title: Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain. Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia. TREC-Rio trial: a randomised controlled trial for rapid tranquillisation for agitated patients in emergency psychiatric rooms [ISRCTN44153243] Components of variance and intraclass correlations for the design of community-based surveys and intervention studies: data from the Health Survey for England 1994. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Current practices in managing acutely disturbed patients at three hospitals in Rio de Janeiro-Brazil: a prevalence study The use of midazolam in acutely agitated psychiatric patients. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droperidol, ziprasidone, and midazolam. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Efficacy of combinations of intramuscular antipsychotics and sedative-hypnotics for control of psychotic agitation. The Overt Agitation Severity Scale for the objective rating of agitation. Acute high-dose parenteral haloperidol treatment of psychosis. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. A Double-Blind, Randomized Comparison of the Efficacy and Safety of Intramuscular Injections of Olanzapine, Lorazepam, or Placebo in Treating Acutely Agitated Patients Diagnosed With Bipolar Mania Parenteral lorazepam versus parenteral haloperidol for the control of psychotic disruptive behavior. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine. Risperidone versus Haloperidol, in Combination with Lorazepam, in the Treatment of Acute Agitation and Psychosis: A Pilot, Randomized, Double-Blind, Placebo-Controlled Trial Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department. Efficacy of lorazepam and haloperidol for rapid tranquilization in a psychiatric emergency room setting Calming versus sedative effects of intramuscular olanzapine in agitated patients. Unpublished rating scales: a major source of bias in randomised controlled trials of treatments for schizophrenia. The expert consensus guideline series. Treatment of behavioral emergencies 2005.
abstract: OBJECTIVE The authors examined the efficacy of intramuscular flunitrazepam compared with intramuscular haloperidol for the immediate control of agitated or aggressive behavior in acutely psychotic patients . METHOD Twenty-eight actively psychotic in patients , aged 20 - 60 years , who were under treatment with neuroleptic agents were selected for the study . Each was r and omly assigned on a double-blind basis to receive either 5 mg i.m . of haloperidol ( N=13 ) or 1 mg i.m . of flunitrazepam ( N=15 ) during an aggressive event . Verbal and physical aggression was measured over time with the Overt Aggression Scale . Patients were also rated with the Brief Psychiatric Rating Scale and the Clinical Global Impression scale . RESULTS Both flunitrazepam and haloperidol exhibited acute antiaggressive activity . This beneficial effect , as assessed by the Overt Aggression Scale , was obtained within 30 minutes . CONCLUSIONS Intramuscular flunitrazepam may serve as a convenient , rapid , safe , and effective adjunct to neuroleptics in reducing aggressive behavior in emergency psychiatric setting OBJECTIVES To determine if midazolam is superior to lorazepam or haloperidol in the management of  violent and severely agitated patients in the emergency department . Superiority would be determined if midazolam result ed in a significantly shorter time to sedation and shorter time to arousal . METHODS This was a r and omized , prospect i ve , double-blind study of a convenience sample of patients from an urban , county teaching emergency department . Participants included 111 violent and severely agitated patients . Patients were r and omized to receive intramuscular midazolam ( 5 mg ) , lorazepam ( 2 mg ) , or haloperidol ( 5 mg ) . RESULTS The mean ( + /-SD ) age was 40.7 ( + /-13 ) years . The mean ( + /-SD ) time to sedation was 18.3 ( + /-14 ) minutes for patients receiving midazolam , 28.3 ( + /-25 ) minutes for haloperidol , and 32.2 ( + /-20 ) minutes for lorazepam . Midazolam had a significantly shorter time to sedation than lorazepam and haloperidol ( p < 0.05 ) . The mean difference between midazolam and lorazepam was 13.0 minutes ( 95 % confidence interval [ 95 % CI ] = 5.1 to 22.8 minutes ) and that between midazolam and haloperidol was 9.9 minutes ( 95 % CI = 0.5 to 19.3 minutes ) . Time to arousal was 81.9 minutes for patients receiving midazolam , 126.5 minutes for haloperidol , and 217.2 minutes for lorazepam .  Time to arousal for midazolam was significantly shorter than for both haloperidol and lorazepam ( p < 0.05 ) . The mean difference in time to awakening between midazolam and lorazepam was 135.3 minutes ( 95 % CI = 89 to 182 minutes ) and that between midazolam and haloperidol was 44.6 minutes ( 95 % CI = 9 to 80 minutes ) . There was no significant difference over time by repeated- measures analysis of variance between groups in regard to changes in systolic and diastolic blood pressure ( p = 0.8965 , p = 0.9581 ) , heart rate ( p = 0.5517 ) , respiratory rate ( p = 0.8191 ) , and oxygen saturation ( p = 0.8991 ) . CONCLUSIONS Midazolam has a significantly shorter time to onset of sedation and a more rapid time to arousal than lorazepam or haloperidol . The efficacies of all three drugs appear to be similar The mechanisms underlying the clinical properties of atypical antipsychotics have been postulated to be mediated , in part , by interactions