Trends in Psychopharmacology

Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant-Augmenting Agent

Adjunct Professor of Psychiatry, University of California, San Diego

First published in Psychiatry Weekly, Volume 2, Issue 41, on October 29, 2007

Folate Deficiency

Folate deficiency may increase the risk of depression and reduce the action of antidepressants. Individuals with an inherited polymorphism that reduces the efficiency of folate formation may be at high risk for folate deficiency and for major depression. The effects of antidepressants have been reported when antidepressants are augmented with folic acid, folinic acid, or the centrally active L-methylfolate (known formally as (6(S)-5-methyltetrahydrofolate [MTHF]), particularly in depressed patients with folate deficiency whose major depressive episodes have failed to respond to antidepressants. The putative mechanism of action of MTHF as an augmenting agent to antidepressants is that it acts as a trimonoamine modulator, enhancing the synthesis of the three monoamines: dopamine, norepinephrine, and serotonin, resulting in a boost to the efficacy of antidepressants.

Folate and Depression

A substantial body of literature suggests that depression is associated with folate deficiency, and that patients with folate deficiency either experience a later onset of action, lesser improvement, a more severe depressive episode, or higher chances of relapse when taking antidepressants. The link between folate and depression is supported by observations that a common genetic variant of an enzyme that reduces one’s ability to convert folate to its centrally active metabolite, MTHF, specifically, the C677T variant of the enzyme methylene tetrahydrofolate reductase, is more common in patients with depression. The formation of MTHF from foods containing dihydrofolate or enriched with synthetic folic acid is shown in Figure 1. The enzyme methylene tetrahydrofolate reductase forms this centrally active metabolite, MTHF, in the final step of this process. The link between folate and depression is also supported by numerous studies suggesting that folic acid, folinic acid, or MTHF, either have antidepressant action or enhance the therapeutic benefits of antidepressants or lithium.

Disclosure: Dr. Stahl is a consultant to, is on the speaker’s bureaux of, or receives grant/research support from Acadia, Amylin, AstraZeneca, Biolaunch, Biovail, Bristol-Myers Squibb, Boehringer-Ingelheim, Cephalon, CSC Pharmaceuticals, Cyberonics, Cypress, Eli Lilly, Epix, Forest, GlaxoSmithKline, Janssen, Neurocrine, Neuromolecular, Neuronetics, NovaDel, Novartis, Organon, Otsuka, Pfizer, Pierre Fabre, Sanofi, ScheringPlough, Sepracor, Shire, Solvay, Somaxon, Tetragenix, and Wyeth.