L-methylfolate dosage for depression

L-Methylfolate for the Treatment of Depression: Can We Use it During Pregnancy?

Last summer, we posted a blog about using folate to treat (and perhaps prevent) depression in women of childbearing age. Supporting that recommendation are the several reports indicating that people with lower folate levels are at higher risk of major depression or may experience more severe depressive symptoms. Other studies have indicated that in folate-deficient patients, antidepressants may be less effective or may take longer to take effect.

But is folate an effective treatment for depression? A recent report indicates that augmentation with L-methylfolate may be effective for treating patients with depression who are partial- or non-response to selective serotonin reuptake inhibitors (SSRIs). In this multicenter trial, 75 patients with SSRI-resistant major depressive disorder were randomly assigned to receive: (1) l-methylfolate for 60 days (15 mg/day); (2) placebo for 30 days followed by L-methylfolate (15 mg/day) for 30 days; or (3) placebo for 60 days. In all groups SSRI dosages were kept constant throughout the study.

Adjunctive treatment with l-methylfolate at 15 mg/day showed significantly increased response rates and decreased the severity of depressive symptoms. (It seems as if lower doses of l-methylfolate were not effective. A somewhat larger trial included in this report failed to show any improvement when l-methylfolate was used at a lower dose of 7.5 mg/day.) L-methylfolate was well tolerated, with rates of adverse events similar to those reported in the placebo group.

In an earlier double-blind placebo-controlled study of folic acid (500 mcg/day) added to fluoxetine, Coppen and Bailey found that adjunctive folic acid was effective in women but not in men. In three other studies where patients with major depression were selected without regard to folate deficiency, it seems that positive results were seen only when higher doses of l-methylfolate (above 10 mg/day) were used.

Pregnancy and L-methylfolate

As there has been an increasing interest in the use of folate to treat depression, we have received more questions regarding the use of L-methylfolate (sold as Deplin) during pregnancy either alone or in combination with an antidepressant. We all know that folate is important for pregnant women. Because women with low folate levels are at increased risk of having a child with a neural tube defects (NTDs) and other types of malformations, the U. S. Public Health Service and CDC recommend that all women of childbearing age consume 0.4 mg (400 mcg) of folic acid daily. (Most prenatal vitamins contain 0.8 mg or 800 mcg of folic acid.)

Folate is typically taken in its synthetic form (as in vitamin supplements) or as naturally occurring dihydrofolate in foods. For those of you interested in the nitty gritty details of folate metabolism, these folates are converted to the active form of l-methylfolate by 5,10-methylenetetrahydrofolate reductase (MTHFR). Importantly the MTHFR gene has various polymorphisms that affect this conversion. About half of all Caucasians have a less efficient form of the MTHFR gene, and the prevalence may be even higher in certain groups (e.g., Californian Hispanics, African Americans). Those individuals with these less efficient forms of the MTHFR gene may be more prone to folate deficiency; however, taking l-methylfolate bypasses the MTHFR enzyme and leads to higher levels of the biologically active l-methylfolate.

It’s Safe: But How Much?

Because l-methylfolate is the naturally occurring, biologically active form of folic acid, synthesized by the human body, it is safe to take during pregnancy. Where things get a bit murky is determining how much is safe during pregnancy. When we make recommendations regarding the use of vitamin supplements, we refer to the Recommended Dietary Allowance (RDA) to determine what amount to use. The upper limit established for synthetic forms of folate in dietary supplements and fortified foods is 1000 mcg for pregnant and lactating women. While the amount of l-methylfolate used in the Coppen and Bailey study (500 mcg/day) does not exceed the recommended limit, most studies demonstrating efficacy for l-methylfolate uses doses that are 10 to 15 times higher than the recommended limit.

Some might wonder if l-methylfolate may be better for treating depression than conventional antidepressants during pregnancy; however, we cannot say that using high doses of l-methylfolate in pregnancy is safer. No published studies have assessed the safety of high doses of l-methylfolate in pregnancy. Yet there are certain situations where higher doses of folate may be used during pregnancy (usually 4 to 5 mg) “under medical supervision” (e.g., if a woman has given birth to a child with a neural tube defect in a previous pregnancy).

Given the uncertainty regarding the use of high doses of folate during pregnancy, antidepressants remain the first choice when pharmacologic treatment of depression is indicated. But there are other situations where the decision might not be so straightforward. What if you have a patient who responded to antidepressant only when augmented with l-methylfolate? Or what if you have a pregnant woman with a partial response to an SSRI? Would you opt to augment with l-methylfolate before you would consider augmenting with lithium or an atypical antipsychotic agent?

Ruta Nonacs, MD PhD

Bentley S, et al. Comparative effectiveness of a prenatal medical food to prenatal vitamins on hemoglobin levels and adverse outcomes: a retrospective analysis. Clin Ther. 2011;33:204–210.

Morrell MJ. Folic acid and epilepsy. Epilepsy Curr. 2002;2:31–4

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

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

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.

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.

L-methylfolate: Another weapon against depression

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Combination therapies for major depressive disorder (MDD) may enhance antidepressant efficacy and long-term results by working synergistically to regulate monoamines availability. Low levels of serum and red blood cell folate are linked to severe symptoms of depression and some patients are less likely to respond to antidepressants.1 Even in patients with normal serum or red blood cell folate levels, CNS folate levels may be suboptimal.1

L-methylfolate is the centrally active derivative of folate that regulates synthesis of trimonoamines serotonin, dopamine, and norepinephrine and is a key regulator of the cofactor tetrahydrobiopterin (BH4). BH4 is required by tryptophan hydroxylase for serotonin synthesis and by tyrosine hydroxylase for dopamine and norepinephrine synthesis.2

Evidence suggests adding L-methylfolate to selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) when starting pharmacotherapy leads to greater reduction of depressive symptoms in a shorter time compared with SSRI or SNRI monotherapy.1 In a study of patients with MDD who partially responded or did not respond to SSRIs, adjunctive L-methylfolate, 15 mg/d, produced greater response rates compared with SSRIs plus placebo.3 L-methylfolate also was well tolerated in combination with SSRI or SNRI therapy. The rates of adverse effects were not significantly different in patients taking L-methylfolate plus an SSRI or SNRI compared with those taking SSRI or SNRI monotherapy.1

MDD patients who may benefit from L-methylfolate include those with low levels of folate and its active metabolites—such as L-methylfolate—and inadequate response to antidepressants. Patients who have an alcohol use disorder, eating disorders, genetic C677-T polymorphism (present in half of the general population), or gastrointestinal disorders are at risk for low folate levels, as well as those who are pregnant.2

Folic acid needs to be converted to L-methylfolate to cross the blood-brain barrier, whereas L-methylfolate can be used directly by the brain.2 Therefore, patients who take medications that can interfere with the conversion of folate to L-methylfolate might benefit from adjunctive L-methylfolate. These medications include lamotrigine, valproate, oral contraceptives, metformin, warfarin, fenofibrates, and certain retinoids.1 Patients with C677-T polymorphism and patients from Hispanic or Mediterranean populations have shown impaired ability to convert folic acid to L-methylfolate.2


Dr. Fluitt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

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