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. Author manuscript; available in PMC: 2019 Jan 15.
Published in final edited form as: Am J Cardiol. 2017 Nov 13;121(2):182–187. doi: 10.1016/j.amjcard.2017.10.010

Risk of Cardiac Events Associated with Antidepressant Therapy in Patients with Long QT Syndrome

Meng Weng a,b, Barbara Szepietowska a, Bronislava Polonsky a, Scott McNitt a, Arthur J Moss a, Wojciech Zareba a, David S Auerbach c,d
PMCID: PMC5742310  NIHMSID: NIHMS914303  PMID: 29174490

Abstract

Long QT Syndrome (LQTS) patients are at a high risk for cardiac events. Many LQTS patients are treated with antidepressant drugs (ADs). We investigated the LQTS genotype specific risk of recurrent cardiac arrhythmic events (CAEs) associated with ADs therapy. The study included 59 LQT1 and 72 LQT2 patients from the Rochester-based LQTS Registry with QTc prolongation and a history of AD therapy. Using multivariate Anderson-Gill models we estimated the LQTS genotype specific risk of recurrent CAEs (ventricular tachyarrhythmias, aborted cardiac arrest, or sudden cardiac death) associated with time-dependent ADs. Specifically, we examined the risk associated with all ADs, SSRIs, and ADs classified on the CredibleMeds list (www.CredibleMeds.org) as “Conditional” or “Known risk of Torsades de pointe (TdP)”. After adjusting for baseline QTc, sex, and time-dependent beta blocker usage, there was an increased risk of recurrent CAEs associated with ADs in LQT1 patients (HR=3.00, 95%CI: 1.55–5.84, p=0.001), but not in LQT2 patients (HR=1.05, 95%CI: 0.56–1.99, p=0.872; LQT1 vs. LQT2 interaction, p<0.001). Similarly, LQT1 patients who were on SSRIs or ADs with “Known risk of TdP” had a higher risk of recurrent CAEs than those off all ADs, whereas there was no association in LQT2 patients. ADs with “Conditional risk of TdP” were not associated with the risk of recurrent CAEs in any of the groups. In conclusion, the risk of recurrent CAEs associated with time-dependent ADs is higher in LQT1 patients, but not in LQT2 patients. Results suggest a LQTS genotype-specific effect of ADs on the risk of arrhythmic events.

Keywords: Antidepressant Drug, Long QT Syndrome, Cardiac Arrhythmia, Sudden Cardiac Death, Depression

Introduction

Long QT Syndrome (LQTS) is a genetic disease due to mutations in genes encoding cardiac ion channels (or interacting) proteins1,2. LQT1 and LQT2 are due to loss-of-function mutations in KCNQ1 (LQT1) and KCNH2 (LQT2) genes that encode cardiac slow and rapid delayed rectifier potassium channels, respectively3. These mutations lead to corrected QT (QTc) prolongation on the cardiac electrocardiogram (ECG), and a higher risk of ventricular arrhythmias and sudden cardiac death (SCD)3. The disease manifestations may raise psychological burdens, such as depression4,5, and many LQTS patients are treated with antidepressants (ADs)6. Many studies investigating the pro-arrhythmic effect of ADs used QT duration as the endpoint 7,8. However, QT prolongation is not a perfect surrogate for ventricular arrhythmias9,10. Case reports11,12 and epidemiological studies 13–18 with a clinical endpoint yielded mixed results whether ADs are associated with a higher risk of ventricular arrhythmias and SCD. Since LQTS patients are at an increased risk of ventricular arrhythmias, ADs use in this clinical population requires careful evaluation. The present study evaluated the LQTS genotype specific risk of recurrent cardiac arrhythmias associated with AD use.

Methods

The Rochester-based LQTS Registry includes detailed clinical, pharmacologic, and genetic information about LQTS probands and their affected and unaffected family members19. A 12 lead ECG was obtained at enrollment. QTc duration was calculated using the Bazett’s formula. The present study consisted of 59 LQT1 and 72 LQT2 patients with QTc prolongation (male QTc>450ms, female QTc>470ms) and a history of AD use (eTable 1). All patients had only one mutant LQTS gene. The LQTS Registry is approved by the University of Rochester Research Subject Review Board (RSRB00025305). HIPAA requirements for accounting for disclosure, consent, and withdrawal of consent were followed. There was no race/ethnicity or sex restriction for inclusion.

