[Summary text]
—sb
—3 centres
52 weeks
N=46
—Schizophrenia, DSM-IV, with a
history of violence
1. Zuclopenthixol i.m. (mean
233 mg biweekly)
2. Oral zuclopenthixol (mean
35 mg daily)
—Primary study outcome was
avoidance of violence
—Depot patients had more
positive symptoms at baseline
Study design:
Study grouping:
Open Label:
Cluster RCT:
Baseline Characteristics
Risperidone LAI
SGA physician's choice
Included criteria:
Excluded criteria:
Intervention Characteristics
Risperidone LAI
SGA physician's choice
Dichotomous:
Sponsorship source:
Country:
Setting:
Comments:
Authors name:
Institution:
Email:
Address:
Identification:
Participants:
Study design:
Baseline characteristics:
Intervention characteristics:
Pretreatment:
Continuous outcomes:
Dichotomous outcomes:
Adverse outcomes:
—db (double dummy)
—Single-centre
52 weeks
N=36
—Schizophrenia, Present State
Examination
—49.5
1. Fluphenazine decanoate i.m.
biweekly+ oral PBO (dose n.i.,
n= 19
2. Oral pimozide+ PBO i.m., (dose
n.i., n= 17)
All patients were stable on
fluphenazine depot (“enriched
design”)
Study design: Randomized controlled trial
Study grouping: Parallel group
Open Label: YES
Cluster RCT:
Baseline Characteristics
Risperidone LAI
SGA physician's choice
Included criteria: schizophrenia or schizoaffective disorder, 18-65 y, symptom exacerbation within 12 monhts of screening, community dwelling for at least 4 weeks, at least moderately ill (CGI 4 or above)
Excluded criteria: first episode of psychosis, allergy to study medication, indadequate prior response to risperidone, treatment-refractoriness, lack of response to clozapine, medical instability
Intervention Characteristics
Risperidone LAI
SGA physician's choice
Dichotomous:
Sponsorship source: NIMH
Country: US, 8 centers
Setting: outpatients
Comments:
Authors name: Peter F. Buckley
Institution: Medical College of Georgia, Georgia Regents University, Augusta, GA
Email:
Address:
Identification:
Participants:
Study design:
Baseline characteristics:
Intervention characteristics:
Pretreatment:
Continuous outcomes:
Dichotomous outcomes:
Adverse outcomes:
Study design:
Study grouping:
Open Label:
Cluster RCT:
Baseline Characteristics
Risperidone LAI
SGA physician's choice
Included criteria:
Excluded criteria:
Intervention Characteristics
Risperidone LAI
SGA physician's choice
Dichotomous:
Sponsorship source:
Country:
Setting:
Comments:
Authors name:
Institution:
Email:
Address:
Identification:
Participants:
Study design:
Baseline characteristics:
Intervention characteristics:
Pretreatment:
Continuous outcomes:
Dichotomous outcomes:
Adverse outcomes:
—sb
—Single-centre
Terminated at 69 weeks, planned
for 104 weeks
Terminated at 69 weeks, planned
for 104 weeks
N=58
—Schizophrenia, clinical diagnosis
—Range 20–50
1. Fluphenazine enanthate+ oral
PBO (25 mg biweekly)
2. Fluphenazine hydrochloride+
PBO i.m. (mean 21.7 mg daily,
range 5–80 mg daily)
—Nurse 24 h available for patients
—Flexible oral dose, fixed depot
dose
—Terminated prematurely at
69 weeks
Study design: Randomized controlled trial
Study grouping: Parallel group
Open Label: YES
Cluster RCT:
Baseline Characteristics
Olanzapine LAI
Olanzapine oral
