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MTHFR and Depression

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Conor Sheehy - PharmD, BCPS

Medical Reviewer:

Dr. Conor Sheehy - PharmD, BCPS
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

January 22, 2025

Table of Contents

    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.

    The Role of Folate in Mental Health and 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

    Causes for Folate Deficiency (including the MTHFR Gene Mutation)

    The most common causes of folate deficiency include: 

    • Inadequate intake of folate in the diet. 
    • Increased demand for folate in the body, such as during pregnancy or while breastfeeding.
    • Impaired absorption of folate in the gut. This can occur due to digestive disorders such as celiac disease or the use of certain medications. Some of the drugs that impair folate metabolism include 5-Fluorouracil, metformin, methotrexate, phenobarbital, phenytoin, triamterene, and trimethoprim. Those taking warfarin should also consult their doctor about their folate levels. 
    • Inadequate bioavailability of folate in the diet (e.g., lack of raw green vegetables or fortified foods). Prolonged cooking destroys folate in food, which can affect intake. 
    • Increased excretion of ingested folate due to gastrointestinal disorders or renal dialysis.
    • Excess alcohol consumption. Alcohol affects the breakdown and absorption of folate. 
    • The MTHFR genetic mutation, which impairs the conversion of folic acid and folate to methylfolate in the body.

    Can MTHFR cause depression?

    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.

    Depression and the Brain

    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

    Different Types of Depressive Disorders

    Major Depressive Episode and Major Depressive Disorder

    • Depressed mood and/or loss of interest or pleasure in life activities for at least 2 weeks and at least five of the following symptoms that cause clinically significant impairment to daily life: Depressed mood most of the day, diminished interest or pleasure in all or most activities; significant unintentional weight loss or gain; insomnia or sleeping too much; agitation or psychomotor retardation; fatigue or loss of energy; feelings of worthlessness or excessive guilt; diminished ability to think or concentrate, or indecisiveness; recurrent thoughts of death.

    Dysthymic Disorder

    • Depressed mood more often than not for at least 2 years, and the presence of two or more of the above symptoms.

    Bipolar Disorder

    • Manic, or rapid (daily) cycling episodes of mania and depression.


    Substance-Induced Mood Disorder

    • Common in those struggling with substance abuse.


    Adjustment Disorder With Depressed Mood

    • A psychological reaction to overwhelming emotional or psychological stress, resulting in depression or other symptoms. 


    Personality Disorders

    • People with personality disorders are particularly susceptible to depression and/or substance use disorders

    How to know that depression is related to folate deficiency

    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.

    MTHFR and postpartum depression

    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.

    The takeaway

    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.

    MTHFR and Depression

    Key Takeaways

    • Icon The MTHFR genetic mutation may increase the risk of developing depression due to its interference with folate metabolism1
    • Icon Depression is linked to low folate levels, high homocysteine, and poor neurotransmitter production2
    • Icon Research has shown that supplementing with L-methylfolate may support healthy mood by assisting with neurotransmitter production3

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    Frequently Asked Questions

    How does MTHFR affect mental health?

    The MTHFR gene mutation may lead to low folate levels, which can affect the production of neurotransmitters in the brain. Poor neurotransmitter production may then increase the risk of developing mental health disorders such as depression, bipolar disorder, schizophrenia, and other mental health conditions.

    What does MTHFR feel like?

    MTHFR affects different people in different ways, largely depending on their nutritional status and lifestyle. People with MTHFR who have low levels of B vitamins - particularly folate - may experience issues such as low mood, anxiety, fatigue, poor energy, or nerve pain. However, those who support their nutritional needs with supplements such as L-methylfolate are often able to live normal, healthy lives.

    References

    1. Yu-Xin Zhang, Lu-Ping Yang, Cong Gai, Cui-Cui Cheng, Zhen-yu Guo, Hong-Mei Sun, Die Hu; "Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis"; Front. Psychiatry, Sec. Public Mental Health, Vol.13; 2022 Aug

      https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.976428/full

    2. Timur Liwinski ,Undine E Lang; "Folate and Its Significance in Depressive Disorders and Suicidality: A Comprehensive Narrative Review"; Nutrients. 2023 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10490031/

    3. Richard C Shelton, J Sloan Manning, Lori W Barrentine, Eleanor V Tipa; "Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial"; The Primary Care Companion For CNS Disorders; 2013 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616/

