Annotation of Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline information
for amitriptyline and CYP2C19, CYP2D6

last updated 03/15/2017

Summary

The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

Annotation

December 2016 Update

Advance online publication December 2016.

Table 1: Dosing recommendations for amitriptyline based on CYP2D6 phenotype:

Adapted from Tables 1 and 2 of the 2016 guideline update.

Likely phenotypeActivity scoreGenotypesExamples of diplotypesImplicationsTherapeutic Recommendationsa, bClassification of recommendation for amitriptyline and nortriptylinec
CYP2D6 Ultrarapid metabolizer (~1-20% of patients)d>2.0An individual carrying more than two copies of functional alleles*1/*1xN, *1/*2xNIncreased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure.Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6.
If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments.e
Strong
CYP2D6 Normal metabolizer (~72-88% of patients)d1.0-2.0fAn individual carrying two normal function alleles or two decreased function alleles or one normal and no function allele or one normal and decreased function allele or combinations of duplicated alleles that result in an activity score of 1.0-2.0*1/*1, *1/*2, *2/*2, *1/*9, *1/*41, *41/*41, *1/*4, *1/*5Normal metabolism of TCAs.Initiate therapy with recommended starting dose.gStrong
CYP2D6 Intermediate metabolizer (~1-13% of patients)d0.5An individual carrying one decreased and one no function allele*4/*41, *5/*9, *4/*10Reduced metabolism of TCAs to less active compounds when compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.Consider 25% reduction of recommended starting dose.g Utilize therapeutic drug monitoring to guide dose adjustments.eModerate
CYP2D6 Poor metabolizer (~1-10% of patients)d0An individual carrying only no function alleles*4/*4, *4/*4xN, *3/*4, *5/*5, *5/*6Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6.
If a TCA is warranted, consider 50% reduction of recommended starting dose.g Utilize therapeutic drug monitoring to guide dose adjustments.e
Strong

a For tertiary amines (e.g., amitriptyline), if CYP2C19 genotype results are also available, see Table 2 for CYP2C19-based dosing recommendations and Table 3 below for CYP2D6/CYP2C19-based dosing recommendations.

b Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations in the guideline for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

c The rating scheme for the recommendation of classification is described in the Supplement.

d CYP2D6 and CYP2C19 metabolizer status frequencies are based on average multi-ethnic frequencies. See the CYP2C19 and CYP2D6 Frequency Tables for population-specific allele and phenotype frequencies.

e Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

f Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.

g Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

Table 2: Dosing recommendations for amitriptyline based on CYP2C19 phenotype:

Adapted from Tables 1 and 3 of the 2016 guideline update.

Likely phenotypeGenotypesExamples of diplotypesImplicationsTherapeutic recommendationsa,bClassification of recommendations for amitriptylinec
CYP2C19 Ultrarapid metabolizer (~2-5% of patients)dAn individual carrying two increased function alleles*17/*17Increased metabolism of tertiary amines compared to normal metabolizers. Greater conversion of tertiary amines to secondary amines may affect response or side effects.Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine.
If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.e
Optional
CYP2C19 Rapid metabolizer (~2-30% of patients)dAn individual carrying one normal and one increased function allele*1/*17Increased metabolism of tertiary amines compared to normal metabolizers. Greater conversion of tertiary amines to secondary amines may affect response or side effects.Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine.
If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.e
Optional
CYP2C19 Normal metabolizer (~35-50% of patients)dAn individual carrying two normal function alleles*1/*1Normal metabolism of tertiary amines.Initiate therapy with recommended starting dose.fStrong
CYP2C19 Intermediate metabolizer (~18-45% of patients)dAn individual carrying one normal and one no function allele or one no and one increased function allele*1/*2, *1/*3, *2/*17gReduced metabolism of tertiary amines compared to normal metabolizers.Initiate therapy with recommended starting dose.fStrong
CYP2C19 Poor metabolizer (~2-15% of patients)dAn individual carrying two no function alleles*2/*2, *2/*3, *3/*3Greatly reduced metabolism of tertiary amines compared to normal metabolizers. Decreased conversion of tertiary amines to secondary amines may affect response or side effects.Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine.
For tertiary amines, consider a 50% reduction of the recommended starting dose.f Utilize therapeutic drug monitoring to guide dose adjustments.e
Moderate

a For tertiary amines (e.g., amitriptyline), if CYP2D6 genotype results are also available, see Table 1 for CYP2D6-based dosing recommendations above and Table 3 below for CYP2D6/CYP2C19-based dosing recommendations.

b Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations in the guideline for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

c The rating scheme for the recommendation of classification is described in the Supplement.

d CYP2D6 and CYP2C19 metabolizer status frequencies are based on average multi-ethnic frequencies. See the CYP2C19 and CYP2D6 Frequency Tables for population-specific allele and phenotype frequencies.

e Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

f Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

g The predicted metabolizer phenotype for the*2/*17 genotype is a provisional classification. The currently available evidence indicates that the CYP2C19*17 increased function allele is unable to completely compensate for the CYP2C19*2 no function allele.

Table 3: Dosing recommendations for amitriptyline based on both CYP2D6 and CYP2C19 phenotype:

Adapted from Table 4 of the 2016 guideline update. a,b

PhenotypeCYP2D6 Ultrarapid metabolizerCYP2D6 Normal metabolizerCYP2D6 Intermediate metabolizerCYP2D6 Poor metabolizer
CYP2C19 Ultrarapid or Rapid metabolizerAvoid amitriptyline use.c Classification of recommendationd: OptionalConsider alternative drug not metabolized by CYP2C19.c, e Classification of recommendationd: OptionalConsider alternative drug not metabolized by CYP2C19.c, e Classification of recommendationd: OptionalAvoid amitriptyline use.c Classification of recommendationd: Optional
CYP2C19 Normal metabolizerAvoid amitriptyline use. If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers).f, g Classification of recommendationd: StrongInitiate therapy with recommended starting dose. h Classification of recommendationd: StrongConsider 25% reduction of recommended starting dose. f, h Classification of recommendationd: ModerateAvoid amitriptyline use. If amitriptyline is warranted, consider 50% reduction of recommended starting dose. f, h Classification of recommendationd: Strong
CYP2C19 Intermediate metabolizerAvoid amitriptyline use.c Classification of recommendationd: OptionalInitiate therapy with recommended starting dose. h Classification of recommendationd: StrongConsider 25% reduction of recommended starting dose. f, h Classification of recommendationd: OptionalAvoid amitriptyline use. If amitriptyline is warranted, consider 50% reduction of recommended starting dose.f, h Classification of recommendationd: Optional
CYP2C19 Poor metabolizerAvoid amitriptyline use.c Classification of recommendationd: OptionalAvoid amitriptyline use.c If amitriptyline is warranted, consider a 50% reduction of recommended starting dose. f, h Classification of recommendationd: ModerateAvoid amitriptyline use.c Classification of recommendationd: OptionalAvoid amitriptyline use.c Classification of recommendationd: Optional

a Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

b The dosing recommendations are based on studies focusing on amitriptyline. Because tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply these guidelines to other tertiary amines including clomipramine, doxepin, imipramine and trimipramine (the classification of this recommendation is optional).

c If amitriptyline is warranted, utilize therapeutic drug monitoringf to guide dose adjustment.

d The rating scheme for the recommendation classification is described in the Supplement.

e TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine.

f Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

g Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

h Patients may receive an initial low dose of TCAs, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

May 2013

Advance online publication January 2013.

CPIC TCAs guideline

Total publications: 2

Reference
1. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC®) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update. Clinical pharmacology and therapeutics. 2016. Kevin Hicks J, Sangkuhl Katrin, Swen Jesse J, Ellingrod Vicki L, Müller Daniel J, Shimoda Kazutaka, Bishop Jeffrey R, Kharasch Evan D, Skaar Todd C, Gaedigk Andrea, Dunnenberger Henry M, Klein Teri E, Caudle Kelly E, Stingl Julia C. PubMed
2. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants. Clinical pharmacology and therapeutics. 2013. Hicks J K, Swen J J, Thorn C F, Sangkuhl K, Kharasch E D, Ellingrod V L, Skaar T C, Müller D J, Gaedigk A, Stingl J C. PubMed

Guideline History