Goody S M G, Cannon K E, Liu M, Kallman M J, Martinolle J P, Mazelin-Winum L, Giarola A, Ardayfio P, Moyer J A, Teuns G, Hudzik T J
Pfizer Drug Safety Research & Development, Groton, CT, USA.
Halozyme Inc, San Diego, CA, USA.
Regul Toxicol Pharmacol. 2017 Oct;89:288-301. doi: 10.1016/j.yrtph.2017.07.030. Epub 2017 Jul 27.
Given the serious nature of suicidal ideation and behavior (SIB) and the possibility of treatment-emergent SIB, pharmaceutical companies are now applying more proactive approaches in clinical trials and are considering the value of nonclinical models to predict SIB. The current review summarizes nonclinical approaches to modeling three common risk factors associated with SIB: aggression, impulsivity, and anhedonia. For each risk factor, a general description, advantages and disadvantages, species considerations, nonclinical to clinical translation, and pharmacological validation with respect to treatments associated with SIB are summarized. From this review, several gaps were identified that need to be addressed before use of these nonclinical models can be considered a viable option to predict the relative risk for SIB. Other future directions that may compliment these nonclinical approaches, including the use of selectively-bred or genetically-modified rodent models, transgenic models, gene expression profiling, and biomarker analysis, are discussed. This article was developed with the support of the DruSafe Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org).
鉴于自杀意念和行为（SIB）的严重性以及治疗中出现SIB的可能性，制药公司目前在临床试验中采用了更积极主动的方法，并正在考虑非临床模型对预测SIB的价值。本综述总结了对与SIB相关的三个常见风险因素（攻击、冲动和快感缺乏）进行建模的非临床方法。对于每个风险因素，总结了一般描述、优缺点、物种考量、从非临床到临床的转化以及与SIB相关治疗的药理学验证。通过本综述，确定了几个差距，在将这些非临床模型视为预测SIB相对风险的可行选项之前，需要加以解决。还讨论了可能补充这些非临床方法的其他未来方向，包括使用选择性繁殖或基因改造的啮齿动物模型、转基因模型、基因表达谱分析和生物标志物分析。本文由药物研发创新与质量国际联盟（IQ，www.iqconsortium.org）的DruSafe领导小组提供支持撰写而成。
