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Characteristics of studies
Characteristics of included studies [ordered by study ID]
Ir a:
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: not stated. Duration: 72 hours. Setting: hospital ‐ psychiatric emergency service, US. | |
| Participants | Diagnosis: all participants fulfilled DSM‐III‐R criteria for schizophrenia. n = 28. Age: mean 33 years. Gender: 11 men, 17 women. Ethnicity: black (n = 23). Consent: gave informed consent. History: not stated. Inclusion: 18‐60 years old, actively psychotic with a minimum score of 12 on the abbreviated BPRS. Exclusion: coexisting major axis disorder, significant medical illness, pregnancy, use of non‐prescription psychoactive drug or alcohol in previous 72 hours. | |
| Interventions | Benzodiazepines plus antipsychotics vs same antipsychotics. 1. Alprazolam 1 mg oral tablet + haloperidol 5 mg oral concentrate, mean 3.2 doses (n = 14). 2. Haloperidol 5 mg oral concentrate + placebo tablet, mean 2.1 doses (n = 14). Repeat dose given within first 24 hours if psychotic subscale was ≥ 11. Total dose administered on day 1 repeated days 2 and 3. Each participant received a minimum of 2 doses. | |
| Outcomes | Global state: no improvement*. Mental state: mean endpoint score (BPRS and BPRS‐psychosis subscale). Adverse effects/events: use of medication for EPS. Hospital and service outcomes: discharged. Unable to use ‐ Global state: level of positive psychiatric symptoms (SAPS); level of negative psychiatric symptoms (SANS) (no data within 48 hours). Adverse effects/events: EPS (no useable data). | |
| Notes | *'Improvement' ‐ undefined; this result included the number of participants who demonstrated lower mean baseline scores on the SAPS and BPRS subscale and were subsequently discharged before the completion of the study. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised ‐ participants were 'randomly allocated;' however, no further description of randomisation provided. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Low risk | Double‐blind ‐ the investigators who administered the scales were blind to each other's ratings, and trial author DMM was blind to the dose and schedule of treatment. Both investigators were blind to drug assignment. Rating scales: trial author JGB administered the BPRS‐psychosis subscale, SANS, SAPS and trial author DMM administered the full‐scale version of the BPRS ‐ ratings were not a self‐report or completed by an independent rater. |
| Incomplete outcome data (attrition bias) | Unclear risk | Follow‐up: 69%. 9 participants were permitted to leave the study early for 'humanitarian reasons,' as they had sufficiently improved to allow for early discharge. In this case, a final set of ratings were administered before discharge, and the results were included in the analyses. High attrition rate but last observation carried forward used for the analysis. |
| Selective reporting (reporting bias) | Unclear risk | Use of Simpson‐Angus Side Effects Profile and 'another side effects rating scale' was mentioned, but no data were reported. |
| Other bias | Unclear risk | Funding: supported in part by a grant from The Upjohn Company (now Pfizer). We are unsure whether Pfizer were involved in the study design and reporting process. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: parallel. Duration: 2 hours. Setting: psychiatric emergency services, Canada. | |
| Participants | Diagnosis: bipolar (n = 7), chronic schizophrenia (n = 5), schizoaffective disorder (n = 3), brief reactive psychosis (n = 1). n = 16 (14 were psychiatric inpatients at l'Hôpital Louis‐H. Lafontaine, Montreal; 2 were recruited from the emergency department of the Royal Victoria Hospital, Montreal, Canada). Age: 18‐60 years (mean 35 years). Gender: 10 men, 6 women. Ethnicity: not stated. Consent: participants gave voluntary, informed, written consent; in addition, signatures from 2 staff psychiatrists were required. History: not stated. Inclusion criteria: aged 18‐60 years with DSM‐III diagnosis of bipolar affective illness (manic phase, schizoaffective disorder, schizophrenia, schizophreniform disorder, brief reactive psychosis or atypical psychosis) and score of ≥ 4 on 1 of 4 items: hyperactivity, agitation, intrusiveness and impulsive behaviour on the Target Manic Behaviour Scale. Exclusion criteria: symptoms of organic brain syndromes, drug or alcohol abuse, epileptic disorders or ECT within past 6 months. | |
| Interventions | Benzodiazepines vs antipsychotics. 1. Clonazepam 1‐2 mg IM, mean dose 5.4 mg + procyclidine placebo, mean dose 15.9 mg (n = 8). 2. Haloperidol 5‐10 mg IM, mean dose 19.4 mg + procyclidine, mean dose 12.5 mg (n = 8). Given at 0, 0.5 and 1‐hour intervals. Dosage adjusted by blinded psychiatrist; procyclidine given to haloperidol group and procyclidine placebo given to clonazepam group. No other psychotropic medication was used during the study. | |
| Outcomes | Global impression: no improvement*; sedation; mean score (IMPS). Adverse effects/events: EPS. Leaving the study early**. Unable to use ‐ Global impression: using a modified 9‐point CGI‐S scale (not validated). Behaviour: Target Manic Behaviour Symptom Scale (not validated). Mental state: NOSIE (only selected items/questions from the actual validated tool were reported). | |
| Notes | *'Improvement' ‐ defined as a reduction of ≥ 50% on the baseline IMPS score. **Both participants who left the study early were included in the statistical analysis by using the endpoint score at time of exclusion. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised participants "were randomly assigned to one of two drug treatment groups;" however, no further description of randomisation provided. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Double blind ‐ the evaluating psychiatrist was "blind to treatment allocations" and determined the exact dose of medication. The haloperidol group also received procyclidine with each dose ‐ to maintain double‐blind conditions, the clonazepam group received procyclidine placebo with each dose. Rating scales: > 80% completed by a study psychiatrist, it was unclear whether the rater was blinded. |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 88%* ‐ low attrition rate and last observation carried forward. 2 participants withdrew from the study; 1 due to 'parkinsonian reaction' and 1 due to 'sedation.' |
| Selective reporting (reporting bias) | Low risk | All outcomes reported. |
| Other bias | Unclear risk | Funding: "Supported in part through a grant from Hoffmann La Roche Ltd." We are unclear whether Hoffmann La Roche Ltd were involved in the study design and reporting process. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: not stated. Duration: 24 hours. Setting: inpatients, Chinese hospital. | |
| Participants | Diagnosis: schizophrenia (n = 19), mood disorder (n = 19), schizoaffective psychosis (n = 6), epileptic mental disorder (n = 1), alcohol‐induced psychosis (n = 1) from Chinese Classification of Mental Disorders (CCMD‐2‐R). n = 46. Age: mean 32 years. Gender: 32 men, 14 women. Ethnicity: not stated. Consent: not stated. History: not stated. Inclusion criteria: aggressive people with mental illness. Exclusion criteria: not stated. | |
| Interventions | Benzodiazepines vs antipsychotics. 1. Clonazepam 2 mg IM (n = 22). 2. Haloperidol 10 mg IM (n = 24). | |
| Outcomes | Behaviour: mean endpoint (OAS). Mental state: mean endpoint score (BPRS). Adverse effects/events: EPS, tremor, high heart rate. | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "Subject randomised" ‐ no further description. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Not stated. Rating scales: unclear who administered the rating scales. |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 100%. |
| Selective reporting (reporting bias) | Low risk | All measured outcomes were reported. |
| Other bias | Unclear risk | Funding: not stated. Unsure whether there was potential bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blinding, not state who was blinded. Design: parallel. Duration: 24 hours. Setting: inpatients, Chinese hospital. | |
| Participants | Diagnosis: schizophrenia (CCMD‐III). n = 45. Age: 18‐45 years. Gender: 20 men and 25 women. Ethnicity: not stated. Consent: yes. History: not stated. Inclusion criteria: schizophrenia (CCMD‐3), aged 18‐45 years, ≥ 4 on the agitation item from BPRS, ≥ 4 on any 1 of the following items from BPRS: unco‐operativeness, hostility, tension, mannerisms and posturing. Exclusion criteria: serious physical illness, substance or alcohol dependence, received the study drugs 1 month prior to randomisation but with poor response. | |
| Interventions | Combined benzodiazepines/antipsychotics vs same antipsychotics + placebo vs same benzodiazepine + placebo. 1. Clonazepam 2‐6 mg IM + haloperidol 5‐15 mg IM (n = 15). 2. Haloperidol 5‐15 mg IM + placebo (n = 15). 3. Clonazepam 2‐6 mg IM + placebo (n =15). Participants were administered scopolamine where EPS occurred. | |
| Outcomes | Mental state: no improvement*. Mental state: mean score (total score of agitation items on BPRS, positive symptom score on BPRS). Adverse effects/events. | |
| Notes | * decrease rate of BPRS score < 30%. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised ‐ participants were "randomly allocated" based on random numbers. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Double blind, not state who was blinded. |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 100%. |
| Selective reporting (reporting bias) | Low risk | All measured outcomes were reported. |
| Other bias | Low risk | Funding: American John M Davis Funding. We did not detect any other potential bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: not stated. Duration: 24 hours. Setting: Eitanim Psychiatric Hospital, Israel. | |
| Participants | Diagnosis: paranoid schizophrenia (n = 9), schizoaffective schizophrenia (n = 9), schizophrenia subtypes (n = 5), paranoid states (n = 2), mania (n = 5), no diagnosis (n = 10). n = 40. Age: 20‐49 years (mean 33 years). Gender: 27 men, 13 women. Ethnicity: not stated. Consent: not stated. History: previous hospitalisation (mean 3 instances). Inclusion criteria: newly admitted psychotic people aged 20‐50 years after 2 days of drug‐free observation. Exclusion criteria: physical illness. | |
| Interventions | Benzodiazepines vs antipsychotics. 1. Diazepam 30‐40 mg IV (n = 20). 2. Haloperidol 20‐35 mg IV (n = 20). In the haloperidol group, 10 participants received high‐dose haloperidol and 10 participants received moderately high‐dose haloperidol; these scores were analysed together. Doses were given over a 3‐hour period. All participants were free from neuroleptics for 48 hours before the study began. | |
| Outcomes | Global impression: sedation; mean score (CGI). | |
| Notes | Note: assumptions were made regarding missing SDs data ‐ SDs for the CGI‐S and BPRS mean scores were estimated from the range. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised "patients were randomly assigned" to treatment ‐ no further description provided. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Observer blind ‐ it is unclear how trial authors remained blinded to alternation and decrease of haloperidol dosage. Rating scales: BPRS and CGI were performed by consensus of 2 physicians (trial authors EL and YL), who were "unaware of the treatment administered." |
| Incomplete outcome data (attrition bias) | High risk | Follow‐up: 50%. Reasons for dropout were reported; 16 due to treatment and 4 due to 'raters' being unavailable. |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | Low risk | Funding: supported by a grant from the Gralnick Foundation, High Point Hospital, Port Chester, NY. We did not detect any other bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: not stated. Duration: 2 hours. Setting: psychiatric hospital, Israel. | |
| Participants | Diagnosis: schizophrenia (n = 19), schizoaffective disorder (n = 7), bipolar (n = 2, DSM‐IV, Axis I Structured Clinical Interview). n = 28. Age: 20‐60 years (mean 36.8 years). Gender: 13 men, 15 women. Ethnicity: not stated. Consent: need for informed consent waived. History: not stated. Inclusion criteria: active psychosis, disruptive or aggressive behaviour; pronounced psychomotor agitation or violent outbursts; hospitalisation in an acute ward. Exclusion criteria: not stated. | |
| Interventions | Benzodiazepines vs antipsychotics. 1. Flunitrazepam 1 mg IM, single dose (n = 15). 2. Haloperidol 5 mg IM, single dose (n = 13). Participants were monitored for 120 minutes. | |
| Outcomes | Global impression: no improvement*; sedation. Adverse effects/events: EPS. Unable to use ‐ Behaviour: OAS scores (variance not reported). | |
| Notes | *'Improvement' ‐ defined as reduction of ≥ 50% in the OAS score at 90 minutes. Participants in each group were taking additional medications leading up to the study, including the following in the haloperidol group: haloperidol 5‐10 mg/day (n = 4); perphenazine 5‐20 mg/day (n = 5); levomepromazine 50‐200 mg/day (n = 2); zuclopenthixol 25 mg/day (n = 2); and the following in the flunitrazepam group: perphenazine 5‐20 mg/day (n = 4); haloperidol 5‐15 mg/day (n = 6); levomepromazine 75 mg/day (n = 1); zuclopenthixol 25‐50 mg/day (n = 4). 4 participants (2 from each group) were also taking mood stabilisers (carbamazepine and valproic acid) and lorazepam. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Participants were randomised "using a table of random numbers." |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Not state whether investigators were blinded. Rating scales: trial coauthor administered rating scales used for study. All rating scales (OAS, BPRS and CGI) were completed by author NK, who was blind to the study medications; unclear whether dose adjustment was blind. |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 100%. |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | Unclear risk | Funding: not stated. Unsure whether there was potential bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: non‐blind. Design: not stated. Duration: "more than 60 minutes." Setting: metropolitan psychiatric hospital, US. | |
| Participants | Diagnosis: manic (n = 22), schizophrenia (n = 16), atypical psychotics (n = 16), miscellaneous diagnoses (n = 14). n = 68. Age: not stated. Gender: 41 men, 27 women. Ethnicity: not stated. Consent: not stated. History: not stated. Inclusion criteria: requiring immediate treatment for agitated or assaultive behaviour and had to score > 50 mm on a 100‐mm VAS for agitation. All had failed to respond to non‐pharmacological interventions to control agitation. Exclusion criteria: not stated. | |
| Interventions | Benzodiazepines + antipsychotics vs same benzodiazepine vs same antipsychotic. 1. Lorazepam + haloperidol: haloperidol 5 mg IM + lorazepam 4 mg IM (n = 24). 2. Lorazepam 4 mg IM (n = 23). 3. Haloperidol 5 mg IM (n = 21). All given as a single dose. | |
| Outcomes | Global impression: sedation. | |
| Notes | The balance of men/women differed between treatment groups. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised; however, no further description of randomisation provided. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | High risk | Non‐blind, authors stated, "we considered that the degree of tranquillisation desired when treating agitated patients is easily ascertained, and thus we did not use control subjects and a blind design." Rating scales: unclear who administered rating scales used to determine baseline agitation ratings. |
| Incomplete outcome data (attrition bias) | Unclear risk | Follow‐up: 100%. |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | Unclear risk | Funding: not stated. Unsure whether there was potential bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: prospective. Duration: 48 hours ‐ intervention in an emergency situation; participants in both groups usually required only 1 parenteral injection for behavioural control during the study period (mean number of injections for lorazepam group = 1.13; mean number of injections for haloperidol group = 1.10). Setting: locked intensive care unit at Massachusetts Mental Health Center, Boston, US. | |
| Participants | Diagnosis: schizophrenia (n = 16), bipolar (n = 11), schizoaffective disorder (n = 4), organic mental disorder (n = 6), other (n = 13). n = 60*. Age: mean 34 years. Gender: not stated. Ethnicity: not stated. Consent: not required. History: not stated. Inclusion: psychotic participants on a locked intensive care unit who required parenteral medication to control aggressive, assaultive or disruptive behaviour. Exclusion: known substance abuse documented by positive toxicology screen on admission. | |
| Interventions | Benzodiazepines vs antipsychotics. 1. Lorazepam 2 mg IM, mean 1.13 injections (n = 30). 2. Haloperidol 5 mg IM, mean 1.10 injections (n = 30). Unclear when additional doses were given. | |
| Outcomes | Global impression: no improvement*. Global impression: sedation. Adverse effects/events: EPS. Unable to use ‐ Behaviour: OAS (no SD available). Mental state: BPRS (no SD available). | |
| Notes | *'Improvement' ‐ defined as a greater than mean decrease in OAS scores at 2 hours. "More bipolar participants received haloperidol by chance." *At the time of entering the study: ‐ n = 4 in the lorazepam group and n = 6 in the haloperidol group were receiving lithium carbonate. During the study period: ‐ n = 3 in the lorazepam group and n = 3 in the haloperidol group also received anticonvulsants. ‐ n = 3 in the lorazepam group and n = 3 in the haloperidol group also received beta‐blocking agents. ‐ n = 7 in the lorazepam group and n = 3 in the haloperidol group also received benzodiazepines. (Separate data analyses were conducted for participants receiving these additional psychotropic medications, but results did not differ.) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised ‐ no further description. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Low risk | Investigators were likely to have been blinded as the parenteral medication was prepared in advance by a member of the research staff who had no direct clinical responsibility for the participant. Rating scales: raters were blind to the treatment condition received by the participant. OAS ratings were obtained by staff nurses. BPRS ratings were obtained by "trained study psychiatrists." Adverse effects and sedation were assessed by clinicians who did not participate in evaluating therapeutic results. |
| Incomplete outcome data (attrition bias) | Unclear risk | Follow‐up: sedation 88%; EPS 67%. ITT: not stated. Many participants were unavailable for all ratings ‐ "the number of patients available for rating after baseline declined in both treatment groups because some were discharged or transferred from the locked intensive care unit." |
| Selective reporting (reporting bias) | Unclear risk | Complete data not available ‐ SDs not available for most reported outcomes. BPRS and CGI data not reported for 48 hours post injection. |
| Other bias | Unclear risk | Funding: supported in part by Wyeth Laboratories. Unsure whether Wyeth Laboratories were involved in study design and reporting process. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: prospective, parallel, multi‐centre. Duration: 24 hours. Setting: emergency departments in 5 university/general hospitals in the US: University of Texas Southwestern Medical Center, Dallas; Harbor‐UCLA Medical Centre, Los Angeles; University of Nebraska Medical Center, Omaha; Albert Einstein Medical Centre, Philadelphia; and Harborview Medical Center, Seattle. | |
| Participants | Diagnosis: schizophrenia (n = 47), psychosis (n = 27), psychoactive substance abuse (n = 16), mania (n = 13), schizophreniform disorder (n = 1). n = 98. Age: mean 34 years. Gender: 73 men, 25 women. Ethnicity: not stated. Consent: informed consent wherever possible. History: all participants exhibited psychosis and behavioural dyscontrol (agitated, aggressive, destructive, assaultive or restless behaviour). Inclusion: presentation to emergency department with psychosis and behavioural dyscontrol to the extent they were capable of harming themselves or others. Score of ≥ 5 on ≥ 3 psychosis/anxiety items from the BPRS. Exclusion: obvious alcohol intoxication, central nervous system depression, allergic hypersensitivity, delirium, neuroleptic malignant syndrome, airway obstruction, severe hypotension or hypertension, acute narrow‐angle glaucoma, benzodiazepine or antipsychotic in previous 24 hours, fluphenazine decanoate in previous 2 weeks, haloperidol decanoate in previous 4 weeks, pregnancy. | |
| Interventions | Benzodiazepine + antipsychotic vs benzodiazepine vs same antipsychotic. 1. Lorazepam 2 mg IM + haloperidol 5 mg IM, maximum 6 doses (n = 32). 2. Lorazepam 2 mg IM, maximum 6 doses (n = 31). 3. Haloperidol 5 mg IM, maximum 6 doses (n = 35). Administered over 12 hours with ≤ 6 doses. First 3 injections at least 1 hour apart and remainder 2 hours apart. Need for subsequent doses made by blinded evaluator. Most participants had < 3 doses (lorazepam: 74%; haloperidol: 71%; combination: 91%). | |
