What kind of genetic testing is done to determine the most effective antidepressants for an individual?

Genetic Testing for Antidepressant Selection

The genetic testing used to determine optimal antidepressants involves testing for cytochrome P450 (CYP450) enzyme polymorphisms, specifically CYP2D6 and CYP2C19 genes, though current evidence does not support routine use of this testing to improve clinical outcomes in depression treatment. 1

What These Tests Measure

The pharmacogenetic tests identify specific DNA polymorphisms in genes encoding drug-metabolizing enzymes:

• CYP2D6 testing detects genetic variants that determine how quickly someone metabolizes many antidepressants including fluoxetine, paroxetine, venlafaxine, and tricyclic antidepressants 2, 3
• CYP2C19 testing identifies polymorphisms affecting metabolism of SSRIs, particularly citalopram, escitalopram, and sertraline 2, 4
• FDA-approved tests like the Roche AmpliChip® CYP450 Test can identify these genotypes and predict metabolizer status 5, 3

Metabolizer Categories Identified

Testing classifies patients into four phenotypes based on enzyme activity:

• Poor Metabolizers (PM): Two inactive gene alleles, resulting in very slow drug breakdown—affects 5-8% of Caucasians for CYP2D6 and up to 25% of East Asians for CYP2C19 2, 3
• Intermediate Metabolizers (IM): One active and one inactive allele, leading to reduced enzyme activity 5
• Extensive/Normal Metabolizers (EM): Two active alleles with normal enzyme function 5
• Ultrarapid Metabolizers (UM): Three or more active alleles causing very rapid drug breakdown—affects up to 29% in North Africa and Middle East for CYP2D6 2, 3

Technical Performance

The tests demonstrate high accuracy for common genetic variants:

• Analytic sensitivity ranges from 94-100% for common polymorphisms 1
• Analytic specificity is 100% for all genes tested 1
• Limitations exist for rare polymorphisms and gene deletion/duplication testing, where estimates are less reliable 1

Critical Evidence Gap: Clinical Utility

The EGAPP Working Group found insufficient evidence that CYP450 genetic testing improves clinical outcomes (response rates, quality of life, adverse events) in adults starting SSRI treatment for nonpsychotic depression. 1, 2

This represents a crucial disconnect:

• While tests accurately identify genotypes and predict drug metabolism in controlled settings, studies of patients on steady-state SSRI doses showed mixed results linking genotype to actual drug levels 1
• Only five studies evaluated genotype versus clinical response, with inconsistent findings 1
• No evidence demonstrates that using test results to guide SSRI choice or dose actually improves patient outcomes 1

When Testing May Have Value

Despite insufficient evidence for routine use, testing may be considered in specific high-risk scenarios:

• Before starting medications with narrow therapeutic windows primarily metabolized by CYP2D6, such as tricyclic antidepressants 5, 3
• Patients with prior severe adverse reactions or multiple treatment failures with antidepressants 2, 3
• When taking multiple medications that are substrates or inhibitors of CYP2D6 or CYP2C19 5
• To prevent toxicity in suspected poor metabolizers rather than to improve efficacy 2

Practical Limitations

Multiple factors beyond genetics affect antidepressant metabolism:

• Drug interactions with CYP450 inhibitors can create "phenocopying," where an extensive metabolizer temporarily functions as a poor metabolizer 5, 6
• Diet, concomitant medications, and individual patient characteristics significantly influence drug metabolism independent of genotype 1, 2
• Most psychiatric medications are metabolized by multiple enzyme pathways, so deficiency in one enzyme may be partially compensated by alternative routes 2

Clinical Recommendations Based on Genotype (If Testing Performed)

For CYP2D6 Poor Metabolizers:

• Reduce fluoxetine, paroxetine, and venlafaxine doses by 50% with mandatory therapeutic drug monitoring 2
• Avoid or use extreme caution with tricyclic antidepressants and typical antipsychotics 3

For CYP2D6 Ultrarapid Metabolizers:

• Consider higher doses or alternative agents for fluoxetine, paroxetine, and venlafaxine 2
• Close monitoring required as standard doses may be ineffective 2

For CYP2C19 Poor Metabolizers:

• Reduce citalopram and escitalopram doses by 50% 2

Preferred alternatives for patients with polymorphisms:

• Select medications with more predictable pharmacokinetics: sertraline, mirtazapine, or bupropion 2

Key Pitfalls to Avoid

• Do not use genetic testing as routine screening for all patients starting antidepressants—the evidence does not support improved outcomes 1, 5
• Do not rely solely on genotype without considering drug interactions, as enzyme inhibitors can override genetic metabolizer status 5, 6
• Do not assume testing will shorten time to response or prevent all adverse effects—other factors play substantial roles 1
• Recognize that laboratory-developed tests vary in which specific polymorphisms they detect, potentially missing rare variants 1