CNS Neuroscience Therapeutics - 2023 - Shu

Received: 27 December 2022 | Revised: 21 March 2023 | Accepted: 30 March 2023
DOI: 10.1111/cns.14215
ORIGINAL ARTICLE
Cardiac adverse events associated with quetiapine:

Disproportionality analysis of FDA adverse event reporting
system
Yamin Shu1 | Yiling Ding2 | Lulu Liu3 | Qilin Zhang4
1
Department of Pharmacy, Tongji
Hospital, Tongji Medical College, Abstract
Huazhong University of Science and
Objective: Quetiapine, an atypical second-generation antipsychotic drug, is approved
Technology, Wuhan, China
2
Graduate School of Pharmaceutical
for treatment of schizophrenia, bipolar disorder, and depression. Due to the limita-
Sciences, University of Tokyo, Tokyo, tions of clinical trials, the association between quetiapine and rare cardiac adverse
Japan
3
events (AEs) is still unclear. This study is to evaluate quetiapine-associated cardiac AEs
School of Pharmaceutical Science and
Technology, Tianjin University, Tianjin, through data mining of FDA Adverse Event Reporting System (FAERS).
China Methods: Reporting odds ratio (ROR) was used to quantify the signals of quetiapine-
4
Department of Pharmacy, Union
related cardiac AEs from the first quarter (Q1) of 2018–2022 Q1. Serious and nonseri-
Hospital, Tongji Medical College,
Huazhong University of Science and ous cases were compared, and signals were prioritized using a rating scale.
Technology, Wuhan, China
Results: A total of 1004 cases of quetiapine-associated cardiac AEs were identified, with
Correspondence 31 signals being detected, among which 13 AEs were identified as new and unexpected
Qilin Zhang, Department of Pharmacy,
signals. Besides, nine and 22 cardiac AEs were identified as moderate and weak clini-
Union Hospital, Tongji Medical College,
Huazhong University of Science and cal priority. The median TTO for moderate and weak clinical priority signals were 0 and
Technology, No.1277 Jiefang Avenue,
4 days, respectively. All of the cardiac AEs had early failure type characteristics, suggest-
Wuhan 430022, China.
Email: [email protected] ing that most of the patients developed cardiac AEs in a few days after quetiapine treat-
Lulu Liu, School of Pharmaceutical Science ment, and that the risk of cardiac AEs occurrence would be gradually decreased over time.
and Technology, Tianjin University, No. Conclusion: Our study provided valuable evidence for health-care professionals to
92 Weijin Road Nankai District, Tianjin,
300072, China. mitigate the risk of quetiapine-associated cardiac AEs based on an extensive analysis
Email: [email protected] of a real-world, large-sample FAERS database, and prioritize cardiac AE signals.
Funding information
National Natural Science Foundation of KEYWORDS
China, Grant/Award Number: 82104476 cardiac adverse events, data mining, disproportionality analysis, FAERS, pharmacovigilance,
quetiapine
1 | I NTRO D U C TI O N receptors and serotonin 5-HT2 receptors.1 According to the 2018 an-
nual report of the American Association of Poison Control Centers
Quetiapine, an atypical second-generation antipsychotic drug, is ap- based on the National Poison Data System, antipsychotics are
proved by US Food and Drug Administration (FDA) for the treatment the second largest group of toxic drugs in adults after painkillers,
of schizophrenia, bipolar disorder, and depression. The antipsychotic and quetiapine is one of the most frequently prescribed second-
activity of quetiapine is achieved by blocking central dopamine D2 generation antipsychotics.2 In recent years, an increasing number of
The first two authors contributed equally to this work.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.
CNS Neurosci Ther. 2023;29:2705–2716. wileyonlinelibrary.com/journal/cns | 2705

|
17555949, 2023, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cns.14215 by Nat Prov Indonesia, Wiley Online Library on [21/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2706 SHU et al.
new or serious adverse events (AEs) have been reported related to between a target drug (case) and all other drugs (non-case).16 A sig-
the long-term use of quetiapine. Particularly, studies have observed nificant safety signal occurs when a target drug is reported more
significant associations between quetiapine and metabolic and en- frequently to induce a target AE than all other drugs. The data were
docrine system (hyperglycemia, galactorrhea, dyslipidemia, etc.) and sourced from the FAERS Quarterly Data Extract Files, available at
cardiovascular (cardiomyopathy, myocarditis, tachycardia, hypoten- https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.
sion, prolonged QT interval, etc.) symptoms, although more serious html. To get the latest reports, all reports recorded in FAERS cover-
consequences, including death, have been reported.3–6 ing the period between the first quarter (Q1) of 2018 and the 2022
Evidence is accumulating from the reports and mechanism stud- Q1, were extracted in our study.
ies to support a possible association between quetiapine and cardio-
toxicity. A case-crossover study using a nationwide population-based
sample obtained from Taiwan's National Health Insurance Research 2.2 | Data extraction and descriptive analysis
Database reported that antipsychotic drug use such as quetiapine was
associated with a 1.53-fold increased risk of ventricular arrhythmia The database included seven data files, namely patient demographic
7
and/or sudden cardiac death. According to the International Drug information (DEMO), drug/biologic information (DRUG), adverse
Monitoring Program of the World Health Organization, quetiapine- events (REAC), patient outcomes (OUTC), report sources (RPSR),
induced myocarditis and cardiomyopathy have become the common start/end dates of drug therapy (THER), and indications for drug
manifestations in pathology.8 Berge et al6 reported that treatment (INDI).14 In the FAERS database architecture, a relation was built
with low-dose quetiapine/olanzapine for 6–12 months was signifi- to connect each data file by some special identification numbers
cantly associated with an increased risk of cardiometabolic mortality (such as caseid, primaryid). Moreover, the cases deleted by FDA or
(adjusted HR 1.89; 95% CI, 1.22–2.92, p = 0.004). Both researches by manufacturers for various reasons were collected in Deleted files.
Wenzel-Seifert et al9 and Hasnain et al10 observed that torsade de Because multiple versions of a report would be reported, the dedu-
pointes (TdP) was in association with the use of newer antipsychotic plication process should be performed before statistical analysis, to
drugs, which mainly included quetiapine. The widely reported cardio- ensure the uniqueness of the report.17 The caseid and the primaryid
vascular side effects have also raised concerns of the Danish Medicine were used as the key filters in our study to remove duplicate records.
Agency or the European Medicine Agency, which has therefore been First, the reports in the Deleted files were deleted. Then, the report
11,12
cautious about expanding the use of quetiapine. In particular, with the higher primaryid was selected when the caseid was the
the FDA have warned in the instructions that elderly patients with same. We further removed reports where the data were not avail-
dementia-related psychosis was associated with an increased risk of able, when we counted patient information (e.g., sex and age). We
death from cardiovascular diseases (e.g., heart failure, sudden death) extracted reports using generic name (quetiapine in drugname and
and infections (e.g., pneumonia) when treated with quetiapine. prod_ai columns) and trade name (SEROQUEL in drugname column)
Due to the limitations of clinical trials, such as specific popu- in the DRUG file. To improve the reported association between drug
lation, relatively small sample size, limited duration of follow-ups, and AEs, only the role_cod as primary suspected (PS) was selected.
and strict inclusion and exclusion criteria, the association between AEs in FAERS were coded using the preferred term (PT) according to
quetiapine and rare cardiac AEs is still unclear, suggesting continu- standardized Medical Dictionary for Regulatory Activities (MedDRA
ous post-marketing surveillance is urgent.13 The long-term safety of 25.0), which were divided into five levels: system organ class (SOC),
drugs and the occurrence of rare or serious AEs are largely assessed high level group term (HLGT), high level term (HLT), preferred term
using post-marketing surveillance data, which increases the value (PT), and lowest level term (LLT).18 The quetiapine-associated AEs
of spontaneous reporting systems such as Food and Drug Adverse extracted from the REAC files, were used to calculate the frequency
Event Reporting System (FAERS).14 The FAERS database is now and intensity at PT and SOC levels. All the PTs under the SOC of
widely used to identify pharmacovigilance risk signals in real-world cardiac disorders (SOC: 10007541) in the MedDRA 25.0 were calcu-
clinical settings.15 The purpose of this study was to utilize standard- lated in our study. Further, because a PT can be normally affiliated to
ized information from the FAERS, to describe the characteristics of more than one SOC in MedDRA 25.0, the Aes in reports were classi-
quetiapine-related cardiac AE reports from stratification analysis, fied to the corresponding PT and SOC levels. All data processing was
clinical priority of signals, time-to-onset, and the serious outcomes. performed using MYSQL 8.0 (Oracle, Sweden), Navicat Premium
15, Microsoft EXCEL 2019, and the GraphPad Prism 8 (GraphPad
Software, CA, USA).
2 | M E TH O D S Subsequently, descriptive analyses were carried out to sum-
marize the clinical characteristics of all quetiapine-
associated
2.1 | Study design and data sources reports. Detailed information will be calculated if the data are
available, such as gender, age, weight, reporting countries, indi-
A disproportionality analysis, designed as a case/non-case study, cations, outcomes, and time-to-onset, etc. A flowchart including
was used to quantify the association between quetiapine and car- the multistep process of data extraction, processing, and analysis
diological AEs. It calculated the proportion of occurring target AEs is shown in Figure 1.
|
SHU et al. 2707
F I G U R E 1 Multistep process of data

