Brugada Syndrome ECG Is Highly Prevalent in Schizophrenia
The causes of increased risk of sudden cardiac death in schizophrenia are not resolved. We aimed to establish (1) whether ECG markers of sudden cardiac death risk, in particular Brugada-ECG pattern, are more prevalent among patients with schizophrenia, and (2) whether increased prevalence of these ECG markers in schizophrenia is explained by confounding factors, notably sodium channel–blocking medication.
Methods and Results—
In a cross-sectional study, we analyzed ECGs of a cohort of 275 patients with schizophrenia, along with medication use. We determined whether Brugada-ECG was present and assessed standard ECG measures (heart rate, PQ-, QRS-, and QT-intervals). We compared the findings with nonschizophrenic individuals of comparable age (the Netherlands Study of Depression and Anxiety [NESDA] cohort; N=179) and, to account for assumed increased aging rate in schizophrenia, with individuals 20 years older (Hoorn cohort; n=1168), using multivariate regression models. Brugada-ECG was significantly more prevalent in the schizophrenia cohort (11.6%) compared with NESDA controls (1.1%) or Hoorn controls (2.4%). Moreover, patients with schizophrenia had longer QT-intervals (410.9 versus 393.1 and 401.9 ms; both P<0.05), increased proportion of mild or severe QTc prolongation (13.1% and 5.8% versus 3.4% and 0.0% [NESDA], versus 5.1 and 2.8% [Hoorn]), and higher heart rates (80.8 versus 61.7 and 68.0 beats per minute; both P<0.05). The prevalence of Brugada-ECG was still increased (9.6%) when patients with schizophrenia without sodium channel–blocking medication were compared with either of the control cohorts.
Brugada-ECG has increased prevalence among patients with schizophrenia. This association is not explained by the use of sodium channel–blocking medication.
Patients with severe mental illness have 14 to 32 years reduced life expectancy.1 Schizophrenia is associated with increased standardized mortality ratios for all-cause death,2 cardiovascular death,3 and sudden cardiac death (SCD).4 The causes for SCD risk in schizophrenia are unresolved.5 SCD is mostly caused by lethal cardiac arrhythmias resulting from disrupted cardiac electrophysiology (depolarization or repolarization).6 Many researchers ascribe SCD in schizophrenia to antipsychotics, because antipsychotics may cause such disruptions.7 For instance, increased SCD risk during the use of first-generation or second-generation antipsychotics is commonly ascribed to their repolarization-blocking effects, signaled by QTc prolongation.8,9 However, individual susceptibility is crucial. Comorbidities that increase susceptibility may be acquired, for example, cardiovascular disease; such conditions are more prevalent among schizophrenic individuals.3 The possibility that inherited factors are also relevant has so far received less recognition.
Editorial see p 365
Clinical Perspective on p 391
These considerations prompted us to conduct the present study. We systematically compared ECGs of a cohort of patients with schizophrenia to ECGs of 2 cohorts of nonschizophrenia control subjects and took covariates for ECG abnormalities into account. Our primary aim was to establish whether ECG markers of SCD risk are more prevalent in patients with schizophrenia than in nonschizophrenic controls. This included the Brugada ECG pattern (Brugada-ECG) and QTc duration. Our secondary aim was to study whether differences in the prevalence of these ECG markers may be explained by use of sodium channel blockers or QTc-prolonging drugs and/or presence of cardiovascular risk factors.
In a cross-sectional study, all outpatients at the Department of Severe Mental Illness, Mental Health Care Center-North Holland North (n=603), typically in psychiatric care for >10 years, were asked to participate in yearly metabolic screening in February 2008 to January 2011. Among 387 patients who agreed to participate, 275 with Diagnostic and Statistical Manual of Mental Disorders–IV classification 295.xx (schizophrenia, schizoaffective disorder, schizophreniform disorder) were included in the study cohort (Schizophrenia cohort). This study was conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained from all participants who underwent ajmaline testing.10 The Ethics Committee of the Academic Medical Center approved this study.
