Introduction
Aripiprazole (brand names Abilify or Aristada) is an atypical antipsychotic used to manage schizophrenia, bipolar disorder, major depressive disorder, irritability associated with autistic disorder, and in the treatment of Tourette syndrome. (1)
The metabolism and elimination of aripiprazole is mainly mediated through 2 enzymes, CYP2D6 and CYP3A4. Approximately 8% of Caucasians, 3–8% of Black/African Americans and up to 2% of Asians cannot metabolize CYP2D6 substrates and are classified as “poor metabolizers.” (2)
The FDA-approved drug label for aripiprazole states that in CYP2D6 poor metabolizers, half of the usual dose should be administered. In CYP2D6 poor metabolizers who are taking concomitant strong CYP3A4 inhibitors (for example, itraconazole, clarithromycin), a quarter of the usual dose should be used (Table 1) (1). The dosage reduction is the same regardless of the administration route (oral or long-acting injectable). (3)
The Dutch Pharmacogenetics Working group (DPWG) also recommends a reduced dosage for CYP2D6 poor metabolizers, “no more than 10 mg/day or 300 mg/month” (Table 2). No action is recommended for intermediate or ultrarapid metabolizers. While both of these metabolic variations alter the plasma concentrations of aripiprazole, there is no evidence that this increases the risk of reduced effectiveness or risk of side effects. (4)
In contrast to the recommendations by the FDA and DPWG, some recent studies have suggested CYP2D6 intermediate metabolizers may also require a dose decrease, but this was only based on aripiprazole clearance. (5, 6, 7, 8)
Table 1.
The FDA Dosing Recommendations for Aripiprazole and CYP2D6 Metabolizer Status and Comedications (2020)
View in own window
| Factors | Dosage adjustments for aripiprazole tablets |
|---|
| Known CYP2D6 poor metabolizers | Administer half of usual dose |
| Known CYP2D6 poor metabolizers taking concomitant strong CYP3A4 inhibitors (for example, itraconazole, clarithromycin) | Administer a quarter of usual dose |
| Strong CYP2D6 (for example, quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (for example, itraconazole, clarithromycin) | Administer half of usual dose |
| Strong CYP2D6 and CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP3A4 inducers (for example, carbamazepine, rifampin) | Double usual dose over 1–2 weeks |
This FDA table is adapted from (1).
Table 2.
The DPWG Dosing Recommendations for Aripiprazole and CYP2D6 Metabolizer Status (2018)
View in own window
| CYP2D6 metabolizer type | Action needed | Background |
|---|
| Poor metabolizer | Administer no more than 10 mg/day or 300 mg/month (67–75% of the standard maximum dose of aripiprazole)1 | The risk of side effects is increased. The genetic variation leads to an increase in the sum of the plasma concentrations of aripiprazole and the active metabolite. |
| Intermediate metabolizer (IM) | NO action is needed for this gene-drug interaction | The genetic variation alters the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness for UM or risk of side effects for IM. |
| Ultrarapid metabolizer (UM) |
DPWG: Dutch Pharmacogenetics Working Group
1 Drug labeling within the European Union states that 15 mg/day is the starting maximum dose (9).
This DPWG table is adapted from (4) .
Drug: Aripiprazole
Aripiprazole is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. Aripiprazole may also be used as part of the management of major depressive disorder, irritability associated with autism, and in the treatment of Tourette syndrome. (1, 3)
The first antipsychotics to be discovered in the 1950s were haloperidol and chlorpromazine. Known as “first-generation” or “typical” antipsychotics, these drugs are used to treat psychosis (regardless of the cause), chronic psychotic disorders (for example, schizophrenia), and other psychiatric conditions. However, prominent adverse effects included extrapyramidal side effects such as tardive dyskinesia, muscle rigidity, tremors, and Parkinsonian-like symptoms.
Newer antipsychotics, known as “second generation” or “atypical” antipsychotics, have a lower risk of extrapyramidal side effects such as tardive dyskinesia. However, many have serious metabolic effects. Aripiprazole is an atypical antipsychotic that is noted for having fewer metabolic side effects than other atypicals, such as clozapine, olanzapine, risperidone, and quetiapine. Other atypicals approved by the FDA include asenapine, brexpiprazole, cariprazine, lurasidone, paliperidone, and ziprasidone.
