Linda Driscoll Powers
Psychiatry Should Consider MTHFR Gene Polymorphisms
Mental health issues are extremely common, to the extent that fourteen percent of the global disease burden can be attributed to neuropsychiatric disorders. Twenty-five percent of adults in the U.S. currently suffer from a mental illness, and at least half will develop one or more mental illnesses in their lifetime (Gardner). In addition to emotional strain, mental illness places significant economic burden on individuals, families, and communities. According to The National Institute of Mental Health (NIMH), the annual costs of mental disorders exceed the costs of diabetes, respiratory disorders, and cancers combined (Insel).
Despite the frequency of mental health issues among the general population, psychiatric medicine is largely imprecise. Mental illnesses are difficult to diagnose and treat because the field lacks precise diagnostic tools that help create targeted pharmacological treatment plans, tailored to each individual. For the last forty years, clinicians have relied on a symptom cluster approach to diagnostics rather than tools such as imaging or physiological biomarkers obtained through laboratory tests, which are the mainstay of internal medicine. The DSM-5, a book referred to as the Bible of psychiatry, contains “a standard classification of mental disorders . . . and a listing of diagnostic criteria for every psychiatric disorder.” This guide, which focuses on observable symptoms rather than measurable biometric data, is viewed as the diagnostic gold standard (“American Psychiatric Association DSM-5 Development”).
Once symptoms are grouped together and a diagnosis is decided upon, psychiatric treatment primarily relies on pharmacological (medication) interventions, prescribed using a wait-and-see, trial-and-error approach. Unfortunately, this educated guesswork results in lower than desired success rates, and some medications do more harm than good. Each medication false start can result in months of suffering for patients. Research shows that fifty percent of patients suffering from depression do not respond to first-line therapies and/or experience severe adverse reactions or side effects to the medications prescribed by clinicians (Gardner).
While there are many commonalities in how mental health disorders present, every patient–and their illness–is unique and presents on a spectrum of severity. The field of psychiatry should leverage every available tool to improve the diagnostic process and better target treatments to the individual. Personal genomic data is one of these promising tools. In the case of MTHFR gene polymorphisms, looking at genomic data is critical for uncovering the biological underpinnings of mental illnesses.
EVOLVING BEYOND THE TRIAL-AND-ERROR APPROACH
When the most recent update to the DSM was released in 2013, The NIMH Director, Thomas Insel, MD, said that the updated manual is reliable, but lacks validity and that “patients with mental disorders deserve better” (Brauser). The NIMH recently announced their intention to take charge of evolving the way psychiatry is practiced with the Research Domain Criteria (RDoC) project, which will incorporate genetics, imaging, and other data into a new psychiatric classification system (Brauser). It is fantastic that the NIMH stands behind the clinical validity of genomic data in psychiatry, but a long waiting period is expected before the project becomes clinically useful. While the NIMH may eventually replace the current symptoms-focused diagnostic model, millions of people would benefit from more personalized approaches right now.
The heritability of mental health issues are widely known and accepted. Since the launch of the Human Genome Project in 2001, researchers have been looking for biomarkers that might advance predictive neuroscience and revolutionize psychiatric medicine. Thousands of studies and a few meta-analyses have made headway in determining underlying genetic factors, yet the resounding caveat is that more investigation is needed to confirm results. As with any field of scientific research, there are a wide range of variables to consider, such as: length of illness; lack of medication adherence monitoring; variable genetic phenotypes (differences in how genes are expressed from person to person); and epigenetic factors (how environmental influences such as stress, diet, inflammation, etc., affect gene expression) (Malhotra).
These ambiguous and unpredictable variables are the sticking point of frustration and confusion for researchers, resulting in hesitancy to announce the validity of genomic data in psychiatric care. In addition to the overwhelmingly complex variables, some psychiatrists are comfortable with the status quo and are flat-out resistant to changing the diagnostic and treatment models that they’re used to. In a branch of medicine with such high stakes, every possible resource should be used to improve treatment outcomes.
