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Supraventricular Tachycardia Associated With Methylphenidate Treatment in a Heart Transplant Recipient

Received July 31, 2003; revision received Aug. 7, 2004; accepted Sept. 13, 2004. From Brigham and Women’s Hospital, Boston; and the College of Physicians and Surgeons, Columbia University. Address correspondence and reprint requests to Dr. Shapiro, 622 W. 168 St., Box 427, New York, NY 10032; pas3{at}columbia.edu (e-mail).

INTRODUCTION

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The safety of stimulants in patients with cardiac disease is a matter of concern for psychiatrists. We present a case of supraventricular tachycardia associated with the initiation of methylphenidate treatment in a heart transplant recipient.

Case Report

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Ms. A, a 58-year-old married woman with a history of hypertrophic cardiomyopathy, mitral regurgitation, hypertension, and depression, underwent orthotopic heart transplantation. Her postoperative course was complicated by humoral and cellular rejection, allograft dysfunction, volume overload, gram-positive bacteremia, and acute renal failure requiring hemodialysis. There were no arrhythmias after the transplant except for one episode, on postoperative day 39, of supraventricular tachycardia (heart rate=208 bpm) while she was receiving dobutamine. The arrhythmia was terminated by intravenous adenosine, and the dobutamine was discontinued.

On postoperative day 41, the transplant team psychiatrist started treatment with methylphenidate, 5 mg/day, and sertraline, 25 mg/day, for increasing symptoms of depression and psychomotor retardation. Ms. A’s concurrent medicines included tacrolimus, cyclophosphamide, prednisone (40 mg b.i.d.), dopamine (2.5 µg/kg/minute), valganciclovir, erythropoietin, pravastatin, aspirin, calcium citrate, pantoprazole, docusate sodium, amphotericin B nebulizer, trimethoprim/sulfamethoxazole, furosemide, levofloxacin, isophane insulin, vancomycin, nystatin, subcutaneous heparin, ferrous gluconate, and a multivitamin.

Before the onset of antidepressant treatment, Ms. A’s ECG showed a normal sinus rhythm and no conduction abnormalities. One day after the initiation of sertraline and methylphenidate, she began to experience intermittent episodes of asymptomatic supraventricular tachycardia (heart rates up to 180 bpm). Her potassium and magnesium levels were normal. An electrophysiologist reviewing her ECGs felt that the arrhythmia arose from a right atrial (crista terminalis) focus. Occasionally, the supraventricular tachycardia manifested periods of Mobitz I atrioventricular block (Figure 1).

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FIGURE 1.  Supraventricular Tachycardia During Methylphenidate Treatment (top)a and Normal Sinus Rhythm (bottom)b in a Heart Transplant Recipient aThe atrial rate is up to 180 bpm, and Mobitz I atrioventricular block is evident. bSinus rhythm at 90–95 bpm was present between episodes of paroxysmal supraventricular tachycardia.

Paroxysmal supraventricular tachycardia continued despite discontinuation of dopamine. An endomyocardial biopsy from the right ventricle of the cardiac allograft revealed reduced signs of rejection compared to a biopsy 1 week earlier. Verapamil was begun in an attempt to prevent recurrence of the supraventricular tachycardia. After a single oral 40-mg dose, Ms. A became hypotensive and had a cardiac arrest. She responded to cardiopulmonary resuscitation, which included intravenous calcium and norepinephrine. Paroxysms of supraventricular tachycardia continued until methylphenidate was discontinued on postoperative day 44.

After cessation of methylphenidate, there were no further episodes of arrhythmia. Ms. A improved and was doing well at her last outpatient follow-up 12 months after surgery while taking a maintenance dose of sertraline, 50 mg/day.

