Pharmacopsychiatry 2022; 55(03): 139-147
DOI: 10.1055/a-1681-2047

Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders

Abdullah Al Maruf
1   College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Manitoba, Canada
2   Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada
3   Departments of Psychiatry and Physiology & Pharmacology, University of Calgary, Alberta, Canada
Ethan A. Poweleit
4   Divisions of Biomedical Informatics, Clinical Pharmacology & Research in Patient Services, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
5   Department of Biomedical Informatics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
Lisa C. Brown
6   Tempus Labs, Chicago, IL, USA
Jeffrey R. Strawn
7   Departments of Psychiatry and Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
Chad A. Bousman
2   Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada
8   Department of Medical Genetics, University of Calgary, Alberta, Canada
9   Department of Community Health Sciences, University of Calgary, Alberta, Canada
10   Alberta Children’s Hospital Research Institute, University of Calgary, Alberta, Canada
› Author Affiliations


Objectives  Partial response to pharmacotherapy is common in major depressive disorder (MDD) and many patients require alternative pharmacotherapy or augmentation, including adjunctive L-methylfolate. Given that L-methylfolate augmentation is rarely included in major clinical practice guidelines, we sought to systematically review evidence for L-methylfolate augmentation in adults with MDD and to examine its efficacy meta-analytically.

Methods  We systematically searched PubMed for articles up to December 31, 2020, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Included studies were published in peer-reviewed, English-language journals and examined L-methylfolate adjunctive therapy in depressive disorders or its effect on antidepressant response. A fixed- and random-effects meta-analysis and risk of bias assessment using the Cochrane Risk of Bias Tool were conducted.

Results  Qualitative assessment of nine articles (N=6,707 patients) suggests that adjunctive L-methylfolate improved antidepressant response. In the meta-analysis of categorical Hamilton Rating Scale for Depression-17 response, (three studies, N=483) adjunctive L-methylfolate was associated with a small effect versus antidepressant monotherapy (relative risk: 1.25, 95% confidence interval [CI]=1.08 to 1.46, p=0.004). A meta-analysis of four studies (N=507) using a continuous measure of depressive symptoms showed a similar effect of adjunctive L-methylfolate (standardized mean difference=− 0.38, 95% CI=− 0.59 to−0.17, p=0.0003).

Conclusion  Adjunctive L-methylfolate may have modest efficacy in antidepressant-treated adults with MDD.

Publication History

Received: 02 June 2021
Received: 17 September 2021

Accepted: 18 October 2021

Article published online:
18 November 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
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