Plausable uses of genetic data in psychiatry. Many studies have shown a correlation between specific disease phenotypes and genetic mutations (polymorphisms) in more than 3,000 genes (Dubovsky). While controversial, there are a number of ways that mental health researchers are investigating genetic data in both laboratory and clinical settings. Examples of ongoing research include: pharmacogenetics (PGx) studies, drug transporter studies, pharmacodynamics studies, gene network studies, prospective treatment studies, and gene expression studies (Dubovsky). Of this list, PGx and gene expression are the most promising.
PGx primarily looks at detox genes to estimate how quickly a person will metabolize certain classes of drugs, in addition to whether negative side effects are likely (Daley). PGx has gotten the most attention in psychiatry, to the extent that new businesses have emerged to fill the gap in PGx testing and reporting tools that are available for clinical use. Much of the opposition to using genetic data in psychiatry is focused on dismantling PGx validity, since there are multiple genetic factors that can affect drug levels and disposition and drug interactions can be impossible to predict (Dubovsky). Therefore, the remainder of this essay will focus on gene expression, particularly the MTHFR gene and how its polymorphisms, or naturally-occurring variations, may impact mental health.
A PRIMER TO GENE EXPRESSION STUDIES – SNPs, GENOTYPE, AND PHENOTYPE
Before diving into the supportive MTHFR evidence, it will be helpful to explain how researchers work with genetic data: DNA information is essentially a code that is made up of four protein building blocks called nucleotide bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA has around three billion bases, and more than ninety-nine percent of those bases are the same in all people. How the bases (A,G,C,T) are configured determines how information is “coded” for building and maintaining the body, similar to how letters of the alphabet appear in a certain order to form words and sentences (“What is DNA?”).
SNPs. Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation among people and are also the most studied. Each SNP represents a difference in a single DNA nucleotide building block. For example, refer to the image on the left (see fig. 1): a SNP section of DNA may replace the nucleotide building block cytosine with the nucleotide building block thymine. When certain SNPs, such as MTHFR are altered, the enzyme shape can become distorted, changing the enzyme’s ability to bind to the active site on a substrate and initiate a chemical reaction. It is similar to the grooves on a key: If the grooves are slightly different than the lock, the key may fit and turn the lock a little, but it does not unlock the door (Lynch).
While most SNPs have no effect on health, researchers have found that some SNPs serve as valuable predictors of health risk. For example, SNPs are widely accepted and used to track the inheritance of disease within families, such as breast cancer risk via the BRCA1 and BRCA2 genes (“What are single nucleotide polymorphisms (SNPs)?”). In terms of mental health, these nucleotide changes (polymorphisms) are particularly important when it comes to transcription of enzymes that affect neurotransmitter synthesis.
Genotype and phenotype. Genotype refers to a particular gene or set of genes, including inheritable SNP polymorphisms. Phenotypes are the harder-to-predict “wild cards” of genetic studies that are influenced by the genotype (hard-coding) along with epigenetic factors, or the unique circumstances that may alter the transcription of genes found in the genotype. Think of genotype as “nature” (the unique genome you carry), and phenotype and “nurture” (how environment, stress, diet, etc. can alter genetic expression) (“What is genotype?”).
GENE EXPRESSION AND MTHFR POLYMORPHISMS
One SNP in particular, MTHFR, pops up over and over in mental health research. The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a central role in folate metabolism by converting food folate and supplemental folic acid into the usable form within the body, 5-methylenetetrahydrofolate. (Note that both the gene and the enzyme it codes for are called MTHFR.) The methylated form of folate does some very important things in the body and brain, such as recycling the inflammatory amino acid, homocysteine; synthesizing biopterin (BH4), a major cofactor for neurotransmitter synthesis; synthesizing DNA and tRNA; and helping to build red and white blood cells, and platelets (Lynch). Methyl-folate also donates a methyl group to homocysteine to make SAMe (the brain’s main methyl donor), which is responsible for the formation of phospholipids, glutathione, myelin, coenzyme q10, carnitine, and creatine. SAMe also helps to build the monoamine neurotransmitters of mood, motivation, and pleasure: serotonin, norepinephrine, and dopamine (Marano, Gilbody).