The main action of both first-generation and second-generation antipsychotics is thought to be the post-synaptic blockade of D2 dopamine receptors. All antipsychotics, with the exception of aripiprazole, are D2 antagonists.
Aripiprazole is a partial D2 agonist. Aripiprazole binds to the D2 receptor with a high affinity similar to dopamine. However, because it has low intrinsic activity, it causes much lower activation of the receptor compared with dopamine.
The combination of a high affinity for the D2 receptor and its partial agonist activity may result in aripiprazole reducing the high-frequency firing of dopamine neurons in the brain’s mesolimbic system. Overactivity in this region is thought to underlie psychosis and other positive symptoms of schizophrenia. In addition, the preservation of some D2 receptor activity in other dopamine-rich pathways in the brain (mesocortical and nigrostriatal areas) may provide more protection against extrapyramidal side effects. (10, 11)
Aripiprazole also has a high affinity for the serotonin 5-HT2A receptors, where it acts as an antagonist and it moderately blocks the alpha 1 adrenergic and histamine H1 receptors, which may account for the lower incidence of orthostatic hypotension and sedation compared with other antipsychotics. (12)
Adverse events with aripiprazole therapy include increased mortality in elderly individuals with psychosis caused by dementia, suicidal thoughts and behavior in children and young adults, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes including hyperglycemia, pathological gambling, and other compulsive behaviors. Additionally, orthostatic hypotension, leukopenia, neutropenia, and agranulocytosis, seizures/convulsions and potential cognitive and motor impairment have been reported. Commonly observed adverse reactions in adult schizophrenic individuals that should be reported to the FDA include akathisia. Adverse events in pediatric individuals (13–17 years old) that should be reported are extrapyramidal disorder, somnolence, and tremor. (1)
Aripiprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) superfamily of enzymes, mainly CYP2D6 and CYP3A4. Aripiprazole activity is thought to be primarily due to the parent drug, and to a lesser extent its major metabolite, dehydroaripiprazole. The mean elimination half-life is approximately 75 hours for aripiprazole, but in individuals who have no appreciable CYP2D6 activity (poor metabolizers), the mean elimination half-life for aripiprazole is around 146 hours. (1) The mean aripiprazole exposure for CYP2D6 poor and intermediate metabolizers is increased 1.5-fold compared with normal metabolizers (6).
While aripiprazole has been reported to have a minimal effect on prolactin levels (13), more recent studies have found a correlation between reduced CYP2D6 enzyme activity and increases in prolactin. (14, 15) These increases in prolactin levels were more pronounced in females and individuals with no functional CYP2D6, raising the possibility of a higher risk for hyperprolactinemia adverse reactions. Hyperprolactinemia can have significant effect in the pediatric population during growth and development and may warrant additional monitoring. (14)
Rare cardiac adverse reactions have also been observed in clinical trials with aripiprazole. (3) Two recent case reports suggest that CYP2D6 activity may play a role in predisposing an individual to atrial fibrillation or abnormal heart electrophysiology. (16, 17) One small study reported that palpitations were more commonly experienced by females versus males taking aripiprazole and more often with aripiprazole versus olanzapine treatment. (18)
The FDA-approved drug label warns that “neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.” (1) These exposures should be considered in light of the disease-associated maternal or embryo/fetal, or both, risks of untreated schizophrenia or bipolar I disorder. The FDA-approved label states that neonates who are exposed to aripiprazole during pregnancy should be closely monitored, as symptoms vary in severity and duration (hours to days) and may require prolonged hospitalization. The FDA encourages healthcare providers to register individuals who have aripiprazole exposure while pregnant to monitor pregnancy outcomes. For more information see (1, 3).
Limited data from scientific literature suggests a low level of aripiprazole can be present in breast milk. The literature reports the relative infant dose ranges between 0.7% and 8.3% of the maternal weight-adjusted dosage. (1) Though aripiprazole has a minimal effect on prolactin levels compared with the phenothiazines, case reports have documented both decreased lactation and hyperprolactinemia in nursing mothers taking aripiprazole, and other medications may be considered, as needed. (19)
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 very polymorphic and can result in decreased, absent, or increased enzyme activity.
