Clozapine-induced Cardiotoxicity Research Articles

Therapeutic action of ashwagandha extract on apoptosis and cell proliferation in the heart of rat fetuses prenatally treated with clozapine

ABSTRACT An effective atypical antipsychotic medication for treating psychosis is clozapine, especially for patients who have failed to respond to other treatments. However, clozapine-induced cardiotoxicity has generated safety concerns as it may result in sudden mortality. In addition, there is relatively little information on the safety of clozapine during pregnancy. According to several earlier studies, Withania somnifera (ashwagandha) extract has a cardioprotective effect. Therefore, this study aimed to investigate the therapeutic potential of ashwagandha root extract on clozapine-induced cardiotoxicity in rat fetuses. Pregnant rats were administered clozapine (40 mg/kg bw) and/or ashwagandha extract (300 mg/kg bw.) from the sixth to fifteenth day of gestation. Clozapine-induced oxidative stress in developing hearts by decreasing superoxide dismutase and catalase activities and increasing the concentration of cardiac malondialdehyde. Moreover, there was a significant increase in the percentage of apoptotic cells and a decrease in the proliferative capacity of cardiomyocytes. Evidently, clozapine triggered severe pathological changes in fetal cardiac tissue. In conclusion, ashwagandha root extract can be used to improve the heart oxidative stress, apoptotic and proliferation rates and histopathological changes induced by clozapine in rat fetuses during gestation.

Clozapine metabolism and cardiotoxicity: A prospective longitudinal study

BackgroundClozapine-induced myocarditis and cardiomyopathy are difficult to detect clinically and may be fatal if not detected early. The current/routine biomarkers for clozapine-induced myocarditis are non-specific indicators of inflammation (C-reactive protein) or cardiomyocyte damage (troponins I and T) that lack sensitivity, and for which changes often arise too late to be clinically useful. MethodsThe Clozapine Safety Study was a prospective, longitudinal, observational study to determine what, if any, the plasma concentrations of clozapine, N-desmethylclozapine, and clozapine-N-oxide in patients contribute to cardiotoxicity. Samples were collected and analysed using liquid chromatography mass spectrometry over a 41-month period from patients in the Auckland District Health Board. ResultsSixty-seven patients were included. Six patients were diagnosed with myocarditis; none were diagnosed with cardiomyopathy in the study period. In patients not undergoing dose titration, clozapine biotransformation may shift to the N-oxide pathway rather than the N-desmethyl pathway with increasing dose. During dose titration, the timeframe in which myocarditis occurs, the rate of increase in the plasma concentration of clozapine-N-oxide, as well as the ratio of N-oxidation relative to N-desmethylation, were significantly higher in patients diagnosed with myocarditis. ConclusionsThe assessment of clozapine-N-oxide formation, and N-oxidation relative to N-desmethylation ratios during treatment, may help identify a biomarker to aid the early detection of patients at risk of developing clozapine-induced cardiotoxicity.

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

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 clozapine-induced 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.

Early Manifestation of Clozapine-Induced Cardiotoxicity: Detection, Pathophysiology, and Management

Schizoaffective disorder, bipolar type is a chronic mental health disorder that may manifest as mania. Clozapine is effective in treating acute mania and in achieving mood stabilization. However, on rare occasions, the use of clozapine has been associated with cardiotoxicity. Here, we present a case of a 31-year-old man who at baseline is known to have schizoaffective disorder, bipolar type, and cannabis dependence and was admitted to our hospital with a psychotic relapse. He was treated with clozapine, uptitrated to a maximum daily dose of 200mg twice daily by day 10. Thereafter he became febrile and experienced malaise, myalgias, and chest pain. He was noted on electrocardiogram to have sinus tachycardia without ischemic changes. In this context, he had a troponin leak, increased white blood cell count, serologies and cultures were negative and chest x-ray revealed no acute disease of the chest. Due to the suspicion of clozapine-induced cardiotoxicity, a transthoracic echocardiogram was done, which revealed mildly depressed left ventricular (LV) systolic function without pericardial effusion. Thereafter, clozapine was withdrawn and switched to lithium. Additionally, the cardioselective, metoprolol tartrate was initiated. Within 36-48 hours, he had resolution of symptoms and remained cardiovascularly stable. Clozapine uncommonly causes cardiotoxicity and early features may be non-specific. Awareness of this and recognizing early features aids in reducing the associated cardiovascular morbidity and mortality.