extraction, processing, and analysis from
Food and Drug Administration adverse
event reporting system (FAERS) database.
2.3 | Statistical analysis death, characterization as designated medical events (DMEs) or

important medical events (IMEs), and evidence evaluation.19,20
Based on the disproportionality analysis using a 2 × 2 table (Table S1), According to three levels of clinical importance, a composite score
the reporting odds ratio (ROR) was employed to identify an associa- between 0–4, 5–7, or 8–10 was identified as AEs with weak, mod-
tion between a drug and an AE. All cardiological AE reports were se- erate, or strong clinical priority, respectively. The detailed infor-
lected to perform signal strength of reports of quetiapine at both PT mation is shown in Table S2.
(cardiological AEs) and SOC (cardiac disorders) levels in FAERS data-
base. To reduce the likelihood of false positives, the threshold was set,
and a significant signal was defined when the lower limit of the ROR 2.5 | Time-to-onset analysis and
95% confidence interval (CI) exceeded 1 with at least five reports. 19
sensitivity analysis
The outcomes of AE reports were classified as serious or
nonserious in FAERS. The serious outcomes included death (DE), Time-to-onset (TTO) was calculated as the duration between the
life-threatening (LT), inpatient hospitalization or prolongation of occurrence date of AEs (EVENT_DT in DEMO file) and start date
existing hospitalization (HO), disability (DS), congenital anomaly of quetiapine use (START_DT in THER file).13 Only the reports with
(CA), required intervention to prevent permanent impairment/ available TTO data were analyzed, and reports with input errors
damage (RI), as well as other serious/important medical event (EVENT_DT earlier than START_DT) were excluded before analysis,
(OT). Some reports might list more than one specific outcome (e.g., to ensure the accuracy of calculation. The incidence of AEs often
one report experienced DS, LT, and then DE), which recorded in varies over time, and the Weibull shape parameter (WSP) test is used
the OUTC file. However, the serious and nonserious reports were for statistical analysis of TTO to describe the risk that the incidence
also compared to clarify the severity of the detected safety sig- of AEs increases or decreases over time. 21–23 The shape of Weibull
nals and identify risk factors (gender, age, weight, and types of distribution was described by two parameters: scale (α) and shape
AEs) in patients. Proportions were compared using a Pearson's (β). In the analysis of WSP test, the shape parameter β of the Weibull
chi-s quared (χ2) or Fisher's exact test, and Mann–W hitney U test distribution will be considered and discussed to forecast the haz-
was applied for continuous non-n ormal distribution data, such as ard without a reference population. However, three hazard types
age and weight. Data were analyzed using SPSS (v22.0; IBM Corp., are described in WSP test: early failure type means the hazard of
Armonk, NY, United States), and statistical significance was set at the AEs decreases over time (β < 1 and 95% CI < 1); random failure
a two-t ailed p < 0.05. To further explore the influence of different type means the hazard of the AEs constantly occurs over time (β was
stratification regimens on the correlation between quetiapine and equal to or nearly 1 and its 95% CI included the value 1); wear-out
cardiac disorders, we performed subgroup analysis by gender (fe- failure type means the hazard of the AEs increases over time (β > 1
male and male), age (<18, 18 ≤ and ≤ 65, >65 years), weight (<80, and 95% CI > 1).
80 ≤ and ≤ 100, and >100 kg), and reporters (health-c are profes- In order to predict the risk of increase or decrease of these
sional and consumer) separately. quetiapine-associated cardiological AEs over time, we calculated
the median TTO and WSP of signals with moderate or weak clinical
priority after quetiapine use. The WSP tests were performed using
2.4 | Clinical prioritization of signals Minitab statistical software (v20.0; Minitab LLC).
Moreover, we also considered the effect of concomitant drugs
AEs with significant disproportionality were scored and ranked ac- on quetiapine-related cardiac AEs, and concomitant therapy was
cording to clinical priority in our study. A semiquantitative score defined as quetiapine being the “primary suspect.” and other drugs
was performed to prioritize disproportionality signals by assess- were listed as “second suspect,” “concomitant,” or “interacting.”
ing five different features, including number of AE reports, the Subsequently, the sensitivity analysis was performed after the ex-
lower limit of the ROR 95% CI (ROR 025) values, proportion of clusion of the reports associated with potential suspicious drugs. 24
|
2708 SHU et al.
3 | R E S U LT S (χ2 = 9.549, p = 0.002), and palpitations (χ2 = 10.671, p = 0.001)

