Negative Symptoms of Schizophrenia: From Phenomenology to Targeted Treatment

精神分裂症的阴性症状：从现象学到针对性治疗

• 批准号: 7750019
• 负责人: ARIELLE D STANFORD
• 金额: $ 17.71万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750019
• 关键词: Abnormal Cell; Adverse event; Age; Attention; Audiometry; Brain; Characteristics; Chemistry; Clinical Trials; Cognition; Cognitive; Controlled Clinical Trials; Data; Demographic Factors; Development Plans; Disease; Dose; Double-Blind Method; Dropout; Etiology; Fathers; Frequencies; Functional Imaging; Goals; Grouping; Hamilton Rating Scale for Depression; Heterogeneity; Image; Inferior; Intervention; Left; Link; Location; Maps; Mediating; Mediator of activation protein; Memory; Mental Depression; Mentored Patient-Oriented Research Career Development Award; Movement Disorders; Neurobiology; Neurons; Outcome; Parietal Lobe; Paternal Age; Patients; Pharmaceutical Preparations; Physiology; Positioning Attribute; Prefrontal Cortex; Quality of life; Randomized; Randomized Clinical Trials; Reporting; Research; Research Design; Research Personnel; Research Training; Resistance; Resolution; Rest; Role; Safety; Sampling; Schizophrenia; Severe Acute Respiratory Syndrome; Shapes; Site; Social Functioning; Subgroup; Symptoms; Testing; Variant; active method; age related; arm; career; career development; deficit syndrome; depressive symptoms; design; executive function; experience; improved functioning; neural circuit; neuropsychological; novel; offspring; regional difference; relating to nervous system; repetitive transcranial magnetic stimulation; response; sex; skills; skills training; therapy development; tool; treatment site; treatment strategy

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development Award will provide Dr. Arielle Stanford with the training and skills needed to become an independent investigator with expertise in the development of treatments targeting the negative symptoms of schizophrenia. Negative symptoms are among the strongest predictors of poor outcome and are not very responsive to treatment. Novel treatments are needed to alleviate these symptoms and improve functioning. Most treatment studies have not focused on the large between-patient variability in phenomenology and etiology that may contribute to reduced response rates. This project will evaluate the potential utility of repetitive transcranial magnetic stimulation (rTMS) as an intervention that may test etiological hypotheses linked to heterogeneity and treat negative symptoms. While it has been difficult to meaningfully separate schizophrenia disease variants, there are subgrouping strategies that could be explored with respect to negative symptoms, including the division of patients into Deficit Syndrome (DS) and nonDS groups, and data supporting Paternal Age Related Schizophrenia (PARS) as an independent variant. Studies suggest that different types of negative symptoms map to disparate neural circuits. Thus, noninvasive focal brain stimulation may have specific advantages over medications, which lack spatial resolution. rTMS can modulate neuronal activity and produce regionally specific excitatory or inhibitory effects through modulation of local physiology and chemistry. The efficacy of rTMS may be enhanced by site-specific application targeted to patient subgroups. None of the existing studies of rTMS in schizophrenia have entailed full characterization of patients, nor has DS been considered as a response mediator. Lastly, studies of negative symptoms have only targeted the DLPFC, omitting the potential role of other cortical regions. The aims of this Mentored Patient-Oriented Research Career Development Award are to 1) to examine the efficacy and safety of rTMS as a treatment for the negative symptoms of schizophrenia and 2) to characterize responders vs. non-responders to rTMS with respect to etiological subgroup (DS vs. non-DS) and other baseline characteristics, including cognitive and demographic, using the focality of rTMS as a brain probe to test hypotheses regarding the neural underpinnings of negative symptoms. The candidate's career goal is to develop novel treatment strategies tailored to the symptom profile and schizophrenia subtype of the patient, i.e. to shape this novel intervention to the heterogeneity of schizophrenia. The career development plan will provide expertise in: 1) the neurocircuitry of negative symptoms, 2) the use of TMS as a neurobiological probe and as a treatment tool; and 3) clinical trial research design and statistical analysis. This training and research experience will position Dr. Stanford to become an independent investigator in the field of intervention development in the study and treatment of schizophrenia.

描述（由申请人提供）：这项以患者为导向的指导研究职业发展奖将为Arielle Stanford博士提供所需的培训和技能，使其成为一名独立的研究者，具有针对精神分裂症阴性症状的治疗方法的开发方面的专业知识。阴性症状是预后不良的最强预测因子之一，而且对治疗反应不大。需要新的治疗方法来减轻这些症状并改善功能。大多数治疗研究并没有关注患者之间在现象和病因学上的巨大差异，这可能导致反应率降低。本项目将评估重复经颅磁刺激（rTMS）作为一种干预措施的潜在效用，该干预措施可能测试与异质性相关的病因学假设并治疗阴性症状。虽然很难有意义地分离精神分裂症疾病变体，但可以探索有关阴性症状的亚组策略，包括将患者分为缺陷综合征（DS）和非DS组，以及支持父亲年龄相关精神分裂症（PARS）作为独立变体的数据。研究表明，不同类型的负面症状映射到不同的神经回路。因此，非侵入性局灶性脑刺激可能比缺乏空间分辨率的药物有特殊的优势。rTMS可以通过调节局部的生理和化学作用，调节神经元的活动，产生区域特异性的兴奋或抑制作用。rTMS的疗效可以通过针对患者亚组的部位特异性应用而增强。现有的关于精神分裂症的rTMS研究都没有涉及到患者的完整特征，也没有认为DS是一种反应介质。最后，对阴性症状的研究仅针对DLPFC，而忽略了其他皮质区域的潜在作用。这项以指导患者为导向的研究职业发展奖的目的是：1)检查rTMS作为精神分裂症阴性症状治疗的有效性和安全性；2)利用rTMS的焦点作为大脑探针，通过病因亚组（DS与非DS）和其他基线特征（包括认知和人口统计学）来表征rTMS的应答者和无应答者，以检验关于阴性症状神经基础的假设。候选人的职业目标是针对患者的症状特征和精神分裂症亚型制定新的治疗策略，即塑造这种针对精神分裂症异质性的新型干预措施。职业发展计划将提供以下方面的专业知识：1)阴性症状的神经回路，2)使用经颅磁刺激作为神经生物学探针和治疗工具；3)临床试验研究设计与统计分析。这一培训和研究经验将使斯坦福博士成为精神分裂症研究和治疗干预发展领域的独立研究者。