The New York State Psychiatric Institute, Columbia University Irving Medical Center, New York, N.Y, USA.
The New York State Psychiatric Institute, Columbia University Irving Medical Center, New York, N.Y, USA.
J Psychiatr Res. 2019 Jan;108:57-83. doi: 10.1016/j.jpsychires.2018.07.006. Epub 2018 Jul 21.
Since the discovery of chlorpromazine in the 1950's, antipsychotic drugs have been the cornerstone of treatment of schizophrenia, and all attenuate dopamine transmission at the dopamine-2 receptor. Drug development for schizophrenia since that time has led to improvements in side effects and tolerability, and limited improvements in efficacy, with the exception of clozapine. However, the reasons for clozapine's greater efficacy remain unclear, despite the great efforts and resources invested therewith. We performed a comprehensive review of the literature to determine the fate of previously tested, non-dopamine-2 receptor experimental treatments. Overall we included 250 studies in the review from the period 1970 to 2017 including treatments with glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormone-based, dopaminergic, metabolic, vitamin/naturopathic, histaminergic, infection/inflammation-based, and miscellaneous mechanisms. Despite there being several promising targets, such as allosteric modulation of the NMDA and α7 nicotinic receptors, we cannot confidently state that any of the mechanistically novel experimental treatments covered in this review are definitely effective for the treatment of schizophrenia and ready for clinical use. We discuss potential reasons for the relative lack of progress in developing non-dopamine-2 receptor treatments for schizophrenia and provide recommendations for future efforts pursuing novel drug development for schizophrenia.
自 20 世纪 50 年代氯丙嗪被发现以来，抗精神病药物一直是治疗精神分裂症的基石，所有药物都能在多巴胺 2 受体上减弱多巴胺的传递。自那时以来，精神分裂症药物的开发导致了副作用和耐受性的改善，以及疗效的有限改善，除了氯氮平。然而，尽管投入了大量的努力和资源，氯氮平疗效更好的原因仍不清楚。我们对文献进行了全面回顾，以确定以前测试过的、非多巴胺 2 受体的实验治疗的结果。总的来说，我们从 1970 年到 2017 年期间的综述中纳入了 250 项研究，包括谷氨酸能、5-羟色胺能、胆碱能、神经肽能、激素、多巴胺能、代谢、维生素/顺势疗法、组胺能、感染/炎症和其他机制的治疗方法。尽管有几个有前途的靶点，如 NMDA 和 α7 烟碱型乙酰胆碱受体的变构调节，但我们不能自信地说，本综述中涵盖的任何机制新颖的实验治疗方法肯定对精神分裂症的治疗有效，并且可以准备用于临床使用。我们讨论了在开发非多巴胺 2 受体治疗精神分裂症方面相对缺乏进展的潜在原因，并为未来开发新型精神分裂症药物的努力提供了建议。
