Heart Rate Variability in Schizophrenic Patients ...

Original Paper Neuropsychobiology 2008;57:200–205 DOI: 10.1159/000149818

Received: September 13, 2005 Accepted after revision: May 25, 2008 Published online: August 5, 2008

Heart Rate Variability in Schizophrenic Patients Switched from Typical Antipsychotic Agents to Amisulpride and Olanzapine 3-Month Follow-Up

Ying-Chieh Wang a, b Cheryl C.H. Yang c, d Ya-Mei Bai b, e Terry B.J. Kuo c, d a Institute of Medical Sciences, Tzu Chi University, and b Department of Psychiatry, Yu-Li Veterans Hospital, Hualien, and c Institute of Brain Science, d Sleep Research Center and e Institute of Public Health, National Yang-Ming University, Taipei, Taiwan

Key Words Antipsychotics ⴢ Heart rate variability ⴢ Schizophrenia

more vagotonic effect, suggesting greater cardiovascular safety as compared with olanzapine when subjects are switched from typical antipsychotic agents. Copyright © 2008 S. Karger AG, Basel

Abstract Schizophrenia is a severe mental disorder that requires lifelong treatment, and therefore information on the cardiovascular safety and tolerance of antipsychotics is of significant clinical importance. Atypical antipsychotics have been used to treat schizophrenia patients since the 1990s, and more and more patients have been switched to these from typical antipsychotics; however, there is still no accessible evaluation tool for assessing cardiovascular safety. In this study, we used a computer-assisted 5-min measurement of resting heart rate variability (HRV) in schizophrenia patients who were switched to atypical antipsychotic agents (amisulpride and olanzapine) due to severe side effects (tardive dyskinesia). In 15 patients who switched to amisulpride and 18 to olanzapine, HRV was evaluated before the medication was switched, and patients were followed up every month for 3 months after the switch. Frequency-domain analyses of short-term and stationary respiratory rate (RR) intervals were performed to evaluate low-frequency power (LF; 0.04–0.15 Hz), high-frequency power (HF; 0.15–0.40 Hz), the ratio of LF to HF (LF/HF), and LF in normalized units (LF%). Our results showed significant increases in the mean, variance and HF of RR intervals in the amisulpride group, but not in the olanzapine group. These results indicate that amisulpride has a

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Introduction

Information on the cardiovascular safety and tolerance of antipsychotics is of significant clinical importance because antipsychotics can promote cardiac arrhythmias, anomalies implicated as a cause of sudden death among antipsychotic-treated patients with schizophrenia [1, 2]. Most antipsychotics prolong repolarization, in this way increasing the risk of ventricular arrhythmia. Ventricular fibrillation can be induced in animals by stimulating the posterior hypothalamus, an effect mediated via sympathetic neural input into the heart [3]. The vagal activity seems to have myocardioprotective and antiarrhythmogenic effects that arise from direct inhibitory activity on the myocardium and from interference with sympathetic neurons [4, 5]. Autonomic nervous system (ANS) regulation is important in preventing, promoting and precipitating arrhythmias and sudden death [6]. Frequency-domain analysis of resting heart rate variability (HRV) is a sophisticated and noninvasive tool used for the detection of ANS regulation of the heart. It has been Terry B.J. Kuo Institute of Brain Science, National Yang-Ming University No. 155, Sec. 2, Linong St. 11221 Taipei (Taiwan) Tel. +886 2 2826 7058, Fax +886 2 2827 3123, E-Mail [email protected]

well established that HRV can be categorized into highfrequency power (HF; 0.15–0.40 Hz) and low-frequency power (LF; 0.04–0.15 Hz) components, according to its oscillating frequency and development mechanism [7]. The HF component is equivalent to the well-known respiratory sinus arrhythmia, and is considered to represent vagal control of heart rate. LF in normalized units (LF%) and the ratio of LF to HF (LF/HF) are considered by some investigators to mirror sympathovagal balance or to reflect sympathetic modulation [8, 9]. Evidence now exists of an association between reduced HRV and an increased risk of sudden cardiac death [10, 11]. Consistent with this, both the occurrence of cardiovascular complications and a higher risk of cardiovascular mortality are associated with a reduction in HRV in a number of clinical conditions [12–14]. It had been reported that schizophrenic patients treated with clozapine show diminished HRV parameters [15]. These results were mainly interpreted as being a consequence of the effects of the medication, such as the anticholinergic effects of clozapine [16]. Few reports have evaluated other atypical antipsychotic agents [15, 17], and those studies lacked a long period of evaluation. In this study, we monitored HRV changes every month in schizophrenia patients who switched from typical antipsychotic agents to atypical agents (amisulpride and olanzapine) throughout a 3-month follow-up. It is our hope that this study can provide some evidence regarding cardiovascular safety during the switching of medications.

