MTHFR and Mental Health

MTHFR genetic mutations and/or folate deficiency have been associated with many psychiatric disorders, including schizophrenia, bipolar disorder, depression, autism, and ADHD. This appears to be due to the role of folate in the production of neurotransmitters, which are essential for maintaining normal mood and overall mental health.

This article will cover the relationship between MTHFR and mental health, and current insights into how MTHFR mutations may contribute to mood disorders.

The clinical definition of a mood disorder is a “pervasive and sustained feeling that is endured internally, and that impacts nearly all aspects of a person’s thoughts, feelings, and actions.¹” Those affected by mood disorders frequently experience extreme disruptions to their emotions, including severe lows (such as depression) or highs (mania).² These episodes can cause severe functional impairment and reduced quality of life.

The broad categories of mood disorders include bipolar disorders and depressive disorders.

Folate plays a key role in mental health, and folate deficiency is a factor in several mood disorders, including anxiety, depression, postpartum depression, bipolar disorder, and schizophrenia ⁴.

Folate is an important component of the one-carbon cycle, a biochemical pathway that leads to the methylation of compounds in the body which fundamentally impacts health and wellbeing. Folate works alongside vitamins B12 and B6 in converting the amino acid homocysteine to methionine. This process is critical to healthy mood and overall wellbeing.

Methionine is a precursor for S-adenosylmethionine (SAMe), a compound also involved in producing and regulating chemicals including serotonin and dopamine that affect our mood ⁵. Dopamine provides a sense of temporary pleasure, while serotonin contributes to long-lasting feelings of happiness or well-being. Low levels of methionine are prevalent in depression, likely due to low neurotransmitter production ⁶.

Folate deficiency has also been shown to be a risk factor in developing more severe depressive symptoms, longer episodes of depression, and symptom relapse ⁷. Elevated levels of homocysteine have also been linked to both depression and anxiety ⁸.

People with lower levels of folate are less likely to respond to antidepressants, while those with higher levels tend to have better response rates ⁹.

Other symptoms of folate deficiency may include sleeplessness, irritability, poor cognitive function, and fatigue, which also impact mood.

A gene mutation is a change in a person's DNA. This change can be inherited or it can happen due to mistakes in DNA replication during cell division. Gene mutations can also be caused by exposure to mutagens like radioactive substances, ultraviolet radiation, certain chemicals, or viral infections ¹⁰.

Previous studies have found genetic links to mental health. A 2016 study found that people with the genetic mutation DISC1 had changes in the structure of their brain linked with the severity of their symptoms. The researchers explained that similar genetic effects can increase the risk of major mental illnesses ¹¹.

One mutation that has been linked to mental health is the MTHFR gene mutation. The MTHFR gene provides the body with instructions for making the enzyme methylenetetrahydrofolate reductase (MTHFR). The MTHFR enzyme is needed for the one-carbon metabolism of folic acid into methylfolate. However, the enzyme is affected by the C677T polymorphism, a genetic variation that can impair the conversion to L-methylfolate ¹².

MTHFR mutations have been associated with an increased risk of depression (including treatment-resistant depression), bipolar disorder, schizophrenia, and some behavioral disorders such as attention-deficit hyperactivity disorder (ADHD) and autism. While these are not technically genetic mental disorders, it does appear that genes are involved.

A mutation in the MTHFR gene can reduce the enzyme's activity to metabolize folate by 20-40%, making it harder for the body to convert folic acid into L-methylfolate.¹³ Since MTHFR is crucial for one-carbon metabolism, this mutation can impact the production of neurotransmitters linked to psychiatric disorders ¹⁴.

This level of enzyme function reflects how much methylfolate may or may not be available to convert homocysteine to methionine. For example, people with a heterozygous MTHFR C677T mutation (a single mutation) have only 65% of normal MTHFR enzymatic function, while those who are homozygous for MTHFR C677T (a double mutation) have only 30% function ¹⁵.

A 2022 meta-analysis of 81 published studies assessed the association between MTHFR mutations and susceptibility to psychiatric disorders. The researchers found a significant link between both major depression and one of the most common MTHFR mutations, MTHFR C677T. This particular mutation was also linked to a higher risk of bipolar disorder. The other common MTHFR mutation, MTHFR A1298C, had only a minor link to major depression ¹⁶.

A 2024 study reviewed 186 patients who were tested for an MTHFR deficiency and compared their psychiatric diagnoses and the number of failed medication attempts. Of those 186 patients, 77 had normal MTHFR enzyme function, 85 were found to have a moderate MTHFR deficiency, and 24 had a severe MTHFR deficiency ¹⁷.