| Outcomes | Global impression: no improvement*; need for additional medication; sedation. Behaviour: mean behaviour score (ABS). Mental state: mean endpoint score (BPRS psychosis subscale). Adverse effects/events: EPS; use of medication for EPS; ataxia, dizziness, dry mouth, speech disorder. Unable to use ‐ Global impression: CGI (no useable data). | |
| Notes | *'Improvement' ‐ defined as a decrease of 1 from baseline or ≥ 2 from baseline on the CGI (at 3 hours). Sample numbers were not clear, as the authors stated that data were only collected if the participant was awake. Note: assumptions made regarding missing SDs data. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised ‐ eligible participants were "sequentially assigned using a computer‐generated table of random numbers to receive one of three therapies." |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Low risk | Double‐blind ‐ "the emergency department psychiatrist who treated and rated the patient remained blinded to the identity of the patient's medication throughout treatment." Rating scales: administered by emergency department psychiatrist, who also treated the participant, but "remained blinded to the identity of the patient's medication throughout." |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 100%. The data from 2 participants were excluded from the efficacy analysis, as it was later determined that they had both received prescribed antipsychotic medication shortly before entering the study. Unclear which group(s) these 2 participants were excluded from. |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | Unclear risk | Funding: supported in part by a grant from Wyeth‐Ayerst Research (now Pfizer). Unsure whether Pfizer were involved in study design and reporting process. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: not stated. Duration: 4 hours. Setting: Psychiatric Emergency Service, Eastern Pennsylvania Psychiatric Institute, US. | |
| Participants | Diagnosis: schizophrenia (n = 13), bipolar (n = 13), schizoaffective (n = 4), psychotic disorder not otherwise specified (n = 7). n = 37. Age: 18‐61 years. Gender: 26 men, 11 women. Ethnicity: white (n = 21), African‐American (n = 14), Hispanic (n = 2). Consent: need for informed consent waived. History: drug abuse or dependence n = 10. Inclusion criteria: highly agitated people exhibiting psychotic symptoms, judged by emergency department staff to be an imminent danger to themselves, required restraint, scored ≥ 5 on ≥ 3 BPRS items and ≥ 4 on CGI. Exclusion criteria: not stated. | |
| Interventions | Benzodiazepines vs antipsychotics. 1. Lorazepam 2 mg oral or IM (n = 17). 2. Haloperidol 5 mg oral or IM (n = 20). Medication administered every 30 minutes for 4 hours 'as needed' until the participant was sedated or no longer posed a danger to themselves or staff. | |
| Outcomes | Global impression: sedation; mean endpoint score (CGI‐S). Mental state: mean endpoint score (BPRS). Adverse effects/events: EPS. | |
| Notes | More bipolar participants received lorazepam (n = 10) than haloperidol (n = 3). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised; however, no further description of randomisation provided. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Double blind; however, no further description of blinding provided. Rating scales: symptom ratings were conducted by 1 of 4 raters (psychiatry residents or psychiatric nursing staff). Raters were trained by trial author SF. |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 100%. |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | Low risk | Funding: supported in part by a grant from the National Alliance for Research on Schizophrenia and Depression. We detect no other bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: not stated. Duration: 7 days. Setting: Sterkfontein Psychiatric Hospital, Krugersdorp, South Africa. | |
| Participants | Diagnosis: DSM‐III‐R organic (psychoactive substance) hallucinosis or delusional disorder (n = 24), schizophrenia (n = 16), bipolar disorder (n = 14), no diagnosis (n = 6). n = 60. Age: 18‐45 years. Gender: 46 men, 14 women. Ethnicity: not stated. Consent: signed informed consent obtained ‐ when consent was difficult to obtain, relatives were called upon to provide consent. History: not stated. Inclusion criteria: aged 18‐45 years, with aggressive and disorganised behaviour. Exclusion criteria: physical illness, pregnancy, abnormal routine blood tests. | |
| Interventions | Benzodiazepines + antipsychotics vs antipsychotics + antipsychotics. 1. Lorazepam 4 mg IM + haloperidol 10 mg oral (n = 30). 2. Clothiapine 40 mg IM + haloperidol 10 mg oral (n = 30). Dose repeated 6 hourly 'if warranted.' | |
| Outcomes | Behaviour: mean aggression score (OAS). Leaving the study early. Unable to use ‐ Mental state: mean score (BPRS) (no data within 48 hours). Extrapyramidal adverse effects (SAS) (no data within 48 hours). | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised ‐ no further description provided. |
| Allocation concealment (selection bias) | Unclear risk | Not stated: medication administered as "determined by the emergency room nursing and physician staff." |
| Blinding (performance bias and detection bias) | Unclear risk | Medications administered using "double blind procedures." Not stated who was blinded. Rating scales were completed by 1 of 4 people who were "trained" by study author (SF). |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 100%. |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | Unclear risk | Funding: not stated. Unsure whether there was potential bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: not stated. Duration: 3 hours. Setting: psychiatric emergency service, US hospital. | |
| Participants | Diagnosis: bipolar (n = 9), psychosis (n = 4), paranoid schizophrenia (n = 3), brief reactive psychosis (n = 1), undifferentiated schizophrenia (n = 1), substance‐induced (n = 2). n = 20. Age: mean 36 years. Gender: 13 men, 7 women. Ethnicity: not stated. Consent: waiver of informed consent obtained. History: not stated. Inclusion criteria: aged 18‐50 years presenting to psychiatry emergency service with acutely agitated behaviour that met clinical criteria for chemical restraint, defined by a minimum score of 4, with a score of ≥ 2 on at least 1 OAS item, and a minimum rating of 50 on a 100‐point VAS reflecting agitation and hostility (n = 20). Exclusion criteria: pregnancy, HIV positive, history of seizures, severe head trauma, psychopathology due to suspected general medical condition or those whose symptoms related to drug or alcohol abuse. | |
| Interventions | Benzodiazepine + antipsychotic vs same benzodiazepine. 1. Lorazepam 2 mg IM + haloperidol 5 mg IM (n = 9). 2. Lorazepam 2 mg IM (n = 11). (Repeated once at 60 minutes if participants were still severely agitated.) | |
| Outcomes | Global impression: no improvement*; need for additional medication. Adverse effects/events: EPS. Leaving the study early. Unable to use ‐ Global impression: CGI (variance was not reported). Behaviour: mean aggression score (VAS) (variance was not reported); OAS scores (variance was not reported). | |
| Notes | *'Improvement' ‐ defined as participants who demonstrated a decrease in ≥ 4 points on OAS scale. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised ‐ "Participants were assigned to treatment according to computer‐generated forced randomisation blocks of four." |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Double blind ‐ "a member of nursing staff, independent of patient assessment or treatment, prepared and coded each injection of equal volume." Rating scales: administered by an investigator ‐ unclear whether this investigator was an independent rater. |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 100%. |
| Selective reporting (reporting bias) | High risk | Authors changed criteria for 'improvement' on the VAS post‐study, after analysis had taken place. Full data not reported (i.e. continuous data for rating scales). Ratings for CGI, VAS and OAS taken at 30, 60, 120 and 180 minutes but no data were reported. |
| Other bias | Unclear risk | Funding: not stated. Unsure whether there was potential bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: not stated. Duration: 24 hours. Setting: hospitals in Romania and US. | |
| Participants | Diagnosis: manic, mixed with psychotic features (52.3%; n = 105/201), mood congruent (87.5%; n = 176/201), rapid cycling (52.2%; n = 105/201). n = 201. Age: mean 40 years. Gender: 107 men, 94 women. Ethnicity: white (n = 146), black (n = 32), other (n = 23). Consent: written informed consent. History: age of onset mania or hypomania (mean 23.8), depression (mean 22.6), mixed episode (mean 24.7). Inclusion criteria: aged ≥ 18 years with DSM‐IV bipolar disorder (manic or mixed), deemed by a physician to have agitation severe enough to receive injections, minimum total PANSS‐EC score of 14, and ≥ 1 individual item score of ≥ 4. Exclusion criteria: not stated. | |
| Interventions | Benzodiazepines vs antipsychotics vs placebo. 1. Lorazepam 2‐5 mg IM (n = 51). 2. Olanzapine 10‐25 mg IM (n = 99). 3. Placebo (first and second injections were placebo, the third injection was olanzapine 10 mg; participants requiring the third injection were excluded from 24‐hour analysis, n = 21, n = 51). Participants received 1‐3 doses over 3‐20 hours based on the clinical judgement of the investigator. | |
| Outcomes | Global impression: no improvement*; sedation; need for additional medication; mean change (CGI‐S). Behaviour: mean behaviour score (ABS). Mental state: mean change (PANSS and PANSS‐EC). Adverse effects/events: EPS, use of medication for EPS, dizziness, vomiting, nausea. Leaving the study early. Unable to use ‐ Agitation‐Calmness Evaluation Scale (not validated ‐ developed by trial sponsors). | |
| Notes | *'Improvement' ‐ defined as a reduction of ≥ 40% on the PANSS‐EC subscale. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised ‐ no further description. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Double blind ‐ no further description. Rating scales: Agitation‐Calmness Evaluation Scale ‐ single‐item 9‐point scale, developed by trial sponsors Eli Lilly and Company (results not included). Unclear who administered the rating scales used. |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 91.6%. ITT analysis used (last observation carried forward). |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | High risk | Funding: study sponsored by Eli Lilly and Company ‐ Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, US. Lead trial author KM and coauthors FZ, SD, MT, KK, RR, DW, PT and AB were each employed by trial sponsors Eli Lilly and Company at time of the study. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: open. Design: parallel. Duration: 2 weeks. Setting: Department of Psychiatry, Christian Medial College, Vellore, Tamil Nadu, India. | |
| Participants | Diagnosis: schizophrenia (n = 37), acute psychosis (n = 22), mania (n = 97), depression (n = 19), substance misuse (n = 10), other (n = 15). n = 200. Age: mean 32.2 (lorazepam group); mean 30.9 (combination group). Gender: 119 men, 81 women. Ethnicity: not stated. Consent: consent was obtained from a responsible relative if participants refused, or lacked capacity to consent to treatment by virtue of severe mental illness. Relatives were fully informed and written consent obtained. History: not stated. Inclusion criteria: where treating clinician felt that participants needed acute IM sedation due to agitation and dangerous behaviour; where treating physician did not feel that either intervention would pose an addition risk to the participant. Exclusion criteria: participants without a responsible relative were excluded. | |
| Interventions | Benzodiazepines vs antipsychotics plus antihistamines. 1. Lorazepam 4 mg IM (n = 100). 2. Haloperidol 10 mg IM + promethazine 25/50 mg IM (n = 96 received 50 mg; n = 4 received 25 mg, drawn into the same syringe, n = 100). All doses were given at the discretion of the treating physician. | |
| Outcomes | Global impression: clinical improvement*; need for additional medication, sedation, mean score (CGI). Adverse effects/events: airway management, nausea. Hospital and service outcomes: discharged. Leaving the study early: loss to follow‐up. Unable to use ‐ Use of physical restraints (not in remit of review). Leaving the study early (no data within 48 hours). | |
| Notes | *'Improvement' ‐ defined as 'clinically improved' under the CGI ‐ improvement scale dichotomised; much and very much improved. Participants in each group were receiving other medications at the time of entering the study: anticonvulsants (n = 15), anticholinergics (n = 14), antidepressants (n = 17), antipsychotics (n = 53), benzodiazepines (n = 23), beta‐blockers (n = 1), lithium (n = 14). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised; 'pragmatic' ‐ computer‐generated random numbers list in varying sized blocks < 10. |
| Allocation concealment (selection bias) | Low risk | A table of allocation sequence independent of block size was produced. Tables were then sent to a colleague independent of the TREC team who ensured that the correct drug was in the consecutively numbered local pack before it was sealed. These packs were constructed of cardboard, were identical and were sealed firmly with tape, across which the consecutive number was written. |
| Blinding (performance bias and detection bias) | High risk | Investigators not blinded, as blinding was kept until point of treatment assignment, which minimised selection bias. Rating scales: study co‐ordinators, who were blind to interventions given, undertook ratings. |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 100% in lorazepam group at 4 hours; 99% in combination group at 4 hours. Missing data were reported at each level of assessment (total n = 12). |
| Selective reporting (reporting bias) | Low risk | All measured outcomes were reported. |
| Other bias | Low risk | Funding: funded by intramural research grants from Fluid Research Fund (Christian Medical College, Vellore), and Cochrane Schizophrenia Group general fund. We detected no other potential bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: prospective. Duration: 90 minutes. Setting: university affiliated emergency department, US. | |
| Participants | Diagnosis: schizophrenia (n = 13), substance abuse (n = 8), bipolar (n = 4), personality disorder (n = 2), schizoaffective (n = 1), not stated (n = 2). n = 30. Age: mean 40 years. Gender: 23 men, 7 women. Ethnicity: not stated. Consent: informed consent required. History: not stated. Inclusion criteria: aged 18‐65 years, agitated or acutely psychotic (or both) people who required immediate treatment for symptom reduction. Exclusion criteria: medically unstable conditions, inability to provide informed consent, known allergy or adverse reaction to study drugs, pregnancy, administration of sedatives or antipsychotics in the emergency department prior to enrolment. | |
| Interventions | Benzodiazepines + antipsychotics vs same benzodiazepines. 1. Lorazepam 2 mg IM + placebo oral (n = 10). 2. Lorazepam 2 mg IM + risperidone 2 mg oral (n = 10). 3. Lorazepam 2 mg IM + haloperidol 5 mg oral (n = 10). | |
| Outcomes | Global impression: no improvement*; need for additional medication. Mental state: mean score (BPRS) (skew); mean score (PANSS) (skew). Leaving the study early. | |
| Notes | *'Improvement' ‐ defined as number of participants who returned for the 24‐hour follow‐up visit and demonstrated a marked improvement on both BPRS and PANSS. 30% of participants tested positive on the urine screen for marijuana or cocaine; 33% of participants had positive blood alcohol levels. Pilot study. SDs calculated using the mean and confidence intervals. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "Patients were randomly assigned to one of three double‐blind groups" ‐ no further description. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Double blind ‐ no further description. Rating scales: administered by trained study evaluators, with inter‐rater reliability assessed by independent evaluation of a video‐taped mode |
| Incomplete outcome data (attrition bias) | High risk | Follow‐up: 91%; 2 people withdrew after providing consent and before trial commenced and 1 participant was unable to stay awake after intervention, therefore, scores of interview not included in data analysis. |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | Unclear risk | Funding: study funded by a grant from Janssen Pharmaceutica. Unsure whether Janssen Pharmaceutica was involved in the study design and reporting. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: not stated. Design: parallel. Duration: 120 minutes. Setting: South Korea. | |
| Participants | Diagnosis: acute psychotic agitation. n = 37. Age: ≥ 18 years. Gender: not stated. Ethnicity: not stated. Consent: not stated. History: not stated. Inclusion criteria: men and women, ≥ 18 years, DSM‐IV diagnosis of schizophrenia, schizophreniform disorder, brief psychotic disorder, or schizoaffective disorder, bipolar disorder; and who had an excited component score ≥ 14 on the PANSS with a score of ≥ 4 on at least 1 item (1‐ to 7‐point scale). Psychotic disorders were brief psychotic disorder (8.1%), schizophreniform disorder (8.1%), schizophrenia (45.9%), schizoaffective disorder (2.7%), bipolar disorder (35.1%). Exclusion criteria: not stated. | |
| Interventions | Benzodiazepines + antipsychotic vs same antipsychotics. 1. Haloperidol 5 mg IM (n = 10). 2. Olanzapine* 10 mg IM (n = 12). 3. Haloperidol 5 mg IM + lorazepam 4 mg IM (n=15). | |
| Outcomes | Adverse events. Unable to use ‐ PANSS‐EC, CGI‐S, CGI‐I (no data reported), seclusion state (need to contact the author and confirm whether it should read 'sedation state'). | |
| Notes | Only abstract available. We tried to contact the author, but received no reply. *We did not use the data from this group as it did not meet our inclusion criteria. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not stated. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Not stated. |
| Incomplete outcome data (attrition bias) | Unclear risk | Not stated. |
| Selective reporting (reporting bias) | Unclear risk | Only abstract is available, no full text. Unsure whether there was selective reporting. |
| Other bias | Unclear risk | None known. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: open. Design: parallel. Duration: 24 hours. Setting: Institute of Mental Health, Hyderabad, India. | |
| Participants | Diagnosis: acute psychotic agitation. n = 60 Age: not stated. Gender: not stated. Ethnicity: not stated. Consent: not stated. History: not stated. Inclusion criteria: not stated. Exclusion criteria: not stated. | |
| Interventions | Benzodiazepines vs antipsychotics + antihistamines. 1. Lorazepam 4 mg IM (n = not stated). 2. Haloperidol 10 mg IM + promethazine 50 mg IM (n = not stated). | |
| Outcomes | Unable to use ‐ ABS, CGI‐S, CGI‐I, requires restraints, additional medication, being tranquil, asleep and adverse events (no data reported). | |
| Notes | Only abstract available. We tried to contact the author, but received no reply. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not stated. |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | High risk | Open label. |
| Incomplete outcome data (attrition bias) | Unclear risk | Not stated. |
| Selective reporting (reporting bias) | Unclear risk | As only abstracts were available, we did not know how many outcomes were reported in the full text. |
| Other bias | Unclear risk | Not stated. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: open. Design: parallel. Duration: 2 weeks. Setting: 3 public psychiatric hospitals, Rio de Janeiro, Brazil. | |
| Participants | Diagnosis: psychosis (n = 219), substance misuse (n = 51), not stated (n = 30)*. n = 301. Age: mean 38 years. Gender: 146 men, 155 women. Ethnicity: not stated. Consent: not required from participant in the emergency setting; if relatives were present, they were fully informed and consent was requested. History: 9% of participants included had no previous psychiatric attendance. Inclusion criteria: where treating clinician was uncertain of which treatment to implement where participants needed acute IM sedation due to agitation and dangerous behaviour. Exclusion criteria: where treating clinician believed 1 treatment represented an additional risk for the participant. | |
| Interventions | Benzodiazepines vs antipsychotics + antihistamines. 1. Midazolam 15 mg IM (n = 150). 2. Haloperidol 5‐10 mg IM (n = 77 received 5 mg; n = 71 received 10 mg) + promethazine 50 mg IM (n = 147 received 50 mg; n = 1 received 25 mg, drawn into the same syringe, n = 148). The benzodiazepine antagonist flumazenil was made available at each centre for use in the event of midazolam toxicity. | |
| Outcomes | Global impression: sedation**. Adverse effects/events: seizure, airway management. Leaving the study early. Unable to use ‐ Global impression: sedation (no data within 48 hours). Hospital and service outcomes: discharged (no data within 48 hours). | |
| Notes | *1 participant unaccounted for in diagnosis. **The primary interest of this trial was defined as 'tranquillised or asleep by 20 minutes' ‐ participants were considered tranquillised when they were calm and peaceful, i.e. neither agitated nor restless, and not showing threatening verbal behaviour or physical aggression against objects, other people or themselves. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised ‐ 'pragmatic' ‐ Microsoft Excel used to generate even random numbers less than 10 ‐ blocks were then applied to a table of random numbers. |
