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Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2018 Ene-Feb;18(1):e7155 doi: 10.5867/medwave.2018.01.7155
Is augmentation with folate effective for major depressive disorder?
Javier Trincado, Constanza Caneo
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Abstract

INTRODUCTION
Antidepressant treatment does not lead to a satisfactory response in a significant proportion of patients with depression. It has been postulated that co-administration of pharmacologically standardized nutrients (nutraceuticals), such as folate, would potentiate the effect of antidepressants.

METHODS
To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS
We identified four systematic reviews including nine studies overall, of which eight were randomized trials. We concluded augmentation with folate for the treatment of major depressive disorder probably results in little or no difference in depressive symptoms. It would be interesting to evaluate the effects of specific presentation forms of folate or in population with objective folate deficit.


 
Problem

After the introduction of antidepressants in the 1950s, the number of pharmacological treatments for major depressive disorder has increased, but the efficacy of these has remained largely unchanged. Approximately 50% of patients who initiate antidepressant treatment show little or no response after a first trial.  Moreover, after several therapeutic approaches, non-remission rates are still around 30% [1],[3]. Adding a drug of a different pharmacological class to the current antidepressant treatment has showed an enhancing effect. Most of the evidence is focused in lithium and atypical antipsychotics. New approaches, such as co-administration of nutraceuticals, in particular folate, as both folic acid and its active presentation (methylfolate), could provide a novel and safer alternative for the treatment of depression [1],[2],[3].

Folate deficiency is a common finding in psychiatric patients and low folate levels have been associated with a worse response to pharmacological treatment. In addition, an association between folate and serotonin metabolism has been observed in patients with congenital defects of the metabolism of the former and in patients with neuropsychiatric disorders. This association could be explained by the role that folate plays in the methylation of homocysteine, necessary for its conversion into s-adenosyl methionine, which has been shown to influence the metabolism of serotonin. Another hypothesis is folate is involved in the methylation reactions of tetrahydrobiopterin, an essential cofactor for the hydroxylation enzymes involved in the synthesis of serotonin [1],[4]. However, the clinical impact of the use of folate as an augmentation strategy in depressive disorders is still controversial.

Methods

To answer the question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making. 

Key messages

  • The addition of folate as augmentation in the treatment of major depressive disorder probably results in little or no difference in depressive symptoms at the end of treatment.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found four systematic reviews [1],[2],[3],[4], which included nine primary studies overall [5],[6],[7],[8],[9],[10],[11],[12],[13], of which eight were randomized trials [6],[7],[8],[9],[10],[11],[12],[13]. This table and the summary in general are based on the latter, since the observational study did not increase the certainty of the existing evidence or provide relevant additional information.

What types of patients were included*

Six trials [6],8],[9],[10],[12] included patients diagnosed with major depressive disorder according to DSM III or IV criteria, and two trials included patients with the same diagnosis according to ICD-10 [7],[13].

Of the eight trials selected, only one [9] exclusively included patients with low folate levels. On the contrary, two trials [6],[7] only included patients without baseline folate or B12 deficiency, and one trial [8] excluded patients with altered laboratory tests (including megaloblastic anemia). The rest of the trials [10],[12],[13] did not report this data.

What types of interventions were included*

All of the trials used selective serotonin reuptake inhibitors (SSRIs) as antidepressant, except two trials that did not report which antidepressant was used [7],[9].

Methylfolate was used as supplementation in three trials [9],[10] and folic acid in five trials [6],[7],[8],[12],[13].

Six trials compared against placebo [7],[8],[9],[10],[12], one trial compared against antidepressant monotherapy [6] and another trial compared different ranges of folate doses [13].

What types of outcomes
were measured

The trials measured multiple outcomes, which were grouped by the systematic reviews identified as follows:

  • Improvement of depressive symptoms: Meassured with Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI), Montgomery-Asberg Depression Rating Scale (MADRS)
  • Dropout rate
  • Hospital admission
  • Adverse effects
  • Mortality.
The average follow-up of the trials was eight weeks with a range from 6 to 26 weeks.

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of Findings

The information on the effects of folate augmentation for depression is based in four randomized trials [7],[8],[9],[12] that included 591 patients.

