Impact of the CYP2D6 phenotype on hyperprolactinemia development as an adverse event of treatment with atypical antipsychotic agents in pediatric patients

Grădinaru, Raluca Claudia; Andreescu, Nicoleta; Nussbaum, Laura Alexandra; Suciu, Liana; Puiu, Maria

doi:10.1007/s11845-019-01985-x

Cited by 12 publications

(8 citation statements)

References 13 publications

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“…The situation is similar for ABCB1, with some studies having found association [17,18] with antipsychotic responses while others have not [19] . There have also been reports of association with genetic variation in CYPs and ABCB1 with adverse effects [20][21][22][23] . These studies focus on particular adverse effects, such as QT interval prolongation, dyskinesias and prolactinemia.…”

Section: Introductionmentioning

confidence: 99%

The influence of CYP enzymes and ABCB1 on treatment outcomes in schizophrenia: association of CYP1A2 activity with adverse effects

Cendrós¹,

Arranz²,

Torra³

et al. 2020

JTGG

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Aim: Genetic variants on metabolic and transport enzymes are good candidates to explain inter-individual differences in response to antipsychotics. The aim of this study is to evaluate and compare the influence of the CYP2D6 , CYPC19, CYP1A2 and ABCB1 variants on plasma levels, treatment response and side effects of antipsychotics. Methods: Twenty polymorphisms in selected genes were genotyped in 318 patients diagnosed with schizophrenia, schizoaffective or delusional disorder treated with antipsychotics (clozapine, olanzapine, paliperidone, risperidone, aripiprazole and quetiapine). Plasma drug levels were determined after 6 weeks of treatment. The Positive and Negative Symptoms Scale (PANSS) and UKU scale of side effects were recorded at baseline and after 12 weeks of treatment. The effect of gene variants on plasma drug levels, treatment response and adverse effects were examined by multinomial regression. Results: CYP1A2 was found to be associated with psychic side effects (P = 0.02), with variants predicting higher enzyme activity associated with lower adverse effects, and was the strongest predictor for this adverse effect of all the studied factors. Functional variants in CYP genes were associated with plasma level differences, with higher activity variants associated with lower plasma levels. No association with improvement of the condition, as measured by the PANSS score, was found in this study. Conclusion: The results suggest that increased CYP1A2 activity protects against psychic side effects. Few studies have evaluated the impact of genetic factors on treatment response or side effects, and only in relation to a selection of adverse reactions. These results are a step towards better understanding of the factors behind the different aspects of clinical outcomes, such as various adverse effects.

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Section: Introductionmentioning

confidence: 99%

The influence of CYP enzymes and ABCB1 on treatment outcomes in schizophrenia: association of CYP1A2 activity with adverse effects

Cendrós¹,

Arranz²,

Torra³

et al. 2020

JTGG

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“…Cytochromes genotyping (and phenotyping) was the preferred approach when investigating ADRs, especially in pediatric studies. Studies relying on large sample size underlined increased weight gain [51], prolactin levels [77], risk of EPS [71], and impaired treatment response [52] in patients deprived from at least one functional allele for CYP2D6, resulting in increased drug exposure. While the findings regarding movement abnormalities and lack of therapeutic effect concur with existing evidence [84,85], AIWG [86] and hyperprolactinemia [87] were not consistently linked with CYP2D6 impairments.…”

Section: Discussionmentioning

confidence: 99%

“…They also reported a case of a CYP2D6 *4/*41 (PM) adolescent with, among other ADRs, galactorrhea and constipation, treated with clozapine and loxapine. In patients treated with atypical APs, Grădinaru et al [77] found that the mean level of prolactin was higher for IMs than for extensive (normal) metabolizers (EMs) at each time point except baseline. Menus et al [61] noted a significant effect of CYP3A4 expression on constipation (47.1% in normal/high CYP3A4 expressers, 71.4% in low CYP3A4 expressers, OR = 3.6 (95% CI = 0.9-14.1), p = 0.06).…”

