Protocol for Clozapine Rechallenge in a Case of Clozapine-Induced Myocarditis

Abstract

Objective:

Protocol for clozapine rechallenge in patients with a history of clozapine-induced myocarditis.

Method:

Clozapine-related cardiovascular adverse effects including myocarditis and cardiomyopathy have limited its widespread use in treatment-resistant schizophrenia. Here, we present a case of clozapine-induced myocarditis and successful cautious rechallenge. Ms. AA, a young female patient with severe psychosis developed myocarditis during her initial clozapine titration phase, which was thus discontinued. Subsequent response to other medications was poor, and she remained significantly disabled. We reviewed blood-based biomarkers identified during the emergence of her index episode of myocarditis and developed a successful clozapine rechallenge protocol, based on careful monitoring of changes in these indices and a very slow clozapine re-titration.

Results and Conclusions:

This protocol may have utility in the management of patients with a history of clozapine-induced myocarditis.

Introduction

Clozapine, unlike any other antipsychotic, has proven efficacy in successfully managing treatment-resistant schizophrenia.¹ Agranulocytosis is a well-recognized side effect of clozapine; however, a potentially equally serious and fatal complication is its association with myocarditis and cardiomyopathy.² While this association has remained controversial in the past, there are now more than 250 documented cases of clozapine-induced myocarditis,³ and emerging evidence reports mortality from myocarditis a significant risk not to be ignored.⁴ Myocarditis tends to manifest early on following clozapine initiation and can occur as early as Week 1 and up to Week 3 and very occasionally later in treatment.^3,5 The incidence of clozapine-induced myocarditis is variable from 0.06% to >3%, and this highlights the diagnostic challenge in this group, and underreporting and missed detection is likely to play a role in these figures.⁵ Mortality rates in this group range from 24% up to 50% when undiagnosed.^5,6 Cardiomyopathy tends to occur later on in the course of treatment and has a higher mortality rate of about 64%.⁷ Existing guidelines for treating myocarditis recommend immediate cessation of clozapine, and in general, future rechallenge is not recommended due to the high risk of recurrence and mortality.

Despite the risks and probably due to the lack of other clinical alternatives to clozapine, clinicians have embarked on rechallenges with mixed results—some successful,⁸ most unsuccessful, and presumably majority of failed trials don’t get reported in literature.⁴ It is thus important to develop a rechallenge protocol that is carefully thought through and attempts to mitigate the multitude of risk factors for those patients who are in real need of it. Below we describe one such case of clozapine-induced myocarditis and the titration protocol utilized 7 years later to successfully rechallenge the patient with clozapine.

Case Outline

Ms. AA, a 34-year-old nonsmoking female of Southeast Asian descent was diagnosed with schizophrenia in 2005. Clozapine was initiated in November 2008 after multiple trials of antipsychotic medications in inpatient settings failed to satisfactorily improve her symptom burden. Pre-clozapine cardiovascular screening was normal, including echocardiogram, troponin and ECG (Electrocardiogram), and clozapine titration commenced with concomitant administration of sodium valproate (1,500 mg/day). By Day 9, she was on a cumulative clozapine dose of 750 mg and by Day 15, her clozapine titration had reached 250 mg daily. At this point, she became febrile and tachycardic, and upon review, her serum troponin was raised to 0.05 µg/L (normal <0.03 µg/L). Two days later, by Day 17, her troponin was elevated to 0.17 µg/L alongside raised C-reactive protein (CRP) of 44 mg/L (normal < 5 mg/L). This was associated with eosinophilia and biphasic T-wave changes on electrocardiogram. The diagnosis of probable myocarditis was made by the cardiology team based on clinical picture and increase in troponin levels on serial measurements. Clozapine was ceased following admission to a general medical ward, and troponin and ECG normalized over the following 6 days, with a normal transthoracic echocardiogram (TTE); however, eosinophilia persisted. Over the next 2 years, her treatment (both as an inpatient and within the community) consisted of numerous trials of alternative antipsychotic medications; however, despite satisfactory adherence, dosage and duration of medication trials, she remained unwell with minimal response.

