Background

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.

Methods

Based on a review of the relevant literature, we formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery.

Results

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.

Conclusions

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.

中文翻译：

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是时候通过加强对临床前精神药理学的信心重新参与精神科药物的发现了

背景

迫切需要治疗精神疾病的新药物。预计到 2030 年，精神疾病将成为全球致残的主要原因。然而，在过去的二十年里，制药行业在代价高昂的后期试验失败后退出了精神药物发现，其中临床前预测的临床疗效尚未实现，导致对临床前精神药理学的信心危机。

方法

在回顾相关文献的基础上，我们制定了一些原则，以改善针对精神药物发现的转化神经科学的投资。

结果

我们提出以下 8 项原则，可用于各种组合，以增强 CNS 药物发现：（1）考虑纳入 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扰动；(4) 通过基因组分析和患者来源的多能干细胞识别分子靶点；(5) 拥抱整体神经科学：与心理神经免疫学合作；(6) 使用神经元激活的平移测量；(7) 通过独立合作验证调查结果的可重复性；(8) 学习和反思。我们提供了最近有希望的药物发现项目从动物到人类的翻译的例子，并强调了一些提供再利用机会的例子。

结论

我们希望这次审查能够重新唤醒制药行业和心理健康倡导者，让他们认识到改善精神药物治疗的机会，从而恢复信心并证明对该领域的再投资是合理的。