Cytochrome P450 (CYP450) Genetic Testing for SSRI Metabolism
The test is called CYP450 genotyping or pharmacogenetic testing, which specifically tests for polymorphisms in the CYP2D6 and CYP2C19 genes to determine metabolizer status for SSRIs. 1, 2
Test Name and Components
The FDA-approved commercial test is the Roche AmpliChip® CYP450 Test, which delivers results as both a genotype and a predicted metabolizer status (phenotype) for CYP2D6 and CYP2C19 enzymes. 1 Many laboratories also offer their own "laboratory-developed tests" or "home brew tests" for CYP450 genotyping that meet Clinical Laboratory Improvement Amendment standards. 1
What the Test Measures
CYP450 genotyping identifies genetic polymorphisms in two primary liver enzymes:
- CYP2D6 - breaks down many common antidepressants including fluoxetine, paroxetine, and venlafaxine, with approximately 5-8% of Caucasians being "poor metabolizers" and 1-7% being "ultrarapid metabolizers" 2
- CYP2C19 - works alongside CYP2D6 to metabolize SSRIs and is particularly important for citalopram and escitalopram metabolism, with about 2-5% of Caucasians being poor metabolizers 2
Metabolizer Categories
The test classifies patients into four metabolizer phenotypes: 1, 2
- Ultra-rapid Metabolizers (UM) - have more than 2 copies of active enzyme genes, leading to subtherapeutic drug concentrations at usual doses and possible non-response
- Extensive Metabolizers (EM) - have 2 copies of active genes, achieving expected drug concentrations and response at usual doses
- Intermediate Metabolizers (IM) - have 1 inactive and 1 reduced activity allele, with drug effects between EMs and PMs
- Poor Metabolizers (PM) - have 2 copies of inactive genes, leading to higher than expected drug concentrations and increased risk of adverse reactions
Technical Performance
The analytic validity of CYP450 genotyping is high for common polymorphisms: 1, 2
- Analytic sensitivity ranges from 94-100% for common polymorphisms
- Analytic specificity is 100% for all genes tested
- Less common polymorphisms and gene deletion/duplication testing have less reliable estimates
Critical Limitation: Lack of Evidence for Routine Use
The EGAPP (Evaluation of Genomic Applications in Practice and Prevention) Working Group found insufficient evidence to recommend routine CYP450 genetic testing before starting SSRI treatment for nonpsychotic depression. 1, 2, 3 This represents the most authoritative guideline-level recommendation available.
The evidence gaps include: 1, 4
- Mixed results linking genotype to SSRI blood levels in patients on steady-state doses
- Only five studies evaluated genotype versus clinical response, with inconsistent findings
- No data demonstrating that using test results to guide SSRI choice or dose actually improves patient outcomes (response rates, quality of life, adverse events)
- Multiple factors beyond genotype (drug interactions, diet, concomitant medications, individual patient characteristics) significantly influence drug metabolism
When Testing May Be Considered
While routine testing is not recommended, CYP450 genotyping may be considered: 2, 3
- After treatment failure or repeated poor response to antidepressant therapy
- After intolerable side effects on standard SSRI doses
- In patients with prior adverse reactions to multiple psychotropic medications
- For known poor metabolizers requiring dose adjustments (50% dose reduction for citalopram/escitalopram in CYP2C19 PMs) 3
Important Caveat
Fluoxetine metabolism involves CYP2D6, and about 7% of the population are poor metabolizers of this enzyme, achieving higher concentrations of S-fluoxetine. 5 However, the total pharmacodynamic activity at steady state is not significantly different between poor and normal metabolizers because alternative, non-saturable pathways also contribute to fluoxetine metabolism. 5 This illustrates why genotype alone does not reliably predict clinical outcomes.