Kristen Ward, PharmD

Mr. J, age 30, a Black man with major depressive disorder (MDD), has been your patient for the past year. At the time of his diagnosis, Mr. J received sertraline, 100 mg/d, but had little to no improvement. During the past year, he received trials of citalopram and paroxetine, but they were not effective for his recurrent depressive symptoms and/or resulted in significant adverse effects.

During a recent visit, Mr. J asks you about “the genetic tests that help determine which medications will work.” He mentions that his brother had this testing done and that it had “worked for him,” but offers no other details. You research the different testing panels to see which test you might use. After a brief online review, you identify at least 4 different products, and are not sure which test—if any—you should consider.

During the last few years, there has been a rise in commercial pharmacogenetic testing options, including tests available to clinicians at academic medical centers as well as direct-to-consumer testing (Table). Clinician and patient interest regarding pharmacogenetic testing in practice is often followed by the question, “Which test is best?” Although this is a logical question, providing an answer is multifactorial.^1-3 Because none of the currently available tests have been compared in head-to-head clinical trials, it is nearly impossible to identify the “best” test.

In this article, we focus on the evidence-based principles that clinicians should consider when adopting pharmacogenetic testing in their practice. We discuss which genes are of most interest when prescribing psychotropic medications, the value of decision support tools, cost considerations, and patient education regarding this type of testing.

Which genes and variants should be tested?

The genes relevant to medication treatment outcomes can be broadly classified into those with pharmacokinetic vs pharmacodynamic effects. Pharmacogenes, such as those coding for the drug-metabolizing enzymes cytochrome P450 (CYP) 1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, and UDP-glucuronosyltransferase (UGT)2B1, may alter the rate at which medications are metabolized, thus varying the serum drug concentration across patients. Variants that impact the function of these enzymes are considered pharmacokinetic. Up to 40% of the variance in patients’ response to antidepressants may be due to variations in the pharmacokinetic genes.⁴ Alternatively, pharmacodynamic pharmacogenes impact drug action and therefore may affect the degree of receptor activation at a given drug concentration, overall drug efficacy, and/or the occurrence of medication sensitivity. These pharmacogenes may include:

• brain-derived neurotrophic factor (BDNF)
• catechol-O-methyltransferase (COMT)
• human leukocyte antigens A (HLA-A)
• serotonin receptor subtype 2 (HTR2)
• serotonin receptor subtype 2C (HTR2C)
• opioid receptor mu 1 (OPRM1)
• solute carrier family 6 member 4 (SLC6A4).

In articles previously published in Current Psychiatry, we outlined some of the evidence regarding these pharmacogenes, and resources available to clinicians to support their use of these tests.^1,2

Currently, there is no standardization among commercial pharmacogenetic tests on:

• which genes to test
• which variants specific to a gene need to be included
• how the genetic data is translated to phenotype
• how the phenotype is translated to a treatment recommendation.

Continue to: Due to these factors...

Due to these factors, the FDA has advised clinicians to consult the dosing recommendations provided in a medication’s package insert for information regarding how genetic information should be used in making treatment decisions.²

The value of decision support tools

Researchers have assessed how various manufacturers’ decision support tools (DSTs) (ie, the reports the commercial testing companies send to the clinician who orders the test) agree on genotypes, predicted phenotypes, and medication recommendations.⁴ Overall, this research found varying levels of disagreement in the medication recommendations of the testing panels they studied, which indicates that not all tests are equivalent or interchangeable.⁴ Of the actionable recommendations for antidepressants, 16% were conflicting; the recommendations for fluoxetine and imipramine were most frequently in disagreement.⁴ Similarly, 20% of the actionable antipsychotic advice was conflicting, with the recommendations for aripiprazole and clozapine most frequently in disagreement.⁴ Researchers also reported a situation in which 4 testing panels agreed on the patient’s phenotyping status for CYP2C19, but the dosing recommendations provided for the CYP2C19 substrate, amitriptyline, differed.⁴ Thus, it is understandable why DSTs can result in confusion, and why clinicians should use testing panels with recommendations that best align with their individual practices, their patient’s needs, and FDA information.

Additionally, while the genes included on these panels vary, these testing panels also may not evaluate the same variants within a specific gene. These differences may impact the patient’s reported phenotypes and medication recommendations across DSTs. For example, the FDA has recommended HLA gene testing prior to prescribing carbamazepine. However, few of the available tests may include the HLA-B*15:02 variant, which has been associated with carbamazepine-induced severe cutaneous reactions in patients of Asian descent, and fewer may include the HLA-A*31:01 variant, for which testing is recommended prior to prescribing carbamazepine in patients of Caucasian descent.⁴ Additionally, some of the CYP enzymes—such as CYP2D6*17 and CYP2C19*3 variants, which may be more common in certain populations of patients who are members of ethnic or racial minority groups—may not be consistently included in the various panels. Thus, before deciding on a specific test, clinicians should understand which gene variants are relevant to their patients with regard to race and ethnicity, and key variants for specific medications. Clinicians should refer to FDA guidance and the Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines to determine the appropriate interpretations of genetic test results.^1,2

Despite the disagreement in recommendations from the various testing companies, DSTs are useful and have been shown to facilitate implementation of relevant psycho­pharmacology dosing guidelines, assist in identifying optimal medication therapy, and improve patient outcomes. A recently published meta-analysis of randomized controlled trials (RCTs) of pharmacogenetic testing found that DSTs improved symptom remission among individuals with MDD by 70%.⁵ This suggests that pharmacogenetic-guided DSTs may provide superior treatment compared with treatment for DSTs were not used. However, the RCTs in this meta-analysis only included patients who had previously failed an antidepressant trial.⁵ Therefore, it is currently unknown at what point in care DSTs should be used, and whether they would be more beneficial if they are used when starting a new therapy, or after several trials have failed.

Consider the cost

The cost and availability of pharmacogenetic testing can be an issue when making treatment decisions, and such testing may not be covered by a patient’s insurance plan. Recently, the Centers for Medicare & Medicaid Services announced that Medicare would cover FDA-approved genomic tests that encompass broad gene panels if the evidence supports their use. Similarly, commercial insurers such as UnitedHealthcare have begun to cover some pharmacogenetic tests.⁶ Medicare or Medicaid plans cover some testing panels’ costs and patients do not incur any out-of-pocket costs; however, some private insurance companies require patients to pay at least a portion of the cost, and many companies offer financial assistance for patients based on income and other factors. Although financial coverage for testing has improved, patients may still face out-of-pocket costs; therefore, clinicians may need to weigh the benefits of pharmacogenetic testing vs its cost.⁷ Clinicians should also determine what timeline best suits their patient’s financial and clinical needs, and test accordingly.