We compared the patients of the Schizophrenia cohort with age-comparable control persons from the Netherlands Study of Depression and Anxiety (NESDA), an ongoing longitudinal cohort study in the Netherlands.11 We used data from 179 individuals, selected randomly from a large sample of control volunteers in the NESDA study without psychiatric disorder, of whom ECG and cardiovascular measurements were made (cardiovascular subsample).12
Because several studies suggested that schizophrenic patients have higher biological age relative to their calendar age with commensurately increased prevalence of cardiovascular and metabolic disorders,13,14 we studied a second control cohort (the Hoorn Study cohort) ≈20 years older than the study cohort, in which participants, selected randomly from the population registry of the town of Hoorn, have been followed since 1989.15 After excluding 7 participants whose medication data were missing and 4 participants who used antipsychotics, we studied the ECGs of 1168 participants (Hoorn cohort).
To ensure consistent classification, all ECGs were analyzed by 1 cardiologist (H.L.T.), who was blinded to cohort status. Brugada-ECG was defined as type 1 or type 2/3 Brugada-ECG according to the Brugada syndrome (BrS) consensus criteria (Figure 1).10 Prolongation of QTc-interval (Bazett rate correction) was defined as mild (men, 431–450 ms; women, 451–470 ms) or severe (men, >450 ms; women >470 ms).16
Brugada-ECG and BrS
The diagnosis of BrS requires typical ST-segment elevations in right precordial ECG leads (type 1 Brugada-ECG) and events suggestive of cardiac arrhythmia or a family history of BrS or SCD. In most BrS patients, the baseline ECG is only suspicious for BrS (type 2/3 Brugada-ECG). To confirm or refute this suspicion, they must undergo provocation testing with a sodium channel–blocking drug (Figure 1).10 Accordingly, patients with schizophrenia with baseline type 2/3 Brugada-ECG were invited for ajmaline testing in the Academic Medical Center. All patients with type 1 Brugada-ECG (at baseline or after ajmaline testing) underwent DNA screening of SCN5A.17SCN5A encodes the α-subunit of the cardiac sodium channel,18 which drives depolarization. Moreover, family screening was offered. In the NESDA and Hoorn cohorts, ajmaline testing could not be performed. Therefore, the prevalences of baseline Brugada-ECG (type 1 or 2/3) were compared between cohorts.
Risk factors for cardiovascular disease and SCD (previous myocardial infarction, hypertension, hypercholesterolemia, diabetes mellitus, body mass index [BMI]) were derived from patient files (Schizophrenia cohort) or from medication use and patient files (control cohorts).12,15 Drug use during ECG recording or ajmaline testing was derived from patient records (Schizophrenia cohort), questionnaire (Hoorn cohort), or drug container inspection (NESDA cohort). We assessed the use of sodium channel blockers,19 QTc-prolonging drugs,20 First-generation antipsychotics, second-generation antipsychotics, antidepressants, cardiovascular drugs (nitrates, β-blockers, calcium channel antagonists, antithrombotics), and lipid-lowering drugs.
To analyze differences between cohorts in the prevalence of comorbidities and medication use, we used χ2 statistics (Pearson/Fisher exact where appropriate) for categorical variables and ANOVA for continuous variables. We performed multivariate logistic regression analyses to assess differences between cohorts in Brugada-ECG, correcting for sex and factors that were significantly (P<0.05) different between cohorts. Multivariate linear and logistic regression analyses were performed to investigate differences in quantitative ECG parameters, correcting for sex and factors that were significantly (P<0.05) different between cohorts. To evaluate the association between sodium channel blocker use and ECG outcomes, we compared schizophrenic patients with or without sodium channel blockers and performed separate analyses with patients from the Schizophrenia cohort who used no sodium channel blockers during ECG recording, using the statistical methods described above. All statistics were performed in SPSS (version 20.0 for Mac, Chicago, IL).
