Optimal Injectable Haloperidol Dose Assessment in the Older Hospitalized Inpatient.

BACKGROUND: Haloperidol can be used off-label for agitation and/or delirium in older individuals. The recommended initial intramuscular or intravenous dose is 0.5 to 1 mg. However, the evidence to support these doses is nominal. OBJECTIVES: The primary outcome was to determine whether low-dose injectable haloperidol (≤0.5 mg) was similar in effect to higher doses by assessing the need for repeat doses within 4 hours as a surrogate marker. Secondary outcomes include comparison of length of stay, utilization of restraints, and discharge outcomes between dosage groups. METHODS: This was a retrospective, single-center, cohort study. Patients aged ≥65 years who received haloperidol injectable who were not on antipsychotics prior to admission were reviewed. RESULTS: In the low-dose group (n = 15), no patients required additional haloperidol doses within 4 hours compared with 1 patient each in the medium-dose (n = 23) and high-dose (n = 19) groups (P = 0.94). There was a difference regarding length of stay, utilization of restraints, and discharge to facility when admitted from home favoring low-dose haloperidol. CONCLUSIONS AND RELEVANCE: While limited by sample size and retrospective design, patients who received low-dose haloperidol demonstrated similar efficacy to those who received higher doses of haloperidol. In addition, secondary outcomes mentioned above favored the use of low-dose haloperidol as well. Based on these findings, low-dose haloperidol is a reasonable initial dose for the agitated older patient.

Cost-Effectiveness of Midazolam Versus Haloperidol Versus Olanzapine for the Management of Acute Agitation in the Accident and Emergency Department.

OBJECTIVES: A multicenter randomized clinical trial in Hong Kong Accident and Emergency (A&E) departments concluded that intramuscular (IM) olanzapine is noninferior to haloperidol and midazolam, in terms of efficacy and safety, for the management of acutely agitated patients in A&E setting. Determining their comparative cost-effectiveness will further provide an economic perspective to inform the choice of sedative in this setting. METHODS: This analysis used data from a randomized clinical trial conducted in Hong Kong A&E departments between December 2014 and September 2019. A within-trial cost-effectiveness analysis comparing the 3 sedatives was conducted, from the A&E perspective and a within-trial time horizon, using a decision-analytic model. Sensitivity analyses were also undertaken. RESULTS: In the base-case analysis, median total management costs associated with IM midazolam, haloperidol, and olanzapine were Hong Kong dollar (HKD) 1958.9 (US dollar [USD] 251.1), HKD 2504.5 (USD 321.1), and HKD 2467.6 (USD 316.4), respectively. Agitation management labor cost was the main cost driver, whereas drug costs contributed the least. Midazolam dominated over haloperidol and olanzapine. Probabilistic sensitivity analyses supported that midazolam remains dominant > 95% of the time and revealed no clear difference in the cost-effectiveness of IM olanzapine versus haloperidol (incremental cost-effectiveness ratio 667.16; 95% confidence interval -770.89, 685.90). CONCLUSIONS: IM midazolam is the dominant cost-effective treatment for the management of acute agitation in the A&E setting. IM olanzapine could be considered as an alternative to IM haloperidol given that there is no clear difference in cost-effectiveness, and their adverse effect profile should be considered when choosing between them.

Stroke Risk Among Elderly Users of Haloperidol and Typical Antipsychotics Versus Atypical Antipsychotics: A Real-World Study From a US Health Insurance Claims Database.

