Health Professionals: More about the EGAPP™ CYP450 Genotyping Recommendation
|Test||Application||Quality of Evidence
Adequacy of information to address:
|Analytic Validity||Clinical Validity||Clinical Utility|
|CYP450 Polymorphisms||Pharmacogenomic||Adequate||Inadequate to demonstrate impact on—
||No evidence available||Insufficient evidence to recommend for or against use
Discourage use until further clinical trials completed
*Overall recommendation was decided on the basis of (a) evidence indicating a low level of certainty of net health benefits, and (b) Contextual Factors .
EGAPP™ Recommendation Statement
“EGAPP™ Working Group found insufficient evidence to support a recommendation for or against use of CYP450 testing in adults beginning SSRI treatment for nonpsychotic depression. In the absence of supporting evidence, and with consideration of other contextual issues, EGAPP™ discourages use of CYP450 testing for patients beginning SSRI treatment until further clinical trials are completed.”
- CYP450 is a family of enzymes involved in the metabolism of many drugs, including SSRIs. CYP2D6 and CYP2C19 are the primary CYP450 enzymes responsible for the breakdown of SSRIs.
- Clinical validity findings:
- Some studies of single SSRI dose in healthy patients suggest a significant association between CYP450 genotypic metabolizer status and circulating SSRI levels. However, this association was not confirmed by similar studies of patients taking maintenance doses of SSRIs.
- Studies did not consistently identify a significant association between the CYP450 genotype and clinical response to SSRI treatment and/or to adverse events. Studies were generally small and of poor quality.
- No studies addressed the influence of CYP450 genotyping results on SSRI prescribing decisions or patient outcomes (clinical utility).
- Potential harms of CYP450 genotyping include:
- Increased health care cost without benefit to the patient.
- Patient may receive less effective treatment with SSRI drugs.
- Genotype information may be used inappropiately for managing other drugs metabolized by CYP450 enzymes.
Note: See Contextual Factors for more information.
Note: See More Considerations for Practice for additional information that is not part of the EGAPP™ recommendation.
The CYP450 family of enzymes is a major subset of all drug-metabolizing enzymes. In theory, CYP450 genotyping to determine a patient’s metabolizer status could guide decisions regarding the choice of SSRI or dosing.
EGAPP™ reviewed data on the relationship between testing for the CYP450 genotype and metabolic status* and concluded—
- In general, “poor-metabolizers” with two inactive alleles had clearly reduced metabolic function; however,
- other metabolizers, such as “intermediate,” “extensive,” and “ultra-rapid” metabolizers, overlap considerably in metabolic function.
*Examples of how variations in one CYP450 gene (CYP2D6) have been proposed to affect SSRI drug metabolism (based on test manufacturer** information):
- Ultra-rapid metabolizer (UM): more than two copies of active alleles; possible sub-therapeutic drug concentration, and non-response with usual dose
- Extensive metabolizer (EM): two copies of active alleles; usual doses lead to expected drug concentrations and response
- Intermediate metabolizer (IM): one inactive and one reduced activity alleles, or two reduced activity alleles; drug effects between those of EMs and PMs
- Poor metabolizer (PM): two copies of inactive alleles; usual doses may lead to higher than expected drug concentrations and possible adverse reactions.
**These examples do not represent all possible genotypes; more genotype-phenotype examples are available in the AmpliChip® package insert. Top of Page
Additional contextual issues were taken into account in the final recommendation statement because the EGAPP™ Working Group found insufficient evidence on clinical validity and utility to support a recommendation for or against use of CYP450 genotyping in adults beginning SSRI treatment for nonpsychotic depression.
Contextual factors that suggest potential benefits of CYP450 genotyping include:
- Depression is a major health problem in the United States commonly treated by SSRIs.
- There is evidence of variable treatment effectiveness with use of SSRIs. In some cases, this leads to discontinuation of treatment.
Some issues considered by the EGAPP™ Working Group which led to their final recommendation to discourage the use of CYP450 genotyping for SSRI treatment include the following:
- Impact of genotyping for CYP450 polymorphisms on physician prescribing decisions for SSRIs is unknown.
- Widespread use of CYP450 genotyping is potentially costly, especially in the absence of evidence showing improved patient outcomes.
- Cost-effectiveness analyses are needed: cost of testing and follow-up is not known, although the test itself is relatively inexpensive.
The EGAPP™ Working Group identified the need for research to address the following:
- Well-designed clinical validity studies to address relationship between genotype and clinical response to SSRIs.
- If conclusive evidence of clinical validity is acquired, prospective studies to address the relationship of CYP450 genotyping on clinical outcomes.
- Studies need to incorporate information on confounding variables (i.e., medications that inhibit or induce certain CYP450 enzymes, and should examine specific SSRIs one at a time).
- General studies are needed to address the psychosocial and ethical impact of pharmacogenetic testing on individuals with depression, as well as implications for family members.
More information about CYP450 genotyping and the use of SSRI drugs for depression in adults that is not part of the EGAPP™ recommendation.