Human Molecular Genetics Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.
Pharmacogenomics. 2012 Jul;13(10):1119-27. doi: 10.2217/pgs.12.86.
The conventional practice of using trial and error mode to select antipsychotic drugs in treatment of schizophrenia can result in symptom exacerbations, relapse and severe side effects, resulting in higher costs of treatment. P-glycoprotein (ABCB1) is known to regulate the concentration of antipsychotic drugs in the brain. Variable expressivity based on polymorphism in the gene ABCB1 may reflect on the drug response and its relationship to dosage.
MATERIALS & METHODS: All antipsychotic dosages administered to patients were converted to common chlorpromazine equivalents. Response to antipsychotics was based on 50% cutoff in Brief Psychiatric Rating Scale ratings after 1-year of follow-up. Using a case-control study design, ABCB1 polymorphisms were screened in 192 individuals grouped into responders and nonresponders.
A strong allelic, genotypic and haplotypic association, was observed, which was predictive of good response to antipsychotics. Individuals carrying the favorable homozygous genotypes of rs1045642 and rs2032582 displayed better response with increased dosage while those carrying risk genotype manifested refractoriness on increased dosage.
The study suggests that a priori knowledge of ABCB1 genotypes can provide a significant input into evaluating the patient's response to medication, and minimizing redundant dosing and refractoriness.
在治疗精神分裂症时，采用试错法选择抗精神病药物的传统做法可能导致症状恶化、复发和严重的副作用，从而增加治疗成本。众所周知，P-糖蛋白（ABCB1）可调节大脑中抗精神病药物的浓度。ABCB1 基因多态性导致的表达可变可能反映药物反应及其与剂量的关系。
将患者接受的所有抗精神病药物剂量转换为常见的氯丙嗪等效物。根据 1 年随访后简明精神病评定量表评分的 50%截断值，判断抗精神病药物的反应。采用病例对照研究设计，对 192 名分为反应者和非反应者的个体进行 ABCB1 多态性筛选。
观察到强等位基因、基因型和单倍型关联，与抗精神病药物的良好反应具有预测性。携带 rs1045642 和 rs2032582 有利纯合基因型的个体，随着剂量增加反应更好，而携带风险基因型的个体则表现出剂量增加时的耐药性。
该研究表明，ABCB1 基因型的先验知识可以为评估患者对药物的反应提供重要依据，并最大限度地减少冗余剂量和耐药性。
