奥氮平治疗早发精神分裂症的疗效与血药浓度及5-HTR2A、DRD2、COMT基因多态性的关联研究

Early-onset schizophrenia (EOS) is the World Health Organization ranked psychosis as the third most disabling condition worldwide in youth, and may lead to obvious social dysfunction and interfere seriously with neurodevelopmental processes in a young person, which in turn has the potential to irreversibly alter the trajectory of his or her life. To improve the outcome of the patients of EOS, elaborate and individualized therapeutic regimen is urgently needed. The functional gene polymorphisms and drug (antipsychotics) plasma concentration can both influence the drug response, but few studies explore the contributions of genetic heterogeneity, drug plasma concentration and clinical features of patients to drug response together and interactions of above factors in EOS patients. In this study we will recruit 100 DSM-Ⅴdefined EOS Han patients, older than 7 years old and onset of illness before 17 years old, and all EOS patients will receive a 8-week systematic olanzepine titration treatment and a battery of assessments of treatment effect and safety. Blood olanzepine plasma concentration will be tested regularly and genotyping of 8 polymorphisms of 5-HTR2A, DRD2 and COMT genes will be conducted by Polymerase Chain Reaction （PCR）, Restriction Fragment Length Polymorphism (RFLP) and TaqMan probes genotyping technology. The aim of the study is to explore the predictive factors on olanzepine treatment response in EOS, which can guide the individualized treatment and improve the cure rate of EOS in clinical setting.

早发精神分裂症（early-onset schizophrenia, EOS）是世界卫生组织确定的年轻人中第三大致残精神障碍，常导致患儿心理发育明显滞后，需要尽早给予个体化的治疗以改善患者预后。既往研究提示功能候选基因多态性、血药浓度都可能影响疗效，而目前国内外尚未见将两者结合在EOS中的疗效研究。本研究拟给予100例汉族EOS患者（17岁以前发病）八周抗精神病药物奥氮平治疗，定期评估患者的精神症状、副反应，并监测血药浓度和相关实验室指标。同时通过TaqMan等位基因分析技术或限制性片段长度多态性等成熟的方法检测检测患者5-HTR2A、DRD2和COMT三个基因8个多态性位点的基因型，从遗传多态性、血药浓度和临床特征全面考察奥氮平疗效的影响因素及其交互作用，阐明影响奥氮平疗效差异的分子遗传学机制，寻找有价值的疗效预测指标并建立疗效预测回归方程，以指导临床个体化治疗方案,提高EOS的治愈率。

早发精神分裂症(Early-Onset Schizophrenia，EOS)是儿童青少年群体中的一种严重导致个体社会功能损害的精神疾病，需要尽早给予个体化的治疗以改善患者预后。本研究旨在探索患者的临床特征、血药浓度、以及5-HTR2A、DRD2、COMT等候选基因多态性位点对奥氮平治疗EOS患儿疗效的影响，寻找有价值的疗效预测指标。本研究纳入96例7-17岁起病的符合国际疾病分类第10版(International Classification of Diseases-10，ICD-10)诊断标准的精神分裂症患者为研究对象，对所有EOS患儿依照体重给予12周系统的奥氮平剂量滴定治疗并评估疗效，在治疗达到最适剂量后的4~6天进行奥氮平血药浓度测定，并采用 MassArray等位基因分型技术检测上述3个基因共9个多态性位点。结果显示：（1）在云南省EOS患者样本中，12周的奥氮平单药治疗有效率为72.9%（PANSS减分率≥25%），对阳性、阴性、一般病理症状、以及抑郁症状都有改善，患者社会功能好转，且药物对阳性和一般病理症状的改善优于阴性症状。（2）奥氮平血药浓度可能随着EOS服用奥氮平公斤体重剂量的增加而增高，性别及年龄不影响奥氮平血药浓度，血药浓度高低和疗效不相关。（3）行×列表分析显示携带5-HT2A rs6313多态性A/A、G/A基因型和5-HT2A rs6311多态性C/T基因型的EOS治疗有效率高；二元Logistic回归分析显示IQ高、母亲受教育程度高、家族史为阴性且携带5-HT2A rs63116311 C/T基因型等因素预测奥氮平治疗有效，而血药浓度高低不预测疗效。综合临床特征、血药浓度及易感基因多态性对EOS疗效进行预测的研究在国内外尚未见报道，具有一定的创新性。此外，本研究结果可指导临床医生对该类患者进行个体化的治疗，提高EOS治疗有效率，改善患者预后。