Ministry of Health Mental Health Center, Faculty of Health-Sciences, Anxiety and Stress Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Correspondence: Hagit Cohen, Anxiety and Stress Research Unit, Ministry of Health Mental Health Center, Faculty of Health-Sciences, Ben-Gurion University of the Negev, PO Box 4600, Beer-Sheva, Israel. Fax: 972-8-6401742; e-mail: hagitc{at}bgumail.bgu.ac.il
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ABSTRACT |
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Aims To supply power spectral analysis of heart rate variability as a tool to examine the arrythmogenic effects of neuroleptics.
Method Heart rate analysis was carried out in patients with schizophrenia on standard doses of neuroleptic monotherapy 21 were on clozapine, 18 on haloperidol and 17 on olanzapine and in 53 healthy subjects.
Results Patients with schizophrenia on clozapine had significantly higher heart rate, lower heart rate variability and lower high-frequency and higher low-frequency components compared with patients on haloperidol or olanzapine and matched control subjects. Prolonged QTc intervals were more common in patients than controls.
Conclusions Patients treated with neuroleptic medications, especially clozapine, showed autonomic dysregulation and cardiac repolarisation changes. Physicians should be aware of this adverse reaction.
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INTRODUCTION |
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METHOD |
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Controls
It proved impossible both to recruit a sufficient number of untreated
patients with schizophrenia, because these are rare in Israel today, and
certainly to create an age- and gender-matched control group. We therefore
used a healthy control group for comparison. The 53 healthy volunteers were
matched for age, gender, smoking and time of day of electrocardiogram (ECG)
recordings. None had any serious or disabling coexisting diseases. Controls
had not taken any psychotropic or other medications known to alter autonomic
activity for at least 4 weeks prior to the study.
The Helsinki Ethics Committee of the hospital approved the study. All participants gave their written consent after having received detailed information about the study.
Procedure
Electrocardiographic recordings were performed by connecting the subjects
to a Holter monitor (Oxford 4-24) in a seated position at complete rest. After
allowing 10 min for stabilisation, a 10-min ECG recording was made. Subjects
were instructed to breathe normally and the respiratory rate was monitored by
a strain-gauge-based respiration transducer, wrapped around the chest and
abdomen halfway between the rib cage and navel.
Analysis of recordings
Electrocardiographic data were amplified, digitised (500 Hz, width
pass=0.05-35 Hz) and stored using a personal-computer-based software system.
QRS complexes were classified. Premature ventricular beats, electrical
noise or aberrant beats were rejected. The threshold for
rejection was set at ±15% of the reference RR duration. The R-R
intervals between normal QRS complexes were extracted and a regularly spaced
time series was sampled at 2 Hz with the use of a low-pass filter. Finally, we
transformed the time signal into a frequency signal by using a fast Fourier
transform (Task Force,
1996).
Frequency domain analysis
Two frequency bands were calculated: the low-frequency (LF) band (0.04-0.15
Hz), which gives a measure of sympathetic activity with some influence from
the parasympathetic nervous system; and the high-frequency (HF) band
(0.15-0.40 Hz), which solely reflects parasympathetic activity. The area
(ms2) under the curve was calculated for each frequency band. There
is some disagreement over the low-frequency component. Some investigators
regard it as a marker of sympathetic activity, whereas others consider it an
index influenced by both sympathetic and vagal systems. To cancel out the
influence of the parasympathetic activity on the low-frequency spectral power,
the LF/HF ratio was calculated. This ratio provides a measure of the
sympathovagal balance, where an increase in the LF/HF ratio reflects a
predominance of sympathetic over parasympathetic activity. We calculated the
total variability of the heart rate oscillations in the total power spectrum
(0.01-0.4 Hz) as an expression of the overall variability. Because total power
varies greatly between individual subjects, power was determined in both
absolute units and as normalised values. The power in normalised units was
calculated by dividing the absolute power of a given component (area under the
component curve) by the total power minus the 0-0.04 Hz component.
An independent observer, who was blind as to whether the data referred to a patient or a control subject, performed all ECG recordings.
