Aripiprazole depot 2012.

Study characteristics
Methods	Randomisation: sponsor‐prepared computer‐generated randomisation code (2:1 ratio), stratified by region and by last stabilisation dose of study drug. Allocation: interactive voice/web response system. Blinding: IM trial medications had different appearance, but were prepared and administered by an unblinded Trial Drug Manager. Duration: terminated early after the first pre‐planned interim analysis (64 events); pre‐planned duration: 52 weeks. Design: parallel. Location: multi‐centre (108 centres). Setting: outpatients.
Participants	Diagnosis: Schizophrenia (DSM‐IV‐TR), diagnosed at least 3 years before. N = 403. Gender: 241 men, 162 women. Age: 40.6 years. History: duration stable‐ at least 12 weeks, duration ill‐ 14.6 years, number of previous hospitalisations‐ n.i., age at onset‐ 26 years, severity of illness‐ mean PANSS total score 54.5, mean CGI‐S total score 2.9, baseline antipsychotic dose‐ 391.6 mg/4 weeks, remission at baseline‐ not in remission (at least moderately ill at CGI‐S).
Interventions	1. Drug: aripiprazole IM, 1‐month formulation. N = 269 Flexible dose. Mean dose: 396.3 mg/4 weeks. Allowed dose range: either 300 mg or 400 mg/4 weeks. 2. Placebo: duration of taper: depending on the aripiprazole depot half‐life (between 29.9 and 46.5 days). N = 134. Rescue medication: benzodiazepines (maximum 6 mg/day) and anticholinergics (antiparkinson) were permitted, although not within 8 to 12 hours (respectively) of rating scale assessments.
Outcomes	Examined Relapse (rating scale defined and/or need for hospitalisation and/or emergent violent behaviour). Leaving the study early (any cause, adverse events, inefficacy). Global state ‐ Number of participants in sustained remission (Andreasen criteria). Service use ‐ Number of participants hospitalised. Participants´satisfaction with care: Patient Satisfaction with Medication Questionnaire. Social functioning: Personal and Social Performance scale. Adverse effects. Death. Suicide ideation and behaviour: CGI‐SS, Columbia Suicide Severity Rating Scale and Columbia Classification Algorythm of Suicide Assessment. Violent/aggressive behaviour. Unable to use/Not included Global state ‐ number of participants improved (no usable data). Mental state: Positive and Negative Symptoms Scale total scores and subscales (no predefined outcome of interest). Neurocognitive function: Trail Making Test (A), Tower of London, Letter‐Number Span (no predefined outcome of interest). Compliance to treatment: Drug Attitude Inventory Score, Medication Adherence Questionnaire (no predefined outcome of interest). Carer´s satisfaction with care: Investigator´s Assessment Questionnaire (no usable data).
Notes	Sponsored by Otsuka.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sponsor‐prepared computer‐generated randomisation code (2:1 ratio), stratified by region and by last stabilisation dose of study drug
Allocation concealment (selection bias)	Low risk	Interactive voice/web response system.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	IM trial medications had different appearance (aripiprazole: milky white suspension; placebo: clear solution); they were prepared and administered by an unblinded Trial Drug Manager.
Blinding (performance bias and detection bias) Subjective outcomes	Unclear risk	IM trial medications had different appearance (aripiprazole: milky white suspension; placebo: clear solution); they were prepared and administered by an unblinded Trial Drug Manager. Two participants were unblinded at the site level (one incident with depot dose log, one incidental access to the drug storage cabinet given by the monitor), both withdrawn from the study.
Blinding (performance bias and detection bias) Objective outcomes	Low risk	IM trial medications had different appearance (aripiprazole: milky white suspension; placebo: clear solution); they were prepared and administered by an unblinded Trial Drug Manager. Two participants were unblinded at the site level (one incident with depot dose log, one incidental access to the drug storage cabinet given by the monitor), both withdrawn from the study.
Incomplete outcome data (attrition bias) All outcomes	High risk	The total attrition rate (35%) was higher than 25% but could still be acceptable. However more participants in the placebo group dropped out, mostly due to relapse (reasons are unbalanced between groups). The primary outcome (relapse) was assessed using the Kaplan‐Meier survival curve analysis. Data for secondary outcomes were analysed on an ITT basis (LOCF).
Selective reporting (reporting bias)	Low risk	No evidence for selective reporting.
Other bias	High risk	Study terminated early after an interim analysis (64 relapse events), but it was pre‐planned.