The primary endpoint was cardiac arrhythmic events (CAEs). This was a composite endpoint of recurrent ventricular tachyarrhythmia (sustained ventricular tachycardia, Torsades de pointe [TdP], and ventricular fibrillation), aborted cardiac arrest (ACA), and SCD. Multiple sources were used to ascertain the endpoint. For probands, ventricular tachyarrhythmia and ACA were collected from both patients’ self-reports and physicians’ reports. For family members, ventricular tachyarrhythmias and ACA were first assessed by direct contact with patients or relatives and then by medical record review of self-reported cardiac events. Implantable cardiac defibrillator (ICD) interrogations were obtained from patients in the LQTS ICD Registry. All SCDs were adjudicated by LQTS investigators based on medical records and descriptions surrounding death.

AD and beta blocker use, drug name, and dates of start/discontinuation of drugs were collected from enrollment and annual follow-up questionnaires from patients and physicians. We examined the risk of recurrent CAEs associated with overall AD use, as well as the most commonly used AD group, selective serotonin reuptake inhibitor (SSRIs). Furthermore, ADs were classified according to the CredibleMeds QTDrug list classification of the risk of TdP [dataset]20. The risk of TdP was assigned based on multiple sources of evidence (e.g. FDA’s Adverse Event Reporting System, case reports of TdP, studies of QT prolongation, and laboratory studies of relevant pharmacologic action, etc.)21. Drugs were classified as: (1) not on the CredibleMeds QTDrug list; (2) Conditional risk of TdP (these drugs prolong QT and have a risk of developing TdP but only under certain known conditions such as overdose or drug-drug interaction); (3) Possible risk of TdP (these drugs can cause QT prolongation but there is insufficient evidence that the drugs, when used as directed in labeling, have a risk of causing TdP); and (4) Known risk of TdP (these drugs prolong QT intervals and have a risk of TdP when used as directed in labeling)21.

Comparisons of clinical characteristics between LQT1 and LQT2 patients were performed by Chi-square test for categorical variables and two-sample t-test or Mann-Whitney U test (for skewed distributions) for continuous variables. Incidence rates of recurrent CAEs were calculated as the number of events per 100 person-years.

We performed Andersen-Gill models22 with time-dependent AD use (a patient’s status of AD use could switch between on and off ADs over time) to assess the association of on vs. off ADs with the risk of recurrent CAEs. Follow-up was from birth to (1) last contact, (2) death due to reasons other than sudden cardiac death, (3) March 2016, or (4) sudden cardiac death or 10th CAEs (97% of all patients developed ≤10 ventricular arrhythmic events), whichever occurred first. To estimate the hazard ratios (HRs) of recurrent CAEs associated with ADs by LQTS genotype, we fitted a model including time-dependent ADs, LQTS genotype (LQT1 vs. LQT2), and an interaction term of these two variables. As many LQTS patients were prescribed SSRIs, we also assessed the risk of recurrent CAEs associated with SSRIs in LQT1 and LQT2 patients separately. Briefly, SSRIs was analyzed as a time-dependent categorical variable with four mutually exclusive groups: on SSRIs only, on other ADs only, on SSRIs and other ADs simultaneously, and off all ADs. We presented the HR of CAEs associated with on SSRIs only vs. off all ADs.

Next, we estimated the HR of recurrent CAEs associated with ADs in each class on the CredibleMeds list. We analyzed ADs as a time-dependent categorical variable with five levels. At any given time point, patients were classified into five mutually exclusive groups: 1) patients on ADs that are not on the CredibleMeds list, 2) patients on ADs with “Conditional risk of TdP”, 3) patients on ADs with “Possible risk of TdP”, 4) patients on ADs with “Known risk of TdP”, and 5) patients off all ADs (reference group). If a patient was on more than one class of ADs simultaneously, the patient was classified in the AD group with the highest risk level (known>possible>conditional>not on the list). To further estimate the effect of the most commonly used drug in the “Known risk of TdP” and SSRI group (Citalopram), we compared the risk of recurrent CAEs between patients on Citalopram to those off all ADs, in a similar way as described above (with six mutually exclusive groups: on Citalopram, on other ADs with “Known risk of TdP”, on ADs with “Possible risk of TdP”, on ADs with “Conditional risk of TdP”, on ADs not on the list, and off all ADs).

Using SAS software version 9.4 (SAS Institute, North Carolina), all analyses were stratified by sex, and adjusted for baseline QTc duration and time-dependent beta blocker therapy. Significance (two-tailed tests) was defined as p<0.05.

