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Elevated Clozapine Serum Level After Treatment With Amiodarone

Received November 14, 2006; accepted November 28, 2006. From the Dept. of Psychiatry, Massachusetts General (MGH) and McLean Hospitals, Boston, MA; the MGH Schizophrenia Program, Massachusetts General Hospital, Boston, MA. Send correspondence and reprint requests to Jonathan Stevens, M.D., 15 Parkman St., MGH, WACC 812, Boston, MA 02114. e-mail: jrstevens{at}partners.org
© 2008 The Academy of Psychosomatic Medicine

Key Words: Clozapine • Amiodarone • Side Effects

INTRODUCTION

TOP INTRODUCTION Case Report Discussion REFERENCES

 
Cardiovascular conditions, including arrhythmias, occur in many patients with psychotic disorders, just as they do in patients without psychiatric disturbances. Therefore, awareness of potential drug–drug interactions between psychotropics (e.g., atypical antipsychotics) and cardiac medications (e.g., antiarrhythmics) is crucial for practitioners of medicine and psychiatry. Although elevated serum clozapine levels and clozapine toxicity have been reported as unintended consequences of the coadministration of clozapine with a variety of drugs (e.g., fluvoxamine, cimetidine, and modafinil),^1,2 it has not yet been associated with coadministration of amiodarone (Cordarone). Amiodarone, a Class III antiarrhythmic agent, widely used in intensive care units for the treatment of life-threatening ventricular arrhythmias (its FDA-approved use),³ is also increasingly used to treat common tachyarrhythmias (e.g., atrial fibrillation, atrial flutter, and supraventricular tachycardias [its off-label uses]).⁴ Given that amiodarone and its metabolites are potent inhibitors of the hepatic metabolism of many drugs, potentially harmful drug–drug interactions may result from their coadministration with other agents.⁵

We describe the development of an elevated serum clozapine concentration in an elderly man who received amiodarone to manage ventricular tachycardia (VT) and discuss potential mechanisms of this interaction.

Case Report

TOP INTRODUCTION Case Report Discussion REFERENCES

 
"Mr. C," a 75-year-old nonsmoker with a long-standing history of schizophrenia, was well-managed on clozapine (300 mg/day) and divalproex sodium (1,000 mg/day) for the past 3 years. He was stoic, and he rarely complained about medication side effects. His medical problems included hypertension, chronic obstructive pulmonary disease, a dilated cardiomyopathy, and a history of VT, for which he had received an automatic implanted cardioverter defibrillator (AICD).

Four months after placement of his AICD, he was noted to be hypoxic during a routine outpatient AICD interrogation. He reported having cough, shortness of breath, and chills in the 10 days before this appointment. Mr. C was therefore sent to the emergency department, where a transthoracic echocardiogram revealed a large circumferential pericardial effusion, without tamponade. A subxiphoid pericardial window was created, and his AICD generator lead was removed as the suspected cause of his hemopericardium (via perforation of the right ventricle).

Within 48 hours of this procedure, Mr. C developed VT (with rates up to 240 bpm). Amazingly, he was alert, responsive, and maintained an adequate blood pressure (systolic blood pressure in the 80s); a "code" was called. He received magnesium and intravenous amiodarone (150 mg), which resulted in a return to normal sinus rhythm within 10 minutes. In light of his AICD-related complication and his relatively preserved left-ventricular function, Mr. C was loaded on amiodarone rather than replacing his AICD. Mr. C remained hemodynamically stable for the remainder of his hospital stay and was discharged (on Hospital Day 22) on a regimen of amiodarone (400 mg/day) and his preadmission doses of clozapine and divalproex sodium. His other medications included ipratropium, albuterol, metoprolol, pantoprazole, magnesium gluconate, and iron supplements.

Mr. C returned to his group home and resumed biweekly outpatient visits in the clozapine clinic. A clozapine serum level obtained as part of routine therapeutic monitoring revealed a concentration of 1,580 ng/ml (his combined clozapine-plus-norclozapine level was 1,786 ng/ml), which was significantly greater than his prehospital level (242 ng/ml). He denied having either undue sedation or dizziness (symptoms of clozapine toxicity) but was, according to his outpatient psychiatrist, more tangential and disorganized. Staff at his group home confirmed that he had been adherent to his medication regimen. His clozapine dose was cut in half (to 150 mg/day), and his serum clozapine level had decreased (to 355 ng/ml) at the next determination 2 weeks later. During follow-up visits, Mr. C remained psychiatrically stable.

Discussion

TOP INTRODUCTION Case Report Discussion REFERENCES

 
Drug–drug interactions are increasingly viewed as preventable complications in medical practice. However, when a MEDLINE search (using the keywords amiodarone and clozapine) was conducted, no reports of adverse drug–drug interactions were found, despite previous observations that both clozapine and amiodarone are metabolized through the Cytochrome P450 isoenzyme (CYP) systems. Clozapine is primarily metabolized through CYP 1A2, but numerous secondary pathways (including 2C9/19, 2D6, and 3A3/4) are also involved.^6,7 Clozapine’s primary metabolite, norclozapine (or desmethylclozapine), is only weakly active at D₂ and 5-HT₂ receptors, and the literature on clozapine serum levels is based on levels of clozapine alone.

Amiodarone is a pan-inhibitor of CYP systems. Although amiodarone primarily inhibits CYP 3A4, its major active metabolite, desethylamiodarone, is a potent inhibitor of 1A1/2, 2B6, and 2D6.⁵ Therefore, both amiodarone and clozapine have a complex hepatic metabolism, each involving several overlapping isoenzyme systems.