Clozapine Induced Developmental and Cardiac Toxicity on Zebrafish Embryos by Elevating Oxidative Stress.

Clozapine is one of the antipsychotic drugs for treating schizophrenia, but its cardiotoxicity was the primary obstacle for its clinical use, due to the unknown mechanism of clozapine-induced cardiotoxicity. In this study, we studied the cardiotoxicity of clozapine by employing zebrafish embryos. Acute clozapine exposure showed dose-dependent mortality with the LC50 at 59.36μmol L-1 and 49.60μmol L-1 when determined at 48 and 72h post exposure, respectively. Morphological abnormalities like pericardial edema, incompletely heart looping, and bradycardia were detected after clozapine exposure in a time- and dose-dependent manner. Clozapine treatment also resulted in a slower heart rate and disturbed rhythm in zebrafish embryos. Also, oxidative stress was observed after clozapine exposure by measurement of ROS (reactive oxygen species), MDA (a lipid peroxidation marker), antioxidant enzyme activities, and oxidative stress-related gene expression. The elevation of inflammation coincided with oxidative stress by the assay of inflammation-related genes expression accompanied by clozapine incubation. Collectively, the data indicate that clozapine might achieve cardiotoxic effect in zebrafish larva through increasing oxidative stress, attenuation in antioxidant defense, and up-regulation of inflammatory cytokines. The data could provide experimental explanations for myocarditis and pericarditis induced by clozapine in clinics, and help find an effective solution to reduce its cardiotoxicity.

Ellagic acid alleviates clozapine‑induced oxidative stress and mitochondrial dysfunction in cardiomyocytes

Clozapine (CLZ) as an antipsychotic agent is very effective in treating of psychosis disorders and resistant schizophrenia, but the risk of severe cardiac toxicity effects restricts its clinical use. There are several interrelated hypotheses to explain clozapine-induced cardiotoxicity which all of them may be related to oxidative stress. Therefore, the current study investigated the harmful effects of clozapine on cardiomyocytes and assessed the cytoprotective effect of ellagic acid (EA). Freshly isolated adult rat ventricular cardiomyocytes were incubated for 4 h at 37 °C with 00.05% ethanol as control, CLZ (50 µM), CLZ (50 µM) + a series of EA concentrations (10, 20 and 50 µM) and EA (50 µM). To evaluate the protective effect of EA, the markers of cell viability, reactive oxygen species (ROS) formation, mitochondria membrane potential (ΔΨm) collapse, lysosomal membrane integrity, malondialdehyde (MDA) and oxidized/reduced glutathione (GSH/GSSG) content were checked by biochemical and flowcytometry techniques. Our results demonstrated that EA (10, 20 and 50 µM) effectively inhibited CLZ-induced cytotoxicity which is associated with ROS overproduction and amelioration of mitochondrial and lysosomal damages. In addition, EA (10, 20 and 50 µM) in the presence of CLZ reduced the production of MDA as a specific marker lipid peroxidation and GSSG. Collectively, these findings suggested that EA protects cardiomyocytes from oxidative injury through inhibiting ROS formation, mitochondria dysfunction, and lysosomal damages, which suggest a potential therapeutic strategy of EA for CLZ-induced oxidative stress and cardiotoxicity.

