drug-resistant depression

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New Hope for People with Drug-Resistant Depression

You’ve done it all, you’ve gone to therapy and followed their advice, you’ve taken the medicine, gone through the long process of switching from one drug to another, and then another—but nothing helps your depression. You have major depression. Although there isn’t a “depression gene” like that for cystic fibrosis, your major depression may actually have its roots in a genetic variation in an enzyme that you’ve never heard of, methylenetetrahydrofolate reductase (MTFHR). There is now a simple genetic test to see if you have the MTFHR defect, and if you do there is evidence that antidepressants plus L-methylfolate can help you battle your depression.

Mental problems are complex. They have long been thought to be caused by a combination of genetic and environmental factors. As early the 1960s researchers tied together depression and folic acid levels and carried out many studies testing the effects of dietary supplements of folic acid (Vitamin B9) on depression with limited success. These efforts failed because folic acid can’t be used by the body, it must go through many chemical modifications in the liver and intestines. A series of enzymes convert folate into its active form, L-methylfolate.

Why is this important to people with depression? Because only the active form gets into the brain. A mutated MTFHR gene means that a small amount of L-methylfolate will be produced, so the brain will be starved of this chemical. One of L-methylfolate’s critical roles is to regulate the synthesis of the monoamine neurotransmitters serotonin, dopamine, and norepinephrine.

You get one copy of the MTFHR gene from each parent. Although a number of mutations of MTFHR have been identified, in the most common one the cell incorporates a wrong amino acid (substituting an alanine for a valine) into the growing MTFHR enzyme. Unfortunately, people with this MTFHR defect only use 10-20% of the folic acid they ingest.

The frequency of this mutation varies in different populations (lower in Africans), but it is estimated to occur in about 12% of all people. The lucky 33% of people have Cs in both of their 667 positions, which means they do not have this inborn error in folate metabolism. The rest of us have one of each—a T in one 667, a C in the other. The MTFHR gene is located on the short arm of (each of your) chromosome 1 at position 36.3.

No one would ask a person with sickle cell anemia (another inborn error with a single nucleotide substitution) to “suck it up” or try harder, yet many people believe that depression can be overcome simply by changing one’s attitude or life circumstances. Society needs a shift in understanding for people suffering from treatment-resistant depression—they should all be tested for the MTHFR mutation.

How do you find out if you have the mutation? A number of companies can test for the MTHFR defect, and a sample (cheek swab) can be processed in about a week. Ask about the MTHFR SNP test at your doctor’s office, it’s even covered by some insurance companies. A physician can prescribe L-methylfolate (also known as Levomefolic acid, 5-MTHF, and 5-methyltetrahydrofolate and various proprietary names), or you can buy it over the counter.  If you have depression it is very important to continue to take any antidepressants prescribed to you. L-methylfolate is meant to be taken in addition to antidepressants, not as a substitute for them.


Stahl SM. L-methylfolate: a vitamin for your monoamines. J Clin Psychiatry 69:1352-3, 2008. This one is most generally readable

Frosst, P., Blom, H. J., Milos, R., Goyette, P., Sheppard, C. A., Matthews, R. G., Boers, G. J. H., den Heijer, M., Kluijtmans, L. A. J., van den Heuvel, L. P., Rozen, R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet. 10: 111-113, 1995. This one found the mutation!

Shelton RC, Sloan Manning J, Barrentine LW, Tipa EV. Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial. The Primary Care Companion for CNS Disorders. 15(4):PCC.13m01520. doi:10.4088/PCC.13m01520, 2013. A study of two doses of L-methyl folate

Trimmer, E. Methylenetetrahydrofolate Reductase: Biochemical Characterization and Medical

Significance Current Pharmaceutical Design 19: 2574-2593, 2013. A review of the enzyme specific things about the enzyme.

http://www.snpedia.com/index.php/Rs1801131 Accessed 1/15/2015


Ms. Durant Medical EditorLearn more about ScienceDocs Editor Ms. Durant


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