Methods

Allocation: random.

Blinding: single blind, rater blind.

Duration: 12 weeks.

Design: parallel.

Setting: inpatient, large psychiatric teaching hospital, Taiwan.

Participants

Diagnosis: schizophrenia (DSM‐IV).

Age: 18‐65 years.

N = 50.

Sex: 25 M and 25 F.

History: symptomatically stable defined as PANSS total < 80, CGI‐no change in score between screening and baseline, previous treatment with oral risperidone for > 3 months.

Included: 'good health' based on physical examination, medical history and blood biochemistry and haematology.

Exclusion: History of NMS or organic CNS disorder; current seizure disorder; current risk of violent behaviour against others; current suicidal ideas or suicidal ideas in the last 6 months.

Consent and ethics: study performed in accordance with the Declaration of Helsinki and approved by Ethics Review Committee. All participants provided written informed consent before starting the study.

Interventions

1. Risperidone depot: 25 mg, 37.5 mg or 50 mg once every 2 weeks, n = 25.

2. Risperidone oral: mean 3.8 +/‐ 1.6 mg/day, n = 25.

Outcomes

Quality of life (SF‐36).

Adverse events (recorded spontaneously); AIMS; BARS; SAS; UKU; movement disorder.

Mental state: PANSS.

Global state: CGI‐S, GAF.

Leaving study early.

Unable to use ‐

Satisfaction with treatment ‐ non‐peer reviewed scale.

Pain at injection site (visual analogue scale) ‐ no SD reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "this trial was a randomized, parallel‐group, rater‐blind study of 52 weeks duration." No information on how randomisation was achieved.

Allocation concealment (selection bias)

Unclear risk

No information.

Blinding (performance bias and detection bias)
All outcomes

High risk

Implied to be an open‐label study. Not explicit, but implied open‐label with regard to participants and study drug administrators. Detection: "rater blind", but no information on how the blinding was maintained.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

N = 49 participants completed the study (98%).

Selective reporting (reporting bias)

Low risk

All outcomes listed in methods appear to be reported.

Other bias

High risk

Funding: supported by Jassen‐Cilag Taiwan, Johnson & Johnson co.

Methods

Allocation: random.
Blinding: double.*
Duration: 12 weeks (preceded by 8‐week open‐label run‐in).
Design: parallel, international multi‐centre.

Setting: inpatient, 95 sites, UK, mainland Europe, North America, Africa.

Participants

Diagnosis: schizophrenia (DSM‐IV).

Age: mean 40 ± 15 years, range 18‐65.
N = 640.**
Sex: 415 M, 225 F.
History: inpatient or outpatient; PANSS score ≥ 50, but ˜47% "not ill or only mildly ill" on CGI, stabilised 8/52 on oral risperidone.

Included: stable CGI scores for the previous 4 weeks of the oral risperidone run‐in period.
Excluded: moderate or severe symptoms of tardive dyskinesia at study entry; history of neuroleptic malignant syndrome; known to be unresponsive to risperidone; required mood stabilisers; treated with clozapine in past 2 months before screening; treated with a depot antipsychotic within one treatment cycle of screening, or with antidepressants within 30 days before run‐in period.

Consent and ethics: study performed in accordance with the Declaration of Helsinki; consent obtained from participant, relative, guardian or legal representative at study entry.

Interventions

1. Risperidone depot: 25, 50 or 75 mg, every two weeks + daily placebo tablets, n = 319.
2. Risperidone oral: 2, 4 or 6 mg/day + placebo injections every two weeks, n = 321.

Outcomes

Global state: needing use of benzodiazepines or sedative drugs; CGI (dichotomised).

Mental state: PANSS.
Leaving the study early.
Adverse events: others as reported by participants; death.

Unable to use ‐
Global state: CGI (data on subgroups only).
Adverse events: ESRS (no usable data).
Body weight: change (no usable data).
Pain at injection site (no usable data).
Physiological tests: including ECG (no usable data).

Notes

* Blindness was maintained with different doses by using the same volume of diluent.

** Numbers randomised not consistent in presentations (426 vs 640).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomization was stratified according to site, PANSS score, ESRS total score, use of depot antipsychotics in the previous 6 months and daily dose of oral risperidone at randomization" (p112).

Allocation concealment (selection bias)

Unclear risk

Not described.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Placebo tablets and injections used to blind participants. "Double blind" stated but it is not clearly expressed who exactly was blinded, cannot be sure if rater blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

N = 541 participants completed the study (85%). Completer‐only data for PANSS.

