Pharmacogenetic Interpretation for Psychotropic Medications
Critical Genetic Information Required
Your genetic testing results for CYP2D6 and CYP2C19 metabolizer status are essential for safe and effective psychotropic medication prescribing. These two enzymes are the primary metabolic pathways for most psychiatric medications, and genetic variations can lead to 5-8% of Caucasians being poor metabolizers (PMs) and 1-7% being ultrarapid metabolizers (UMs) for CYP2D6, with similar variability for CYP2C19 1, 2.
JSON Report Structure
{
"patient_genetic_profile": {
"CYP2D6_status": "[REQUIRED: PM/IM/EM/UM]",
"CYP2C19_status": "[REQUIRED: PM/IM/EM/UM]",
"COMT_genotype": "[OPTIONAL: Val/Val, Val/Met, Met/Met]"
},
"high_risk_medications": {
"avoid_or_use_extreme_caution": [],
"reasoning": []
},
"medications_requiring_dose_adjustment": {
"reduce_dose_by_50_percent": [],
"increase_dose_considerations": [],
"standard_dosing_acceptable": []
},
"preferred_medications": {
"first_line_options": [],
"rationale": []
},
"monitoring_recommendations": {
"therapeutic_drug_monitoring": [],
"adverse_effect_surveillance": [],
"frequency": ""
},
"clinical_alerts": []
}Medication-Specific Recommendations by Metabolizer Status
For CYP2D6 Poor Metabolizers (PM)
Fluoxetine and paroxetine require immediate dose reduction or alternative selection in PMs due to 4-7 fold higher drug exposure and documented fatalities. 1, 3
- Avoid or reduce initial dose by 50%: Fluoxetine, paroxetine, venlafaxine 1
- Risk profile: PMs experience 419% increase in paroxetine plasma concentrations, leading to severe adverse effects including QT prolongation, seizures, cardiac arrest, and death 1
- Documented fatality: A 9-year-old CYP2D6 PM on high-dose fluoxetine (80-100 mg/day) died from metabolic toxicity, seizures, and cardiac arrest 1
- FDA warning: Fluoxetine should be used with extreme caution in CYP2D6 PMs due to QT prolongation risk 1
Atomoxetine is contraindicated or requires 50% dose reduction in CYP2D6 PMs. 4
- Standard dosing in PMs leads to excessive drug exposure and severe adverse effects 4
For CYP2D6 Ultrarapid Metabolizers (UM)
UMs metabolize drugs too rapidly, leading to subtherapeutic levels and treatment failure. 1, 2
- Higher doses may be required: Fluoxetine, paroxetine, venlafaxine 1
- Alternative medications: Consider drugs not primarily metabolized by CYP2D6 (sertraline, citalopram, escitalopram) 1
- Prevalence: 1-7% of Caucasian population 1, 2
For CYP2C19 Poor Metabolizers (PM)
Citalopram and escitalopram require dose reduction in CYP2C19 PMs. 1
- Reduce dose by 50% for citalopram and escitalopram in PMs 1
- Tricyclic antidepressants (amitriptyline, imipramine, clomipramine) require dose reduction and therapeutic drug monitoring 1, 5
- Prevalence: 3-5% of Caucasians, 15-30% of Asians 5
For CYP2C19 Ultrarapid Metabolizers (UM)
Standard doses may be insufficient; consider dose increase or alternative agents. 1, 6
COMT Genotype Considerations
COMT Val/Val carriers have increased risk of cognitive impairment and may experience altered response to SSRIs. 7
- Val/Val genotype: Higher enzyme activity, faster dopamine metabolism, potential for reduced SSRI efficacy 7
- Met/Met genotype: Lower enzyme activity, higher risk of gastrointestinal side effects with SSRIs, may require lower doses 7
- Val/Met genotype: Intermediate enzyme activity, intermediate dosing considerations 7
Therapeutic Drug Monitoring Protocol
Combine pharmacogenetic testing with therapeutic drug monitoring (TDM) for optimal outcomes. 1, 6
- Mandatory TDM for: All PMs and UMs on fluoxetine, paroxetine, venlafaxine, tricyclic antidepressants 1
- Timing: Obtain levels at steady state (4-5 weeks for fluoxetine due to long half-life, 1-2 weeks for other SSRIs) 3
- Target ranges: Use established therapeutic ranges; PMs will have 2-7 fold higher levels at standard doses 1
Critical Drug Interactions
CYP2D6 inhibitors can convert extensive metabolizers into phenotypic poor metabolizers. 1, 3
- Strong CYP2D6 inhibitors: Fluoxetine itself (at 20 mg/day converts 43% of EMs to PMs), paroxetine, bupropion, quinidine 1, 3
- Clinical implication: Avoid combining CYP2D6 substrates with CYP2D6 inhibitors in all patients, especially IMs and PMs 3
- Duration of effect: Fluoxetine inhibition persists for 5 weeks after discontinuation due to long half-life 3
Medications Least Affected by CYP2D6/CYP2C19 Polymorphisms
Sertraline, mirtazapine, and bupropion have more predictable pharmacokinetics across metabolizer phenotypes. 1
- Sertraline: Multiple metabolic pathways, less dependent on single CYP enzyme 1
- Mirtazapine: Metabolized by CYP1A2, CYP2D6, and CYP3A4; genetic variation has less clinical impact 1
- Bupropion: Primarily CYP2B6 substrate, not affected by CYP2D6/CYP2C19 polymorphisms 1
Evidence Quality and Limitations
The EGAPP Working Group found insufficient evidence that CYP genetic testing improves clinical outcomes for depression treatment, but this does not negate safety benefits in preventing toxicity. 1
- Efficacy evidence: Mixed results; some studies show improved response rates with genotype-guided treatment, others show no difference 1, 8
- Safety evidence: Strong evidence for preventing adverse effects and toxicity in PMs 1, 9
- Actionability: 38-48% of adverse drug reactions are attributable to CYP2D6/CYP2C19 genotype 9
- Current recommendation: Consider genotyping when side effects or inefficacy occur; use available genotype information to select appropriate drug and dose 6
Clinical Decision Algorithm
Obtain CYP2D6 and CYP2C19 genotype before initiating psychotropic medications, especially in patients with prior adverse reactions or treatment failures 6
If PM for CYP2D6:
If PM for CYP2C19:
If UM for CYP2D6 or CYP2C19:
For all patients: Avoid combining CYP2D6 substrates with CYP2D6 inhibitors; wait 5 weeks after fluoxetine discontinuation before starting another CYP2D6 substrate 3