Psychiatry and Clinical Neurosciences 2014; 68: 353–356
doi:10.1111/pcn.12136
Regular Article
Changes in PR and QTc intervals after switching from olanzapine to risperidone in patients with stable schizophrenia Yutaro Suzuki, MD, PhD,* Takuro Sugai, MD, PhD, Shin Ono, MD, PhD, Kazushi Sawamura, MD, PhD, Naoki Fukui, MD, PhD, Junzo Watanabe, MD, PhD, Nobuto Tsuneyama, MD, Mami Saito, MD and Toshiyuki Someya, MD, PhD Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Aim: We examined the difference between the effects of olanzapine (OLZ) and risperidone (RIS) on PR and QT intervals among patients with stable schizophrenia using a cohort analysis. Methods: Twenty-one subjects treated with OLZ were enrolled in the study. Following baseline assessments, which included PR and QT intervals, OLZ was switched to RIS for each subject. The same parameters were evaluated following the switch to RIS. Results: All patients who had been treated with OLZ were successfully switched to RIS. In all patients, we observed a significant decrease in PR interval (t = 2.397, P = 0.029) and no change in either QTc or
HERE HAS BEEN growing concern among clinicians and researchers that the use of secondgeneration antipsychotics (SGA) may be related to QT prolongation, which can lead to torsades de pointes (TdP). However, it is unknown precisely what effect SGA have on cardiac conduction systems other than QT interval. Although there have been several reports on first-degree heart block being attributed to olanzapine (OLZ),1,2 there have been no reports showing any atrioventricular block associated
T
*Correspondence: Yutaro Suzuki, MD, PhD, Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan. Email: [email protected] Received 23 July 2013; revised 16 September 2013; accepted 28 October 2013.
RR interval. In female patients, the QTc interval was significantly decreased (t = 3.495, P = 0.008) following the switch, while in male patients, the QTc interval did not change. No patients showed a PR interval of >200 ms or a QTc interval of >500 ms.
Conclusion: OLZ treatment has a greater prolonging effect on PR and QT intervals compared with RIS. Careful attention may need to be paid to the cardiac conduction system in addition to QT prolongation during OLZ treatment. Key words: AV block, PR interval, QT interval, risperidone, olanzapine.
with risperidone (RIS). Furthermore, in our previous cross-sectional study, OLZ treatment had a greater impact on QTc interval than RIS, and this effect was especially evident in female patients.3 However, there were large individual differences in QTc intervals in both OLZ and RIS treatment groups. Therefore, a cohort study is needed to clarify the difference in the effects of these two SGA on QTc intervals. The aim of this study was to examine the difference between the effects of OLZ and RIS on PR and QT intervals using a cohort analysis.
METHODS Subjects The study was conducted in 21 outpatients aged 18–60 years who had received a stable dose of OLZ
© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
353
354 Y. Suzuki et al.
for ≥3 months for the treatment of schizophrenia at the outpatient psychiatric clinic at Niigata University Medical and Dental Hospital and who were diagnosed with schizophrenia based on the DSM-IV-TR. Each patient’s condition at entry had to be stable (no significant improvement or worsening of symptoms within the past 3 months). We excluded participants with the following conditions: atrial fibrillation or bundle-branch block, pre-existing cardiac disease, family history of congenital QT syndrome, hypertension, diabetes, dyslipidemia, concurrent treatment with other antipsychotic agents, or concurrent treatment with any drugs other than benzodiazepines. This study was conducted with the approval of the Gene Ethics Committee of Niigata University Graduate School of Medical and Dental Sciences. All patients were provided thorough explanations of the study prior to obtaining their consent in writing.
Methods for drug administration and evaluation At baseline, scores on the Brief Psychiatric Rating Scale (BPRS) were evaluated, and fasting blood samples were drawn after an overnight fast of at least 8 h to examine electrolytes and fasting plasma glucose. Electrocardiographic measurements were also conducted between 09.00 and 10.00 hours, and the QT interval was corrected using Bazett’s correction formula (QTc = QT/RR1/2). Systolic and diastolic blood pressures were measured. The body mass index (BMI [weight in kilograms divided by the square of the height in meters]) was calculated. Following the baseline assessments, OLZ was switched to RIS at a starting dose of 1 mg/day while tapering off OLZ over a period of 8 weeks. The RIS dose was adjusted based on clinical judgments. At the time when the clinician confirmed no significant worsening of symptoms with a stable dose of RIS for ≥3 weeks (end-point), the same evaluations as at baseline, and fasting blood sampling, were conducted.