Selective reporting (reporting bias)

Unclear risk

All outcomes reported, however not all presented as usable data, particularly continuous data, with no means or SD.

Other bias

High risk

Funding: supported by Janssen Research Foundation, Beerse, Belgium.

Methods

Allocation: random.

Blinding: open‐label, blinded clinical raters.

Duration: 6 months (+ 6 months naturalistic follow‐up).

Design: parallel.

Setting: National Institute of Mental Health Schizophrenia Trials Network and five sites in Conneticut's public mental health system, USA.

Participants

Diagnosis: schizophrenia (DSM‐IV).

Age: ≥18 years, mean age 48 yrs (risperidone depot: 48.5 ± 12.2; haloperidol/fluphenazine depot: 47.3 ± 9.1).

N = 62.

Sex: 44 M (22 in each group), 18 F.

History: currently taking fluphenazine decanoate or haloperidol decanoate, "may benefit from changing medication" and "willing to change", able to afford own medication, at least one 3‐monthly clinic visit in past 6 months.

Included: eligible patients were those who might benefit from switching to risperidone microspheres (with sub‐optimal response to treatment because of persistent psychopathology or significant side effects); people where change in medical opinion was a reasonable clinical opinion, but not required; willingness to change antipsychotic medication; access to medication without financial burden; at least 1 clinic visit every 3 months for past 6 months.

Excluded: symptom severity indicating immediate change; exacerbation in previous 3/12; pregnancy; pending criminal charges; non‐independent living; antipsychotic polypharmacy.

Consent and ethics: written informed consent after thorough description of the study to participants and assessment of understanding consent materials.

Interventions

1. Risperidone depot: 25, 37.5 or 50 mg/ 2 weeks, n = 32.

2. Haloperidol decanoate OR fluphenazine*, n = 30.

*No data on dosages actually prescribed in this arm ‐ "clinician's judgement".

Outcomes

Primary ‐ time to all‐cause treatment discontinuation.

Mental state: PANSS (completer‐only).

Hospitalisation by 6 months.

Adverse events: Arizona Sexual Experiences Scale; weight; prolactin (completer‐only, skew data).

Unable to use ‐

AIMS (adapted scale used).

Subjective Side‐effect Rating Scale (no data reported).

EPS (SAS); tardive dyskinesia (incomplete data for all participants ‐ only 44% accounted for).

Tardive dyskinesia (more than 50% participants did not complete assessment).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised, quote, "stratified by gender and baseline decanoate. No exceptions were made to the predetermined randomisation streams" (p670).

Allocation concealment (selection bias)

Unclear risk

No details given of how this was achieved. Quote, "eligible patients were those who might benefit from a switch to risperidone microspheres" (p670).

Blinding (performance bias and detection bias)
All outcomes

High risk

Open‐label study with assessment by blinded clinical raters.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Data relating to loss to follow‐up are given and overall attrition is < 50%. Lost to follow‐up n = 8: reasons for discontinuation included increase in psychiatric symptoms (n = 4), EPS concerns (n = 1), participant preference (n = 2), hypertension and weight gain (n = 1). However, not all participants completed continuous outcome measures; LOCF carried forward used in primary study citation, completer‐only data provided with means and SD for additional requested information (unpublished).

Selective reporting (reporting bias)

High risk

Not all data reported, including means and SDs for most continuous outcomes.

Other bias

Unclear risk

Funding: quote, "research presented in this article was funded by the National Institute of Mental Health grant number MH71663 and MH59312." One author (Schooler) "has previously received grant/research support from... Janssen‐Cilag, and Johnson & Johnson."

Methods

Allocation: random.

Blinding: double.

Duration: 53 weeks.

Design: parallel.

Setting: international, multi‐centre, 19 countries: North America, Australia, New Zealand, Western and Eastern Europe.

Participants

Diagnosis: schizophrenia (DSM‐IV).

Age: ≥ 18 years of age.

N = 749.

Sex: 444 M, 305 F.

History: DSM‐IV diagnosis of schizophrenia for at least one year before screening.

Included: PANSS score between 60‐120; acutely symptomatic at screening and baseline; BMI ≥ 15 kg.

Excluded: DSM‐IV Axis I diagnosis other than schizophrenia; decrease of ≥ 25% in the PANSS total score between screening and baseline; substance dependence during the three months preceding screening; history of treatment resistance; history of neuroleptic malignant syndrome or any significant or unstable systematic disease; suicidal or violent behaviour; pregnant or nursing or women planning pregnancy.

