Prevalence of ECG abnormalities and risk factors for QTc interval prolongation in hospitalized psychiatric patients



research-article20192019 TPP0010.1177/2045125319891386Therapeutic Advances in PsychopharmacologyN Ansermot, M Bochatay


Therapeutic Advances in Psychopharmacology

Original Research

Nicolas Ansermot , Meredith Bochatay, Jürg Schläpfer, Mehdi Gholam, Ariane Gonthier, Philippe Conus and Chin B Eap


Background: Psychiatric patients are at risk of cardiovascular diseases, and many psychotropic drugs can prolong QTc interval. Requirements for electrocardiogram (ECG) monitoring have been set up in our psychiatric university hospital. The objective of this study was to determine the proportion of adult patients who had an ECG during their hospitalization, the prevalence of ECG abnormalities, the evolution of the QTc after admission, and the risk factors for QTc prolongation. Methods: Retrospective analysis of ECGs and clinical data of all patients with a complete hospitalization in 2015. Assessment of the influence of covariates on QTc using linear mixed- effects models.

Results: At least one ECG (n = 600) was performed during 37.6% of the stays (n = 1198) and in 45.5% of the patients (n = 871). Among the patients with an ECG, 17.9% had significant ECG abnormalities, including 7.6% with a prolonged QTc. QTc measured at admission and during hospitalization did not change significantly (n = 46, 419.4 ± 29.7 ms, 417.2 ± 27.6 ms, p = 0.71). In the multivariate model (292 patients, 357 ECGs), the covariates significantly associated with the QTc were gender (+15.9 ms if female, p < 0.0001), age (+0.4 ms/year, p = 0.0001), triglyceride levels (+5.7 ms/mmol/l, p = 0.005), and drugs with known risk of torsades de pointes (+6.2 ms if ⩾1 drug, p = 0.028).

Conclusions: The prevalence of hospitalized psychiatric patients with an abnormal ECG indicates that ECGs should be performed systematically in this population. Prescription of psychotropic drugs should be done cautiously, particularly in patients with QTc prolongation risk factors.

Keywords: electrocardiogram, psychiatric inpatients, psychotropic drugs, QTc interval Received: 5 July 2019; revised manuscript accepted: 21 October 2019.

Correspondence to:

Nicolas Ansermot

Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Hospital of Cery, 1008 Prilly, Switzerland

Meredith Bochatay
Chin B Eap
Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, Switzerland

Institute of Pharmaceutical Sciences of Western Switzerland, University
of Geneva, Geneva, Switzerland

Jürg Schläpfer

Department of Cardiology, Lausanne University Hospital and University
of Lausanne, Lausanne, Switzerland

Mehdi Gholam

Centre of Psychiatric Epidemiology and Psychopathology, Department of Psychiatry, Lausanne University Hospital and University

of Lausanne, Prilly, Switzerland

Ariane Gonthier

General Internal Medicine Practice, Lausanne, Switzerland; University Institute of Medicine of the Family, University

Ther Adv Psychopharmacol

2019, Vol. 9: 1–13 hDttOpsI:://d1o0i.o.r1g1/170.711/77/2045125319891386


© The Author(s), 2019. Article reuse guidelines: permissions


Psychiatric patients have poor physical health and shortened life expectancy,1 with a higher rate of sudden cardiac death than in the general popula- tion.2,3 Of note, patients treated with antipsy- chotic drugs have twice the risk of cardiac death compared with nonusers,4 and an association between antidepressant use and cardiac arrest has also been documented.5

Many psychotropic drugs can block the human ether-a-go-go-related gene (hERG) voltage-gated potassium channels that are implicated in the

repolarization of the cardiac action potential.6,7 This blockage can result in a prolongation of the QTc interval on an electrocardiogram (ECG), which may induce malignant polymorphic ven- tricular tachycardia, so-called torsades de pointes, associated with syncope and sudden death.8 Other risk factors for QTc prolongation include female sex, increased age, congenital long QT syndrome, electrolyte abnormalities, heart (e.g. acute ischemia), and other medical conditions.9

In a study performed at admission in hospitalized psychiatric patients in Switzerland (n = 6790),

of Lausanne, Lausanne, Switzerland

Philippe Conus

Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, Switzerland

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (


Therapeutic Advances in Psychopharmacology 9

27.3% of the ECGs were classified as abnormal.10 The prevalence of patients with a prolonged QTc interval (⩾470–499 ms) was 6.1%, and another 1.6% had long QTc interval (⩾500 ms), with 58% of the latter qualified as induced by a drug. Most importantly, 19.4% of the patients with drug-induced long QTc had torsades de pointes or sudden death within 72 h of detection.10

The National Institute for Health and Care Excellence (NICE) clinical guideline indicates an ECG should be offered before starting antipsy- chotic medication in hospitalized patients.11 The Danish Society of Cardiology and the Danish Psychiatric Society developed a clinical guideline for reduction of the risk of arrhythmia induced by psychotropicdrugs.Theauthorsproposedadeci- sional algorithm that takes into account the indi- vidual risk factors of the patients, and the risk associated with the pharmacological treatments.12 A medico–economic analysis showed that per- forming systematic ECG screening at admission in psychiatric hospitals helps to reduce the number of sudden cardiac deaths in a cost-effective way.13

Based on these publications, in the autumn of 2014, we introduced a clinical directive for the cardiac follow up of adult patients hospitalized in the service of General Psychiatry (Department of Psychiatry, Lausanne University Hospital).14 This directive includes an ECG at admission, as well as later during the stay if a drug that poses a risk of cardiac toxicity is prescribed or after a sig- nificant dose increase.

