A Review of l-Methylfolate as Adjunctive Therapy in the Treatment of Major Depressive Disorder

Abstract

Objective: To examine the potential of using l-methylfolate (LMF) as an adjunctive therapy for major depressive disorder (MDD) and assess its role in filling current treatment gaps for patients who are overweight/obese and have chronic inflammation.

Data Sources: The PubMed database was searched using the key words l-methylfolate, adjunctive, and depression to identify studies published from January 2000 to April 2021.

Study Selection: Identified studies included 2 randomized controlled trials (RCTs), an open-label extension of these RCTs, and a real-world prospective study. Post hoc analyses that explored subgroups and their response to LMF treatment, including patients who were overweight and had elevated inflammatory biomarkers, were also included.

Results: These studies support the use of LMF as an adjunctive treatment in patients with MDD not responding to antidepressant monotherapy. The most effective dose tested was 15 mg/day. Treatment response was higher in individuals with a body mass index (BMI) ≥ 30 kg/m² and elevated levels of inflammatory biomarkers. Inflammation is associated with increased production of proinflammatory cytokines, which interferes with the synthesis and turnover of monoamine neurotransmitters, thereby contributing to expression of depressive symptomatology. LMF may mitigate these effects by facilitating the synthesis of tetrahydrobiopterin (BH₄), a critical coenzyme in neurotransmitter production. Furthermore, LMF does not cause adverse reactions commonly associated with other adjunctive MDD treatment agents (eg, atypical antipsychotics), such as weight gain, metabolic perturbations, and movement disorders.

Conclusion: LMF is effective as an adjunctive treatment in MDD and may especially benefit patients with higher BMI and inflammation.