clozapine and Cardiotoxicity

To review the published literature on clozapine associated cardiotoxicity (CACT), summarize diagnostic features, and evaluate monitoring procedures for safe clozapine re-challenge.. Clozapine-associated Myocarditis (CAM) - Incidence of early myocarditis (≤2 months) is infrequent but serious. Clinical diagnosis is confounded by variability in presentation and non-specificity of symptoms. Re-challenge considerations include clozapine impact on symptomatic severity and associated disability and risk of suicidality. Re-challenging is recommended only after full clinical resolution of myocarditis and cardiac function impairment, under closely controlled conditions, starting at very low dosage, extremely slow titration and frequent assays of lab and cardio biomarkers. Clozapine associated cardiomyopathy (CAC) -develops later but mortality has been reported at 12.5-24.0%. Re-challenge is generally not recommended due to paucity of outcome data. Monitoring Cardiac Toxicity: Plausible steps include closer clinical monitoring, repeated assays of biomarkers, and echocardiographic studies, and cardiac MRI changes with unremarkable findings of cardiac dysfunction with echocardiography. Subclinical clozapine associated cardiotoxicity is more prevalent than CAM and CAC. Diagnosis is often challenging due to non specific presentation. Active monitoring is recommended. Rechallenging is feasible but should be done under close monitoring conditions. A protocol is proposed based on literature review and clinical experience in order to reduce the risk of CACT.. Clozapine-associated myocarditis and cardiomyopathy may have been underreported worldwide. Identification of subclinical cardiotoxic effects can improve outcomes by earlier recognition before clinical manifestations of cardiac impairments. A pragmatic close clinical monitoring protocol including cardiac biomarkers aimed at timely detection of cardiac toxicity, in the initial phase of treatment is proposed.

Topics: Antipsychotic Agents; Cardiomyopathies; Cardiotoxicity; Clozapine; Humans; Myocarditis; Schizophrenia

Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization's (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Cardiotoxicity; Clozapine; Connexin 43; Humans; Pneumonia; Schizophrenia; Seizures; Signal Transduction; Treatment Outcome

This review discusses the rare but potentially life-threatening cardiovascular side-effects of myocarditis and dilated cardiomyopathy associated with the use of Clozapine. The clinical presentation of these conditions is non-specific, making it difficult to both risk-stratify and identify patients who develop these consequences. This review aims to examine the proposed aetiologies, diagnostic approaches and subsequent management strategies of cardiotoxicity associated with clozapine use; offering guidance to psychiatrists and general physicians. Current evidence highlights the importance of accurate diagnosis to prevent premature and unnecessary cessation of clozapine. Guidance on monitoring and reintroduction of the drug is emerging and current practice recommends a combination of regular monitoring of biomarkers and imaging to make a diagnosis of cardiotoxicity although further work is needed to establish evidence-based guidelines.

Topics: Antipsychotic Agents; Cardiomyopathies; Cardiotoxicity; Clozapine; Humans; Myocarditis; Psychiatry

Clozapine is exceptionally effective in psychotic disorders and can reduce suicidal risk. Nevertheless, its use is limited due to potentially life-threatening adverse effects, including myocarditis and cardiomyopathy. Given their clinical importance, we systematically reviewed research on adverse cardiac effects of clozapine, aiming to improve estimates of their incidence, summarize features supporting their diagnosis, and evaluate proposed monitoring procedures. Incidence of early (≤2 months) myocarditis ranges from <0.1 to 1.0 % and later (3-12 months) cardiomyopathy about 10 times less. Diagnosis rests on relatively nonspecific symptoms, ECG changes, elevated indices of myocardial damage, cardiac MRI findings, and importantly, echocardiographic evidence of developing ventricular failure. Treatment involves stopping clozapine and empirical applications of steroids, diuretics, beta-blockers, and antiangiotensin agents. Mortality averages approximately 25 %. Safety of clozapine reuse remains uncertain. Systematic studies are needed to improve knowledge of the epidemiology, avoidance, early identification, and treatment of these adverse effects, with effective and practicable monitoring protocols.

