CYP2D6 and Antidepressants: Which Drugs Are Affected?

The CYP2D6 gene is one of the most important drug-metabolizing enzymes for psychiatric medications. Approximately 25% of all prescribed drugs are metabolized by CYP2D6, and antidepressants represent one of the largest affected drug classes.

This page provides a categorized list of antidepressants and related psychiatric medications with documented CYP2D6 involvement. The list focuses on medications with CPIC or DPWG guideline evidence, but also notes medications where CYP2D6 plays a recognized metabolic role without a published pharmacogenomic guideline.

Important: This list is not exhaustive and may not reflect the most current guideline updates. CYP2D6 relevance differs by medication — for some drugs it is the primary metabolic pathway, while for others it plays a secondary role. Dose adjustments are always prescriber decisions made in the context of the full clinical picture. See the CPIC guidelines at cpicpgx.org for the most current recommendations.

SSRIs (Selective Serotonin Reuptake Inhibitors)

Several SSRIs are metabolized by CYP2D6, though the clinical significance varies. For some SSRIs, CYP2C19 metabolism is the more important pharmacogene.

• Fluoxetine (Prozac): Metabolized by CYP2D6. CPIC provides dosing guidance for CYP2D6 poor and ultrarapid metabolizers. Poor metabolizers may have elevated fluoxetine levels. Fluoxetine is also a potent CYP2D6 inhibitor, which can affect the metabolism of other drugs.
• Paroxetine (Paxil): Primarily metabolized by CYP2D6. CPIC Level A guideline. Poor metabolizers may have higher exposure. Paroxetine also inhibits CYP2D6.
• Fluvoxamine (Luvox): CYP2D6 plays a role in metabolism. CPIC provides guidance. Fluvoxamine is also a potent inhibitor of CYP1A2 and CYP2C19.
• Sertraline (Zoloft): CYP2D6 is a secondary pathway; CYP2C19 is more clinically significant. CPIC guidelines for sertraline are based on CYP2C19 status.
• Escitalopram (Lexapro): CYP2D6 is a minor pathway; CYP2C19 is primary. CPIC guidelines for escitalopram are based on CYP2C19 status.

SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

• Venlafaxine (Effexor): Metabolized by CYP2D6 to its active metabolite O-desmethylvenlafaxine (desvenlafaxine). CYP2D6 poor metabolizers have higher venlafaxine levels but also have compensatory desvenlafaxine levels. CPIC provides guidance.
• Duloxetine (Cymbalta): Metabolized partially by CYP2D6 and CYP1A2. CYP2D6 status may affect drug levels. No CPIC guideline currently published for this specific pair.

Tricyclic Antidepressants (TCAs)

Tricyclic antidepressants have some of the strongest pharmacogenomic evidence for CYP2D6. CPIC has published Level A guidelines for several TCAs covering both CYP2D6 and CYP2C19.

• Nortriptyline (Pamelor): Primarily metabolized by CYP2D6. CPIC Level A guideline provides specific dose adjustments for poor and ultrarapid metabolizers.
• Amitriptyline (Elavil): Metabolized by both CYP2D6 and CYP2C19. CPIC Level A guideline. Dose adjustments recommended for poor metabolizers of either gene.
• Desipramine (Norpramin): Metabolized by CYP2D6. CPIC provides dosing recommendations based on CYP2D6 phenotype.
• Imipramine (Tofranil): Metabolized by both CYP2D6 and CYP2C19. CPIC provides combined genotype-guided dosing.
• Clomipramine (Anafranil): Metabolized by CYP2D6 and CYP2C19. CPIC provides guidance for both genes.

Other Psychiatric Medications Affected by CYP2D6

• Atomoxetine (Strattera): ADHD medication primarily metabolized by CYP2D6. CPIC Level A guideline. Poor metabolizers have significantly higher atomoxetine exposure, and dose adjustments are recommended.
• Aripiprazole (Abilify): Atypical antipsychotic metabolized by CYP2D6 and CYP3A4. CYP2D6 poor metabolizers may have higher aripiprazole levels. FDA labeling includes pharmacogenomic information.
• Haloperidol: Typical antipsychotic metabolized by CYP2D6. CYP2D6 status affects plasma levels and may influence side-effect risk.
• Risperidone: Atypical antipsychotic metabolized by CYP2D6 to its active metabolite 9-hydroxyrisperidone. CYP2D6 poor metabolizers have altered risperidone/metabolite ratios.
• Vortioxetine (Trintellix): Antidepressant metabolized by several CYP enzymes including CYP2D6. FDA labeling recommends dose adjustments for CYP2D6 poor metabolizers.

Understanding CYP2D6 Relevance by Medication

Not all medications on this list are equally affected by CYP2D6 variants. For some drugs (nortriptyline, atomoxetine, paroxetine), CYP2D6 is the primary metabolic pathway and variant effects are substantial. For others (sertraline, escitalopram), CYP2D6 plays a secondary role and CYP2C19 metabolism is more clinically important.

CPIC guidelines account for this by assigning evidence levels and providing gene-specific recommendations. A CYP2D6 poor metabolizer result does not have the same clinical implications for every drug on this list. Your Psychiatric Medication Report maps your specific genotype to each relevant medication with the appropriate CPIC context.

What Your Metabolizer Status Means

• Ultrarapid Metabolizer: You may clear CYP2D6 substrates faster than normal. For prodrugs, this can mean faster activation. For active drugs, it can mean lower plasma levels and potentially reduced effectiveness.
• Normal Metabolizer: Standard enzyme activity. Standard dosing guidelines typically apply.
• Intermediate Metabolizer: Reduced enzyme activity. Some medications may accumulate at higher levels than in normal metabolizers. Dose adjustments may be warranted for specific drugs.
• Poor Metabolizer: Severely reduced or absent CYP2D6 activity. Medications primarily cleared by CYP2D6 can accumulate significantly, increasing side-effect risk. CPIC guidelines recommend dose reductions or alternative drugs for several medications.

Using Consumer DNA Data

Consumer genotyping arrays from 23andMe and AncestryDNA include many CYP2D6 variants that define common star alleles (*4, *10, *41, and others). However, consumer arrays cannot reliably detect gene deletions (*5) or duplications, which are important for poor and ultrarapid metabolizer classification. See our limitations page for details.

DecodeMyBio's Psychiatric Medication Report extracts CYP2D6 and CYP2C19 variants from your raw data, assigns your diplotype and phenotype, and maps the results to CPIC guidelines for each psychiatric medication. Learn what to do with your 23andMe raw data or how to upload your data.