Bioactivation of clozapine by mitochondria of the murine heart: Possible cause of cardiotoxicity

The mechanism of clozapine-associated cardiotoxicity has not been elucidated. The formation of a reactive nitrenium ion from the drug has been suggested as the cause, however, the reason why the heart is a target remains unknown. The heart is one of the most perfused organs; therefore, it contains a large number of mitochondria per cell; these organelles are responsible for both oxygen metabolism and energy production due to high energy expenditure. Given that mitochondria play critical roles in cellular homeostasis and maintenance, this study tested the hypothesis that cardiac mitochondria are both a target and initiator of clozapine-induced cardiotoxicity through activating the drug. We investigated whether murine heart receives a relatively high amount of systemically administered drug (20 mg/kg, i.p., Wistar albino rats) and whether cardiac mice (Swiss albino) and rat (Wistar albino) mitochondria locally activate clozapine (100 μM) to a reactive metabolite. We observed a relatively large distribution of clozapine to heart tissue as well as the formation of reactive metabolites by cardiac mitochondria in situ. Mitochondrial cytochrome P450 enzymes (CYP) in cardiac tissue responsible for biotransformation of clozapine were also characterized. CYP3A4 has been found to be the major enzyme catalyzes CLZ bioactivation, while CYP1A largely and CYP3A4 partially catalyzes the formation of stable metabolites of CLZ. At 100 μM concentration, clozapine caused a significant decline in mitochondrial oxygen consumption rate in vitro as much as positive control (antimycin A), while it did not induce mitochondrial permeability transition pore opening. These data provide an explanation as to why the heart is a target for clozapine adverse effects.

Circulating microRNA as biomarkers of clozapine-induced cardiotoxicity

Purpose: This work investigated the utility of circulating microRNA (miRNA) as biomarkers of clozapine (CLZ)-induced cardiotoxicities: serious adverse events with an unusually high incidence in Australia and New Zealand.Methods: Global plasma miRNA expression was analysed by microarray in patients taking CLZ, to investigate differential expression between CLZ-induced cardiotoxicity cases (n = 6) and matched control patients (n = 12). The results were validated by RT-qPCR using a panel of 17 miRNA, and their expression was examined in both CLZ-naïve healthy volunteers (n = 12) and an expanded cohort of CLZ-taking patients (n = 21). Temporal changes were also examined in two healthy volunteers and two CLZ-induced cardiotoxicity patients.Results: No miRNA were differentially expressed between cases of CLZ-induced cardiotoxicity and control patients. Circulating levels of several miRNA were significantly altered in CLZ-taking patients compared to healthy volunteers, with miR-16-5p, miR-25-3p, miR-92a-3p, miR-320a-3p, and miR-486-3p upregulated and miR-22-3p, miR-126-3p, and miR-142-3p downregulated in the patients. Five of these (miR-16-5p, miR-22-3p, miR-92a-3p, miR-126-3p, miR-142-3p) were stably expressed over time in both CLZ-induced cardiotoxicity patients and CLZ-naïve healthy volunteers.Conclusions: Plasma miRNA are not useful biomarkers of CLZ-induced cardiotoxicity, however patients taking CLZ have significantly altered circulating miRNA compared to healthy volunteers.

Forskolin Effect on FOXO1 Expression and Relationship of FOXO1 Activation to Oxidative Stress: From Molecular to Therapeutic Strategy

Background: Reactive Oxygen Species (ROS) production has been established as an essential contributor in the development cardiotoxicity. The increase of ROS production simultaneously leads to the inhibition of anti-oxidant systems. Forkhead transcription factor O1 (FOXO1) plays an important role in regulating metabolism and oxidant stress. Clozapine was used to induce cardiotoxicity. Forskolin the well-known anti-oxidant and anti-inflammatory agent was used to modulate the effect on both FOXO1 gene and its target gene catalase and to what extent it may protect against clozapine-induced cardiotoxicity. Methods: The animals were classified into: control group, forskolin group; forskolin was administered for 8 weeks; clozapine group, and forskolin + clozapine group; forskolin was pre-administered for 5 weeks then continued along with clozapine for the last 3 weeks. RT-qPCR and gel electrophoresis were done. We analyzed the relation between FoxO1 gene and oxidative stress. Results: These effects are achieved by the ability of Forskolin to modulate the expression of Foxo-1 and catalase, the levels of CKMB, troponin I, GST, MDA, and TNF- α, Caspase-3 were decreased, histopathological changes were improved. Forskolin reduce cardiomyocytes damage, and improve cardiac function by decreasing oxidative stress. Conclusion: Forkolin with its biological activities and anti-oxidative effects control cardiotoxicity induced by ROS in addition to its anti-inflammatory activity. This may be considered as therapy in cardiac problems management.

