clozapine and Arrhythmias--Cardiac

Clozapine is an atypical neuroleptic used to manage treatment-resistant schizophrenia which is known to inhibit cardiac hERG/K

Topics: Antipsychotic Agents; Arrhythmias, Cardiac; Clozapine; DNA-Binding Proteins; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Ion Channels; Torsades de Pointes

Signalling via Gq-coupled receptors is of profound importance in many cardiac diseases such as hypertrophy and arrhythmia. Nevertheless, owing to their widespread expression and the inability to selectively stimulate such receptors in vivo, their relevance for cardiac function is not well understood. We here use DREADD technology to understand the role of Gq-coupled signalling in vivo in cardiac function.. We generated a novel transgenic mouse line that expresses a Gq-coupled DREADD (Dq) in striated muscle under the control of the muscle creatine kinase promotor. In vivo injection of the DREADD agonist clozapine-N-oxide (CNO) resulted in a dose-dependent, rapid mortality of the animals. In vivo electrocardiogram data revealed severe cardiac arrhythmias including lack of P waves, atrioventricular block, and ventricular tachycardia. Following Dq activation, electrophysiological malfunction of the heart could be recapitulated in the isolated heart ex vivo. Individual ventricular and atrial myocytes displayed a positive inotropic response and arrhythmogenic events in the absence of altered action potentials. Ventricular tissue sections revealed a strong co-localization of Dq with the principal cardiac connexin CX43. Western blot analysis with phosphor-specific antibodies revealed strong phosphorylation of a PKC-dependent CX43 phosphorylation site following CNO application in vivo.. Activation of Gq-coupled signalling has a major impact on impulse generation, impulse propagation, and coordinated impulse delivery in the heart. Thus, Gq-coupled signalling does not only modulate the myocytes' Ca2+ handling but also directly alters the heart's electrophysiological properties such as intercellular communication. This study greatly advances our understanding of the plethora of modulatory influences of Gq signalling on the heart in vivo.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium Signaling; Clozapine; Connexin 43; Creatine Kinase, MM Form; GTP-Binding Protein alpha Subunits, Gq-G11; Heart Rate; Isolated Heart Preparation; Male; Mice, Inbred C57BL; Mice, Transgenic; Myocardium; Phosphorylation; Promoter Regions, Genetic; Protein Kinase C; Receptors, G-Protein-Coupled

Administration of second-generation antipsychotic drugs (SGAs) often leads to weight gain and consequent cardio-metabolic side effects. We observed that clozapine but not six other antipsychotic drugs reprogrammed the gene expression pattern of differentiating human adipocytes ex vivo, leading to an elevated expression of the browning marker gene UCP1, more and smaller lipid droplets and more mitochondrial DNA than in the untreated white adipocytes. Laser scanning cytometry showed that up to 40% of the differentiating single primary and Simpson-Golabi-Behmel syndrome (SGBS) adipocytes had the characteristic morphological features of browning cells. Furthermore, clozapine significantly upregulated ELOVL3, CIDEA, CYC1, PGC1A and TBX1 genes but not ZIC1 suggesting induction of the beige-like and not the classical brown phenotype. When we tested whether browning induced by clozapine can be explained by its known pharmacological effect of antagonizing serotonin (5HT) receptors, it was found that browning cells expressed 5HT receptors 2A, 1D, 7 and the upregulation of browning markers was diminished in the presence of exogenous 5HT. Undifferentiated progenitors or completely differentiated beige or white adipocytes did not respond to clozapine administration. The clozapine-induced beige cells displayed increased basal and oligomycin-inhibited (proton leak) oxygen consumption, but these cells showed a lower response to cAMP stimulus as compared with control beige adipocytes indicating that they are less capable to respond to natural thermogenic anti-obesity cues. Our data altogether suggest that novel pharmacological stimulation of these masked beige adipocytes can be a future therapeutic target for the treatment of SGA-induced weight gain.

