Abstract
Background
There are limited data on electrocardiogram (ECG) characteristics and their association with psychotropic drugs in schizophrenia.
Methods
Using a cross-sectional design, we included Danish primary care patients with first-time digital ECGs from 2001 to 2015. Patients diagnosed with schizophrenia before ECG recording were matched 1:5 on age, sex, and ECG recording year to controls without psychiatric disease. Multivariable logistic regression was used to compute odds ratios (ORs) with 95% confidence intervals (CIs).
Results
We included 4486 patients with schizophrenia matched with 22 430 controls (median age, 47 years; male, 55%). Between groups, the prevalence of abnormal ECGs was similar (54%, P = .536), but patients with schizophrenia demonstrated higher median heart rate (79 vs 69 beats per minute, P < .001) and Fridericia-corrected QT (QTc) interval (416 vs 412 ms, P < .001) than controls. QTc prolongation was also more prevalent among patients with schizophrenia (3.4% vs 1.1%, P < .001), and so were pathological Q waves (5.3% vs 3.9%, P < .001). Patients with schizophrenia less frequently demonstrated left ventricular hypertrophy (6.1% vs 9.6%, P < .001) and atrial fibrillation or flutter (0.7% vs 1.4%, P < .001). Among patients with schizophrenia only, particularly antipsychotics were associated with abnormal ECGs (OR, 1.20; 95% CI, 1.04–1.39).
Conclusions
Patients with schizophrenia demonstrate a different cardiovascular risk profile than matched controls without psychiatric disease, with higher prevalence of elevated heart rate, QTc prolongation, and pathological Q waves, and lower prevalence of left ventricular hypertrophy and atrial fibrillation or flutter. Particularly antipsychotics were associated with abnormal ECGs. This underscores an integrated care approach when ECG abnormalities are detected in this group.
Keywords: antipsychotics, cardiovascular disease, electrocardiogram, schizophrenia, polypharmacy, QT prolongation
Introduction
Schizophrenia is associated with a nearly 20-year reduced life expectancy compared with the general population.1 Reasons for this excess mortality are multifactorial, but cardiovascular disease represents the leading cause of death.2,3 This may partly be attributed to antipsychotics, which are known to prolong the QT interval4,5 occasionally leading to Torsades de Pointes ventricular tachycardia and potentially sudden cardiac death.6 Other major causes of sudden cardiac death in this group also include ischemic heart disease and myocardial infarction.7 Furthermore, around 20% of patients with schizophrenia receive antipsychotic polypharmacy (ie exposure to more than one antipsychotic), and most also receive concomitant psychotropic drugs often causing unpredictable QT prolongation.8 Adverse effects of antipsychotics may further result in cardiovascular risk factors including diabetes, obesity, or dyslipidemia.9 Patients with schizophrenia additionally have unhealthy lifestyle habits including poor diet, sedentary lifestyle, excessive smoking, or substance abuse,9 and they rarely follow screening programs or attend regular health examinations.10
As patients with schizophrenia are less likely to have timely and proper medical care, they tend to neglect cardiovascular symptoms such as chest pain, palpitations, or pre-syncope.11 Therefore, early detection of cardiovascular disease using objective screening tools may improve clinical outcomes in this group. Electrocardiography (ECG) remains essential in assessing cardiovascular risk and may be particularly valuable as it is readily available, noninvasive, and inexpensive. However, to date, no large-scale epidemiological studies have thoroughly and systematically assessed ECGs in the setting of schizophrenia.
As such, using a large contemporary clinical laboratory database including nearly 1 million digital ECGs, we investigated ECG characteristics of patients with schizophrenia compared with matched controls without prior psychiatric diagnoses or psychotropic drug use. Furthermore, among patients with schizophrenia only, we investigated the association of redeemed prescriptions of psychotropic drugs with abnormal ECGs.
Methods
Study Design and Population
This was a Danish register-based cross-sectional study including the first-time digital ECG recorded following schizophrenia onset and the first-time digital ECG recorded for age-, sex- and ECG recording year-matched controls without prior psychiatric diagnoses or psychotropic drug use. We chose the first rather than, eg, the latest available ECG recording to study a more homogeneous population, where differences in number of recorded ECGs, development of cardiovascular risk factors or comorbidities, redeemed prescriptions of cardiovascular drugs, or mortality risk over time between patients with schizophrenia and controls were less likely to affect our findings.
Patients with schizophrenia (International Classification of Diseases, 10th Edition [ICD-10]: F20) were identified by in- and outpatient hospital contacts in the Danish Psychiatric Central Research Register.12 Diagnoses from emergency room visits were disregarded due to low validity. Controls were identified as those without prior psychiatric diagnoses (ICD-10: F00–99) or as those not redeeming any prescriptions of antipsychotics, antidepressants, lithium, or benzodiazepines within 180 days prior to ECG recording. Data on age and sex of patients were obtained from the Danish Civil Registration System.13 Patients with missing age or sex and those <16 years of age at time of ECG recording were excluded. Data on vital status was obtained from the Danish Register of Causes of Death14 to ensure that patients were not erroneously registered with a death date prior to ECG recording.
