Comparative effectiveness and safety of pharmacological treatments for rapid tranquilisation in emergency settings: a systematic review and individual participant data network meta-analysis.

Description
Salanti and Leucht contributed equally to this work.
DOI
Publisher DOI
PubMed ID
42259329
Abstract
Background
Several medications are available for rapid tranquilisation in psychomotor agitation, but choosing among them varies across local practices and this variation is compounded by inconsistent guidelines. We performed a systematic review with individual participant data network meta-analysis to inform evidence-based recommendations.Methods
In this systematic review and individual participant data meta-analysis, we searched multiple databases from database inception to Nov 14, 2025, for randomised trials comparing intramuscular or intravenous treatments for rapid tranquilisation (primary outcome defined as sedation within 15-30 min) in patients with psychomotor agitation in general or psychiatric emergency settings. Anonymised individual participant data were collected and harmonised into a common dataset. Risk of bias was assessed using the RoB 2 tool. We performed Bayesian one-stage random-effects individual participant data network meta-regressions, accounting for between-study heterogeneity, drug classes, prognostic factors, and subgroup effects based on agitation severity. We combined individual participant data and aggregate data to evaluate side-effects. Confidence in the evidence was assessed using the Confidence In Network Meta Analysis (CINeMA) framework. People with lived experience were involved in the design and interpretation of the findings. The protocol was registered with PROSPERO (CRD42023402365).Findings
We included 18 trials across eight regions (3411 participants; 1988 [58·3%] men, 1423 [41·7%] women; mean age 36·0 [SD 11·7] years), of which 13 trials (2705 participants) provided individual participant data for antipsychotics, benzodiazepines, and their combination. In moderate agitation, odds of achieving sedation relative to haloperidol monotherapy were higher with antipsychotic-benzodiazepine combinations (odds ratio [OR] 12·93, 95% credible interval [95% CrI] 3·00-50·91; relative risk [RR] 1·58), benzodiazepines (5·52, 1·37-21·02; 1·49), and other antipsychotics (4·54, 1·35-14·45; 1·45). In severe agitation, antipsychotic-benzodiazepine combinations were more effective than haloperidol (4·86, 1·28-17·54; 1·73), whereas results were uncertain for benzodiazepines (2·09, 0·58-6·99; 1·38) and other antipsychotics (1·70, 0·62-4·59; 1·28). Confidence in these estimates was very low, mainly due to imprecision and heterogeneity. Haloperidol monotherapy was associated with higher risk of extrapyramidal side-effects and benzodiazepines, alone or in combination, with hypotension.Interpretation
Antipsychotic-benzodiazepine combinations might be among the most effective options for rapid tranquilisation in patients with psychomotor agitation but carry a risk of hypotension, whereas haloperidol monotherapy appeared among the least effective and is associated with extrapyramidal side-effects. These findings should be contextualised to the specific setting and patient characteristics, including the underlying agitation aetiology. Large trials are needed to provide more precise recommendations.Funding
German Ministry of Research, Technology and Space and Swiss National Science Foundation.
Date Issued
2026-07
Publication Type
Article
Language(s)
en
Author(s)
Siafis, Spyridon
Nomura, Nobuyuki
Milosavljević, Filip
Schneider-Thoma, Johannes
Bighelli, Irene
Lorenz, Carolin
Dib, Joseph E
Tharyan, Prathap
Chan, Esther Wy
Knott, Jonathan C
Yap, Celene Yl
Mantovani, Célia
Martel, Marc L
Honer, William G
Scheuring, Elfriede
Huf, Gisele
Alexander, Jacob
Raveendran, Nirmal S
Coutinho, Evandro Sf
Priller, Josef
Adams, Clive E
Leucht, Stefan
Additional Credits
Journal
The lancet. Psychiatry
ISSN
2215-0374
Funding(s)
Access(Rights)
Unknown
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