Amisulpride and symptomatic bradycardia: A case report Li-Chung Huang MD, Li-Yen Huang MD, Shih-Yen Tseng, Yuh-Ming Hou MD, Cheng-Cheng Hsiao MD PII: DOI: Reference:
S0163-8343(13)00370-8 doi: 10.1016/j.genhosppsych.2013.12.005 GHP 6801
To appear in:
General Hospital Psychiatry
Received date: Revised date: Accepted date:
9 October 2013 10 December 2013 10 December 2013
Please cite this article as: Huang Li-Chung, Huang Li-Yen, Tseng Shih-Yen, Hou YuhMing, Hsiao Cheng-Cheng, Amisulpride and symptomatic bradycardia: A case report, General Hospital Psychiatry (2013), doi: 10.1016/j.genhosppsych.2013.12.005
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
T
Amisulpride and symptomatic bradycardia: a case report
RI P
Li-Chung Huang1, MD; Li-Yen Huang2, MD; Shih-Yen Tseng3 ; Yuh-Ming Hou1, MD;
SC
Cheng-Cheng Hsiao1*, MD
MA NU
Author Affiliations:
Department of Psychiatry, Ditmanson Medical Foundation Chia-Yi Christian Hospital
2.
Department of Cardiology, Taoyuan Armed Forced General Hospital
3.
Department of Pharmachology, Taichung Veterans General Hospital Chia Yi Branch
PT
ED
1.
CE
*Address for correspondence: Cheng-Cheng Hsiao, MD, Department of Psychiatry,
Taiwan
AC
Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539 Jhongsiao Rd, Chia-Yi City,
(E-mail: [email protected]) Running title: Amisulpride induced bradycardia Keywords: Bradycardia; Psychotic disorder; Amisulpride; Adverse drug reaction;
Word count:
849 word in text, 18 references, 1 table
ACCEPTED MANUSCRIPT Abstract
T
Objective: Amisulpride is a second generation antipsychotic agent indicated
RI P
for the treatment of schizophrenia and other major psychotic illnesses. Amisulpride-induced
SC
bradycardia is a rare condition of unknown etiology and mechanism. Asymptomatic bradycardia has been associated with amisulpride in only two cases. In our case, the
MA NU
association was rated as “probable” on the Naranjo adverse drug reaction probability scale. Method: Case report.
ED
Results: A 45-year-old male patient developed symptomatic bradycardia during usage of
PT
amisulpride (400–800 mg/day), which dramatically improved after the complete termination
CE
of amisulpride usage. The psychiatric condition remained relatively stable without
AC
bradycardia after administration of another antipsychotic agent (risperidone [3 mg/day]). Conclusion: This is the first case report of symptomatic bradycardia associated with the use of amisulpride. Although bradycardia is a rare adverse reaction to antipsychotics, this finding may alert psychiatrists and physicians to this antipsychotic drug side effect. Further study is needed to disclose the role of antipsychotics in bringing about symptomatic bradycardia.
ACCEPTED MANUSCRIPT
T
Introduction
RI P
Second generation antipsychotic agents are now the first line medications for
SC
schizophrenia, bipolar disorder, and augmentation in major depressive disorder [1]. Cardiovascular events and arrhythmias such as QT prolongation or torsade de pointes are
MA NU
sometimes a lethal complication of long-term treatment with antipsychotics [2]. Second generation antipsychotics can also induce bradycardia in susceptible patients. Previous reports have described episodes of bradycardia associated with the use of clozapine [3],
ED
olanzapine [4], quetiapine [5], and risperidone [6]. The mechanism of neuroleptic-related
PT
bradycardia is still not fully understood.
CE
Amisulpride is a second-generation neuroleptic which blocks pre- and postsynaptic
AC
dopamine D2 and D3 receptors and is widely used for the treatment of schizophrenia [7]. Insomnia, anxiety, and agitation are the most common side effects of amisulpride, and constipation, nausea, vomiting, and hyperprolactinemia may occur as well [8]. Only two cases of amisulpride-induced asymptomatic bradycardia have been reported [9, 10]. We describe a unique case of amisulpride-induced bradycardia in a schizophrenia patient who had normal sinus rhythm before amisulpride treatment. The bradycardia resolved after termination of amisulpride. Case report
ACCEPTED MANUSCRIPT
T
Mr. L, a 46-year-old male with the diagnosis of schizophrenia according to DSM-IV-TR
RI P
criteria was admitted to our emergency department with severe auditory hallucinations and
SC
religious delusions after he had discontinued all psychiatric medications for 3 months. His medical history revealed no prior diagnosis of bradycardia or other cardiovascular disease.