Included criteria: Outpatients, 18 to 65 years old,meeting criteria for schizophrenia based on the Diagnosticand Statistical Manual of Mental Disorders, Fourth Edition(DSM-IV) or the DSM-IV Text Revision. Patients were requiredto be considered ‘‘at risk for relapse,’’ defined as having experienced at least 2 episodes of clinical worsening of schizophreniasymptoms in the previous 24 months such that thepatient was hospitalized or required an increased level of caresurrounding the episode. Increased level of care could includethe addition of or change to any of the following from a lowerlevel of care: day hospital program; outpatient crisis management;short-term psychiatric treatment in an emergency department;or an addition, increase, or switch of medication.Patients were also required to be sufficiently clinically stableat the time of study entry, defined as no acute hospitalization forpsychosis in the 8 weeks before visit 1, a Positive and NegativeSyndrome Scale (
Excluded criteria: Exclusion criteria included previous participationin studies of olanzapine LAI, treatment resistanceto olanzapine, previous withdrawal from olanzapine treatmentdue to clinically significant and/or intolerable adverseevents, substance dependence (other than nicotine or caffeine)within the past 30 days, pregnancy, breast-feeding,or serious or unstable medical illness
Intervention Characteristics
Olanzapine LAI
Olanzapine oral
Continuous:
Dichotomous:
Sponsorship source: Eli Lilly, role of sponsor not explicitly described
Country:
Setting: Outpatients
Comments:
Authors name: Holland C. Detke
Institution: Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285
Email:
Address:
Identification:
Participants:
Study design:
Baseline characteristics:
Intervention characteristics:
Pretreatment:
Continuous outcomes:
Lone Baandrup QLS outcome is from Ascher-Svanum 2014 who reports on the same study (and therefore no separate risk of bias assessment for that study)
Dichotomous outcomes:
Adverse outcomes:
—db (double dummy)
—Single-centre
52 weeks
N=44
—Schizophrenia, Present State
Examination
—39
1. Fluphenazine decanoate i.m.+
oral PBO (25 mg fortnightly, up to
50 mg weekly)
2. Oral pimozide+ PBO i.m.(8 mg
daily, max. 16 mg daily)
—Tablet defaulting patients were a
priori excluded
—Nurse contacted patients who
failed to attend visits
—Occurred in the acute phase
—The allocation of 9 dropouts is
unclear
Study design: Randomized controlled trial
Study grouping: Parallel group
Open Label:
Cluster RCT:
Aripiprazole LAI 400 mg
Aripiprazole oral
Included criteria: 18–60 years and a diagnosis ofschizophrenia according to DSM-IV-TR10 criteria for more than 3 yearsand a history of symptom exacerbation when not receivingantipsychotic treatment.
Excluded criteria: a DSM-IV-TR diagnosis other thanschizophrenia; uncontrolled thyroid function abnormalities; ahistory of seizures, neuroleptic malignant syndrome, clinically relevant tardive dyskinesia, or other medical condition thatwould expose the patient to undue risk or interfere with studyassessments. Patients who had been admitted to hospital,including for psychosocial reasons, for 430 days total of the90 days preceding entry into phase 1 or 2 of the study afterscreening were excluded. Individuals were also excluded if theymet DSM-IV-TR criteria for substance dependence, includingalcohol and benzodiazepines but excluding nicotine and caffeine.
Intervention Characteristics
Olanzapine LAI
Olanzapine oral
Aripiprazole LAI 400 mg
Aripiprazole oral
Continuous:
Dichotomous:
Sponsorship source: This study was supported by Otsuka Pharmaceutical Commercialization, Inc. (Tokyo, Japan).Editorial support for the preparation of this manuscript was provided by Suzanne Patel atOgilvy Healthworld Medical Education and Amy Roth Shaberman, PhD, and Brett D. Mahon,PhD, at C4 MedSolutions, LLC, a CHC Group company; funding was provided by OtsukaPharmaceutical Commercialization, Inc. and H. Lundbeck A/S.
