Huang Junchao, Zhang Ping, Zhou Yanfang, Tong Jinghui, Cui Yimin, Tan Shuping, Wang Zhiren, Yang Fude, Kochunov Peter, Tian Baopeng, Tian Li, Hong L Elliot, Tan Yunlong
Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, PR China.
Department of Pharmacy, Peking University First Hospital, Beijing, PR China.
J Psychiatr Res. 2022 Jan;145:339-346. doi: 10.1016/j.jpsychires.2021.11.002. Epub 2021 Nov 8.
About a third of patients with schizophrenia do not respond adequately to currently available antipsychotics and thus experiences symptoms of greater severity, known as treatment-resistant schizophrenia (TRS). Some evidence suggests that the tryptophan (TRP) pathway (comprising 5-HT and kynurenine sub-pathways) has an important influence on response to antipsychotics. We therefore hypothesized that TRS is linked to metabolites of TRP pathway.
We measured TRP metabolites in 54 patients with TRS and compared them to 49 age- and sex-matched patients who responded to antipsychotics (NTRS), and 62 healthy controls using liquid chromatography-tandem mass spectrometry. Psychopathology and clinical symptoms were assessed by means of schizophrenia positive and negative scales. Working memory abilities, cortical thickness and white matter diffusion tensor imaging fractional anisotropy were appraised in enrolled subjects by neurophysiological tests, as spatial span and digital sequencing tests, and 3T magnetic resonance imaging.
Patients with TRS had a significantly higher 5-HT/TRP ratio (p = 0.009) than patients with NTRS. However, the two groups did not differ in kynurenine-pathway metabolites or ratios. Additionally, 5-HT/TRP was positively correlated with disorganized symptoms in TRS (r = 0.59, p < 0.001), and negatively correlated with digit-sequencing test scores (r = -0.34, p = 0.02). These correlations were insignificant among patients with NTRS and healthy controls. In patients with TRS, 5-HT/TRP was strongly linked to the right supramarginal cortex (t = -3.2, p = 0.003), and in healthy controls, to the right transverse temporal (t = 3.40, p = 0.001), but significance disappeared after FDR correction.
Present results indicate that an upregulated 5-HT biosynthetic pathway can be associated to TRS, suggesting that targeting mechanisms of 5-HT conversion from tryptophan could shed light on the development of new pharmacological approaches of TRS.
约三分之一的精神分裂症患者对目前可用的抗精神病药物反应不佳，因此会经历更严重的症状，即难治性精神分裂症（TRS）。一些证据表明，色氨酸（TRP）途径（包括5-羟色胺和犬尿氨酸子途径）对抗精神病药物的反应有重要影响。因此，我们假设TRS与TRP途径的代谢产物有关。
我们使用液相色谱-串联质谱法测量了54例TRS患者的TRP代谢产物，并将其与49例年龄和性别匹配的对抗精神病药物有反应的患者（NTRS）以及62名健康对照者进行了比较。通过精神分裂症阳性和阴性量表评估精神病理学和临床症状。通过神经生理学测试（如空间跨度和数字序列测试）以及3T磁共振成像，对纳入研究的受试者的工作记忆能力、皮质厚度和白质扩散张量成像分数各向异性进行评估。
TRS患者的5-羟色胺/色氨酸比值（p = 0.009）显著高于NTRS患者。然而，两组在犬尿氨酸途径代谢产物或比值方面没有差异。此外，5-羟色胺/色氨酸与TRS中的紊乱症状呈正相关（r = 0.59，p < 0.001），与数字序列测试分数呈负相关（r = -0.34，p = 0.02）。这些相关性在NTRS患者和健康对照者中不显著。在TRS患者中，5-羟色胺/色氨酸与右侧缘上回密切相关（t = -3.2，p = 0.003），而在健康对照者中，与右侧颞横回相关（t = 3.40，p = 0.001），但在FDR校正后显著性消失。
目前的结果表明，5-羟色胺生物合成途径上调可能与TRS有关，这表明针对色氨酸转化为5-羟色胺的机制可能为TRS新的药理学方法的开发提供线索。