BACKGROUND: We estimated stroke risk associated with new exposure to haloperidol, or any typical antipsychotic, versus atypical antipsychotic among patients aged ≥65 years regardless of dementia status. METHODS: IBM MarketScan Medicare Supplemental Database data (January 1, 2001 to December 31, 2017) were used. Stroke risk for new users of typical antipsychotics (T1 cohort) or haloperidol (T2 cohort) was compared with new users of atypical antipsychotics (C1 cohort) aged ≥65 years. Crude incidence rate (IR) and incidence proportion of stroke were estimated within each cohort and gender subgroup. Three propensity score (PS) matching strategies were employed: Unadjusted (crude), Sentinel PS replication, and a large-scale regularized regression model (adapted PS). RESULTS: Overall, 36,734 (T1), 24,074 (T2), and 226,990 (C1) patients were included. Crude IRs for stroke per 1000 person-years were 17.67 (T1), 23.74 (T2), and 14.17 (C1). In preplanned analyses, PS-matched calibrated hazard ratio (cHR) for stroke T1 versus C1 cohort was 1.08 (95% calibrated confidence interval [cCI] = 0.75, 1.55) with Sentinel PS strategy and 1.31 (95% cCI = 1.07, 1.60) with adapted PS strategy. The cHR for stroke in patients of T2 versus C1 was 1.69 (95% cCI = 1.08, 2.75) with Sentinel PS strategy and 1.45 (95% cCI = 1.17, 1.80) with adapted PS strategy. CONCLUSION: Stroke risk in elderly new users of haloperidol was elevated compared to new users of atypical antipsychotics and was elevated for typical antipsychotics using the adapted PS strategy.

Randomized Phase II Trial to Compare the Efficacy of Haloperidol and Olanzapine in the Control of Chemotherapy-Induced Nausea and Vomiting in Nepal.

PURPOSE: The purpose of the study was to compare efficacy and toxicity of olanzapine (OLN; a higher-cost drug) and haloperidol (HAL; a lower-cost drug) in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients who receive highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS: In a randomized, phase II trial, patients were randomly assigned to receive either OLN 10 mg orally on days 1 to 4 or HAL 1 mg orally on day 1 and 0.5 mg twice daily on days 2 to 4. Both groups received ondansetron 16 mg and dexamethasone 12 mg intravenously on day 1. Patients recorded their nausea using the Edmonton Symptom Assessment Scale (ESAS) and recorded daily episodes of vomiting from day 1 to day 5. The primary end point was complete nausea prevention (CNP; ie, ESAS of 0). Secondary end point was complete emesis prevention (CEP). RESULTS: Sixty-five patients were randomly assigned, and 64 received their allocated treatment (n = 32 in each arm). There was no difference in CNP during the overall period (days 1 to 5) between OLN and HAL (68.7% v 71.8%; P = .78). In the acute period (day 1) and the delayed period (days 2 to 5), CNP was similar between OLN and HAL (acute: 84.3% v 81.2%; delayed: 68.7% v 75%). No difference was identified in the rate of CEP during the overall period (81.2% with OLN v 78.1% with HAL; P = .75), during the acute period (93.7% with OLN v 90.6% with HAL), or during the delayed period (84.3% with OLN v 84.3% with HAL). No difference in toxicities was noted between treatment arms. CONCLUSION: In this study, HAL had comparable efficacy to OLN in the management of CINV, which suggests that it is the higher-value option in patients who receive HEC in resource-scarce countries.

Antipsychotics for treatment of delirium in hospitalised non-ICU patients.

