When, Why and How to Re-challenge Clozapine in Schizophrenia Following Myocarditis

Abstract

Clozapine-induced myocarditis (CIM) is among the most important adverse events limiting the use of clozapine as the most effective treatment for schizophrenia. CIM necessitates the immediate termination of clozapine, often resulting in its permanent discontinuation with considerable detrimental effects on patients' psychopathology and long-term outcome. Consequently, a clozapine re-challenge after CIM is increasingly regarded as a viable alternative, with published reports indicating a success rate of approximately 60%. However, published cases of re-challenges after CIM remain limited. Here, we provide a narrative review of the current state of research regarding the epidemiology, pathophysiology, risk factors, diagnosis and clinical management of CIM as well as a synthesis of current recommendations for re-challenging patients after CIM. This includes a step-by-step guide for this crucial procedure based on the current evidence regarding the pathophysiology and risk factors for CIM. Slow dose titration regimes and addressing risk factors including concomitant valproate and olanzapine are crucial both to prevent CIM and to ensure a safe and successful re-challenge. Furthermore, we discuss the utility of C-reactive protein, troponin, N-terminal-pro hormone and brain natriuretic peptide, therapeutic drug-monitoring and cardiac magnetic resonance imaging for CIM screening and diagnosis as well as for post-CIM re-challenges.

Fig. 1

CIM clinical presentation. Patients with CIM report unspecific clinical symptoms as CIM can affect several organs including cardiovascular system, gastrointestinal and urogenital tract. Clinical findings are accompanied by electrophysiological and laboratory abnormalities which include increased troponin and CRP as well as BNP and NT-proBNP. ECG may encompass ambiguous changes. TTE findings can include left ventricular impairment and pericardial effusion. CMR can serve as a more precise approach to detect myocardial inflammation. EMB allows to rule out viral myocarditis. BNP brain natriuretic peptide, CIM clozapine-induced myocarditis, CMR cardiac magnetic resonance imaging, CRP C-reactive protein, ECG electrocardiogram, EMB endomyocardial biopsy, NT-proBNP N-terminal-pro hormone and brain natriuretic peptide, TTE transthoracic echocardiogram. Adapted from ‘Human Internal Organs’, by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates

Fig. 2

Optimal CIM monitoring and management. Optimal cardiovascular monitoring includes frequent screening for clinical, electrophysiological and laboratory signs at baseline and during the first 8 weeks. Laboratory screening parameters for CIM comprise CRP and troponin, CK and the myocardium-specific isoenzyme CK-MB. Adding a screening of BNP (or NT-proBNP) at least at baseline and in case of suspected CIM allows detecting CIM at early stages. Electrophysiological monitoring includes weekly ECG, daily measurements of heart rate, blood pressure and body temperature. Cardiovascular imaging includes TTE (at baseline and in case of suspected CIM) and if available CMR for confirmation of suspected CIM. EMB should be considered in case of suspected viral myocarditis. Commonly CIM diagnosis is based on laboratory parameters (i.e. CRP and troponin). CRP increases with blood levels that fall in the range of 50–100 mg/L and troponin increases with blood levels that fall in the range of < 2× ULN necessitate intensified monitoring (daily laboratory assessment; ECG and TTE) and a search for alternative causes. Increases in CRP blood levels exceeding the safety threshold of > 100 mg/L and increasing troponin blood levels exceeding the threshold of 2× ULN necessitate termination of clozapine, daily monitoring, initiation of a cardioprotective treatment and a search for an alternative cause. Confirmed CIM also requires avoiding physical exercise for at least 3 months. BNP brain natriuretic peptide, BP blood pressure, CIM clozapine-induced myocarditis, CK creatine kinase, CK-MB muscle–brain type CK, CMR cardiac magnetic resonance imaging, CRP C-reactive protein, ECG electrocardiogram, ECT electroconvulsive therapy, EMB endomyocardial biopsy, HR heart rate, NT-proBNP N-terminal-pro hormone and brain natriuretic peptide, TTE transthoracic echocardiogram, ULN upper limit of normal. Created with BioRender.com

Fig. 3

Post-CIM re-challenge workflow. Slow titration regimens need to be complemented with clinical, electrophysiological and laboratory screening. Here, the same principles relevant for any clozapine treatment apply. This includes a comprehensive baseline assessment encompassing ECG and TTE as well as CRP, troponin T, NT-proBNP, CK and CK-MB. Frequency, scope and duration of CIM screening measures during the actual re-challenge in published case reports vary considerably. Given that patients’ safety should be paramount, all standard screening measures should be performed at least as often as during a regular clozapine treatment initiation, i.e. at least once per week or even twice. In line with this approach, many published case reports encompass the following: troponin and CRP at least twice per week, vital signs at least once daily and ECG twice per week. If available, this screening should be expanded to TTEs and monitoring of NT-proBNP in cases of suspected CIM. Conducting a CMR during a re-challenge without any clinical or laboratory indication for CIM is not warranted. Furthermore, repeated TDM after every 50 mg of clozapine dose increase without waiting for a steady state is crucial to ensure a sufficiently slow titration regime. This regime should be continued until a therapeutic dose has been reached. BP blood pressure, CIM clozapine-induced myocarditis, CK creatine kinase, CK-MB muscle–brain type CK, CMR cardiac magnetic resonance imaging, CRP C-reactive protein, ECG electrocardiogram, HR heart rate, NT-proBNP N-terminal-pro hormone and brain natriuretic peptide, TDM therapeutic drug monitoring, TTE transthoracic echocardiogram