Continue to: Patient education is critical

Although the benefits of using pharmacogenetic testing information when making certain treatment decisions is promising, it is important for both patients and clinicians to understand that test results do not always change therapy. A study on the impact of pharmacogenetic testing on clinical outcomes of patients with MDD found that 79% of patients were already prescribed medications that aligned with recommendations.⁸ Therefore, switching medications based on the test results of a patient who is doing well clinically is not recommended. However, DSTs may help with clinical decisions for ambiguous cases. For example, if a patient has a genotype and/or phenotype that aligns with medication recommendations, the DST might not be able to identify a better medication to use, but may be able to recommend dosing guidance to improve the tolerability of the patient’s current therapy.⁶ It is also important to understand that the results of such testing may have a broader use beyond the initial reason for obtaining testing, such as when prescribing a common blood thinner such as warfarin or clopidogrel. However, for many of the pharmacodynamic genes that are included in these panels, their use beyond the treatment of depression may be limited because outcome studies for pharmacodynamic pharmacogenes may vary based on psychiatric diagnosis. Regardless, it may be beneficial to securely save and store patient test results in a standardized place within the medical record for future use.

CASE CONTINUED

You work with Mr. J to help him understand the benefits and limitations associated with pharmacogenetic testing. Assuming Mr. J is comfortable with the costs of obtaining testing, you contact the testing companies you identified to determine the specific pharmacogene variants included on each of these panels, and which would be the most appropriate given his race. If the decision is made to order the testing, provide Mr. J with a copy of his testing report so that he can use this information should he need any additional pharmacotherapy in the future, and also maintain a copy in his patient records using a standardized location for easy future access. If Mr. J is not comfortable with the costs associated with the testing, find out which medication his brother is currently receiving for treatment; this information may help identify a treatment plan for Mr. J.

Impact on practice

As psychiatry continues to gain experience in using pharmacogenetic testing and DSTs to help guide treatments for depression and other disorders, clinicians need to learn about these tools and how to use an evidence-based approach to best implement them in their practice. Many academic medical centers have developed continuing education programs or consult services to help with this.^9,10 Just as the choice of which medication to use may be based partly on clinician experience, so too may be which pharmacogenetic test to use.

Bottom Line

Pharmacogenetic tests have not been examined in head-to-head clinical trials, which makes it nearly impossible to identify which test is best to use. Although the testing companies’ decision support tools (DSTs) often disagree in their recommendations, research has shown that using DSTs can facilitate implementation of relevant psychopharmacology dosing guidelines, assist in identifying optimal medication therapy, and improve patient outcomes. Clinicians should use testing panels with recommendations that best align with their individual practices, their patient’s needs, and FDA information.

Related Resources

• PGx Gene-specific information tables. www.pharmgkb.org/page/pgxGeneRef
• Clinical Pharmacogenetics Implementation Consortium. https://cpicpgx.org/guidelines/

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Fluoxetine • Prozac
Imipramine • Tofranil
Paroxetine • Paxil
Sertraline • Zoloft
Warfarin • Coumadin, Jantoven

Mr. J, age 30, a Black man with major depressive disorder (MDD), has been your patient for the past year. At the time of his diagnosis, Mr. J received sertraline, 100 mg/d, but had little to no improvement. During the past year, he received trials of citalopram and paroxetine, but they were not effective for his recurrent depressive symptoms and/or resulted in significant adverse effects.

During a recent visit, Mr. J asks you about “the genetic tests that help determine which medications will work.” He mentions that his brother had this testing done and that it had “worked for him,” but offers no other details. You research the different testing panels to see which test you might use. After a brief online review, you identify at least 4 different products, and are not sure which test—if any—you should consider.

During the last few years, there has been a rise in commercial pharmacogenetic testing options, including tests available to clinicians at academic medical centers as well as direct-to-consumer testing (Table). Clinician and patient interest regarding pharmacogenetic testing in practice is often followed by the question, “Which test is best?” Although this is a logical question, providing an answer is multifactorial.^1-3 Because none of the currently available tests have been compared in head-to-head clinical trials, it is nearly impossible to identify the “best” test.

In this article, we focus on the evidence-based principles that clinicians should consider when adopting pharmacogenetic testing in their practice. We discuss which genes are of most interest when prescribing psychotropic medications, the value of decision support tools, cost considerations, and patient education regarding this type of testing.

Which genes and variants should be tested?

The genes relevant to medication treatment outcomes can be broadly classified into those with pharmacokinetic vs pharmacodynamic effects. Pharmacogenes, such as those coding for the drug-metabolizing enzymes cytochrome P450 (CYP) 1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, and UDP-glucuronosyltransferase (UGT)2B1, may alter the rate at which medications are metabolized, thus varying the serum drug concentration across patients. Variants that impact the function of these enzymes are considered pharmacokinetic. Up to 40% of the variance in patients’ response to antidepressants may be due to variations in the pharmacokinetic genes.⁴ Alternatively, pharmacodynamic pharmacogenes impact drug action and therefore may affect the degree of receptor activation at a given drug concentration, overall drug efficacy, and/or the occurrence of medication sensitivity. These pharmacogenes may include:

• brain-derived neurotrophic factor (BDNF)
• catechol-O-methyltransferase (COMT)
• human leukocyte antigens A (HLA-A)
• serotonin receptor subtype 2 (HTR2)
• serotonin receptor subtype 2C (HTR2C)
• opioid receptor mu 1 (OPRM1)
• solute carrier family 6 member 4 (SLC6A4).

In articles previously published in Current Psychiatry, we outlined some of the evidence regarding these pharmacogenes, and resources available to clinicians to support their use of these tests.^1,2

Currently, there is no standardization among commercial pharmacogenetic tests on:

• which genes to test
• which variants specific to a gene need to be included
• how the genetic data is translated to phenotype
• how the phenotype is translated to a treatment recommendation.

Continue to: Due to these factors...

Due to these factors, the FDA has advised clinicians to consult the dosing recommendations provided in a medication’s package insert for information regarding how genetic information should be used in making treatment decisions.²

The value of decision support tools

Researchers have assessed how various manufacturers’ decision support tools (DSTs) (ie, the reports the commercial testing companies send to the clinician who orders the test) agree on genotypes, predicted phenotypes, and medication recommendations.⁴ Overall, this research found varying levels of disagreement in the medication recommendations of the testing panels they studied, which indicates that not all tests are equivalent or interchangeable.⁴ Of the actionable recommendations for antidepressants, 16% were conflicting; the recommendations for fluoxetine and imipramine were most frequently in disagreement.⁴ Similarly, 20% of the actionable antipsychotic advice was conflicting, with the recommendations for aripiprazole and clozapine most frequently in disagreement.⁴ Researchers also reported a situation in which 4 testing panels agreed on the patient’s phenotyping status for CYP2C19, but the dosing recommendations provided for the CYP2C19 substrate, amitriptyline, differed.⁴ Thus, it is understandable why DSTs can result in confusion, and why clinicians should use testing panels with recommendations that best align with their individual practices, their patient’s needs, and FDA information.