In the current study, we retrospectively analyzed all ECGs performed during a 1-year period fol- lowing the introduction of the directive. The aims were to determine the proportion of patients who had an ECG, the prevalence of ECG abnormali- ties, the evolution of the QTc interval during hos- pitalization, and the risk factors associated with QTc prolongation in this population.


Study design and patients

A retrospective, cross-sectional study was per- formed in the service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital. All adult patients aged 18–65 years with a complete hospital stay (admission and dis- charge) between 1 January and 31 December 2015, and at least one valid ECG, performed at

admission or during the stay, were included. ECG measurements and laboratory analyses were part of the clinical monitoring of the patients. The study protocol, examining clinical data retro- spectively, was approved by the Ethics Committee Vaud local Ethics Committee (approval number: 2015-00067).

Data extraction

Demographic (age, gender, length of stay, time elapsed between hospital admission and ECG recording), clinical (ECG parameters, psychiatric diagnoses), biological (potassium, creatinine, glu- cose, triglyceride, and cholesterol plasma levels), and pharmacological (drugs administered) data were extracted from the electronic medical records. Potassium and creatinine values were included if they were measured ± 3 days from the date of the ECG; in the case of more than one analysis, only the value closer to the ECG was selected for the analyses. For the other biological values, all measurements performed during the stay were considered, and mean values were included in the analyses. Drugs were included if they were administered within 5days before the ECG recording. Psychiatric and somatic drugs potentially affecting the QTc interval were classi- fied as known, possible, or conditional risks of torsades de pointes, according to CredibleMeds.15 Drugs were also classified as strong inhibitors or strong inducers of cytochromes P450 (CYP).16 Psychiatric diagnoses were based on the International Statistical Classification of Diseases and Related Health Problems (ICD-10).

ECG assessment

All ECG recordings were performed using the Cardiovit-MS 2015 electrocardiograph (Schiller AG, Baar, Switzerland). ECGs recorded at 25 mm/s speed and 10 mm/mV amplification were initially interpreted automatically by the inte- grated measurement software. However, due to the limitations in diagnostic accuracy of comput- erized interpretation,17 all ECGs were read over by a senior cardiologist (JS). All final ECG param- eters were included in a database, and were dou- ble checked. ECGs that did not allow reliable measurementoftheQTcinterval(e.g.poorqual- ity or agitated patients) were considered artifacts and excluded. ECGs performed within a short interval (i.e. less than 1 h for most cases) were consideredduplicates,andonlythefirstECGwas included unless the quality of the second was


N Ansermot, M Bochatay et al. Table 1. Classification of the 71 patients (17.9%) with at least one abnormal ECG, among the 396 patients with

at least one valid ECG.


Number of patients (%)a

Prolonged QTc (male: ⩾450 ms; female: ⩾460 ms)

30 (7.6)

Repolarization abnormalities (excluding prolonged QTc and early repolarization)

23 (5.8)

Atrioventricular conduction disturbances (PR <100 ms; PR > 200 ms)

10 (2.5)

Intraventricular conduction disturbances (QRS >120 ms)

5 (1.3)

Sinus bradycardia (<50 bpm)

13 (3.3)

Sinus tachycardia (>120 bpm)

2 (0.5)

Arrhythmias (premature beats; atrial fibrillation)

10 (2.5)

Remote myocardial infarction

3 (0.8)

aMore than one type of ECG abnormality possible per patient. bpm, beats per minute; ECG, electrocardiogram.

better. Automatic QT interval was defined as the interval between the earliest beginning of the QRS complex and the latest T-wave end taken from all 12 averaged leads. According to Postema and col- leagues, the QT interval is measured manually in stable sinus rhythm from the beginning of the QRS complex to the end of the T-wave defined as the intersection of the tangent to the steepest slope of the last limb of the T-wave, and the baseline in lead II or V5.18,19 Manual QT measurement was performed in only 13 cases of gross misinterpreta- tion of the deepest slope of the T-wave descent by the automatic measure. Cardiac diagnoses were corrected for 28 ECGs. A significant Uwave was present in only one patient with severe hypoka- lemia; in this case alone, the U wave was included in QT interval measurement. QT values were cor- rected for heart rate (QTc). As the commonly used Bazett’s correction formula is known to undercorrect in cases of bradycardia and overcor- rect in tachycardia, this formula was used for heart rates between 60 and 100 bpm20: QTcB (ms) = QT (ms)/(RR)1/2 (s), where RR represents the duration of a cardiac cycle. For heart rates <60 or >100 bpm, Fridericia’s correction for- mula, which is less sensitive to heart rate, was used: QTcF (ms) = QT (ms)/(RR)1/3 (s). Additional analyses were also performed using Bazett’s and Fridericia’s correction formulas for all ECGs; these results are presented in the sup- plementary data. ECGs with irregular rhythms (marked sinus arrhythmias, atrial fibrillation) were excluded for the measurement of the QT interval,

but were kept for the determination of the preva- lence of ECG abnormalities. The defined ECG abnormalities used in the present study are enu- merated in Table 1.

Statistical analyses

Mean values for continuous variables were com- pared using Student’s t test for independent sam- ples or the paired t test for dependent samples. To test for independence among the categorical vari- ables, we used the Pearson Chi-square test. Differences in proportion of prolonged QTc were assessed using a generalized linear mixed model (logistic regression), fit by maximum likelihood to detect potential differences among the two groups, without adjusting these models for any covariates except for repeated measurements per admission. A linear mixed-effects model fit by restricted maximum likelihood was used to assess the influence of the covariates on QTc interval simultaneously.21 Two nested random effects (one at the admission level nested in another random effect at the individual level) were used to take into account the repeated measurements of QTc per admission and for each individual. We used graphic tools to assess the fit and results were satis- factory. A p-value <0.05 was considered statisti- cally significant. Statistical analyses were performed using Stata software, version 15.0 (StataCorp, College Station, TX, USA), and R language and environment for statistical computing


Therapeutic Advances in Psychopharmacology 9


Figure 1. Flow chart for inclusion and exclusion of the ECGs in the various parts of the study. ECG, electrocardiogram.