MA NU
Amisulpride at a daily dose of 400 mg augmented by clonazepam 4 mg and depakine 750 mg per day was started on admission. After 10 days, the dose of amisulpride was titrated up to 800 mg for management of severe auditory hallucinations and persistent psychotic symptoms.
ED
Despite the high dosage of amisulpiride, the patient experienced no physical discomfort
PT
except bradycardia, fatigue, and light-headedness. Blood pressure (BP) was always within the
CE
normal range, and laboratory studies, including, calcium, phosphate, and magnesium were
AC
all normal. Family and the patient denied alcohol consumption and other severe medical disease within the last 5 years. The patient then developed fatigue, light-headedness, and bradycardia with heart rate (HR) 50–39 beats/min, and the 12-lead EKG revealed sinus bradycardia with normal conduction time. During the bradycardia episodes, no significant difference was found between orthostatic supine and standing blood pressure. Bradycardia resolved in 10 days after amisulpride was stopped and clonazepam was decreased to 2 mg per day. Cardiovascular examinations including a Holter EKG and cardiac sonography showed no obvious abnormalities.
ACCEPTED MANUSCRIPT
T
Two weeks later, only depakine 750 mg and clonazepam 2 mg daily were prescribed, all
RI P
antipsychotics were stopped, and heart rate returned to the normal range (63–83 beats/min);
SC
however, severe psychotic symptoms including disorganized speech, and religious delusions reappeared. Amisulpride 200 mg per day was started and slowly titrated up to 400 mg per day.
MA NU
The patient again developed symptomatic bradycardia (heart rate, 55–42 beats/min) with symptoms of fatigue. Amisulpride was discontinued, risperidone 3 mg/day was prescribed along with the previous doses of depakine and clonazepam, and the psychiatric and physical
ED
conditions (heart rate, 65–90 beats/min) improved and no further episodes of bradycardia
AC
Discussion
CE
PT
occurred during the six-month follow-up period.
To the best of our knowledge this is the first case report of symptomatic bradycardia without QT prolongation in the presence of amisulpride. Bradycardia is caused by a disruption in the normal electrical impulses which control the rate of the heart's pumping action. The reasons for bradycardia include: 1. heart tissue damage related to aging or a heart attack, 2. hypertension, 3. congenital heart defect, 4. myocarditis, 5. hypothyroidism, 6. electrolyte imbalance, 7. sleep apnea, and 8. medication [11]. As the patient’s baseline HR was within
ACCEPTED MANUSCRIPT normal limits and he had none of the medical conditions mentioned above, we suspected
T
medication was the cause of his symptomatic bradycardia and the relationship between
RI P
amisulpride and symptomatic bradycardia was assessed as “probable” based on the Naranjo
SC
ADR scale [12] (Table 1).
MA NU
Fatigue did not occur when clonazepam and depakine alone were used, appeared twice during the use of amisulpride, and disappeared when amisulpride was stopped. Clonazepamor depakine-induced sedation may worsen the bradycardia condition because of interactions
ED
with antipsychotics. However, the kidney metabolized amisulpride while the liver
CE
PT
metabolized the other neuroleptics in this case.
AC
Most second generation antipsychotics with mixed receptor activity have been linked to bradycardia [14]. Previous studies have shown an association of 5-hydroxytryptamine (5-HT) receptors with vagal-mediated bradycardia, especially 5-HT1A, 5-HT2A/2B/2C, and 5-HT7 receptors [15–17]. Amisulpride has an affinity for 5-HT2B and 5-HT7 receptors but not for 5-HT1A, 5-HT2A receptors. 5-HT2B and 5-HT7 antagonism as well as the action of amisulpride on muscarinic cholinergic receptors [18] may underlie amisulpride-induced bradycardia.
