What’s the Deal with MTHFR and Psychiatric Conditions?

A while back, my psych nurse suggested we send some of my cheek cells to a lab for genetic testing. I was severely depressed and hadn’t had much success with the antidepressants I’d tried. With a significant family history of depression and other mental health issues, it seemed likely that there was a genetic component for me.

L-methylfolate: My Silver Bullet?

My psych nurse told me that for some people, a genetic abnormality affects the activity of a particular enzyme that’s implicated in psychiatric conditions (and many other illnesses). People with this mutation can be helped by taking what’s essentially a supplement (I believe she even said it was “like a vitamin”), L-methylfolate. By taking the product of this hindered metabolic process in pill form, it fills in the gaps that your faulty enzymes have left behind. Because it was a rather serious situation, we decided that we may as well add this supplement to see if it helped. I told her I’d think about the genetic testing.

A couple of weeks later, we revisited the idea. The methylfolate seemed to be helping a little, but not dramatically. I had figured that the testing would be unnecessary; if the methylfolate helped, we’d know I was a mutant. If it didn’t, we’d move on to something else. It wasn’t that cut and dry.

Why the Reluctance, You Ask?

Perhaps there was a little anxiety about what I might find out about myself, but I suppose that’s a topic for my therapist. Mostly, I was skeptical. Genetic research has advanced tremendously, but the mechanistic aspects of mental illnesses are still rather poorly understood. Could a DNA profile really tell me why I was depressed?

Well, I’ll spoil the ending for you and say “Yes. Kind of.” Curiosity won out, and I agreed to part with some of my genetic material in the name of science and not wanting to be depressed forever. The results, pared down to what’s important for clinicians and patients to understand, were interesting- and rather ambiguous.

The Science

The gene in question is called Methylenetetrahydrofolate Reductase (rather appropriately shortened to MTHFR, precisely my response to finding out my gene is screwy.) I actually was oddly relieved to learn this about my DNA. It seemed to validate my entire experience of depression, even symptoms that I brushed off as “laziness” or “not as bad as what other people feel”. I didn’t want to get too far ahead of myself, though. The packet that the lab had sent listed my genotype for the MTHFR gene as providing “intermediate activity”. What did this mean?

First, Some Background

Harken back to your high school or college biology class; remember alleles?  A gene and an allele are not the same thing. A gene is essentially a small segment of a chromosome that codes for specific sequences of amino acids, which are the building blocks of proteins. An allele, however, is a variation of a gene. That’s why humans are so wonderfully diverse (although, we’re remarkably similar compared to, say, chimpanzees). Probably what comes to mind most commonly are dominant and recessive genes. Unfortunately for students in genetics classes, it’s not always that simple. It turns out that it’s a lot more complicated than dominance and recessivity, but suffice to say, the complex interactions of genes and environment (epigenetics) are how our physical appearances (and internal functioning) are determined. Now, back to MTHFR.

Two Mutations

I had done some digging after my psych nurse had brought it up the first time, and found that there are two main mutations that seem to affect this enzyme’s activity. As usual, the names are cryptic; they’re called C677T and A1298C. The numbers and letters refer to the location of the polymorphism, or where in the allele one nucleotide has been changed to another, and the substitution that’s taken place. The “normal” individual is referred to as wild-type. Heterozygotes have one abnormal allele, while homozygotes have both alleles altered.

For example, I’m a heterozygote for both of the mutations. My genotype for C677T is C/T. The C (cytosine) is the normal allele and the T (thymine) is the mutant allele. I’m also a heterozygote when it comes to the A1298C mutation. My genotype is A/C, where the A (adenosine) is the normal allele and the C is the mutant.

The problem lies in the metabolism of a key metabolic precursor: a biologically-active form of folate. The product of this reaction is 5-tetrahydrofolate, which provides a methyl group for epigenetic regulation. In other words, when MTHFR is mutated, the system that controls gene expression is affected by a lack of 5-THF and, consequently, methyl groups.

Enzyme Activity

Meta-analyses suggest that C677T homozygous mutants have a 75% reduction in MTHFR activity, and A1298C homozygous mutants have a 39% reduction in enzyme activity. Heterozygotes for each mutation have less severe reductions in activity, but if you’re a compound heterozygote (like me), that results in a 52% reduction. So, I have slightly less than half the enzymatic activity for MTHFR than a normal, non-mutant.

MTHFR and Mental Illness

That all seems pretty straightforward, but take a look at the plethora of studies that exist on the interwebs, and you’ll see why I was skeptical. Some have found significant relationships between MTHFR polymorphisms and psychiatric conditions, and yet others haven’t. There are plenty of studies that say that there is no difference between mutant and control subjects when it comes to depression. Others suggest that carrying a mutated MTHFR allele predicts depression when the person is exposed to childhood trauma. Most of the studies I’ve seen lean towards accepting a link between MTHFR and depression, especially for homozygotes, who have the least MTHFR activity.

The consensus seems to be that more research is needed. There does seem to be a relationship between MTHFR and mental illnesses, although whether that’s a causative relationship is up for debate.

For me, I’m content to believe that at least some of my struggles can be traced back to this m*****f***** of a gene. The supplement does seem to make my antidepressants more effective. Even if it is a small improvement- I’ll take it. Plus, that’s not all that my genetic report showed. I also have a weird serotonin transporter that makes SSRIs less effective and increases my cortisol release in response to stress. Yay, anxiety! I’m glad I did the test, at the very least because it helped me to accept my disorder as valid.

The Future of Mental Health Treatment

Is this a sure-fire way to treat mental illness? I’d say not yet, but it’s certainly valuable. Personalized medicine seems to be a buzzword floating around these days, and the implications of genetic research for how we approach mental illness are fascinating. Maybe when the relationships between genes and mental illness are elucidated a little more clearly, we can finally kick the stigma and misconceptions out the door. One can hope, at least.