of L-Methylfolate (MTHF) Compared With Placebo asan Adjunct to SSRIs in Patients With SSRI-ResistantDepression

Placebo (N=54)aMTHF, 15 mg/day

(N=42)a

Side Effect Category N % N % p

Gastrointestinal 8 14.8 7 16.7 0.98Sleep 3 5.5 1 2.4 0.80Psychological 9 16.7 4 9.5 0.47Somatic 16 29.6 6 14.3 0.13Infectious 7 13.0 5 11.9 0.66Cardiovascular 0 0.0 0 0.0 0.99Sexual 0 0.0 1 2.4 0.90Miscellaneous 5 9.3 1 2.4 0.34a Ns are based on the total numbers of patients who receivedplacebo or 15 mg of L-methylfolate, respectively, at some pointduring the trial.






from grants at the Harvard School of Public Health. Dr. Bottiglieri hasreceived research support from and has served as a consultant forPamlab, has served as the chairman of the advisory board forMethylation Sciences, and holds stock options in MethylationSciences. Dr. Nelson has received research support from AstraZeneca,Eli Lilly, GlaxoSmithKline, and Pamlab. Dr. Mischoulon has receivedresearch support or honoraria for consulting, speaking, and writingfrom the Bowman Family Foundation, Bristol-Myers Squibb, Cederroth,FisherWallace, Ganeden, Lichtwer Pharma, Nordic Naturals, andPamlab and has received royalties from Back Bay Scientific andLippincott Williams & Wilkins. Dr. Alpert has received researchsupport from or served as an adviser, consultant, or speaker forAbbott, Alkermes, APA, Lichtwer Pharma, Lorex, Aspect MedicalSystems, AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, EliLilly, Forest, GlaxoSmithkline, J & J Pharmaceuticals, MGH PsychiatryAcademy/Reed Medical Education, MGH Psychiatry Academy/Prime-dia, Novartis, Organon, Pamlab, Pfizer, Pharmavite, Roche, Sanofi/Synthelabo, Solvay, Wyeth-Ayerst, and Xian-Janssen and has receivededitorial fees from Belvoir Publishing. Dr. Barbee has receivedresearch support from or served as a speaker for AstraZeneca,Bristol-Myers Squibb, Dey Pharmaceuticals, Eli Lilly, Forest, Merck,Pfizer, and Sheppard Pratt Health System and has done forensicconsulting work for various attorneys. Dr. Zisook has receivedresearch support from Pamlab. Dr. Fava has received researchsupport from Abbott, Alkermes, Aspect Medical Systems, AstraZe-neca, BioResearch, BrainCells, Bristol-Myers Squibb, Cephalon, Bio-Pharma, Clinical Trials Solutions, Clintara, Covidien, Eli Lilly, EnVivoPharmaceuticals, Euthymics Bioscience, Forest, Ganeden Biotech,GlaxoSmithKline, Icon Clinical Research, i3 Innovus, Johnson &Johnson Pharmaceutical Research and Development, LichtwerPharma, Lorex Pharmaceuticals, NARSAD, National Center forComplementary and Alternative Medicine, National Institute on DrugAbuse, NIMH, Novartis, Organon, Pamlab, Pfizer, Pharmavite, Photo-thera, Roche, RCT Logic, Sanofi-Aventis, Shire, Solvay, Synthelabo,and Wyeth-Ayerst; he has served as an adviser or consultant (unpaidexcept as otherwise noted) for Abbott Laboratories, Affectis Pharma-ceuticals, Alkermes, Amarin Pharma, Aspect Medical Systems,AstraZeneca, Auspex Pharmaceuticals, Bayer, Best Practice ProjectManagement, BioMarin Pharmaceuticals, Biovail, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clinical Trials Solutions,CNS Response, Compellis Pharmaceuticals, Cypress Pharmaceutical,DiagnoSearch Life Sciences, Dinippon Sumitomo Pharma, DovPharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly, ePhar-maSolutions, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer, Forest, GenOmind, GlaxoSmithKline, Grunenthal, i3 Innovus,Janssen Pharmaceutica, Jazz Pharmaceuticals, Johnson & JohnsonPharmaceutical Research and Development (remunerated), KnollPharmaceuticals, Labopharm, Lorex Pharmaceuticals, Lundbeck,MedAvante, Merck, MSI Methylation Sciences, Naurex, Neuronetics,Novartis, Nutrition 21, Orexigen Therapeutics, Organon, Otsuka,Pamlab, Pfizer, PharmaStar, Pharmavite, PharmoRx Therapeutics,Precision Human Biolaboratory, Prexa Pharmaceuticals, PuretechVentures, PsychoGenics, Psylin Neurosciences, Rexahn Pharmaceut-icals, Ridge Diagnostics, Roche, RCT Logic, Sanofi-Aventis, Sepracor,Servier Laboratories, Schering-Plough, Solvay, Somaxon, SomersetPharmaceuticals, Sunovion, Synthelabo, Takeda, Tetragenex, Trans-Form Pharmaceuticals, Transcept Pharmaceuticals, and VandaPharmaceuticals; he has provided speaking/publishing (unpaidexcept as otherwise noted) for Adamed, Advanced Meeting Partners,APA, American Society of Clinical Psychopharmacology, AstraZeneca,Belvoir Media Group (remunerated), Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, CME Institute/Physicians Postgraduate Press(remunerated), Eli Lilly, Forest, GlaxoSmithKline, Imedex, MGHPsychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsev-ier (remunerated), Novartis, Organon, Pfizer, PharmaStar, UnitedBioSource, and Wyeth-Ayerst; he has equity holdings in Compellis; heis a patent holder for the sequential parallel design used in this study(the patent is owned by Massachusetts General Hospital) and hasa patent application for a combination of ketamine and scopolaminein major depression; and he receives royalties from LippincottWilliams & Wilkins. The other authors report no financial relation-ships with commercial interests.Both trials were funded by Pamlab.Clinicaltrials.gov identifiers: NCT00321152 and NC00955955.