Results

Table 1 lists the clinical and demographic characteristics of the study population. There was no difference in follow-up and total time on any ADs, SSRIs, and ADs in each CredibleMeds risk of TdP classes between LQT1 and LQT2 patients. Baseline QTc was similar between the two groups. There were 53 CAEs in 59 LQT1 patients during a mean follow-up of 53±20 years, and 91 CAEs in 72 LQT2 patients during a mean follow-up of 48±17 years. The percentage of patients who developed CAEs during follow-up was higher in LQT2 than in LQT1 patients (54% vs. 25%).

Table 1.

Patient Characteristics

Characteristics QTc Prolongation
LQT1 (n=59) LQT2 (n=72) LQT1 vs. LQT2
Male 9 (15%) 26 (36%) 0.007
Follow-up (years) 53±20 48±17 0.163
ADs use and time on ADs
 Overall ADs 59 (100%) 72 (100%) 1.000
 Total time per patient on any ADs (years) 5.92±5.60 5.44±5.01 0.965
 SSRIs 48 (81%) 53 (74%) 0.294
 Total time per patient on SSRI (years) 5.00±4.98 3.28±3.61 0.065
 ADs with conditional TdP risk 41 (69%) 38 (53%) 0.052
 Total time per patient on ADs with conditional TdP risk (years) 3.02±4.05 2.47±4.46 0.146
 ADs with possible TdP risk 5 (8%) 8 (11%) 0.616
 Total time per patient on ADs with Possible TdP risk (years) 0.43±2.36 0.33±1.24 0.628
 ADs with known TdP risk 21 (36%) 31 (43%) 0.385
 Total time per patient on ADs with known TdP risk (years) 2.34±4.09 1.74±2.94 0.832
 ADs not on the CredibleMeds list 10 (17%) 18 (25%) 0.263
 Total time per patient on ADs not on the list (years) 0.76±2.31 1.14±2.82 0.279
Anti-arrhythmic Treatment
 Beta-blockers 50 (85%) 66 (92%) 0.216
 Left cardiac sympathetic denervation 0 4 (6%) 0.127
 Pacemaker 4 (7%) 19 (26%) 0.003
 Implantable Cardiac Defibrillator 26 (44%) 43 (60%) 0.074
Electrocardiogram
 Age at baseline ECG (years) 36±20 29±16 0.048
 RR (sec) 893±198 879±195 0.691
 PR (sec) 161±27 149±25 0.015
 QRS (sec) 82±14 85±21 0.355
 QTc (sec) 515±52 519±53 0.572
Number of patients with cardiac arrhythmic events (CAEs)
 Ventricular tachyarrhythmias 15 (25%) 36 (50%) 0.004
 Aborted cardiac arrest (ACA) 6 (10%) 13 (18%) 0.202
 Sudden cardiac death (SCD) 0 1 (1%) 1.000
 CAEs (Ventricular tachyarrhythmias, ACA, or SCD) 15 (25%) 39 (54%) <0.001
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Data are mean ± SD for continuous variables and number of patients (%) for categorical variables. ADs: antidepressant drugs; CAEs: cardiac arrhythmic events; LQTS: Long QT Syndrome; SSRIs: selective serotonin reuptake inhibitor; TdP: Torsades de pointe; ACA: aborted cardiac arrest; SCD: sudden cardiac death.

In both groups, patients had a higher incidence rate of CAEs when on vs. off ADs (Figure 1). LQT1 patients had a greater difference in the rate of CAEs on vs. off ADs (5.73 vs. 1.20 CAEs per 100 person years) compared to LQT2 patients (3.58 vs. 2.53 CAEs per 100 person-years). As is shown in Figure 2, after stratifying for sex, and adjusting for baseline QTc and time-dependent beta-blocker therapy, there was an increased risk of recurrent CAEs when LQT1, but not LQT2, patients were on ADs (LQT1 vs. LQT2 interaction, p<0.001.)

Figure 1. Rate of recurrent CAEs when LQT1 and LQT2 patients were on ADs.

Figure 1

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Rate of recurrent CAEs (ACA, SCD, ventricular tachyarrhythmia, censored at 10 events) while on all ADs, SSRI ADs, ADs classified on the CredibleMeds List as Known Risk of TdP and Conditional (Cond.) Risk of TdP, and off all ADs. A. LQT1. B. LQT2. ADs: antidepressant drugs; CAEs: cardiac arrhythmic events; Cond: conditional; LQTS: Long QT Syndrome; SSRIs: selective serotonin reuptake inhibitor; TdP: Torsades de pointe; ACA: aborted cardiac arrest; SCD: sudden cardiac death.

