Uliana Daniela L, Zhu Xiyu, Gomes Felipe V, Grace Anthony A
Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States.
Front Behav Neurosci. 2022 Aug 24;16:935320. doi: 10.3389/fnbeh.2022.935320. eCollection 2022.
Animal models of psychiatric disorders have been highly effective in advancing the field, identifying circuits related to pathophysiology, and identifying novel therapeutic targets. In this review, we show how animal models, particularly those based on development, have provided essential information regarding circuits involved in disorders, disease progression, and novel targets for intervention and potentially prevention. Nonetheless, in recent years there has been a pushback, largely driven by the US National Institute of Mental Health (NIMH), to shift away from animal models and instead focus on circuits in normal subjects. This has been driven primarily from a lack of discovery of new effective therapeutic targets, and the failure of targets based on preclinical research to show efficacy. We discuss why animal models of complex disorders, when strongly cross-validated by clinical research, are essential to understand disease etiology as well as pathophysiology, and direct new drug discovery. Issues related to shortcomings in clinical trial design that confound translation from animal models as well as the failure to take patient pharmacological history into account are proposed to be a source of the failure of what are likely effective compounds from showing promise in clinical trials.
精神疾病的动物模型在推动该领域发展、识别与病理生理学相关的神经回路以及确定新的治疗靶点方面一直非常有效。在本综述中，我们展示了动物模型，尤其是基于发育的动物模型，如何提供了有关疾病相关神经回路、疾病进展以及干预和潜在预防新靶点的重要信息。尽管如此，近年来出现了一种抵制声音，主要由美国国立精神卫生研究所（NIMH）推动，即从动物模型转向关注正常受试者的神经回路。这主要是由于缺乏新的有效治疗靶点的发现，以及基于临床前研究的靶点未能显示出疗效。我们讨论了为什么复杂疾病的动物模型在经过临床研究的强力交叉验证后，对于理解疾病病因和病理生理学以及指导新药研发至关重要。临床试验设计中的缺陷导致难以从动物模型进行转化，以及未能考虑患者用药史，这些问题被认为是可能有效的化合物在临床试验中未能显示出前景的原因之一。
