Clozapine-induced pericarditis: an ethical dilemma

Abstract

Clozapine is an atypical antipsychotic used most frequently in the management of treatment-resistant schizophrenia, where severely unwell patients have failed to respond to standard antipsychotic therapy. Clozapine is associated with a number of risks, such as agranulocytosis and long-term cardiometabolic morbidity. Reported less frequently is the risk of severe cardiac complications. The case reported here provides an important example of chronic clozapine toxicity leading to pericarditis. This case also describes a difficult ethical dilemma, where the physical risk to a patient with a diagnosis of schizophrenia must be balanced with the potentially adverse psychiatric risk that would follow, if the patient were to be weaned off this effective antipsychotic therapy. It is frequently reported that clozapine is stopped due to its toxicity. In this case however, the mental health and functional benefit of continuing with clozapine was deemed to outweigh the physical risk of progression of the pericarditis.

Background

Clozapine is an atypical antipsychotic used most frequently in the management of treatment-resistant schizophrenia (TRS), where severely unwell patients have failed to respond to standard antipsychotic therapy. While significantly effective for the treatment of psychotic symptoms such as hallucinations and delusions, clozapine is commonly associated with a risk of agranulocytosis (1%–2% after 1 year of therapy, which can be fatal if not detected and treated early) and long-term cardiometabolic morbidity (diabetes, dyslipidaemia, high body mass index). Overall, clozapine is associated with reduced risk of mortality from natural causes.¹ However, mortality can occur as a result of sudden and severe cardiac complications. Among these are cardiomyopathy, myocarditis and pericarditis; the former of which are frequently reported in the existing literature.² By contrast, there are fewer than 10 reports of clozapine-induced pericarditis and, less frequent still, is the reporting of pericarditis in patients who have been on clozapine therapy for years.

Clozapine is converted to its active metabolite norclozapine via the hepatic cytochrome P450 microsomal system. The serum norclozapine level is determined by several metabolic and individual factors, for example, the patient’s smoking status and gender.³ Clozapine is frequently augmented by other psychotropics and there is some evidence to suggest that co-prescription with amisulpride may have some benefits.⁴ It is associated with a significant range of side effects, including hypersalivation, tachycardia, life-threatening constipation and agranlucocytosis. Myocarditis is the only serious cardiac adverse effect reported in the Maudsley Prescribing Guidelines,⁴ as the guidance suggests that patients are closely monitored for symptoms of myocarditis during the first 2 months of therapy, such as chest pain, palpitations and shortness of breath.

There have been some reports of clozapine-associated serositis and a recent review concluded that polyserositis most frequently occurs when initiating clozapine therapy.⁵ In the 22 cases reviewed, 25% of patients were on combined therapy of valproate and clozapine. Valproate is a known inhibitor of the cytochrome P450 system, thus it can increase the bioavailability of clozapine to potentially toxic levels. Another case also recognised the non-psychiatric cytochrome P450 interactions,⁶ as clozapine toxicity manifested following the administration of antifungal therapy (flucanazole and micanazole). Conversely, clozapine levels can decrease secondary to the induction of cytochrome P450 isoenzymes by cigarette smoke hydrocarbons.³

Given the sparsity of evidence, the prevalence of pericarditis associated with clozapine therapy has not been established, which necessitates reports of a potentially life-threatening complication. There is similarly insufficient literature on the drug interactions that precipitate clozapine toxicity. As the evidence suggests that clozapine toxicity usually occurs as an acute presentation in the early stages of treatment, the present case reported here provides an important example of chronic clozapine toxicity. This case also describes a difficult ethical dilemma, where the physical risk to a patient with a diagnosis of schizophrenia must be balanced with the potentially adverse psychiatric risk that would follow, if the patient were to be weaned off this effective antipsychotic therapy.

Case presentation

A man aged 52 years presented to the Medical Assessment Unit after being found confused and slumped on the floor in his home with symptoms of drowsiness and wheezing. On examination, he was found to have reduced consciousness and widespread wheezing on auscultation of the chest. He was mildly tachycardic and dyspnoeic, with reduced O₂ saturations (89% on 4 L/min). Of note was his psychiatric and medical background. He had a long-standing diagnosis of TRS, which had been managed for 15 years by clozapine 500 mg/day, sodium valproate 1000 mg twice a day and amisulpride 200 mg/day. He denied substance abuse but had an extensive smoking history. He was a known asthmatic. As a result of the clozapine therapy, he had become morbidly obese and developed type 2 diabetes mellitus and hypertension. He had also developed obstructive sleep apnoea secondary to this obesity.

