Sage Journals: Discover world-class research

Abstract

Background:

Many antipsychotic medications are responsible for prolonging QTc, a risk factor for sudden death, which is one of the main causes of reduced life expectancy in patients with mental health disorders.

Objectives:

To evaluate the cardiac safety profile of clotiapine in a naturalistic setting.

Design:

This observational, retrospective study included 70 subjects hospitalized at the Service of Psychiatry Diagnosis and Care in Modena from February 1, 2023 to July 31, 2024, treated with clotiapine.

Methods:

Demographic and clinical data were collected, along with electrocardiographic measurements (QTc) taken at the start of treatment (T0), after at least 7 days of therapy (T1), and at further follow-up (T2) after 7–21 days. Prolongation was considered when QTc exceeded 500 ms or an increase of 60 ms compared to baseline, according to international standards.

Results:

QTc prolongation was limited (m = 4.59 ms), representing an increase of 1.07%, without reaching thresholds of significant clinical risk. Subjects with an increase equal to or greater than the median (M = 3.5) of QTc increase at T1 accounted for half of the sample, and only one patient had an increase greater than 60 ms.

Conclusion:

Clotiapine treatment, also in combination with haloperidol, had minimal prolongation of QTc within the limits of clinical safety. A stabilization of QTc over time was observed, indicating a possible adaptation to treatment. Methodological limitations of this study call for further research.

Plain language summary

Monitoring clotiapine safety in subjects hospitalized over one year in an acute psychiatric ward

Many antipsychotic drugs are responsible for sudden death, which is a major cause of reduced life expectancy in patients with mental health disorders. In a naturalistic setting of an acute psychiatric ward, we evaluate the cardiac safety profile of clotiapine, an antipsychotic drug often used for the management of agitated behavior. We analyzed an ECG parameter (QTc) that may be responsible for arrhythmia and sudden death. We found that this drug, even in combination with haloperidol, had minimal QTc prolongation within the limits of clinical safety.

Keywords

observational setting QTC monitoring risk of prolonged QTc typical antipsychotic drugs

Introduction

In individuals with schizophrenia, cardiovascular diseases are responsible for nearly 50% of deaths and a reduction in life expectancy, and the incidence of sudden cardiac death (SCD) is about four times higher than in the general population. While most SCDs are due to ischemic heart disease, which is recognized as a specific risk factor, about 10% of SCDs are unexplained and are thought to be caused by cardiac arrhythmias.¹

A Japanese study evaluated parasympathetic activity in 53 Japanese patients with schizophrenia suggesting that parasympathetic dysfunction leads to a sympathetic predominance which could influence the severity of schizophrenia² and represent a risk factor for SCD.³ Whole-genome studies in schizophrenic subjects suggested evidence of an association for the non-synonymous single nucleotide polymorphism within the neuregulin 1 (NRG1) gene, which could also contribute to the risk of SCD.^4,5 Blom et al. suggested that a Brugada pattern was more frequent in patients with schizophrenia (11.6%) compared to controls.⁶ The incidence of the Brugada pattern in individuals with schizophrenia is approximately 4%.⁷ The extent to which this higher incidence of the Brugada pattern contributes to increased mortality is uncertain, but a 2014 study suggested it could play a role.⁸ In addition, polymorphisms or subclinical mutations of the Na⁺ channel can cause drug-induced long QT syndrome (LQTS) and potentially lead to Torsades de Pointes.^9,10A retrospective cohort study in the United States evaluated the possible correlation between antipsychotic drugs and the incidence of SCD in patients with mental disorders, suggesting that typical and atypical antipsychotics had an adjusted incidence ratio for SCD of 2.00 and 2.27 (1.89–2.73), respectively. Moreover, the risk increased with higher doses. For typical antipsychotics, the risk was 1.31 at low doses and 2.42 at high doses. Among atypical drug users, the ratio increased from 1.59 to 2.86, without any significant difference.¹¹ Other authors estimated the risk of SCD at 2.9 events per 1000 patient-years and 3.3 events per 1000 patient-years for high-dose treatment.¹²

QT interval prolongation: risk factor for Torsade de Pointes and SCD

The association between drug use and QT interval prolongation, leading to potentially fatal cardiac arrhythmias, was first recognized in 1964, when cases of quinidine-induced syncope due to polymorphic ventricular tachycardia were reported.¹³ The QT interval represents the time between the onset and the end of ventricular repolarization, which is measured in milliseconds (ms) on the electrocardiogram (ECG).^14,15 In 1966, Francois Dessertenne identified Torsade de Pointes (TdP) as a specific form of polymorphic ventricular tachycardia that is invariably preceded by QT interval prolongation and is potentially life-threatening.

The European Society of Cardiology defines a threshold for diagnosing LQTS in symptomatic patients as >500 ms.¹⁶ Above this level, the risk of significant arrhythmia and TdP is high and is considered a threshold for re-evaluating potential pharmacotherapies. Some drugs have been withdrawn due to the unacceptably high risk of ventricular arrhythmias and SCD.^15,17–19 Since 2005, all new drugs with systemic effects have undergone rigorous testing to assess pro-arrhythmic risk before receiving regulatory approval. Although drug-induced QT prolongation has been considered a de facto surrogate biomarker for drug’s pro-arrhythmic risk, the risk of SCD and TdP due to drug-induced QT prolongation is also determined by several other factors, such as age, concomitant medications, and associated clinical conditions, such as bradycardia, hypokalemia, hypomagnesemia, ventricular hypertrophy, renal insufficiency, central nervous system disorders, and cardiac disease, as well as the baseline QT/QTc interval.^20,21 Drug-induced QT prolongation occurs when cardiac repolarization is prolonged by alterations in the function of ion channels responsible for potassium ion efflux in phases II and III of the action potential, involving the IKr and IKs currents.^22,23–28