Evaluation of the role of captopril on clozapine-induced cardiotoxicity and hematotoxicity in adult male albino rats

Clozapine (CLZ) is considered the most effective drug in treatment of resistant schizophrenia. However, its cardiotoxic effect has raised concerns about its safety. Captopril is a well-known angiotensin-converting enzyme inhibitor with unique antioxidant properties. The aim of this study was to investigate the protective effect of captopril against CLZ-induced myocarditis, and since both drugs have hematotoxic effects, this study aimed to clarify the effect of their combined use on the bone marrow. The study was conducted for 4 weeks on 50 adult male albino rats divided into five groups: group I (negative control), group II (positive control), group III treated with captopril 5 mg/kg/day, group IV treated with CLZ 25 mg/kg/day, and group V treated with captopril (5 mg/kg) 1 hour before CLZ (25 mg/kg/day). CLZ group showed a significant increase in serum troponin I, marked histopathological changes, and immunohistochemical staining of DNA degradation product 8-hydroxy-2-deoxy guanosine (8-OHdG). It significantly increased malondialdehyde level and decreased glutathione peroxidase. Captopril coadministration decreased the histopathological hallmarks and biochemical marker of myocarditis and attenuated CLZ effects on the oxidative stress parameters and 8-OHdG, suggesting its protective action against CLZ-induced myocarditis. Complete blood count and bone marrow evaluation was normal indicating that captopril, in the protective dose given, didn’t increase the risk of CLZ-induced hematotoxicity

Clozapine in a patient with treatment-resistant schizophrenia and hypertrophic cardiomyopathy: a case report.

BackgroundThere is currently limited experience in the initiation and maintenance of clozapine for treatment-resistant psychosis in adults with established structural heart disease. These complex patients require close supervision and liaison between colleagues. Here we present the successful experience of treating one such patient within our service and describe a monitoring plan to ensure that these treatments can be provided both safely and effectively.Case presentationA 36-year-old man with treatment-resistant schizophrenia and known hypertrophic cardiomyopathy (HCM) was admitted to a specialist unit for a trial of clozapine. His psychiatric illness was characterised by multimodal hallucinations and delusions combined with low mood and poor motivation. The diagnosis of HCM was made 3 years previously following a routine electrocardiogram (ECG), and he had remained asymptomatic throughout this time; there were concerns about the risk of initiating clozapine given his pre-existing cardiac condition.Baseline investigations were performed as per local guidelines prior to commencing clozapine; these were within normal limits other than a mildly raised troponin level of 54 ng/L (normal <16 ng/L), which was attributed to the HCM. In addition, baseline transthoracic echocardiography (TTE) was performed which showed no change in the structural heart disease in comparison with previous TTEs.Clozapine was started at 12.5 mg daily and up-titrated to 150 mg twice daily over 14 days as per our institute’s guidelines. The patient was monitored with regular testing of troponins, inflammatory markers and ECG. On day 18, the troponin level increased to 1371 ng/L. Creatine kinase and inflammatory markers remained stable. No changes in ECG or TTE were noted and the patient remained clinically asymptomatic.Cardiology opinion was sought and reported that the finding of an isolated elevated troponin was likely to reflect a ‘troponin leak’ in the context of increased cardiac muscle mass associated with HCM. In the absence of any clinical compromise, it was not felt to be of concern. Clozapine was continued with good effect on mental state. Troponin levels gradually reduced and the patient remained well.ConclusionsWhile multiple cases of clozapine-induced cardiotoxicity have been reported in the literature, its implications for pre-existing structural disease are unclear. This case report suggests that clozapine can be safely introduced in pre-existing HCM, explores strategies for monitoring and highlights the importance of liaising with experienced cardiologists.Declaration of interestNone.Copyright and usage© The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

Clozapine-Induced Cardiotoxicity: Role of Oxidative Stress, Tumour Necrosis Factor Alpha and NF-κβ.

