Associations between MDR1 gene polymorphisms and schizophrenia and therapeutic response to olanzapine in female schizophrenic patients

Božina, Nada; Kuzman, Martina Rojnić; Medved, Vesna; Jovanović, Nikolina; Sertić, Jadranka; Hotujac, Ljubomir

doi:10.1016/j.jpsychires.2006.10.002

Cited by 71 publications

(46 citation statements)

References 58 publications

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“…Carriers of 2677T/3435T haplotypes would be prone to effects of risperidone treatment, including effects on weight gain, having higher risperidone brain concentrations, whereas carriers of G2677/C3435 haplotype would be more "resistant" to risperidone effects, including induced weight gain. This hypothesis is also supported by the finding of significantly better treatment response among carriers of 2677TT and 3435TT genotype, which was observed in this study, and compatible with previous studies (Bozina et al, 2006. That would suggest a pharmacokinetic effect of MDR1 on weight gain.…”

Section: Discussionsupporting

confidence: 93%

“…52 out of 108 female patients were included in a previous study by our group, described in Bozina et al, (2006). Inclusive criteria, diagnosis and illness description were the same as described in the mentioned publication.…”

Section: Subjectsmentioning

confidence: 99%

“…With regard to the -759 polymorphisms, the C allele is denoted by 126 bp fragment and the T allele by a 160 bp fragment. Analysis of 2677 G/T/A polymorphisms in exon 21 of MDR1 and 3435C/T polymorphism in exon 26 were previously described in Bozina et al, (2006).…”

Section: Genotypingmentioning

confidence: 99%

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The influence of 5-HT2C and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

Kuzman

Medved

Božina

et al. 2008

Psychiatry Research

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Section: Discussionsupporting

confidence: 93%

Section: Subjectsmentioning

confidence: 99%

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The influence of 5-HT2C and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

Kuzman

Medved

Božina

et al. 2008

Psychiatry Research

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“…Overexpression of this protein may result in drug resistance. Positive findings of association between MDR1 polymorphisms (2677-T/T and 3455-T/T) with better response and cognitive improvement 150,151 were not supported in a recent study. 149 However, the biological importance of alterations in MDR1 activity warrants further investigation of its genetic variants.…”

Section: Developmental and Regulatory Genesmentioning

confidence: 71%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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“…[45][46][47] The difference in drugs is likely not the reason for the discrepant results, because risperidone has a higher affinity for P-glycoprotein than olanzapine and thus a stronger effect would be expected. 10 It is not clear which of the ABCB1 polymorphisms is functional, and variable patterns of LD in the region can lead to different association results.…”

Section: Pharmacogenetics Of Risperidone In Autismmentioning

confidence: 99%

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

Almeida²,

et al. 2009

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Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G4A, DRD3 Ser9Gly, HTR2C c.995G4A and ABCB1 1236C4T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G4A, HTR2C c.68G4C (p.C33S), HTR6 c.7154-2542C4T and BDNF c.196G4A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G4C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism.

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Associations between MDR1 gene polymorphisms and schizophrenia and therapeutic response to olanzapine in female schizophrenic patients

Cited by 71 publications

References 58 publications

The influence of 5-HT2C and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

The influence of 5-HT2C and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

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