Methods

Randomisation: randomised, no further details.
Allocation: pharmacists held the key.
Blinding: double, identical capsules.
Duration: 42 weeks.
Design: parallel.
Location: single‐centre.
Setting: hospital.

Participants

Diagnosis: schizophrenia (clinical diagnosis), continuously in hospital for at least 6 years (mean 28 years).
N=32.
Gender: 32 men.
Age: mean 58 years.
History: duration stable‐8 weeks, duration ill NI‐ mean duration of hospitalisation 28 years, number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ mean Wing Behaviour Scale Withdrawal Score 2.14, baseline antipsychotic dose‐216mg/day CPZ equivalent

Interventions

1. Drug: Chlorpromazine ‐ mean dose: 216mg/day. N=15.

Allowed dose range: the participants were kept on their initial dose.

2. Placebo: Duration of taper 0 days. N=17.

Rescue medication: benzodiazepines, anticholinergics.

Outcomes

Examined:

Relapse (need of antipsychotic medication).

Leaving the study early.

Unable to use / Not included:

Behaviour: Ward Behaviour Rating Scale of Wing (no SD / no prespecified outcome of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised, no further details.

Allocation concealment (selection bias)

Low risk

Pharmacists held the key.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, identical capsules.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, identical capsules.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants completed the trial.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No obvious other bias.

Methods

Randomisation: random, computer‐generated randomisation code.
Allocation: procedure not described.
Blinding: double.
Duration: 12 months.
Design: parallel.
Location: multi‐centre.
Setting: inpatient.

Participants

Diagnosis: chronic, stable schizophrenia (DSM‐III‐R), less than markedly ill on Clinical Global Impression Scale.

N=278.
Gender: 203 men, 75 women.
Age: mean 49.7 years.
History: duration stable‐ n.i., duration ill‐ mean 21.8 years, number of previous hospitalisations‐ mean 10.1, age at onset‐ mean 27.9 years, severity of illness‐ mean PANSS 85.8, mean CGI severity 4.02, baseline antipsychotic dose n.i..  

Interventions

1. Drug: ziprasidone ‐ Fixed doses of 40, 80 or 160 mg/day.** N=207.

2. Placebo: Duration of taper <3 days. N=71.

Rescue medication: anticholinergics, lorazepam, temazepam, no additional antipsychotic medication.

Outcomes

Examined:

Relapse: (Clinical Global Impressionof much worse or more, PANSS items hostility or uncooperativeness > 6, or in need for additional treatment for exacerbation of symptoms).

Leaving the study early.

Adverse events: binary outcome for generel, specific (movement disorders) ‐ interviews.

Unable to use / Not included:

Mental state: PANSS total score and subscores (no predefined outcome of interest).

Global state: much worse or more ‐ Clinical Global Impression Severity Scale (no prespecified outcome of interest).

Functioning: Global Assessment of Functioning Scale (no prespecified outcome of interest).

Adverse effects: extrapyramidal symptoms (Simpson Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movements Scale ‐ all no SD / continous side‐effect results were not among the prespecified outcomes of interest).

Physiological measures: ECG, vital signs, weight, ophthalmological assessment, lab tests (all no SD, no data / not prespecified outcomes of interest).

Notes

** The results of the three dose groups were pooled. 16 participants from one centre were excluded due to protocol violations. Intention‐to‐treat were only those participants who had received at least one dose. How many did not receive one dose is unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised, computer‐generated randomised code.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, no further details.

Incomplete outcome data (attrition bias)
All outcomes

High risk

64% of the participants left the study early, most due to relapse. The rate was higher in the placebo group (86%) than in the medication group (˜57%). This was probably not a problem for the primary outcome relapse, but for secondary outcomes for which the last‐observation‐carried‐forward method was used. Appropriate survival curve analysis was used for the primary outcome relapse.

Selective reporting (reporting bias)

Low risk

No selective reporting.

Other bias

Low risk

No obvious other bias.

Methods

Randomisation: matched pairs were formed and then randomised, no further details.
Allocation: procedure not described.
Blinding: double, indistinguishable placebo.
Duration: 10 weeks.
Design: parallel.
Location: single‐centre.
Setting: hospital, sponsored.

