Aripiprazol (intramuscular) para la agresión o agitación inducida por la psicosis (tranquilización rápida)
Información
- DOI:
- https://doi.org/10.1002/14651858.CD008074.pub2Copiar DOI
- Base de datos:
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- Cochrane Database of Systematic Reviews
- Versión publicada:
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- 08 enero 2018see what's new
- Tipo:
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- Intervention
- Etapa:
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- Review
- Grupo Editorial Cochrane:
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Grupo Cochrane de Esquizofrenia
- Copyright:
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- Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cifras del artículo
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Autores
Contributions of authors
EGO: screened and retrieved papers against eligibility criteria, appraised quality of papers, extracted data from papers, entered data into RevMan and analysed data, interpreted data and took the lead in writing and finalising the review (2014 search, 2017 search).
Salwan Jajawi: study selection, data extraction, entered data into RevMan and analysed data, and writing up first draft of review (2014 search).
Styliani Spyridi: help with study selection, help with extraction (2014 search).
Kamlaj Sayal: help with study selection (2014 search).
Mahesh Jayaram ‐ developing and writing up (protocol only).
Sources of support
Internal sources
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Università degli Studi di Milano, Milan, Italy.
Employs lead author Edoardo G Ostinelli.
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Rotherham, Doncaster and South Humber NHS Foundation Trust, Rotherham, UK.
Employs review author Salwan Jajawi.
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Cyprus University of Technology, Lemesos, Cyprus.
Employs review author Styliani Spyridi.
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UK LLP, Dewsbury, UK.
Employs review author Styliani Spyridi.
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Cygnet Hospital Derby, UK.
Employs review author Kamlaj Sayal.
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Melbourne Neuropsychiatry Centre, Melbourne, Australia.
Employs review author Mahesh B Jayaram.
External sources
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No sources of support supplied
Declarations of interest
Edoardo G Ostinelli: none known.
Salwan Jajawi: none known.
Styliani Spyridi: has received financial support from pharmaceutical companies to attend scientific conferences, no direct conflict of interest for this review.
Kamlaj Sayal: none known.
Mahesh Jayaram: none known.
Acknowledgements
We are grateful for the support we received from the Cochrane Schizophrenia Group editorial base, Nottingham, UK. We have used their methods template for the Data collection and analysis section. We would also like to thank Lopamudra Mitra and Bhuvaneshwar Pagadala for their contribution to writing the protocol.
We would like to thank Tarek Nassif and Ayesha Kotecha for peer reviewing the review version.
Version history
| Published | Title | Stage | Authors | Version |
| 2018 Jan 08 | Aripiprazole (intramuscular) for psychosis‐induced aggression or agitation (rapid tranquillisation) | Review | Edoardo G Ostinelli, Salwan Jajawi, Styliani Spyridi, Kamlaj Sayal, Mahesh B Jayaram | |
| 2009 Oct 07 | Aripiprazole for psychosis‐induced aggression or agitation | Protocol | Bhuvaneshwar Pagadala, Mahesh B Jayaram, Lopamudra Mitra | |
Differences between protocol and review
Title change: addition of 'intramuscular' and 'rapid tranquillisation' to title.
Objectives: slight change in wording to clarify intervention
Protocol objectives: To evaluate the effects of intramuscular aripiprazole in the treatment of psychosis‐induced agitation and aggression.
Review objectives: To evaluate the effects of intramuscular (IM) aripiprazole in the treatment of psychosis‐induced aggression and agitation (rapid tranquillisation).
Use of new methods template. Since publication of the protocol, Cochrane methodology has evolved (for example, the inclusion of 'Summary of findings' tables and GRADE). The Cochrane Schizophrenia group maintain a methods template for use in their reviews. We have updated our methods section with this template.
