Introduction
Imipramine is a tricyclic antidepressant (TCA) used in the treatment of several psychiatric disorders, including major depression, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bulimia. Imipramine may also be useful as an adjunctive treatment for managing panic attacks, neuropathic pain, attention-deficit disorder, and childhood enuresis (bedwetting) (1).
Tricyclic antidepressants primarily mediate their therapeutic effect by inhibiting the reuptake of both serotonin and norepinephrine, increasing the concentration of these neurotransmitters in the synaptic cleft stimulating the neuron. Because tricyclics can also block different receptors (histamine H1, α1-adrenergic, and muscarinic receptors), side effects are common. Consequently, more selective serotonin reuptake inhibitors have largely replaced TCAs. However, TCAs still have an important role in treating specific types of depression and other conditions.
Imipramine is primarily metabolized via CYP2C19 to active metabolites, including desipramine, another TCA. Further metabolism is catalyzed by CYP2D6 to create inactive metabolites. Individuals who are “CYP2D6 ultrarapid metabolizers” (CYP2D6 UM) have more than 2 normal-function alleles (multiple copies), whereas individuals who are “CYP2C19 ultrarapid metabolizers” (CYP2C19 UM) have 2 increased-function alleles. Individuals who are CYP2D6 or CYP2C19 “poor metabolizers” (PM) have 2 no-function alleles for CYP2D6 or CYP2C19. Individuals who are CYP2D6 or CYP2C19 “intermediate metabolizers” (IM) have one no-function allele. Individuals with one normal-function and one increased-function allele for CYP2C19 are classified as “rapid metabolizers” (CYP2C19 RM).
The FDA-approved drug label for imipramine states that CYP2D6 PMs have higher-than-expected plasma concentrations of TCAs when given usual doses. The FDA recommendations include monitoring TCA plasma levels whenever a TCA is co-administered with another drug known to inhibit CYP2D6 (Table 1) (1).
The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Pharmacists Association has also issued dose-adjustment recommendations based on CYP2C19 and CYP2D6, as well (Table 2) (2). Individuals who are CYP2D6 IM should take 70% of the standard dose and be monitored for side effects and appropriate plasma levels of imipramine and desipramine. A genotype associated with CYP2D6 PM status warrants a decrease to 30% of the standard dose, with similar monitoring for adverse effects and plasma concentration to optimize dosing. The DPWG recommends a dose increase for CYP2D6 UM individuals, up to 1.7 times the standard dose if the potentially cardiotoxic hydroxy metabolites can be tolerated; otherwise, imipramine should be avoided. For CYP2C19 PMs, DPWG recommends taking 70% of the standard dose, along with close monitoring for side effects or plasma levels of imipramine and desipramine to determine an appropriate maintenance dose; alternatively, avoidance of imipramine is recommended (2). No dosing changes are recommended for CYP2C19 UM or IM individuals. When monitoring plasma levels of the active drug and metabolites, the combined levels of imipramine and desipramine should remain within 150–300 ng/mL; levels above 500 ng/mL are considered toxic (2).
In 2016, the Clinical Pharmacogenetics Implementation Consortium (CPIC) provided dosing recommendations for TCAs based on CYP2C19 and CYP2D6 genotype, either alone (Table 3) or in combination (Table 4). Amitriptyline and nortriptyline were used as model drugs for the guideline because most pharmacogenomic studies have focused on these 2 drugs. According to the CPIC guideline, because TCAs have comparable pharmacokinetic properties, the recommendations may be reasonably applied to other tricyclics, including imipramine (3).
For CYP2D6 UMs, CPIC recommends avoiding the use of a tricyclic due to the potential lack of efficacy and suggests considering an alternative drug not metabolized by CYP2D6. If a TCA is still warranted, CPIC recommends titrating the TCA to a higher target dose (compared to normal metabolizers [NM]) and using therapeutic drug monitoring (TDM) to guide dose adjustments. For CYP2D6 IMs, CPIC recommends a 25% reduction of the starting dose, while for CYP2D6 PMs, advises avoiding tricyclics due to the potential for side effects. If a TCA is still warranted for CYP2D6 PMs, CPIC recommends a 50% reduction in the starting dose with drug plasma concentration monitoring to avoid side effects. 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 (3).
