clozapine and Cardiovascular-Diseases

Mortality from cardiovascular disease is increased in people with mental health disorders in general and schizophrenia in particular. The causes are multifactorial, but it is known that antipsychotic medication can cause cardiac side-effects beyond the traditional coronary risk factors. Schizophrenia itself is a contributor to an increased risk of cardiovascular mortality via cardiac autonomic dysfunction and a higher prevalence of metabolic syndrome, both contributing to a reduced life expectancy. The pro-arrhythmic impact of traditional antipsychotics, especially via the hERG-potassium channel, has been known for several years. Newer antipsychotics have a reduced pro-arrhythmic profile but might contribute to higher cardiac death rates by worsening the metabolic profile. Clozapine-induced cardiomyopathy, which is dose independent, is a further concern and continuous monitoring of these patients is required. Prophylaxis with angiotensin-converting enzyme inhibitors is currently under review. Overall, management of cardiovascular risk within this population group must be multifaceted and nuanced to allow the most effective treatment of serious mental illness to be conducted within acceptable parameters of cardiovascular risk; some practical measures are presented for the clinical cardiologist.

Topics: Antipsychotic Agents; Autonomic Nervous System Diseases; Cardiovascular Diseases; Clozapine; Humans; Metabolic Syndrome; Risk Assessment; Schizophrenia

Clozapine is the first second generation antipsychotic with different receptor profile of action. Clozapine is the most efficacious drug for the treatment of psychotic disorder and is the drug of choice in treatment resistant schizophrenia. Clozapine is used in elderly patients infrequently owing to its adverse effects profile and tolerability. There is paucity of literature with respect to clozapine use in late life. In this narrative review, we discuss clozapine use in elderly and challenges associated with its use.

Topics: Aged; Aging; Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Cognitive Dysfunction; Humans; Metabolic Diseases; Schizophrenia; Seizures

Myocarditis occurs in about 3% of those initiated on clozapine but monitoring reduces the risk of serious outcome. Cardiomyopathy may develop after myocarditis, or from prolonged tachycardia. Monitoring using echocardiography is not deemed cost effective. Tachycardia, orthostatic hypotension and reduced heart rate variability are a group of clozapine-related adverse effects associated with autonomic dysfunction and may have serious consequences in the long term. Elevated heart rate and poor heart rate variability can be treated with a β-blocker or a non-dihydropyridine calcium channel blocker, while orthostatic hypotension can be alleviated by increased fluid intake and abdominal binding, but may require pharmacological intervention. Adequate correction for heart rate may show that clozapine does not prolong the QT interval. Other cardiovascular effects, pulmonary embolism, metabolic syndrome, sudden cardiac death and particularly the excessive mortality from cardiovascular disease events may be more strongly associated with the combination of mental illness, lifestyle factors and poor treatment of cardiovascular disease and its risk factors than with clozapine treatment. In view of the efficacy of clozapine and the evidence of reduced mortality relative to other antipsychotics, clozapine should be prescribed when indicated and recipients should be enrolled in lifestyle programmes to increase exercise and improve diet, and referred for diagnosis and treatment of cardiovascular disease and its risk factors.

Topics: Antipsychotic Agents; Cardiomyopathies; Cardiovascular Diseases; Clozapine; Drug Monitoring; Humans; Life Style; Myocarditis; Risk Factors

Patients with schizophrenia die on average 25 years earlier than the general population, and this gap appears to be increasing. Most of the excess mortality is due to premature cardiovascular deaths rather than suicide. Many psychotropic agents are orexigenic and can increase weight and promote dyslipidaemia. Traditional cardiac risk factors are undertreated among patients with schizophrenia, and they are less likely to receive cardiac revascularisation than those without a mental illness. Clozapine is an atypical antipsychotic medication effective for treatment of refractory schizophrenia, but is associated with the risk of myocarditis and cardiomyopathy. Established protocols in Australia screen for myocarditis for patients who are initiating clozapine therapy and for long term monitoring for cardiomyopathy with echocardiography. Coordinated care between tertiary providers, general practitioners and primary health care professionals should monitor the physical health of people with psychosis or schizophrenia at least annually and treatment should be offered accordingly.

Topics: Antipsychotic Agents; Australia; Cardiomyopathies; Cardiovascular Diseases; Clozapine; Delivery of Health Care; Echocardiography; Humans; Mass Screening; Mental Health Services; Metabolic Syndrome; Myocarditis; Risk Factors; Schizophrenia

Antipsychotic medications are mainstays in the treatment of schizophrenia and a range of other psychotic disorders.. Recent meta-analyses of antipsychotic efficacy and tolerability have been included in this review, along with key papers on antipsychotic use in schizophrenia and other psychotic illnesses.. The heterogeneity in terms of individuals' response to antipsychotic treatment and the current inability to predict response leads to a trial-and-error strategy with treatment choice. Clozapine is the only effective medication for treatment-resistant schizophrenia.. There are a significant number of side effects associated with antipsychotic use. With a reduction in the frequency of extrapyramidal side effects with the use of second-generation antipsychotics, there has been a significant shift in the side effect burden, with an increase in the risk of cardiometabolic dysfunction.. There exist small and robust efficacy differences between medications (other than clozapine), and response and tolerability to each antipsychotic drug vary, with there being no first-line antipsychotic drug that is suitable for all patients.. A focus on the different symptom domains of schizophrenia may lead to endophenotypic markers being identified, e.g. for negative symptoms and cognitive deficits (as well as for positive symptoms) that can promote the development of novel therapeutics, which will rationally target cellular and molecular targets, rather than just the dopamine 2 receptor. Future developments will target additional processes, including glutamatergic, cholinergic and cannabinoid receptor targets and will utilize personalized medicine techniques, such as pharmacogenetic variants and biomarkers allowing for a tailored and safer use of antipsychotics.

