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OBJECTIVE To identify the outcome of potentially serious adverse effects of clozapine, particularly those frequently cited as reasons for clozapine discontinuation, and to characterize management strategies for adverse effects that do not warrant discontinuation. DATA SOURCES A structured search was performed of PubMed and EMBASE from database inception until September 10, 2012, without any language restrictions, using clozapine as the search term. Reference lists of retrieved articles were cross-checked for additional relevant studies. STUDY SELECTION Included in this review were studies that reported on the frequency of the specified clozapine-related adverse effects and that either reported on the grounds for or against clozapine discontinuation or reported on management techniques to maintain patients on clozapine or enable successful clozapine rechallenge. The following side effects were considered important for this review as potential grounds for clozapine discontinuation: neutropenia or agranulocytosis, leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, leukocytosis, QTc prolongation, electrocardiogram changes, atrial flutter, tachycardia, myocarditis, cardiomyopathy, fever, syncope, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma, neuroleptic malignant syndrome, ileus, liver enzyme elevation, or seizure. DATA EXTRACTION Study results that supported continuation or discontinuation of clozapine or that provided information on management techniques were abstracted. RESULTS Of a total of 13,385 search results, data from 81 studies were included in this review. Results suggest that prompt discontinuation of clozapine without rechallenge is indicated for agranulocytosis, myocarditis, cardiomyopathy, and a QTc interval > 500 milliseconds that is confirmed and derived using the appropriate correction method. Clozapine discontinuation with potential rechallenge (provided there is appropriate surveillance and management or prophylactic therapy) is indicated for ileus or subileus, neuroleptic malignant syndrome, venous thromboembolism, and diabetic ketoacidosis or hyperosmolar coma. Neutropenia, leukocytosis, seizures, orthostatic hypotension, severe constipation, and weight gain and metabolic abnormalities, including metabolic syndrome and its components, as well as moderately prolonged myocardial repolarization, need to be managed but do not generally warrant clozapine discontinuation. Eosinophilia, leukocytosis, drug-induced fever, and tachycardia (provided that myocarditis and neuroleptic malignant syndrome are ruled out) can be managed and should rarely lead to clozapine discontinuation. CONCLUSIONS A number of side effects commonly cited as medical reasons for clozapine discontinuation do not necessarily warrant such action. Management techniques are available that allow continuation or rechallenge in relation to a number of clozapine-related side effects.

In January 2009, the New England Journal of Medicine published data from a retrospective cohort study, demonstrating an increased risk of sudden cardiac death in patients 30–74 years of age treated with antipsychotic drugs (1). The study compared the incidence of sudden cardiac death in a large cohort of users of typical antipsychotics, users of atypical antipsychotics and propensity score-matched nonusers of antipsychotics, all Medicaid enrollees in Tennessee. According to death certificates, during the 1,042,159 person-years of cohort follow up, there were 1,870 (1.79 per thousand person-years) sudden deaths that occurred in the absence of a known, non-cardiac condition as the proximate cause of death. After adjustments for demographic variables and the presence of comorbid somatic conditions, the incidence-rate ratios of sudden cardiac death were 1.99 for users of typical antipsychotics and 2.26 for individuals treated with atypical antipsychotics (1). The study confirmed and expanded previous work by the same group using the death certificates matched to the Tennessee Medicaid database, in which current users of moderate dose antipsychotics (>100 mg thioridazine equivalents) were shown to have a sudden cardiac death ratio of 2.39 compared to nonusers. Among cohort members with detectable cardiovascular disease the rate ratio was 3.53 (2). In a methodologically similar assessment of three state-wide Medicaid programs, patients treated with antipsychotics had a 1.7 to 3.2 incidence-rate ratios of cardiac arrest and ventricular arrhythmias compared with nonusers, depending on the antipsychotic used (3). The authors of these epidemiological studies suggested that the excess of sudden cardiac death in patients treated with antipsychotics is due to the effect that these drugs have on myocardial repolarization, evident in their well-established potential for inducing the prolongation of the rate-corrrected QT interval (QTc) on electrocardiogram (4). A prolonged QT is a risk factor for torsade de pointes (TdP), a ventricular arrhythmia that may degenerate into ventricular fibrillation and lead to sudden death (4.5). However, TdP has not been identified in the epidemiological surveys on sudden death in users of antipsychotic drugs. The findings indicating that typical and atypical antipsychotic use is associated with a similar excess of sudden cardiac deaths (1) have been disputed by the American Psychiatric Association (APA) Council on Research in a “Guidance on the Use of Antipsychotic Drugs and Cardiac Sudden Death” (6). The APA Council felt that the use of death certificates may have led to an overestimation of the sudden cardiac death incidence, an underestimation of the cardiovascular morbidity of users of antipsychotic drugs, and to inadequate control for important confounding variables. Sudden and otherwise unexplained deaths are commonly due to ventricular fibrillation arising as a consequence of coronary artery disease (7). Nonetheless, the determination of the cause of sudden and unexpected death is seldom easy or straightforward. The individual who develops chest pain and who is found to have ischemic changes on the electrocardiogram just before dying en route to the emergency room of the nearest hospital can be safely assumed to have had an acute coronary event. In many other cases, particularly in patients dying alone or in unclear circumstances, the death may remain unexplained even after careful postmortem assessments. This reality, which is more likely to occur in patients with severe mental disorders, is indeed poorly captured in the death certificate (8, 9). A root cause analysis performed by a multidisciplinary team with access to all relevant information is clearly superior for the investigation of unexpected deaths. In fact, compared with a physician-based procedure that used clinical records, autopsy reports and an informant (next-of-kin) interview, the death certificates had a sensitivity of only 24% and a specificity of 85% for the correct classification of cardiovascular and noncardiovascular deaths (9). In this study, we reviewed the root cause analyses of 100 consecutive cases of sudden death that occurred among the patients receiving care in a single behavioral health institution in New York City and compared the groups with explained and unexplained deaths. We hypothesized that unexplained sudden deaths reflect a high prevalence of major risk factors for coronary artery disease, rather than a greater utilization of antipsychotic drugs.