The CYP2D6 enzyme is responsible for the metabolism of many commonly prescribed drugs, including antidepressants, antipsychotics, analgesics, and beta-blockers.
CYP2D6 Alleles
The CYP2D6 gene is highly polymorphic, as over 100 star (*) alleles have been described and cataloged at the Pharmacogene Variation (PharmVar) Consortium, and each allele is associated with either normal, decreased, or absent enzyme function (Table 3) (20). The combination of CYP2D6 alleles that a person has is used to determine their diplotype (for example, CYP2D6*4/*4). Based on function, each allele can be assigned an activity score from 0 to 1, which in turn is often used to assign a phenotype (for example, CYP2D6 poor metabolizer). When duplicated alleles are detected, both copies are assigned an activity score for phenotyping. However, the activity score system is not standardized across clinical laboratories or CYP2D6 genotyping platforms. CPIC revised their activity scoring guidelines in October 2019 to promote harmonization. The CYP2D6 phenotype is defined by the sum of the allele activity scores, which is usually in the range of 0–3.0: (21)
An ultrarapid metabolizer (UM) has an activity score greater than 2.25
A normal metabolizer phenotype (NM) has an activity score of 1.25 to 2.25
An intermediate metabolizer (IM) has an activity score of >0 to 1.25
A poor metabolizer (PM) has an activity score of 0
Table 3.
Activity Status of Selected CYP2D6 Alleles
View in own window
| Allele type | Activity score | CYP2D6 alleles |
|---|
| Normal function | 1.0 |
*1, *2, *27, *33
|
| Decreased function | 0.25-0.5 |
*10, *17, *41, *49
|
| No function | 0 |
*3, *4, *5, *6, *36
|
For a comprehensive list of CYP2D6 alleles, please See PharmVar. Activity scores from (22).
The
CYP2D6*1 allele is considered the wild-type allele when no variants are detected and is associated with normal enzyme activity and the “normal metabolizer” phenotype. In addition, 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, *5, and *6) (23, 24, 25) or an enzyme with decreased activity (for example, *10, *17, and *41) (26, 27, 28) (see Table 3). There are large inter-ethnic differences in the frequency of these alleles, with *3, *4, *5, *6, and *41 being more common in Caucasians, *17 more common in Africans, and *10 more common in Asians. (29)(30)
Allele Frequencies Vary between Populations
Among Asians and in individuals of Asian descent, only approximately 50% of CYP2D6 alleles are normal function, and the frequency of CYP2D6 duplications is as high as 45%, although this may have been overestimated by not accounting for tandem hybrid alleles (for example, *36+*10) (31). Other studies of a US individual population suggested less than 50% of alleles detected within Asian-descent individuals are normal-function alleles in a single copy, with 30% of alleles arising from structural variants (duplications or deletions) (32). Common no-function variants are CYP2D6*36 and CYP2D6*4 (32). Both these alleles contain the variant “c.100C>T” (see Allele Nomenclature table) (29, 31, 33, 34). The CYP2D6*36 allele is the result of a gene conversion event with the pseudogene CYP2D7 (35). This no-function allele is most commonly found in individuals of Asian ancestry (32).
Among Africans and African Americans, only approximately 50% of CYP2D6 alleles are normal function (23, 28, 29, 36). African Americans also have been found to have a higher frequency of no-function structural variants or decreased-function single-copy variant alleles versus Caucasian or Hispanic Americans (32).
Middle Eastern countries show a great diversity in phenotypic and allelic distribution for CYP2D6 (37), though on average, these individuals show a lower frequency of poor metabolizer phenotypes (0.91%) and higher ultrarapid phenotypes (11.2%) than other ethnicities (Note: Oceania and Middle Eastern ethnicities combined in this study) (2).
Among European countries, there is diversity of allelic distribution (38). Gene duplications were more common in the south-eastern countries (Greece, Turkey: 6%) and less common in north-western countries (Sweden and Denmark, <1%). Meanwhile, CYP2D6*4 and *5 alleles were generally more common in the north and less common in the south. (38) Worldwide CYP2D6 genotype and phenotype frequencies have been catalogued and recently published (2).
