Health Professionals: More about the EGAPP™ CYP450 Genotyping Recommendation

EGAPP™ Evidence Review at a Glance

CYP450 test including application, analytic and clinical validity, clinical utility, cost effectiveness and overall recommendation
Test Application Quality of Evidence
Adequacy of information to address:
Overall Recommen-dation*
Analytic Validity Clinical Validity Clinical Utility
CYP450 Polymorphisms Pharmacogenomic Adequate Inadequate to demonstrate impact on—
  • circulating SSRI levels
  • clinical response
  • adverse drug effects
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 .

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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.”

Considerations for Practice

  • 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.

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Testing Information

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


Contextual Factors

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.

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Research Gaps

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.

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More information about CYP450 genotyping and the use of SSRI drugs for depression in adults that is not part of the EGAPP™ recommendation.

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Page last reviewed: October 21, 2011