BACKGROUND: Guidelines suggest limited and cautious use of antipsychotics for treatment of delirium where nonpharmacological interventions have failed and symptoms remain distressing or dangerous, or both. It is unclear how well these recommendations are supported by current evidence. OBJECTIVES: Our primary objective was to assess the efficacy of antipsychotics versus nonantipsychotics or placebo on the duration of delirium in hospitalised adults. Our secondary objectives were to compare the efficacy of: 1) antipsychotics versus nonantipsychotics or placebo on delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects; and 2) atypical vs. typical antipsychotics for reducing delirium duration, severity, and resolution, hospital mortality and length of stay, discharge disposition, health-related quality of life, and adverse effects. SEARCH METHODS: We searched MEDLINE, Embase, Cochrane EBM Reviews, CINAHL, Thomson Reuters Web of Science and the Latin American and Caribbean Health Sciences Literature (LILACS) from their respective inception dates until July 2017. We also searched the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database, Web of Science ISI Proceedings, and other grey literature. SELECTION CRITERIA: We included randomised and quasi-randomised trials comparing 1) antipsychotics to nonantipsychotics or placebo and 2) typical to atypical antipsychotics for the treatment of delirium in adult hospitalised (but not critically ill) patients. DATA COLLECTION AND ANALYSIS: We examined titles and abstracts of identified studies to determine eligibility. We extracted data independently in duplicate. Disagreements were settled by further discussion and consensus. We used risk ratios (RR) with 95% confidence intervals (CI) as a measure of treatment effect for dichotomous outcomes, and between-group standardised mean differences (SMD) with 95% CI for continuous outcomes. MAIN RESULTS: We included nine trials that recruited 727 participants. Four of the nine trials included a comparison of an antipsychotic to a nonantipsychotic drug or placebo and seven included a comparison of a typical to an atypical antipsychotic. The study populations included hospitalised medical, surgical, and palliative patients.No trial reported on duration of delirium. Antipsychotic treatment did not reduce delirium severity compared to nonantipsychotic drugs (standard mean difference (SMD) -1.08, 95% CI -2.55 to 0.39; four studies; 494 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (SMD -0.17, 95% CI -0.37 to 0.02; seven studies; 542 participants; low-quality evidence). There was no evidence antipsychotics resolved delirium symptoms compared to nonantipsychotic drug regimens (RR 0.95, 95% CI 0.30 to 2.98; three studies; 247 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (RR 1.10, 95% CI 0.79 to 1.52; five studies; 349 participants; low-quality evidence). The pooled results indicated that antipsychotics did not alter mortality compared to nonantipsychotic regimens (RR 1.29, 95% CI 0.73 to 2.27; three studies; 319 participants; low-quality evidence) nor was there a difference between typical and atypical antipsychotics (RR 1.71, 95% CI 0.82 to 3.35; four studies; 342 participants; low-quality evidence).No trial reported on hospital length of stay, hospital discharge disposition, or health-related quality of life. Adverse event reporting was limited and measured with inconsistent methods; in those reporting events, the number of events were low. No trial reported on physical restraint use, long-term cognitive outcomes, cerebrovascular events, or QTc prolongation (i.e. increased time in the heart's electrical cycle). Only one trial reported on arrhythmias and seizures, with no difference between typical or atypical antipsychotics. We found antipsychotics did not have a higher risk of extrapyramidal symptoms (EPS) compared to nonantipsychotic drugs (RR 1.70, 95% CI 0.04 to 65.57; three studies; 247 participants; very-low quality evidence); pooled results showed no increased risk of EPS with typical antipsychotics compared to atypical antipsychotics (RR 12.16, 95% CI 0.55 to 269.52; two studies; 198 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: There were no reported data to determine whether antipsychotics altered the duration of delirium, length of hospital stay, discharge disposition, or health-related quality of life as studies did not report on these outcomes. From the poor quality data available, we found antipsychotics did not reduce delirium severity, resolve symptoms, or alter mortality. Adverse effects were poorly or rarely reported in the trials. Extrapyramidal symptoms were not more frequent with antipsychotics compared to nonantipsychotic drug regimens, and no different for typical compared to atypical antipsychotics.

USING OF CELL LINE HepG2 FOR ASSESSMENT OF TOXIC AND METABOLIC EFECTS OF ANTIPSYCHOTIC DRUGS.

In order to study in vitro the toxic and metabolic effects of antipsychotic drugs (AP) on the cells of hepatic origin we used human hepatoblastoma cell line HepG2. We cultured HepG2 cells in the presence of two AP of the first and second generations (haloperidol and olanzapine, respectively) adding them to the culture medium in concentrations that may at the therapeutic use of AP take place in liver and other tissues of a high lipid content. In the process of cultivation, we detected several products of carbohydrate and lipid metabolism, measured activity of four hepatocellular enzymes in the culture medium, and estimated cell viability/proliferation in the MTS-test. We observed that both AP performed a toxic effect on HepG2 cells, the effect was manifested by a decrease in cell viability/proliferation and an increase in alkaline phosphatase activity in the culture medium. The toxic effect of olanzapine was less pronounced in comparison to haloperidol. According to the data from literature, AP upregulate the expression of lipogenesis genes in the cells of central nervous system, adipose tissue and liver, that might lead to hyperlipidemia. However, we observe in our experiments no increase in the levels of total cholesterol, of cholesterol in lipoproteins of high and low density, of triglycerides in the culture medium containing haloperidol or olanzapine. That observation may have been due to the fact that both AP, which are cationic amphiphiles, are capable to inhibit intracellular traffic of lipids. We also found no effects of haloperidol and olanzapine on the activity of aspartate aminotransferase and gamma-glutamyltransferase, while both AP did reduce the alanine aminotransferase activity. Our work proves that HepG2 cells can be helpful as an in vitro model to obtain new data on metabolic effects of drugs on the cells of hepatic origin and to assess the risk of a drug hepatotoxicity in preclinical studies.