Outcomes: We have clarified the timings of the secondary outcome ‐ not tranquil or asleep to include > 30 minutes (IM) or > 60 minutes (orally) to distinguish it from our pre‐stated primary outcome of not tranquil or asleep by 30 minutes (IM) or 60 minutes (orally). We have renamed global outcomes to global state, and some outcomes are now measured as 'improvement' rather than 'no improvement'. This is in line with the methods template of the Cochrane Schizophrenia Group where avoidance of double negatives is encouraged. We have clarified the 'Summary of findings' outcomes list.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
- Aggression [*drug effects, psychology];
- Antipsychotic Agents [*administration & dosage, adverse effects];
- Aripiprazole [*administration & dosage, adverse effects];
- Benzodiazepines [administration & dosage];
- Haloperidol [administration & dosage];
- Injections, Intramuscular;
- Olanzapine;
- Psychomotor Agitation [*drug therapy, psychology];
- Randomized Controlled Trials as Topic;
- Tranquilizing Agents [administration & dosage];
Medical Subject Headings Check Words
Humans;
PICO
Aripiprazole structure
Study flow diagram (2014 search).
Study flow diagram (2017 search).
'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 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 1 Repeated need for tranquillisation.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 2 Specific behaviour: 1a. Agitation ‐ clinically important change (PANSS‐EC reduction ≥ 40% from baseline).
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 3 Specific behaviour: 1b. Agitation ‐ average scores ‐ i. up to 2 hours.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 4 Global state: 1. Various.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 5 Global state: 2. Average scores ‐ i. up to 2 hours.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 6 Mental state: 1. Average scores ‐ i. up to 2 hours.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 7 Adverse effects: 1a. General.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 8 Adverse effects: 1b. General ‐ serious.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 9 Adverse effects: 2a. Specific ‐ arousal.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 10 Adverse effects: 2b. Specific ‐ cardiovascular.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 11 Adverse effects: 2c. Specific ‐ movement disorders.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 12 Adverse effects: 2d. Specific ‐ miscellaneous.
Comparison 1 ARIPIPRAZOLE (intramuscular) vs PLACEBO/NIL, Outcome 13 Leaving the study early.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 1 Repeated need for tranquillisation.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 2 Specific behaviour: 1a. Agitation ‐ clinically important change (PANSS‐ EC reduction ≥ 40% from baseline).
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 3 Specific behaviour: 1b. Agitation ‐ average scores ‐ i. up to 2 hours.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 4 Global state: 1. Various.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 5 Global outcome: 2. Average scores ‐ i. up to 2 hours.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 6 Mental state: 1. Average scores ‐ i. up to 2 hours.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 7 Adverse effects: 1a. General.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 8 Adverse effects: 1b. General ‐ serious.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 9 Adverse effects: 2a. Specific ‐ arousal.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 10 Adverse effects: 2b. Specific ‐ cardiovascular.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 11 Adverse effects: 2c. Specific ‐ movement disorders.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 12 Adverse effects: 2d. Specific ‐ miscellaneous.
Comparison 2 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: a. HALOPERIDOL (intramuscular), Outcome 13 Leaving the study early.
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 1 Specific behaviour: 1a. Agitation ‐ clinically important change (PANSS‐ EC reduction ≥ 40% from baseline).
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 2 Specific behaviour: 1b. Agitation ‐ average scores ‐ i. up to 2 hours.
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 3 Global state: 1. Average scores ‐ i. up to 2 hours.
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 4 Adverse effects: 1a. General.
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 5 Adverse effects: 1b. General ‐ serious.
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 6 Adverse effects: 2a. Specific ‐ arousal.
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 7 Adverse effects: 2b. Specific ‐ cardiovascular.
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 8 Adverse effects: 2c. Specific ‐ movement disorders ‐ i. dichotomous.
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 9 Adverse effects: 2d. Specific ‐ movement disorders ‐ ii. average scores.
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 10 Adverse effects: 2e. Specific ‐ miscellaneous.