Table 1 shows patient characteristics. Compared with NESDA controls, patients with schizophrenia were slightly younger and more often men. They had higher BMI (27.6 versus 25.4; P<0.05), higher prevalence of diabetes mellitus (8.0% versus 1.7%; P<0.05), and a trend toward higher lipid-lowering drug use (10.5% versus 5.6%; P=0.07). Antidepressants use was significantly more frequent among schizophrenia patients (tricyclic antidepressants, 6.5%; selective serotonin receptor inhibitors, 25.1%; other antidepressants, 4.7%); 1 participant of the NESDA cohort used low-dose amitriptyline (10 mg once daily) for neuralgy. Higher antidepressants and antipsychotics use caused higher use of sodium channel blockers (28.0% versus 0.6%) and QTc-prolonging drugs (64.4% versus 1.1%).
|Schizophrenia Cohort (N=275)||NESDA Cohort (N=179)||Hoorn Cohort (N=1168)|
|Mean age, y||44.8||9.9||47.7||12.5*||66.4||6.7*|
|Sodium channel blockers||77||28.0||1||0.6*||75||6.4*|
|Selective serotonin reuptake inhibitors||69||25.1||0||0.0*||9||0.8*|
|FGA and SGA||40||14.5|
|Most commonly used antipsychotics|
Compared with Hoorn controls, schizophrenia patients were more often men and ≈20 years younger (by design). The prevalence of diabetes mellitus was comparable (8.2% versus 10.1%), but schizophrenia patients had lower prevalence of previous myocardial infarction, hypertension, and hypercholesterolemia (1.5%, 14.2%, and 16.7% versus 5.9%, 40.4%, and 37.6%; all P<0.05). Accordingly, they less often used cardiovascular drugs (5.5% versus 23.2%; P<0.05), but had comparable use of lipid-lowering drugs. They used antidepressants more often compared with Hoorn controls (tricyclic antidepressants, 6.5% versus 0.4%; selective serotonin reuptake inhibitors, 25.1% versus 0.8%; other, 4.7% versus 0.3%; all P<0.05). Antipsychotics were only used by schizophrenia patients. First-generation antipsychotics were used by 18%, second-generation antipsychotics by 54%, and both second- and first-generation antipsychotics by 15%; 14% used no antipsychotics. Sodium channel blockers and QTc-prolonging drugs were used more frequently by schizophrenia patients (28.0% versus 6.4% and 64.4% versus 3.8%).
Brugada-ECG in Schizophrenia Cohort
In the Schizophrenia cohort, 32 patients (11.6%) had Brugada-ECG at baseline: 1 had type 1 Brugada-ECG, whereas 31 had type 2/3 Brugada-ECG (Table 2). This was significantly more compared with NESDA or Hoorn controls, where no patient had type 1 Brugada-ECGs, whereas 2 (1.1%) and 28 (2.4%; both P<0.05 versus Schizophrenia cohort), respectively, had type 2/3 Brugada-ECG. Figure 2 shows Brugada-ECG prevalences in study cohorts and reported prevalences.21 In the Schizophrenia cohort, ajmaline testing was offered to the 31 patients with type 2/3 Brugada-ECG, accepted by 23 and found positive in 10. Thus, at least 11 patients had type 1 Brugada-ECG at baseline or after ajmaline testing (4% of all schizophrenia patients; 6 men; age, 48.1±10.2 years). One patient had a mutation in SCN5A (c.3956G>T). Family screening was offered to all 11 patients with type 1 Brugada-ECG, but only conducted in 5 relatives of 4 patients, because other relatives were unavailable or declined investigation; no investigated relative had Brugada-ECG. Table I in the Data Supplement shows ECG parameters, comorbidities, and medication use of all patients with type 1 Brugada-ECG. Four schizophrenia patients with type 2/3 Brugada-ECG who declined ajmaline testing provided additional medical and family history; none had syncope, dizziness, or palpitations. No SCD at age <45 years had occurred in the family, and no family members had schizophrenia.