Drug-induced ion channel blockade is necessary but not the only condition for TdP.²⁹ The variable risk of TdP and drug-induced QT prolongation in different individuals has been explained by the concept of “repolarization reserve,” which implies that a decrease in the function of any ion channel involved in the repolarization phase of the action potential can remain subclinical if other pathways are intact.³⁰ Other risk factors for TdP with QT-prolonging drugs include the following: female sex, advanced age, recent conversion from atrial fibrillation with QT-prolonging drugs, concurrent use of multiple drugs that can prolong the QT interval, electrolyte disturbances (hypokalemia, hypomagnesemia, and hypocalcemia), diuretic use, hepatic or renal dysfunction, bradycardia, and occult congenital LQTS or silent mutations in the LQTS genes.³¹

Antipsychotic drugs and QT prolongation

One of the main mechanisms by which antipsychotics increase the risk of SCD is QT prolongation. A recent meta-analysis, which assessed 15 studies covering 15,540 patients with schizophrenia taking antipsychotics, showed that the prevalence of QTc prolongation in this population was about 4.0%.³² The CATIE study demonstrated that 3% of patients with schizophrenia treated with atypical antipsychotics had QT prolongation.³³ Crediblemeds.org published a table detailing the effects of antipsychotic medications in patients, categorizing them into known risk (droperidol, haloperidol, sulpiride, thioridazine, methadone), conditional risk (risperidone, olanzapine, amisulpride, quetiapine, ziprasidone), and possible risk (clozapine, sertindole, zotepine).³⁴ Xiong et al. in 2020 collected data from three studies^35–37 on the effects of antipsychotics on the QTc interval, reporting antipsychotics’ classification based on QTc prolongation from the highest (thioridazine) to the lowest (perphenazine) risk.³⁸ A large, real-world study suggests that first-generation antipsychotics have been associated with a greater risk of QT prolongation than second-generation antipsychotics and that antipsychotics with higher hERG affinity are more likely to be associated with QT prolongation.³⁹Among patients with long QT, 85.5% had two or more comorbidities such as hypokalemia, human immunodeficiency virus or hepatitis C infection, abnormal T-wave morphology, and methadone treatment. The prevalence of drug-induced long QT interval (500 ms) in patients with schizophrenia treated with antipsychotics has been reported to range from 0.9% to 2.6%.^40,41 For this reason, from 2007 up to now, haloperidol intravenous injection has been contraindicated by most guidelines.⁴²

Clotiapine

Clotiapine is a dibenzoepine that interacts with multiple receptors, including the serotonergic and dopaminergic receptors of neurotransmitter systems. Its properties are generally similar to those of the phenothiazine class of neuroleptics (e.g., chlorpromazine), but it also exhibits some properties similar to clozapine (this dibenzoepine presents a similar chemical structure to clotiapine).⁴³ A review of clotiapine’s use⁴⁴ documented the possibility of apparent efficacy in patients unresponsive to other typical antipsychotics. Clotiapine clearly induces extrapyramidal syndromes (EPS) like other typical drugs and in this respect differs from clozapine.⁴⁵ Clotiapine acts on multiple receptors like clozapine and olanzapine. The ratio of D2 to 5HT2 blockade by clotiapine is similar to that of clozapine.^45–47 By antagonizing dopamine D2 receptors, clotiapine treats the positive psychotic symptoms of schizophrenia. However, D2 antagonism in the basal ganglia can potentially cause dose-related EPS, and cardiac D2 blockade may increase the risk of cardiac arrhythmia. Clotiapine’s affinity for 5HT2 receptors treats the negative psychotic symptoms of schizophrenia and can reduce EPS, while selective GABA blockade provides sedative and anxiolytic effects.^45,48–51 Clotiapine has been reported to exacerbate obsessive-compulsive disorder, similar to clozapine.^52–54 This drug is indicated for acute and chronic psychoses, paranoid psychosis, psycho-reactive or neurotic syndromes, and anxiety states. The main side effects are represented by anticholinergic effects, CNS-related dopaminergic effects, orthostatic hypotension, and sialorrhea.^43,55–57 Regarding the cardiac effects and in particular on the QTc, studies report conflicting data.^41,58,59 Despite its widespread use in clinical practice, especially for the pharmacotherapeutic management of agitation,⁶⁰ there is insufficient literature on the potential effects of clotiapine on the QTc of treated patients. Given its widespread use in clinical practice and the lack of specific data in the literature, we explored the potential cardiac impact of clotiapine in a naturalistic setting.

The primary objective of this study was to evaluate the potential cardiac effects of clotiapine based on electrocardiographic changes. The secondary objectives were to deepen knowledge on correlations between selected parameters and QTc prolongation in patients treated with clotiapine.

Methods

Study design and setting

This study design was observational, longitudinal, retrospective, cohort, and single center. The setting was an acute psychiatric ward: Service for Psychiatric Diagnosis and Care (SPDC) in the General Hospital in Baggiovara (Modena).

Eligibility criteria

Inclusion criteria: the cohort consists of subjects over 18 years old admitted to the SPDC in Modena from February 2023 to July 2024. They were prescribed and administered clotiapine and had at least two ECGs performed, the first at admission to the ward or on the same day of clotiapine administration (T0), and the second one after at least 7 days of clotiapine administration (T1). Exclusion criteria: all subjects who were not prescribed clotiapine or were not given any ECG at T0 and T1.

Selected variables

From the medical records of patients included in the study, the following variables were selected:

Length of hospitalization

Discharge diagnoses according to ICD-9-CM

Weight and BMI

Blood pressure, heart rate, and oxygen saturation were recorded during the hospitalization period

Comorbid cardiac conditions

Period of clotiapine treatment

Clotiapine therapy formulation (oral vs intramuscular)

Therapies associated with clotiapine

Combination with other non-psychiatric medications

Any electrolyte abnormalities

Toxicology test for substance use screening.

Study procedure

Data relating to clinical and electrocardiographic parameters were collected between February 2023 and July 2024. The data were anonymized before being entered into a database.

