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.
Siafis et al. (Mon,) studied this question.