Amitriptyline Pharmacogenetics - Genetic Drug Testing Gene2Rx

Drug Overview

Amitriptyline (brand name Elavil) is a tricyclic antidepressant first approved in the 1960s. It is widely used for the treatment of major depressive disorder. Off-label, it may be prescribed for neuropathic pain, migraine prophylaxis, and chronic tension headaches.

The drug is indicated primarily for depression, where it helps restore the balance of neurotransmitters in the brain. Clinicians may also use low doses to relieve nerve pain or as a preventative treatment for migraines.

Amitriptyline works by inhibiting the reuptake of serotonin and norepinephrine at nerve terminals, increasing their availability in the synaptic cleft. This modulation of neurotransmitter levels helps improve mood and pain signals over time.

Relevant Genes and Their Roles

Two liver enzymes, CYP2D6 and CYP2C19, play a central role in processing amitriptyline. CYP2D6 primarily converts tertiary amines into less active compounds, while CYP2C19 also contributes to this metabolism and to conversion of tertiary amines into secondary amines.

Variations in these genes can change how quickly the body breaks down amitriptyline. A "metabolizer" status—from poor to ultrarapid—describes how active the enzyme is. Poor metabolizers break down the drug slowly, raising blood levels, while ultrarapid metabolizers clear it quickly, potentially reducing efficacy.

Impact of Genetics on Drug Response

Genetic variations in CYP2D6 and CYP2C19 group patients into different metabolizer phenotypes. These categories influence plasma drug concentrations, risk of side effects, and likelihood of therapeutic success. Adjusting dose or choosing an alternative therapy can help tailor treatment.

Expected Clinical Effects of Genetic Variation

Individuals fall into one of several metabolizer categories based on their CYP2D6 and CYP2C19 genotypes. These categories predict amitriptyline exposure and associated benefits or risks.

Ultrarapid/Rapid Metabolizer

Effect on drug levels: Lower than expected plasma concentrations
Clinical consequence: Increased risk of treatment failure or sub-optimal response
Side effects: Generally fewer side effects; efficacy may be reduced

Normal Metabolizer

Effect on drug levels: Expected therapeutic range
Clinical consequence: Typical efficacy and tolerability
Side effects: As described in the drug label; moderate frequency

Intermediate Metabolizer

Effect on drug levels: Moderately increased plasma concentrations
Clinical consequence: Higher likelihood of dose-related side effects
Side effects: Increased risk of anticholinergic effects (dry mouth, sedation)

Poor Metabolizer

Effect on drug levels: Significantly elevated plasma concentrations
Clinical consequence: Higher risk of toxicity and anticholinergic side effects
Side effects: Severe sedation, confusion, cardiac conduction changes

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 available guidelines for amitriptyline from the Clinical Pharmacogenetics Implementation Consortium (CPIC).

CYP2D6 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Lower plasma concentrations; risk of therapeutic failure	Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, titrate to a higher target dose and utilize therapeutic drug monitoring.
Normal Metabolizer	Expected metabolism and exposure	Initiate therapy with recommended starting dose.
Intermediate Metabolizer	Moderately increased exposure; higher side-effect risk	Consider 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring.
Poor Metabolizer	Significantly increased exposure; high side-effect risk	Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider 50% dose reduction and utilize therapeutic drug monitoring.
Indeterminate	Unknown impact	Initiate therapy with recommended starting dose.
Not available	Unknown impact	Initiate therapy with recommended starting dose.

CYP2C19 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Increased conversion of tertiary to secondary amines; potential sub-optimal response	Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19 (e.g., nortriptyline, desipramine). If a tertiary amine is warranted, utilize therapeutic drug monitoring.
Rapid Metabolizer	Increased conversion; potential sub-optimal response	Avoid tertiary amine use; consider alternatives not metabolized by CYP2C19. Utilize therapeutic drug monitoring if needed.
Normal Metabolizer	Expected metabolism and exposure	Initiate therapy with recommended starting dose.
Intermediate Metabolizer	Reduced metabolism; slightly higher exposure	Initiate therapy with recommended starting dose.
Poor Metabolizer	Greatly reduced conversion; potential for increased side effects	Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. For tertiary amines, consider 50% dose reduction and utilize therapeutic drug monitoring.
Likely Intermediate Metabolizer	Reduced metabolism; slightly higher exposure	Initiate therapy with recommended starting dose.
Likely Poor Metabolizer	Greatly reduced conversion; potential for increased side effects	Avoid tertiary amine use; consider alternative drug not metabolized by CYP2C19. For tertiary amines, consider 50% dose reduction and utilize therapeutic drug monitoring.
Indeterminate	Unknown impact	Initiate therapy with recommended starting dose.
Not available	Unknown impact	Initiate therapy with recommended starting dose.

Alternative Treatment Options

Examples of alternative therapies include secondary amine tricyclics such as nortriptyline and desipramine, which are less dependent on CYP2C19 metabolism. Other options may include non-TCA antidepressants (e.g., SSRIs) not significantly metabolized by CYP2D6 or CYP2C19. These are provided as examples; clinical decisions should be individualized.

Sources and References

CPIC – Guideline for tricyclic antidepressants and CYP2D6 and CYP2C19