Topics: Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Drug Administration Schedule; Drug Resistance; Drug Substitution; Humans; Medication Adherence; Schizophrenia

Patients with schizophrenia have a shorter life expectancy and their risk of dying from a cardiovascular disease is higher than the general population. Both facts have been attributed to the raised presence of metabolic syndrome. There is a big amount of scientific publications that deals with the relationship between schizophrenia, antipsychotic treatment, and the development of metabolic syndrome. There is also information about recommendations and clinical guides to achieve an adequate prevention, screening, and treatment of the disease. The aim of this review is to update the current information about this issue and to understand related etiologic factors, differences between antipsychotic drugs, and the current recommendations for patient's care.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cardiovascular Diseases; Clozapine; Comorbidity; Follow-Up Studies; Humans; Hypothalamus; Incidence; Life Expectancy; Lipid Metabolism; Metabolic Syndrome; Obesity, Abdominal; Olanzapine; Practice Guidelines as Topic; Schizophrenia; Weight Gain

Metabolic syndrome and cardiovascular diseases are important causes of morbidity and mortality among patients with severe mental illnesses. Atypical or second-generation antipsychotics (SGAs) are associated with obesity and other components of metabolic syndrome, particularly abnormal glucose and lipid metabolism. This review aims to provide a summary of recent evidence on metabolic risks associated with SGAs, current recommendations for metabolic monitoring, and efficacy of treatment options currently available.. Studies have identified younger, antipsychotic-naive patients with first-episode psychosis as a population vulnerable to adverse metabolic effects from SGAs. These patients gained more weight and developed evident lipid and glucose abnormalities as soon as 8-12 weeks after treatment initiation. Findings are more striking among children and adolescents. The differential effects of various SGAs are well described, with clozapine and olanzapine associated with the highest metabolic risk. In addition to behavioral therapy, emerging data suggest that pharmacological therapy, most notably metformin, is efficacious in the treatment and possibly prevention of SGA-associated metabolic derangements.. More data have become available on the burden from metabolic complications associated with SGAs. New and effective treatment options are required in the near future to improve cardiovascular health in this susceptible population.

Topics: Antipsychotic Agents; Benzodiazepines; Cardiovascular Diseases; Clozapine; Humans; Metabolic Syndrome; Metformin; Obesity; Olanzapine; Practice Guidelines as Topic; Psychotic Disorders; Severity of Illness Index; Weight Gain

Dyslipidemia is an increasing problem in most industrialized societies and is a risk factor for coronary heart disease (CHD). Imbalances in individual lipid components, including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and serum triglycerides, have each been shown to contribute to this increased risk. Certain psychiatric patient populations, such as those afflicted with schizophrenia, are of particular concern. Psychiatric patients with schizophrenia are naturally at increased risk for dyslipidemia and obesity, in part due to poor diet and sedentary lifestyle, but these conditions can be exacerbated by some antipsychotic medications. Clozapine and olanzapine, for example, appear to be associated with hyperlipidemia, which may be associated with changes in body weight. Other, newer antipsychotic agents may exhibit less liability for weight gain and the development of dyslipidemia. This review is intended to briefly highlight the association between dyslipidemia and cardiovascular disease, the changes in serum lipids associated with some antipsychotic agents, and how these changes in serum lipids affect the monitoring of schizophrenia patients.

Topics: Antipsychotic Agents; Benzodiazepines; Cardiovascular Diseases; Cholesterol; Cholesterol, VLDL; Clozapine; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Obesity; Olanzapine; Risk Factors; Schizophrenia; Triglycerides; Weight Gain

Clozapine has demonstrated superior efficacy in relieving positive and negative symptoms in treatment-resistant schizophrenic patients; unlike other antipsychotics, it causes minimal extrapyramidal side effects (EPS) and has little effect on serum prolactin. Despite these benefits, the use of clozapine has been limited because of infrequent but serious side effects, the most notable being agranulocytosis. In recent years, however, mandatory blood monitoring has significantly reduced both the incidence of agranulocytosis and its associated mortality. The occurrence of seizures appears to be dose-related and can generally be managed by reduction in clozapine dosage. Less serious and more common side effects of clozapine including sedation, hypersalivation, tachycardia, hypotension, hypertension, weight gain, constipation, urinary incontinence, and fever can often be managed medically and are generally tolerated by the patient. Appropriate management of clozapine side effects facilitates a maximization of the benefits of clozapine treatment, and physicians and patients alike should be aware that there is a range of benefits to clozapine use that is wider than its risks.