|Schizophrenia Cohort||NESDA Cohort (N=179)||Hoorn Cohort (N=1168)|
|All (N=275)||With Sodium Channel Blockers (N=77)||Without Sodium Channel Blockers (N=198)|
|Mild (men, 431–450 ms; women, 451–470 ms)||36||13.1||14||18.2||22||11.1||6||3.4||60||5.1|
|Severe (men, >450 ms; women, >470 ms)||16||5.8||7||9.1||9||4.5||0||0.0||33||2.8|
|Heart rate, beats per minute||80.8||16.9||82.9||16.0||80.0||17.2||61.7||9.8*,†||68.0||11.9‡,§|
|QRS duration, ms||91.6||11.8||94.5||13.6||90.5||10.8*||91.0||10.3||101.8||16.9‡,§|
|PR duration, ms||159.8||21.5||165.8||22.7||157.4||20.6*||152.5||32.6||174.0||25.3‡,§|
|QTc duration, ms||410.9||29.8||416.3||31.9||408.8||28.7||393.1||25.1*,†||401.9||28.5|
Analysis of QTc-Interval and Other ECG Variables
Compared with NESDA controls, patients with schizophrenia had higher heart rate (80.8 versus 61.7 beats per minute; P<0.05) and longer QTc-interval (410.9 versus 393.1 ms; P<0.05). They also had higher proportion of mild or severe QTc prolongation (13.1% and 5.8% versus 3.4% and 0.0%), but not when corrected for relevant covariates (BMI, diabetes mellitus status, use of sodium channel blockers or QTc-prolonging drugs). Compared with Hoorn controls, patients with schizophrenia had higher heart rate (80.8 versus 68.0 beats per minute; P<0.05), but shorter QRS-interval (91.6 versus 101.8 ms; P<0.05) and PR-interval (159.8 versus 174.0 ms; P<0.05). QTc-interval was not different (410.9 versus 401.9 ms; P=0.251). The proportion of mild or severe QTc prolongation was higher in the schizophrenia cohort (13.1% and 5.8% versus 5.1% and 2.8%), but not significantly different when corrected for relevant covariates (BMI, cardiovascular medication use, use of sodium channel blockers or QTc-prolonging drugs).
Effects of Sodium Channel Blockers on ECG Parameters
To study whether the use of sodium channel blockers affected the prevalence of Brugada-ECG and ECG parameters in schizophrenia, we compared schizophrenia patients who used sodium channel blockers (n=77) to those who did not (n=198; Table 2). The groups differed in PR and QRS duration (165.8 versus 157.4 and 94.5 versus 90.5 ms; both P<0.05), but were otherwise similar. The prevalence of Brugada-ECG was not different (16.9% versus 9.6%; P=0.091).
To study whether ECG differences between the Schizophrenia and control cohorts may be attributed to the use of sodium channel blockers, we compared ECG parameters between schizophrenia patients who used no sodium channel blockers with both control cohorts. Compared with NESDA controls, this schizophrenia subset had more Brugada-ECG (9.6% versus 1.1%; P<0.05), higher heart rate (80.0 versus 61.7 beats per minute; P<0.05), and longer QTc duration (408.8 versus 393.1 ms; P<0.05). Mild or severe QTc prolongation was more prevalent in this schizophrenia subset (11.1% and 4.5% versus 3.4% and 0.0%; P<0.05), but not significantly when corrected for relevant covariates (sex, BMI, QT-prolonging drugs, and diabetes mellitus).
Similarly, compared with Hoorn controls, this schizophrenia subset had higher prevalence of Brugada-ECG (9.6% versus 2.4%; P<0.05), higher heart rate, and shorter QRS- and PR-intervals. Mild or severe QTc prolongation was more prevalent in this schizophrenia subset (11.1% and 4.5% versus 5.1% and 2.8%; P<0.05), but not significantly when corrected for relevant covariates (sex, BMI, QT-prolonging drugs, and diabetes mellitus).
We found that Brugada-ECG has higher prevalence in schizophrenia patients than in similarly aged or ≈20 years older nonschizophrenic controls. Importantly, the prevalence was also significantly increased in patients with schizophrenia who used no sodium channel–blocking drugs (notably antipsychotics). In contrast, although we also found in accordance with previous studies7,22,23 that schizophrenia is associated with QTc prolongation, QTc prolongation was largely explained by confounding factors, including the use of QTc-prolonging (antipsychotics) drugs.