Psychiatry and Clinical Neurosciences 2014; 68: 353–356
RESULTS All 21 patients who had been treated with OLZ were successfully switched from OLZ to RIS, and their clinical characteristics are shown in Table 1. The mean length of time from baseline to end-point was 32.3 ± 19.1 weeks. Changes in ECG and clinical parameters from baseline to end-point are shown in Table 2. In all patients, we observed a significant decrease in PR interval (t = 2.397, P = 0.029) and no change in either the QTc or RR interval. In female patients, the QTc interval significantly decreased (t = 3.495, P = 0.008) after switching, while, in male patients, the QTc interval did not change. No patients showed a PR interval of more than 200 ms or a QTc interval of more than 500 ms.
DISCUSSION The results of this study revealed that switching from OLZ to RIS treatment decreased the PR interval in patients with stable schizophrenia, and decreased the QTc interval in female patients but not in male patients. To the extent of our knowledge, this is the first study to indicate that OLZ has a PR prolonging effect compared with RIS. Although some cases of first-degree heart block associated with OLZ have been reported,1,2 there have been no reports showing any atrioventricular block associated with RIS. In the present study, there were no patients in whom the onset of first-degree heart block with a PR interval exceeded 200 ms following OLZ treatment; however, close attention may be required in the case of patients that are already suffering from atrioventricular block or patients that are already concomitantly taking other drugs that induce atrioventricular block, such as a β-blocker, calcium antagonist, or digoxin, for example. On the other hand, conduction disorders, such as AV block, are not
Table 1. Sample description
Statistical analysis The paired t-test was performed to evaluate the changes in clinical parameters, PR and QTc intervals after switching from OLZ to RIS. The threshold for statistical significance was defined as P < 0.05. SPSS19.0 (IBM Japan, Tokyo, Japan) was used for statistical calculations.
Variables Mean ± SD age (years) Male/female (n) Mean ± SD duration of illness (years) Smoker/non-smoker (n) SD, standard deviation.
© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
26.9 ± 11.6 8/13 5.5 ± 7.8 5/16
Psychiatry and Clinical Neurosciences 2014; 68: 353–356
Olanzapine, risperidone and PR interval 355
Table 2. Changes in PR and QTc intervals in switching from olanzapine to risperidone treatment Olanzapine treatment
Risperidone treatment
P-value
Dose (mg) CP equivalence (mg/day) BPRS Body mass index (kg/m2)
16.1 ± 7.8 642.9 ± 314.0 25.4 ± 5.9 20.3 ± 9.5
3.8 ± 2.2 381.0 ± 215.9 27.6 ± 6.9 19.7 ± 9.3
P < 0.001 NS NS
Electrolyte (mEq/L) Na K Mg Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)
140.5 ± 1.5 4.1 ± 0.2 2.3 ± 0.2 116.8 ± 11.5 72.8 ± 8.6
140.2 ± 1.3 4.1 ± 0.2 2.3 ± 0.1 112.8 ± 13.8 72.9 ± 10.1
NS NS NS NS NS
QTc (ms) All Male Female PR interval (ms) RR interval (ms) Fasting plasma glucose (mg/dL)
397.7 ± 16.5 383.4 ± 9.1 410.3 ± 9.5 139.2 ± 16.6 850.1 ± 135.3 94.8 ± 5.5
389.9 ± 13.7 387.5 ± 13.3 392.1 ± 14.4 135.3 ± 17.0 907.2 ± 138.3 93.7 ± 8.4
NS NS 0.008 0.029 NS NS
All values are expressed as mean ± SD. BPRS, brief psychiatric rating scale; CP, chlorpromazine; NS, not significant.
typical in acute OLZ poisoning patients.4 Moreover, the mechanism by which OLZ prolongs the PR interval is not known, and further investigation is therefore required. In our previous cross-sectional study, OLZ treatment had a greater impact on the QTc interval than RIS, and this effect was especially evident in female patients.3 Our previous results are corroborated by those of the present cohort study. During OLZ treatment, none of the patients exhibited a QTc value exceeding 500 ms, which is the upper limit for the onset of TdP. However, because the QT interval can be affected by various other factors, such as age, electrolytes, and drug–drug interactions,5 the QT prolonging effect of OLZ cannot be ignored in the patients who have such risk factors. There are three methodological limitations of the present study. First, the sample size in this study was small. Although some gene mutations have been reported to affect drug-induced QT prolongation,6 we did not make use of a pharmacogenetic approach because of the small sample size. Second, the mean CP equivalent dose of OLZ was significantly higher than that of RIS (Table 2). These differences may have affected each of the mean QTc intervals for
OLZ and RIS. Third, we previously demonstrated a concentration-dependent effect of paliperidone (9-OH-RIS), the major active metabolite of RIS, but not of RIS, on QT interval;7 therefore, the pharmacokinetics of RIS can affect QT interval. However, we did not assess plasma paliperidone levels.