Rechallenge

Given the persistence of severe and debilitating psychotic symptoms after adequate trials of numerous antipsychotics and electroconvulsive therapy, rechallenge with clozapine was raised as a potential treatment option in 2015, following second opinions and consultation with cardiology and immunology services. Prior to rechallenge, pharmacogenetic testing (MyDNA, South Yarra, Victoria, Australia) was ordered for Ms. AA, which suggested she was a normal metabolizer of clozapine [CYP1A2: *1A (normal function)/*1F (higher inducibility); CYP2D6: *1 (normal function)/*41 (decreased function); CYP2C19: *1 (normal function)/*1 (normal function)]. Her initial myocarditis episode in 2008 was also reevaluated including an assessment of markers of inflammation and cardiac toxicity (Figure 1), demonstrating that monocytosis developed by Day 7 of clozapine titration and peaked at 1.2 × 10⁹/L on Day 14. This commenced prior to any clinical symptoms at Day 15 or elevation in troponin while eosinophilia was apparent at Day 21. We hypothesized that monocytosis may be an early marker of clozapine-induced myocarditis, while eosinophilia may be a late marker of a hypersensitivity reaction. Clinical observations of clozapine titrations on our unit suggested that cardiac side effects were fewer with a slower titration.

Figure 1.

Ms. AA’s biomarkers during the event of acute myocarditis, 2008. First dose of clozapine was given on December 01, 2008. Y-axis on left relates to troponin, WCC (white cell count), neutrophils; Y-axis on right relates to eosinophils and monocytes.

We monitored blood and cardiac indices during clozapine rechallenge and developed a protocol of slow incremental titration modulated according to changes in these indices (Figure 2). The mechanism of clozapine-induced myocarditis is not clear; however, around 66% of patients with clozapine-induced myocarditis have eosinophilia, and it is thought this mechanism is an immunoglobulin E (IgE)-modulated hypersensitivity reaction. Hence, we devised our rechallenge protocol taking this into account and performed a “desensitization” of Ms. AA to clozapine, by way of extremely cautious dose increments while closely monitoring all relevant blood indices.

Figure 2.

Proposed model for clozapine rechallenge post-myocarditis.

Ms. AA was initiated on a slow titration of clozapine in August 2015 with daily and then biweekly complete blood count/troponin/CRP and regular TTE/ECG, with close cardiology supervision. She was on a combination of carvedilol 3.125 mg twice daily and perindopril 2.5 mg once daily as recommend by the cardiologist, and this is the routine combination utilized to reduce cardiac complications in the long term. She was also on chlorpromazine 300 mg daily for an extended period during the rechallenge as this was the only antipsychotic medication with which patient got some benefits. Ms. AA commenced 5 mg clozapine syrup and titrated in increments of 5 mg biweekly, assuming the above serum lab results were satisfactory. As demonstrated in Figure 3, the monitoring of laboratory results with the protocol resulted in multiple instances of eosinophilia and monocytosis, prompting a temporary cessation in “up-titration” and repeat testing/further workup before proceeding with dose titration. This was based on evidence that asymptomatic patients can exhibit eosinophilia on clozapine,^9,10 which may suggest it represents another marker of developing myocardial inflammation. No evidence of myocarditis was detected during the desensitization procedure, as indexed by no rise in CRP or troponin levels. Further, there were no anomalies detected on routine TTE. With the aforementioned protocol, Ms. AA reached a dose of 150 mg successfully with associated clinical improvement, including clinically significant reduction in positive psychotic symptoms, agitation, and disorganized behavior. However, she absconded from the treatment unit in February 2016, which necessitated re-titration of clozapine again commencing at 5 mg, which was successful. There has been no evidence of a recurrence of myocarditis in Ms. AA, and she has complied with treatment to date. Her clinical improvement included reduction in previously debilitating positive symptoms, significant insight about her condition and need for treatment, and improved cognitive function indexed by the Montreal Cognitive Assessment (scoring 17/30 pre-clozapine and 29/30 post-clozapine). After a 7-year continuous inpatient admission, Ms. AA was successfully discharged from hospital on clozapine monotherapy at a dose of 450 mg daily and was able to recommence university studies.

Figure 3.