Four trials [7],[8],[9],[12] measured the outcome depressive symptoms at the end of the trial (591 patients), one trial [8] reported hospital admission (127 patients) and only one trial [8] reported the rate of adverse effects (127 patients).

The summary of findings is as follows:

  • The addition of folate as augmentation in the treatment of major depressive disorder probably results in little or no difference in depressive symptoms at the end of treatment. The certainty of the evidence is moderate.
  • The addition of folate as augmentation in the treatment of major depressive disorder probably results in little or no difference in adverse effects. The certainty of the evidence is moderate.

Following the link to access the interactive version of this table (Interactive Summary of Findings – iSoF)

Other considerations for decision-making

To whom this evidence does and does not apply

  • The conclusions of this summary are applicable to adult patients diagnosed with major depressive disorder.
  • The objective of this article was to include any type of folate (folic acid or methylfolate) in any population (with or without folate deficiency). It would be interesting to explore the effects of folate augmentation in population with objective deficit, its role associated with other B-complex nutraceuticals and the specific effects of methylfolate.
About the outcomes included in this summary
  • The outcomes selected are those considered critical for decision-making by the authors of this summary. In general, they coincide with those reported by the identified reviews.
  • Although only one trial [8] presented data about adverse effects suitable to estimate an effect measure, the other seven trials [6],[7],[9],[10],[12],[13] were in agreement with the first, reporting folate was generally well tolerated, with gastrointestinal symptoms (constipation, abdominal discomfort and diarrhea) being the most commonly reported.
  • Only one trial reported hospitalization rate with a single event in the placebo group.
Balance between benefits and risks, and certainty of the evidence
  • Folate would be an intervention probably ineffective, but without adverse effects in comparison to placebo.
  • One systematic review [3] emphasizes there might be adverse effects when used in high doses, prolonged periods of time or in combination with certain medications. Possible carcinogenic, neurological and haematological effects are highlighted.
  • Folic acid has also been implicated in the acceleration of age-related cognitive deterioration and reduction of the effect of certain antifolate drugs such as immunosuppressants [3].
  • It should be taken into account that in the context of a deficit of B12, the addition of folate can have harmful consequences at a neurological and hematological level [2].
Resource considerations
  • Folate is generally a low-cost intervention, so this factor should not play an important role in decision-making.
What would patients and their doctors think about this intervention
  • The use of nutraceuticals in psychiatry corresponds to a relatively emerging field. Over the past two decades and fostered by both experimental and epidemiological studies [2], the influence of nutritional factors has experienced increasing attention by the scientific community.
  • On the other hand, the interest for alternative treatments versus traditional medicine has grown in the general population, and studies have suggested higher willingness-to-pay for them and higher placebo effect properties [14],[15],[16]. Therefore, it is relevant for mental health professionals to be aware of the best available evidence in this area.
  • Regarding folate, most patients and physicians should lean against the intervention based on the information presented in this summary.

Differences between this summary and other sources

  • In two systematic reviews [1],[4], concluded the available evidence suggested folate could have a potential role as an augmentation treatment, but it was not clear if this applied to both people with normal and low levels of folate. In addition, they remarked the eventual appearance of one or two relatively small trials with neutral or negative results could have a substantial impact on the estimate.
  • In the most current systematic reviews [2],[3], which include more studies and more recent, the authors conclude there is a non-significant difference between folic acid and placebo. In relation to methylfolate in particular, they estimate there is too little evidence to reach firm conclusions yet. They mention it could be tentatively recommended, but they also note that although trials had a sound methodology, there might be bias towards positive results since they are funded by industry.
  • Regarding the main clinical guidelines, both the 2010 American Psychiatric Association's (APA) Practice Guideline for the Treatment of Patients with Major Depressive Disorder [17] and the 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder of the Canadian Network for Mood and Anxiety Treatments (CANMAT) [18] agree on the recommendation for the use of folate. On one hand, the APA considers there is modest evidence to recommend the addition of folate, but it is a low-risk intervention with general health benefits. On the other hand, CANMAT recommends folate augmentation as a third-line alternative for mild to moderate major depressive disorder. It should be noted that the guideline Depression in adults: recognition and management guide of the National Institute for Health and Care Excellence (NICE) [19] does not mention folate or other nutraceuticals as alternatives for enhancement, indicating the possibilities of using lithium, antipsychotics such as quetiapine or other antidepressants such as mirtazapine
Could this evidence change in the future?
  • The likelihood that the information provided in this summary changes with future evidence is low, since the investigation provides a good indication of the likely effect.
  • More evidence is needed to assess if there are benefits in populations with folate deficiency, or with the use of methylfolate.
  • We identified at least one ongoing systematic review [20] in PROSPERO and at least five ongoing trials [21],[22],[23],[24],[25] in the International Clinical Trials Registry Platform of the World Health Organization, which could provide relevant information in the future.
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Folate for depressive disorders

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier.