were more likely to be reported as serious AEs, while other 28
3.1 | Descriptive analysis AEs were more tended to be reported as nonserious AEs with
p > 0.05, such as tachycardia (χ2 = 0.239, p = 0.625), arrhythmia
From January 2018 to March 2022, the FAERS database has re- (χ2 = 1.000, p = 0.317), and myocarditis (p = 0.161), etc. Of note,
corded 6,437,182 AE reports after exclusion of duplicates, includ- all AEs outcomes for cardiorespiratory arrest (n = 57), atrial sep-
ing 1415 quetiapine-associated cardiac AEs in 1004 patients. The tal defect (n = 19), torsade de pointes (n = 13), ventricular extra-
clinical characteristics of quetiapine-induced AEs are described in systoles (n = 11), ventricular tachycardia (n = 9), ventricular septal
Table 1. Among all reports, females accounted for a larger propor- defect (n = 8), ventricular fibrillation (n = 8), Brugada syndrome
tion than males (61.89% vs 38.11%). Patients were mainly aged (n = 7), ventricular arrhythmia (n = 5), and tachyarrhythmia (n = 5)
18–65 years (72.60%) and >65 years (19.82%), with a median age of were severe cases.
44.03 (IQR 28–59) years. Serious outcomes of cardiac and overall
AE reports, including 143 (16.49%) and 757 (16.19%) deaths, were
recorded in 867 and 4677 cases, respectively. Additionally, 21.61% 3.4 | Subgroup analysis
of the patients reported onset time of the cardiac AEs, with the me-
dian time-to-onset of 1 day (IQR 0–30 days). The most reported in- As shown in Figure 3, cardiac disorders were separately assessed
dication of quetiapine was psychiatric disorders (n = 443, 90.22%). stratifying by sex, age, weight, and type of reporters. Results dem-
Most reports were submitted by health-care professionals (n = 654, onstrated that the lower limits of ROR values were >1 when strati-
70.70%) and consumers (n = 271, 29.30%), respectively. The country fied by sex and reporters' type, indicating there was still a strong
with the most cardiac AE reports was USA (n = 297, 29.58%), fol- statistical correlation between quetiapine and cardiac disorders. In
lowed by United Kingdom (n = 164, 16.33%) and Canada (n = 105, females, ROR025 was found to be 1.48, whereas it was 1.20 in males,
10.46%). indicating a significant association of quetiapine with cardiac AEs in
both male and females. Moreover, it suggested that women were
more likely to experience cardiotoxicity with quetiapine than men.
3.2 | Disproportionality analysis The majority of quetiapine-associated cardiac AEs cases were found
in the 18–65 years age groups. However, it did not show significant
During the study period, a total of 31 different PTs of quetiapine- association between cardiac disorders and quetiapine treatment
associated cardiac AEs were identified in FAERS database in at when stratified by age and body weight, primarily in subgroups of
least five cases (Figure 2). The most commonly reported cardiac patients >65 years old and body weight <80 kg and >100 kg.
AEs were dizziness (n = 205), tachycardia (n = 138), palpitations
(n = 57), and cardiorespiratory arrest (n = 57). Figure 2 presented a
full list of disproportionality analysis results. In the entire database, 3.5 | Clinical prioritization of the
quetiapine-
related cardiac disorders were reported significantly disproportionality signals
more frequently than non-
quetiapine, with an ROR025 of 1.48.
Further, investigation of cardiac AE signals revealed that 31 cardiac In total, 14 of the 31 AEs (45.16%) with statistically significant dis-
AEs showed statistically significant signal strengths after quetiapine proportionality signals were categorized as IMEs, whereas only two
treatment compared with non-quetiapine-related cardiac AEs, with represented DMEs (6.45%), including torsade de pointes and ven-
values of signals ranging from a ROR025 of 1.19 (supraventricular tricular fibrillation (Table 3). According to the clinical priority as-
tachycardia) to 52.96 (Brugada syndrome). Other quetiapine-related sessment, 22 (70.97%), nine (29.03%), and zero cardiac AEs were
nonpositive cardiac AE signals are shown in Table S3. Results of sig- identified as weak, moderate, and strong clinical priority, respec-
nal strength of quetiapine at the SOC level in Table S4 demonstrated tively. Cardiorespiratory arrest (n = 57, ROR025 = 4.64) and myocar-
that there were 12 SOCs exhibiting remarkable association with ditis (n = 28, ROR025 = 5.55) were graded as moderate clinical priority
quetiapine treatment, among which including cardiac disorders with with the highest priority scores of 7. Besides, 18 AEs were evaluated
the ROR of 1.58 (1.48–1.70). as strong clinical evidences with “++.”
3.3 | Serious vs. Nonserious cases 3.6 | Time-to-onset analysis and

sensitivity analysis
Data in Table 2 showed that there were no statistically signifi-
cant differences in sex (χ2 = 1.395, p = 0.237), age (43 vs 51 years; As shown in Table 4, the median onset time of moderate and weak
p = 0.093), and body weight (71 vs 70 kg; p = 0.476) between se- AE signals associated with quetiapine was 0 (IQR 0–8) and 4 (IQR 0–
vere and non-s evere cases of cardiac AE patients receiving que- 59.5) days, respectively. In the WSP analysis, the upper limits of 95%
tiapine. Dizziness (χ2 = 13.362, p < 0.001), cardiorespiratory arrest CI of the shape parameters β were <1, suggesting these moderate
|
SHU et al. 2709
TA B L E 1 Clinical characteristics of patients with quetiapine-associated cardiac adverse events.
Quetiapine induced cardiac AEs (n = 1004) Quetiapine induced overall AEs (n = 6170)
Characteristics Available number Value Available number Value
Gender, n (%) 929 (92.53%) - 5709 (92.53%) -

Female - 575 (61.89%) - 3356 (58.78%)
Male - 354 (38.11%) - 2353 (41.22%)
Age (years), n (%) 792 (78.88%) - 4728 (76.63%) -
<18 - 60 (7.58%) - 345 (7.30%)
18 ≤ and ≤ 65 - 575 (72.60%) - 3403 (71.98%)
>65 - 157 (19.82%) - 980 (20.72%)
Median (IQR) - 44.03 (28–59) - 45 (31–61)
Weight (Kg), n (%) 278 (27.69%) - 1350 (21.88%) -
<80 - 167 (60.07%) - 864 (64.00%)
80 ≤ and ≤ 100 - 72 (25.90%) - 322 (23.85%)
>100 - 39 (14.03%) - 164 (12.15%)
Median (IQR) - 70.55 (56.34–90.70) - 70.30
(58.50–88.34)
Reported countries, n (%) 1004 (100%) - 6170 (100%) -
America (USA) - 297 (29.58%) - 1936 (31.38%)
United Kingdom (UK) 164 (16.33%) 765 (12.40%)
Italy (IT) 61 (6.08%) 577 (9.35%)
Germany (DE) 100 (9.96%) 514 (8.33%)
Canada (CA) 105 (10.46%) 503 (8.15%)
Others - 277 (27.59%) - 1875 (30.39%)
Indications, n (%) 491 (48.90%) - 3147 (51.00%) -
Psychiatric disorders - 443 (90.22%) - 2835 (90.09%)
Others - 48 (9.78%) - 312 (9.91%)
Outcomes, n (%) 1004 (100%) - 6170 (100%) -
Nonserious outcome - 137 (13.65%) - 1493 (24.20%)
Serious outcome - 867 (86.35%) - 4677 (75.80%)
Death - 143 (16.49%) - 757 (16.19%)
Life-threatening - 116 (13.38%) - 398 (8.51%)
Hospitalization - 397 (45.79%) - 1829 (39.11%)
Disability - 44 (5.07%) - 185 (3.96%)
Other serious outcomes - 636 (73.36%) - 3093 (66.13%)
Time-to-onset (days) 217 (21.61%) - 1271 (20.60%) -
Median (IQR) - 1 (0–3 0) - 1 (0–31)
Reporters, n (%) 925 (92.13%) - 5729 (92.86%) -
Health professional - 654 (70.70%) - 4271 (74.55%)
Consumer - 271 (29.30%) - 1458 (25.45%)
Reporting year, n (%) 1004 (100%) - 6170 (100%) -
2022 Q1* - 60 (5.98%) - 357 (5.79%)
2021 - 231 (23.01%) - 1437 (23.29%)
2020 - 202 (20.12%) - 1412 (22.88%)
2019 - 252 (25.10%) - 1585 (25.69%)
2018 - 259 (25.80%) - 1379 (22.35%)
Abbreviations: AEs: Adverse events; n: number of cases.