| Allocation concealment (selection bias) | Low risk | Table of allocation sequence independent of block size was produced. Tables were then sent to a colleague independent of the TREC team who ensured that the correct drug was in the consecutively numbered local pack before it was sealed. These packs were constructed of cardboard, were identical, and were sealed firmly with tape, across which the consecutive number was written. |
| Blinding (performance bias and detection bias) | High risk | Investigators were not blinded as the blinding was kept until point of treatment assignment, which minimised selection bias. Doses of medication administered were "at the treating doctors discretion." Rating scales: raters were nurses/doctors not involved in the management of the emergency ‐ unknown to treating clinicians. |
| Incomplete outcome data (attrition bias) | Low risk | Follow‐up: 99%. |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | Low risk | Funding: jointly funded by Fundação Oswaldo Cruz, the Cochrane Schizophrenia Group, the British Council, CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and FAPERJ (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro). We did not detect any other potential bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double blind. Design: not stated. Duration: 100 minutes. Setting: emergency department of a large metropolitan Australian university hospital. | |
| Participants | Diagnosis: mental illness (ICD‐10 codes F09‐F69 and F99, n = 100), no diagnosis (n = 53). n = 170. Age: 15‐67 years (median 34 years). Gender: 98 men, 55 women*. Ethnicity: not stated. Consent: not required. History: not stated. Inclusion criteria: adults, aged 18‐65 years, acutely agitated because of mental illness and required medication restraint. Exclusion criteria: hypersensitivity to either drug, pregnancy, readily reversible causes for agitation, agitation believed to be due to acute alcohol withdrawal. | |
| Interventions | Benzodiazepines vs antipsychotics. 1. Midazolam 4 mg + saline solution 1 mg IV (n = 74). 2. Droperidol 4 mg + saline solution 1 mg IV (n = 79). Participants were given the 5 mg doses every 5 minutes until adequate sedation was achieved. For participants weighing < 50 kg, dose was 2.5 mg. Physicians could choose subsequent therapy if adequate sedation was not achieved with the full 20 mg dose. | |
| Outcomes | Global impression: sedation; need for additional medication. Adverse effects/events: low blood pressure, airway management, vomiting, seizure, hypoxia, low heart rate, EPS. Leaving the study early. | |
| Notes | *Numbers for gender for the 170 originally randomised participants were not given, only numbers from 153 available for analysis were given. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Random number tables and serially numbered study packs. |
| Allocation concealment (selection bias) | Low risk | Codes from study packs remained with the pharmacy until study was complete. |
| Blinding (performance bias and detection bias) | Unclear risk | Double blind; blinding was maintained by returning sealed envelopes contained in study pack. It is stated, however, that "if necessary for patient treatment, unblinding of the drug could be achieved by opening [the sealed envelope];" unclear whether this was done. A blinded explicit review of the participant's medical record was performed after discharge. 2 participants from each treatment group (n = 4) were treated on an 'unblinded' basis ‐ no further details are given. Rating scale: not stated who administered rating scales. |
| Incomplete outcome data (attrition bias) | High risk | Follow‐up: 90%. Data from 17 study packs were lost, so only data from the remaining 153 participants were used. |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | Low risk | Funding: supported by a postgraduate scholarship from the National Health and Medicine Research Council and a research grant from the Australasian College for Emergency Medicine (Morson Taylor Award). We did not detect any potential bias. |
| Study characteristics | ||
| Methods | Allocation: randomised. Blinding: double. Design: not stated. Duration: 12 hours. Setting: psychiatric emergency department of Santa Casa de Sao Paulo, Brazil. | |
| Participants | Diagnosis: bipolar (n = 62), psychotic disorder (n = 88). n = 150. Age: 18‐50 years, mean 32.1 years. Gender: 91 men, 59 women. Ethnicity: not stated. Consent: informed written consent ‐ before and after participation in the study, which was reviewed and approved by the institutional review board. Written consent was obtained before admission to the emergency unit by a legal guardian and after 12 hours by the participant (when he/she was able to understand the information) or by the guardian. History: agitation caused by psychotic or bipolar disorder. Inclusion: signs of agitation, aged 18‐50 years, bipolar (manic or mixed episode) or psychotic disorder diagnosis (DSM‐IV‐TR criteria), OASS total score ≥ 20 and OAS with ≥ 4 positive items. Exclusion: disorders due to drug abuse, organic disorder, anxiety or personality disorder (DSM‐IV‐TR criteria), failure to agree to participate in study, incapability of completing all steps of the study and unstable clinical disease. | |
| Interventions | Benzodiazepines + antipsychotics vs antihistamines + antipsychotics vs same antipsychotics vs different antipsychotics. 1. Midazolam 15 mg IM + haloperidol 5 mg IM (n = 30). 2. Promethazine 50 mg IM + haloperidol 5 mg IM (n = 30). 3. Olanzapine 10 mg IM (n = 30). 4. Ziprasidone 20 mg IM (n = 30). 5. Haloperidol 5 mg IM (n = 30). After the initial dose, only additional doses of combined haloperidol/promethazine could be used according to clinical judgement. If a participant needed another intervention, he/she was immediately removed from study. | |
| Outcomes | Global impression: no improvement*, need for additional medication mean dose (skew), numbers sedated, sedation (RSS change scores). Behaviour: mean aggression change (OAS), mean behaviour change (OASS agitation scale). Adverse effects/events: hypotension, EPS. | |
| Notes | *'Improvement' ‐ defined as the number of participants with < 10 points on the OAS and OASS after 12 hours. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised ‐ allocation by "permuted blocks ‐ each drug regimen was assigned to blocks of five patients and distributed in this order: olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. This assignment was repeated until the total number of subjects (150) was reached." |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding (performance bias and detection bias) | Unclear risk | Double blind ‐ study medications were packaged in identical colour‐coded boxes. Rating scales were repeatedly administered by 2 raters ‐ unclear whether these were independent raters. |
| Incomplete outcome data (attrition bias) | Unclear risk | Follow‐up: 100%. |
| Selective reporting (reporting bias) | Low risk | All measure outcomes were reported. |
| Other bias | Unclear risk | Funding: not stated. |
General: ECT: electroconvulsive therapy; EPS: extrapyramidal symptoms; IM: intramuscular; IV: intravenous; ITT: intention‐to‐treat; n: number of participants; SD: standard deviation; TREC: Tranquilização Rápida‐Ensaio Clínico (Rapid Tranquillisation‐Clinical Trial).
Diagnostic tools: DSM: Diagnostic and Statistical Manual of Mental Disorders; CCMD: Chinese Classification of Mental Disorders; ICD‐10: The International Statistical Classification of Diseases and Related Health Problems, 10th Revision.
Rating Scales:Behaviour: ABS; Agitated Behaviour Scale; OAS; Overt Aggression Scale; OASS; Overt Agitation Severity Scale; VAS; visual analogue scale; Global state: CGI; Clinical Global Impression; CGI‐S; Clinical Global Impression Severity Scale; RSS; Ramsey Sedation Scale; Mental state: BPRS; Brief Psychiatric Rating Scale; IMPS; Inpatient Multidimensional Psychiatric Scale; NOSIE; Nurses' Observation Scale for Inpatient Evaluation; PANSS; Positive and Negative Syndrome Scale; PANSS‐EC; Positive and Negative Syndrome Scale‐Excited Component; SANS; Scale for the Assessment of Negative Symptoms; SAPS; Scale for the Assessment of Positive Symptoms; Adverse effects: SAS; Simpson‐Angus Scale.
Characteristics of excluded studies [ordered by study ID]
Ir a:
| Study | Reason for exclusion |
| Allocation: not randomised ‐ controlled design. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: ziprasidone + clonazepam vs olanzapine. Outcomes: no useable data ‐ all exceeded 48 hours. | |
| Allocation: randomised. Participants: acutely agitated psychotic participants. Intervention: risperidone + lorazepam vs haloperidol + lorazepam. | |
| Allocation: randomised. Participants: acutely agitated psychotic patients. Intervention: risperidone + lorazepam vs haloperidol + lorazepam. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: haloperidol vs clonazepam vs haloperidol + clonazepam. Outcomes: no useable data. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: risperidone + clonazepam vs chlorpromazine. Outcomes: no useable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: acutely agitated people presenting with medical diseases, drug poisoning or trauma. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: risperidone + clonazepam vs haloperidol. Outcomes: no useable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: people requiring sedation for medical diseases, drug poisoning or trauma. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: haloperidol + lorazepam vs haloperidol + placebo. Outcomes: no useable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: clonazepam + risperidone vs clozapine. | |
| Allocation: randomised. Participants: acutely agitated people with and without schizophrenia. Intervention: chlorpromazine vs chlordiazepoxide vs meprobamate vs placebo. Outcomes: no useable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: acutely disturbed psychiatric patients. Intervention: fluphenazine + chlordiazepoxide vs fluphenazine + imipramine. Outcomes: no useable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: acutely agitated people with and without schizophrenia. Intervention: aripiprazole + clonazepam vs haloperidol + aripiprazole. Outcomes: no useable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: lorazepam + risperidone vs haloperidol + promethazine. | |
| Allocation: randomised. Participants: acutely agitated psychotic patients. Intervention: haloperidol vs haloperidol + promethazine. | |
| Allocation: randomised. Participants: people with schizophrenia displaying moderate to severe agitation. Intervention: olanzapine vs haloperidol + lorazepam. | |
| Allocation: randomised. Participants: acutely disturbed/aggressive/agitated behaviour believed to be secondary to psychotic illnesses. | |
| Allocation: randomised. Participants: schizophrenia. Interventions: quetiapine + clonazepam vs chlorpromazine vs clozapine. Outcomes: no usable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: people with schizophrenia or related disorder displaying acute behavioural agitation. Intervention: olanzapine (+ as needed lorazepam) vs haloperidol (+ as needed lorazepam). | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia, schizophreniform or schizoaffective disorder. Intervention: olanzapine (+ as needed lorazepam) vs haloperidol (+ as needed lorazepam). | |
| Allocation: randomised. Participants: bipolar illness, manic type ‐ not acutely psychotic. | |
| Allocation: not randomised. | |
| Allocation: randomised. Participants: people requiring emergent sedation in emergency department ‐ aggression was not psychosis‐induced (agitation was ascribed to alcohol intoxication in 94% of participants). | |
| Allocation: randomised. Participants: people with schizophrenia. Interventions: quetiapine + clonazepam vs haloperidol + scopolamine. Outcomes: no usable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: olanzapine vs haloperidol + lorazepam. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia or schizoaffective disorders. Intervention: risperidone plus clonazepam vs haloperidol. | |
| Allocation: randomised. Participants: people with schizophrenia ‐ not acutely psychotic. | |
| Allocation: randomised. Participants: aggression was not psychosis‐induced (violent and severely agitated people). | |
| Allocation: randomised. Participants: agitated people without psychosis. | |
| Allocation: not randomised ‐ a prospective, naturalistic study. | |
| Allocation: randomised. Participants: people with schizophrenia. Interventions: haloperidol + lorazepam vs haloperidol. Outcomes: no usable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: people with schizophrenia. Interventions: risperidone + clonazepam vs haloperidol + scopolamine. Outcomes: no usable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: acutely psychotic people with schizophrenia. Intervention: benzodiazepines vs valproic acid. | |
| Allocation: randomised. Participants: agitated/aggressive people with schizophrenia. Interventions: risperidone + clonazepam vs haloperidol vs chlorpromazine. Outcomes: no usable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: clonazepam + risperidone vs clozapine vs haloperidol. | |
| Allocation: randomised. Participants: participants with retarded catatonia. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: clonazepam + risperidone vs haloperidol. | |
| Allocation: randomised. Participants: people with schizophrenia. Interventions: midazolam vs haloperidol. Outcomes: no usable data. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: clonazepam + risperidone vs clozapine vs haloperidol. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: quetiapine (+ as needed lorazepam) vs haloperidol. | |
| Allocation: not randomised. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: clonazepam + olanzapine vs haloperidol. | |
| Allocation: randomised. Participants: agitated/aggressive people with schizophrenia. Interventions: quetiapine + clonazepam vs haloperidol. Outcomes: no usable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: clonazepam + risperidone vs haloperidol. | |
| Allocation: randomised. Participants: agitated/aggressive people with schizophrenia. Interventions: risperidone + clonazepam vs haloperidol. Outcomes: no usable data ‐ all exceed 48 hours. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: clonazepam + ziprasidone vs haloperidol. | |
| Allocation: randomised. Participants: acutely agitated people with schizophrenia. Intervention: sodium valproate + risperidone vs clonazepam + risperidone. |
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Tranquillisation or asleep: 1. sedation Show forest plot | 1 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.42, 6.61] |
| Analysis 1.1  Comparison 1: Benzodiazepines versus placebo, Outcome 1: Tranquillisation or asleep: 1. sedation | ||||
| 1.1.1 medium term | 1 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.42, 6.61] |
| 1.2 Behaviour: 1. mean change score (Agitated Behaviour Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.2  Comparison 1: Benzodiazepines versus placebo, Outcome 2: Behaviour: 1. mean change score (Agitated Behaviour Scale, high = worse) | ||||
| 1.2.1 medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.3 Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC)) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.3  Comparison 1: Benzodiazepines versus placebo, Outcome 3: Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC)) | ||||
| 1.3.1 short term | 1 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.69, 1.16] |
| 1.3.2 medium term | 1 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.40, 0.97] |
| 1.4 Global state: 2. need for additional medication Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.4  Comparison 1: Benzodiazepines versus placebo, Outcome 4: Global state: 2. need for additional medication | ||||
| 1.4.1 medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5 Global state: 3. mean change score (Clinical Global Impression Severity Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.5  Comparison 1: Benzodiazepines versus placebo, Outcome 5: Global state: 3. mean change score (Clinical Global Impression Severity Scale, high = worse) | ||||
| 1.5.1 medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.6 Mental state: 1. mean change score (Positive and Negative Syndrome Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.6  Comparison 1: Benzodiazepines versus placebo, Outcome 6: Mental state: 1. mean change score (Positive and Negative Syndrome Scale, high = worse) | ||||
| 1.6.1 medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.7 Mental state: 2. mean change score (PANSS‐EC, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.7  Comparison 1: Benzodiazepines versus placebo, Outcome 7: Mental state: 2. mean change score (PANSS‐EC, high = worse) | ||||
| 1.7.1 medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.8 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.8  Comparison 1: Benzodiazepines versus placebo, Outcome 8: Adverse effects/events: 1. extrapyramidal symptoms (EPS) | ||||
| 1.8.1 medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.9 Adverse effects/events: 2. use of medication for EPS Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.9  Comparison 1: Benzodiazepines versus placebo, Outcome 9: Adverse effects/events: 2. use of medication for EPS | ||||
| 1.9.1 medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.10 Adverse effects/events: 3. specific Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.10  Comparison 1: Benzodiazepines versus placebo, Outcome 10: Adverse effects/events: 3. specific | ||||
| 1.10.1 dizziness ‐ medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.10.2 nausea ‐ medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.10.3 vomiting ‐ medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.11 Leaving the study early: 1. any reason Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.11  Comparison 1: Benzodiazepines versus placebo, Outcome 11: Leaving the study early: 1. any reason | ||||
| 1.11.1 medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Tranquillisation or asleep: 1. sedation Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.1  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 1: Tranquillisation or asleep: 1. sedation | ||||
| 2.1.1 vs droperidol ‐ short term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.71 [1.55, 4.73] |
| 2.1.2 vs haloperidol ‐ short term | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.53, 2.59] |
| 2.1.3 vs haloperidol ‐ medium term | 8 | 434 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.83, 1.54] |
| 2.1.4 vs olanzapine ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.28, 1.98] |
| 2.2 Behaviour: 2. mean change/endpoint score (Agitated Behaviour Scale, high = worse) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.2  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 2: Behaviour: 2. mean change/endpoint score (Agitated Behaviour Scale, high = worse) | ||||
| 2.2.1 vs haloperidol ‐ medium term | 1 | 66 | Mean Difference (IV, Fixed, 95% CI) | 1.80 [‐2.39, 5.99] |
| 2.2.2 vs olanzapine ‐ medium term | 1 | 149 | Mean Difference (IV, Fixed, 95% CI) | 2.91 [0.80, 5.02] |
| 2.3 Behaviour: 4. mean change score (Overt Aggression Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 2.3  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 3: Behaviour: 4. mean change score (Overt Aggression Scale, high = worse) | ||||
| 2.3.1 vs haloperidol ‐ medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.4 Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC)) Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.4  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 4: Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC)) | ||||
| 2.4.1 vs olanzapine ‐ short term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.26 [0.95, 1.66] |
| 2.4.2 vs olanzapine ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.84 [1.06, 3.18] |
| 2.4.3 vs haloperidol ‐ medium term | 5 | 188 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.71, 1.11] |
| 2.5 Global state: 2. need for additional medication Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 2.5  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 5: Global state: 2. need for additional medication | ||||
| 2.5.1 vs droperidol ‐ short term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.5.2 vs haloperidol ‐ medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.5.3 vs olanzapine ‐ medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.6 Global state: 3. mean change/endpoint score (Clinical Global Impression Severity Scale, high = worse) Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 2.6  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 6: Global state: 3. mean change/endpoint score (Clinical Global Impression Severity Scale, high = worse) | ||||