Study population

During a total of 1198 complete hospital stays recorded in 2015 (871 patients), 867 ECGs were performed. After exclusion of 118 ECGs due to duplication, and 149 that were considered arti- facts or of poor quality, 600 valid ECGs were included in the analysis of the prevalence of abnormalities, corresponding to 37.6% of the stays (n = 450) and 45.5% of the patients (n = 396) (see Figure 1).

The length of stay of the patients with at least one ECG was significantly longer (mean ± SD: 30.5±26.5days) than that of the rest of the patients (mean ± SD: 20.5 ± 22.5 days, p < 0.0001). The proportion of females was signifi- cantly lower in the group of patients with an ECG (42.4%) compared with the rest of the patients (55.1%), p < 0.001. The age of the patients with an ECG (mean ± SD: 38.4 ± 12.2 years) was similar to the rest of the patients (mean ± SD: 38.6 ± 11.8years), p=0.75.

The mean ± SD number of ECGs per stay was 1.3 ± 0.7. The number of stays with 1, 2, 3, 4, and 5 ECGs were 347, 70, 20, 12, and 1, respec- tively. The mean ± SD time elapsed between hospital admission and the first ECG recording

was 5.1 ± 10.6 days (range 0.02–138). The num- ber of stays with an ECG performed within 24, 48, and 72h after admission was 143 (11.9%), 251 (21.0%) and 302 (25.2%), respectively. The mean ± SD time elapsed between hospital admission and all ECGs was 8.9 ± 14.3days (range 0.02–138).

Prevalence of ECG abnormalities

Among the 600 valid ECGs, an abnormality (as defined in Table 1) was detected in 16.5% of the ECGs (n = 99), which corresponds to 17.1% of the stays (n = 77) and 17.9% of the patients (n = 71). A prolonged QTc interval (⩾450 ms for males; ⩾460 ms for females) was observed in 7.6% of the patients (n = 30), including a patient with a very high risk QTc at 595 ms. This extreme value was observed in a 27-year-old female, with a low potas- sium value of 2.5 mmol/l (ref 3.5–4.6 mmol/l), and treated with psychotropic drugs at risk of QTc pro- longation (lithium 24 mmol/d and amisulpride 400 mg/d) and magnesium. Detailed characteris- tics of the 30 patients (37 ECGs) with QTc pro- longation, including at risk medications, are presented in supplementary Table S1. At least one and two drugs classified in any CredibleMeds’ cat- egories were present in 84% and 59% of these ECGs, respectively. However, due to multiple fac- tors for QTc prolongation, it was not possible to

N Ansermot, M Bochatay et al.


Figure 2. Distribution of the QTc values in the 595 valid ECGs.
ECG, electrocardiogram.

incriminate a particular drug, especially in patients taking several drugs. Nevertheless, it can be noted that, among the drugs classified in the highest QTc prolongation risk category, there were 10 ECGs with citalopram or escitalopram, 5 with metha- done, and 4 with haloperidol. Other abnormalities, observed either in the same or in different patients, were repolarization abnormalities (other than QTc prolongation), sinus bradycardia and tachycardia, atrioventricular and intraventricular conduction disturbances, arrhythmias, and old myocardial infarction (see Table 1). Of note, no patients were treated with specific antiarrhythmic drugs, espe- cially with amiodarone or sotalol, both drugs known to prolong QT interval. No case of acute ischemic ECG changes that could justify a special- ized support or a transfer to an intensive care unit was documented, neither was there any case of tor- sades de pointes or sudden cardiac death. The prevalence of ECG abnormalities using Bazett’s and Fridericia’s corrections for all ECGs are pre- sented in supplementary Tables S2 and S3, respectively.

Evolution of QTc interval during hospitalization

For the specific analysis of the QTc interval, 5 of the 600 valid ECGs were further excluded due to a normal but unreliable QTc value: 4 with pro- nounced sinus arrhythmias and 1 with atrial fibrillation (Figure 1). Bazett’s correction was used for 478 ECGs that had a heart rate between 60 and 100bpm, and Fridericia’s correction for 63 and 54 ECGs that had a heart rate <60 or >100bpm, respectively. Mean ± SD QTc inter- val in the 595 remaining ECGs was 419 ± 25 ms (range 352–595), see Figure 2.

The evolution of the QTc interval was studied in patients having an ECG recorded within 48 h after admission (considered the baseline value) and another ECG between 3 and 30days later (n=46). There were no significant differences between the two measurements: mean ± SD: 419.4 ± 29.7 ms versus 417.2 ± 27.6 ms, p=0.71. When the proportion of patients with a QTc prolongation was considered, no signifi- cant change was observed between the two study periods: 10.9% versus 10.9%, p = 1.0. However, in the patients with a baseline value in the upper quartile (n = 12), a significant decrease was observed: 456.4±14.1 ms versus 430.8±27.5, p=0.025. Among these patients, for those who had available data, six had a med- ical condition at admission that has been, or could have been, corrected later in the stay, and that could have therefore explained the short- ening of QTc (two urinary screening positive for cocaine, two hypokalemia, one high amisul- pride plasma level and one diagnosis of alcohol dependence, see Table S4). Similar results were obtained if cutoffs of 24 h (n = 28) and 72 h (n = 54) after admission were used for the base- line ECG (data not shown). The evolution of the QTc using Bazett’s and Fridericia’s correc- tions for all ECGs is presented in the supple- mentary data.