Consent and ethics: Independent Ethics Committee or Institutional Review Board at each study site approved the protocol. Study conducted in accordance with Declaration of Helsinki and consistent with Good Clinical Practice (GCP) and applicable regulatory requirements. All participants provided written informed consent before entry.

Interventions

1. Risperidone depot*: IM, 25, 37.5 mg or 50 mg (placebo injections matched to risperidone depot on day 1, with first active injection delayed until day 8), n = 370.

2. Paliperidone palmitate (PP): IM, 25, 50, 75 or 100 mg eq (placebo injections matched to PP on day 22 then monthly thereafter), n = 379.

*1‐6 mg oral risperidone/ placebo supplementation was given for the first 4 weeks of the double‐blind treatment period. Oral risperidone (1‐4 mg) supplementation was also given at any dose increase from day 36 onwards, continuing up to week 3.

Outcomes

Adverse effects: various events, AIMS, BARS, SAS scores, laboratory results: various mean change in serum levels, EKGs, evaluations of injection site (all adverse data relate to participants who received at least one dose of the study drug).

Leaving the study early.

Death.

Unable to use ‐

Primary outcome: Non inferiority of PP with risperidone (high attrition and unable to obtain data).

Secondary outcomes: average change in PANSS total score (high attrition and unable to obtain data).

Global state: relapse, change in CGI‐S (high attrition and unable to obtain data).

Social functioning: Change in PSP (high attrition and unable to obtain data).

Mental state: average change in PANSS (high attrition and unable to obtain data).

Notes

Antiparkinson medication (at permitted maximum daily doses) as rescue treatment for EPS; oral lorazepam (2‐6 mg) or other short‐acting benzodiazepines for agitation, anxiety or sleep difficulties; oral propranolol for akithisia were permitted. Antidepressents permitted if used at a stable dose for at least 30 days before screening.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised: "computer generated randomisation schedule (prepared by the sponsor), balanced by using permuted blocks of treatments, stratified by centre and implemented using an interactive voice response system (IVRS)".

Allocation concealment (selection bias)

Low risk

Use of interactive voice response system.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Participants were not allowed to view the preparation or administration of the injection. Blinded raters used to measure outcomes.

Incomplete outcome data (attrition bias)
All outcomes

High risk

High study attrition (55%): PP group drop‐out rate at n = 224 (n = 95 lack of efficacy; n = 29 adverse events; n = 55 patient choice; n = 13 lost to follow‐up; n = 1 pregnancy; n = 2 death; n = 29 other); risperidone depot group drop‐out rate at n = 186 (n = 56 lack of efficacy; n = 25 adverse events; n = 62 patient choice; n = 11 lost to follow‐up; n = 1 pregnancy; n = 0 death; n‐31 other).

Selective reporting (reporting bias)

Unclear risk

Missing outcomes in a supplementary table (not obtainable ‐ contact made with study author, but no reply).

Other bias

High risk

Funding: sponsored by Johnson & Johnson Pharmaceutical Research and Development, L.L.C. The sponsor provided a formal review of the manuscript. Two study authors (Mr Remmerie and Dr Eerdekens) were employees of Johnson & Johnson Pharmaceutical Research and Developement, Division of Janssen Pharmaceutica.

Methods

Allocation: random.

Blinding: open‐label.

Duration: 2 year.

Design: parallel.

Setting: international, multi‐centre, 25 countries (Europe).

Participants

Diagnosis: schizophrenia or schizoaffective (DSM‐IV).

N = 710.

Age: ≥ 18 years, mean 40.6 +/‐ 12.5 in depot risperidone group; 42.6 +/‐ 13.1 quetiapine group; 40.9 +/‐ 12.94 in aripiprazole group.

Sex: 442 M, 270 F.

History: symptomatically stable.

Included: switching therapy because of insufficient symptom control with current treatment, side effects or patient request; symptomatically stable‐ using stable dose of antipsychotic for ≥ 4 weeks and living in same residence for ≥ 30 days.

Excluded: previous non‐response to risperidone, quetiapine or ≥ 2 antipsychotics despite adequate drug plasma levels; DSM IV axis I diagnosis other than schizophrenia or schizoaffective disorder; phenylketonuria or hypersensitivity to risperidone or quetiapine; drug or alcohol dependence during preceding 1 month; acute risk of suicide or history of suicide attempt.

Consent and ethics: study conducted in accordance with guidelines of the International Conference on Harmonisation for Good Clinical Practice. Study protocol and consent were approved by ethics committees/ institutional review boards; informed consent obtained from all participants before enrolment.