| 2.6.1 vs haloperidol ‐ short term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.6.2 vs haloperidol ‐ medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.6.3 vs haloperidol ‐ medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.6.4 vs olanzapine ‐ medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.7 Global state: 4. mean endpoint score (Inpatient Multidimensional Psychiatric Scale, high = worse) Show forest plot | 1 | 16 | Mean Difference (IV, Fixed, 95% CI) | 2.60 [‐3.04, 8.24] |
| Analysis 2.7  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 7: Global state: 4. mean endpoint score (Inpatient Multidimensional Psychiatric Scale, high = worse) | ||||
| 2.7.1 vs haloperidol ‐ medium term | 1 | 16 | Mean Difference (IV, Fixed, 95% CI) | 2.60 [‐3.04, 8.24] |
| 2.8 Mental state: 1. no improvement (decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) Show forest plot | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.73, 1.18] |
| Analysis 2.8  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 8: Mental state: 1. no improvement (decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) | ||||
| 2.8.1 vs haloperidol ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.73, 1.18] |
| 2.9 Mental state: 2. mean change/endpoint score (BPRS, high = worse) Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.9  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 9: Mental state: 2. mean change/endpoint score (BPRS, high = worse) | ||||
| 2.9.1 vs haloperidol ‐ short term | 1 | 37 | Mean Difference (IV, Fixed, 95% CI) | ‐3.26 [‐10.65, 4.13] |
| 2.9.2 vs haloperidol ‐ medium term | 3 | 123 | Mean Difference (IV, Fixed, 95% CI) | 1.67 [‐1.84, 5.18] |
| 2.10 Mental state: 3. mean endpoint score (BPRS psychosis subscale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.10  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 10: Mental state: 3. mean endpoint score (BPRS psychosis subscale, high = worse) | ||||
| 2.10.1 vs haloperidol ‐ medium term | 1 | 66 | Mean Difference (IV, Fixed, 95% CI) | 0.70 [‐7.20, 8.60] |
| 2.11 Mental state: 3a. mean endpoint score (BPRS positive subscale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.11  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 11: Mental state: 3a. mean endpoint score (BPRS positive subscale, high = worse) | ||||
| 2.11.1 vs haloperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.80 [‐1.83, 3.43] |
| 2.12 Mental state: 4a. mean endpoint score (BPRS‐excited component, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.12  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 12: Mental state: 4a. mean endpoint score (BPRS‐excited component, high = worse) | ||||
| 2.12.1 vs haloperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 1.27 [‐0.49, 3.03] |
| 2.13 Mental state: 2a. mean change score (Positive and Negative Syndrome Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.13  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 13: Mental state: 2a. mean change score (Positive and Negative Syndrome Scale, high = worse) | ||||
| 2.13.1 vs olanzapine ‐ medium term | 1 | 146 | Mean Difference (IV, Fixed, 95% CI) | 5.64 [2.20, 9.08] |
| 2.14 Mental state: 4. mean change score (PANSS‐EC, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.14  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 14: Mental state: 4. mean change score (PANSS‐EC, high = worse) | ||||
| 2.14.1 vs olanzapine ‐ medium term | 1 | 149 | Mean Difference (IV, Fixed, 95% CI) | 2.85 [1.14, 4.56] |
| 2.15 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot | 8 | 536 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.06, 0.39] |
| Analysis 2.15  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 15: Adverse effects/events: 1. extrapyramidal symptoms (EPS) | ||||
| 2.15.1 vs haloperidol ‐ medium term | 6 | 233 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.13 [0.04, 0.41] |
| 2.15.2 vs olanzapine ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.03, 1.89] |
| 2.15.3 vs droperidol ‐ medium term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.90] |
| 2.16 Adverse effects/events: 2. use of medication for EPS Show forest plot | 2 | 216 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.40 [0.15, 1.05] |
| Analysis 2.16  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 16: Adverse effects/events: 2. use of medication for EPS | ||||
| 2.16.1 vs haloperidol ‐ medium term | 1 | 66 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.50 [0.17, 1.47] |
| 2.16.2 vs olanzapine ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.03, 1.89] |
| 2.17 Adverse effects/events: 3. specific Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.17  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 17: Adverse effects/events: 3. specific | ||||
| 2.17.1 vs haloperidol ‐ akathisia ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.58] |
| 2.17.2 vs droperidol ‐ airway management ‐ medium term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.47 [0.39, 142.14] |
| 2.17.3 vs haloperidol ‐ ataxia ‐ medium term | 1 | 66 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.26 [0.22, 23.71] |
| 2.17.4 vs droperidol ‐ low blood pressure ‐ medium term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [0.33, 6.15] |
| 2.17.5 vs haloperidol ‐ dizziness ‐ medium term | 1 | 66 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.25, 5.19] |
| 2.17.6 vs olanzapine ‐ dizziness ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.51 [0.60, 3.82] |
| 2.17.7 vs haloperidol ‐ drowsiness ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.07, 14.55] |
| 2.17.8 vs haloperidol ‐ dry mouth ‐ medium term | 1 | 66 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.88 [0.49, 7.24] |
| 2.17.9 vs droperidol ‐ low heart rate ‐ medium term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.01, 8.59] |
| 2.17.10 vs haloperidol ‐ high heart rate ‐ medium term | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.22 [0.01, 4.29] |
| 2.17.11 vs droperidol ‐ hypoxia ‐ medium term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [0.33, 6.15] |
| 2.17.12 vs olanzapine ‐ nausea ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.76 [0.89, 67.67] |
| 2.17.13 vs droperidol ‐ seizure ‐ medium term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 2.17.14 vs haloperidol ‐ speech disorder ‐ medium term | 1 | 66 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.11, 2.87] |
| 2.17.15 vs haloperidol ‐ tremor ‐ medium term | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.10 [0.01, 1.69] |
| 2.17.16 vs droperidol ‐ vomiting ‐ medium term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 2.17.17 vs olanzapine ‐ vomiting ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 13.46 [0.71, 255.70] |
| 2.18 Leaving the study early: 1. any reason Show forest plot | 3 | 339 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.48 [0.70, 3.13] |
| Analysis 2.18  Comparison 2: Benzodiazepines versus antipsychotics, Outcome 18: Leaving the study early: 1. any reason | ||||
| 2.18.1 vs droperidol ‐ medium term | 1 | 173 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.51 [0.60, 3.79] |
| 2.18.2 vs haloperidol ‐ medium term | 1 | 16 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.01, 3.61] |
| 2.18.3 vs olanzapine ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.82 [0.62, 54.58] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Tranquilisation or asleep: 1. sedation Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 3.1  Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 1: Tranquilisation or asleep: 1. sedation | ||||
| 3.1.1 vs haloperidol + promethazine ‐ immediate term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.77, 0.99] |
| 3.1.2 vs haloperidol + promethazine ‐ short term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.77, 0.95] |
| 3.1.3 vs haloperidol + promethazine ‐ medium term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.84, 0.98] |
| 3.1.4 vs haloperidol + promethazine ‐ short term | 1 | 301 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.32 [1.16, 1.49] |
| 3.1.5 vs haloperidol + promethazine ‐ medium term | 1 | 301 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [1.04, 1.23] |
| 3.2 Global state: 1. no improvement (Clinical Global Impression (CGI) ‐ improvement scale dichotomised; much and very much improved) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 3.2  Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 2: Global state: 1. no improvement (Clinical Global Impression (CGI) ‐ improvement scale dichotomised; much and very much improved) | ||||
| 3.2.1 vs haloperidol + promethazine ‐ immediate term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.79 [1.36, 2.37] |
| 3.2.2 vs haloperidol + promethazine ‐ short term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.47 [1.51, 4.03] |
| 3.2.3 vs haloperidol + promethazine ‐ medium term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.17 [1.16, 4.05] |
| 3.3 Global state: 2. need for additional medication Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 3.3  Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 3: Global state: 2. need for additional medication | ||||
| 3.3.1 vs haloperidol + promethazine ‐ immediate term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.3.2 vs haloperidol + promethazine ‐ short term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.12, 72.77] |
| 3.3.3 vs haloperidol + promethazine ‐ medium term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.33 [0.31, 5.81] |
| 3.4 Global state: 3. mean endpoint score (CGI, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 3.4  Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 4: Global state: 3. mean endpoint score (CGI, high = worse) | ||||
| 3.4.1 vs haloperidol + promethazine ‐ immediate term | 1 | 200 | Mean Difference (IV, Fixed, 95% CI) | 0.49 [0.23, 0.75] |
| 3.4.2 vs haloperidol + promethazine ‐ short term | 1 | 200 | Mean Difference (IV, Fixed, 95% CI) | 0.60 [0.34, 0.86] |
| 3.4.3 vs haloperidol + promethazine ‐ medium term | 1 | 200 | Mean Difference (IV, Fixed, 95% CI) | 0.23 [‐0.05, 0.51] |
| 3.5 Adverse effects/events: 1. specific Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 3.5  Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 5: Adverse effects/events: 1. specific | ||||
| 3.5.1 vs haloperidol + promethazine ‐ airway management ‐ medium term | 2 | 501 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.99 [0.31, 28.54] |
| 3.5.2 vs haloperidol + promethazine ‐ nausea ‐ medium term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.12, 72.77] |
| 3.5.3 vs haloperidol + promethazine ‐ seizure ‐ medium term | 1 | 301 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 8.06] |
| 3.6 Hospital and service outcomes: 1. changes in hospital status Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 3.6  Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 6: Hospital and service outcomes: 1. changes in hospital status | ||||
| 3.6.1 vs haloperidol + promethazine ‐ not discharged ‐ medium term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.86, 1.48] |
| 3.7 Leaving the study early: 1. any reason Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 3.7  Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 7: Leaving the study early: 1. any reason | ||||
| 3.7.1 vs haloperidol + promethazine ‐ medium term | 2 | 501 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.43 [0.06, 2.87] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | ||||||||||||||||||||||||||||||||||||||
| 4.1 Tranquillisation or asleep: 1. sedation Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.1  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 1: Tranquillisation or asleep: 1. sedation | ||||||||||||||||||||||||||||||||||||||||||
| 4.1.1 + haloperidol ‐ short term | 1 | 47 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.92 [1.10, 3.35] | ||||||||||||||||||||||||||||||||||||||
| 4.1.2 + haloperidol ‐ medium term | 2 | 110 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.59, 1.19] | ||||||||||||||||||||||||||||||||||||||
| 4.2 Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.2  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 2: Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse) | ||||||||||||||||||||||||||||||||||||||||||
| 4.2.1 + haloperidol ‐ medium term | 1 | 63 | Mean Difference (IV, Fixed, 95% CI) | ‐1.60 [‐5.94, 2.74] | ||||||||||||||||||||||||||||||||||||||
| 4.3 Global state: 1. no improvement mean endpoint change in Clinical Global Impression score) Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.3  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 3: Global state: 1. no improvement mean endpoint change in Clinical Global Impression score) | ||||||||||||||||||||||||||||||||||||||||||
| 4.3.1 + haloperidol ‐ short term | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.11 [0.01, 1.74] | ||||||||||||||||||||||||||||||||||||||
| 4.3.2 + haloperidol ‐ medium term | 3 | 113 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.76, 1.20] | ||||||||||||||||||||||||||||||||||||||
| 4.3.3 + risperidone ‐ medium term | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.45, 1.64] | ||||||||||||||||||||||||||||||||||||||
| 4.4 Global state: 2. need for additional medication Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.4  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 4: Global state: 2. need for additional medication | ||||||||||||||||||||||||||||||||||||||||||
| 4.4.1 + haloperidol ‐ medium term | 3 | 103 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.79, 1.32] | ||||||||||||||||||||||||||||||||||||||
| 4.4.2 + risperidone ‐ medium term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable | ||||||||||||||||||||||||||||||||||||||
| 4.5 Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.5  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 5: Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) | ||||||||||||||||||||||||||||||||||||||||||
| 4.5.1 + haloperidol ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.76, 1.32] | ||||||||||||||||||||||||||||||||||||||
| 4.6 Mental state: 2a. mean endpoint score (BPRS, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.6  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 6: Mental state: 2a. mean endpoint score (BPRS, high = worse) | ||||||||||||||||||||||||||||||||||||||||||
| 4.6.1 + risperidone ‐ short term | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 1.10 [‐23.17, 25.37] | ||||||||||||||||||||||||||||||||||||||
| 4.6.2 + risperidone ‐ medium term | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐1.70 [‐24.26, 20.86] | ||||||||||||||||||||||||||||||||||||||
| 4.7 Mental state: 2b. mean endpoint score (BPRS, high = worse, skew) Show forest plot | 1 | Other data | No numeric data | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.7
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 7: Mental state: 2b. mean endpoint score (BPRS, high = worse, skew) | ||||||||||||||||||||||||||||||||||||||||||
| 4.7.1 + haloperidol ‐ short term | 1 | Other data | No numeric data | |||||||||||||||||||||||||||||||||||||||
| 4.7.2 + haloperidol ‐ medium term | 1 | Other data | No numeric data | |||||||||||||||||||||||||||||||||||||||
| 4.8 Mental state: 2c. mean endpoint score (Positive and Negative Syndrome Scale (PANSS), high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.8  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 8: Mental state: 2c. mean endpoint score (Positive and Negative Syndrome Scale (PANSS), high = worse) | ||||||||||||||||||||||||||||||||||||||||||
| 4.8.1 + risperidone ‐ short term | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 6.40 [‐36.50, 49.30] | ||||||||||||||||||||||||||||||||||||||
| 4.8.2 + risperidone ‐ medium term | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 3.20 [‐29.41, 35.81] | ||||||||||||||||||||||||||||||||||||||
| 4.9 Mental state: 2d. mean endpoint score (PANSS, high = worse, skew) Show forest plot | 1 | Other data | No numeric data | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.9
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 9: Mental state: 2d. mean endpoint score (PANSS, high = worse, skew) | ||||||||||||||||||||||||||||||||||||||||||
| 4.9.1 + haloperidol ‐ short term | 1 | Other data | No numeric data | |||||||||||||||||||||||||||||||||||||||
| 4.9.2 + haloperidol ‐ medium term | 1 | Other data | No numeric data | |||||||||||||||||||||||||||||||||||||||
| 4.10 Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.10  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 10: Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse) | ||||||||||||||||||||||||||||||||||||||||||
| 4.10.1 + haloperidol ‐ medium term | 1 | 63 | Mean Difference (IV, Fixed, 95% CI) | 1.20 [‐6.28, 8.68] | ||||||||||||||||||||||||||||||||||||||
| 4.11 Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.11  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 11: Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse) | ||||||||||||||||||||||||||||||||||||||||||
| 4.11.1 vs haloperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.06 [‐2.73, 2.85] | ||||||||||||||||||||||||||||||||||||||
| 4.12 Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.12  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 12: Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse) | ||||||||||||||||||||||||||||||||||||||||||
| 4.12.1 vs haloperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.80 [‐2.41, 0.81] | ||||||||||||||||||||||||||||||||||||||
| 4.13 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.13  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 13: Adverse effects/events: 1. extrapyramidal symptoms (EPS) | ||||||||||||||||||||||||||||||||||||||||||
| 4.13.1 + haloperidol ‐ medium term | 2 | 83 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.94 [0.18, 20.30] | ||||||||||||||||||||||||||||||||||||||
| 4.14 Adverse effects/events: 2. use of medication for EPS Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.14  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 14: Adverse effects/events: 2. use of medication for EPS | ||||||||||||||||||||||||||||||||||||||||||
| 4.14.1 + haloperidol ‐ medium term | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.18, 2.99] | ||||||||||||||||||||||||||||||||||||||
| 4.15 Adverse effects/events: 3. specific Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.15  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 15: Adverse effects/events: 3. specific | ||||||||||||||||||||||||||||||||||||||||||
| 4.15.1 + haloperidol ‐ akathisia ‐ medium term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable | ||||||||||||||||||||||||||||||||||||||
| 4.15.2 + haloperidol ‐ ataxia ‐ medium term | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.26, 8.11] | ||||||||||||||||||||||||||||||||||||||
| 4.15.3 + haloperidol ‐ dizziness ‐ medium term | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.65 [0.12, 3.61] | ||||||||||||||||||||||||||||||||||||||
| 4.15.4 + haloperidol ‐ drowsiness ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.07, 14.55] | ||||||||||||||||||||||||||||||||||||||
| 4.15.5 + haloperidol ‐ dry mouth ‐ medium term | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.15, 2.23] | ||||||||||||||||||||||||||||||||||||||
| 4.15.6 + haloperidol ‐ speech disorder ‐ medium term | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.26, 8.11] | ||||||||||||||||||||||||||||||||||||||
| 4.16 Leaving the study early: 1. any reason Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||||||||||||||||
| Analysis 4.16  Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 16: Leaving the study early: 1. any reason | ||||||||||||||||||||||||||||||||||||||||||
| 4.16.1 + haloperidol ‐ medium term | 2 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.34, 1.50] | ||||||||||||||||||||||||||||||||||||||
| 4.16.2 + risperidone ‐ medium term | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.45, 1.64] | ||||||||||||||||||||||||||||||||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Tranquillisation or asleep: 1. sedation Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.1  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 1: Tranquillisation or asleep: 1. sedation | ||||
| 5.1.1 +/vs haloperidol ‐ short term | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.25 [1.18, 4.30] |
| 5.1.2 +/vs haloperidol ‐ medium term | 3 | 172 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [1.14, 2.67] |
| 5.2 Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.2  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 2: Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse) | ||||
| 5.2.1 +/vs haloperidol ‐ medium term | 1 | 67 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐5.05, 4.65] |
| 5.3 Behaviour: 2. mean endpoint score (Overt Aggression Scale (OAS), high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.3  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 3: Behaviour: 2. mean endpoint score (Overt Aggression Scale (OAS), high = worse) | ||||
| 5.3.1 +/vs haloperidol ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 1.20 [‐0.04, 2.44] |
| 5.3.2 +/vs haloperidol ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 2.40 [0.59, 4.21] |
| 5.4 Behaviour: 3. mean endpoint score (Overt Agitation Severity Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.4  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 4: Behaviour: 3. mean endpoint score (Overt Agitation Severity Scale, high = worse) | ||||
