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Cardioversion of Persistent Atrial Arrhythmia After Treatment With Venlafaxine in Successful Management of Major Depression and Posttraumatic Stress Disorder

Received September 13, 2005; accepted November 10, 2005. From the Dept. of Psychiatry, Queen’s University, Kingston, Ontario, Canada. Address correspondence and reprint requests to Dr. Finch, Hotel Dieu Hospital, 166 Brock St., Kingston, Ontario, Canada K7L 5G2. e-mail: sjf{at}post.queensu.ca

ABSTRACT

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There is increasing evidence linking depression and cardiovascular disease. However, the authors could find no literature directly linking depression with atrial fibrillation or atrial flutter. The authors report the case of a patient with uncontrolled atrial arrhythmia who cardioverted to normal sinus rhythm after treatment of major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) with venlafaxine. The authors discuss comorbidity of MDD and atrial fibrillation, and explore evidence of venlafaxine as an antiarrhythmic agent. Further research is needed to establish the clinical role of venlafaxine as a Class 1 antiarrhythmic agent and any association between atrial arrhythmias and MDD and PTSD.

INTRODUCTION

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Atrial fibrillation is the most common arrhythmia of clinical significance,^1,2 with a prevalence rate of 4% in the adult population.³ In clinical practice, atrial fibrillation and atrial flutter are often associated.⁴ Sometimes, atrial fibrillation can convert to atrial flutter and vice versa.⁴ Major depressive disorder (MDD) is also common, with a lifetime prevalence rate of about 15%. There is increasing evidence that depression adversely affects cardiovascular health. Depression has been implicated as an independent risk factor for the development of congestive heart failure and ischemic heart disease,⁵ and the comorbidity of ischemic heart disease and MDD is associated with increased mortality and cardiovascular events.^6,7 Tricyclic antidepressants are Class I antiarrhythmic agents,⁸ and venlafaxine is a first-line antidepressant that has also been shown to be a cardiac sodium channel-blocker.⁹

We report a case of a patient with uncontrolled atrial arrhythmia and comorbid MDD and posttraumatic stress disorder (PTSD) who cardioverted to a normal sinus rhythm after initiation of venlafaxine and effective treatment of her psychiatric illness.

Case Report

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"Anne," a 53-year-old married woman with no previous cardiac history and no cardiac risk factors, presented to the emergency department with a 6-month history of palpitations. She described an increase in palpitations associated with shortness of breath over the week before presentation. At presentation, her only medication was Celebrex (celecoxib). She was diagnosed with atrial flutter and congestive heart failure with pulmonary edema, and was admitted to the hospital. During her admission, she was diuresed, and metoprolol 50 mg twice daily and digoxin 0.125 mg daily were started for ventricular rate control. Over 2 days in the hospital, she lost 1.7 kg in weight. Heart-rate control was not achieved, and she underwent electrical cardioversion to normal sinus rhythm and was discharged on amiodarone for rhythm maintenance. Recommended amiodarone dose was 400 mg tid for 10 days, then 200 mg daily. Other discharge medications included warfarin and furosemide, and discharge diagnosis was atrial flutter and tachycardia-induced cardiomyopathy.

The patient returned to the emergency department 3 days later with palpitations and atrial fibrillation on ECG. She had poor sleep and anxiety, and she was treated with lorazepam, which decreased her heart rate. One week later, she again returned to the emergency department. Her ECG showed atrial flutter, with a variable 3–4:1 block and irregular heart rate of 80–110 bpm. She had mild congestive heart failure. Anxiety, sleep deprivation, and depression were identified as exacerbating the atrial arrhythmia, so urgent outpatient psychiatric consultation was arranged.

She was seen by Psychiatry 17 days post-discharge. The patient gave a history of longstanding symptoms of depression and anxiety. Symptoms worsened a few days before admission, when the patient saw an uncle who had sexually abused her as an adolescent. She met criteria for and was diagnosed with MDD and PTSD, and she was started on citalopram 20 mg daily.

The patient was followed by Psychiatry every 1–2 weeks for about 2 months, and engaged in solution-focused therapy with a social worker. Citalopram, up to 30 mg over 6 weeks, had no impact on the MDD and PTSD symptoms, and atrial arrhythmia persisted. This was likely not a high enough dose or a long enough trial to determine whether citalopram might have been effective treatment for the MDD and PTSD. Because there had been no change in the symptoms at all, the decision was made to switch medications. At about 9 weeks post-discharge, citalopram was discontinued, and venlafaxine was started and increased to a dose of 75 mg daily. Within 2 weeks of starting venlafaxine, the patient noticed significant improvement in depression, anxiety symptoms, and sleep. Her atrial arrhythmia spontaneously converted to normal sinus rhythm, and she returned to work. This was in the context of no changes to her cardiac medications, which included amiodarone, 200 mg daily; ramipril, 2.5 mg daily; furosemide, 40 mg daily; and warfarin, 3.5 mg daily. At subsequent cardiology appointments, 5 and 11 weeks after initiation of venlafaxine, the normal sinus rhythm was maintained, with occasional episodes of palpitations lasting less than 3 minutes about 1–2 times per week.