Interventions

1. Risperidone depot: 25‐50 mg IM every 2 weeks, n = 329.

2. Quetiapine oral: 25 mg twice a day: day 1, 300‐ 400 mg by day 4, max 750 mg a day, n = 337.

3. Aripiprazole oral: 10‐30 mg per day, n = 46.

Outcomes

Adverse events.

Leaving the study early.

Death.

Unable to use ‐ (all due to high attrition)

Time to relapse.

Global state: CGI.

Mental state: PANSS.

Functioning assessment: SOFAS.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified randomisation according to previous treatment.

Allocation concealment (selection bias)

Unclear risk

No details given.

Blinding (performance bias and detection bias)
All outcomes

High risk

Open‐label study. No evidence for any rater blinding‐ follow‐up methods differed between treatment groups (phone calls for quetiapine group and in person with depot risperidone).

Incomplete outcome data (attrition bias)
All outcomes

High risk

High attrition: treatment completed by n = 151/329 in risperidone depot; n = 120/337 oral quetiapine; n = 9 oral aripiprazole. Total follow‐up of n = 280/710 (39%) ‐ only leaving study early and adverse event data used.

Selective reporting (reporting bias)

Unclear risk

Some outcomes comprising relapse are not reported on their own.

Other bias

High risk

Funding: study sponsored by Janssen‐Cilag Medical Affairs EMEA.

Methods

Allocation: random.
Blinding: double.
Duration: 12 weeks (preceded by up to 4 mg risperidone/day for 1 week).
Design: parallel.

Setting: inpatient and outpatient, multi‐centre (41 centres in the USA).

Participants

Diagnosis: schizophrenia (DSM‐IV).
N = 400.
Age: 18 to 55 years of age; mean˜37 ± 20 years.
Sex: 301 M, 99 F.
History: diagnosis of schizophrenia.

Included: baselines PANSS of 60 to 120; good general health; standard laboratory test results 'within reference ranges or not clinically significant'.
Excluded: received depot in past 120 days before start of trial; substance dependant diagnosis; tardive dyskinesia; history of neuroleptic malignant syndrome; clinically significant ECG abnormality; pregnant (or likely to become pregnant) or lactating; at risk of violent behaviour; current suicide ideation; history of severe drug sensitivity/ allergy (sensitivity to risperidone); people who were unresponsive to risperidone.

Consent: trial conducted in accordance with 'current ICH‐Good Clinical Practice guidelines and the Declaration of Helsinki and its subsequent revisions'; written informed consent obtained from each participant or guardian/ legal representative.

Interventions

1. Risperidone depot: 25 mg 2 weekly + 2 mg/day oral risperidone for 3/52, n = 99.
2. Risperidone depot: 50 mg 2 weekly + 4 mg/day oral risperidone for 3/52, n = 100.
3. Risperidone depot: 75 mg 2 weekly + 6 mg/day oral risperidone for 3/52, n = 100.
4. Placebo injections: 2 weekly + placebo tablets for first 3/52, n = 100.

Outcomes

Adverse events: ESRS and others as reported by participants.

Leaving the study early.

Unable to use ‐

Global state: CGI.
Mental state: 20% reduction PANSS.
Body weight: change.
Pain at injection site.
Physiological tests: including ECG.
Mental state: change PANSS (no SD).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised: quote, "a dynamic method (22) was used to randomly assign patients to treatment groups. Stratification factors included investigator, inpatient/outpatient status, and Positive and Negative Syndrome Scale (23) total score at randomization."

Allocation concealment (selection bias)

Unclear risk

No details of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"Double blind study" but not clear who exactly was blinded, no indication given of whether the raters were blinded. Study controlled with "placebo injections that were identical in appearance [to the study drug injections]".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Greater than 50% attrition by study end.

Selective reporting (reporting bias)

Unclear risk

Unclear risk

Other bias

High risk

Funding: "supported by Johnson & Johnson Pharmaceutical Research and development, Titusville, N.J."

Methods

Allocation: random.

Blinding: open‐label.

Duration: 12 months.

Design: parallel.

Setting: international, multi‐centre (48 centres in Australia, Belguim, France, Germany, Greece, Luxumbourg, Poland, Russia, Spain, The Netherlands and UK).

Participants

Diagnosis: schizophrenia or schizoaffective disorder (DSM‐IV).

N = 629* (n = 11 not treated).

Age: mean˜35 years, minimum 18 years.

Sex: 312 M, 235 F.

History: acute exacerbation of psychosis in previous 2 months and another episode during previous 2 years.

Excluded: prior treatment with clozapine or depot antipsychotic.