Topics: Adipocytes, Beige; Adipocytes, Brown; Adipocytes, White; Adult; Aged; Antipsychotic Agents; Arrhythmias, Cardiac; Cell Differentiation; Cells, Cultured; Clozapine; Cyclic AMP; DNA, Mitochondrial; Female; Gene Expression; Genetic Diseases, X-Linked; Gigantism; Heart Defects, Congenital; Humans; Intellectual Disability; Lipid Droplets; Male; Middle Aged; Oxygen Consumption; Phenotype; Receptors, Serotonin; Thermogenesis; Uncoupling Protein 1; Up-Regulation; Weight Gain; Young Adult

Drug-induced long QT syndrome (LQTS) can cause critical cardiovascular side effects and has accounted for the withdrawal of several drugs from the market. Blockade of the potassium ion channel encoded by the human ether-a-go-go-related gene (hERG) has been identified as a major contributor to drug-induced LQTS. Experimental measurement of hERG activity for each compound in development is costly and time-consuming, thus it is beneficial to develop a predictive hERG model. Here, we present a hERG classification model formulated using support vector machines (SVM) as machine learning method and using atom types as molecular descriptors. The training set used in this study was composed of 977 corporate compounds with hERG activities measured under the same conditions. The impact of soft margin and kernel function on the performance of the SVM models was examined. The robustness of SVM was evaluated by comparing the predictive power of the models built with 90%, 50%, and 10% of the training set data. The final SVM model was able to correctly classify 94% of an external testing set containing 66 drug molecules. The most important atom types with respect to discriminative power were extracted and analyzed.

Topics: Animals; Arrhythmias, Cardiac; CHO Cells; Computer Simulation; Cricetinae; Cricetulus; Discriminant Analysis; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Models, Chemical; Patch-Clamp Techniques; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Predictive Value of Tests; ROC Curve

Topics: Administration, Oral; Aged; Antipsychotic Agents; Aripiprazole; Arrhythmias, Cardiac; Benzodiazepines; Clozapine; Databases, Factual; Dementia; Dibenzothiazepines; Drug Utilization Review; Health Services for the Aged; Humans; Olanzapine; Pharmaceutical Services; Piperazines; Quetiapine Fumarate; Quinolones; Risk Assessment; Risperidone; Stroke; Thiazoles; Treatment Outcome

To examine the rates of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia and in non-schizophrenic controls.. Cohort study of outpatients using administrative data.. 3 US Medicaid programmes.. Patients with schizophrenia treated with clozapine, haloperidol, risperidone, or thioridazine; a control group of patients with glaucoma; and a control group of patients with psoriasis.. Diagnosis of cardiac arrest or ventricular arrhythmia.. Patients with treated schizophrenia had higher rates of cardiac arrest and ventricular arrhythmia than controls, with rate ratios ranging from 1.7 to 3.2. Overall, thioridazine was not associated with an increased risk compared with haloperidol (rate ratio 0.9, 95% confidence interval 0.7 to 1.2). However, thioridazine showed an increased risk of events at doses > or =600 mg (2.6, 1.0 to 6.6; P=0.049) and a linear dose-response relation (P=0.038).. The increased risk of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia could be due to the disease or its treatment. Overall, the risk with thioridazine was no worse than that with haloperidol. Thioridazine may, however, have a higher risk at high doses, although this finding could be due to chance. To reduce cardiac risk, thioridazine should be prescribed at the lowest dose needed to obtain an optimal therapeutic effect.

Topics: Adult; Aged; Antipsychotic Agents; Arrhythmias, Cardiac; Clozapine; Cohort Studies; Confidence Intervals; Death, Sudden, Cardiac; Female; Haloperidol; Heart Arrest; Humans; Male; Medicaid; Middle Aged; Risperidone; Schizophrenia; Thioridazine; United States

Antipsychotic medication causes a wide range of predictable adverse effects, and has long been associated with sudden unexplained and unexpected death in psychiatric patients, despite controversies surrounding the issue. In light of the evidence that sudden cardiovascular-related death is associated with neuroleptic medication, we are especially interested in examining whether measurements of the power spectral analysis (PSA) of heart rate variability (HRV) are differentially affected by various antipsychotic medications. We will also examine the cases in which PAS provides information regarding the relative safety of the various groups of drugs under investigation, in terms of their influence on the sympathetic-parasympathetic balance.. The primary aim of this study is to utilize spectral analysis of heart rate variability as a tool to examine the differential arythmogenic effects of antipsychotic medications. The secondary aim was to examine the QT interval in schizophrenic patients receiving this treatment.. Standardized heart rate analysis was carried out in twenty-one schizophrenic patients receiving monotherapy with the following medications: treatment with 300-700 mg/day of clozapine, eighteen schizophrenic patients treated with 5-10 mg/day haloperidol, seventeen schizophrenic patients treated with 5-20 mg/day Olanzapine, and 53 healthy subjects.. Our results show that schizophrenic patients treated with clozapine had significantly higher HR, lower HRV, lower high frequency (HF) and higher low frequency (LF) components compared to the patients treated with haloperidol, olanzapine, and the matched control subjects. Prolonged QTc intervals were more common in patients receiving treatment than in the control group, although the PR and QRS intervals did not differ significantly.. The overall results showed that, patients treated with neuroleptic medication, especially clozapine, presented autonomic dysregulation and cardiac repolarization changes. Care should be taken in prescribing clozapine to patients prone to cardiovascular side effects.

