Is there a dose-dependent relationship between amitriptyline and cardiovascular risk?

Comment by InpharmD Researcher

There is limited data on amitriptyline’s dose-dependent cardiovascular effects, especially in patients with a history of ventricular arrhythmias. Current evidence suggests that lower doses may not significantly increase this risk, but doses above 100 mg are associated with an elevated risk of sudden cardiac death (Table 1). While the 2020 American Heart Association statement did not associate amitriptyline with atrial fibrillation or flutter, it highlighted a potential risk of Brugada Syndrome with tricyclic antidepressants (TCAs) as a class. An examination of amitriptyline serum concentrations revealed a potential association between higher nortriptyline levels and prolonged QTc intervals, indicating a potential cardiac risk. Case reports, such as those documenting instances of amitriptyline toxicity-induced myocarditis, highlight the need for cautious use, particularly in individuals with a history of ventricular arrhythmias.

Background

According to a 2020 scientific statement from the American Heart Association in drug-induced arrhythmias, amitriptyline or tricyclic antidepressants (TCAs) as a whole therapeutic class were not listed as potential agents that may cause or exacerbate atrial fibrillation or atrial flutter. On the other hand, the use of TCAs was associated with a 2.3 to 15.3% incidence of drug-induced Brugada Syndrome and 0% incidence of ventricular arrhythmias via INa blockade. Data on the incidence of TCA-induced Brugada Syndrome are available only in patients having overdosed, and not in patients on therapeutic doses. [1]

A 2022 systematic review and meta-analysis (N= 6 studies; 2,626,746 participants) evaluated the association between the use of antidepressants and the risk of cardiac arrhythmias, specifically atrial fibrillation and ventricular arrhythmias/sudden cardiac death (VA/SCD). Three studies explored the link between antidepressants and VA/SCD. One study indicated higher SCD risk in women using antidepressants, while another showed reduced risk with specific antidepressants (citalopram and escitalopram) in older adults. However, results from the overall pooled analysis revealed no association between antidepressant usage and increased VA/SCD risk (relative risk 1.33; 95% confidence interval [CI] 0.88 to 2.01; p= 0.18). Although high heterogeneity (I2= 87%) was noted, heterogeneity decreased to 0% after excluding one study. Additionally, a subgroup analysis based on antidepressant classes, including TCAs, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors, revealed that none of the classes were associated with an increased risk of VA/SCD. Due to only three included studies focusing on VA/SCD within the scope of multiple antidepressant drug classes, the direct applicability of these findings to amitriptyline alone may be limited. [2]

In a 2020 study, the connection between serum concentrations and QTcB, QTcF, PQ, and QRS intervals was investigated to assess the predictive value of cardiac risk associated with amitriptyline serum concentrations. The study analyzed serum concentrations of amitriptyline and doxepin, including their metabolites, along with ECG parameters. The average amitriptyline dose administered was 122.4 ± 48.2 mg. The study revealed significant associations between QTcB and QTcF intervals and serum concentrations of nortriptyline (p<0.001) and the active moiety of amitriptyline (amitriptyline and nortriptyline [p= 0.012]). Patients with elevated serum concentrations of nortriptyline and the active moiety exhibited prolonged QTcB and QTcF intervals. Notably, age, sex, and dose did not exert influence on QTcB and QTcF intervals. Patients with summed serum concentrations above the alert level (300 ng/mL) experienced significantly longer QTcB intervals. However, QTcF intervals (p= 0.098) did not differ between the two groups. Regarding nortriptyline, patients with serum concentrations above the upper limit of the reference range (170 ng/mL) demonstrated significantly longer QTcB (p= 0.007) and QTcF intervals (p= 0.02). The PQ interval also exhibited a significant association with serum concentrations of nortriptyline (p = 0.007) and the sum of amitriptyline and nortriptyline (p = 0.020). Increasing serum concentrations correlated with a longer PQ interval. The impact of amitriptyline on ECG parameters may be attributed to nortriptyline alone. Consequently, as nortriptyline concentrations rise, the potential risk for atrioventricular block, bundle branch block, and QTc interval prolongation may significantly increase. [3]