*
The first quarter of 2022.
|
2710 SHU et al.
F I G U R E 2 Reporting odds ratios (ROR) with 95% CI for all positive quetiapine-associated cardiac adverse events with at least five counts.
and weak clinical priority signals had early failure types, and the risk reviews highlighting the association between exposure to antip-
of cardiac AEs occurrence gradually decreased over time. sychotics and cardiac AEs. According to a recent epidemiological
Among quetiapine-induced cardiac AEs reports, there were 721 study, Weeke et al25 found that quetiapine, as the only atypical
cases (71.81%) in combination with other drugs. The reports of que- antipsychotic drug, was associated with 3.64 times increased
tiapine combined with one, two, and three drugs were recorded in risk of out-
of-
h ospital cardiac arrest. In a randomized double-
157 (15.64%), 124 (12.35%), and 97 (9.66%) cases, respectively. The blind study by Nielsen et al, 26 results revealed that there were
top 20 concomitant drugs are shown in Table 5, and the top five 11 patients (9.6%) receiving quetiapine who experienced more
were lorazepam (n = 88, 12.21%), sertraline hydrochloride (n = 75, than 20 ms QTcF prolongation. Hagiwara et al27 have reported a
10.40%), mirtazapine (n = 65, 9.02%), aripiprazole (n = 64, 8.88%), 37-year-old man who developed myocarditis after starting treat-
and lamotrigine (n = 62, 8.60%). The sensitivity analysis was per- ment with quetiapine for bipolar disorder. The cytokine release
formed after exclusion of drugs (aripiprazole, risperidone, and olan- and catecholamine hyperactivation suggested to be associated
zapine) that belonged to the second-
generation antipsychotics. with quetiapine administration may have been the etiological
Although the number of quetiapine-related cardiac AE reports were mechanism. However, studies on quetiapine-induced cardiac AEs
decreased from 1004 to 868 (ROR 1.33; 95% CI 1.24–1.43) after based on the large-s ample real-world data were quite limited, and
removing the reports of suspicious drugs, it still had a significant none of the studies provided data after stratifying by sex, age, and
association between quetiapine and cardiac disorders. Moreover, weight, strongly underling the need for constant post-marketing
five PTs no longer showed significant signals, including long QT syn- surveillance.
drome, supraventricular tachycardia, ventricular arrhythmia, extra- Fortunately, we innovatively used multidimensional analytic ap-
systoles, and bundle branch block right. The detailed changes are proaches, such as subgroup analysis, clinical priority of signals and
shown in Table S5. the serious outcomes, to provide insight into the primary results. In
our study, a total of 1004 reports of quetiapine-associated cardiac
AEs were obtained, and 31 significant AEs with at least five reports
4 | DISCUSSION were detected. The most frequently reported cardiac AEs of que-
tiapine were dizziness (n = 205, ROR = 1.60), tachycardia (n = 138,
This pharmacovigilance study comprehensively and systemati- ROR = 5.70), palpitations (n = 57, ROR = 1.87), and cardiorespiratory
cally provided the latest findings of quetiapine-associated cardiac arrest (n = 57, ROR = 6.03), which were consistent with clinical tri-
safety profiles by post-marketing based on the FAERS database. als.7,28 Among the 31 AEs, 13 AEs which were not reported in the
Our results are in line with previous clinical trials and literature drug label, were identified as new and unexpected signals, such as
|
SHU et al. 2711
TA B L E 2 Differences in clinical characteristics of severe and non-severe reports.
Serious cases (n = 867) Nonserious cases (n = 137) Statistics p value
Gender, n (%)
Female 503 (87.48%) 72 (12.52%) 1.395a 0.237b
Male 300 (84.75%) 54 (15.25%) - -
c
Age, years (Median) 43 51 −1.679 0.093d
c
Weight, Kg (Median) 71 70 −0.713 0.476d
Types of AEs, n (%) - - - -
Dizziness 161 44 13.362a < 0.001b
Tachycardia 121 17 0.239a 0.625b
e a
Cardiorespiratory arrest 57 0 9.549 0.002b
Syncope 52 4 2.128a 0.145b
Cardiac arreste 43 2 3.385a 0.066b
a
Palpitations 41 16 10.671 0.001b
Sinus tachycardia 37 11 3.677a 0.055b
a
Arrhythmia 34 3 1.000 0.317b
Bradycardia 31 4 - 1.000 f
Myocarditis 27 1 - 0.161f
Atrial septal defecte 19 0 - 0.094f
e
Cardiogenic shock 15 1 - 0.711f
Torsade de pointes 13 0 - 0.235f
e
Ventricular extrasystoles 11 0 - 0.378f
Cardiomyopathy 11 2 - 0.694f
Dizziness postural 10 1 - 1.000 f
Ventricular tachycardia 9 0 - 0.619f
e
Cyanosis 9 2 - 0.653f
Cardiovascular disorder 9 0 - 0.619f
e
Ventricular septal defect 8 0 - 0.608f
Ventricular fibrillatione 8 0 - 0.608f
Long QT syndrome 7 1 - 1.000 f
Brugada syndromee 7 0 - 0.602f
e
Tricuspid valve incompetence 6 1 - 1.000 f
Patent ductus arteriosuse 6 0 - 1.000 f
Congestive cardiomyopathy 6 1 - 1.000 f
Ventricular arrhythmia 5 0 - 1.000 f
Tachyarrhythmia 5 0 - 1.000 f
Supraventricular tachycardia 4 2 - 0.192f
e
Extrasystoles 4 1 - 0.521f
Bundle branch block righte 4 1 - 0.521f
Note: The AEs listed above were AEs with significant signal strengths.p ˂ 0.05 were considered statistically significant.
a
The chi-square (χ2) statistic of the Pearson chi-square test.
b
Proportions were compared using Pearson chi-square test.
c
The Z statistic of the Mann–Whitney U test.
d
Mann–Whitney U test.
e
Emerging findings of quetiapine-associated cardiac AEs from FAERS database.
f
Fisher's exact test.
atrial septal defect, ventricular extrasystoles, and tricuspid valve in- This study suggests that there are significant differences
competence, etc. The full list of all new quetiapine-associated car- (p < 0.05) in three AEs among the 31 cardiac AEs, when compared
diac AEs is presented in Figure 2. serious cases with nonserious cases. Patients gender (p = 0.237),
|
2712 SHU et al.
F I G U R E 3 Subgroup analysis of quetiapine-related cardiac disorders.
age (p = 0.093), and weight (p = 0.476) may not be associated with younger ages than non-severe cases (median age 43 vs 51 years), but
increased risk of quetiapine-related cardiac AEs severity. However, there was no statistical difference among the two groups (p = 0.093).
the descriptive analysis (Table 1) showed that females (61.89%) were However, Yunusa et al35 reported the opposite results that antipsy-
more likely to report cardiac AEs than males (38.11%), in agreement chotics were associated with potentially serious AEs in vulnerable
with a study based on FAERS that females (58.4%) had a higher older adults with higher RORs of hospitalization due to age-related
proportion of cardiac AEs than males (41.6%) after antipsychotics reduction in the ability to metabolize and excrete drugs, thus leading
treatment. 29 Further comparison of severe and non-severe cases to a higher plasma concentration of quetiapine. Another study also
demonstrated that the proportion of females with serious cardiac demonstrated an increased risk of cardiovascular events in older pa-
AEs was numerically higher than that of males (87.48% vs 84.75%), tients with antipsychotic drugs, including quetiapine.36 Therefore,
but there was no statistically significant difference between the two cautions are necessary when prescribing quetiapine to older women
groups. Results were consistent with previous studies that women and children.
were at a higher risk of reporting severe cardiac AEs after receiving We conducted subgroup analysis by body weight (<80, 80–100,
30–32 31 32
antipsychotics. Both studies by Harrigan et al and Roe et al and >100 kg), and found that only the subgroup of body weight
found that although women were at a lower risk of sudden cardiac 80–100 kg presented significant signal strength with ROR025 = 1.
death, they had a higher risk of induced long QT syndrome from The other two groups (<80 and >100 kg) did not show an associa-
antipsychotic drugs. To date, sex differences in quetiapine-induced tion between quetiapine and cardiac AEs because of ROR025 < 1. A
AEs have not been well studied, but some AEs, such as weight gain, Bayesian meta-analysis of 41 short-term trials of second-generation
elevated lipids, and cardiac effects, have been reported to be par- antipsychotics found a significant mean weight gain (1.74 kg; 95% CI,
ticularly associated with women.30 The present subgroup analysis 0.99–2.50) during treatment with quetiapine.37 Jensen et al38 also
revealed that females were associated with more cardiac AEs than reported that quetiapine was associated with significantly greater
males with a higher ROR value (1.62 vs. 1.35). The mechanism of weight gain and adverse changes in cardiometabolic outcomes in
gender-specific effects on quetiapine-related cardiotoxicity may be youths. Results suggested body weight might, in part, be associated
related to hormones and pharmacokinetic properties.33 with quetiapine-induced cardiac AEs.
In our study, patients aged 18–65 years reported more fre- Clinical prioritization assessment was employed to prioritize
quently cardiac AEs (n = 575, 72.60%) than those aged >65 years quetiapine-related cardiac safety signals. Our results showed that
(n = 157, 19.82%) and <18 years (n = 60, 7.58%), which were consis- zero strong, nine moderate, and 22 weak clinical priority signals
tent with a FAERS study that the median patient age among queti- were identified. The strongest priority signals were cardiorespira-
apine abuse-related event reports was 44 years (IQR = 31–55).34 On tory arrest and myocarditis with score 7. In addition, the most fre-
the contrary, younger patients generally had numerically higher ROR quently reported quetiapine-associated priority cardiac AEs were
estimates than older adults (2.34 vs. 1.43) in the subgroup analysis tachycardia (n = 138, score 6), palpitations (n = 57, score 5), sinus
(Figure 2), suggesting youths taking quetiapine might be more likely tachycardia (n = 48, score 6), arrhythmia (n = 37, score 6), torsade
to have cardiac AEs. Moreover, severe cases were also reported at de pointes (n = 13, score 6), and cardiomyopathy (n = 13, score 5),
|
SHU et al. 2713
TA B L E 3 Clinical priority assessing results of disproportionality signals.
Relevant evidence Priority level