    4. Simon N Young; "Folate and depression—a neglected problem"; Journal of Psychiatry & Neuroscience; 2007 Mar

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810582

    5. Yu-Xin Zhang, Lu-Ping Yang, Cong Gai, Cui-Cui Cheng, Zhen-yu Guo, Hong-Mei Sun, Die Hu; "Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis"; Front. Psychiatry, Sec. Public Mental Health, Vol.13; 2022 Aug

      https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.976428/full

    6. M W Carney; "Serum folate values in 423 psychiatric patients"; British Medical Journal; 1967 Dec

      https://pubmed.ncbi.nlm.nih.gov/6065984/

    7. Timur Liwinski ,Undine E Lang; "Folate and Its Significance in Depressive Disorders and Suicidality: A Comprehensive Narrative Review"; Nutrients. 2023 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10490031

    8. Zhuoqing Li, Bo He, Jian Xu, Nan Dai, Liangliang Ping, Cong Zhou, Zonglin Shen, Xiufeng Xu, Yuqi Cheng; "Roles of 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphisms in First-Episode, Drug-Naive Adult Patients With Depression"; Front. Psychiatry, ec. Behavioral and Psychiatric Genetics, Vol. 11; 2020 Dec

      https://www.frontiersin.org/articles/10.3389/fpsyt.2020.531959/full

    9. Vanessa Cavalcante da Silva, Allan Chiaratti de Oliveira, Vânia D’Almeida; "Homocysteine and Psychiatric Disorders", Journal of Inborn Errors of Metabolism and Screening; 2017 Apr

      https://journals.sagepub.com/doi/full/10.1177/2326409817701471

    10. Siaw-Cheok Liew, Esha Das Gupta; "Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases"; European Journal Of Medical Genetics; 2015 Jan

      https://pubmed.ncbi.nlm.nih.gov/25449138/

    11. Yu-Xin Zhang, Lu-Ping Yang, Cong Gai, Cui-Cui Cheng, Zhen-yu Guo, Hong-Mei Sun, Die Hu; "Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis"; Front Psychiatry, 2022 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9433753/

    12. Simona Corina Trifu, Arina Cipriana Trifu, Ecaterina Aluaş, Mihai Alexandru Tătaru, Radu Virgil Costea; "Brain changes in depression"; Romanian Journal Of Morphology and Embryology; 2020 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864313/

    13. Simona Corina Trifu, Arina Cipriana Trifu, Ecaterina Aluaş, Mihai Alexandru Tătaru, Radu Virgil Costea; "Brain changes in depression"; Romanian Journal Of Morphology and Embryology; 2020 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864313/

    14. Stephen M Strakowski, Caleb M Adler, Jorge Almeida, Lori L Altshuler, Hilary P Blumberg, Kiki D Chang, Melissa P DelBello, Sophia Frangou, Andrew McIntosh, Mary L Phillips, Jessika E Sussman, Jennifer D Townsend; "The functional neuroanatomy of bipolar disorder: a consensus model"; Author Manuscript, Bipolar Disorder; 2012 Jun

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874804

    15. Golo Kronenberg, Christoph Harms, Robert W Sobol, Fernando Cardozo-Pelaez, Heinz Linhart, Benjamin Winter, Mustafa Balkaya, Karen Gertz, Shanna B Gay, David Cox, Sarah Eckart, Michael Ahmadi, Georg Juckel, Gerd Kempermann, Rainer Hellweg, Reinhard Sohr, Heide Hörtnagl, Samuel H Wilson, Rudolf Jaenisch, Matthias Endres; "Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase"; The Journal Of Neuroscience; 2008 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844834/

    16. Ryota Araki, Shoji Nishida, Yuki Nakajima, Arimi Iwakumo, Hayato Tachioka, Ayami Kita, Takeshi Yabe; "Low folate induces abnormal neuronal maturation and DNA hypomethylation of neuronal differentiation-related genes in cultured mouse neural stem and progenitor cells"; Heliyon, Vol. 7 Iss. 9; 2021 Sep

      https://www.sciencedirect.com/science/article/pii/S2405844021021745

    17. Courtney E Kandler, Sherrell T Lam; "Methylenetetrahydrofolate Reductase Screening in Treatment-Resistant Depression"; Federal Practitioner; 2019 May

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530664

    18. Lorena Carboni; "Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health"; Inetgrative Medicine: A Clinician's Journal; 2022 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380836/

    19. Matthew Macaluso; "L-Methylfolate in Antidepressant Non-responders: The Impact of Body Weight and Inflammation"; Frontiers in Psychiatry; 2022 Mar

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968318

    20. Emily Morris, Catriona Hippman, Arianne Albert, Caitlin Slomp, Angela Inglis, Prescilla Carrion, Rolan Batallones, Heather Andrighetti, Colin Ross, Roger Dyer, William Honer, Jehannine Austin; "A prospective study to explore the relationship between MTHFR C677T genotype, physiological folate levels, and postpartum psychopathology in at-risk women"; PLoS One; 2020 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735580/

    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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