For CYP2C19 UMs, CPIC recommends avoiding tertiary amines (for example, imipramine) due to the potential for a sub-optimal response and suggests considering an alternative drug not metabolized by CYP2C19, such as the secondary amines nortriptyline or desipramine. For CYP2C19 PMs, CPIC similarly recommends avoiding tertiary amines 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 a 50% reduction of the starting dose while monitoring drug plasma concentrations to minimize side effects (3).
Table 1:
CYP2D6 Status and Imipramine Therapy Management, FDA 2023
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| CYP2D6 status | Clinical impact | Recommended action |
|---|
| Genetic PM | Higher-than-expected plasma concentration of TCAs at usual doses | (none) |
| Reduced activity due to drug-drug interaction | Clinically similar to genetic PMs | Monitor plasma levels when co-administered with a known CYP2D6 inhibitor; adjustment of dosage may be needed. |
PM: poor metabolizer; TCA: Tricyclic antidepressant
Table 4:
Dosing Recommendations for TCA with both CYP2D6 and CYP2C19 Phenotypes (CPIC, 2016)
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| Phenotype | CYP2D6 UM | CYP2D6 NM | CYP2D6 IM | CYP2D6 PM |
|---|
|
CYP2C19 UM or RM
| Avoid imipramine1 use | Consider alternative drug not metabolized by CYP2C19 | Consider alternative drug not metabolized by CYP2C19 | Avoid imipramine1 use |
|
CYP2C19 NM
| Avoid imipramine1 use. If imipramine1 is warranted, consider titrating to a higher target dose (compared to NM) | Initiate therapy with recommended starting dose | Consider a 25% reduction of recommended starting dose | Avoid imipramine1 use. If imipramine1 is warranted, consider a 50% reduction of recommended starting dose |
|
CYP2C19 IM
| Avoid imipramine1 use | Initiate therapy with recommended starting dose | Consider a 25% reduction of recommended starting dose | Avoid imipramine1 use. If imipramine1 is warranted, consider a 50% reduction of recommended starting dose |
|
CYP2C19 PM
| Avoid imipramine1 use | Avoid imipramine1 use. If imipramine1 is warranted, consider a 50% reduction of recommended starting dose | Avoid imipramine1 use | Avoid imipramine1 use |
- 1
Original table from CPIC written for amitriptyline dosing, however CPIC states that “Because tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply these guidelines to other tertiary amines including …imipramine… (the classification of this recommendation is optional).” (3)
UM: Ultrarapid metabolizer; NM: normal metabolizer; IM: Intermediate metabolizer; PM: Poor metabolizer; TCA: tricyclic antidepressant; CPIC: Clinical Pharmacogenetics Implementation Consortium
Drug Class: Tricyclic Antidepressants
Tricyclic antidepressants (TCAs) are mixed serotonin-norepinephrine reuptake inhibitors that increase the amount of neurotransmitter in the synaptic cleft, a mechanism thought to mediate their antidepressant effects.
From the 1960s to the 1980s, tricyclics were the first-line treatment for depression, until the introduction of SSRIs, which have fewer side effects and are safer. The common side effects of tricyclics include anticholinergic effects (for example, blurred vision, dry mouth, constipation, and sedation), cardiac effects, and orthostatic hypotension.
Today, the main therapeutic use of tricyclics is chronic pain management, such as neuropathic pain. However, tricyclics are still used to treat depression as well as other psychiatric disorders, including obsessive-compulsive disorder, panic attacks, generalized anxiety disorder, post-traumatic stress disorder, bulimia nervosa, smoking cessation, and enuresis (bedwetting).
Tricyclics are named after their chemical structure of 3 central rings and a side chain critical for their function and activity. This structure determines whether a drug is classified a tertiary amine (amitriptyline, clomipramine, doxepin, imipramine, and trimipramine) or secondary amine (desipramine and nortriptyline).
Tertiary amines are generally more potent at blocking serotonin reuptake, whereas secondary amines are more potent at blocking norepinephrine reuptake. Secondary amines are better tolerated and associated with fewer anticholinergic side effects.
The CYP2C19 enzyme metabolizes tertiary amines into the active secondary amines, such as desipramine (the active metabolite of imipramine) and nortriptyline (the active metabolite of amitriptyline). Both tertiary and secondary amines are metabolized by CYP2D6 into less active metabolites.
The effectiveness and tolerability of tricyclics are affected by CYP2D6 metabolism and partially by CYP2C19 metabolism. Individuals with CYP2D6 or CYP2C19 variants that affect enzyme activity may be at an increased risk of treatment failure (if plasma drug levels are decreased) or drug toxicity (if plasma drug levels are increased).
