clozapine and Heart-Diseases

Clozapine was approved by the US Food and Drug Administration in 1989 for the management of treatment-resistant schizophrenia, and has since proven to reduce symptom burden and suicide risk, increase quality of life, and reduce substance use in individuals with psychotic disorders. Nevertheless, clozapine's psychiatric benefits have been matched by its adverse effect profile. Because they are likely to encounter medical complications of clozapine during admissions or consultations for other services, hospitalists are compelled to maintain an appreciation for these iatrogenic conditions. The authors outline common (eg, constipation, sialorrhea, weight gain) and serious (eg, agranulocytosis, seizures, myocarditis) medical complications of clozapine treatment, with internist-targeted recommendations for management, including indications for clozapine discontinuation.

Topics: Adult; Antipsychotic Agents; Clozapine; Disease Management; Female; Gastrointestinal Diseases; Heart Diseases; Humans; Internal Medicine; Male; Middle Aged; Practice Guidelines as Topic; Schizophrenia

Clozapine is the most effective antipsychotic medication for treatment-refractory schizophrenia and is also approved for suicidality in schizophrenia patients. However, it can cause significant medical morbidity and requires intensive medical monitoring once prescribed. Perhaps due to lack of familiarity with its use, it is underused in clinical practice and its initiation often delayed. This article reviews the literature on clozapine in order to measure its potential effectiveness against its adverse effects and ultimately aims to serve as a useful summary for clinicians in their everyday prescribing.

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Heart Diseases; Hematologic Diseases; Humans; Metabolic Diseases; Practice Guidelines as Topic; Practice Patterns, Physicians'; Quality of Life; Schizophrenia; Suicide Prevention; Venous Thromboembolism; Weight Gain

Clozapine treatment remains the gold standard for treatment-resistant schizophrenia, but treatment with clozapine is associated with several side-effects that complicate the use of the drug. This clinical overview aims to provide psychiatrists with knowledge about how to optimize clozapine treatment. Relevant strategies for reducing side-effects and increasing the likelihood of response are discussed.. Studies of clozapine available in MEDLINE were reviewed.. A slow up-titration of clozapine is recommended in order to reach the optimal dosage of clozapine and diminish the risk of dose-dependent side-effects. Particularly, in case of partial response or non-response, the use of therapeutic drug monitoring of clozapine is recommended. Plasma levels above the therapeutic threshold of 350-420 ng/ml are necessary to determine non-response to clozapine. To ease the burden of dose-dependent side-effects, dose reduction of clozapine should be tried and combination with another antipsychotic drug may facilitate further dose reduction. For most side-effects, counteracting medication exists. Augmentation with lamotrigine, antipsychotics, or electroconvulsive therapy may be beneficial in case of partial response to clozapine.. Treatment with clozapine should be optimized in order to increase the rate of response and to minimize side-effects, thus diminishing the risk of discontinuation and psychotic relapse.

Topics: Antipsychotic Agents; Calcium Channel Blockers; Central Nervous System Diseases; Clozapine; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Electroconvulsive Therapy; Heart Diseases; Humans; Lamotrigine; Schizophrenia; Treatment Outcome; Triazines

To review the published literature on serious adverse cardiac events associated with the atypical antipsychotic agent, clozapine, and to make recommendations for cardiac assessment of candidates for clozapine treatment and for monitoring of cardiac status after treatment is initiated.. We searched the PubMed and MEDLINE databases for articles published from 1970 to 2004 that contain the keywords "clozapine and myocarditis," "clozapine and cardiomyopathy," "clozapine and cardiotoxicity," "clozapine and sudden death" or "clozapine and mortality." We also manually searched the bibliographies of these articles for related sources.. We reviewed the 30 case reports, case series, laboratory and clinical trials, data mining studies, and previous reviews identified by this search.. Recent evidence suggests that clozapine is associated with a low (0.015% to 0.188%) risk of potentially fatal myocarditis or cardiomyopathy. The drug is not known to be independently associated with pathologic prolongation of the QTc interval, but it may contribute to pathologic QTc prolongation in patients with other risk factors for this condition.. The low risk of a serious adverse cardiac event should be outweighed by a reduction in suicide risk for most patients taking clozapine. We provide recommendations for assessing and monitoring cardiac status in patients prior to and after initiation of treatment with clozapine.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Death, Sudden, Cardiac; Heart Diseases; Humans; Myocarditis