Risk factors for QTc prolongation

A total of 357 ECGs with complete clinical data sets were included in the multivariate model, corresponding to 313 stays and 292 patients (Figure 1 and Table 2). Bazett’s correction was used for 295 ECGs that had a heart rate between 60 and 100bpm, and Fridericia’s correction for 34 and 28 ECGs that had a heart rate <60 or >100bpm, respectively. The covariates signifi- cantly associated with the QTc interval in the multivariate model were (β, p): gender (+15.9 ms if female, p<0.0001), age (+0.4 ms/year, p = 0.0001), triglyceride plasma levels (+5.7 ms/ mmol/l, p = 0.005), and administration of at least one drug with known risk of torsades de pointes (+6.2 ms if ⩾ 1 drug, p = 0.028), see Table 3. The results of the multivariate model obtained using Bazett’s and Fridericia’s corrections for all ECGs are presented in the supplementary data (Table S5). Other psychiatric diagnoses (F20- 29, F30-31 and F32-34) were also tested in the multivariate model, but they were not signifi- cantly associated with QTc interval (data not shown).


Therapeutic Advances in Psychopharmacology 9

Table 2. Description of the covariates included in the linear mixed-effects model (n = 357 ECGs).



Females, n (%)

149 (41.7)

Age (years), mean ± SD (range)

39 ± 12 (18–64)

Potassium (mmol/l, ref. 3.5–4.6), mean ± SD (range)

4.0 ± 0.4 (2.3–5.3)

Glucose (mmol/l, ref. 3.7–5.6), mean ± SD (range)

5.1 ± 1.1 (2.5–12.9)

Triglycerides (mmol/l, ref. < 2.0), mean ± SD (range)

1.3 ± 0.7 (0.4–7.8)

Cholesterol total (mmol/l, ref. < 5.0), mean ± SD (range)

4.8 ± 1.1 (2.6–10.1)

Creatinine (μmol/l, ref. 62–106), mean ± SD (range)

75 ± 19 (39–302)

At least one drug with known risk of TdP, n (%)a

102 (28.6)

At least one drug with possible risk of TdP, n (%)b

139 (38.9)

At least one drug with conditional risk of TdP, n (%)c

137 (38.4)

At least one strong CYP inhibitor, n (%)d

17 (4.8)

At least one strong CYP inducer, n (%)e

5 (1.4)

Time between admission and ECG (days), mean ± SD (range)

5.4 ± 10.8 (0.02–87.7)

F10-F19 ICD diagnosis, n (%)

106 (29.7)

QTc (ms), mean ± SD (range)

418 ± 24 (352–487)

Drugs classified according to their risk of TdP (
aKnown risk: haloperidol (n = 38), escitalopram (n = 32), methadone (n = 19), citalopram (n = 15), levomepromazine (n = 6), domperidone (n = 2).
bPossible risk: olanzapine (n = 40), risperidone (n = 29), mirtazapine (n = 25), aripiprazole (n = 20), venlafaxine (n = 19), clozapine (n = 10), lithium (n = 10), buprenorphine (n = 4), tizanidine (n = 2), paliperidone (n = 1), clomipramine (n = 1). cConditional risk: quetiapine (n = 70), amisulpride (n = 33), sertraline (n = 18), trazodone (n = 12), fluoxetine (n = 6), hydroxyzine (n = 5), pantoprazole (n = 4), paroxetine (n = 3), indapamide (n = 2), amitriptyline (n = 1), hydrochlorothiazide (n = 1), metoclopramide (n = 1), ritonavir (n = 1).
Drugs classified according to their CYP inhibitor or inducer profile (
dStrong inhibitors: fluoxetine (n = 6), levomepromazine (n = 6), paroxetine (n = 3), darunavir (n = 1), fluvoxamine (n = 1), ritonavir (n = 1).
eStrong inducers: oxcarbazepine (n = 2), dexamethasone (n = 1), phenobarbital (n = 1), ritonavir (n = 1).
CYP, cytochrome P450; ECG, electrocardiogram; F10-F19, ICD diagnosis: mental and behavioral disorders due to psychoactive substance use; SD, standard deviation; TdP, torsades de pointes.


Proportion of patients with at least one ECG recorded
Among the 1198 stays recorded during a 1-year period in a psychiatric university hospital (871 patients), a total of 600 valid ECGs were ana- lyzed retrospectively. The proportion of stays with at least one ECG performed within 24 h after admission was 11.9%, which is relatively low, but this proportion increased to 25.2% after 72 h, and to 37.6% during the whole stay. Taking into account that some patients were

hospitalized more than once during the study period, the proportion of patients with at least one ECG was 45.5%. These results are satisfac- tory, considering the psychiatric context (e.g. agitation of the patients, particularly at the beginning of the hospitalization), and the intro- duction of the ECG directive in our hospital a few months before the study started. A signifi- cantly longer length of stay was observed for patients with at least one ECG compared with the rest of the patients, suggesting that the patients with more complex situations were more susceptible to having an ECG during the


Table 3. Linear mixed-effects model (357 ECGs, 313 stays, 292 patients).

N Ansermot, M Bochatay et al.



Beta a (ms)



+ 15.9


Age (years)

+ 0.4


Potassium (mmol/l)

– 3.7


Glucose (mmol/l)

+ 1.3


Triglycerides (mmol/l)

+ 5.7


Cholesterol total (mmol/l)

– 1.6


Creatinine (μmol/l)

+ 0.006


At least one drug with known risk of TdP b

+ 6.2


At least one drug with possible risk of TdP b

+ 3.6


At least one drug with conditional risk of TdP b

+ 3.6


At least one strong CYP inhibitor c

+ 6.4


At least one strong CYP inducer c

– 0.01


Time between admission and ECG (days)

– 0.1


F10-F19 ICD diagnosis

+ 0.5


aEffect of the covariate on the QTc.
bBased on the classification of CredibleMeds (
cBased on the classification of the Geneva University Hospitals (
CYP, cytochrome P450; ECG, electrocardiogram; F10-F19, ICD diagnosis: mental and behavioral disorders due to psychoactive substance use; TdP, torsades de pointes.

stay, but we cannot exclude the possibility that a longer stay increases the likelihood of receiv- ing an ECG.

