Amitriptyline Therapy and and Genotype

Amitriptyline is a tricyclic antidepressant used in the treatment of several psychiatric disorders, including major depression, obsessive-compulsive disorder, panic attacks, generalized anxiety disorder, post-traumatic stress disorder, and bulimia. Amitriptyline also has different off-label uses, including migraine prevention, neuropathic pain management, fibromyalgia, and enuresis (bedwetting) (1). Tricyclic antidepressants (TCAs) primarily mediate their therapeutic effect by inhibiting the reuptake of both serotonin and norepinephrine, leaving more neurotransmitter in the synaptic cleft stimulating the neuron. Given that the tricyclics can also block different receptors (H1 histamine, α1-adrenergic, and muscarinic receptors), side effects are common. As such, selective serotonin reuptake inhibitors (SSRIs) have largely replaced the use of TCAs; however, TCAs still have an important use in specific types of depression and other conditions. Amitriptyline is metabolized mainly via CYP2C19 and CYP2D6 pathways. Metabolism by CYP2C19 results in active metabolites, including nortriptyline, which is also a tricyclic antidepressant. Metabolism catalyzed by CYP2D6 results in the formation of the less active 10-hydroxy metabolite. Both the and genes are highly polymorphic, resulting in proteins with different enzyme activity or expression levels. Individuals who are CYP2D6 “ultrarapid metabolizers” (UM) have more than 2 normal function alleles (multiple copies), whereas CYP2C19 UM have 2 increased function alleles. Individuals who are CYP2D6 or CYP2C19 “poor metabolizers” (PM) have 2 no function alleles for or . The FDA-approved drug label for amitriptyline states that CYP2D6 PM have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. The FDA recommendations also include monitoring tricyclic antidepressant plasma levels whenever a tricyclic antidepressant is co-administered with another drug known to be an inhibitor of CYP2D6 (Table 1) (1). The Dutch Pharmacogenetic Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) have issued recommendations for altered dosing based on CYP2D6 metabolizer phenotype (Table 2) (2, 3). Individuals who are CYP2D6 UM may require up to 1.6 times the normal dose, though cardiac toxicity risk may indicate use of an antidepressant that is less dependent upon CYP2D6 metabolism, such as citalopram or sertraline. Dose reductions are recommended for CYP2D6 intermediate metabolizer (IM) individuals (75% of normal dose) and CYP2D6 PM individuals (60% of normal dose), along with monitoring for side effects and plasma drug levels. (3). The DPWG does not recommend any changes in dosing based on CYP2C19 metabolizer status, since the combined dose of amitriptyline and the active metabolite nortriptyline are not significantly impacted. (2) In 2016, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published dosing recommendations for tricyclic antidepressants based on CYP2C19 and CYP2D6 metabolizer status, either individually or in combination (Table 3, Table 4) (4). For CYP2D6 UM, CPIC recommends avoiding the use of a tricyclic due to the potential lack of efficacy, and to consider an alternative drug not metabolized by CYP2D6. If a TCA is still warranted, CPIC recommends considering titrating the TCA to a higher target dose (compared with CYP2D6 normal metabolizers, “NM”) and using therapeutic drug monitoring to guide dose adjustments. For CYP2D6 IM, CPIC recommends considering a 25% reduction of the starting dose, and for CYP2D6 PM, to avoid the use of tricyclics because of the potential for side effects. If a tricyclic is still warranted for CYP2D6 PM, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects. For CYP2C19 UM, CPIC recommends avoiding the use of tertiary amines (for example, amitriptyline) due to the potential for a sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19, such as the secondary amines nortriptyline or desipramine. For CYP2C19 PMs, CPIC recommends avoiding tertiary amine use due to the potential for sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19. If a tertiary amine is still warranted for CYP2C19 PMs, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects (4). For gene-based dosing of TCAs for neuropathic pain, where the initial doses are lower, CPIC does not recommend dose modifications for PMs or IMs (either CYP2D6 or CYP2C19). For CYP2D6 UM individuals, CPIC optionally recommends considering an alternative medication due to a higher risk of therapeutic failure of TCAs for neuropathic pain (4).