L-methylfolate Plus Antidepressant Improves MDD

A new study published in Innovations in Clinical Neuroscience suggests that when L-methylfolate, a medical food available commercially and by prescription, is used for dietary management of depression in combination with an antidepressant drug at the start of depression therapy, it results in significantly more patients experiencing major improvement (2.5 times) and more rapid improvement than antidepressant monotherapy alone.(1)

It is reported that approximately 70 percent of major depressive disorder (MDD) patients have a genetic abnormality that results in an imbalance of L-methylfolate. (2) Adjunctive L-methylfolate administered early in therapy has demonstrated that there are clear synergies between antidepressant drugs and L-methylfolate that result in better patient outcomes and earlier in the course of treatment.

The study was a retrospective two-arm chart review of 242 adults, ages 18-70, diagnosed with MDD and experiencing some degree of functional impairment (Clinical Global Impression – Severity (CGI-S) score of four (moderately ill) or five (markedly ill)) Charts were divided into those patients who were treated with SSRI/SNRI plus dietary management using L-methylfolate at the start of treatment and a control arm of 147 patients using SSRI/SNRI monotherapy.

More than two and a half times as many patients in the combination SSRI/SNRI drug + L-methylfolate medical food arm achieved major improvement than those in the control arm. 18.5 percent of the L-methylfolate and antidepressant treated patients showed a major improvement at 60 days in depression symptoms represented by a 2 points or greater reduction in CGI-S versus 7.04 percent of the control group (p = 0.01).

Forty percent of combination patients rated severe (CGI-S = 5) improved significantly within 60 days compared to 16.3 percent of patients in the control group (p= 0.02). Median time to a 2-point or greater CGI-S reduction in the combination group was 177 days compared to 231 days for the control group (p= 0.03) and discontinuation rates due to adverse events were significantly lower in the combination group (17.9 percent) versus the antidepressant monotherapy group (34 percent) (p=0.0078), although the overall rates of adverse events in both groups were not statistically different

L-methylfolate is the only form of folate that crosses the blood-brain barrier to help regulate neurotransmitters associated with depression. According to the authors the use of adjunctive L-methylfolate along with an antidepressant may represent a paradigm shift in the therapy of major depressive disorder.


1. Ginsberg LD, Oubre A, Daoud Y. Innov Clin Neurosci. 2011;8(1):19-28.

2. Stahl SM. CNS Spectrums. 2007;12(10):739-44.