Country: Multinational, 105 centres
Setting: outpatients
Comments:
Authors name: W. Wolfgang Fleischhacker,
Institution: Department of Psychiatry and Psychotherapy, Medical University Innsbruck, Innsbruck, Austria
Email:
Address:
Identification:
Participants:
Study design:
Baseline characteristics:
Intervention characteristics:
Pretreatment:
Continuous outcomes:
Dichotomous outcomes:
Adverse outcomes:
—Open
—Multi-centre
104 weeks, study was terminated after planned interim analysis
N=710
—Schizophrenia, DSM-IV, stable
under antipsychotic treatment for
at least 4 weeks
—41.6
1.Risperidone i.m. (25 mg 2
weekly, increased by 12.5 mg
every 4 weeks as needed, mean
modal dose 33.6± 10.1 mg
biweekly, n= 355)
2.Oral quetiapine (300–400 mg
daily, mean modal dose 413.3
± 159.2 mg daily, n= 355)
relapse definition: as Buckley 2014
Study design:
Study grouping:
Open Label:
Cluster RCT:
Baseline Characteristics
Risperidone LAI
SGA physician's choice
Included criteria:
Excluded criteria:
Intervention Characteristics
Risperidone LAI
SGA physician's choice
Dichotomous:
Sponsorship source:
Country:
Setting:
Comments:
Authors name:
Institution:
Email:
Address:
Identification:
Participants:
Study design:
Baseline characteristics:
Intervention characteristics:
Pretreatment:
Continuous outcomes:
Dichotomous outcomes:
Adverse outcomes:
—db (double dummy)
—Single-center
104 weeks
N=105
—Schizophrenia, clinical diagnosis
—34.2
1. Fluphenazine decanoate i.m.+
oral PBO (mean 34 mg biweekly,
n= 55)
2. Fluphenazine hydrochloride+
PBO i.m. (mean 9.9 mg daily,
n= 50)
—13 patients left the trial after
12 months, it is unclear to which
group they were assigned
—Randomisation occurred in the
acute phase
Study design:
Study grouping:
Open Label:
Cluster RCT:
Baseline Characteristics
Risperidone LAI
SGA physician's choice
Included criteria:
Excluded criteria:
Intervention Characteristics
Risperidone LAI
SGA physician's choice
Dichotomous:
Sponsorship source:
Country:
Setting:
Comments:
Authors name:
Institution:
Email:
Address:
Identification:
Participants:
Study design:
Baseline characteristics:
Intervention characteristics:
Pretreatment:
Continuous outcomes:
Dichotomous outcomes:
Adverse outcomes:
Study design:
Study grouping:
Open Label:
Cluster RCT:
Baseline Characteristics
Risperidone LAI
SGA physician's choice
Included criteria:
Excluded criteria:
Intervention Characteristics
Risperidone LAI
SGA physician's choice
Dichotomous:
Sponsorship source:
Country:
Setting:
Comments:
Authors name:
Institution:
Email:
Address:
Identification:
Participants:
Study design:
Baseline characteristics:
Intervention characteristics:
Pretreatment:
Continuous outcomes:
Dichotomous outcomes:
Adverse outcomes:
open
52 weeks
N=320
—Schizophrenia CCMD-2
—37.2
1.Haloperidol i.m. (range 100 –
150 mg 4-weekly)
2. Other oral antipsychotics
(dose n.i.)
The allocation of 28 participants
who dropped out is unclear
104 weeks
N=355
Pts with sch who experienced at least 2 psychotic relapses in the past 2 years, and have been stabilised for >=2 months
RIS LAI
ARI
relapse: worsening of psychiatric symptoms, increase >25% PANSS T, self-injury, drug discontinuation
Study design: Randomized controlled trial
Study grouping: Parallel group
Open Label: YES
Cluster RCT:
Baseline Characteristics
Risperidone LAI
SGA physician's choice
Included criteria: between 18 and 30 years of age; had a PANSS total score between 60 and120 at screening; and received a DSM-IV TR diagnosis for schizophrenia,schizophreniform or schizoaffective disorder based on the Structured Clinical Interviewfor DSM-IV (SCID-IV) no longer than 3 years prior to study entry.. In addition, femaleswere required to be surgically sterile or engaging in effective birth control methods.
