Document Type

Peer-Reviewed Article

Publication Date



Objective: Evaluate depression scores, response, and remission rates in patients with major depression receiving adjunct therapy with folate (L-Methylfolate or folic acid) compared to selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor (SSRI or SNRI) monotherapy.

Methods: Academic Search Premier, CINAHL Complete, Cochrane Database of Systematic Reviews, Medline with Full Text, PsychInfo, PubMed,, and Google Scholar were searched utilizing specific key words. Identified studies were independently screened for inclusion by two reviewers, were assessed for risk of bias using the Revised Cochrane risk-of-bias tool (RoB2), then meta-analyzed using a random effects model with Review Manager (5.4) software.

Results: The initial search revealed 293 articles with 6 randomized control trials ultimately meeting inclusion criteria. In patients with depression, analysis of 5 studies revealed a significantly lower Hamilton Depression Rating Scale (HAM-D) score in individuals treated with adjunct therapy with l-Methylfolate/folic acid [Mean Difference (MD): -2.16 (95 % CI -3.62 to -0.69), p = 0.004], as well a combined HAM-D and Beck Depression Inventory-II (BDI-II) scores [standardized mean difference (SMD): -0.61 (95 % Confidence Interval {CI} -0.97 to -0.24), p = 0.002]. This adjunct therapy also yielded an improved response rate [Risk Ratio (RR): 1.36 (95 % CI: 1.16-1.59) P = 0.0001], increase in remission rate [RR: 1.39 (95 % CI: 1.00-1.92) P = 0.05], and reduction in depression scores after varying durations of treatment, 4 week: [SMD = -0.38 (95 % CI: -0.55 to -0.22) P ≤ 0.00001]; 6 week: [SMD = -0.94 (95 % CI: -1.85 to -0.03) P = 0.04]; ≥ 8 week: [SMD= -0.57 (95 % CI: -0.91 to -0.23) P = 0.0009].

Conclusion: Adjunct therapy with l-Methylfolate or folic acid improves depression scale scores, patient response, and remission rates.


Available online 24 August 2021.

Rabail Altaf and Irasema Gonzalez are graduate students in the Physician Assistant Studies program at Sacred Heart University.

Open access under Attribution-NonCommercial-NoDerivatives 4.0 International license.






Complementary Therapies in Medicine









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