Marek Gerard, Merchant Kalpana
Neuroscience Division, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
NeuroRx. 2005 Oct;2(4):579-89. doi: 10.1602/neurorx.2.4.579.
Although the second-generation or atypical antipsychotic drugs have been breakthrough medicines for the treatment of schizophrenia and other psychotic conditions, cognitive dysfunction and to some extent negative symptoms of the disease continue to be the main cause of poor vocational status of the patients. Thus, the majority of investigational drug development efforts today target these unmet medical needs. This review postulates that the field of schizophrenia research has advanced sufficiently to develop biochemical hypotheses of the etiopathology of the disease and target the same for revolutionary disease modifying therapy. This postulate is based on recent studies that have begun to provide a testable etiopathology model that integrates interactions between genetic vulnerability factors, neurodevelopmental anomalies, and neurotransmitter systems. This review begins with a brief overview of the nosology and etiopathology of schizophrenia and related psychotic disorders to establish a context for subsequent detailed discussions on drug discovery and development for psychotic disorders. Particular emphasis is placed on recent advances in genetic association studies of schizophrenia and how this can be integrated with evidence supporting neurodevelopmental abnormalities associated with the disease to generate a testable model of the disease etiopathology. An in-depth review of the plethora of new targets and approaches targeting the unmet medical need in the treatment of schizophrenia exemplify the challenges and opportunities in this area. We end the review by offering an approach based on emerging genetic, clinical, and neurobiological studies to discover and validate novel drug targets that could be classified as disease modifying approaches.
尽管第二代或非典型抗精神病药物是治疗精神分裂症和其他精神病性疾病的突破性药物，但认知功能障碍以及该疾病在一定程度上的阴性症状仍是患者职业状况不佳的主要原因。因此，当今大多数研究性药物开发工作都针对这些未满足的医疗需求。本综述假定，精神分裂症研究领域已经取得了足够的进展，能够提出该疾病病因病理学的生化假说，并将其作为革命性疾病改善疗法的靶点。这一假定基于最近的一些研究，这些研究已开始提供一个可检验的病因病理学模型，该模型整合了遗传易感性因素、神经发育异常和神经递质系统之间的相互作用。本综述首先简要概述精神分裂症及相关精神病性障碍的疾病分类学和病因病理学，为后续关于精神病性障碍药物发现与开发的详细讨论奠定背景。特别强调了精神分裂症遗传关联研究的最新进展，以及如何将其与支持该疾病相关神经发育异常的证据相结合，以生成一个可检验的疾病病因病理学模型。对针对精神分裂症治疗中未满足医疗需求的大量新靶点和方法进行深入综述，例证了该领域的挑战与机遇。我们通过提出一种基于新兴的遗传学、临床和神经生物学研究的方法来结束本综述，以发现和验证可归类为疾病改善方法的新型药物靶点。
