Association of genetic polymorphisms with psychotropic-response in mental disorders

遗传因素在个体间药物反应差异中的重要性已逐渐明确。因此，为了明确临床反应的标志物、实现个体化用药、发现新药，作为研究药理学反应及其受遗传影响的改变的科学的遗传药理学得到了广泛的开展。为此，我们对精神药物进行了以下遗传药理学研究。1.利培酮的反应：D2和5-HT 2A基因单倍型与利培酮治疗精神分裂症的临床疗效相关。2. SSRI反应：新发现的5-HT转运体基因氨基酸替换与难治性家族性强迫症相关。3.多巴胺转运体基因VNTR多态性是甲基苯丙胺所致精神病的危险因素，我们还阐明了与精神障碍或治疗反应相关的遗传多态性的功能意义。利用培养细胞的表达研究显示，非典型抗精神病药物包括佐替平、利培酮、氯氮平对5-HT 5A受体具有高亲和力，并且与氯氮平反应相关的5-HT 2C受体基因中Ser 15的Bmax约为Per15.2.Cys23Ser的50%：利用培养细胞进行的表达研究表明，Ser 23等位基因可能比Cys 231更具有组成性活性。我们将继续进行精神药物的药物遗传学研究，以获得药物反应的标志物，并为新药的开发开辟道路。

The importance of genetic factors among inter-individual diversities of drug response has been steadily clarified. As a result, pharmacogenetics, which is defined as the science of pharmacological response and its modification by hereditary influence has been extensively carried out in order to clarify a marker of clinical response, put individualized medicine into a reality, and discover a new drug.Thus, we carried out the following pharmacogenetic studies of psychotropics.1.Risperidone response : D2 and 5-HT2A gene haplotype is associated with clinical efficacy of risperidone in schizophrenia.2.SSRI response : Newly identified amino acid substitution in 5-HT transporter gene is associated with treatment resistant familiar obsessive compulsive disorder3.Amphtamine response : VNTR polymorphism of the dopamine transporter gene is a risk factor for methamphetamine induced psychosisWe also elucidated the functional meanings of genetic polymorphism associated with mental disorders or treatment response.1.Pro15Ser in 5-HT5A receptor gene associated with schizophrenia : The expression study using cultured cell revealed that atypical antipsychotics including zotepine, risperidone, clozpine have high affinity to 5-HT5A receptor and the Bmax of the Ser15 is about 50% of that of the Per15.2.Cys23Ser in 5-HT2C receptor gene associated with Clozapine response : The expression study using cultured cell revealed that the Ser23 allele may be constitutively more active than Cys23lWe are going to continue pharmacogenetic studies of psychotropics to obtain a marker for the drug response and open the road to the development of a new drug.