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Torsades de Pointes Associated With Ziprasidone

Received February 11, 2005; revised June 2, 2005; accepted June 23, 2005. From the Dept. of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, WI. Send correspondence and reprint requests to Dr. Heinrich, Dept. of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. e-mail: theinric{at}mail.mcw.edu
© 2006 The Academy of Psychosomatic Medicine

Key Words: antipsychotics • side effects • ziprasidone • torsades de pointes

INTRODUCTION

TOP INTRODUCTION Case Report DISCUSSION Conclusion REFERENCES

 
Medication-induced prolongation of the Q–T interval, which may result in arrhythmias such as torsades de pointes, has long been associated with the antiarrhythmic class of medications.¹ Recently, however, many classes of non-cardiac medications, such as antihistamines, antipsychotics, and antimicrobials, have been associated with secondary Q–T interval prolongation and the risk of torsades de pointes.^2–4

This potentially deadly treatment complication came to psychiatry’s general attention in the United States with the failed new drug application of sertindole. Sertindole was linked to cases of sudden cardiac death, syncope, and Q–T interval prolongation.⁵ The failure of sertindole to make it to the marketplace, coupled with the reports of arrhythmias and sudden cardiac death with other antipsychotics, have ensured that Q–T interval and torsades de pointes will remain a significant clinical issue for psychiatrists for years to come.

It is with these important points in mind that we would like to present a case where torsades de pointes developed in a young woman who was being treated with multiple non-cardiac medications, one of which was ziprasidone. This case represents the first report in which torsades de pointes developed in an individual being treated with ziprasidone. This case also underscores the critical importance of communication between consultation psychiatrists, medical consultees, and the patient’s primary psychiatrist.

Case Report

TOP INTRODUCTION Case Report DISCUSSION Conclusion REFERENCES

 
Ms. TG, a 28-year-old Hispanic woman, had a medical history significant for systemic lupus erythematosus (SLE) and hypothyroidism, along with a complicated psychiatric history of mood disorder, not otherwise specified, with psychotic features, posttraumatic stress disorder, and borderline personality disorder. She came to the attention of the psychiatric consultation service after an Intensive Care Unit (ICU) admission for severe lithium toxicity presenting as an altered mental status. Lithium level on admission to the emergency department was 5.57 mmol/L (normal: 0.6 mmol/L–1.5 mmol/L), with a creatinine level of 3.0 mg/dL (normal: 0.4 mg/dL–1.0 mg/dL). Before this medical admission, she had been hospitalized psychiatrically for approximately 4 months, on both acute and long-term psychiatric units, for self-harming behaviors, along with psychosis. Ms. TG was on multiple medications, including ziprasidone and lithium, in an attempt to control these symptoms. Lithium toxicity was presumed to be secondary to dehydration due to the patient’s very poor oral intake over the previous week, compounded by resulting renal insufficiency. There was no report of overdose.

On admission, the patient had stable vital signs (temperature: 99°F; blood pressure: 111/67 mmHg; pulse: 77 beats per minute (bpm); respiration: 16 breaths per minute). Pertinent findings on physical and mental status examinations included a coarse upper-extremity tremor, impaired attention, confusion, and psychotic symptoms. In addition to the toxic lithium level and elevated creatinine, a substantial battery of other laboratory tests revealed that the patient had hypokalemia (2.7 mmol/L), normal magnesium level (2.1 mg/dL), and normal calcium (8.7 mg/dL). Admission electrocardiogram (ECG) demonstrated a prolonged Q–T interval, 600 msec at 68 bpm. Q–T interval had been normal (390 msec at 83 bpm) on the last known ECG, 3 years before admission.

