Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute’s Connectivity Map to identify drugs that can be repurposed to treat psychiatric disorders. Human neuronal (NT2-N) cells were treated with a combination of atypical antipsychotic drugs commonly used to treat psychiatric disorders (such as schizophrenia, bipolar disorder, and major depressive disorder), and differential gene expression was analysed. Biological pathways with an increased gene expression included circadian rhythm and vascular endothelial growth factor signalling, while the adherens junction and cell cycle pathways were transcriptionally downregulated. The Connectivity Map (CMap) analysis screen highlighted drugs that affect global gene expression in a similar manner to these psychiatric disorder treatments, including several other antipsychotic drugs, confirming the utility of this approach. The CMap screen specifically identified metergoline, an ergot alkaloid currently used to treat seasonal affective disorder, as a drug of interest. In mice, metergoline dose-dependently reduced MK-801- or methamphetamine-induced locomotor hyperactivity confirming the potential of metergoline to treat positive symptoms of schizophrenia in an animal model. Metergoline had no effects on prepulse inhibition deficits induced by MK-801 or methamphetamine. Taken together, metergoline appears a promising drug for further studies to be repurposed as a treatment for schizophrenia and possibly other psychiatric disorders.

需要新的方法来寻找精神分裂症和其他神经精神疾病的新疗法。这项研究结合了体外转录组学和计算机分析与 BROAD 研究所的连接图来确定可重新用于治疗精神疾病的药物。使用常用于治疗精神疾病（如精神分裂症、双相情感障碍和重度抑郁症）的非典型抗精神病药物组合治疗人类神经元（NT2-N）细胞，并分析差异基因表达。基因表达增加的生物途径包括昼夜节律和血管内皮生长因子信号传导，而粘附连接和细胞周期途径转录下调。连接图（CMap）分析屏幕突出显示了以与这些精神疾病治疗类似的方式影响全局基因表达的药物，包括其他几种抗精神病药物，证实了这种方法的实用性。CMap 筛选特别将麦角林（一种目前用于治疗季节性情感障碍的麦角生物碱）确定为一种感兴趣的药物。在小鼠中，米角林剂量依赖性地减少 MK-801 或甲基苯丙胺诱导的运动亢进，证实了米角林治疗动物模型中精神分裂症阳性症状的潜力。麦角林对 MK-801 或甲基苯丙胺诱导的前脉冲抑制缺陷没有影响。总而言之，米角林似乎是一种有前景的药物，有待进一步研究，以重新用于治疗精神分裂症和其他可能的精神疾病。