Schizophrenia Pharmacogenetics: cognition and symptom response to antipsychotics

描述（由申请人提供）：拟进行的研究目的是研究在没有或很少有抗精神病药物治疗史的首发精神分裂症患者中，选定的谷氨酸基因变异与对抗精神病药物利培酮的认知反应和阴性症状反应的关系。精神分裂症是一种非常普遍的疾病（占人口的-1%），与明显和持续的认知功能障碍有关，而且费用昂贵。这种疾病的精神病症状，如幻觉和妄想，通常对利培酮等抗精神病药物反应良好。然而，治疗后认知和阴性症状的改善是适度的，因人而异。对治疗的不同反应可能部分与药物反应和神经递质活性的个体间遗传差异有关，这些差异会影响患者从给定药物中获益的可能性。描述这些变异的来源并研究针对个体患者的最佳治疗方法将改善长期结果。这将是一项药物遗传学研究，对100名首次发作的精神分裂症患者进行了4-6周的利培酮单药治疗。将评估两种谷氨酸基因中选定的变异与治疗过程中认知生物标志物、神经心理学表现和临床症状变化的关系。将比较所选基因型组的性能变化，同时用全基因组标记进行种群分层控制。这项研究将与认知神经科学和遗传学的培训计划一起进行，为未来的药物遗传学研究做准备，利用中间认知表型和临床症状来研究反应变异的来源和药物作用的新机制。公共卫生相关性：此应用程序的目标是通过推进精神病学个性化医学领域来产生新的科学知识，从而改善精神分裂症患者的治疗。通过研究大脑功能的敏感指标与药物治疗和疾病相关基因的常见变异之间的关系，我们将提高我们预测个体患者反应的能力。

DESCRIPTION (provided by applicant): The goal of the proposed research is to investigate the relationship of selected glutamate gene variants with cognitive and negative symptom response to the antipsychotic risperidone in first episode patients with schizophrenia who have little or no prior antipsychotic treatment history. Schizophrenia is a highly prevalent (-1% of population) and costly disease associated with marked and persistent cognitive dysfunction. Psychotic symptoms like hallucinations and delusions that occur with this disease often respond well to antipsychotic agents like risperidone. However, cognitive and negative symptom improvement after treatment is modest and highly variable from person to person. Variable responses to treatment are likely in part related to inter-individual genetic differences in drug response and neurotransmitter activity that affect a patient's likelihood of benefiting from a given medication. Characterizing these sources of variability and investigating ways to optimize treatments for individual patients will improve long term outcomes. This will be a pharmacogenetic study of 100 first episode schizophrenia subjects who have been treated with risperidone monotherapy for 4-6 weeks. Selected variants within two glutamate genes will be assessed for their relationships to change in cognitive biomarkers, neuropsychological performance, and clinical symptoms over the course of treatment. Changes in performance will be compared across selected genotype groups while controlling for population stratification assessed with genome wide markers. This research will be conducted in conjunction with a training program in cognitive neuroscience and genetics to prepare the PI for future pharmacogenetic studies using intermediate cognitive phenotypes and clinical symptoms to investigate sources of response variability and novel mechanisms of drug action. PUBLIC HEALTH RELEVANCE: The goal of this application is to generate new scientific knowledge that will improve the treatment of patients with schizophrenia by advancing the field of personalized medicine in psychiatry. Through the investigation of relationships between sensitive measures of brain function with common variations in genes related to drug treatments and disease we will advance our ability to predict response in individual patients.