title: Tardive dyskinesia treated with pimozide What does the PANSS mean? TREC-Rio trial: a randomised controlled trial for rapid tranquillisation for agitated patients in emergency psychiatric rooms [ISRCTN44153243] [Patients in a state of agitation at the admission service of a Rouen hospital emergency department]. Components of variance and intraclass correlations for the design of community-based surveys and intervention studies: data from the Health Survey for England 1994. Current practices in managing acutely disturbed patients at three hospitals in Rio de Janeiro-Brazil: a prevalence study Effects of selected phenothiazines on REM sleep in schizophrenics. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Risperidone, 2 mg/day vs. 4 mg/day, in first-episode, acutely psychotic patients: treatment efficacy and effects on fine motor functioning. The Overt Agitation Severity Scale for the objective rating of agitation. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine 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. A RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS Unpublished rating scales: a major source of bias in randomised controlled trials of treatments for schizophrenia. Antipsychotic efficacy of the antidepressant trimipramine: a randomized, double-blind comparison with the phenothiazine perazine. A pilot study of the role of prophylactic antiparkinson treatment during neuroleptic therapy.
abstract: We have investigated the action of pimozide in  tardive dyskinesia induced by prolonged administration of phenothiazines .  Improvement was recorded in a double blind study of 18 patients treated with maximum tolerated dosage ( mean 18.8 mg/day ) for 6 weeks . There was no deterioration in the therapeutic action of pimozide over this time . Parkinsonism and sedation were the main adverse effects . They were corrected by reduction of the dose of pimozide , but often recurred so that further adjustments of dosage were necessary . Our findings support the view that tardive dyskinesia is produced by a disturbance in the balance of central transmitters such that dopaminergic transmission is increased OBJECTIVE Despite the frequent use of the Positive and Negative Syndrome Scale ( PANSS ) for rating the symptoms of schizophrenia , the clinical meaning of its total score and of the cut-offs that are used to define treatment response ( e.g. at least 20 % or 50 % reduction of the baseline score ) are as yet unclear . We therefore compared the PANSS with simultaneous ratings of Clinical Global Impressions ( CGI ) . METHOD PANSS and CGI ratings at baseline ( n = 4091 ) , and after one , two , four and six weeks of treatment taken from a pooled data base of seven pivotal , multi-center antipsychotic drug trials on olanzapine or amisulpride in patients with exacerbations of schizophrenia were compared using equipercentile linking . RESULTS Being considered " mildly ill " according to the CGI approximately corresponded to a PANSS total score of 58 , " moderately ill " to a PANSS of 75 , " markedly ill " to a PANSS of 95 and severely ill to a PANSS of 116 . To be " minimally improved " according to the CGI score was associated with a mean percentage PANSS reduction of 19 % , 23 % , 26 % and 28 % at weeks 1 , 2 , 4 and 6 , respectively . The corresponding figures for a CGI rating " much improved " were 40 % , 45 % , 51 % and 53 % . CONCLUSIONS The results provide a better framework for underst and ing the clinical meaning of the PANSS total score in drug trials of schizophrenia patients with acute exacerbations . Such studies may ideally use at least a 50 % reduction from baseline cut-off to define response rather than lower thresholds . In treatment resistant population s , however , even a small improvement can be important , so that a 25 % cut-off might be appropriate 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 OBJECTIVE To determine the incidence and causes of agitation states in patients presenting at the Rouen University Hospital emergency room and to analyze the management scheme . PATIENTS AND METHOD A prospect i ve study was conducted over a 9 month period in 100 consecutive patients presenting a state of agitation assessed using the Overt Aggression Scale . A pre-planned management protocol was applied . RESULTS The incidence of states of agitation was 0.56 % . There were 43 women and 57 men , mean age 33 years . Most of the agitated patients were admitted between 6 p.m. and 4 a.m. ( 69 % ) . Over the 9 month period , 2 patients were admitted twice for agitation and 2 absconded . Low glucose level was the cause of agitation in 4 cases . Alcohol and /or drug use concerned 73 % of the agitated patients and was the most frequently observed triggering factor ( 17 % ) . Only 6 % of the patients had a regular employment . Physical restraining measures and sedation were required in 86 % and 84 % of the cases respectively . Among 67 patients given loxapine for sedation , 2 developed