We selected all cases of patients hospitalized in our ward during the 6-month study period who were treated with clotiapine and had undergone an ECG and heart rate registration. The QT interval was measured, and QTc interval correction was performed using Bazett’s and Fridericia’s formula.

We considered: T0, the first day of clotiapine intake, when the first ECG was performed;

T1, the second ECG recorded after 7 days of clotiapine use in the same patient;

T2, the third ECG recorded after 7–21 days of clotiapine use from T1 in the same patient.

At T1 and T2, we recorded the mean dose of clotiapine expressed in mg/day, the number of concomitant psychotropic drugs, the haloperidol combination as concomitant therapy, and the presence or absence of other concomitant psychotropic drugs.

We considered a prolonged QTc interval if it was greater than 500 ms in absolute terms or increased by 60 ms if compared to the previous ECG, in accordance with the European Society of Cardiology.⁶¹

Statistical analysis

Continuous variables were analyzed as mean and standard deviation, and categorical variables as frequencies. Continuous variables were compared using the t test, and categorical variables were compared using the Pearson chi-square test. Statistical significance was set at p < 0.05. Statistical analysis was performed using the STATA program (StatSoft Inc., Tulsa, OK, USA).

Ethical considerations

The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki (version of the 64th WMA General Assembly, Fortaleza, Brazil, October 2013; World Medical Association, 2013). It was approved with code 0026032/24 on September 11, 2024 by the Ethics Committee of the Emilia Nord Vast Area (335/2024/OSS/AUSLMO SIRER ID 7668—ClotQTc). The study was subsequently authorized by the Modena AUSL (Decision No. 2847 of 13 November 2024).

We applied the STROBE checklist⁶² to control the appropriateness of reporting in the manuscript (Table S1).

Results

Demographic and clinical characteristics of the sample

We collected an initial sample of 70 patients, 51 males and 19 females, at T0, who were evaluated at T1 (n = 70) after 1 week. Following, at T2, only 15 patients, 12 males and 3 females, from the initial sample used clotiapine and/or received one ECG. Females were slightly older than males, with a mean age of 43.53 ± 3.01 years compared to 36.63 ± 12.80 years for males, a marginally significant difference (p = 0.05); regarding ethnicity, the sample was predominantly Caucasian, with no statistically significant difference between the two sexes (p = 0.323). Examining other physical parameters, BMI (kg/m²) did not show a statistically significant difference between males (19.52 ± 11.94 m ± SD) and females (23.63 ± 1.48 m ± SD; p = 0.41), blood pressure values were essentially homogeneous between the two sexes, and oxygen saturation (%O2) was consistent across groups. The mean heart rate recorded was slightly higher in females (86.72 ± 7.87 m ± SD) than in males (83.49 ± 5.34 m ± SD). Significant electrolyte abnormalities included hyponatremia (two cases, all females) and hypokalemia (five cases, four of which were females), with a significant difference between males and females (p = 0.001).

As shown in Table 1, regarding the psychiatric diagnoses at discharge of our sample, schizophrenia spectrum disorders accounted for the majority of cases, affecting 75.71% of patients (53 out of 70). Bipolar disorders were diagnosed in 12.86% of cases (9 of 70), followed by personality disorders in 5.71% (4 of 70). At toxicology tests, cannabinoid use was significantly more frequent in males (91.7%, 11 out of 12), confirming a gender-differentiated pattern of substance use, with a male predominance (Table 1).

Table 1.

Psychiatric diagnoses and substance use in our sample.

Variables	Male (n = 51)	Female (n = 19)	Total (n = 70)	Statistical testProbability
Psychiatric diagnosis at discharge (ICD-9-CM), n (%)
Schizophrenia spectrum disorders	39 (76.5%)	14 (23.5%)	53 (75.71%)	Pearson χ² = 4.98 p = 0.289
Organic psychosis	0 (0%)	1 (100%)	1 (1.43%)
Bipolar disorders	7 (77.8%)	2 (22.2%)	9 (12.86%)
Personality disorders	2 (50%)	2 (50%)	4 (5.71%)
Depressive disorders	3 (100%)	0 (0%)	3 (4.29%)
Substance use, n (%)
Not present	25 (67.6%)	12 (32.4%)	37 (69.81%)	Pearson χ² = 14.90p = 0.037
Cannabinoids	11 (91.7%)	1 (8.3%)	12 (22.64%)
Opiates	1 (100%)	0 (0%)	1 (1.89%)
Cocaine + cannabinoids	1 (100%)	0 (0%)	1 (1.89%)
Methadone + cannabinoids	2 (100%)	0 (0%)	2 (3.77%)

Pharmacological therapy with clotiapine and other drugs

Regarding pharmacological treatments, only 16.67% of patients had already treated with clotiapine for at least seven previous days before the study period. Oral administration was the most common, involving 98.57% of the sample (69 out of 70). The number of associated pharmacological therapies was slightly higher in females (2.78 ± 1.06 m ± SD) than in males (2.24 ± 1.01 m ± SD), with a trend toward significance (p = 0.06).

The prescription of haloperidol in combination was prevalent (76.81%; 53 out of 70), with no significant differences between males (74.51%) and females (83.33%; p = 0.446). Furthermore, 82.61% of the sample (57 of 70) received other psychotropic medications (including benzodiazepines), with a similar distribution between genders (p = 0.414).

Regarding the presence of concomitant non-psychiatric medications, 57.3% of patients (35 of 70) did not receive any concomitant medications. The remaining sample received treatments that included antibiotics (6.56%), anti-hypertensives (13.11%), anticoagulants or antiplatelet drugs (1.64%), and proton pump inhibitors (6.56%). Polypharmacy, defined as the use of more than one of these classes of non-psychiatric medications, was observed in 14.75% of patients (9 of 70), with a slight prevalence in males compared to females (55.6% vs 44.4%; p = 0.68).

Clotiapine and other drug therapy and ECG/heart rate monitoring in males and females at T1 and T2

At T1, the mean clotiapine dose (mg/day) administered was 147.36 ± 85.85 m ± SD for the whole sample, with no significant differences between males and females (Table 2). However, differences were underscored in the number of concomitant therapies: 63.16% of females received three or more therapies, compared to 27.45% of males (p = 0.023; Table 2).

