Centre for Neuroimaging Sciences, Institute of Psychiatry Psychology and Neuroscience, King's College, London, UK.
Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, CB23EB, Cambridge, UK.
Psychopharmacology (Berl). 2021 Jun;238(6):1417-1436. doi: 10.1007/s00213-021-05787-x. Epub 2021 Mar 10.
There is urgent need for new medications for psychiatric disorders. Mental illness is expected to become the leading cause of disability worldwide by 2030. Yet, the last two decades have seen the pharmaceutical industry withdraw from psychiatric drug discovery after costly late-stage trial failures in which clinical efficacy predicted pre-clinically has not materialised, leading to a crisis in confidence in preclinical psychopharmacology.
Based on a review of the relevant literature, we formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery.
We propose the following 8 principles that could be used, in various combinations, to enhance CNS drug discovery: (1) consider incorporating the NIMH Research Domain Criteria (RDoC) approach; (2) engage the power of translational and systems neuroscience approaches; (3) use disease-relevant experimental perturbations; (4) identify molecular targets via genomic analysis and patient-derived pluripotent stem cells; (5) embrace holistic neuroscience: a partnership with psychoneuroimmunology; (6) use translational measures of neuronal activation; (7) validate the reproducibility of findings by independent collaboration; and (8) learn and reflect. We provide recent examples of promising animal-to-human translation of drug discovery projects and highlight some that present re-purposing opportunities.
We hope that this review will re-awaken the pharma industry and mental health advocates to the opportunities for improving psychiatric pharmacotherapy and so restore confidence and justify re-investment in the field.
对于精神疾病的治疗药物，目前存在着迫切的需求。到 2030 年，精神疾病预计将成为全球导致残疾的首要原因。然而，在过去的二十年里，制药行业已经退出了精神药物的研发，因为在花费巨大的后期临床试验中，临床疗效并未如临床前预测的那样实现，这导致了人们对临床前精神药理学的信心危机。
基于对相关文献的回顾，我们制定了一些旨在改善转化神经科学投资以促进精神药物发现的原则。
我们提出了以下 8 条原则，可以结合使用，以增强中枢神经系统药物的发现：（1）考虑采用 NIMH 研究领域标准（RDoC）方法；（2）利用转化和系统神经科学方法的力量；（3）使用与疾病相关的实验干扰；（4）通过基因组分析和患者来源的多能干细胞来识别分子靶标；（5）拥抱整体神经科学：与心理神经免疫学合作；（6）使用转化的神经元激活测量方法；（7）通过独立合作验证发现的可重复性；（8）学习和反思。我们提供了一些有希望的药物发现项目从动物到人类的转化的最新例子，并强调了一些具有重新应用机会的例子。
我们希望这篇综述能重新唤起制药行业和精神卫生倡导者对改善精神药物治疗的机会的关注，从而恢复对该领域的信心，并证明重新投资的合理性。