with the 5-HT2A receptor . Recently , it has been recognized that clinical ly effective antipsychotic drugs are 5-HT2A receptor inverse agonists rather than neutral antagonists . In the present study , which is part of the clinical development of the novel , selective 5-HT2A receptor inverse agonist ACP-103 , we applied positron emission tomography ( PET ) with the radiolig and [11C]N-methylspiperone ( [11C]NMSP ) to study the relationship between oral dose , plasma level , and uptake of ACP-103 in living human brain . The safety of drug administration was also assessed . Four healthy volunteers were examined by PET at baseline , and after the oral administration of various single doses of ACP-103 . Two subjects each received 1 , 5 , and 20 mg doses , and two subjects each received 2 , 10 , and 100 mg doses , respectively . ACP-103 was well tolerated . Detectable receptor binding was observed at very low ACP-103 serum levels . Cortical [11C]NMSP binding was found to be dose-dependent and fitted well to the law of mass action . A reduction in binding was detectable after an oral dose of ACP-103 as low as 1 mg , and reached near maximal displacement following the 10 - 20 mg dose . In conclusion , administration of ACP-103 to healthy volunteers was found to be safe and well tolerated , and single oral doses as low as 10 mg were found to fully saturate 5-HT2A receptors in human brain as determined by PET OBJECTIVE While neuroleptics remain the mainstay of drug intervention in the emergency management of psychosis , a variety of agents have received study as alternatives or adjuncts to these drugs in an attempt to improve the safety and efficacy of acute treatment . The purpose s of this study were to investigate the efficacy and safety of alprazolam as a neuroleptic adjunct for schizophrenic patients in psychotic relapse and to clarify the effects of combination treatment on specific aspects of the psychotic process . METHOD Twenty-eight acutely psychotic patients with schizophrenia who were admitted to an emergency psychiatric service were r and omly assigned to treatment with either haloperidol and alprazolam or haloperidol with placebo under double-blind conditions . Drug administration lasted 72 hours . RESULTS Both groups improved significantly . The combination-treated group required significantly less medication and had 56 % fewer dystonic reactions . The addition of alprazolam was most effective for symptoms of excitement and uncooperativeness , particularly in the initial hours of treatment . CONCLUSIONS The combination of alprazolam and haloperidol seems to be the most effective for agitated patients , particularly in the first 48 hours of treatment . It may also result in fewer dystonic reactions Background Agitated or violent patients constitute 10 % of all emergency psychiatric treatment . Management guidelines , the preferred treatment of clinicians and clinical practice all differ . Systematic review s show that all relevant studies are small and none are likely to have adequate power to show true differences between treatments . Worldwide , current treatment is not based on evidence from r and omised trials . In Brazil , the combination haloperidol-promethazine is frequently used , but no studies involving this mix exist . Methods TREC-Rio ( Tranquilização Rápida-Ensaio Clínico [ Translation : Rapid Tranquillisation- Clinical Trial ] ) will compare midazolam with haloperidol-promethazine mix for treatment of agitated patients in emergency psychiatric rooms of Rio de Janeiro , Brazil . TREC-Rio is a r and omised , controlled , pragmatic and open study . Primary measure of outcome is tranquillisation at 20 minutes but effects on other measures of morbidity will also be assessed . TREC-Rio will involve the collaboration of as many health care professionals based in four psychiatric emergency rooms of Rio as possible . Because the design of this trial does not substantially complicate clinical management , and in several aspects simplifies it , the study can be large , and treatments used in everyday practice can be evaluated The authors estimated components of variance and intraclass correlation coefficients ( ICCs ) to aid in the design of complex surveys and community intervention studies by analyzing data from the Health Survey for Engl and 1994 . This cross-sectional survey of English adults included data on a range of lifestyle risk factors and health outcomes . For the survey , households were sample d in 720 postal code sectors nested within 177 district health authorities and 14 regional health authorities . Study subjects were adults aged 16 years or more .  ICCs and components of variance were estimated from a nested r and om-effects analysis of variance . Results are presented at the district health authority , postal code sector , and household levels . Between-cluster variation was evident at each level of clustering . In these data , ICCs were inversely related to cluster size , but design effects could be substantial when the cluster size was large . Most ICCs were below 0.01 at the district health authority level , and they were mostly below 0.05 at the postal code sector level . At the household level , many ICCs were in the range of 0.0 - 0.3 . These data may provide useful information for the design of epidemiologic studies in which the units sample d or allocated range in size from households to large administrative areas Rapid tranquilization is a routinely practice d method of calming