Included: PANSS total score > 50; at least 18 years of age; BMI not exceeding 40 mg/kg².

resistance or sensitivity to risperidone or olanzapine

pregnant or breast feeding women, child bearing age women if not using contraception

Consent: study protocol and amendments reviewed by independent ethics committees/ institutional review boards; conducted in accordance with Declaration of Helsinki and guidelines of International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Written informed consent required.

Interventions

1. Risperidone depot: 25, 50 or 75 mg*, n = 318.

2. Oral olanzapine: 5‐20 mg/day, n = 300.

Outcomes

Mental state: PANSS.

Specific adverse events; movement disorder; death and serious adverse events.

Leaving the study early.

Notes

*After study initiation protocol was amended to restrict the doses of depot risperidone to 25 or 50 mg; 64 patients who had already received 75 mg of depot risperidone were withdrawn from the study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised, "using a central dynamic randomisation procedure. Randomisation was based on a minimisation algorithm that used a probability of assignment other than 0.5 to maintain balance of treatment groups within levels of each stratification factor" (p132). stratification factors of PANSS total score, number of previous psychiatric hospitalisations, BMI, inpatient or outpatient status, using a central dynamic randomisation procedure.

Allocation concealment (selection bias)

Low risk

Interactive voice response system (IVRS) used to obtain randomisation number.

Blinding (performance bias and detection bias)
All outcomes

High risk

Open‐label study. No evidence of rater blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

N = 618 originally randomised and treated; n = 264 (42%) completed at 12 months. LOCF used for endpoint data including n = 361 participants (58%).

Selective reporting (reporting bias)

High risk

Protocol amended to restrict risperidone doses to 20 or 50 mg after investigators found that, quote, "75 mg doses provide no greater benefit than lower doses" (p132). The n = 64 participants receiving 75 mg doses completed the study, their data were withdrawn and they were invited to enrol in an open‐label extension study.

Other bias

High risk

Funding: "M.I., A.K. and K.K. are employees of Johnson & Johnson... study was supported by Johnson & Johnson Pharmaceutical Research and Development" (p138).

Methods

Allocation: random.

Blinding: open‐label.

Duration: 12 weeks (with 7 week washout pre‐randomisation).

Design: parallel.

Setting: multi‐centre, China.

Participants

Diagnosis: schizophrenia (DSM‐IV).

N = 452.

Age: ≥18 years of age.

Sex: 181 M, 271 F.

History: DSM‐IV diagnosis of schizophrenia for at least one year before screening.

Included: PANSS total score between 60 to 120; BMI of 17.0 kg/m² or greater.

Excluded: DSM IV axis I diagnosis other than schizophrenia; 25% decrease in total PANSS score between screening and baseline; active substance dependence within 3 months; significant risk of suicidal or violent behaviour; presence or history of any significant or unstable systemic disease; history of treatment resistance towards two different antipsychotic treatments; pregnancy or planning; clozapine within 3 months before baseline; RIS‐LAI within 6 weeks before screening; PP within 10 months before baseline; ECT within 60 days before screening.

Consent: Independent Ethics Committee or Institutional Review Board at each study site approved the protocol; study conducted in accordance with ethical principles of Declaration of Helsinki, consistent Good Clinical Practices and applicable regulatory requirements. Written informed consent required.

Interventions

1. Risperidone depot: once every two weeks, mean dose 29.8 ± 4.67 mg, n = 223.

2. Paliperidone palmitate: once monthly injections, mean dose 115.8 ± 9.07 mg, n = 229.

(Plus supplementary oral risperidone for risperidone depot participants: mean daily dose 2.5 ± 0.98 mg from days 1 to 28; 1.8 ± 0.52 mg from day 36 to 57; 1.7 ± 0.47 mg from day 64 to 85).*

Outcomes

Global state: CGI‐S scale score change from baseline.

Mental state: change in PANSS total score; number of patients with a 30% or more reduction in PANSS total score.

Adverse events: treatment‐emergent adverse events; EPSE; prolactin‐related.

General functioning; Personal and Social Performance (PSP).

Notes

*Other medications permitted, including: antiparkinson medication; benzodiazepines; beta‐blockers; treatment for insomnia; topical anaesthetic cream; antidepressants; individual psychotherapy.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised: (1:1) "based on a computer‐generated randomization schedule balanced by using permuted blocks of treatments."

Allocation concealment (selection bias)

Unclear risk

Not described.

