According to previous research, treatment-resistant schizophrenia affects 30% of patients with a schizophrenia diagnosis.1 Clozapine notably reduces psychosis symptoms by 40%.1

Despite the relative success of clozapine therapy in this patient population, research indicates that clozapine prescription rates remain low.2 According to Rishi K. Patel, MD, department of cardiology, Imperial College Healthcare NHS Trust, London, England, and colleagues, “Underuse is thought to arise from the side effect profile and underlies a tendency to discontinue clozapine at the earliest sign of toxicity.”1

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Cardiotoxicity Overview

The most commonly cited toxic adverse effect of clozapine is agranulocytosis. Cardiovascular (CV) adverse effects, although rare, include “life-threating myocarditis and dilated cardiomyopathy.”1 Currently, there are no published guidelines to monitor patients for these conditions.

Recent trial results of various novel antipsychotic agents have “proven inconclusive” in providing physicians with alternative pharmaceutical options for treatment-resistant schizophrenia. As a result of this and the overall lack of clozapine guidelines, Dr Patel and cardiologist colleagues created a review for diagnosing and managing clozapine-associated cardiotoxicity, published in Psychiatry Research.1

The incidence of clozapine-induced myocarditis is currently “ill-defined” and is estimated at 0.2% to 3%.3 A literature review suggested that >80% of myocarditis cases occurred within the first 4 weeks of clozapine treatment.1 In contrast, clozapine-induced cardiomyopathy occurs less frequently, in <1/1000 patients. This condition also manifests later in the therapeutic course; symptoms typically occur between 3 weeks and 4 years of initiation,1 with one review citing an average of 14.4 months.1,4

Symptoms and Risk Factors

Current National Institute for Health and Care Excellence guidelines recommend incremental dose increases until the minimum effective clozapine dose is reached, typically 250 mg/d to 400 mg/d.1 Evidence examining the potential dose-dependent relationship between clozapine and cardiotoxicity is inconclusive1: One review identified myocarditis at a median dose of 250 mg/d whereas another identified myocarditis condition at a dose of 12.5 mg/d.

Multiple risk factors for clozapine-induced cardiotoxicity have been suggested, including rapid dose titration, increased age, concomitant use of sodium valproate, and concomitant selective serotonin reuptake inhibitor use1,5,6; however, according to Dr Patel and colleagues, “there are no established specific risks and it is the authors’ opinion that since myocarditis occurs early with the initiation of any causative drug, up-titration is more of a coincidence than a risk during this time period.”1

Another potential risk factor is the significant underlying CV risk present in patients with psychiatric issues.1 One large meta-analysis of patients with “severe mental illness” found that 10% of patients had ≥1 comorbid CV condition along with “significantly increased [CV] morbidity and mortality.”1,7 As a result, patients who are prescribed clozapine may already have an increased burden of risk; a holistic approach, including assessment for and treatment of baseline CV or metabolic comorbidity, could help reduce the burden on this patient population.1

According to Dr Patel and colleagues, there is no so-called classical presentation of clozapine-induced cardiotoxicity. Myocarditis presentation includes a “spectrum” of features, including low-grade fever or fulminant cardiogenic shock. The most common features include fever, chest pain, new breathlessness, and/or palpitations, but symptoms vary and, per the authors, may be absent unless the patient is in cardiogenic shock.1 In fact, symptoms in some cases may be so mild that patients who experience myocarditis may not ever be aware of the condition.

In contrast, clozapine-induced cardiomyopathy is “rarely asymptomatic.”1 This chronic, long-term disease presents with breathlessness, orthopnea, paroxysmal nocturnal dyspnea, and increasing peripheral edema, as well as decreased exercise tolerance and evidence of central congestion, such as raised jugular venous pressure.

Because it is a “common feature” of clozapine use, sinus tachycardia is not, in isolation, considered evidence of clozapine-induced cardiotoxicity.1 However, the development of new sinus tachycardia should prompt a patient examination.

Cardiotoxicity Diagnostics, Monitoring, and Therapy

Currently, no clear diagnostic criteria exist for clozapine-induced cardiotoxicity.1 Although some guidance has been proposed, these guidelines are, according to Dr Patel and colleagues, “not in line with current cardiac practice, such that there is a significant risk [for] both under- and over-diagnosing patients.”1

It should be noted that clozapine-induced cardiotoxicity both manifests and is treated in the same fashion as any other incidence of myocarditis or cardiomyopathy — through dose reduction and cessation of the causative therapy. To ensure the best treatment for patients with clozapine-induced cardiotoxicity, Dr Patel and colleagues emphasized that “it should be investigated and diagnosed in [the] same manner, given the large evidence base underpinning this guidance.”1

Diagnostic guidelines for myocarditis are as follows:

Electrocardiography: Electrocardiography is not recommended because of low sensitivity and specificity in diagnosing myocarditis; results may be normal or show sinus tachycardia, among other potential abnormalities. Although it is not recommended for diagnosis, an electrocardiogram should “remain a routine part of the work-up.”1

Biomarkers: The cardiac-specific biomarker troponin is an “established marker of cardiac damage.”1 Myocarditis would result in the presence of very high troponin levels. In young patients with new-onset symptoms of chest pain or breathlessness, myocarditis should be considered, and cardiac imaging should be performed.

Additional nonspecific biomarkers, including C-reactive protein (CRP), have been associated with clozapine-induced myocarditis. Research has found that in 90% of cases, CRP levels increased before an increase in troponin.1 More recent research indicated that it is unclear how relevant the CRP biomarker remains, given the advent of high-sensitivity troponin.

Previously, creatine kinase was used as a biomarker for myocardial injury; however, troponin is “significantly more sensitive,” and creatine kinase is not an effective diagnostic measure.