agitated psychotic patients by use of neuroleptics , benzodiazepines , or both in combination . Although several studies have examined the efficacy of the three approaches , none have compared these treatments in a prospect i ve , r and omized , double-blind , multicenter trial . Ninety-eight psychotic , agitated , and aggressive patients ( 73 men and 25 women ) were prospect ively enrolled during an 18-month period in emergency departments in five university or general hospitals . Patients were r and omly assigned to receive intramuscular injections of lorazepam ( 2 mg ) , haloperidol ( 5 mg ) , or both in combination . Patients in each treatment group received 1 to 6 injections of the same study drug within 12 hours , based on clinical need . They were evaluated hourly after the first injection until at least 12 hours after the last . Efficacy was assessed on the Agitated Behavior Scale ( ABS ) , a modified Brief Psychiatric Rating Scale ( MBPRS ) , Clinical Global impressions ( CGI ) scale , and an Alertness Scale . Effective symptom reduction was achieved in each treatment group with significant ( P < .01 ) mean decreases from baseline at every hourly ABS evaluation . Significant ( P < .05 ) mean differences on the ABS ( hour 1 ) and MBPRS ( hours 2 and 3 ) suggest that tranquilization was most rapid in patients receiving the combination treatment . Study event incidence ( side effects ) did not differ significantly between treatment groups , although patients receiving haloperidol alone tended to have more extrapyramidal system symptoms . The superior results produced by the combination treatment support the use of lorazepam plus haloperidol as the treatment of choice for acute psychotic agitation Background The medical management of aggressive and violent behaviour is a critical situation for which there is little evidence . In order to prepare for a r and omised trial , due to start in the psychiatric emergency rooms of Rio de Janeiro in 2001 , a survey of current practice was necessary . Methods A seven day survey of pharmacological management of aggressive people with psychosis in the emergency rooms of all four public psychiatric hospitals in Rio de Janeiro , Brazil . Results In one hospital data were not available . Of the 764 people with psychosis attending these ERs , 74 were given IM medication for rapid tranquillisation ( 9.7 % , 2.1/week/100,000 ) . A haloperidol-promethazine mix ( with or without other drugs ) was used for the majority of patients ( 83 % ) . Conclusion The haloperidol-promethazine mix , given intramuscularly for rapid tranquilization , is prevalent in Rio , where it is considered both safe and efficient . However , scientific evaluation of all pharmacological approaches to rapid tranquilization of psychotic people is inadequate or incomplete and a r and omized trial of IM haloperidol-promethazine is overdue Agents currently used for acutely agitated patients such as sodium amytal and haloperidol are disadvantageous because of their adverse effects on the respiratory and extrapyramidal systems . Because of this , a rapid , safe , well-absorbed agent such as midazolam would be useful . This study compares the effectiveness of midazolam , sodium amytal , and haloperidol in agitated schizophrenic patients . Five male patients between 28 and 59 years were r and omly assigned to each group . They were administered intramuscularly either 10 mg of haloperidol , 250 mg of sodium amytal , or 5 mg of midazolam . Over a 2-hour period , patients were rated for motor agitation , hostility , auditory hallucinations , and flight of ideas . Both midazolam and sodium amytal were significantly more effective than haloperidol in controlling motor agitation . There were no treatment differences on any other symptom rated . These results indicate that further studies on the use of midazolam to achieve rapid tranquilization would be useful OBJECTIVE To compare the effectiveness of intramuscular olanzapine , ziprasidone , haloperidol plus promethazine , haloperidol plus midazolam and haloperidol alone as the first medication(s ) used to treat patients with agitation and aggressive behavior . METHOD One hundred fifty patients with agitation caused by psychotic or bipolar disorder were r and omly assigned under double-blind conditions to receive olanzapine , ziprasidone , haloperidol plus midazolam , haloperidol plus promethazine or haloperidol alone . The Overt Agitation Severity Scale , Overt Aggression Scale and Ramsay Sedation Scale were applied within 12 hours after the first dosage . RESULTS All medications produced a calming effect within one hour of administration , but only olanzapine and haloperidol reduced agitation by less than 10 points , and only olanzapine reduced aggression by less than four points in the first hour . After twelve hours , only patients treated with haloperidol plus midazolam had high levels of agitation and aggression and also more side effects . Ziprasidone , olanzapine and haloperidol alone had more stable results for agitation control , while ziprasidone , haloperidol plus promethazine and olanzapine had stable results for aggression control . CONCLUSION Olanzapine , ziprasidone , haloperidol plus promethazine , haloperidol plus midazolam and haloperidol were effective in controlling agitation and aggression caused by mental illness over 12 hours . Although all the drugs had advantages and disadvantages , haloperidol plus midazolam was associated with the worst results in all