Successful rechallenge after clozapine-associated myocarditis
- John Holden and
- Milia Begum
- Psychiatry, NHS Ayrshire and Arran Woodland View, Irvine, UK
- Correspondence to Dr John Holden; john.holden@live.com
Abstract
Clozapine is a highly effective medication used in management of treatment-resistant schizophrenia. Clozapine-associated myocarditis (CAM) is a rare but increasingly recognised complication of clozapine titration. Following an episode of CAM, clinicians can face a challenging dilemma of balancing the risks of recurrent myocarditis against the harms of ongoing psychosis. We describe the case of a woman in her 60s who developed acute myocarditis during clozapine titration and was then cautiously rechallenged with a successful outcome.
Background
The second-generation antipsychotic clozapine is a widely used treatment for adults with schizophrenia who have not responded adequately to trials of at least two antipsychotic drugs.1 Clozapine is the superior treatment option2 3 in such cases and is effective at improving symptoms,3 reducing hospitalisations4 and reducing mortality.5
Unfortunately, clozapine treatment is associated with a significant burden of side effects and complications. In addition to the common side effects of anticholinergic symptoms, sedation and propensity to cause metabolic syndrome, clozapine titration is proinflammatory.6 The pathophysiological mechanisms of clozapine-related inflammation are not known, but the consequences include a common generalised inflammatory response and rarer organ-specific manifestations. These include but are not limited to myocarditis, pancreatitis, pneumonia and interstitial nephritis.6 7
Clozapine-associated myocarditis (CAM, also known as clozapine-induced myocarditis) is a potentially fatal adverse event associated with clozapine titration. The event rate of CAM varies between countries and is significantly higher (3%) in Australia than in European nations (0.03%).8 Whether these discrepancies represent closer monitoring in Australia9 or more cautious titration in Europe6 is disputed.
CAM typically occurs in the first 3 weeks of treatment and presents with symptoms ranging from non-specific (nausea, malaise, flu-like symptoms) to classical features of myocarditis (chest pain, fever, collapse, sudden cardiac death).10 Of the 3274 cases previously reported to the WHO’s global database VigiBase, 43% were non-serious, 52% serious but non-fatal and 5% were fatal.8
A diagnostic gold standard of cardiac muscle biopsy exists for CAM, but Ronaldson et al 11 have suggested surrogate diagnostic criteria for use in the absence of histology. They define CAM as a combination of new signs of cardiac dysfunction combined with a cardiac-specific diagnostic parameter occurring within 45 days of starting clozapine. The same group recommends use of biomarkers including a C reactive protein (CRP)>100 mg/L or a troponin greater than 2× the normal upper limit as indications for clozapine cessation.11 Imaging (echocardiography, cardiac MRI) and serum bone-natriuretic peptide (BNP) provide evidence of cardiac dysfunction to further support the diagnosis.
Clinicians, patients and families face a dilemma when a patient for whom clozapine is the only effective medication develops a life-threatening adverse event. Cautiously resuming treatment (clozapine rechallenge) runs the risk of causing further life-threatening events, while switching to an alternative antipsychotic often means worse control of the psychotic symptoms and a reduction in quality of life.
Electroconvulsive therapy (ECT) has been shown to be non-inferior to clozapine in cases of treatment-resistant schizophrenia (TRS),12 13 but limitations to study design, low evidence quality and concerns regarding adverse effects mean ECT in this setting remains controversial and limited to specific indications such as unremitting positive symptoms, catatonia, suicidality and violence and agitation.14
Previously reported cases of rechallenge following CAM have met with mixed success. Due to the small numbers of reported cases, there is not yet clear guidance on appropriate candidates and strategies for rechallenge.
We report the case of a patient who has undertaken a successful rechallenge following a confirmed diagnosis of clozapine-induced myocarditis.
