Incidence and investigation of potential risk-factors for clozapine-associated myocarditis and cardiomyopathy in a New Zealand cohort

Bellissima, Brandi L.; Vara, Alisha; Helsby, Nuala A.; Garavan, Fintan; Tingle, Malcolm D.

doi:10.1016/j.psychres.2021.113873

Cited by 12 publications

(41 citation statements)

References 24 publications

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“…All seven of the included articles were case‐control in design. Six of the studies were retrospective in design 4,17‐19,27,31 . Five studies were carried out in Australia, 17,18,27,30,31 while one was conducted in New Zealand 4 and one in Turkey 19 .…”

Section: Resultsmentioning

confidence: 99%

“…We identified 52 different potential risk factors, which were assessed across the included articles. The most commonly assessed potential risk factors included age, 4,17‐19,27,30,31 gender, 4,17‐19,27,30,31 BMI, 4,17,18,27,30,31 sodium valproate use, 4,17‐19,27,31 ethnicity, 4,17,18,27 smoking, 4,17,18,30 cardiovascular disease, 19,27,30,31 cumulative clozapine dose, 4,17,18,31 antidepressant use, 4,19,27,31 selective serotonin reuptake inhibitor (SSRI) use, 4,27,31 lithium use, 17,19,31 benzodiazepine use, 4,19,27 other antipsychotic use, 4,27,31 second generation antipsychotic use, 17,19,31 primary psychiatric diagnosis, 17,19,31 duration of psychiatric illness, 17,19,30 diabetes, 4,30,31 illicit drug use, 17,18,31 alcohol use, 17,18 hypertension, 4,30 abnormal lipid profile, 4,31 first time taking clozapine, 17,31 first or second generation antipsychotic use 19,31 and quetiapine use 17,31 . The frequency of all potential risk factors assessed by the included studies is shown in Table .…”

Section: Resultsmentioning

confidence: 99%

“…We identified 2423 unique articles of which 2369 were excluded at title and abstract level. At full-text review, 54 articles were assessed and seven 4,[17][18][19]27,30,31 met the inclusion criteria and were included in the final systematic review and meta-analysis. A PRISMA diagram demonstrating reasons for exclusion is shown in Figure 1.…”

Section: Characteristics Of Included Articlesmentioning

confidence: 99%

“…17,19 We identified 52 different potential risk factors, which were assessed across the included articles. The most commonly assessed potential risk factors included age, 4,[17][18][19]27,30,31 gender, 4,17-19,27,30,31 BMI, 4,17,18,27,30,31 sodium valproate use, 4,[17][18][19]27,31 ethnicity, 4,17,18,27 smoking, 4,17,18,30 cardiovascular disease, 19,27,30,31 cumulative clozapine dose, 4,17,18,31 antidepressant use, 4,19,27,31 selective serotonin reuptake inhibitor (SSRI) use, 4,27,31 lithium use, 17,19,31 benzodiazepine use, 4,19,…”

Section: Characteristics Of Included Articlesmentioning

confidence: 99%

“…[1][2][3] Despite its efficacy, clozapine initiation is often delayed because of a potential side-effect profile, which includes agranulocytosis, sedation, hypotension, constipation, myocarditis and cardiomyopathy. 2,[4][5][6][7] Typically, myocarditis is acute and occurs within 30 days of clozapine initiation, while cardiomyopathies are more chronic in nature and occur months to years later. 4,7,8 Reported rates of myocarditis are higher in Australia and New Zealand, at 2% compared with 0.3% in the rest of the world, while cardiomyopathy rates are 1.4% in Australia and New Zealand compared with 0.2% elsewhere.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Risk factors for clozapine‐induced myocarditis and cardiomyopathy: A systematic review and meta‐analysis

Vickers

Ramineni

Malacova

et al. 2022

Acta Psychiatr Scand

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Objective: Clozapine is the most effective medication for treatment-refractory schizophrenia, but it is associated with severe cardiac adverse events including myocarditis and cardiomyopathy. To aid treatment decision-making for clinicians, patients and their carers, we conducted a systematic review and metaanalysis to identify potential risk factors for clozapine-induced myocarditis and cardiomyopathy.Methods: A systematic search was conducted of PubMed, Embase, CINAHL, Web of Science, Cochrane and PsycInfo for studies reporting myocarditis and cardiomyopathy among people on clozapine and potential risk factors. We calculated pooled effect sizes on risk factors using a random-effects meta-analytic model. Risk of publication bias was assessed using the Newcastle-Ottawa scale.Results: Seven studies met the inclusion criteria, of which six studies had quantitative data included in the meta-analysis. The odds of clozapine-induced myocarditis increased with concurrent sodium valproate use (k = 6, n = 903, pooled OR 3.58, 95% CI 1.81-7.06), but were not significantly greater with the use of quetiapine, lithium or selective serotonin reuptake inhibitors. Our qualitative review identified conflicting results reported for increasing age and higher clozapine dose as risk factors for myocarditis. No other factors, including genetic risk, sex, ethnicity, smoking, alcohol, substance abuse or cardiometabolic disease, were associated with greater odds of myocarditis. No risk factors for cardiomyopathy were identified in the literature. Conclusion: Concurrent use of sodium valproate increases the odds of clozapineinduced myocarditis. Thus, clinicians should consider the temporary cessation of sodium valproate during the initial titration phase of clozapine.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Characteristics Of Included Articlesmentioning

