Gould Todd D
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-3711, USA.
Expert Opin Ther Targets. 2006 Jun;10(3):377-92. doi: 10.1517/14728222.10.3.377.
Historically, success in the pharmacological treatment of bipolar disorder has arisen either from serendipitous findings or from studies with drugs (antipsychotics and anticonvulsants) developed for other indications (schizophrenia and epilepsy, respectively). Lithium has been in widespread clinical use in the treatment of bipolar disorder for > 30 years. Development of lithium-mimetic compounds has the potential to result in a more specific medication, with fewer side effects and a less narrow dose range. However, novel medications based upon a known mechanism of action of this drug are yet to be developed. Increasing evidence suggests that a next-generation lithium compound may derive from knowledge of a direct target of lithium, glycogen synthase kinase-3 (GSK-3). GSK-3 is an intracellular enzyme implicated as a critical component in many neuronal signalling pathways. However, despite the large body of preclinical data discussed in this review, definitive validation of GSK-3 as therapeutically relevant target of lithium will require clinical trials with novel GSK-3 inhibitors. A number of recent reports suggest that it is possible to develop selective, small-molecule GSK-3 inhibitors.
从历史上看，双相情感障碍药物治疗的成功要么源于偶然发现，要么源于针对其他适应症（分别为精神分裂症和癫痫）开发的药物（抗精神病药和抗惊厥药）的研究。锂盐已在双相情感障碍的治疗中广泛临床应用超过30年。开发锂盐模拟化合物有可能产生一种更具特异性的药物，副作用更少且剂量范围不那么狭窄。然而，基于该药物已知作用机制的新型药物尚未开发出来。越来越多的证据表明，下一代锂化合物可能源于对锂的直接靶点糖原合酶激酶-3（GSK-3）的了解。GSK-3是一种细胞内酶，被认为是许多神经元信号通路中的关键成分。然而，尽管本综述中讨论了大量临床前数据，但要确定GSK-作为锂盐治疗相关靶点，还需要使用新型GSK-3抑制剂进行临床试验。最近的一些报告表明，开发选择性小分子GSK-3抑制剂是可能的。
