This study aims to determine the efficacy of L-methylfolate for treatment of depressive symptoms and the roles of C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) mutations.

Folate deficiency is implicated as a risk factor for MDD and is also associated with greater severity of depressive symptoms and poor responsiveness to antidepressants. While supplementation with folic acid has been shown to improve depressive symptoms, polymorphisms in the gene which encode the MTHFR enzyme may reduce some patients’ ability to convert dietary folate and folic acid into active L-methylfolate. Supplementation with active L-methylfolate therefore may be efficacious in treating depressive symptoms.

Charts were retrospectively reviewed for 182 patients (44±18, F=108, M=74). The primary outcome was change in severity of depressive symptoms, indicated by change in the 9-item Patient Health Questionnaire (PHQ-9) score, from baseline to minimally two months of treatment.

Patients treated with L-methylfolate experienced a 25% reduction in PHQ-9 score as compared to baseline and demonstrated significant score improvement (p<0.001). Patients taking anticonvulsants or those who had metabolic disorder, Bipolar Disorder, migraine without aura, concussion, or those 41-50 years old were more likely to demonstrate an improvement in PHQ-9. Patients who experienced a substantial reduction in PHQ-9 of at least five points had a longer duration of treatment (p=0.018) and were more likely to be homozygous for the 677TT mutation (p=0.016).

The significant association of the 677T genotype with improvement in depressive symptoms following L-methylfolate treatment is consistent with the literature indicating the 677TT genotype contributes to L-methylfolate deficiency and depressive symptoms. The effect of migraine diagnosis on PHQ-9 improvement is noteworthy because past studies have concluded that MTHFR C677T polymorphisms are associated with migraine with aura. Further studies are needed to explore the impact of disease severity at baseline and co-morbid diagnoses on the efficacy of L-methylfolate treatment for depression.