ABCB1 and CYP2D6 polymorphisms and treatment response of psychotic patients in a naturalistic setting

Papazisis, Georgios; Goulas, A.; Sarrigiannidis, A.; Bargiota, Stavroula I.; Antoniadis, Diomidis; Raikos, Νikolaos; Basgiouraki, Emmanouela; Bozikas, Vasilis P.; Garyfallos, George

doi:10.1002/hup.2644

Cited by 8 publications

(7 citation statements)

References 47 publications

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“…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. However, olanzapine is mostly metabolized by CYP1A2 (and to a lesser extent by CYP2D6 and CYP3A4) [88,89], clozapine is mainly metabolized by CYP3A4 and CYP1A2 (with CYP2D6 playing a minor role) [16,90], and loxapine is primarily metabolized by CYP1A2 (then by CYP3A4 and CYP2D6) [19].…”

Section: Discussionsupporting

confidence: 79%

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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Section: Discussionsupporting

confidence: 79%

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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“…ABCB1 has also been studied regarding efficacy. Papazisis et al [17] found an involvement of ABCB1 in the evolution of PANSS, but only in patients with decreased CYP2D6 activity, and also only for the rs2032582 (2677G>T/A) polymorphism in ABCB1, but not rs1045642 (3435C>T), which is the one used in the present study. Other authors, however, have been able to find an effect of 3435C>T on clinical improvement [18,40] .…”

Section: Discussionmentioning

confidence: 55%

“…For CYP2D6, there are negative reports [15] , although it has also been reported that improvement of the condition is affected by the metabolizing phenotype [7,16] . 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] .…”

Section: Introductionmentioning

confidence: 87%

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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“…Consensus on the association between ABCB1 SNPs and drug response has been lacking, due to their unclear effect on protein expression and activity, with no established clinical indication for analysis of variants. Despite this, in a recent study, Papazisis and colleagues conclude that an interaction between ABCB1 and CYP2D6 might affect patients’ response to antipsychotic treatments . Indeed, patients carrying a combination of a loss of function (LOF) CYP2D6 allele and an ABCB1 rs2032582 TT genotype presented a significantly worse response to antipsychotic drug treatment compared to non‐carriers.…”

Section: Discussionmentioning

confidence: 98%

Pharmacogenetic variants in bipolar disorder with elevated treatment resistance and intolerance: Towards a personalized pattern of care

et al. 2019

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Although available treatments for bipolar disorder (BD) are effective in reducing the risk of recurrence, over 90% of patients experience relapses and a significant minority have a poor outcome.Among patients who do respond, mild and subthreshold symptoms of the disorder are frequently observed and greatly affect their quality of life.Interindividual variability in drug response and side effects depends on a variety of non-genetic factors such as gender, ethnicity, age, smoking, diet, psychiatric diagnosis, disease status and concomitant medications, but also genetic ones. 1 As most antipsychotic medications undergo first-pass metabolism, cytochrome (CYP) 450 enzymes play a crucial role in drug response, influencing bioavailability, clearance and, for some antipsychotics like risperidone and clozapine, bioactivation. Furthermore, pharmacodynamic-related gene variants are hypothesized to affect both drug response and susceptibility to side effects. Overall, specific predictor biomarkers of treatment response are still lacking. 2 Despite the difficulty of clearly defining genetic variants that can guide clinicians towards a prediction of individual drug response, retrospective analysis of specific cases is considered useful in the development of a personalized approach to care.We report on the case of a patient with a long history of drug resistance and adverse reactions that led to poor compliance and severe chronicity. A retrospective analysis on the patient's pharmacogenetic profile revealed polymorphisms that could explain otherwise puzzling peculiarities of the patient's history. | C A S E REP ORTEDP is a 48-year-old Caucasian, smoking female with good premorbid social and cognitive functioning and no reported familiar psychiatric history. The only child of a married couple, whose mother described a physiological perinatal period and early-life psychomotor development, EDP had a clinical onset at the age of 28, with a manic episode characterized by elevated mood, increased psychomotor activity, persecutory and grandiose delusions with abnormal behaviour and a significant lack of insight. Abuse of neither alcohol nor any other substance was reported. A diagnosis of BD was made according to DSM-IV criteria and a treatment regimen with a first-generation antipsychotic started. The patient soon complained of severe muscular postural rigidity and a switch to a second-generation antipsychotic and a mood stabilizer was initiated with a rapid emergence of similar adverse reactions. During her long clinical history, she was treated with most available antipsychotics, mood stabilizers and antidepressants, showing severe adverse reactions with almost all of them even at the lowest dose. This often limited the possibility of reaching effective doses and jeopardized her compliance.EDP presented with a severe disorder with continuous hospitalizations and a progressive deterioration of her psychosocial

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ABCB1 and CYP2D6 polymorphisms and treatment response of psychotic patients in a naturalistic setting

Cited by 8 publications

References 47 publications

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

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

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

Pharmacogenetic variants in bipolar disorder with elevated treatment resistance and intolerance: Towards a personalized pattern of care

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