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Cardiomyopathies; Cardiotoxicity; Clozapine; Drug Monitoring; Humans; Psychotic Disorders

To investigate ethnic disparities in the treatment and incidence of cardiotoxicity for patients prescribed clozapine in New Zealand.. A post hoc analysis was undertaken using data from four studies investigating clozapine cardiotoxicities in New Zealand: two population studies (one prospective, one retrospective) conducted in the Auckland District Health Board (2011-2017), and two studies of coronial autopsy records (2001-2016). The relationship between ethnicity and cases (N=26) of myocarditis and/or cardiomyopathy was examined in comparison to non-cases in the rest of the study population (N=161). Patient demographics, comorbidities, and risk factors were investigated for any associations with ethnicity, where data was available.. Māori and Pacific patients were over-represented in the population studies. Moreover, across the cohorts investigated 46% of myocarditis and cardiomyopathy cases were Māori. In contrast, only one case (4%) of cardiomyopathy was identified in a patient of Pacific descent. Where clozapine titration data was available, the rate of dose escalation was higher in Māori and Pacific peoples, as was the cumulative dose received before the first case of cardiotoxicity (day 13 of dose titration). Māori patients were more likely to be co-medicated with sodium valproate than others during clozapine titration, and sodium valproate was also significantly associated with myocarditis in these patients.. The factors underpinning the more rapid titration of Māori and Pacific patients onto clozapine and the increased use of concomitant sodium valproate in Māori are unclear. While the latter may explain the heightened risk of clozapine-induced myocarditis in Māori, further work is required to mitigate the effects of this inequity on the safe use of clozapine in New Zealand.

Topics: Cardiotoxicity; Clozapine; Ethnicity; Health Status Disparities; Humans; New Zealand; Prospective Studies; Retrospective Studies

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.

Topics: Animals; Cardiotoxicity; Clozapine; Embryo, Nonmammalian; Zebrafish

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.

Topics: Animals; Cardiotoxicity; Clozapine; Ellagic Acid; Glutathione Disulfide; Membrane Potential, Mitochondrial; Mitochondria; Myocytes, Cardiac; Oxidative Stress; Rats; Reactive Oxygen Species

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.

Topics: Animals; Antipsychotic Agents; Cardiotoxicity; Clozapine; Male; Mice; Microsomes, Liver; Mitochondria, Heart; Mitochondrial Membranes; Rats; Rats, Wistar

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 LC

Topics: Animals; Antipsychotic Agents; Cardiotoxicity; Clozapine; Cytokines; Embryonic Development; Gene Expression Regulation; Heart Diseases; Heart Rate; Lipid Peroxidation; Oxidative Stress; Zebrafish; Zebrafish Proteins

The generation of a reactive nitrenium ion by microsomal/mitochondrial cytochrome P450 (CYPs) from clozapine (CLZ) has been suggested as the main cause of cardiotoxicity by this drug. Previous studies indicated that thymoquinone (TQ) as an active constituent of Nigella sativa has pharmacological effects such as antioxidant, reactive oxygen species (ROS) scavenger, and inhibitory effect on CYPs enzymes. Therefore, we hypothesized that TQ with these pharmacological effects can reduce CLZ-induced toxicity in isolated cardiomyocytes and mitochondria. Rat left ventricular cardiomyocytes and mitochondria were isolated by collagenase perfusion and differential centrifugation respectively. Then, isolated cardiomyocytes and mitochondria were pretreated with different concentrations of TQ (1, 5, and 10 μmol/l) for 30 min and then followed by exposure to CLZ (50 μmol/l) for 6 h. After 6 h of incubation, using biochemical evaluations and flow cytometric analysis, the parameters of cellular toxicity including cytotoxicity, the level of oxidized/reduced glutathione (GSH/GSSG), malondialdehyde (MDA), reactive oxygen species (ROS) formation, lysosomal membrane integrity, mitochondria membrane potential (ΔΨm) collapse, and mitochondrial toxicity including succinate dehydrogenase (SDH) activity and mitochondrial swelling were analyzed. We observed a significant toxicity in isolated cardiomyocytes and mitochondria after exposure with CLZ which was related to ROS formation, oxidative stress, GSH depletion, lysosomal and mitochondrial damages, and mitochondrial dysfunction and swelling, while TQ pretreatment reverted the above toxic effect of CLZ on isolated cardiomyocytes and mitochondria. Our results indicate that TQ prevents and reverses CLZ-induced cytotoxicity and mitochondrial damages in isolated cardiomyocytes and mitochondria, providing an experimental basis for clinical treatment on CLZ-induced cardiotoxicity.