CYP2D6 Phenotype
CYP2D6 Phenotype Frequencies Vary between Populations
Normal metabolizers: Approximately 77–92% of individuals have 2 normal-function alleles (*1 or *2), or one normal-function allele and one decreased-function allele. These individuals are “normal metabolizers” and are most likely to have a phenotypically normal response to the drug.
Intermediate metabolizers: Approximately 2–11% of individuals are intermediate metabolizers—they have either 2 decreased-function alleles or one normal- or decreased-function and one no-function allele (2). A study of a diverse US urban population of children found that roughly 8% of subjects were intermediate metabolizers (39), Within the US, it has been observed that individuals of African or Asian descent were most likely to be classified as intermediate metabolizers (20–28% of population by ethnicity) (32).
Poor metabolizers: Approximately 5–10% of individuals are poor metabolizers—they have 2 no-function alleles (40). Poor metabolizers are more commonly found in European Caucasians and their descendants. The no-function CYP2D6*4 and *5 alleles largely account for the poor metabolizer phenotype in these populations (27, 41, 42). It should be noted that the frequency of poor metabolizers can be much lower in certain populations including East Asian, Oceania and Middle Eastern (2). Studies of US multi-ethnic populations have estimated the prevalence of poor metabolizers to be between 1.5–5.7% (32, 39).
Ultrarapid metabolizers: Individuals who are ultrarapid metabolizers have at least 3 copies of the CYP2D6 gene. The ultrarapid metabolizer phenotype has been estimated to be present in 1–2% of individuals, but the prevalence varies widely in different populations. It is estimated to be present in up to 28% of North Africans, Ethiopians, and Arabs; up to 10% in Caucasians; 3% in African Americans, and up to 1% in Hispanics, Chinese, and Japanese (40, 43). Ultrarapid metabolizers made up 9% of subjects in an urban multi-ethnic population with a large portion of Hispanic/Latino subjects (39). A larger study of US individuals predicted an ultrarapid metabolizer phenotype in only 2.2% of individuals, regardless of ethnicity (32).
Linking Gene Variation with Treatment Response
Genetic variations in the CYP2D6 gene have been found to impact serum levels of aripiprazole and dehydroaripiprazole. (8)(44, 45) Because standard doses of aripiprazole lead to higher plasma levels of aripiprazole and dehydroaripiprazole, the dose of aripiprazole should be adjusted for individuals that have 2 no-function CYP2D6 alleles causing poor metabolizer status.
The FDA recommends that individuals who are known to be CYP2D6 poor metabolizers should receive half the standard dose of aripiprazole, or a quarter of the standard dose if they are also taking medicines that strongly inhibit CYP3A4 (for example, itraconazole, clarithromycin) (see Table 1). Multiple studies substantiate the FDA recommendations by concluding that poor metabolizers should receive a reduced dose of aripiprazole (30–50% reduction). (5, 6, 8, 45, 46)
One study further suggested that individuals with increased CYP2D6 activity (ultrarapid metabolizers) may need to take an alternative antipsychotic not metabolized by CYP2D6 because of reduced drug levels. (46) Additional studies have suggested that intermediate metabolizers should also have a reduced dosage, in contrast with the current FDA-approved drug labeling. (5, 6, 7, 47) This is particularly relevant among individuals of Asian descent, where the intermediate metabolizer phenotype is highly prevalent. (7) One study reported that females and poor metabolizers are at an elevated risk for adverse events. (8)
Phenoconversion from a CYP2D6 normal metabolizer status to reduced metabolic activity has also been suggested due to drug-drug interactions in individuals with one or more wild-type CYP2D6*1 allele. (47) The drugs observed by this study to have an effect on CYP2D6 activity were risperidone, metoprolol and propranolol. (47) Additionally, phenoconversion has been associated with a higher rate of aripiprazole discontinuation (48). Aripiprazole can lead to drug-drug interactions with other CYP2D6 substrates, particularly those with weaker affinity for the CYP2D6 enzyme—for example, the antidepressant mirtazapine—resulting in an increase in plasma concentration for the co-medication (49). The FDA drug label recommends reducing the aripiprazole dosage with concomitant use of strong CYP2D6 inhibitors (for example quinidine, fluoxetine and paroxetine) or CYP3A4 inhibitors. (1)
Genetic Testing
The NIH Genetic Testing Registry provides examples of the genetic tests that are available for aripiprazole response and for the CYP2D6 gene.
