伴有自杀意念的抑郁症患者犬尿氨酸代谢及与临床症状的动态关联分析

Study of kynurenine pathway metabolites and their dynamic association with clinical symptoms in depressed patients with suicidal ideation

目的探讨伴有自杀意念的抑郁症患者犬尿氨酸代谢通路是否存在异常,及与临床症状的动态关系。方法根据DSM-5诊断标准前瞻性纳入2019年7月至2022年7月于上海市精神卫生中心心境障碍就诊的68例抑郁症患者,其中男28例,女40例,年龄[M(Q_(1),Q_(3))]为22.0(17.3,47.8)岁。根据贝克自杀意念量表(Beck Scale for Suicide Ideation,BSI)第4、5题认为是否有“弱”或“中等到强烈”的自杀意念将抑郁症患者分为伴自杀意念的抑郁症组(n=41)和不伴自杀意念的抑郁症组(n=27)。同时网络招募性别匹配的健康对照者72名,其中男29名,女43名,年龄为25.5(24.0,36.8)岁。使用24项汉密尔顿抑郁量表(Hamilton Depression Rating Scale-24,HAMD_(24))、汉密尔顿焦虑量表(Hamilton Anxiety Rating Scale,HAMA)、BSI分别评估抑郁症患者的抑郁症状、焦虑症状及自杀意念;并采集空腹静脉血检测所有受试者的血浆犬尿氨酸代谢物水平。对伴自杀意念的抑郁症患者进行随访,在第2、4周末重复抑郁症状、焦虑症状及自杀意念的评估和外周犬尿氨酸代谢物的检测。使用超高效液相色谱-三重四极杆质谱联用仪测定血浆中犬尿氨酸代谢物的水平。对血液学指标对数转化后进行Z-score标准化,不同代谢物的多重比较使用误报率校正。分析基线犬尿氨酸代谢物与量表分之间的关系;采用线性混合效应模型分析随访过程中犬尿氨酸代谢物与量表分的关系。结果抑郁症患者的外周吡啶甲酸(0.39±0.87比-0.23±1.09,t=3.89)、3-羟基犬尿氨酸与犬尿氨酸比值(3-hydroxykynurenine/kynurenine,3-HK/KYN)(0.38±0.85比-0.09±1.01,t=2.98)和3-HK(0.31±0.81比0.14±1.04,t=2.78)低于健康对照(均P<0.05)。在伴或不伴自杀意念的抑郁症患者之间,犬尿氨酸代谢物之间的差异无统计学意义(均P>0.05)。在伴有自杀意念的抑郁症患者中,基线HAMD_(24)、HAMA评分均与血浆3-HK(HAMD_(24):r=0.38;HAMA:r=0.39)和3-HK/KYN(HAMD_(24):r=0.34;HAMA:r=0.37)水平呈正相关(均P<0.05)。纳入年龄、性别因素后,对该组患者的随访量表评分与犬尿氨酸代谢物水平建立线性混合效应模型,结果显示HAMA评分在随访过程中对3-HK/KYN的正向影响具有统计学意义(B=0.04,t=2.46,P<0.05)。结论抑郁症患者存在犬尿氨酸代谢通路异常,3-HK及3-HK/KYN与伴有自杀意念的抑郁症患者的抑郁、焦虑水平存在相关关系,其中3-HK/KYN代表的犬尿氨酸-3-单加氧酶的活性与焦虑水平存在动态关联。

ObjectiveThis study aimed to explore whether there are abnormalities in the kynurenine pathway in patients with depression and suicidal ideation,and their dynamic relationship with clinical symptoms.MethodsAccording to the DSM-5 diagnostic criteria,a total of 68 patients with depression were prospectively enrolled,including 28 males and 40 females,aged(M(Q_(1),Q_(3)))22.0(17.3,47.8)years,who were the inpatients in the Division of Mood Disorders of Shanghai Mental Health Center from July 2019 to July 2022.The depressed patients were divided into groups with(n=41)or without suicidal ideation(n=27)based on whether they chose"weak"or"moderate to strong"suicidal ideation in questions 4 and 5 of the Beck Scale for Suicide Ideation(BSI).And 72 gender-matched healthy controls were also enrolled,including 29 males and 43 females,aged 25.5(24.0,36.8)years.Hamilton Depression Rating Scale-24(HAMD_(24)),Hamilton Anxiety Rating Scale(HAMA),and BSI were used to evaluate the depression symptoms,anxiety symptoms,and suicidal ideation of depressed patients.All the participants received fasting venous blood collection to measure the levels of kynurenine metabolites in plasma.Among them,depressed patients with suicidal ideation were followed up,and the assessment s of depression symptoms,anxiety symptoms,and suicidal ideation,as well as kynurenine metabolites measurements,were repeated at the end of the 2nd and 4th weeks.Ultra-high performance liquid chromatography-triple quadrupole mass spectrometry was used to measure the levels of kynurenine metabolites in plasma.The hematological indicators were log-transformed,Z-score standardized,and false discovery rate correction was used for multiple comparisons of different metabolites.The relationship between baseline kynurenine metabolites and scale scores was analyzed.The relationship between kynurenine metabolites and scale scores during the follow-up process was analyzed by a linear mixed-effects model.ResultsThe peripheral picolinic acid(0.39±0.87 vs-0.23±1.09,t=3.89),3-hydroxykynurenine/kynurenine(3-HK/KYN)(0.38±0.85 vs-0.09±1.01,t=2.98)and 3-HK(0.31±0.81 vs 0.14±1.04,t=2.78)of patients with depression were lower than those of healthy controls(both P<0.05).No statistically significant difference was found between patients with depression with or without suicidal ideation in kynurenine metabolites.In patients with depression and suicidal ideation,baseline HAMD_(24)and HAMA scores were positively correlated with plasma 3-HK(HAMD_(24):r=0.38;HAMA:r=0.39)and 3-HK/KYN(HAMD_(24):r=0.34;HAMA:r=0.37)levels(all P<0.05).After adjusting for age and gender factors,a linear mixed-effects model was established for the follow-up scale scores,and kynurenine metabolite levels of this group of patients,and the results showed that the positive effect of HAMA score on 3-HK/KYN during follow-up was statistically significant(B=0.04,t=2.46,P<0.05).ConclusionThere are abnormalities in the kynurenine pathway of tryptophan metabolism in patients with depression.3-HK and 3-HK/KYN are related to the severity of depression and anxiety in patients with depression and suicidal ideation,among which 3-HK/KYN,representing the activity of kynurenine-3-monooxygenase,is dynamically associated with anxiety level.