Conclusion OLZ treatment has a greater prolonging effect on PR and QT intervals compared with RIS. Careful attention may also need to be paid to atrioventricular block in addition to QT prolongation during OLZ treatment.
ACKNOWLEDGMENTS We would like to express our gratitude to the study participants. We thank Hiroshi Kusano and Nanako Yamazaki for their excellent technical assistance. Dr Someya has received research support and honoraria from Asahi Kasei, Astellas Pharma, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan, Shionogi, Takeda Pharmaceutical, and Yoshitomiyakuhin. Dr Suzuki has
© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
356 Y. Suzuki et al.
Psychiatry and Clinical Neurosciences 2014; 68: 353–356
received research support and honoraria from Janssen Pharmaceutical, Otsuka Pharmaceutical and Mitsubishi Tanabe Pharma Corporation. The other authors have no conflicts of interest to disclose.
4. Suzuki Y, Sugai T, Fukui N et al. Sex differences in the effect of four second-generation antipsychotics on QTc interval in patients with schizophrenia. Hum. Psychopharmacol. 2013; 28: 215–219. 5. Roden DM. Long QT syndrome: Reduced repolarization reserve and the genetic link. J. Intern. Med. 2006; 259: 59– 69. 6. Paulussen AD, Gilissen RA, Armstrong M et al. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J. Mol. Med. (Berl) 2004; 82: 182–188. 7. Suzuki Y, Fukui N, Watanabe J et al. QT prolongation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite paliperidone. Hum. Psychopharmacol. 2012; 27: 39–42.
REFERENCES 1. Kosky N. A possible association between high normal and high dose olanzapine and prolongation of the PR interval. J. Psychopharmacol. 2002; 16: 181–182. 2. Rajput MI, Singh T, Rais T. Olanzapine and prolonged PR interval. Psychiatry (Edgmont) 2006; 3: 9. 3. Ciszowski K, Sein Anand J. [Electrocardiographic abnormalities in acute olanzapine poisonings]. Przegl. Lek. 2011; 68: 422–425 (in Polish).
© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
doi:10.1111/pcn.12136
Regular Article
Changes in PR and QTc intervals after switching from olanzapine to risperidone in patients with stable schizophrenia Yutaro Suzuki, MD, PhD,* Takuro Sugai, MD, PhD, Shin Ono, MD, PhD, Kazushi Sawamura, MD, PhD, Naoki Fukui, MD, PhD, Junzo Watanabe, MD, PhD, Nobuto Tsuneyama, MD, Mami Saito, MD and Toshiyuki Someya, MD, PhD Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Aim: We examined the difference between the effects of olanzapine (OLZ) and risperidone (RIS) on PR and QT intervals among patients with stable schizophrenia using a cohort analysis. Methods: Twenty-one subjects treated with OLZ were enrolled in the study. Following baseline assessments, which included PR and QT intervals, OLZ was switched to RIS for each subject. The same parameters were evaluated following the switch to RIS. Results: All patients who had been treated with OLZ were successfully switched to RIS. In all patients, we observed a significant decrease in PR interval (t = 2.397, P = 0.029) and no change in either QTc or
HERE HAS BEEN growing concern among clinicians and researchers that the use of secondgeneration antipsychotics (SGA) may be related to QT prolongation, which can lead to torsades de pointes (TdP). However, it is unknown precisely what effect SGA have on cardiac conduction systems other than QT interval. Although there have been several reports on first-degree heart block being attributed to olanzapine (OLZ),1,2 there have been no reports showing any atrioventricular block associated
T
*Correspondence: Yutaro Suzuki, MD, PhD, Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan. Email: [email protected] Received 23 July 2013; revised 16 September 2013; accepted 28 October 2013.
RR interval. In female patients, the QTc interval was significantly decreased (t = 3.495, P = 0.008) following the switch, while in male patients, the QTc interval did not change. No patients showed a PR interval of >200 ms or a QTc interval of >500 ms.
Conclusion: OLZ treatment has a greater prolonging effect on PR and QT intervals compared with RIS. Careful attention may need to be paid to the cardiac conduction system in addition to QT prolongation during OLZ treatment. Key words: AV block, PR interval, QT interval, risperidone, olanzapine.
with risperidone (RIS). Furthermore, in our previous cross-sectional study, OLZ treatment had a greater impact on QTc interval than RIS, and this effect was especially evident in female patients.3 However, there were large individual differences in QTc intervals in both OLZ and RIS treatment groups. Therefore, a cohort study is needed to clarify the difference in the effects of these two SGA on QTc intervals. The aim of this study was to examine the difference between the effects of OLZ and RIS on PR and QT intervals using a cohort analysis.