the observed parameters OBJECTIVES To compare the efficacy of sedation , need for rescue sedation , rates of respiratory depression , and complications of droperidol , ziprasidone , and midazolam when used for the treatment of emergency department ( ED ) patients requiring sedation for acute undifferentiated agitation . METHODS A prospect i ve , r and omized , double-blind trial of agitated ED patients requiring emergent sedation  was performed . Patients were r and omized to receive droperidol 5 mg , ziprasidone 20 mg , or midazolam 5 mg intramuscularly . Interval measurements were made at 0 , 15 , 30 , 45 , 60 , and 120 minutes and included Altered Mental Status Scale ( AMS ) scores , oxygen saturations , and end-tidal carbon dioxide levels . RESULTS A total of 144 patients were enrolled ; 50 patients received droperidol , 46 received ziprasidone , and 48 received midazolam .  Adequate sedation ( mean AMS score < 0 ) was achieved at 15 minutes in patients receiving midazolam ( mean AMS score , -0.81 ) and 30 minutes for patients receiving droperidol ( mean AMS score , -1.3 ) and ziprasidone ( mean AMS score , -0.74 ) . Rescue medication for sedation was necessary in 38 of 144 patients ( droperidol , 5 of 50 ; ziprasidone , 9 of 46 ; midazolam , 24 of 48 ; p < 0.05 ) . No cardiac dysrhythmias were identified in any treatment group . Respiratory depression that clinical ly required treatment with supplemental oxygen occurred in 21 of 144 patients ( droperidol , 4 of 50 ; ziprasidone , 7 of 46 ; midazolam , 10 of 48 ; p = 0.20 ) . No patients required endotracheal intubation . CONCLUSIONS Acutely agitated ED patients se date d with droperidol or ziprasidone required rescue medications to achieve adequate sedation less frequently than those se date d with midazolam . The onset of adequate sedation is delayed with ziprasidone , relative to the other agents BACKGROUND An intramuscular ( IM ) formulation of olanzapine has been developed because there are no rapid-acting IM atypical antipsychotic drugs currently available in the United States for treating acute agitation in patients with schizophrenia . METHODS Recently hospitalized acutely agitated patients with schizophrenia ( N = 270 ) were r and omized to receive 1 to 3 IM injections of olanzapine ( 2.5 , 5.0 , 7.5 , or 10.0 mg ) , haloperidol ( 7.5 mg ) , or placebo within 24 hours . A dose-response relationship for IM olanzapine in the reduction of agitation was assessed by measuring the reduction in Positive and Negative Syndrome Scale Excited Component ( PANSS-EC ) scores 2 hours after the first injection . Safety was assessed by recording adverse events and with extrapyramidal symptom scales and electrocardiograms at 24 hours after the first injection . RESULTS Olanzapine exhibited a dose-response relationship for reduction in agitation ( F(1,179)= 14.4 ; P<.001 ) . Mean PANSS-EC reductions 2 hours after the first injection of olanzapine ( 2.5 mg = -5.5 ; 5.0 mg = -8.1 ; 7.5 mg = -8.7 ; 10.0 mg = -9.4 ) were superior to those with placebo ( -2.9 ; P = .01 vs olanzapine at 2.5 mg ; P<.001 for each other olanzapine dose ) but not with haloperidol ( -7.5 ) . A dose of 5.0 , 7.5 , or 10.0 mg of olanzapine caused a greater reduction in agitation than placebo 30 minutes after the first injection . There were no differences between treatment groups for hypotension , the most frequently reported adverse event , or for clinical ly relevant changes in the QTc interval . There was a greater incidence of treatment-emergent parkinsonism during treatment with IM haloperidol ( 16.7 % ) than with 2.5 ( P = .03 ) , 5.0 ( P = .03 ) , or 7.5 mg ( P = .01 ) of IM olanzapine ( 0 % ) or with placebo ( 0 % ) ( P = .01 ) . CONCLUSIONS Intramuscular olanzapine at a dose of 2.5 to 10.0 mg per injection exhibits a dose-response relationship in the rapid treatment of acute agitation in patients with schizophrenia and demonstrates a favorable safety profile The combination of haloperidol , 5 mg , and lorazepam , 4 mg , was both effective and safe for managing agitated behavior in an open trial with acutely psychotic patients . The combination also appeared to be superior to its individual components when studied in a r and omized , nonblind trial . The principle of the combined use of antipsychotics and sedative-hypnotics was further tested by comparing two new combinations : thiothixene , 5 mg , and lorazepam , 4 mg , versus haloperidol , 5 mg , and phenobarbital sodium , 130 mg . These combinations had comparable efficacy and safety , and the level of transquilization approached that produced by the haloperidol-lorazepam combination in the preceding studies Two studies tested the reliability and validity of the  Overt Agitation Severity Scale ( OASS )  , a new instrument developed to define and objective ly rate the severity of  agitated behavior . The authors postulate that agitation should be conceptualized as vocal and motor behaviors on a continuum of expressions that extends from anxiety to aggression . Content validity through expert agreement was achieved in the development of test construction over a 2-year period . Results of two pilot studies ( n = 25 and n = 14 subjects ) established the reliability and validity of the OASS  to measure agitation severity . The OASS differs from other agitation scales in that it confines its rating exclusively to observable behavioral manifestations of agitation After 2 days of drug-free observation , 20 newly admitted psychotic patients received 20 - 35 mg of haloperidol intravenously and 20 patients received 30 - 40 mg of diazepam intravenously . Posttreatment ratings at 4 and 24 hours with the Brief Psychiatric Rating Scale and the Clinical Global Impressions revealed significant improvement in both groups but no significant differences between the two treatments STUDY OBJECTIVE To compare the utility of intramuscular lorazepam ( LZ ) with the combination of intramuscular haloperidol ( HDL ) and LZ to control  acutely agitated behavior .  