Table 2.

Treatment with clotiapine at T1 and T2 in males and females.

Variables	Male	Female	Total	Statistical testProbability
T1	n = 51	n = 19	n = 70	Statistical testProbability
Clotiapine dose, mg
m ± SD	149.62 ± 86.97	141.28 ± 84.78	147.36 ± 85.85	t = 0.359; p = 0.720
Number of associated drugs, n (%)
1	12 (23.53%)	2 (10.53%)	14 (20%)	Pearson χ² = 7.59; p = 0.023
2	25 (49.02%)	5 (26.32%)	30 (42.86%)
3 or more	14 (27.45%)	12 (63.16%)	26 (37.14%)
Haloperidol in combination, n (%)
Not present	14 (27.45%)	4 (21.05%)	18 (25.71%)	Pearson χ² = 0.30; p = 0.59
Present	37 (72.55%)	15 (78.95%)	52 (74.29%)
Other associated psychotropic drugs, n (%)
Not present	9 (17.65%)	2 (10.53%)	11 (15.71%)	Pearson χ² = 0.53; p = 0.47
Present	42 (82.35%)	17 (89.47%)	59 (84.29%)
QTc
m ± SD
Bazett’s formula	428.96 ± 23.39	439.32 ± 18.34	431.77 ± 22.49	t = −1.74; p = 0.087
Fridericia’s formula	412 ± 17.49	415.51 ± 19.83	412.93 ± 18.05	t = −0.70; p = 0.4837
Heart rate
m ± SD	77.73 ± 16.77	82.25 ± 9.39	78.68 ± 15.51	t = −0.73; p = 0.47
Variables	Male	Female	Total	Statistical testProbability
T2	(n = 12)	(n = 3)	(n = 15)	Statistical testProbability
Clotiapine dose, mg
m ± SD	150.5546	284.1267	175.5994	t = −2.101; p = 0.054
Number of associated drugs, n (%)
1	2 (15.38%)	0 (0%)	2 (12.5%)	Pearson χ² = 4.75; p = 0.09
2	7 (53.85%)	0 (0%)	7 (43.75%)
3 or more	4 (30.77%)	3 (100%)	7 (43.75%)
Haloperidol in combination, n (%)
Not present	0 (0%)	1 (33.33%)	1 (6.25%)	Pearson χ² = 4.62; p = 0.03
Present	13 (100%)	2 (66.67%)	15 (93.75%)
Other associated psychotropic drugs, n (%)
Not present	2 (15.38%)	0 (0%)	2 (12.5%)	Pearson χ² = 0.53; p = 0.47
Present	11 (84.62%)	3 (100%)	14 (87.5%)	Pearson χ² = 0.53; p = 0.47
QTc, m ± SD
Bazett’s formula	434.08 ± 20.32	442.58 ± 17.65	436.39 ± 19.87	t = −1.61; p = 0.11
Fridericia’s formula	403.66 ± 24.41 (n = 11)	428.69 (n = 1)	405.75
Heart rate
m ± SD	83.13 ± 13.90	93.25 ± 8.10	85.26 ± 13.46	t = −1.96; p = 0.06

Haloperidol use was prevalent, with 74.29% of patients receiving this drug, with no significant differences between genders (p = 0.59). 84.29% of patients received concomitant psychotropic drugs, including benzodiazepines, with a similar distribution between males (82.35%) and females (89.47%; p = 0.47). Regarding electrocardiographic parameters, the mean QTc expressed in ms at T1 was 431.77 ± 22.49 (m ± SD), with values slightly higher in females (439.32 ± 18.34 m ± SD) than in males (428.96 ± 23.39 m ± SD; p = 0.087). The mean heart rate (bpm) was 78.68 ± 15.51 (m ± SD) for the entire sample, with a slight trend toward higher values in females (82.25 ± 9.39 m ± SD) compared to males (77.73 ± 16.77 m ± SD; p = 0.47). At T2, the mean clotiapine dose (mg/day) increased to 175.60 ± 94.99 (m ± SD), with a non-significant difference between males and females (p = 0.054). Electrocardiographic parameters also showed a mean QTc at T2 of 436.39 ± 19.87 (m ± SD), a slight increase compared to T1, but without reaching statistical significance (p = 0.11). The mean heart rate (bpm) at T2 was 85.26 ± 13.46 (m ± SD), a marginally significant difference from T1 (p = 0.06). Females continued to receive a greater number of combination therapies (100% with three or more drugs) than males (30.77%; p = 0.09). Haloperidol use was also significantly higher in males (100%) than females (66.67%; p = 0.03; Table 2). Regarding the difference in the QTc interval (ms) between time points T1 and T2 (which has a minimum duration of 7 days and a maximum of 21 days), a slight mean increase was observed in both males (5.12 ± 23.72 m ± SD) and females (3.26 ± 22.40 m ± SD), with an overall value of 4.61 ± 23.23 (m ± SD), without any statistically significant difference (t = 0.29; p = 0.77; t test). The change in heart rate (bpm) between T1 and T2 showed a mean increase in males of 5.40 ± 17.98 (m ± SD) and in females of 11.00 ± 9.13 (m ± SD), with an overall value of 6.58 ± 16.57 (m ± SD), with greater increase in females than in males, without any statistically significant difference (t = −0.85; p = 0.40; t test).

Comparison between the follow-ups

In Table 3, the mean QTc values (m ± SD) between T0, T1, and T2 are shown. In the comparison between T0 and T1, the mean QTc (ms), evaluated through Bazett’s formula, increased from 431.79 ± 22.49 (m ± SD) to 436.37 ± 19.78 (m ± SD), showing a mean increase of 4.59 ± 22.90 (m ± SD), equal to a change of 1.1%. Despite this slight increase, it was not statistically significant (p = 0.0984). Comparing T1 and T2 in 15 individuals, the mean QTc (ms) decreased slightly, from 432.13 ± 21.59 (m ± SD) to 430.94 ± 24.49 (m ± SD), with a mean difference of −1.19 ± 26.45 ms, equivalent to a negative change of 0.3%. Again, the reduction was not significant (p = 0.8599).