Comparison 3 ARIPIPRAZOLE (intramuscular) vs OTHER ANTIPSYCHOTIC: b. OLANZAPINE (intramuscular), Outcome 11 Leaving the study early.
| Methods | Allocation: randomised, clearly described, concealed. |
| Participants | Diagnosis: thought to be psychoses. History: acutely ill, aggressive and/or agitated. |
| Interventions | 1. Aripiprazole IM: dose flexible within recommended limits. N = 150. |
| Outcomes | All outcomes are grouped by time: by 30 minutes, up to two hours, up to four hours, up to 24 hours, and over 24 hours. Tranquillisation or asleep ‐ tranquil; asleep. Repeated need for tranquillisation ‐ needing additional injections. Quality of life outcomes. |
| Notes | * Powered to be able to identify a difference of ˜20% between groups for primary outcome with adequate degree of certainty |
| IM: intramuscular | |
| Aripiprazole | Combination | Comparison #1 | Comparison #2 | Excluded study | Suggested title of review | Cochrane review | |
| IM | Short acting | + quetiapine | aripiprazole + olanzapine | quetiapine + olanzapine | Antipsychotic combinations for psychosis‐induced aggression or agitation (rapid tranquillisation) | None | |
| Long acting (441mg) | Long acting (882 mg) | placebo | Aripiprazole for long‐term aggression in psychosis; Placebo for long‐term aggression in psychosis | None | |||
| Oral | aripiprazole + magnesium valproate | Magnesium valproate (+/‐aripiprazole) for psychosis‐induced aggression | None | ||||
| oral olanzapine | Aripiprazole (oral) for psychosis‐induced aggression or agitation (rapid tranquillisation); Olanzapine (oral) for psychosis‐induced aggression or agitation (rapid tranquillisation); | ? expansion of this review | |||||
| + clonazepam | oral clozapine | Aripiprazole plus benzodiazepines for psychosis‐induced aggression or agitation (rapid tranquillisation); Clozapine for psychosis‐induced aggression or agitation (rapid tranquillisation); | ? expansion of this review; Toal 2012 | ||||
| Non‐aripiprazole | |||||||
| IM haloperidol + lorazepam + benztropine | oral quetiapine | Benzodiazepines for psychosis‐induced aggression or agitation (rapid tranquillisation); Haloperidol for psychosis‐induced aggression or agitation (rapid tranquillisation); Quetiapine for psychosis‐induced aggression or agitation (rapid tranquillisation) | |||||
| * One sub‐study with people with aggression/agitation. | |||||||
| ARIPIPRAZOLE compared to PLACEBO/NIL for psychosis‐induced aggression or agitation (rapid tranquillisation) | ||||||
| Patient or population: psychosis‐induced aggression or agitation (rapid tranquillisation) | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with PLACEBO/NIL | Risk with ARIPIPRAZOLE | |||||
| Tranquillisation or asleep | Not reported | |||||
| Repeated need for tranquillisation ‐ needing additional injections during 24 hours | Low | RR 0.69 | 382 | ⊕⊝⊝⊝ | ||
| 250 per 1.000 | 173 per 1.000 | |||||
| Moderate | ||||||
| 600 per 1.000 | 414 per 1.000 | |||||
| High | ||||||
| 750 per 1.000 | 518 per 1.000 | |||||
| Specific behaviour: Agitation ‐ clinically important change (PANSS ‐EC reduction ≥ 40% from baseline) ‐ up to 2 hours | Low | RR 1.50 | 382 | ⊕⊝⊝⊝ | ||
| 100 per 1.000 | 150 per 1.000 | |||||
| Moderate | ||||||
| 350 per 1.000 | 525 per 1.000 | |||||
| High | ||||||
| 700 per 1.000 | 1000 per 1.000 | |||||
| Global state: non‐responders to the first injection | Low | RR 0.49 | 263 | ⊕⊕⊝⊝ | ||
| 200 per 1.000 | 98 per 1.000 | |||||
| Moderate | ||||||
| 450 per 1.000 | 221 per 1.000 | |||||
| High | ||||||
| 700 per 1.000 | 343 per 1.000 | |||||
| Adverse effects: one or more adverse events during 24 hours (only reported if occurred in ≥ 5% of people) | Study population | RR 1.51 | 117 | ⊕⊝⊝⊝ | ||
| 295 per 1.000 | 446 per 1.000 | |||||
| Economic outcomes | Not reported | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated 'serious' (downgraded by 1) ‐ randomisation procedure is not reported for both the included studies, and allocation concealment procedure is not consistently reported in Bristol‐Myers 2005. While for the 'randomisation' bias, studies are at least reported as 'randomised', as for the latter that allocation concealment was correctly handled could not be implied. 2 Indirectness: rated 'very serious' (downgraded by 2) ‐ participants included in the studies had levels of agitation not so pronounced by inclusion criteria, potentially under‐estimating or more likely over‐estimating true effectiveness. | ||||||
