SCHRES-07769; No of Pages 4

Schizophrenia Research xxx (2018) xxx–xxx

Contents lists available at ScienceDirect

Schizophrenia Research

journal homepage: www.elsevier.com/locate/schres

Persistent tachycardia in clozapine treated patients: A 24-hour

ambulatory electrocardiogram study
Björn M. Nilsson a,⁎, Leif Lindström a, Issam Mohsen b, Karolina Holmlöv a, Robert Bodén a
a
Department of Neuroscience, Psychiatry, Uppsala University, SE-75185 Uppsala, Sweden
b
Department of Medical Sciences, Clinical Physiology, Uppsala University, SE-75185 Uppsala, Sweden

a r t i c l e i n f o a b s t r a c t

Article history: Tachycardia is associated with cardiovascular mortality. Tachycardia is also a known clozapine adverse effect.
Received 25 August 2017 However, whether clozapine-associated tachycardia is persistent is not known. Thirty clozapine-treated patients
Received in revised form 9 March 2018 with clinical tachycardia were investigated with 24-hour ambulatory electrocardiography (ECG). Baseline pe-
Accepted 11 March 2018
ripheral heart rate (HR) was 106.7 ± 7.8. The ambulatory ECG 24-hour-HR was 98.7 ± 9.7. Baseline HR and
Available online xxxx
24-hour-HR correlated strongly (r = 0.74, p = 0.000003). Daytime HR was 106.4 ± 9.9 and nighttime HR 89.2
Keywords:
± 12.0. Low dose bisoprolol reduced HR significantly. The high 24-hour-HR indicates a persistent tachycardia.
Schizophrenia Tachycardia should not discourage from clozapine use but the findings indicate a need of guidelines for detection
Clozapine and treatment of clozapine-associated tachycardia.
Tachycardia © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
Heart rate creativecommons.org/licenses/by-nc-nd/4.0/).
Cardiovascular health
Holter ECG

1. Introduction Clozapine may be the only efficient pharmacotherapy in treatment

About one third of individuals with schizophrenia are considered to
be treatment resistant or minimally responsive to conventional antipsy-
chotics. In these cases, clozapine is the preferred treatment option
(Leucht et al., 2013; McEvoy et al., 2006). Clozapine has superior efficacy
for psychotic symptoms but several typical side effects, among them an-
ticholinergic and positive chronotropic properties (Cohen et al., 2001;
Merrill et al., 2005). Clozapine associated tachycardia is accordingly a
well-known but often over-looked problem in daily clinical work. We
previously reported a tachycardia prevalence of 33% based on all cloza-
pine-treated patients (n = 174) in a defined catchment area (Nilsson et
al., 2017). The tachycardia was in most cases not detected or treated.
Hitherto there is a lack of knowledge whether this clozapine associated
tachycardia is persistent or transient. There is also a paucity of studies
on the pharmacological treatment of clozapine associated tachycardia
(Lally et al., 2016). In the general population, tachycardia is reported
as an independent risk factor for both cardiovascular and all-cause mor-
tality (Greenland et al., 1999; Palatini et al., 2006). Total mortality has
also been shown to increase with a higher sleeping heart rate (Ben-
Dov et al., 2007; Hansen et al., 2008; Johansen et al., 2013). Tachycardia
is thus a potentially serious long-term side effect in clozapine treatment.
⁎ Corresponding author.
E-mail addresses: bjorn.nilsson@neuro.uu.se, bjorn.nilsson@akademiska.se
(B.M. Nilsson).
resistant schizophrenia. Therefore, clozapine implies a treatment that
often is unchangeable, the patient must stay on clozapine and the side
effects have to be managed (Nielsen et al., 2013). Tachycardia may in-
frequently be a reason for treatment discontinuation (Legge et al.,
2016) but clozapine associated tachycardia is often covert, i.e. neither
the patient nor the caregivers are aware of the problem. Consequently,
a significant tachycardia might persist during years without adequate
treatment implying a considerable cardiac health risk in the long run.
The aims of the present study were; 1) to assess the chronotropic
properties of clozapine during day and night with ambulatory 24-hour
electrocardiogram (ECG) in patients with a clinical routine measure-
ment of peripheral heart rate (HR) indicative of tachycardia, 2) to com-
pare single peripheral HR measurement with the heart rate during 24-h
ECG monitoring, 3) to assess variables that may influence 24-h HR like
hemoglobin concentration, Body Mass Index (BMI) or clozapine serum
concentration, and 4) to test the hypothesis that low-dose beta-
blocking pharmacotherapy will lower the HR in clozapine associated
tachycardia without a clinical relevant reduction in blood pressure.
2. Methods
The study was approved by the regional ethics review board in Upp-
sala, Sweden. Tachycardia was defined as a resting HR of N100 beats per
minute (bpm). According to clinical routines, clozapine-treated patients
were examined with resting peripheral pulse measurements by the
means of an automatic blood pressure and pulse monitor (Omron

