Doxepin Pharmacogenetics - Genetic Drug Testing Gene2Rx

Drug Overview

Doxepin is a tricyclic antidepressant marketed under brand names such as Sinequan, Quitaxon, and Aponal. It is approved for the treatment of depressive disorders, anxiety, and insomnia.

It works by blocking the reuptake of neurotransmitters serotonin and norepinephrine in the brain, increasing their availability in neuronal synapses. Doxepin also has strong antihistamine activity, which contributes to its sedative effects and makes it useful for treating insomnia at lower doses.

Relevant Genes and Their Roles

This guideline focuses on the genes CYP2D6 and CYP2C19. Both genes encode liver enzymes that metabolize doxepin through chemical modifications (phase I metabolism). CYP2D6 performs N-demethylation of tertiary amine TCAs like doxepin, while CYP2C19 contributes to hydroxylation and additional oxidative pathways.

Genetic variations in these enzymes can alter how quickly or slowly a patient processes doxepin. “Metabolizer” categories (ultrarapid, normal, intermediate, poor) describe enzyme activity levels relative to the average population, affecting drug clearance and blood concentrations.

Impact of Genetics on Drug Response

Patients with ultrarapid or rapid metabolizer phenotypes clear doxepin more quickly, leading to lower blood levels and potential therapeutic failure. Poor and intermediate metabolizers process the drug more slowly, resulting in higher plasma concentrations and an increased risk of side effects. Normal metabolizers are expected to have balanced drug levels and standard efficacy.

Expected Clinical Effects of Genetic Variation

Ultrarapid/Rapid Metabolizer

Effect on drug levels: Significantly lower plasma concentrations due to increased metabolism
Clinical consequence: Reduced efficacy and risk of therapeutic failure
Side effects: Fewer side effects; mild and infrequent

Normal Metabolizer

Effect on drug levels: Expected therapeutic plasma concentrations
Clinical consequence: Standard efficacy and response
Side effects: Typical profile (mild to moderate; common)

Intermediate Metabolizer

Effect on drug levels: Moderately elevated plasma concentrations
Clinical consequence: Increased risk of dose-related side effects
Side effects: Mild to moderate sedation, anticholinergic symptoms; common

Poor Metabolizer

Effect on drug levels: Markedly increased plasma concentrations
Clinical consequence: High risk of adverse effects and toxicity
Side effects: Pronounced sedation, dry mouth, constipation; moderate to severe; frequent

Indeterminate/Not Available

Effect: Unknown
Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring

Dosing Guidelines

The following dosing guidelines are based on the CPIC guideline for tricyclic antidepressants and CYP2D6/CYP2C19.

CYP2D6 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Increased metabolism leads to lower active drug levels and risk of therapeutic failure.	Avoid tricyclic use; consider alternative drug not metabolized by CYP2D6. If TCA is warranted, titrate to a higher target dose and use therapeutic drug monitoring.
Normal Metabolizer	Expected metabolism and standard plasma concentrations.	Initiate therapy with recommended starting dose.
Intermediate Metabolizer	Reduced metabolism leads to higher active drug levels and increased side effect risk.	Consider 25% reduction of starting dose; utilize therapeutic drug monitoring to guide adjustments.
Poor Metabolizer	Greatly reduced metabolism causes high plasma concentrations and toxicity risk.	Avoid tricyclic use; consider alternative drug not metabolized by CYP2D6. If TCA is warranted, consider 50% reduction of starting dose and use therapeutic drug monitoring.
Indeterminate/Not available	Unknown impact	Initiate standard starting dose.

CYP2C19 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Increased conversion of tertiary amines may reduce efficacy.	Avoid tertiary amine use; consider alternative drug not metabolized by CYP2C19 (e.g., nortriptyline, desipramine). If tertiary amine is warranted, use therapeutic drug monitoring.
Rapid Metabolizer	Increased conversion of tertiary amines may reduce efficacy.	Avoid tertiary amine use; consider alternative drug not metabolized by CYP2C19 (e.g., nortriptyline, desipramine). If tertiary amine is warranted, use therapeutic drug monitoring.
Normal Metabolizer	Normal metabolism and expected response.	Initiate therapy with recommended starting dose.
Intermediate Metabolizer	Reduced metabolism; potential for slightly higher levels.	Initiate therapy with recommended starting dose.
Poor Metabolizer	Greatly reduced metabolism may lead to altered response or side effects.	Avoid tertiary amine use; consider alternative drug not metabolized by CYP2C19 (e.g., nortriptyline, desipramine). For tertiary amines, consider 50% reduction of starting dose and use therapeutic drug monitoring.
Likely Intermediate Metabolizer	Reduced metabolism; similar to intermediate metabolizer.	Initiate therapy with recommended starting dose.
Likely Poor Metabolizer	Greatly reduced metabolism; similar to poor metabolizer.	Avoid tertiary amine use; consider alternative drug not metabolized by CYP2C19. For tertiary amines, consider 50% reduction of starting dose and use therapeutic drug monitoring.
Indeterminate/Not available	Unknown impact	Initiate standard starting dose.

Alternative Treatment Options

Examples from guidelines include using antidepressants not primarily metabolized by CYP2D6 (for CYP2D6 ultrarapid or poor metabolizers) or choosing secondary amine TCAs such as nortriptyline or desipramine (for CYP2C19 ultrarapid, rapid, or poor metabolizers). These are provided as illustrative options and not individual medical advice.

Sources and References

CPIC – Guideline for Tricyclic Antidepressants and CYP2D6/CYP2C19