Life-Threatening Effects of Antipsychotic Drugs

Peter Manu, Robert J. Flanagan, Kathlyn J. Ronaldson

• Publisher: Academic Press
• Year: 2016
• Print ISBN:
  9780128033760
• eBook ISBN:
  9780128033906
• Topic: Medicine
• Subtopic: Psychiatry & Mental Health

Life-Threatening Effects of Antipsychotic Drugs describes in detail more than 20 life-threatening effects associated with antipsychotics, presents the best available data on their incidence and case fatality, and gives comprehensive advice on diagnosis, management and preventive strategies. In addition, the book discusses the benefit of antipsychotic medication in a range of therapeutic indications, and demonstrates the gain in life-expectancy associated with clozapine use in severe mental illness despite its serious, potentially life-threatening adverse effects. - Covers cardiovascular, neurological, muscular, hematological, gastrointestinal, autonomic and metabolic effects - Gives advice on risk factors, confounding diagnoses and measures to minimise seriousness - Discusses clozapine rechallenge after each of its serious adverse reactions - Makes suggestions for optimum management of somatic disease in those with severe mental illness, to improve life-expectancy - Includes data on post-mortem considerations

Part I

Cardiovascular Adverse Effects of Antipsychotic Drugs

Outline

Chapter 1 Sudden Cardiac Death and Ventricular Arrhythmias

Chapter 2 Myocarditis and Cardiomyopathy

Chapter 3 Pulmonary Embolism

Chapter 4 Orthostatic Hypotension

Chapter 1

Sudden Cardiac Death and Ventricular Arrhythmias

Peter Manu^1,2, Anca Dan³ and Gheorghe-Andrei Dan^3,4, ¹Hofstra Northwell School of Medicine, Hempstead, NY, United States, ²South Oaks Hospital, Amityville, NY, United States, ³Colentina Hospital, Bucharest, Romania, ⁴Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Abstract

Antipsychotic-related sudden death became a prominent concern at the turn of the 21st century, when these drugs were shown to bind to the potassium rectifier channel of the myocyte, block its rapidly activating component, delay repolarization, and create conditions for the emergence of torsade de pointes (TdP), a polymorphic arrhythmia that can lead to ventricular fibrillation. At the time, thioridazine was considered the drug associated with the highest risk of TdP and sudden death, a complication documented also during treatment with haloperidol, droperidol, sertindole, and pimozide. The relationship between delayed repolarization, manifest as prolongation of the rate-corrected Q-T interval (QTc) on electrocardiograms was considered imprecise, as the association had not been demonstrated for a number of second-generation antipsychotics, that is, risperidone, olanzapine, quetiapine, and ziprasidone. A QTc duration exceeding 500 ms or an increase of 60 ms from baseline were suggested as markers for a significant risk of TdP. Other risk factors mentioned for the sequence delayed repolarization–TdP–sudden death included electrolyte imbalance, old age, bradycardia, heart failure, hepatic and renal impairment, pharmacokinetic interactions, and slow metabolizer status.

Keywords

Sudden cardiac death; torsade de pointes; ventricular fibrillation; antipsychotic drug

1.1 Epidemiology

Large epidemiological studies of sudden cardiac death (SCD) in persons treated with antipsychotic drugs in the United States have been first performed at Vanderbilt University School of Medicine in Nashville, TN (Ray et al., 2001, 2009).

An early study evaluated retrospectively the relationship between treatment with first-generation antipsychotics and SCD in a cohort of 481,744 of Tennessee Medicaid enrollees aged 15–84 with 1,282,996 person-years of follow-up from Jan. 1, 1988 through Dec. 31, 1993. There were 1487 SCDs, defined as a pulseless condition, fatal within 48 hours of onset, occurring in the absence of other causes of death and consistent with a ventricular tachyarrhythmia. The sample included 26,749 person-years with current antipsychotic use at a dose greater than 100 mg thioridazine equivalent, 31,881 person-years with current use of a lower dose, and 37,881 person-years of antipsychotic use in the past year. Multivariate rate-ratios of SCD were calculated from Poisson regression models that included age, sex, race, calendar year, cardiovascular disease, and medical or surgical hospital admission for noncardiac illness. The magnitude of confounding by smoking was assessed in a secondary analysis of a subsample given a diagnosis of bronchitis or emphysema.

Overall, the cohort had 11.6 SCDs/10,000 person-years of follow-up. Compared with nonusers, current antipsychotic use at doses greater than 100 mg thioridazine equivalent had a rate-ratio of 2.39 (95% confidence interval 1.77–3.22). The corresponding rate-ratios were 1.30 (95% confidence interval 0.98–1.72) for patients taking lower daily doses and 1.20 (95% confidence interval 0.91–1.58) for past treatment with first-generation antipsychotics. Females treated with antipsychotics had a higher rate-ratio (2.97, 95% confidence interval 1.96–4.50) than males (1.91, 95% confidence interval 1.24–2.95). The rate-ratios differed considerably from drug to drug, with the worst being observed for thiothixene and the lowest for haloperidol (Table 1.1). The presence of cardiovascular disease did not change significantly the magnitude of the difference in the risk of SCD between current users and nonusers of antipsychotic drugs. The rate-ratio of SCD between users and nonusers of moderate doses of antipsychotics with comparable cardiovascular disease were 3.18 (95% confidence interval 1.95–5.16) for a mild condition, 2.12 (95% confidence interval 1.08–4.14) for moderate severity, and 3.53 (95% confidence interval 1.66–7.51) for a disorder with high severity.

