What are the considerations when prescribing common psychiatric medications that undergo 2D6 (cytochrome P450 2D6) metabolism, such as selective serotonin reuptake inhibitors (SSRIs) like fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft)?

Common Psychiatric Medications Undergoing CYP2D6 Metabolism

Major CYP2D6-Metabolized Psychiatric Medications

The most clinically significant psychiatric medications metabolized by CYP2D6 include SSRIs (fluoxetine, paroxetine, sertraline), tricyclic antidepressants (TCAs), venlafaxine, and most antipsychotics. 1, 2

Antidepressants

SSRIs:

• Fluoxetine (Prozac) - Potent CYP2D6 inhibitor and substrate; single-dose AUC is 3.9-fold higher in poor metabolizers (PMs) vs extensive metabolizers (EMs), and at 60mg doses, S-fluoxetine AUC increases 11.5-fold in PMs 1
• Paroxetine (Paxil) - Potent CYP2D6 inhibitor and substrate; median AUC of 30mg dose is 7-fold higher in PMs vs EMs (though this declines to 1.7-fold with chronic use) 1, 3
• Sertraline (Zoloft) - Moderate CYP2D6 inhibitor and substrate; shows less pronounced CYP2D6 inhibition than fluoxetine/paroxetine due to lower steady-state plasma concentrations 3, 4, 5

TCAs:

• Desipramine - Major CYP2D6 substrate; plasma concentrations increase 3-4 fold when co-administered with fluoxetine or paroxetine 1, 3, 6
• Imipramine - CYP2D6 substrate; shows 3-4 fold AUC increases with fluoxetine co-administration 3
• Nortriptyline - CYP2D6 substrate with narrow therapeutic index 1

SNRIs:

• Venlafaxine - CYP2D6 substrate; fatal cardiac arrest has been documented in a CYP2D6 PM with elevated venlafaxine blood concentration (4.5 mg/kg) 1

Antipsychotics

Most antipsychotics are CYP2D6 substrates, including: 1, 2

• Phenothiazines - Multiple agents metabolized via CYP2D6
• Thioridazine - Contraindicated with fluoxetine due to risk of serious ventricular arrhythmias and sudden death from elevated plasma levels 2
• Haloperidol - Elevated blood levels observed with concomitant fluoxetine 2
• Clozapine - Elevated blood levels with fluoxetine co-administration 2
• Risperidone - CYP2D6 substrate 3
• Pimozide - Contraindicated with fluoxetine due to QTc prolongation risk 2

Other Psychiatric Medications

• Doxepin - CYP2D6 substrate with active metabolite demethyldoxepin 1
• Trimipramine - CYP2D6 substrate with active metabolite desmethyltrimipramine 1

Critical Clinical Considerations for CYP2D6 Metabolism

Genetic Polymorphism Impact

CYP2D6 poor metabolizers (PMs) face substantially elevated drug exposure and toxicity risk, while ultrarapid metabolizers (UMs) may have subtherapeutic levels. 1

• PM phenotype (two null alleles): Results in 3.9-11.5 fold higher AUCs for fluoxetine depending on dose 1
• IM phenotype (one normal + one null allele, or two decreased activity alleles): Intermediate risk; case report of serotonin syndrome with paroxetine 20mg/day showing elevated plasma concentration (70 ng/mL; reference <23 ng/mL) in IM patient 1
• EM phenotype (two normal activity alleles): Standard metabolism 1
• UM phenotype (two increased activity alleles): May require higher doses for efficacy 1

Drug-Drug Interactions

Fluoxetine and paroxetine are the most problematic SSRIs for CYP2D6-mediated drug interactions, while sertraline, citalopram, and escitalopram have lower interaction potential. 3, 4, 5

Rank order of CYP2D6 inhibitory potency: 3, 5

• Paroxetine > Fluoxetine ≈ Norfluoxetine ≥ Sertraline > Fluvoxamine > Venlafaxine

Critical interaction considerations:

• Fluoxetine at 20mg/day converts approximately 43% of EMs to PM phenotype through auto-inhibition, creating a "phenocopy" effect 1
• Norfluoxetine's long half-life causes significant and prolonged (approximately 3 weeks) elevation of co-administered CYP2D6 substrate levels after fluoxetine discontinuation 3
• Desipramine + fluoxetine (20mg/day) produces approximately 4-fold elevation in peak desipramine concentrations 3
• Desipramine + paroxetine produces approximately 3-fold increase in desipramine concentration 3
• Desipramine + sertraline (50mg/day) produces only modest 30% elevation in desipramine concentrations 3

Safety Warnings and Contraindications

The FDA has issued specific safety warnings for fluoxetine regarding CYP2D6 PMs: 1

• Use with caution in patients with congenital long QT syndrome, previous QT prolongation history, family history of long QT syndrome/sudden cardiac death
• CYP2D6 PM status and co-administration of CYP2D6 inhibitors predispose to QT prolongation and ventricular arrhythmia

Absolute contraindications: 2

• Thioridazine + fluoxetine/paroxetine: Do not administer together or within minimum 5 weeks after fluoxetine discontinuation
• Pimozide + fluoxetine: Contraindicated due to QTc prolongation risk

Dosing Adjustments for CYP2D6 Substrates

When initiating CYP2D6 substrates with narrow therapeutic indices in patients on fluoxetine/paroxetine: 2

• Start at the low end of dose range
• Use conservative titration schedules
• Consider need for decreased dose if fluoxetine/paroxetine added to existing CYP2D6 substrate
• Monitor clinical status closely

Drugs requiring particular caution (narrow therapeutic index): 2, 3

• Flecainide and propafenone (antiarrhythmics)
• TCAs (especially desipramine, nortriptyline)
• Vinblastine
• Thioridazine

Common Pitfalls to Avoid

Do not assume all SSRIs have equivalent interaction profiles - fluoxetine and paroxetine require significantly more caution than sertraline, citalopram, or escitalopram when co-prescribing CYP2D6 substrates 6, 4, 5

Remember fluoxetine's prolonged washout period - inhibitory effects on CYP2D6 persist for several weeks after discontinuation due to norfluoxetine's 7-15 day half-life 3, 7

Monitor for dose-dependent toxicity - a VA study found that 36% of patients receiving fluoxetine/paroxetine plus CYP2D6 substrates with narrow therapeutic indices were receiving high enough doses to be at moderate-to-high risk of serious drug interactions, with no dose adjustments made 6

Consider therapeutic drug monitoring when combining potent CYP2D6 inhibitors with substrates having narrow therapeutic indices, particularly TCAs 1, 5