Topics: Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Drug Monitoring; Humans; Respiration Disorders; Seizures; Sialorrhea; Weight Gain

Clozapine has been found to be superior to traditional neuroleptics in the treatment of refractory schizophrenia and is increasingly being used to treat schizophrenia, affective disorders, some neurological disorders, and aggression. For many patients, clozapine offers new hope for the successful pharmacological management of a disabling mental disorder. However, up to 17 percent of patients must discontinue treatment with clozapine because of adverse effects, which also limit the rate at which the dose can be increased and the maximum dose that can be tolerated. This article reviews strategies for minimizing and managing the adverse effects of clozapine, including agranulocytosis, seizures, sedation, delirium, obsessive-compulsive symptoms, hypotension, tachycardia, weight gain, sialorrhea, elevated liver enzymes, constipation, nausea, enuresis, fever, and neuromuscular effects. Incidence and morbidity are presented first. Then, the known or hypothesized pathophysiology of the adverse effects are described. Finally, nonpharmacological and pharmacological interventions are reviewed. Under-standing the incidence, pathophysiology, and treatments of adverse effects is essential for a positive therapeutic outcome when prescribing clozapine.

Topics: Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Central Nervous System Diseases; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Gastrointestinal Diseases; Humans; Schizophrenia

Most atypical antipsychotics derive from a high dropout of drug treatments due to adverse cardiometabolic side effects. These side effects are caused, in part, by the H1 receptor blockade. The current work sought a clozapine derivative with a reduced affinity for the H1 receptor while maintaining its therapeutic effect linked to D2 receptor binding. Explicit molecular dynamics simulations and end-point free energy calculations of clozapine in complex with the D2 and H1 receptors embedded in cholesterol-rich lipid bilayers were performed to analyze the intermolecular interactions and address the relevance of clozapine-functional groups. Based on that, free energy perturbation calculations were performed to measure the change in free energy of clozapine structural modifications. Our results indicate the best clozapine derivative is the iodine atom substitution for chlorine. The latter is mainly due to electrostatic interaction loss for the H1 receptor, while the halogen orientation out of the D2 active site reduces the impact on the affinity.Communicated by Ramaswamy H. Sarma.

Topics: Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Humans; Molecular Dynamics Simulation; Receptors, Histamine H1

Clozapine use is associated with higher risks of metabolic side effects and cardiovascular diseases (CVD). Thus, this study aims to establish and compare the cardiometabolic profiles between non-clozapine antipsychotic and clozapine users with schizophrenia.. Data from 88 non-clozapine and 166 clozapine users were extracted from existing databases - demographics, medications, smoking and medical histories, anthropometric parameters, serum lipid and fasting glucose levels. Prevalence of metabolic syndrome (MetS) was established using the AHA/NHLBI criteria. Cardiovascular risk profiles were established using the Framingham risk score (FRS).. The clozapine group had significantly higher proportions of diagnosed hypertension (10.8 % vs. 3.4 %, p = 0.041), diabetes mellitus (15.7 % vs. 3.4 %, p = 0.003) and dyslipidemia (36.7 % vs. 12.5 %, p < 0.001). However, the non-clozapine antipsychotic group had poorer anthropometric, serum lipids and glucose levels. The prevalence rates of MetS in the clozapine and non-clozapine antipsychotic groups were not statistically significant at 42.8 % and 43.2 %, respectively. As for CVD risk, the non-clozapine antipsychotic group had significantly higher FRS (6.59 % vs. 6.12 %, p = 0.001).. Although clozapine users had higher rates of diagnosed metabolic conditions, other cardiometabolic parameters appeared better compared to non-clozapine antipsychotic users, which could be due to greater awareness, earlier detection and treatment. Regardless of the type of antipsychotic used, metabolic abnormalities are prevalent in individuals with schizophrenia; physical healthcare should be prioritised alongside mental healthcare in this group.

Topics: Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Glucose; Heart Disease Risk Factors; Humans; Metabolic Syndrome; Risk Factors; Schizophrenia

Reports of decreased mortality among patients with schizophrenia who use clozapine may be biased if clozapine is prescribed to relatively healthy patients and if intensive monitoring during its use prevents (under-treatment of) somatic disorder. We aimed to assess whether there is a difference in: (1) somatic comorbidity between patients who start with clozapine and those who start with other antipsychotics and (2) prescribed somatic medication, between patients using clozapine and those using olanzapine. Cohort study based on insurance claims (2010-2015). After selecting new users of antipsychotics and those who subsequently switched to clozapine (N = 158), aripiprazole (N = 295), olanzapine (N = 204) or first-generation antipsychotics (N = 295), we compared the clozapine starters to others on cardiovascular or diabetic comorbidity. Those using clozapine and olanzapine were compared on new prescriptions for cardiovascular or antidiabetic drugs. The ORadj of cardiovascular or diabetic comorbidity among other starters compared with clozapine starters was 0.77 [95% confidence interval (CI): 0.43-1.39], that is, a nonsignificantly increased prevalence associated with clozapine was found. Users of clozapine received significantly more new prescriptions for cardiovascular or antidiabetic medication (ORadj: 2.70, 95% CI: 1.43-5.08). Starters with clozapine were not cardiovascular/metabolic healthier than starters with other antipsychotics. During its use, they received more somatic treatment.