Blinding (performance bias and detection bias)
All outcomes

High risk

Open‐label. Rater blinding: "all efficacy assessments were administered and evaluated by independent, blinded and trained raters at each site."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

N = 350 (77%) completed the study; n = 64 withdrawn from the PP groups for adverse events (n = 4), pregnancy (n = 2), protocol deviation (n = 3), lack of efficacy (n = 22), lost to follow‐up (n = 9), withdrew consent (n = 16), other reasons (n = 8). From the risperidone depot group, n = 38 were withdrawn for adverse events (n = 5), protocol deviation (n = 1), lack of efficacy (n = 9), lost to follow‐up (n = 14), withdrew consent (n = 5), other reasons (n = 4). ITT used.

Selective reporting (reporting bias)

Unclear risk

Not known.

Other bias

High risk

Funding: "funded by Xian‐Janssen Pharmaceutical Limited, Beijing, PR China. The sponsor provided a formal review of the manuscript." A number of the authors were employed by Xian‐Janssen or Johnson & Johnson at time of publication.

Methods

Allocation: random.

Blinding: open‐label, rater blind.

Duration: 2 years.

Design: parallel.

Setting: international, multi‐centre (USA, South America, India).

Participants

Diagnosis: schizophrenia (DSM‐IV).

N = 355.

Age: ≥18 years of age.

Sex: 210 M, 139 F.

History: not described.

Included: DSM‐IV schizophrenia not controlled by current medication (judged by clinician); 2+ relapses (defined as "psychiatric hospitalisation caused by worsening of psychiatric symptoms; a change in antipsychotic treatment or significant increase in antipsychotic dose because of inadequate efficacy; a newly emergent, clinically important symptom such as 'suicidality'; or a clinically notable increase in the frequency or intensity of subject contact") in the past 2 years. Stable for 2 months before randomisation.

Excluded: PANSS ≥100, current hospitalisation, major medication changes, or worsening of psychiatric symptoms within two months before study entry. Current treatment with clozapine, carbamazepine or depot antipsychotics. Evidence of alcohol or drug dependence (DSM‐IV Axis I criteria) within six months before entry.

Consent: study conducted in accordance with Declaration of Helsinki and Good Clinical Practice; approved by Institutional Review Board or independent ethics committee at each centre. Written informed consent required.

Interventions

1. Risperidone depot: 25‐50 mg/2 weeks, n = 177.

2. Oral aripiprazole: 5‐30 mg/daily, n = 172.*

Outcomes

Global state: mean time to relapse/time in remission.

Mental state: PANSS.

Specific adverse events; weight; movement disorders; death; serious adverse events.

Laboratory tests.

Notes

*Other medications permitted, including antidepressants, anxiolytics, mood stabilisers. At clinician's judgement, if psychotics symptoms worsened, another antipsychotic was added (excluding clozapine) for up to seven days; this treatment continued if considered appropriate by investigators. If this proved ineffective, the investigator had the option to use another different secondary antipsychotic.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised: "subjects were randomly assigned in a 1:1 ratio" but no details on how this was achieved.

Allocation concealment (selection bias)

Unclear risk

Concealment not described.

Blinding (performance bias and detection bias)
All outcomes

High risk

Open‐label, participants and study drug administrators were not blinded, but with blinded raters.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"The proportions of injectable RLAT and aripiprazole subjects who discontinued the study before completing two years were 29.6% and 28.4%, respectively" and reasons for discontinuation are given. Of the original n = 355 randomised, n = 346 were included in ITT analysis.

Selective reporting (reporting bias)

Unclear risk

None detected.

Other bias

High risk

Study authors employed by Janssen: "Dr. Macfadden was with Ortho‐McNeil Janssen Scientific Affairs, LLC, Titusville, New Jersey, at the time of this analysis; Drs. Ma and Haskins are with Johnson & Johnson Pharmaceutical Research and Development, LLC, Titusville, New Jersey; and Drs. Bossie and Alphs are with Ortho‐McNeil Janssen Scientific Affairs, LLC, Titusville, New Jersey."

Methods

Allocation: random.

Blinding: double.

Duration: 13 weeks.

Design: parallel, double dummy, non‐inferiority comparative study.

Setting: international multi‐centre, 89 centres from 14 countries (Bulgaria; Czech Republic; Estonia; Hungary; Lithuania; Poland; Russia; Ukraine; USA; Austria; France; Germany; Spain; India).

Participants

Diagnosis: schizophrenia (DSM‐IV).

N = 1220.

Age: ≥18 years of age.

Sex: 701 M, 513 F.