Electrocardiogram Acquisition
We obtained ECGs from a large contemporary population of mainly primary care patients referred to the central core facility Copenhagen General Practitioners’ Laboratory (CGPL) for ECG recording from 2001 to 2015, as described elsewhere.15 Of note, CGPL serviced both primary care and specialty outpatient clinics including psychiatry. All 12-lead ECGs were recorded at rest and in supine position, digitally stored in the MUSE Cardiology Information System (GE Healthcare), and processed and automatically scored using the Marquette 12SL algorithm.16 Furthermore, at CGPL, trained ECG technicians have manually described all recorded ECGs that further have been overread by a consultant cardiologist. Using statements generated by the 12SL algorithm, we excluded ECGs of poor quality and with pacemaker rhythms.
Definition of Electrocardiogram Measurements
The 12SL algorithm was used to calculate ECG measurements including heart rate, P-wave duration, PR interval, QRS duration, QT interval, and corrected QT (QTc) interval. We disregarded certain ECGs not suitable for interpretation of these measurements (supplementary table S1). Bazett, Fridericia, and Framingham correction formulas were used to derive the QTc interval. For each formula, we calculated linear regression slopes and R2 values of the QTc interval against the RR interval to identify the most applicable to our study population. Slopes and R2 values closest to 0 indicated the least remaining influence of the RR interval. We observed that the Fridericia formula demonstrated superior correction performance over the remaining formulas, with a lower slope and R2 value (supplementary figure S1). QTc prolongation was defined as >450 ms for males and >470 ms for females.17
Definition of Electrocardiogram Abnormalities
The 12SL algorithm was further used to define ECG abnormalities including Sokolow–Lyon or Cornell voltage criteria for left ventricular hypertrophy (LVH), atrial fibrillation or flutter, first-degree atrioventricular block, right bundle branch block (RBBB), incomplete RBBB, left bundle branch block (LBBB), incomplete LBBB, left anterior fascicular block (LAFB), left posterior fascicular block (LPFB), pathological Q waves, ST depression or inverted T waves, and ST elevation. Furthermore, we defined ECGs with intraventricular conduction disturbance based on QRS duration >120 ms not fulfilling criteria for RBBB or LBBB. We disregarded certain ECGs not suitable for interpretation of these abnormalities (supplementary table S1). Supplementary table S2 displays criteria used to define these ECG abnormalities.
Medical Comorbidities, Procedures, and Concomitant Drugs
To increase the likelihood of excluding ECGs with pacemaker rhythms, we used the Danish National Patient Register18 to identify patients with a prior pacemaker or implantable cardioverter defibrillator using ICD and Nordic Classification of Surgical Procedures (NCSP) codes, whichever came first. Furthermore, we used ICD codes in the Danish National Patient Register to identify heart failure, myocardial infarction, atrial fibrillation or flutter, valvular heart disease, hypertension, hyperlipidemia, diabetes, chronic obstructive pulmonary disease, and chronic kidney disease diagnosed prior to ECG recording. We also used NCSP codes to identify percutaneous coronary intervention for myocardial infarction, radiofrequency ablation for atrial fibrillation or flutter, aortic or mitral valve surgery for valvular heart disease, and renal replacement therapy for chronic kidney disease.
The Danish National Prescription Register19 was used to identify redeemed prescriptions of the psychotropic drugs (ie antipsychotics, antidepressants, lithium, and benzodiazepines) within 180 days prior to ECG recording using Anatomical Therapeutic Chemical (ATC) codes. We used definitions of first- and second-generation antipsychotics and antipsychotic polypharmacy from a prior study.20 Furthermore, redeemed prescriptions of cardiovascular drugs were identified. Usually, hypertension, hyperlipidemia, diabetes, and chronic obstructive pulmonary disease are managed in primary care, and patients may not necessarily have ICD codes registered. Therefore, prior redeemed prescriptions of antihypertensives (at least dual therapy), lipid-lowering drugs, antidiabetics, and beta adrenergic or anticholinergic inhalants were further used to define these comorbidities, as performed previously.21Supplementary table S3 displays ICD, NCSP, and ATC codes. Finally, we used an internet-based register of QT-prolonging drugs (https://crediblemeds.org) to identify drugs other than antipsychotics, antidepressants, and lithium with known or possible QT prolongation risk (supplementary table S4).
Statistical Analysis
Continuous variables were reported as medians with 25th–75th percentiles and categorical variables as counts with percentages. Differences between variables were compared using Mann–Whitney U and chi-square tests, as appropriate.