Our results are in accordance with a study that reviewed records of mental health inpatient admissions and revealed that an ECG was per- formed in 19% of the patients.23 In another study including patients who had been pre- scribed antipsychotic drugs on hospital admis- sion, a higher proportion of patients (40% in the baseline audit and 70% in the reaudit) had ECG monitoring before or after taking antipsy- chotics.24 Different protocols for ECG moni- toring of psychiatric patients and management plans for patients with abnormal ECG findings have been proposed recently to reduce the risk of arrhythmia.12,24–27

Prevalence of ECG abnormalities

Among the 396 patients with a valid ECG, the prevalence of patients with an abnormal ECG was 17.9%. The most frequently observed abnormalities were linked to the QTc values. This prevalence of abnormal ECGs justifies rou- tine recordings in hospitalized psychiatric patients. In a study by Girardin and colleagues, performed at admission in hospitalized psychiat- ric patients, 27.3% of the ECGs were classified as abnormal.10 The most frequent abnormalities identified were supraventricular tachycardia (6.6% of all ECGs), followed by QTc lengthen- ing (6.1%) and repolarization abnormalities other than QTc prolongation (4.1%).10 In nonpsychiatric patients (age 35–74 years), major ECG abnormalities were identified in 7.9% and 11.3% of women and men, respectively.28 In


Therapeutic Advances in Psychopharmacology 9

primary care patients, the prevalence of ECG abnormalities in the age group from 20 to 39.9years was 19.4% in females and 29.3% in males, and increased in older age groups.29 Comparison of these results with ours is diffi- cult, however, as the populations are not the same, and the categories used for the classifica- tion of the abnormalities are different.

A prolonged QTc interval was observed in our study in 7.6% of the patients, but only one case had a QTc interval ⩾500 ms, which is the thresh- old considered to be a strong predictor of drug’s risk to cause torsades de pointes in both sexes.30 This prevalence is consistent with the observed rates of QTc prolongation reported in the main studies performed in hospitalized psychiatric patients, with the majority of the values ranging between 2% and 17%,10,23,25–27,31–43 but up to 38% in some studies.33,44 In somatic inpatients, the prevalence of QTc prolongation seems to be higher than in psychiatric inpatients, with rates varying between 22% and 35%. These differences may be explained by older populations and a higher prevalence of cardiovascular comorbidities in somatic inpatients.45–47

The mean QTc (419 ± 25 ms) values measured in

our study are in accordance with values reported in

other studies performed in psychiatric inpatients.

The mean QTc values in these studies ranged between 391 ms and 423 ms,25,32,35,36,38,39,43,48,49

but a higher mean QTc of 451 ms was also reported in one study.44

Comparison across studies is limited due to dif- ferent factors such as the heterogeneity in cut-off values used for the definition of QTc prolonga- tion (421–480 ms), study designs, characteristics of patients (inclusion and exclusion criteria, gen- der, age, ethnic origin, comorbidities), drugs pre- scribed (first- or second-generation antipsychotics, doses, polymedications), and QT correction methods (Bazett, Fridericia or nomogram), which could explain the large range of values reported. Other QT correction formulas exist, such as Framingham or Hodges, but were not used in these studies.50,51

Evolution of the QTc interval during
When the ECGs performed at admission were compared with the ECGs later in the stay, the QTc interval, as well as the proportion of patients

with a prolonged QTc, were not significantly dif- ferent. These results suggest that, in our study, hospitalization of patients was not a risk factor for QTc prolongation nor a protective situation. However, in patients with a baseline value in the upper quartile, QTc values decreased significantly after admission, suggesting for these patients a risk reduction due to hospitalization, but a regression to the mean cannot be excluded. In a cross-sec- tional study performed in 74 hospitalized patients in a general psychiatry ward in Iran, the propor- tion of patients with a prolonged QTc interval increased between admission and 1 week of hospi- talization, from 14% to 37% in males (QTc > 450 ms) and from 6% to 26% in females (QTc > 470 ms). A significant increase in the mean QTc interval was also observed between admission (436 ± 26 ms) and 1 week of hospitali- zation (451 ± 30ms). Due to the small sample size, no possible cause was identified.44 In another study performed in 95 patients acutely admitted to an emergency ward for psychosis in Norway, the proportion of prolonged QTc interval (>450 ms for males and >470 ms for females) decreased from 11.6% at admission to 4.2% at discharge or after 6 weeks of hospitalization at the latest. A positive association was observed between the QTc interval and the agitation score.39

Risk factors for QTc prolongation

A highly significant association between female gender and QTc interval was observed in our study using a multivariate model. This result is in accord- ance with previous studies performed in psychiat- ric inpatients,32,38,41 although discordant results have been published.39,42 A suggested mechanism in sex difference is the presence of androgens in males between puberty, and around the age of 50 that may shorten the QTc interval.38,52

A significant association between age and QTc intervalwasobservedinthepresentstudy.Similar results were observed in some other studies per- formed in psychiatry,37,41,42 but not all.40 The increase in QTc interval with age might be explained by the physiological changes in the heart observed in healthy elderly subjects, which include, among others, cardiac hypertrophy or fibrosis and alterations in the sympatho-vagal balance.53,54