acute dyskinesia and 9 low blood pressure . One out of 4 patients were referred to a psychiatric unit . CONCLUSION Patients in a state of agitation are young , often female , and in a difficult socio-economic situation . Hypoglycemia is the main differential diagnosis . A triggering factor can often be identified . A state of agitation is not a repetitive condition but occurs as a short-lived episode in the patientís history . Such patients need rapid care to avoid further aggravation and disruption of the emergency room activity , and to prevent the patient from fleeing . Loxapine provides effective sedation but requires regular monitoring of blood pressure and can provoke acute dyskinesia in young subjects 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 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 SINCE THE discovery of rapid eye movements ( REMs ) associated with a desynchronized electroencephalogram ( EEG ) during behavioral sleep 1 and the correlation of this sleep stage with dreaming , 2 considerable investigation of REM sleep has been instituted to assess its significance in normal man and in various psychiatric illnesses . The similarity between mentation during dreaming in normal people and thought patterns in schizophrenia has led to many investigations of REM sleep in this disease . These studies have not consistently demonstrated marked differences in REM sleep between schizophrenics and normal subjects . 3 Similarly , REM sleep does not appear to be markedly altered in mental illness characterized primarily by depression . 3 Several recent studies have suggested , however , that Stage 4 or delta sleep may be decreased in schizophrenia 4 and depressive psychosis . 5,6 Various drugs used in the treatment of mental illness have 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 BACKGROUND The aim of this study was to examine differences in the improvement of clinical psychopathology and in fine motor functions at 2 doses of risperidone in first-episode , acutely psychotic patients . METHOD In a double-blind , fixed-dose study , 49 acutely psychotic , neuroleptic-naive patients who were admitted for the first time and who met DSM-IV criteria for schizophrenia , schizophreniform disorder , or schizoaffective disorder were r and omly assigned to 2 or 4 mg/day of risperidone .  Treatment efficacy was measured using the Brief Psychiatric Rating Scale , the Scale for the Assessment of Negative Symptoms , The Clinical Global Impressions scale , and the Social and Occupational Functioning Assessment Scale . Fine motor functions were assessed using a computerized device ( the Vienna Test System ) and were compared with those of a control group of 20 healthy subjects who were matched for age , gender , and educational level . RESULTS Treatment with doses of 2 and 4 mg of risperidone daily significantly reduced positive ( p < .0001 ) and negative ( p < .01 ) symptoms at 8 weeks . Although there were no significant differences in motor movements as measured using the Barnes Akathisia Scale and the Simpson-Angus Scale , computerized fine motor assessment showed significantly less motor dysfunction in the 2-mg/day group at 8 weeks . No significant correlations to plasma concentration of active moiety were found for data on psychopathology and fine motor functions . CONCLUSION The 2 doses of risperidone did not differ in terms of clinical improvement , but the 2-mg/day dose produced fewer fine motor dysfunctions . These results suggest that a dose as low as 2 mg/day of risperidone may be effective for patients with first-episode psychosis 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 Objective To determine whether haloperidol alone results in swifter and safer tranquillisation and sedation than haloperidol plus promethazine . Design Pragmatic r and omised open trial ( January-July 2004 ) . Setting Psychiatric emergency room , Rio de Janeiro , Brazil . Participants 316 patients who needed urgent intramuscular sedation because of agitation , dangerous behaviour , or both . Interventions Open treatment with intramuscular haloperidol 5 - 10 mg or intramuscular haloperidol 5 - 10 mg plus intramuscular promethazine up to 50 mg ; doses were at the discretion of the prescribing clinician . Main outcome measures The primary outcome was proportion tranquil or asleep by 20 minutes . Secondary outcomes were asleep by 20 minutes ; tranquil or asleep by 40 , 60 , and 120 minutes ; physically restrained or given additional drugs within 2 hours ; severe adverse events ; another episode of agitation or aggression ; additional visit from the doctor during the subsequent 24 hours ; overall antipsychotic load in the first 24 hours ; and still in hospital after 2 weeks . Results Primary outcome data were available for 311 ( 98.4 % ) people , 77 % of whom were thought to have a psychotic illness . Patients allocated haloperidol plus promethazine were more likely to be tranquil or asleep by 20 minutes