Schizophrenia and Brugada-ECG
As many as 4% of patients with schizophrenia had type 1 Brugada-ECG compared with an estimated prevalence of 0.05% in the general population.21 This suggests a higher prevalence of BrS in schizophrenia. This could partly explain the increased SCD risk in schizophrenia. Indeed, the yearly SCD incidence in our Schizophrenia cohort (19 of 8561 patient-years; 0.2%; not shown) is higher than the incidence in the general population in the Netherlands (0.1%).24 Schizophrenia patients with BrS would be vulnerable to the arrhythmia-causing effects of sodium channel–blocking medication, which include many antipsychotics,25 particularly in combination with the increased prevalence of cardiovascular risk factors that increase SCD risk. Still, it must be noted that type 1 Brugada-ECG per se is not sufficient for the diagnosis BrS if associated signs are absent. We did not find such signs in the schizophrenia cohort. However, these signs are difficult to ascertain or obtain in patients with schizophrenia. For instance, unexplained syncope (a presumed symptom of cardiac arrhythmias in BrS) is nonspecific in these patients, often resulting from the blood pressure–lowering effects of antipsychotics. Moreover, we had little opportunity to obtain a family history, because most patients had sparse contact with their relatives, and most available relatives declined investigation. Therefore, although the association between schizophrenia and Brugada-ECG suggested that BrS is more prevalent in schizophrenia, we could not prove this. It could be argued that the use of antipsychotics may provoke a Brugada-ECG, thereby facilitating easier detection by ECG analysis. This may especially apply to sodium channel blockers.25,26 Still, >50% of patients with Brugada-ECG used no sodium channel blockers (Table I in the Data Supplement), and differences remained significant when correcting for and stratifying according to the use of sodium channel blockers. Furthermore, it is unlikely that the use of sodium channel blockers alone results in Brugada-ECG when an innate factor is absent.27 Therefore, the high prevalence of Brugada-ECG found here can probably not be solely attributed to the use of sodium channel–blocking antipsychotics.
Future studies are required to establish the causes for the increased prevalence of Brugada-ECG (or BrS) in schizophrenia. Emerging evidence indicates that schizophrenia and acute psychosis may impact on cardiac electrophysiology.22 Accordingly, genetic studies suggest that the pathobiology of schizophrenia involves various voltage-gated ion channels.28–30 Because these proteins also control cardiac electrophysiology, variants in their encoding genes (KCNH2, CACNA1C) may increase arrhythmia and SCD risk. We did not screen KCNH2 and CACNA1C in the patients with Brugada-ECG, but only SCN5A, because SCN5A is the only gene routinely screened at our institution in BrS patients.17 Nevertheless, our observations lend support to the more general notion that (nonstructural) brain disease and (electric) heart disease share common underlying pathomechanisms. For instance, in epilepsy, too, the increased incidence of SCD31 may stem from the expression of the same (mutant) ion channel in brain and heart.32,33 Furthermore, a recent study34 showed that Neuregulin1, related with both epilepsy and schizophrenia, is also associated with SCD. Autonomic dysregulation may also explain the association between BrS and schizophrenia, being reported in both conditions. However, although reduced vagal tone exists in patients with schizophrenia (including those not using antipsychotics),35 the increased vagal tone may unmask Brugada-ECG and cause SCD in BrS.26
Schizophrenia and SCD Risk
If proven in future studies that increased prevalence of Brugada-ECG in schizophrenia reflects increased prevalence of BrS, this finding could contribute to a better understanding of excess SCD risk in patients with schizophrenia, especially those using (antipsychotic or nonantipsychotic) medication that blocks cardiac depolarization. The risk for lethal cardiac arrhythmias in BrS is mediated by dysfunctional (impaired) depolarizing ion channels, notably the cardiac sodium channel. BrS patients, through their innately impaired cardiac sodium channels (reduced depolarization reserve), are particularly vulnerable to additional sodium channel block exerted by some antipsychotics (and other drugs). BrS patients may also be more vulnerable to the depolarization-blocking effects of concomitant conditions.36 In particular, acute myocardial ischemia/infarction (more likely to occur in schizophrenic patients, given their higher prevalence of diabetes mellitus) impairs cardiac depolarization.37 BrS patients may have particularly increased risk of lethal cardiac arrhythmias during acute myocardial ischemia/infarction. Thus, the combined effects of higher prevalence of Brugada-ECG and concomitant factors that impair cardiac depolarization, such as drug use or (risk factors for) ischemic heart disease, may partly explain the increased incidence of SCD in schizophrenia.