Ziprasidone is a second-generation antipsychotic with proven effectiveness for pediatric bipolar disorder Tourette’s syndrome, pervasive developmental disorder and obsessive-compulsive disorder (1–3). In addition to high-affinity antagonist activity at 5HT2A and dopamine D2 receptors, this antipsychotic has partial agonist activity at 5-HT1A receptors and affinity for norepinephrine and serotonin transporters (4). Ziprasidone is associated with substantially less weight gain and adverse metabolic effects than most other widely used atypical antipsychotics, both in adults (5), and in youth (1,6) and is considered a reasonable treatment choice for minimizing these metabolic complications (6). However, ziprasidone has the potential to prolong the rate-corrected QT interval (QTc) in the electrocardiogram. This effect is greater than the QTc prolongation observed during treatment with haloperidol, risperidone, olanzapine and quetiapine (7,8). Significant prolongation of QTc is generally considered a risk factor for torsades de pointes (TdP), ventricular fibrillation and sudden death, particularly when the QTc is greater than 500 msec (9–11). Antipsychotics produce QTc prolongation by blocking the rapid component of the delayed rectifier current, which promotes potassium efflux from the ventricular myocytes during repolarization (10,11). The mechanism is similar to the QTc prolongation produced by many widely used drugs, such as the antiarrhythmic agents amiodarone and sotalol, quinolone and macrolide antibiotics, and methadone (11). The incidence of TdP in patients treated with these drugs is extremely low, a fact that raises doubts about the value of QTc prolongation as the single electrocardiographic predictor for the risk of TdP. One the other hand, the risk of TdP is clearly increased when the QTc prolongation is associated with a concurrent prolongation of the intramyocardial dispersion of repolarization (10). A larger difference between the action potential duration in adjacent regions of the ventricular myocardium enables circular reentry activity between areas with delayed repolarization and those with excitable myocytes (10,12). The phenomenon is assessed by measuring the QTc dispersion, i.e., the inter-lead variability of QTc on the electrocardiogram. A QTc dispersion >120 msec was shown to be a strong correlate of inducible ventricular tachycardia and its predictive value was not influenced by gender, mean QTc, and left ventricular systolic function (13). QTc dispersion is also a stronger predictor for cardiovascular mortality than QTc duration in the general population (14), patients with myocardial infarction (15), subjects with congenital long QT syndromes (16) and patients who developed TdP after intravenous administration of haloperidol (17). A four-year post-marketing evaluation (4) and a one-year randomized comparison between ziprasidone and olanzapine in 18,000 adult patients, resulting in similar non-suicide related death rates of 0.9% in both groups (18), have indicated that the ziprasidone-induced QTc prolongation is not linked to the occurrence of TdP in adults, and only one case of TdP related to treatment with ziprasidone has been reported in the literature (19). Although one case of sudden death in a child treated with ziprasidone was reported, the authors made it clear that they believed after extensive investigation that this death was unrelated to the ziprasidone treatment (20). In contrast to the large adult databases (4,18), the effect of ziprasidone on myocardial repolarization in children and adolescents has been reported only in a total of 102 patients who were included in five published, open-label studies (1–3,21–22). In these studies, the mean QTc change ranged from −3 msec to +28 msec, and none of these pediatric patients was reported to have experienced syncope or other cardiovascular events. The QTc dispersion was not assessed in any of these studies. In this prospective study, we evaluated the QTc duration and QTc dispersion in 29 children and adolescents monitored carefully during treatment with ziprasidone. Based on the absence of ziprasidone related TdP cases after 8 years of clinical use, we hypothesized that ziprasidone has a low torsadogenic potential because the drug-induced QTc prolongation is not accompanied by a concomitant increase in QTc dispersion.