The limitations of this report include the absence of plasma amisulpride measurement,
ACCEPTED MANUSCRIPT treadmill exercise electrocardiography, and electrophysiological studies; however, these
T
examinations were not practical because of the patient's dramatic improvement after
RI P
switching antipsychotics. In addition, fatigue as a side effect of amisulpride could not be
SC
completely ruled out [8].
MA NU
Amisulpride-induced bradycardia is relatively rare and often asymptomatic. Because the risk factors for amisulpride-induced bradycardia are unknown, we strongly suggest ECG monitoring during titration of amisulpride and when prescribing other
AC
CE
PT
ED
neuroleptics in the amisulpride induced bradycardia case.
ACCEPTED MANUSCRIPT References
T
[1] Nemeroff CB. Use of atypical antipsychotics in refractory depression and anxiety. J Clin
RI P
Psychiatry 2005;66 suppl 8:13-21.
SC
[2] Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr Pharm Des 2004;10:2463-75.
MA NU
[3] Pitner JK, Mintzer JE, Pennypacker LC, Jackson CW. Efficacy and adverse effects of clozapine in four elderly psychotic patients. J Clin Psychiatry 1995;56:180-5. [4] Lee TW, Tsai SJ, Hwang JP. Severe cardiovascular side effects of olanzapine in an elderly
ED
patient: case report. Int J Psychiatry Med 2003;33:399-401.
PT
[5] Janse A, Marijnissen RM. Quetiapine-induced bradycardia without QT interval
CE
prolongation in an elderly woman. Prim Care Companion J Clin Psychiatry 2009;11:172-3.
AC
[6] Ovsyshcher I, Barold SS. Drug induced bradycardia to pace or not to pace? Pacing Clin Electrophysiol 2004;27:1144-7. [7] Perrault G, Depoortere R, Morel E, et al. Psychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity. J Pharmacol Exp Ther 1997;280:73-82. [8] Rein W, Coulouvrat C, Dondey-Nouvel L. Safety profile of amisulpride in short- and long-term use. Acta Psychiatri Scand Suppl 2000;400:23-7. [9] Prikryl R, Ustohal L, Prikrylova-Kucerova H. Amisulpride therapeutic dose-induced
ACCEPTED MANUSCRIPT asymptomatic bradycardia. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:290.
T
[10] Pedrosa GF, Grohmann R, Rüther E. Asymptomatic bradycardia associated with
RI P
amisulpride. Pharmacopsychiatry 2001;34:259-61.
SC
[11]Ganz LI. Sinus bradycardia. http://www.uptodate.com/contents/sinus-bradycardia Jul. 3, 2012
MA NU
[12] Naranjo CA, Shear NH, Lanctôt KL. Advances in the diagnosis of adverse drug reactions. J Clin Pharmacol 1992;32:897-904.
[13] Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of
ED
adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.
PT
[14] Goyal RS, and Goyal SB. Symptomatic bradyarrhythmia secondary to risperidone. Am
CE
J Psychiatry 2003;160:2243.
AC
[15] Jordan D. Vagal control of the heart: central serotonergic (5‐HT) mechanisms. Exp Physiol 2005;90:175-81. [16] Knowles ID, Ramage AG. Evidence for a role for central 5‐HT2B as well as 5‐HT2A receptors in cardiovascular regulation in anaesthetized rats. Br
J Pharmacol
1999;128:530-42. [17] Ramage A. Central cardiovascular regulation and 5-hydroxytryptamine receptors. Brain Res Bull 2001;56:425-39. [18] Christensen A, Fjalland B, Nielsen IM. On the supersensitivity of dopamine receptors, induced by neuroleptics. Psychopharmacology 1976;48:1
ACCEPTED MANUSCRIPT
T
Table1. Adverse Drug Reaction (ADR) Probability Scale and the present bradycardia
RI P
patient’s scores
Score
1. Are there previous conclusive reports of this reaction? 2. Did the adverse event occur after the suspected drug was administered? 3. Did the adverse reaction improve after the drug was discontinued or after a specific antagonist was administered?
No Yes
0 +2
Yes
+1
4. Did the adverse reaction reappear when the drug was re-administered? 5. Are there possible alternative causes (other than the drug) that could on their own have caused the reaction? 6. Did the reaction reappear when a placebo was given?
Yes
+2
Do not know
0
Do not know
0
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?