Topics: Aged; Antipsychotic Agents; Cardiovascular Agents; Cardiovascular Diseases; Clozapine; Diabetes Mellitus; Drug Administration Schedule; Drug Monitoring; Female; Health Status; Humans; Hypoglycemic Agents; Insurance Claim Review; Male; Middle Aged; Netherlands; Schizophrenia

Many drugs in current practice require additional safety labels in order to prevent potential risks to the major organ system. Psychotropic agent clozapine has been reported to produce myocarditis and other cardiac complications on repeated use. Our study aimed to establish the role of clozapine in vascular damage associated with nitric oxide metabolism.. Isolated aortic strips incubated with clozapine at different dose levels were estimated for nitrite release and antioxidant systems such as glutathione and catalase. Vascular integrity assessment was performed by recording the acetylcholine induced relaxation of phenyephrine pre-contracted aorta.. From our study, it was found that clozapine depletes the nitric oxide level in the endothelium and enhance the oxidative stress. The aorta fails to relax completely after the addition of acetylcholine indicates the deranged eNOS signaling in the endothelium.. From the experimental findings, it was concluded that clozapine could depress the eNOS regulation and thereby perhaps initiates cardiovascular complications through subsequent vascular events.

Topics: Acetylcholine; Animals; Antioxidants; Aorta; Cardiovascular Diseases; Cardiovascular System; Catalase; Clozapine; Endothelium; Glutathione; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Psychotropic Drugs; Rats; Rats, Wistar; Signal Transduction

To estimate 20-year mortality risk in people with schizophrenia treated with second-generation antipsychotics (SGA) and examine the effects of cigarette smoking on mortality. Of the 1199 individuals with schizophrenia in the study, estimated 20-year all-cause mortality risk by Kaplan Meier Curve was 30% and leading causes of death included 27% cardiovascular disease, 13% cancer, 12% non-HIV infection, 5% respiratory causes, 20% other causes and 18% had unknown cause of death. For all-cause mortality, we found that white race and male sex were significant risk factors (HR = 1.5, p = 0.002 and HR = 1.33, p = 0.033, respectively). For cardiovascular mortality risk, we showed that cigarette smokers and white race were at higher risk (HR = 1.86, p = 0.017 and HR = 1.71, p = 0.045, respectively). Cardiovascular mortality risk at 20-years is 11%. Kaplan-Meier Survival Curve showed a statistical difference for smokers and non-smokers in cardiovascular mortality over the 20-year follow-up (Log rank chi-square = 5.35, df = 1, p = 0.02). 20-year all-cause mortality risk for individuals with schizophrenia was found to be 30% with cardiovascular disease as a leading cause. Cigarette smokers and white race were associated with an increased risk of death. Regarding cardiovascular mortality specifically, cigarette smoking increased risk by 86% over a 20-year period. Clozapine was neither a risk factor for all-neither cause nor cardiovascular mortality. This data suggests that long-term cardiovascular mortality continues to be increased in schizophrenia for those who are or have been cigarette smokers.

Topics: Adult; Aged; Antipsychotic Agents; Cardiovascular Diseases; Cause of Death; Cigarette Smoking; Clozapine; Comorbidity; Female; Follow-Up Studies; Humans; Male; Middle Aged; Schizophrenia

Studies show that individuals with schizophrenia have impaired cardiovascular fitness (i.e., low peak aerobic power (VO

Topics: Adult; Antipsychotic Agents; Cardiovascular Diseases; Chronic Disease; Clozapine; Cross-Sectional Studies; Female; Haloperidol; Humans; Male; Oxygen Consumption; Physical Fitness; Schizophrenia

The present study is a review of a cardiometabolic clinic for consumers taking clozapine. This clinic was recently established and co-located with the clozapine clinic at a regional hospital in New South Wales, Australia, to enhance engagement and improve the physical health outcomes of consumers taking antipsychotic medication. A descriptive analysis of clients' (n = 73) information collected during routine care for the first 6 months of the clinic's operation, from January 2016 to July 2016, was conducted. First-visit data were analysed to establish a client profile, consisting of weight, height, blood pressure, pulse, a range of blood measurements, smoking status, alcohol consumption, and eating and exercise habits. Data collected for clients who had three or more visits with the general practitioner (n = 40) were analysed separately for outcomes. Two case studies are used to depict the service received and client profile. At the first appointment, the majority of clients had metabolic syndrome that was mostly left untreated; many of these clients were commenced on metformin. The outcomes are positive, and show that the majority of clients lost weight (82.5%) and had a reduction in body mass index (84.6%); nearly half (44.4%) had a reduction in waist circumference. The majority of clients self-reported increased physical activity (72.5%, n = 29) and positive dietary changes (77.5%, n = 31) since their first appointment. The model trialled by the cardiometabolic clinic integrated a specialist mental health and primary care service, and demonstrates success in engaging clients with severe mental illness in physical health care. Co-location is conceptualized as critical for positive patient outcomes and high levels of engagement.

