Abstract
Philip Reid, Milford McArthur and Saxby Pridmore, Department of Psychological Medicine, Royal Hobart Hospital, Hobart, Australia:
We present a case of clozapine rechallenge after myocarditis. Recently, the frequency of the side-effect of myocarditis from clozapine has been reported at a higher level than was once thought; Australian data suggests an incidence of one in five hundred in the first month [1]. This has prompted recommendations for further monitoring in the form of regular electrocardiograms (ECG), echocardiograms and blood tests. This monitoring is likely to detect subclinical cases. Clinicians will increasingly face the difficult decision of discontinuation when interpreting the significance of more subtle ECG changes.
In June 1994, a 23-year-old former university student with deteriorating, treatment-resistant schizophrenia was started on clozapine. He had no history of cardiac disease or alcoholism and was physically fit. Clozapine was begun at 12.5 mg and increased slowly to 200 mg over 3 weeks. Initially, he exhibited the side-effects of hypersalivation, mild sedation and some dizziness from hypotension but these passed with time. His mental state improved significantly with a reduction of his positive symptoms. He was discharged on clozapine only and attended an outpatient clinic with regular blood testing.
Five weeks after starting clozapine, he complained of shortness of breath and non-specific aches and pains in his legs and body. On examination, he had a regular pulse of 120 beats/min, but no signs of heart failure. An ECG was taken which revealed marked ST-depression and T-wave inversion in the lateral and inferior leads. Eosinophilia was absent and creatine kinase was not elevated. Echocardiogram showed a hyperdynamic heart with left ventricular chamber size at the upper limit of normal. Heart valves and function were reported as normal. A consultant cardiologist diagnosed myocarditis secondary to clozapine as no other confounding comorbidity was identified.
The clozapine was ceased, but a deterioration in his mental state with thought-blocking and grimacing ensued 2 weeks after ceasing the medication. He started on resperidone which was later augmented with lithium. However, he continued to deteriorate, with marked anhedonia, alogia, amotivation and blunting of affect. A trial of haloperidol did not lead to any obvious improvement.
In 1996 clozapine was resumed. This decision was made after consultation with the patient, his family and the cardiologist who had made the diagnosis of myocarditis in 1994. Because of his steady decline in mental state and poor quality of life, another trial of clozapine was attempted with weekly ECG and eosinophil counts. Repeat echocardiogram prior to the commencement of clozapine was normal, apart from the trivial mitral regurgitation. His ECG had improved but still had evidence of T-wave flattening and ST depression.
The dose of clozapine was built up to a dose of 225 mg at night, his ECG remained unchanged and there was no rise in eosinophils. Again, his symptoms and functioning improved significantly over the initial 2 months with further subtle but significant positive change over years. He remains well and free of cardiac side-effects.
Myocarditis is a difficult condition to define and diagnose even with endocardial biopsy [2]. The pathophysiology of clozapine myocarditis is not known and complicated by the high likelihood of previous antipsychotic exposure. However IgE-mediated hypersensitivity, type 3 allergic reaction and direct toxic effects have been postulated in its aetiology [1].
Australian figures suggest clozapine-associated myocarditis is most likely to occur within the first 3 weeks of therapy. In the present case, symptoms developed in the sixth week. There are reports of numerous organ systems including the cardiovascular system being involved in clozapine-induced allergy which is invariably associated with eosinophilia [3]. The lack of eosinophilia and the later timing of the episode may suggest a toxic rather that allergic response in this patient. Some suggest that the ultimate test for causality of a drug reaction is dechallenge followed by rechallenge [4], thereby ruling out clozapine in this case. However, the timing and ECG findings, together with cardiology opinion, suggested this to be clozapine-induced myocarditis at the time of discontinuation.
This case highlights the significant and unique contribution that clozapine can make to some individuals with treatment-resistant schizophrenia. For this patient quality of life improvement outweighed the risk of further clozapine therapy. This is the first reported case of rechallenge of clozapine after myocarditis. It was achieved after considering the risk benefit, receiving the informed consent of the patient and with close cardiac monitoring.