The authors acknowledge Dr. Bruce Lydiard for his role as a siteprincipal investigator in this study.

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Higher dose L-methylfolate may bean effective adjunctive therapy foradults with major depression whohave inadequate response to SSRIsdoi:10.1136/eb-2013-101269

QUESTIONQuestion: In adults with major depression who have had apartial or non-response to selective serotonin reuptake inhi-bitors (SSRIs), is the addition of L-methylfolate effective?Patients: 148 adults (trial 1) and 75 adults (trial 2) withDiagnostic Statistical Manual of Mental Disorders - IV (DSM-IV) major depressive disorder who had not responded to atleast 8 weeks adequate treatment with an SSRI (≥20 mg/dayof fluoxetine, citalopram or paroxetine; ≥10 mg/day escitalo-pram; or ≥50 mg/day of sertraline). Exclusion criteria: preg-nancy, breastfeeding or being of child-bearing age and notusing contraception; ≥25% improvement in depressivesymptom severity in the 2 weeks between screening and base-line; substance use disorder within the previous 6 months;unstable medical or psychiatric illness; hypothyroidism; pastfailure of sufficient symptom improvement after more thantwo antidepressant trials; those taking supplements contain-ing >400 mg folate or >6 mg vitamin B12.Setting: Multicentre clinical sites in the US (both trials).Intervention: In trial 1 participants were randomised in a2 : 3:3 ratio to one of the three treatment groups:L-methylfolate for 60 days (7.5 mg/day for 30 days followedby 15 mg/day for 30 days); placebo for 30 days followed byL-methylfolate for 30 days (7.5 mg/day); or placebo for60 days. Trial 2 had the same study design as trial 1, exceptthat the dosing of L-methylfolate was 15 mg during both30 day periods. Current SSRI treatment was continuedthroughout the trials.Outcomes: Primary outcome (both trials): difference inHamilton Depression Scale (HAM-D) response rates,defined as a reduction of ≥50% in HAM-D score duringtreatment or a final score of ≤7; and degree of improvementin HAM-D score. Secondary outcomes: changes in scores on

the Clinical Global Impression Scale (CGI) severity andimprovement scales and quick inventory of depressivesymptomology-self-rated (QIDS-SR); HAM-D remissionrate and QIDS-SR response and remission rates.Assessments were carried out every 10 days, and analysesconducted for each of the two, 30-day phases of treatment.Patient follow-up: Study completion 80% in trial 1 and81.3% in trial 2.