Topics: Adult; Aged; Cardiovascular Diseases; Clozapine; Female; General Practitioners; Health Status; Humans; Male; Mental Disorders; Middle Aged; New South Wales; Program Evaluation; Psychotropic Drugs; Risk Reduction Behavior; Treatment Outcome; Young Adult

Topics: Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Humans; Male; Middle Aged; Schizophrenia

Patients with schizophrenia (SCZ) are at higher risk for developing cardiovascular disease (CVD) and neuregulin-1 (NRG1)/ErbB signaling has been identified as a common susceptibility pathway for the comorbidity. Antipsychotic treatment can change NRG1/ErbB signaling in the brain, which has been implicated in their therapeutic actions, whereas the drug-induced alterations of NRG1/ErbB pathway in cardiovascular system might be associated with the prominent cardiac side-effects of antipsychotic medication. To test this hypothesis, we examined NRG1/ErbB system in rat prefrontal cortex (PFC) and myocardium following 4-week intraperitoneal administration of haloperidol, risperidone or clozapine. Generally, the antipsychotics significantly enhanced NRG1/ErbB signaling with increased expression of NRG1 and phosphorylation of ErbB4 and ErbB2 in the brain and myocardium, except that clozapine partly blocked the cardiac NRG1/ErbB2 activation, which could be associated with its more severe cardiac adverse actions. Combined, our data firstly showed evidence of the effect of antipsychotic exposure on myocardial NRG1/ErbB signaling, along with the activated NRG1/ErbB system in brain, providing a potential link between the therapeutic actions and cardiotoxicity.

Topics: Animals; Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Comorbidity; Genetic Predisposition to Disease; Haloperidol; Injections, Intraperitoneal; Male; Myocardium; Neuregulin-1; Phosphorylation; Prefrontal Cortex; Rats, Sprague-Dawley; Receptor, ErbB-2; Receptor, ErbB-4; Risk; Risperidone; Schizophrenia; Signal Transduction; Time Factors

We tested the hypothesis that uric acid levels are higher in subjects with schizophrenia treated with clozapine than in healthy control and they correlate with anthropometric measurements, laboratory tests and results of bioimpedance analysis of body composition.. Data for 24 subjects with schizophrenia treated with clozapine and 24 age- and sex-matched healthy volunteers was analyzed.. There was no difference of fasting uric acid concentrations between clozapine and control groups (4.5 ± 1.4 vs. 4.3 ± 1.3 mg/dl, P = 0.87). Regarding the whole group, uric acid levels were significantly higher in men (5.2 ± 1.2 vs. 3.6 ± 0.9, P < 0.001). Uric acid levels correlated with weight (R = 0.58, P = 0.003), body mass index (BMI; R = 0.49, P = 0.01), abdominal circumference (R = 0.45, P = 0.03), waist circumference (R = 0.47, P = 0.02), waist-to-hip ratio (R = 0.42, P = 0.04), insulin (R = 0.50, P = 0.01), homoeostasis model assessment of insulin resistance 2 (HOMA2-IR; R = 0.49, P = 0.01), basal metabolic rate (R = 0.56, P = 0.004), lean body mass (R = 0.55, P = 0.005) and body water (R = 0.55, P = 0.005). There were no significant differences of uric acid levels for smoking status, impaired fasting glucose, abdominal obesity, obesity/overweight and dyslipidemia. Uric acid levels did not correlate with age, duration of clozapine treatment, clozapine dose, leg circumference, systolic blood pressure, diastolic blood pressure, total body fat, triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), homocysteine, corrected calcium, glucose and homoeostasis model assessment of insulin resistance 1 (HOMA1-IR).. We did not find significant differences in blood uric acid levels between subjects with schizophrenia and controls. Association with weight, BMI, abdominal and waist circumferences, insulin levels and insulin resistance may support uric acid role as an important cardiovascular risk factor. Association with lean weight may explain why men have higher levels of uric acid than women.

Topics: Adult; Anthropometry; Cardiovascular Diseases; Case-Control Studies; Clozapine; Female; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Reference Values; Risk Factors; Schizophrenia; Sex Factors; Uric Acid

The efficacy of clozapine for the treatment of schizophrenia has been demonstrated. However, a range of adverse events have been associated with its use. To date, there remains a paucity of data regarding the prevalence of clozapine-induced cardiovascular (CV) and parameters associated with the development of metabolic syndrome, alongside associated risk factors for their development.. An observational, clinical cohort study design of 355 clozapine patients who were enrolled in the Barwon Health Clozapine Program at Geelong Hospital, Victoria, Australia, between 2008-12. Medical records were accessed retrospectively. Multivariate logistic regression was used to determine associations with adverse event(s).. Older age of commencement with clozapine was consistently associated with increased risk of CV abnormalities, with the exception of tachycardia where older age was protective (Odds Ratio [OR]: 0.97; 95% Confidence Intervals [CI]: 0.95, 0.99). Males had significantly greater odds of most metabolic disturbances with the exception of being obese (BMI: ≥30 OR: 0.45; 95% CIs: 0.24, 0.85). Older age of commencement was a significantly associated variable with High- Density Lipoprotein-cholesterol (OR: 1.03; 95% CIs: 1.01, 1.07) and fasting glucose (OR:1.04; 95% CIs: 1.02, 1.07). An increase in BMI was consistently and significantly associated with all metabolic events.. Male patients who are obese at any point during treatment and older at treatment commencement may be the most vulnerable to adverse CV and metabolic events. While future studies using a matched case-control design may be required to verify these findings, we recommend that treating clinicians consider these risks when assessing patient suitability to clozapine therapy.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Blood Glucose; Cardiovascular Diseases; Cholesterol, HDL; Clozapine; Cohort Studies; Female; Humans; Male; Metabolic Diseases; Middle Aged; Prevalence; Retrospective Studies; Risk Factors; Schizophrenia; Sex Factors; Substance-Related Disorders; Victoria

