Zotepine 2000.

Study characteristics
Methods	Randomisation: computer‐generated randomisation list. Allocation: allocation to treatment was on a double‐blind basis, codes were not broken until the time of analysis. Blinding: double‐blind, no further details. Duration: 26 weeks. Design: parallel. Location: multi‐centre, multi‐national. Setting: inpatient (N = 33) and outpatient (N = 86), sponsored.
Participants	Diagnosis: chronic schizophrenia (DSM‐III‐R), at least mildly ill according to CGI, had a history of recurrence in last 18 months, currently maintained on antipsychotic medication. N = 121. Gender: 82 men, 37 women (intent‐to‐treat dataset). Age: 42.3 years. History: duration stable‐ n.i., duration ill‐ mean 13.6 years, number of previous hospitalisations‐ n.i., age at onset‐ mean 28.7 years, severity of illness‐ mean BPRS 49.1, mean CGI 4.2, baseline antipsychotic dose‐ n.i..
Interventions	1. Drug: zotepine. Fixed dose of 300 mg/day which could be reduced once to 150 mg/day. Mean dose: n.i.. N = 63. 2. Placebo:duration of taper: 0 days. N = 58. Rescue medication: antipsychotic drugs not allowed, but benzodiazepines.
Outcomes	Examined Relapse: (i) a moderate clinical deterioration from baseline (an increase in CGI severity score of at least 2 points plus an increase of 2 points in at least two positive symptom items on the BPRS persisting for two assessments over 3 days, but not requiring hospitalisation; (ii) deterioration requiring hospitalisation accompanied, on one assessment, by an increase in CGI severity score of at least 2 points plus an increase of 2 points in at least two positive symptom items on the BPRS; and (iii) severe clinical deterioration (an increase in CGI severity score to ‘severely ill’ for 24 hours, or, if in hospital, requiring special observation for suicidal or aggressive behaviour). Leaving the study early. Global state: number of participants improved (CGI based). Global state: number of participants in remission (CGI based). Adverse effects: binary outcomes ‐ open interview. Suicide ideation Unable to use/Not included Mental state: BPRS, SANS (no prespecified outcomes of interest). Adverse effects: extrapyramidal side‐effects (SAS, AIMS, no SD/continuous side‐effect results were not among the prespecified outcomes). Physiological measures: laboratory, vital signs, ECG (all no data/no prespecified outcomes of interest).
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation list.
Allocation concealment (selection bias)	Low risk	Allocation to treatment was on a double‐blind basis, codes were not broken until the time of analysis.
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	The overall rate of participants leaving the study early was very high (76%) and many more participants in the placebo group than in the drug group dropped out due to relapse. Kaplan‐Meier survival analysis was used for primary outcome relapse. No full ITT analysis, only those participants with at least one post‐baseline assessment were included, but only two participants were excluded on this basis.
Selective reporting (reporting bias)	High risk	Only those adverse events that were reported on at least four occasions and serious adverse events were reported.
Other bias	Low risk	No clear other bias.

General abbreviations

CNS: central nervous system
CPZ: chlorpromazine
DSM: Diagnostic and Statistical Manual of Mental Disorders
ECG: electrocardiography
ECT: electroconvulsive therapy
EASY: Early Assessment Service for Young People with Psychosis
EEG: electroencephalography
EPS: extrapyramidal symptoms
HbA1c: glycated haemoglobin
ICD: International Statistical Classification of Diseases and Related Health Problems
IM: intramuscular injection
ITT: intention to treat
LAI: long‐acting injectable
LOCF: last observation carried forward
n.i.: not indicated
SD: standard deviation

Rating scales

AIMS: Abnormal Involuntary Movement Scale
AMDP: Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie
BAS: Barnes Akathisia Scale
BPRS: Brief Psychiatric Rating Scale
CGI: Clinical Global Impression ‐S: severity, ‐I: improvement
GAS: Global Assessment Scale
IMPS: Inpatient Multidimensional Psychiatric Rating Scale
MMPI: Minnesota Multiphasic Personality Inventory
NOSIE: Nurses Observation Scale for Inpatient Evaluation
PANSS: Positive And Negative Syndrome Scale
PRP: Psychotic Reaction Profile
PRS: Psychiatric Rating Scale
PSE: Present State Examination
RDC: Research Diagnostic Criteria
SADS: Schedule for Affective Disorders
SANS: Scale for the Assessment of Negative Symptoms
SAS: Simpson‐Angus Scale