Managing Psychiatric Medications in CYP2D6 Poor Metabolizers
Primary Recommendation
For CYP2D6 poor metabolizers taking psychiatric medications primarily metabolized by this enzyme, reduce the starting dose to 50% of the usual dose, and for those on medications metabolized by both CYP2D6 and CYP3A4 (or taking concomitant CYP3A4 inhibitors), reduce to 25% of the usual dose. 1
Medication-Specific Dosing Adjustments
SSRIs (Fluoxetine and Paroxetine)
Poor metabolizers experience dramatically elevated drug concentrations: Single-dose fluoxetine 20 mg produces a 3.9-fold higher AUC in PMs versus EMs, and at 60 mg, the increase is 11.5-fold for S-fluoxetine. 2
Paroxetine shows similar patterns: A 30 mg single dose produces a 7-fold higher AUC in PMs versus EMs, though this decreases to 1.7-fold with chronic dosing due to enzyme saturation. 2
Critical safety concern: The FDA has issued warnings that fluoxetine should be used with caution in CYP2D6 PMs due to QT prolongation risk and potential for sudden cardiac death. 2
Start with lower doses and titrate slowly: Given the substantially elevated plasma concentrations (e.g., paroxetine levels of 70 ng/mL versus reference <23 ng/mL in one PM case), initiate at 50% of standard dosing. 2
Aripiprazole
Reduce dose by 50% in known CYP2D6 poor metabolizers: This is an FDA-mandated dosing adjustment per the drug label. 1
Further reduction to 25% if combined with strong CYP3A4 inhibitors: When PMs are also taking drugs like itraconazole or clarithromycin, quarter the usual dose. 1, 2
Metabolic ratio can identify PMs retrospectively: A log(MR) ≥1.5 for aripiprazole has 97.8% predictive accuracy for identifying PM phenotype through therapeutic drug monitoring. 3
Risperidone
Reduce initial dose to 0.25-0.5 mg in PMs: Standard starting dose is 0.5 mg, but PMs require lower dosing to avoid extrapyramidal side effects. 2
Monitor for elevated concentrations: Metabolic ratio (risperidone/9-hydroxyrisperidone) ≥0.0 on log scale has 93% predictive value for PM phenotype. 3
Venlafaxine
PMs show dramatically altered O-desmethylvenlafaxine to venlafaxine ratios: A ratio <1 (or log(MR) ≥0.1) identifies PM phenotype with 97.2% accuracy. 3
Start at 50% of standard dose: Given the substantial accumulation of parent compound in PMs. 2
Tricyclic Antidepressants (Nortriptyline, Clomipramine)
Dose-corrected serum concentrations are markedly elevated in PMs: Log(CDR) ≥0.5 for nortriptyline predicts PM status with 85.6% accuracy. 3
Intermediate metabolizers also at risk: A patient with CYP2C19 *1/*2 and CYP2D6 *4/*41 (double intermediate metabolizer) showed considerably elevated clomipramine and desmethylclomipramine levels after 2.5 years of treatment. 4
Initiate at 25-50% of standard dose and use therapeutic drug monitoring: TCAs have narrow therapeutic indices, making PMs particularly vulnerable to toxicity. 2
Atomoxetine
Poor metabolizers comprise 5-8% of Caucasian populations: Failing to identify PM status before initiating therapy leads to excessive drug exposure and adverse effects. 5
Reduce dose by 50% in known PMs: This prevents accumulation to toxic levels. 5
Critical Clinical Considerations
Phenoconversion: A Major Pitfall
24% of patients on venlafaxine with non-PM genotypes convert to PM phenotype: This occurs through drug-drug interactions, making genotype alone insufficient for clinical decision-making. 6
Fluoxetine converts 43% of extensive metabolizers to poor metabolizers: At 20 mg/day chronic dosing, fluoxetine acts as a potent CYP2D6 inhibitor, creating "phenocopy" PM status. 2
Always assess concomitant medications: Strong CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine) can convert any metabolizer status to functional PM. 1
Adverse Event Profile in Poor Metabolizers
4-fold increased risk of adverse drug reactions: In a German study, 29% of patients with ADRs were CYP2D6 PMs versus 7% expected population frequency (P <0.0001). 7
Documented fatalities: A 34-year-old man died from cardiac arrest with venlafaxine blood concentration of 4.5 mg/kg, attributed to CYP2D6 PM phenotype. 2
Serotonin syndrome risk: Elevated paroxetine levels (70 ng/mL) in an intermediate metabolizer led to serotonin syndrome. 2
QT prolongation: PMs are at increased risk for cardiac arrhythmias, particularly with fluoxetine and other QT-prolonging agents. 2
When to Consider CYP2D6 Testing
Genetic Testing Indications
Before starting medications with narrow therapeutic indices: Particularly TCAs, atomoxetine, and certain antipsychotics. 8
When taking multiple CYP2D6 substrates or inhibitors: Polypharmacy increases phenoconversion risk. 8
After unexplained adverse reactions or treatment failures: Retrospective testing can explain poor outcomes. 8, 7
NOT recommended as routine screening: The EGAPP Working Group found insufficient evidence for routine CYP450 testing in all patients starting SSRIs for nonpsychotic depression. 2
Therapeutic Drug Monitoring as Alternative
Metabolic ratios can diagnose PM phenotype without genotyping: For venlafaxine, risperidone, aripiprazole, and nortriptyline, specific MR thresholds achieve >92% sensitivity and >64% specificity. 3
More practical than universal genotyping: TDM captures both genetic PMs and phenoconverted PMs, providing real-time metabolic status. 3, 6
Practical Algorithm for Dose Adjustment
Identify if patient is known CYP2D6 PM (via genetic testing or previous TDM): Reduce dose by 50% 1
Assess for strong CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine): If present with PM genotype, reduce to 25% 1
Assess for strong CYP3A4 inhibitors (itraconazole, clarithromycin) in PM patients: If present, reduce to 25% 1
If both CYP2D6 and CYP3A4 inhibitors present in PM: Reduce to 25% of usual dose 1
Monitor closely for adverse effects: Particularly cardiovascular (QT prolongation), neurological (EPS, serotonin syndrome), and tolerability issues 2
Consider TDM 2-4 weeks after initiation: Verify that concentrations are within therapeutic range and identify phenoconversion 3
Reassess if adding/removing interacting medications: Phenotype can change dynamically with polypharmacy 6
Key Takeaway
The combination of preemptive dose reduction (50% for PMs, 25% for PMs with inhibitors) and vigilant monitoring for drug interactions prevents the majority of serious adverse events in CYP2D6 poor metabolizers taking psychiatric medications. 1, 2 Therapeutic drug monitoring offers a practical alternative to genetic testing by capturing both genetic and acquired poor metabolizer phenotypes. 3, 6