Additionally, while the genes included on these panels vary, these testing panels also may not evaluate the same variants within a specific gene. These differences may impact the patient’s reported phenotypes and medication recommendations across DSTs. For example, the FDA has recommended HLA gene testing prior to prescribing carbamazepine. However, few of the available tests may include the HLA-B*15:02 variant, which has been associated with carbamazepine-induced severe cutaneous reactions in patients of Asian descent, and fewer may include the HLA-A*31:01 variant, for which testing is recommended prior to prescribing carbamazepine in patients of Caucasian descent.⁴ Additionally, some of the CYP enzymes—such as CYP2D6*17 and CYP2C19*3 variants, which may be more common in certain populations of patients who are members of ethnic or racial minority groups—may not be consistently included in the various panels. Thus, before deciding on a specific test, clinicians should understand which gene variants are relevant to their patients with regard to race and ethnicity, and key variants for specific medications. Clinicians should refer to FDA guidance and the Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines to determine the appropriate interpretations of genetic test results.^1,2

Despite the disagreement in recommendations from the various testing companies, DSTs are useful and have been shown to facilitate implementation of relevant psycho­pharmacology dosing guidelines, assist in identifying optimal medication therapy, and improve patient outcomes. A recently published meta-analysis of randomized controlled trials (RCTs) of pharmacogenetic testing found that DSTs improved symptom remission among individuals with MDD by 70%.⁵ This suggests that pharmacogenetic-guided DSTs may provide superior treatment compared with treatment for DSTs were not used. However, the RCTs in this meta-analysis only included patients who had previously failed an antidepressant trial.⁵ Therefore, it is currently unknown at what point in care DSTs should be used, and whether they would be more beneficial if they are used when starting a new therapy, or after several trials have failed.

Consider the cost

The cost and availability of pharmacogenetic testing can be an issue when making treatment decisions, and such testing may not be covered by a patient’s insurance plan. Recently, the Centers for Medicare & Medicaid Services announced that Medicare would cover FDA-approved genomic tests that encompass broad gene panels if the evidence supports their use. Similarly, commercial insurers such as UnitedHealthcare have begun to cover some pharmacogenetic tests.⁶ Medicare or Medicaid plans cover some testing panels’ costs and patients do not incur any out-of-pocket costs; however, some private insurance companies require patients to pay at least a portion of the cost, and many companies offer financial assistance for patients based on income and other factors. Although financial coverage for testing has improved, patients may still face out-of-pocket costs; therefore, clinicians may need to weigh the benefits of pharmacogenetic testing vs its cost.⁷ Clinicians should also determine what timeline best suits their patient’s financial and clinical needs, and test accordingly.

Continue to: Patient education is critical

Although the benefits of using pharmacogenetic testing information when making certain treatment decisions is promising, it is important for both patients and clinicians to understand that test results do not always change therapy. A study on the impact of pharmacogenetic testing on clinical outcomes of patients with MDD found that 79% of patients were already prescribed medications that aligned with recommendations.⁸ Therefore, switching medications based on the test results of a patient who is doing well clinically is not recommended. However, DSTs may help with clinical decisions for ambiguous cases. For example, if a patient has a genotype and/or phenotype that aligns with medication recommendations, the DST might not be able to identify a better medication to use, but may be able to recommend dosing guidance to improve the tolerability of the patient’s current therapy.⁶ It is also important to understand that the results of such testing may have a broader use beyond the initial reason for obtaining testing, such as when prescribing a common blood thinner such as warfarin or clopidogrel. However, for many of the pharmacodynamic genes that are included in these panels, their use beyond the treatment of depression may be limited because outcome studies for pharmacodynamic pharmacogenes may vary based on psychiatric diagnosis. Regardless, it may be beneficial to securely save and store patient test results in a standardized place within the medical record for future use.

CASE CONTINUED

You work with Mr. J to help him understand the benefits and limitations associated with pharmacogenetic testing. Assuming Mr. J is comfortable with the costs of obtaining testing, you contact the testing companies you identified to determine the specific pharmacogene variants included on each of these panels, and which would be the most appropriate given his race. If the decision is made to order the testing, provide Mr. J with a copy of his testing report so that he can use this information should he need any additional pharmacotherapy in the future, and also maintain a copy in his patient records using a standardized location for easy future access. If Mr. J is not comfortable with the costs associated with the testing, find out which medication his brother is currently receiving for treatment; this information may help identify a treatment plan for Mr. J.

Impact on practice

As psychiatry continues to gain experience in using pharmacogenetic testing and DSTs to help guide treatments for depression and other disorders, clinicians need to learn about these tools and how to use an evidence-based approach to best implement them in their practice. Many academic medical centers have developed continuing education programs or consult services to help with this.^9,10 Just as the choice of which medication to use may be based partly on clinician experience, so too may be which pharmacogenetic test to use.

Bottom Line

Pharmacogenetic tests have not been examined in head-to-head clinical trials, which makes it nearly impossible to identify which test is best to use. Although the testing companies’ decision support tools (DSTs) often disagree in their recommendations, research has shown that using DSTs can facilitate implementation of relevant psychopharmacology dosing guidelines, assist in identifying optimal medication therapy, and improve patient outcomes. Clinicians should use testing panels with recommendations that best align with their individual practices, their patient’s needs, and FDA information.

Related Resources

• PGx Gene-specific information tables. www.pharmgkb.org/page/pgxGeneRef
• Clinical Pharmacogenetics Implementation Consortium. https://cpicpgx.org/guidelines/

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Fluoxetine • Prozac
Imipramine • Tofranil
Paroxetine • Paxil
Sertraline • Zoloft
Warfarin • Coumadin, Jantoven

Mr. J, age 30, a Black man with major depressive disorder (MDD), has been your patient for the past year. At the time of his diagnosis, Mr. J received sertraline, 100 mg/d, but had little to no improvement. During the past year, he received trials of citalopram and paroxetine, but they were not effective for his recurrent depressive symptoms and/or resulted in significant adverse effects.

During a recent visit, Mr. J asks you about “the genetic tests that help determine which medications will work.” He mentions that his brother had this testing done and that it had “worked for him,” but offers no other details. You research the different testing panels to see which test you might use. After a brief online review, you identify at least 4 different products, and are not sure which test—if any—you should consider.

During the last few years, there has been a rise in commercial pharmacogenetic testing options, including tests available to clinicians at academic medical centers as well as direct-to-consumer testing (Table). Clinician and patient interest regarding pharmacogenetic testing in practice is often followed by the question, “Which test is best?” Although this is a logical question, providing an answer is multifactorial.^1-3 Because none of the currently available tests have been compared in head-to-head clinical trials, it is nearly impossible to identify the “best” test.

In this article, we focus on the evidence-based principles that clinicians should consider when adopting pharmacogenetic testing in their practice. We discuss which genes are of most interest when prescribing psychotropic medications, the value of decision support tools, cost considerations, and patient education regarding this type of testing.