CYP2D6 is a particularly complex gene that is difficult to genotype because of the large number of variants and the presence of gene deletions, duplications, multiplications, and pseudogenes. The complexity of genetic variation complicates making a correct determination of CYP2D6 genotype.
Targeted genotyping typically includes up to 30 variant CYP2D6 alleles (over 100 alleles have been identified so far). Test results are reported as a diplotype, such as CYP2D6 *1/*1. However, it is important to note that the number of variants tested can vary among laboratories, which can result in diplotype result discrepancies between testing platforms and laboratories. (50)
A result for copy number, if available, is also important when interpreting CYP2D6 genotyping results. Gene duplications and multiplications are denoted by “xN” for example, CYP2D6*1xN with xN representing the number of CYP2D6 gene copies. The functional status of the duplicated allele is also critical in interpretation of the test results, as duplication of a no-function versus a normal-function allele would result in a different total activity score and potentially different metabolizer phenotype.
If the test results include an interpretation of the individual’s predicted metabolizer phenotype, such as “CYP2D6 *1/*1, normal metabolizer”, this can be confirmed by checking the diplotype and assigning an activity score to each allele (for example, 0 for no function, 0.5 for decreased function, and 1.0 for each copy of a normal-function allele, Table 3). See the CYP2D6 alleles section above for more information.
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.
2020 Statement from the US Food and Drug Administration (FDA):
Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 2). When the coadministered drug is withdrawn from the combination therapy, aripiprazole dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, aripiprazole dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response.
[…]
Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3% to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM).
Please review the complete therapeutic recommendations that are located here:(1).
2018 Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)
CYP2D6 PM: aripiprazol [aripiprazole]
The risk of side effects is increased. The genetic variation leads to an increase in the sum of the plasma concentrations of aripiprazole and the active metabolite.
administer no more than 10 mg/day or 300 mg/month (67-75% of the standard maximum dose of aripiprazole).
CYP2D6 IM: aripiprazol [aripiprazole]
NO action is needed for this gene-drug interaction.
The genetic variation increases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is insufficient evidence that this increases the risk of side effects.
CYP2D6 UM: aripiprazol [aripiprazole]
NO action is needed for this gene-drug interaction.
The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness.
Please review the complete therapeutic recommendations that are located here: (4).
Nomenclature for Selected CYP2D6 Alleles
View in own window
-
[1]
In the literature, 1023C>T is also referred to as 1111C>T
-
[2]
In the literature, 2850C>T is also referred to as 2938C>T
-
[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.
Pharmacogenetic Allele Nomenclature: International Workgroup Recommendations for Test Result Reporting (51).
Guidelines for the description and nomenclature of gene variations are available from the Human Genome Variation Society (HGVS).
Nomenclature for Cytochrome P450 enzymes is available from the Pharmacogene Variation (PharmVar) Consortium.
Acknowledgments
The authors would like to thank Francisco Abad Santos, MD, PhD, Clinical Pharmacology Department, Hospital Universitario de la Princesa, Madrid, Spain and Marin Jukic, MSc, PhD, Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden for reviewing this summary.
2016 Edition:
The author would like to thank Megan J. Ehret, PharmD, MS, BCPP Behavioral Health Clinical Pharmacy Specialist, Fort Belvoir Community Hospital, Fort Belvoir, VA, USA; Andrea Gaedigk, MS, PhD, Director, Pharmacogenetics Core Laboratory, Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, and Professor, School of Medicine, University of Missouri-Kansas City, KS, USA; and Steven Leeder, PharmD, PhD, Marion Merrell Dow/Missouri Endowed Chair in Pediatric Clinical Pharmacology, and Director, Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children’s Mercy Hospital, Kansas City, KS, USA; for reviewing this summary.
Version History
The previous version of this chapter, published 22 September 2016, is available here.
References
- 1.
- 2.
- 3.
- 4.
Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharamcogenetic Guidelines [Internet]. Netherlands. CYP2D6 : aripiprazole [Cited July 2020]. Available from:
https://www.knmp.nl/media/1058.
- 5.
Tveito M., Molden E., Hoiseth G., Correll C.U., et al. Impact of age and CYP2D6 genetics on exposure of aripiprazole and dehydroaripiprazole in patients using long-acting injectable versus oral formulation: relevance of poor and intermediate metabolizer status.
