精神分裂症相关的QTc延长危险因素分析及预测模型建立

Analysis of risk factors for QTc prolongation relating to schizophrenia and development of predictive model

目的探索与精神分裂症相关的QTc延长危险因素,验证危险因素的交互作用,建立精神分裂症患者QTc延长的预测模型。方法选取341例精神分裂症患者基线期资料进行单因素分析及多因素Cox回归分析,基于多因素Cox回归结果预测精神分裂症患者1年QTc延长风险。结果341例患者中有44例患者发生QTc延长,发生率为12.90%。QTc延长的患者中应用高危药物的人数比例高于QTc正常患者(P<0.05)。多因素Cox回归结果提示性别及代谢综合征之间存在交互作用(P<0.05)。单因素分析结果显示女性QTc延长患者中应用高危抗精神病药物及患有代谢综合征的人数比例较高(P<0.05)。女性多因素分析结果显示,应用高危抗精神病药物及代谢综合征为女性患者发生QTc延长的危险因素(P<0.05)。建立了女性精神分裂症患者QTc延长预测模型,C-index为0.736,校准度曲线较贴合y=x。结论女性精神分裂症患者中患有代谢综合征或应用高危抗精神病药物的患者发生QTc延长的风险较大。本研究建立的女性精神分裂症患者QTc延长预测模型能帮助临床医生快速识别高风险患者。

Objective QTc interval,representing the process of ventricular repolarization,is an important marker for the evaluation of drug safety.Schizophrenics have a higher risk of QTc prolongation compared to healthy people.The reasons are complex.On one hand,QTc prolongation can be induced by atypical antipsychotics as reported;on the other hand,some factors from schizophrenia may influence the QTc prolongation,such as metabolic abnormalities caused by disease.However,the current studies on risk factors of QTc prolongation exit limitations,and it is hard for clinicians to identify high-risk patients because of the absence of a prediction model of QTc prolongation.This study aims to explore the risk factors for QTc prolongation relating to schizophrenia and to verify their interactions,developing a predictive model for QTc prolongation in patients with schizophrenia.Methods The data of this study was collected based on a cohort study from August 2016 to December 2020.341 patients with schizophrenia were included and their statuses of QTc prolongation were checked in 1-year follow-up.The risk factors for QTc prolongation were analyzed by comparing the demographic data(gender,age,BMI),disease data(antipsychotics,concomitant diseases),and laboratory tests from the baseline of 341 patients.Univariate analysis(Mann-Whitney U test was used for non-normally distributed measurement data,Pearsonχ2 or Fisher exact probability test was used for enumeration data),and multivariate Cox regression analysis were used for the quantification of risks.The possibility of QTc prolongation in 1-year was predicted based on the results of multivariate Cox regression,and visualized by nomogram.Results During the 1-year study period,44 out of 341 patients had QTc prolongation,and the incidence rate of QTc prolongation was 12.90%.Taking 341 patients as a whole,the univariate analysis showed that the proportion of patients using high-risk antipsychotics(ziprasidone,amisulpride,chlorpromazine,haloperidol)in patients with QTc prolongation was significantly higher than that in patients with normal QTc(P<0.05).The differences in the proportions of metabolic syndrome,genders and ages between two groups were non-significant(P>0.05).Multivariate Cox regression indicated that there existed an interaction between gender and metabolic syndrome(P<0.05).After taking gender as a subgroup,univariate analysis in females suggested that the proportions of patients with metabolic syndrome and using high-risk antipsychotics in patients with QTc prolongation were significantly higher than those in patients with normal QTc(P<0.05).The differences in ages and BMIs were non-significant between the two kinds of female patients(P>0.05).Univariate analysis in males suggested there existed no differences in the proportions of using high-risk antipsychotics and metabolic syndrome,ages and BMIs between the two kinds of male patients(P>0.05).Multivariate analysis in females displayed that metabolic syndrome and high-risk antipsychotics were risk factors for QTc prolongation(P<0.05).A QTc prolongation predictive model for female patients with schizophrenia was developed based on the Cox regression model,with a C-index of 0.736,and the calibration curve fitted y=x.Nomogram was used for visualizing the possibility of QTc prolongation in 1-year.Conclusion This study finds that the risk factors in schizophrenic patients were different in genders.Female patients with metabolic syndrome or using high-risk antipsychotics(ziprasidone,amisulpride,chlorpromazine,haloperidol)are at a higher risk of QTc prolongation.The QTc prolongation predictive model for female schizophrenics is developed in this study,which can help clinicians quickly identify high-risk patients.