| ARIPIPRAZOLE compared to OTHER ANTIPSYCHOTIC: a. HALOPERIDOL for psychosis‐induced aggression or agitation (rapid tranquillisation) | ||||||
| Patient or population: psychosis‐induced aggression or agitation (rapid tranquillisation) | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with OTHER ANTIPSYCHOTIC: a. HALOPERIDOL | Risk with ARIPIPRAZOLE | |||||
| Tranquillisation or asleep | Not reported | |||||
| Repeated need for tranquillisation ‐ needing additional injections during 24 hours | Low | RR 1.28 | 477 | ⊕⊝⊝⊝ | , | |
| 100 per 1.000 | 128 per 1.000 | |||||
| Moderate | ||||||
| 300 per 1.000 | 384 per 1.000 | |||||
| High | ||||||
| 500 per 1.000 | 640 per 1.000 | |||||
| Specific behaviour: Agitation ‐ clinically important change (PANSS ‐EC reduction ≥ 40% from baseline) ‐ up to 2 hours | Study population | RR 0.94 | 477 | ⊕⊝⊝⊝ | ||
| 576 per 1.000 | 541 per 1.000 | |||||
| Global state: non‐responders to the first injection | Study population | RR 1.18 | 360 | ⊕⊕⊝⊝ | ||
| 184 per 1.000 | 217 per 1.000 | |||||
| Adverse effects: one or more adverse events during 24 hours (only reported if occurred in ≥ 5% of people) | Study population | RR 0.91 | 113 | ⊕⊝⊝⊝ | ||
| 491 per 1.000 | 447 per 1.000 | |||||
| Adverse effects: movement disorders ‐ EPS during 24 hours (only reported if occurred in ≥ 5% of people) | Low | RR 0.29 | 471 | ⊕⊝⊝⊝ | ||
| 50 per 1.000 | 14 per 1.000 | |||||
| Moderate | ||||||
| 100 per 1.000 | 29 per 1.000 | |||||
| High | ||||||
| 300 per 1.000 | 87 per 1.000 | |||||
| Economic outcomes | Not reported | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated 'serious' (downgraded by 1) ‐ randomisation procedure is not reported for both the included studies, and allocation concealment procedure is not consistently reported in Bristol‐Myers 2005. While for the 'randomisation' bias studies are at least reported as 'randomised', as for the latter that allocation concealment was correctly handled could not be implied. 2 Indirectness: rated 'very serious' (downgraded by 2) ‐ participants included in the studies had levels of agitation not so pronounced by inclusion criteria, potentially under‐estimating or more likely over‐estimating true effectiveness. | ||||||
| ARIPIPRAZOLE compared to OTHER ANTIPSYCHOTIC: b. OLANZAPINE for psychosis‐induced aggression or agitation (rapid tranquillisation) | ||||||
| Patient or population: psychosis‐induced aggression or agitation (rapid tranquillisation) | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with OTHER ANTIPSYCHOTIC: b. OLANZAPINE | Risk with ARIPIPRAZOLE | |||||
| Tranquillisation or asleep | Not reported | |||||
| Repeated need for tranquillisation | Not reported | |||||
| Specific behaviour: Agitation ‐ clinically important change (PANSS ‐EC reduction ≥ 40% from baseline) ‐ up to 2 hours | Low | RR 0.77 | 80 | ⊕⊕⊝⊝ | ||
| 500 per 1.000 | 385 per 1.000 | |||||
| Moderate | ||||||
| 800 per 1.000 | 616 per 1.000 | |||||
| High | ||||||
| 900 per 1.000 | 693 per 1.000 | |||||
| Global state: CGI‐S change score up to 2 hours | MD 0.58 | ‐ | 80 | ⊕⊕⊝⊝ | ||
| Adverse effects: one or more adverse effects during 24 hours | Study population | RR 0.75 | 80 | ⊕⊝⊝⊝ | ||
| 500 per 1.000 | 375 per 1.000 | |||||
| Adverse effects: somnolence during 24 hours | Low | RR 0.25 | 80 | ⊕⊕⊝⊝ | ||
| 100 per 1.000 | 25 per 1.000 | |||||
| Moderate | ||||||
| 300 per 1.000 | 75 per 1.000 | |||||
| High | ||||||
| 700 per 1.000 | 175 per 1.000 | |||||
| Economic outcomes | Not reported | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Imprecision ‐ rated 'serious' (downgraded by 1): Optimal Information Size (OIS) criterion is not met meaning that imprecision of effect estimates could not be properly handled. 2 Imprecision ‐ rated 'very serious' (downgraded by 2): Optimal Information Size (OIS) criterion is not met and CI overlaps no effect. High imprecision of effect estimates could not be properly excluded. 3 Indirectness ‐ rated 'serious' (downgraded by 1): attribution to the intervention drugs is suspected but can not be confirmed since in the study results it is showed that almost all the participants were administered with 'treatment as usual' drugs. | ||||||
