L-Methylfolate: A Promising Therapy for Treatment-Resistant Depression?
I am excited to be adding L-methylfolate into my treatment plan. It’s back to nutrition and genetic mechanisms gone awry.
Folic acid in and of itself does not alleviate depression. Our brain must convert folic acid into L-methylfolate before it can manufacture enough serotonin, norepinephrine, and dopamine to alleviate depression. However, certain individuals lack the ability to convert folic acid to l-methylfolate, rendering folic acid supplements ineffective for this group of patients.
This processing deficiency is caused by the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which is quite common among patients with depression. Up to 70% of patients with depression test positive for the polymorphism and therefore cannot convert folic acid into L-methylfolate.
For most psychiatrists, treating depression tends to be a frustrating search for the right therapy to help a patient reach remission. Nearly 2 out of 3 patients with depression do not achieve remission with selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) monotherapy—in clinical practice, this means that a psychiatrist treating 20 patients for depression could see 14 come back with little to no initial improvement of symptoms.(1) “It’s demoralizing,” said Rakesh Jain, MD, MPH, Director of Psychiatric Drug Research at the R/D Clinical Research Center in Lake Jackson, Texas. “Treatment-resistant depression is really the rule and not the exception.”
Treatment-resistant depression (TRD) is a term used to describe patients with major depressive disorder who do not reach remission after multiple antidepressant trials, including augmentation strategy, explained Jon W. Draud, MS, MD, Clinical Professor of Psychiatry at University of Tennessee College of Medicine in Memphis.
Individuals with ongoing depression are more likely to incur high medical costs (2), have employment problems (3), and experience suicidal ideation (4). “The ruinous effects of depression are amplified for people with treatment-resistant depression, so therefore there’s great urgency to treat these patients,” said Michael Thase, MD, Professor of Psychiatry at the University of Pennsylvania in Philadelphia.
Although the disease remains difficult to treat, researchers are continually seeking better solutions for patients with treatment-resistant depression. New studies, particularly a paper published by Papakostas et al in 2012 (5), have compelled psychiatrists to consider augmenting traditional antidepressants with the medical food L-methylfolate.
Unique Neurobiology
A medical food is a nutraceutical—essentially, a vitamin—rather than a pharmaceutical. However, unlike a vitamin, a prescription medical food such as L-methylfolate is regulated by the US Food and Drug Administration (FDA).
L-methylfolate (Deplin), is indicated for the distinct nutritional requirements of individuals who have suboptimal L-methylfolate levels in the CSF, plasma, and/or red blood cells and have major depressive disorder, with particular emphasis as adjunctive support for patients taking antidepressant medications. The medical food has attracted attention due to its benign side-effect profile and unique neurobiology. “It has a mechanism of action that is very different from what we are used to,” said Dr. Jain.
Traditional drugs such as SSRIs and SNRIs block reuptake of neurotransmitters, while L-methylfolate spurs the production of more neurotransmitters. “It primes the pump from within,” said Dr. Draud.
Dr. Draud added that clinicians might hesitate to use the compound because the mechanism of action is unfamiliar and because of a misconception that a prescription for folic acid is just as effective as L-methylfolate.
Literature suggests that depression is linked with folate deficiency (6) and that patients with insufficient folate are less likely to respond to treatment (7) and more likely to experience a relapse (8). Folate supplementation does help some patients, acknowledged Dr. Jain, but the full story is more complicated.
Folic acid in and of itself does not alleviate depression. Our brain must convert folic acid into L-methylfolate before it can manufacture enough serotonin, norepinephrine, and dopamine to alleviate depression. However, certain individuals lack the ability to convert folic acid to l-methylfolate, rendering folic acid supplements ineffective for this group of patients.
This processing deficiency is caused by the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which is quite common among patients with depression. Up to 70% of patients with depression test positive for the polymorphism and therefore cannot convert folic acid into L-methylfolate.
“In a scenario like that,” said Dr. Jain, “it becomes important to not use folate but to use L-methylfolate directly. That way you don’t have to worry about the patient potentially having the genetic polymorphism.”
Ellie Bell 