PTs n ROR025 Death (n) IMEs-DMEs evaluation (score)
Dizziness 205 1.39 8 NA ++ Weak (4)

Tachycardia 138 4.82 3 IME ++ Moderate (6)
a
Cardiorespiratory arrest 57 4.64 57 IME + Moderate (7)
Palpitations 57 1.44 0 IME ++ Moderate (5)
Syncope 56 1.59 0 NA ++ Weak (4)
Sinus tachycardia 48 10.33 0 IME ++ Moderate (6)
a
Cardiac arrest 45 1.73 25 IME + Moderate (5)
Arrhythmia 37 2.12 11 IME ++ Moderate (6)
Bradycardia 35 1.57 6 IME ++ Weak (4)
Myocarditis 28 5.55 9 IME ++ Moderate (7)
Atrial septal defect a 19 5.7 0 NA − Weak (3)
Cardiogenic shocka 16 2.51 1 NA − Weak (2)
Torsade de pointes 13 3.77 0 DME ++ Moderate (6)
Cardiomyopathy 13 2.13 1 IME ++ Moderate (5)
Dizziness postural 11 2.36 0 NA ++ Weak (4)
a
Ventricular extrasystoles 11 2.77 0 NA − Weak (2)
Cyanosisa 11 1.74 0 NA − Weak (1)
Cardiovascular disorder 9 1.32 3 NA ++ Weak (3)
Ventricular tachycardia 9 1.25 1 IME ++ Weak (3)
Long QT syndrome 8 4.47 0 NA ++ Weak (3)
a
Ventricular fibrillation 8 1.64 0 DME − Weak (2)
a
Ventricular septal defect 8 2.77 0 NA − Weak (1)
Congestive cardiomyopathy 7 2.48 0 IME ++ Weak (4)
a
Brugada syndrome 7 11.82 0 NA − Weak (2)
Tricuspid valve incompetencea 7 2.18 0 NA − Weak (1)
Supraventricular tachycardia 6 1.19 0 IME ++ Weak (3)
Patent ductus arteriosusa 6 2.85 0 NA − Weak (1)
Ventricular arrhythmia 5 1.7 2 IME ++ Weak (4)
Tachyarrhythmia 5 2.97 0 IME ++ Weak (4)
a
Bundle branch block right 5 2.12 0 NA − Weak (1)
Extrasystolesa 5 1.24 0 NA − Weak (0)
Abbreviations: NA, Not Applicable (for relevant criteria); n, number of cases; PTs, preferred Terms; ROR025, the lower limit of 95% confidence interval
of ROR.A priority score between 8–10, 5–7, or 0–4 represents the signal with strong, moderate, or weak clinical priority, respectively.
a
Emerging finding of quetiapine-associated cardiac AEs from FAERS database.
TA B L E 4 Results of time-to-onset analysis for signals with moderate/weak prioritization.
TTO (days) Weibull distribution
Cases - Scale parameter Shape parameter
Median
Prioritization n (IQR) Min-max α 95% CI β 95% CI Failure type
Moderate 93 0 (0–8) 0–517 0.13 0.03–0.58 0.15 0.13–0.17 Early failure