Antidepressants, including TCAs, are known to influence cardiac conduction. These drugs have been associated with an increased risk of QTc prolongation and cardiac arrhythmias. However, the majority of evidence stems from observational studies where the indication and duration of exposure is unknown. This complicates clinical decision-making for patients with atrial fibrillation or with risk factors for atrial fibrillation. [4]

A 2013 cross-sectional study utilized electronic health records to assess the relationship between antidepressant use and corrected QT interval (QTc) prolongation. Of the total study population, 11% (4,228) of patients included were receiving pharmacotherapy with amitriptyline. Electrocardiographic reports were used to extract QTc measurements; only QTc measurements obtained 14-30 days after prescription were included to allow patients ample time to fill the prescription and start medication. Study results revealed a correlation between amitriptyline dose and increased QTc. The overall effect of amitriptyline on QTc 14-90 days after prescription was an adjusted beta of 0.11 ± 0.03 (p<0.001). When escalating the dose of amitriptyline, a significant effect on QTc over the previous dose was seen when increasing from 25 to 50 mg with an adjusted beta of 3.4 ± 1.4 (p<0.05). It was suggested that a modest prolongation of QT interval was possible with the use of certain antidepressants. [5]

A prospective analysis of a UK healthcare database assessed associations between antidepressant use and the occurrence of myocardial infarction, stroke, and arrhythmia (N= 238,963). During the five years of follow-up, 1,452 patients were diagnosed with arrhythmia. The authors found antidepressants were not significantly associated with arrhythmia, although the risk was significantly increased during the first 28 days of treatment with tricyclic and related antidepressants (adjusted hazard ratio [aHR] 1.99; 95% CI 1.27 to 3.13). Amitriptyline was associated with an increase in absolute risk of 16 (95% CI 10 to 27) per 10,000 over 1 year. [6]

A retrospective cohort study of an Italian healthcare database (N= 199,569) did not find amitriptyline use (odds ratio [OR] 1.49, 95% CI 0.71 to 3.14) or TCAs (OR 1.52; 95% CI 0.81 to 2.85) as a class to be significantly associated with arrhythmias However the authors found antidepressants use as a whole to be associated with a risk of arrhythmias, especially in the elderly. No further discussion on the association between the increased dose of amitriptyline and cardiovascular risks were provided. [7]

References:

[1] Tisdale JE, Chung MK, Campbell KB, et al. Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association. Circulation. 2020;142(15):e214-e233. doi:10.1161/CIR.0000000000000905
[2] Cao Y, Zhou M, Guo H, Zhu W. Associations of Antidepressants With Atrial Fibrillation and Ventricular Arrhythmias: A Systematic Review and Meta-Analysis. Front Cardiovasc Med. 2022;9:840452. Published 2022 Mar 25. doi:10.3389/fcvm.2022.840452
[3] Scherf-Clavel M, Zebner J, Hommers L, Deckert J, Menke A, Unterecker S. Nortriptyline serum concentration as a predictor for cardiac risk in amitriptyline-treated patients. Eur J Clin Pharmacol. 2020;76(1):73-80. doi:10.1007/s00228-019-02766-2
[4] Andrade C. Antidepressants and Atrial Fibrillation: The Importance of Resourceful Statistical Approaches to Address Confounding by Indication. J Clin Psychiatry. 2019;80(1):19f12729. Published 2019 Jan 22. doi:10.4088/JCP.19f12729
[5] Castro VM, Clements CC, Murphy SN, et al. QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ. 2013;346:f288. Published 2013 Jan 29. doi:10.1136/bmj.f288
[6] Coupland C, Hill T, Morriss R, Moore M, Arthur A, Hippisley-Cox J. Antidepressant use and risk of cardiovascular outcomes in people aged 20 to 64: cohort study using primary care database. BMJ. 2016;352:i1350. Published 2016 Mar 22. doi:10.1136/bmj.i1350
[7] Biffi A, Rea F, Scotti L, et al. Antidepressants and the risk of arrhythmia in elderly affected by a previous cardiovascular disease: a real-life investigation from Italy. Eur J Clin Pharmacol. 2018;74(1):119-129. doi:10.1007/s00228-017-2352-x
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there a dose-dependent relationship between amitriptyline and cardiovascular risk?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-4 for your response.