DESIGN R and omized double-blind comparison . SETTING Psychiatric emergency service of a large , university-affiliated , municipal hospital . PATIENTS Twenty subjects treated on the psychiatric emergency service . INTERVENTIONS Patients received an injection of either LZ 2 mg ( 11 patients ) or HDL 5 mg plus LZ 2 mg ( 9 patients ) . The Overt Aggression Scale ( OAS ) , visual analog scales reflecting agitation and hostility , and the Clinical Global Impressions ( CGI ) severity scale were administered at baseline and 30 , 60 , 120 , and 180 minutes after the injection . MEASUREMENTS AND MAIN RESULTS Planned data comparisons included categoric assignment of patients as improved , as defined by decreases in outcome measures 60 minutes after the injection , as well as continuous variables up to 180 minutes after the injection . A significantly greater percentage of subjects receiving combined treatment improved on the specific measures 60 minutes after dosing ( p<0.05 ) . Kaplan-Meier survival analyses showed significant between-group differences in survival curves plotted for the entire study period ( p<0.05 ) . Repeated measures analyses of variance study ing group differences showed that both groups improved over time , but between-group differences were not significant . The powers of these analyses were low due to the small sample . No serious adverse effects occurred in either treatment group . CONCLUSION Our results suggest superior efficacy for HDL-LZ over LZ alone . Categoric tests of improvement at 60 minutes provided the strongest evidence of group differences There are no rapid-acting intramuscular formulations of atypical antipsychotics available for quickly calming an agitated patient with bipolar disorder . In this study , 201 agitated patients with bipolar mania were r and omly assigned to receive one to three injections of the atypical antipsychotic olanzapine ( 10 mg , first two injections ; 5 mg , third injection ) , the benzodiazepine lorazepam ( 2 mg , first two injections ; 1 mg , third injection ) , or placebo ( placebo , first two injections ; olanzapine , 10 mg , third injection ) within a 24-hour period . Agitation was measured at baseline , every 30 minutes for the first 2 hours , and at 24 hours after the first injection using the Positive and Negative Syndrome Scale – Excited Component subscale and two additional agitation scales . At 2 hours after the first injection , patients treated with olanzapine showed a significantly greater reduction in scores on all agitation scales compared with patients treated with either placebo or lorazepam . At 24 hours after the first injection , olanzapine remained statistically superior to placebo in reducing agitation in patients with acute mania , whereas patients treated with lorazepam were not significantly different from those treated with placebo or olanzapine . Furthermore , no significant differences among the three treatment groups were observed in safety measures , including treatment-emergent extrapyramidal symptoms , the incidence of acute dystonia , or QTc interval changes . These findings suggest that intramuscular olanzapine is a safe and effective treatment for reducing acute agitation in patients with bipolar mania In a double-blind , prospect i ve study , 2 mg of intramuscular lorazepam and 5 mg of intramuscular haloperidol were equally effective in controlling aggression , agitation , and assaultive behavior .  Although lorazepam and haloperidol produced an equivalent mean decrease in aggression , significantly more subjects who received lorazepam had a greater decrease in aggression ratings than haloperidol recipients ; this effect was independent of sedation . Lorazepam produced significantly fewer extrapyramidal symptoms . These data support the current clinical practice of using lorazepam ( alone , or in combination with a neuroleptic ) for control of acute aggressive and assaultive behavior Abstract Objective To compare two widely used drug treatments for people with aggression or agitation due to mental illness . Design Pragmatic , r and omised clinical trial . Setting Three psychiatric emergency rooms in Rio de Janeiro , Brazil . Subjects 301 aggressive or agitated people . Interventions Open treatment with intramuscular midazolam or intramuscular haloperidol plus promethazine . Main outcome measures Patients tranquil or se date d at 20 minutes . Secondary outcomes : patients tranquil or asleep by 40 , 60 , and 120 minutes ; restrained or given extra drugs within 2 hours ; severe adverse events ; another episode of agitation or aggression ; needing extra visits from doctor during first 24 hours ; overall antipsychotic load in first 24 hours ; and not discharged by two weeks . Results 151 patients were r and omised to midazolam , and 150 to haloperidol-promethazine mix . Follow up for the primary outcome was available for 298 ( 99 % ) : 134/151 ( 89 % ) of patients given midazolam were tranquil or asleep after 20 minutes compared with 