Folate methylation is fundamentally critical to healthy cell function, and folate’s connections to neurological health and psychiatric disorders are well documented (Gillbody). Folate is so important to human health that the USDA requires that refined, bleached flours are enriched with folic acid, while doctors communicate the importance of folic acid to expecting mothers (think neural tube defects). It is important to note that methyl-folate does not work alone. The vitamins B2, B6, and B12, plus other cofactors such as magnesium, are necessary to support optimal methylation cycle function in the body (Brogan).
The methylation cycle is disturbed by many factors, such as lack of the aforementioned cofactors, antacid medications, and MTHFR polymorphisms (Lynch). Furthermore, psychiatric disorders such as depression, schizophrenia, and bipolar disorder have been positively linked to low folate levels, defective folate metabolism, and MTHFR polymorphisms (Gilbody). Research has shown that disorders such as schizophrenia correlate with abnormally high homocysteine levels, a clinical symptom of a low-functioning MTHFR gene (Kevere).
There are two common (inherited) polymorphisms of the MTHFR gene, where replacements of single nucleotides may result in reduced enzyme activity at SNPs C677T and A1298C. Both SNPs affect nucleotide synthesis and DNA methylation, forming a “plausible biologic explanation for potential associations between genetic variation in folate metabolism and both depression and schizophrenia” (Gillbody).
MTHFR C677T SNP polymorphism. One base change (CT) on C677T equates to a forty percent loss in MTHFR enzyme function, and two base changes (TT) equates to an astounding seventy percent loss of function. The C677T polymorphism has been studied the most in psychiatry and has been positively correlated with “a reduction in the bioavailability of folate and folate metabolites, ‘mimicking’ low dietary folate intake” (Gillbody). The C677T polymorphism commonly produces issues with cardiovascular health, mental health, the ability to conceive and/or carry pregnancy to term, high homocysteine levels, DNA regulation, and low methylfolate levels (“Methylation and MTHFR Defects”).
A 2006 meta-review focused on MTHFR polymorphisms and psychiatric disorders demonstrated a strong association between the C677T variant and depression, schizophrenia, and bipolar disorder (Gillbody). For patients who had the C677T polymorphism in heterozygotic form (one base pair change – CT), a more serious pace of schizophrenia illness was observed (Gillbody). The meta-review also showed that the highest levels of homocysteine were observed in patients with severe paranoid schizophrenia and were credibly higher in those with the CT genotype (1 base change) rather than the common “wild type” (CC), where methylation functions optimally (Kevere). Yet another meta-analysis involving ten studies showed that there was an increased risk of depression and schizophrenia among persons with the homozygous variant TT genotype involving 2 base changes at the C677T SNP (Gillbody). As reminder, the homozygous TT base changes on the C677T SNP are said to reduce MTHFR activity by as much as seventy percent (Gillbody). In other words, the MTHFR research matches the clinical findings reported in the aforementioned clinical studies involving actual patients and their lab tests.
MTHFR A1298C SNP polymorphism. This polymorphism is the lesser studied of the two, but no less important. Polymorphisms of A1298C have been implicated in altering neurological health by primarily reducing the production of two critical mood-balancing neurotransmitters, serotonin and dopamine, while inhibiting the breakdown of ammonia (Lynch). This polymorphism is more controversial than C677T due to challenges with finding a biochemical explanation of how the defect is working. Regardless, MTHFR A1298C polymorphisms are commonly found alongside C677T polymorphisms. When both copies of the A1298C SNP are mutated, it is estimated that thirty percent of the gene’s function is lost. If polymorphisms are found on both the C677T and A1298C SNPs, there is a high likelihood that the conversion of folic acid into methyl-folate is significantly hampered (Lynch).