All medications, including ziprasidone, were held upon admission to the ICU except the patient’s regular thyroid replacement and steroid. Also, she underwent two emergency hemodialysis (HD) treatments for her severe lithium toxicity. Lithium level decreased to 2.57 mmol/L and 1.42 mmol/L after each of the HD treatments. The patient also received aggressive supportive care, including rehydration with intravenous fluids. Renal functioning improved, yielding a creatinine of 1.4 mg/dL on Day 3 of hospitalization. Magnesium remained >2.0 mg/dL, and potassium >3.8 mmol/L throughout the remainder of the hospitalization. The patient’s delirium and tremor improved as lithium levels trended downward. However, as her level of consciousness improved, she began to display more purely psychotic behavior. Olanzapine was initiated at 5 mg twice per day and required titration to 5 mg every morning and 10 mg in the evening on Day 5 of hospitalization. Lithium level on discharge from the medical service was 0.73 mmol/L, and Q–T interval was 440 msec at 77 bpm. Lithium and ziprasidone were not restarted.

Ms. TG was readmitted to the general medical hospital approximately 2 weeks after the above hospitalization, with complaints of chest pain. Admission evaluation revealed a prolonged Q–T interval of 540 msec at 58 bpm. Electrolytes and cardiac enzymes were normal. She was stable upon admission, with a blood pressure of 134/77 mmHg and a heart rate of 72 bpm. She was maintained on her medical and psychiatric medications. Significantly, olanzapine had been discontinued because of its ineffectiveness in controlling her psychosis, and ziprasidone was restarted and titrated to 80 mg bid. Also, trazodone, levetiracetam, fluconazole, and ciprofloxacin had been started. On the second day of this hospitalization, the Q–T interval was prolonged, at 560 msec at a rate of 69 bpm. Potassium level was 3.3 mmol/L, and supplementation was given. Ciprofloxacin was discontinued. On Day 3 of hospitalization, telemetry revealed an asymptomatic non-sustained polymorphic ventricular tachycardia preceded by a prolonged Q–T interval (Figure 1). Ziprasidone was discontinued. Her magnesium level was 1.9 mg/dL, and potassium was 3.8 mmol/L the morning before the run of torsades de pointes. The next morning (Day 4), the Q–T remained prolonged, without further runs of torsades de pointes. Potassium and magnesium were 3.5 mmol/L and 1.9 mg/dL, respectively. Fluconazole was discontinued, and metoprolol, 50 mg every 12 hours, was started. On Day 5, blood pressure was low (systolic: 90 mmHg–100 mmHg), and so metoprolol was decreased to 12.5 mg every 12 hours, and trazodone was discontinued. The Q–T interval remained between 455 msec and 480 msec for the remainder of her hospitalization, with no return of the arrhythmia or hypotension. The patient remained psychotic throughout hospitalization, which necessitated psychiatric consultation and initiation of aripiprazole at 15 mg per day.

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FIGURE 1.  Tracing of Torsades de Pointes During the Second Hospitalization

Pathophysiology
The Q–T interval serves as a measure of the time required for ventricular depolarization (QRS complex) and repolarization (ST segment and T wave). The majority of the Q–T interval time, however, represents repolarization of the ventricular myocytes. The Q–T interval is related to heart rate. Bradycardia leads to Q–T interval prolongation, whereas tachycardia leads to Q–T interval shortening. The Q–Tc, or corrected Q–T interval, attempts to compensate for the influence of heart rate. Many formulas, such as the Bazett formula, calculate the "corrected" Q–T interval. Unfortunately, the software on most ECG machines measures the Q–T interval incorrectly and thus determines an aberrant Q–Tc interval. Therefore, clinicians must be able to reliably measure the Q–T interval and calculate the corrected Q–T interval (Q–Tc) from the 12-lead ECG.

The upper of limit of normal, for the Q–T interval, is 440 msec.⁶ Prolongation of the Q–Tc interval over 500 msec presents an increased risk of torsades de pointes and sudden cardiac death.⁷ It is, however, important to note that Q–T interval prolongation merely serves as a surrogate marker for risk of torsades de pointes. The relationship is complex; some medications, such as amiodarone, prolong the Q–T interval without increasing the risk of torsades de pointes.⁸

Repolarization of the myocardium involves calcium, sodium, and potassium currents. For some medications, including the antipsychotics, the degree of Q–T prolongation appears dependent on the drug’s ability to block the rapid component of the delayed potassium-rectifier channel (I_kr).⁹ This blockade slows the outward potassium current across the cell membrane, resulting in a prolongation of the plateau phase of the action potential and increased refractory period, thus making the myocardium susceptible to arrhythmias. Lengthening of the action potential duration is reflected on the 12-lead ECG as prolongation of the Q–T interval.