 

Cyclic antidepressants and the risk of sudden cardiac death

Design

Retrospective cohort study

N= 481,744

Objective

To quantify the risk of sudden cardiac death among TCA users, according to dose, as well as among users of selective serotonin reuptake inhibitors (SSRIs)

Study Groups

Cohort N= 481,744

Inclusion Criteria

Age 15 to 84 years; not in a nursing home free of life-threatening noncardiac illness

Exclusion Criteria

In a long-term care facility in the past 365 days; evidence of a life-threatening, noncardiac illness (chronic renal failure, chronic liver disease, metastatic or other cancer with very poor prognosis, severe chronic obstructive pulmonary disease, or human immunodeficiency virus infection)

Methods

The researchers used data from a prior population-based study of sudden cardiac death, comprised of incidents from January 1, 1988, to December 31, 1993. The previous study necessitated a multi-year, intensive field investigation of medical records for thousands of potentially qualifying fatalities. The current investigation compares the hazards of antidepressants to a set of verified unexpected fatalities in a population having information on prescription medication use. Filled prescriptions, outpatient visits, inpatient admissions, and nursing home stays were all recorded in encounter files. These data were utilized to identify the study cohort, determine medication exposure, identify possible cases of sudden cardiac death, and categorize cohort members based on pre-existing cardiovascular and other disorders.

Duration

From Jan 1, 1988, to Dec 31, 1993

1,282,091 person-years of follow-up

Outcome Measures

Sudden cardiac death occurring in a community setting

Baseline Characteristics

  

Nonuser

Past year only

  TCA SSRI  

Person-years of follow-up

 1,120,625 96,220 58,956 6,291  

Female

68.9% 77.1% 76.6%  78.6%  

White

 56.0% 76.5% 78.4% 86.3%  

Age, years, mean

 44.2 46.5 52.0 44.9  

Age ≥ 65, years

 25.5% 19.2% 25.2% 9.4%  

No filled prescription

 27.9% 1.7% 1.3% 0.9%  

Cardiovascular disease medical care

 32.3% 51.2% 53.2% 56.2%  

Other medical hospital admission

 11.2% 22.7% 19.7% 23.1%  

Enrollment in aid to disabled

 43.9% 50.0% 58.3% 56%  

No outpatient service visit

 23.5% 3.7% 5.1% 3.6%  

Psychotropic medication

Antipsychotic

Benzodiazepine

Lithium

Trazodone

 

5.0%

10.4%

0.7%

1.4%

 

22.1%

39.7%

2.6%

9.2%

 

31.8%

38.1%

3.6%

6.3%

 

25.0%

43.0%

6.4%

18.2%

  

Mental diagnosis other than depression

 7.3% 30.1% 30.1% 34.5%  

Separated based on the use of antidepressants

Results

Endpoint

Person-years

Deaths

Adjusted rate/10,000

 Adjusted IRR

95% CI

TCA, all

≥ 300 mg

200 mg

100 mg

< 100 mg 

 

58,956

1,878

5,051

18,096

 33,931 

 

94

5

9

28

52 

 

12.9

29.1

19.2

14.4

11.1 

 

1.12

2.53

1.67

1.25

0.9

 

0.89-1.40

1.04-6.12

0.86-3.26

0.85-1.85

0.72-1.29

 

SSRI, all

 6,291 6 10.9 0.95 0.42-2.15

Former

 96,219 99 9.9 0.86 0.68-1.05

Nonuser

 1,120,625 1,288 11.5 1 --

Adjusted rates of sudden cardiac death by study antidepressant* and TCA dose in amitriptyline equivalents

IRR: Incidence rate ratio; CI: confidence interval

*Adjusted by Poisson regression. IRRs are calculated directly from the regression model. Rates are calculated by multiplying the unadjusted rate in nonusers of antidepressants by the adjusted IRR.