We observed a significant association between triglyceride plasma levels and QTc interval. This parameter has been studied less frequently than other well-known risk factors. In a large


cross-sectional study that determined the asso- ciation between QTc interval and metabolic syndrome and its components, using a multiple linear regression analysis, QTc was positively associated with triglyceride levels in men, but not in women. After adjusting for covariates, QTc interval increased with increasing numbers of metabolic syndrome components in a dose- response manner.55 In another cross-sectional survey, triglycerides were significantly associ- ated with QTc interval in unadjusted regression analyses,butnotinmultivariateanalysis.56Ina retrospective study that included patients with type 2 diabetes, triglyceride levels were associ- ated with prolonged QTc only in the univariate analyses.57 The explanation regarding the asso- ciation between triglyceride levels and QTc prolongation is not clear. It has been suggested that dyslipidemia may induce atherosclerotic changes accompanying oxidative stress and can subsequently cause endothelial dysfunction and damage.55

Our multivariate model showed that patients who received at least one drug with known risk of tor- sades de pointes had significantly higher QTc intervals than the other patients. Using the clas- sification from CredibleMeds, significant associa- tions between drug prescriptions with known risk of torsades de pointes and QTc prolongation were also observed in other studies.25,40,47 A large cross-sectional survey in Italy found that first- generation antipsychotics, age, gender, alcohol misuse, and concurrent risky drugs prolonged QTc interval.58 In a retrospective review of antip- sychotic overdoses, there appeared to be a signifi- cant risk of QTc prolongation with amisulpride and thioridazine.59 These results indicate that use of psychotropic drugs should be undertaken with caution, particularly in patients with other risk factors for QTc prolongation. However, a com- prehensive review concluded that current litera- ture does not provide sufficient and consistent information to stratify second-generation antipsy- chotics and antidepressants for their potential to prolong QTc interval or cause torsades de pointes.30 QTc prolongation associated with these drugs is, in itself, not sufficient to cause torsades de pointes, which can occur at therapeutic doses and with QTc interval <500 ms.30

Hypokalemia is a well-known risk factor for QTc prolongation, as observed in some previous stud- ies,10,27,41 but not all.39 Potassium plays an impor- tant role in maintaining the electrical potential

across the cellular membrane, as well as in depo- larization and repolarization of the cardiac myo- cytes. Alterations in potassium levels may lead to ECG changes and severe arrhythmias.60 In our study, potassium plasma levels were not signifi- cantly associated with QTc, except when Bazett’s formula was used for all ECGs (supplementary Table S5). An explanation could be that potas- sium was included if it was measured at ±3days from the ECG. In unstable patients, a modifica- tion of this parameter between the ECG record- ing and laboratory measurement cannot be excluded. Of note, this might concern a minority of patients, as around half of the measurements were performed the day of the ECG and three- quarters at ±1 day.

Different scores for QTc prolongation have been developed in recent years. A risk score for QT prolongation in hospitalized patients was, for example, developed by Tisdale and colleagues.61 The Mayo Clinic also created a pro-QTc score that reflects patients’ multimorbidity and polyp- harmacy. This score has been shown to be an age- independent predictor of mortality.62 A genetic QT score was also developed, which explained a significant proportion of the variability in drug- induced QT prolongation. This score was a sig- nificant predictor of drug-induced torsades de pointes.63


The classification from CredibleMeds was used in this study, but different results might have been obtained if a different classification was used. Due to the retrospective design of the study, all clinical and biological parameters possibly linked to the QTc interval were not measured systemati- cally for all patients. For example, due to a low number of observations, calcium or magnesium plasma levels were not studied, and only the ECGs with all covariates were included in the multivariate model, corresponding to 60% of the valid ECGs. To increase the amount of available data, potassium and creatinine plasma levels were included if they were measured at ± 3 days from the ECG, which could have decreased the accuracy. Another limitation is the representativeness of the sample included. A selection bias is possible, as an ECG was performed in less than half of the eligible subjects. An ECG could have been performed more frequently in patients with known cardiovascular risk factors, which could have overestimated the

N Ansermot, M Bochatay et al.


Therapeutic Advances in Psychopharmacology 9

prevalence of abnormal ECGs. On the other hand, an underestimation of abnormal ECGs was also possible because of the impossibility of per- forming ECGs in very agitated patients, some of which might have been under the influence of drugs or alcohol, which can increase the QTc interval. Our results can therefore not be general- ized to the whole hospitalized psychiatric popula- tion. In addition, the sample size of the subgroup of patients included in order to study the evolu- tion of the QTc during hospitalization was small, limiting the statistical power of these results. Finally, due to the design of the study (cross-sec- tional), only associations between clinical factors and QTc prolongation were observed, rather than causal relationships.


In the current study, performed over a 1-year period, 45.5% of hospitalized psychiatric patients had at least one ECG recording. Among them, 17.9% had a significantly abnormal ECG and 7.6% a prolonged QTc interval, which confirms the utility of performing ECGs in this population. The QTc of the patients with an ECG performed at admission, and a second during hospitaliza- tion, did not change significantly, which suggests that the hospitalization of the patients was not a risk factor for QTc prolongation. However, in the patients with a baseline value in the upper quar- tile, the QTc decreased significantly. The covari- ates that were positively associated with QTc interval were female gender, age, triglyceride lev- els, and administration of at least one drug with known risk of torsades de pointes. Psychotropic drugs should thus be prescribed with caution in psychiatric inpatients, particularly in those with other risk factors for QTc prolongation.


We wish to thank the Data Science and Research Group (Lausanne University Hospital) for the extraction of the data from the electronic medical records.

Authors’ note

Part of this work was presented at the 20th Journées Franco-Suisses de Pharmacie Hospitalière, 1–2 December 2016, Bern, Switzerland.

Ethical Approval

The study protocol, examining clinical data retro- spectively, was approved by the local Ethics Committee Vaud (approval code is 2015-00067).