Excluded criteria: primary axis-I diagnosis was not within SSDSM-IV TR categories; if they were receiving mood stabilizers or antidepressants at thetime of entering the study; displayed current drug or alcohol dependence; were treatedwith depot antipsychotics within 3 months of study entry; had or were suspected of ahistory of hypersensitivity or allergy to risperidone; were risperidone non-responders;failed to respond to 2 or more adequate treatment trials of antipsychotics; had a clinicallysignificant laboratory abnormality or a serious unstable and untreated medical illness;were at significant risk of suicide or violence at study entry; required electroconvulsivetreatment within 3 months of study entry; received or used an experimental drug ordevice within 30 days before study entry; had previous treatment with clozapine; or ifthey were in a conflict of interest with the investigation
Intervention Characteristics
Risperidone LAI
SGA physician's choice
Dichotomous:
Sponsorship source: This study was sponsored and funded by Janssen Canada
Country: Canada
Setting: outpatient/inpatient setting not described
Comments:
Authors name: Ashok Malla
Institution: Department of Psychiatry, McGill University, Montreal, Quebec
Email:
Address:
Identification:
Participants:
Study design:
Baseline characteristics:
Intervention characteristics:
Pretreatment:
Continuous outcomes:
Dichotomous outcomes:
Louise Klokker Madsen Adverse event in table= weight gain (>7%)Discont. due to adverse events for both groups: Reasons for dropout among those who reachedstabilization included adverse events (n = 3)Reasons for dropout among participants who had not stabilizedincluded adverse events (n = 2);Reasons for hospitalization includedexacerbation of symptoms, relapse, or adverse events. The latter included alcoholdependence syndrome (n =1), a depressive state marked by suicidal ideation (n = 1) inparticipants receiving RLAI, and lacerations to the face (n = 1), nausea andthrombocytopenia (n = 1) for those receiving oral SGAs.
Adverse outcomes:
Open
52 weeks
N=20
—Schizophrenia, PANSS>60
—34.9
1. Risperidone i.m. (41.7±
10.6 mg biweekly)
2. Oral olanzapine (15.9± 5,0 mg
daily)
Study design:
Study grouping:
Open Label:
Cluster RCT:
Baseline Characteristics
Risperidone LAI
SGA physician's choice
Included criteria:
Excluded criteria:
Intervention Characteristics
Risperidone LAI
SGA physician's choice
Dichotomous:
Sponsorship source:
Country:
Setting:
Comments:
Authors name:
Institution:
Email:
Address:
Identification:
Participants:
Study design:
Baseline characteristics:
Intervention characteristics:
Pretreatment:
Continuous outcomes:
Dichotomous outcomes:
Adverse outcomes:
—db (double dummy)
—Four centres
52 weeks
N=214
—Schizophrenia, DSM-II, at least
moderately ill on at least one BPRS
positive symptom
—29 years
1. Fluphenazine decanoate+ oral
PBO (mean 34.2 mg/i.m. 3 weekly,
range 12.5–100 mg/im, n= 107)
2. Fluphenazine hydrochloride+
i.m. PBO (mean 24.8 mg daily,
range 2.5–60 mg daily, n= 107)
—Patients who failed to attend
visits were contacted by
telephone or home visits
—Randomisation occurred in the
acute phase
this conference abstract of the study is excluded and the full report (Detke 2014) included instead
Article written in Japanese, not possible to asses risk of bias, even though data were extracted in Kishimoto 2014
Article written in Japanese, not possible to asses risk of bias, even though data were extracted in Kishimoto 2014
Patients were required to be in stable remission to be included
this conference abstract is excluded and instead the full report of this study (Buckley 2014) has been included
Wrong intervention
Wrong intervention
Wrong intervention
Wrong intervention
Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
cf. Leucht 2011
no info
cf. Leucht 2011
Comment: randomly assigned, not further specified
cf. Leucht 2011
Comment: Randomized, not further described
cf Leucht 2011
Comment: Not described in the text
cf. Leucht 2011
Quote: "were randomly assigned"
Comment: Unclear how randomization was done.Does not seem random??
Quote: "19 were randomly assigned to the quetiapine group, and 10 were randomly assigned to the haloperidol decanoate group."
Comment: Unclear how randomization was done.
cf. Leucht 2011
Quote: "randomly assigned, in a 1:1:2:1:2 ratio,"
Quote: "randomised controlled week, open-label, randomised controlled international study"
Quote: "Randomisation numbers were probabilities. Randomisation numbers were allocated by an interactive voice response allocated by an interactive voice response system (IVRS)."
cf. Leucht 2011
Quote: "Subjects were randomly assigned in a 1:1 ratio"
Quote: "Eligible patients were randomly assigned to one of two treatment conditions."