MTHFR and treatment-resistant depression. Genetic testing is especially important in cases of treatment-resistant depression, where selective serotonin reuptake inhibitors (SSRIs) have proven ineffective. People with MTHFR polymorphisms may have a hard time getting relief with SSRIs. This is why: The serotonin that the body makes is broken down in the receptor, so it is only used for a short time. A SSRI prevents the breakdown and reuptake of serotonin, so the brain gets more use out of the serotonin that is naturally released. The SSRI does not help the body build more serotonin; it simply helps get prolonged use from the serotonin that naturally exists. The issue for people with MTHFR polymorphisms is that there may not be adequate levels of serotonin available for use due to methylation issues that slow neurotransmitter synthesis, so SSRIs won’t be as effective (or effective at all). Some people are prescribed very high doses of SSRIs but don’t get results, while still getting the side effects (Neuzil). MTHFR polymorphisms are a plausible explanation for this situation, yet these polymorphisms are rarely considered.
MTHFR and addiction. MTHFR has an interesting connection to alcohol and drug addiction as well. According to Amy Neuzil, ND, addictions are common in the family trees of people with MTHFR polymorphisms. She says that people with reduced MTHFR enzyme tend to process alcohol less efficiently and therefore have a lower tolerance. In addition, there is more addictive potential due to the associated neurotransmitter deficiency issues. While there is a great deal of willpower stigma in addiction issues, the truth is that addictions are used as self-medication. People with addictions are trying to “fix” a problem that exists, be it unhealed trauma, neurotransmitter deficiency, or both! With MTHFR polymorphisms, the neurotransmitters are less available, so people are prone to looking for substances that make them feel better in whatever way possible (Neuzil).
MTHFR polymorphism prevalence. MTHFR polymorphisms are quite common. This table, showing MTHFR polymorphism frequency by race (and thus genetic makeup), was taken from a presentation that Lynch created in 2012 (see fig. 2). MTHFR polymorphisms may be affecting a significant portion of the population in one way or another. With such high prevalence, it is unfortunate that conventional family physicians and psychiatrists do not look for and address MTHFR polymorphisms proactively.
PSYCHIATRY MUST BEGIN CONSIDERING MTHFR POLYMORPHISMS
When MTHFR polymorphisms cause problems with neurotransmitter synthesis, no amount of SSRI or antipsychotic is going to help balance the brain, because the specific mechanisms of action do not address foundational serotonin deficits. MTHFR experts suggest that anyone with mental health issues, especially treatment-resistant depression, carry out a $200 genetic test through 23andme.com, measure homocysteine levels via blood, and exercise caution with folic acid supplementation, since it may not be converted to methyl-folate optimally (Lynch).
Those with compromised methylation can take pre-methylated forms of folate (methylfolate) and its most critical cofactor, B-12 (methylcobalamin), together to overcome the methylation issues (Lynch). All MTHFR polymorphism treatment protocols are best carried out under the supervision of an MTHFR-literate Integrative or Functional Medicine practitioner. Although MTHFR polymorphisms are likely to impair methylation status and potentially disrupt neurotransmitter synthesis, clinicians cannot make assumptions and must carefully consider all factors (including patient-reported symptoms) during the diagnostic and treatment process.
WHERE DO WE GO FROM HERE?
Although controversial, a recent study found that physicians in the psychiatric departments of three different academic institutions endorsed the use of genetic testing and found it to be most useful in cases of treatment resistant depression and medication intolerance (Gardner). The demand for genetic testing in psychiatry is evident, and there will certainly be more research to establish widespread clinical validity. Until then, I am hopeful that pioneering psychiatrists will embrace the current research, pursue further education, and push against status quo, insurance-directed treatment methods to better detect the underlying causes of poor neurotransmitter synthesis, such is the case with MTHFR polymorphisms.
Medication is not the end-all-be-all cure for mental health disorders. Seeking out and addressing the underlying biological factors that contribute to mental dysfunction is where the field of psychiatry must turn. Certain genetic data can—and should—be brought into the current model of care, especially when patients show little-to-no improvement using standard pharmacological approaches. The MTHFR gene and its polymorphisms are but one facet of the complex genomic gem—yet one that can be used to nudge psychiatry closer to personalized, targeted, timely, and overall more effective mental health treatment.