After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described here (http://dx.doi.org/10.5867/medwave.2014.06.5997)

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

Potential conflicts of interest

The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

INTRODUCCIÓN
En una proporción importante de los pacientes con depresión, el tratamiento antidepresivo no lleva a una respuesta satisfactoria. Actualmente se postula que la coadministración de nutrientes estandarizados farmacológicamente (nutracéuticos), como el folato en este caso, podrían potenciar los efectos de los antidepresivos.

MÉTODOS
Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE.

RESULTADOS Y CONCLUSIONES
Identificamos cuatro revisiones sistemáticas que en conjunto incluyen nueve estudios primarios, de los cuales, ocho son ensayos aleatorizados. Concluimos que la potenciación con folato en el tratamiento del trastorno depresivo mayor probablemente resulta en poca o nula diferencia en los síntomas depresivos. Pudiese ser interesante evaluar el efecto de formas de presentación específicas del folato o en población con déficit objetivado.

Authors: Javier Trincado[1,2], Constanza Caneo[2,3]

Affiliation:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Departamento de Psiquiatría, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: cmcaneo@uc.cl

Author address:
[1] Centro Evidencia UC
Pontificia Universidad Católica de Chile
Centro de Innovación UC Anacleto Angelini
Avda.Vicuña Mackenna 4860
Macul
Santiago
Chile

Citation: Trincado J, Caneo C. Is augmentation with folate effective for major depressive disorder?. Medwave 2018 Ene-Feb;18(1):e7155 doi: 10.5867/medwave.2018.01.7155

Submission date: 4/12/2017

Acceptance date: 21/12/2017

Publication date: 25/2/2018

Origin: This article is a product of the Evidence Synthesis Project of Epistemonikos Fundation, in collaboration with Medwave for its publication.

Type of review: Non-blinded peer review by members of the methodological team of Epistemonikos Evidence Synthesis Project.