We used logistic regression to investigate the association of redeemed prescriptions of psychotropic drugs with abnormal ECGs (ie at least one of the predefined ECG abnormalities). Each drug was analyzed individually, with no drug use as reference, adjusted for age, sex, medical comorbidities, and other psychotropic and other QT-prolonging drugs. Odds ratios (ORs) with 95% confidence intervals (CIs) were computed.
A two-sided P value <.05 was considered statistically significant. All data management and analysis were performed using SAS, version 9.4 (SAS Institute Inc.) and R, version 3.5.0 (R Foundation for Statistical Computing, Vienna, Austria).
Ethics
The Danish Data Protection Agency approved use of data (reference, 2007-58-0015; internal reference, GEH-2014-014; I-Suite number, 02732). By Danish law, ethical approval is not required for retrospective register-based studies.
Results
Patient Characteristics
Of 978 901 ECGs, we included the first-time ECG recording from 4486 patients with schizophrenia matched to 22 430 controls without prior psychiatric diagnoses or psychotropic drug use (supplementary figure S2). Median age at time of ECG recording was 47 (36–57) years, and 55% of patients were male. Compared with controls, patients with schizophrenia had higher prevalence of heart failure, hyperlipidemia, diabetes, chronic obstructive pulmonary disease, and chronic kidney disease and of receiving other QT-prolonging and cardiovascular drugs. The prevalence of myocardial infarction, atrial fibrillation or flutter, valvular heart disease, and hypertension was similar between groups. Nearly 75% of patients with schizophrenia received antipsychotics, and more than 30% of patients received antipsychotic polypharmacy, antidepressants, and benzodiazepines, respectively (table 1).
Table 1.
Patient Characteristics
| Patients With Schizophrenia (n = 4486) |
Matched Controls (n = 22 430) |
P-value | |
|---|---|---|---|
| Demographics | |||
| Age at ECG recording, years | 47.0 [36.0–57.0] | 47.0 [36.0–57.0] | 1.000 |
| Males | 2449 (54.6) | 12 245 (54.6) | 1.000 |
| Age at schizophrenia onset, years | 38.0 [28.0–49.0] | NA | NA |
| Schizophrenia duration, years | 7.0 [3.0–12.0] | NA | NA |
| Medical comorbidities | |||
| Heart failure | 99 (2.2) | 227 (1.0) | <.001 |
| Myocardial infarction | 75 (1.7) | 359 (1.6) | .778 |
| Atrial fibrillation or flutter | 73 (1.6) | 334 (1.5) | .532 |
| Valvular heart disease | 29 (0.6) | 95 (0.4) | .059 |
| Hypertension | 330 (7.4) | 1498 (6.7) | .106 |
| Hyperlipidemia | 409 (9.1) | 1559 (7.0) | <.001 |
| Diabetes | 452 (10.1) | 1018 (4.5) | <.001 |
| Chronic obstructive pulmonary disease | 491 (10.9) | 1337 (6.0) | <.001 |
| Chronic kidney disease | 69 (1.5) | 226 (1.0) | .002 |
| Psychotropic drugs | |||
| Antipsychotics | 3340 (74.5) | NA | NA |
| Antipsychotic polypharmacy | 1414 (31.5) | NA | NA |
| Low-potency FGAs | 771 (17.2) | NA | NA |
| Mid-potency FGAs | 754 (16.8) | NA | NA |
| High-potency FGAs | 294 (6.6) | NA | NA |
| Amisulpride | 61 (1.4) | NA | NA |
| Aripiprazole | 413 (9.2) | NA | NA |
| Clozapine | 606 (13.5) | NA | NA |
| Olanzapine | 873 (19.5) | NA | NA |
| Paliperidone | 84 (1.9) | NA | NA |
| Quetiapine | 529 (11.8) | NA | NA |
| Risperidone | 572 (12.8) | NA | NA |
| Sertindole | 58 (1.3) | NA | NA |
| Ziprasidone | 127 (2.8) | NA | NA |
| Antidepressants | 1412 (31.5) | NA | NA |
| SSRIs | 866 (19.3) | NA | NA |
| TCAs | 239 (5.3) | NA | NA |
| SNRIs | 218 (4.9) | NA | NA |
| NaSSAs | 232 (5.2) | NA | NA |
| Lithium | 106 (2.4) | NA | NA |
| Benzodiazepines | 1512 (33.7) | NA | NA |
| Concomitant drugs | |||
| Other QT-prolonging drugs | 689 (15.4) | 2342 (10.4) | <.001 |
| Loop diuretics | 241 (5.4) | 374 (1.7) | <.001 |
| Thiazide diuretics | 239 (5.3) | 1164 (5.2) | .731 |
| ACEIs or ARBs | 332 (7.4) | 2161 (9.6) | <.001 |
| Mineralocorticoid receptor antagonists | 47 (1.0) | 81 (0.4) | <.001 |
| Beta blockers | 213 (4.7) | 1072 (4.8) | .959 |
| Calcium channel blockers | 190 (4.2) | 1199 (5.3) | .002 |
| Digoxin | 34 (0.8) | 118 (0.5) | .075 |
| Antianginal drugs | 49 (1.1) | 165 (0.7) | .018 |
| Antiplatelets | 307 (6.8) | 1151 (5.1) | <.001 |
| Anticoagulants | 31 (0.7) | 205 (0.9) | .169 |
Note: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ECG, electrocardiogram; FGA, first-generation antipsychotic; NA, not available; NaSSA, noradrenergic and specific serotonergic antidepressant; p25–p75, 25th–75th percentiles; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. Data reported as median (p25–p75) or n (%). P-values based on Mann–Whitney U and chi-square tests, as appropriate.