Adverse Events

Serious Adverse Events: See results

Study Author Conclusions

Our data suggest that SSRI antidepressants and TCAs in doses of less than 100 mg (amitriptyline equivalents) did not increase the risk of sudden cardiac death. However, higher doses of TCAs were associated with increased relative risk, which suggests that such doses should be used cautiously, particularly in patients with an elevated baseline risk of sudden death.

InpharmD Researcher Critique

Although the cohort comprised a substantial number of TCA users and sudden cardiac fatalities, the number of those taking dosages of 100 mg or above (amitriptyline equivalents) linked with increased risk was smaller. Despite a statistically significant dose-response pattern, the confidence intervals for the point estimates for particular doses were large. The precision of the SSRI point estimate was also restricted by the lower number of SSRI users.



References:

Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther. 2004;75(3):234-241. doi:10.1016/j.clpt.2003.09.019

 

Comparative Risk of Ventricular Arrhythmia and Sudden Cardiac Death Across Antidepressants in Patients With Depressive Disorders

Design

Retrospective cohort study (Taiwan)

N= 793,460 patients; 245 events

Objective

To evaluate the risk of ventricular arrhythmia (VA) and/or sudden cardiac death (SCD) associated with antidepressant use

Study Groups

Amitriptyline patients (n= 13,098)

Inclusion Criteria

New antidepressant users with diagnosis of depressive disorder, age ≥ 20 years

Exclusion Criteria

Patients with schizophrenia and bipolar disorders (to avoid underlying psychopathology and complex concomitant psychotropic drug exposure)

Methods

Patient data were compiled via review of Taiwan's National Health Insurance Research Database (NHIRD), which contains medical claims records from the National Health Insurance (NHI) program in Taiwan. ICD-9 codes were used to identify diagnoses and medication use. 

For the analysis, antidepressant use was categorized into groups based on class as well as dose range (low dose vs. moderate-high dose) based on the daily dose of the first antibiotic prescription. The date of the first documented VA/SCD diagnosis (per ICD-9 code) was defined as the study end point. While different classes of antidepressants (selective serotonin reuptake inhibitors [SSRIs], serotonin and norepinephrine reuptake inhibitors [SNRIs], serotonin antagonist and reuptake inhibitors [SARIs]) were included within the analysis, the current summary table will focus on tricyclic antidepressants (TCAs), specifically amitriptyline. 

Duration

Patients diagnosed between January 1, 2002 and December 31, 2012

Outcome Measures

First occurrence of VA or SCD

Baseline Characteristics

  

Amitriptyline patients (n= 13,098)

Age, years

20 to 40

40 to 64

≥ 65

 

27.1%

58.1%

21.1%

Male

 38.1%

Psychiatric disorders

Dementia

Anxiety

 

1.1%

35.7%

Common medical comorbidities

Hypertension

Dyslipidemia

Diabetes mellitus

COPD

Coronary heart disease

 

27.9%

14.1%

12.7%

11.7%

10.6%

COPD, chronic obstructive pulmonary disease

Results

Endpoint

Adjusted hazard ratio (95% confidence interval)

Risk of VA and SCD

SSRI

TCAs

Amitriptyline

SARIs

SNRIs

 

Reference

0.54 (0.36 to 0.83)

0.45 (0.10 to 2.03) 

0.65 (0.43 to 0.99)

1.47 (0.92 to 2.35)

TCA average daily dose 

Low

High

 

Reference

4.37 (1.23 to 15.60)

The overall incidence rate of VA/SCD among antidepressant users was 1.5 (95% CI 1.3 to 1.7) per 1000 person-years. 