Review of the Literature and Discussion

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Our review of the literature revealed only one previous case report of a patient developing supraventricular tachycardia during methylphenidate treatment.¹ Gracious reported the case of a 13-year-old girl who was taking sertraline for obsessive-compulsive disorder and developed new-onset symptomatic atrioventricular nodal re-entrant tachycardia after the addition of an amphetamine for attention deficit hyperactivity disorder. The tachycardia was terminated by intravenous adenosine but recurred after the amphetamine was restarted. The patient had recurrent similar symptoms on two occasions after her medication was changed to slow-release methylphenidate. However, those episodes were not documented with ECGs.

Other arrhythmias have also rarely been reported with methylphenidate treatment. Lucas et al.² reported the development of unifocal premature ventricular contractions in two of eight patients given intravenous methylphenidate in a study of borderline personality disorder. The arrhythmia developed within 5 to 6 minutes of the onset of infusion. Neither patient had had arrhythmia documented by a monitor before receiving the drug. Deshmankar and Lewis³ reported that a 60-year-old man being treated with guanethidine developed ventricular tachycardia at 180 bpm shortly after administration of oral methylphenidate, 5 mg b.i.d. The patient had no known prior arrhythmia, and none was detected after discontinuation of guanethidine and methylphenidate.

Supraventricular tachycardia of multiple types has been reported in heart transplant patients.⁴ In our case, the supraventricular tachycardia also occurred in the setting of transplant rejection and renal failure, both of which can predispose patients to atrial arrhythmias.^5,6 However, the abrupt onset of paroxysmal supraventricular tachycardia after beginning methylphenidate and its abrupt termination with discontinuation of the medication are highly suggestive of an etiological role for methylphenidate in our patient’s arrhythmia.

Methylphenidate is a CNS stimulant with indirect sympathomimetic activity. It enhances dopaminergic and adrenergic activity by releasing intraneuronal stores of these transmitters into neuronal synapses.⁷ Methylphenidate has also been shown to increase levels of circulating epinephrine.⁸

In our patient, an increase in circulating catecholamines during methylphenidate treatment and the documented ß-adrenergic supersensitivity of the denervated heart^9,10 may have acted synergistically to promote the patient’s arrhythmia. An increase in receptor sensitivity may also have contributed to the isolated supraventricular tachycardia seen earlier with dobutamine infusion. The effect of methylphenidate to increase synaptic catecholamines might also predispose toward atrial arrhythmias in certain patients, although the denervation of the transplanted heart makes that mechanism unlikely in this case. Reinnervation of transplanted hearts has been reported but not this early after transplantation.^11,12

Another consideration as to the etiology of our patient’s arrhythmia is the effect of potential medication interactions. No adverse interactions between methylphenidate and our patient’s other medications have been reported. In a rat model, sertraline increased amphetamine-induced motor activity and brain amphetamine concentration, an effect independent of increased CNS serotonin. This finding suggests that sertraline inhibition of amphetamine metabolism mediated by cytochrome 2D1 (in rats) and 2D6 (in humans) underlies augmented amphetamine effects.¹³ Increased amphetamine levels might predispose vulnerable patients to tachyarrhythmias and/or ventricular ectopic activity. Methylphenidate, however, undergoes minimal hepatic microsomal metabolism and is unlikely to be affected by the effects of sertraline on the cytochrome system. We should also consider whether the patient’s other medications themselves may have caused the arrhythmia. In particular, sertraline has been associated with arrhythmias in occasional case reports, including presumed sudden cardiac death in a patient with schizophrenia treated with sertraline plus clozapine¹⁴ and the loss of sinus rhythm and development of a junctional rhythm in a patient with atrial flutter treated with direct current cardioversion, sotalol, thiopental, and digoxin.¹⁵ In our case, the arrhythmia did not recur with ongoing sertraline treatment after methylphenidate cessation. We must also acknowledge that humoral and cellular rejection, allograft dysfunction, volume overload, gram-positive bacteremia, and acute renal failure requiring hemodialysis comprised the setting in which the arrhythmia occurred.

