Li Chao, Yang Lei, Zhang Qiuyu, Zhang Ying, Li Ranli, Jia Feng, Wang Lina, Ma Xiaoyan, Tian Hongjun, Zhuo Chuanjun
Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin, China.
Laboratory of Psychiatric-Neuroimaging-Genetic and Co-Morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin, China.
CNS Neurosci Ther. 2025 Apr;31(4):e70383. doi: 10.1111/cns.70383.
Lurasidone monotherapy has been approved for the treatment of bipolar depression. However, several case reports have indicated treatment with lurasidone-induced acute mania in people with bipolar depression. The mechanism by which this occurs remains to be elucidated.
In this study, we systematically explored the mechanism of action of lurasidone-induced acute mania in bipolar depression using network pharmacology and molecular docking.
Putative target genes for lurasidone were obtained from the GeneCards, PharmMapper, SwissTargetPrediction, and DrugBank databases. Targets for bipolar depression and acute mania were collected from the DisGeNET and GeneCards databases. A protein-protein interaction (PPI) network was built to screen the hub targets. The Bioinformatics platform and Database for Annotation, Visualization, and Integrated Discovery were used for the visualization of the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of the top 20 core targets. The drug-pathway-target-disease network was constructed using Cytoscape. Finally, molecular docking was performed to evaluate the binding affinity between lurasidone and potential targets.
In total, 327, 1253, and 429 targets of lurasidone, bipolar depression, and acute mania were identified, respectively. A topological analysis of the PPI network revealed the top 20 hub targets. Based on PPI, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the top 20 hub targets, lurasidone was found to induce acute manic episodes in people with bipolar depression by targeting the serotonergic synapse signaling pathway via MAOB, HTR1A, HTR2A, HTR3A, SLC18A2, HTR1B, and HTR7. Molecular docking revealed good binding affinities between lurasidone and these potential targets.
This study revealed that lurasidone may regulate the serotonergic synapse signaling pathway by interacting with the identified core targets MAOB, HTR1A, HTR2A, HTR3A, SLC18A2, HTR1B, and HTR7 to induce treatment-emergent mania in people with bipolar depression. Our work provides a theoretical basis for the pharmacology of lurasidone-induced acute mania in bipolar depression and further basic research.
鲁拉西酮单药治疗已被批准用于双相抑郁的治疗。然而，有几例病例报告表明，鲁拉西酮治疗可诱发双相抑郁患者出现急性躁狂。其发生机制仍有待阐明。
在本研究中，我们使用网络药理学和分子对接系统地探究鲁拉西酮诱发双相抑郁患者急性躁狂的作用机制。
从GeneCards、PharmMapper、SwissTargetPrediction和DrugBank数据库中获取鲁拉西酮的潜在靶基因。从DisGeNET和GeneCards数据库中收集双相抑郁和急性躁狂的靶点。构建蛋白质-蛋白质相互作用（PPI）网络以筛选枢纽靶点。利用生物信息学平台和注释、可视化与整合发现数据库对前20个核心靶点进行基因本体论和京都基因与基因组百科全书分析的可视化。使用Cytoscape构建药物-通路-靶点-疾病网络。最后，进行分子对接以评估鲁拉西酮与潜在靶点之间的结合亲和力。
分别确定了鲁拉西酮、双相抑郁和急性躁狂的327个、1253个和429个靶点。对PPI网络的拓扑分析揭示了前20个枢纽靶点。基于对前20个枢纽靶点的PPI、基因本体论和京都基因与基因组百科全书通路分析，发现鲁拉西酮通过单胺氧化酶B（MAOB）、5-羟色胺受体1A（HTR1A）、5-羟色胺受体2A（HTR2A）、5-羟色胺受体3A（HTR3A）、囊泡单胺转运体2（SLC18A2）、5-羟色胺受体1B（HTR1B）和5-羟色胺受体7（HTR7）靶向血清素能突触信号通路，从而在双相抑郁患者中诱发急性躁狂发作。分子对接显示鲁拉西酮与这些潜在靶点之间具有良好的结合亲和力。
本研究表明，鲁拉西酮可能通过与已确定的核心靶点MAOB、HTR1A、HTR2A、HTR3A、SLC18A2、HTR1B和HTR7相互作用来调节血清素能突触信号通路，从而在双相抑郁患者中诱发治疗中出现的躁狂。我们的工作为鲁拉西酮诱发双相抑郁患者急性躁狂的药理学及进一步的基础研究提供了理论依据。
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