Methods Subjects Thirty-three schizophrenic patients who were being treated with typical antipsychotic agents and who suffered from tardive dyskinesia [18] were recruited in this study. All patients agreed to switch their medication to atypical antipsychotic agents (amisulpride and olanzapine). All enrolled patients were chronic inpatients at Yu-Li Veterans Hospital; a diagnosis for each patient was made according to the DSM-IV criteria of schizophrenia by 2 certificated psychiatrists, based on an interview, clinical observation, medical records and past history. The clinical variables measured in the study include gender, age, blood pressure, antipsychotic dosage, body weight, height and duration of illness at baseline. Clinical symptoms were evaluated using the Brief Psychotic Rating Scale. Treatment with typical antipsychotic agents was gradually tapered; then, 1 month later, the atypical antipsychotic dosage was gradually increased over 1 month, and dosage adjustment was determined by clinical need. The previous typical antipsychotic medications of the amisulpride group were: haloperidol (n = 4), trifluoperazine (n = 1), chlorpromazine (n = 1), sulpiride (n = 5), flupenthixol (n = 2) and thioridazine (n = 2);

Antipsychotics and Heart Rate Variability in Schizophrenia

those of the olanzapine group were: haloperidol (n = 5), sulpiride (n = 4), trifluoperazine (n = 1), flupenthixol (n = 3), chlorpromazine (n = 4) and zuclopenthixol (n = 1). Combined medications were permitted as indicated by clinical need, and in the amisulpride group these included: benzodiazepine (n = 7), valproic acid (n = 2), lithium (n = 1), ␤-blocker (n = 1), trihexyphenidyl (n = 9) and biperiden (n = 2); in the olanzapine group these included: benzodiazepine (n = 12), valproic acid (n = 1), carbamazepine (n = 1), ␤-blocker (n = 3), trihexyphenidyl (n = 7) and biperiden (n = 4). HRV was evaluated prior to the switch in antipsychotic medication and 1, 2 and 3 months after the switch. Baseline refers to the time before the medication switch; 1 month means the patient had just completed the cross-titration period. In order to exclude the effects of diurnal variation, evaluations were always performed in the same order between 9: 00 a.m. and 11: 00 a.m. Patients with the following exclusion criteria were not recruited into this study: history of mood disorder, organic mental disorder, substance abuse, neurological illness, diabetes mellitus, age over 65 or under 18. All of the patients were ethnic Chinese. The study was described in full to all patients, and informed consents were obtained prior to HRV evaluation. This study was reviewed and approved by Yu-Li Veterans Hospital Institutional Review Board (YLVH-IRB No. 92-11-04A). Processing of Electrocardiogram Signals The detailed procedures for HRV analysis have been previously reported [19, 20]. In brief, a precardial ECG was taken for 5 min in the daytime, while each subject lay quietly and breathed normally. ECG signals were recorded using an analog-to-digital converter with a sampling rate of 256 Hz. The digitized ECG signals were analyzed online and simultaneously stored on a hard disk for offline verification. Signal acquisition, storage and processing were performed on an IBM-compatible portable personal computer. Our computer algorithm identified each QRS complex, and rejected each ventricular premature complex or noise, according to its likelihood in a standard output record separator template. Stationary respiratory rate (RR) values were resampled and interpolated at a rate of 7.11 Hz to produce continuity in the time domain. Frequency-Domain Analysis of HRV Frequency-domain analysis was performed using a nonparametric method of fast Fourier transformation. The direct current component was deleted, and a Hamming window was used to attenuate the leakage effect [21]. For each time segment (288 s; 2,048 data points), our algorithm estimated the power spectrum density based on the fast Fourier transformation. The resulting power spectrum was corrected for attenuation resulting from the sampling and the Hamming window. The power spectrum was subsequently quantified into standard frequency-domain measurements, as defined previously [7], including total variance, HF (0.15–0.40 Hz), LF (0.04–0.15 Hz), LF% and LF/HF. Variance, HF, LF and LF/HF were logarithmically transformed to correct for the skewed distribution [19]. Statistical Analysis Values are expressed as means 8 SE. The general data of the 2 groups were compared using an unpaired t test. The comparisons of HRV between treatment groups at various time points were conducted by 2-way repeated-measures analyses of covari-

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Table 1. Demographic data

Amisulpride (n = 15) Gender (female/male), n Age, years Height, cm Weight, kg BMI Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Heart rate, beats/min Chlorpromazine equivalence, mg Duration of illness, years Brief Psychotic Rating Scale score

Olanzapine (n = 18)

7/8 9/9 48.282.1 49.482.2 159.883.1 160.082.2 62.481.9 63.083.3 24.680.6 24.781.2 109.286.3 (91–128) 118.384.1 (92–151) 67.183.6 (57–83) 73.482.6 (61–99) 73.382.8 (52–90) 74.483.4 (53–104) 7788123 (250–1,500) 728883 (250–1,350) 22.183.0 (3–44) 24.182.5 (4–42) 35.581.6 34.882.1

Values are expressed as means 8 SD with ranges in parentheses.

ance (rANCOVA), in which the treatment drug was set as the between-subject variable, the treatment time as the within-subject variable and the baseline HRV as the covariate. Once the main effects of time were observed, changes in HRV within each drug group at each time point from the baseline were then assessed by a 1-way rANCOVA followed by the post hoc Bonferroni procedure. Differences were considered statistically significant at p ! 0.05. All analyses were performed using SPSS 10.0 for Windows.