No
0
Yes
+1
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? Total score
No
0
Yes
+1
AC
CE
PT
ED
MA NU
SC
Answer
7
S0163-8343(13)00370-8 doi: 10.1016/j.genhosppsych.2013.12.005 GHP 6801
To appear in:
General Hospital Psychiatry
Received date: Revised date: Accepted date:
9 October 2013 10 December 2013 10 December 2013
Please cite this article as: Huang Li-Chung, Huang Li-Yen, Tseng Shih-Yen, Hou YuhMing, Hsiao Cheng-Cheng, Amisulpride and symptomatic bradycardia: A case report, General Hospital Psychiatry (2013), doi: 10.1016/j.genhosppsych.2013.12.005
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
T
Amisulpride and symptomatic bradycardia: a case report
RI P
Li-Chung Huang1, MD; Li-Yen Huang2, MD; Shih-Yen Tseng3 ; Yuh-Ming Hou1, MD;
SC
Cheng-Cheng Hsiao1*, MD
MA NU
Author Affiliations:
Department of Psychiatry, Ditmanson Medical Foundation Chia-Yi Christian Hospital
2.
Department of Cardiology, Taoyuan Armed Forced General Hospital
3.
Department of Pharmachology, Taichung Veterans General Hospital Chia Yi Branch
PT
ED
1.
CE
*Address for correspondence: Cheng-Cheng Hsiao, MD, Department of Psychiatry,
Taiwan
AC
Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539 Jhongsiao Rd, Chia-Yi City,
(E-mail: [email protected]) Running title: Amisulpride induced bradycardia Keywords: Bradycardia; Psychotic disorder; Amisulpride; Adverse drug reaction;
Word count:
849 word in text, 18 references, 1 table
ACCEPTED MANUSCRIPT Abstract
T
Objective: Amisulpride is a second generation antipsychotic agent indicated
RI P
for the treatment of schizophrenia and other major psychotic illnesses. Amisulpride-induced
SC
bradycardia is a rare condition of unknown etiology and mechanism. Asymptomatic bradycardia has been associated with amisulpride in only two cases. In our case, the
MA NU
association was rated as “probable” on the Naranjo adverse drug reaction probability scale. Method: Case report.
ED
Results: A 45-year-old male patient developed symptomatic bradycardia during usage of
PT
amisulpride (400–800 mg/day), which dramatically improved after the complete termination
CE
of amisulpride usage. The psychiatric condition remained relatively stable without
AC
bradycardia after administration of another antipsychotic agent (risperidone [3 mg/day]). Conclusion: This is the first case report of symptomatic bradycardia associated with the use of amisulpride. Although bradycardia is a rare adverse reaction to antipsychotics, this finding may alert psychiatrists and physicians to this antipsychotic drug side effect. Further study is needed to disclose the role of antipsychotics in bringing about symptomatic bradycardia.
ACCEPTED MANUSCRIPT
T
Introduction
RI P
Second generation antipsychotic agents are now the first line medications for
SC
schizophrenia, bipolar disorder, and augmentation in major depressive disorder [1]. Cardiovascular events and arrhythmias such as QT prolongation or torsade de pointes are
MA NU
sometimes a lethal complication of long-term treatment with antipsychotics [2]. Second generation antipsychotics can also induce bradycardia in susceptible patients. Previous reports have described episodes of bradycardia associated with the use of clozapine [3],
ED
olanzapine [4], quetiapine [5], and risperidone [6]. The mechanism of neuroleptic-related
PT
bradycardia is still not fully understood.
CE
Amisulpride is a second-generation neuroleptic which blocks pre- and postsynaptic
AC
dopamine D2 and D3 receptors and is widely used for the treatment of schizophrenia [7]. Insomnia, anxiety, and agitation are the most common side effects of amisulpride, and constipation, nausea, vomiting, and hyperprolactinemia may occur as well [8]. Only two cases of amisulpride-induced asymptomatic bradycardia have been reported [9, 10]. We describe a unique case of amisulpride-induced bradycardia in a schizophrenia patient who had normal sinus rhythm before amisulpride treatment. The bradycardia resolved after termination of amisulpride. Case report
ACCEPTED MANUSCRIPT
T
Mr. L, a 46-year-old male with the diagnosis of schizophrenia according to DSM-IV-TR
RI P
criteria was admitted to our emergency department with severe auditory hallucinations and
SC
religious delusions after he had discontinued all psychiatric medications for 3 months. His medical history revealed no prior diagnosis of bradycardia or other cardiovascular disease.