Participants

Diagnosis: chronic psychotic hospitalised patients mainly with schizophrenic and paranoid behaviour patterns, suspected of relapsing after withdrawal of medication (clinical diagnosis).
N=26.
Gender: 26 men.
Age: n.i.
History: duration stable‐ 8 months pre‐treatment with penfluridol to find optimum dose, duration ill‐ n.i., number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ n.i., but hospitalised, baseline antipsychotic dose‐ 23.4mg/day.

Interventions

1. Drug: penfluridol once weekly ‐ Fixed dose, mean dose: n.i., range 10‐40mg/weekly. N=13.

2. Placebo: Duration of taper: 0 days. N=13.

Rescue medication: sedative neuroleptics allowed for 2 weeks, dexbenzitide.

Outcomes

Examined:

Relapse: need of medication as decided by two psychiatrists.

Unable to use / Not included:

Mental state: Psychiatric Evaluation Scale (no predefined outcome of interest).

Adverse effects: movement disorders (Factor Construct Outcome Scale, no data for randomised phase / continous side‐effect results were not among the prespecified outcomes of interest), neurologic effects (graphometric and tapping test, no data for randomised phase / no prespecified outcomes of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Matched pairs were formed and then randomised, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, indistinguishable placebo.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, indistinguishable placebo.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Apart from those participants who relapsed no participant left the study early and relapse was the only outcome.

Selective reporting (reporting bias)

High risk

Adverse events were not reported for the double‐blind phase.

Other bias

Low risk

No obvious other bias.

Methods

Randomisation: randomised, 2:1 ratio, by an interactive voice response system.
Allocation: interactive voice response system.
Blinding: double, no further details.
Duration: one year, but the study was terminated early. Maximum length was 30 weeks.
Design: parallel.
Location: multi‐centre.
Setting: outpatient.

Participants

Diagnosis: schizophrenia (n=266) or schizoaffective disorder (n=60, DSM‐IV). BPRS total score <36, positive symptoms at most mild, Global Assessment of Functioning at least 40, currently on maintenance antipsychotic medication.

N=326.
Gender: 173 men, 153 women.
Age: mean 35.9 years.
History: duration stable‐ 8 weeks, duration ill‐ mean 11.1 years, number of previous hospitalisations‐ n.i., age at onset‐ mean 24.7 years, severity of illness‐ mean PANSS total score at baseline 43, baseline antipsychotic dose‐ mean 13.4 mg olanzapine/day.

Interventions

Participants were first converted to olanzapine and then stabilized for 8 weeks before randomisation.

1. Drug: olanzapine ‐ Fixed dose of either 10, 15 or 20 mg/day. Mean dose 13.4 mg/day. N=224.

2. Placebo: Duration of taper: 0 days. N=102.

Rescue medication: a one time increase of the same medication (olanzapine or placebo) was allowed. Furthermore, antiparkinson medication and benzodiazepines were allowed.

Outcomes

Examined:

Relapse: any BPRS positive item > 4, absolute increase of a positive item or of the positive subscore, hospitalisation due to positive symptoms, suicide or suicide attempt.

Leaving the study early.

Adverse effects: binary outcomes for general, specific (movement disorders) ‐ open interviews.

Quality of life: Heinrich Carpenter Quality of Life Scale.

Unable to use / Not included:

Mental state: PANSS (no prespecified outcome of interest).

Adverse effects: adverse effects with an incidence < 10% (no data), laboratory, EPS‐scales (in part no data / no prespecified outcome of interest), EPS‐scales (no SD / continous side‐effect results were not among the prespecified outcomes).

Physiological measures: vital signs (no prespecified outcome of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised, 2:1 ratio, by an interactive voice response system.

Allocation concealment (selection bias)

Low risk

Interactive voice response system.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, no further details.

Incomplete outcome data (attrition bias)
All outcomes

High risk

The overall attrition of 26% was acceptable, but many more participants in the placebo group than in the olanzapine group left the study early. Kaplan‐Meier survival analysis was used for the analysis of relapse, ANOVA based on last‐observation‐carried‐forward was used for continuous outcomes.