| Focus of review | Reference |
| Completed and maintained reviews | |
| 'As required' medication regimens for seriously mentally ill people in hospital | |
| Benzodiazepines for psychosis‐induced aggression or agitation | |
| Chlorpromazine for psychosis‐induced aggression or agitation | |
| Clotiapine for acute psychotic illnesses | |
| Containment strategies for people with serious mental illness | |
| De‐escalation techniques for psychosis‐induced aggression | |
| Droperidol for acute psychosis | |
| Haloperidol for long‐term aggression in psychosis | |
| Haloperidol for psychosis‐induced aggression or agitation (rapid tranquillisation) | |
| Haloperidol plus promethazine for psychosis‐induced aggression | |
| Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses | |
| Seclusion and restraint for serious mental illnesses | |
| Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses | |
| Reviews in the process of being completed | |
| Risperidone for psychosis‐induced aggression or agitation | |
| Loxapine inhaler for psychosis‐induced aggression | |
| Clozapine for people with psychosis‐induced aggression or agitation | |
| Quetiapine for psychosis‐induced aggression or agitation | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Repeated need for tranquillisation Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 needing additional injections during 24 hours | 2 | 382 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.56, 0.85] |
| 1.2 needing 1 additional injection during 24 hours | 1 | 119 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.38 [0.69, 2.80] |
| 1.3 needing 2 additional injections during 24 hours | 1 | 119 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.19, 0.70] |
| 2 Specific behaviour: 1a. Agitation ‐ clinically important change (PANSS‐EC reduction ≥ 40% from baseline) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 up to 2 hours | 2 | 382 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.50 [1.17, 1.92] |
| 3 Specific behaviour: 1b. Agitation ‐ average scores ‐ i. up to 2 hours Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1 change score (ABS, high=worse) | 2 | 380 | Mean Difference (IV, Fixed, 95% CI) | ‐3.77 [‐5.39, ‐2.16] |
| 3.2 change score (ACES, low=agitated, high=sedated) | 2 | 380 | Mean Difference (IV, Fixed, 95% CI) | ‐0.71 [‐1.15, ‐0.28] |
| 3.3 change score (PANSS‐EC, high=worse) | 1 | 261 | Mean Difference (IV, Fixed, 95% CI) | ‐2.49 [‐4.28, ‐0.70] |
| 3.4 change score (PANSS‐EC, high=worse, schizophrenia subgroup) | 2 | 263 | Mean Difference (IV, Fixed, 95% CI) | ‐2.55 [‐3.78, ‐1.32] |
| 3.5 change score (PANSS‐EC, high=worse, non‐sedated patients subgroup based on ACES) | 2 | 355 | Mean Difference (IV, Fixed, 95% CI) | ‐2.68 [‐3.75, ‐1.62] |
| 3.6 change score (PANSS‐EC, high=worse, non‐sedated patients subgroup based on AEs) | 2 | 365 | Mean Difference (IV, Fixed, 95% CI) | ‐2.83 [‐3.92, ‐1.75] |
| 4 Global state: 1. Various Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 non‐responders to the first injection | 1 | 263 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.34, 0.71] |
| 4.2 need for benzodiazepine up to 24 hours | 2 | 382 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.48 [0.28, 0.80] |
| 5 Global state: 2. Average scores ‐ i. up to 2 hours Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.1 endpoint score (CGI‐I, high=worse) | 2 | 380 | Mean Difference (IV, Fixed, 95% CI) | ‐0.73 [‐0.97, ‐0.49] |
| 5.2 endpoint score (CGI‐I, high=worse, schizophrenia subgroup | 1 | 75 | Mean Difference (IV, Fixed, 95% CI) | ‐0.71 [‐1.17, ‐0.25] |
| 5.3 change score (CGI‐S, high=worse) | 2 | 380 | Mean Difference (IV, Fixed, 95% CI) | ‐0.56 [‐0.86, ‐0.26] |
| 6 Mental state: 1. Average scores ‐ i. up to 2 hours Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 6.1 change score up to 2 hours (BPRS total, high=worse) | 1 | 110 | Mean Difference (IV, Fixed, 95% CI) | ‐3.39 [‐7.03, 0.25] |
| 6.2 change score up to 2 hours (BPRS positive subscale, high=worse) | 1 | 110 | Mean Difference (IV, Fixed, 95% CI) | ‐0.62 [‐1.65, 0.41] |
| 7 Adverse effects: 1a. General Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1 one or more drug related adverse events during 24 hours | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.51 [0.93, 2.46] |