Eur J Clin Pharmacol. 2020;76(1):41–49. [
PubMed: 31637453]
- 6.
Jukic M.M., Smith R.L., Haslemo T., Molden E., et al. Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study.
Lancet Psychiatry. 2019;6(5):418–426. [
PubMed: 31000417]
- 7.
Zhang X., Xiang Q., Zhao X., Ma L., et al. Association between aripiprazole pharmacokinetics and CYP2D6 phenotypes: A systematic review and meta-analysis.
J Clin Pharm Ther. 2019;44(2):163–173. [
PubMed: 30565279]
- 8.
Belmonte C., Ochoa D., Roman M., Saiz-Rodriguez M., et al. Influence of CYP2D6, CYP3A4, CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers.
Basic Clin Pharmacol Toxicol. 2018;122(6):596–605. [
PubMed: 29325225]
- 9.
- 10.
Potkin S.G., Saha A.R., Kujawa M.J., Carson W.H., et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder.
Arch Gen Psychiatry. 2003;60(7):681–90. [
PubMed: 12860772]
- 11.
Swainston Harrison T., Perry C.M. Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder.
Drugs. 2004;64(15):1715–36. [
PubMed: 15257633]
- 12.
- 13.
Leucht S., Cipriani A., Spineli L., Mavridis D., et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.
Lancet. 2013;382(9896):951–62. [
PubMed: 23810019]
- 14.
Gradinaru R., Andreescu N., Nussbaum L., Suciu L., et al. Impact of the CYP2D6 phenotype on hyperprolactinemia development as an adverse event of treatment with atypical antipsychotic agents in pediatric patients.
Ir J Med Sci. 2019;188(4):1417–1422. [
PubMed: 30771137]
- 15.
Koller D., Belmonte C., Saiz-Rodriguez M., Zubiaur P., et al. Effects of aripiprazole on circadian prolactin secretion related to pharmacogenetics in healthy volunteers.
Basic Clin Pharmacol Toxicol. 2020;126(3):236–246. [
PubMed: 31520576]
- 16.
D'Urso G., Anastasia A., Toscano E., Patti S., et al. Aripiprazole-induced atrial fibrillation in a patient with concomitant risk factors.
Exp Clin Psychopharmacol. 2018;26(5):509–513. [
PubMed: 30035575]
- 17.
Mazer-Amirshahi M., Porter R., Dewey K. Prolonged QRS Widening After Aripiprazole Overdose.
Pediatr Emerg Care. 2019;35(11):e209–e212. [
PubMed: 29746361]
- 18.
Koller D., Almenara S., Mejia G., Saiz-Rodriguez M., et al. Safety and cardiovascular effects of multiple-dose administration of aripiprazole and olanzapine in a randomised clinical trial.
Hum Psychopharmacol. 2020 [
PubMed: 32991788]
- 19.
- 20.
Reny J.L., Fontana P. Antiplatelet drugs and platelet reactivity: is it time to halt clinical research on tailored strategies?
Expert Opin Pharmacother. 2015;16(4):449–52. [
PubMed: 25495963]
- 21.
Caudle K.E., Sangkuhl K., Whirl-Carrillo M., Swen J.J., et al. Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group.
Clin Transl Sci. 2020;13(1):116–124. [
PMC free article: PMC6951851] [
PubMed: 31647186]
- 22.
- 23.
Yokota H., Tamura S., Furuya H., Kimura S., et al. Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism.
Pharmacogenetics. 1993;3(5):256–63. [
PubMed: 8287064]
- 24.
- 25.
Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity.
Pharmacogenomics J. 2005;5(1):6–13. [
PubMed: 15492763]
- 26.
- 27.
- 28.
- 29.
Bradford L.D. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants.
Pharmacogenomics. 2002;3(2):229–43. [
PubMed: 11972444]
- 30.
Zhou Y., Ingelman-Sundberg M., Lauschke V.M. Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects.
Clin Pharmacol Ther. 2017;102(4):688–700. [
PMC free article: PMC5600063] [
PubMed: 28378927]
- 31.
Ramamoorthy A., Flockhart D.A., Hosono N., Kubo M., et al. Differential quantification of CYP2D6 gene copy number by four different quantitative real-time PCR assays.