https://doi.org/10.1016/j.schres.2018.03.017
0920-9964/© 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: Nilsson, B.M., et al., Persistent tachycardia in clozapine treated patients: A 24-hour ambulatory electrocardiogram study,
Schizophr. Res. (2018), https://doi.org/10.1016/j.schres.2018.03.017
2 B.M. Nilsson et al. / Schizophrenia Research xxx (2018) xxx–xxx
M6W, Omron Health Care, Kyoto, Japan). Thirty patients with HR N 100
were then referred for an ambulatory 24-hour ECG monitoring. There
was an interval between the baseline peripheral pulse measurement
and 24-hour ECG of about 1–2 months.
Ambulatory 24-h Holter ECG was recorded in a 2-channel, 5-elec-
trode paradigm with a GE SEER Light Ambulatory Recorder and ana-
lyzed with the GE Marquette MARS Holter system (GE Medical
systems, Milwaukee, WI 53223 USA). Electrode placements were
below right and left clavicle, over I5 sin, I4 dx on the right sternal edge
and on the lower right chest wall (ground). When persistent tachycar-
dia was present, the clinical routine was to initiate beta-blocking phar-
macotherapy (Stryjer et al., 2009). In 11 patients, beta-adrenergic
antagonists were not introduced due to relatively lower 24-h HR, non-
adherence for add-on beta-block or comorbid low blood-pressure/
orthostatism. Most patients were treated with bisoprolol (n = 15)
while atenolol and metoprolol were used in two patients respectively.
Doses of 25 mg atenolol and 50 mg metoprolol were considered
equipotent with 2.5 mg bisoprolol (Lithell et al., 1987). Follow-up pe-
ripheral HR and blood pressure was measured in patients with add-on
beta-blocking therapy. Means and standard deviations are expressed
for normally distributed data, medians and inter quartile ranges other-
wise. Student's t-tests were used for comparisons of means. Correlation
analyses for variables that might influence HR like hemoglobin concen-
tration, BMI or clozapine concentration, were performed with Pearson
product-moment correlation and Spearman's rank correlation.
3. Results
Baseline characteristics as well as 24-hour ECG data are shown in
Table 1. The mean resting peripheral HR at baseline was 106.9 ±
7.9 bpm. Ambulatory ECG performed 47 ± 35 days after resting pulse
measurement, showed a mean 24-h HR of 98.7 ± 9.7 during the hours
of day and night. The fluctuations in mean HR over 24 h for all patients
are depicted in Fig. 1. Baseline resting HR and 24-h ECG HR where highly
correlated (r = 0.74, p b 0.0001). The tachycardia found was of sinus
type in all patients. Very high mean HR's were recorded during both
12 h daytime and 6 h during nighttime (Table 1). The number of ar-
rhythmias was low in the majority of patients. There was no significant
correlation between any HR measure and clozapine dose, clozapine
plasma concentration, BMI or hemoglobin concentration in this study.
The initiation of low dose beta-blocking agents reduced HR significantly
Table 1
Characteristics of patients and results from ambulatory 24-hour ECG measurement.
All clozapine treated patients n = 30
Gender, male/female 20/10
Age, years, Md (IQR) 33.5 (26–41)
Body Mass Index 29.1 ± 6.7
Hemoglobin, g/L 145.5 ± 13.5
Smokers/non-smokers 8/22
Duration of disease, years, Md (IQR) 11 (5–17)
Duration of clozapine treatment, years, Md (IQR) 7 (3−13)
Clozapine dose, mg 394.2 ± 196.3
Clozapine concentration, ng/mL, Md (IQR) 451 (337–569)a
Systolic blood pressure, mm Hg 128.4 ± 12.5
Diastolic blood pressure, mm Hg 80.8 ± 9.7
Heart rate at baseline, bpm 106.9 ± 7.9
Ambulatory 24-hour ECG monitoring
Mean Heart rate during 24 h, bpm 98.7 ± 9.7
Mean Daytime HR 09-21, bpm 106.4 ± 9.9b
Mean Nighttime HR 24-06, bpm 89.2 ± 12.0c
Supraventricular arrhythmias during 24 h, Md (IQR) 2 (0–14)
Ventricular arrhythmias during 24 h, Md (IQR) 4 (0–8)
Data are mean ± (SD) unless otherwise noted. HR = Heart rate, Md = median. IQR = Inter quartile range. bpm = beats per minute.
