Pharmacogenetics Panel for Psychotropics

Content Review: July 2022 Last Update:
  • Use to assess genetic variants that may inform selection and dosing of common and many other psychotropic medications
  • Test is appropriate for individuals with personal or family history of therapeutic failure or adverse events related to psychotropic medications

Refer to the Laboratory Test Directory for additional testing to assess genetic risk of abnormal drug metabolism for specific substrates, including CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and the methylenetetrahydrofolate reductase variant.

Variation in genes affecting pharmacokinetics and/or pharmacodynamics (pharmacogenetics) may influence medication selection and dose planning.  For example, variants in genes that code for metabolizing enzymes (CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and UGT2B15) may be associated with altered (slower or faster) metabolism, which would affect the kinetics of medication activation, inactivation, and/or elimination. Other genes may predict the risk of side effects and/or the likelihood of response (ANKK1, COMT, DRD2, GRIK4, HTR2A, HTR2C, MTHFR, and OPRM1). This panel can provide information that may guide selection and dosing for many prescription medications, including medications relevant to psychiatry such as psychostimulants (eg, ADHD medication), antidepressants, antipsychotics, and anxiolytics. The potential roles of the pharmacogenes included in this test are summarized below.

Treatment Issues

  • Actual metabolic phenotype is subject to interactions related to pharmacogenes, medications, supplements, food, lifestyle choices, clinical factors, as well as genetic and nongenetic factors not identified by this test. This test is intended only to identify targeted pharmacogene variants.
  • Therapeutic and clinical monitoring are needed to guide pharmacotherapy for a particular patient. For more information about pharmacogenetic testing and ARUPs test offerings, see the ARUP Consult topic Germline Pharmacogenetics - PGx.
  • A table providing known clinical associations between the gene variants detected in this test and several common psychotropic medications can be found here.
  • The U.S. Food and Drug Administration (FDA) has published a table  characterizing gene-medication associations based on whether current data support therapeutic management decisions, indicate a potential impact on safety or response, or demonstrate a potential impact on pharmacokinetic properties only.
  • The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published dosing guidelines for several psychotropic medications such as atomoxetine,  selective serotonin reuptake inhibitors  (eg, citalopram), and tricyclic antidepressants  (eg, amitriptyline). For more detailed information, refer to the CPIC guidelines website. 
  • The Pharmacogenomics Knowledge Base  provides evidence for additional medication-gene associations with relevant clinical associations, medication labeling, and gene-based dosing guidelines.

Testing Considerations

  • This panel provides a comprehensive analysis for multiple genes that have strong pharmacogenomic associations with medications used in the treatment of psychiatric disorders, including depression. Specific gene-drug interactions are supported by guidelines from CPIC, Association for Molecular Pathology (AMP), or Dutch Pharmacogenetics Working Group (DPWG) (CYP2B6, CYP2C19, CYP2C9, CYP2D6, and CYP3A4).
  • This panel also provides analysis for multiple genes that have level 3 evidence linking the genes to psychotropic medications according to PharmGKB (MTHFR, CYP3A5, DRD2, ANKK1, GRIK4, HTR2A, HTR2C, UGT2B15, COMT, and OPRM1). More details are available in the PharmGKB Levels of Evidence for Selected Medication/Gene Associations table or on the PharmGKB website. 
  • Some of the genes tested in the psych panel are part of other panels offered by ARUP, and hence there might be instances where some of the alleles reported in the psych panel are not linked to psychotropic medications. Caution must be taken when clinically interpreting these findings relevant to the medications patients are using.
  • The test result does not replace the need for therapeutic medication or clinical monitoring.

Genetics

Genes

ANKK1, COMT, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, DRD2, GRIK4, HTR2A, HTR2C, MTHFR, OPRM1, UGT2B15

Inheritance

Autosomal codominant­­

Variants Tested

Variant(s) from a reference sequence are detected by targeted genotyping (not full gene sequencing) and by copy number determinations (CYP2D6 only). Conventional nomenclature for describing the variants and predicting phenotype is applied, when available. For many pharmacogenes, variants are grouped and classified as “star” (*) alleles that are associated with predicted enzyme or protein function, based on international consensus nomenclature. However, not all variants in a gene are tested, and assumptions about phase or diplotype assignments are made. More details about the nomenclature, allele frequencies, and phenotype predictions are available at the PharmVar  and PharmGKB  websites.
Gene (Transcript) and Brief Summary of Associated Protein Function Alleles Predicted Allele Functiona

ANKK1 (NM_178510) (DRD2 associated)

This variant in ANKK1 represents the Taq1A polymorphism that affects the expression of binding sites for dopamine on the D2 receptor and can influence response to psychotropic medications that target the dopaminergic system

rs1800497, c.2137G>A

Drug dependentb

COMT (NM_000754)

Codes for catechol-o-methyltransferase, an enzyme that metabolizes catecholamines such as dopamine and is involved in response to several medications

rs4680, c.472G>A

Drug dependentb

CYP2B6 (NM_000767)

Codes for the cytochrome P450 2B6 enzyme, which is involved in metabolism of many medications; impact of the phenotype depends on whether a medication is activated or inactivated by this enzyme

