By Amanda Batterbee, PMHNP-BC, MSN, BSN, RN – February 2024
I have spoken with colleagues who are hesitant to jump into genetic testing with relation to mental health care. Wouldn’t it be great if we collectively treated mental illness as aggressively as we treat other physical illnesses? Providers don’t hesitate to do genetic testing within other specialties, so why are so many mental health professionals timid when it comes to using the tools available to us?
In my last post, I discussed the implications of personalized medicine and pharmacogenetic testing. I would love to focus in on specific implications of the MTHFR genotypes and their role in psychiatric care.
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that is vital to DNA and RNA synthesis as well as production of neurotransmitters including serotonin, dopamine, and norepinephrine. The MTHFR enzyme methylates folic acid which is a catalyst for nucleotide synthesis. We cannot effectively absorb and metabolize the folic acid we receive from foods, so we rely on the methylation process to convert folic acid for absorption. We can consider MTHFR to be a catalyst for the chain reaction of neurotransmitter production. We know that while the monoamine theory of depression may be outdated, neurotransmitter regulation is still a crucial target in the treatment of mental health conditions.
Most psychotropics we use act on the receptor site of a neuron to either increase available neurotransmitters for transmission, increase excitatory transmission, inhibit chemical messages, or influence other chemical messengers than impact neurotransmission and communication. Psychotropic medications don’t “create” or “produce” more neurotransmitters, they work with what the brain already has.
We know that certain mutations of the MTHFR gene result in decreased enzyme activity, which results in a decrease of neurotransmitter production and thus reduced levels of neurotransmitters available in the brain.
Now, let’s use the analogy discussed in my previous post of concert goers.
Imagine the concert goers in attendance are neurotransmitters. The venue is a neuron, the band playing is the MTHFR enzyme, and the Ubers waiting are neurotransmitter transporters.
The venue has done a great job of ensuring that enough Ubers will be available after the concert to take every one home and the employees at the venue have been well-trained to efficiently lead everyone outside after the concert is over. Everything is set up to work perfectly. But let’s say the band is Nickelback and how effective is Nickelback at producing concert goers? Not very, right? The venue is only 40% full and they can’t even give those tickets away! So even though everything else – the Ubers, the venue, the employees at the venue – are set up and efficient, we won’t be moving many concertgoers out of the venue after the concert since there aren’t many to begin with. And how will these concertgoers spread the message that Nickelback is the WORST if there aren’t many being sent out into the world? Tragic.
At this point, we know Nickelback isn’t going to improve. You guys, I think after this many years of terrible music, we should just accept that they’re never going to be Taylor Swift and produce many concert goers. Similarly, we don’t have control over our genetics, nor have we found a way to modify MTHFR enzyme activity. If our patient has an MTHFR mutation that is a lazy worker, can we do anything about that?
A lot of my patients ask about increasing their folic acid intake. Increasing folic acid would be akin to giving a lazy worker more work to do. Probably won’t make them a more efficient worker, right? Studies suggest that increasing folic acid is not particularly beneficial in addressing MTHFR mutations. In order to increase neurotransmitter production, we need to bypass the MTHFR enzyme (think of it as a nepo baby that can’t be fired). An easy way to do that is to recommend intake of folate that is already methylated (activated) and thus available for absorption – l-methylfolate.
Evidence-based research suggests a dose of 15 mg daily is optimum in maintaining intracellular homeostasis and statistically significant in overcoming metabolic defects. In some studies, patients with specific MTHFR genotypes with Major Depressive Disorder were instructed to take 15 mg of l-methylfolate daily. With 90% compliance, 67.9% of these patients reported statistically significant improvement in depression symptoms and 45.7% achieved remission in 12 weeks (Shelton et al., 2013).
Many insurance companies cover pharmacogenetic testing including testing MTHFR genotypes and alleles. If an insurance plan does not cover this testing, in my experience many of the companies I work with have sliding scale payment plans available.
Anecdotally, what I see clinically with patients who have an MTHFR mutation and haven’t been tested for it prior to establishing care with me are reports of years of frustration with multiple failed medication trials. For some, medications work for a bit and then seem to lose efficacy. For others with severely reduced enzyme activity, many haven’t received any benefit from psychotropic medications. Testing for MTHFR mutations may not be the “end all, be all” but it is certainly an evidence-based tool that we as providers should be using more frequently.
Shelton, R.C., Manning, J.S., Barrentine, L.W., & Tipa, E.V. (2013) 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). doi: 10.4088/PCC.13m01520. Epub 2013 Aug 29. PMID: 24392264; PMCID: PMC3869616.