Table 3.

Comparison of QTc, heart rate, clotiapine dose, and other associated drugs between T0, T1, and T2..

Variables	T0 (n = 70)	T1 (n = 70)	T2 (n = 15)	Statistical testProbability
QTc, m ± SD
ms (Bazett’s formula)	431.77 ± 22.49	436.39 ± 19.87		T0 vs T1t = −1.66, p = 0.1010, t test
T0–T1, Δm ± SD (%)		4.61 ± 23.22 (1.07%)
			431.00 ± 25.34	T1 vs T2t = 0.61, p = 0.5544, t test
T1–T2, Δm ± SD (%)		−5.39 ± 23.02 (−1.24%)
ms (Fridericia’s formula)	412.93 ± 18.05	412.49 ± 17.67		T0 vs T1t = 0.19, p = 0.0984, t test
T0–T1, Δm ± SD (%)		−0.44 ms ± −0.38 (−0.1%)
			405.75 ± 24.37	T1 vs T2t = 0.42, p = 0.6788, t test
T1–T2, Δm ± SD (%)		−2.05 ± 6.72 (−1%)
Heart rate, m ± SD
bpm	78.68 ± 15.51	85.26 ± 13.46	95.87 ± 9.34	T0 vs T1t = −2.4480, p = 0.0192, t testT1 vs T2t = −1.812, p = 0.1129, t test
Clotiapine dose, m ± SD
mg		147.36 ± 85.85	175.60 ± 09.98	T1 vs T2t = 1.10, p = 0.2878, t test
Number of associated drugs, n (%)
1		14 (20%)	1 (6.7%)	T1 vs T2Pearson χ² = 18.04, p = 0.001
2		30 (42.86%)	7 (46.7%)
3 or more		26 (37.14%)	7 (46.7%)
Haloperidol in combination, n (%)
Not present		18 (25.71%)	1 (6.7%)	T1 vs T2Pearson χ² = 63.71, p = 0.000
Present		52 (74.29%)	14 (93.3%)
Other associated psychotropic drugs, n (%)
Not present		11 (15.71%)	1 (13.3%)	T1 vs T2Pearson χ² = 62.16, p = 0.000
Present		59 (84.29%)	14 (93.3%)

In the comparison between T0 and T1, the mean QTc (ms), evaluated by means of Fridericia’s formula, changed from 412.93 ± 18.05 (m ± SD) to 412.49 ± 17.67 (m ± SD), showing a reduction of −0.44 ms ± −0.38 (m ± SD), equal to a change of −0.1%, without any statistically significant difference (t = 0.19; p = 0.8511; t test). Comparing T1 and T2, in 15 individuals, the mean QTc (ms) decreased slightly, from 407.80 ± 17.64 (m ± SD) to 405.75 ± 24.37 (m ± SD), with a mean difference of −2.05 ± 6.72 ms, equivalent to a negative change of −1%. Again, the reduction was not significant (t = 0.42; p = 0.6788; t test).

The percentile distribution of QTc interval changes (Figure 1) between time T0 and time T1 shows that, at the 50th percentile (median), the QTc (Bazett’s formula) increase was 3.5 ms. Subjects with an increase equal to or greater than the median (M = 3.5) of QTc increase at T1 accounted for half of the sample, but only 0.7% (only one patient) had an increase greater than 60 ms.

Figure 1.

Differences of QTc between T0 and T1 in all participants (n = 70).

We did not observed any statistically significant difference of the clotiapine dose between the two follow-ups, but we reported the following statistically significant differences between T1 and T2: the number of associated drugs (Pearson χ² = 18.04; p = 0.001); haloperidol in combination (Pearson χ² = 63.71; p = 0.000); other associated psychotropic drugs (Pearson χ² = 62.16; p = 0.000; Table 3).

Discussion

This naturalistic study investigated the effects of clotiapine on electrocardiographic parameters in a sample of individuals admitted to the Psychiatric Service for Diagnosis and Care in Modena. The primary objective of the study was to evaluate the potential cardiac effect of clotiapine on QTc prolongation, which was evaluated through a retrospective longitudinal analysis. Furthermore, the demographic and clinical characteristics of the sample were assessed, as well as any correlations between QTc prolongation and selected cardiovascular and pharmacological parameters in patients treated with clotiapine.

The analysis of demographic and clinical characteristics highlighted some significant differences between the two sexes. Females had a higher mean age than males, which may reflect the more frequent late-onset schizophrenia spectrum disorders in females⁶³ or, as suggested by the literature, different rates of health care utilization by males and females.⁶ Another difference between the two sexes is heart rate, which is slightly higher in females than in males, which may reflect greater autonomic sensitivity, as reported by some authors,² who highlight reduced parasympathetic activity in women with psychiatric conditions. Females in our sample also had a higher frequency of cardiac comorbidities, although this difference was not statistically significant. This trend may be relevant, considering that female gender is a known independent risk factor for QTc prolongation.^31,64

Schizophrenia spectrum disorders constitute the majority of diagnoses at discharge in our sample. This finding is consistent with the literature showing that patients with schizophrenia are often treated with antipsychotic medications, including clotiapine,⁴³ often at high doses and in combination, indirectly suggesting the complexity and severity of these patients’ conditions. Our data show significantly higher substance use in males than in females, as confirmed in the literature.⁶⁵ The high rate of substance use, particularly in males, highlights the importance of considering addictions as an additional risk factor for QTc prolongation in antipsychotic treatments.⁶⁶

The different sample sizes of the two follow-up periods, with few individuals of the original sample at T2 in comparison to T1, could be interpreted as the use of clotiapine in urgent and acute clinical situations as a sedative drug for agitation, as suggested by the literature.⁶⁰ This observation may be further supported by the data that only 16.67% of subjects were receiving clotiapine therapy during the 7 days before the study, indicating its use primarily as an emergency medication in an acute hospital setting although its predominantly oral administration could reflect a clinical practice of favoring patient adherence. The greater number of combination therapies suggests a more intensive therapeutic approach, which may reflect greater clinical severity and complexity. The widespread use of haloperidol as a combination therapy highlights a pharmacological strategy aimed at the immediate control of acute symptoms. Co-administration of clotiapine and haloperidol did not appear to result in a significant increase in cardiac risk (observed through an increase in QTc), confirming the safety profile of clotiapine even in combination.