Selective reporting (reporting bias)

High risk

Only those adverse events with a frequency of at least 10% were reported. Use of antiparkinson medication has not been reported.

Other bias

High risk

The study was terminated early when there was a sufficient difference, but this was preplanned.

Methods

Randomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, thiamine chloride used as placebo, participants and nurses were told that a new medication was given, but nurses soon new that this was a placebo.
Duration: 16 weeks.
Design: parallel.
Location: single‐centre.
Setting: in hospital.

Participants

Diagnosis: schizophrenia (clinical diagnosis).

N=45.
Gender: 45 men.
Age: 20‐40 years.
History: duration stable‐ n.i., but clinically tranquilised and making a satisfactory adjustment on phenothiazine medication, duration ill‐ n.i., but mean length of current hospitalisation 45 months (range 3‐129), number of previous hospitalisations‐ all more than one, age at onset‐ n.i., severity of illness‐ n.i., but all in open hospital ward, baseline antipsychotic dose‐ prochlorpromazine 15‐150mg/day, perphenazine 12‐24mg/day, chlorpromazine 50‐800mg/day, promazine 200‐400mg/day, trifluoperazine 6mg/day.

Interventions

1. Drug: prochlorpromazine, perphenazine, chlorpromazine, promazine or trifluoperazine. Fixed doses continued with the same drug and dose taken before the study. Mean dose: n.i. N=30.

2. Placebo: Duration of taper: 0 days. N=15*.

Rescue medication: not allowed.

Outcomes

Examined:

Relapse (need of medication or deterioriation of state or transfer to closed ward)

Unable to use / Not included:

Behaviour: Patient Adjustment Report (no prespecified outcome of interest).

Mental state: Taylor Manifest Anxiety Scale (no prespecified outcome of interest).

Notes

* Another 15 participants were treated only for 8 weeks with placebo and then switched back to their initial antipsychotic drug.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

High risk

Double, thiamine chloride used as placebo, participants and nurses were told that a new medication was given, but nurses soon new that this was a placebo.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, thiamine chloride used as placebo, participants and nurses were told that a new medication was given, but nurses soon new that this was a placebo.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only completers were included in the statistical analysis, but because the drop‐out rate was only 13% we did not consider this a source of bias.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No clear other risk of bias.

Methods

Randomisation: An independent rater created randomisation lists stratified for gender with randomly permuted blocks of 4 allocation groups.

Allocation: procedure not described.
Blinding: open.
Duration: 24 months.
Design: parallel.
Location: multi‐center.
Setting: outpatient.

Participants

Diagnosis: first episode schizophrenia (DSM‐IV).

N=20.
Gender: 17 men, 3 women.
Age: mean 29.8 years.
History: duration stable‐ 1 year, duration ill‐ 2.6 years, number of previous hospitalisations‐ 0, age at onset‐ 27.3 years, severity of illness‐ PANSS total score 49, baseline antipsychotic dose‐ 3mg/day haloperidol equivalents (olanzapine, risperidone, quetiapine, zuclopenthixol).

Interventions

1. Drug: olanzapine, risperidone, quetiapine, zuclopenthixol. Flexible doses. Mean dose: n.i. N=9.

2. No treatment: Duration of taper: 6‐12 weeks. N=11.

Rescue medication: not indicated.

Outcomes

Examined:

Relapse: clinicial judgement.

Leaving the study early.

Rehospitalisation.

Notes

Sponsor: The Netherlands Organisation for Health Research and Development and EliLilly.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

An independent rater created randomisation lists stratified for gender with randomly permuted blocks of 4 allocation groups.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

High risk

Open study.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Open study.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

5 out of 20 participants left the study early (25%). Probably an acceptable rate, there was no big difference between drug and placebo group. Kaplan‐Meier survival curves were used for the primary outcome relapse.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

High risk

Premature termination after interim analysis.

Methods

Randomisation: randomised, no further details.
Allocation: procedure not described.
Blinding: double, identical tablets. However, placebo dose reduction group received medication only every other day. Therefore, blinding was not fully maintained.
Duration: 16 weeks.
Design: parallel.
Location: multi‐centre.
Setting: in hospital.