 

CYP2B6*4: rs2279343, c.785A>G

Increased function

CYP2B6*6: rs3745274, c.516G>T; rs2279343, c.785A>G

Decreased function

CYP2B6*7: rs3745274, c.516G>T; rs2279343, c.785A>G; rs3211371, c.1459C>T

Decreased function

CYP2B6*9: rs3745274, c.516G>T

Decreased function

CYP2B6*18: rs28399499, c.983T>C

No function

CYP2B6*22: rs34223104, c.-82T>C

Increased function

CYP2B6*36: rs34223104, c.-82T>C; rs3745274, c.516G>T; rs2279343, c.785A>G

Decreased function

CYP2C19 (NM_000769)

Codes for the cytochrome P450 2C19 enzyme, which is involved in metabolism of many medications; impact of the phenotype depends on whether a medication is activated or inactivated by this enzyme

 

CYP2C19*2: rs4244285, c.681G>A; rs12769205, c.332-23A>G

No function

CYP2C19*3: rs4986893, c.636G>A

No function

CYP2C19*4A: rs28399504, c.1A>G

No function

CYP2C19*4B: rs28399504, c.1A>G, rs12248560, c.-806C>T;

No function

CYP2C19*5: rs56337013, c.1297C>T

No function

CYP2C19*6: rs72552267, c.395G>A

No function

CYP2C19*7: rs72558186, c.819+2T>A

No function

CYP2C19*8: rs41291556, c.358T>C

No function

CYP2C19*9: rs17884712, c.431G>A

Decreased function

CYP2C19*17: rs12248560, c.-806C>T

Increased function

CYP2C19*35: rs12769205, c.332-23A>G

No function

CYP2C9 (NM_000771)

Codes for the cytochrome P450 2C9 enzyme, which is involved in metabolism of many medications; impact of the phenotype depends on whether a medication is activated or inactivated by this enzyme

 

CYP2C9*2: rs1799853, c.430C>T

Decreased function

CYP2C9*3: rs1057910, c.1075A>C

Decreased function

CYP2C9*4: rs56165452, c.1076T>C

Decreased function

CYP2C9*5: rs28371686, c.1080C>G

Decreased function

CYP2C9*6: rs9332131, c.818del

No function

CYP2C9*8: rs7900194, c.449G>A

Decreased function

CYP2C9*11: rs28371685, c.1003C>T

Decreased function

CYP2C9*12: rs9332239, c.1465C>T

Decreased function

CYP2D6c (M33388 sequence)

Codes for the cytochrome P450 2D6 enzyme, which is involved in metabolism of many medications; impact of the phenotype depends on whether a medication is activated or inactivated by this enzyme. The test also evaluates copy number variations and can discriminate which allele is affected in most cases that exhibit gene duplication.

CYP2D6*2: rs16947, g.2850C>T; rs1135840, g.4180G>C

Functional

CYP2D6*2A: rs1080985, g.-1584C>G; rs16947, g.2850C>T; rs1135840, g.4180G>C

Functional

CYP2D6*3: rs35743686, g.2549del

No function

CYP2D6*4: rs1065852, g.100C>T; rs3892097, g.1846G>A; rs1135840, g.4180G>C

No function

CYP2D6*5: gene deletion

No function

CYP2D6*6: rs5030655, g.1707del; rs1135840, g.4180G>C

No function

CYP2D6*7: rs5030867, g.2935A>C

No function

CYP2D6*8: rs5030865, g.1758G>T; rs16947, g.2850C>T; rs1135840, g.4180G>C

No function

CYP2D6*9: rs5030656, g.2615_2617del

Decreased function

CYP2D6*10: rs1065852, g.100C>T; rs1135840, g.4180G>C

Decreased function

CYP2D6*11: rs1080985, g.-1584C>G; rs201377835, g.883G>C; rs16947, g.2850C>T; rs1135840, g.4180G>C

No function

CYP2D6*13: a CYP2D7-derived exon 1 conversion

No function

CYP2D6*14: rs5030865, g.1758G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C

Decreased function

CYP2D6*15: rs774671100, g.137_138insT

No function

CYP2D6*17: rs28371706, g.1023C>T; rs16947, g.2850C>T; rs1135840, g.4180G>C

Decreased function

CYP2D6*29: rs16947, g.2850C>T; rs59421388, g.3183G>A; rs1135840, g.4180G>C

Decreased function

CYP2D6*35: rs769258, g.31G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C; rs1080985, g.-1584C>G

Functional

CYP2D6*36: a CYP2D6*10 carrying a CYP2D7-derived exon 9 conversion

No function

CYP2D6*36-*10: a CYP2D6*36 and a CYP2D6*10 in tandem

Decreased function

CYP2D6*40: rs28371706, g.1023C>T, rs72549356, c.1863_1864ins TTTCGCCCCTTTCGCCCC, rs16947, g.2850C>T; rs1135840, g.4180G>C

No function

CYP2D6*41: rs16947, g.2850C>T; rs28371725, g.2988G>A; rs1135840, g.4180G>C

Decreased function

CYP2D6*42: rs16947, g.2850C>T; rs72549346, g.3260_3261insGT; rs1135840, g.4180G>C