MA NU
Amisulpride at a daily dose of 400 mg augmented by clonazepam 4 mg and depakine 750 mg per day was started on admission. After 10 days, the dose of amisulpride was titrated up to 800 mg for management of severe auditory hallucinations and persistent psychotic symptoms.
ED
Despite the high dosage of amisulpiride, the patient experienced no physical discomfort
PT
except bradycardia, fatigue, and light-headedness. Blood pressure (BP) was always within the
CE
normal range, and laboratory studies, including, calcium, phosphate, and magnesium were
AC
all normal. Family and the patient denied alcohol consumption and other severe medical disease within the last 5 years. The patient then developed fatigue, light-headedness, and bradycardia with heart rate (HR) 50–39 beats/min, and the 12-lead EKG revealed sinus bradycardia with normal conduction time. During the bradycardia episodes, no significant difference was found between orthostatic supine and standing blood pressure. Bradycardia resolved in 10 days after amisulpride was stopped and clonazepam was decreased to 2 mg per day. Cardiovascular examinations including a Holter EKG and cardiac sonography showed no obvious abnormalities.
ACCEPTED MANUSCRIPT
T
Two weeks later, only depakine 750 mg and clonazepam 2 mg daily were prescribed, all
RI P
antipsychotics were stopped, and heart rate returned to the normal range (63–83 beats/min);
SC
however, severe psychotic symptoms including disorganized speech, and religious delusions reappeared. Amisulpride 200 mg per day was started and slowly titrated up to 400 mg per day.
MA NU
The patient again developed symptomatic bradycardia (heart rate, 55–42 beats/min) with symptoms of fatigue. Amisulpride was discontinued, risperidone 3 mg/day was prescribed along with the previous doses of depakine and clonazepam, and the psychiatric and physical
ED
conditions (heart rate, 65–90 beats/min) improved and no further episodes of bradycardia
AC
Discussion
CE
PT
occurred during the six-month follow-up period.
To the best of our knowledge this is the first case report of symptomatic bradycardia without QT prolongation in the presence of amisulpride. Bradycardia is caused by a disruption in the normal electrical impulses which control the rate of the heart's pumping action. The reasons for bradycardia include: 1. heart tissue damage related to aging or a heart attack, 2. hypertension, 3. congenital heart defect, 4. myocarditis, 5. hypothyroidism, 6. electrolyte imbalance, 7. sleep apnea, and 8. medication [11]. As the patient’s baseline HR was within
ACCEPTED MANUSCRIPT normal limits and he had none of the medical conditions mentioned above, we suspected
T
medication was the cause of his symptomatic bradycardia and the relationship between
RI P
amisulpride and symptomatic bradycardia was assessed as “probable” based on the Naranjo
SC
ADR scale [12] (Table 1).
MA NU
Fatigue did not occur when clonazepam and depakine alone were used, appeared twice during the use of amisulpride, and disappeared when amisulpride was stopped. Clonazepamor depakine-induced sedation may worsen the bradycardia condition because of interactions
ED
with antipsychotics. However, the kidney metabolized amisulpride while the liver
CE
PT
metabolized the other neuroleptics in this case.
AC
Most second generation antipsychotics with mixed receptor activity have been linked to bradycardia [14]. Previous studies have shown an association of 5-hydroxytryptamine (5-HT) receptors with vagal-mediated bradycardia, especially 5-HT1A, 5-HT2A/2B/2C, and 5-HT7 receptors [15–17]. Amisulpride has an affinity for 5-HT2B and 5-HT7 receptors but not for 5-HT1A, 5-HT2A receptors. 5-HT2B and 5-HT7 antagonism as well as the action of amisulpride on muscarinic cholinergic receptors [18] may underlie amisulpride-induced bradycardia.
The limitations of this report include the absence of plasma amisulpride measurement,
ACCEPTED MANUSCRIPT treadmill exercise electrocardiography, and electrophysiological studies; however, these
T
examinations were not practical because of the patient's dramatic improvement after
RI P
switching antipsychotics. In addition, fatigue as a side effect of amisulpride could not be
SC
completely ruled out [8].