| 5.4.1 +/vs haloperidol ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 8.50 [7.07, 9.93] |
| 5.4.2 +/vs haloperidol ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 6.70 [5.94, 7.46] |
| 5.5 Global state: 1. no improvement Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.5  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 5: Global state: 1. no improvement | ||||
| 5.5.1 +/vs haloperidol ‐ medium term | 4 | 185 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.93, 1.46] |
| 5.6 Global state: 2. need for additional medication Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.6  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 6: Global state: 2. need for additional medication | ||||
| 5.6.1 +/vs haloperidol ‐ medium term | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.79, 1.15] |
| 5.7 Global state: 3. need for additional medication (mean dose, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.7  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 7: Global state: 3. need for additional medication (mean dose, high = worse) | ||||
| 5.7.1 +/vs haloperidol ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐0.33, 0.73] |
| 5.8 Global state: 4. mean change score (Ramsey Sedation Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.8  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 8: Global state: 4. mean change score (Ramsey Sedation Scale, high = worse) | ||||
| 5.8.1 +/vs haloperidol ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.50 [‐0.01, 1.01] |
| 5.8.2 +/vs haloperidol ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.36, 0.56] |
| 5.9 Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.9  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 9: Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) | ||||
| 5.9.1 +/vs haloperidol ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.73, 1.18] |
| 5.10 Mental state: 2. mean endpoint score (BPRS, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.10  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 10: Mental state: 2. mean endpoint score (BPRS, high = worse) | ||||
| 5.10.1 +/vs haloperidol ‐ medium term | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐7.26, 7.28] |
| 5.11 Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.11  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 11: Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse) | ||||
| 5.11.1 +/vs haloperidol ‐ medium term | 2 | 95 | Mean Difference (IV, Fixed, 95% CI) | ‐1.19 [‐4.60, 2.23] |
| 5.12 Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.12  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 12: Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse) | ||||
| 5.12.1 vs haloperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.86 [‐1.62, 3.34] |
| 5.13 Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.13  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 13: Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse) | ||||
| 5.13.1 vs hoperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.47 [‐1.32, 2.26] |
| 5.14 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.14  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 14: Adverse effects/events: 1. extrapyramidal symptoms (EPS) | ||||
| 5.14.1 +/vs haloperidol ‐ medium term | 2 | 127 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.16, 1.17] |
| 5.15 Adverse effects/events: 2. use of medication for EPS Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.15  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 15: Adverse effects/events: 2. use of medication for EPS | ||||
| 5.15.1 +/vs haloperidol ‐ medium term | 2 | 95 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.27, 1.01] |
| 5.16 Adverse effects/events: 3. specific Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.16  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 16: Adverse effects/events: 3. specific | ||||
| 5.16.1 +/vs haloperidol ‐ akathisia ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.58] |
| 5.16.2 +/vs haloperidol ‐ ataxia ‐ medium term | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.28 [0.36, 29.97] |
| 5.16.3 +/vs haloperidol ‐ dizziness ‐ medium term | 2 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.54 [0.12, 2.32] |
| 5.16.4 +/vs haloperidol ‐ drowsiness ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.07, 14.55] |
| 5.16.5 +/vs haloperidol ‐ dry mouth ‐ medium term | 2 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.26 [0.32, 4.92] |
| 5.16.6 +/vs haloperidol ‐ hypotension ‐ medium term | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 11.00 [0.64, 190.53] |
| 5.16.7 +/vs haloperidol ‐ speech disorder ‐ medium term | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.20, 3.39] |
| 5.17 Hospital and service outcomes: 1. changes in hospital status Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.17  Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 17: Hospital and service outcomes: 1. changes in hospital status | ||||
| 5.17.1 +/vs haloperidol ‐ not discharged ‐ medium term | 1 | 28 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.54, 1.50] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Behaviour: 3. mean endpoint score (Overt Aggression Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 6.1  Comparison 6: Benzodiazepines + antipsychotics versus antipsychotics plus antipsychotics, Outcome 1: Behaviour: 3. mean endpoint score (Overt Aggression Scale, high = worse) | ||||
| 6.1.1 + haloperidol vs clothiapine + haloperidol ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐5.83 [‐27.60, 15.94] |
| 6.2 Leaving the study early: 1. any reason Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 6.2  Comparison 6: Benzodiazepines + antipsychotics versus antipsychotics plus antipsychotics, Outcome 2: Leaving the study early: 1. any reason | ||||
| 6.2.1 + haloperidol vs clothiapine + haloperidol ‐ medium term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 7.1 Tranquilisation or asleep: 1. sedation Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 7.1  Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 1: Tranquilisation or asleep: 1. sedation | ||||
| 7.1.1 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 12.00 [1.66, 86.59] |
| 7.2 Behaviour: 1. mean endpoint score (Overt Aggression Scale (OAS), high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 7.2  Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 2: Behaviour: 1. mean endpoint score (Overt Aggression Scale (OAS), high = worse) | ||||
| 7.2.1 + haloperidol vs haloperidol + promethazine ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐3.30 [‐5.25, ‐1.35] |
| 7.2.2 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 1.70 [‐0.06, 3.46] |
| 7.3 Behaviour: 2. mean endpoint score (Overt Agitation Severity Scale (OASS) agitation scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 7.3  Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 3: Behaviour: 2. mean endpoint score (Overt Agitation Severity Scale (OASS) agitation scale, high = worse) | ||||
| 7.3.1 + haloperidol vs haloperidol + promethazine ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐16.00 [‐18.98, ‐13.02] |
| 7.3.2 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐2.70 [‐3.73, ‐1.67] |
| 7.4 Global state: 1. no improvement (number of participants with < 10 points on the OAS and OASS after 12 hours) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 7.4  Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 4: Global state: 1. no improvement (number of participants with < 10 points on the OAS and OASS after 12 hours) | ||||
| 7.4.1 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 25.00 [1.55, 403.99] |
| 7.5 Global state: 2. need for additional medication (mean dose, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 7.5  Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 5: Global state: 2. need for additional medication (mean dose, high = worse) | ||||
| 7.5.1 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.63 [0.15, 1.11] |
| 7.6 Global state: 3. mean change score (Ramsey Sedation Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 7.6  Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 6: Global state: 3. mean change score (Ramsey Sedation Scale, high = worse) | ||||
| 7.6.1 + haloperidol vs haloperidol + promethazine ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.60 [0.07, 1.13] |
| 7.6.2 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐0.46, 0.46] |
| 7.7 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 7.7  Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 7: Adverse effects/events: 1. extrapyramidal symptoms | ||||
| 7.7.1 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.16, 2.29] |
| 7.8 Adverse effects/events: 2. specific Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 7.8  Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 8: Adverse effects/events: 2. specific | ||||
| 7.8.1 + haloperidol vs haloperidol + promethazine ‐ hypotension ‐ medium term | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.44, 6.36] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 8.1 Tranquilisation or asleep: 1. sedation Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 8.1  Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 1: Tranquilisation or asleep: 1. sedation | ||||
| 8.1.1 unclear risk of bias | 6 | 340 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.56, 1.26] |
| 8.1.2 low risk of bias | 3 | 247 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.22 [1.52, 3.25] |
| 8.2 Global state: 1. no improvement Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 8.2  Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 2: Global state: 1. no improvement | ||||
| 8.2.1 unclear risk of bias | 3 | 214 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.78, 1.63] |
| 8.2.2 low risk of bias | 3 | 124 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.80, 1.28] |
| 8.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 8.3  Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms | ||||
| 8.3.1 unclear risk of bias | 5 | 285 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.05, 0.47] |
| 8.3.2 low risk of bias | 3 | 247 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.16 [0.03, 0.85] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 9.1 Tranquilisation or asleep: 1. sedation Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 9.1  Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 1: Tranquilisation or asleep: 1. sedation | ||||
| 9.1.1 unclear risk of bias | 8 | 434 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.79, 1.48] |
| 9.1.2 low risk of bias | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.71 [1.55, 4.73] |
| 9.2 Global state: 1. no improvement Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 9.2  Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 2: Global state: 1. no improvement | ||||
| 9.2.1 unclear risk of bias | 6 | 338 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.86, 1.32] |
| 9.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 9.3  Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms | ||||
| 9.3.1 unclear risk of bias | 7 | 379 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.06, 0.41] |
| 9.3.2 low risk of bias | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.90] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 10.1 Tranquilisation or asleep: 1. sedation Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 10.1  Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 1: Tranquilisation or asleep: 1. sedation | ||||
| 10.1.1 high risk of bias | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.56, 2.34] |
| 10.1.2 unclear risk of bias | 6 | 424 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.34 [0.93, 1.94] |
| 10.1.3 low risk of bias | 2 | 119 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.66 [1.05, 2.64] |
| 10.2 Global state: 1. no improvement Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 10.2  Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 2: Global state: 1. no improvement | ||||
| 10.2.1 unclear risk of bias | 4 | 224 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.88, 1.59] |
| 10.2.2 low risk of bias | 2 | 114 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.60, 1.07] |
| 10.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 10.3  Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms | ||||
| 10.3.1 unclear risk of bias | 6 | 426 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.19 [0.05, 0.68] |
| 10.3.2 low risk of bias | 2 | 106 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.12 [0.03, 0.48] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 11.1 Tranquilisation or asleep: 1. sedation Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 11.1  Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 1: Tranquilisation or asleep: 1. sedation | ||||
| 11.1.1 high risk of bias | 2 | 193 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.78 [1.15, 2.75] |
| 11.1.2 unclear risk of bias | 3 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.62, 1.83] |
| 11.1.3 low risk of bias | 4 | 260 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [0.83, 2.03] |
| 11.2 Global state: 1. no improvement Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 11.2  Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 2: Global state: 1. no improvement | ||||
| 11.2.1 unclear risk of bias | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.32, 0.97] |
| 11.2.2 low risk of bias | 5 | 290 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.23 [0.98, 1.56] |
| 11.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 11.3  Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms | ||||
| 11.3.1 high risk of bias | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.90] |
| 11.3.2 unclear risk of bias | 2 | 77 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.09 [0.01, 0.65] |
| 11.3.3 low risk of bias | 5 | 302 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.18 [0.06, 0.60] |
Funnel plot of comparison: 2 benzodiazepines versus antipsychotics, outcome: 2.1 Tranquillisation or asleep: 1. sedation.
Study flow diagram.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Comparison 1: Benzodiazepines versus placebo, Outcome 1: Tranquillisation or asleep: 1. sedation
Comparison 1: Benzodiazepines versus placebo, Outcome 2: Behaviour: 1. mean change score (Agitated Behaviour Scale, high = worse)
Comparison 1: Benzodiazepines versus placebo, Outcome 3: Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC))
Comparison 1: Benzodiazepines versus placebo, Outcome 4: Global state: 2. need for additional medication
Comparison 1: Benzodiazepines versus placebo, Outcome 5: Global state: 3. mean change score (Clinical Global Impression Severity Scale, high = worse)
Comparison 1: Benzodiazepines versus placebo, Outcome 6: Mental state: 1. mean change score (Positive and Negative Syndrome Scale, high = worse)
Comparison 1: Benzodiazepines versus placebo, Outcome 7: Mental state: 2. mean change score (PANSS‐EC, high = worse)
Comparison 1: Benzodiazepines versus placebo, Outcome 8: Adverse effects/events: 1. extrapyramidal symptoms (EPS)
Comparison 1: Benzodiazepines versus placebo, Outcome 9: Adverse effects/events: 2. use of medication for EPS
Comparison 1: Benzodiazepines versus placebo, Outcome 10: Adverse effects/events: 3. specific
Comparison 1: Benzodiazepines versus placebo, Outcome 11: Leaving the study early: 1. any reason
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 1: Tranquillisation or asleep: 1. sedation
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 2: Behaviour: 2. mean change/endpoint score (Agitated Behaviour Scale, high = worse)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 3: Behaviour: 4. mean change score (Overt Aggression Scale, high = worse)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 4: Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC))
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 5: Global state: 2. need for additional medication
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 6: Global state: 3. mean change/endpoint score (Clinical Global Impression Severity Scale, high = worse)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 7: Global state: 4. mean endpoint score (Inpatient Multidimensional Psychiatric Scale, high = worse)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 8: Mental state: 1. no improvement (decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 9: Mental state: 2. mean change/endpoint score (BPRS, high = worse)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 10: Mental state: 3. mean endpoint score (BPRS psychosis subscale, high = worse)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 11: Mental state: 3a. mean endpoint score (BPRS positive subscale, high = worse)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 12: Mental state: 4a. mean endpoint score (BPRS‐excited component, high = worse)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 13: Mental state: 2a. mean change score (Positive and Negative Syndrome Scale, high = worse)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 14: Mental state: 4. mean change score (PANSS‐EC, high = worse)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 15: Adverse effects/events: 1. extrapyramidal symptoms (EPS)
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 16: Adverse effects/events: 2. use of medication for EPS
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 17: Adverse effects/events: 3. specific
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 18: Leaving the study early: 1. any reason
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 1: Tranquilisation or asleep: 1. sedation
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 2: Global state: 1. no improvement (Clinical Global Impression (CGI) ‐ improvement scale dichotomised; much and very much improved)
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 3: Global state: 2. need for additional medication
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 4: Global state: 3. mean endpoint score (CGI, high = worse)
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 5: Adverse effects/events: 1. specific
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 6: Hospital and service outcomes: 1. changes in hospital status
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 7: Leaving the study early: 1. any reason
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 1: Tranquillisation or asleep: 1. sedation
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 2: Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse)
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 3: Global state: 1. no improvement mean endpoint change in Clinical Global Impression score)
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 4: Global state: 2. need for additional medication
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 5: Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%)
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 6: Mental state: 2a. mean endpoint score (BPRS, high = worse)
| Mental state: 2b. mean endpoint score (BPRS, high = worse, skew) | ||||
| Study | Intervention | Mean | SD | N |
|---|---|---|---|---|
| + haloperidol ‐ short term | ||||
| Lorazepam 2006, USA | Lorazepam | 40.8 | 28.12 | 10 |
| Lorazepam+haloperidol | 48.2 | 65.46 | 10 | |
| + haloperidol ‐ medium term | ||||
| Lorazepam 2006, USA | Lorazepam | 35.5 | 25.61 | 10 |
| Lorazepam+haloperidol | 40.1 | 51.23 | 10 | |
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 7: Mental state: 2b. mean endpoint score (BPRS, high = worse, skew)
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 8: Mental state: 2c. mean endpoint score (Positive and Negative Syndrome Scale (PANSS), high = worse)
| Mental state: 2d. mean endpoint score (PANSS, high = worse, skew) | ||||
| Study | Intervention | Mean | SD | N |
|---|---|---|---|---|
| + haloperidol ‐ short term | ||||
| Lorazepam 2006, USA | Lorazepam | 59.4 | 36.22 | 10 |
| Lorazepam+haloperidol | 74.6 | 100.22 | 10 | |
| + haloperidol ‐ medium term | ||||
| Lorazepam 2006, USA | Lorazepam | 53.9 | 35.53 | 10 |
| Lorazepam+haloperidol | 65.8 | 100.4 | 10 | |
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 9: Mental state: 2d. mean endpoint score (PANSS, high = worse, skew)
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 10: Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse)
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 11: Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse)
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 12: Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse)
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 13: Adverse effects/events: 1. extrapyramidal symptoms (EPS)
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 14: Adverse effects/events: 2. use of medication for EPS
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 15: Adverse effects/events: 3. specific
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 16: Leaving the study early: 1. any reason
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 1: Tranquillisation or asleep: 1. sedation
