olanzapine and Death--Sudden--Cardiac

The QTc prolongation by antipsychotic drugs is of major concern, especially in light of the data indicating an increased risk of sudden death in psychiatric patients taking these drugs. Sudden death in psychiatric patients could be partially attributed to drug-induced torsades de pointes and for this reason careful evaluation of QTc prolonging properties of antipsychotic drugs is needed. Antipsychotic drugs prolong QT interval usually by blocking the potassium IKr current. Improved understanding of ion channel structure and kinetics and its role in repolarization has tremendous impact on understanding of the mechanisms of drug-induced QT prolongation and torsades de pointes. Proarrhythmia caused by a QT-prolonging drug occurs infrequently, and usually multiple factors need to operate to precipitate such an event including a combination of two or more drugs affecting the same pathway, hypokalemia, and possibly genetic predisposition. Currently prescribed antipsychotics might cause QT prolongation ranging from 4-6 ms for haloperidol and olanzapine to 35 ms for thioridazine. The response of a patient to a drug is very individual and therefore an individualized system of drug administration and monitoring needs to be developed which takes into account baseline QTc duration and its changes after a drug was introduced. A systematic approach while stratifying psychiatric patients as those with short QTc (QTc < or = 0.41 sec), borderline QTc (QTC = 0.42-0.44 sec), and prolonged QTc (0.45 sec) is being proposed to improve the safety of administering antipsychotic drugs and to decrease the risk of drug-related sudden death in psychiatric patients.

Topics: Age Factors; Algorithms; Antipsychotic Agents; Benzodiazepines; Death, Sudden, Cardiac; Dopamine Antagonists; Drug Labeling; Haloperidol; Humans; Long QT Syndrome; Olanzapine; Pirenzepine; Sex Factors; Thioridazine; Torsades de Pointes

Most antipsychotic agents can cause QT prolongation, which causes torsades de pointes. The QT interval in healthy subjects is longer during nighttime than during daytime. The QT interval of patients treated with antipsychotics may be prolonged during nighttime, and the effects of antipsychotics on the QT interval may differ between antipsychotics. This study investigated the circadian dynamics of the QT interval in patients treated with antipsychotics and healthy controls, using a 24-hour Holter electrocardiogram in a clinical setting. Sixty-six patients with a diagnosis of schizophrenia that were treated with risperidone or olanzapine and 40 healthy volunteers were enrolled. The QT intervals were corrected using the Fridericia formula (QTcF = QT / RR). Mean ± SD nighttime QTcFs were 411.6 ± 29.0, 395.9 ± 21.2, and 387.8 ± 19.0 milliseconds (ms) in the risperidone, olanzapine, and control groups, respectively. The mean daytime QTcFs were 397.7 ± 23.4, 392.4 ± 18.9, and 382.6 ± 17.3 ms, respectively. The mean nighttime QTcF of the risperidone group was significantly longer than that of the olanzapine and control groups, although there was no significant difference in the mean daytime QTcF between the risperidone and olanzapine groups. The current study used 24-hour Holter electrocardiograms to reveal significantly longer QT intervals in the risperidone group especially during nighttime. In clinical practices, evaluations of the QT interval have been conducted over short periods in the daytime, but it is believed that such methods may not be able to fully elucidate the effects of antipsychotics on the QT interval.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Circadian Rhythm; Death, Sudden, Cardiac; Electrocardiography, Ambulatory; Female; Humans; Long QT Syndrome; Male; Middle Aged; Olanzapine; Risperidone; Schizophrenia; Schizophrenic Psychology; Signal Processing, Computer-Assisted; Torsades de Pointes

The authors compared 1-year mortality rates associated with ziprasidone and olanzapine in real-world use.. The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) was an open-label, randomized, postmarketing large simple trial that enrolled patients with schizophrenia (N=18,154) in naturalistic practice in 18 countries. The primary outcome measure was nonsuicide mortality in the year after initiation of assigned treatment. Patients were randomly assigned to receive treatment with either ziprasidone or olanzapine and followed for 1 year by unblinded investigators providing usual care. A physician-administered questionnaire was used to collect baseline demographic information, medical and psychiatric history, and concomitant medication use. Follow-up information on hospitalizations and emergency department visits, patients' vital status, and current antipsychotic drug status was collected and reported by treating psychiatrists. Post hoc analyses of sudden death, a secondary endpoint, were also conducted.. The incidence of nonsuicide mortality within 1 year of initiating pharmacotherapy was 0.91 for ziprasidone (N=9,077) and 0.90 for olanzapine (N=9,077). The relative risk was 1.02 (95% CI=0.76-1.39). This finding was confirmed in numerous secondary and sensitivity analyses.. Despite the known risk of QTc prolongation with ziprasidone treatment, the findings of this study failed to show that ziprasidone is associated with an elevated risk of nonsuicidal mortality relative to olanzapine in real-world use; the study excludes a relative risk larger than 1.39 with a high probability. However, the study was neither powered nor designed to examine the risk of rare events like torsade de pointes.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Cause of Death; Cross-Sectional Studies; Death, Sudden, Cardiac; Diabetic Ketoacidosis; Female; Hospitalization; Humans; Incidence; Kaplan-Meier Estimate; Long QT Syndrome; Male; Middle Aged; Myocardial Infarction; Olanzapine; Piperazines; Product Surveillance, Postmarketing; Prospective Studies; Risk; Schizophrenia; Suicide; Thiazoles