101/150 ( 67 % ) of those given haloperidol plus promethazine ( relative risk 1.32 ( 95 % confidence interval 1.16 to 1.49 ) ) . By 40 minutes , midazolam still had a statistically and clinical ly significant 13 % relative advantage ( 1.13 ( 1.01 to 1.26 ) ) . After 1 hour , about 90 % of both groups were tranquil or asleep . One important adverse event occurred in each group : a patient given midazolam had transient respiratory depression , and one given haloperidol-promethazine had a gr and e mal seizure . Conclusions Both treatments were effective . Midazolam was more rapidly sedating than haloperidol-promethazine , reducing the time people are exposed to aggression . Adverse effects and re sources to deal with them should be considered in the choice of the treatment BACKGROUND The pharmacological management of violence in people with psychiatric disorders is under- research ed . AIMS To compare interventions commonly used for controlling agitation or violence in people with serious psychiatric disorders . METHOD We r and omised 200 people to receive intramuscular lorazepam ( 4 mg ) or intramuscular haloperidol  ( 10 mg ) plus promethazine ( 25 - 50 mg mix ) . RESULTS At blinded assessment s 4 h later ( 99.5 % follow-up ) , equal numbers in both groups ( 96 % ) were tranquil or asleep . However , 76 % given the haloperidol-promethazine mix were asleep compared with 45 % of those allocated lorazepam ( RR=2.29,95 % CI 1.59 - 3.39 ; NNT=3.2,95 % CI 2.3 - 5.4 ) . The haloperidol-promethazine mix produced a faster onset of tranquillisation/sedation and more clinical improvement over the first 2 h. Neither intervention differed significantly in the need for additional intervention or physical restraints , numbers absconding , or adverse effects . CONCLUSIONS Both interventions are effective for controlling violent/agitated behaviour . If speed of sedation is required , the haloperidol-promethazine combination has advantages over lorazepam Objective . To compare oral risperidone and intramuscular ( IM ) haloperidol , both in combination with IM lorazepam , in the management of acute agitation and psychosis in the medical emergency department . Methods . In this prospect i ve , r and omized , placebo-controlled , double-blind study of 30 patients presenting to the emergency department with acute agitation and /or psychosis , three groups of 10 patients received oral and IM medications : 1 ) 2 mg oral risperidone and 2 mg IM lorazepam ; 2 ) 5 mg oral haloperidol and 2 mg IM lorazepam ; 3 ) oral placebo and 2 mg IM lorazepam . Each treatment group received both an injection and a tablet to reduce treatment group variability . Patients were evaluated using the Brief Psychiatric Rating Scale ( BPRS ) and the Positive and Negative Syndrome Scale ( PANSS ) before receiving medication and at 30 and 90 minutes after medication was administered . The intergroup mean percent reductions in rating scale scores were compared using ANOVA , chi-square , and Kruskal-Wallis tests . Results . There were no statistically significant differences among the groups at any point . The two groups receiving an antipsychotic plus lorazepam showed a trend towards increased symptom reduction compared with the group receiving lorazepam alone , although this trend was not statistically significant . Conclusions . Lorazepam alone was as effective as lorazepam plus haloperidol or lorazepam plus risperidone in this small trial . While not statistically significant , a trend toward better outcomes with combined treatment warrants further study STUDY OBJECTIVE We compare intravenous midazolam and droperidol for the onset of sedation of acutely agitated patients in the emergency department ( ED ) . METHODS This was a double-blind , r and omized , clinical trial set in the ED of a university teaching hospital . Subjects were adults , acutely agitated because of mental illness , intoxication , or both , who received midazolam or droperidol , 5 mg intravenously , every 5 minutes until se date d. We analyzed time to sedation using survival analysis , median times to sedation , and proportions se date d at 5 and 10 minutes . RESULTS Seventy-four patients received midazolam ; 79 patients , droperidol .  Survival analysis showed no difference in time to sedation ( hazard ratio 0.86 ; 95 % confidence interval [ CI ] 0.61 to 1.23 ) , P=.42 . Median time to sedation was 6.5 minutes for midazolam ( median dose 5 mg ) and 8 minutes for droperidol ( median dose 10 mg ) , P=.075 ( effect size 1.5 minutes ; 95 % CI 0 to 4 minutes ) . At 5 minutes , 33 of 74 ( 44.6 % ) patients from the midazolam group were adequately se date d compared with 13 of 79 ( 16.5 % ) patients from the droperidol group , a difference of 28.1 % ( 95 % CI 12.9 % to 43.4 % ; P<.001 ) . By 10 minutes , 41 of 74 ( 55.4 % ) from the midazolam group were se date d compared to 42 of 79 ( 53.2 % ) from droperidol , a difference of 2.2 % ( 95 % CI -14.9 % to 19.3 % ; P=.91 ) . Eleven adverse events occurred in the midazolam group and 10 in the droperidol group . Three patients required active airway management ( 3 patients with assisted ventilation and 1 patient intubated ) ; all received midazolam . CONCLUSION There is no difference in onset of adequate sedation of agitated patients using midazolam or droperidol . Patients se date d with midazolam may have an increased need for active airway management The efficacy of a benzodiazepine was compared with that of a neuroleptic for the rapid tranquilization of