confidence: 99%

Section: Characteristics Of Included Articlesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Risk factors for clozapine‐induced myocarditis and cardiomyopathy: A systematic review and meta‐analysis

Vickers

Ramineni

Malacova

et al. 2022

Acta Psychiatr Scand

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Protective effects of salvianolic acid A on clozapine‐induced cardiotoxicity in zebrafish

Lin

Yan

et al. 2022

J of Applied Toxicology

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The clinical use of clozapine (CLZ), an atypical antipsychotic drug, was affected by side effects, such as cardiotoxicity. We selected normally developing zebrafish embryos to explore the antagonism of salvianolic acid A (SAA) against clozapineinduced cardiotoxicity. Embryos were treated with CLZ and SAA, and zebrafish phenotypes were observed at 24 h, 48 h, 72 h, and 96 h after treatment. The observed phenotypes included heart shape, heart rate, and venous sinus-arterial bulb (SV-BA) interval. Real-time quantitative PCR was used to detect changes in the expression of genes involved in heart inflammation, oxidative stress, and apoptosis. The results showed that SAA relieved pericardial edema, increased heart rate, and reduced the SV-BA interval. The PCR results also showed that when the zebrafish embryos were incubated with SAA and CLZ for 96 h, the expression of il-1b and nfkb2 were significantly downregulated, the expression of sod1 and cat were significantly upregulated, and the expressions of mcl1a and mcl1b were significantly downregulated. In summary, SAA can antagonize clozapine-induced cardiotoxicity.

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A systematic review of clozapine‐associated inflammation and related monitoring

Leung,

Zhang,

Markota

et al. 2023

Pharmacotherapy

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Clozapine is an effective antipsychotic medication used for treatment‐resistant schizophrenia. However, it is underutilized due to rigorous hematologic monitoring requirements and many adverse drug reactions. Publications have highlighted the occurrence of inflammatory reactions, some life‐threatening, particularly during the early stages of clozapine treatment. Although guidelines have suggested monitoring for inflammatory processes during clozapine initiation, screening in clinical practice is not universal. This systematic review aimed to investigate the relationship between clozapine and inflammation and assess the importance of monitoring for inflammatory reactions. A comprehensive literature search yielded 6,915 unique publication records after removal of duplicates. After a rigorous screening process, 75 publications were included in the review, which focused on three main aspects: i) the impact of clozapine on inflammatory markers, ii) monitoring cardiac and other organ function during clozapine‐associated inflammatory processes, and iii) monitoring non‐specific signs and symptoms of inflammation. Elevated levels of C‐reactive protein (CRP) and several proinflammatory cytokines have been observed in association with clozapine treatment. However, the practicality of measuring specific markers in clinical practice remains uncertain. Current evidence supports monitoring CRP levels during the first 4 to 8 weeks of treatment, especially to facilitate myocarditis screening. Further research is needed to establish clinically‐relevant CRP thresholds for intervention. The implementation of monitoring protocols during the early phase of clozapine treatment may mitigate adverse reactions and allow for continued use of clozapine. Future studies should also explore the association between clozapine‐associated inflammation and pneumonia, as well as investigate the impact of inflammation on clozapine metabolism to predict the need for dose adjustment. These endeavors may facilitate the development and implementation of evidence‐based guidelines for the monitoring of clozapine‐associated inflammation.

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Incidence and investigation of potential risk-factors for clozapine-associated myocarditis and cardiomyopathy in a New Zealand cohort

Cited by 12 publications

References 24 publications

Risk factors for clozapine‐induced myocarditis and cardiomyopathy: A systematic review and meta‐analysis

Risk factors for clozapine‐induced myocarditis and cardiomyopathy: A systematic review and meta‐analysis

Protective effects of salvianolic acid A on clozapine‐induced cardiotoxicity in zebrafish

A systematic review of clozapine‐associated inflammation and related monitoring

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