Electrocardiogram Characteristics
The prevalence of abnormal ECGs between patients with schizophrenia and controls was similar (54.0% vs 54.5%, P = .536). Of note, 241 patients with schizophrenia (5.4%) and 1876 controls (8.4%) had missing data on heart rate, P-wave duration, PR interval, QRS duration, QT interval, and QTc interval as they demonstrated ECG abnormalities that were not suitable for interpretation of these measurements (supplementary table S1).
Compared with controls, patients with schizophrenia demonstrated higher median heart rate (79 [68–91] vs 69 [61–77] beats per minute, P < .001) and QTc interval (416 [402–431] vs 412 [400–425] ms, P < .001). QTc prolongation was also more prevalent among patients with schizophrenia compared with controls (3.4% vs 1.1%, P < .001), and so were pathological Q waves (5.3% vs 3.9%, P < .001) that were most often located anteriorly and inferiorly. Patients with schizophrenia less frequently demonstrated ECG criteria for LVH (6.1% vs 9.6%, P < .001) and atrial fibrillation or flutter (0.7% vs 1.4%, P < .001; table 2). We did not observe any other differences in ECG characteristics that were both clinically meaningful and statistically significant.
Table 2.
ECG Characteristics
| Patients With Schizophrenia (n = 4486) |
Matched Controls (n = 22 430) |
P-value | |
|---|---|---|---|
| ECG measurementsa | |||
| Heart rate, bpm | 79.0 (68.0–91.0) | 68.5 (61.0–77.0) | <.001 |
| P-wave duration, ms | 106.0 (98.0–114.0) | 108.0 (100.0–116.0) | .002 |
| PR interval, ms | 154.0 (140.0–166.0) | 154.0 (142.0–170.0) | <.001 |
| QRS duration, ms | 90.0 (84.0–98.0) | 92.0 (86.0–100.0) | <.001 |
| QT interval, ms | 380.0 (360.0–404.0) | 394.0 (376.0–412.0) | <.001 |
| QTc interval, ms | 416.0 (402.0–431.0) | 412.0 (400.0–425.0) | <.001 |
| ECG abnormalities | |||
| Left ventricular hypertrophy | 273 (6.1) | 2151 (9.6) | <.001 |
| Atrial fibrillation or flutter | 32 (0.7) | 311 (1.4) | <.001 |
| First-degree atrioventricular block | 78 (1.7) | 487 (2.2) | .074 |
| Right conduction disturbance | 131 (2.9) | 791 (3.5) | .046 |
| Right bundle branch block | 47 (1.0) | 249 (1.1) | .774 |
| Incomplete right bundle branch block | 84 (1.9) | 542 (2.4) | .031 |
| Left conduction disturbance | 105 (2.3) | 429 (1.9) | .069 |
| Left bundle branch block | 18 (0.4) | 109 (0.5) | .524 |
| Incomplete left bundle branch block | 6 (0.1) | 43 (0.2) | .523 |
| Left anterior fascicular block | 36 (0.8) | 128 (0.6) | .086 |
| Left posterior fascicular block | 45 (1.0) | 149 (0.7) | .019 |
| Intraventricular conduction disturbance | 34 (0.8) | 186 (0.8) | .694 |
| QTc prolongation | 151 (3.4) | 248 (1.1) | <.001 |
| Pathological Q waves | 237 (5.3) | 883 (3.9) | <.001 |
| Anterior | 143 (3.2) | 528 (2.4) | .001 |
| Inferior | 100 (2.2) | 382 (1.7) | .018 |
| Lateral | 7 (0.2) | 43 (0.2) | .752 |
| ST-T deviations | 131 (2.9) | 676 (3.0) | .774 |
| ST depression or inverted T waves | 85 (1.9) | 361 (1.6) | .193 |
| Anterior | 61 (1.4) | 257 (1.1) | .256 |
| Inferior | 22 (0.5) | 97 (0.4) | .681 |
| Lateral | 24 (0.5) | 96 (0.4) | .390 |
| ST elevation | 48 (1.1) | 336 (1.5) | .033 |
| Anterior | 35 (0.8) | 239 (1.1) | .098 |
| Inferior | 13 (0.3) | 86 (0.4) | .418 |
| Lateral | 3 (0.1) | 30 (0.1) | .350 |
Note: bpm, beats per minute; ECG, electrocardiogram; p25–p75, 25th–75th percentiles; QTc, corrected QT. Data reported as median (p25–p75) or n (%). P-values based on Mann–Whitney U and chi-square tests, as appropriate.