Pharmacogenet Genomics. 2010;20(7):451–4. [
PMC free article: PMC4411953] [
PubMed: 20421845]
- 32.
- 33.
Wu X., Yuan L., Zuo J., Lv J., et al. The impact of CYP2D6 polymorphisms on the pharmacokinetics of codeine and its metabolites in Mongolian Chinese subjects.
Eur J Clin Pharmacol. 2014;70(1):57–63. [
PubMed: 24077935]
- 34.
Hosono N., Kato M., Kiyotani K., Mushiroda T., et al. CYP2D6 genotyping for functional-gene dosage analysis by allele copy number detection.
Clin Chem. 2009;55(8):1546–54. [
PubMed: 19541866]
- 35.
Gaedigk A., Bradford L.D., Alander S.W., Leeder J.S. CYP2D6*36 gene arrangements within the cyp2d6 locus: association of CYP2D6*36 with poor metabolizer status.
Drug Metab Dispos. 2006;34(4):563–9. [
PubMed: 16415111]
- 36.
Sistonen J., Sajantila A., Lao O., Corander J., et al. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure.
Pharmacogenet Genomics. 2007;17(2):93–101. [
PubMed: 17301689]
- 37.
- 38.
- 39.
Virbalas J., Morrow B.E., Reynolds D., Bent J.P., et al. The Prevalence of Ultrarapid Metabolizers of Codeine in a Diverse Urban Population.
Otolaryngol Head Neck Surg. 2019;160(3):420–425. [
PubMed: 30322340]
- 40.
- 41.
Ingelman-Sundberg M., Sim S.C., Gomez A., Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects.
Pharmacology & therapeutics. 2007;116(3):496–526. [
PubMed: 18001838]
- 42.
Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity.
The pharmacogenomics journal. 2005;5(1):6–13. [
PubMed: 15492763]
- 43.
- 44.
van der Weide K., van der Weide J. The Influence of the CYP3A4*22 Polymorphism and CYP2D6 Polymorphisms on Serum Concentrations of Aripiprazole, Haloperidol, Pimozide, and Risperidone in Psychiatric Patients.
J Clin Psychopharmacol. 2015;35(3):228–36. [
PubMed: 25868121]
- 45.
Hendset M., Molden E., Knape M., Hermann M. Serum concentrations of risperidone and aripiprazole in subgroups encoding CYP2D6 intermediate metabolizer phenotype.
Ther Drug Monit. 2014;36(1):80–5. [
PubMed: 24232129]
- 46.
Lisbeth P., Vincent H., Kristof M., Bernard S., et al. Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol.
Eur J Clin Pharmacol. 2016;72(2):175–84. [
PubMed: 26514968]
- 47.
Kiss A., Menus A., Toth K., Deri M., et al. Phenoconversion of CYP2D6 by inhibitors modifies aripiprazole exposure.
Eur Arch Psychiatry Clin Neurosci. 2020;270(1):71–82. [
PubMed: 30604050]
- 48.
Jallaq S.A., Verba M., Strawn J.R., Martin L.J., et al. CYP2D6 Phenotype Influences Aripiprazole Tolerability in Pediatric Patients with Mood Disorders.
J Child Adolesc Psychopharmacol. 2020 [
PMC free article: PMC8255312] [
PubMed: 32845723]
- 49.
Matos A., Bain K.T., Bankes D.L., Furman A., et al. Cytochrome P450 (CYP450) Interactions Involving Atypical Antipsychotics are Common in Community-Dwelling Older Adults Treated for Behavioral and Psychological Symptoms of Dementia.
Pharmacy (Basel). 2020;8(2) [
PMC free article: PMC7355621] [
PubMed: 32276526]
- 50.
Hicks J.K., Swen J.J., Gaedigk A. Challenges in CYP2D6 phenotype assignment from genotype data: a critical assessment and call for standardization.
Curr Drug Metab. 2014;15(2):218–32. [
PubMed: 24524666]
- 51.
Kalman L.V., Agundez J., Appell M.L., Black J.L., et al. Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting.
Clin Pharmacol Ther. 2016;99(2):172–85. [
PMC free article: PMC4724253] [
PubMed: 26479518]
-
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.