Similarly, we found increased prevalence of QTc prolongation in patients with schizophrenia. Although mostly mild and not hazardous per se, this QTc prolongation may identify individuals at increased risk for lethal cardiac arrhythmias and SCD if concomitant factors that cause further QTc prolongation (eg, cardiac hypertrophy or heart failure caused by hypertension or heart disease) are also present. However, QTc prolongation observed in patients with schizophrenia was largely explained by confounding factors, suggesting that QTc prolongation is not strongly associated with schizophrenia per se, in contrast with the occurrence of Brugada-ECG. We used Bazett formula for heart rate correction, because this method is most widely used and allows for easy comparison with other studies. Although Bazett formula may overestimate QTc duration at higher heart rates when compared with other rate correction methods, it is not resolved which method best captures the covariates of QT duration.38
Strengths and Limitations
A major strength of our study is that it involved a large group of patients with schizophrenia with data on medication use and relevant comorbidities during ECG recording. Although it is difficult to gather these data in patients with severe mental illness, the newly introduced yearly cardiovascular screening among schizophrenic patients enabled us to perform this study. Moreover, we compared our findings with 2 well-defined control cohorts.
Our study has some limitations. We were unable to perform ajmaline testing in both control cohorts, and 8 patients with schizophrenia declined ajmaline testing. Furthermore, data on family history of SCD in the Schizophrenia cohort were limited due to disturbed family relations, precluding a firm diagnosis of BrS. Clinical implications of type 2/3 Brugada-ECG are not well defined. Nonetheless, the difference in the prevalence of type 2/3 Brugada-ECG seems sufficient to warrant further research (eg, replication of our findings in a separate cohort of patients with schizophrenia) and prudence with drug prescription.
We found a strongly elevated prevalence of Brugada-ECG in patients with schizophrenia. Additional studies are required to elucidate whether this increased prevalence reflects an association of BrS and schizophrenia, and the underlying causes. If confirmed, our findings warrant ECG recording as part of periodic cardiovascular screening in patients with schizophrenia and prudent prescription of sodium channel blockers, to minimize SCD risk.39
We wish to express our gratitude to Jan Peetoom, MD, internist, who performed the initial ECG analysis in the schizophrenia cohort; Remco Boerman, BSc, nurse practitioner, who recorded all ECGs in the schizophrenia cohort; and Irene Beems who contributed to data collection. We greatly appreciate the contributions of Paulien Homma, MSc, and Loes Bekkers, MSc, for data collection and data entry; Julien Barc, PhD, and Leander Beekman, BSc, for DNA analysis; and Patrick Souverein, PhD, for his help in analyzing medication data.
Sources of Funding
H.L.T. was supported by the
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The causes of increased risk of sudden cardiac death (SCD) in schizophrenia are unresolved. Many researchers ascribe SCD in schizophrenia to the use of antipsychotics, because these drugs affect cardiac electrophysiology, evoking lethal cardiac arrhythmias. QTc-interval–prolonging properties, in particular, have been implicated. Innate factors may also increase SCD risk, but are little studied. We aimed to establish (1) whether ECG markers of SCD risk, in particular Brugada-ECG pattern and QTc prolongation, are more prevalent in schizophrenia, and (2) whether increased prevalence of these ECG markers in schizophrenia is explained by confounding factors, notably sodium channel– or potassium channel–blocking drugs. In a cross-sectional study, we analyzed ECGs, along with drug use, of a cohort of 275 patients with schizophrenia, focusing on Brugada-ECG and QTc duration. We compared findings with a cohort of nonschizophrenic individuals of comparable age (the Netherlands Study of Depression and Anxiety [NESDA] cohort; N=179) and, to account for assumed increased aging rate in schizophrenia, with individuals 20 years older (Hoorn cohort; n=1168), using multivariate regression models. Brugada-ECG was significantly more prevalent in the Schizophrenia cohort (11.6%) compared with NESDA controls (1.1%) or Hoorn controls (2.4%). Moreover, schizophrenia patients had longer QT-intervals, increased proportion of mild/severe QTc prolongation, and higher heart rates compared with either of the control cohorts. The prevalence of Brugada-ECG remained increased (9.6%) when patients with schizophrenia without sodium channel–blocking drugs were compared with either of the control cohorts. In contrast, QTc prolongation was largely explained by confounding factors, including the use of QTc-prolonging (antipsychotic) drugs. If confirmed, our findings warrant ECG recording as part of periodic cardiovascular screening in schizophrenia patients and prudent prescription of sodium channel–blocking drugs.