Weak 94 4 (0–59.5) 0–520 4.75 1.50–15.04 0.18 0.15–0.22 Early failure
Note: n: number of cases with available time-to-onset; IQR: interquartile range; TTO: time-to-onset.When TTO is 0 days, the adverse event occurred
within the same day with the therapy.
|
2714 SHU et al.
which were consistent with the drug label. Of note, 12 of the 31 of cardiac AEs occurrence would be gradually decreased over time.
AEs were serious cases (Table 2). Quetiapine-related cardiac ar- Hence, clinicians should be aware of the potential toxicity of queti-
rest was more likely to be reported as a severe AE. Wu et al7 re- apine and that cardiac AEs may occur on the day of treatment, partic-
ported a significantly increased risk of ventricular arrhythmia and/ ularly when treating patients sharing risk factors with females and the
or sudden cardiac death for quetiapine (adjusted OR = 1.29; 95% CI, older population. To correctly grasp the balance between the efficacy
1.07–1.56). According to data from Danish Cardiac Arrest Register and safety of quetiapine, timely and effective treatment of cardiac
(2001–2010), 2205 (7.6%) of 28,947 out-of-hospital cardiac arrest AEs, and helping patients to maintain long-term medication, prospec-
patients received antipsychotics treatment at the time of the event, tive studies and long-term follow-ups are needed to verify our results.
and quetiapine was identified to be associated with cardiac arrest The exact mechanisms underlying quetiapine-induced cardiac in-
25
(OR = 3.64; 95% CI, 1.59–8.30). Other large epidemiological stud- jury are still far to be completely understood. Toxicological studies
ies have also found a dose-dependent relationship between queti- have shown that quetiapine promoted the necroptotic cell death to
apine and sudden cardiac death.4,39 Particularly, in our study, a total induce cardiac toxicity, and selective CB1R antagonists or CB2R ag-
of 57 and 45 cases of quetiapine-associated cardiorespiratory arrest onists might provide beneficial potentials against quetiapine-induced
and cardiac arrest were obtained from FAERS database, and there cardiotoxicity.8 Recently, a number of preclinical studies have pro-
were 57 (100.00%) and 25 (55.56%) death, respectively (Table 3), posed the potential role of pro-inflammatory cytokines, catechol-
which were corresponding to previous reports and emerging data amines, and oxidative stress in antipsychotic-induced cardiotoxicity.1
from the World Health Organization pharmacovigilance database Furthermore, concomitant medications should also be considered be-
40,41
(VigiBase) and FAERS. Thus, physicians should perform baseline cause the use of other antipsychotics or neurologic agents has been
measurements of cardiovascular-related indicators before prescrip- reported to significantly increase the risk of cardiac AEs. In our anal-
tion to maximize patient benefit. ysis, lorazepam, sertraline hydrochloride, mirtazapine, aripiprazole,
In the TTO analysis (Table 4), the median TTO for moderate and and lamotrigine were the top five concomitant drugs of quetiapine.
weak clinical priority signals were 0 and 4 days, respectively, reveal- Recently, both the manufacturer of sertraline hydrochloride and the
ing quetiapine-related moderate signals often occurred on the day of US FDA have warned the drug-induced QTc interval prolongation and
treatment. Furthermore, all of the cardiac AEs had early failure type torsade de pointes when using sertraline hydrochloride.42 Besides, a
characteristics, suggesting that most of the patients developed car- study have demonstrated that lamotrigine toxicity manifested with
diac AEs in a few days with quetiapine treatment, and that the risk moderate neurologic and/or electrocardiographic effects.43
minor-
Therefore, we cannot exclude the possibility that quetiapine com-
TA B L E 5 Top 20 concomitant drugs for quetiapine-related
bined with other drugs may increase the risk of cardiac AEs.
cardiac AEs from FAERS databases.
There are some limitations inherently shared by all pharmacovig-
Concomitant drugs (TOP 20) N (%) ilance databases. First, due to the nature of spontaneous reporting
Lorazepam 88 (12.21) mechanism of the FAERS database (e.g., false, overreported, inac-
Sertraline hydrochloride 75 (10.40) curate, incomplete, and delayed reports), our analysis is subject to
Mirtazapine 65 (9.02)
inevitable and unquantifiable biases. Second, because the total num-
ber of patients using quetiapine is not available in FAERS, we can-
Aripiprazole 64 (8.88)
not calculate AE incidence and establish causality. Third, we focus
Lamotrigine 62 (8.60)
only on AEs in cardiac disorders, and the deep relationship between
Venlafaxine hydrochloride 59 (8.18)
quetiapine and other systemic organ classes remain unknown.
Clonazepam 56 (7.77)
Notwithstanding the above limitations, we systematically and com-
Aspirin 49 (6.80)
prehensively reveal the association between quetiapine and cardio-
Risperidone 49 (6.80) toxicity through an extensive analysis of a real-world, large-sample
Diazepam 45 (6.24) FAERS database, and prioritize cardiac AE signals, which provides
Olanzapine 45 (6.24) valuable evidence for healthcare professionals to mitigate the risk of
Trazodone hydrochloride 45 (6.24) quetiapine-associated cardiac AEs.
Acetaminophen 43 (5.96)
Escitalopram oxalate 43 (5.96)
Gabapentin 39 (5.41) 5 | CO N C LU S I O N
Pregabalin 37 (5.13)
Our pharmacovigilance study systematically explored and quantified
Levothyroxine sodium 33 (4.58)
the potential cardiotoxicity induced by quetiapine, which obtained
Metformin hydrochloride 33 (4.58)
novel safety information about quetiapine. Among the 31 cardiac
Zopiclone 32 (4.44)
AEs, 13 new and unexpected AEs signals are confirmed. Besides,
Fluoxetine hydrochloride 31 (4.30)
nine and 22 cardiac AEs were identified as moderate and weak clini-
Note: N, number of adverse event reports. cal priority. The median TTO for moderate and weak clinical priority
|
SHU et al. 2715
signals were 0 and 4 days, respectively, and all of the cardiac AEs had 10. Hasnain M, Vieweg WV. QTc interval prolongation and torsade
early failure type characteristics. The characteristics of cardiotoxic- de pointes associated with second- generation antipsychot-
ics and antidepressants: a comprehensive review. CNS Drugs.
ity spectrum found in this study are helpful for clinicians to recog-
2014;28(10):887-920.
nize different cardiotoxicity and guide clinical practice. Some cardiac 11. Jakobsen KD, Wallach-K ildemoes H, Bruhn CH, et al. Adverse
AEs have not received enough attention, and more cardiac examina- events in children and adolescents treated with queti-
tions are recommended for high-risk patients. apine: an analysis of adverse drug reaction reports from the
Danish medicines agency database. Int Clin Psychopharmacol.
2017;32(2):103-106.
AU T H O R C O N T R I B U T I O N S 12. Lee SH, Kim HR, Han RX, Oqani RK, Jin DI. Cardiovascular risk
Qilin Zhang and Yamin Shu contributed to conception and study assessment of atypical antipsychotic drugs in a zebrafish model. J
design, and took responsibility for the collection, integrity, and ac- Appl Toxicol. 2013;33(6):466-470.
13. Chen C, Wu B, Zhang C, Xu T. Immune-related adverse events asso-
curacy of the data. All authors drafted the article, participated in
ciated with immune checkpoint inhibitors: an updated comprehen-
data analyses and interpretation, and revisions of the article, and ap- sive disproportionality analysis of the FDA adverse event reporting
proved the final version. system. Int Immunopharmacol. 2021;95:107498.
14. Shu Y, Ding Y, Liu Y, Wu P, He X, Zhang Q. Post-marketing safety con-
cerns with Secukinumab: a disproportionality analysis of the FDA
F U N D I N G I N FO R M AT I O N
adverse event reporting system. Front Pharmacol. 2022;13:862508.
This study was supported by grants from National Natural Science 15. Shu Y, Ding Y, Dai B, Zhang Q. A real-world pharmacovigilance
Foundation of China (No. 82104476). study of axitinib: data mining of the public version of FDA adverse
event reporting system. Expert Opin Drug Saf. 2022;21(4):563-572.
