Lorazepam 2001, RO and USA.

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) All outcomes	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) All outcomes	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.