Of course, no clinician should use genetic data in a vacuum, and all genomic data-related decisions should be carefully weighed against the individual’s treatment history and current evidence-based standards of care. However, if spending a few more minutes with patients, running a few hundred dollars worth of lab tests, learning how to interpret the results, and prescribing methylated forms of nutrients could help even a small percentage of patients feel better faster, it is worth every penny and every second.
It is high time that the field of psychiatry is brought out of the dark ages and is allowed to blossom in the light of recent scientific discoveries. To do so, mental health clinicians must remain steadfast in pursuing ongoing education and push status quo boundaries in effort to improve patient outcomes. The millions of psychiatric patients in the U.S. and around the world deserve the opportunity to view their illnesses as what they really are: problems with brain biology rather than character defects. It is the duty of psychiatrists and mental health clinicians to help patients step away from cycles of despair, stigma, and ineffective treatments, so they may live longer, fuller, and more satisfying lives; a mission that is better realized using every tool available.
“American Psychiatric Association DSM-5 Development.” About DSM-5, APA. May 2013, http://www.dsm5.org/about/pages/default.aspx.
Brauser, Deborah. “NIMH, APA Clash Over Upcoming DSM-5.” Medscape, 7, May 2013, http://www.medscape.com/viewarticle/803752.
Brogan, MD Kelly. “Folate and You: Perfect Together.” Kelly Brogan MD, 2 July 2015, kellybroganmd.com/folate-perfect-together/.
Dubovsky, Steven L. “The Limitations of Genetic Testing in Psychiatry.” National Center for Biotechnology Information, U.S. National Library of Medicine, 5 Apr. 2016, DOI: 10.1159/000443512
Gardner, Kathryn R., et al. “The Potential Utility of Pharmacogenetic Testing in Psychiatry.” Hindawi Publishing Corporation, 17 Dec. 2014, www.hindawi.com/journals/psychiatry/2014/730956/.
Gillbody, Simon et al. “Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms and Psychiatric Disorders: A HuGE Review.” Am. J. Epidemiol., 30 Oct. 2006, Academic Search Premier, DOI: kwj347v1.
Insel, Thomas. “Mental Health Awareness Month: By the Numbers.” National Institutes of Health, U.S. Department of Health and Human Services, 15 May 2015, https://www.nimh.nih.gov/about/directors/thomas-insel/blog/2015/mental-health-awareness-month-by-the-numbers.shtml
Kevere, Laura, et al. “Homocysteine And MTHFR C677T Polymorphism In Children And Adolescents With Psychotic And Mood Disorders.” Nordic Journal Of Psychiatry, 68.2 (2014): 129-136, Academic Search Premier, DOI: 10.3109/08039488.2013.782066.
Lynch, Ben. “What is MTHFR? Learn What the MTHFR Gene is. – MTHFR.net.” MTHFRNet, 4 Nov. 2011, mthfr.net/what-is-mthfr/2011/11/04/.
Malhotra, A K, et al. “Pharmacogenetics In Psychiatry: Translating Research Into Clinical Practice.” Molecular Psychiatry 17.8 (2012): 760-769. Academic Search Premier. DOI: 10.1038/mp.2011.146
Marano, Hara Estroff. “The SAM-e Story.” Psychology Today, 1 Mar. 2002, http://www.psychologytoday.com/articles/200203/the-same-e-story.
“Methylation and MTHFR Defects,” director. Dr. Ben Lynch, 25 Apr. 2012, http://www.youtube.com/watch?v=qrhif2avpvw.
Neuzil, Amy. “MTHFR with Dr. Amy Neuzil ND.” BlogTalkRadio RSS Main, www.blogtalkradio.com/erinchamerlik/2016/09/22/mthfr-with-dr-amy-neuzil-nd.
“What is DNA? – Genetics Home Reference.” U.S. National Library of Medicine, National Institutes of Health, https://ghr.nlm.nih.gov/primer/basics/dna.
“What Is Genotype? What Is Phenotype?” PgEd.org, Personal Genetics Education Project, pged.org/what-is-genotype-what-is-phenotype/.