Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study

Jukić, Marin M.; Smith, Robert L.; Haslemo, Tore; Molden, Espen; Ingelman‐Sundberg, Magnus

doi:10.1016/s2215-0366(19)30088-4

Cited by 134 publications

(151 citation statements)

References 29 publications

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“…Amongst the individuals recruited are individuals diagnosed with a variety of psychiatric disorders and the upper study goal is the identification of biomarkers associated with antipsychotic/antidepressant drug responses [21]. Regarding the other effort, as run by the Karolinska Institute, findings from this study indicate that CYP2D6 pre-emptive genotyping would be valuable for individualising risperidone and aripiprazole dosing, thus leading to treatment optimisation [20].…”

Section: Discussionmentioning

confidence: 94%

“…So far, only a few psychiatric clinical pharmacogenomics and psychiatric PGx GWAS studies have been published thus pointing to a need for properly designed psychiatric pharmacogenomics. Two characteristic examples of clinical psychiatric PGx studies, which are currently on-going, are the following: one is the "PREPARE" by the Ubiquitous Pharmacogenomics (U-PGx; http:// www.upgx.eu) Consortium and the other one is an effort run at the Karolinska Institute [20,21]. The "PREPARE" study aims to perform pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, whilst being implemented across healthcare institutions in seven European countries.…”

Section: Discussionmentioning

confidence: 99%

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Delineating significant genome-wide associations of variants with antipsychotic and antidepressant treatment response: implications for clinical pharmacogenomics

Koromina¹,

Koutsilieri²,

Patrinos³

2020

Hum Genomics

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Background: Genome-wide association studies (GWAS) have significantly contributed to the association of many clinical conditions and phenotypic characteristics with genomic variants. The majority of these genomic findings have been deposited to the GWAS catalog. So far, findings uncovering associations of single nucleotide polymorphisms (SNPs) with treatment efficacy in mood disorders are encouraging, but not adequate. Methods: Statistical, genomic, and literature information was retrieved from EBI's GWAS catalog, while we also searched for potential clinical information/clinical guidelines in well-established pharmacogenomics databases regarding the assessed drug-SNP correlations of the present study. Results: Here, we provide an overview of significant genome-wide associations of SNPs with the response to commonly prescribed antipsychotics and antidepressants. Up to date, this is the first study providing novel insight in previously reported pharmacogenomics associations for antipsychotic/antidepressant treatment. We also show that although there are published CPIC guidelines for antidepressant agents, as well as the FDA labels include genome-based drug prescription information for both antipsychotic and antidepressant treatments, there are no specific clinical guidelines for the assessed drug-SNP correlations of this study. Conclusions: Our present findings suggest that more effort should be implemented towards identifying GWAsignificant antipsychotic and antidepressant pharmacogenomics correlations. Moreover, additional functional studies are required in order to characterise the potential role of the assessed SNPs as biomarkers for the response of patients to antipsychotic/antidepressant treatment.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Delineating significant genome-wide associations of variants with antipsychotic and antidepressant treatment response: implications for clinical pharmacogenomics

Koromina¹,

Koutsilieri²,

Patrinos³

2020

Hum Genomics

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“…Risperidone is an example of a drug that is metabolized predominantly by CYP2D6, and in a study of 1,288 patients, approximately 1.4-and 1.6-fold risperidone exposure increase was observed in IMs and PMs, respectively (14). Since the therapeutic window for risperidone is quite narrow, this exposure increase is likely the reason behind the higher incidence of risperidone-associated adverse drug reactions (36) and treatment failure (14) observed among PMs compared with NMs. Furthermore, an increased treatment failure rate is also observed in Ums (14), indicating that they might be exposed to insufficient drug levels.…”

Section: Phenotypic Classification Based On Cyp2c19 and Cyp2d6 Genotypementioning

confidence: 99%

“…Since the therapeutic window for risperidone is quite narrow, this exposure increase is likely the reason behind the higher incidence of risperidone-associated adverse drug reactions (36) and treatment failure (14) observed among PMs compared with NMs. Furthermore, an increased treatment failure rate is also observed in Ums (14), indicating that they might be exposed to insufficient drug levels. Many other antipsychotics, such as aripiprazole and haloperidol, are metabolized by CYP2D6.…”

