Enhancing the Prospective Prediction of Psychosis

描述（由申请人提供）：这个3点合作R01旨在提高在疾病的初始前驱阶段，在完全精神分裂症综合征发作之前，将发展为精神分裂症精神病（包括短暂精神障碍、精神分裂症样障碍、精神分裂症或精神分裂症情感性障碍）的个体的识别。对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。由于缺乏敏感和特异性的前驱诊断策略，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，但这些标准没有考虑出现在精神病前驱阶段的阴性症状，而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，我们开发了一个修改版本的“前驱症状综合征标准”（COPS），保留了减轻的阳性症状，但也考虑了前驱状态诊断中选定的阴性症状。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，即精神分裂症是在妊娠期前脑发育的关键阶段发生的病理神经发育过程，主要影响丘脑、前额叶和额叶皮质以及大脑边缘区域的神经元发育（丘脑-皮质回路[TLCC]）。这些神经发育异常可能在发病前通过细微的行为、认知和结构“易感性标记”表现出来。在大多数情况下，这些异常需要特定的乳腺过程（即突触消除，髓鞘形成），这些过程发生在青春期前后，以揭示易感性并引发功能障碍，导致减弱的阳性和阴性症状的发展或恶化（临床定义为“危险”状态），以及社会功能，社会认知，神经认知功能，嗅觉和运动功能等多种但特定的损伤。我们假设，随着TLCC的连通性变得更加功能失调，其结果将是随着更多区域在更大程度上受到影响，可测量损伤的严重程度将增加。因此，TLCC电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，这些环境事件通常发生在青春期，如压力生活事件或药物滥用。这些压力源可能超过了相关神经回路的适应能力，从而产生疾病发作的特征性症状。为了建立精神分裂症精神病风险评估模型，我们提出了一项3点前瞻性研究，包括180名符合修订的“前驱综合征标准”的个体，以及80名寻求帮助的对照组，他们将在2-5年内进行精神分裂症精神病发展风险的前瞻性评估。该合作团队在该领域开发了领先的仪器，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。在之前的合作中，每个站点都证明了其招募前驱症状患者的能力。

DESCRIPTION (provided by applicant): This 3-site collaborative R01 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 mamrational 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.