Measurements of QT interval
The corrected QT interval was calculated by the method of Bazett
(QTc=QT/(RR)). The mean QT and the mean RR were used to calculate the
mean QTc for each lead. Heart rate was derived from the mean of the RR
intervals. The QT and RR intervals were measured manually with callipers by a
single observer. The QT intervals were measured from the onset of the QRS
complex to the end of the T wave. The end of the T wave was defined as the
point of return to the isoelectric line.
Statistical analysis
To compare effects between groups, the variables were analysed by analysis
of covariance (one-way ANCOVA), with age and smoking status as the covariates.
Age was entered as a covariate because HRV decreases with increasing age
(r=-0.81, r2=0.66; P<0.01). Post
hoc comparisons employed Scheffé's test.
Because of the skewness of the data, logarithmic transformation was performed
on the absolute units of the spectral components of the HRV before the
statistical analysis.
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RESULTS |
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The patients treated with clozapine had significantly lower HRV than those treated with haloperidol or olanzapine or the matched control subjects (P=0.00017). The patient study population showed a significantly lower HRV than the matched controls (P=0.002). The clozapine-treated group had a significantly high low-frequency component compared with patients treated with olanzapine or haloperidol or the control group.
Prolonged QTc intervals were more common in treated patients than in controls although the PR and QRS intervals did not differ significantly. Prolonged QTc intervals were observed in 15 patients treated with clozapine (71.43%), 11 patients treated with olanzapine (64.7%) and 12 patients treated with haloperidol (66.67%).
A T-wave inversion was observed in fourteen patients treated with clozapine (66.6%), three patients treated with olanzapine (17.6%), three patients treated with haloperidol (16.6%) and in one subject from the control group (1.6%).
Spontaneous fluctuations in interbeat interval and power spectral analysis of HRV in treated patients and normal controls are presented in Fig. 1.
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There were no significant changes in the respiratory rate (range 13-17 cycles/min) in any of the subjects. This implies that any significant differences in the high-frequency component can be attributed to non-respiratory effects on parasympathetic tone.
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DISCUSSION |
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The possible association between sudden death and antipsychotic pharmacotherapy has been reviewed most extensively by a task force of the American Psychiatric Association, whose disappointingly vague conclusion is that: "the role played by the drug in a given individual is difficult, if not impossible, to determine" (Task Force, 1988). Despite the inconclusive results of the task force, the possibility of arrythmogenic properties of antipsychotic drugs cannot be excluded.
Association of autonomic dysfunction and clozapine
The results of this study provide evidence that power spectral analysis of
HRV may be of value in assessing the effects of medications on the
physiological parameters of patients. Patients with schizophrenia under
prolonged clozapine therapy exhibited marked differences in ANS functioning
compared with those treated with haloperidol or olanzapine, as shown by
increased heart rate and low-frequency components and lower HRV and
high-frequency components. This reflects a basal autonomic dysfunction with
increased sympathetic and decreased parasympathetic tone. Our findings are in
complete agreement with those of Zahn & Pickar
(1993) and Rechlin et
al (1998), who
demonstrated normal HRV in unmedicated patients with schizophrenia and a
dose-related effect of clozapine on HRV. We thus attribute these findings to
clozapine and not to the disease.
The difference between the effects of clozapine, olanzapine and haloperidol
on HRV is very interesting. On the one hand, haloperidol is known to be
relatively free of clinically significant effects on receptors for
neurotransmitters other than dopamine (except for a low affinity for
2- and 5-HT2a-receptors), whereas both clozapine
and olanzapine have more wide-ranging receptor affinity profiles of clinical
significance (Shiloh et al,
1999). On the other hand, the findings of this study show a
greater in vivo similarity between the HRV effects (i.e. clinical ANS
effects) of olanzapine and haloperidol than those of clozapine. This clinical
finding is difficult to explain in terms of a simple neurotransmitter/receptor
paradigm and is probably the net result of complex interactions between
peripheral and central mechanisms (Jacobs,
1987).
Antipsychotics and QT interval
Some of the effects of antipsychotic medications appear to be direct and
local. A high prevalence of QTc prolongation was found in all our treated
patients compared with controls, a finding consistent with the trend of the
findings in other clinical reports
(Barnett, 1996;
Reilly et al, 2000).