Antipsychotics and Q–Tc Prolongation: Torsades de Pointes
Prolongation of the Q–T interval and the potential for sudden cardiac death with antipsychotic agents are now well recognized.¹⁰ Reilly et al.¹¹ compared the 12-lead ECGs of healthy reference individuals to those of treated psychiatric patients. They found that antipsychotics, particularly thioridazine and droperidol, produced Q–Tc interval lengthening in a dose-related manner. In an autopsy study by Mehtonen et al.,¹² phenothiazines, particularly thioridazine, were overrepresented in patients who died suddenly. Tennessee Medicaid enrollees studied by Ray et al.¹³ who were prescribed moderate doses of antipsychotic medication (100 mg thioridazine or equivalent) had a significantly increased risk of sudden cardiac death when compared with those enrollees prescribed lower doses of antipsychotics or those with distant antipsychotic exposure.

Antipsychotics appear to vary in their ability to block I_kr and thus differ in their propensity to prolong the Q–T interval and induce torsades de pointes. Harrigan et al.¹⁴ examined the influence of six typical and atypical antipsychotics on the Q–Tc interval in the presence and absence of appropriate metabolic inhibitors. Thioridazine produced the greatest Q–Tc interval prolongation at steady state (30.1 msec), followed by ziprasidone (15.9 msec). All six of the antipsychotics studied induced Q–Tc-interval lengthening. Olanzapine, however, was associated with the least Q–Tc interval prolongation (1.7 msec). Vieweg¹⁵ recently conducted a review of the literature in which he searched for cases in which atypical antipsychotics were associated with Q–T interval prolongation. He noted that additional risk factors, alone or in combination with atypical antipsychotics, may have accounted for the observed ECG abnormalities. No cases of torsades de pointes appeared in any of the nine cases of Q–T-interval prolongation identified by Vieweg.

DISCUSSION

TOP INTRODUCTION Case Report DISCUSSION Conclusion REFERENCES

 
The case presented is consistent with Vieweg’s observation that reports of Q–T-interval prolongation associated with the new generation of antipsychotics are rarely, if ever, simple. The causative relationships between the antipsychotic drug and the ECG abnormalities are often confounded by multiple concurrent risk factors for Q–T-interval prolongation. It is, therefore, frequently impossible to determine a specific cause-and-effect relationship. Ms. TG’s episodes of Q–T-interval prolongation and torsades de pointes were complex, with multiple potential contributing and confounding factors. However, several important points are clear: 1) the patient experienced significant Q–T-interval prolongation on two distinct admissions to the medical hospital; 2) an asymptomatic run of torsades de pointes complicated one of these episodes of Q–T-interval prolongation; 3) a shortening of the Q–T interval separated these two admissions.

Potential explanations for the episodes of Q–T-interval prolongation are difficult to tease apart. The two episodes may be secondary to the same insult or due to completely unrelated events. If they share the same underlying etiology, then it is possible that medications prescribed on both admissions may have played an active role in the adverse event. The medications prescribed on both admissions included ziprasidone, prednisone, levothyroxine, clonazepam, and lansoprazole. Of these, only the atypical antipsychotic ziprasidone has been associated with Q–T-interval prolongation. This association with ziprasidone has been reported in a few complex case reports^16–19 and in Pfizer’s pre-marketing studies.²⁰ However, the fact that the Q–T interval was found to be prolonged on two separate occasions when the patient was challenged with ziprasidone and that the Q–T interval shortened with discontinuation of ziprasidone, also on both of these occasions, suggests a causal relationship between ziprasidone and the observed repolarization abnormalities. These facts differentiate this case from those previously reported.