Objective To evaluate the epidemiology, pathobiology, and management of benign ethnic neutropenia and determine the extent to which these factors should influence measures designed to avoid clozapine-induced agranulocytosis. Data sources A structured MEDLINE search with no language limitation was performed from database inception until March 31, 2015, using the terms clozapine and benign ethnic neutropenia. Retrieved articles were cross-checked for additional relevant studies. Study selection Included in the study were articles that reported on the prevalence, etiology, and complications of benign ethnic neutropenia and the hematologic outcome of clozapine treatment in patients with this condition. Data extraction Study results that documented the epidemiology, pathobiology, and clozapine utilization in persons of African, Arabian, and Mediterranean descent with a neutrophil count in the 1,000-1,800/mm³ range. Results The search identified 342 publications. Forty-two articles described the epidemiology, pathobiology, and management of benign ethnic neutropenia. Of these, 12 articles described patients with benign ethnic neutropenia whose neutrophil count decreased during treatment with clozapine. Persons with benign ethnic neutropenia do not have signs of impaired phagocytosis, and the frequency, severity, and outcome of their infections are similar to those observed in the general population. These features suggest that a neutrophil count > 1,000/mm³ is safe for initiating and/or resuming clozapine therapy. Conclusions The presence of benign ethnic neutropenia should not prevent treatment with clozapine. Patients with benign ethnic neutropenia who develop a clozapine-induced decrease in the neutrophil count, but have no evidence of infection or impaired phagocytosis, may resume clozapine as soon as they have > 1,000 neutrophils/mm³.

BACKGROUND Psychiatric hospital readmissions correlate with illness severity, drug selection, and compliance with treatment in the outpatient setting. The risk factors for psychiatric rehospitalization have been mainly assessed in databases lacking information regarding somatic comorbidity and anthropometric variables, such as body mass index (BMI), which are known to predict readmissions in nonpsychiatric settings. OBJECTIVE To determine independent predictors of 1-year readmission occurring among unselected adults consecutively admitted for treatment of severe mental illness to an academic, freestanding psychiatric hospital in New York City from August 2010 through January 2011. METHOD After identifying univariate correlates of readmission, we used logistic regression with backward elimination to identify independent predictors of readmissions within 1 year after the index psychiatric hospitalization. RESULTS Among 224 (23.7%) of 945 readmitted patients, psychiatric readmission was significantly associated with age (P = .0029), length of stay (P = .036), schizophrenia/schizoaffective disorder (P < . 0001), dementia (P = .027), major depressive disorder (P = .0006), treatment with atypical antipsychotic drugs (P = .0054), electroconvulsive therapy (P < .0001), and BMI (P = .0079), but not with physical comorbidities and routine laboratory data.The independent predictors of readmission were higher BMI (median = 28.5 kg/ m2; odds ratio [OR] = 3.6; Cl, 1.2-10.6), a diagnosis of schizophrenia/schizoaffective disorder (OR = 2.2; Cl, 1.5-3.4), clozapine treatment (OR = 2.8; CI, 1.1-6.9), no electroconvulsive therapy (OR = 0.13; Cl, 0.02-0.45), and shorter length of stay (median = 18 days; OR = 0.08; Cl, 0.01-0.42). CONCLUSIONS Body mass index was identified, for the first time, as an independent predictor of psychiatric rehospitalization. Enhanced outpatient treatment programs for overweight and obese psychiatric patients might influence readmission rates and should be explored in prospective studies.

OBJECTIVE To examine the relationship between presence of metabolic syndrome and the risk of coronary heart disease (CHD) events (angina pectoris, myocardial infarction, and sudden cardiac death) in patients treated with second-generation antipsychotic medications. METHOD 367 adults treated with second-generation antipsychotics randomly selected from consecutive psychiatric admissions to a single hospital between August 1, 2004, and March 1, 2005, underwent assessments evaluating the presence of metabolic syndrome. The 10-year risk of CHD events was calculated according to the Framingham scoring system for age, smoking, total cholesterol, high-density lipoprotein (HDL)-cholesterol, blood pressure, and history of diabetes and was compared in patients with and without the metabolic syndrome. RESULTS Metabolic syndrome, present in 137 patients (37.3%), was associated with a significantly greater age- and race-adjusted 10-year risk of CHD events, i.e., 11.5% vs. 5.3% for men (risk ratio = 2.18, 95% CI = 1.88 to 2.48, p < .0001) and 4.5% vs. 2.3% for women (risk ratio = 1.94, 95% CI = 1.65 to 2.23, p = .0005). The increased risk of CHD events in patients with metabolic syndrome remained significant after the exclusion of diabetic patients. In a logistic regression analysis of variables independent of the Framingham scoring system, triglyceride levels (p < .0001), waist circumference (p = .035), and white race (p = .047) were significantly associated with the 10-year risk of CHD events (R2 = 0.134; p < .0001). CONCLUSIONS These data confirm the high prevalence of metabolic syndrome in patients receiving second-generation anti-psychotics, indicate that metabolic syndrome doubles the 10-year risk of CHD events in this population, and emphasize the importance of the "hypertriglyceridemic waist" for the identification of psychiatric patients at high risk of CHD.