Which genes and variants should be tested?

The genes relevant to medication treatment outcomes can be broadly classified into those with pharmacokinetic vs pharmacodynamic effects. Pharmacogenes, such as those coding for the drug-metabolizing enzymes cytochrome P450 (CYP) 1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, and UDP-glucuronosyltransferase (UGT)2B1, may alter the rate at which medications are metabolized, thus varying the serum drug concentration across patients. Variants that impact the function of these enzymes are considered pharmacokinetic. Up to 40% of the variance in patients’ response to antidepressants may be due to variations in the pharmacokinetic genes.⁴ Alternatively, pharmacodynamic pharmacogenes impact drug action and therefore may affect the degree of receptor activation at a given drug concentration, overall drug efficacy, and/or the occurrence of medication sensitivity. These pharmacogenes may include:

• brain-derived neurotrophic factor (BDNF)
• catechol-O-methyltransferase (COMT)
• human leukocyte antigens A (HLA-A)
• serotonin receptor subtype 2 (HTR2)
• serotonin receptor subtype 2C (HTR2C)
• opioid receptor mu 1 (OPRM1)
• solute carrier family 6 member 4 (SLC6A4).

In articles previously published in Current Psychiatry, we outlined some of the evidence regarding these pharmacogenes, and resources available to clinicians to support their use of these tests.^1,2

Currently, there is no standardization among commercial pharmacogenetic tests on:

• which genes to test
• which variants specific to a gene need to be included
• how the genetic data is translated to phenotype
• how the phenotype is translated to a treatment recommendation.

Continue to: Due to these factors...

Due to these factors, the FDA has advised clinicians to consult the dosing recommendations provided in a medication’s package insert for information regarding how genetic information should be used in making treatment decisions.²

The value of decision support tools

Researchers have assessed how various manufacturers’ decision support tools (DSTs) (ie, the reports the commercial testing companies send to the clinician who orders the test) agree on genotypes, predicted phenotypes, and medication recommendations.⁴ Overall, this research found varying levels of disagreement in the medication recommendations of the testing panels they studied, which indicates that not all tests are equivalent or interchangeable.⁴ Of the actionable recommendations for antidepressants, 16% were conflicting; the recommendations for fluoxetine and imipramine were most frequently in disagreement.⁴ Similarly, 20% of the actionable antipsychotic advice was conflicting, with the recommendations for aripiprazole and clozapine most frequently in disagreement.⁴ Researchers also reported a situation in which 4 testing panels agreed on the patient’s phenotyping status for CYP2C19, but the dosing recommendations provided for the CYP2C19 substrate, amitriptyline, differed.⁴ Thus, it is understandable why DSTs can result in confusion, and why clinicians should use testing panels with recommendations that best align with their individual practices, their patient’s needs, and FDA information.

Additionally, while the genes included on these panels vary, these testing panels also may not evaluate the same variants within a specific gene. These differences may impact the patient’s reported phenotypes and medication recommendations across DSTs. For example, the FDA has recommended HLA gene testing prior to prescribing carbamazepine. However, few of the available tests may include the HLA-B*15:02 variant, which has been associated with carbamazepine-induced severe cutaneous reactions in patients of Asian descent, and fewer may include the HLA-A*31:01 variant, for which testing is recommended prior to prescribing carbamazepine in patients of Caucasian descent.⁴ Additionally, some of the CYP enzymes—such as CYP2D6*17 and CYP2C19*3 variants, which may be more common in certain populations of patients who are members of ethnic or racial minority groups—may not be consistently included in the various panels. Thus, before deciding on a specific test, clinicians should understand which gene variants are relevant to their patients with regard to race and ethnicity, and key variants for specific medications. Clinicians should refer to FDA guidance and the Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines to determine the appropriate interpretations of genetic test results.^1,2

Despite the disagreement in recommendations from the various testing companies, DSTs are useful and have been shown to facilitate implementation of relevant psycho­pharmacology dosing guidelines, assist in identifying optimal medication therapy, and improve patient outcomes. A recently published meta-analysis of randomized controlled trials (RCTs) of pharmacogenetic testing found that DSTs improved symptom remission among individuals with MDD by 70%.⁵ This suggests that pharmacogenetic-guided DSTs may provide superior treatment compared with treatment for DSTs were not used. However, the RCTs in this meta-analysis only included patients who had previously failed an antidepressant trial.⁵ Therefore, it is currently unknown at what point in care DSTs should be used, and whether they would be more beneficial if they are used when starting a new therapy, or after several trials have failed.

Consider the cost

The cost and availability of pharmacogenetic testing can be an issue when making treatment decisions, and such testing may not be covered by a patient’s insurance plan. Recently, the Centers for Medicare & Medicaid Services announced that Medicare would cover FDA-approved genomic tests that encompass broad gene panels if the evidence supports their use. Similarly, commercial insurers such as UnitedHealthcare have begun to cover some pharmacogenetic tests.⁶ Medicare or Medicaid plans cover some testing panels’ costs and patients do not incur any out-of-pocket costs; however, some private insurance companies require patients to pay at least a portion of the cost, and many companies offer financial assistance for patients based on income and other factors. Although financial coverage for testing has improved, patients may still face out-of-pocket costs; therefore, clinicians may need to weigh the benefits of pharmacogenetic testing vs its cost.⁷ Clinicians should also determine what timeline best suits their patient’s financial and clinical needs, and test accordingly.

Continue to: Patient education is critical

Although the benefits of using pharmacogenetic testing information when making certain treatment decisions is promising, it is important for both patients and clinicians to understand that test results do not always change therapy. A study on the impact of pharmacogenetic testing on clinical outcomes of patients with MDD found that 79% of patients were already prescribed medications that aligned with recommendations.⁸ Therefore, switching medications based on the test results of a patient who is doing well clinically is not recommended. However, DSTs may help with clinical decisions for ambiguous cases. For example, if a patient has a genotype and/or phenotype that aligns with medication recommendations, the DST might not be able to identify a better medication to use, but may be able to recommend dosing guidance to improve the tolerability of the patient’s current therapy.⁶ It is also important to understand that the results of such testing may have a broader use beyond the initial reason for obtaining testing, such as when prescribing a common blood thinner such as warfarin or clopidogrel. However, for many of the pharmacodynamic genes that are included in these panels, their use beyond the treatment of depression may be limited because outcome studies for pharmacodynamic pharmacogenes may vary based on psychiatric diagnosis. Regardless, it may be beneficial to securely save and store patient test results in a standardized place within the medical record for future use.

