Li Xiaohua, Ketter Terence A, Frye Mark A
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-4400, USA.
J Affect Disord. 2002 May;69(1-3):1-14. doi: 10.1016/s0165-0327(00)00361-x.
Treatment of bipolar disorders has progressed significantly in the last decade due to advances in basic and clinical research. Much of this progress has centered on the development of a new generation of mood stabilizers-anticonvulsants. Valproic acid (VPA) and carbamazepine (CBZ) have clear mood stabilizing properties, while lamotrigine (LTG), topiramate (TPM), and gabapentin (GBP) have been investigated to varying degrees. We provide an overview of mechanisms of these potentially mood-stabilizing anticonvulsants, review their commonalities and dissociations to the gold standard non-anticonvulsant mood stabilizer lithium. Regulations of the glutamate excitatory neurotransmission and/or gamma aminobutyric acid (GABA) inhibitory neurotransmission are mostly studied mechanisms of anticonvulsants. The divergent effects of these agents indicate that this mode of action represents initial effect of anticonvulsants in regulating mood. Similar to lithium, intracellular mechanisms of anticonvulsants, primarily VPA and CBZ, include regulation of several protein kinase signaling pathways, leading to regulation of gene expression. Common genes that can be regulated by mood stabilizers are more likely to be the final normalizing components in bipolar disorders. Several anticonvulsants, such as VPA, LTG, and TPM, show neuronal protective function, a commonality with recently identified neuroprotective function of lithium, although the meaning of neuroprotection in bipolar disorders remains to be identified. Understanding the mechanisms of anticonvulsant mood stabilizers, integrated with clinical observations, may ultimately provide important new insights into the pathophysiology and treatment of bipolar disorders.
由于基础研究和临床研究的进展，双相情感障碍的治疗在过去十年中取得了显著进步。这一进展主要集中在新一代情绪稳定剂——抗惊厥药物的开发上。丙戊酸（VPA）和卡马西平（CBZ）具有明确的情绪稳定特性，而拉莫三嗪（LTG）、托吡酯（TPM）和加巴喷丁（GBP）也得到了不同程度的研究。我们概述了这些潜在的情绪稳定抗惊厥药物的作用机制，回顾了它们与金标准非抗惊厥情绪稳定剂锂的共性和差异。谷氨酸兴奋性神经传递和/或γ-氨基丁酸（GABA）抑制性神经传递的调节是抗惊厥药物研究最多的作用机制。这些药物的不同作用表明，这种作用模式代表了抗惊厥药物调节情绪的初始效应。与锂类似，抗惊厥药物（主要是VPA和CBZ）的细胞内机制包括对几种蛋白激酶信号通路的调节，从而导致基因表达的调节。可被情绪稳定剂调节的常见基因更有可能是双相情感障碍最终的正常化组成部分。几种抗惊厥药物，如VPA、LTG和TPM，具有神经保护功能，这与最近发现的锂的神经保护功能相同，尽管双相情感障碍中神经保护的意义仍有待确定。了解抗惊厥情绪稳定剂的机制，并结合临床观察，最终可能为双相情感障碍的病理生理学和治疗提供重要的新见解。