PubMed record

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  1. Taylor, M. J., Carney, S. M., Goodwin, G. M., & Geddes, J. R. (2004). Folate for Depressive Disorders: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Psychopharmacology, 18(2), 251–256. | CrossRef |
  2. Schefft, C., Kilarski, L. L., Bschor, T., & Köhler, S. (2017). Efficacy of adding nutritional supplements in unipolar depression: A systematic review and meta-analysis. European Neuropsychopharmacology, 27(11), 1090–1109. | CrossRef |
  3. Sarris, J., Murphy, J., Mischoulon, D., Papakostas, G. I., Fava, M., Berk, M., & Ng, C. H. (2016). Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. American Journal of Psychiatry, 173(6), 575–587. | CrossRef |
  4. Taylor, M. J., Carney, S. M., Geddes, J., & Goodwin, G. (2003, April 22). Folate for depressive disorders. (J. Geddes, Ed.), Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. | CrossRef |
  5. Alpert JE, Mischoulon D, Rubenstein GE, Bottonari K, Nierenberg AA, Fava M. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry. 2002 Mar;14(1):33-8. | PubMed |
  6. BaşoğIu, C., Ateş, M. A., AIgüI, A., İpçioğIu, O. M., Geçici, Ö., Yılmaz, O., Semiz, Ü. B., Ebrinç, S., Gülsün, M., Özcan, Ö., Kılıç, S., Çetin, M. Adjuvant Folate with Escitalopram Treatment and Homocystein, Folate, Vitamin B-12 Levels in Patients with Major Depressive Disorder. Klinik Psikofarmakoloji Bulteni. 2009 Jun;19(2):135-142. | Link |
  7. Bedson E, Bell D, Carr D, Carter B, Hughes D, Jorgensen A, Lewis H, Lloyd K, McCaddon A, Moat S, Pink J, Pirmohamed M, Roberts S, Russell I, Sylvestre Y, Tranter R, Whitaker R, Wilkinson C, Williams N. Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation. Health Technol Assess. 2014 Jul; 18(48):vii-viii, 1-159. | CrossRef | PubMed | PMC |
  8. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000 Nov;60(2):121-30. | PubMed |
  9. Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990 Aug 18;336(8712):392-5. | PubMed |
  10. Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L, Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T, Nelson E, Mischoulon D, Alpert JE, Barbee JG, Zisook S, Fava M. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012 Dec;169(12):1267-74. | CrossRef | PubMed |
  11. Procter A. Enhancement of recovery from psychiatric illness by methylfolate. Br J Psychiatry. 1991 Aug; 159:271-2. | PubMed |
  12. Resler G, Lavie R, Campos J, Mata S, Urbina M, García A, Apitz R, Lima L. Effect of folic acid combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and serotonin levels in lymphocytes. Neuroimmunomodulation. 2008;15(3):145-52. | CrossRef | PubMed |
  13. Venkatasubramanian R, Kumar CN, Pandey RS. A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes. J Affect Disord. 2013 Sep 5;150(2):644-8. | CrossRef | PubMed |
  14. Kaptchuk TJ. The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med. 2002 Jun 4;136(11):817-25. Review. | PubMed |
  15. Hansen AH, Kristoffersen AE. The use of CAM providers and psychiatric outpatient services in people with anxiety/depression: a cross-sectional survey. BMC Complement Altern Med. 2016 Nov 11;16(1):461. | PubMed | PMC |
  16. Kemppainen LM, Kemppainen TT, Reippainen JA, Salmenniemi ST, Vuolanto PH. Use of complementary and alternative medicine in Europe: Health-related and sociodemographic determinants. Scand J Public Health. 2017 Oct 1:1403494817733869. | CrossRef | PubMed |
  17. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. APA; 2010.
  18. Ravindran AV, Balneaves LG, Faulkner G, Ortiz A, McIntosh D, Morehouse RL, Ravindran L, Yatham LN, Kennedy SH, Lam RW, MacQueen GM, Milev RV, Parikh SV; CANMAT Depression Work Group. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments. Can J Psychiatry. 2016 Sep;61(9):576-87. | CrossRef | PubMed | PMC |
  19. National Institute for Health and Care Excellence. Depression in adults: recognition and management. NICE Guideline (CG90). London: NICE; 2009.
  20. Sandra Yvonne Goumans, Maurits van Tulder, Sidney Rubenstein. Effect of folate on depressive disorders. PROSPERO 2013 CRD42013005727. | Link |
  21. Chavan BS. Use of bioavailable form of Folic acid for Treatment of Depression. CTRI/2017/03/008255. | Link |
  22. Gholampour N. Effect of Folic acid supplementation on the therapeutic regimen for major depressive disorder. IRCT2014082518922N1. | Link |
  23. Tatari F. The effects of folic acid in treatment of patients with depression. IRCT2013033112825N2. | Link |
  24. Palatnik A. Folic Acid and Omega -3 Fatty Acid Supplementation in Depressed Older Adults. NCT00480207. | Link |
  25. Dunn R. Phase 4 Study: An Open Study of the Efficacy and Tolerability in Unipolar Depression of Augmentation of the One-carbon Cycle With L-methionine, Betaine and Folate. NCT00226356. | Link |
Taylor, M. J., Carney, S. M., Goodwin, G. M., & Geddes, J. R. (2004). Folate for Depressive Disorders: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Psychopharmacology, 18(2), 251–256. | CrossRef |

Schefft, C., Kilarski, L. L., Bschor, T., & Köhler, S. (2017). Efficacy of adding nutritional supplements in unipolar depression: A systematic review and meta-analysis. European Neuropsychopharmacology, 27(11), 1090–1109. | CrossRef |

Sarris, J., Murphy, J., Mischoulon, D., Papakostas, G. I., Fava, M., Berk, M., & Ng, C. H. (2016). Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. American Journal of Psychiatry, 173(6), 575–587. | CrossRef |