Although it is not certain that our patient’s arrhythmia was secondary to methylphenidate, it seems likely. Thus, it should be recognized that this is a potential side effect of methylphenidate treatment. To put this event in perspective, more than 20 heart transplant recipients have been treated with methylphenidate in our institution over the past 10 years, with no episodes of arrhythmia seen before the present case. This suggests the need for caution and monitoring when initiating treatment but not a need to preclude the use of methylphenidate in heart transplant patients.

REFERENCES

TOP INTRODUCTION Case Report Review of the Literature... REFERENCES

 

1. Gracious BL: Atrioventricular nodal re-entrant tachycardia associated with stimulant treatment. J Child Adolesc Psychopharmacol 1999; 9:125–128[Medline]
2. Lucas PB, Gardner DL, Wolkowitz OM, Tucker EE, Cowdry RW: Methylphenidate-induced cardiac arrhythmias. N Engl J Med 1986; 315:1485[Medline]
3. Deshmankar BS, Lewis JA: Ventricular tachycardia associated with the administration of methylphenidate during guanethidine therapy. Can Med Assoc J 1967; 97:1166–1167[Medline]
4. Pavri BB, O’Nunain SS, Newell JB, Ruskin JN, Dec GW: Prevalence and prognostic significance of atrial arrhythmias after orthotopic cardiac transplantation. J Am Coll Cardiol 1995; 25:1673–1680[Abstract]
5. Scott CD, Dark JH, McComb JM: Arrhythmias after cardiac transplantation. Am J Cardiol 1992; 70:1061–1063[CrossRef][Medline]
6. Markides V, Peters NS: Mechanisms underlying the development of atrial arrhythmias in heart failure. Heart Failure Reviews 2002; 7:243–253[CrossRef][Medline]
7. Fawcett J, Busch KA: Stimulants in psychiatry, in The American Psychiatric Press Textbook of Psychopharmacology. Edited by Schatzberg AF, Nemeroff CB. Washington, DC, American Psychiatric Press, 1995, pp 422–423
8. Joyce PR, Nicholls MG, Donald RA: Methylphenidate increases heart rate, blood pressure and plasma epinephrine in normal subjects. Life Sci 1984; 34:1707–1711[CrossRef][Medline]
9. Yusuf S, Theodoropoulos S, Mathias CJ, Dhalla N, Wittes J, Mitchell A, Yacoub M: Increased sensitivity of the denervated transplanted human heart to isoprenaline both before and after ß-adrenergic blockade. Circulation 1987; 75:696–704[Abstract/Free Full Text]
10. Gilbert EM, Eiswirth CC, Mealey PC, Larrabee P, Herrick CM, Bristow MR: ß-Adrenergic supersensitivity of the transplanted human heart is presynaptic in origin. Circulation 1989; 79:344–349[Abstract/Free Full Text]
11. Brunner-La Rocca HP, Weilenmann D, Bracht C, Carli S, Schlumpf M, Follath F, Kiowski W: Relative frequency of functional sympathetic and parasympathetic reinnervation after heart transplantation. J Heart Lung Transplant 1998; 17:725–728[Medline]
12. Shapiro PA, Sloan RP, Bagiella E, Bigger JT, Gorman JM: Heart rate reactivity and heart period variability throughout the first year after heart transplantation. Psychophysiology 1996; 33:54–62[Medline]
13. Sills TL, Greenshaw AJ, Baker GB, Fletcher PJ: The potentiating effect of sertraline and fluoxetine on amphetamine-induced locomotor activity is not mediated by serotonin. Psychopharmacology (Berl) 1999; 143:426–432[Medline]
14. Hoehns JD, Fouts MM, Kelly MW, Tu KB: Sudden cardiac death with clozapine and sertraline combination. Ann Pharmacother 2001; 35:862–866[Abstract]
15. Hansen MG, Gill SU, Hansen HS: Severe nodal arrhythmia following direct current cardioversion for atrial flutter. Scand Cardiovasc J 1999; 33:250–251[Medline]

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