Adverse Events

 N/A

Study Author Conclusions

There was no difference in VA/SCD risk across antidepressant classes except that TCAs were associated with a lower risk than SSRIs. However, the observed comparative risk of TCAs might be attributable to low-dose TCA use, which is quite common in current clinical practice. It would be of importance to carry out further investigations to scrutinize the influence of antidepressants on VA/SCD.

InpharmD Researcher Critique

 Since only 245 VA/SCD events were identified, the included sample size within this study may not have been adequately powered to identify small, yet significant, differences. Furthermore, the reliability of the current data are dependent on accuracy of ICD-M codes within patient records. Lastly, the study was limited to patients in Taiwan, hindering generalizability to other patient populations. 



References:

Wu CS, Tsai YT, Hsiung CA, Tsai HJ. Comparative Risk of Ventricular Arrhythmia and Sudden Cardiac Death Across Antidepressants in Patients With Depressive Disorders. J Clin Psychopharmacol. 2017;37(1):32-39. doi:10.1097/JCP.0000000000000631

 

A Case of Amitriptyline-induced Myocarditis

Design

  Case report

Case presentation

A 21-year-old male with a history of depression attempted suicide by taking an amitriptyline overdose. Upon arrival at the emergency department, he presented with significantly reduced consciousness, scoring a Glasgow Coma Scale of three, necessitating intubation and admission to the intensive care unit. The patient admitted to taking 41 tablets of amitriptyline 50 mg and denied recent flu symptoms or contact with sick individuals. Tests ruled out common viruses, and amitriptyline was his only prescribed medication. Additionally, levels were not measured as he was still conscious after ingesting the 41 tablets, which was confirmed by counting tablets from his prescription bottle. Initial assessments revealed lactic acidosis, normal kidney and liver functions, and metabolic acidosis (pH 7.2) with respiratory compensation on arterial blood gas analysis. Electrocardiogram findings showed wide complex tachycardia with a ventricular rate of 146 bpm, a QRS complex duration of 118 msec, and a prolonged QTc of 576, accompanied by nonspecific ST-T wave changes.

Further evaluations via transthoracic echocardiogram (TTE) indicated a preserved ejection fraction (EF) of 65% without wall segment motion abnormalities. Treatment involved intravenous fluids and sodium bicarbonate to target a pH of 7.5-7.55. By the second day of admission, the patient's condition improved, leading to extubation, with concurrent improvements in QRS complex and QTc durations. However, cardiac troponin levels began to rise, peaking at 4.08 mcg/L. The patient also developed fever, elevated white blood cell count (13.2 x 109/L), increased brain natriuretic peptide levels (399 pg/mL), and elevated inflammatory markers (erythrocyte sedimentation rate of 46 mm/hr and C-reactive protein of 18 mg/L).

Cardiology service was consulted, and a repeat TTE revealed a mildly reduced EF ranging between 45% and 50% and mild to moderate pericardial effusion. No wall segment motion abnormalities were observed. Subsequent cardiac magnetic resonance imaging (CMR) aimed to investigate suspected acute myocarditis indicated a moderately dilated left ventricle with a mildly reduced EF at 45%. CMR findings included scattered non-territorial areas of myocardial edema and moderate pericardial effusion, supporting the diagnosis of acute myocarditis attributed to amitriptyline-induced cardiotoxicity. The treatment, involving supportive care with intravenous fluids, sodium bicarbonate, and electrolyte correction, led to significant clinical improvement, resulting in discharge after a seven-day hospital stay. At the one-month follow-up, troponin levels were within normal limits, and a subsequent TTE demonstrated resolved pericardial effusion and a normal left ventricular function with an EF of 65%.