Drug: Imipramine
Imipramine was the first tricyclic used to treat depression in the late 1950s. Imipramine is still used to relieve the symptoms of major depressive disorder and it may also serve as temporary adjunctive therapy for reducing enuresis (bedwetting) in children aged 6 years and older. Off-label uses of imipramine also include the treatment of neuropathic pain and attention-deficit disorder.
Imipramine is a tertiary amine and is similar in structure to amitriptyline, another tertiary amine. Both drugs potently block the reuptake of serotonin and, to a lesser extent, norepinephrine. Imipramine also has strong affinities for alpha-1 adrenergic, histamine H1, and muscarinic M1 receptors, which account for its side effects of orthostatic hypotension, sedation, weight gain, and anticholinergic effects. However, these side effects are generally less intense than those associated with amitriptyline (4). Anticholinergic effects include peripheral nervous system symptoms such as tachycardia, urinary retention, constipation, dry mouth, and blurred vision, as well as central nervous system anticholinergic effects such as cognitive impairment, psychomotor slowing, confusion, sedation, and delirium (5).
Imipramine is metabolized by CYP2C19 to desipramine, which is also a TCA with distinct clinical features that differ from the imipramine. Both imipramine and desipramine are metabolized by CYP2D6 into the less active hydroxy-desipramine and hydroxy-imipramine. For TDM, the levels of both imipramine and desipramine should be monitored (6).
The optimal therapeutic range for imipramine is well defined (7). Most individuals achieve an optimal response to imipramine when combined serum levels of imipramine and desipramine are between 150 and 300 ng/mL (8). A minimum plasma level of 200 ng/mL for the combined levels of imipramine and desipramine is recommended for unipolar major depression (4). However, individuals with certain variants in CYP2D6 or CYP2C19 (or both) may have drug levels outside this range when treated with standard doses of imipramine, increasing the risk of side effects (if the level of imipramine and its active metabolite are too high) or treatment failure (if drug levels are too low).
There are no well-controlled studies of imipramine use in pregnant women, and animal reproduction studies have yielded inconclusive results. Clinical reports have associated imipramine use with congenital malformations in humans, but no causal relationship has been established. The FDA-approved drug label recommends that imipramine should only be used during pregnancy if the clinical condition clearly justifies the potential risk to the fetus (1). The Health Canada-approved label states that TCA exposure during mid to late pregnancy may increase the risk of preeclampsia (5). Like the FDA, Health Canada states that imipramine is not recommended during pregnancy unless clearly necessary and only after consideration of the risks and benefits (5). Both the FDA and Health Canada recommend avoiding imipramine during breastfeeding (1, 5). Other sources report that levels of imipramine and desipramine in maternal breastmilk were low and have not been detected in the serum of breastfed infants (9). Further, imipramine use during breastfeeding is not expected to cause adverse effects in breastfed infants, especially those over 2 months of age. However, other agents may be preferred if mother is nursing a preterm infant or newborn or if large doses are required (9).
The FDA has approved imipramine for short-term management of nocturnal enuresis in individuals 6 years of age or older (1). Health Canada has not approved imipramine for use in individuals under 18 years of age (5). While the FDA-approved label states that no additional adverse effects were observed in an elderly (age 65 and older) study cohort, no direct comparison was made to a younger study cohort (1). Both the FDA and Health Canada recommend cautious dose selection for elderly individuals, initiating treatment at low doses with careful observation (1, 5). The Canadian drug label states that geriatric individuals are particularly sensitive to anticholinergic effects, which may increase their risk for falls (5).
Gene: CYP2D6
The cytochrome P450 superfamily (CYP450) is a large and diverse group of enzymes that form the major system for metabolizing lipids, hormones, toxins, and drugs in the liver. The CYP450 genes are highly polymorphic and can result in decreased, absent, or increased enzyme activity. One prominent member, CYP2D6, is responsible for the metabolizing many commonly prescribed drugs, including antidepressants, antipsychotics, analgesics, and beta-blockers.
The CYP2D6 Alleles
The CYP2D6 gene is highly polymorphic, with over 170 star (*) alleles described and cataloged by the Pharmacogene Variation (PharmVar) Consortium. Each allele is associated with either normal, decreased, or absent enzyme function (Table 5) (10, 11). Star alleles are defined by the variants detected on one chromosome (haplotype).