Atypical antipsychotics have significantly improved the quality of life for schizophrenic patients. Despite their beneficial effects, these antipsychotics induce weight gain, diabetes, and dyslipidemia. The aims of this study were to investigate the antioxidative activity of paraoxonase and assess lipid profile as a cardiovascular risk factor in patients with schizophrenia under long-term clozapine or risperidone treatment.. The study included 66 patients with schizophrenia under clozapine or risperidone treatment and 19 healthy control subjects. Serum paraoxonase activities against paraoxon (PON(PO)), phenylacetate (PON(PA)), dihydrocoumarin (PON(DHC)), serum Trolox equivalent antioxidant activity (TEAC), antioxidant gap (GAP), and lipid profile were determined.. PON(DHC) activity was reduced in both antipsychotic drug-treated groups (clozapine 43.46 ± 1.06 U/ml, p < 0.001; risperidone 50.57 ± 1.54 U/ml, p < 0.01; control 52.27 ± 1.34 U/ml). A similar pattern was observed for the PON(DHC)/HDL-cholesterol (HDLC) ratio. On the contrary, PON(PO) and PON(PA) were increased in the treated group, but the corresponding paraoxonase/HDLC ratios were not significantly different from controls, except for PON/HDLC in the clozapine group. TEAC and GAP were only decreased in the clozapine-treated group.. In patients with schizophrenia, clozapine or risperidone treatment had different effects on various paraoxonase activities. The results of the present study suggest that patients with schizophrenia might be at increased risk for metabolic and cardiovascular disease related to reduced PON(DHC), TEAC, and GAP.

Topics: Adult; Antipsychotic Agents; Aryldialkylphosphatase; Cardiovascular Diseases; Clozapine; Female; Humans; Lipids; Male; Middle Aged; Risk Factors; Risperidone; Schizophrenia; Weight Gain

Compare long-term costs and outcomes of lurasidone to aripiprazole among adults with schizophrenia in the US who previously failed ≥1 atypical antipsychotic (olanzapine, risperidone, quetiapine, or ziprasidone) based on an indirect comparison of outcomes data from clinical trials.. A 5-year Markov cohort model was developed to compare long-term effectiveness of lurasidone to aripiprazole, including total discontinuations, relapse rates, and hospitalization rates. Cost inputs included pharmacy, mental health, and medical costs associated with cardiometabolic risks (diabetes and cardiovascular [CV] events). Effectiveness inputs were derived from an indirect comparison of aripiprazole and lurasidone using common comparators from CATIE. Cardiometabolic risks were derived from claims data analysis for diabetes, weight change and CV events, and Framingham body mass index (BMI) risk equation. Cost inputs were derived from published sources and Red Book. Costs and outcomes were discounted at 3% and tested with sensitivity analyses.. Over 5 years, total discounted costs for lurasidone and aripiprazole patients were $86,480 and $90,500, respectively. During this period, the number of relapses per patient, hospitalizations per patient, diabetes rates, and CV events per 1000 patients, respectively, were estimated to be lower for lurasidone (0.442, 0.245, 7.29%, and 37.3) than aripiprazole (0.478, 0.369, 7.36%, and 37.8). Results were sensitive to lurasidone and aripiprazole hospitalization rates. At a willingness-to-pay threshold of $50,000 per hospitalization avoided, lurasidone had a 100% probability of being more cost-effective than aripiprazole.. The model was based on results from various comparative clinical trials. Differences in patient population and study methods may change estimates from the model. The model does not account for patient heterogeneity.. Based on this model, when switching from another atypical antipsychotic, lurasidone had fewer relapses and hospitalizations with a lower incidence of diabetes and CV events than aripiprazole. Additionally, lurasidone may be less costly than aripiprazole among adults with schizophrenia.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Cardiovascular Diseases; Clinical Trials as Topic; Clozapine; Comorbidity; Cost-Benefit Analysis; Diabetes Mellitus; Hospitalization; Humans; Isoindoles; Lurasidone Hydrochloride; Markov Chains; Models, Economic; Outcome Assessment, Health Care; Piperazines; Quinolones; Recurrence; Schizophrenia; Thiazoles; United States