Study Author Conclusions

 Amitriptyline toxicity is life-threatening and can cause acute myocarditis in addition to the known cardiotoxic profile of tricyclic anti-depressant medications. Physicians should be aware of this rare entity as a differential diagnosis for myocarditis with an unknown etiology.
References:

Kassim T, Mahfood Haddad T, Rakhra A, et al. A Case of Amitriptyline-induced Myocarditis. Cureus. 2018;10(6):e2840. Published 2018 Jun 19. doi:10.7759/cureus.2840

Amitriptyline-induced ventricular tachycardia: a case report

Design

Case report

Case Presentation

A 25-year-old woman with a prior history of self-harm presented to the emergency department with an impaired level of consciousness after intentionally ingesting 100 × 25 mg (2500 mg total) tablets of amitriptyline approximately 10 h prior to arrival.

Her blood pressure was 140/80 mmHg, heart rate 140 beats/min, respiratory rate 24 breaths/min, and a Glasgow coma scale score of 10/15. Abdominal examination revealed a distended urinary bladder. There was no lateralizing sign in the neurological examination.

Electrocardiograph revealed wide complex tachycardia with a QRS duration of 178 ms. She was immediately transferred to a cardiac coronary unit (CCU) for monitoring and management. She was treated initially with 100 ml 8.4% sodium bicarbonate due to a blood pH of 7.36. Her heart rate reduced to 115 beats/minute within 10 minutes of bicarbonate.

In the limb leads, QRS duration came to 100 ms and in chest leads, ST/T wave changes were seen on ECG. Over the next 24 h, sodium bicarbonate infusion consisting of 125 mL dissolved in 375 mL normal saline was started and titrated according to the report of arterial blood gas analysis done 6 h to maintain the pH 7.5-7.55.

She regained consciousness on day 2 and her ST/T wave abnormality persisted. On Day 3, she was transferred to post-CCU and evaluated by a psychiatrist. On Day 4, she was discharged with a heart rate of 124 beats/min with QRS duration in the limb lead 90 ms in ECG along with other normal vital signs.

Study Author Conclusions

Amitriptyline is lipophilic and has a large volume of distribution. It is metabolized hepatically, with the most active metabolites being nortriptyline and 10-hydroxynortriptyline. In therapeutic doses, the elimination half-life of amitriptyline and its metabolites is 19-72 h; in overdoses, its average half-life is 37 h but can be greater than 60 h.

In amitriptyline overdose, the progression of clinical toxicity is unpredictable. Acute ingestion of >5 mg/kg causes significant cardiovascular, CNS, and anticholinergic symptoms. The lowest reported dose of amitriptyline toxicity was 300 mg in a young adult.

Acute cardiovascular toxicity is primarily responsible for the mortality in amitriptyline overdose. Sinus tachycardia (rate 120–160 beats/min in an adult) occurs due to inhibition of presynaptic norepinephrine reuptake and anticholinergic action. Amitriptyline also inhibits the fast sodium channel in the His-Purkinje system and myocardial. As a result, depolarization of the cardiac action potential is slowed and propagation of depolarization through both myocardial and conducting tissue is delayed. Ultimately, this decreases conduction velocity, increases the duration of repolarization, and prolongs the absolute refractory period.

Amitriptyline also blocks hERG human cardiac potassium channel which contributes to arrhythmogenic side effects of amitriptyline. This can contribute to prolongation of the PR, QRS and QT intervals, nonspecific ST-segment and T-wave changes, atrioventricular block, right axis deviation of the terminal 40 ms vector of the QRS complex in the frontal plane (T 40 ms axis) and the Brugada pattern (downsloping ST-segment elevation in leads V1–V3 in association with right bundle branch block).

Fatal dysrhythmias are rare as ventricular tachycardia (VT) and ventricular fibrillation (VF) occur in only approximately 4% of all cases. This happens most commonly in patients with prolonged QRS complex duration and/or hypotension. Hypoxia, acidosis, hyperthermia, seizures, and β-adrenergic agonist use may also predispose this risk.
References:

Sabah KMN, Chowdhury AW, Islam MS, Saha BP, Kabir SR, Kawser S. Amitriptyline-induced ventricular tachycardia: a case report. BMC Res Notes. 2017;10(1):286. Published 2017 Jul 14. doi:10.1186/s13104-017-2615-8