Pole for Innovation in Neurosciences, IDR Servier, 125 chemin de ronde, 78290 Croissy sur Seine, France.
University Department of Psychiatry, Oxford University, Warneford Hospital, Oxford OX3 7JX, England, UK.
Eur Neuropsychopharmacol. 2015 May;25(5):599-656. doi: 10.1016/j.euroneuro.2015.01.016. Epub 2015 Feb 7.
Modern neuropsychopharmacology commenced in the 1950s with the serendipitous discovery of first-generation antipsychotics and antidepressants which were therapeutically effective yet had marked adverse effects. Today, a broader palette of safer and better-tolerated agents is available for helping people that suffer from schizophrenia, depression and other psychiatric disorders, while complementary approaches like psychotherapy also have important roles to play in their treatment, both alone and in association with medication. Nonetheless, despite considerable efforts, current management is still only partially effective, and highly-prevalent psychiatric disorders of the brain continue to represent a huge personal and socio-economic burden. The lack of success in discovering more effective pharmacotherapy has contributed, together with many other factors, to a relative disengagement by pharmaceutical firms from neuropsychiatry. Nonetheless, interest remains high, and partnerships are proliferating with academic centres which are increasingly integrating drug discovery and translational research into their traditional activities. This is, then, a time of transition and an opportune moment to thoroughly survey the field. Accordingly, the present paper, first, chronicles the discovery and development of psychotropic agents, focusing in particular on their mechanisms of action and therapeutic utility, and how problems faced were eventually overcome. Second, it discusses the lessons learned from past successes and failures, and how they are being applied to promote future progress. Third, it comprehensively surveys emerging strategies that are (1), improving our understanding of the diagnosis and classification of psychiatric disorders; (2), deepening knowledge of their underlying risk factors and pathophysiological substrates; (3), refining cellular and animal models for discovery and validation of novel therapeutic agents; (4), improving the design and outcome of clinical trials; (5), moving towards reliable biomarkers of patient subpopulations and medication efficacy and (6), promoting collaborative approaches to innovation by uniting key partners from the regulators, industry and academia to patients. Notwithstanding the challenges ahead, the many changes and ideas articulated herein provide new hope and something of a framework for progress towards the improved prevention and relief of psychiatric and other CNS disorders, an urgent mission for our Century.
现代神经精神药理学始于 20 世纪 50 年代，第一代抗精神病药和抗抑郁药的偶然发现具有治疗效果，但具有明显的不良反应。如今，有了更广泛的、更安全、更耐受的药物可供选择，以帮助患有精神分裂症、抑郁症和其他精神疾病的人，而心理治疗等补充方法在治疗这些疾病方面也发挥着重要作用，无论是单独使用还是与药物联合使用。尽管已经付出了相当大的努力，但目前的治疗方法仍然只是部分有效，大脑中高度流行的精神疾病仍然给个人和社会经济带来巨大负担。在发现更有效的药物治疗方法方面的失败，加上许多其他因素，导致制药公司相对退出神经精神药理学领域。尽管如此，人们的兴趣仍然很高，学术中心之间的合作也在不断增加，这些学术中心越来越多地将药物发现和转化研究纳入其传统活动。因此，现在是一个过渡时期，也是全面审视该领域的恰当时机。因此，本文首先记录了精神药物的发现和发展，特别关注它们的作用机制和治疗效果，以及如何最终克服所面临的问题。其次，讨论了从过去的成功和失败中吸取的教训，以及如何将这些教训应用于促进未来的进展。第三，全面调查了新兴策略，包括 (1) 提高我们对精神疾病的诊断和分类的理解；(2) 加深对其潜在风险因素和病理生理基础的认识；(3) 改进用于发现和验证新型治疗药物的细胞和动物模型；(4) 改进临床试验的设计和结果；(5) 朝着可靠的患者亚群和药物疗效的生物标志物迈进；(6) 通过联合监管机构、行业和学术界的关键合作伙伴与患者，促进创新的合作方法。尽管面临挑战，但本文所述的许多变化和思路为改善精神疾病和其他中枢神经系统疾病的预防和缓解提供了新的希望和某种框架，这是我们这个世纪的一项紧迫任务。