Consumers with a mental illness have a significantly higher risk of physical health problems than the general population. The role of health behaviour beliefs and their part in the health of consumers with a mental illness has been poorly explored in the literature.. To understand the relationship between physical health risk factors and health behaviour beliefs in consumers with schizophrenia.. A cross-sectional survey study design using the European Health and Behaviour Survey and assessing (n=99) consumer's blood pressure, waist circumference, body mass index, smoking history, exercise levels, demographics, family history of diabetes and cardiovascular disease was used.. The study was conducted in a 76-bed psychiatric facility located within a 550-bed metropolitan generalist hospital in Sydney, Australia.. Patients attending an outpatient clozapine clinic at the mental health service were asked to participate in the survey by a nurse working in the clinic during the study period.. Of the 163 consumers asked to be involved in the study, n=99 agreed to participate. Mean waist circumference and body mass index for both males and females were significantly above normal population limits. Overall, consumer's beliefs toward their health on the European Health and Behaviour Survey were positive, having statistically significantly more positive attitudes to the statements 'avoiding too much sugar', 'drinking no alcohol' and 'yearly blood pressure checks' than a previously published non-mental health consumer sample. Whilst having positive attitude toward their healthcare, consumers' physical health risk parameters were higher than general population norms.. Consumers with a mental illness have a significantly higher risk for serious physical health problems, yet possess high positive attitudes toward their physical health care. Models of care need to explore this contradiction within mental health services to improve patient outcomes.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Attitude to Health; Cardiovascular Diseases; Clozapine; Cross-Sectional Studies; Female; Health Behavior; Humans; Hypertension; Life Style; Male; Mental Disorders; Models, Psychological; New South Wales; Obesity; Outpatients; Risk Assessment; Risk Factors; Self Care; Smoking; Surveys and Questionnaires

Cardiovascular disease (CVD) mortality in schizophrenia is more frequent than in the general population. Whether second-generation antipsychotics (SGAs) increase risk of CVD morbidity and mortality has yet to be determined.. We conducted a retrospective cohort study using an administrative database to identify patients with DSM-III- or DSM-IV-diagnosed schizophrenia, treated in Maryland, who started clozapine treatment (n = 1,084) or were never treated with clozapine (initiated on risperidone; n = 602) between 1994 and 2000. Deaths between 1994 and 2004 were identified by the Social Security Death Index, and death records were obtained.. During the 6- to 10-year follow-up period, there were 136 deaths, of which 43 were attributed to CVD. Cardiovascular disease mortality in patients aged younger than 55 years at medication start was approximately 1.1% (clozapine, 1.1%; risperidone, 1.0%) in both groups at 5 years and 2.7% (clozapine) and 2.8% (risperidone) at 10 years (chi(2)(1) = 0.12, P = .73). Patients who started treatment at ages >or= 55 years had CVD mortality of 8.5% (clozapine) and 3.6% (risperidone) at 5 years and 16.0% (clozapine) and 5.7% (risperidone) at 10 years (chi(2)(1) = 2.13, P = .144). In a Cox regression model, patients aged >or= 55 years were at greater risk of mortality than younger patients (hazard ratio = 4.6, P < .001); whites were at greater risk than nonwhites (HR = 2.1, P = .046); however, SGA treatment (HR = 1.2; 95% CI, 0.6-2.4; P = .61) and sex (HR = 0.9, P = .69) were not statistically significant predictors of CVD, nor was there a significant age x clozapine interaction (chi(2)(1) = 1.52, P = .22). Age-, race-, and gender-adjusted standardized mortality ratios were significantly elevated (clozapine, 4.70; 95% CI, 3.19-6.67; risperidone, 2.88; 95% CI, 1.38-5.30) compared to year 2000 rates for the Maryland general population but did not differ by antipsychotic group (chi(2)(1) = 1.42, P = .23).. The risk of CVD mortality in schizophrenia does not differ between clozapine and risperidone in adults despite known differences in risk profiles for weight gain and metabolic side effects. However, we cannot rule out an increased risk of CVD mortality among those starting treatment at ages 55 years or older.

Topics: Adult; Age Distribution; Age Factors; Aged; Antipsychotic Agents; Cardiovascular Diseases; Chronic Disease; Clozapine; Cohort Studies; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Maryland; Middle Aged; Outcome Assessment, Health Care; Prevalence; Psychiatric Status Rating Scales; Retrospective Studies; Risk Factors; Schizophrenia; United States

Clozapine is an atypical, neuroleptic medication that can cause myocarditis. While the "gold standard" for diagnosis of myocarditis is perceived to be via myocardial biopsy, cardiovascular magnetic resonance (CMR) has also proven its utility in this respect, primarily through its ability to detect myocardial scar by late-gadolinium enhancement (LGE). Until recently, however, clozapine-induced myocarditis specifically has not been known to be associated with LGE on CMR. In that particular case, LGE was demonstrated in a patient with clozapine-induced myocarditis. However, quite important, that patient also had specific abnormalities on the electrocardiogram (ECG) and echocardiogram that corresponded to the area of LGE demonstrated by CMR. We highlight a case series of three patients with clozapine-induced myocarditis and provide a literature review to discuss and critically appraise the true incremental diagnostic value of CMR in such patients with normal ECG and echocardiography.

