Methylfolate and Depression

Peter Forster Major Depression, Treatments of Depression

The role of methylfolate in the treatment of patients with depression has once again been highlighted by an article published in the American Journal of Psychiatry in 2016.

After successfully treating treatment resistant depression in a patient deficient in cerebrospinal fluid (CSF) tetrahydrobiopterin (necessary for biosynthesis of several neurotransmitters) with sapropterin (a synthetic form of tetrahydrobiopterin’s active isomer), investigators searched for this and other potential metabolic abnormalities in 33 patients with treatment resistant depression.

The study found that a very high proportion of teenagers and young adults with well documented treatment resistant depression had some kind of CSF metabolite abnormality (an abnormality in some metabolite suggesting a disorder in the production of neurotransmitters) and by far the most common abnormality was normal serum folate and a low 5-methyltetrahydrofolate (5-MTHF) level, suggesting a functional deficit in the active form of folate that is involved in the production of the monoamine neurotransmitters that seem to be closely tied to depression.

The researchers then treated these patients in an open label fashion and found some evidence that reversing this apparent deficiency improved depression:

Of the 12 patients with CFD, all were treated with folinic acid (1–2 mg/kg per day) for at least 6 weeks (range 6–79 weeks), while continuing their pre-evaluation treatment regimen. Ten of the 12 patients showed reductions in symptom inventory scores at follow-up.

We do know that some people with depression have a gene that may predispose to folate deficiency even when they are getting an adequate dietary supply of folate because they have difficulty converting folate to the active form of the vitamin which is methylfolate.

The MTHFR gene affects the enzyme involved in breaking down the amino acid, homocysteine and converting folate and folic acid into its active form, L-methylfolate.

Roughly one third of Americans carry one copy of a common MTHFR gene mutation (C677T). People who carry two C677T mutations, which is about 11% of Americans, have a 16% higher chance of developing coronary heart disease compared to people without these mutations and have elevated levels of homocysteine in their blood (homocysteinemia) or urine (homocystinuria) (NIH Genetic and Rare Disease Information Center). MTHFR gene mutations are also associated with an increased risk of other conditions, including depression, but a cause-and-effect relationship has not been established (Liew, Eur J Med Genet 2015; Gilbody, Am J Epidemiol 2007).

  • In theory, it makes sense to believe that for people with this gene mutation supplementation with the active form of folate (l-methylfolate) may be helpful. There are several methylfolate supplements that are available as “medical foods” for the treatment of depression associated with methylfolate deficiency.

It is worth considering what a medical food is, and is not, according to Up To Date (a well regarded review of medicine):

A medical food is formulated to be administered enterally under the supervision of a physician and is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements are established by medical evaluation. Medical foods are not drugs and, therefore, are not subject to any FDA regulatory requirements that specifically apply to drugs (eg, requirement for written/oral prescription prior to dispensing, premarket review or approval, proof of safety and efficacy).

Currently available medical foods are –

  • Deplin tablets 7.5 or 15: l-methylfolate 7.5 mg or 15 mg
  • L-Methylfolate Formula 7.5 or 15: l-methylfolate 7.5 or 15 mg
  • L-Methylfolate Forte: l-methylfolate 7.5 mg or 15 mg
  • Generic  tablets l-methylfolate 15 mg
  • Deplin capsules 7.5 or 15: l-methylfolate 7.5 mg or 15 mg
  • Elfolate capsules: 7.5 mg, 15 mg
  • Generic capsules: 7.5 mg or 5 mg
  • Enlyte: contains a mix of folate, folinic acid and l-methylfolate

Note that the biologically active form of methylfolate is l-methylfolate and there is at least a theoretical possible that mixtures of d-methylfolate and l-methylfolate (which is what you will find in many online supplements, whether or not they advertise themselves as containing l-methylfolate) might be less effective.

Other forms of folate supplements include folate itself (which is what is added to fortified wheat in this country), folinic acid and tetrahydrofolate. There is reason to think that in people with C677T mutations folate may not be effective. Folinic acid is a “vitamer” – meaning a compound that appears to have similar activity to the vitamin itself. It is not clear to me that it is useful in patients with C677T mutations. Tetrahydrofolate (levomefolate) is another active form of folate and, if it is not metabolized in the body before entering the brain, should be at least as active as L-methylfolate.

Jarrow Formula Methyl Folate is an over the counter formulation that has been tested by an independent research laboratory and approved.

People with C677T mutations may be more likely to have a deficiency in vitamin B-12 (Zittan, Am J Physiol Heart Circ Physiol 2007) as well as in brain methylfolate levels. Supplementation with both methylfolate and vitamin B-12 may be helpful.

For more on genetic testing please follow this link.

We have long been interested in using methylfolate as an augmenting agent both because of small but reasonably well-designed studies suggesting that it may be effective and because, since it is a vitamin, is presumed to be safe treatment with relatively few side effects.

Unfortunately the prescribed form of l – methylfolate (Deplin) can be expensive and for that reason it would be helpful to know who is likely to respond and who will not.

A small study that was presented in poster form a year and a half ago at the United States Psychiatric Congress suggested that those people most likely to respond not only had treatment resistant depression but also were overweight (obese) and had evidence of an ongoing low-level inflammatory process (an elevated C-reactive protein).

The study seems pretty well-designed and the result was very significant. On the right you can see a graph that shows that the response rate to methyl folate was significantly higher in those whose BMI (Body Mass Index) was high.

The study found that an elevated C-reactive protein also predicted greater likelihood of response to methylfolate.

However one concern that I have is that this study has not been published and usually a well-designed study with an interesting result would find its way into a journal in less than a year and a half.


“Clinical Effect of L-methylfolate in Patients Stratified by Baseline Obesity and Inflammation in a Randomized Clinical Trial of Patients with Major Depression.” Charles Raison, MD; Richard C. Shelton, MD; Stephen M. Stahl, MD, PhD; et al. Presented at the US Psychiatric and Mental Health Congress. September 30, 2013.

Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior Lisa A. Pan, Petra Martin, Thomas Zimmer, Anna Maria Segreti, Sivan Kassiff, Brian W. McKain, Cynthia A. Baca, Manivel Rengasamy, Keith Hyland, Nicolette Walano, Robert Steinfeld, Marion Hughes, Steven K. Dobrowolski, Michele Pasquino, Rasim Diler, James Perel, David N. Finegold, David G. Peters, Robert K. Naviaux, David A. Brent, and Jerry Vockley. American Journal of Psychiatry 2016