Rupniak N M J
Clinical Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
Behav Pharmacol. 2003 Sep;14(5-6):385-90. doi: 10.1097/01.fbp.0000087738.21047.91.
Clinically effective antidepressant drugs have been available for many years but our understanding of how these drugs bring about their therapeutic effects, and how to develop more diverse, better treatments has progressed little. At a time when informed choices need to be taken early on in drug development programs in order to exploit the opportunities for innovation created through genomics, this article considers the strengths and weaknesses of behavioral pharmacology assays and their various roles in the drug discovery process. In the past, a widespread lack of confidence in animal models of depression, combined with the high failure rate of clinical trials and escalating costs of drug development, has stifled a more entrepreneurial approach to drug discovery. In order to encourage greater confidence in discovery programs, the gap between exploratory preclinical and clinical studies needs to be bridged. Functional pharmacology markers need to be developed in patient populations, and in normal volunteers and preclinical species, so that selection of new drug targets can be made with greater confidence at earlier stages of discovery programs. The use of functional brain imaging to quantify drug actions in the human CNS is developing rapidly and may provide powerful new techniques to filter active new drugs of the future from those that are less promising.
临床有效的抗抑郁药物已经问世多年，但我们对这些药物如何产生治疗效果，以及如何开发更多样化、更好的治疗方法的理解进展甚微。在药物开发项目需要尽早做出明智选择以利用基因组学创造的创新机会之际，本文探讨了行为药理学检测方法的优缺点及其在药物发现过程中的各种作用。过去，对抑郁症动物模型普遍缺乏信心，加上临床试验的高失败率和药物开发成本的不断攀升，抑制了更具创业精神的药物发现方法。为了鼓励对发现项目更有信心，需要弥合探索性临床前研究和临床研究之间的差距。需要在患者群体、正常志愿者和临床前物种中开发功能药理学标志物，以便在发现项目的早期阶段更有信心地选择新的药物靶点。利用功能性脑成像来量化药物在人类中枢神经系统中的作用正在迅速发展，可能会提供强大的新技术，以便从那些前景不太乐观的药物中筛选出未来的活性新药。
