Paliperidone 2007.

Study characteristics
Methods	Randomisation: randomised, computerised randomisation and stratification scheme. Allocation: interactive voice‐response system. Blinding: double‐blind, no further details. Duration: variable. Design: parallel. Location:  multi‐centre. Setting: outpatient, sponsored.
Participants	Diagnosis: schizophrenia (DSM‐IV), 80% paranoid subtype, 14% undifferentiated subtype, initially with acute exacerbation, then 8 weeks run in and 6 weeks stabilisation phase. N = 207. Gender: 121 men, 86 women. Age: 38.3 years. History: duration stable‐ at least 8 weeks, duration ill‐ mean 12.1 years, number of previous hospitalisations‐ median 3, age at onset‐ 26.2 years, severity of illness‐ mean PANSS total score 52.2, mean CGI severity 2.6, baseline antipsychotic dose‐ 10.8 mg/day paliperidone.
Interventions	1. Drug: paliperidone‐ Flexible doses. Allowed dose range: 3 mg/day to 15 mg/day Mean dose: 10.8 mg/day. N = 105. 2. Placebo: duration of taper: 0 days. N = 102. Rescue medication: benzodiazepines, antiparkinson medication, propanolol, antidepressants when the dose was stable for at least 3 months before the study.
Outcomes	Examined Relapse: (a) psychiatric hospitalisation (involuntary or voluntary admission); b) increase in PANSS total score by 25% for 2 consecutive days for patients who scored more than 40 at randomisation or a 10‐point increase for patients who scored 40 or below at randomisation; c) increase in the Clinical Global Impression‐Severity (CGI‐S) score to at least 4, for patients who scored 3 or below at randomisation, or to at least 5, for patients whose CGI‐S scores were 4 at randomisation, for 2 consecutive days; d) deliberate self‐injury or aggressive behavior, or suicidal or homicidal ideation and aggressive behavior that was clinically significant; e) increase in prespecified individual PANSS item scores to at least 5, for patients whose scores were 3 or below at randomisation, or to at least 6, for patients whose scores were 4 at randomisation, for 2 consecutive days). Leaving the study early. Global state ‐ number of participants improved. Global state ‐ number of participants in remission (CGI‐based). Service use: number of participants hospitalised. Quality of life: Schizophrenia Quality‐of‐Life Scale (SQLS) Social functioning: Personal and Social Performance scale. Adverse effects. Violent/aggressive behaviour. Death; Suicide attempts. Unable to use/Not included Mental state: PANSS (no predefined outcome of interest). Physiological measures: laboratory (except for metabolic problems no data), vital signs, ECG, prolactin (all no data/no predefined outcomes of interest).
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised, computerised randomisation and stratification scheme.
Allocation concealment (selection bias)	Low risk	Interactive voice‐response system.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind, no further details.
Blinding (performance bias and detection bias) Subjective outcomes	Unclear risk	Double‐blind, no further details.
Blinding (performance bias and detection bias) Objective outcomes	Low risk	Double‐blind, no further details.
Incomplete outcome data (attrition bias) All outcomes	High risk	Only 28 out of 207 participants left the study prematurely for another reason than relapse. Therefore, missing outcomes may not pose a problem for the primary outcome which was assessed with the Kaplan‐Meier method. Nevertheless, high discontinuations due to relapse (75/207) which were much more frequent in the placebo group than in the drug group pose a major problem for secondary outcomes. No full ITT (participants had to receive at least one dose post‐baseline) but only two participants were excluded on this basis.
Selective reporting (reporting bias)	Low risk	No evidence for selective reporting.
Other bias	High risk	Study was terminated after an interim analysis showed a clear advantage of paliperidone.