Assessment of Safety Margin of an Antipsychotic Drug Haloperidol for Torsade de Pointes Using the Chronic Atrioventricular Block Dogs.

Since an antipsychotic drug haloperidol has been clinically reported to induce QT interval prolongation and torsade de pointes, in this study its risk stratification for the onset of torsade de pointes was performed by using the chronic atrioventricular block canine model with a Holter electrocardiogram. Haloperidol in a dose of 3 mg kg-1 p.o. prolonged the QT interval, but it did not induce torsade de pointes during the observation period of 21 h (n = 4), indicating that the dose would be safe. Meanwhile, haloperidol in a dose of 30 mg kg-1 p.o. significantly increased the short-term variability in beat-to-beat analysis of QT interval (n = 4), and it induced torsade de pointes in 4 animals out of 4, showing that the dose could be torsadogenic. Since 3 mg kg-1 p.o. of haloperidol in this study can be estimated to provide about 8 times higher plasma concentrations than its therapeutic level, haloperidol may be used safely for most of the patients, as long as its plasma drug concentration is kept within the therapeutic range.

Risk management of QTc-prolongation in patients receiving haloperidol: an epidemiological study in a University hospital in Belgium.

BACKGROUND: Many drugs, including haloperidol, are linked with a risk of QTc-prolongation, which can lead to Torsade de Pointes and sudden cardiac death. OBJECTIVE: To investigate the prevalence of concomitant risk factors for QTc-prolongation in patients treated with haloperidol, and the use of safety measures to minimize this risk. SETTING: University Hospitals of Leuven, Belgium. Methods A retrospective epidemiological study was performed. On 15 consecutive Mondays, all patients with a prescription for haloperidol were included. A risk score for QTc-prolongation, inspired by the pro-QTc score of Haugaa et al., was calculated based on gender, comorbidities, lab results and concomitant QTc-prolonging drugs (each factor counting for one point). Available electrocardiograms before and during the treatment of haloperidol were registered. MAIN OUTCOME MEASURE: Management of the risk of QTc-prolongation. RESULTS: Two hundred twenty-two patients were included (59.0 % men, median age 77 years) of whom 26.6 % had a risk score of ≥4 (known to significantly increase the mortality). Overall, 24.3 % received haloperidol in combination with other drugs with a known risk of Torsade de Pointes. Half of the patients had an electrocardiogram in the week before the start of haloperidol; only in one-third a follow-up electrocardiogram during haloperidol treatment was performed. Of the patients with a moderately (n = 41) or severely (n = 14) prolonged QTc-interval before haloperidol, 48.8 % and 42.9 % respectively had a follow-up electrocardiogram. In patients with a risk score ≥4, significantly more electrocardiograms were taken before starting haloperidol (p = 0.020). CONCLUSIONS: Although many patients had risk factors for QTc-prolongation (including the use of other QTc-prolonging drugs) or had a prolonged QTc on a baseline electrocardiogram, follow-up safety measures were limited. Persistent efforts should be taken to develop decision support systems to manage this risk.

A Cost-effectiveness Analysis of Antipsychotics for Treatment of Schizophrenia in Uganda.