Investigations and treatment

The patient was treated for an acute asthma exacerbation and the drowsiness was attributed to obesity-hypoventilation syndrome. A chest X-ray was arranged to investigate his hypoxaemia, which unexpectedly revealed a large heart (figure 1). A subsequent echocardiogram confirmed the presence of a large pericardial effusion, without evidence of cardiac tamponade or haemodynamic collapse (table 1). He was reviewed by the cardiology team who did not consider this effusion to be life-threatening, thus it was not drained, given the considerable risks associated with pericardiocentesis. They believed this effusion had been long-standing, due to both its size and the presence of an enlarged cardiac silhouette on a chest X-ray performed 18 months previously, which had been noted retrospectively (figure 1). He was therefore managed medically, with a reducing dose of prednisolone and a 3-month course of colchicine—a novel therapy to prevent recurrence of acute pericarditis, where non-steroidal anti-inflammatory drugs are contraindicated.⁷

Figure 1.

Chest X-rays performed on the patient at the time of presentation (A) and 18 months prior to this (B). The pericardial effusions are demarcated in white.

Table 1.

Summary of echocardiogram reports

Timing of echocardiogram	Summary of findings
Initial presentation	Moderate-to-large pericardial effusion (about 1–2 cm in depth), not causing tamponade or haemodynamic compromise.
Three weeks after initial presentation	Circumferential pericardial effusion noted, appears consistent in size to previous scan. No clear evidence of haemodynamic compromise.
Four months after initial presentation	Circumferential pericardial effusion, appears consistent in size to previous scans. No clear evidence of haemodynamic compromise. Preserved systolic function.

Outcome and follow-up

The patient was followed up at 4 and 6 weeks after discharge by the cardiology team for reassessment of the effusion, which had not changed noticeably in size. During this time he had been admitted as an inpatient to an acute psychiatric ward. His Community Mental Health Team decided to reduce his clozapine dose due to the physical health risk, in an inpatient ward given his historic risks of aggression and sexually disinhibited behaviour when he had relapsed. He was placed under Section 3 of the Mental Health Act as his mental state began to deteriorate shortly after admission. He became increasingly disinhibited with staff on the ward and was observed to be responding to unseen stimuli more frequently. His amisulpride was increased incrementally, while his clozapine was weaned down. Other cytochrome P450 inhibitors were stopped, for instance, his omeprazole, however he remained on the same dose of sodium valproate.

The opinion of the Clinical Ethics Committee (CEC) was sought, as to whether the psychiatric team should stop or continue the clozapine therapy. The cardiology team also participated in the CEC meeting. Having applied the four-stage test for capacity,⁸ the patient did not demonstrate understanding of the issues or an ability to deliberate the risks and benefits, despite several attempts to maximise his capacity. He reiterated the statement that he trusted the doctors to make the right decision and was not willing to engage on a discussion about the subject. On balance, the CEC concluded that it would be of greater benefit to the patient to continue the clozapine therapy and they reversed the decision of the Community Mental Health Team. Their rationale was that clozapine offered a degree of psychiatric stability vis-à-vis a pericardial effusion had not been worsening over a period of months (table 1) while still on clozapine. Furthermore, there was new input from the cardiology team that a pericardial window could be created, to facilitate drainage of the effusion. This could even be done urgently if required. Importantly, his maintenance of good mental health would allow him to engage in cardiology treatment if that were to be required. The patient was therefore reinstated on his initial clozapine dose. His mental state improved and returned to his baseline, prior to being discharged back to the community.

One year after these events, the patient continued to attend routine cardiology outpatient follow-up and both his physical condition and mental state remained stable. He had settled into his supported accommodation well. He had set personal goals, such as improving his diet and stopping smoking, which he was slowly achieving.

Discussion

This case raises several ethical issues and contrasts to previous case reports, where clozapine therapy has been stopped. Central to this case is the concept of best interests decision-making. The patient lacked capacity to decide whether he should continue or stop clozapine therapy. Despite significant efforts to improve his understanding, a decision was ultimately made in his best interests. Several factors were considered, principally what he valued and what maintained his well-being.

