Folate for Treatment-Resistant Depression

Folic-acid and related deficiencies have been associated with depression. A promising strategy for treatment-resistant depression is to target the one-carbon cycle involving homocysteine's conversion to methionine, where l-methylfolate, facilitated by vitamin B₁₂, acts as a methyl donor; methionine next combines with ATP to form S-adenosylmethionine, a methyl donor facilitating dopamine, norepinephrine, and serotonin synthesis. Researchers recently reported results from two manufacturer-funded, randomized, controlled, double-blind, l-methylfolate studies using a complex, two-phase “sequenced parallel comparison design.”

First, 148 nonpsychotic, unipolar depressed patients who failed to respond to selective serotonin reuptake inhibitors (SSRI…