BACKGROUND: Reductions in prices following the expiry of patents on second-generation antipsychotics means that they could be made available to patients with schizophrenia in low-income countries. In this study we examine the cost effectiveness of antipsychotics for schizophrenia in Uganda. METHODS: We developed a decision-analytic 10-state Markov model to represent the clinical and treatment course of schizophrenia and the experience of the average patient within the Uganda healthcare system. The model was run for a base population of 25-years-old patients attending Butabika National Referral Mental Hospital, in annual cycles over a lifetime horizon. Parameters were derived from a primary chart abstraction study, a local community pharmacy survey, published literature, and expert opinion where necessary. We computed mean disability-adjusted life-years (DALYs) and costs (in US$ 2012) for each antipsychotic, incremental cost, and DALYs averted as well as incremental cost-effectiveness ratios (ICERs). RESULTS: In the base-case analysis, mean DALYs were highest with chlorpromazine (27.608), followed by haloperidol (27.563), while olanzapine (27.552) and risperidone had the lowest DALYs (27.557). Expected costs were highest with quetiapine (US$4943), and lowest with risperidone (US$4424). Compared to chlorpromazine, haloperidol was a dominant option (i.e. it was less costly and more effective); and risperidone was dominant over both haloperidol and quetiapine. The ICER comparing olanzapine to risperidone was US$5868 per DALY averted. CONCLUSION: When choosing between first-generation antipsychotics, clinicians should consider haloperidol as the first-line agent for schizophrenia. However, overall, risperidone is a cost-saving strategy; policymakers should consider its addition to essential medicines lists for treatment of schizophrenia in Uganda.

Comparison of droperidol and haloperidol for use by paramedics: assessment of safety and effectiveness.

BACKGROUND: Since the 2001 "black box" warning on droperidol, its use in the prehospital setting has decreased substantially in favor of haloperidol. There are no studies comparing the prehospital use of either drug. The goal of this study was to compare QTc prolongation, adverse events, and effectiveness of droperidol and haloperidol among a cohort of agitated patients in the prehospital setting. METHODS: In this institutional review board-approved before and after study, we collected data on 532 patients receiving haloperidol (n = 314) or droperidol (n = 218) between 2007 and 2010. We reviewed emergency department (ED) electrocardiograms when available (haloperidol, n = 78, 25%; droperidol, n = 178, 76%) for QTc length (in milliseconds), medical records for clinically relevant adverse events (defined a priori as systolic blood pressure (SBP) <90 mmHg, seizure, administration of anti-dysrhythmic medications, cardioversion or defibrillation, bag-valve-mask ventilation, intubation, cardiopulmonary arrest, and prehospital or in-hospital death). We also compared effectiveness of the medications, using administration of additional sedating medications within 30 minutes of ED arrival as a proxy for effectiveness. RESULTS: The mean haloperidol dose was 7.9 mg (median 10 mg, range 4-20 mg). The mean droperidol dose was 2.9 mg (median 2.5 mg, range 1.25-10 mg.) Haloperidol was given i.m. in 289 cases (92%), and droperidol was given i.m. in 132 cases (61%); in all other cases, the medication was given i.v.. There was no statistically significant difference in median QTc after medication administration (haloperidol 447 ms, 95% CI: 440-454 ms; droperidol 454 ms, 95% CI: 450-457). There were no statistically significant differences in adverse events in the droperidol group as compared to the haloperidol group. One patient in the droperidol group with a history of congenital heart disease suffered a cardiopulmonary arrest and was resuscitated with neurologically intact survival. There was no significant difference in the use of additional sedating medications within 30 minutes of ED arrival after receiving droperidol (2.9%, 95% CI: -2.5-8.4%). CONCLUSIONS: In this cohort of agitated patients treated with haloperidol or droperidol in the prehospital setting, there was no significant difference found in QTc prolongation, adverse events, or need for repeat sedation between haloperidol and droperidol.

Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study.

OBJECTIVE: To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes. DESIGN: Population based cohort study with linked data from Medicaid, Medicare, the Minimum Data Set, the National Death Index, and a national assessment of nursing home quality. SETTING: Nursing homes in the United States. PARTICIPANTS: 75,445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥ 65, were eligible for Medicaid, and lived in a nursing home in 2001-5. MAIN OUTCOME MEASURES: Cox proportional hazards models were used to compare 180 day risks of all cause and cause specific mortality by individual drug, with propensity score adjustment to control for potential confounders. RESULTS: Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine. CONCLUSIONS: Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need. The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.

Impact of geographical and cultural factors on clinical trials in acute mania: lessons from a ziprasidone and haloperidol placebo-controlled study.