Comment: Randomized, not further described
Not clear how randomization was done
cf. Leucht 2011
Quote: "Randomization was conducted centrally and strat- ified according to site because of potential prac- tice differences. Randomization was conducted with the use of randomly permuted blocks of variable size to ensure an approximate balance over time."
cf. Leucht 2011
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
cf. Leucht 2011
cf. Leucht 2011
Comment: Not described
cf. Leucht 2011
Comment: Not described
cf Leucht 2011
Comment: Not described in the text
cf. Leucht 2011
Comment: No described, probably not done.
cf. Leucht 2011
Comment: Not described but probably done.
Quote: "Randomisation numbers were probabilities. Randomisation numbers were allocated by an interactive voice response allocated by an interactive voice response system (IVRS). When a participant was system (IVRS). When a participant was ready to be randomised, the investigator ready to be randomised, the investigator called the IVRS by telephone and entered called the IVRS by telephone and entered the person’s stratification information. the person’s stratification information."
Comment: Probably difficult to foresee or influence
cf. Leucht 2011
Comment: Not described
Comment: Not described
cf. Leucht 2011
no info
cf. Leucht 2011
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
cf. Leucht 2011
Quote: "ran- domized, prospective, single-blind study"
Comment: Unclear how blinding was performed, but outcomes are objective in this study.. Probably low risk in this item.
cf. Leucht 2011
Comment: unblinded
cf. Leucht 2011
Comment: Unblinded
cf Leucht 2011
Comment: double-blinded, double-dummy approach
cf. Leucht 2011
Quote: "open-label, ran- domized trial,"
Comment: No blinding.
cf. Leucht 2011
Quote: "Patients and study personnel were blind to treatment assign- ment. All patients received four oral tablets (drug or placebo) each day and an injection (drug or placebo) every 2 weeks. The staff administering injections were not part of the study team and provided no clinical ratings."
Quote: "Randomised, controlled, open-label study"
cf. Leucht 2011
Quote: "open-label,"
Comment: Open-label study
cf. Leucht 2011
Comment: Not possible t blind patients or treating personnel
cf. Leucht 2011
Detection bias due to knowledge of the allocated interventions by outcome assessors
cf. Leucht 2011
Quote: "Clinical efficacy and side effects were assessed by trained investigators at baseline and weeks 4, 8, 12, 24, 36, and 48."
Comment: not described
cf. Leucht 2011
Comment: masked, centralized assessors, monitored bi-weekly by on-site clinicians and assessors who knew treatment assignment, scale of functioning completed by on-site, undblinded raters
no info
cf. Leucht 2011
Comment: No methods described to blind outcome assessors, so probably undblinded
cf Leucht 2011
Comment: Probably done
cf. Leucht 2011
Quote: "All ratings were performed by clinicians who were not aware of the patient’s treat- ment assignment."
cf. Leucht 2011
Quote: "Symptom severity was assessed using the 30-item Positive and Negative Syndrome Scale (PANSS [9]), the PANSS-derived BPRS, and the Clinical Global Impressions-Severity of Illness (CGI-S [8]). Efficacy assessments were performed weekly for the first 12 weeks and every 2 weeks thereafter."
Comment: Not described. I does not in general seem as tough efforts have been done to blind assessors - or personnel in general.
cf. Leucht 2011
Quote: "Relapse was determined by a five- member RMB blinded to subject treatment;"
Comment: Open-label study
not described. It does not in general seem as though efforts were doneto blind assessors.
cf. Leucht 2011
Quote: "Blinded videoconference assessments were com- pleted every 3 months on measures of symptoms, quality of life, and functioning."
cf. Leucht 2011
Attrition bias due to amount, nature or handling of incomplete outcome data
cf. Leucht 2011
Quote: "All 5 patients with- drawn from the study were from the risperidone long- acting injection group. One patient withheld informed consent due to gastrointestinal side effects at week 5, 2 patients were discharged in stable condition, and 2 pa- tients taking 25 mg risperidone long-acting injection q 2 weeks (original oral risperidone doses of 3 mg/day and 4 mg/day, respectively) had symptom relapses."