Case presentation
Our patient is a Caucasian woman in her 60s with treatment-resistant schizoaffective disorder. Her medical history is notable only for essential hypertension and dyspepsia, treated with atenolol 25 mg once daily and omeprazole, respectively. She is a non-smoker, with a body mass index of 30kg/m2 pre clozapine.
The patient had been relatively stable for a long time on oral thioridazine after several trials of other antipsychotic medications. Unfortunately, thioridazine had to be discontinued due to supply-side problems when the drug was withdrawn from the UK market. Trials of alternative antipsychotic medications including amisulpride, olanzapine, quetiapine, risperidone, sulpiride and aripiprazole were either ineffective or not tolerated. Previously, she required acute hospitalisation on several occasions, exhibiting positive symptoms of psychosis (olfactory hallucinations, disordered thinking, persecutory and sexual delusions) and mood lability. The intervening periods of wellness appeared to shorten with recurrent relapses.
The patient was on oral haloperidol prior to commencing clozapine. Haloperidol was discontinued the day before she commenced on clozapine. The speed of titration and monitoring was in accordance with the local NHS clozapine titration protocol, with total daily doses (mg) increasing as follows (12.5, 25, 37.5, 50, 75, 100, 125). Baseline observations including ECG, blood pressure (BP), heart rate (HR) and temperature were normal, as were biochemical markers including full blood count (FBC), C reactive protein (CRP) and high-sensitivity troponin T (TnT).
The patient was observed to respond very quickly to clozapine, with a rapid improvement in mood and psychotic symptomatology within days of commencing clozapine. The observed improvement was remarkable, with a degree of improvement not seen during previous trials of antipsychotic medications. The patient reported a significant improvement in her well-being and had insight that clozapine may be responsible for this.
On day 8, at a divided daily dose of 150 mg/day of clozapine, she developed nausea, vomiting and tachycardia (116–132 bpm). Clozapine was withheld for one dose until investigations returned. ECG and biochemistry were normal and clozapine was restarted.
On day 10, she developed another episode of nausea and tachycardia along with fever (38.5°C). Blood investigations revealed elevated white blood cell count (WCC) (13.4×109/L), neutrophils (9.9×109/L), CRP (61 mg/L (<5)) and elevated troponin (17 ng/L) (baseline of 11). Repeat ECGs were normal. Clozapine was again withheld for 2 days while investigations including chest X-ray and urinalysis were performed. These tests were normal and CRP and TnT settled. Clozapine was again restarted with a lower dose of 100 mg/day. Figure 1 shows the biomarker trends during initial and subsequent titration.
Serum levels of C reactive protein (mg/L), troponin T (TnT) (ng/L) and neutrophils (×109/L) plotted against time since first dose of clozapine. Shaded areas illustrate total daily clozapine dose (mg) during titration and later rechallenge. Illustrated by JH.
On day 18, at a dose of 100 mg/day, the patient was again nauseous, tachycardic and feverish (38.2°C–38.5°C). Blood investigations revealed an elevated WCC (11.9×109/L, neutrophils 8.5×109/L), CRP (76 mg/L) and TnT (28 ng/L). She was transferred to the acute medical hospital for further investigations and clozapine was stopped. Further investigations (shown in table 1) led to cardiologist confirming a diagnosis of CAM.
summarises investigations performed at the time of diagnosis and upon cardiology follow up.
| Investigations | ||
| Haematology | WCC 13.4 (×109/L) Neutrophils 9.9 (×109/L) |
Eosinophil count later rose to 1.3×109/L (day 30) |
| C reactive protein | Peak of 78 (mg/L) | |
| Troponin T | 17, rising to 28 (ng/L) | |
| D-dimer | 570 ng/mL (<610 normal) | |
| Bone-natriuretic peptide | 590 pg/mL | |
| Echocardiograph (day 20) | Non-dilated left ventricle (LV) cavity with sluggish LV, mild LV systolic dysfunction; non-dilated right ventricular cavity with good systolic function; mild mitral regurgitation | 6 months: visual improvement in LV function since previous study |
| ECG | No abnormality | 6 months: normal ECG |
| Chest X-ray | Lungs clear | |
| Cardiac MRI (day 59) | No evidence of myocarditis or pericarditis or cardiomyopathy on this scan | |
| Clozapine serum trough level (total daily dose 75 mg) | Clozapine 0.21 mg/L; norclozapine 0.09 mg/L | Typical therapeutic window 0.35–0.5 mg/L |
| Microbiology | COVID-19 not detected; urine culture—no significant growth |
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WCC, white blood cell count.