Discussion

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In this case, the patient developed an atrial arrhythmia in the absence of cardiac risk factors, history of cardiac or pulmonary disease, hyperthyroidism, alcoholism, or any other known causative factors. She did suffer from major depressive disorder and posttraumatic stress disorder, neither of which is identified as a risk factor for atrial fibrillation or atrial flutter. Cardiac, depressive, and anxiety symptoms all worsened at about the time she encountered a previous abuser. Throughout the period of acute treatment and follow-up, the atrial arrhythmia switched back and forth between atrial fibrillation and atrial flutter, both by diagnosis and on ECG. After electrical cardioversion and subsequent recurrence of the atrial arrhythmia, amiodarone was initiated with a loading dose over 10 days then continued at 200 mg daily for over 2 months, when spontaneous cardioversion occurred. Antidepressant treatment with citalopram failed to improve symptoms of MDD or PTSD and did not affect the arrhythmia. The timeline and course of the atrial fibrillation suggest that initiation of venlafaxine and effective treatment of MDD and PTSD correlated with cardioversion to normal sinus rhythm.

There is increasing evidence that depression adversely affects cardiovascular health. Most of the research linking MDD and cardiovascular disease involves patients with comorbid ischemic heart disease and MDD.^5,7 Although this is only one case, it suggests that MDD and/or PTSD may be causative risk factors for atrial fibrillation and/or atrial flutter.

Several mechanisms have been postulated to explain the contribution of depression to the pathogenesis of ischemic heart disease, and vice versa.⁵ Depression has been associated with activation of some aspects of the cellular immune system, resulting in increased secretion of proinflammatory cytokines.¹⁰ Studies suggest that cytokines, such as tumor-necrosis factor and interleukin-6, have a cardiotoxic effect.⁵ A recent study¹¹ concluded that an interleukin-6 promoter gene variant appears to influence the inflammatory response to surgery and the development of atrial fibrillation after cardiac surgery. The data suggest an inflammatory component of postoperative atrial arrhythmias and a genetic predisposition to this complication.¹¹ Despite this indirect link, we were unable to find anything in the literature directly linking MDD or PTSD with atrial fibrillation or atrial flutter. Further research is needed into the association between atrial arrhythmias and major depressive disorder and PTSD.

This case may suggest that the "spontaneous" cardioversion could be ascribed to a direct antiarrhythmic effect of venlafaxine alone or in combination with amiodarone. Antiarrhythmic drug actions based on cellular electrophysiological effects have been classified by Vaughan Williams into four classes.¹² Amiodarone is considered to be a Class III antiarrhythmic agent, but it has properties of all four classes.^13,14 Amiodarone has a long half-life—about 55 days.^13,15 In this patient, amiodarone alone may be responsible for cardioversion, with a delayed onset of effect due to the long half-life. However, loading doses of amiodarone are recommended so as to limit this delay.^13,15 This patient received a loading dose consistent with guidelines outlined in the CPS 2005.¹³ With loading doses of amiodarone, antiarrhythmic effect is expected within 1–3 days or at least within 1–3 weeks.¹³ Cardioversion occurred in this patient about 10–11 weeks after initiation of amiodarone.

Class I antiarrhythmic agents are sodium channel-blockers. Atrial fibrillation and atrial flutter may be converted to sinus rhythm in some patients using Class I drugs. In their study on guinea pig ventricular myocytes,⁹ Khalifa et al. demonstrated that venlafaxine is a relatively potent cardiac sodium channel-blocker. As is the case with other Class I anitarrhythmic agents, overdose with venlafaxine may be associated with proarrhythmic effects.¹⁶

Amiodarone and its metabolite, desethylamiodarone, are both inhibitors of cytochrome P450 enzymes. Amiodarone inactivates CYP3A4, and desethylamiodarone inactivates CYP2D6, among other enzymes.^13,14 Venlafaxine is metabolized by both CYP2D6 and 3A4, so it is expected that the presence of amiodarone would inhibit venlafaxine metabolism.¹³ This probable interaction would result in a higher plasma level of venlafaxine than expected, given the oral dose. Unfortunately, no plasma levels of venlafaxine were drawn during treatment for this patient. Since venlafaxine has a linear dose–response curve for depression,¹³ this interaction would have led to the amplification of venlafaxine’s antidepressant activity and, possibly, antiarrhythmic activity beyond that expected by the relatively low dose of 75 mg daily. This would help explain the rapid response of MDD and PTSD, and may help explain the cardioversion of the atrial arrhythmia.

The question arises as to whether venlafaxine, as a Class I antiarrhythmic agent, may be of clinical value in the management of selected patients with difficult-to-treat atrial arrhythmias, and whether this might be safely done. The CAST studies demonstrated that Class 1A and 1C antiarrhythmics caused an increase in mortality when used to treat patients with ischemic heart disease.^8,17,18 Tricyclic antidepressants, also Class 1 antiarrhythmics, are contraindicated for use during the acute recovery phase after a myocardial infarction and in the presence of acute congestive heart failure.¹³ Depression is common and is a risk factor for increased mortality after myocardial infarction.^6,7

Further research is needed to establish the clinical role, if any, of venlafaxine as a Class I antiarrhythmic agent, and to determine any precautions related to its use in patients with a history of ischemic heart disease.

REFERENCES

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Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by Finch, S. J. Articles by van Zyl, L. T. Search for Related Content PubMed Citation Articles by Finch, S. J. Articles by van Zyl, L. T. Depression Posttraumatic Stress Disorder Syndromes Secondary to General Medical Disorders Antidepressants

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