patients presenting at a psychiatric emergency room service . Thirty-seven highly agitated patients exhibiting psychotic symptoms were r and omly assigned to receive either 2 mg lorazepam or 5 mg haloperidol as needed every 30 min for 4 h. Administration route was either intramuscular injection or oral concentrate . Symptom ratings were conducted each hour using double-blind procedures . Both medications reduced symptom ratings on the Brief Psychiatric Rating Scale and Global Clinical Impression of Overall Symptom Severity Scale . Global Clinical Impression scores for the two medication groups did not differ significantly either at baseline or at 4 h after entry into the study . However , Global Clinical Impression scores of patients in the lorazepam group were less severe at intermittent ratings . The groups did not differ on the Brief Psychiatric Rating Scale at any rating time . No differences were found either in the number of doses administered or in the administration route selected . Given the potential for severe extrapyramidal symptoms developing hours or days after a single dose of haloperidol , lorazepam may provide an excellent alternative for the rapid tranquilization of the acutely agitated psychotic patient in the emergency room setting Distinct calming rather than nonspecific sedation is desirable for the treatment of acute agitation . In 3 double-blind studies , acutely agitated patients with schizophrenia ( N = 311 ) , bipolar mania ( N = 201 ) , or dementia ( N = 206 ) were treated with intramuscular ( 1 - 3 injections/24 hrs ) olanzapine ( 2.5 - 10.0 mg ) , haloperidol ( 7.5 mg ) , lorazepam ( 2.0 mg ) , or placebo . The Agitation-Calmness Evaluation Scale ( ACES ; Eli Lilly and Co. ) and treatment-emergent adverse events assessed sedation . Across all studies , 1 patient ( lorazepam-treated , bipolar ) became unarousable . There were no significant between-group differences in ACES scores of deep sleep or unarousable at any time across . Excluding asleep patients , agitation remained significantly more reduced with olanzapine than placebo ( P < .05 ) . The incidences of adverse events indicative of sedation were not significantly different with olanzapine versus comparators . For the treatment of acute agitation associated with schizophrenia , bipolar mania , or dementia , intramuscular olanzapine-treated patients experienced no more sedation than haloperidol- or lorazepam-treated patients and experienced distinct calming rather than nonspecific sedation BACKGROUND A recent review suggested an association between using unpublished scales in clinical trials and finding significant results . AIMS To determine whether such an association existed in schizophrenia trials . METHOD Three hundred trials were r and omly selected from the Cochrane Schizophrenia Group 's Register . All comparisons between treatment groups and control groups using rating scales  were identified . The publication status of each scale was determined and cl aims of a significant treatment effect were recorded . RESULTS Trials were more likely to report that a treatment was superior to control when an unpublished scale was used to make the comparison ( relative risk 1.37 ( 95 % CI 1.12 - 1.68 ) ) . This effect increased when a ' gold-st and ard ' definition of treatment superiority was applied ( RR 1.94 ( 95 % CI 1.35 - 2.79 ) ) . In non-pharmacological trials , one-third of ' gold-st and ard ' cl aims of treatment superiority would not have been made if published scales had been used . CONCLUSIONS Unpublished scales are a source of bias in schizophrenia trials OBJECTIVES Due to inherent dangers and barriers to research in emergency setting s , few data are available to guide clinicians about how best to manage behavioral emergencies . Key constructs such as agitation are poorly defined . This lack of empirical data led us to undertake a survey of expert opinion , results of which were published in the 2001 Expert Consensus Guidelines on the Treatment of Behavioral Emergencies . Several second-generation ( atypical ) antipsychotics ( SGAs ) are now available in new formulations for treating behavioral emergencies ( e.g. , intramuscular [ i.m . ] olanzapine and ziprasidone ; rapidly dissolving tablets of olanzapine and risperidone ) . Critical questions face the field . The SGAs are significantly different from the FGAs and from each other and have not been studied in unselected patients as were the FGAs . Can the SGAs can be thought of as a class , do all antipsychotics have similar anti-agitation effects in different conditions , and , if equally effective , what limits might their safety profiles impose ? Should antipsychotics be used more specifically to treat psychotic conditions , while benzodiazepines ( BNZs ) alone are used nonspecifically ? Few data are available concerning combinations of SGAs and BNZs , and findings concerning the traditional combination of haloperidol plus a BNZ may not be relevant to combinations with SGAs . The culture is also evolving with more emphasis on patient involvement in treatment decisions . An international consensus has been developing that calming rather than sedation is the appropriate endpoint of behavioral emergency interventions . We undertook a new survey of expert opinion to up date recommendations from the earlier survey . METHOD A written survey of 61 questions ( 1,020 options ) was mailed to 50 experts in the field , 48 ( 96 % ) of whom completed it . The survey sought to define