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 2: Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 3: Behaviour: 2. mean endpoint score (Overt Aggression Scale (OAS), high = worse)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 4: Behaviour: 3. mean endpoint score (Overt Agitation Severity Scale, high = worse)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 5: Global state: 1. no improvement
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 6: Global state: 2. need for additional medication
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 7: Global state: 3. need for additional medication (mean dose, high = worse)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 8: Global state: 4. mean change score (Ramsey Sedation Scale, high = worse)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 9: Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 10: Mental state: 2. mean endpoint score (BPRS, high = worse)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 11: Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 12: Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 13: Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 14: Adverse effects/events: 1. extrapyramidal symptoms (EPS)
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 15: Adverse effects/events: 2. use of medication for EPS
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 16: Adverse effects/events: 3. specific
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 17: Hospital and service outcomes: 1. changes in hospital status
Comparison 6: Benzodiazepines + antipsychotics versus antipsychotics plus antipsychotics, Outcome 1: Behaviour: 3. mean endpoint score (Overt Aggression Scale, high = worse)
Comparison 6: Benzodiazepines + antipsychotics versus antipsychotics plus antipsychotics, Outcome 2: Leaving the study early: 1. any reason
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 1: Tranquilisation or asleep: 1. sedation
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 2: Behaviour: 1. mean endpoint score (Overt Aggression Scale (OAS), high = worse)
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 3: Behaviour: 2. mean endpoint score (Overt Agitation Severity Scale (OASS) agitation scale, high = worse)
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 4: Global state: 1. no improvement (number of participants with < 10 points on the OAS and OASS after 12 hours)
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 5: Global state: 2. need for additional medication (mean dose, high = worse)
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 6: Global state: 3. mean change score (Ramsey Sedation Scale, high = worse)
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 7: Adverse effects/events: 1. extrapyramidal symptoms
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 8: Adverse effects/events: 2. specific
Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 1: Tranquilisation or asleep: 1. sedation
Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 2: Global state: 1. no improvement
Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms
Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 1: Tranquilisation or asleep: 1. sedation
Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 2: Global state: 1. no improvement
Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms
Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 1: Tranquilisation or asleep: 1. sedation
Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 2: Global state: 1. no improvement
Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms
Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 1: Tranquilisation or asleep: 1. sedation
Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 2: Global state: 1. no improvement
Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms
| Methods | Allocation: randomised, fully described in terms of methods of randomisation and allocation concealment. Blinding: double/single blind, with methods of maintenance of blinding fully described. Setting: psychiatric emergency settings/hospital. Duration: immediate term (0‐15 minutes); short term (15 minutes to 1 hour); medium term (1‐48 hours); long term (≥ 48 hours). |
|---|---|
| Participants | Diagnosis: primary diagnosis of schizophrenia or related disorders, including schizophreniform disorder, schizoaffective disorder and delusional disorder with psychosis‐induced aggression or agitation. Subgroups: dual diagnoses or drug/alcohol use, or both. Age: adults, with age specified in trial. Sex: both. |
| Comparisons | a. Benzodiazepines ‐ given alone. Including: alprazolam, bretazenil, bromazepam, chlordiazepoxide, cinolazepam, clonazepam, clorazepate, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, flunitrazepam, halazepam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, quazepam, temazepam, tetrazepam or triazolam. Any dose, any means of administration. Compared with: 1. Other benzodiazepine ‐ given alone. Any dose, any means of administration. 2. Antipsychotics. First generation/typical, including: chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, droperidol, flupentixol/flupenthixol, fluphenazine, haloperidol, levomepromazine, loxapine, mesoridazine, molindone, periciazine, perphenazine, pimozide, prochlorperazine, promazine, promethazine, thioridazine, thiothixene, trifluoperazine, triflupromazine or zuclopenthixol. Second generation/atypical, including: amisulpride, aripiprazole, asenapine, clozapine, clothiapine, clotiapine, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone or zotepine. Any dose, any means of administration. 3. Other combinations of drugs. 3.1. Benzodiazepines + antipsychotics. 3.2. Antipsychotics + antihistamine/anticholinergic drugs. Antihistamines include: azelastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, deschlorpheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, levocetirizine, loratadine, meclozine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, rupatadine, tripelennamine or triprolidine. Any dose, any means of administration. 4. Non‐pharmacological approaches. b. Benzodiazepines plus antipsychotics. Compared with: 1. Placebo. 2. Antipsychotics. Any dose, any means of administration. 3. Other combinations. 3.1. Benzodiazepines plus antipsychotics. 3.2. Antipsychotics plus antihistamines. 4. Non‐pharmacological approaches. c. Benzodiazepines (specific named drug) ‐ given alone. 1. High dose (as defined by each study). 2. Low or standard dose (as defined by each study). d. Benzodiazepines (specific named drug) ‐ given alone. 1. Oral. 2. Intramuscular or intravenous. e. Benzodiazepines (specific named drug) ‐ given alone. 1. Low frequency (as defined by each study). 2. High frequency (as defined by each study). |
| Outcomes measures | Primary outcomes. 1. Global impression. 1.1. Specific. 1.1.1. No improvement: as defined by each study. If more than 1 measure of improvement was reported, then improvement in behaviour is used, followed by improvement in mental state, and then improvement in symptoms. 1.1.2. Tranquillisation (feeling of calmness or calm, non‐sedated behaviour (or both)). Secondary outcomes. 2. Global impression ‐ CGI. 2.1. General. 2.1.1. No clinically important change in general functioning. 2.2. Specific. 2.2.1. Aggression. 3. Behaviour. 3.1. General. 3.1.1. No clinically important change in behaviour. 4. Mental state ‐ BPRS. 4.1. General. 4.1.1. No clinically important change in general mental state scores. 5. Adverse effects/events. 5.1. General. 5.1.1. Incidence of side effects, general or specific. 5.2. Specific. 5.2.1. EPS. 6. Hospital and service outcomes. 6.1. Hospitalisation. 6.1.1. Time to hospitalisation. 6.2. Seclusion. 6.2.1. Time in seclusion. 7. Satisfaction with treatment. 7.1. Specific. 7.1.1. Consumers. 8. Economic outcomes. 8.1. Cost‐effectiveness. 8.2. Direct costs. 8.3. Indirect costs. 9. Leaving the study early. 9.1. For any reason. 9.2. For reasons treatment related. 9.3. For reasons unrelated to treatment. 9.4. Due to relapse. 9.5. Due to adverse effects. |
| Notes | ‐ |
| BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; EPS: extrapyramidal symptoms. | |
| Methods | Allocation: randomised, fully described in terms of methods of randomisation and allocation concealment. Blinding: double/single blind, with methods of maintenance of blinding fully described. Setting: psychiatric emergency settings/hospital. Duration: follow‐up 72 hours. |
|---|---|
| Participants | Diagnosis: primary diagnosis of schizophrenia or related disorders, including schizophreniform disorder, schizoaffective disorder and delusional disorder with psychosis‐induced aggression or agitation. Subgroups: dual diagnoses or drug/alcohol use (or both) Number of participants > 400. Age: adults, with age specified in trial. Sex: both. |
| Interventions | 1. Benzodiazepines ‐ given alone. Including: alprazolam, bretazenil, bromazepam, chlordiazepoxide, cinolazepam, clonazepam, clorazepate, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, flunitrazepam, halazepam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, quazepam, temazepam, tetrazepam or triazolam. Any dose, any means of administration. Compared with: a. Other benzodiazepine ‐ given alone. Any dose, any means of administration. b. Antipsychotics. First generation/typical, including: chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, droperidol, flupentixol/flupenthixol, fluphenazine, haloperidol, levomepromazine, loxapine, mesoridazine, molindone, periciazine, perphenazine, pimozide, prochlorperazine, promazine, promethazine, thioridazine, thiothixene, trifluoperazine, triflupromazine or zuclopenthixol. Second generation/atypical, including: amisulpride, aripiprazole, asenapine, clozapine, clothiapine, clotiapine, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone or zotepine. Any dose, any means of administration. c. Other combinations of drugs. i. Benzodiazepines plus antipsychotics. ii. Antipsychotics plus antihistamine/anticholinergic drugs. Antihistamines including: azelastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, deschlorpheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, levocetirizine, loratadine, meclozine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, rupatadine, tripelennamine or triprolidine. Any dose, any means of administration. d. Non‐pharmacological approaches. 2. Benzodiazepines plus antipsychotics. Compared with: a. Placebo. b. Antipsychotics. Any dose, any means of administration. c. Other combinations. i. Benzodiazepines plus antipsychotics. ii. Antipsychotics plus antihistamines. d. Non‐pharmacological approaches. |
| Outcomes | 1. Global impression: no improvement (as defined by each study. If more than 1 measure of improvement was reported, then improvement in behaviour was used, followed by improvement in mental state, and then improvement in symptoms). 2. Global impression; general/specific (including tranquillisation/sedation/need for additional medication/decrease in medication/injury to others/self‐harm/aggression or agitation/compulsory administration of treatment). 3. Behaviour: no clinically important change in behaviour. 4. Mental state: no clinically important change in general mental state scores. 5. Adverse effects/events (including incidence of specific adverse effects/severity of symptoms/death/EPS/use of medication for EPS). 6. Hospital and service outcomes (including time to hospitalisation/duration of hospital stay/seclusion/time in seclusion/changes in hospital status/use of mechanical restraints). 7. Satisfaction with treatment. 8. Economic outcomes. 9. Leaving the study early. |
| Notes | Any outcomes measured using scale‐derived data should be interpreted in such a way as to make clear the real‐life relevance of changes in scale score. |
| EPS: extrapyramidal symptoms. | |
| Benzodiazepines compared to placebo for psychosis‐induced aggression or agitation | ||||||
| Patient or population: people with psychosis‐induced aggression or agitation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | Benzodiazepines | |||||
| Tranquillisation or asleep: sedation ‐ medium term | 59 per 10001 | 98 per 1000 | RR 1.67 | 102 | ⊕⊝⊝⊝ | ‐ |
| Global state: no improvement ‐ medium term | 569 per 10001 | 353 per 1000 | RR 0.62 | 102 | ⊕⊝⊝⊝ | ‐ |
| Global state: need for additional medication ‐ medium term | 529 per 10001 | 529 per 1000 | RR 1.00 | 102 | ⊕⊝⊝⊝ | ‐ |
| Adverse effects/events: extrapyramidal symptoms ‐ medium term | 59 per 10001 | 19 per 1000 | RR 0.33 | 102 | ⊕⊝⊝⊝ | ‐ |
| Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Economic outcomes: cost‐effectiveness ‐ clinically important | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Assumed risk: mean baseline risk presented for single study. Equates with that of control group. | ||||||
| Benzodiazepines compared to antipsychotics for psychosis‐induced aggression or agitation | ||||||
| Patient or population: people with psychosis‐induced aggression or agitation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Antipsychotics | Benzodiazepines | |||||
| Tranquillisation or asleep: sedation ‐ medium term vs haloperidol Number of participants sedated | Low | RR 1.13 | 434 | ⊕⊕⊝⊝ | ‐ | |
| 100 per 1000 | 113 per 1000 (83 to 154) | |||||
| Moderate5 | ||||||
| 227 per 1000 | 257 per 1000 | |||||
| High | ||||||
| 500 per 1000 | 565 per 1000 | |||||
| Global state: no improvement ‐ vs haloperidol ‐ medium term As defined in each study | Low | RR 0.89 | 188 | ⊕⊕⊝⊝ | ‐ | |
| 77 per 1000 | 68 per 1000 (55 to 85) | |||||
| Moderate3 | ||||||
| 619 per 1000 | 551 per 1000 | |||||
| High | ||||||
| 933 per 1000 | 830 per 1000 | |||||
| Global state: no improvement ‐ vs olanzapine ‐ medium term As defined in each study | 192 per 1000 | 353 per 1000 (203 to 610) | RR 1.84 | 150 | ⊕⊝⊝⊝ | ‐ |
| Global state: need for additional medication ‐ medium term | See comment | See comment | Not estimable | 216 | ⊕⊝⊝⊝ | High levels of heterogeneity between included studies (Chi2 = 16.41; I2 = 94%) ‐ data not pooled.4 |
| Adverse effects/events: extrapyramidal symptoms ‐ vs haloperidol ‐ medium term Number of instances of extrapyramidal symptoms | Low | RR 0.13 | 233 | ⊕⊕⊝⊝ | ‐ | |
| 0 per 1000 | 0 per 1000 | |||||
| Moderate6 | ||||||
| 186 per 1000 | 24 per 1000 | |||||
| High | ||||||
| 500 per 1000 | 65 per 1000 | |||||
| Satisfaction with treatment: from the perspective of consumer, family and informal care givers or professionals/carers at any point during the acute management stage | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Economic outcomes: cost‐effectiveness | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Risk of bias: 'serious' ‐ most trials received funding from a pharmaceutical institute and there was potential risk of selection bias. 3Assumed risk: calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (61.9%). 4Inconsistency: 'serious' ‐ one study indicated significant favour of antipsychotics, while the other study indicated favour for benzodiazepines (non‐significant). 5Assumed risk: calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (22.7%). 6Assumed risk: calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (18.6%). 7Only one small study reporting data. | ||||||
| Benzodiazepines compared to antihistamines + antipsychotics for psychosis‐induced aggression or agitation | ||||||
| Patient or population: people with psychosis‐induced aggression or agitation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Antihistaimes + antipsychotics | Benzodiazepines | |||||
| Tranquillisation or asleep: sedation ‐ medium term ‐ lorazepam vs haloperidol + promethazine | 970 per 10001 | 883 per 1000 | RR 0.91 | 200 | ⊕⊕⊝⊝ | ‐ |
| Tranquillisation or asleep: sedation ‐ medium term ‐ midazolam vs haloperidol + promethazine | 827 per 10001 | 934 per 1000 | RR 1.13 | 301 | ⊕⊕⊝⊝ | ‐ |
| Global state: no improvement ‐ medium term | 120 per 10001 | 260 per 1000 | RR 2.17 | 200 | ⊕⊕⊝⊝ | ‐ |
| Global state: need for additional medication ‐ medium term | 30 per 10001 | 40 per 1000 | RR 1.33 | 200 | ⊕⊕⊝⊝ | ‐ |
| Adverse effects/events: extrapyramidal symptoms ‐ medium term | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Economic outcomes: cost‐effectiveness | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Assumed risk: mean baseline risk presented for single study. Equates with that of control group. | ||||||
| Benzodiazepines + antipsychotics compared to same benzodiazepinesfor psychosis‐induced aggression or agitation | ||||||
| Patient or population: people with psychosis‐induced aggression or agitation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Same benzodiazepines | Benzodiazepines+ antipsychotics | |||||
| Tranquillisation or asleep: sedation ‐ medium term‐ + haloperidol ‐ medium term Number of participants sedated | Moderate5 | RR 0.84 | 110 | ⊕⊕⊝⊝ | ‐ | |
| 556 per 1000 | 467 per 1000 | |||||
| Global state: no improvement ‐ + haloperidol ‐ medium term As defined in each study | Low | RR 0.96 | 113 | ⊕⊕⊝⊝ | ‐ | |
| 677 per 1000 | 650 per 1000 | |||||
| Modertate3 | ||||||
| 732 per 1000 | 703 per 1000 (556 to 879) | |||||
| High | ||||||
| 867 per 1000 | 832 per 1000 | |||||
| Global state: no improvement ‐ lorazepam + risperidone vs lorazepam ‐ medium term | 700 per 1000 | 602 per 1000 | RR 0.86 | 20 | ⊕⊕⊝⊝ | ‐ |
| Global state: need for additional medication ‐ + haloperidol ‐ medium term Number of participants requiring additional medication | Low | RR 1.02 | 103 | ⊕⊕⊝⊝ | ‐ | |
| 0 per 1000 | 0 per 1000 | |||||
| Moderate4 | ||||||
| 500 per 1000 | 510 per 1000 (395 to 660) | |||||
| High | ||||||
| 774 per 1000 | 789 per 1000 | |||||
| Adverse effects/events: extrapyramidal symptoms ‐ + haloperidol ‐ medium term Number of instances of extrapyramidal symptoms | 24 per 10006 | 46 per 1000 (4 to 483) | RR 1.94 (0.18 to 20.30) | 83 | ⊕⊕⊝⊝ | ‐ |
| Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Economic outcomes: cost‐effectiveness | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Risk of bias: 'serious' ‐ most trials received funding from a pharmaceutical institute and there was potential risk of selection bias. 3Assumed risk: calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (73.2%). 4Assumed risk: calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (50%). 5Calculated from the included studies ‐ 'moderate' risk equates with that of control group (55.6%). 6Calculated from the included studies ‐ 'moderate' risk equates with that of control group (2.4%). | ||||||
| Benzodiazepines + antipsychotics compared to same antipsychotics for psychosis‐induced aggression or agitation | ||||||
| Patient or population: people with psychosis‐induced aggression or agitation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Same antipsychotics | Benzodiazepines+ antipsychotics | |||||
| Tranquillisation or asleep: sedation ‐ medium term ‐ +/vs haloperidol Number of participants sedated | Moderate5 | RR 1.75 | 172 | ⊕⊝⊝⊝ | ‐ | |
| 256 per 1000 | 448 per 1000 | |||||
| Low | ||||||
| 100 per 1000 | 175 per 1000 | |||||
| High | ||||||
| 380 per 1000 | 665 per 1000 | |||||
| Global state: no improvement ‐ +/vs haloperidol ‐ medium term As defined in each study | Moderate4 | RR 1.17 | 185 | ⊕⊕⊝⊝ | ‐ | |
| 521 per 1000 | 610 per 1000 | |||||
| Low | ||||||
| 33 per 1000 | 39 per 1000 | |||||
| High | ||||||
| 933 per 1000 | 1000 per 1000 | |||||
| Global state: need for additional medication Number of participants requiring additional medication | See comment | See comment | Not estimable | 67 | ⊕⊕⊝⊝ | ‐ |
| Adverse effects/events: extrapyramidal symptoms ‐ +/vs haloperidol ‐ medium term Number of instances of extrapyramidal symptoms | Moderate6 | RR 0.44 | 127 | ⊕⊕⊝⊝ | ‐ | |
| 185 per 1000 | 81 per 1000 | |||||
| Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Economic outcomes: cost‐effectiveness | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Inconsistency: 'serious' ‐ high levels of heterogeneity. 4Calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (52.1%). 5Calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (25.6%). 6Calculated from the included studies ‐ 'moderate' risk equates with that of control group (18.5%). | ||||||
| Benzodiazepines + antipsychotics compared to antipsychotics + antipsychotics for psychosis‐induced aggression or agitation | ||||||
| Patient or population: people with psychosis‐induced aggression or agitation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Antipsychotics+ antipsychotics | Benzodiazepines+ antipsychotics | |||||
| Tranquillisation or asleep: sedation ‐ medium term | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Global state: no improvement ‐ medium term | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Global state: need for additional medication ‐ medium term | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Adverse effects/events: extrapyramidal symptoms ‐ medium term | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Economic outcomes: cost‐effectiveness | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Benzodiazepines + antipsychotics compared to antihistamines + antipsychotics for psychosis‐induced aggression or agitation | ||||||
| Patient or population: people with psychosis‐induced aggression or agitation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Antihistamine + antipsychotics | Benzodiazepines+ antipsychotics | |||||
