Pharmacogenetics Panel for Psychotropics

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). These panels may be used to assess genetic variants that may inform selection and dosing for many prescription medications, including medications relevant to psychiatry such as psychostimulants (eg, ADHD medication), antidepressants, antipsychotics, and anxiolytics. These tests are appropriate for individuals with a personal or family history of therapeutic failure or adverse events related to psychotropic medications.

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, refer to the ARUP Consult Germline Pharmacogenetics - PGx topic.
• A table providing known clinical associations between the gene variants detected in this test and several common psychotropic medications can be found here.
• Additional resources are available through the U.S. Food and Drug Administration (FDA),  the Clinical Pharmacogenetics Implementation Consortium (CPIC),  and the Pharmacogenomics Knowledge Base. 

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 PharmGKB  and PharmVar  websites.

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 refer to 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.
• The assay used to detect the CYP2D6*40 allele cannot distinguish between insertions of one or two copies; it also cannot distinguish between heterozygous and homozygous mutant samples due to unavoidable cross reactivity with the wild type sequence. Additional assays will be used to help differentiate the CYP2D6*40 allele from other CYP2D6 star alleles.
• 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 ARUP Laboratory Test Directory.