Cardiomyopathy is a potentially fatal adverse drug reaction (ADR) associated with clozapine in psychotic patients, although it is considered very rare.1 However, one recent study has reported an incidence of echocardiographic evidence of clozapine‐induced cardiomyopathy of 4.65%. This suggests that the real incidence of this reaction might be greatly underestimated.2
To date, this ADR has been described in relatively young psychotic patients, with higher incidence rates reported in Oceania.1 But, in addition to its main use in treatment‐resistant schizophrenia, clozapine is also considered to be the gold‐standard treatment for psychotic symptoms in patients with Parkinson's disease (PD),3, 4 disease in which the prevalence and incidence increase nearly exponentially with age. Although some reports have shown that clozapine is seldom used in these patients,5 1 study carried in France estimated that approximately 25% of all new clozapine prescriptions were indeed for patients with PD.6
Concern about this ADR affecting patients with PD in addition to young schizophrenic patients was raised as early as 2000.7 However, to the best of our knowledge, to date, only one case of myocarditis associated with clozapine has been reported in a patient with PD,8 whereas no cases of clozapine‐associated cardiomyopathy have been reported in individuals with this disease.
The Pharmacovigilance Unit of the Basque Country was searched for spontaneously reported cases of cardiomyopathy associated with clozapine among patients with PD in the European pharmacovigilance database (EudraVigilance), which includes ADRs reported from the European Economic Area and, in the case of clozapine (the product of a marketing authorization holder based in Switzerland [Novartis]), notifications from anywhere in the world.
First, we performed the search using a standardized MedDRA query for “cardiomyopathy” in the EudraVigilance database until February 2015. Then, cases that involved patients with PD were selected and further analyzed. Patients with PD were identified by analyzing the structured medical history record in EudraVigilance.
We identified 5 cases of cardiomyopathy in patients with PD (see Table 1). The mean age of these patients was 70 ± 11.4 years (range, 54–86 years), and all 5 patients were men. Two patients were identified in Ireland, and one patient each was identified in France, Germany, and the United States. The clozapine dose was known in only in 3 patients and was 12.5, 25, and 100 mg/day. Latency was 6 years in one patient and unknown in all others. The ADR was considered severe in all patients, and one patient died. Although it was not possible to establish causality in any of the cases, and important data were lacking, our analysis of the EudraVigilance database indicates that the risk of clozapine‐associated cardiomyopathy might not be limited to young schizophrenic patients.
Table 1.
Cases of cardiomyopathy in Parkinson's disease associated with clozapine in the EudraVigilance database
| Year | Sex | Age, y | Country | Clozapine indication | Comorbidity | Other drugs | Antiparkinsonian treatment | Dose, mg/d | Latency | Severe by EU Criteriaa | Causality |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 2004 | Man | 67 | Germany | Psychotic disorder | Unknown | — | Levodopa/benserazide | 25 | Unknown | Yes | Unknown |
| 2005 | Man | 72 | France | Erotomanic delusion | Unknown | — | Pergolide, levodopa/carbidopa | 12.5 | 6 y | Yes | Unknown |
| 2010 | Man | 86 | USA | Unknown | Dementia | — | Unknown | Unknown | Unknown | Yesb | Unknown |
| 2010 | Man | 54 | Ireland | Unknown | Schizophrenia, chromosomal deletion (22q11), affective disorder | Valproic acid | Levodopa/carbidopa | 100 | Unknown | Yes | Unknown |
| 2013 | Male | 71 | Ireland | Unknown | Dementia, depression, anxiety | Clarithromycin, donepezil, clonazepam, escitalopram | Unknown | Unknown | Unknown | Yes | Unknown |
Severity was assessed according to European Union (EU) criteria. The EU Codification Directive (2001/83/EEC) defines a serious reaction as an adverse reaction that results in death, is life‐threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect.
The patient died as a consequence of the adverse reaction.
The mean age of patients with PD who suffered from cardiomyopathy associated with clozapine was 70 years, compared with a mean age of 33.5 years in the systematic review of published cases affecting young psychotic patients.1 Recognizing this rare ADR in PD is not easy because of the high prevalence of present comorbidities, such as coronary heart disease, arrhythmia, and congestive heart failure, which make it difficult to identify small increases in these problems and also increase the possibility of a coincidental association. Furthermore, apart from these age‐related comorbidities, other important causes of cardiac disease were possible in at least 2 of the 5 reported patients. The second patient was being treated with pergolide, which was withdrawn from the US market in 2007 because of its effect on cardiac valves. The fourth patient had the 22q11 deletion syndrome, which has a known association not only with PD but also with congenital cardiac disease and often requires cardiac surgery.9
As expected, the mean clozapine dose was considerably lower in patients who had PD compared with psychotic patients (45.8 vs. 360 mg, respectively). All patients with PD and the vast majority of psychotic patients were men.
Many possible different mechanisms for this ADR have been proposed, including accumulated α‐adrenergic blocking effects, direct toxicity similar to that from anthracycline‐induced cardiotoxicity, and selenium depletion and high ozone concentrations, leading to increased rates of cholinergic M2 receptor blockade. Nevertheless, to date, the mechanism for the association between clozapine and cardiomyopathy remains unknown. Alternative drugs to treat psychotic symptoms in patients with PD (quetiapine, pimavanserin) have not demonstrated the same risk to date.4 We disagree with the latest version of the Beers Criteria about aripiprazole being on the same level as clozapine and quetiapine.10
In conclusion, this potentially fatal ADR ought to be considered when prescribing clozapine to elderly patients, such as those with PD who suffer from psychotic symptoms or tremor.11
Author Roles
1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.
U.L.: 1A, 3A, 3B
R.H.: 1A, 3A, 3B
J.M.: 1A, 3A, 3B
S.D.: 1A, 3A, 3B
M.G.: 1A, 1B, 3A, 3B
C.A.: 1A, 1B, 3A, 3B
Disclosures
Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflict of Interest: This study was supported by a grant from the Araba Mental Health Network.
Financial Disclosures for the previous 12 months: The authors report no sources of funding and no conflicts of interest.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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