CASE CONTINUED

You work with Mr. J to help him understand the benefits and limitations associated with pharmacogenetic testing. Assuming Mr. J is comfortable with the costs of obtaining testing, you contact the testing companies you identified to determine the specific pharmacogene variants included on each of these panels, and which would be the most appropriate given his race. If the decision is made to order the testing, provide Mr. J with a copy of his testing report so that he can use this information should he need any additional pharmacotherapy in the future, and also maintain a copy in his patient records using a standardized location for easy future access. If Mr. J is not comfortable with the costs associated with the testing, find out which medication his brother is currently receiving for treatment; this information may help identify a treatment plan for Mr. J.

Impact on practice

As psychiatry continues to gain experience in using pharmacogenetic testing and DSTs to help guide treatments for depression and other disorders, clinicians need to learn about these tools and how to use an evidence-based approach to best implement them in their practice. Many academic medical centers have developed continuing education programs or consult services to help with this.^9,10 Just as the choice of which medication to use may be based partly on clinician experience, so too may be which pharmacogenetic test to use.

Bottom Line

Pharmacogenetic tests have not been examined in head-to-head clinical trials, which makes it nearly impossible to identify which test is best to use. Although the testing companies’ decision support tools (DSTs) often disagree in their recommendations, research has shown that using DSTs can facilitate implementation of relevant psychopharmacology dosing guidelines, assist in identifying optimal medication therapy, and improve patient outcomes. Clinicians should use testing panels with recommendations that best align with their individual practices, their patient’s needs, and FDA information.

Related Resources

• PGx Gene-specific information tables. www.pharmgkb.org/page/pgxGeneRef
• Clinical Pharmacogenetics Implementation Consortium. https://cpicpgx.org/guidelines/

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Fluoxetine • Prozac
Imipramine • Tofranil
Paroxetine • Paxil
Sertraline • Zoloft
Warfarin • Coumadin, Jantoven

Ms. T, age 55, presents to her psychiatrist’s clinic with a chief complaint of ongoing symptoms of anhedonia and lethargy related to her diagnosis of major depressive disorder (MDD). She also has a history of peripheral arterial disease, hypothyroidism, and generalized anxiety disorder. Her current antidepressant regimen is duloxetine, 60 mg/d, and mirtazapine, 15 mg at night. She recently elected to undergo pharmacogenetic testing, which showed that she is heterozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation (MTHFR C677T CT carrier). Her test report states that she may have impaired folate metabolism. Her psychiatrist adds L-methylfolate, 15 mg/d, to her current antidepressant regimen.

What is the relationship between folic acid and MTHFR?

Methylenetetrahydrofolate reductase is an intracellular enzyme responsible for one of several steps involved in converting dietary folic acid to its physiologically active form, L-methylfolate.¹ Once active, L-methylfolate can be transported into the CNS, where it participates in one-carbon transfer reactions.^2,3 Mutations in the MTHFR gene have been associated with decreased activity of the enzyme, which has been shown to result in accumulation of homocysteine and may lead to decreased synthesis of neurotransmitters.^2,4Commercial pharmacogenetic testing panels may offer MTHFR genetic testing to assist with prescribing decisions for patients with mental illness. The most well-characterized mutation currently is C677T (rsID1801133), which is a single amino acid base pair change (cytosine [C] to thymine [T]) that leads to increased thermolability and instability of the enzyme.⁵ Carrying 1 or 2 T alleles can lead to a 35% or 70% reduction in enzyme activity, respectively. The T variant allele is most frequent in Hispanics (20% to 25%), Asians (up to 63%), and Caucasians (8% to 20%); however, it is relatively uncommon in African Americans (<2%).^5,6 Another variant, A1289C (rs1801131), has also been associated with decreased enzyme function, particularly when analyzed in combination with C677T. However, carrying the 1289C variant allele does not appear to result in as large of a reduction of enzyme function as the 677T variant.⁷

What is the relationship between MTHFR C677T and depression?

Some researchers have proposed that the C677T mutation in MTHFR may be associated with depression as a result of decreased neurotransmitter synthesis, but studies have not consistently supported this hypothesis. Several studies suggest an association between MTHFR mutations and MDD^8-10:

Jiang et al⁸ performed a meta-analysis of 13 studies including 1,295 Chinese patients and found that having at least 1 C677T variant allele was significantly associated with an increased risk of depression (for T vs C odds ratio 1.52, 95% confidence interval 1.24 to 1.85). The authors noted a stronger association identified in the Northern Chinese population compared with the Southern Chinese population.⁸

Bousman et al⁹ found that American patients with MDD and the 677CC genotype had greater Patient Health Questionnaire-9 (PHQ-9) scores at assessments at 24, 36, and 48 months post-baseline compared with those with the 677TT genotype (P = .024), which was unexpected based on previously reported associations.⁹

Schiepers et al¹⁰ also assessed the association between the MTHFR genotype in a Dutch ambulatory care population over 12 years. There was no association identified between scores on the depression subscale of the Symptom Checklist 90 and C677T diplotype.¹⁰

Table 1^6,8-12 provides summaries of these and other selected studies on MTHFR and MDD. Overall, although a pathophysiological basis for depression and decreased MTHFR function has been proposed, the current body of literature does not indicate a consistent link between MTHFR C677T genetic variants alone and depression.

Continue to: Medication changes based on MTHFR: What is the evidence?

Medication changes based on MTHFR: What is the evidence?

Some evidence supports the use of active folate supplementation to improve symptoms of MDD.

Shelton et al³ conducted an observational study that assessed the effects of adding L-methylfolate (brand name: Deplin), 7.5 or 15 mg, to existing antidepressant therapy in 502 patients with MDD who had baseline PHQ-9 scores of at least 5. After an average 95 days of therapy, PHQ-9 scores were reduced by a mean of 8.5 points, with 67.9% of patients achieving at least a 50% reduction in PHQ-9 scores. The study did not take into account patients’ MTHFR genotype or differentiate results between the 2 doses of L-methylfolate.³

Papakostas et al¹³ performed 2 randomized, double-blind, parallel-sequential, placebo-controlled trials of L-methylfolate for patients with MDD. The first compared L-methylfolate, 7.5 and 15 mg, to placebo, without regard to MTHFR genotype.¹³ There was no significant difference between the 7.5-mg dose and placebo, or the 15-mg dose and placebo. However, among the group receiving the 15-mg dose, the response rate was 24%, vs 9% in the placebo group, which approached significance (P = .1). Papakostas et al¹³ followed up with a smaller trial comparing the 15-mg dose alone to placebo, and found the response rate was 32.3% in patients treated with L-methylfolate compared with 14.6% in the placebo group (P = .04).¹³

Although the Shelton et al³ and Papakostas et al¹³ studies showed some improvement in depressive symptom scores among patients who received L-methylfolate supplementation, an important consideration is if MTHFR genotype may predict patient response to this therapy.

