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

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Clozapine-Induced Cardiovascular Side Effects and Autonomic Dysfunction: A Systematic Review

“…Of note, only animals treated with CLZ displayed significantly different RR, TP, and LF% values compared to controls regardless of consciousness. HAL and risperidone did not significantly influence HRV in the same manner as CLZ, which the authors attributed to CLZ's strong anticholinergic and antiadrenergic properties (Wang et al, 2012 ).…”

“…The sole HRV preclinical study identified in our literature search was conducted by Wang et al ( 2012 ), on male Wistar-Kyoto rats. This study also took into consideration the influence of antipsychotics on sleeping patterns and consequently autonomic activity during sleep-wake cycles.…”

“…Results show rats treated with CLZ displayed accelerated HR and decreased RR, TP, HF, and LF%. When sleep-wake cycles were accounted for, the CLZ group demonstrated longer periods of wakefulness, to which the magnitude of the RR decrease was found to be less than that during sleep, implying CLZ-induced tachycardia was more severe during sleep (Wang et al, 2012 ). Of note, only animals treated with CLZ displayed significantly different RR, TP, and LF% values compared to controls regardless of consciousness.…”

Effects of cold exposure on autonomic changes during the last rapid eye movement sleep transition and morning blood pressure surge in humans

“…One-sample t-tests were used to analyze the differences between the delta value and baseline. The effects of the two factors (ambient temperature and sleep stage) on changes of autonomic activities were assessed by two-way mixed design ANOVA (two ambient temperatures × two sleep stages) [33]. When pinpointed by a significant F-statistic, the differences between states were isolated using post-hoc comparisons and Fisher's least-significant difference test.…”

Polypharmacy in psychiatry: A review

“…Polypharmacy is strongly associated with excessive dosing and early death (Ito et al ., 2005[16]). Use of thioridazine is a predictor of QTc prolongation, and even moderate doses of antipsychotics would increase the risk of sudden cardiac death (Wang et al ., 2012[55]). Antipsychotic polypharmacy, compared with monotherapy, is found to be independently associated with an increased risk of having pre-metabolic syndrome, even after adjusting for patients’ lifestyle characteristics (Misawa et al ., 2011[27]).…”