Topics: Animals; Antipsychotic Agents; Benzoquinones; Cardiotoxicity; Cell Death; Clozapine; Dose-Response Relationship, Drug; Glutathione; Male; Malondialdehyde; Membrane Potential, Mitochondrial; Mitochondria, Heart; Mitochondrial Swelling; Myocytes, Cardiac; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species

Second-generation antipsychotics (SGAs) are first-line drugs that are prescribed for mental disorders in clinic. Severe cardiotoxicity has been widely reported and thus limits their clinical application. This study aimed to identify the common mechanism underlying SGAs-induced cardiotoxicity using dual-omics analyses. Balb/C mice were intraperitoneally injected with two representative SGAs, olanzapine (2.5 mg/kg) and clozapine (25 mg/kg), at clinically comparable doses for 0, 7, 14 and 21 days. Our results showed that both SGAs induced cardiomyocyte degeneration, inflammation infiltration, and cardiac fibrosis, all of which worsened with time. Proteomic analysis revelaed that 22 differentially expressed (DE) proteins overlapped in olanzapine and clozapine-treated hearts. These proteins were significantly enriched in muscle contraction, amino acid metabolism and spliceosomal assembly by GO term analysis and spliceosome signaling was among the top enriched pathways by KEGG analysis. Among the 22 DE proteins, three spliceosome signal proteins were validated in a dynamic detection, and their expression significantly correlated with the extent of SGAs-induced cardiac fibrosis. Following the spliceosome signaling dysregulation, RNA sequencing revealed that alternative splicing events in the mouse hearts were markedly enhanced by SGAs treatments, and the production of vast transcript variants resulted in dysregulation of multiple pathways that are critical for cardiomyocytes adaptation and cardiac remodeling. Pladienolide B, a specific inhibitor of mRNA splicing, successfully corrected SGAs-induced alternative splicing and significantly attenuated the secretion of pro-inflammatory factors and cell deaths induced by SGAs exposure. Our study concluded that the spliceosome signaling was a common pathway driving SGAs cardiotoxicity. Pharmacological inhibition of the spliceosome signaling represents a novel therapeutic strategy against SGAs cardiotoxicity.

Topics: Alternative Splicing; Animals; Antipsychotic Agents; Cardiotoxicity; Clozapine; Gene Expression Profiling; Gene Regulatory Networks; Heart Diseases; Mice, Inbred BALB C; Olanzapine; Proteome; Proteomics; Signal Transduction; Spliceosomes; Transcriptome

Topics: Adult; Antipsychotic Agents; Biomarkers; Cardiotoxicity; Case-Control Studies; Circulating MicroRNA; Clozapine; Female; Gene Expression Profiling; Heart Diseases; Humans; Male; Middle Aged; Predictive Value of Tests; Risk Factors; Young Adult

Clozapine is an atypical antipsychotic drug that is very efficacious in treating psychosis, but the risk of severe cardiotoxicity limits its clinical use. The present study investigated the harmful effects of clozapine on myocardium and assessed the involvement of cannabinoid receptors in its cardiotoxicity.. Clozapine alone or in combination with selective cannabinoid receptor antagonists or agonists were used to treat mice and cardiomyocytes.. Clozapine induced myocardial inflammation and infiltration 7 days after i.p. injection. Mice survival rate and myocardial infiltration, and fibrotic lesions were dose-dependently worsened by clozapine. Clozapine decreased major endocannabinoid levels in sera and cultured cardiomyocytes. Cannabinoid CB. Our data provide evidence that cannabinoid CB