Participants

Diagnosis: schizophrenia (clinical diagnosis), one third paranoid subtype, without central nervous system disease, without lobotomy.

N=259.
Gender: all men.
Age: mean 40 years.
History: duration stable‐ stable doses for at least 3 months before the study, duration ill‐ n.i., but currently hospitalized for a mean of 10 years, number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ chlorpromazine mean 400mg/day, thioridazine mean 350mg/day.

Interventions

1. Drug: chlorpromazine or thioridazine.* Fixed dose, continuation of the dose given in the stabilization phase. Mean dose: chlorpromazine mean 400mg/day, thioridazine mean 350mg/day. N=88.

2. Placebo: Duration of taper: 1 ‐ 8 days. N=171.

Rescue medication: not indicated.

Outcomes

Examined:

Relapse: definitive worsening of the condition and medication again necessary, usually joint decision of treatment team.

Unable to use / Not included:

Mental state: Inpatient Multidimensional Psychiatric Scale (no prespecified outcome of interest).

Behaviour: Psychotic Reaction Profile Scale (no prespecified outcome of interest).

Notes

* There was another group which received half the original dose. It was not considered in this review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

High risk

Double, identical tablets. However, placebo dose reduction group received medication only every other day. Therefore, blinding was not fully maintained.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, identical tablets. However, placebo dose reduction group received medication only every other day. Therefore, blinding was not fully maintained.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

It is unclear whether there were dropouts or whether the authors analysed only study completers.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Unclear risk

22 participants who had relapsed in the first 8 weeks were entered in the study again. As the number is small, it is unclear whether they affected the results.

Methods

Randomisation: n.i., but double‐blind study.
Allocation: procedure not described.
Blinding: double, identical capsules.
Duration: 12 weeks.
Design: parallel.
Location: single‐centre.
Setting: unclear.

Participants

Diagnosis: chronic schizophrenia (DSM‐III), all on maintenance medication for control of continuous symptoms, all stable for at least 6 months.

N=30.
Gender: 16 men, 12 women.
Age: mean 36.0 years.
History: duration stable‐ at least 6 months, duration ill‐ mean 11.1 years, number of previous hospitalisations‐ n.i., age at onset‐ 24.9 years, severity of illness‐ n.i., baseline antipsychotic dose‐ mean 297.5 mg/day chlorpromazine equivalent.

Interventions

1. Drug: penfluridol. Fixed dose of 55mg/week. N=15.

2. Placebo: Duration of taper: 0 days. N=15.

Rescue medication: antiparkinson medication and haloperidol, but this was considered to be a relapse.

Outcomes

Examined:

Relapse (need of additional haloperidol medication).

Unable to use / Not included:

Mental state (Scale for the Assessment of Positive Symptoms and Negative Symptoms ‐ no data /no predefined outcome of interest).

Adverse effects: extrapyramidal side‐effects (Simpson Angus Scale ‐ no data / continuous side‐effect results were not among the prespecified outcomes).

Physiological measures: mean body weight, pulse rate, blood pressure, laboratory (all no data / no prespecified outcomes of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

N.i., but double‐blind study.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, identical capsules.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, identical capsules.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only study completers were used in the final analysis, but as there were only two dropouts (one in each group) this was not necessarily a problem.

Selective reporting (reporting bias)

Low risk

Rating scale results were not reported, but these were not of interest for the review.

Other bias

Low risk

No clear evidence for other bias.

Methods

Randomisation: sequence by computer, fixed block size of four without stratification.
Allocation: AstraZeneca prepared individually numbered sets of study drugs, packed them according to the randomisation sequence and then shipped them to the study team in numbered but apparently identical sets.
Blinding: identical capsules, "investigators, patients and all research staff were blind to the study drugs and the block size".
Duration: 1 year.
Design: parallel.
Location: single‐center (all in Early Assessment Service for Young People with Psychosis (EASY) in Hong Kong).
Setting: outpatient.