The combination of CYP2D6 haplotypes that an individual has is used to determine their diplotype (for example, CYP2D6 *4/*4). Based on their impact on enzyme function, each allele is assigned an activity score from 0 to 1, which in turn is then used to assign a phenotype (for example, CYP2D6 PM). However, the activity score system is not standardized across all clinical laboratories or CYP2D6 genotyping platforms, leading to variability among results.
To promote harmonization, the CPIC and DPWG standardized their CYP2D6 genotype-to-phenotype methods in October 2019, creating a consensus activity scoring guideline. The CYP2D6 phenotype is predicted from the diplotype activity score, which is defined by the sum of the allele score values and typically ranges from 0–3.0: (12)
● An ultrarapid metabolizer (UM) has an activity score greater than 2.25
● A normal metabolizer phenotype (NM) has an activity score of 1.25–2.25
● An intermediate metabolizer (IM) has an activity score of >0–<1.25
● A poor metabolizer (PM) has an activity score of 0
Table 5.
Activity Status of Selected CYP2D6 Alleles
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| Allele type | CYP2D6 alleles | Activity score |
|---|
| Normal function |
*1, *2, *27, *33
| 1 |
| Decreased function |
*17, *41, *49
| 0.5 |
| Strongly decreased function |
*10
| 0.25 |
| No function |
*3, *4, *5, *6, *36
| 0 |
The CYP2D6*1 allele is the wild-type allele, detected when no variants are present, and is associated with normal enzyme activity and the NM phenotype. The CYP2D6*2, *27, and *33 alleles are also considered to have near-normal activity.
Other CYP2D6 alleles include variants that produce a non-functioning enzyme (for example, *3, *4, and *6) (14, 15, 16) or an enzyme with decreased activity (for example, *10, *17, and *41) (11, 17) (see Table 5). There are significant interethnic differences in the frequency of these alleles. For example, *3, *4, *6, and *41 are more common in individuals of European ancestry, *17 is more common in African ancestry, and *10 is more common in Asian ancestry. (18)
Larger structural variants at the CYP2D6 locus have also been described, including gene duplications, deletions, tandem alleles, gene hybrids (namely, CYP2D6-CYP2D7), and gene conversions. As expected, deletions result in a no-function allele (for example, the *5 allele is a deletion). Duplications have been reported for alleles with normal function and decreased function. In cases of allele duplications, the activity scores for the full complement of CYP2D6 alleles are summed to determine the predicted metabolizer phenotype. Additional details on structural variants are available from PharmVar (see the document Structural Variation for CYP2D6) (19).
The frequency of the CYP2D6 star (*) alleles with altered function varies across global populations, resulting in different frequencies of the resulting metabolizer phenotype. Given CYP2D6’s role in the metabolism of many drugs, the literature on allele and phenotype frequency is expansive. Most populations have a high frequency of normal-function star alleles, leading to a high proportion of the NM individuals. However, reduced-function alleles like CYP2D6*10 are highly prevalent in East Asian populations, leading to a higher proportion of IM phenotype individuals in this ancestral group. Many groups in sub-Saharan Africa have higher frequencies of decreased-function alleles like CYP2D6*17 and *29, which can correlate with lower metabolizer scores in these individuals. More information on allele and phenotype frequencies is available in the CYP2D6 supplemental chapter.
Pharmacologic Conversion of CYP2D6 Phenotype
Factors other than genotype can influence CYP2D6 enzyme activity and, consequently, the metabolizer phenotype of any individual. The administration of an interacting medication can lead to a phenomenon called phenoconversion, wherein an individual with one metabolizer genotype exhibits the enzymatic activity of a different metabolizer group (higher or lower, depending on the medications).
The enzymatic activity of CYP2D6 can be inhibited or reduced by medications, including strong inhibitors such as paroxetine, fluoxetine, bupropion, and quinidine, as well as moderate inhibitors like duloxetine (20, 21, 22). This can potentially result in NMs or IMs to respond to medications as if they were PMs, depending on the strength of the enzyme inhibition. Strong inhibitors can completely inhibit CYP2D6 activity, while moderate inhibitors can reduce activity by 50%. Consequently, co-medication with multiple CYP2D6 strong or moderate inhibitors may result in reduced metabolism of drug substrates, as has been observed in psychiatric pharmacotherapy (23, 24). In contrast, discontinuing a concomitant CYP2D6 inhibitor can restore the individual's CYP2D6 activity to their genetically predicted phenotype baseline. Integration of CYP2D6 phenoconversion into clinical practice requires knowledge of multiple clinical factors. Tools have been developed to support clinicians in this process (25).