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

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

To comprehensively assess cardio-metabolic risk factors and their management in a large sample of outpatients treated with clozapine.. Observational cross-sectional study of all clozapine users attending specialized clozapine monitoring outpatient clinics in three public hospitals in Sydney, Australia were approached to participate over the one-year period 01/10/2015-30/09/2016. Cardio-metabolic risk factors including metabolic syndrome, risk for future development of diabetes, smoking, physical activity, nutrition, and prescribed medications were assessed at face-to-face interview and through medical record review. Among patients who had cardio-metabolic risk factors, the proportion receiving appropriate management was assessed.. Of 451 registered clozapine clinic attenders, 92.2% completed questionnaires and anthropometric measurements. 58.3% met criteria for metabolic syndrome. 79.6% were overweight or obese. 55.9% had blood pressure meeting metabolic syndrome criteria. 46.6% had elevated fasting blood glucose and 55.2% had elevated blood triglycerides. 43.6% were current smokers. Only 10% achieved recommended weekly physical activity levels. Unhealthy food categories were highly consumed. 32.1% were on additional antipsychotics. In the majority of individuals, cardio-metabolic risk factors were untreated or under-treated.. Clozapine use was associated with very high rates of cardiovascular and metabolic risk factors, which were frequently under-treated. Management of both physical and mental health should be prioritized. Polypharmacy should be rationalized. Future research should investigate the effectiveness of smoking cessation and lifestyle interventions in this high-risk population.

Topics: Adult; Aged; Ambulatory Care; Antipsychotic Agents; Clozapine; Cohort Studies; Cross-Sectional Studies; Female; Heart Diseases; Humans; Male; Metabolic Syndrome; Middle Aged; Polypharmacy; Prevalence; Psychotic Disorders; Risk Factors; Schizophrenia

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 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 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.

Topics: Animals; Antioxidants; Apoptosis Regulatory Proteins; Biomarkers; Clozapine; Disease Models, Animal; DNA Damage; Heart Diseases; Hemodynamics; Inflammation Mediators; Male; Myocardium; NF-kappa B; Oxidative Stress; Rats, Wistar; Signal Transduction; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Topics: Antipsychotic Agents; Clozapine; Heart Diseases; Humans; Mass Screening; Practice Guidelines as Topic

Cardiovascular side effects of clozapine are not uncommon, but few systematic studies of these effects have been performed. In this study, we reviewed data on the electrocardiographic (ECG) abnormalities in patients treated with clozapine.. Sixty-one patients treated with clozapine were selected from the Seoul National University Hospital Treatment-Resistant Schizophrenia Clinic. A retrospective chart review was conducted to identify ECG abnormalities and cardiovascular side effects.. The prevalence of ECG abnormalities in patients who had been using antipsychotics other than clozapine was 13.6% at baseline, which increased significantly to 31.1% after commencement of clozapine treatment. Among the 53 patients without baseline ECG abnormalities, 13 showed new-onset ECG abnormalities after using clozapine. Normal ECG under previous antipsychotic medication reduced the risk of new-onset ECG abnormalities, whereas increased age was found to increase the risk. The occurrence of orthostatic hypotension or tachycardia was not related to the development of ECG abnormalities. Most of the newly developed abnormalities had little clinical significance, and they tended to occur during the initial phase of treatment. In 10 patients, ECGs normalized despite the continued use of clozapine. Clozapine increased corrected QT interval (QTc) in a dose-dependent fashion; however, the clinical significance of this observation is uncertain. Pathologic prolongation of QTc was found to be rare.. Although a substantial portion of patients treated with clozapine developed ECG abnormalities, most of the abnormalities were benign and did not hinder further treatment.

Topics: Adolescent; Adult; Antipsychotic Agents; Arrhythmias, Cardiac; Clozapine; Comorbidity; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Diseases; Humans; Hypotension, Orthostatic; Male; Middle Aged; Prevalence; Regression Analysis; Retrospective Studies; Sex Factors; Tachycardia

To report a case of symptomatic cardiomyopathy induced during treatment with clozapine, an antipsychotic of the dibenzodiazepine class.. A patient with a long psychiatric history significant for schizophrenia and no prior cardiac history developed dyspnea, malaise, and edema with a low ventricular ejection fraction during clozapine therapy.. The literature concerning cardiorespiratory complications with clozapine therapy is reviewed.. Cardiorespiratory complications associated with clozapine use are rare. Caution may be warranted in patients treated with other medications, such as benzodiazepines, and in patients with underlying cardiac disease.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Heart Diseases; Humans; Schizophrenia; Stroke Volume