MA NU
Amisulpride-induced bradycardia is relatively rare and often asymptomatic. Because the risk factors for amisulpride-induced bradycardia are unknown, we strongly suggest ECG monitoring during titration of amisulpride and when prescribing other
AC
CE
PT
ED
neuroleptics in the amisulpride induced bradycardia case.
ACCEPTED MANUSCRIPT References
T
[1] Nemeroff CB. Use of atypical antipsychotics in refractory depression and anxiety. J Clin
RI P
Psychiatry 2005;66 suppl 8:13-21.
SC
[2] Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr Pharm Des 2004;10:2463-75.
MA NU
[3] Pitner JK, Mintzer JE, Pennypacker LC, Jackson CW. Efficacy and adverse effects of clozapine in four elderly psychotic patients. J Clin Psychiatry 1995;56:180-5. [4] Lee TW, Tsai SJ, Hwang JP. Severe cardiovascular side effects of olanzapine in an elderly
ED
patient: case report. Int J Psychiatry Med 2003;33:399-401.
PT
[5] Janse A, Marijnissen RM. Quetiapine-induced bradycardia without QT interval
CE
prolongation in an elderly woman. Prim Care Companion J Clin Psychiatry 2009;11:172-3.
AC
[6] Ovsyshcher I, Barold SS. Drug induced bradycardia to pace or not to pace? Pacing Clin Electrophysiol 2004;27:1144-7. [7] Perrault G, Depoortere R, Morel E, et al. Psychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity. J Pharmacol Exp Ther 1997;280:73-82. [8] Rein W, Coulouvrat C, Dondey-Nouvel L. Safety profile of amisulpride in short- and long-term use. Acta Psychiatri Scand Suppl 2000;400:23-7. [9] Prikryl R, Ustohal L, Prikrylova-Kucerova H. Amisulpride therapeutic dose-induced
ACCEPTED MANUSCRIPT asymptomatic bradycardia. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:290.
T
[10] Pedrosa GF, Grohmann R, Rüther E. Asymptomatic bradycardia associated with
RI P
amisulpride. Pharmacopsychiatry 2001;34:259-61.
SC
[11]Ganz LI. Sinus bradycardia. http://www.uptodate.com/contents/sinus-bradycardia Jul. 3, 2012
MA NU
[12] Naranjo CA, Shear NH, Lanctôt KL. Advances in the diagnosis of adverse drug reactions. J Clin Pharmacol 1992;32:897-904.
[13] Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of
ED
adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.
PT
[14] Goyal RS, and Goyal SB. Symptomatic bradyarrhythmia secondary to risperidone. Am
CE
J Psychiatry 2003;160:2243.
AC
[15] Jordan D. Vagal control of the heart: central serotonergic (5‐HT) mechanisms. Exp Physiol 2005;90:175-81. [16] Knowles ID, Ramage AG. Evidence for a role for central 5‐HT2B as well as 5‐HT2A receptors in cardiovascular regulation in anaesthetized rats. Br
J Pharmacol
1999;128:530-42. [17] Ramage A. Central cardiovascular regulation and 5-hydroxytryptamine receptors. Brain Res Bull 2001;56:425-39. [18] Christensen A, Fjalland B, Nielsen IM. On the supersensitivity of dopamine receptors, induced by neuroleptics. Psychopharmacology 1976;48:1
ACCEPTED MANUSCRIPT
T
Table1. Adverse Drug Reaction (ADR) Probability Scale and the present bradycardia
RI P
patient’s scores
Score
1. Are there previous conclusive reports of this reaction? 2. Did the adverse event occur after the suspected drug was administered? 3. Did the adverse reaction improve after the drug was discontinued or after a specific antagonist was administered?
No Yes
0 +2
Yes
+1
4. Did the adverse reaction reappear when the drug was re-administered? 5. Are there possible alternative causes (other than the drug) that could on their own have caused the reaction? 6. Did the reaction reappear when a placebo was given?
Yes
+2
Do not know
0
Do not know
0
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?
No
0
Yes
+1
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? Total score
No
0
Yes
+1
AC
CE
PT
ED
MA NU
SC
Answer
7