Trend of biomarkers during the clozapine rechallenge process in 2015 to 2016. Y-axis on left relates to clozapine daily dose, WCC; Y-axis on right relates to troponin, C reactive protein, eosinophils, neutrophils, and monocytes.

Hypothesis and Protocol

The etiology of clozapine myocarditis remains unclear. The clinical features include a median time of 15 days from initiation of clozapine to the onset of symptoms and a monocytic/eosinophilic picture of the white cell differential with a predominant role of monocytes.^5,10,11 This suggests a delayed hypersensitivity reaction (type II or IV—cell-mediated), rather than a type I (i.e., IgE-mediated) reaction. We posit that clozapine forms an antigen with cardiac myocytes to which monocytes attach. This results in cardiac inflammation, damaging the myocardium leading to myocarditis in the acute phase and as dilated cardiomyopathy in the long-term. Concomitant sodium valproate use while commencing clozapine has been associated with a significant increase in the risk of myocarditis.¹² Valproate significantly decreases the signaling of peroxisome proliferator-activated receptor-gamma (PPAR-γ).¹³ PPAR-γ is a member of the nuclear receptor family of transcription factors, and agonists to PPAR-γ receptor inhibit monocyte activation.¹⁴ Given this, we propose that valproate, through antagonist action on these receptors, results in greater activation of monocytes within the circulation and consequent increased risk of a hypersensitivity reaction to the clozapine–myocyte antigen complex. While the median time of onset suggests that for at least a proportion of cases, it is possible that there are a variety of mechanisms underlying clozapine-associated myocarditis, with some of the earlier onset ones representing type I hypersensitivity, and/or a direct toxic effect to the myocardium.^15,16

We noted that monocytosis was a feature prior to Ms. AA’ index episode of clozapine-induced myocarditis (see Figure 1), while eosinophilia was only seen later on (perhaps as a late phase reaction) occurring after the rise of troponin. Careful measurement of blood-based indices allowed us to monitor and pause the “up-titration” until these indices returned to normal and thus enable a successful rechallenge, which presumably desensitized her to clozapine (see Figure 3). Furthermore, elevation in CRP has been observed as the initial blood-based biomarker in a case of clozapine-related myocarditis (associated with nonspecific clinical signs of inflammation, such as fever and tachycardia) and may be detected prior to any changes in troponin or other blood indices.¹⁷ The benefit of identifying such early markers is that it allows a slower titration until indices normalize and provides a window for medical investigations before development of myocarditis. In contrast, any rise in troponin above the normal range would require immediate cessation of clozapine and further investigation for possible myocarditis.

The very slow and careful titration of clozapine forms the basis of our protocol and has been noted elsewhere as well to be a consistent factor in successfully rechallenging patients with clozapine.^14,17,18 This is postulated to desensitize the immunological impact of clozapine by incrementally increasing the immunological load only when early markers of inflammation, such as monocytes, are within normal limits.^14,18,19 A formalized protocol for clozapine rechallenge based on our observations is provided in Figure 2. We did not observe any increase in troponin, despite changes in other white cell markers of inflammation. Our approach suggests that the slow titration combined with interruption of titration once any indices increased (monocytes, neutrophils, or eosinophils above the normal range, or rise in CRP) may have been important in ameliorating any direct effects of clozapine upon the myocardium. Further studies are needed to assess whether such a cautious approach is needed for all patients, or only for those where the diagnosis has been confirmed, for example, elevated CRP as well as troponin, and/or using cardiac MRI.

Conclusion

We described a successful clozapine rechallenge protocol that used slow clozapine titration with careful monitoring of inflammatory indices for a patient with a history of clozapine-induced myocarditis. This is based on a single case report and thus has its limitations. Current international efforts provide promise that selection of individuals most suitable for clozapine therapy and perhaps rechallenge could be informed by biological or clinical markers in the future.²⁰ Until then, protocols such as ours provide a strategy to improve clinical outcomes for those showing a suboptimal response to alternative therapies for treatment-resistant psychoses. There are always a proportion of patients suspected of having myocarditis rather than confirmed cases, and although our protocol is not specific toward those situations, this cautious approach may be applicable in this population as well, especially when other alternatives to clozapine are not appropriate.