Investigations
Relevant investigations and their results are demonstrated in table 1.
Outcome and follow-up
On day 23, the patient returned to the psychiatric inpatient unit following improvement in all parameters. Despite not taking any antipsychotic medication at the time, her mental health appeared good, with no evidence of psychosis or significant mood disorder at the time. She retained insight and decision-making capacity.
There were concerns that without treatment a rapid deterioration in mental health and loss of decision-making capacity would be seen. It was important to reach an expedient decision regarding clozapine rechallenge while the patient retained full capacity to weigh risks and benefits of rechallenge.
The patient reflected on her experience of taking clozapine and felt it was the first time she had experienced a significant improvement in her mental health in decades. Opinions were sought from a cardiologist (who had provided the diagnosis), local pharmacists, nursing and medical staff. The cardiologist’s view was that the CAM was mild and that a rechallenge could be considered. A literature review of all cases of rechallenge was carried out. The patient was fully informed of the potential risks and benefits of rechallenge. Regrettably it was not possible to involve the patient’s family in the decision-making process.
The patient thereafter made an informed and capacitous decision to progress to a clozapine rechallenge.
Clozapine dosage was commenced at 12.5 mg and cautiously increased at only 25 mg/week until a dose of 75 mg per day was reached. The dose was split between morning and night. The dose schedule was as follows: 12.5 mg on day 1, 25 mg for 7 days, 50 mg for 7 days and 75 mg thereafter.
Monitoring during the retitration involved bi-daily observations of vital parameters (HR, respiratory rate, BP and temperature), twice weekly bloods (FBC, CRP, TnT) with twice weekly ECG. Retitration was uneventful.
At a year of follow-up, the patient continues to take clozapine with no further relapses and a relatively stable mental state that has never previously been achieved. She has been discharged to an independent tenancy. Follow-up cardiac investigations (table 1) have been reassuring with normal echocardiograph and normal cardiac MRI.
Discussion
There are only 26 previously reported cases of rechallenge following CAM, of which 16 have been successful and 10 have been unsuccessful (success rate 62%). Previous cases have significant heterogeneity in the level of detail provided, diagnostic features and treatment approach. To date there are no official or consensus guidelines for how to proceed in such a case.
This patient presented with a typical clinical presentation of fever, tachycardia and nausea on day 10 of clozapine titration. Laboratory investigations showed elevated CRP, WCC and TnT (meeting the case definition previously proposed).11 There was evidence of cardiac dysfunction with a sluggish left ventricle (LV) on echo and an elevated BNP, which resolved on follow-up. Local cardiology specialists endorsed a diagnosis of clozapine-induced myocarditis.
Patients with TRS have limited choices when clozapine is ineffective or not tolerated. Often, they resume a less effective antipsychotic, accepting poorer control of symptoms. In some situations ECT is considered. In this case, the patient’s symptoms were not sufficiently severe or acute to suggest that treatment with ECT would be beneficial. In addition, the previous marked subjective and objective improvement in mental health meant the patient had a strong preference to be reconsidered for clozapine. Furthermore, it was understood that the initial CAM was mild and that rechallenge could be safe if undertaken with caution.