Gene: CYP2C19
The CYP2C19 enzyme contributes to the metabolism of a range of clinically important drugs, including antidepressants, benzodiazepines, voriconazole (26), some proton pump inhibitors, and the antiplatelet agent, clopidogrel. The variability in clopidogrel metabolism and treatment outcomes between individuals is partly determined by variant alleles of the CYP2C19 gene.
The CYP2C19 gene is highly polymorphic, with over 35 variant star (*) alleles cataloged by the PharmVar Consortium. The CYP2C19*1 is considered the wild-type allele when no variants are detected and is categorized with normal enzyme activity and the “normal metabolizer” phenotype. Notably, the CYP2C19*1 haplotype has been determined to include a single nucleotide polymorphism in the coding region. However, the frequency of the variant nucleotide (G) is nearly 94% globally, and this missense variant does not alter protein function (27, 28, 29).
The CYP2C19*17 allele is associated with increased enzyme activity and, depending on the number of alleles present, is associated with the “rapid” (one *17 allele) and “ultrarapid” (2 *17 alleles) metabolizer phenotype. Non-functional alleles include CYP2C19*2 and *3. The CYP2C19 IMs have one copy of an allele that encodes a non-functional enzyme (for example, *1/*2), whereas “PMs” have 2 non-functional alleles (for example, *2/*2, *2/*3) (Table 6).
Table 6.
Activity Status of Selected CYP2C19 Alleles
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| Allele type | Alleles |
|---|
| Increased function |
CYP2C19*17
|
| Normal function |
CYP2C19*1
CYP2C19*13
|
| Decreased function^ |
CYP2C19*9
CYP2C19*10
CYP2C19*16
CYP2C19*19
|
| No function |
CYP2C19*2
CYP2C19*3
CY
P2C19*4
|
| Uncertain function |
CYP2C19*12
CYP2C19*23
|
This table is adapted from (30).
- ^
Note: the evidence supporting the activity status of decreased-function alleles is limited.
Approximately 2% of Caucasians, 4% of African Americans, 14% of Chinese, and 57% of Oceanians are CYP2C19 PM, while up to 45% of individuals are CYP2C19 IM (31).
The most common no-function variant is CYP2C19*2, which contains the NM_000769.1:c.681G>A variant in exon 5. This results in an aberrant splice site and produces a truncated, non-functioning protein. The CYP2C19*2 allele frequencies are between 12–18% in individuals of European, American, or African ancestry; 25–35% in Asians, Native Hawaiians, and Pacific Islanders; and up to 60% in Oceanian populations (31, 32). Approximately 6–12% of the observed variability in antiplatelet effect of clopidogrel is thought to be attributed to CYP2C19 variants (33).
For CYP2C19, another commonly tested no-function variant is CYP2C19*3, which contains a c.636G>A variant in exon 4 that causes a premature stop codon. The CYP2C19*3 allele frequencies are ~2–9% in Asian populations, but are rare in other ancestral populations (32). Other non-functional variants, such as CYP2C19*4–*8, occur in less than 1% of the general population (34).
The frequency of the CYP2C19*17 allele is approximately 22% in individuals of European ancestry, 8% in individuals from the Americas, 0.5–5.7% in Asian, Native Hawaiian, and Pacific Islander populations, 17% in African populations, and 20% in African American and Afro-Caribbean populations (31, 32).
The CYP2C19*2, *3, and *17 alleles are the ‘Tier 1’ alleles recommended by the Association for Molecular Pathology (AMP) for inclusion in CYP2C19 clinical genotyping assays (35). The AMP further recommends that testing laboratories consider *4, *5, *6, *7, *8, *9, *10, and *35 alleles as optional ‘Tier 2’ alleles. These alleles have all been shown to have decreased or no function but have either a low minor allele frequency, limited data characterizing the impact on enzyme function, or lack reference materials. Among the ‘Tier 2’ alleles, the CYP2C19*35 allele is the most common, with a frequency of 9% in African populations (35).