Topics: Adult; Antipsychotic Agents; Arrhythmias, Cardiac; Benzodiazepines; Clozapine; Female; Haloperidol; Heart Rate; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Schizophrenia

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

Topics: Adult; Antipsychotic Agents; Arrhythmias, Cardiac; Clozapine; Humans; Male; Schizophrenia

Topics: Antipsychotic Agents; Arrhythmias, Cardiac; Clozapine; Electrocardiography; Humans; Male; Middle Aged; Myocardial Infarction; Syncope

Twenty patients suffering from schizophrenia and 36 patients suffering from endogenous depression underwent a standardized heart rate analysis before drug therapy. The patient's parameters of heart rate variability (HRV), which are controlled by the parasympathetic nervous system and which are independent of heart rate, did not significantly differ from the HRV parameters of normal control subjects. Ten of the patients with schizophrenia were treated with 200-400 mg of clozapine/day as monotherapy, while the other ten patients received a combination of different psychotropic drugs. The depressed patients were either treated with 150 mg of amitriptyline/d (n = 24) or 20 mg of paroxetine/d (n = 12) as monotherapy, respectively. After treatment with an average of 300 mg of clozapine/d for 4 weeks or with 150 mg of amitriptyline/day for 2 weeks, all of the patients HRV parameters had significantly decreased (P < 0.001). At this time, about 90% of these patients fulfilled the criteria of cardiovascular autonomic neuropathy. However, treatment with 20 mg of paroxetine/day for 2 weeks had no impact on any of the heart rate parameters. Under amitriptyline treatment, HRV parameters were found to correlate significantly with the plasma levels of amitriptyline/nortriptyline in a group of 104 depressed patients. Thus, determination of decreased HRV parameters is suggested to be a useful tool for the detection of overdosage with amitriptyline. It has not yet been elucidated whether or not the observed HRV decrease, which is probably at least in part due to the anticholinergic side effects of clozapine and amitriptyline, has any impact on patient health.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Amitriptyline; Arrhythmias, Cardiac; Autonomic Nervous System; Clozapine; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Overdose; Drug Therapy, Combination; Electrocardiography; Exercise Test; Female; Heart Rate; Humans; Male; Middle Aged; Psychotropic Drugs; Schizophrenia

Since intoxication with tricyclic antidepressants is common, a supplementary screening method for differentiation between therapeutic and supratherapeutic ranges would be a valuable diagnostic tool, particularly in delirious and unconscious patients.. 108 patients treated with amitriptyline, 8 patients treated with doxepin, 10 patients treated with clozapine, and 72 normal control subjects matched for age and sex were tested for heart rate variability while resting.. Considering time and frequency derived measures, which are rather independent of heart rate, the patients showed significantly decreased heart rate variability parameters (p < 0.0001), as compared with the normal subjects. Of the patients presenting delirious symptoms 6 showed coefficients of variation more than 4 standard deviations below the mean control value.. As heart rate variability can be easily calculated, this measurement is suggested as a useful tool to quickly exclude or support the diagnosis of chronic intoxication with tricyclic antidepressants or clozapine.

Topics: Adult; Aged; Amitriptyline; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Arrhythmias, Cardiac; Case-Control Studies; Clozapine; Doxepin; Drug Monitoring; Electrocardiography; Female; Heart Rate; Humans; Male; Middle Aged; Substance Abuse Detection

Topics: Adult; Arrhythmias, Cardiac; Clozapine; Dibenzazepines; Endocarditis; Humans; Male; Pericarditis; Schizophrenia