Midazolam 2011, BZ.

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) All outcomes	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) All outcomes	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.