Participants

Diagnosis: schizophrenia and related  psychoses (DSM‐IV), all first episode, all well remitted, all had remained well on maintenance medication for 1 year.

N=178.
Gender: 24.2
Age: 80 men, 98 women.
History: duration stable‐ 1 year, duration ill‐ 2.3 years, number of previous hospitalisations‐ 0 (first episode), age at onset‐ 21.9 years, severity of illness‐ mean PANSS 36, baseline antipsychotic dose‐ 153mg/day chlorpromazine equivalents.

Interventions

1. Drug: quetiapine. Fixed dose of 400mg/day. N=89.

2. Placebo: Duration of taper (days): 35. N=89.

Rescue medication: antipsychotics not allowed.

Outcomes

Examined:

Relapse: (i)  an increase in at least one of the following Positive and Negative Syndrome Scale psychotic symptom items to a threshold  score (delusion, hallucinatory behaviour, conceptual disorganisation, unusual thought content, suspiciousness; (ii) Clinical Global  Impression Severity of Illness 3 or above and (iii) CGI  change 5 or above).

Leaving the study early.

Rehospitalisation.

Suicide attempts.

Adverse effects: akathisia, tardive dyskinesia, tremor, sedation, weight gain.

Open employment status.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sequence by computer, fixed block size of four without stratification.

Allocation concealment (selection bias)

Low risk

AstraZeneca prepared individually numbered sets of study drugs, packed them according to the randomisation sequence and then shipped them to the study team in numbered but apparently identical capsules.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Identical capsules, "investigators, patients and all research staff were blind to the study drugs and the block size".

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Identical capsules, "investigators, patients and all research staff were blind to the study drugs and the block size".

Incomplete outcome data (attrition bias)
All outcomes

High risk

72% of the participants left the study early. As most participants dropped out after relapse this outcome was not affected, but it is a source of bias for other outcomes. Survival analysis for the primary outcome relapse.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No clear other bias.

Methods

Randomisation: randomly in group of 15 each, no further details.
Allocation: procedure not indicated.
Blinding: double, no further details.
Duration: 18 months.
Design: parallel.
Location: single‐centre.
Setting: outpatient.

Participants

Diagnosis: schizophrenia (mainly Schneiderian first‐rank symptoms), last relapse 30‐60 months ago, fully remitted since and maintained on antipsychotic drugs.

N=30.
Gender: 12 men, 18 women.
Age: 39.9 years.
History: duration stable‐ mean 44 months, duration ill‐ mean 10.2 years, number of previous hospitalisations‐ mean 1.6, age at onset‐ mean 29.7 years, severity of illness‐ n.i., baseline antipsychotic dose‐ 151 mg/day chlorpromazine equivalents.

Interventions

1. Drug: switched to various antipsychotic drugs with similar profile as the previous one. Fixed/flexible dose: probably flexible. Allowed dose range: n.i.. Mean dose: n.i.. N=15.

2. Placebo: benzodiazepine (‘active placebo’). Duration of taper 0 days. N=15.

Rescue medication: n.i..

Outcomes

Examined:

Relapse: recurrence of symptoms definitely of schizophrenic type, or symptoms not diagnostic of schizophrenia (e.g. sleep problems) which could not be controlled with other measures than antipsychotic drugs or ECT.

Leaving the study early.

Quality of life: subjective distress (Symptom Questionnaire of Kellner and Sheffield).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomly in group of 15 each, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, no further details.

Incomplete outcome data (attrition bias)
All outcomes

High risk

12 participants left the study early (40%), among those 10 from the placebo group and 8 for relapse. Outcomes other than relapse and leaving early are clearly prone to bias due to this difference in leaving the study early.

Selective reporting (reporting bias)

Low risk

Use of benzodiazepines was not indicated, but this was not an outcome of interest in our review.

Other bias

Low risk

No evidence for other bias.

Methods

Randomisation: random, in blocks of eight, stratified for age, duration ill and time since last admission.
Allocation: procedure not described.
Blinding: double, identical capsules, each participant had an individual stock bottle.
Duration: 24 weeks.
Design: parallel.
Location: single‐centre.
Setting: outpatient.