The patient expressed that for the last 15 years, he was able to ‘live a good, holy life’ and ‘say (his) prayers and read (his) bible’. This coincided with initiation of clozapine. His perception of this period was that his life had improved and the CEC therefore considered factors that maintained his well-being. There are several theories of well-being that can be considered in modern ethics. One theory considers hedonism and states that an action that maximises pleasure over pain is likely to further one’s well-being.⁹ For the patient, living a ‘good, holy life’ provided him with pleasure. Clozapine offered psychiatric stability to facilitate this. It also enabled him to develop relationships and friendships with mental health services staff and pursue knowledge of a religious context; two objective measures of well-being suggested by ‘objective list theorists’.¹⁰ He referred to himself, prior to achieving a stable mental state, as being a ‘very bad man’; suggesting that he did have insight into his past actions despite not fully understanding the role of antipsychotics in managing his mental disorder. While the pericarditis did create literal pain, which the patient referred to as ‘spiritual pains in the chest’, this alleviated as the effusion was treated with oral corticosteroids and colchicine. Thus, clozapine was, in many ways, considered to be in his best interests. Furthermore, in this case the pericardial effusion was a stable complication of his clozapine therapy; not unlike diabetes and obesity, both of which are tolerable strains on physical health when weighed against the benefit of antipsychotic agents.

The patient stated that he had complained of these ‘spiritual chest pains’ for several months, however it was unclear whether this complaint had been fully investigated in the community. This, in turn, raises questions regarding how much physical ailments could be underdiagnosed, in the sense that they be misinterpreted as symptoms of an existing psychiatric disorder. There has been a push to protect the physical wellness of patients with severe and enduring mental illness, in particular, where antipsychotic treatment may have increased the burden of physical morbidity. This is of both public health and ethical relevance because access to physical healthcare is reduced in psychiatric patients,¹¹ as compared with the general population. A review by De Hert et al found that the quality of healthcare received by patients with mental illness was poorer than in the general population, and argued that this was unforgivably detrimental, as the maintenance of physical well-being was crucial in protecting the quality of life of these individuals.¹² Maj attributed this to a failure of mental health professionals to perform basic medical tasks and primary care staff’s reluctance to treat patients with mental illness.¹¹While the CEC decided not to prioritise the management of the patient’s physical morbidity (pericarditis) over his schizophrenia in this case, there was indeed a considerable improvement to the patient’s quality of life after his pericarditis was conservatively managed.

The ethical dilemma in this situation was, however, complicated by the lack of alternative therapies to clozapine available. Clozapine is used in TRS, where at least two other antipsychotic drugs have failed. Amisulpride is frequently used to augment the effects of clozapine, in patients who show a partial response⁴; hence, the rationale for increasing the patient’s amisulpride dose while his clozapine was weaned down. However, a large meta-analysis found that augmentation of clozapine with a second antipsychotic agent was only modestly beneficial in partial responders.¹³ There is insufficient literature showing a significant response to clozapine augmentation, thus preventing the development of an evidence-based algorithm for patients where clozapine is cautioned or ineffective.

Patient’s perspective.

The patient’s reflection on these events was sought 1 year after his inpatient admission.

“When I was in hospital last year I was very nervous. I was talking more to people who were talking to me. I turned on things but I didn’t want to. I didn’t want to talk to the opposite sex… The authorities made a big difference, especially (my care coordinator), who has been a very important person in my life.

I have got better because of my faith. It has made a big difference. I am reading scriptures and praying everyday… I remember when my medication was changed and started again. The medication change worked together with my prayers and religion. I am talking to my God. I am a better person now, better than when I walked around aimlessly smoking herb.

The pains in my chest have got a lot better. I am eating a lot of fruit and less desserts. I am smoking less, only nine to ten a day. I have cut back a lot and my breathing is better… I went to the doctor a few weeks ago who tells me my heart condition is not that bad… I am doing my own washing now and looking after my own money.

I would like to get better. I will be better when I am slim, independent, have a shine in my eyes, have lost weight, keep believing, keep reading scripture and keep saying prayers. I know that I will need to be on medication for the rest of my life”.

Learning points.

• Pericarditis is typically an acute complication of clozapine therapy, most commonly occurring soon after its initiation.

• This case provides a new example of subacute pericarditis secondary to long-term clozapine therapy.

• In all other case reports, clozapine was stopped due to its toxicity. In this case, the mental health and functional benefit of continuing with clozapine outweighed the physical risk of progression of the effusion.

• The ethical considerations chiefly surrounded the patient’s well-being, however the lack of alternative therapies to clozapine was also discussed.

• Overall, this case highlights the difficulties in managing the physical health of patients with severe mental illness and reiterates the importance of engaging mental health professionals in the management of physical healthcare.