MTHFR and Depression

Did you know that depression has been linked to folate deficiency?

Studies dating back to the 1960s show a high incidence of low folate in depressed people. In fact, around one-third of depressed patients are deficient in folate ⁴.

This is where a MTHFR genetic mutation can be a factor. A mutation on the MTHFR gene impairs the body’s ability to convert vitamin B9 to methylfolate, the active form of folate required to support healthy mood.

Because folate is essential to mental health, MTHFR mutations have been associated with many psychiatric disorders, including schizophrenia, bipolar disorder, and depression ⁵.

This article will explore the link between the MTHFR mutations and depression and how MTHFR affects mental health. We will also discuss how supplementation with various nutrients may support mental health and reduce the risk of developing a mood disorder such as depression.

Folate deficiency has been observed in up to one-third of patients with severe depression ⁶. Low folate is not only linked to a higher risk of developing depression but to more severe depressive symptoms, longer episodes of depression, and greater likelihood of symptom relapse ⁷.

Up to 50 percent of the general population suffers from the MTHFR gene mutation. This means that they cannot properly utilize folate or folic acid ingested from food or supplements. In many cases, this can lead to insufficient folate levels in the body.

Defects in the MTHFR enzyme can impair methionine synthesis, resulting in reduced SAMe production and a decrease in methylation reactions ⁸. This can then lead to reduced production of monoamine neurotransmitters, especially those required for healthy mood (such as serotonin, norepinephrine, glutamate, dopamine, and γ-aminobutyric acid).

Low folate is also a factor in increased homocysteine levels, as folate is required for the conversion of homocysteine to methionine. Higher homocysteine levels may also contribute to increased oxidative stress (an imbalance between harmful molecules and the body's ability to neutralize them) and inflammation, which are linked to further chronic health issues ⁹.

Every case of depression may have a range of causes. However, the MTHFR gene mutation has been highlighted as a risk factor for depression and several other mental health conditions.

MTHFR plays a critical role in the one-carbon metabolism process which involves folate, homocysteine, vitamin B12, and the methylation of DNA. Mutations of this gene affect MTHFR enzyme activity, which in turn will impact the production of neurotransmitters - the brain chemicals that support healthy mood. A MTHFR mutation may also lead to increased levels of homocysteine in the blood, which has also been linked to a wide range of mental, neurological, and vascular dysfunctions due to increased levels of inflammation in the brain and body ¹⁰.

A 2022 meta-analysis of 81 published studies found a significant link between both major depression and one of the most common MTHFR mutations, MTHFR C677T ¹¹. The C677T mutation has also been linked to a higher risk of bipolar disorder. Meta-analytic evidence has indicated that individuals with the TT genotype are approximately 1.37 times more likely to have a diagnosis of depression compared to those with the CC genotype. The TT genotype represents a double-mutated gene, the CT genotype is a single-mutated version, and the CC genotype is the non-mutated gene.

The MTHFR A1298C polymorphism has not yet been correlated with depression, but this may be due to a lack of studies to date. 

Studies in patients with depression have shown that depressive disorders impact the brain's plasticity and how synapses work.

Neurons are highly adaptable to both internal and external influences. Neuroplasticity is the process in which the brain changes and rewires itself in response to the stimulation of learning, memory, and experience ¹². However, recent research shows that these brain modifications may also occur in response to stress. This has been linked to a range of neurological disorders and depression.

Stress can lead to the atrophy (shrinking) of the hippocampus and prefrontal cortex, with the amount of shrinkage depending on the duration and severity of the depression.

Brain shrinkage is typically caused by an increase in the stress hormone cortisol. During a depressive episode, the hippocampus increases levels of cortisol, which then impacts neuron development in the brain. The thalamus and frontal cortex are also found to change substantially during depression. The hippocampus, the part of the brain involved in verbal declarative memory, is particularly sensitive to stress, and smaller volumes of gray matter in the hippocampus are primarily correlated with poor memory performance ¹³.

While high levels of cortisol may lead to atrophy in some areas of the brain, it can also increase the size of the amygdala. The amygdala is responsible for emotion, and greater volume of this area may lead to problems with sleep, mood swings, and other hormone-related issues. Later in life, larger amygdala volumes have been reported in people with bipolar disorder ¹⁴.

Brain changes may also be linked to folate deficiency. Studies in mice show that low folate low folate may cause mental health disorders by preventing proper brain cell development ¹⁵. Further research has suggested that low SAMe levels may cause reduced DNA methylation in genes related to brain cell development and growth. This lack of methylation could be linked to immature brain cells caused by folate deficiency ¹⁶.

If you are experiencing symptoms of depression, it’s important that you seek help from a medical professional as soon as possible. We suggest that you consider getting tested for folate deficiency and for the MTHFR mutation. These tests can be done by your doctor.

Low folate levels may indeed be a contributing factor to your depression, and your doctor may prescribe folic acid. However, if you also have the MTHFR gene mutation, neither folic acid nor antidepressants will be effective. As explained above, the MTHFR mutation results in poor metabolism of folic acid, so those with this mutation will not benefit from taking it.

Antidepressants work by balancing neurotransmitters in the brain. However, if the brain is lacking in methylfolate, these neurotransmitters won’t be available for the drugs to balance ¹⁷.

In both cases, supplementing with L-methylfolate may be the most effective solution. L-methylfolate has been shown to improve folate levels in the body much more efficiently than folic acid ¹⁸. It is also shown to drastically improve response to antidepressant medications.

L-methylfolate is suitable for those with impaired folate metabolism as it can bypass the MTHFR deficiency and cross the blood-brain barrier to participate in methylation processes that support healthy mood.

Methylfolate is an approved nutritional adjunctive antidepressant treatment that increases central neurotransmitter levels, which then improves the effectiveness of antidepressant mediation. Studies show that methylfolate can improve response to antidepressants in people with major depressive disorder (MDD) and who are otherwise resistant to medications ¹⁹.

If your symptoms improve after taking L-methylfolate, it is likely that your depression is related to your folate levels.

During pregnancy, women with MTHFR mutations are at greater risk of depression due to the body’s increased demands for folate. However, there is limited research into whether women with MTHFR are prone to postpartum depression.

A 2020 study found that women with an MTHFR C677T genotype with low folate levels may be more likely to suffer from postpartum depression. However, there was no relationship between folate levels and mania symptoms in women with a TT genotype (homozygous) ²⁰. However, as most of the women in this study were taking folic acid supplements, and all were living in Canada (a country with folic acid-fortified foods), the researchers concluded that women with homozygous MTHFR and low folate levels may also be affected by depression. Further research is pending.

Good mood depends on the production of various neurotransmitters, many of which are produced via the methylation process. Deficiencies in specific nutrients, especially folate, have been shown to contribute to mental health issues such as depression.

For many people, supporting the body’s key methylation processes may require supplementation with folate, particularly in the case of an MTHFR deficiency.

L-Methylfolate is a safe and effective means of supporting serum folate levels. L-Methylfolate is suitable for those with mood disorders and impaired folate metabolism as it can bypass the MTHFR deficiency. Methyl-Life® offers a range of supplements designed to support healthy mood and cognition.