Topics: Animals; Antipsychotic Agents; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cardiotoxicity; Cell Line; Clozapine; Male; Mice; Myocardium; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Schizophrenia has a 1% prevalence in the population; 30% of these patients are treatment refractory. Clozapine is the only drug licensed to treat treatment refractory psychosis, but concerns about potential adverse effects result in only a proportion of eligible patients being treated. Although a well-documented neutropenia risk is mitigated by routine blood testing, cardiac toxicity is a commonly cited reason to discontinue clozapine treatment. However, there is little data on the real-life cardiac outcomes in those receiving clozapine treatment.. Retrospective review of electrocardiogram, echocardiogram, and clinical outcomes in 39 inpatients with treatment-refractory schizophrenia, treated with clozapine and other antipsychotic medication, referred for cardiology opinion.. Commonest reasons for referral were development of left ventricular (LV) impairment or sinus tachycardia with normal LV function. Patients were reviewed by a range of cardiologists, receiving varied interventions.Median LV ejection fraction in the clozapine group was normal (52%). Serial echocardiograms demonstrated that clozapine-treated patients with LV impairment had no change in LV ejection fraction over a 4-month follow-up. Left ventricular ejection fraction did not differ between patients treated with clozapine and other antipsychotics. However, over an 11-year follow-up period, 48% of patients had discontinued clozapine treatment.. This naturalistic study demonstrates that clozapine is not associated with significant cardiac mortality or morbidity. There is a real need for multidisciplinary working between specialist cardiologists and psychiatrists caring for these complex patients to facilitate optimal long-term physical and mental health outcomes.

Topics: Adult; Antipsychotic Agents; Cardiotoxicity; Clozapine; Female; Follow-Up Studies; Humans; Male; Middle Aged; Retrospective Studies; Schizophrenia; Ventricular Dysfunction, Left

Driven by the need of pharmacovigilance centres and companies to routinely collect and review all available data about adverse drug reactions (ADRs) and adverse events of interest, we introduce and validate a computational framework exploiting dominant as well as emerging publicly available data sources for drug safety surveillance.. Our approach relies on appropriate query formulation for data acquisition and subsequent filtering, transformation and joint visualization of the obtained data. We acquired data from the FDA Adverse Event Reporting System (FAERS), PubMed and Twitter. In order to assess the validity and the robustness of the approach, we elaborated on two important case studies, namely, clozapine-induced cardiomyopathy/myocarditis versus haloperidol-induced cardiomyopathy/myocarditis, and apixaban-induced cerebral hemorrhage.. The analysis of the obtained data provided interesting insights (identification of potential patient and health-care professional experiences regarding ADRs in Twitter, information/arguments against an ADR existence across all sources), while illustrating the benefits (complementing data from multiple sources to strengthen/confirm evidence) and the underlying challenges (selecting search terms, data presentation) of exploiting heterogeneous information sources, thereby advocating the need for the proposed framework.. This work contributes in establishing a continuous learning system for drug safety surveillance by exploiting heterogeneous publicly available data sources via appropriate support tools.

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Cardiotoxicity; Cerebral Hemorrhage; Clozapine; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Haloperidol; Humans; Information Storage and Retrieval; Pharmacovigilance; Pyrazoles; Pyridones

Clozapine is a second-generation antipsychotic drug used in treatment-resistant schizophrenia. Fever induced by clozapine is a rather frequent side-effect which usually occurs in the first 4 weeks of treatment. Despite its effectiveness, there are potentially life-threatening adverse effects, such as cardiotoxicity.. We present the case of a 31-year-old caucasian male with refractory schizophrenia who developed benign fever, increase of C-reactive protein and high troponin levels, without presenting any other signs to myocarditis, on the 13th day under clozapine treatment, which declined progressively upon discontinuation of the drug.. This case hints at the presence of initially subclinical cardiotoxicity as an underlying factor in patients developing fever.. Taking advantage of more sensitive methods for measuring troponin, clinicians would be promptly aware of this possible side-effect. This would allow for significant reduction of the risk of cardiac dysfunction, further attained by carefully monitoring the patient.

Topics: Adult; Antipsychotic Agents; Autoimmunity; Cardiotoxicity; Clozapine; Electrocardiography; Fever; Humans; Male; Schizophrenia