than those who received intramuscular haloperidol alone ( relative risk 1.30 , 95 % confidence interval 1.10 to 1.55 ; number needed to treat 6 , 95 % confidence interval 4 to 16 ; P=0.002 ) . No differences were found after 20 minutes . However , 10 cases of acute dystonia occurred , all in the haloperidol alone group . Conclusions Haloperidol plus promethazine is a better option than haloperidol alone in terms of speed of onset of action and safety . Enough data are now available to change guidelines that continue to recommend treatments that leave people exposed to longer periods of aggression than necessary and patients vulnerable to distressing and unsafe adverse effects . Trial registration Current Controlled Trials IS RCT N83261243 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 A modification of an earlier rating scale for extrapyramidal system disturbance is described , and evidence for the validity and reliability of the scale is presented . The usefulness of the scale in studies of neuroleptic drugs is discussed . By its application it is possible to quantify extrapyramidal side effects and to separate them into four principal factors 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 BACKGROUND The tricyclic antidepressant trimipramine exhibits several features ( e. g. , dopaminergic effect , molecular structure similar to a neuroleptic , receptor-binding profile similar to clozapine ) that suggest its potential as an antipsychotic medication . The aim of the study was to investigate the antipsychotic potential of trimipramine in a controlled clinical trial comparing its antipsychotic efficacy with that of a neuroleptic . METHOD In a German multi-center , r and omized , double-blind trial , the antipsychotic efficacy of trimipramine was compared with that of the phenothiazine neuroleptic perazine , using the Brief Psychiatric Rating Scale ( BPRS ) , the Positive and Negative Syndrome Scale ( PANSS ) , and Clinical Global Impressions ( CGI ) . Antidepressant efficacy of both agents was measured by use of the Bech-Rafaelsen Melancholia Scale ( BRMES ) .  Ninety-five patients with acute schizophrenia ( DSM-III-R ) and a BPRS total score > 40 at baseline were treated with either 300 - 400 mg trimipramine or 450 - 600 mg perazine for 5 weeks . RESULTS Therapeutic equivalence of both treatments ( in the dosages used ) could not be demonstrated ( change in BPRS total score , per- protocol [ PP ] analysis , one-sided equivalence testing ) . However , intention-to-treat ( ITT ) as well as PP analysis showed a statistically significant decrease in the BPRS total scores in both treatment groups ( PP : trimipramine , 56.5 + /- 9.8 to 44.1 + /- 17.9 ; perazine , 56.4 + /- 10.8 to 37.9 + /- 12.9 ) . Significant decreases in all BPRS and PANSS subscores as well as CGI results and response rate support the antipsychotic efficacy of trimipramine . The BRMES total scores significantly decreased in both treatment groups without showing a significant difference between the two agents . Trimipramine was better tolerated than perazine and did not elicit extrapyramidal symptoms . CONCLUSION Trimipramine failed to exhibit therapeutic equivalence to perazine in the dosages used . However , there was evidence of a substantial antipsychotic effect of trimipramine . It may be a useful medication if depressive symptoms in psychotic patients require antidepressant treatment or if other antipsychotics can not be administered The authors administered haloperidol 4.5 mg t.i.d . to 33 drug-free schizophrenic patients . Ten patients did not receive anything else ( group HPL ) , while ten patients received procyclidine 5 mg t.i.d . , and 13 patients were given promethazine 25 mg t.i.d . ( groups HPRC and HPRM respectively ) in addition . Seven patients dropped out of the HPL group and three out of the HPRM group , but none out of the HPRC group . These drop outs were due to the development of early extrapyramidal side effects , which were absent in the HPRC group . The findings suggest that antiparkinson prophylaxis is useful during commencement of therapy with high-potency neuroleptic agents
target: This review suggests that both benzodiazepines work , but that midazolam has a faster onset and thereby reduces the risk of exposure to violence .
  Most evidence , however , exists for the haloperidol plus promethazine mix , with currently more than 400 people r and omised to the combination .
  The onset of action is swift and faster than lorazepam .
  The combination also seems safe with no clear longer term consequences .
background: BACKGROUND Health services often manage agitated or violent people and for emergency psychiatric services such behaviour is particularly prevalent ( 10 % ) .
  The drugs used in this situation should ensure that the person swiftly and safely becomes calm .
  OBJECTIVES To examine whether haloperidol plus promethazine is an effective treatment for psychosis induced agitation/aggression .