Clozapine-Induced Myocarditis: Prevention and Considerations in Rechallenge

Cook, Sarah; Ferguson, Britnay A.; Cotes, Robert O.; Heinrich, Thomas; Schwartz, Ann C.

doi:10.1016/j.psym.2015.07.002

Cited by 30 publications

(26 citation statements)

References 25 publications

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“…Respiratory (such as dyspnea/cough/subjective sensations of chest discomfort/orthopnea) and cardiovascular symptoms (such as persistent resting tachycardia/palpitations/chest pain/syncope/arrhythmias/hypotension) are the 'core' symptoms which may be helpful in the diagnosis. However, clozapine-related myocarditis may also develop in an often fatal and atypical form [92]. It has been suggested that rapid dose titration and metabolic AEs may be favour the onset of cardiovascular AEs.…”

Section: Adverse Effectsmentioning

confidence: 99%

An update of safety of clinically used atypical antipsychotics

Orsolini

Tomasetti

Valchera

et al. 2016

Expert Opinion on Drug Safety

121

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A critical issue in the treatment with atypical APs is represented by their metabolic side effect profile (e.g. weight gain, lipid and glycaemic imbalance, risk of diabetes mellitus and diabetic ketoacidosis) which may limit their use in particular clinical samples. Electrolyte imbalance, ECG abnormalities and cardiovascular adverse effects may recommend a careful baseline and periodic assessments.

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Section: Adverse Effectsmentioning

confidence: 99%

An update of safety of clinically used atypical antipsychotics

Orsolini

Tomasetti

Valchera

et al. 2016

Expert Opinion on Drug Safety

121

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“…Online supplementary Box S9 [38, 66,162,[174][175][176][177][178][179] describes our model of clozapine-induced myocarditis as a hypersensitivity reaction similar to when rapid titrations of lamotrigine induce Stevens-Johnson syndrome and how to prevent it. Online supplementary Box S10 [16,21,26,27,33,36,45,46,48,50,54,58,69,87,[180][181][182][183][184][185][186][187] further describes the published data supporting this model in which rapid clozapine titration is key to explaining clozapine-induced myocarditis. Any titration that is too fast for a specific patient can cause clozapine-induced myocarditis or, more correctly, any kind of clozapine-induced inflammation [66].…”

Section: Myocarditismentioning

confidence: 99%

A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology

Leon

Ruan

Schoretsanitis

et al. 2020

Psychother Psychosom

121

113

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Using Richardson and Davidson's model and the sciences of pharmacokinetics and clinical pharmacopsychology, this article reviewed the: (1) poor life expectancy associated with treatment-resistant schizophrenia (TRS), which may be improved in patients who adhere to clozapine; (2) findings that clozapine is the best treatment for TRS (according to efficacy, effectiveness and well-being); and (3) potential for clozapine to cause vulnerabilities, including potentially lethal adverse drug reactions such as agranulocytosis, pneumonia, and myocarditis. Rational use requires: (1) modification of the clozapine package insert worldwide to include lower doses for Asians and to avoid the lethality associated with pneumonia, (2) the use of clozapine levels for personalizing dosing, and (3) the use of slow and personalized titration. This may make clozapine as safe as possible and contribute to increased life expectancy and well-being. In the absence of data on COVID-19 in clozapine patients, clozapine possibly impairs immunological mechanisms and may increase pneumonia risk in infected patients. Psychiatrists should call their clozapine patients and families and explain to them that if the patient develops fever or flu-like symptoms, the psychiatrist should be called and should consider halving the clozapine dose. If the patient is hospitalized with pneumonia, the treating physician needs to assess for symptoms of clozapine intoxication since halving the dose may not be enough for all patients; consider decreasing it to one-third or even stopping it. Once the signs of inflammation and fever have disappeared, the clozapine dose can be slowly increased to the prior dosage level. 46, 48, 52-67] describes the important pharmacokinetic variables for clozapine clearance. Higher clozapine C/D ratios, indicating lower clearance, are associated with females, non-smokers, Asians, genetic poor metabolizers, inhibitors, obesity, inflammation, and possibly with renal impairment and pregnancy. Lower clozapine C/D ratios indicate lack of adherence or higher clearance associated with males, smokers, non-Asians, and inducers.Two prior TDM review articles [68,69] are summarized in online supplementary Box S3 [31, 44, 50, 51, 55, 58-61, 63, 65, 68-91] which also describe our extensive experience with thousands of inpatient clozapine TDMs under standard conditions (trough and steady-state levels) in the US [44] and China [45,65]. Many of these inpatients were followed for months and/or years after changes in important pharmacokinetic variables [31, 44, 50, 58-61, 63, 65, 74, 79, 86-91].Published review articles [92][93][94] usually insist on the wide variability of clozapine TDM among individuals and the difficulty of interpreting a single clozapine level, but they fail to pay attention to findings from these two sciences: pharmacokinetics and clinical pharmacopsychology, which help in interpreting variability in clozapine levels. In inpatients, repeated measures allow the calculation of average clozapine clearance in an individual through a...

