LMF Effective as Adjunct Treatment in SSRI-Resistant Depression, Review Finds
According to a literature review presented in a poster at the 2025 NEI Spring Congress, L-methylfolate (LMF) is an effective adjunct treatment in selective serotonin reuptake inhibitor (SSRI)-resistant depression, particularly at 15 mg/day.
“Due to its safety, tolerability, and ability to cross the blood-brain barrier, LMF may be an effective adjunctive treatment for major depressive disorder (MDD). However, supporting clinical evidence is limited and fragmented across a few trials,” wrote Arif Reda, MS4, Ross University School of Medicine, Bridgetown, Barbados, and study coauthors. The review aimed to more clearly establish the efficacy of LMF supplementation as an MDD intervention by synthesizing findings from randomized controlled trials (RCTs).
The researchers extracted data related to the study population, dosage, adverse effects, and changes in psychometric scales from the selected RCTs. According to pooled data from 2 RCTs, 15mg/day of LMF yielded higher response rates in patients with SSRI-resistant depression than placebo, though results for lower doses were not clinically significant. An open-label study also found that 38% of patients on LMF remained in remission for up to 12 months.
The authors noted that individuals with methylenetetrahydrofolate reductase (MTHFR) mutations have also shown greater improvements on LMF, which suggests that there is a genetic component to therapeutic response. An additional study included in this analysis found that LMF produced greater clinical improvement than SSRI intervention alone in patients with a BMI ≥30 and high serum inflammatory markers.
“These findings support [LMF’s] role in personalized treatment, particularly for patients with poor antidepressant response and relevant clinical characteristics such as obesity,” researchers wrote.
To further explore the intervention’s potential, the authors suggest that future research focus on LMF’s efficacy in MDD patients with pro-inflammatory states, including post–myocardial infarction and cardiovascular disease.
Reference
Arif R, Arikian T, Imtiaz A, Zaidi M. Adjunctive l-methylfolate in major depressive disorder: implications for personalized psychiatry. NEI Spring Congress; May 8-10; Philadelphia, Pennsylvania.