Clinical trials today are conducted in multiple countries to enhance patient recruitment and improve efficiency of trials. However, the demographic and cultural diversity may contribute to variations in study outcomes. Here we conducted post-hoc analyses for a placebo-controlled study with ziprasidone and haloperidol for the treatment of acute mania to address the demographic, dosing, and outcome disparities in India, Russia and the USA. We compared the baseline characteristics, outcomes and discontinuations in patients and explored the relationship between the outcome measures across these countries. We found substantial differences in baseline characteristics of subjects, administered dosage and disease severity in India compared to the USA and Russia. Conversely, US subjects had a higher placebo response compared to subjects in Russia and India. These results are probably due to demographic differences in patient populations and psychiatric clinical practice across countries. While we offer initial ideas to address the disparities identified in this analysis, it is clear that further research to improve our understanding of geographical differences is essential to ensure globally applicable results for clinical trials in psychiatry.

Comparative utility of aripiprazole and haloperidol in schizophrenia: post hoc analysis of two 52-week, randomized, controlled trials.

BACKGROUND: Since their introduction, second-generation antipsychotics (SGAs) have become the drugs of choice for the treatment of schizophrenia. However, recent findings have questioned the benefits of SGAs over first-generation antipsychotics (FGAs). OBJECTIVE: This post hoc analysis sought to compare the utility of the SGA aripiprazole with the FGA haloperidol in patients with early-phase schizophrenia (ES) or chronic schizophrenia (CS). METHOD: Data were pooled from two identical 52-week, randomized, active comparator trials (31-98-217 and 31-98-304) of aripiprazole 20-30 mg/day versus haloperidol 7-10 mg/day. Patients in the efficacy sample were classified as having ES if they were

Intramuscular haloperidol versus intramuscular olanzapine for treatment of acute agitation: a cost-minimization study.

STUDY OBJECTIVES: To investigate prescribing patterns for antipsychotic regimens based on intramuscular haloperidol or intramuscular olanzapine for treating acute agitation; to compare the costs of each drug regimen, which included adjunctive anxiolytics and/or anticholinergics; and to compare the effectiveness and safety of each drug regimen. DESIGN: Retrospective medical record review. SETTING: State psychiatric facility. PATIENTS: Twenty-seven patients who received intramuscular haloperidol to treat 47 episodes of acute agitation and 26 patients who received intramuscular olanzapine to treat 38 episodes. MEASUREMENTS AND MAIN RESULTS: Data from patients receiving the antipsychotic regimens between August 2004 and March 2007 were reviewed. Mean +/- SD doses were 6.4 +/- 2.4 mg (range 2.5-10 mg) for haloperidol and 8.1 +/- 2.3 mg (range 5-10 mg) for olanzapine. The mean +/- SD cost of treating an episode of agitation with haloperidol was significantly lower at $4.06 +/- 3.98 (range $1.74-18.35) versus $27.84 +/- 10.40 (range $21.58-52.46) for olanzapine (p<0.0001). Significantly fewer patients who received haloperidol than patients who received olanzapine required additional pharmacotherapy to manage agitation (41% vs 69%, chi(2)=4.34, p=0.04). No significant differences were found between groups in the mean number of repeat doses of psychotropic drugs needed/episode (0.6 [range 0-5] for haloperidol vs 0.8 [range 0-3] for olanzapine, p=0.47), in the percentages of patients who required seclusion and/or restraints (59% for haloperidol vs 58% for olanzapine, chi(2)=0.01, p=0.91), or in time spent in seclusion and/or restraints (3.7 +/- 7.1 for haloperidol vs 3.6 +/- 6.5 hrs for olanzapine, p=0.92). No adverse events were documented with either drug. CONCLUSION: For the treatment of acute episodes of agitation, regimens based on intramuscular haloperidol were significantly less expensive than and at least as effective as those based on intramuscular olanzapine.

The treatment of challenging behaviour in intellectual disabilities: cost-effectiveness analysis.