No function

CYP2D6*49: rs1065852, g.100C>T; rs1135822, g.1611T>A; rs1135840, g.4180G>C

Decreased function

CYP2D6*69: rs1065852, g.100C>T; rs16947, g.2850C>T; rs28371725, g.2988G>A; rs1135840, g.4180G>C

No function

CYP2D6*114: rs1065852, g.100C>T; rs5030865, g.1758G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C

No function

 

DUP: complete gene duplication

Varies based on the allele that is duplicated

CYP3A4 (NM_017460)

Codes for the cytochrome P450 3A4 enzyme, which is involved in metabolism of many medications; impact of the phenotype depends on whether a medication is activated or inactivated by this enzyme

CYP3A4*1A: rs2740574, c.-392G>A

 

Normal function

 

CYP3A4*22: rs35599367, c.522-191C>T

Decreased function

CYP3A5 (NM_000777)

Codes for the cytochrome P450 3A5 enzyme, which is involved in metabolism of many medications; impact of the phenotype depends on whether a medication is activated or inactivated by this enzyme

CYP3A5*3: rs776746, c.219-237A>G

No function

CYP3A5*6: rs10264272, c.624G>A

No function

CYP3A5*7: rs41303343, c.1035dup

No function

DRD2 (NM_000795)

Codes for the D2 dopamine receptor that is involved in medication dependence and response to psychotropic medications, particularly antipsychotics

rs1799978, c.-585A>G

Drug dependentb

GRIK4 (NM_014619)

Codes for the ionotropic glutamate receptor also known as AMPA 4, kainate type subunit 4. This receptor is involved in response to psychotropic medications, particularly antidepressants.

rs1954787, c.83-10039T>C

Drug dependentb

HTR2A (NM_000621)

Codes for a serotonin receptor that is involved in response to many psychotropic medications, including antidepressants and antipsychotics

rs6311, c.-998G>A

Drug dependentb

rs7997012, c.614-2211T>C

Drug dependentb

HTR2C (NM_001256760)

Codes for a serotonin receptor that is involved in response to psychotropic medications, particularly antipsychotics

rs3813929, c.-850C>T

Drug dependentb

MTHFR (NM_005957)

Codes for methylenetetrahydrofolate reductase, an enzyme that is involved in folate metabolism and is implicated in response to l-methylfolate supplementation and response to several psychotropic medications, particularly antipsychotics

rs1801131, c.1286A>C

Drug dependentb

rs1801133, c.665C>T

Drug dependentb

OPRM1 (NM_000914)

Codes for the mu 1 opioid receptor that is involved in response to opioid agonists and antagonists, as well as several other medications

rs1799971, c.118A>G

Drug dependentb

UGT2B15 (NM_001076)

Codes for UDP glucuronosyl-transferase family 2 member B15 that is involved in metabolism of many medications, such as the anxiolytics oxazepam and lorazepam

rs1902023, c.253T>G

Drug dependentb

aPredicted allele function based on PharmVar unless otherwise indicated.

bSee www.pharmgkb.org  for allele frequency and other data about these variants.

cGenomic coordinates for CYP2D6 variants are based on reference sequence M33388.

Test Interpretation

Clinical sensitivity is drug and patient dependent.

Analytic sensitivity/specificity is greater than 99%.

Results

  • Genetic variant(s) detected: alleles detected are reported. The combination of alleles detected is used to predict phenotype and activity scores, as applicable (eg, CYP2D6).
  • Phenotype predictions, allele definitions, and associations with specific medications are subject to change as the scientific and clinical evidence evolves.
  • When appropriate, results are reported as “star” (*) alleles based on consensus nomenclature. No variants detected is reported as “Negative” and is predictive of *1 functional allele.
  • For more information about the association between certain genes and medications, please see the PharmGKB Levels of Evidence for Selected Medication/Gene Associations table.

Limitations

  • Only the targeted variants will be detected by this panel. Assumptions about phase and content are made to assign alleles.
  • Diagnostic errors can occur due to rare sequence variations.
  • A combination of the CYP2D6*5 (gene deletion) and a CYP2D6 gene duplication cannot be specifically identified; however, this combination is not expected to adversely affect the phenotype prediction.
  • Risk of therapeutic failure or adverse reactions with gene substrates may be affected by genetic and nongenetic factors that are not detected by this test.
  • HLA-B*15:02 (an allele that is more common in individuals of Asian descent) and other HLA alleles with pharmacogenetic relevance are not included due to analytical limitations. For additional test options, including testing for HLA-B*15:02 status, refer to the Laboratory Test Directory.

References

  1. PharmGKB

    Clinical Pharmacogenetics Implementation Consortium, Dutch Pharmacogenetics Working Group, Canadian Pharmacogenomics Network for Drug Safety. PharmGKB. Accessed Jul 2022.

  2. PharmVar

    Pharmacogene Variation Consortium. PharmVar. Updated Nov 2020; accessed Dec 2020.

Related Information
Cytochrome P450 Genotyping
Methylenetetrahydrofolate Reductase (MTHFR) Testing