The high prevalence of QTc prolongation is in keeping with the trend of the
findings reported by Reilly et al
(2000), although the
proportion of patients with QTc prolongation is far greater in our study.
Preclinical (animal) studies also support this trend
(Drici et al, 1998).
The PR and QRS intervals did not differ significantly. This probably suggests
that neuroleptics affect cardiac repolarisation rather than conduction, owing
to their sodium/potassium as well as calcium-ion-channel blocking actions.
Drugs that significantly prolong the QT interval may have the potential to
trigger complex forms of polymorphic ventricular arrhythmias (e.g. torsade de
points), which can lead to sudden death.
Our findings imply that patients with schizophrenia taking clozapine have decreased parasympathetic activity, elevated sympathetic activity and prolonged QT intervals. Because decreased parasympathetic tone lowers the threshold for ventricular tachycardia (Suttmann et al, 2000), it is possible, although as yet unproven, that the decreased high-frequency component may reflect the mechanism that underlies the increased rate of cardiovascular mortality in patients with schizophrenia.
Possible mechanisms by which neuroleptic medications cause malignant
cardiac arrhythmias
The precise cellular mechanisms by which neuroleptic medications cause
malignant cardiac arrhythmias are poorly understood. The triggering mechanism
is thought to be the interruption of repolarisation early in phase 3 of the
action potential by early after-depolarisations
(Drici et al, 1998).
Early after-depolarisations are induced by interventions that decrease
repolarising (potassium) currents (antiarrhythmic drugs) and/or that increase
inward currents carried by calcium or sodium
(January et al, 1988;
Roden et al, 1996).
These changes may produce early after-depolarisations directly, or they may
alter the trajectory of the antipsychotic to produce secondary changes in
otherwise normal ion currents that then result in early after-depolarisations.
These early after-depolarisations may reach a threshold amplitude and trigger
ventricular arrhythmias (Viskin,
1999). Additionally, the QT prolongation, resulting from the
blockade of one or more repolarising potassium channels
(Viskin, 1999), may cause a
surplus of potassium ions in the intracellular volume of the myocardium,
enabling the genesis of early after-depolarisations. This phenomenon is seen
in the long-QT syndrome, which is characterised by similar
features and is associated with fatal arrhythmias, presumably secondary to the
attainment of depolarisation threshold. Autonomic dysregulation also has been
associated with arrhythmic effects in otherwise healthy individuals, as the
result of sympathetic hyperactivity and/or parasympathetic hypoactivity. The
emergence of torsade de pointes also may be facilitated by electrolyte
disturbances (hypokalaemia, hyponatraemia, hypomagnesaemia), secondary to
clinical or subclinical syndrome of inappropriate antidiuretic hormone
secretion (SIADH), a rare toxic effect of neuroleptic medication. Independent
risk factors, such as smoking, may contribute.
Clinical experience has shown that many patients with schizophrenia require long-term pharmacotherapy, and the reports of a possible association between antipsychotic drugs and sudden death cause concern for practitioners. Our present experience in applying power spectral analysis of HRV as an index of cardiac autonomic balance is rather encouraging. The method is non-invasive, relatively inexpensive, straightforward and uncomplicated to operate and provides a real-time dynamic assessment of sympathetic and parasympathetic tone, reflecting the interactions between the two. This study raises the question of potentially important prognostic implications of protracted autonomic dysfunction in medicated psychiatric patient populations, especially for cardiovascular morbidity and mortality. Diagnostic measurement of the ANS may improve identification of patients at high risk for sudden cardiac death. Measurement of heart rate and QT are far less specific than power spectral analysis of HRV. Heart rate is affected by too many non-specific factors and QT changes are near-universal effects of neuroleptic medication, whereas HRV clearly reflects ANS pathophysiology.
The results of this study raise the possibility that the cardiovascular effects of neuroleptics may, at least in part, be mediated by autonomic dysregulation, in addition to other simultaneous effects accounting for the cardiac cellular electrophysiological level. Prospective studies may identify electrocardiographic markers of cardiac damage in at-risk patients, which may be useful in screening for these important adverse outcomes.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication August 11, 2000. Revision received February 22, 2001. Accepted for publication March 7, 2001.