Figure 2. LQT1 patients are at an increased risk of CAEs when on ADs.

Figure 2

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Hazard ratios of recurrent CAEs associated with all ADs, SSRI ADs, ADs with known risk of TdP, and ADs with conditional risk of TdP. Patients off all ADs were used as the reference group. Models were stratified by sex, and adjusted for baseline QTc duration and time-dependent beta blocker usage. ADs: antidepressant drugs; CAEs: cardiac arrhythmic events; Cond: conditional; HR: hazard ratio; LQTS: Long QT Syndrome; SSRIs: selective serotonin reuptake inhibitor; TdP: Torsades de pointe; ACA: aborted cardiac arrest; SCD: sudden cardiac death.

Similar to the results of overall AD use, both groups had higher rates of CAEs when on SSRIs compared to off all ADs (Figure 1). LQT1 patients had a greater difference in the rate of CAEs while on SSRIs vs. off all ADs compared to LQT2 patients. After adjusting for the same covariates as above, we observed similar LQTS genotype-specific effects of SSRIs on the risk of recurrent CAEs. LQT1, but not LQT2, patients were at an increased risk of recurrent CAEs on SSRIs vs. off all ADs (Figure 2).

As ADs with “Possible risk of TdP” and ADs not on the CredibleMeds list had 0 CAEs in many groups, rates of recurrent CAEs and HR estimates are not presented for these two groups. As shown in Figure 1, LQT1 patients had a higher rate of CAEs while on ADs with “Known risk of TdP” vs. when off all ADs, whereas LQT2 patients had a lower rate of CAEs while on ADs with “Known risk of TdP” vs. off all ADs.

Consistent with findings of overall ADs and SSRIs, the LQTS genotype-specific effect on the risk of CAEs was also observed for ADs with “Known risk of TdP.” LQT1 patients on ADs with “Known risk of TdP” had a higher risk of recurrent CAEs compared to those off all ADs. By contrast, in LQT2 patients the risk did not differ significantly when on ADs with “Known risk of TdP vs. off all ADs. ADs with “Conditional risk of TdP” were not associated with a change in the risk of recurrent CAEs in any group. Furthermore, in LQT1 patients we examined the most commonly used AD in the “Known risk of TdP” group, Citalopram (17 patients reported a history of Citalopram usage), which is a SSRI. LQT1 patients on Citalopram were at an increased risk of recurrent CAEs compared to those off all ADs (HR=6.79, 95% CI 3.18–14.51, p<0.001). Due to limited number of LQT2 patients on Citalopram, we were unable to compute the HR for Citalopram in LQT2 patients.

Discussion

This study provides insights into the LQTS genotype specific effect of ADs on the risk of recurrent CAEs. We observed an increased risk of recurrent CAEs associated with overall AD use, SSRIs, and ADs with “Known risk of TdP” in LQT1, but not in LQT2 patients.

Findings from prior epidemiologic studies investigating the association between ADs and the risk of cardiac events are inconsistent13,14,16,17. These studies used administrative databases and included diverse clinical populations. A study using a case-time-control design demonstrated an increased risk of out-of-hospital cardiac arrest associated with ADs, specifically SSRIs and tricyclic antidepressants (TCAs)13. The increased risk associated with SSRIs was primarily driven by Citalopram13. In line with these results, we found an increased risk of recurrent CAEs associated with overall ADs use, SSRIs, and Citalopram vs. off all ADs in the LQT1 group. Several other studies compared Citalopram to a specific antidepressant. In a large Canada cohort, Citalopram was associated with a higher risk of cardiac events within 90 days of Citalopram prescription, compared to Paroxetine or Sertaline18. By contrast, two large studies of Medicaid enrollees reported no change in the risk of sudden cardiac death or ventricular arrhythmias associated with Citalopram, compared to reference antidepressants (Fluoxetine, Paroxetine, or Sertraline)14,17.

Our finding of ADs classified on the CredibleMeds list as “Known risk of TdP” is consistent with a Swedish case-control study of people 65 years and older, although for a different endpoint. This Swedish study reported a higher all-cause mortality associated with both ADs with “Known risk of TdP” and ADs with “Conditional risk of TdP” 23.

