Schizophrenia is a chronic mental illness that affects up to 1% of the population. While efficacious therapies are available for positive symptoms, effective treatment of cognitive and negative symptoms remains an unmet need after decades of research. New developments in the field of neuroimaging are accelerating our knowledge gain regarding the underlying pathophysiology of symptoms in schizophrenia and psychosis spectrum disorders, inspiring new targets for drug development. However, no validated and qualified biomarkers are currently available to support the development of new therapeutics. This review summarizes the current use of neuroimaging technology in clinical drug development for psychotic disorders. As exemplified by drug development programs that target NMDA receptor hypofunction, neuroimaging results play a critical role in target discovery and establishing target engagement and dose selection. Furthermore, pharmacological neuroimaging may provide response biomarkers that allow for early decision making in proof-of-concept studies that leverage pharmacological challenge models in healthy volunteers. That said, while response and predictive biomarkers are starting to be evaluated in patient populations, they continue to play a limited role. Novel approaches to neuroimaging data acquisition and analysis may aid the establishment of biomarkers that are predictive at the individual level in the future. Nevertheless, various gaps in knowledge need to be addressed and biomarkers need to be validated to establish them as “fit for purpose” in drug development.

中文翻译：

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用于精神分裂症药物发现和开发的神经影像生物标志物

精神分裂症是一种慢性精神疾病，影响高达 1% 的人口。虽然对阳性症状有有效的治疗方法，但经过数十年的研究，对认知和阴性症状的有效治疗仍然是一个未得到满足的需求。神经影像学领域的新发展正在加速我们对精神分裂症和精神病谱系疾病症状的潜在病理生理学的了解，激发药物开发的新目标。然而，目前还没有经过验证和合格的生物标志物来支持新疗法的开发。本综述总结了目前神经影像技术在精神障碍临床药物开发中的应用。正如针对 NMDA 受体功能减退的药物开发计划所证明的那样，神经影像学结果在靶点发现、建立靶点参与和剂量选择中发挥着关键作用。此外，药理学神经影像可以提供反应生物标志物，允许在利用健康志愿者的药理学挑战模型的概念验证研究中进行早期决策。也就是说，虽然反应和预测生物标志物开始在患者群体中进行评估，但它们的作用仍然有限。神经影像数据采集和分析的新方法可能有助于建立未来在个体水平上进行预测的生物标志物。然而，需要解决各种知识差距，并且需要验证生物标志物以使其在药物开发中“适合目的”。