Topics: Adolescent; Antipsychotic Agents; Cardiovascular Diseases; Chest Pain; Clozapine; Echocardiography; Electrocardiography; Humans; Magnetic Resonance Imaging; Male; Myocarditis; Schizophrenia

Numerous reports have linked atypical antipsychotics, especially clozapine and olanzapine, to the development of cardiovascular risk factors. In this retrospective chart review study, we investigated the blood pressure changes in Korean schizophrenic inpatients treated with clozapine or olanzapine.. We reviewed the medical record of schizophrenic patients treated with clozapine or olanzapine for 8 weeks. A total of 167 patients were included in the study; 70 patients in clozapine group and 97 patients in olanzapine group. Systolic and diastolic blood pressures prior to medication and at post-treatment (8-week) were assessed, and changes in blood pressure were analyzed. The prevalence of hypertension at the time of study period was assessed and compared between the two groups.. There was a significant difference in hypertension prevalence in comparisons between the clozapine and olanzapine group. The systolic and diastolic blood pressures in the clozapine group were significantly increased after treatment, but systolic and diastolic blood pressures in olanzapine group did not change significantly.. Our findings suggest that clozapine treatment may be associated with increased blood pressure and higher prevalence of hypertension, which may have a significant impact on medical morbidity and mortality.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Pressure; Body Weight; Cardiovascular Diseases; Clozapine; Cross-Sectional Studies; Female; Humans; Hypertension; Male; Middle Aged; Olanzapine; Republic of Korea; Retrospective Studies; Risk Factors; Schizophrenia

The goal of this 10-year naturalistic study was to examine, in clozapine-treated patients, the change in cardiovascular risk factors following clozapine initiation and the mortality estimates from cardiovascular disease.. Data were collected from medical records from January 1992 to December 2003 and included age, gender, race, diagnosis, family history of diabetes, and age at clozapine initiation for clozapine-treated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria). Clozapine dosage and laboratory results were recorded at 12-month intervals.. At the time of clozapine initiation, the mean +/-?SD age of the 96 patients studied was 36.5 +/- 7.9 years; 28% (N = 27) were women. The Kaplan-Meier estimate for 10-year mortality from cardiovascular disease was 9%. African American and Hispanic American patients exhibited elevated risk of cardiovascular disease-related mortality (odds ratio [OR] = 7.2, p = .09; OR = 11.3, p = .04, respectively) compared to white patients. Body mass index (BMI) significantly increased the odds ratio of mortality (OR = 1.2, p < .01). The Kaplan-Meier estimate for new-onset diabetes mellitus was approximately 43%, and Hispanic American (OR = 4.3, p = .027) and African American (OR = 11.5, p = .0001) patients showed elevated risks of developing diabetes mellitus compared to white patients. Additionally, BMI (OR = 1.11, p = .0006), total cholesterol level (OR = 1.006, p = .04), and serum triglyceride level (OR = 1.002, p = .04) modestly increased the odds ratio for the development of diabetes mellitus.. These results support the hypothesis that clozapine-treated patients appear to be at risk for death from cardiovascular disease secondary to clozapine-associated medical disorders such as obesity, diabetes, hypertension, and hyperlipidemia.

Topics: Adult; Antipsychotic Agents; Black or African American; Cardiovascular Diseases; Cause of Death; Clozapine; Comorbidity; Diabetes Mellitus; Female; Hispanic or Latino; Humans; Hyperlipidemias; Longitudinal Studies; Male; Metabolic Syndrome; Psychotic Disorders; Risk Factors; Risperidone; Schizophrenia; Survival Analysis

Topics: Animals; Benzamides; Cardiovascular Diseases; Clinical Trials as Topic; Clozapine; Depression; Drug Approval; Drug Design; Drug Evaluation, Preclinical; Drug Industry; Gefitinib; Humans; Imatinib Mesylate; Neoplasms; Piperazines; Pyrimidines; Quinazolines; Sensitivity and Specificity; Substrate Specificity; Therapeutics; United States; United States Food and Drug Administration

Clozapine (Clozaril), a tricyclic dibenzodiazepine, causes fewer extrapyramidal side effects than do other antipsychotic drugs. Because it can induce agranulocytosis, however, clozapine is indicated only for schizophrenia that is not responsive to other therapies. To describe the drug's effects on mortality, we compared rates of various causes of death in 67,072 current and former clozapine users. We linked data from a national registry of clozapine recipients to the National Death Index and Social Security Administration Death Master Files, obtained death certificates, and calculated mortality rates for underlying causes of death using standardization to adjust for age, sex, and race. During 1991-1993, there were 396 deaths in 85,399 person-years for patients ages 10-54 years. Mortality was lower during current clozapine use than during periods of non-use. Mortality from suicide was decreased in current clozapine users by comparison with past users [rate ratio (RR) = 0.17; 95% confidence interval (CI) = 0.10-0.30]. During clozapine use, there were elevations in mortality rates for less common causes of death, including pulmonary embolism (RR for current exposure compared with past clozapine use = 5.2) and respiratory disorders (RR = 2.9). Clozapine appears to reduce mortality in severe schizophrenics, mostly by decreasing suicide rates.

Topics: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Antipsychotic Agents; Cardiovascular Diseases; Cause of Death; Child; Clozapine; Cohort Studies; Confidence Intervals; Cross-Sectional Studies; Databases, Factual; Female; Humans; Male; Middle Aged; Odds Ratio; Product Surveillance, Postmarketing; Registries; Respiratory Tract Diseases; Risk Assessment; Schizophrenia; Suicide; Suicide Prevention; Time Factors; United States

Topics: Adult; Age Factors; Aged; Bradycardia; Cardiovascular Diseases; Clozapine; Drug Administration Schedule; Humans; Psychotic Disorders; Respiration Disorders