Participants

Diagnosis: chronic schizophrenia (clinical diagnosis), 22 undifferentiated, 7 paranoid, 1 schizoaffective, no severe other psychiatric or somatic illnesses, no severely ill participants.

N=40.
Gender: 40 women.
Age: mean 42.8 years (range 24‐60).
History: duration stable‐ maintained on medication in an outpatient status for at least 3 months, "relatively stable state of health”, duration ill‐ mean 11.6 years, number of previous hospitalisations‐ mean 6.1, age at onset ‐ NI , severity of illness‐ mean CGI severity score 2.94, baseline antipsychotic dose‐ n.i..

Interventions

1. Drug: pimozide.* Flexible dose. Allowed dose range: 2‐20mg/day. Mean dose: 5.3 mg/day. N=15.

2. Drug: thioridazine.* Flexible dose. Allowed dose range: 75‐750mg/day. Mean dose: 189mg/day. N=15.

3. Placebo: Duration of taper: 0 days. N=10.

Rescue medication: antiparkinson medication, bedside sedation.

Outcomes

Examined:

Relapse (worsening of global state).

Leaving early.

Global state: number of participants improved according to Clinical Global Impressions Scale.

Adverse effects: binary outcomes ‐ open interview.

Unable to use / Not included:

Mental state: BPRS (no SD / no prespecified outcome of interest).

Functioning: Katz Lyerly Scale of Social Adjustment, Patient Rating Form, Family Rating Form (all no SD / no prespecified outcomes of interest).

Physiological measures: biological parameters (temperature, mean weight, pulse, blood pressure, all no data / all no prespecified outcomes of interest), laboratory (blood count, urine analysis, liver enzymes, blood sugar, protein bound iodine, all no prespecified outcomes of interest).

Notes

* The results of pimozide and thioridazine were combined in the analysis.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random, in blocks of eight, stratified for age, duration ill and time since last admission.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, identical capsules, each participant had an individual stock bottle.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, identical capsules, each participant had an individual stock bottle.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Overall 36% left the study early. The specific reasons why the participants dropped out were not indicated by group.

Selective reporting (reporting bias)

Low risk

No clear source for selective reporting.

Other bias

Low risk

No clear other sources of bias.

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 300mg/day which could be reduced once to 150mg/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).

Global state: number of participants improved according to CGI.

Adverse effects: binary outcomes ‐ open interview.

Unable to use / Not included:

Mental state: BPRS, SANS (no prespecified outcomes of interest).

Adverse effects: extrapyramidal side‐effects (SAS, AIMS, no SD / continous 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 (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.

Methods

Randomisation: random, no further details.
Allocation: allocation lists prepared by pharmacy for five antipsychotic drugs mentioned below, concealment is unclear.
Blinding: double, no further details.
Duration: 104 weeks.
Design: parallel.
Location: multi‐centre.
Setting: outpatient.

Participants

Diagnosis: first episode of schizophrenia (Present State Examination).

N=120.
Gender: 74 men, 46 women.
Age: mean 26.3 years (range 16‐59 years).
History: duration stable‐ 30 days after discharge all on active medication, duration ill‐ 2.8 months (between illness onset and admission to hospital), number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ most participants were ‘well’ at the beginning of the study (91 well, 13 psychotic features, 10 defect state, 6 unspecific symptoms), baseline antipsychotic dose‐ n.i..

Interventions

1. Drug: flupenthixol i.m., chlorpromazine, haloperidol, pimozide, trifluoperazine Flexible dose. Allowed dose range: no upper limit, but lower limit was flupenthixol i.m. 40mg/month, chlorpromazine 200mg/day, haloperidol 3mg/day, pimozide 4mg/day, trifluoperazine 5mg/day. Mean dose: flupenthixol 84mg/month (n=31), chlorpromazine 366mg/day (n=3), haloperidol 11.8mg/day (n=3), pimozide 7.8mg/day (n=5), trifluoperazine 11.5mg/day (n=12). N=54.

2. Placebo: Duration of taper (days): 30 days on drug, then received half dose for 30 days before they were put on placebo. N=66.