| 7.2 onset or increased severity of adverse effects after 2nd injection | 1 | 262 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.40 [1.36, 4.23] |
| 8 Adverse effects: 1b. General ‐ serious Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 death | 1 | 262 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 8.2 rated as serious | 2 | 379 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.77 [0.63, 22.60] |
| 8.3 tonic clonic seizure | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.26 [0.14, 78.49] |
| 9 Adverse effects: 2a. Specific ‐ arousal Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.1 insomnia during 24 hours | 1 | 262 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.25, 1.52] |
| 9.2 "over" sedated during 24 hours | 1 | 262 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.59 [0.60, 4.20] |
| 9.3 somnolence during 24 hours | 2 | 379 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.52 [0.57, 4.00] |
| 10 Adverse effects: 2b. Specific ‐ cardiovascular Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 10.1 dizziness during 24 hours | 2 | 379 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.77 [0.66, 4.70] |
| 10.2 sinus tachycardia during 24 hours | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.72] |
| 10.3 tachycardia during 24 hours | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.36 [0.50, 37.82] |
| 11 Adverse effects: 2c. Specific ‐ movement disorders Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 11.1 akathisia during 24 hours | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.61 [0.40, 144.21] |
| 11.2 dystonia during 24 hours | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.26 [0.14, 78.49] |
| 11.3 EPS during 24 hours | 1 | 262 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.5 [0.06, 36.45] |
| 12 Adverse effects: 2d. Specific ‐ miscellaneous Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 12.1 agitation during 24 hours | 2 | 379 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.33, 2.37] |
| 12.2 headache during 24 hours | 2 | 379 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.66 [0.74, 3.71] |
| 12.3 pain at injection site | 2 | 379 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.30, 3.94] |
| 12.4 nausea during 24 hours | 2 | 379 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.97 [1.13, 13.92] |
| 12.5 vomiting during 24 hours | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.18 [0.20, 23.37] |
| 13 Leaving the study early Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 13.1 any reason | 2 | 382 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.35, 4.74] |
| 13.2 lack of efficacy | 2 | 382 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.47 [0.07, 3.06] |
| 13.3 withdrew consent | 2 | 382 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.68 [0.23, 12.46] |
| 13.4 adverse effects | 2 | 382 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.25 [0.25, 20.54] |
| 13.5 other | 2 | 382 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.15, 7.44] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Repeated need for tranquillisation Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 needing additional injections during 24 hours | 2 | 477 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.28 [1.00, 1.63] |
| 1.2 needing 1 additional injection during 24 hours | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.34 [0.66, 2.70] |
| 1.3 needing 2 additional injections during 24 hours | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.37 [0.77, 7.26] |
| 2 Specific behaviour: 1a. Agitation ‐ clinically important change (PANSS‐ EC reduction ≥ 40% from baseline) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 up to 2 hours | 2 | 477 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.80, 1.11] |
| 3 Specific behaviour: 1b. Agitation ‐ average scores ‐ i. up to 2 hours Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1 change score (ABS, high=worse) | 2 | 473 | Mean Difference (IV, Fixed, 95% CI) | 0.55 [‐1.00, 2.10] |
| 3.2 change score (ACES, low=agitated, high=sedated) | 2 | 473 | Mean Difference (IV, Fixed, 95% CI) | 0.12 [‐0.30, 0.55] |
| 3.3 change score (PANSS‐EC, high=worse) | 1 | 357 | Mean Difference (IV, Fixed, 95% CI) | 0.48 [‐1.16, 2.12] |