Several case reports of successful rechallenge have recommended slow retitration and frequent monitoring, as rapid titration has been implicated with the onset of myocarditis15 and most cases of successful rechallenge have adopted a slower rate of titration.14–19
In this case, an extremely slow titration and close monitoring of vital signs, CRP, TnT and FBC was followed. During initial (rapid) titration, CRP spiked at a total daily dose of 100 mg and a myocarditis developed in the following 3 days. During the slower retitration, no significant inflammatory response was detected and an effective dose of 75 mg/day was reached safely.
One possible explanation for the patient’s sensitivity to rapid titration is highlighted by the steady-state serum clozapine level measured 5 weeks after retitration. The Maudsley prescribing guidelines20 recommend a typical starting dose of 300 mg for target therapeutic levels of 0.35–0.5 mg/L. A linear relationship has been observed between dose and serum concentration,21 so a clozapine level of 0.21 mg/L at a dose of 75 mg/day is relatively high. Furthermore, the clozapine:norclozapine ratio of 2.33 is greater than expected (<1.55).22 Both results suggest that our patient is a slow metaboliser of clozapine, though this was not investigated further.
It is also worth noting that our patient was taking atenolol for hypertension throughout this period. The beta-blockers carvedilol, metoprolol and bisoprolol have been suggested as a useful adjunct to retitration following CAM in a recently published protocol.15 It may be that atenolol played a role in the complete recovery in this case, though clinicians should be wary of the possibility that beta-blockade could lead to delay in diagnosis by masking tachycardia in early myocarditis.
Though the patient was frightened by the episode of myocarditis, her main regret now is the years of her life she spent trialling antipsychotics other than clozapine. This is an example of a case in which a desire to protect patients from harm might have prevented a significant improvement in quality of life. Fortunately, her instincts to take a well informed risk led to a beneficial outcome.
This case demonstrates a successful rechallenge following a confirmed case of clozapine-associated myocarditis. This adds to the body of previously published cases that suggest that clozapine rechallenge is a strategy that may be offered to patients for whom there are no alternative antipsychotic options. In these instances, the decision should involve a well informed patient or family and consider their views and priorities. Our patient’s decision-making capacity regarding her treatment, being able to understand the full risks and benefits of rechallenge was most helpful in this case.
If pursued, a rechallenge should be slow and cautious with frequent monitoring and a low threshold for a cascade of cardiac investigations. In this case a rate of increase of 25 mg/week was successful. As with initial titration, non-specific clinical features or an elevation in CRP alone need not necessitate cessation of the rechallenge unless accompanied by a rise in cardiac biomarkers or decreased LV function.
Patient’s perspective
The following are direct quotes from an interview held with the patient with the expressed purpose of learning her perspective for this report. She has granted permission to use these quotes.
On her treatment prior to clozapine—‘it’s been unbelievably frustrating, quite a rocky road’.
‘In the last few years, I’ve had 4 admissions in 4 years, that was sad. There was not very long between admissions. After the death of my dad, I was mostly in hospital’.
On her experience of myocarditis—‘I remember being so weak and tired, falling, I had no strength. I was scared’.
On her feelings towards rechallenge—‘I was a bit apprehensive, but everyone reassured me that I could get through it and that there was the possibility of a light and the end of the tunnel’.
Her perspective now—‘Independence is fantastic, I love it. I’ve got my confidence and personality back. I think I’ve got my life back again. I do feel robbed for all the years that I could have been on clozapine. I am glad I stuck with it. I can’t find the words for how grateful I am’.
Learning points
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Clozapine-associated myocarditis (CAM) is an increasingly recognised side effect of clozapine titration and can range in severity from mild to fatal.
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Rechallenge with clozapine following CAM can be safe and successful in a majority of cases, including those with objective evidence of cardiac dysfunction.
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Patients and families perspectives should be considered when balancing the risks and benefits in this scenario.
Ethics statements
Patient consent for publication
Footnotes
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Contributors MB was responsible for clinical management of the case and remains responsible medical person for the patient. JH collected the information, wrote the case report under supervision of MB and met with the patient to gain her perspective and consent.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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