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“…The most common abnormalities observed in the course of CIM in laboratory tests are: an increase in the blood serum of C-reactive protein (CRP) concentration but also of troponin I and T. Rarely encountered and not quite used in routine diagnostics and monitoring of the patient's clinical condition are changes in the concentration of creatine kinase (CK) in the serum and of its creatine kinase -myocardial band (CK-MB), B-type natriuretic peptide (BNP) and its prohormone NT proBNP (N-terminal proBNP) [41,60,69].…”

Section: Objawy I Przebieg Cim Oraz Wyniki Badań Dodatkowychmentioning

confidence: 99%

“…Najczęstszymi nieprawidłowościami stwierdzanymi w przebiegu CIM w badaniach laboratoryjnych są wzrost stężenia w surowicy białka C-reaktywnego (C-reactive protein -CRP) oraz troponiny I i T. Rzadziej spotykanymi i nieznajdującymi zastosowania w rutynowej diagnostyce i monitorowaniu stanu klinicznego są zmiany stężenia w surowicy kinazy kreatynowej (creatine kinase -CK) oraz jej izoenzymu sercowego (creatine kinase -myocardial band -CK-MB), peptydu natriuretycznego typu B (B-type natriuretic peptide -BNP) oraz jego prohormonu NT proBNP (N-terminal proBNP) [41,60,69].…”

Section: Objawy I Przebieg Cim Oraz Wyniki Badań Dodatkowychunclassified

“…The re-introduction of clozapine is always carried out in a hospital setting, after all signs of myocarditis have disappeared, both in the clinical examination and in additional tests. In such cases, the dose is increased slowly, patients are closely monitored for any signs of relapse, and close cooperation is necessary between psychiatrists and cardiologists [25,69,87,[103][104][105][106]. Cook et al point out that there are relative contraindications to reintroducing clozapine after CIM, such as the existence of pre-clozapine treatment symptoms that might imitate CIM symptoms, e.g.…”

Section: Discontinuation Of Clozapine Treatment What Next?mentioning

confidence: 99%

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Clozapine-induced myocarditis

Jahołkowski¹,

Mierzejewski²,

Świtaj³

2019

ppn

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Purpose: Presentation of the current state of knowledge on the epidemiology, pathogenesis, clinical picture, diagnosis and treatment of clozapine-induced myocarditis (CIM). Views: Clozapine is widely used in patients with psychotic disorders for whom previous therapy was inadequate or not tolerated. However, in some cases its use may be associated with serious side-effects. In addition to agranulocytosis, ketoacidosis and intestinal obstruction, CIM is the most serious and potentially life-threatening complication of clozapine therapy, as it encompasses the inflammation and injury of the heart muscle. Attempts to estimate the incidence of CIM are characterized by a large discrepancy of results. To date, the pathomechanism of CIM has not been well investigated. The variability of the clinical spectrum and the lack of pathognomonic signs significantly hinder diagnosis, which is usually based on clinical symptoms, echocardiography, concentration of troponin and C-reactive protein in the serum samples and, in some cases, by myocardial biopsy and cardiac magnetic resonance imaging. In patients with suspected/confirmed CIM, the main recommendation is to discontinue clozapine and monitor the patient's vital signs. Clinical observations indicate that a β-blocker and/or angiotensin-converting enzyme inhibitor might be useful in at least same cases of CIM. Conclusions: We point out that patients receiving clozapine should be carefully monitored for the symptoms of CIM. The publication contains guidelines for dealing with suspected CIM.

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Clozapine-Induced Myocarditis: Prevention and Considerations in Rechallenge

Cited by 30 publications

References 25 publications

An update of safety of clinically used atypical antipsychotics

An update of safety of clinically used atypical antipsychotics

A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology

Clozapine-induced myocarditis

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