Phenoconversion due to CYP2C19 Inhibitors and Inducers
Many medicines are metabolized by the CYP2C19 enzyme, and the enzyme’s activity level can be altered by the administration of medications or supplements. Significant changes in effective enzyme activity due to co-medication or non-genetic factors is called phenoconversion. Increased enzymatic activity can result from the induction of CYP2C19, for example, this effect can occur with medications like rifampin. St. John’s wort and smoking may also increase CYP enzyme activity (36). Inhibitors of CYP2C19 may also impact the target drug metabolism.
Linking CYP2D6 and CYP2C19 Genetic Variation with Treatment Response
Pharmacogenetics-informed treatment methods incorporating CYP2D6 and CYP2C19 genotypes to guide dosing have led to a shorter time to achieve therapeutic plasma concentrations of imipramine than standard dosing regimens (37). Similarly, individuals receiving genotype-guided dosing experienced adverse effects with lower frequency and severity than individuals managed with standard dosing (37).
Reduced CYP2C19 activity reduces the rate of conversion of imipramine to desipramine and may increase the total concentration of these 2 active compounds. Higher plasma levels of the active compounds can result in increased side effects (2). Increased CYP2C19 activity may or may not result in reduced efficacy; CPIC and DPWG provide conflicting insight on the clinical and pharmacokinetic impacts of the RM and UM phenotype (2, 3).
Reduced CYP2D6 activity results in higher plasma levels of imipramine and desipramine, correlating with increased rates of adverse effects. Conversely, increased CYP2D6 activity can raise the concentration of hydroxy metabolites, which may lead to cardiotoxic side effects, while lowering the concentration of the active compounds (2). Higher dosing may be beneficial for CYP2D6 UM individuals, though TDM is recommended (38).
Genetic Testing
Clinical genotyping tests are available for many CYP2D6 and CYP2C19 alleles. The NIH’s Genetic Testing Registry (GTR) provides a list of test providers for “imipramine response,” and the CYP2D6 and CYP2C19 genes.
The available CYP2D6 tests include targeted single-gene tests as well as multi-gene panels. In addition, the AMP has recommended variant CYP2D6 alleles to be included in clinical genotyping assays (39). For CYP2D6, the AMP recommends that the minimum panel of ‘Tier 1’ variant alleles include *2, *3, *4, *5, *6, *9, *10, *17, *29, *41 and copy number interrogation. Guidance on specific alleles for clinical testing of CYP2C19 is also available from the AMP, with CYP2C19*2, *3 and *17 as ‘Tier 1’ alleles (35).
Usually, an individual’s result is reported as a diplotype, such as CYP2C19 *1/*1 or CYP2D6 *1/*1 and may also include an interpretation of the individual’s predicted metabolizer phenotype (ultrarapid, rapid, normal, intermediate, or poor). It is important to note that copy number testing is critical when interpreting CYP2D6 results (38). When individuals have more than 2 copies of CYP2D6, the allele copies are denoted by an “xN”, where the “N” can either be quantified or unquantified (for example, CYP2D6*1/*2x2 or CYP2D6 *1/*2xN). Some laboratories also use the notation of DUP to indicate an increase in copy number; however, the report may not always specify the number of duplications or the allele duplicated due to technical limitations.
The test results may include an interpretation of the individual’s predicted metabolizer phenotype, which can be confirmed by checking the diplotype and calculating the CYP2D6 activity score, as described in the “CYP2D6 Alleles” section above. When a test report does not provide a predicted metabolizer phenotype, resources such as PharmVar are available to assist with predicting the functional impact of identified variants.
Multiple studies have reported successful implementation of pharmacogenetic testing to guide medication selection or dosing in real-world clinical settings (40, 41, 42). Of particular concern are cases where individuals are prescribed multiple medications for chronic health conditions, where gene-drug or gene-drug-drug interactions may negatively impact the individual’s response to medications (43).
Therapeutic Recommendations based on Genotype
This section contains excerpted1
information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.
2023 Statement from the US Food and Drug Administration (FDA)
The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interaction may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary.
FDA Table of Pharmacogenetic Associations, Section 3: Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only
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| Imipramine | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
Please review the complete therapeutic recommendations that are located here: (1, 44).
2023 Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)
CYP2D6 IM: imipramine - The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and desipramine.
CYP2D6 PM: imipramine - The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and the active metabolite desipramine.
CYP2D6 UM: imipramine - The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites.
use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose
if a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine.
Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
CYP2C19 IM: imipramine - NO action is required for this gene-drug interaction.