aMissing data for 241 patients with schizophrenia (5.4%) and 1876 controls (8.4%).
To test the robustness and consistency of our findings, we performed a sensitivity analysis of patients without medical comorbidities diagnosed prior to ECG recording. This yielded 3176 patients with schizophrenia (71%) and 18 018 controls (80%) for further analysis. Overall, we observed no differences in ECG characteristics compared with the main analysis (supplementary table S5).
Psychotropic Drugs and Abnormal Electrocardiograms
Among patients with schizophrenia only, redeemed prescriptions of antipsychotics (OR, 1.20; 95% CI, 1.04–1.39), antipsychotic polypharmacy (OR, 1.29; 95% CI, 1.13–1.48), and benzodiazepines (OR, 1.15; 95% CI, 1.01–1.32) were associated with abnormal ECGs. This was consistent with most of the individual antipsychotics, particularly clozapine (OR, 2.08; 95% CI, 1.73−2.51), with the exception of aripiprazole (OR, 0.73; 95% CI, 0.59−0.90). Redeemed prescriptions of antidepressants, with the exception of serotonin and norepinephrine reuptake inhibitors (OR, 0.75; 95% CI, 0.57–0.99), lithium, and other QT-prolonging drugs were not associated with differential risk of abnormal ECGs (table 3). An additional analysis confirmed that QTc prolongation, right (ie RBBB and incomplete RBBB) and left (ie LBBB, incomplete LBBB, LAFB, and LPFB) conduction disturbances, and pathological Q waves primarily drove these associations (table 3).
Table 3.
Results From Multivariable Logistic Regression of the Association of Redeemed Prescriptions of Psychotropic Drugs With Abnormal ECGs Among Patients With Schizophrenia Only
| Abnormal ECG | LVH | AF | 1° AV Block | RCD | LCD | IVCD | QTc Prolongation | Pathological Q Waves | ST-T Deviations | |
|---|---|---|---|---|---|---|---|---|---|---|
| Antipsychotics |
1.20
(1.04–1.39) |
0.99 (0.73–1.35) |
0.63 (0.20–2.00) |
0.79 (0.42–1.47) |
1.21 (0.76–1.93) |
1.07 (0.65–1.78) |
1.62 (0.58–4.50) |
0.73 (0.47–1.14) |
1.10 (0.78–1.56) |
0.82 (0.53–1.26) |
| Antipsychotic polypharmacy |
1.29
(1.13–1.48) |
1.03 (0.75–1.40) |
0.86 (0.27–2.71) |
0.57 (0.30–1.10) |
1.58
(1.07–2.33) |
1.62
(1.04–2.52) |
1.16 (0.53–2.55) |
1.18 (0.80–1.73) |
1.26 (0.92–1.74) |
0.68 (0.42–1.09) |
| Low-potency FGAs |
1.26
(1.07–1.48) |
0.81 (0.54–1.23) |
0.99 (0.23–4.22) |
1.01 (0.49–2.10) |
1.11 (0.68–1.82) |
1.17 (0.67–2.05) |
2.11 (0.92–4.85) |
1.50 (0.98–2.30) |
1.44 (0.99–2.09) |
0.76 (0.42–1.38) |
| Mid-potency FGAs |
1.21
(1.02–1.42) |
1.08 (0.75–1.55) |
1.53 (0.51–4.64) |
1.25 (0.68–2.31) |
1.03 (0.63–1.68) |
1.62 (0.99–2.66) |
0.66 (0.20–2.14) |
1.54 (1.00–2.39) |
0.79 (0.53–1.18) |
1.18 (0.72–1.93) |
| High-potency FGAs | 1.09 (0.85–1.39) |
1.16 (0.69–1.96) |
0.87 (0.10–7.64) |
0.41 (0.12–1.42) |
1.48 (0.77–2.84) |
0.93 (0.40–2.15) |
1.08 (0.24–4.84) |
1.47 (0.81–2.67) |
1.93
(1.22–3.03) |
0.84 (0.35–2.00) |
| Amisulpride | 0.94 (0.56–1.57) |
2.32 (0.94–5.71) |
NA | NA | 0.62 (0.08–4.72) |
1.01 (0.13–7.77) |
NA | 0.89 (0.20–4.00) |
0.34 (0.04–2.69) |
NA |
| Aripiprazole |
0.73
(0.59–0.90) |
1.11 (0.71–1.72) |
0.22 (0.01–5.11) |
0.45 (0.14–1.46) |
0.87 (0.47–1.64) |
0.54 (0.22–1.30) |
0.43 (0.09–1.94) |
0.33
(0.14–0.80) |