METHODS Subjects The study was conducted in 21 outpatients aged 18–60 years who had received a stable dose of OLZ
© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
353
354 Y. Suzuki et al.
for ≥3 months for the treatment of schizophrenia at the outpatient psychiatric clinic at Niigata University Medical and Dental Hospital and who were diagnosed with schizophrenia based on the DSM-IV-TR. Each patient’s condition at entry had to be stable (no significant improvement or worsening of symptoms within the past 3 months). We excluded participants with the following conditions: atrial fibrillation or bundle-branch block, pre-existing cardiac disease, family history of congenital QT syndrome, hypertension, diabetes, dyslipidemia, concurrent treatment with other antipsychotic agents, or concurrent treatment with any drugs other than benzodiazepines. This study was conducted with the approval of the Gene Ethics Committee of Niigata University Graduate School of Medical and Dental Sciences. All patients were provided thorough explanations of the study prior to obtaining their consent in writing.
Methods for drug administration and evaluation At baseline, scores on the Brief Psychiatric Rating Scale (BPRS) were evaluated, and fasting blood samples were drawn after an overnight fast of at least 8 h to examine electrolytes and fasting plasma glucose. Electrocardiographic measurements were also conducted between 09.00 and 10.00 hours, and the QT interval was corrected using Bazett’s correction formula (QTc = QT/RR1/2). Systolic and diastolic blood pressures were measured. The body mass index (BMI [weight in kilograms divided by the square of the height in meters]) was calculated. Following the baseline assessments, OLZ was switched to RIS at a starting dose of 1 mg/day while tapering off OLZ over a period of 8 weeks. The RIS dose was adjusted based on clinical judgments. At the time when the clinician confirmed no significant worsening of symptoms with a stable dose of RIS for ≥3 weeks (end-point), the same evaluations as at baseline, and fasting blood sampling, were conducted.
Psychiatry and Clinical Neurosciences 2014; 68: 353–356
RESULTS All 21 patients who had been treated with OLZ were successfully switched from OLZ to RIS, and their clinical characteristics are shown in Table 1. The mean length of time from baseline to end-point was 32.3 ± 19.1 weeks. Changes in ECG and clinical parameters from baseline to end-point are shown in Table 2. In all patients, we observed a significant decrease in PR interval (t = 2.397, P = 0.029) and no change in either the QTc or RR interval. In female patients, the QTc interval significantly decreased (t = 3.495, P = 0.008) after switching, while, in male patients, the QTc interval did not change. No patients showed a PR interval of more than 200 ms or a QTc interval of more than 500 ms.
DISCUSSION The results of this study revealed that switching from OLZ to RIS treatment decreased the PR interval in patients with stable schizophrenia, and decreased the QTc interval in female patients but not in male patients. To the extent of our knowledge, this is the first study to indicate that OLZ has a PR prolonging effect compared with RIS. Although some cases of first-degree heart block associated with OLZ have been reported,1,2 there have been no reports showing any atrioventricular block associated with RIS. In the present study, there were no patients in whom the onset of first-degree heart block with a PR interval exceeded 200 ms following OLZ treatment; however, close attention may be required in the case of patients that are already suffering from atrioventricular block or patients that are already concomitantly taking other drugs that induce atrioventricular block, such as a β-blocker, calcium antagonist, or digoxin, for example. On the other hand, conduction disorders, such as AV block, are not
Table 1. Sample description
Statistical analysis The paired t-test was performed to evaluate the changes in clinical parameters, PR and QTc intervals after switching from OLZ to RIS. The threshold for statistical significance was defined as P < 0.05. SPSS19.0 (IBM Japan, Tokyo, Japan) was used for statistical calculations.
Variables Mean ± SD age (years) Male/female (n) Mean ± SD duration of illness (years) Smoker/non-smoker (n) SD, standard deviation.
© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
26.9 ± 11.6 8/13 5.5 ± 7.8 5/16
Psychiatry and Clinical Neurosciences 2014; 68: 353–356
Olanzapine, risperidone and PR interval 355
Table 2. Changes in PR and QTc intervals in switching from olanzapine to risperidone treatment Olanzapine treatment
Risperidone treatment
P-value
Dose (mg) CP equivalence (mg/day) BPRS Body mass index (kg/m2)
16.1 ± 7.8 642.9 ± 314.0 25.4 ± 5.9 20.3 ± 9.5
3.8 ± 2.2 381.0 ± 215.9 27.6 ± 6.9 19.7 ± 9.3
P < 0.001 NS NS
Electrolyte (mEq/L) Na K Mg Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)
140.5 ± 1.5 4.1 ± 0.2 2.3 ± 0.2 116.8 ± 11.5 72.8 ± 8.6
140.2 ± 1.3 4.1 ± 0.2 2.3 ± 0.1 112.8 ± 13.8 72.9 ± 10.1
NS NS NS NS NS
QTc (ms) All Male Female PR interval (ms) RR interval (ms) Fasting plasma glucose (mg/dL)
397.7 ± 16.5 383.4 ± 9.1 410.3 ± 9.5 139.2 ± 16.6 850.1 ± 135.3 94.8 ± 5.5
389.9 ± 13.7 387.5 ± 13.3 392.1 ± 14.4 135.3 ± 17.0 907.2 ± 138.3 93.7 ± 8.4
NS NS 0.008 0.029 NS NS
All values are expressed as mean ± SD. BPRS, brief psychiatric rating scale; CP, chlorpromazine; NS, not significant.
typical in acute OLZ poisoning patients.4 Moreover, the mechanism by which OLZ prolongs the PR interval is not known, and further investigation is therefore required. In our previous cross-sectional study, OLZ treatment had a greater impact on the QTc interval than RIS, and this effect was especially evident in female patients.3 Our previous results are corroborated by those of the present cohort study. During OLZ treatment, none of the patients exhibited a QTc value exceeding 500 ms, which is the upper limit for the onset of TdP. However, because the QT interval can be affected by various other factors, such as age, electrolytes, and drug–drug interactions,5 the QT prolonging effect of OLZ cannot be ignored in the patients who have such risk factors. There are three methodological limitations of the present study. First, the sample size in this study was small. Although some gene mutations have been reported to affect drug-induced QT prolongation,6 we did not make use of a pharmacogenetic approach because of the small sample size. Second, the mean CP equivalent dose of OLZ was significantly higher than that of RIS (Table 2). These differences may have affected each of the mean QTc intervals for
OLZ and RIS. Third, we previously demonstrated a concentration-dependent effect of paliperidone (9-OH-RIS), the major active metabolite of RIS, but not of RIS, on QT interval;7 therefore, the pharmacokinetics of RIS can affect QT interval. However, we did not assess plasma paliperidone levels.
Conclusion OLZ treatment has a greater prolonging effect on PR and QT intervals compared with RIS. Careful attention may also need to be paid to atrioventricular block in addition to QT prolongation during OLZ treatment.
ACKNOWLEDGMENTS We would like to express our gratitude to the study participants. We thank Hiroshi Kusano and Nanako Yamazaki for their excellent technical assistance. Dr Someya has received research support and honoraria from Asahi Kasei, Astellas Pharma, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan, Shionogi, Takeda Pharmaceutical, and Yoshitomiyakuhin. Dr Suzuki has
© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
356 Y. Suzuki et al.
Psychiatry and Clinical Neurosciences 2014; 68: 353–356
received research support and honoraria from Janssen Pharmaceutical, Otsuka Pharmaceutical and Mitsubishi Tanabe Pharma Corporation. The other authors have no conflicts of interest to disclose.
4. Suzuki Y, Sugai T, Fukui N et al. Sex differences in the effect of four second-generation antipsychotics on QTc interval in patients with schizophrenia. Hum. Psychopharmacol. 2013; 28: 215–219. 5. Roden DM. Long QT syndrome: Reduced repolarization reserve and the genetic link. J. Intern. Med. 2006; 259: 59– 69. 6. Paulussen AD, Gilissen RA, Armstrong M et al. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J. Mol. Med. (Berl) 2004; 82: 182–188. 7. Suzuki Y, Fukui N, Watanabe J et al. QT prolongation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite paliperidone. Hum. Psychopharmacol. 2012; 27: 39–42.
REFERENCES 1. Kosky N. A possible association between high normal and high dose olanzapine and prolongation of the PR interval. J. Psychopharmacol. 2002; 16: 181–182. 2. Rajput MI, Singh T, Rais T. Olanzapine and prolonged PR interval. Psychiatry (Edgmont) 2006; 3: 9. 3. Ciszowski K, Sein Anand J. [Electrocardiographic abnormalities in acute olanzapine poisonings]. Przegl. Lek. 2011; 68: 422–425 (in Polish).
© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