BACKGROUND: Antipsychotic drugs are used in the routine treatment of adults with intellectual disabilities (ID) and challenging behaviour in the UK despite limited evidence of their effectiveness. There is no evidence on their cost-effectiveness. METHODS: The relative cost-effectiveness of risperidone, haloperidol and placebo in treating individuals with an ID and challenging behaviour was compared from a societal perspective in a 26-week, double-blind, randomised controlled trial. Outcomes were changes in aggression and quality of life. Costs measured all service impacts and unpaid caregiver inputs. RESULTS: After 26 weeks, patients randomised to placebo had lower costs compared with those in the risperidone and haloperidol treatment groups. Aggression was highest for patients treated with risperidone and lowest for patients treated with haloperidol; however, quality of life was lowest for patients treated with haloperidol and highest for patients treated with risperidone. CONCLUSION: The treatment of challenging behaviour in ID with antipsychotic drugs is not a cost-effective option.

Belgian Schizophrenia Outcome Survey - results of a 2-year naturalistic study in patients stabilised on monotherapy with olanzapine, risperidone or haloperidol.

OBJECTIVES: This Schizophrenia Outcome Survey compared medical costs, psychopathology and adverse events in outpatients for 2 years following hospitalisation for an acute schizophrenic episode. METHODS: Adults stabilised with haloperidol, olanzapine or risperidone entered this observational study or=1 EPS; 69% (p<0.013), 40 and 44%, respectively, had >or=1 sexual problem (NS). Mean weight gain was 0.4 (NS), 2.6 (p<0.05) and 2.6 kg (p<0.05), respectively. CONCLUSIONS: In this naturalistic study, treatment allocation might have introduced a bias in the interpretation of efficiency results, but olanzapine and risperidone caused less EPS than haloperidol during 2 years of outpatient follow-up.

Bayesian adaptive non-inferiority with safety assessment: retrospective case study to highlight potential benefits and limitations of the approach.

Adaptive trial design applied to randomized clinical trials of psychiatric medicines offers the potential to make clinical trials more efficient. In the current analysis, we retrospectively applied Bayesian adaptive allocation methods to a case study in agitated patients with schizophrenia and related diseases. The original study used a randomized, double-blind, parallel design. The objective of this analysis was to demonstrate the potential benefits of Bayesian adaptive designs by shortening the study duration and therefore limiting patient exposure to ineffective placebo or an active comparator with a known side effect. Bayesian methods allowed us to fully leverage historical data along with data observed as the study was ongoing to calculate predictive probabilities of patient response to treatment without experiencing a specified side effect. Using the Bayesian adaptive approach would have required less than half the number of patients as the original study to draw the same conclusion. Sample size was reduced from 311 to 156 patients, thereby decreasing the number of patients exposed to placebo from 54 to 30 and the number exposed to the active control with a known side effect from 126 to 60.

Long-term antipsychotic monotherapy for schizophrenia: disease burden and comparative outcomes for patients treated with olanzapine, quetiapine, risperidone, or haloperidol monotherapy in a pan-continental observational study.

OBJECTIVE: Noninterventional, naturalistic studies facilitate examination of current clinical practices and provide an understanding of the impact of the biopsychosocial aspects of schizophrenia. This article describes disease burden and patient outcomes, with an emphasis on the comparative effectiveness and tolerability of antipsychotic monotherapy. METHOD: Outpatients initiating or changing antipsychotic therapy for DSM-IV- or ICD-10-defined schizophrenia (N = 7658) were allocated to olanzapine or nonolanzapine cohorts (November 2000 to December 2001). Treatment was at the psychiatrist's discretion, including flexible dosing and use of concomitant therapies and medications, with assessments at 0, 3, 6, 12, 18, 24, 30, and 36 months. Longitudinal clinical, pharmacologic, functional, and social data were collected over 36 months across 27 countries. RESULTS: At entry, 76% of patients were initiated/switched to antipsychotic monotherapy, most commonly with olanzapine (N = 3222), risperidone (N = 1117), quetiapine (N = 189), or haloperidol (N = 257). Patients prescribed olanzapine were more likely to maintain their baseline monotherapy (p < .001) and did so for a longer period (p < .001) compared with other antipsychotics. Median time to discontinuation (in months) was as follows: olanzapine 30.0, risperidone 23.1, quetiapine 13.9, haloperidol 12.5. Olanzapine-treated patients were also more likely to respond, and did so more rapidly than patients on other monotherapies (p < .001). Response data were also favorable for risperidone; median time to response (in months) was as follows: olanzapine 5.2, risperidone 6.3, quetiapine 11.3, haloperidol 11.7. Treatment-emergent adverse events varied: olanzapine patients had less favorable odds for significant weight gain (p < .001); haloperidol patients, for motor dysfunction (p < or = .002). CONCLUSION: These naturalistic data from less-studied outpatient communities highlight the variability in clinical and functional outcomes associated with long-term antipsychotic treatment.