0.42
(0.21–0.85) |
0.34
(0.13–0.87) |
| Clozapine |
2.08
(1.73–2.51) |
0.55
(0.31–0.97) |
1.31 (0.19–8.80) |
0.45 (0.13–1.60) |
3.08
(1.97–4.81) |
2.87
(1.68–4.91) |
1.41 (0.51–3.92) |
1.17 (0.68–2.01) |
1.72
(1.13–2.62) |
0.56 (0.25–1.25) |
| Olanzapine | 1.07 (0.92–1.25) |
1.25 (0.90–1.74) |
1.32 (0.40–4.30) |
1.25 (0.67–2.34) |
0.84 (0.52–1.37) |
1.01 (0.60–1.72) |
1.56 (0.70–3.47) |
0.81 (0.51–1.28) |
1.10 (0.77–1.58) |
1.12 (0.69–1.81) |
| Paliperidone | 0.72 (0.46–1.12) |
0.86 (0.33–2.28) |
NA | NA |
2.47
(1.03–5.94) |
0.46 (0.06–3.49) |
NA | 0.49 (0.11–2.22) |
0.51 (0.15–1.78) |
0.74 (0.17–3.23) |
| Quetiapine |
0.82
(0.68–0.99) |
1.03 (0.68–1.56) |
0.49 (0.06–4.16) |
1.03 (0.49–2.20) |
0.71 (0.38–1.31) |
0.53 (0.24–1.19) |
0.67 (0.20–2.20) |
0.75 (0.43–1.31) |
0.92 (0.59–1.45) |
0.92 (0.50–1.69) |
| Risperidone | 0.96 (0.80–1.15) |
0.96 (0.65–1.42) |
0.46 (0.12–1.81) |
0.77 (0.37–1.61) |
1.01 (0.59–1.74) |
1.81
(1.09–3.00) |
0.72 (0.21–2.48) |
0.59 (0.32–1.08) |
0.81 (0.52–1.26) |
0.94 (0.53–1.64) |
| Sertindole | 1.39 (0.82–2.37) |
0.54 (0.07–4.08) |
NA | NA | NA | NA | NA |
13.47
(5.84–31.06) |
3.58
(1.29–9.94) |
1.23 (0.16–9.37) |
| Ziprasidone | 0.89 (0.62–1.28) |
0.77 (0.29–2.02) |
NA | NA | 0.74 (0.21–2.63) |
0.31 (0.04–2.66) |
0.99 (0.10–9.58) |
0.66 (0.18–2.35) |
1.16 (0.48–2.81) |
1.11 (0.35–3.54) |
| Antidepressants | 0.93 (0.81–1.07) |
0.66
(0.48–0.92) |
1.88 (0.63–5.59) |
1.48 (0.84–2.60) |
1.16 (0.77–1.73) |
1.00 (0.62–1.61) |
1.68 (0.78–3.62) |
1.49
(1.02–2.19) |
0.90 (0.65–1.25) |
0.95 (0.61–1.49) |
| SSRIs | 0.99 (0.85–1.16) |
0.74 (0.50–1.08) |
2.49 (0.79–7.89) |
1.19 (0.62–2.26) |
0.82 (0.50–1.35) |
1.15 (0.68–1.95) |
1.29 (0.54–3.10) |
1.67
(1.11–2.51) |
0.71 (0.47–1.07) |
1.06 (0.64–1.75) |
| TCAs | 1.16 (0.88–1.52) |
0.84 (0.43–1.63) |
1.31 (0.15–11.30) |
1.74 (0.64–4.76) |
2.28
(1.21–4.31) |
0.95 (0.34–2.70) |
5.10
(1.90–13.68) |
1.10 (0.51–2.37) |
1.08 (0.58–2.05) |
0.99 (0.39–2.56) |
| SNRIs |
0.75
(0.57–0.99) |
0.51 (0.23–1.14) |
NA | 0.65 (0.14–2.92) |
1.22 (0.54–2.72) |
0.98 (0.35–2.76) |
1.15 (0.23–5.76) |
1.04 (0.46–2.33) |
1.11 (0.57–2.13) |
1.31 (0.57–2.97) |
| NaSSAs | 1.00 (0.76–1.31) |
0.98 (0.54–1.79) |
1.50 (0.16–14.29) |
1.55 (0.61–3.97) |
0.97 (0.42–2.22) |
1.08 (0.43–2.68) |
0.98 (0.21–4.67) |
1.14 (0.58–2.26) |
1.14 (0.63–2.08) |
0.81 (0.31–2.10) |
| Lithium | 1.35 (0.90–2.03) |
1.41 (0.60–3.30) |
NA | 0.58 (0.06–5.77) |
2.05 (0.77–5.46) |
1.68 (0.48–5.85) |
3.83 (0.83–17.74) |
1.67 (0.58–4.76) |
1.37 (0.56–3.38) |
1.63 (0.48–5.54) |
| Benzodiazepines |
1.15
(1.01–1.32) |
0.94 (0.69–1.27) |
1.07 (0.35–3.28) |
0.86 (0.48–1.54) |
1.09 (0.73–1.64) |
0.91 (0.57–1.45) |
1.02 (0.47–2.20) |
1.92
(1.31–2.81) |
0.97 (0.70–1.34) |
0.73 (0.47–1.14) |
| Other QT-prolonging drugs | 0.94 (0.80–1.12) |
1.08 (0.75–1.56) |
0.81 (0.19–3.44) |
1.56 (0.86–2.85) |
0.88 (0.52–1.49) |
1.11 (0.64–1.90) |
0.43 (0.11–1.72) |
1.90
(1.25–2.88) |
1.01 (0.69–1.49) |
1.13 (0.68–1.89) |
