Schizophrenia Pharmacogenetics: cognition and symptom response to antipsychotics

描述(申请人提供)：拟议研究的目标是调查在首发精神分裂症患者中，具有认知和阴性症状反应的选定谷氨酸基因变种与抗精神病药物利培酮的关系，这些患者以前很少或没有抗精神病药物治疗史。精神分裂症是一种高度流行(占人口的1%)且代价高昂的疾病，与显著和持续的认知功能障碍有关。与这种疾病相关的精神症状，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，而且因人而异。对治疗的不同反应可能在一定程度上与药物反应和神经递质活动的个体间遗传差异有关，这些差异影响了患者从特定药物中受益的可能性。确定这些可变性来源的特征并研究如何优化对个别患者的治疗将会改善长期结果。这将是一项对100名首发精神分裂症患者进行的药物遗传学研究，这些患者已经接受了4-6周的利培酮单一治疗。将评估两个谷氨酸基因内的选定变异与治疗过程中认知生物标记物、神经心理表现和临床症状变化的关系。性能的变化将在选定的基因型组之间进行比较，同时控制使用全基因组标记评估的人群分层。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好准备，使用中间认知表型和临床症状来调查反应变异性的来源和药物作用的新机制。

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.