Papakostas et al¹⁴ performed a post hoc analysis of their earlier study to assess potential associations amongst multiple other biomarkers of inflammation and metabolic disturbances hypothesized by the authors to be associated with MDD, as well as body mass index (BMI), with treatment outcome.¹⁴ When change in the Hamilton Depression Rating Scale-28 (HDRS-28) was analyzed by C677T and A1298C variant groups (677 CT vs TT and 1298 AC vs CC), no statistically significant improvements were identified (C677T mean change from baseline −3.8 points, P = .087; A1298C mean change from baseline −0.5 points, P = .807).¹⁴ However, statistically significant improvements in HDRS-28 scores were observed compared with baseline when the C677T genotype was pooled with other biomarkers, including methionine synthase (MTR 2756 AG/GG, −23.3 points vs baseline, P < .001) and a voltage-dependent calcium channel (CACNAIC AG/AA, −9 points vs baseline, P < .001), as well as with BMI ≥ 30 kg/m² (−9.9 points vs baseline, P = .001).¹⁴

Continue to: Mech and Farah...

Mech and Farah¹⁵ performed a random­ized, double-blind, placebo-controlled study of the use of EnLyte, a supplement containing 7-mg L-methylfolate, in patients with at least 1 variant of MTHFR (either C677T or A1298C) over an 8-week period. In addition to L-methylfolate, this supplement contains other active ingredients, including leucovorin (or folinic acid), magnesium ascorbate, and ferrous glycine cysteinate. Montgomery-Åsberg Depression Scale (MADRS) scores improved by 12 points in patients who received the supplement and by 1.3 points in patients who received placebo. However, because the supplement contained many ingredients, the response observed in this study cannot be attributed to L-methylfolate alone.¹⁵

Table 2^3,13,15,16 contains summaries of these and other selected studies assessing active folate supplementation in MDD.

CASE CONTINUED

Over the next several weeks, Ms. T experiences some modest improvement in mood while taking L-methylfolate and her antidepressant regimen, and she experiences no notable adverse effects. Unfortunately, after 3 months, Ms. T discontinues the supplement due to the cost.

The value of MTHFR testing

Ms. T’s case is an example of how clinicians may respond to MTHFR pharmacogenetic testing. Although L-methylfolate has shown some benefit in several randomized clinical trials, available data do not confirm the relevance of MTHFR functional status to symptom response. Additionally, there is likely interplay among multiple factors affecting patients’ response to L-methylfolate. Larger randomized trials prospectively assessing other pharmacogenetic and lifestyle factors may shed more light on which patients would benefit.

Based on available data, the decision to prescribe L-methylfolate should not necessarily hinge on MTHFR genetics alone. Both patients and clinicians must be aware of the potentially prohibitive cost if L-methylfolate is recommended, as prescription insurance may not provide coverage (eg, a recent search on GoodRx.com showed that generic L-methylfolate was approximately $40 for 30 tablets; prices may vary). Additionally, clinicians should be aware that L-methylfolate is regulated as a medical food product and is not subject to strict quality standards required for prescription medications. Future prospective studies assessing the use of L-methylfolate specifically in patients with a MTHFR variants while investigating other relevant covariates may help identify which specific patient populations would benefit from supplementation.

Continue to: Related Resources

• Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007;165(1):1-13.
• Trimmer E. Methylenetetrahydrofolate reductase: biochemical characterization and medical significance. Current Pharmaceutical Design. 2013;19(4):2574-3595.

Drug Brand Names

Citalopram • Celexa
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
L-methylfolate • Deplin
Mirtazapine • Remeron
Paroxetine • Paxil
Sertraline • Zoloft

Ms. T, age 55, presents to her psychiatrist’s clinic with a chief complaint of ongoing symptoms of anhedonia and lethargy related to her diagnosis of major depressive disorder (MDD). She also has a history of peripheral arterial disease, hypothyroidism, and generalized anxiety disorder. Her current antidepressant regimen is duloxetine, 60 mg/d, and mirtazapine, 15 mg at night. She recently elected to undergo pharmacogenetic testing, which showed that she is heterozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation (MTHFR C677T CT carrier). Her test report states that she may have impaired folate metabolism. Her psychiatrist adds L-methylfolate, 15 mg/d, to her current antidepressant regimen.

What is the relationship between folic acid and MTHFR?

Methylenetetrahydrofolate reductase is an intracellular enzyme responsible for one of several steps involved in converting dietary folic acid to its physiologically active form, L-methylfolate.¹ Once active, L-methylfolate can be transported into the CNS, where it participates in one-carbon transfer reactions.^2,3 Mutations in the MTHFR gene have been associated with decreased activity of the enzyme, which has been shown to result in accumulation of homocysteine and may lead to decreased synthesis of neurotransmitters.^2,4Commercial pharmacogenetic testing panels may offer MTHFR genetic testing to assist with prescribing decisions for patients with mental illness. The most well-characterized mutation currently is C677T (rsID1801133), which is a single amino acid base pair change (cytosine [C] to thymine [T]) that leads to increased thermolability and instability of the enzyme.⁵ Carrying 1 or 2 T alleles can lead to a 35% or 70% reduction in enzyme activity, respectively. The T variant allele is most frequent in Hispanics (20% to 25%), Asians (up to 63%), and Caucasians (8% to 20%); however, it is relatively uncommon in African Americans (<2%).^5,6 Another variant, A1289C (rs1801131), has also been associated with decreased enzyme function, particularly when analyzed in combination with C677T. However, carrying the 1289C variant allele does not appear to result in as large of a reduction of enzyme function as the 677T variant.⁷

What is the relationship between MTHFR C677T and depression?

Some researchers have proposed that the C677T mutation in MTHFR may be associated with depression as a result of decreased neurotransmitter synthesis, but studies have not consistently supported this hypothesis. Several studies suggest an association between MTHFR mutations and MDD^8-10:

Jiang et al⁸ performed a meta-analysis of 13 studies including 1,295 Chinese patients and found that having at least 1 C677T variant allele was significantly associated with an increased risk of depression (for T vs C odds ratio 1.52, 95% confidence interval 1.24 to 1.85). The authors noted a stronger association identified in the Northern Chinese population compared with the Southern Chinese population.⁸

Bousman et al⁹ found that American patients with MDD and the 677CC genotype had greater Patient Health Questionnaire-9 (PHQ-9) scores at assessments at 24, 36, and 48 months post-baseline compared with those with the 677TT genotype (P = .024), which was unexpected based on previously reported associations.⁹

Schiepers et al¹⁰ also assessed the association between the MTHFR genotype in a Dutch ambulatory care population over 12 years. There was no association identified between scores on the depression subscale of the Symptom Checklist 90 and C677T diplotype.¹⁰

Table 1^6,8-12 provides summaries of these and other selected studies on MTHFR and MDD. Overall, although a pathophysiological basis for depression and decreased MTHFR function has been proposed, the current body of literature does not indicate a consistent link between MTHFR C677T genetic variants alone and depression.

Continue to: Medication changes based on MTHFR: What is the evidence?