| Tranquillisation or asleep: sedation ‐ medium term | 33 per 10005 | 400 per 1000 | RR 12.00 | 60 | ⊕⊝⊝⊝ | ‐ |
| Global state: no improvement ‐ medium term | 0 per 10001 | 0 per 1000 | RR 25.00 | 60 | ⊕⊝⊝⊝ | ‐ |
| Global state: need for additional medication ‐ medium term | ‐ | The mean global impression: need for additional medication ‐ medium term in the intervention groups was | ‐ | 60 | ⊕⊝⊝⊝ | Skewed data ‐ see 'data and analysis'. |
| Adverse effects/events: extrapyramidal symptoms ‐ medium term | 167 per 10005 | 100 per 1000 | RR 0.60 | 60 | ⊕⊝⊝⊝ | ‐ |
| Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| Economic outcomes: cost‐effectiveness | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Assumed risk: mean baseline risk ‐ only one trial reported with 0 events in the control group and 12 events in the intervention group. | ||||||
| Name | Code | Chemical name |
|---|---|---|
| Benzodiazepines | ||
| Bromazepam | Ro 5‐3350 | 7‐bromo‐1, 3‐dihydro‐5‐(2‐pyridyl)‐2H‐1, 4‐benzodiazepin‐2‐one |
| Camazepam | SB 5833 | 7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one dimethylcarbamate |
| Chlordiazepoxide | Ro 5‐0690 | 7‐chloro‐2‐methylamino‐5‐phenyl‐3H‐1, 4‐benzodiazepin‐4‐oxide |
| Cinolazepam | OX 373 | 7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐3‐hydroxy‐2‐oxo‐1H‐1, 4‐benzodiazepine‐1‐ propionitrile |
| Clobaza | HR 376 H 4723 LM 2717 | 7‐chloro‐1‐methyl‐5‐phenyl‐1H‐1, 5‐benzodiazepine‐2, 4‐(3H, 5H)‐dione |
| Clonazepam | Ro 5‐4023 | 5‐(o‐chlorophenyl)‐1, 3‐dihydro‐7‐nitro‐2H‐1, 4‐benzodiazepin‐2‐one |
| Clorazepate | 4306CB A35.616 | dipotassium 7‐chloro‐2, 3‐dihydro‐2, 2‐oxo‐5‐phenyl‐1H‐1, 4‐benzodiazepine‐3‐carboxylate |
| Cp 1414 S | ‐ | 2‐amino‐7‐nitro‐5‐phenyl‐3H‐1, 5‐benzodiazepin‐4‐one |
| Cyprazepam | W 3623 | 7‐chloro‐2‐[(cyclopropylmethyl)amino]‐5‐phenyl‐3H‐1, 4‐benzodiazepin‐4‐oxide |
| Delorazepam chlordemethyldiazepam | ‐ | 7‐chloro‐5‐(o‐chlorophenyl)‐1, 3‐dihydro‐2H‐1, 4‐benzodiazepin‐2‐one |
| Diazepam | Ro 5‐2807 WY 3467 LA III | 7‐chloro‐1, 3‐dihydro‐1‐methyl‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Doxefazepam | SAS 643 | 7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐1‐(2‐hydroxyethyl)‐2H‐1, 4‐benzodiazepin‐2‐one |
| Elfazepam | SKF 72.517) | 7‐chloro‐1‐[2‐(ethylsulfonyl)ethyl]‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐2H‐1, 4‐benzodiazepin‐2‐one |
| Ethyl carfluzepate | ‐ | ethyl ester of 7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐1‐ (methylcarbamoyl)‐2‐oxo‐1H‐1, 4‐benzodiazepine‐3‐carboxylic acid |
| Ethyl dirazepate | ‐ | ethyl 7‐chloro‐5‐(o‐chlorophenyl)‐2, 3‐dihydro‐2‐oxo‐1H‐1, 4‐benzodiazepine‐3‐carboxylate |
| Ethyl loflazepate | CM 6912 | ethyl 7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐2‐oxo‐1H‐1, 4‐ benzodiazepine‐3‐carboxylate |
| Fletazepam | SCH 15.698 | 7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐1‐(2, 2, 2‐trifluoroethyl)‐1H‐1, 4‐benzodiazepine |
| Fludiazepam | ID 540 | 7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐1 methyl‐2H‐1, 4‐benzodiazepine‐2‐0 |
| Flunitrazepam | Ro 5‐4200 | 5‐(o‐fluorophenyl)‐1, 3‐dihydro‐1‐methyl‐7‐nitro‐2H‐1, 4‐ benzodiazepin‐2‐one |
| Flurazepam | Ro 5‐6901 | 7‐chloro‐1‐[2‐(diethylamino)ethyl]‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐2H‐1, 4‐benzodiazepin‐2‐one. dihydrochloride |
| Flutemazepam | ‐ | 7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐2H‐1, 4‐benzodiazepine‐2‐one |
| Flutoprazepam | KB 509 ID 1937 | 7‐chloro‐1‐(cyclopropylmethyl)‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐2H‐1, 4‐benzodiazepin‐2‐one |
| Fosazepam | HR 930 | 7‐chloro‐1‐[(dimethylphosphinyl)methyl]‐1, 3‐dihydro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Girisopam | GYKI 51.189 EGIS 5810 | 1‐(3‐chlorophenyl)‐4‐methyl‐7, 8‐dimethoxy‐5H‐2, 3‐benzodiazepine |
| Gv 150013 | ‐ | (R)‐N‐[(adamantane‐1‐methyl)‐2, 4‐dioxo‐5‐phenyl‐2, 3, 4, 5‐tetrahydro‐1H‐1, 5‐benzodiazepin‐3‐yl]‐N‐phenylurea |
| Halazepam | SCH 12.041 | 7‐chloro‐1, 3‐dihydro‐5‐phenyl‐1‐(2, 2, 2‐trifluoroethyl)‐2H‐1, 4‐benzodiazepin‐2‐one |
| Iclazepam clazepam (formerly) | ‐ | 7‐chloro‐1‐[2‐(cyclopropylmethoxy)ethyl]‐1, 3‐dihydro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Lorazepam | WY 4036 | 7‐chloro‐5‐(o‐chlorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐2‐1, 4‐benzodiazepin‐2‐one |
| Lormetazepam | WY 4082 | 7‐chloro‐5‐(o‐chlorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| M ORF8063 | WE 352 | 1‐methyl‐5‐phenyl‐7‐(trifluoromethyl)‐1H‐1, 5‐benzodiazepine‐2, 4(3H, 5H)dione |
| Meclonazepam | (3‐methylclonazepam) Ro 11‐3128 (meclonazepam, Roche) Ro 11‐3624 (steric antipode of meclonazepam) | (+)‐(S)‐5‐(o‐chlorophenyl)‐1, 3‐dihydro‐3‐methyl‐7‐nitro‐2H‐1, 4‐benzodiazepin‐2‐one |
| Medazepam | Ro 5‐4556 | 7‐chloro‐2, 3‐dihydro‐1‐methyl‐5‐phenyl‐1H‐1, 4‐benzodiazepine |
| Menitrazepam | CB 4857 | 5‐(1‐cyclohexen‐1‐yl)‐1, 3‐dihydro‐1‐methyl‐7‐nitro‐2H‐1, 4‐benzodiazepin‐2‐one |
| Metaclazepam (formerly: Brometazepam) | KC 2547 KC 3755 (normetaclazepam (active metabolite) | 7‐bromo‐5‐(o‐chlorophenyl)‐2, 3‐dihydro‐2‐(methoxymethyl)‐1‐methyl‐1H‐1, 4‐benzodiazepine |
| Nimetazepam | S 1530 | 1, 3‐dihydro‐1‐methyl‐7‐nitro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Nitrazepam | Ro 4‐5360 Ro 5‐3059 CB 4395 (potassium salt) | 1, 3‐dihydro‐7‐nitro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Nordazepam | Ro 5‐2180 A 101 | 7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Normetrazepam | CB 4260 | 7‐chloro‐5‐(1‐cyclohexen‐1‐yl)‐1, 3‐dilhydro‐2H‐1, 4‐benzodiazepin‐2‐one |
| Oxazepam | WY 3498 8092 CB Ro 5‐6789 | 7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Oxazepam hemisuccinate | SAS 538 | 7‐chloro‐2, 3‐dihydro‐3‐hydroxy‐2‐(1H)‐oxo‐5‐phenyl‐1, 4‐benzodiazepin‐3‐yl hydrogen succinate |
| Pinazepam | Z 905 | 7‐chloro‐1, 3‐dihydro‐5‐phenyl‐1‐(2‐propynyl)‐2H‐1, 4‐benzodiazepin‐2‐one |
| Potassium nitrazepate | CB 4335 | 2, 3‐dihydro‐7‐nitro‐2‐oxo‐5‐phenyl‐1H‐1, 4‐benzodiazepin‐3‐carboxylic acid monopotassium salt |
| Prazepam | W 4020 | 7‐chloro‐1‐(cyclopropylmethyl)‐1, 3‐dihydro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Quazepam | SCH 16.134 | 7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐1‐(2, 2, 2‐trifluoroethyl)‐2H‐1, 4‐benzodiazepine‐2‐thione |
| Reclazepam | SC 33.963 | 2‐[7‐chloro‐5‐(o‐chlorophenyl)‐2, 3‐dihydro‐1H‐1, 4‐benzodiazepin‐1‐yl]‐2‐oxazolin‐4‐one |
| Sc 32.855 | ‐ | 7‐chloro‐5‐(o‐chlorophenyl)‐1‐ (4, 5‐dihydro‐2‐oxazolyl)‐2, 3‐dihydro‐1H‐1, 4‐benzodiazepine |
| Sulazepam | W3676 | 7‐chloro‐1, 3‐ dihydro‐1‐methyl‐5‐phenyl‐ 2H‐1, 4‐ benzodiazepin‐ 2‐thione |
| Temazepam | ER 115 Ro 5‐5345 WY 3917 | 7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Tetrazepam | CB 4261 | 7‐chloro‐5‐(cyclohexen‐1‐yl)‐1, 3‐dihydro‐1‐methyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Tofisopam | EGYT 341 | 5‐ethyl‐7‐8‐dimethoxy‐1‐(3, 4‐dimethoxyphenyl)‐4‐methyl‐5H‐2, 3‐benzodiazepine |
| Uldazepam | U 31.920 | 2‐[(allyloxy)amino]‐7‐chloro‐5‐(o‐chlorophenyl)‐3H‐1, 4‐benzodiazepine |
| Tricyclic benzodiazepines | ||
| 1‐Hydroxytriazolam | ‐ | 8‐chloro‐6‐(o‐chlorophenyl)‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine‐1‐methanol |
| Adinazolam | U 41.123 F (mesylate) U 41.123 (base) | 8‐chloro‐1‐[(dimethylamino)methyl]‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine (mesylate) |
| Alprazolam | U 31.889 | 8‐chloro‐1‐methyl‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine |
| Climazolam | ‐ | 8‐chloro‐6‐(o‐chlorophenyl)‐1‐methyl‐4H‐imidazo[1, 5‐a][1, 4]benzodiazepine |
| Cloxazolam | CS 370 MT 14‐411 | 10‐chloro‐11b‐(o‐chlorophenyl)‐2, 3, 7, 11b‐tetrahydro‐oxazolo[3, 2‐d][1, 4]benzodiazepin‐6 (5H)‐one |
| Estazolam noralprazolam | D 40 TA Lu 7426 Abbott 47631 | 8‐chloro‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4] benzodiazepine |
| Flutazolam | MS 4101 | 10‐chloro‐11b‐(2‐flurophenyl)‐2, 3, 7, 11b‐tetrahydro‐7‐(2‐hydroxyethyl‐oxazolo[ 3, 2‐d] [1, 4] benzodiazepin‐6(5H)‐one |
| Gp 55.129 | U 40125 | 8‐chloro‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine‐1‐methanol |
| Haloxazolam | CS 430 | 10‐bromo‐11b‐(o‐fluorophenyl)‐2, 3, 7, 11b‐tetrahydrooxazolo[3, 2‐d][1, 4]benzodiazepin‐6(5H)‐one |
| Ketazolam | U 28.774 | 11‐chloro‐8, 12b‐dihydro‐2, 8‐dimethyl‐12b‐phenyl‐4H‐[1, 3]oxazino[3, 2‐d][1, 4]benzodiazepine‐4, 7(6H)‐ dione |
| Loprazolam | RU 31.158 HR 158 | (Z)‐6‐(o‐chlorophenyl)‐2, 4‐dihydro‐2‐[(4‐methylpiperazin‐1‐yl)methylene]‐8‐nitro‐1H‐ imidazo[1, 2‐a][1,~ 4]benzodiazepin‐1‐one |
| Mexazolam | CS 386 | 10‐chloro‐11b‐(o‐chlorophenyl)‐2, 3, 7, 11b‐tetrahydro‐3‐methyl‐oxazolo[3, 2‐d][1, 4]benzodiazepin‐6(5)‐one |
| Midazolam | Ro 21‐3981 (maleate) Ro 21‐3981/003 (HCl) | 8‐chloro‐6‐(o‐fluorophenyl)‐1‐methyl‐4H‐imidazo [1, 5‐a][1, 4]benzodiazepine maleate (1: 1) |
| Noradinazolam | U 42.352 | 8‐chloro‐1‐(methylamino)methyl]‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine |
| Oxazolam | ‐ | 10‐chloro‐2, 3, 7, 11b‐tetrahydro‐2‐methyl‐11b‐phenyloxazolo[3, 2‐d][1, 4]benzodiazepin‐ 6(5H)‐one |
| Ru 31.124 | ‐ | 8‐chloro‐6‐(o‐chlorophenyl)‐2‐(4‐ethylpiperazin‐1‐yl)methyl]‐2, 4‐dihydro‐1H‐imidazo[1, 2‐a][1, 4]benzodiazepin‐1‐one (methyl bridge or methylene group uncertain) |
| Triazolam | U 33.030 | 8‐chloro‐6‐(o‐chlorophenyl)‐1‐methyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine |
| Benzodiazepines with atypical mode of action | ||
| Arfendazam | ‐ | ethyl 7‐chloro‐2, 3, 4, 5‐tetrahydro‐4‐oxo‐5‐phenyl‐1H‐1, 5‐benzodiazepine‐1‐carboxylate |
| Devazepide | L 364.718 (former designation) MK 329 (Merck and Co., USA) L 365.031(Merck) | (S)‐N‐(2, 3‐dihydro‐1‐methyl‐2‐oxo‐5‐phenyl‐1H‐1, 4‐ benzodiazepin‐3‐yl)‐indole‐2‐carboxamideL 365031 N‐(2, 3‐ dihydro‐1‐methyl‐2‐oxo‐5‐phenyl‐1H‐1, 4‐benzodiazepin‐3‐yl)‐1H‐p‐bromobenzamide |
| Gyki 52.322 | EGIS 6775 | 1‐(4‐aminophenyl)‐4‐methyl‐7, 8‐dimethoxy‐5H‐2, 3‐benzodiazepine 2, 3‐ |
| L 365260 | ‐ | (R)‐N‐(2, 3‐dihydro‐1‐methyl‐2‐oxo‐5‐phenyl‐1H‐1, 4‐benzodiazepin‐3‐yl)‐N’‐(3‐methylphenyl)‐urea |
| Ro 15‐4513 | ‐ | ethyl 8‐azido‐5, 6‐dihydro‐6‐oxo‐4H‐imidazo[1, 5‐a][1, 4]benzodiazepine‐3‐carboxylate |
| Ro 5‐4864 | ‐ | 7‐chloro‐5‐(p‐chlorophenyl)‐1, 3‐dihydro‐1‐methyl‐2H‐1, 4‐benzodiazepin‐2‐one |
| Tifluadom | KC 5103 (+)‐tifluadom KC 6128 (Sandoz/Kali‐ Chemie, BRD) (‐)‐tifluadom KC5911 | (+/‐)‐N‐[[5‐(o‐fluorophenyl)‐2, 3‐dihydro‐1‐methyl‐1H‐1, 4‐benzodiazepin‐2‐yl]methyl]‐3‐thiophenecarboxamide |
| Fused benzodiazepines | ||
| Brotizolam Ladormin (provisional name) | We 941 | 2‐bromo‐4‐(o‐chlorophenyl)‐9‐methyl‐6H‐thieno [3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine |
| Ciclotizolam | We 973‐BS | 2‐bromo‐4‐(o‐chlorophenyl)‐9‐cyclohexyl‐6H‐thieno[3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine |
| Clotiazepam | Y 6047 | 5‐(o‐chlorophenyl)‐7‐ethyl‐1, 3‐dihydro‐1‐methyl‐2H‐thieno[2, 3‐e][1, 4]diazepin‐2‐one |
| Etizolam | AHR 3219 Y 7131 | 4‐(o‐chlorophenyl)‐2‐ethyl‐9‐methyl‐6H‐thieno [3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine |
| Lopirazepam | D 12524 | 7‐chloro‐5‐(o‐chlorophenyl)‐1, 2‐dihydro‐3‐hydroxy‐3H‐pyrido[3, 2‐ e][1, 4]diazepin‐2‐one |
| Premazepam | MDL 181 | 3, 7‐dihydro‐6, 7‐dimethyl‐5‐phenylpyrrolo[3, 4‐e][1, 4]diazepin‐2(1H)‐one |
| Razobazam | Hoe 175 | 4, 8‐dihydro‐3, 8‐dimethyl‐4‐phenylpyrazolo[3, 4‐b][1, 4]diazepine‐5, 7(1H, 6H)‐dione |
| Ripazepam | CI 683 | 1‐ethyl‐4, 6‐dihydro‐3‐methyl‐8‐phenylpyrazolo[4, 3‐e][1, 4]diazepin‐5(1H)‐one |
| Ro 11‐7800 | ‐ | 9‐aminomethyl‐2‐chloro‐4‐(o‐chlorophenyl)‐6H‐thieno[3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4] diazepine |
| Thiadipone | CI 718 bentazepam QM 6008 | 1, 3, 6, 7, 8, 9‐hexahydro‐5‐phenyl‐2H‐[1]benzothieno[2, 3‐e][1, 4]diazepin‐2‐one |
| Zapizolam | ‐ | 8‐chloro‐6‐(o‐chlorophenyl)‐4H‐pyrido[2, 3‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine |
| Zomebazam | ‐ | 4, 8‐dihydro‐1, 3, 8‐trimethyl‐4‐phenylpyrazolo [3, 4‐b][1, 4]diazepine‐5, 7(1H, 6H)‐dione |
| Zometapine | CI 781 | 7, 8‐dihydro‐1, 3‐dimethyl‐4‐phenyl‐6H‐pyrazolo[3, 4‐e][1, 4] diazepine |
| Benzodiazepine | Half‐life |
|---|---|
| 1. Long | |
| Chlordiazepoxide | 5‐30 hours |
| Clobazam | 16‐60 hours |
| Clorazepate | 1‐2 hours |
| Diazepam | 20‐40 hours |
| Flurazepam | 1‐2 hours |
| Ketazolam | ~30 hours |
| Metaclazepam | 7‐23 hours |
| Oxazolam | ~30 hours |
| 2. Medium/short | |
| Alprazolam | 10‐15 hours |
| Bromazepam | 10‐20 hours |
| Brotizolam | 4‐7 hours |
| Clotiazepam | 3‐15 hours |
| Loprazolam | 6‐8 hours |
| Lorazepam | 8‐24 hours |
| Lormetazepam | 8‐14 hours |
| Nitrazepam | 15‐30 hours |
| Oxazepam | 4‐15 hours |
| Temazepam | 5‐14 hours |
| 3. Extremely short | |
| Midazolam | 1‐7 hours |
| Triazolam | 1.5‐5 hours |
| Focus of review | Reference |
|---|---|
| Aripiprazole for psychosis‐induced agitation/aggression | |
| Benzodiazepines for schizophrenia | |
| Containment strategies for people with serious mental illness | |
| Chlorpromazine for psychosis‐induced agitation/aggression | |
| Haloperidol (rapid tranquillisation) for psychosis‐induced agitation/aggression | |
| Haloperidol for long‐term aggression in psychosis | |
| Haloperidol plus promethazine for psychosis‐induced agitation/aggression | |
| Loxapine for schizophrenia | |
| Loxapine inhaler for psychosis‐induced aggression or agitation | |
| Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses | |
| Quetiapine for psychosis‐induced aggression or agitation | |
| Risperidone for psychosis‐induced agitation/aggression | |
| Seclusion and restraint for people with serious mental illnesses | |
| Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses |
| Attrition | Study | % loss | Duration | Notes |
|---|---|---|---|---|
| High | 31 | 72 hours | ‐ | |
| 12 | 2 hours | ‐ | ||
| 10 | 100 minutes | ‐ | ||
| 50 | 24 hours | ‐ | ||
| 33 | 48 hours | 33% participants lost to follow‐up for EPS outcome and 12% loss for 'sedation' | ||
| 10 | 90 minutes | ‐ | ||
| Low | 0 | 7 days | ‐ | |
| 0 | 2 hours | ‐ | ||
| 4 | 24 hours | ‐ | ||
| 0 | 7 days | ‐ | ||
| 1 | 2 weeks | ‐ | ||
| 0.5 | 4 hours | ‐ | ||
| 0 | 24 hours | ‐ | ||
| 0 | 24 hours | ‐ | ||
| 0 | 60 minutes | ‐ | ||
| 0 | 24 hours | ‐ | ||
| 0 | 4 hours | ‐ | ||
| 0 | 12 hours | ‐ | ||
| Unclear | Unclear | 120 minutes | Only abstract available. | |
| Unclear | 24 hours | Only abstract available. | ||
| Trials were considered to have a high attrition rates if it was more than 5% within the first two hours or 25% to 50% overall. EPS: extrapyramidal symptoms. | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Tranquillisation or asleep: 1. sedation Show forest plot | 1 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.42, 6.61] |
| 1.1.1 medium term | 1 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.42, 6.61] |
| 1.2 Behaviour: 1. mean change score (Agitated Behaviour Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.2.1 medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.3 Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC)) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 short term | 1 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.69, 1.16] |
| 1.3.2 medium term | 1 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.40, 0.97] |
| 1.4 Global state: 2. need for additional medication Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4.1 medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5 Global state: 3. mean change score (Clinical Global Impression Severity Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.5.1 medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.6 Mental state: 1. mean change score (Positive and Negative Syndrome Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.6.1 medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.7 Mental state: 2. mean change score (PANSS‐EC, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.7.1 medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.8 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.8.1 medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.9 Adverse effects/events: 2. use of medication for EPS Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.9.1 medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.10 Adverse effects/events: 3. specific Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.10.1 dizziness ‐ medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.10.2 nausea ‐ medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.10.3 vomiting ‐ medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.11 Leaving the study early: 1. any reason Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.11.1 medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Tranquillisation or asleep: 1. sedation Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1.1 vs droperidol ‐ short term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.71 [1.55, 4.73] |
| 2.1.2 vs haloperidol ‐ short term | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.53, 2.59] |
| 2.1.3 vs haloperidol ‐ medium term | 8 | 434 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.83, 1.54] |
| 2.1.4 vs olanzapine ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.28, 1.98] |
| 2.2 Behaviour: 2. mean change/endpoint score (Agitated Behaviour Scale, high = worse) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.2.1 vs haloperidol ‐ medium term | 1 | 66 | Mean Difference (IV, Fixed, 95% CI) | 1.80 [‐2.39, 5.99] |
| 2.2.2 vs olanzapine ‐ medium term | 1 | 149 | Mean Difference (IV, Fixed, 95% CI) | 2.91 [0.80, 5.02] |
| 2.3 Behaviour: 4. mean change score (Overt Aggression Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.3.1 vs haloperidol ‐ medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.4 Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC)) Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.4.1 vs olanzapine ‐ short term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.26 [0.95, 1.66] |
| 2.4.2 vs olanzapine ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.84 [1.06, 3.18] |
| 2.4.3 vs haloperidol ‐ medium term | 5 | 188 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.71, 1.11] |
| 2.5 Global state: 2. need for additional medication Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.5.1 vs droperidol ‐ short term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.5.2 vs haloperidol ‐ medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.5.3 vs olanzapine ‐ medium term | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.6 Global state: 3. mean change/endpoint score (Clinical Global Impression Severity Scale, high = worse) Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.6.1 vs haloperidol ‐ short term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.6.2 vs haloperidol ‐ medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.6.3 vs haloperidol ‐ medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.6.4 vs olanzapine ‐ medium term | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.7 Global state: 4. mean endpoint score (Inpatient Multidimensional Psychiatric Scale, high = worse) Show forest plot | 1 | 16 | Mean Difference (IV, Fixed, 95% CI) | 2.60 [‐3.04, 8.24] |
| 2.7.1 vs haloperidol ‐ medium term | 1 | 16 | Mean Difference (IV, Fixed, 95% CI) | 2.60 [‐3.04, 8.24] |
| 2.8 Mental state: 1. no improvement (decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) Show forest plot | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.73, 1.18] |
| 2.8.1 vs haloperidol ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.73, 1.18] |
| 2.9 Mental state: 2. mean change/endpoint score (BPRS, high = worse) Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.9.1 vs haloperidol ‐ short term | 1 | 37 | Mean Difference (IV, Fixed, 95% CI) | ‐3.26 [‐10.65, 4.13] |
| 2.9.2 vs haloperidol ‐ medium term | 3 | 123 | Mean Difference (IV, Fixed, 95% CI) | 1.67 [‐1.84, 5.18] |
| 2.10 Mental state: 3. mean endpoint score (BPRS psychosis subscale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.10.1 vs haloperidol ‐ medium term | 1 | 66 | Mean Difference (IV, Fixed, 95% CI) | 0.70 [‐7.20, 8.60] |
| 2.11 Mental state: 3a. mean endpoint score (BPRS positive subscale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.11.1 vs haloperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.80 [‐1.83, 3.43] |
| 2.12 Mental state: 4a. mean endpoint score (BPRS‐excited component, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.12.1 vs haloperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 1.27 [‐0.49, 3.03] |
| 2.13 Mental state: 2a. mean change score (Positive and Negative Syndrome Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.13.1 vs olanzapine ‐ medium term | 1 | 146 | Mean Difference (IV, Fixed, 95% CI) | 5.64 [2.20, 9.08] |
| 2.14 Mental state: 4. mean change score (PANSS‐EC, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.14.1 vs olanzapine ‐ medium term | 1 | 149 | Mean Difference (IV, Fixed, 95% CI) | 2.85 [1.14, 4.56] |
| 2.15 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot | 8 | 536 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.06, 0.39] |
| 2.15.1 vs haloperidol ‐ medium term | 6 | 233 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.13 [0.04, 0.41] |
| 2.15.2 vs olanzapine ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.03, 1.89] |
| 2.15.3 vs droperidol ‐ medium term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.90] |
| 2.16 Adverse effects/events: 2. use of medication for EPS Show forest plot | 2 | 216 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.40 [0.15, 1.05] |