C O N FL I C T O F I N T E R E S T S TAT E M E N T 16. Peng L, Xiao K, Ottaviani S, Stebbing J, Wang YJ. A real-world
disproportionality analysis of FDA adverse event reporting
The authors declare that they have no conflicts of interest.
system (FAERS) events for baricitinib. Expert Opin Drug Saf.
2020;19(11):1505-1511.
DATA AVA I L A B I L I T Y S TAT E M E N T 17. Shu Y, He X, Liu Y, Wu P, Zhang Q. A real-world disproportionality
The data generated during and/or analyzed during this study are analysis of Olaparib: data Mining of the Public Version of FDA ad-
verse event reporting system. Clin Epidemiol. 2022;14:789-8 02.
available from the corresponding author upon reasonable request.
18. Shu Y, Ding Y, He X, Liu Y, Wu P, Zhang Q. Hematological toxicities in
PARP inhibitors: a real-world study using FDA adverse event report-
ORCID ing system (FAERS) database. Cancer Med. 2023;12(3):3365-3375.
Qilin Zhang https://orcid.org/0000-0002-4779-3875 19. Gatti M, Antonazzo IC, Diemberger I, De Ponti F, Raschi E. Adverse
events with sacubitril/valsartan in the real world: emerging signals
to target preventive strategies from the FDA adverse event report-
REFERENCES ing system. Eur J Prev Cardiol. 2021;28(9):983-989.
1. D'Errico S, Russa R, Maiese A, et al. Atypical antipsychotics and 20. Guo H, Wang B, Yuan S, et al. Neurological adverse events associ-
oxidative cardiotoxicity: review of literature and future per- ated with Esketamine: a disproportionality analysis for signal de-
spectives to prevent sudden cardiac death. J Geriatr Cardiol. tection leveraging the FDA adverse event reporting system. Front
2021;18(8):663-685. Pharmacol. 2022;13:849758.
2. Gummin DD, Mowry JB, Spyker DA, et al. 2018 annual report of 21. Sauzet O, Carvajal A, Escudero A, Molokhia M, Cornelius VR.
the American Association of Poison Control Centers' National Illustration of the weibull shape parameter signal detection tool using
Poison Data System (NPDS): 36th annual report. Clin Toxicol (Phila). electronic healthcare record data. Drug Saf. 2013;36(10):995-1006.
2019;57(12):1220-1413. 22. Nakamura M, Umetsu R, Abe J, et al. Analysis of the time-to-onset
3. De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic of osteonecrosis of jaw with bisphosphonate treatment using the
and cardiovascular adverse effects associated with antipsychotic data from a spontaneous reporting system of adverse drug events.
drugs. Nat Rev Endocrinol. 2011;8(2):114-126. J Pharm Health Care Sci. 2015;1:34.
4. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsy- 23. Abe J, Umetsu R, Mataki K, et al. Analysis of Stevens-Johnson syn-
chotic drugs and the risk of sudden cardiac death. N Engl J Med. drome and toxic epidermal necrolysis using the Japanese adverse
2009;360(3):225-235. Drug event report database. J Pharm Health Care Sci. 2016;2:14.
5. Wu CS, Wu KY, Lo YR, et al. Psychotropic use and risk of stroke 24. Sharma A, Kumar A. Identification of novel signal of clobazam-
among patients with bipolar disorders: 10-year nationwide popula- associated drug reaction with eosinophilia and systemic symp-
tion based study. J Affect Disord. 2018;226:77-8 4. toms syndrome: a disproportionality analysis. Acta Neurol Scand.
6. Berge J, Abri P, Andell P, Movahed P, Ragazan DC. Associations be- 2022;146(5):623-627.
tween off-label low-dose olanzapine or quetiapine and cardiomet- 25. Weeke P, Jensen A, Folke F, et al. Antipsychotics and associ-
abolic mortality. J Psychiatr Res. 2022;149:352-358. ated risk of out- of-
hospital cardiac arrest. Clin Pharmacol Ther.
7. Wu CS, Tsai YT, Tsai HJ. Antipsychotic drugs and the risk of ventric- 2014;96(4):490-497.
ular arrhythmia and/or sudden cardiac death: a nation-wide case- 26. Nielsen J, Matz J, Mittoux A, et al. Cardiac effects of sertindole
crossover study. J Am Heart Assoc. 2015;4(2):e001568. and quetiapine: analysis of ECGs from a randomized double-blind
8. Li X, Peng Z, Zhou Y, et al. Quetiapine induces myocardial necro- study in patients with schizophrenia. Eur Neuropsychopharmacol.
ptotic cell death through bidirectional regulation of cannabinoid 2015;25(3):303-311.
receptors. Toxicol Lett. 2019;313:77-90. 27. Hagiwara H, Fukushima A, Iwano H, Anzai T. Refractory cardiac
9. Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psy- myocarditis associated with drug rash with eosinophilia and sys-
chotropic drugs and the risk of torsade de pointes. Dtsch Arztebl Int. temic symptoms syndrome due to anti-bipolar disorder drugs: a
2011;108(41):687-693. case report. Eur Heart J -Case Rep. 2018;2(4):yty100.
|
2716 SHU et al.
28. Huang WL, Liao SC, Kuo TB, et al. The effects of antidepres- psychosis during treatment with quetiapine-extended release ver-
sants and quetiapine on heart rate variability. Pharmacopsychiatry. sus aripiprazole: 12-week results from the tolerance and effect of
2016;49(5):191-198. antipsychotics in children and adolescents with psychosis (TEA)
29. He L, Yu Y, Wei Y, Huang J, Shen Y, Li H. Characteristics and trial. J Am Acad Child Adolesc Psychiatry. 2019;58(11):1062-1078.
Spectrum of cardiotoxicity induced by various antipsychotics: 39. Berling I, Isbister GK. Prolonged QT risk assessment in anti-
a real-world study from 2015 to 2020 based on FAERS. Front psychotic overdose using the QT nomogram. Ann Emerg Med.
Pharmacol. 2021;12:815151. 2015;66(2):154-164.
30. Aichhorn W, Whitworth AB, Weiss EM, Marksteiner J. Second- 40. Poluzzi E, Raschi E, Koci A, et al. Antipsychotics and torsadogenic
generation antipsychotics: is there evidence for sex differ- risk: signals emerging from the US FDA adverse event reporting
ences in pharmacokinetic and adverse effect profiles? Drug Saf. system database. Drug Saf. 2013;36(6):467-479.
2006;29(7):587-598. 41. Meyer-Massetti C, Vaerini S, Rätz Bravo AE, Meier CR, Guglielmo
31. Harrigan EP, Miceli JJ, Anziano R, et al. A randomized evaluation BJ. Comparative safety of antipsychotics in the WHO phar-
of the effects of six antipsychotic agents on QTc, in the absence macovigilance database: the haloperidol case. Int J Clin Pharm.
and presence of metabolic inhibition. J Clin Psychopharmacol. 2011;33(5):806-814.
2004;24(1):62-69. 42. Vieweg WV, Hasnain M, Howland RH, et al. Citalopram, QTc inter-
32. Roe CM, Odell KW, Henderson RR. Concomitant use of anti- val prolongation, and torsade de pointes. How should we apply the
psychotics and drugs that may prolong the QT interval. J Clin recent FDA ruling? Am J Med. 2012;125(9):859-868.
Psychopharmacol. 2003;23(2):197-200. 43. Moore PW, Donovan JW, Burkhart KK, Haggerty D. A case series
33. Seeman MV. The pharmacodynamics of antipsychotic drugs in of patients with lamotrigine toxicity at one center from 2003 to
women and men. Front Psych. 2021;12:650904. 2012. Clin Toxicol (Phila). 2013;51(7):545-549.
34. Evoy KE, Teng C, Encarnacion VG, et al. Comparison of quetiapine
abuse and misuse reports to the FDA adverse event reporting sys-
tem with other second-generation antipsychotics. Subst Abuse: Res S U P P O R T I N G I N FO R M AT I O N
Treat. 2019;13:1178221819844205. Additional supporting information can be found online in the
35. Yunusa I, Teng C, Karaye IM, Crounse E, Alsahali S, Maleki N. Supporting Information section at the end of this article.
Comparative safety signal assessment of hospitalization associated
with the use of atypical antipsychotics. Front Psych. 2022;13:917351.
36. Gareri P, De Fazio P, De Fazio S, Marigliano N, Ferreri Ibbadu G, De
Sarro G. Adverse effects of atypical antipsychotics in the elderly: a
review. Drugs Aging. 2006;23(12):937-956. How to cite this article: Shu Y, Ding Y, Liu L, Zhang Q. Cardiac
37. Cohen D, Bonnot O, Bodeau N, Consoli A, Laurent C. Adverse effects adverse events associated with quetiapine: Disproportionality
of second-generation antipsychotics in children and adolescents: a analysis of FDA adverse event reporting system. CNS Neurosci
Bayesian meta-analysis. J Clin Psychopharmacol. 2012;32(3):309-316.
Ther. 2023;29:2705-2716. doi:10.1111/cns.14215
38. Jensen KG, Correll CU, Rudå D, et al. Cardiometabolic adverse ef-
fects and its predictors in children and adolescents with first-episode