History: 65% PP and 69% RIS‐LAI participants were receiving atypical antipsychotics prior to study, with oral risperidone used by similar percentage of participants in each group;

Included: PANSS total score between 60 and 120, BMI ≥17 kg/m² and <40 kg/m²; schizophrenia DSM‐IV criteria for >1 year.

Excluded: DSM‐IV Axis I diagnoses other than schizophrenia; decrease in at least 25% in PANSS total from screening to baseline; substance dependence within 3 months before screening; history of treatment resistance; significant unstable systemic disease; suicidal or violent behaviour; previously received injections of PP and treatment with any other 'disallowed' medications (including mood stabilisers, lithium and anticonvulsants); exposure to an experimental drug, biologic or medical device within past 6 months pre‐screening; pregnancy/ planning or currently nursing.

Consent: Independent Ethics Committee or Institutional Review Board at each study site approved protocol and amended protocol. Study conducted in accordance with Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent required.

Interventions

1. Risperidone depot: bi‐weekly, oral supplementation (1 mg; mean final dose 3.3 ± 1.59 mg) and placebo injections (matched to PP); 25, 37.5 and 50 mg; mean final dose 31.7 ± 9.28 mg, n = 613.

2. Paliperidone palmitate (PP): initiation regimen*, monthly PP injections, placebo injections (matched to RIS) and placebo oral supplementation; 50, 100 and 150 mg equivalents; mean final dose 104.5 ±3 0.51 mg, n = 607.

Outcomes

Global state: CGI‐ S score change; Shedule for Deficit Syndrome.

Mental state: PANSS total score change; responder rate with more than 30% reduction in PANSS.

Adverse events: treatment‐emergent adverse events; EPS rating scales; Simpson and Angus Rating scale; BARS; AIMS.

General functioning: Personal and Social Performance (PSP).

Notes

*PP deltoid injections day 1, 150 mg eq, day 8, 100 mg eq and subsequent flexible dosing (50, 100 or 150 mg eq) once a month

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised: 1:1, computer‐generated randomisation scheme, stratified by centre, implemented by an interactive voice response system.

Allocation concealment (selection bias)

Low risk

Interactive voice response system used.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Study drug administrator was the only person to contact IVRS to receive medication number and was not allowed to communicate patient‐related information to study site personal or to perform any efficacy and safety assessment. Patient and staff performing study‐related procedures were to be precluded from seeing the contents of syringe or observing the injection.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

N = 927 (76%) completed the study (n = 456 in PP; n = 471 in RIS‐LAI); n = 151 withdrawn from PP group (n = 55 withdrawn consent, n = 40 lack of efficacy, n = 20 adverse events, n = 11 lost to follow‐up, n = 2 death, n = 1 pregnancy, n = 22 'other'); n = 142 withdrawn from RIS‐LAI group (n = 52 withdrawn consent, n = 43 lack of efficacy, n = 10 adverse event, n = 18, lost to follow‐up, n = 19 'other'). 'Safety analysis' conducted (n = 1214), which included all participants that had received at least one dose of the study drug.

Selective reporting (reporting bias)

Unclear risk

Unclear.

Other bias

High risk

Funding: "Johnson & Johnson Pharmaceutical Research and Development, L.L.C. funded this study and was responsible for study design and data collection, analysis and its interpretation..." (p225). Many of the authors are employees of Johnson & Johnson Pharmaceutical Research and Development, L.L.C.

Methods

Allocation: random.

Blinding: open‐label.

Duration: 24 months.

Design: parallel.

Setting: multi‐centre, Canada.

Participants

Diagnosis: schizophrenia, schizophreniform disorder or schizoaffective disorder (DSM‐IV).

N = 85.

Age: risperidone depot mean 22.5 +/‐ 3.12 years of age; oral SGA mean 23.0 +/‐ 2.93 years of age.

Sex: 65 M, 12 F.

History: early onset (within the past 3 years) of psychosis.

Included: no inclusion criteria stated.

Excluded: no exclusion criteria stated.

Consent: no details.

Interventions

1. Risperidone depot: every 2 weeks, median dose at 18 weeks 25 mg; at 9, 12 and final visit 37.5 mg, n = 45.

2. Oral second generation antipsychotics (risperidone, olanzapine or quetiapine) (dosage not specified), n = 40.

Outcomes

Leaving the study early (discontinuation).

Global state (relapse).

Specific adverse events.

Unable to use ‐

Mental state: PANSS; Global state: CGI‐S; Anxiety: Hamilton Anxiety scale; SAFS (unclear as to participant numbers within groups).

Time to stabilisation (no SD).