The proposed relationship between ziprasidone and Q–T-interval prolongation in Ms. TG was complicated at both admissions. At the initial admission, she was lithium-toxic, and lithium has been reported to be associated with Q–T-interval abnormalities¹¹ and arrhythmias.²¹ The patient was also hypokalemic on that presentation, another risk factor identified for Q–T-interval prolongation and progression to torsades de pointes.²² At the second admission, although Ms. TG was no longer on lithium, she was on other medications known to be associated with Q–T-interval prolongation, including ciprofloxacin and fluconazole, in addition to ziprasidone.^23,24 It is possible that one of these new medications alone or some combination of the three potentially arrhythmogenic medications (ziprasidone, ciprofloxacin, and fluconazole) resulted in the episode of torsades de pointes. This possible medication interaction may have been secondary to either pharmacokinetic or pharmacodynamic mechanisms. However, ziprasidone is metabolized primarily via the cytosolic enzyme aldehyde oxidase.²⁵ As a result, oxidation via P450, specifically, 3A4, plays a relatively small role in the metabolism of this novel antipsychotic. This has been confirmed in relation to the Q–T interval by Harrigan et al.,¹⁴ who demonstrated that the co-administration of ziprasidone and ketoconazole, a potent inhibitor of 3A4, did not significantly lengthen Q–Tc duration. Ziprasidone has not been shown to be a significant inhibitor of any of the enzymes of the P450 system and therefore was unlikely to induce an arrhythmia through this pharmacokinetic mechanism. There is also a possibility that another medication prescribed on one of the admissions, by itself, accounted for the ECG abnormalities. Trazodone²⁶ and fluoxetine,²⁷ medications involved only in the second medical admission, for example, have been infrequently associated with arrhythmias through various pharmacodynamic and pharmacokinetic mechanisms.

Another potential confounding factor is that Ms. TG also had a history of SLE, which may affect the myocardium. A normal echocardiogram on her index admission suggested that cardiac involvement by SLE was unlikely. Electrolyte abnormalities may also have contributed to the occurrence of Q–T-interval prolongation. However, the potassium level of 2.7 mmol/L on her index admission was rapidly corrected. Also, Ms. TG had no known history of syncope or family history of arrhythmias or sudden cardiac death.

Conclusion

TOP INTRODUCTION Case Report DISCUSSION Conclusion REFERENCES

 
This case represents the first report of torsades de pointes occurring in a patient prescribed ziprasidone. Confounding factors prevent direct linkage of ziprasidone to the occurrence of Q–T-interval prolongation and torsades de pointes in this case. Nonetheless, ziprasidone had been prescribed on both occurrences of Q–T-interval prolongation and was present during the asymptomatic run of torsades de pointes. Ziprasidone discontinuation was also temporally associated with shortening of the Q–T interval on both occasions. This case highlights the complicated nature of the interaction between several, often diverse, elements of the patient’s presentation and Q–T-interval prolongation. The co-administration of potentially arrhythmogenic medications presents a significant risk for Q–T-interval prolongation.²⁸ The cumulative effect of multiple cardio-active medications likely contributed to the development of torsades de pointes in this patient.

The combination of tolerability and numerous therapeutic indications makes atypical antipsychotic use common. However, antipsychotic medication administration requires knowledge of the associated risks. An awareness of the relationship between Q–T-interval prolongation and antipsychotic medications is imperative, regardless of type of clinical practice. Consultation psychiatrists often treat patients with significant vulnerability to arrhythmias with atypical antipsychotic medications. Therefore, a thorough knowledge of the various risk factors associated with Q–T-interval-prolongation and torsades de pointes are crucial. Not all antipsychotics appear to present the same risk for Q–T-interval prolongation or the same danger of developing torsades de pointes. The antipsychotic medication is likely a "partner" with other medications, electrolyte disturbances, and the underlying cardiac substrate in creating the milieu for this potentially catastrophic event. Given the complexity of many psychiatric patients seen in the medical setting, multiple practitioners are often focused only on their own organ-system of specialty. Without a look at the total patient, several risk factors for lethal Q–T-interval prolongation can accumulate. Unfortunately, this type of fragmented care is common among complex psychiatric patients. Lethal risk factors are often identified only after a crisis in care occurs. The potential for adverse outcomes in all our patients is present: knowledge, communication, and information remain the clinician’s and the patient’s greatest allies in protecting these patients from harm.

REFERENCES

TOP INTRODUCTION Case Report DISCUSSION Conclusion REFERENCES

 

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