The genetic variation increases imipramine plasma concentrations, but not imipramine+desipramine plasma concentrations, which govern effectiveness and side effects.
CYP2C19 PM: imipramine - The risk of side effects is increased. The gene variation results in an increase in the plasma concentration of imipramine+desipramine.
use 70% of the standard dose and monitor the effect and side effects, or the imipramine and desipramine plasma concentrations to determine the maintenance dose.
or avoid imipramine.
Antidepressants that are not or to a lesser extent metabolised by CYP2C19 include, for example, nortriptyline, fluvoxamine and mirtazapine.
CYP2C19 UM: imipramine - NO action is required for this gene-drug interaction.
The genetic variation decreases imipramine plasma concentrations, but not imipramine+desipramine plasma concentrations, which govern effectiveness and side effects.
Please review the complete therapeutic recommendations that are located here: (2).
2016 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC)
Because the TCAs have comparable pharmacokinetic properties, it may be reasonable to extrapolate this guideline to other TCAs including clomipramine, desipramine, doxepin, imipramine, and trimipramine, with the acknowledgement that there are fewer data supporting dose adjustments for these drugs than for amitriptyline or nortriptyline. […]
CYP2D6 dosing recommendations.
[…]. The recommended starting dose of amitriptyline or nortriptyline does not need adjustment for those with genotypes predictive of CYP2D6 normal metabolism. A 25% reduction of the recommended dose may be considered for CYP2D6 intermediate metabolizers. The strength of this recommendation is classified as “moderate” because patients with a CYP2D6 activity score of 1.0 are inconsistently categorized as intermediate or normal metabolizers in the literature, making these studies difficult to evaluate.
CYP2D6 ultrarapid metabolizers have a higher probability of failing amitriptyline or nortriptyline pharmacotherapy due to subtherapeutic plasma concentrations, and alternate agents are preferred. There are documented cases of CYP2D6 ultrarapid metabolizers receiving large doses of nortriptyline in order to achieve therapeutic concentrations. However, very high plasma concentrations of the nortriptyline hydroxy-metabolite were present, which may increase the risk for cardiotoxicity. If a tricyclic is warranted, there are insufficient data in the literature to calculate a starting dose for a patient with CYP2D6 ultrarapid metabolizer status, and therapeutic drug monitoring is strongly recommended. Adverse effects are more likely in CYP2D6 poor metabolizers due to elevated tricyclic plasma concentrations; therefore, alternate agents are preferred. If a tricyclic is warranted, consider a 50% reduction of the usual dose, and therapeutic drug monitoring is strongly recommended.
CYP2C19 dosing recommendations.
[…]. The usual starting dose of amitriptyline may be used in CYP2C19 normal and intermediate metabolizers. Although CYP2C19 intermediate metabolizers would be expected to have a modest increase in the ratio of amitriptyline to nortriptyline plasma concentrations, the evidence does not indicate that CYP2C19 intermediate metabolizers should receive an alternate dose.
Patients taking amitriptyline who are CYP2C19 rapid or ultrarapid metabolizers may be at risk for having low plasma concentrations and an imbalance between parent drug and metabolites causing treatment failure and/or adverse events. Although the CYP2C19*17 allele did not alter the sum of amitriptyline plus nortriptyline plasma concentrations, it was associated with higher nortriptyline plasma concentrations, possibly increasing the risk of adverse events. For patients taking amitriptyline, extrapolated pharmacokinetic data suggest that CYP2C19 rapid or ultrarapid metabolizers may need a dose increase. Due to the need for further studies investigating the clinical importance of CYP2C19*17 regarding tricyclic metabolism and the possibility of altered concentrations, we recommend to consider an alternative tricyclic or other drug not affected by CYP2C19. This recommendation is classified as optional due to limited available data. If amitriptyline is administered to a CYP2C19 rapid or ultrarapid metabolizer, therapeutic drug monitoring is recommended.
CYP2C19 poor metabolizers are expected to have a greater ratio of amitriptyline to nortriptyline plasma concentrations. The elevated amitriptyline plasma concentrations may increase the chance of a patient experiencing side effects. Use an alternative agent not metabolized by CYP2C19 (e.g., nortriptyline and desipramine) or consider a 50% reduction of the usual amitriptyline starting dose along with therapeutic drug monitoring.
Other TCAs.