Notes

Note: extractable data limited due to only available results from this study derived from conference poster.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote, "patients were randomized" ‐ no further details.

Allocation concealment (selection bias)

Unclear risk

Not described.

Blinding (performance bias and detection bias)
All outcomes

High risk

Open‐label described ‐ no further details.

Incomplete outcome data (attrition bias)
All outcomes

High risk

N = 46 (54%) discontinued the study;

Selective reporting (reporting bias)

Unclear risk

Conference poster, therefore results for all outcomes were not provided.

Other bias

High risk

Quinn AM and Mitchell D are both employees of Janssen Inc and Johnson and Johnson Stockholders; Camacho F is consultant to Janssen Inc; Chue P has received research and travel grants from Janssen, Pfizer, Eli Lilly, AstraZeneca, Sunovion, Lundbeck, GlaxoSmithKline, Bristol Mayers Squibb, Mylan, Novartis and Hoffman La Roche, Mella.

Methods

Allocation: random.

Blinding: single (rater).

Duration: 2 years.

Design: parallel.

Setting: multi‐centre, 14 Veteran Affairs (VA) medical centres, inpatient, USA.

Participants

Diagnosis: schizophrenia or schizoaffective disorder (DSM‐IV).

N = 382.

Age: ≥ 18 years of age.

Sex: not stated.

History: 64% participants reported problems with medication adherence in past (43% patient‐reported, and 60% physician‐reported); 37% participants reported active problems with alcohol or drug use (25% patient‐reported, and 36% physician‐reported).

Included: at risk of hospitalisation as evidenced by current hospitalisation; hospitalisation in the previous 2 years, or increased use of services to prevent relapse.

Excluded: detoxification in the previous month; past intolerance to risperidone or IM injections; current treatment with long‐acting injectable antipsychotics; oral clozapine, warfarin or a combination of those agents; serious medical conditions; unstable living arrangements; and a history of assault or suicidal behavior requiring urgent intervention.

Consent: guardian or participant consent permitted; participants' decisional capacity assessed with MacArthur Competence Assessment Tool.

Interventions

1. Risperidone depot: 25 mg to 50 mg every 2 weeks; dosage increments of 12.5 mg permitted every 4 weeks at discretion of treating physician, n = 190.

2. Oral antipsychotics: as prescribed by treating physician, n = 192*.

Outcomes

Service utilisation: hospitalisation; outpatient care.

Global state: use of benzodiazepines or sedative drugs.

Adverse events: death; other specific events.

Not receiving allocation study medication.

Leaving the study early: any reason.

Unable to use ‐

Global state: CGI (follow‐up rates less than 50%).

Metal State: Total PANSS score and Positive, negative and general subscale (follow‐up rates less than 50%).

Quality of life: Heinrichs‐Carpenter Quality of Life Scale, Personal and Social Performance scale (PSP), Quality of well being scale (follow‐up rates less than 50%).

Adverse events: BARS; Abnormal involuntary movements rating scale; Simpson and Angus rating scale for extrapyramidal side effects (follow‐up rates less than 50%).

Notes

*Concomitant psychotropic medication (anti‐anxiety, anti‐depressants, oral antipsychotics and mood stabilisers, as well as anticholinergic medications were permitted.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomly permuted blocks of various size, centrally conducted and stratified according to site.

Allocation concealment (selection bias)

Unclear risk

Not described.

Blinding (performance bias and detection bias)
All outcomes

High risk

Single blind (implied). Blinded video conference assessment for some measures, but others assessed in unblinded meetings.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Of n = 382 randomised, n = 237 completed the study; including n = 75 oral antipsychotic treatment (n = 7 declined participation and did not receive intervention; n = 65 'lost to follow‐up or discontinued'; n = 3 excluded because participant did not have a Social Security number or baseline data), and n = 74 in risperidone depot group (n = 2 declined participation and did not receive intervention; n = 71 'lost to follow‐up or discontinued'; n = 1 excluded because participant did not have a Social Security number or baseline data). ITT analysis used ‐ follow‐up rates in this analysis group included n = 223 (60%) at year 1; n = 170 (46%) at 18 months; n = 107 (29%) at 24 months. Of the deaths, in the risperidone group, n = 1 died in his sleep and n = 1 took his own life; in the oral antipsychotic group, n = 1 died from chronic obstructive pulmonary disease and n = 1 from accidental drowning.

Selective reporting (reporting bias)

Low risk

Supplemental pages cover all outcomes.

Other bias

Unclear risk

Industry funded study but stated that Janssen had no involvement beyond financial and intervention drug provision.