Enhancing the Prospective Prediction of Psychosis

描述（由申请人提供）：这3个研究中心的协作U 01旨在提高在完全精神分裂症综合征发作之前，在疾病的初始前驱期将发展为精神分裂症性精神病（包括短暂精神病性障碍、精神分裂症样障碍、精神分裂症或情感障碍）的个体的识别。准确识别精神分裂症的精神病风险可能是该领域开发更有效的治疗策略的最大希望，包括对这种典型的破坏性疾病的二级预防。由于缺乏敏感和特异的前驱诊断策略，干预研究存在争议，任何研究的结果对临床实践的影响都将有限。迄今为止，鉴定工作主要集中在减弱的阳性症状上，但这些标准不考虑精神病前驱期出现的阴性症状，这些症状是精神分裂症的基础。为了提高前驱症状评估的潜在敏感性，我们开发了一种修改版的“前驱症状标准”（COPS），保留了减弱的阳性症状，但也考虑了前驱状态诊断中的选定阴性症状。我们建议开发一个精神分裂症的精神病风险预测模型，我们提出的风险因素是基于以下假设选择的：精神分裂症是由病理性神经发育过程引起的，该过程发生在妊娠期前脑发育的关键阶段，并影响主要在丘脑、前额叶和额叶皮质以及大脑边缘系统区域（丘脑边缘皮质回路[TLCC]）的神经元发育。这些神经发育异常可能在发病前通过微妙的行为、认知和结构“脆弱性标记”表达。在大多数情况下，这些异常需要特定的成熟过程（即，突触消除、髓鞘形成），其发生在青春期前后，以暴露脆弱性并触发功能障碍，导致减弱的阳性和阴性症状的发展或恶化（临床上定义为“处于危险中”状态），以及社会功能、社会认知、神经认知功能、嗅觉和运动功能的多样但特定的损伤。我们假设，随着TLCC的连接变得更加功能失调，结果将是可测量的损伤的严重程度增加，更多的领域受到更大程度的影响。因此，TLCC回路损伤的症状表现的数量和严重程度是精神分裂症精神病的生物学高风险状态的指标。此外，我们假设这些脆弱的神经回路可能会受到青春期通常发生的环境事件的进一步干扰，例如压力生活事件或药物滥用。这些压力源可能超过相关回路的适应能力，从而产生疾病发作的特征性症状。发展精神分裂症的精神病风险评估模型，我们提出了一个3个网站的前瞻性研究180个人会议修改后的“标准前驱综合征”，和80个寻求帮助的控制对象，将前瞻性评估超过2-5年的发展精神分裂症的精神病的风险。该合作团队开发了该领域的领先仪器，并在社会认知，神经认知，发展精神病理学，统计和数据管理方面拥有丰富的专业知识。每个研究中心都在之前的合作中证明了其招募前驱患者的能力。

DESCRIPTION (provided by applicant): This 3-site collaborative U01 aims to improve identification of individuals who will develop schizophrenic psychosis (including brief psychotic disorder, schizophreniform disorder, schizophrenia, or schizoaffective disorder) at the initial prodromal stage of illness, prior to the onset of the full schizophrenic syndrome. Accurate identification of schizophrenic psychosis risk offers what may be the field's best hope for developing more effective treatment strategies, including secondary prevention of this typically devastating disorder. Without sensitive and specific prodromal diagnosis strategies, intervention studies are controversial, and the results of any studies will have limited impact on clinical practice. Identification efforts to date have focused on attenuated positive symptoms, but these criteria do not consider negative symptoms that occur in the prodromal stages of psychosis and are fundamental to schizophrenia. To enhance the potential sensitivity of prodrome evaluation we have developed a modified version of the "Criteria of Prodromal Syndrome" (COPS) that retains attenuated positive symptoms, but also considers selected negative symptoms in the diagnosis of prodromal state. We propose to develop a schizophrenic psychosis risk prediction model, and our proposed risk factors are selected based on the hypothesis that schizophrenia results from a pathological neurodevelopmental process that occurs during a critical stage of forebrain development in gestation and affects the development of neurons primarily in the thalamic, prefrontal and frontal cortical, and limbic regions of the brain (thalamolimbic- cortical circuitry [TLCC]). These neurodevelopmental abnormalities are likely to be expressed premorbidly by subtle behavioral, cognitive, and structural "vulnerability markers". In most cases, these abnormalities require specific maturational processes (i.e., synaptic elimination, myelination), which occur around puberty, to unmask the vulnerability and trigger dysfunction, resulting in the development or worsening of attenuated positive and negative symptoms (clinically defining the "at risk" state), as well as diverse but specific impairments in social function, social cognition, neurocognitive function, olfaction, and motor function. We hypothesize that as connectivity of the TLCC becomes more dysfunctional, a consequence will be increased severity of measurable impairments with more domains being affected to a greater extent. Thus, the number and severity of symptomatic manifestations of TLCC circuit impairment are indicators of a biologically high-risk state for schizophrenic psychosis. Furthermore, we hypothesize that these vulnerable neural circuits may be further perturbed by environmental events that typically occur during adolescence, such as stressful life events or drug abuse. Such stressors may exceed the adaptive capacity of relevant circuits producing the characteristic symptoms that signal the onset of the illness. To develop the schizophrenic psychosis risk assessment model we propose a 3-site prospective study of 180 individuals meeting modified "Criteria for Prodromal Syndrome", and 80 help-seeking control subjects who will be prospectively evaluated over 2-5 years for risk of developing schizophrenic psychosis. The collaborative team has developed leading instruments in this field and has substantial expertise in social cognition, neurocognition, developmental psychopathology, statistics and data management. Each site has proven its ability to recruit prodromal patients in a previous collaboration.