a
n = 29. Serum clozapine concentration on the same treatment dose as during 24-h ECG was missing in one patient.
b
n = 25. Due to technical problems, data was not extracted separately during daytime in 5 patients.
c
n = 26. Due to technical problems, data was not extracted separately during nighttime in 4 patients. Mean 24-hour HR was registered and available for all patients.
Please cite this article as: Nilsson, B.M., et al., Persistent tachycardia in clozapine treated patients: A 24-hour ambulatory electrocardiogram study,
Schizophr. Res. (2018), https://doi.org/10.1016/j.schres.2018.03.017
to mean 88.8 bpm at follow-up and also reduced diastolic, but not sys-
tolic blood pressure (Table 2).
4. Discussion
The main finding of the study was a very high mean 24-hour HR in
clozapine treated patients. To the best of our knowledge, HR measured
with ambulatory ECG over 24 h has never been studied in this patient
group before. All Holter ECG HR means; the 24-h HR, the daytime HR
and the nighttime HR were remarkably elevated from expected values.
The mean 24-h HR of 98.7 bpm in our study, should thus be compared
with reported mean 24-h HR levels of 73–77 bpm in several large
scale studies in the general population (Aeschbacher et al., 2016;
Hansen et al., 2008; Johansen et al., 2013; Kotsis et al., 2005). The night-
time recordings were correspondingly elevated with 23–25 bpm com-
pared with general population studies (Ben-Dov et al., 2007; Hansen
et al., 2008; Johansen et al., 2013). The second finding was a solid corre-
lation between single clinical measurements of peripheral HR and 24-
hour HR performed 1–2 months later. An isolated high resting HR at a
routine clinical visit may thus be sufficient to raise the suspicion that
the clozapine treated patient is suffering from a persistent tachycardia.
The long-time health risks of clozapine associated sinus tachycardia
are presently unknown. Yet, an elevated heart rate is strongly associated
with mortality in the general population (Greenland et al., 1999; Jensen
et al., 2013; Palatini et al., 2006). Particularly nighttime HR has been re-
ported to show positive correlation with mortality (Ben-Dov et al.,
2007; Johansen et al., 2013). Hansen et al. showed that ambulatory
nighttime HR predicted cardiovascular mortality with a risk increase
of 14% per 10 bpm (Hansen et al., 2008). These data are noteworthy
considering that many patients treated with clozapine also suffer from
increased cardiovascular risk related to smoking and metabolic side ef-
fects with weight gain, hyperlipidaemia and risk for diabetes (Mitchell
et al., 2013). Further, a recent study reports subclinical left ventricular
dysfunction in clozapine treated patients with schizophrenia (Chow et
al., 2014).
24-h ECG measurement might not be a feasible method in everyday
clinical practice. According to the present findings, peripheral HR mea-
surements repeated over at least two visits would give a fairly good es-
timate of whether persistent tachycardia is present or not. It is
important to rule out the possible influence on HR of smoking or con-
comitant treatment with other positive chronotropic agents like anti-
cholinergics, thyroid hormones or central nervous system stimulants.
Patients subsequently treated with bisoprolol n = 19
15/4
34 (27–41)
29.9 ± 7.2
147.9 ± 10.0
7/12
10 (5–17)
6 (1−13)
422 ± 220.3
461 (369–549)
130 ± 12.5
84.5 ± 9.4
107.5 ± 6.8
100.5 ± 7.5
107.9 ± 7.8
90.0 ± 11.1
4 (1–8)
2 (0–14)
 B.M. Nilsson et al. / Schizophrenia Research xxx (2018) xxx–xxx
130
120
110
Mean HR
100
90
80
70
09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 01 02 03 04 05 06 07 08
Fig. 1. Mean ambulatory ECG Heart Rate for the patients and time-points during 24 h. Middle point = mean. Whisker value = 95% confidence interval.
The ECG method used (Holter-ECG) implies a thorough investigation of
HR and the frequency of arrhythmias over an extended time period.