Our observation of an increased clozapine level after coadministration of amiodarone may well be explained by a pharmacokinetic interaction at the level of CYP enzymes (although systems other than CYP may be involved). None of Mr. C’s nonpsychotropic medications have been associated with changes in clozapine serum levels.¹ However, divalproex sodium has been linked with both an increase and a decrease in levels of clozapine.⁵ In the case of Mr. C, the dose of divalproex sodium was stable for a period of several months before his abnormal level was obtained.

Potent CYP inhibitors (e.g., amiodarone) can increase the potential for toxicity when they increase the circulating levels of drugs (e.g., clozapine) with fairly narrow therapeutic indices.⁸ The time-course of CYP inhibition and its effects can be rapid, resulting in clinically significant drug elevations within hours-to-days. One case of suspected cimetidine (another broad CYP inhibitor)-induced clozapine toxicity occurred with coadministration of 900 mg/day of clozapine and cimetidine (400 mg tid). Within 3 days, the patient complained of diaphoresis, vomiting, lightheadedness, and generalized weakness, in the context of an elevated clozapine level (1,559 ng/ml).⁸

For clinicians and their patients, it is also important to recall that the discontinuation of a CYP-inducer (e.g., tobacco smoke) can also lead to increased concentrations of substrates. Polyaromatic compounds in cigarette smoke, as opposed to compounds in nicotine itself, can induce CYP 1A2 and thereby affect the metabolic clearance of clozapine. Derenne and Baldessarini⁹ reported a case of a young woman smoker who abruptly discontinued heavy daily cigarette-smoking while on clozapine (450 mg/day). Within several days, she developed dry mouth, dizziness, blurred vision with dilated pupils, sedation, and confusion. Her clozapine level was markedly elevated (1,615 ng/ml) in comparison to her baseline levels.

Although the practice of routine therapeutic drug-monitoring for clozapine is controversial, it is a reasonable plan. Some authors have emphasized the importance of therapeutic drug-monitoring to avoid clozapine concentrations above 1,000 ng/ml, in order to minimize the potential for confusion, delirium, and generalized seizures.¹⁰ One large retrospective study found electroencephalographic (EEG) abnormalities in nearly half of clozapine-treated patients, a rate substantially higher than is experienced by patients treated with any other atypical antipsychotic.¹¹ In a prospective, randomized study, EEG findings were compared among three different, non-overlapping clozapine serum-level ranges (50–150 ng/ml, 200–300 ng/ml, and 350–450 ng/ml).¹² Patients in the highest serum-level range showed more severe EEG slowing and more sedation as compared with those whose clozapine serum levels were below 300 ng/ml. VanderZwaag and colleagues¹³ concluded that a clozapine serum level between 200 and 300 ng/ml was optimal for clinical response in a cohort of inpatients with treatment-resistant schizophrenia; no added advantage was observed with higher serum levels. Although this study did not examine serum levels above 450 ng/ml, it seems reasonable to conclude that clozapine serum levels should not be unnecessarily high, because seizure risk on clozapine increases with drug dose and serum concentration.¹²

A review by Greenwood-Smith and associates¹⁴ concluded that although the literature does not advocate routine serum testing for patients on clozapine, there is evidence for the usefulness of therapeutic drug-monitoring in specific clinical situations (e.g., when there are signs of toxicity, when the smoking status of the patient changes, and when the physical health of the patient is impaired). We would add to this list of cautions the data indicating that clozapine serum levels cannot be predicted from the administered clozapine dose, because there is high interindividual variability.¹³ Unfortunately, the first sign of clozapine toxicity can be a generalized seizure, particularly if a patient has high serum levels (although tolerated) until a drug–drug interaction leads to an even higher serum level that exceeds the patient’s seizure threshold.

In our case, Mr. C’s elevated clozapine level was identified by routine therapeutic drug-monitoring, as opposed to a level drawn in response to his complaint of side effects. It should be noted that Mr. C. was rather stoic and had not even complained while he was developing a hemopericardium. Also, Mr. C might have been inadvertently protected from seizures by virtue of his concurrent divalproex sodium treatment (used for psychiatric reasons).

Our report is limited by a lack of serial assays that tracked the concentrations of clozapine with and without amiodarone in the same subject over time. Such a relationship may demonstrate an "off-on-off-on" pattern after the addition of amiodarone to a regimen of clozapine; subsequent effects on serum clozapine levels could be tracked. This clinical situation, however, is impractical and potentially dangerous in light of amiodarone’s unusually long elimination half-life (which averages about 58 days)³ and its importance in the prevention of life-threatening arrhythmias.

In our complex medical environment, many patients receive a host of medications from different specialists. Unfortunately, communication between specialties, although desirable, may not always occur, particularly when care is provided in different healthcare systems or on an emergency basis; therefore, medication reconciliation is critical. Since side effects of clozapine can be well tolerated and because complaints of side effects in patients with psychotic disorders are often minimized, therapeutic drug-monitoring by the prescribing psychiatrist may be the only way to avoid seizure as the first sign of clozapine toxicity. Clinicians should pay close attention to any drug that is added to a clozapine-treated patient’s regimen so as to help avoid potentially toxic drug–drug interactions.

REFERENCES

TOP INTRODUCTION Case Report Discussion REFERENCES

 

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