Table 1.1

Rate-Ratios of Sudden Cardiac Death in Persons Treated With Conventional Antipsychotics

Drug	Rate-Ratio	95% Confidence Interval
Thiothixene	4.23	2.00–8.91
Chlorpromazine	3.64	1.36–9.74
Thioridazine	3.19	1.32–7.68
Haloperidol	1.90	1.10–3.30

Source: Data from Ray, W.A., Meredith, S., Thapa, P.B., Meador, K.G., Hall, K., Murray K.T., 2001. Antipsychotics and the risk of sudden cardiac death. Arch. Gen. Psychiatry 58 (12), 1161–1167.

For the assessment of the risk of sudden death in individuals treated with atypical (second-generation) antipsychotics, the Vanderbilt group evaluated retrospectively 46,089 users of single atypical drugs, 44,218 users of first-generation drugs, and 186,600 matched nonusers in a cohort of Medicaid enrollees in Tennessee from Jan. 1, 1990 through Dec. 31, 2005 (Ray et al., 2009). The study end-point was a sudden pulseless condition interpreted as ventricular tachyarrhythmia, as indicated by death certificates linked to medical records retrievable from an electronic database. Hospital deaths, including those occurring 30 days after discharge were not included, because data regarding drug treatment during the hospital stay could not be ascertained. Also excluded were patients with “a cardiac cause that was not consistent with a ventricular tachyarrhythmia (e.g., heart failure)” (p. 227). A cardiovascular risk score was calculated for each subject from baseline variables, which included recorded diagnoses, prescribed medications, compliance with treatment, and utilization of health care resources. Users and nonusers of antipsychotic drugs were matched at a 1:2 ratio, according to a propensity score designed to adjust for age, gender, and severity of psychiatric illness.

The final sample consisted of 67,824 users and 116,069 nonusers age 30–74 with 1,042,159 person-years of follow-up during which there were 1870 sudden deaths or 1.79 per 1000 person-years. The incidence-rate ratios of SCD were 1.99 for users of typical antipsychotics and 2.26 for individuals treated with atypical antipsychotics. Compared with nonusers, current users of haloperidol had a rate-ratio of SCD of 1.61 (95% confidence interval 1.16–2.24), which was substantially lower than the rate-ratio recorded for thioridazine (3.19, 95% confidence interval 2.41–4.21). The rate-ratios were significantly greater in current users of the four atypical antipsychotics studied as compared with nonusers (Table 1.2). Former users did not show an increase in the rate of SCD. The rate-ratios increased linearly according to the dose for both drug classes, but the trend reached statistical significance only for thioridazine and risperidone. Current use of typical and atypical antipsychotics showed a similar increase in rate-ratios in the analyses of cohorts matched according to the propensity score or year of starting treatment with these drugs.

Table 1.2

Rate-Ratios of Sudden Cardiac Death in Persons Treated With Atypical Antipsychotics

Drug	Rate-Ratio	95% Confidence Interval
Clozapine	3.67	1.94–6.94
Risperidone	2.91	2.26–3.76
Olanzapine	2.04	1.52–2.74
Quetiapine	1.88	1.30–2.71

Source: Data from Ray, W.A., Chung, C.P., Murray, K.T., Hall, K., Stein, C.M., 2009. Atypical antipsychotic drugs and the risk of sudden cardiac death. N. Engl. J. Med. 360 (3), 225–235.

A similar project was completed at the Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine in Philadelphia (Hennessy et al., 2002; Leonard et al., 2013). The first report contained data produced by a cohort of outpatients enrolled in the Medicaid program in three states (Hennessy et al., 2002). The cohort included patients with schizophrenia treated with haloperidol (n=41,295), thioridazine (n=23,950), risperidone (n=22,057), and clozapine (n=8330). The control subjects were individuals prescribed medications for glaucoma (n=21,545) and psoriasis (n=7541). The study outcomes were culled from the administrative data covering the period 1993–96 and included the diagnoses of cardiac arrest, sudden death of unknown cause, unexplained death occurring within 24 hours from the onset of symptoms, unattended death, ventricular fibrillation, and ventricular flutter. A large number drugs (e.g., lipid lowering medications, antiarrhyth...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Foreword
• Preface
• Acknowledgments
• Symbols and Conventions
• Part I: Cardiovascular Adverse Effects of Antipsychotic Drugs
• Part II: Hematological Complications of Treatment With Antipsychotic Drugs
• Part III: Antipsychotic-Related Pathology of the Digestive System
• Part IV: Major Neurological and Neuromuscular Adverse Effects of Antipsychotic Drugs
• Part V: Metabolic Complications of Antipsychotic Drug Treatment
• Part VI: Other Life-Threatening Effects of Antipsychotic Drugs
• Part VII: Clinical and Forensic Challenges in the Use of Antipsychotic Drugs
• Guide to the Interpretation of the Results of Some Chemical Pathology Tests
• Index