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

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.