The Ziprasidone Observational study of car DIAC Outcomes (ZODIAC), a large simple trial comparing ziprasidone versus olanzapine in real-world use, showed no difference in risk of sudden death. Upon the request of the US Food and Drug Administration, 205 fatal events were readjudicated applying ICD-10 coding rules for sudden death.. A readjudication committee coded three domains (witness to death, time of symptom onset to death, and most likely cause of death) for use within algorithms consistent with ICD-10 rules. Relative risks (RR) and corresponding 95%CI were calculated for persons randomized to ziprasidone versus olanzapine, comparing 1-year incidence of sudden death, using multiple definitions.. Data on symptom onset to death and diagnosis of specific cardiac arrhythmias required by the ICD-10 rules were often lacking. Sensitivity analyses were conducted to explore the impact of cases suggestive of cardiac origin but missing data required by ICD-10 sudden death codes. Overall, the readjudicated data matched the study's initial findings, with no significant difference in 1-year mortality between ziprasidone and olanzapine for sudden death not otherwise specified and sudden cardiac death (R96.0 or R96.1 or I46.1; RR = 1.11, 95%CI 0.45- 2.77).. After outcome readjudication, ZODIAC found no difference in the risk of sudden death among those randomized to ziprasidone versus olanzapine. However, unlike hospital-based studies, fatal events in general population studies often occur outside hospital and often lack the clinical detail needed for the exact determination of symptom onset and event. Epidemiological evaluations of sudden death need to consider the limitations of the available data.

Topics: Antipsychotic Agents; Benzodiazepines; Cause of Death; Clinical Coding; Death, Sudden; Death, Sudden, Cardiac; Endpoint Determination; Follow-Up Studies; Heart; Humans; Incidence; International Classification of Diseases; Olanzapine; Piperazines; Product Surveillance, Postmarketing; Research Design; Risk; Schizophrenia; Sensitivity and Specificity; Surveys and Questionnaires; Thiazoles; Time Factors; United States; United States Food and Drug Administration

Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden.. As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs).. Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II (http://www.azcert.org , as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011).. Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82-84.60), cyamemazine (11; 15.48, 6.87-34.91), and olanzapine (189; 7.74, 6.45-9.30).. This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk.

Topics: Adverse Drug Reaction Reporting Systems; Amisulpride; Antipsychotic Agents; Arrhythmias, Cardiac; Benzodiazepines; Cardiotoxins; Cardiovascular Agents; Databases, Pharmaceutical; Death, Sudden, Cardiac; Female; Humans; Male; Olanzapine; Phenothiazines; Risk; Sulpiride; Tachycardia; Torsades de Pointes; United States; United States Food and Drug Administration; Ventricular Fibrillation

A 36 year-old man suffering from schizophrenia was found dead in his apartment. Forensic autopsy was performed due to sudden unexpected death but did not yield the cause of death. Histological examination of the heart showed eosinophilic myocarditis (EM) while forensic chemistry showed a raised level of aripripazol. We discuss the risk of sudden cardiac death in patients receiving antipsychotic drugs and the possible connection between raised drug levels and EM, and we emphasise the importance of autopsy and hope for better means in the future of finding patients at risk.

Topics: Adult; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Aripiprazole; Autopsy; Benzodiazepines; Death, Sudden, Cardiac; Drug Therapy, Combination; Eosinophilia; Forensic Pathology; Forensic Toxicology; Humans; Male; Mianserin; Mirtazapine; Myocarditis; Myocardium; Olanzapine; Piperazines; Quinolones; Risk Factors

Topics: Antipsychotic Agents; Benzodiazepines; Death, Sudden, Cardiac; Humans; Olanzapine; Urinary Incontinence