| 2.16.1 vs haloperidol ‐ medium term | 1 | 66 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.50 [0.17, 1.47] |
| 2.16.2 vs olanzapine ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.03, 1.89] |
| 2.17 Adverse effects/events: 3. specific Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.17.1 vs haloperidol ‐ akathisia ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.58] |
| 2.17.2 vs droperidol ‐ airway management ‐ medium term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.47 [0.39, 142.14] |
| 2.17.3 vs haloperidol ‐ ataxia ‐ medium term | 1 | 66 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.26 [0.22, 23.71] |
| 2.17.4 vs droperidol ‐ low blood pressure ‐ medium term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [0.33, 6.15] |
| 2.17.5 vs haloperidol ‐ dizziness ‐ medium term | 1 | 66 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.25, 5.19] |
| 2.17.6 vs olanzapine ‐ dizziness ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.51 [0.60, 3.82] |
| 2.17.7 vs haloperidol ‐ drowsiness ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.07, 14.55] |
| 2.17.8 vs haloperidol ‐ dry mouth ‐ medium term | 1 | 66 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.88 [0.49, 7.24] |
| 2.17.9 vs droperidol ‐ low heart rate ‐ medium term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.01, 8.59] |
| 2.17.10 vs haloperidol ‐ high heart rate ‐ medium term | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.22 [0.01, 4.29] |
| 2.17.11 vs droperidol ‐ hypoxia ‐ medium term | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [0.33, 6.15] |
| 2.17.12 vs olanzapine ‐ nausea ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.76 [0.89, 67.67] |
| 2.17.13 vs droperidol ‐ seizure ‐ medium term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 2.17.14 vs haloperidol ‐ speech disorder ‐ medium term | 1 | 66 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.11, 2.87] |
| 2.17.15 vs haloperidol ‐ tremor ‐ medium term | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.10 [0.01, 1.69] |
| 2.17.16 vs droperidol ‐ vomiting ‐ medium term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 2.17.17 vs olanzapine ‐ vomiting ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 13.46 [0.71, 255.70] |
| 2.18 Leaving the study early: 1. any reason Show forest plot | 3 | 339 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.48 [0.70, 3.13] |
| 2.18.1 vs droperidol ‐ medium term | 1 | 173 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.51 [0.60, 3.79] |
| 2.18.2 vs haloperidol ‐ medium term | 1 | 16 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.01, 3.61] |
| 2.18.3 vs olanzapine ‐ medium term | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.82 [0.62, 54.58] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Tranquilisation or asleep: 1. sedation Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1.1 vs haloperidol + promethazine ‐ immediate term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.77, 0.99] |
| 3.1.2 vs haloperidol + promethazine ‐ short term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.77, 0.95] |
| 3.1.3 vs haloperidol + promethazine ‐ medium term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.84, 0.98] |
| 3.1.4 vs haloperidol + promethazine ‐ short term | 1 | 301 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.32 [1.16, 1.49] |
| 3.1.5 vs haloperidol + promethazine ‐ medium term | 1 | 301 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [1.04, 1.23] |
| 3.2 Global state: 1. no improvement (Clinical Global Impression (CGI) ‐ improvement scale dichotomised; much and very much improved) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.2.1 vs haloperidol + promethazine ‐ immediate term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.79 [1.36, 2.37] |
| 3.2.2 vs haloperidol + promethazine ‐ short term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.47 [1.51, 4.03] |
| 3.2.3 vs haloperidol + promethazine ‐ medium term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.17 [1.16, 4.05] |
| 3.3 Global state: 2. need for additional medication Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.3.1 vs haloperidol + promethazine ‐ immediate term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.3.2 vs haloperidol + promethazine ‐ short term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.12, 72.77] |
| 3.3.3 vs haloperidol + promethazine ‐ medium term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.33 [0.31, 5.81] |
| 3.4 Global state: 3. mean endpoint score (CGI, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.4.1 vs haloperidol + promethazine ‐ immediate term | 1 | 200 | Mean Difference (IV, Fixed, 95% CI) | 0.49 [0.23, 0.75] |
| 3.4.2 vs haloperidol + promethazine ‐ short term | 1 | 200 | Mean Difference (IV, Fixed, 95% CI) | 0.60 [0.34, 0.86] |
| 3.4.3 vs haloperidol + promethazine ‐ medium term | 1 | 200 | Mean Difference (IV, Fixed, 95% CI) | 0.23 [‐0.05, 0.51] |
| 3.5 Adverse effects/events: 1. specific Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.5.1 vs haloperidol + promethazine ‐ airway management ‐ medium term | 2 | 501 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.99 [0.31, 28.54] |
| 3.5.2 vs haloperidol + promethazine ‐ nausea ‐ medium term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.12, 72.77] |
| 3.5.3 vs haloperidol + promethazine ‐ seizure ‐ medium term | 1 | 301 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 8.06] |
| 3.6 Hospital and service outcomes: 1. changes in hospital status Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.6.1 vs haloperidol + promethazine ‐ not discharged ‐ medium term | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.86, 1.48] |
| 3.7 Leaving the study early: 1. any reason Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.7.1 vs haloperidol + promethazine ‐ medium term | 2 | 501 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.43 [0.06, 2.87] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Tranquillisation or asleep: 1. sedation Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1.1 + haloperidol ‐ short term | 1 | 47 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.92 [1.10, 3.35] |
| 4.1.2 + haloperidol ‐ medium term | 2 | 110 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.59, 1.19] |
| 4.2 Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.2.1 + haloperidol ‐ medium term | 1 | 63 | Mean Difference (IV, Fixed, 95% CI) | ‐1.60 [‐5.94, 2.74] |
| 4.3 Global state: 1. no improvement mean endpoint change in Clinical Global Impression score) Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.3.1 + haloperidol ‐ short term | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.11 [0.01, 1.74] |
| 4.3.2 + haloperidol ‐ medium term | 3 | 113 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.76, 1.20] |
| 4.3.3 + risperidone ‐ medium term | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.45, 1.64] |
| 4.4 Global state: 2. need for additional medication Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.4.1 + haloperidol ‐ medium term | 3 | 103 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.79, 1.32] |
| 4.4.2 + risperidone ‐ medium term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 4.5 Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.5.1 + haloperidol ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.76, 1.32] |
| 4.6 Mental state: 2a. mean endpoint score (BPRS, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.6.1 + risperidone ‐ short term | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 1.10 [‐23.17, 25.37] |
| 4.6.2 + risperidone ‐ medium term | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐1.70 [‐24.26, 20.86] |
| 4.7 Mental state: 2b. mean endpoint score (BPRS, high = worse, skew) Show forest plot | 1 | Other data | No numeric data | |
| 4.7.1 + haloperidol ‐ short term | 1 | Other data | No numeric data | |
| 4.7.2 + haloperidol ‐ medium term | 1 | Other data | No numeric data | |
| 4.8 Mental state: 2c. mean endpoint score (Positive and Negative Syndrome Scale (PANSS), high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.8.1 + risperidone ‐ short term | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 6.40 [‐36.50, 49.30] |
| 4.8.2 + risperidone ‐ medium term | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 3.20 [‐29.41, 35.81] |
| 4.9 Mental state: 2d. mean endpoint score (PANSS, high = worse, skew) Show forest plot | 1 | Other data | No numeric data | |
| 4.9.1 + haloperidol ‐ short term | 1 | Other data | No numeric data | |
| 4.9.2 + haloperidol ‐ medium term | 1 | Other data | No numeric data | |
| 4.10 Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.10.1 + haloperidol ‐ medium term | 1 | 63 | Mean Difference (IV, Fixed, 95% CI) | 1.20 [‐6.28, 8.68] |
| 4.11 Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.11.1 vs haloperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.06 [‐2.73, 2.85] |
| 4.12 Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.12.1 vs haloperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.80 [‐2.41, 0.81] |
| 4.13 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.13.1 + haloperidol ‐ medium term | 2 | 83 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.94 [0.18, 20.30] |
| 4.14 Adverse effects/events: 2. use of medication for EPS Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.14.1 + haloperidol ‐ medium term | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.18, 2.99] |
| 4.15 Adverse effects/events: 3. specific Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.15.1 + haloperidol ‐ akathisia ‐ medium term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 4.15.2 + haloperidol ‐ ataxia ‐ medium term | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.26, 8.11] |
| 4.15.3 + haloperidol ‐ dizziness ‐ medium term | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.65 [0.12, 3.61] |
| 4.15.4 + haloperidol ‐ drowsiness ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.07, 14.55] |
| 4.15.5 + haloperidol ‐ dry mouth ‐ medium term | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.15, 2.23] |
| 4.15.6 + haloperidol ‐ speech disorder ‐ medium term | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.26, 8.11] |
| 4.16 Leaving the study early: 1. any reason Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.16.1 + haloperidol ‐ medium term | 2 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.34, 1.50] |
| 4.16.2 + risperidone ‐ medium term | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.45, 1.64] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Tranquillisation or asleep: 1. sedation Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1.1 +/vs haloperidol ‐ short term | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.25 [1.18, 4.30] |
| 5.1.2 +/vs haloperidol ‐ medium term | 3 | 172 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [1.14, 2.67] |
| 5.2 Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.2.1 +/vs haloperidol ‐ medium term | 1 | 67 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐5.05, 4.65] |
| 5.3 Behaviour: 2. mean endpoint score (Overt Aggression Scale (OAS), high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.3.1 +/vs haloperidol ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 1.20 [‐0.04, 2.44] |
| 5.3.2 +/vs haloperidol ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 2.40 [0.59, 4.21] |
| 5.4 Behaviour: 3. mean endpoint score (Overt Agitation Severity Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.4.1 +/vs haloperidol ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 8.50 [7.07, 9.93] |
| 5.4.2 +/vs haloperidol ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 6.70 [5.94, 7.46] |
| 5.5 Global state: 1. no improvement Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.5.1 +/vs haloperidol ‐ medium term | 4 | 185 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.93, 1.46] |
| 5.6 Global state: 2. need for additional medication Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.6.1 +/vs haloperidol ‐ medium term | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.79, 1.15] |
| 5.7 Global state: 3. need for additional medication (mean dose, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.7.1 +/vs haloperidol ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐0.33, 0.73] |
| 5.8 Global state: 4. mean change score (Ramsey Sedation Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.8.1 +/vs haloperidol ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.50 [‐0.01, 1.01] |
| 5.8.2 +/vs haloperidol ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.36, 0.56] |
| 5.9 Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.9.1 +/vs haloperidol ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.73, 1.18] |
| 5.10 Mental state: 2. mean endpoint score (BPRS, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.10.1 +/vs haloperidol ‐ medium term | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐7.26, 7.28] |
| 5.11 Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.11.1 +/vs haloperidol ‐ medium term | 2 | 95 | Mean Difference (IV, Fixed, 95% CI) | ‐1.19 [‐4.60, 2.23] |
| 5.12 Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.12.1 vs haloperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.86 [‐1.62, 3.34] |
| 5.13 Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.13.1 vs hoperidol ‐ medium term | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.47 [‐1.32, 2.26] |
| 5.14 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.14.1 +/vs haloperidol ‐ medium term | 2 | 127 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.16, 1.17] |
| 5.15 Adverse effects/events: 2. use of medication for EPS Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.15.1 +/vs haloperidol ‐ medium term | 2 | 95 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.27, 1.01] |
| 5.16 Adverse effects/events: 3. specific Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.16.1 +/vs haloperidol ‐ akathisia ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.58] |
| 5.16.2 +/vs haloperidol ‐ ataxia ‐ medium term | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.28 [0.36, 29.97] |
| 5.16.3 +/vs haloperidol ‐ dizziness ‐ medium term | 2 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.54 [0.12, 2.32] |
| 5.16.4 +/vs haloperidol ‐ drowsiness ‐ medium term | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.07, 14.55] |
| 5.16.5 +/vs haloperidol ‐ dry mouth ‐ medium term | 2 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.26 [0.32, 4.92] |
| 5.16.6 +/vs haloperidol ‐ hypotension ‐ medium term | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 11.00 [0.64, 190.53] |
| 5.16.7 +/vs haloperidol ‐ speech disorder ‐ medium term | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.20, 3.39] |
| 5.17 Hospital and service outcomes: 1. changes in hospital status Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.17.1 +/vs haloperidol ‐ not discharged ‐ medium term | 1 | 28 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.54, 1.50] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Behaviour: 3. mean endpoint score (Overt Aggression Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 6.1.1 + haloperidol vs clothiapine + haloperidol ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐5.83 [‐27.60, 15.94] |
| 6.2 Leaving the study early: 1. any reason Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.2.1 + haloperidol vs clothiapine + haloperidol ‐ medium term | 1 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 7.1 Tranquilisation or asleep: 1. sedation Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1.1 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 12.00 [1.66, 86.59] |
| 7.2 Behaviour: 1. mean endpoint score (Overt Aggression Scale (OAS), high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 7.2.1 + haloperidol vs haloperidol + promethazine ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐3.30 [‐5.25, ‐1.35] |
| 7.2.2 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 1.70 [‐0.06, 3.46] |
| 7.3 Behaviour: 2. mean endpoint score (Overt Agitation Severity Scale (OASS) agitation scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 7.3.1 + haloperidol vs haloperidol + promethazine ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐16.00 [‐18.98, ‐13.02] |
| 7.3.2 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐2.70 [‐3.73, ‐1.67] |
| 7.4 Global state: 1. no improvement (number of participants with < 10 points on the OAS and OASS after 12 hours) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.4.1 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 25.00 [1.55, 403.99] |
| 7.5 Global state: 2. need for additional medication (mean dose, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 7.5.1 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.63 [0.15, 1.11] |
| 7.6 Global state: 3. mean change score (Ramsey Sedation Scale, high = worse) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 7.6.1 + haloperidol vs haloperidol + promethazine ‐ short term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.60 [0.07, 1.13] |
| 7.6.2 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐0.46, 0.46] |
| 7.7 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.7.1 + haloperidol vs haloperidol + promethazine ‐ medium term | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.16, 2.29] |
| 7.8 Adverse effects/events: 2. specific Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.8.1 + haloperidol vs haloperidol + promethazine ‐ hypotension ‐ medium term | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.44, 6.36] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 8.1 Tranquilisation or asleep: 1. sedation Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1.1 unclear risk of bias | 6 | 340 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.56, 1.26] |
| 8.1.2 low risk of bias | 3 | 247 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.22 [1.52, 3.25] |
| 8.2 Global state: 1. no improvement Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.2.1 unclear risk of bias | 3 | 214 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.78, 1.63] |
| 8.2.2 low risk of bias | 3 | 124 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.80, 1.28] |
| 8.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.3.1 unclear risk of bias | 5 | 285 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.05, 0.47] |
| 8.3.2 low risk of bias | 3 | 247 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.16 [0.03, 0.85] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 9.1 Tranquilisation or asleep: 1. sedation Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.1.1 unclear risk of bias | 8 | 434 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.79, 1.48] |
| 9.1.2 low risk of bias | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.71 [1.55, 4.73] |
| 9.2 Global state: 1. no improvement Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.2.1 unclear risk of bias | 6 | 338 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.86, 1.32] |
| 9.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.3.1 unclear risk of bias | 7 | 379 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.06, 0.41] |
| 9.3.2 low risk of bias | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.90] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 10.1 Tranquilisation or asleep: 1. sedation Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 10.1.1 high risk of bias | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.56, 2.34] |
| 10.1.2 unclear risk of bias | 6 | 424 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.34 [0.93, 1.94] |
| 10.1.3 low risk of bias | 2 | 119 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.66 [1.05, 2.64] |
| 10.2 Global state: 1. no improvement Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 10.2.1 unclear risk of bias | 4 | 224 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.88, 1.59] |
| 10.2.2 low risk of bias | 2 | 114 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.60, 1.07] |
| 10.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 10.3.1 unclear risk of bias | 6 | 426 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.19 [0.05, 0.68] |
| 10.3.2 low risk of bias | 2 | 106 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.12 [0.03, 0.48] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 11.1 Tranquilisation or asleep: 1. sedation Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 11.1.1 high risk of bias | 2 | 193 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.78 [1.15, 2.75] |
| 11.1.2 unclear risk of bias | 3 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.62, 1.83] |
| 11.1.3 low risk of bias | 4 | 260 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [0.83, 2.03] |
| 11.2 Global state: 1. no improvement Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 11.2.1 unclear risk of bias | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.32, 0.97] |
| 11.2.2 low risk of bias | 5 | 290 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.23 [0.98, 1.56] |
| 11.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 11.3.1 high risk of bias | 1 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.90] |
| 11.3.2 unclear risk of bias | 2 | 77 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.09 [0.01, 0.65] |
| 11.3.3 low risk of bias | 5 | 302 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.18 [0.06, 0.60] |
