TABLE 4.

DOSING RECOMMENDATIONS FOR AMITRIPTYLINE BASED ON BOTH CYP2D6 AND CYP2C19 PHENOTYPES^a,^b

Phenotype	CYP2D6 Ultrarapid metabolizer	CYP2D6 Normal metabolizer	CYP2D6 Intermediate metabolizer	CYP2D6 Poor metabolizer
CYP2C19 Ultrarapid or Rapid metabolizer	Avoid amitriptyline usec Classification of recommendationd: Optional	Consider alternative drug not metabolized by CYP2C19c,e Classification of recommendationd: Optional	Consider alternative drug not metabolized by CYP2C19 c,e Classification of recommendationd: Optional	Avoid amitriptyline usec Classification of recommendationd: Optional
CYP2C19 Normal metabolizer	Avoid amitriptyline use. If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers)f,g Classification of recommendationd: Strong	Initiate therapy with recommended starting doseh Classification of recommendationd: Strong	Consider a 25% reduction of recommended starting dosef,h Classification of recommendationd: Moderate	Avoid amitriptyline use. If amitriptyline is warranted, consider a 50% reduction of recommended starting dosef,h Classification of recommendationd: Strong
CYP2C19 Intermediate metabolizer	Avoid amitriptyline usec Classification of recommendationd: Optional	Initiate therapy with recommended starting doseh Classification of recommendationd: Strong	Consider a 25% reduction of recommended starting dosef,h Classification of recommendationd: Optional	Avoid amitriptyline use. If amitriptyline is warranted, consider a 50% reduction of recommended starting dosef,h Classification of recommendationd: Optional
CYP2C19 Poor metabolizer	Avoid amitriptyline usec Classification of recommendationd: Optional	Avoid amitriptyline use. If amitriptyline is warranted, consider a 50% reduction of recommended starting dosef,h Classification of recommendationd: Moderate	Avoid amitriptyline usec Classification of recommendationd: Optional	Avoid amitriptyline usec Classification of recommendationd: Optional

^aDosing 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.

^bThe 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).

^cIf amitriptyline is warranted, utilize therapeutic drug monitoring^f to guide dose adjustment.

^dThe rating scheme for the recommendation classification is described in Supplementary Data. See CYP2D6 and CYP2C19 combined dosing recommendations for explanation of classification of recommendations for this table.

^eTCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine.

^fUtilizing 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.

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

^hPatients 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.