The authors disclosed receipt of the following financial support for the research, authorship, and publication of this article: This work has been funded in part by the Swiss National Research Foundation (CE and PC: 320030-120686, 324730-144064, and 320030-173211). The funding sources had no role in the writing of the manuscript or in the decision to submit it for publication.

Conflict of interest statement

The authors declare that there is no conflict of interest.


Nicolas Ansermot 0001-8350-9416

Supplemental material

Supplemental material for this article is available online.





4. 5.

6. 7. 8.

De Hert M, Correll CU, Bobes J, et al. Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry 2011; 10: 52–77.

Empana JP, Jouven X, Lemaitre RN, et al. Clinical depression and risk of out-of-hospital cardiac arrest. Arch Inter Med 2006; 166: 195– 200.

Ifteni P, Correll CU, Burtea V, et al. Sudden unexpected death in schizophrenia: autopsy findings in psychiatric inpatients. Schizophr Res 2014; 155: 72–76.

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

Weeke P, Jensen A, Folke F, et al. Antidepressant use and risk of out-of-hospital cardiac arrest:
a nationwide case-time-control study. Clin Pharmacol Ther 2012; 92: 72–79.

Witchel HJ, Hancox JC and Nutt DJ. Psychotropic drugs, cardiac arrhythmia, and sudden death. J Clin Psychopharmacol 2003; 23: 58–77.

Roden DM. Drug-induced prolongation of the QT interval. New Engl J Med 2004; 350: 1013–1022.

Glassman AH and Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de


pointes, and sudden death. Am J Psychiatry 2001; 158: 1774–1782.

9. Beach SR, Celano CM, Noseworthy PA, et al. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics 2013; 54: 1–13.

10. Girardin FR, Gex-Fabry M, Berney P, 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.

11. National Institute for Health and Care Excellence (NICE) clinical guideline. Psychosis and schizophrenia in adults: prevention and management (CG178), 2014, (accessed 5 June 2019).

12. Fanoe S, Kristensen D, Fink-Jensen A, et al. Risk of arrhythmia induced by psychotropic medications: a proposal for clinical management. Eur Heart J 2014; 35: 1306–1315.

13. Poncet A, Gencer B, Blondon M, et al. Electrocardiographic screening for prolonged QT interval to reduce sudden cardiac death in psychiatric patients: a cost-effectiveness analysis. PLoS One 2015; 10: e0127213.

14. Directive for the follow-up of the patients hospitalized in the Service of General Psychiatry (Department of Psychiatry, Lausanne University Hospital, Switzerland), 2016, (accessed 5 June 2019).

15. CredibleMeds. A trusted partner providing reliable information on medicines, www. (2016, accessed 8 June 2016).

16. Service of Clinical Pharmacology and Toxicology, University Hospitals of Geneva. Cytochromes P450 Drug Interactions, 2016, www. (accessed 8 June 2016).

17. Schlapfer J and Wellens HJ. Computer-interpreted electrocardiograms: benefits and limitations. J Am Coll Cardiol 2017; 70: 1183–1192.

18. Postema PG, De Jong JS, Van der Bilt IA, et al. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Heart Rhythm 2008; 5: 1015–1018.

19. Postema PG and Wilde AA. The measurement of the QT interval. Curr Cardiol Rev 2014; 10: 287–294.

20. Antoniou CK, Dilaveris P, Manolakou P, et al. QT prolongation and malignant arrhythmia: how serious a problem? Eur Cardiol 2017; 12: 112–120.

21. Pinheiro J, Bates D, DebRoy S, Sarkar D and
R Core Team (2018). nlme: linear and nonlinear

N Ansermot, M Bochatay et al. mixed effects models. R package version 3.1-137,

22. R Core Team R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, https://www.r- (2018).

23. Berling I, Gupta R, Bjorksten C, et al. A review of ECG and QT interval measurement use in
a public psychiatric inpatient setting. Australas Psychiatry 2018; 26: 50–55.

24. Kwan MM, Nguyen DG and Ng RM. Electrocardiographic monitoring of psychiatric in-patients taking antipsychotic medications. East Asian Arch Psychiatry 2018; 28: 28–32.

25. Vandael E, Vandenberk B, Willems R, et al. Risk management of hospitalized psychiatric patients taking multiple QTc-prolonging drugs. J Clin Psychopharmacol 2017; 37: 540–545.

26. Rodriguez-Leal CM, Lopez-Lunar E, Carrascosa- Bernaldez JM, et al. Electrocardiographic surveillance in a psychiatric institution: avoiding iatrogenic cardiovascular death. Int J Psychiatry Clin Pract 2017; 21: 64–66.

27. Shao W, Ayub S, Drutel R, et al. QTc Prolongation associated with psychiatric medications: a retrospective cross-sectional study of adult inpatients. J Clin Psychopharmacol 2019; 39: 72–77.

28. Pinto-Filho MM, Brant LCC, Foppa M, et al. Major electrocardiographic abnormalities according to the Minnesota coding system among Brazilian adults (from the ELSA- Brasil Cohort Study). Am J Cardiol 2017; 119: 2081–2087.

29. Santos J, Ribeiro ALP, Andrade-Junior D, et al. Prevalence of electrocardiographic abnormalities in primary care patients according to sex and age group. A retrospective observational study. Sao Paulo Med J 2018; 136: 20–28.

30. Hasnain M and Vieweg WV. QTc interval prolongation and torsade de pointes associated with second-generation antipsychotics and antidepressants: a comprehensive review. CNS Drugs 2014; 28: 887–920.

31. ChongSA,Mythily,LumA,etal.ProlongedQTc intervals in medicated patients with schizophrenia. Hum Psychopharmacol 2003; 18: 647–649.

32. Lin CH, Chen MC, Wang SY, et al. Predictive factors for QTc prolongation in schizophrenic patients taking antipsychotics. J Formos Med Assoc 2004; 103: 437–441.