However, the resulting mean 24-h HR is also dependent of activity
level and sleep patterns, cofounding factors that the study could not
control for, which is a limitation. Although clozapine has sedative prop-
erties (Kluge et al., 2014), and the drug levels indicated adherence, the
study design could not guarantee that HR was recorded during sleep.
The decline in HR during nighttime may also reflect the influence of cir-
cadian rhythms (Fig. 1).
Clozapine is a multitarget drug that affects several receptors in-
volved in cardiovascular function. The substance is also sensitive to
both genetic and environmental factors, influencing its pharmacody-
namic and pharmacokinetic properties and this will differ considerably
between patients. An individualized monitoring of clozapine's potential
serious cardiovascular side effects is therefore vital (Ronaldson 2017).
When tachycardia is diagnosed, therapeutic drug monitoring is recom-
mended and dose reduction should be considered in patients with high
serum levels. The present findings support that bisoprolol has a potent
negative chronotropic influence in clozapine associated tachycardia
even at low doses. The antihypertensive effect was more modest
which is important as clozapine has strong orthostatic properties. Treat-
ment with bisoprolol was in general well tolerated and also offered re-
lief for tachycardia related symptoms in several patients. Sinus
tachycardia should not discourage from clozapine use as this side effect
is easily treated.
The potential haematological side effects of clozapine have pro-
moted strict guidelines for blood monitoring and some treatment
guidelines may also address tachycardia as a warning sign for
Table 2
Heart rate and blood pressure after initiation of beta-blocker therapy.
Baseline n = 19 Follow-up n = 19
Dose bisoprolol equivalents, mg 0 2.70 ± 1.12
Heart rate, bpm 107.5 ± 6.8 88.8 ± 9.6
Systolic blood pressure, mm Hg 130.0 ± 12.5 123.4 ± 10.7
Diastolic blood pressure, mm Hg 84.5 ± 9.4 75.8 ± 8.7
Data are mean ± SD. bpm = beats per minute.
Please cite this article as: Nilsson, B.M., et al., Persistent tachycardia in clozapine treated patients: A 24-hour ambulatory electrocardiogram study,
Schizophr. Res. (2018), https://doi.org/10.1016/j.schres.2018.03.017
3
Time-point
myocarditis during the titration phase. Nevertheless, guidelines for the
detection and treatment of persistent tachycardia are generally lacking.
We strongly recommend screening for tachycardia by the means of re-
peated peripheral HR measurements. According to the results of ambu-
latory 24-h ECG investigation, we also propose that HR N 100 in routine
clinical measurement is indicative of a persistent sinus tachycardia in a
substantial portion of clozapine treated patients. However, the findings
need to be replicated in further studies.
Role of the funding source
This study was supported by unrestricted grants from Märta and Nicke Nasvell foun-
dation, the Anna-Britta Gustafsson foundation, the Selander foundation, the Linné founda-
tion, and by the Swedish Research Council, grant 2016-02362. The funding source had no
role in study design, in the interpretation of results, in the writing of the report or in the
decision to submit the article for publication.
Contributors
Authors BMN and RB conceived the study. IM performed the Holter ECG analyses.
BMN and KH analyzed the data. BMN, LL and RB drafted the manuscript. All authors con-
tributed in the analysis and interpretation of data, the writing of the paper and approved of
the final manuscript.
Conflicts of interest
RB has been in research collaboration with Janssen for which grant support has been
received by Karolinska Institutet. The other authors report no conflict of interest.
Acknowledgement
We would like to thank the patients and the clinical teams for their help.
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