Monitoring of electrocardiographic parameters during clotiapine therapy shows limited changes in QTc and heart rate. At T0, the mean QTc remains within the physiological limits of this parameter, and the subsequent increase at T1 as well as at T2 was limited, supporting the safety profile of clotiapine compared to other antipsychotics known to prolong the QTc, as highlighted by other authors.³⁸

The differences between the two sexes, with QTc values generally higher in females, are consistent with what has been historically described in the literature.^64,67 However, in our sample, we did not detect any significant changes in QTc variation between the two sexes, confirming the absence of a significant impact of clotiapine on QTc.

It is interesting to note that the percentage change in QTc at the different measurement times is positive between T0 and T1 and tends to become negative between T1 and T2 and, even more so, between T2 and T3. This clinical finding, although limited by the different sample sizes at the three follow-ups, could highlight a tolerance phenomenon to the QTc-prolonging in continuous use of this drug. On the contrary, heart rate showed a tendency to increase during treatment, reflecting an activation of autonomic response, as usual in acute psychiatric conditions.⁶⁸

The percentage distribution of QTc differences between T0 and T1 shows that the majority of patients exhibited modest or no increase, further confirming the absence of a clinically relevant risk. In fact, we observed only one patient at T1 with an increase greater than 60 ms compared to T0, which, however, did not reach the critical QTc prolongation ⩾500 ms. The maximum increase of 100 ms observed in this single patient (representing 0.7% of all patients between T0 and T1) is below the prevalence rate of QTc prolongation induced by psychotropic drugs, which in the literature ranges between 0.9% and 3%.^41,69

In light of our study, we emphasize that ECG measurements must be monitored to ensure accurate assessment of drug-induced QT prolongation. Early identification of QTc alterations and associated risk factors during treatment may help reduce cardiac morbidity and mortality in patients treated with antipsychotic drugs. Furthermore, accurate ECG measurements could help provide a more detailed understanding of the risk of SCD associated with each antipsychotic drug and, simultaneously, implement personalized pharmacological treatment.⁷⁰ Although individual genetic factors and age are considered the main determinants of the QT interval, as highlighted by many authors,^71,72 careful clinical analysis of drug treatment as an additional but avoidable risk factor for QT prolongation may reduce cardiac arrhythmias due to antipsychotic treatment. A relatively safe drug for QTc interval prolongation, even in combination with other antipsychotics, such as clotiapine, could represent an important and effective therapeutic tool to be used especially in emergency situations where cardiac monitoring is not available and characterized by psychiatric agitation for rapid patient tranquilization.

Limitations

Our study has some limitations:

The sample size is limited; it is composed of 70 patients at T1 and subsequently reduced to only 15 patients at T2 due to many participants dropping out as the timing of the ECG did not always match our study’s inclusion criteria. This could lead to attrition bias, potentially overestimating or underestimating the results.

This study is single center, and the sample is predominantly Caucasian, consistent with the ethnic distribution of the local population. These characteristics may limit the generalization of the study results.

All patients were using concomitant medications; ideally, patients would have been taking only clotiapine, but our sample was observational and naturalistic.

Some limitations include the monocentric and retrospective nature of the study, combined with the limited sample size, which restricts the generalizability of the data obtained. Furthermore, the lack of a control group with untreated patients or the presence of concomitant pharmacotherapies in all patients partially limits the possibility of specifically attributing the observed effects to clotiapine.

The advantages of this study include both the contribution of scientific knowledge and the safe use in clinical practice of clotiapine treatment alone or also in combination with other drugs that can potentially lead to QT interval alterations. It also represents a report from a real-world clinical setting, which can be developed in further study with lager sample and non-naturalistic design.

Conclusion

Our results suggest that QTc prolongation, which was reported in a very small number of patients, remained within acceptable limits and did not significantly reach high clinical risk thresholds. This finding is particularly significant given the frequent use of clotiapine, often in combination with other psychotropic drugs, such as haloperidol, which can amplify the risk of QTc prolongation. Another important point emerging from this study concerns the stabilization of electrocardiographic parameters over time, suggesting a possible adaptation or tolerance effect to the QTc effects of clotiapine. The results obtained in this study are preliminary and represent an initial confirmation of an empirical finding. Further prospective research, conducted on larger samples, in multicenter settings, will be necessary to confirm and further explore this topic. In conclusion, the study contributes to a better understanding of the use of clotiapine in clinical practice, highlighting its safety profile. Finding a safe and universally accepted protocol for prescribing antipsychotics remains a persistent challenge in medicine. Predictive models that integrate clinical history with demographic and ECG characteristics can help estimate an individual’s susceptibility to therapy-associated risks, including QTc prolongation.

Supplemental Material

sj-docx-1-taw-10.1177_20420986261430214 – Supplemental material for Monitoring of QTc in subjects hospitalized for 1 year in an acute psychiatric ward treated with clotiapine and other associated antipsychotics: a retrospective study

Supplemental material, sj-docx-1-taw-10.1177_20420986261430214 for Monitoring of QTc in subjects hospitalized for 1 year in an acute psychiatric ward treated with clotiapine and other associated antipsychotics: a retrospective study by Rosaria Di Lorenzo, Andrea Santoro, Jessica Bonisoli, Carolina Bottone, Paola Ferri and Sergio Rovesti in Therapeutic Advances in Drug Safety

Footnotes

Acknowledgements

We thank Dr. R. Fontanesi for his cardiology supervision and O. Raggioli for her linguistic revision.