Section: Othersmentioning

confidence: 99%

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Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

Merino

Fernandez

Gérard³

et al. 2022

Pharmaceuticals

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Children and youth treated with antipsychotic drugs (APs) are particularly vulnerable to adverse drug reactions (ADRs) and prone to poor treatment response. In particular, interindividual variations in drug exposure can result from differential metabolism of APs by cytochromes, subject to genetic polymorphism. CYP1A2 is pivotal in the metabolism of the APs olanzapine, clozapine, and loxapine, whose safety profile warrants caution. We aimed to shed some light on the pharmacogenetic profiles possibly associated with these drugs’ ADRs and loss of efficacy in children and youth. We conducted a systematic review relying on four databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations and checklist, with a quality assessment. Our research yielded 32 publications. The most frequent ADRs were weight gain and metabolic syndrome (18; 56.3%), followed by lack of therapeutic effect (8; 25%) and neurological ADRs (7; 21.8%). The overall mean quality score was 11.3/24 (±2.7). In 11 studies (34.3%), genotyping focused on the study of cytochromes. Findings regarding possible associations were sometimes conflicting. Nonetheless, cases of major clinical improvement were fostered by genotyping. Yet, CYP1A2 remains poorly investigated. Further studies are required to improve the assessment of the risk–benefit balance of prescription for children and youth treated with olanzapine, clozapine, and/or loxapine.

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“…Since aripiprazole is preferentially metabolized by CYP2D6, the safety or effectiveness of this drug might be affected by CYP2D6 genetic variability. Recent studies have found an association between CYP2D6 genetic polymorphisms and hyperprolactinemia, especially in female pediatric populations who are poor CYP2D6 metabolizers ( Grădinaru et al, 2019 ; Koller et al, 2020 ). Hyperprolactinemia may significantly affect the growth and development of pediatric populations ( Grădinaru et al, 2019 ), and therefore, these patients need additional monitoring, especially when diagnosed with ASD.…”

Section: Pharmacogenomics In Asdmentioning

confidence: 99%

Pharmacogenomics and non-genetic factors affecting drug response in autism spectrum disorder in Thai and other populations: current evidence and future implications

Biswas,

Vanwong,

Sukasem

2024

Front. Pharmacol.

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Autism spectrum disorder (ASD) may affect family and social life profoundly. Although there is no selective pharmacotherapy for ASD, the Food and Drug Administration (FDA) has recommended risperidone/aripiprazole to treat the associated symptoms of ASD, such as agitation/irritability. Strong associations of some pharmacokinetic/pharmacodynamic gene variants, e.g., CYP2D6 and DRD2, with risperidone-induced hyperprolactinemia have been found in children with ASD, but such strong genetic associations have not been found directly for aripiprazole in ASD. In addition to pharmacogenomic (PGx) factors, drug–drug interactions (DDIs) and possibly cumulative effects of DDIs and PGx may affect the safety or effectiveness of risperidone/aripiprazole, which should be assessed in future clinical studies in children with ASD. Reimbursement, knowledge, and education of healthcare professionals are the key obstacles preventing the successful implementation of ASD pharmacogenomics into routine clinical practice. The preparation of national and international PGx-based dosing guidelines for risperidone/aripiprazole based on robust evidence may advance precision medicine for ASD.

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Impact of the CYP2D6 phenotype on hyperprolactinemia development as an adverse event of treatment with atypical antipsychotic agents in pediatric patients

Cited by 12 publications

References 13 publications

The influence of CYP enzymes and ABCB1 on treatment outcomes in schizophrenia: association of CYP1A2 activity with adverse effects

The influence of CYP enzymes and ABCB1 on treatment outcomes in schizophrenia: association of CYP1A2 activity with adverse effects

Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

Pharmacogenomics and non-genetic factors affecting drug response in autism spectrum disorder in Thai and other populations: current evidence and future implications

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