Comment: Relatively small dropout. ITT analysis
cf. Leucht 2011
Comment: 48% and 51% attrition rate, not a bias for primary outcome (relapse)
no info
cf. Leucht 2011
Comment: Discontinuation rate>50%, not necessarily a problem for main outcome but for secondary measures
cf Leucht 2011
Comment: Discontinuation 26% vs. 33% after 38 weeks, considered acceptable
cf. Leucht 2011
Quote: "During the first 4 weeks of the study, 3 patients dropped out. Thus, at the first postbase- line assessment (week 4), data were collected from 22 exacerbation-free patients (15 in the quetiapine group, 7 in the haloperidol decanoate group). By the final assess- ment (week 48), only 12 patients (7 in the quetiapine group, 5 in the haloperidol decanoate group) remained in the study."
Comment: No intention to treat analysis.
cf. Leucht 2011
Quote: "All analyses were performed on an intent-to-treat basis"
Quote: "(Patient flow through the study is shown in the data supplement accompanying the online version of this article.)"
Comment: Dropouts described in additional file??
Quote: "Assessments were completed at baseline (randomisation), weeks 5, 9, 13, 25, 37 and (randomisation), weeks 5, 9, 13, 25, 37 and 53 and at end-point (last observation car- 53 and at end-point (last observation car- ried forward, LOCF)."
Comment: 35 % and 38 % dropout respectively. Relatively large but not skewed..
cf. Leucht 2011
Quote: "The efficacy analyses were based on the intent-to-treat (ITT) analysis set, which included all subjects randomly assigned to a treatment group who had received at least one dose of study drug and at least one postbaseline PANSS measurement."
Quote: "Of the 409 subjects screened, 355 were randomly selected to receive study drug and 349 were included in the ITT analysis set."
Comment: Relatively small amount of dropout after two years. Dropout not skewed.
Comment: > 50% dropout from the maintenance phase
not clear
cf. Leucht 2011
Comment: 10 dropouts in oral group, 3 in injection group. ITT analysis and relatively small and not too skewed dropuout.
cf. Leucht 2011
Reporting bias due to selective outcome reporting
cf. Leucht 2011
cf. Leucht 2011
Comment: study protocol available at clinicaltrials.gov, no evidence of selective outcome reporting
cf. Leucht 2011
Comment: No evidence of selective reporting, registered at clinictrials.gov
cf Leucht 2011
Comment: protocol available, primary outcome changed from date of randomization, but justified due to lower-than-anticipated relapse rate
cf. Leucht 2011
Comment: No protocol. Study of low quality. If outcomes seem relevant - unclear.
cf. Leucht 2011
no
Quote: "NCT00236457) http://clinicaltrials.gov"
Comment: Outcome from protocol reported
cf. Leucht 2011
Quote: "(NCT00299702)"
Comment: Outcomes from protocol reported
Comment: No evidence of selective reporting
cf. Leucht 2011
Comment: Outcomes described in protocol. outcomes seem relevant compared with other studies.
cf. Leucht 2011
Bias due to problems not covered elsewhere in the table
cf. Leucht 2011
cf. Leucht 2011
Comment: No other obvious source of bias
cf. Leucht 2011
Comment: Role of funding pharmaceutical company not explicitly described
cf Leucht 2011
Comment: Role of funding pharmaceutical company not clear
cf. Leucht 2011
no other bias
cf. Leucht 2011
no
Quote: "The study was supported by Johnson & Johnson Pharmaceutical Research and Development. The Pharmaceutical Research and Development. The authors thank Ilse Van Hove, MSc (Johnson & John- authors thank Ilse Van Hove, MSc ( Johnson & John- son Pharmaceutical Research and Development, son Pharmaceutical Research and Development, Beerse, Belgium) for completing the statistical ana- Beerse, Belgium) for completing the statistical ana- lyses."
Comment: Ligefrem analyserne!
cf. Leucht 2011
Comment: Kan dette have påvirket grupperne skævt?
Quote: "The biweekly visits and regular assessments with numerous time- intensive scales increased interactions with treatment teams and may have enhanced nonspecific psychotherapeutic effects and increased adherence to oral treatment."
Comment: No other obvious source of bias
cf. Leucht 2011
cf. Leucht 2011