Because the TCAs have comparable pharmacokinetic properties, it may be reasonable to extrapolate this guideline to
other TCAs, including clomipramine, desipramine, doxepin, imipramine, and trimipramine … with the acknowledgment that there are fewer data supporting dose adjustments for these drugs than for amitriptyline or nortriptyline.
CYP2D6 and CYP2C19 combined dosing recommendations.
Although specific combinations of CYP2D6 and CYP2C19 alleles are likely to result in additive effects on the pharmacokinetic properties of TCAs, little information is available on how to adjust initial doses based on combined genotype information. Patients carrying at least one CYP2D6 no function allele and two CYP2C19 normal function alleles had an increased risk of experiencing side effects when administered amitriptyline, while patients with at least one CYP2C19 no function allele and two CYP2D6 normal function alleles had a lower risk of experiencing side effects.
Combinatorial gene-based recommendations are provided in Table 4. Therapeutic drug monitoring may be advised if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, rapid, intermediate, or poor metabolism. There are sparse data in patients with a combinatorial CYP2C19 ultrarapid/rapid/intermediate/poor metabolizer phenotype and CYP2D6 ultrarapid/intermediate/poor phenotype. Because there are limited clinical or pharmacokinetic data regarding these combinatorial phenotypes, pharmacotherapy recommendations are classified as optional.
Please review the complete therapeutic recommendations that are located here: (3).
Nomenclature
Nomenclature for Selected CYP2D6 Alleles
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[1]
-
[2]
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[3]
CYP2D6*36 is a gene conversion with CYP2D7; variants provided here are from the Pharmacogene Variation Consortium.
Alleles described in this table are selected based on discussion in the text above. This is not intended to be an exhaustive description of known alleles.
Guidelines for the description and nomenclature of gene variations are available from the Human Genome Variation Society (45).
Nomenclature for Cytochrome P450 enzymes is available from the Pharmacogene Variation (PharmVar) Consortium (46).
Nomenclature for Selected CYP2C19 Alleles
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[1]
-
[2]
-
[3]
The CYP2C19*17 allele has increased expression due to an upstream, non-coding variant. The legacy HGVS expression for the change relative to the coding sequence is provided, but the correct RefSeq genomic sequence is provided as well.
Guidelines for the description and nomenclature of gene variations are available from the Human Genome Variation Society (HGVS) (45).
Acknowledgments
Version 1.0 (March 2017)
The author would like to thank the following individuals for reviewing this summary: David Kisor, BS, PharmD, Professor and Director of Pharmacogenomics Education, Pharmacogenomics Program, Manchester University, North Manchester, IN, USA; Mohamed Nagy, Clinical Pharmacist, Head of the Personalised Medication Management Unit, Department of Pharmaceutical Services, Children's Cancer Hospital, Cairo, Egypt; Yolande Saab, PharmD, PhD, Associate Professor of Pharmacogenomics, School of Pharmacy, Lebanese American University, Beirut, Lebanon; Stuart Scott, Assistant Professor of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; Ranjit K Thirumaran, MPharm, PhD, Director, Clinical Pharmacogenomics & Clinical Research Trials, YouScript® / Genelex Labs, Seattle, WA, USA; Chakradhara Rao S Uppugunduri, Maître-assistant at the CANSEARCH Laboratory, University of Geneva, Geneva, Switzerland; and Mandy van Rhenen, secretary of the Dutch Pharmacogenetics Working Group (DPWG), Centre for Information on Medicines, Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands.
Version 2.0 (January 2025)
The authors would like to thank Andria L. Del Tredici, PhD, Senior Director of Clinical Development, Myriad Genetics, San Diego, CA, USA; Marga Nijenhuis, PhD, Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands; James Walker, PharmD, MSPGx, Chief Executive Officer, PharmaGx Consultation, Wichita, Kansas, USA for reviewing this summary.
Version History
Version 1.0 was published on March 23, 2017, and is available here.
Version 2.0 was published on January 6, 2025. This version includes new guidelines from the Dutch Pharmacogenetic Working Group (DPWG) that were not included in the previous version of the chapter. The DPWG guidelines include specific dose adjustment recommendations for poor, intermediate, and ultrarapid metabolizer phenotypes by gene; please see the text above for specific recommendations. Additionally, guidelines for which alleles to include in pharmacogenetic testing for CYP2D6 and CYP2C19 are also available from the Association for Molecular Pathology and cited in this updated version.
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1
The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes, and genetic variants may be corrected in accordance with nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.
2.