Safety concerns have been raised about clozapine-induced cardiotoxicity particularly in young patients. The exact mechanism of clozapine cardiotoxicity has not yet been thoroughly studied. This study aimed to investigate the possible mechanisms of clozapine-induced cardiotoxicity in a rat model. Young male Wistar rats were treated with clozapine (10, 15 and 25mg/kg/day, i.p.) for 21days. Haemodynamic and echocardiographic studies were performed for assessment of cardiac functions. Heart sections were studied histopathologically and immunohistochemically. Serum and cardiac markers of cardiotoxicity, oxidative stress, inflammation and apoptosis were evaluated. Heart sections of clozapine-treated animals showed increased cardiac inflammation that correlated with the clozapine dose. Serum levels of CK-MB and LDH levels increased, as did cardiac levels of TNF-α, MDA, NO, myeloperoxidase, 8-OHdG, caspase-3 and NF-κB p65. In contrast, GSH levels and GSH-Px activity decreased. Furthermore, immunohistochemical examination of the heart sections showed positive immunostaining for both 3-nitrotyrosine and caspase-3 in all clozapine-treated groups. Clozapine, particularly in relatively high doses, has a clear cardiotoxic effect. This cardiotoxicity is accompanied by increased myocardial oxidative stress, inflammatory cytokines, DNA damage and apoptosis with attenuation in antioxidant defences, thus explaining the previously reported myocarditis and pericarditis during clozapine therapy in clinical studies.

Clozapine-induced cardiotoxicity in rats: Involvement of tumour necrosis factor alpha, NF-κβ and caspase-3

Clozapine, an ideal antipsychotic drug for the treatment of resistant schizophrenia, is considered the most underutilised treatment for schizophrenia. However, safety concerns have been raised about clozapine-induced cardiotoxicity, which may lead to sudden death, particularly in young patients. The exact mechanism of clozapine cardiotoxicity has not yet been thoroughly studied. This study aimed to investigate the possible mechanisms of clozapine-induced cardiotoxicity in a rat model. Young male Wistar rats were treated with clozapine (10, 15 and 25 mg/kg/day, i.p.) for 21 days. Haemodynamic and echocardiographic studies were performed for assessment of cardiac functions. Heart sections were studied histopathologically and immunohistochemically. Serum and cardiac markers of cardiotoxicity, oxidative stress, inflammation and apoptosis were evaluated. Heart sections of CLZ-treated animals showed increased cardiac inflammation that correlated with the clozapine dose. Serum levels of CK-MB and LDH levels increased, as did cardiac levels of TNF-α, MDA, NO, myeloperoxidase (MPO), 8-OHdG, caspase-3 and NF-κB p65. In contrast, GSH levels and GSH-Px activity decreased. Furthermore, immunohistochemical examination of the heart sections showed positive immunostaining for both 3-nitrotyrosine and caspase-3 in all clozapine-treated groups. Clozapine, particularly in relatively high doses, has a clear cardiotoxic effect. This cardiotoxicity is accompanied by increased myocardial oxidative stress, inflammatory cytokines, DNA damage and apoptosis with attenuation in antioxidant defences, thus explaining the previously reported myocarditis and pericarditis during clozapine therapy in clinical studies.

Clozapine‐induced cardiotoxicity: a clinical update

Clozapine is a valuable drug for patients with treatment-resistant schizophrenia. Myocarditis is the most publicised cardiac complication of clozapine treatment, but cardiomyopathy and pericarditis have also been reported. Myocarditis has heterogeneous and non-specific presenting features, making it difficult to identify patients with clozapine-related myocarditis clinically. A high index of suspicion is required. The gold standard for diagnosis of myocarditis is an endomyocardial biopsy, but this is not a practical initial approach. Transthoracic echocardiography is a valuable, reproducible and widely available tool to assist in diagnosis of clozapine-induced cardiotoxicity. The level of B-type natriuretic peptide, a hormone secreted in response to ventricular wall stress, may be useful for evaluating patients with clozapine-induced cardiac dysfunction and may in the future be useful for screening asymptomatic patients. The mainstay of treatment of clozapine-induced cardiotoxicity is cessation of clozapine and provision of supportive care.