Antipsychotic-drug-induced dilated cardiomyopathy

Abstract

A man in his 30s presented with symptoms of shortness of breath (SOB). He was on clozapine for schizophrenic symptoms. From the initial two presentations it was thought to be and managed as a chest infection, and a perfusion ventilation scan was done to rule out pulmonary embolism. However, with worsening SOB on exertion, he presented for a third time, and was referred and seen in the Department of Medicine on this occasion. The ECG showed evidence of left atrial and ventricular enlargement. The chest x ray showed an increased cardiothoracic ratio. An urgent echocardiogram showed the presence of dilated cardiomyopathy with severe left ventricular systolic function impairment. The patient had a coronary angiogram and other relevant investigations to look for the cause of the dilated cardiomyopathy. These investigations did not reveal any significant abnormality. The cause appeared to be related to the drug clozapine. The patient was treated for heart failure, and clozapine was stopped. He improved and repeat echocardiogram at follow-up showed a definite improvement in the symptoms and the echocardiogram.

BACKGROUND

Use of antipsychotic drugs is on the rise. It is important that the prescribers are fully aware of the serious adverse events of the drugs concerned. Monitoring of these patients is equally important. There have been reports of clozapine-associated myocarditis and cardiomyopathy.¹

It is important that the prescriber is aware of adverse events and monitors the patient for early signs of the serious associations that could be fatal.

CASE PRESENTATION

In January 2007, a young man in his 30s presented to the emergency department with a 4 month history of increasing shortness of breath on exertion that had progressed to breathlessness at rest. There were no symptoms of chest pain, cough, orthopnoea, oedema, wheeze or fever. Clinical examination was said to be unremarkable. His alcohol consumption was only moderate. He had been diagnosed with schizophrenia and treated with clozapine (650 mg) for 3 years. He did not have any other relevant past medical history. He was not known to have any connective tissue disorders, hypertension or ischaemic heart disease. Sinus tachycardia had been noted after commencing clozapine. He had no family history of any cardiovascular disease.

INVESTIGATIONS

ECG showed sinus tachycardia and signs of left atrial enlargement and left ventricular hypertrophy (fig 1). Chest x ray (fig 2B) showed an increase in cardiothoracic ratio compared with October 2006, when he had presented initially with breathlessness (fig 2A). Haematological, biochemical, autoimmune screen and thyroid function tests were normal except for a slightly elevated D-dimer of 344 and a raised γ-glutamyltransferase of 85. A ventilation perfusion scan excluded pulmonary embolus. An ECG showed enlargement of all chambers of the heart with severe left ventricular systolic dysfunction (ejection fraction 22%) and moderately impaired right ventricular function (fig 3A). A coronary angiogram did not demonstrate any underlying coronary disease (fig 4A, B).

Figure 1.

ECG at the time of presentation in January 2007.

Figure 2.

(A) Chest x ray at a previous presentation to the emergency department in October 2006. (B) Chest x ray at the time of the third presentation.

Figure 3.

(A) Coronary angiogram of the left coronary arteries (left anterior descending and circumflex arteries) showing no evidence of coronary artery disease. (B) Coronary angiogram of the right coronary artery showing no evidence of coronary artery disease.

Figure 4.

(A) Echocardiogram in January 2007 showing evidence of dilated cardiomyopathy. (B) Repeat echocardiogram in July 2007 showing a definite improvement in the size of the chambers.

TREATMENT

The patient was thought to have developed dilated cardiomyopathy due to clozapine and he was started on a beta-blocker, an ACE inhibitor and spironolactone. His breathlessness improved. Clozapine was changed to risperidone.

OUTCOME AND FOLLOW-UP

After 7 months, the patient remained well and asymptomatic. Repeat echocardiography showed normalisation of all cardiac chamber sizes and improvement in left ventricular systolic function, increasing from 23% to 43% (fig 4B).

DISCUSSION

Clozapine is a tricyclic dibenzodiazepine derivative used as an antipsychotic drug. The Food and Drug Administration delayed the approval of this drug by a decade due to its side effect of agranulocytosis. Clozapine is believed to act by increasing the ratio of serotonin to dopamine activity, and mesolimbic pathway dopamine antagonism.² There has been increased use of clozapine because of the suggestion of less extrapyramidal side effects, hyperprolactinaemia and tardive dyskinesia compared with other antipsychotic drugs³ and because clozapine has reduced incidence of suicides in patients with schizophrenia and has been effective in cases refractory to other medications.⁴ Despite these benefits, there appears to be growing concern, with reports of seizures, neuroleptic syndrome, myocarditis and dilated cardiomyopathy.^5–7

Merrill proposed direct cardiotoxic effects of clozapine responsible for induced cardiomyopathy.⁶ Other mechanisms may involve an underlying deficiency of cytochrome P450 to IA2, and cytochrome P450 to IA3 hepatic enzymes, thereby increasing clozapine concentrations and/or cardiotoxic effects of eosinophilic-mediated blockage of cholinergic M2 receptors.^6,8

Conclusion

Clozapine can cause slowly progressive toxic dilated cardiomyopathy. Ventricular function can improve when the drug is stopped. Use of clozapine requires awareness of this adverse effect and regular patient review. Patient symptoms suggesting heart failure should be promptly assessed by echocardiography. We feel that this is an avoidable cause of dilated cardiomyopathy and needs to be addressed.

LEARNING POINTS

• Monitoring of adverse effects, especially those of a serious nature, should be done routinely by prescribers of drugs.

• There have been reports of clozapine-associated myocarditis and dilated cardiomyopathy, and use of clozapine needs be selective and requires awareness by patients and doctors.

• Knowledge of drug-induced causes for the presenting symptoms of patients would help in early detection and management of adverse events that could be fatal.