I previously wrote an article on psychiatric genetic testing in 8/21 as a useful guide in making clinical decisions and out of all the genetic tests I review, the single most important gene I examine is MTHFR. What is the MTHFR gene? One of my patients calls it the “Mother Father Gene” but it technically stands for the enzyme, Methylenetetrahydrofolate Reductase, or the methylation gene for short. The MTHFR gene produces the MTHFR enzyme, which is essential for several bodily processes that directly tie into well-being. A variation in the MTHFR gene is highly correlated with psychiatric symptoms; it’s more common than people realize (30-50% have some variation) and it’s very treatable. In this next article, I will discuss how the treatment of this MTHFR gene with L-methylfolate can change a treatment resistant depression into a responsive one or even eliminate the need for an antidepressant entirely.
A great example of the importance of knowing and treating your MTHFR enzyme deficiency happened this past week. A woman in her mid-40s who has been on traditional antidepressants for close to 20 years became increasingly frustrated in recent months with continuing an SSRI antidepressant medication that she didn’t feel was helping her depression anymore. We discussed newer treatment options such as ketamine and TMS (Transcranial Magnetic Stimulation) but before we got to that I suggested getting genetic testing. The results stated that the MTHFR enzyme was only functioning at 60 percent capacity and so she started taking L-methylfolate. Within a week of increasing L-methylfolate to the higher dose of 7.5 MG every day, she has been feeling “significantly better” and “resilient” for the first time in many years. Rather than pursue ketamine or TMS, we have now decided to take her off the antidepressant entirely and just continue L-methylfolate which is addressing perhaps the root cause of her depression. An interesting addendum to this case is that the patient’s teenage son was also tested for the MTHFR gene and he has an even more significant mutation with the MTHFR enzyme functioning at only 45 percent capacity; while he doesn’t have clinical depression, having this information earlier in life can be a great advantage for other health issues even beyond mental health which I will discuss later in this article.
When it’s working right, the MTHFR gene begins a multistep chemical breakdown process called methylation, which ultimately helps you to make important proteins, use antioxidants, combat inflammation, eliminate toxins and heavy metals, keep homocysteine within normal range, optimize brain function, and silence the genes in your body whose overexpression could cause harm. MTHFR is responsible for the conversion of folate (vitamin B9) into the biologically active form of L-methylfolate which is a vital cofactor for the synthesis of serotonin, dopamine, and norepinephrine.
There are two common variants to this MTHFR gene wherein replacements of single nucleotides (pieces of DNA) results in lesser functioning: C677T and A1298C. One mutation at the C677T means your enzyme is functioning at 65 percent while two mutations at C677T means your enzyme is now functioning at 30 percent. One mutation at the A1298C means your enzyme is reduced to 80 percent and two mutations at A1298C means your down to 60 percent. However, you have to add the results from both variants. I’ve only had one patient out of the 30 tests or so I’ve done so far who has no variation at all and the standard recommendation for depression is to supplement with L-methylfolate if the enzyme is working at 45 percent capacity or less.
Knowing your MTHFR status has implications outside of psychiatry. Taking supplemental folate (i.e. folic acid) will do you little good if your body is not able to convert it to the active form, L-methylfolate due to decreased functionality of the MTHFR enzyme. Pregnant women with a significant defect in the MTHFR gene need to take L-methylfolate and not folate. Homocysteine is an inflammatory protein that must be metabolized by vitamin B12 and activated folate so it can be elevated when a person has a significant MTHFR variation; elevated homocysteine is associated with an increased risk of heart disease, stroke, and high blood pressure. However, don’t panic if you test positive for any of the inherited mutations. It just means that you need to be aware of your higher-than-normal risk for deficiencies as a result and for which supplementing with L-methylfolate and its partner, B12, is likely indicated. According to the claims by the manufacturers of the prescription version, L-methylfolate requires DHA (seaweed oil) to help it across the blood brain barrier. So while over-the-counter L-methylfolate-calcium may help homocysteinemia and pregnant mothers, it’s the prescription version that contains DHA that helps depression (again according to the manufacturers). However, I’ve heard from colleagues that people’s depression can improve with an over-the-counter version of L-methylfolate which tends to be a lower dose between 1-5 MG.
L-methylfolate usually takes 2-3 weeks to start working with some time (a week or so) after to observe the changes and for others to notice the changes although some people have reported benefit within a week. A common observation with this supplement is that others often notice the improvement before the patient does. I have also noticed that some people find the L-methylfolate activating and perhaps even anxiety inducing so I will often start people on a lower over the counter version 1-2 MG every day and see if they tolerate that well enough to take the prescription version. If they still can’t tolerate a low dose of L-methylfolate, I will suggest taking it with an amino acid supplement, glycine, which may offset the activating effects. If taking an L-methylfolate supplement is not feasible, one can also get this activated form of folate in foods such as beef liver and leafy green vegetables like spinach, kale, bok choy, and Swiss chard.
I now believe that everyone should be tested at birth right along with their routine phenylketonuria (PKU) screening and given the same attention PKU is from childhood on up through the lifespan (PKU is due to the absence or inactivity of a liver enzyme and the treatment involves a low phenylalanine diet). You don’t need to see a psychiatrist to get the MTHFR mutation test; any health care practitioner can order it or you can even do it on your own with 23andme. Unfortunately, insurance doesn’t always cover L-methylfolate but the prescription version can cost as little as $30 per month out of pocket. I would also suggest if you or someone you know has a significant MTHFR gene mutation, it’s important for other family members to get the MTHFR mutation test as well—it could make a big difference in their lives with significantly improved mental health.