| 3.4 change score (PANSS‐EC, high=worse, schizophrenia subgroup) | 2 | 336 | Mean Difference (IV, Fixed, 95% CI) | 0.07 [‐0.99, 1.13] |
| 3.5 change score (PANSS‐EC, high=worse, non‐sedated patients subgroup based on ACES) | 2 | 422 | Mean Difference (IV, Fixed, 95% CI) | 0.12 [‐0.82, 1.06] |
| 3.6 change score (PANSS‐EC, high=worse, non‐sedated patients subgroup based on AEs) | 2 | 448 | Mean Difference (IV, Fixed, 95% CI) | 0.26 [‐0.68, 1.19] |
| 4 Global state: 1. Various Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 non‐responders to the first injection | 1 | 360 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.78, 1.79] |
| 4.2 need for benzodiazepine up to 24 hours | 2 | 477 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.46, 1.35] |
| 5 Global outcome: 2. Average scores ‐ i. up to 2 hours Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.1 endpoint score (CGI‐I, high=worse) | 2 | 473 | Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.19, 0.23] |
| 5.2 endpoint score (CGI‐I, high=worse, schizophrenia subgroup | 1 | 79 | Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.44, 0.48] |
| 5.3 change score (CGI‐S, high=worse) | 2 | 473 | Mean Difference (IV, Fixed, 95% CI) | ‐0.07 [‐0.36, 0.22] |
| 6 Mental state: 1. Average scores ‐ i. up to 2 hours Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 6.1 change score up to 2 hours (BPRS total, high=worse) | 1 | 102 | Mean Difference (IV, Fixed, 95% CI) | 2.03 [‐1.70, 5.76] |
| 6.2 change score up to 2 hours (BPRS positive subscale, high=worse) | 1 | 103 | Mean Difference (IV, Fixed, 95% CI) | 0.23 [‐0.82, 1.28] |
| 7 Adverse effects: 1a. General Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1 one or more drug related adverse events during 24 hours | 1 | 113 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.61, 1.35] |
| 7.2 onset or increased severity of adverse effects after 2nd injection | 1 | 358 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.57, 0.96] |
| 8 Adverse effects: 1b. General ‐ serious Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 death | 1 | 358 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 8.2 rated as serious | 2 | 471 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.73 [0.54, 5.52] |
| 8.3 tonic clonic seizure | 1 | 113 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.05 [0.13, 73.38] |
| 9 Adverse effects: 2a. Specific ‐ arousal Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.1 insomnia during 24 hours | 1 | 358 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.48 [0.23, 0.97] |
| 9.2 "over" sedated during 24 hours | 1 | 358 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.34, 1.07] |
| 9.3 somnolence during 24 hours | 2 | 471 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.41, 1.58] |
| 10 Adverse effects: 2b. Specific ‐ cardiovascular Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 10.1 dizziness during 24 hours | 2 | 471 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.41 [0.66, 3.01] |
| 10.2 sinus tachycardia during 24 hours | 1 | 113 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.75] |
| 10.3 tachycardia during 24 hours | 1 | 113 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.07 [0.47, 35.31] |
| 11 Adverse effects: 2c. Specific ‐ movement disorders Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 11.1 akathisia during 24 hours | 1 | 113 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.51 [0.13, 1.94] |
| 11.2 dystonia during 24 hours | 1 | 113 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.25 [0.03, 2.21] |
| 11.3 EPS during 24 hours | 2 | 471 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.29 [0.12, 0.70] |
| 12 Adverse effects: 2d. Specific ‐ miscellaneous Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 12.1 agitation during 24 hours | 2 | 471 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.42, 2.58] |
| 12.2 headache during 24 hours | 2 | 471 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.16 [0.62, 2.18] |
| 12.3 pain at injection site | 2 | 471 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.12 [0.75, 12.91] |
| 12.4 nausea during 24 hours | 2 | 471 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.52 [1.63, 18.70] |