Results

Fifteen patients (7 male) accepted amisulpride treatment (mean dosage = 466 8 57.5 mg), and 18 patients (9 male) accepted olanzapine treatment (mean dosage = 10 8 1.28 mg). There were no significant differences between the amisulpride- and olanzapine-treated groups with regards to demographic variables (table 1). Figure 1 illustrates the 5-min resting HRV results of the patients who had switched from typical antipsychotic agents to olanzapine and amisulpride. For RR intervals, 2-way rANCOVA showed that there were significant interactive effects of time-by-drug group (F = 9.157, d.f. = 1, p = 0.005), and significant main effects of time (F = 30.851, d.f. = 1, p ! 0.001) and treatment drug (F = 9.157, d.f. = 1, p = 0.005). One-way rANCOVA followed by the post hoc Bonferroni procedure revealed significant differences in RR intervals from the baseline at 2 months (p = 0.009) and 3 months (p = 0.003) in the amisulpride group. There were no significant differences in RR intervals at various time points from the baseline within the olanzapine group (all p 1 0.05). With regards to variance, 2-way rANCOVA indicated that there was a significant time-by-drug group interac202


tive effect (F = 6.809, d.f. = 1, p = 0.014) as well as a main effect of time (F = 8.469, d.f. = 1, p = 0.007). One-way rANCOVA showed a difference in variance at 3 months (p = 0.059) from the baseline within the amisulpride group; again, there were no significant differences in the variance at various time points from the baseline within the olanzapine group (all p 1 0.05). In the analyses for HF, only the main effect of time was detected after 2-way rANCOVA (F = 8.668, d.f. = 1, p = 0.006). Within the amisulpride group, significant differences in HF from the baseline were observed at 1, 2 and 3 months (p ! 0.001, p ! 0.001 and p ! 0.001, respectively); no significant differences were observed in the olanzapine group (all p values 1 0.005). Two-way rANCOVA showed that the main effect of treatment drug and the interaction effect of time-by-drug group on LF, LF% and LF/HF were all insignificant (all p 1 0.05), except for the main time effect on LF% (F = 6.527, d.f. = 1, p = 0.016) and LF/HF (F = 5.156, d.f. = 1, p = 0.031). However, the post hoc Bonferroni procedure after 1-way rANCOVA within each drug group failed to detect any significant differences at any time point from the baseline for LF% and LF/HF (all p values 1 0.05).

Discussion

The cardiovascular safety and tolerance of antipsychotics in schizophrenia patients is an important clinical issue. The aim of this study was to investigate the influence of atypical antipsychotics (amisulpride and olanzapine) on the ANS when patients switched from typical antipsychotics. To evaluate the ANS, we used a stanWang /Yang /Bai /Kuo

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Fig. 1. 3-Month follow-up values of mean RR interval, variance of the RR interval, HF, LF, normalized LF (LF% in normalized units), and LF/HF in patients who switched to amisulpride and olanzapine. * p ! 0.05, compared to the baseline.

dardized, computer-assisted measurement of 5-min resting HRV, a noninvasive technique that allows for a differentiated quantitative estimation of ANS activity [20].

Our results showed that in patients who switched to amisulpride, the RR interval was prolonged and the HF also increased significantly over the 3 months of observation. This may be explained as follows: typical antipsy-



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chotics show activity at the cholinergic or adrenergic receptor, so parasympathetic activity inhibition may be noted. Amisulpride only acts at the dopamine D2 and D3 receptors, and so has no significant effects on the ANS due to inhibition decrease after the medication switch; an increase in parasympathetic activity was also noted. With regards to olanzapine, in anticholinergic activity, the LF decrease was noted transitionally, but the difference was not seen until the third month, which may be due to physiological tolerance. Agelink et al. [15] reported that medication-free schizophrenia patients were then treated with amisulpride and olanzapine without any significant change in HRV; our results differ somewhat, perhaps because the short-term observation period (2 weeks) of their study may not suitable for schizophrenia patients, and longterm effects may not have been apparent. Another study reported that olanzapine increased HRV in healthy male volunteers and, in a short-term evaluation [17], they concluded that olanzapine may improve cardiac heart function; however, we should treat this conclusion with caution, as single-dose short-term observations in healthy males may not provide evidence of a reliable index for use in schizophrenia patients. Our results did not show any obvious increase in HRV in the olanzapine group, and the hypothesis of improvement of cardiac heart function was not supported by the results of our study. Another possible explanation is that co-medication with benzodiazepine (in 12 of 18 patients in the olanzapine group) may cause a reduction in central vagal tone [25]; however, similar results were not obtained in another study [17]. Our study had some limitations. First, if a suitable control group was recruited and the results compared, the HRV change may prove more meaningful. Second, we proposed that amisulpride might improve parasympathetic activity when patients switch from typical antipsychotic agents, and a better cross-over design could be used to clarify the possible effects. Third, although we attempted to include patients with similar Brief Psychotic

References

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