Good, better, best: clinical scenarios for the use of L-methylfolate in patients with MDD

CNS Spectr. 2020 Dec;25(6):750-764. doi: 10.1017/S1092852919001469. Epub 2019 Dec 13.


Depression is among the most prevalent mental disorders worldwide, and a substantial proportion of patients do not respond adequately to standard antidepressants. Our understanding of the pathophysiology of depression is no longer limited to the chemical imbalance of neurotransmitters, but also involves the interplay of proinflammatory modulators in the central nervous system, as well as folate metabolism. Additional factors such as stress and metabolic disorders also may contribute. Multiple inflammatory, metabolic, and genetic markers have been identified and may provide critical information to help clinicians individualize treatments for patients to achieve optimal outcomes. Recent advancements in research have clarified underlying causes of depression and have led to possible new avenues for adjunctive treatment. Among these is L-methylfolate, a medical food that is thought to enhance synthesis of monoamines (serotonin, norepinephrine, and dopamine), suppress inflammation, and promote neural health. Clinical studies that assessed supplemental use of L-methylfolate in patients with usual care-resistant depression found that it resulted in improved outcomes. Patients with selective serotonin reuptake inhibitor-resistant depression, and particularly subgroups with biomarkers of inflammation or metabolic disorders or folate metabolism-related genetic polymorphisms (or ≥2 of these factors), had the best responses. Considering this, the goals of this review are to 1) highlight recent advances in the pathophysiology of major depressive disorder as it pertains to folate and associated biomarkers and 2) establish the profiles of patients with depression who could benefit most from supplemental use of L-methylfolate.

Keywords: Depression; adjunctive therapy; folate; inflammation; serotonin norepinephrine reuptake inhibitor (SERT and NET); serotonin reuptake inhibitor (SERT).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / metabolism
  • Humans
  • Tetrahydrofolates / metabolism
  • Tetrahydrofolates / therapeutic use*


  • Antidepressive Agents
  • Tetrahydrofolates
  • 5-methyltetrahydrofolate