level of agitation at which emergency interventions are appropriate , scope of assessment depending on urgency and patients ' ability to cooperate , guiding principles for selecting interventions , and appropriate physical and medication strategies at different levels of diagnostic confidence for a variety of provisional diagnoses and complicating conditions . A modified version of the R AND Corporation 's 9-point scale for rating appropriateness of medical decisions was used to score most options . Consensus was defined as a non-r and om distribution of scores by chi-square " goodness-of-fit " test . We assigned a categorical rank ( first line/preferred , second line/alternate , third line/usually inappropriate ) to each option based on the 95 % confidence interval around the mean . Ratings were used to develop guidelines for preferred strategies in key clinical situations . This study received financial support from multiple sponsors , with the panel kept blind to sponsorship to reduce possible bias . Medication ratings were based on responses of only those respondents with direct experience with each drug . In reporting practice patterns , the panel was asked to respond based on actual data rather than estimates . RESULTS The expert panel reached consensus on 78 % of the options rated on the 9-point scale . The responses suggest that physicians can make provisional diagnoses with some confidence and that pharmacological and nonpharmacological interventions are selected differentially based on diagnosis and other salient demographic and medical features . BNZs are recommended when no data are available , when there is no specific treatment ( e.g. , personality disorder ) , or when they may have specific benefits ( e.g. , intoxication ) . No single SGA emerges as a nonspecific replacement for haloperidol ; instead , different SGAs are preferred in various circumstances consistent with current evidence . To the degree that haloperidol is recommended , it is almost always in combination with a BNZ ; haloperidol alone is preferred only in the medically compromised . In contrast , the SGAs are more often recommended for use alone , and the panel would avoid combining BNZs with some SGAs . Oral risperidone alone or combined with a BNZ receives strong support in a variety of situations . Oral olanzapine was rated very similarly to risperidone , with slightly higher ratings than risperidone in situations where it has been studied ( e.g. , schizophrenia , mania ) and slightly lower ratings where it has not been studied or safety may be a concern ; there was less support for combining oral olanzapine with a BNZ . For oral treatment of agitation related to schizophrenia or mania , olanzapine alone , risperidone alone or combined with a BNZ , and haloperidol plus a BNZ are first line , with strong support also for combining divalproex with the antipsychotic for presumed mania . Oral ziprasidone and quetiapine generally received similar second-line ratings in most situations . If a parenteral agent is needed , i.m . olanzapine alone received somewhat more support than i.m . ziprasidone alone ; however , there was more support for i.m . ziprasidone alone or combined with a BNZ than for i.m . olanzapine plus a BNZ , probably reflecting safety concerns . For example , for a provisional diagnosis of schizophrenia , first-line parenteral options are i.m . olanzapine or ziprasidone alone or i.m . haloperidol or ziprasidone combined with a BNZ . Neither of the new parenteral formulations received as much support as traditional agents ( i.m . BNZs , i.m . haloperidol ) when no data are available or the diagnosis involves medical comorbidity or intoxication . When initial intervention with risperidone , ziprasidone , or haloperidol is unsuccessful , the panel recommended adding a BZD to the antipsychotic . However , when initial treatment with olanzapine or quetiapine is unsuccessful , increasing the dosage is recommended . Perphenazine was consistently rated second line and droperidol and chlorpromazine received third-line ratings throughout . CONCLUSIONS Within the limits of expert opinion and with the expectation that future research data will take precedence , these guidelines suggest that the SGAs are now preferred for agitation in the setting of primary psychiatric illnesses but that BNZs are preferred in other situations
target: When haloperidol and midazolam were compared with olanzapine , there was some evidence the combination was superior in terms of improvement , sedation and behaviour .
  There were relatively little good data and most trials are too small to highlight differences in either positive or negative effects .
  Adding a benzodiazepine to other drugs does not seem to confer clear advantage and has potential for adding unnecessary adverse effects .
  Sole use of older antipsychotics unaccompanied by anticholinergic drugs seems difficult to justify .
background: BACKGROUND Acute psychotic illness , especially when associated with agitated or violent behaviour , can require urgent pharmacological tranquillisation or sedation .
  In several countries , clinicians often use benzodiazepines ( either alone or in combination with antipsychotics ) for this outcome .
  OBJECTIVES To estimate the effects of benzodiazepines , alone or in combination with antipsychotics , when compared with placebo or antipsychotics , alone or in combination with antihistamines , to control disturbed behaviour and reduce psychotic symptoms .