Supplementary Material for: Influence of Antipsychotic Agents on Heart Rate Variability in Male WKY Rats: Implications for Cardiovascular Safety

<b><i>Background:</i></b> Sudden cardiac death is higher among schizophrenic patients and is associated with parasympathetic hypoactivity. Antipsychotic agents are highly suspected to be a precipitating factor. Thus, we aimed to test if the antipsychotics haloperidol, risperidone and clozapine affect cardiac autonomic function, excluding the confounding effect of altered sleep structure by the drugs. <b><i>Methods:</i></b> In this study, haloperidol, risperidone and clozapine were given separately by intraperitoneal injection to male Wistar-Kyoto rats for 5 days. Electroencephalogram (EEG), electromyogram (EMG) and electrocardiographic signals were recorded at baseline and 5 days after drug treatments. Sleep scoring was based on EEG and EMG signals. Cardiac autonomic function was assessed using heart rate variability analysis. <b><i>Results:</i></b> Clozapine increased heart rate and suppressed cardiac sympathetic and parasympathetic activity. Cardiac acceleration was more severe during sleep. Haloperidol tended to decrease heart rate while risperidone mildly increased heart rate; however, their effects were less obvious than those of clozapine. There was a significant drug-by-stage interaction on several heart rate variability measures. <b><i>Conclusion:</i></b> Taking this evidence as a whole, we conclude that haloperidol has a better level of cardiovascular safety than either risperidone or clozapine. Application of this approach to other psychotropic agents in the future will be a useful and helpful way to evaluate the cardiovascular safety of the various psychotropic medications that are in clinical use.

<b><i>背景：</i></b> 精神分裂症患者的心源性猝死发生率更高，且与副交感神经功能低下相关。抗精神病药物被高度怀疑为其诱发因素。因此，本研究旨在探究氟哌啶醇、利培酮及氯氮平这三种抗精神病药物是否会影响心脏自主神经功能，并排除药物改变睡眠结构所带来的混杂效应。<b><i>方法：</i></b> 本研究将氟哌啶醇、利培酮及氯氮平分别通过腹腔注射给予雄性Wistar-Kyoto大鼠，连续给药5天。在给药前基线状态及给药5天后，分别记录脑电图（Electroencephalogram, EEG）、肌电图（Electromyogram, EMG）及心电图信号。睡眠分期基于EEG与EMG信号进行判定。心脏自主神经功能通过心率变异性分析进行评估。<b><i>结果：</i></b> 氯氮平可升高心率，并抑制心脏交感与副交感神经活性，且睡眠期间心脏加速效应更为显著。氟哌啶醇有降低心率的趋势，而利培酮则轻度升高心率，但二者的效应均弱于氯氮平。多项心率变异性指标存在显著的药物-阶段交互作用。<b><i>结论：</i></b> 综合上述研究结果，本研究认为氟哌啶醇的心血管安全性优于利培酮与氯氮平。未来将该研究方法应用于其他精神药物，将成为评估临床各类精神药物心血管安全性的有效途径。