33. Polselli GM, Cotugno A, Greco S, et al. Antipsychotics and prolongation of the QTc


Therapeutic Advances in Psychopharmacology 9













interval: a clinical study. Rivista di Psichiatria 2007; 42: 327–332.

Novotny T, Florianova A, Ceskova E, et al. Monitoring of QT interval in patients treated with psychotropic drugs. Int J Cardiol 2007; 117: 329–332.

Correll CU, Frederickson AM, Figen V, et al. The QTc interval and its dispersion in patients receiving two atypical antipsychotics. Eur Arch Psychiatry Clin Neurosci 2009; 259: 23–27.

Ramos-Rios R, Arrojo-Romero M, Paz-Silva E, et al. QTc interval in a sample of long-term schizophrenia inpatients. Schizophr Res 2010; 116: 35–43.

Ozeki Y, Fujii K, Kurimoto N, et al. QTc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 401–405.

Yang FD, Wang XQ, Liu XP, et al. Sex difference in QTc prolongation in chronic institutionalized patients with schizophrenia on long-term treatment with typical and atypical antipsychotics. Psychopharmacology 2011; 216: 9–16.

Johnsen E, Aanesen K, Sriskandarajah S, et al. QTc prolongation in patients acutely admitted to hospital for psychosis and treated with second generation antipsychotics. Schizophr Res Treatment 2013; 2013: 375020.

Xiang YT, Chiu HF, Ungvari GS, et al. QTc prolongation in schizophrenia patients in Asia: clinical correlates and trends between 2004 and 2008/2009. Hum Psychopharmacol 2015; 30: 94–99.

Acciavatti T, Martinotti G, Corbo M, et al. Psychotropic drugs and ventricular repolarisation: the effects on QT interval, T-peak to T-end interval and QT dispersion. J Psychopharmacol 2017; 31: 453–460.

Scott AJ, Dunlop AJ, Brown A, et al. The prevalence of QT prolongation in a population of patients with substance use disorders. Drug Alcohol Rev 2017; 36: 239–244.

Miniati M, Simoncini M, Vanelli F, et al. QT and QTc in male patients with psychotic disorders treated with atypical neuroleptics. Scienti c World J 2017; 2017: 1951628.

Beyraghi N, Rajabi F and Hajsheikholeslami F. Prevalence of QTc interval changes in acute psychiatric care: a cross-sectional study. Int J Psychiatry Clin Pract 2013; 17: 227–231.

Golzari H, Dawson NV, Speroff T, et al. Prolonged QTc intervals on admission









54. 55.



electrocardiograms: prevalence and correspondence with admission electrolyte abnormalities. Conn Med 2007; 71: 389–397.

Seftchick MW, Adler PH, Hsieh M, et al. The prevalence and factors associated with QTc prolongation among emergency department patients. Ann Emerg Med 2009; 54: 763–768.

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

Fujii K, Ozeki Y, Okayasu H, et al. QT is longer in drug-free patients with schizophrenia compared with age-matched healthy subjects. PLoS One 2014; 9: e98555.

Zhang XY, Chen da C, Tan YL, et al. Socio- demographic and clinical characteristics of heavy and non-heavy smokers among schizophrenia inpatients in a Chinese Han population. Psychopharmacology 2014; 231: 305–314.

Malik M. Problems of heart rate correction
in assessment of drug-induced QT interval prolongation. J Cardiovasc Electrophysiol 2001; 12: 411–420.

Chan A, Isbister GK, Kirkpatrick CM, et al. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM 2007; 100: 609–615.

Vink AS, Clur SB, Wilde AAM, et al. Effect of age and gender on the QTc-interval in healthy individuals and patients with long-QT syndrome. Trends Cardiovasc Med 2018; 28: 64–75.

Mangoni AA, Kinirons MT, Swift CG, et al. Impact of age on QT interval and QT dispersion in healthy subjects: a regression analysis. Age Ageing 2003; 32: 326–331.

Rabkin SW, Cheng XJ and Thompson DJ. Detailed analysis of the impact of age on the QT interval. J Geriatr Cardiol 2016; 13: 740–748.

Park B and Lee YJ. Metabolic syndrome and
its components as risk factors for prolonged corrected QT interval in apparently healthy Korean men and women. J Clin Lipidol 2018; 12: 1298–1304.

Grandinetti A, Seifried S, Mor J, et al. Prevalence and risk factors for prolonged QTc in a multiethnic cohort in rural Hawaii. Clin Biochem 2005; 38: 116–122.

Li X, Ren H, Xu ZR, et al. Prevalence and risk factors of prolonged QTc interval among Chinese patients with type 2 diabetes. Exp Diabetes Res 2012; 2012: 234084.


N Ansermot, M Bochatay et al.

58. Carrà G, Crocamo C, Bartoli F, et al. First- generation antipsychotics and QTc: any role for mediating variables? Hum Psychopharmacol 2016; 31: 313–318.

59. Berling I and Isbister GK. Prolonged QT risk assessment in antipsychotic overdose using the QT nomogram. Ann Emerg Med 2015; 66: 154–164.

60. SeveriS,GrandiE,PesC,etal.Calciumand potassium changes during haemodialysis alter ventricular repolarization duration: in vivo and in silico analysis. Nephrol Dial Transplant 2008; 23: 1378–1386.

61. Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 2013; 6: 479–487.

62. Haugaa KH, Bos JM, Tarrell RF, et al. Institution-wide QT alert system identifies patients with a high risk of mortality. Mayo Clin Proc 2013; 88: 315–325.

63. Strauss DG, Vicente J, Johannesen L, et al. Common genetic variant risk score is associated with drug- induced QT prolongation and torsade de pointes risk: a pilot study. Circulation 2017; 135: 1300–1310.

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