| 12.5 vomiting during 24 hours | 1 | 113 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.04 [0.19, 21.82] |
| 13 Leaving the study early Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 13.1 any reason | 2 | 477 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.20, 1.18] |
| 13.2 lack of efficacy | 2 | 477 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.15, 7.43] |
| 13.3 withdrew consent | 2 | 477 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.35 [0.10, 1.28] |
| 13.4 adverse effects | 2 | 477 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.18, 6.04] |
| 13.5 other | 2 | 477 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.15, 3.78] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Specific behaviour: 1a. Agitation ‐ clinically important change (PANSS‐ EC reduction ≥ 40% from baseline) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 up to 2 hours | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.60, 0.99] |
| 2 Specific behaviour: 1b. Agitation ‐ average scores ‐ i. up to 2 hours Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.1 change score (ACES, low=agitated, high=sedated) | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | 0.58 [0.10, 1.06] |
| 2.2 change score (PANSS‐EC, high=worse) | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | 3.30 [1.25, 5.35] |
| 3 Global state: 1. Average scores ‐ i. up to 2 hours Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1 change score (CGI‐S, high=worse) | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | 0.58 [0.01, 1.15] |
| 4 Adverse effects: 1a. General Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 one or more drug related adverse events during 24 hours | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.45, 1.24] |
| 5 Adverse effects: 1b. General ‐ serious Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 rated as serious | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Adverse effects: 2a. Specific ‐ arousal Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 somnolence during 24 hours | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.25 [0.08, 0.82] |
| 7 Adverse effects: 2b. Specific ‐ cardiovascular Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 7.1 systolic blood pressure change up to 2 hours | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | 2.85 [‐6.77, 12.47] |
| 7.2 diastolic blood pressure change up to 2 hours | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | ‐1.05 [‐8.09, 5.99] |
| 7.3 pulse rate change up to 2 hours | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | ‐0.67 [‐6.80, 5.46] |
| 7.4 systolic blood pressure change up to 24 hours | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | 3.37 [‐5.43, 12.17] |
| 7.5 diastolic blood pressure change up to 24 hours | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | ‐1.30 [‐8.55, 5.95] |
| 7.6 pulse rate change up to 24 hours | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | ‐6.05 [‐13.43, 1.33] |
| 8 Adverse effects: 2c. Specific ‐ movement disorders ‐ i. dichotomous Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 akathisia up to 24 hours | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 8.2 dystonia up to 24 hours | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 8.3 rigidity up to 24 hours | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.33 [0.32, 5.58] |
| 8.4 tremor up to 24 hours | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.5 [0.26, 8.50] |
| 9 Adverse effects: 2d. Specific ‐ movement disorders ‐ ii. average scores Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 9.1 SAS change score up to 2 hours (high=worse) | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | ‐0.05 [‐0.26, 0.16] |
| 9.2 SAS change score up to 24 hours (high=worse) | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | ‐0.03 [‐0.29, 0.23] |
| 10 Adverse effects: 2e. Specific ‐ miscellaneous Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 10.1 headache during 24 hours | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.0 [0.19, 21.18] |
| 10.2 pain at injection site during 24 hours | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.67 [0.76, 9.33] |
| 10.3 nausea during 24 hours | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.13, 71.51] |
| 11 Leaving the study early Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
