Schizophrenia Pharmacogenetics: cognition and symptom response to antipsychotics

描述（由申请方提供）：拟定研究的目的是调查选择的谷氨酸基因变异体与抗精神病药利培酮治疗的首次发作精神分裂症患者（既往很少或没有抗精神病药治疗史）的认知和阴性症状反应之间的关系。精神分裂症是一种高度流行的（约1%的人口）和昂贵的疾病与显着和持续的认知功能障碍。精神病症状，如幻觉和妄想，发生这种疾病往往反应良好，抗精神病药物，如利培酮。然而，治疗后认知和阴性症状的改善是适度的，并且因人而异。对治疗的可变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，这些差异影响患者从给定药物中获益的可能性。表征这些变异性来源并研究优化个体患者治疗的方法将改善长期结局。这是一项药物遗传学研究，纳入了100例接受利培酮单药治疗4-6周的首发精神分裂症受试者。将评估两个谷氨酸基因内的选定变体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。将在选定的基因型组之间比较性能的变化，同时控制用全基因组标记物评估的群体分层。本研究将与认知神经科学和遗传学培训项目联合进行，以使PI为未来的药物遗传学研究做好准备，使用中间认知表型和临床症状研究反应变异性的来源和药物作用的新机制。公共卫生相关性：该应用程序的目标是产生新的科学知识，通过推进精神病学个性化医学领域来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.