Note: AF, atrial fibrillation or flutter; AV, atrioventricular; CI, confidence interval; ECG, electrocardiogram; FGA, first-generation antipsychotic; IVCD, intraventricular conduction disturbance; LCD, left conduction disturbance; LVH, left ventricular hypertrophy; NA, not available; NaSSA, noradrenergic and specific serotonergic antidepressant; OR, odds ratio; QTc, corrected QT; RCD, right conduction disturbance; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. Data reported as OR (95% CI). Bold font indicates significant result.
Discussion
In this nationally representative study, we compared differences in cardiovascular-disease-related ECG characteristics between 4486 patients with schizophrenia and 22 430 controls without prior psychiatric diagnoses or psychotropic drug use matched on age, sex, and ECG recording year. We report a series of key findings underscoring the importance of ECG utilization in early detection of potentially unrecognized coexisting cardiovascular disease in this vulnerable group. First, we demonstrated that, compared with controls, patients with schizophrenia had more frequently elevated heart rate, QTc prolongation, and pathological Q waves and less frequently ECG criteria for LVH and atrial fibrillation or flutter. Second, we demonstrated that these findings were consistent in a sensitivity analysis of patients without medical comorbidities. Third, we demonstrated that, among patients with schizophrenia only, redeemed prescriptions of particularly antipsychotics were associated with abnormal ECGs.
Considering the excess premature cardiovascular mortality among patients with schizophrenia, it has become more evident that underrecognition and undertreatment of particularly cardiovascular disease in this vulnerable group represent an important public health problem. Sudden cardiac death risk among patients with schizophrenia is nearly 3-fold and presumed to be an important cause of death.3 Although LVH, atrial fibrillation or flutter, and QRS prolongation have been associated with increased sudden cardiac death risk,7 these ECG abnormalities were surprisingly less common among patients with schizophrenia who more frequently demonstrated elevated heart rate, QTc prolongation, and pathological Q waves. This suggests that patients with schizophrenia appear to have a different cardiovascular risk profile than patients without psychiatric disease, which may explain differences in mechanisms of sudden cardiac death between these groups. Unfortunately, comparative ECG studies within this field are sparse, underpowered, and often without background population controls, thus making it difficult to draw any firm conclusions from their data.22–24
Elevated resting heart rate is associated with increased sudden cardiac death risk,7 and the higher heart rate observed among patients with schizophrenia compared with controls in our study may be attributed to several mechanisms. Sinus tachycardia is a well-recognized adverse effect of antipsychotics,4 and as nearly 75% of patients with schizophrenia received antipsychotics, this may explain our findings. It is also likely that the elevated heart rate among patients with schizophrenia occurred due to mental distress or the high burden of medical comorbidities including heart failure, hyperlipidemia, diabetes, chronic obstructive pulmonary disease, and chronic kidney disease.
