Enhancing the Prospective Prediction of Psychosis

描述(由申请人提供)：这项由3个站点组成的合作U01旨在提高对将在疾病的最初前驱阶段，即在完全精神分裂症综合征发作之前，发展为精神分裂症精神病(包括短暂的精神障碍、分裂样障碍、精神分裂症或分裂情感障碍)的个人的识别。精神分裂症精神病风险的准确识别可能为该领域开发更有效的治疗策略提供了最大的希望，包括对这种典型的破坏性疾病的二级预防。如果没有灵敏和特异的先兆诊断策略，干预研究是有争议的，任何研究的结果对临床实践的影响都是有限的。到目前为止，识别工作的重点是减轻的阳性症状，但这些标准没有考虑出现在精神病前驱阶段的阴性症状，这些症状是精神分裂症的基础。为了提高先兆评估的潜在敏感性，我们开发了一种“前驱综合征标准”(COPS)的修订版，该标准保留了减弱的阳性症状，但也考虑了在诊断先兆状态时所选择的阴性症状。我们建议建立一个精神分裂症精神病风险预测模型，我们提出的风险因素是基于这样的假设，即精神分裂症是发生在妊娠前脑发育的关键阶段的病理性神经发育过程的结果，并主要影响大脑的丘脑、前额叶、额叶和边缘区域(丘脑边缘-皮质回路[TLCC])神经元的发育。这些神经发育异常很可能在发病前通过微妙的行为、认知和结构上的“脆弱标记”表现出来。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)，发生在青春期前后，以揭示脆弱性并触发功能障碍，导致减弱的阳性和阴性症状(临床上定义为“处于危险”状态)的发展或恶化，以及社会功能、社会认知、神经认知功能、嗅觉和运动功能的各种但特定的损害。我们假设，随着TLCC的连接变得更加功能失调，结果将是可测量损伤的严重性增加，更多的领域受到更大程度的影响。因此，TECC回路损害的症状表现的数量和严重程度是精神分裂症精神障碍的生物学高危状态的指标。此外，我们假设，这些脆弱的神经回路可能会进一步受到环境事件的干扰，这些事件通常发生在青春期，如应激生活事件或药物滥用。这种应激源可能会超过相关回路的适应能力，产生发出疾病开始信号的特征症状。为了开发精神分裂症精神病风险评估模型，我们提出了一项三点前瞻性研究，研究对象包括180名符合修改后的“前驱综合征标准”的个体和80名寻求帮助的对照受试者，他们将在2-5年内接受前瞻性评估，以了解精神分裂症精神病的发病风险。合作小组开发了这一领域的领先工具，并在社会认知、神经认知、发展精神病理学、统计学和数据管理方面拥有丰富的专业知识。每个网站都证明了它在之前的合作中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 TECC 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 provefi its ability to recruit prodromal patients in a previous collaboration.