It should be noted that different from previous studies that used large administrative databases and included diverse clinical populations, our study focused on LQTS patients from the Rochester-based LQTS Registry. While administrative databases provide very large sample size, they are prone to non-differential outcome misclassification24. Ventricular arrhythmias may be fatal and thus not identified if they occur outside hospital settings17,24. In our study, SCDs was assessed by direct contact with relatives or friends of the deceased and all cases were adjudicated by LQTS investigators based on a description of the circumstances around death and medical records. Moreover, 53% of our study population had an ICD implanted. ICD interrogation provided ECG recordings of arrhythmic events that occurred outside the hospital. Thus, our study likely captured arrhythmic events more accurately than studies using administrative datasets.

QT prolongation via blockade of cardiac rapid delayed rectifier potassium current (IKr) is the primary proposed pro-arrhythmic mechanism for ADs7,8,25–28. Some ADs have other adverse cardiovascular effects such as increased heart rate, increased sympathetic activity, decreased heart rate variability, and cardiac conduction delays28,29. To explore potential mechanisms we compared ECG measures (heart rate, QTc, and QRS durations) in patients with ECG recordings both on and off ADs. In both LQT1 and LQT2 patients, we did not observe significant difference in these ECG measures while on vs. off ADs (eTable 2). These ECG results are only preliminary due to limited sample size and uncontrolled confounding (e.g. age, ECG readers, and medications at multiple ECG recordings per patient) and need to be examined in a larger prospective cohort with more rigorous control for confounders.

The mechanisms for the LQTS genotype-specific effect are unclear. We propose two potential mechanisms. First, LQT2 mutations in KCNH2, particularly those in the pore-S6 region, which has been suggested as the binding region for hERG blockers 30,31, may lead to the lack of target/binding sites for ADs to bind and exert IKr blocking effects. Therefore, LQT2 patients may be unaffected by the pro-arrhythmic effect of ADs. While we were not powered to perform multivariable analysis by mutation location, exploratory descriptive analyses suggested patients with LQT2 S5-pore-S6 domain mutations (n=18) had a lower rate of recurrent CAEs when on vs. off ADs (eFigure 1). These results indicate LQT2-pore mutations may alter the ability of ADs to exert IKr blocking effects. Our second proposed mechanism is increased sympathetic activity associated with some ADs. Previous studies suggested that TCAs and SNRIs were associated with increased sympathetic activity29,, which is an established trigger for arrhythmias in LQT1 patients32. While emotion and stress are triggers for arrhythmias in LQT2 patients, lethal events arise under many conditions that are not associated with increased sympathetic tone33. It is also possible that both mechanisms operate simultaneously.

Our study has limitations that need to be considered. Except for Citalopram, our limited sample size did not allow us to thoroughly examine the risk of CAEs associated with specific ADs. While the use of ADs and SSRIs were associated with an increased risk of CAEs in LQT1 patients, it does not imply that all ADs and all SSRIs are associated with an increased risk of CAEs in LQT1 patients. Future prospective studies in a large cohort of LQTS patients are needed to confirm these results, and rigorously examine the risk of CAEs associated with specific ADs.

There is an increase in the risk of recurrent CAEs associated with overall AD use, SSRIs, and ADs with “known risk of TdP”, such as Citalopram, in LQT1 patients, but not in LQT2 patients. Results from the study establish the basis for future studies to investigate the mechanisms for this LQTS genotype-specific effect of ADs. It is important to consider genotype when prescribing ADs to LQTS patients.

Supplementary Material

supplement

Acknowledgments

Financial Support

The project was supported by University of Rochester CTSA Career Development award (NIH-NCATS KL2TR000095, DSA, Bethesda, MD, USA) and National Institutes of Health (5U01NS090405-03, DSA, HL-33843, AJM; HL-51618, AJM; & HL-123483, AJM, Bethesda, MD, USA), with no involvement in the study design, analyses, or interpretation.

Acknowledgements & Funding:

The project was supported by University of Rochester CTSA Career Development award (NIH-NCATS KL2TR000095, DSA, Bethesda, MD, USA) and National Institutes of Health (5U01NS090405-03, DSA, HL-33843, AJM; HL-51618, AJM; & HL-123483, AJM, Bethesda, MD, USA.) All authors have read and agree to the journals authorship agreement and policy on disclosure of potential conflicts of interest. None of the authors have any conflicts of interest pertinent to the content of the manuscript.

Footnotes

Disclosures: None

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