Section: Phenotypic Classification Based On Cyp2c19 and Cyp2d6 Genotypementioning

confidence: 99%

“…There is substantial interindividual variability in the response and efficacy of CNS active drugs and it has become evident that genes encoding pharmacokinetic-related biomolecules have significant impact (https://cpicpgx.org/guidelines/). In particular, functional polymorphisms in genes encoding the drug metabolizing enzymes CYP2C19 and CYP2D6 are quite frequent among all populations (12) and these variants are associated with altered drug exposure sufficiently to support the clinical utility of CYP2C19 and CYP2D6 genotyping (13)(14)(15). In contrast, receptors that are currently used as drug targets for psychiatric drugs are evolutionary conserved to a higher extent than genes encoding drug metabolism and the actionability of pharmacodynamic-related genotyping is currently still questionable (16).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?

et al. 2020

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Effect of Routine Cytochrome P450 2D6 and 2C19 Genotyping on Antipsychotic Drug Persistence in Patients With Schizophrenia

et al. 2020

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IMPORTANCEGenetic polymorphism of genes encoding the drug metabolizing enzymes, cytochrome P450 2D6 and 2C19 (CYP2D6 and CYP2C19), is associated with treatment failure of and adverse reactions to psychotropic drugs. The clinical utility of routine CYP2D6 and CYP2C19 genotyping (CYP testing) is unclear. OBJECTIVE To estimate whether routine CYP testing effects the persistence of antipsychotic drug treatment. DESIGN, SETTING, AND PARTICIPANTS This single-masked, 3-group randomized clinical trial included patients aged 18 years or older who had been diagnosed within the schizophrenic spectrum (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, F20-F29) and not previously genotyped. A total of 669 of 1406 potentially eligible patients from 12 psychiatric outpatient clinics in Denmark were approached between July 2008 and December 2009. Overall, 528 patients were genotyped and randomly allocated to 1 of 3 study groups or exclusion in a sequence of 1:1:1:3 using a predictive enrichment design, aiming to double the proportion of poor or ultrarapid metabolizers for CYP2D6 or CYP2C19. Outcome measurements were recorded at baseline and 1-year follow-up. Data analysis was performed in December 2012 and updated March 2019. INTERVENTIONS The trial included 2 intervention groups, where antipsychotic drug treatment was guided by either CYP test (CYP test-guided [CTG]) or structured clinical monitoring (SCM), in which adverse effects and factors influencing compliance were systematically recorded at least once quarterly, and 1 control group. MAIN OUTCOMES AND MEASURES Primary outcome was antipsychotic drug persistence, ie, days to first modification of the initial treatment. Secondary outcomes were number of drug and dose changes, adverse effects, and psychotic symptoms, ie, hallucinations and delusions. RESULTS A total of 528 participants were genotyped, and 311 (median [interquartile range {IQR} age, 41 [30-50] years; 139 [45%] women; median [IQR] duration of illness, 6 [3-13] years) were randomly allocated to 1 of 3 study groups. Overall, 61 participants (20%) were extreme metabolizers.There was no difference in antipsychotic drug persistence between the CTG group and the control group (hazard ratio [HR], 1.02; 95% CI, 0.71-1.45) or SCM and the control group (HR, 0.88; 95% CI, 0.61-1.26). Subanalyses among extreme metabolizers showed similar results (CTG: HR, 0.99; 95% CI, 0.48-2.03; SCM: HR, 0.93; 95% CI, 0.44-1.96).

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Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study

Cited by 134 publications

References 29 publications

Delineating significant genome-wide associations of variants with antipsychotic and antidepressant treatment response: implications for clinical pharmacogenomics

Delineating significant genome-wide associations of variants with antipsychotic and antidepressant treatment response: implications for clinical pharmacogenomics

Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?

Effect of Routine Cytochrome P450 2D6 and 2C19 Genotyping on Antipsychotic Drug Persistence in Patients With Schizophrenia

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