QT prolongation also plays an important role in the increased sudden cardiac death risk in schizophrenia as it ultimately may cause Torsades de Pointes.3 However, QT prolongation per se rarely runs a fatal course except when accompanied by important risk factors including older age, female sex, antipsychotic or other psychotropic polypharmacy, hypokalemia or other electrolyte disturbances, and cardiovascular disease.5 We observed QTc prolongation to be prevalent among patients with schizophrenia, thus corroborating prior studies.23,24 Of note, sertindole was the only antipsychotic strongly associated with QTc prolongation in our study, and this is in keeping with findings from a large meta-analysis that further reported QTc prolongation with several other antipsychotics that we included.25 In contrast, we observed aripiprazole to decrease QTc prolongation risk, which is in line with prior research.26 Although clozapine was associated with abnormal ECGs in our study, mainly right and left conduction disturbances and pathological Q waves, this was most likely driven by confounding by indication as patients receiving clozapine usually suffer from more severe schizophrenia and may consequently have excess cardiovascular risk. However, current evidence suggests that clozapine is overall associated with reduced long-term mortality risk.27
Ischemic heart disease and myocardial infarction are also major causes of sudden cardiac death.7 We observed a higher prevalence of pathological Q waves among patients with schizophrenia compared with controls, thus corroborating findings of a prior small-scale study.24 Importantly, pathological Q waves may be suggestive of prior or silent and potentially unrecognized myocardial infarction, which may occur in up to 75% of patients with schizophrenia, eg due to lack of traditional chest pain symptoms.22 If myocardial infarction is unrecognized (ie pathological Q waves are not detected), outcomes are poor, with increased risks of heart failure and mortality.28
Limitations
The retrospective observational nature of our study carries its own set of limitations. Residual or unaccounted confounding due to unavailable data in our registers on ECG indications, lifestyle habits including smoking status, anthropometric measures, blood samples in relation to ECG recordings, severity of schizophrenia, medication adherence, or changes in prescribing patterns may affect our findings. Furthermore, the impact of each ECG abnormality on outcomes is beyond the scope of our study, as this will require adjustment and exclusion of certain ECG abnormalities for the abnormality of interest. However, this certainly warrants further investigation in future studies.
Clinical Implications
Currently, an ECG is recommended in case of cardiovascular risk factors or symptoms or prescription of psychotropic polypharmacy or an antipsychotic with established increased risks of QT prolongation, Torsades de Pointes, and sudden cardiac death.8 However, among patients with schizophrenia or other severe mental illnesses, clinical guidelines on management when ECG abnormalities are detected remain limited. Our findings of a similar prevalence of abnormal ECGs but a different distribution of type of abnormality between patients with schizophrenia and controls may be valuable in guiding clinicians to pay special attention to timely detect ECG abnormalities suggestive of cardiovascular disease and consequently incorporate a more integrated care approach. This includes (1) closer ECG monitoring; (2) treatment revision if clinically feasible including avoidance of psychotropic polypharmacy and revision of the antipsychotic dosage or drug choice; (3) revision or addition of cardiovascular preventive drugs including statins, aspirin, angiotensin-converting enzyme inhibitors, or beta blockers; and (4) consideration of referral to secondary care for further clinical examination and potentially imaging studies such as echocardiography or cardiac magnetic resonance imaging. We speculate that such an integrated care approach of closer follow-up when ECG abnormalities are detected may help in improving clinical outcomes in this group, but further work is needed to explore this.
Conclusions
Patients with schizophrenia more frequently demonstrate elevated heart rate, QTc prolongation, and pathological Q waves and less frequently ECG criteria for LVH and atrial fibrillation or flutter than patients without psychiatric disease. Among patients with schizophrenia only, particularly antipsychotics were associated with abnormal ECGs, which primarily was driven by QTc prolongation, right and left conduction disturbances, and pathological Q waves. This underscores the importance of an integrated care approach in case of ECG abnormalities in this vulnerable group paying attention to early detection of unrecognized coexisting cardiovascular disease.
Funding
Danish Heart Foundation (18-R125-A8382-22086); Eva and Henry Frænkel Memorial Foundation.
Supplementary Material
Acknowledgements
Dr Polcwiartek reported receiving speaking fees from Lundbeck. Dr Kragholm reported receiving speaking fees from Novartis and research grants from the Laerdal Foundation. Dr Hansen reported receiving speaking fees from AstraZeneca and research grants from TrygFonden, the Danish Heart Foundation, and the Laerdal Foundation. Dr Atwater reported receiving speaking fees from Medtronic and Biosense Webster, research grants from Boston Scientific and Abbott Vascular, and acting as adviser to Biotronik and Medtronic. Dr Friedman reported receiving salary support from the NIH; research grants from the National Cardiovascular Data Registry, Boston Scientific, Biosense Webster, and Abbott; and educational grants from Boston Scientific, Medtronic, Abbott, and Biotronik. Dr Jimmi Nielsen reported receiving speaking fees from Bristol-Myers Squibb and Lundbeck. Prof Søgaard reported receiving research grants from Biotronik, EBR Systems, and GE Healthcare and acting as adviser to AstraZeneca, Biotronik, and Novartis. Prof Torp-Pedersen reported receiving speaking fees from Bayer and research grants from Bayer and Biotronik. Dr Jensen reported receiving research grants from the Obel Family Foundation. The remaining authors have nothing to declare.
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