An in vitro model for assessment of drug-induced torsade de pointes arrhythmia : effects of haloperidol and dofetilide on potential duration, repolarization inhomogeneities, and torsade de pointes arrhythmia.

Torsade de pointes (TdP) is a serious side effect of many drugs. We aimed to establish an in vitro TdP model for drug testing, which includes typical risk factors, such as female gender, hypokalemia, low magnesium levels, and bradycardia. Isolated, spontaneously beating rabbit hearts (female White New Zealand rabbits) were perfused according to the Langendorff technique and submitted to conditions known as risk factors for TdP, i.e., [K(+)](e) = 2.5 mM and [Mg(++)](e) = 0.5 mM, with 10(-8) M noradrenaline and 10(-7) M carbachol. Thereafter, cumulative concentration-response curves for haloperidol (10, 100, 200, 1,000, and 2,000 nM) and dofetilide (1, 10, 20, 100, and 200 nM) were performed, while cardiac activation and repolarization was measured at 256 ventricular sites (unipolar extracellular potentials). We found in three of six hearts under haloperidol TdP arrhythmias in supratherapeutic concentrations > or =100 nM. Dofetilide also induced TdP (three of seven) in concentrations > or =20 nM. The TdP showed a complex pattern being initiated in one region by an early R-on-T ventricular extrasystole, when in the other regions high activation-recovery interval (ARI) dispersion occurred, then spreading in complex beat-to-beat changing patterns until self-termination. Dofetilide and haloperidol significantly prolonged ARI and QTc. Haloperidol significantly increased dispersion predominantly at the right wall and prolonged basic cycle length. Dofetilide also increased dispersion and slowed basic cycle length. Haloperidol (> or =100 nM) and dofetilide (> or =20 nM) can induce TdP by prolongation of ARI, slowing of heart rate, and increasing repolarization inhomogeneities. The linear combination of the independent variables QTc, BCL and dispersion could highly significantly predict TaP (adjusted R(2): 0.896, p < 0.001) The model seems suitable to identify a pharmacological risk for TdP in vitro within a limited number of animals.

Assessment of clinical and metabolic status, and subjective well-being, in schizophrenic patients switched from typical and atypical antipsychotics to ziprasidone.

The objective of this paper was to assess the effects of switching from typical and/or atypical antipsychotics to ziprasidone, owing to inadequate response or intolerance, in chronic schizophrenic patients. A total of 312 patients were switched to an 8-week, open-label, flexible dose (40-160 mg/day) of ziprasidone. Psychiatric status was evaluated by Positive and Negative Syndrome Scale and Clinical Global Impression Severity scale. Other measures included functioning, subjective response and attitude toward therapy, and cognition. Laboratory tests and electrocardiography with QTc interval were carried out. Extrapyramidal symptoms and sexual dysfunction symptoms were also assessed. Of the 312 enrolled patients, 73.1% completed the study. Olanzapine, risperidone, and haloperidol were the most common psychotropic drugs taken before entry. Poor efficacy was the main reason for change in therapy. Significant improvements from baseline to endpoint were reported for mean Positive and Negative Syndrome Scale scores (P<0.0001), Clinical Global Impression Severity (P<0.0001), Global Assessment of Functioning (P<0.0001), Subjective Well-being scores (P<0.0001), and Trail Making Test (P<0.05). Significant improvements were also found for mean Simpson-Angus scale score (P<0.0001), sexual dysfunction, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. In addition, mean body weight significantly decreased from baseline (P<0.0001). A favorable profile for ziprasidone was found with regard to improved subjective tolerability, quality of life, and medication adherence behavior.