CNS Neuroscience Therapeutics - 2023 - Shu

Uploaded by

Copyright:

Available Formats

CNS Neuroscience Therapeutics - 2023 - Shu

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

CNS Neuroscience Therapeutics - 2023 - Shu

Uploaded by

Copyright:

Available Formats

Received: 27 December 2022 | Revised: 21 March 2023 | Accepted: 30 March 2023

Cardiac adverse events associated with quetiapine:

Yamin Shu1 | Yiling Ding2 | Lulu Liu3 | Qilin Zhang4

The first two authors contributed equally to this work.

CNS Neurosci Ther. 2023;29:2705–2716. ﻿ wileyonlinelibrary.com/journal/cns | 2705

F I G U R E 1 Multistep process of data

2.3 | Statistical analysis death, characterization as designated medical events (DMEs) or

3 | R E S U LT S (χ2 = 9.549, p = 0.002), and palpitations (χ2 = 10.671, p = 0.001)

3.3 | Serious vs. Nonserious cases 3.6 | Time-­to-­onset analysis and

TA B L E 1 Clinical characteristics of patients with quetiapine-­associated cardiac adverse events.

Characteristics Available number Value Available number Value

Gender, n (%) 929 (92.53%) -­ 5709 (92.53%) -­

Abbreviations: AEs: Adverse events; n: number of cases.

TA B L E 2 Differences in clinical characteristics of severe and non-­severe reports.

Serious cases (n = 867) Nonserious cases (n = 137) Statistics p value

F I G U R E 3 Subgroup analysis of quetiapine-­related cardiac disorders.

TA B L E 3 Clinical priority assessing results of disproportionality signals.

Relevant evidence Priority level

Dizziness 205 1.39 8 NA ++ Weak (4)

TA B L E 4 Results of time-­to-­onset analysis for signals with moderate/weak prioritization.

TTO (days) Weibull distribution

Cases -­ Scale parameter Shape parameter

Moderate 93 0 (0–­8) 0–­517 0.13 0.03–­0.58 0.15 0.13–­0.17 Early failure

You might also like

CNS Neurosci Ther. 2023;29:2705–2716. wileyonlinelibrary.com/journal/cns | 2705

3.3 | Serious vs. Nonserious cases 3.6 | Time-to-onset analysis and

TA B L E 1 Clinical characteristics of patients with quetiapine-associated cardiac adverse events.

Gender, n (%) 929 (92.53%) - 5709 (92.53%) -

TA B L E 2 Differences in clinical characteristics of severe and non-severe reports.

F I G U R E 3 Subgroup analysis of quetiapine-related cardiac disorders.

TA B L E 4 Results of time-to-onset analysis for signals with moderate/weak prioritization.

Cases - Scale parameter Shape parameter

Moderate 93 0 (0–8) 0–517 0.13 0.03–0.58 0.15 0.13–0.17 Early failure