Taylor, M. J., Carney, S. M., Geddes, J., & Goodwin, G. (2003, April 22). Folate for depressive disorders. (J. Geddes, Ed.), Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. | CrossRef |

Alpert JE, Mischoulon D, Rubenstein GE, Bottonari K, Nierenberg AA, Fava M. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry. 2002 Mar;14(1):33-8. | PubMed |

BaşoğIu, C., Ateş, M. A., AIgüI, A., İpçioğIu, O. M., Geçici, Ö., Yılmaz, O., Semiz, Ü. B., Ebrinç, S., Gülsün, M., Özcan, Ö., Kılıç, S., Çetin, M. Adjuvant Folate with Escitalopram Treatment and Homocystein, Folate, Vitamin B-12 Levels in Patients with Major Depressive Disorder. Klinik Psikofarmakoloji Bulteni. 2009 Jun;19(2):135-142. | Link |

Bedson E, Bell D, Carr D, Carter B, Hughes D, Jorgensen A, Lewis H, Lloyd K, McCaddon A, Moat S, Pink J, Pirmohamed M, Roberts S, Russell I, Sylvestre Y, Tranter R, Whitaker R, Wilkinson C, Williams N. Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation. Health Technol Assess. 2014 Jul; 18(48):vii-viii, 1-159. | CrossRef | PubMed | PMC |

Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000 Nov;60(2):121-30. | PubMed |

Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990 Aug 18;336(8712):392-5. | PubMed |

Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L, Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T, Nelson E, Mischoulon D, Alpert JE, Barbee JG, Zisook S, Fava M. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012 Dec;169(12):1267-74. | CrossRef | PubMed |

Procter A. Enhancement of recovery from psychiatric illness by methylfolate. Br J Psychiatry. 1991 Aug; 159:271-2. | PubMed |

Resler G, Lavie R, Campos J, Mata S, Urbina M, García A, Apitz R, Lima L. Effect of folic acid combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and serotonin levels in lymphocytes. Neuroimmunomodulation. 2008;15(3):145-52. | CrossRef | PubMed |

Venkatasubramanian R, Kumar CN, Pandey RS. A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes. J Affect Disord. 2013 Sep 5;150(2):644-8. | CrossRef | PubMed |

Kaptchuk TJ. The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med. 2002 Jun 4;136(11):817-25. Review. | PubMed |

Hansen AH, Kristoffersen AE. The use of CAM providers and psychiatric outpatient services in people with anxiety/depression: a cross-sectional survey. BMC Complement Altern Med. 2016 Nov 11;16(1):461. | PubMed | PMC |

Kemppainen LM, Kemppainen TT, Reippainen JA, Salmenniemi ST, Vuolanto PH. Use of complementary and alternative medicine in Europe: Health-related and sociodemographic determinants. Scand J Public Health. 2017 Oct 1:1403494817733869. | CrossRef | PubMed |

American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. APA; 2010.

Ravindran AV, Balneaves LG, Faulkner G, Ortiz A, McIntosh D, Morehouse RL, Ravindran L, Yatham LN, Kennedy SH, Lam RW, MacQueen GM, Milev RV, Parikh SV; CANMAT Depression Work Group. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments. Can J Psychiatry. 2016 Sep;61(9):576-87. | CrossRef | PubMed | PMC |

National Institute for Health and Care Excellence. Depression in adults: recognition and management. NICE Guideline (CG90). London: NICE; 2009.

Sandra Yvonne Goumans, Maurits van Tulder, Sidney Rubenstein. Effect of folate on depressive disorders. PROSPERO 2013 CRD42013005727. | Link |

Chavan BS. Use of bioavailable form of Folic acid for Treatment of Depression. CTRI/2017/03/008255. | Link |

Gholampour N. Effect of Folic acid supplementation on the therapeutic regimen for major depressive disorder. IRCT2014082518922N1. | Link |

Tatari F. The effects of folic acid in treatment of patients with depression. IRCT2013033112825N2. | Link |

Palatnik A. Folic Acid and Omega -3 Fatty Acid Supplementation in Depressed Older Adults. NCT00480207. | Link |

Dunn R. Phase 4 Study: An Open Study of the Efficacy and Tolerability in Unipolar Depression of Augmentation of the One-carbon Cycle With L-methionine, Betaine and Folate. NCT00226356. | Link |