Declarations

ORCID iD

Rosaria Di Lorenzo

Supplemental material

Supplemental material for this article is available online.

References

Vohra

. Sudden cardiac death in schizophrenia: a review. Heart Lung Circ 2020; 29: 1427–1432.

Hattori

Suda

Kishida

, et al. Association between dysfunction of autonomic nervous system activity and mortality in schizophrenia. Compr Psychiatry 2018; 86: 119–122.

Montaquila

Trachik

Bedwell

. Heart rate variability and vagal tone in schizophrenia: a review. J Psychiatr Res 2015; 69: 57–66.

Huertas-Vazquez

Teodorescu

Reinier

, et al. A common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac death. Heart Rhythm 2013; 10: 994–998.

Napolitano

. Heart, brain, and the risk of sudden death. Heart Rhythm 2013; 10: 999–1000.

Blom

Cohen

Seldenrijk

, et al. Brugada syndrome ECG is highly prevalent in schizophrenia. Circ Arrhythm Electrophysiol 2014; 7: 384–391.

Postema

. About Brugada syndrome and its prevalence. Europace 2012; 14: 925–928.

Roden

. The Brugada ECG and schizophrenia. Circ Arrhythm Electrophysiol 2014; 7: 365–367.

Makita

Horie

Nakamura

, et al. Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation. Circulation 2002; 106: 1269–1274.

10.

Pacher

Kecskemeti

. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr Pharm Des 2004; 10: 2463–2475.

11.

Ray

Chung

Murray

, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360: 225–235.

12.

Sebastian

Jerry

. Antipsychotic agents and sudden cardiac death—how should we manage the risk? N Engl J Med 2009; 360: 294–296.

13.

Roden

. Predicting drug-induced QT prolongation and torsades de pointes. J Physiol 2016; 594: 2459–2468.

14.

Khatib

Sabir

FRN

Omari

, et al. Managing drug-induced QT prolongation in clinical practice. Postgrad Med J 2021; 97: 452–458.

15.

Parsons

. Mechanisms and management of drug-induced QT prolongation. Prescriber 2022; 33: 19–23.

16.

Priori

Wilde

Horie

, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart rhythm 2013; 10(12): 1932–1963.

17.

Drew

Ackerman

Funk

, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55: 934–947.

18.

Ramos

. Drug-induced QT prolongation and torsades de pointes. P T 2017; 42: 473–477.

19.

Yap

Camm

. Drug induced QT prolongation and torsades de pointes. Heart 2003; 89: 1363–1372.

20.

Antzelevitch

. Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes. Europace 2007; 9(Suppl. 4): iv4–iv15.

21.

Roden

. Long QT syndrome: reduced repolarization reserve and the genetic link. J Intern Med 2006; 259: 59–69.

22.

Haverkamp

Breithardt

Camm

, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J 2000; 21: 1216–1231.

23.

Mohammad

Zhou

Gong

, et al. Blockage of the HERG human cardiac K⁺ channel by the gastrointestinal prokinetic agent cisapride. Am J Physiol 1997; 273: H2534–H2538.

24.

Anderson

Al-Khatib

Roden

, et al. Cardiac repolarization: current knowledge, critical gaps, and new approaches to drug development and patient management. Am Heart J 2002; 144: 769–781.

25.

Mitcheson

Chen

Lin

, et al. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A 2000; 97: 12329–12333.

26.

Mitcheson

Chen

Sanguinetti

. Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate. J Gen Physiol 2000; 115: 229–240.

27.

Porta-Sánchez

Gilbert

Spears

, et al. Incidence, diagnosis, and management of QT prolongation induced by cancer therapies: a systematic review. J Am Heart Assoc 2017; 6: e007724.

28.

Vandenberg

Perozo

Allen

. Towards a structural view of drug binding to hERG K⁺ channels. Trends Pharmacol Sci 2017; 38: 899–907.

29.

Antzelevitch

. Tpeak–Tend interval as an index of transmural dispersion of repolarization. Eur J Clin Investig 2001; 31: 555–557.

30.

Panicker

Karnad

. Mechanisms of drug-induced QT interval prolongation. In: Keller

Sacher

Haïssaguerre

(eds). Sex and cardiac electrophysiology. London: Elsevier, 2020, pp. 283–302.

31.

Nachimuthu

Assar

Schussler

. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf 2012; 3: 241–253.

32.

M-W

F-H

, et al. QTc prolongation in patients with schizophrenia taking antipsychotics: prevalence and risk factors. J Psychopharmacol 2023; 37: 971–981.

33.

Ruiz Diaz

Frenkel

Aronow

. The relationship between atypical antipsychotics drugs, QT interval prolongation, and torsades de pointes: implications for clinical use. Expert Opin Drug Saf 2020; 19: 559–564.

34.

CredibleMeds®. QTdrugs List. AZCERT, Inc. Available at: https://www.crediblemeds.org (accessed 25 March 2026).

35.

Esses

Rosman

, et al. Successful transition to buprenorphine in a patient with methadone-induced torsades de pointes. J Interv Card Electrophysiol 2008; 23: 117–119.

36.

Khalesi

Shemirani

Dehghani-Tafti

. Methadone induced torsades de pointes and ventricular fibrillation: a case review. ARYA Atheroscler 2014; 10: 339–342.

37.

Huffman

Stern

. QTc prolongation and the use of antipsychotics: a case discussion. Prim Care Companion J Clin Psychiatry 2003; 5: 278–281.

38.

Xiong

Pinkhasov

Mangal

, et al. QTc monitoring in adults with medical and psychiatric comorbidities: expert consensus from the Association of Medicine and Psychiatry. J Psychosom Res 2020; 135: 110138.

39.

Bordet

Garcia

Salvo

, et al. Antipsychotics and risk of QT prolongation: a pharmacovigilance study. Psychopharmacology (Berl) 2023; 240: 199–202.