Imaging: When diagnosing myocarditis, the most commonly used diagnostic modality is transthoracic echocardiography (TTE). Typical findings include regional or global left ventricle (LV) or biventricular systolic dysfunction with normal wall thickness. Similar findings are typically seen on cardiac magnetic resonance imaging, which provides “superior information” because of visualizations of scars or edema within myocardial tissues.1

Biopsy: Endomyocardial biopsy remains the gold standard diagnostic tool for myocarditis.1 However, as imaging tests have continued to evolve, it is rarely used.

Diagnostic guidelines for cardiomyopathy are as follows:

Electrocardiography: Electrocardiography is not part of the diagnostic criteria for cardiomyopathy; however, it may provide valuable etiological information.

Biomarkers: Both brain natriuretic peptide and N-terminal prohormone of brain natriuretic peptide hormones are present when the heart is subject to stretch. Normal levels rule out heart failure and cardiomyopathy, and raised levels can indicate both active cardiomyopathy or myocarditis.1

The roles of brain natriuretic peptide and N-terminal prohormone of brain natriuretic peptide in clozapine-induced cardiomyopathy have not been examined sufficiently; however, Dr Patel and colleagues expect these roles to be similar to other causes of heart failure. The authors suggested that in any suspected cases of cardiomyopathy, natriuretic peptide testing should be undertaken. “If elevated, further imaging tests are mandatory,” Dr Patel and colleagues wrote.1

Imaging: Transthoracic echocardiography is the primary imaging test that should be performed. Features of note include a dilated and thin-walled LV with systolic impairment. Cardiac magnetic resonance imaging can provide physicians with additional information to distinguish common causes of cardiomyopathy. Awareness of specific features of clozapine-induced cardiomyopathy is currently lacking because the condition is relatively rare.

Biopsy: Biopsy is not routinely undertaken for this condition.

Only one protocol currently exists outlining how to monitor clozapine-induced cardiotoxicity.1,8 Researchers recommend baseline troponin, CRP, and TTE monitoring, followed by weekly biomarker assessment, every other day examination of vital signs, and daily monitoring of symptoms.8 More frequent monitoring may be performed if abnormalities in either vital signs or biomarkers are present.

Dr Patel and colleagues noted one other frequent cause of acute drug-induced cardiotoxicity: Trastuzumab, a life-prolonging breast cancer drug, is associated with a high incidence of cardiotoxicity during therapy.1

Currently, the mainstay of therapy for clozapine-induced cardiotoxicity is the consideration of clozapine cessation, followed by specialist review and the instigation of disease-modifying cardiac treatment.

Clozapine should be withheld in cases of fulminant myocarditis, and disease-modifying heart failure medications should be considered, under supervision, in the case of LV systolic dysfunction. Both bisoprolol and carvedilol are appropriate cardioselective beta blockers. Routine corticosteroid use is not recommended in this patient populations.

Current literature indicates that after clozapine discontinuation, myocarditis resolves both symptomatically and biochemically.9 Cardiomyopathy evidence is lacking, but one case report suggested that the condition may be partially reversible after clozapine cessation.10 In patients who appropriately recover, clozapine reintroduction should be considered. In patients with preexisting cardiac conditions, specialist cardiology review can provide appropriate guidance regarding the safety of beginning clozapine therapy.1

Conclusions

“Clozapine-induced cardiotoxicity is likely overreported in the literature, with few patients receiving diagnostic cardiac imaging or myocardial biopsy,” Dr Patel and colleagues wrote. “It is possible that this condition is rarer than thought and further, that many patients have therapy continued unnecessarily.”

They concluded, “Effective therapeutic managements exist for stabilization and improvement in LV function in either myocarditis or cardiomyopathy. The authors advocate for early cardiology input and feel that with adequate support, increased clozapine use can be safely facilitated.”

References

1. Patel RK, Moore AM, Piper S, et al. Clozapine and cardiotoxicity — a guide for psychiatrists written by cardiologists. Psychiatry Res. 2019:112491.

2. Warnez S, Alessi-Severini S. Clozapine: a review of clinical practice guidelines and prescribing trends. BMC Psychiatry. 2014;14:102.

3. Cook SC, Ferguson BA, Cotes RO, Heinrich TW, Schwartz AC. Clozapine-induced myocarditis: prevention and considerations in rechallenge. Psychosomatics. 2015;56(6):685-690.

4. Alawami M, Wasywich C, Cicovic A, Kenedi C. A systematic review of clozapine induced cardiomyopathy. Int J Cardiol. 2014;176(2):315-320.

5. Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, Wolfe R, McNeill JJ. Rapid clozapine dose titration and concomitant sodium valproate increase risk of myocarditis with clozapine: A case-control study. Schizophr Res. 2012;141(2-3):173-178.

6. Youssef DL, Narayanan P, Gill N. Incidence and risk factors for clozapine-induced myocarditis and cardiomyopathy at a regional mental health service in Australia. Australas Psychiatry. 2016;24(2):176-180.

7. Correll CU, Solmi M, Veronese N, et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled specific severe mental illness: A large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry. 2017;16(2):163-180.

8. Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, McNeil JJ. A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Aust N Z J Psychiatry. 2011;45(6):458-465.

9. Annamraju S, Sheitman B, Saik S, Stephenson A. Early recognition of clozapine-induced myocarditis. J Clin Psychopharmacol. 2007;27(5):479-483.

10. de Knijff DW, Schepers PH, Blanken-Meijs JT. Cardiomyopathy during clozapine therapy. Ned Tijdschr Geneeskd. 2001;145(35):1697-1699.