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L-Methylfolate: A Promising Therapy for Treatment-Resistant Depression?

May 08, 2013

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.” 

2020 update: Adjunctive L-Methylfolate Offers Benefit in Depression Treatment

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. (9) 

“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.”

Genetics and BMI

Clinicians have differing opinions on whether it is necessary to test patients for the genetic abnormality before prescribing L-methylfolate, as the medical food is approved regardless of patient polymorphism status. “I do the test a lot,” said Dr. Draud. “It depends on the patient. Some don’t care about the test and others want to have it.” Dr. Thase noted that he has made clinical decisions without the test, and Dr. Jain said the test is “not critically necessary” and that the marker does not offer a 100%, definitive indication that the patient will or will not respond to L-methylfolate. 

Yet psychiatrists have other assessment tools besides genetics at their disposal— body mass index (BMI) offers a clue as to how patients may respond to L-methylfolate. Data show that L-methylfolate is particularly effective in patients with depression and a BMI of 30 or greater (10). This may be because of the relationship between obesity, inflammation, and depression and because excess fat increases the body’s methylation needs to the point that some people may require a methyl donor such as L-methylfolate, according to Dr. Draud and Dr. Jain. 

“I recommend to my colleagues that they put a BMI calculator on their smartphone and put the numbers in and calculate on the spot if they’re sitting across from a patient and have any question,” said Dr. Jain. 

Choosing an Adjunctive Therapy

Dr. Jain also recommends that clinicians refer to the 2010 American Psychiatric Association Practice Guideline for the Treatment of Patients With Major Depressive Disorder (11) for guidance on adjunctive depression treatment in general, which often consists of augmentation with second-generation antipsychotics. 

“Antipsychotic medications really work,” added Dr. Thase. “There’s no doubt about that, and when they work they work quickly.” He cautioned, though, that a clinician must carefully consider the risk/benefit equation when making a prescribing decision. 

While often effective as an augmentation therapy, antipsychotic medications have a significant side-effect burden that includes weight gain and tardive dyskinesia. Patients may hesitate to agree to these drugs as a result of the side effects. 

In contrast, L-methylfolate has a relatively benign side-effect profile and has shown adverse events similar to those of placebo in clinical trials (5). 

Dr. Draud typically tries augmentation with L-methylfolate before antipsychotics because of the low risk to patients and because of clinical trial data on timing. L-methylfolate was studied in patients who were newly treatment resistant, not those who had failed five or six other therapies, so “the earlier you use something like this, the better the chance you have to make it work,” he said.

A Game Changer? 

Anecdotally, Dr. Draud and Dr. Jain and have seen patients improve on the medical food, while Dr. Thase remains optimistic about L-methylfolate based on clinical trial data but has not yet treated enough patients to comment personally on its efficacy. 

Although L-methylfolate is a promising new treatment option, psychiatrists should remain realistic in their expectations. “It’s only had two clinical trials, so it’s passed FDA approval, but a lot of other drugs have been on the market for a long time. Is it going to continue to look good? It’s hard to say,” said Dr. Draud. 

Provided the positive findings hold up, “linking the genetic abnormality with the specific indication for use is very 21st century medicine and a truly revolutionary step,” said Dr. Thase. 

—Lauren LeBano


1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.

2. Crown WH, Finkelstein S, Berndt ER, et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psychiatry. 2002;63(11):963-71.

3. Greenberg P, Corey-Lisle PK, Birnbaum H, et al. Economic implications of treatment-resistant depression among employees. Pharmacoeconomics. 2004;22(6):363-373.

4. Papakostas GI, Petersen T, Pava J, et al. Hopelessness and suicidal ideation in outpatients with treatment-resistant depression: prevalence and impact on treatment outcome. J Nerv Ment Dis. 2003;191(7):444-449.

5. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012;169:1267-1274.

6. Tolmunen T, Voutilainen S, Hintikka J, et al. Dietary folate and depressive symptoms are associated in middle-aged Finnish men. J Nutr. 2003;133(10):3233-3236.

7. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 2004;65(8):1090-1095.

8. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psychiatry. 2004;65(8):1096-1098.

9. Kelly CB, McDonnell AP, Johnston TG, et al. The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland. J Psychopharmacol. 2004;18(4):567-571.

10. Papakostas GI, Zejecka J, Shelton R, Fava M. Effect of L-methylfolate on Maier Subscale Scores in a randomized clinical trial of patients with major depression. Poster presented at 25th Annual US Psychiatric and Mental Health Congress; November 8-11, 2012; San Diego, CA. Abstract 106.

11. Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice guideline for the treatment of patients with major depressive disorder, third edition. American Psychiatric Association. 2010; 1-152.

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