40.

Pasquier

Pantet

Hugli

, et al. Prevalence and determinants of QT interval prolongation in medical inpatients. Intern Med J 2012; 42: 933–940.

41.

Girardin

Gex-Fabry

Berney

, et al. Drug-induced long QT in adult psychiatric inpatients: the 5-year cross-sectional ECG Screening Outcome in Psychiatry study. Am J Psychiatry 2013; 170: 1468–1476.

42.

Research C for DE and. Haloperidol (marketed as Haldol, Haldol Decanoate, and Haldol Lactate) Information. FDA, https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/haloperidol-marketed-haldol-haldol-decanoate-and-haldol-lactate-information (2024, accessed 22 August 2025).

43.

Lyseng-Williamson

. Clotiapine in schizophrenia: a guide to its use. Drugs Ther Perspect 2015; 31: 365–371.

44.

Lokshin

Kotler

Kutzuk

, et al. Clotiapine: an old neuroleptic with possible clozapine-like properties. Prog Neuropsychopharmacol Biol Psychiatry 1998; 22: 1289–1293.

45.

Janssen

Awouters

. Is it possible to predict the clinical effects of neuroleptics from animal data? Part V: From haloperidol and pipamperone to risperidone. Arzneimittelforschung 1994; 44: 269–277.

46.

Geller

Gorzaltsan

Shleifer

, et al. Clotiapine compared with chlorpromazine in chronic schizophrenia. Schizophr Res 2005; 80: 343–347.

47.

Leysen

Janssen

Schotte

, et al. Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacology (Berl) 1993; 112: S40–S54.

48.

Casey

. Motor and mental aspects of acute extrapyramidal syndromes. Acta Psychiatr Scand Suppl 1994; 380: 14–20.

49.

Madras

. History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia. J Hist Neurosci 2013; 22: 62–78.

50.

Scigliano

Ronchetti

. Antipsychotic-induced metabolic and cardiovascular side effects in schizophrenia: a novel mechanistic hypothesis. CNS Drugs 2013; 27: 249–257.

51.

Squires

Saederup

. Clozapine and several other antipsychotic/antidepressant drugs preferentially block the same “core” fraction of GABA(A) receptors. Neurochem Res 1998; 23: 1283–1290.

52.

Moore

Gershon

. Which atypical antipsychotics are identified by screening tests? Clin Neuropharmacol 1989; 12: 167–184.

53.

Toren

Samuel

Weizman

, et al. Case study: emergence of transient compulsive symptoms during treatment with clothiapine. J Am Acad Child Adolesc Psychiatry 1995; 34: 1469–1472.

54.

Zawilska

Derbiszewska

Nowak

. Clozapine and other neuroleptic drugs antagonize the light-evoked suppression of melatonin biosynthesis in chick retina: involvement of the D4-like dopamine receptor. J Neural Transm 1994; 97: 107–117.

55.

Juvise Pharmaceuticals. Entumin (clotiapine) 100 mg/ml oral solution, 40 mg tablets and 40 mg/ml solution for injection: patient information (Italy). Villeurbanne: Juvise Pharmaceuticals, 2025.

56.

Jacobsson

Norén

M-B

Perris

, et al. A controlled trial of clothiapine and chlorpromazine in acute schizophrenic syndromes. Acta Psychiatr Scand 1974; 50: 55–70.

57.

Uys

Berk

. A controlled double blind study of zuclopenthixol acetate compared to clothiapine in acute psychosis including mania and exacerbation of chronic psychosis. J Depress Anxiety 2001; 4: 4–9.

58.

Pruccoli

Leone

Di Sarno

, et al. Adjunctive clotiapine for the management of delusions in two adolescents with anorexia nervosa. Behav Sci (Basel) 2021; 11: 173.

59.

C-S

Tsai

Y-T

Tsai

H-J

. Antipsychotic drugs and the risk of ventricular arrhythmia and/or sudden cardiac death: a nation-wide case-crossover study. J Am Heart Assoc 2015; 4: e001568.

60.

Bervoets

Roelant

De Fruyt

, et al. Prescribing preferences in rapid tranquillisation: a survey in Belgian psychiatrists and emergency physicians. BMC Res Notes 2015; 8: 218.

61.

Bednar

Harrigan

Anziano

, et al. The QT interval. Prog Cardiovasc Dis 2001; 43: 1–45.

62.

STROBE Statement. STROBE checklists: cohort, case-control and cross-sectional studies. Available at: https://www.strobe-statement.org/checklists/ (accessed 11 January 2026).

63.

American Psychiatric Association (eds). Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Washington, DC: American Psychiatric Association, 2013.

64.

Makkar

Fromm

Steinman

, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270: 2590–2597.

65.

McHugh

Votaw

Sugarman

, et al. Sex and gender differences in substance use disorders. Clin Psychol Rev 2018; 66: 12–23.

66.

Raschi

Poluzzi

Godman

, et al. Torsadogenic risk of antipsychotics: combining adverse event reports with drug utilization data across Europe. PLoS One 2013; 8: e81208.

67.

Bazett

. The time relations of the blood-pressure changes after excision of the adrenal glands, with some observations on blood volume changes. J Physiol 1920; 53: 320–339.

68.

Göçen

Özden

. Autonomic dysfunction in psychiatric disorders. CurApproach Psychiatry 2024; 16: 401–409.

69.

Lieberman

Stroup

McEvoy

, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.

70.

Shah

Mir

Sharma

, et al. QTc interval in patients on psychotropic medications. Ind Psychiatry J 2025; 34: 402–407.

71.

Hommers

Scherf-Clavel

Stempel

, et al. Antipsychotics in routine treatment are minor contributors to QT prolongation compared to genetics and age. J Psychopharmacol 2021; 35: 1127–1133.

72.

Beach

Celano

Sugrue

, et al. QT prolongation, torsades de pointes, and psychotropic medications: a 5-year update. Psychosomatics 2018; 59: 105–122.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.04 MB