Medication changes based on MTHFR: What is the evidence?

Some evidence supports the use of active folate supplementation to improve symptoms of MDD.

Shelton et al³ conducted an observational study that assessed the effects of adding L-methylfolate (brand name: Deplin), 7.5 or 15 mg, to existing antidepressant therapy in 502 patients with MDD who had baseline PHQ-9 scores of at least 5. After an average 95 days of therapy, PHQ-9 scores were reduced by a mean of 8.5 points, with 67.9% of patients achieving at least a 50% reduction in PHQ-9 scores. The study did not take into account patients’ MTHFR genotype or differentiate results between the 2 doses of L-methylfolate.³

Papakostas et al¹³ performed 2 randomized, double-blind, parallel-sequential, placebo-controlled trials of L-methylfolate for patients with MDD. The first compared L-methylfolate, 7.5 and 15 mg, to placebo, without regard to MTHFR genotype.¹³ There was no significant difference between the 7.5-mg dose and placebo, or the 15-mg dose and placebo. However, among the group receiving the 15-mg dose, the response rate was 24%, vs 9% in the placebo group, which approached significance (P = .1). Papakostas et al¹³ followed up with a smaller trial comparing the 15-mg dose alone to placebo, and found the response rate was 32.3% in patients treated with L-methylfolate compared with 14.6% in the placebo group (P = .04).¹³

Although the Shelton et al³ and Papakostas et al¹³ studies showed some improvement in depressive symptom scores among patients who received L-methylfolate supplementation, an important consideration is if MTHFR genotype may predict patient response to this therapy.

Papakostas et al¹⁴ performed a post hoc analysis of their earlier study to assess potential associations amongst multiple other biomarkers of inflammation and metabolic disturbances hypothesized by the authors to be associated with MDD, as well as body mass index (BMI), with treatment outcome.¹⁴ When change in the Hamilton Depression Rating Scale-28 (HDRS-28) was analyzed by C677T and A1298C variant groups (677 CT vs TT and 1298 AC vs CC), no statistically significant improvements were identified (C677T mean change from baseline −3.8 points, P = .087; A1298C mean change from baseline −0.5 points, P = .807).¹⁴ However, statistically significant improvements in HDRS-28 scores were observed compared with baseline when the C677T genotype was pooled with other biomarkers, including methionine synthase (MTR 2756 AG/GG, −23.3 points vs baseline, P < .001) and a voltage-dependent calcium channel (CACNAIC AG/AA, −9 points vs baseline, P < .001), as well as with BMI ≥ 30 kg/m² (−9.9 points vs baseline, P = .001).¹⁴

Continue to: Mech and Farah...

Mech and Farah¹⁵ performed a random­ized, double-blind, placebo-controlled study of the use of EnLyte, a supplement containing 7-mg L-methylfolate, in patients with at least 1 variant of MTHFR (either C677T or A1298C) over an 8-week period. In addition to L-methylfolate, this supplement contains other active ingredients, including leucovorin (or folinic acid), magnesium ascorbate, and ferrous glycine cysteinate. Montgomery-Åsberg Depression Scale (MADRS) scores improved by 12 points in patients who received the supplement and by 1.3 points in patients who received placebo. However, because the supplement contained many ingredients, the response observed in this study cannot be attributed to L-methylfolate alone.¹⁵

Table 2^3,13,15,16 contains summaries of these and other selected studies assessing active folate supplementation in MDD.

CASE CONTINUED

Over the next several weeks, Ms. T experiences some modest improvement in mood while taking L-methylfolate and her antidepressant regimen, and she experiences no notable adverse effects. Unfortunately, after 3 months, Ms. T discontinues the supplement due to the cost.

The value of MTHFR testing

Ms. T’s case is an example of how clinicians may respond to MTHFR pharmacogenetic testing. Although L-methylfolate has shown some benefit in several randomized clinical trials, available data do not confirm the relevance of MTHFR functional status to symptom response. Additionally, there is likely interplay among multiple factors affecting patients’ response to L-methylfolate. Larger randomized trials prospectively assessing other pharmacogenetic and lifestyle factors may shed more light on which patients would benefit.

Based on available data, the decision to prescribe L-methylfolate should not necessarily hinge on MTHFR genetics alone. Both patients and clinicians must be aware of the potentially prohibitive cost if L-methylfolate is recommended, as prescription insurance may not provide coverage (eg, a recent search on GoodRx.com showed that generic L-methylfolate was approximately $40 for 30 tablets; prices may vary). Additionally, clinicians should be aware that L-methylfolate is regulated as a medical food product and is not subject to strict quality standards required for prescription medications. Future prospective studies assessing the use of L-methylfolate specifically in patients with a MTHFR variants while investigating other relevant covariates may help identify which specific patient populations would benefit from supplementation.

Continue to: Related Resources

• Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007;165(1):1-13.
• Trimmer E. Methylenetetrahydrofolate reductase: biochemical characterization and medical significance. Current Pharmaceutical Design. 2013;19(4):2574-3595.

Drug Brand Names

Citalopram • Celexa
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
L-methylfolate • Deplin
Mirtazapine • Remeron
Paroxetine • Paxil
Sertraline • Zoloft

Ms. T, age 55, presents to her psychiatrist’s clinic with a chief complaint of ongoing symptoms of anhedonia and lethargy related to her diagnosis of major depressive disorder (MDD). She also has a history of peripheral arterial disease, hypothyroidism, and generalized anxiety disorder. Her current antidepressant regimen is duloxetine, 60 mg/d, and mirtazapine, 15 mg at night. She recently elected to undergo pharmacogenetic testing, which showed that she is heterozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation (MTHFR C677T CT carrier). Her test report states that she may have impaired folate metabolism. Her psychiatrist adds L-methylfolate, 15 mg/d, to her current antidepressant regimen.

What is the relationship between folic acid and MTHFR?

Methylenetetrahydrofolate reductase is an intracellular enzyme responsible for one of several steps involved in converting dietary folic acid to its physiologically active form, L-methylfolate.¹ Once active, L-methylfolate can be transported into the CNS, where it participates in one-carbon transfer reactions.^2,3 Mutations in the MTHFR gene have been associated with decreased activity of the enzyme, which has been shown to result in accumulation of homocysteine and may lead to decreased synthesis of neurotransmitters.^2,4Commercial pharmacogenetic testing panels may offer MTHFR genetic testing to assist with prescribing decisions for patients with mental illness. The most well-characterized mutation currently is C677T (rsID1801133), which is a single amino acid base pair change (cytosine [C] to thymine [T]) that leads to increased thermolability and instability of the enzyme.⁵ Carrying 1 or 2 T alleles can lead to a 35% or 70% reduction in enzyme activity, respectively. The T variant allele is most frequent in Hispanics (20% to 25%), Asians (up to 63%), and Caucasians (8% to 20%); however, it is relatively uncommon in African Americans (<2%).^5,6 Another variant, A1289C (rs1801131), has also been associated with decreased enzyme function, particularly when analyzed in combination with C677T. However, carrying the 1289C variant allele does not appear to result in as large of a reduction of enzyme function as the 677T variant.⁷

What is the relationship between MTHFR C677T and depression?