METHODSDesign: Two randomised controlled trials.Allocation: Unclear.Blinding: Both trials were double blinded.Follow-up period: 60 days intervention period in both trials.

MAIN RESULTSIn the first trial 7.5 mg/day adjunctive L-methylfolate didnot improve HAM-D response or degree of improvementcompared with placebo in either phase of the trial.Participants who increased to 15 mg/day for the secondphase of the trial did demonstrate improved response com-pared with placebo, though this fell short of clinical signifi-cance (24% vs 9%; p=0.1). In the second trial 15 mgL-methylfolate improved HAM-D response rates comparedwith placebo (32.3% vs 14.6%; p=0.04) and also gavegreater improvement in HAM-D (−5.58 vs −3.04; p=0.05).In the second trial 15 mg L-methylfolate also improved thesecondary outcomes of score change on CGI severity scale(−0.92 vs −0.34; p=0.01) and QIDS-SR (−4.7 vs −2.62;p=0.04) compared with placebo.

CONCLUSIONSIn people with major depression who have had partial ornon-response to SSRIs alone, augmentation with the 15 mgdose of L-methylfolate may be effective.

ABSTRACTED FROMPapakostas GI, Shelton RC, Zajecka JM, et al. (L)-methylfolate as adjunctive therapyfor SSRI-resistant major depression: results of two randomized, double-blind,parallel-sequential trials. Am J Psychiatry 2012;169:1267–74.

Correspondence to: Dr Papakostas,[email protected]

Sources of funding: Both trials were funded by Pamlab.

COMMEN

TARY

Folate is a B vitamin with an essential role in thebiosynthesis of neurotransmitters, and impli-cated in the pathogenesis and treatment of

depression. Low folate is associated with depressionand a poorer response to antidepressants. Althoughevidence suggests sufficient folate protects againstdepressive symptoms, there is limited evidence tosupport folate alone as an effective treatment. Thus,the focus has been on folate as an adjunct to anti-depressant treatments. With up to 50% of patientsfailing to respond adequately to antidepressants,folate is a potentially appealing means to enhanceantidepressant efficacy.

Papakostas and colleagues add to the growing bodyof evidence in favour of adjuvant folate and antidepres-sant therapy, particularly for treatment-resistant depres-sion, although one relatively robust study showed nobenefit of folic acid and other B vitamins in depression.1

Like previous studies, there are methodological limita-tions to this study, including a relatively small sample

size, short treatment period and short duration offollow-up. Use of high doses of folate is also note-worthy given concerns that exposure to high dosesaccelerates tumour growth in people with a history ofcolorectal cancer.2 A strength of this study is the use ofL-methylfolate instead of synthetic folic acid.

On balance, one must be cautious in recommendingadjunctive antidepressant treatment with folate as theyhave yet to be fully established: (a) any long-term risksand benefits of exposure to high doses, (b) adose-response relationship, or (c) the optimal durationof treatment required. The evidence base needs large,pragmatic clinical trials to replicate promising resultsfrom small-sized and medium-sized studies. Thesemust also measure the important individual differencesin folate metabolism to determine if there are clinicalsubgroups who respond to folate augmentation andhow to identify them. There is still much research to becarried out before we can safely recommend wide-spread adjuvant prescribing for depression.

Seren H Roberts,1 Richard Tranter21Institute of Medical and Social Care Research, BangorUniversity, Wrexham, UK; 2Kawai Clinic, Nelson Hospital,Nelson Marlborough DHB, Nelson, New Zealand

Correspondence to Seren H Roberts, Institute ofMedical and Social Care Research, Bangor University,Cambrian House, Archimedes Centre, WrexhamTechnology Park, Wrexham, LL13 7YP, UK; [email protected]

Competing interests SHR and RTare principalinvestigators on a large NIHR HTA funded trial of folic acidaugmentation of antidepressants (FolATED).

REFERENCES1. Ford AH, Flicker L, Thomas J, et al. Vitamins B12,

B6, and folic acid for onset of depressive symptomsin older men: results from a 2-yearplacebo-controlled randomized trial. J Clin Psych2008;69:1203–9.

2. Cole BF, Baron JA, Sandler RS, et al. Folic acid forthe prevention of colorectal adenomas: a randomizedclinical trial. JAMA 2007;297:2351–9.

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