Some researchers have proposed that the C677T mutation in MTHFR may be associated with depression as a result of decreased neurotransmitter synthesis, but studies have not consistently supported this hypothesis. Several studies suggest an association between MTHFR mutations and MDD^8-10:

Jiang et al⁸ performed a meta-analysis of 13 studies including 1,295 Chinese patients and found that having at least 1 C677T variant allele was significantly associated with an increased risk of depression (for T vs C odds ratio 1.52, 95% confidence interval 1.24 to 1.85). The authors noted a stronger association identified in the Northern Chinese population compared with the Southern Chinese population.⁸

Bousman et al⁹ found that American patients with MDD and the 677CC genotype had greater Patient Health Questionnaire-9 (PHQ-9) scores at assessments at 24, 36, and 48 months post-baseline compared with those with the 677TT genotype (P = .024), which was unexpected based on previously reported associations.⁹

Schiepers et al¹⁰ also assessed the association between the MTHFR genotype in a Dutch ambulatory care population over 12 years. There was no association identified between scores on the depression subscale of the Symptom Checklist 90 and C677T diplotype.¹⁰

Table 1^6,8-12 provides summaries of these and other selected studies on MTHFR and MDD. Overall, although a pathophysiological basis for depression and decreased MTHFR function has been proposed, the current body of literature does not indicate a consistent link between MTHFR C677T genetic variants alone and depression.

Continue to: Medication changes based on MTHFR: What is the evidence?

Medication changes based on MTHFR: What is the evidence?

Some evidence supports the use of active folate supplementation to improve symptoms of MDD.

Shelton et al³ conducted an observational study that assessed the effects of adding L-methylfolate (brand name: Deplin), 7.5 or 15 mg, to existing antidepressant therapy in 502 patients with MDD who had baseline PHQ-9 scores of at least 5. After an average 95 days of therapy, PHQ-9 scores were reduced by a mean of 8.5 points, with 67.9% of patients achieving at least a 50% reduction in PHQ-9 scores. The study did not take into account patients’ MTHFR genotype or differentiate results between the 2 doses of L-methylfolate.³

Papakostas et al¹³ performed 2 randomized, double-blind, parallel-sequential, placebo-controlled trials of L-methylfolate for patients with MDD. The first compared L-methylfolate, 7.5 and 15 mg, to placebo, without regard to MTHFR genotype.¹³ There was no significant difference between the 7.5-mg dose and placebo, or the 15-mg dose and placebo. However, among the group receiving the 15-mg dose, the response rate was 24%, vs 9% in the placebo group, which approached significance (P = .1). Papakostas et al¹³ followed up with a smaller trial comparing the 15-mg dose alone to placebo, and found the response rate was 32.3% in patients treated with L-methylfolate compared with 14.6% in the placebo group (P = .04).¹³

Although the Shelton et al³ and Papakostas et al¹³ studies showed some improvement in depressive symptom scores among patients who received L-methylfolate supplementation, an important consideration is if MTHFR genotype may predict patient response to this therapy.

Papakostas et al¹⁴ performed a post hoc analysis of their earlier study to assess potential associations amongst multiple other biomarkers of inflammation and metabolic disturbances hypothesized by the authors to be associated with MDD, as well as body mass index (BMI), with treatment outcome.¹⁴ When change in the Hamilton Depression Rating Scale-28 (HDRS-28) was analyzed by C677T and A1298C variant groups (677 CT vs TT and 1298 AC vs CC), no statistically significant improvements were identified (C677T mean change from baseline −3.8 points, P = .087; A1298C mean change from baseline −0.5 points, P = .807).¹⁴ However, statistically significant improvements in HDRS-28 scores were observed compared with baseline when the C677T genotype was pooled with other biomarkers, including methionine synthase (MTR 2756 AG/GG, −23.3 points vs baseline, P < .001) and a voltage-dependent calcium channel (CACNAIC AG/AA, −9 points vs baseline, P < .001), as well as with BMI ≥ 30 kg/m² (−9.9 points vs baseline, P = .001).¹⁴

Continue to: Mech and Farah...

Mech and Farah¹⁵ performed a random­ized, double-blind, placebo-controlled study of the use of EnLyte, a supplement containing 7-mg L-methylfolate, in patients with at least 1 variant of MTHFR (either C677T or A1298C) over an 8-week period. In addition to L-methylfolate, this supplement contains other active ingredients, including leucovorin (or folinic acid), magnesium ascorbate, and ferrous glycine cysteinate. Montgomery-Åsberg Depression Scale (MADRS) scores improved by 12 points in patients who received the supplement and by 1.3 points in patients who received placebo. However, because the supplement contained many ingredients, the response observed in this study cannot be attributed to L-methylfolate alone.¹⁵

Table 2^3,13,15,16 contains summaries of these and other selected studies assessing active folate supplementation in MDD.

CASE CONTINUED

Over the next several weeks, Ms. T experiences some modest improvement in mood while taking L-methylfolate and her antidepressant regimen, and she experiences no notable adverse effects. Unfortunately, after 3 months, Ms. T discontinues the supplement due to the cost.

The value of MTHFR testing

Ms. T’s case is an example of how clinicians may respond to MTHFR pharmacogenetic testing. Although L-methylfolate has shown some benefit in several randomized clinical trials, available data do not confirm the relevance of MTHFR functional status to symptom response. Additionally, there is likely interplay among multiple factors affecting patients’ response to L-methylfolate. Larger randomized trials prospectively assessing other pharmacogenetic and lifestyle factors may shed more light on which patients would benefit.

Based on available data, the decision to prescribe L-methylfolate should not necessarily hinge on MTHFR genetics alone. Both patients and clinicians must be aware of the potentially prohibitive cost if L-methylfolate is recommended, as prescription insurance may not provide coverage (eg, a recent search on GoodRx.com showed that generic L-methylfolate was approximately $40 for 30 tablets; prices may vary). Additionally, clinicians should be aware that L-methylfolate is regulated as a medical food product and is not subject to strict quality standards required for prescription medications. Future prospective studies assessing the use of L-methylfolate specifically in patients with a MTHFR variants while investigating other relevant covariates may help identify which specific patient populations would benefit from supplementation.

Continue to: Related Resources

• Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007;165(1):1-13.
• Trimmer E. Methylenetetrahydrofolate reductase: biochemical characterization and medical significance. Current Pharmaceutical Design. 2013;19(4):2574-3595.

Drug Brand Names

Citalopram • Celexa
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
L-methylfolate • Deplin
Mirtazapine • Remeron
Paroxetine • Paxil
Sertraline • Zoloft