Rescue medication: antiparkinson medication, antidepressants, anxiolyties.

Outcomes

Examined:

Relapse: rehospitalisation or rehospitalisation thought necessary although not possible or need of medication.

Unable to use / Not included:

Hallucinations, delusions (no data / no predefined outcomes of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random, no further details.

Allocation concealment (selection bias)

Unclear risk

Allocation lists prepared by pharmacy for five antipsychotic drugs mentioned below, concealment is unclear.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, no further details.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No clear bias. overall rate of leaving early of 11% is acceptable. Survival curve analysis was used for the primary outcome relapse.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

High risk

Blind was broken when a participant relapsed.

Methods

Randomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, identical capsules.
Duration: 26 weeks.
Design: parallel.
Location: single‐centre.
Setting: in hospital.

Participants

Diagnosis: residual schizophrenia (DSM‐II), chronic, currently treated with antipsychotic drugs.

N=40.
Gender: 40 women.
Age: mean 58.5 years.
History: duration stable‐ all participants were switched to two months treatment with pimozide and only those who were treated effectively (=markedly improved) were randomised, duration ill‐ mean 30.5 years, duration of current hospitalisation mean 24.5 years (range 1‐43), number of previous hospitalisations‐ n.i., age at onset‐ mean 28 years, severity of illness‐ n.i., baseline antipsychotic dose‐ pimozide mean 7.72mg/day.

Interventions

1. Drug: pimozide. Flexible dose. Allowed dose range: n.i.. Mean dose: n.i.. N=20.

2. Placebo: Duration of taper: 0 days. N=20.

Rescue medication: not allowed, only dose increase of pimozide or placebo‐pimozide was possible. Additional use of haloperidol meant relapse.

Outcomes

Examined:

Relapse: need of additional haloperido)

Adverse effects: number of participants with at least one movement disorder, rigor and tremor.

Unable to use / Not included:

Mental state: Overall Factor Construct Scale (no mean, no SD / no prespecified outcome of interest)

Behaviour: ‘Psychiatric Evaluation Scale’ (no mean, no SD / no prespecified outcome of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, identical capsules.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, identical capsules.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

2 (5%) of the participants left the study early which is an acceptable rate. Both participants were included in the endpoint analysis.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No clear evidence for other bias.

Methods

Randomisation: no details (just reported as a "randomised study”).
Allocation: procedure not described.
Blinding: "double‐blind” ("patients and authors were not aware of the allocated treatment”).
Duration: 9 months.
Design: randomised, parallel (enriched design: patients, who responded to fluphenazine long‐acting treatment (25 or 50 mg/month) for at least six to 12 months before study entry, were randomised to continue that treatment or to placebo). Ten out of 20 patients had been previously recruited in a study comparing fluphenazine with trifluorazine.
Location: no clear details.
Setting: outpatients.

Participants

Diagnosis: chronic schizophrenia with an acute episode within 6 to 12 months before study entry (no details about diagnostic criteria).

N=20.
Gender: all men.
Age: 19 to 32 years.
History: duration stable at least six months, duration ill‐ some were first episode patients, some were patients with recurrence, number of previous hospitalisations‐ no data, age at onset‐ no data, severity of illness‐ fluphenazine group had a mean BPRS baseline score of 24.56 (SD 3.56); placebo group had a mean BPRS baseline score of 21.71, baseline antipsychotic dose (25 or 50 mg/month).

Interventions

1. Drug: fluphenazine depot. Fixed dose: 25 or 50 mg/month (long‐acting formulation). Mean dose: n.i.. N=10 randomised (but data available only for 9 patients who completed the study).

2. Placebo: Duration of taper (days): n.i.. N=10 randomised (but data available only for 7 patients who completed the study).

Rescue medication: antiparkinson medication at study entry (and then progressively tapered off, without a prespecified schedule).

Outcomes

Examined:

Relapse: defined as worsening of clinical status needing an adjunctive new antipsychotic treatment.

Unable to use / Not included:

Mental state: BPRS (no prespecified outcome of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details (just reported as a "randomised study”).

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double‐blind ("patients and authors were not aware of the allocated treatment”).

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double‐blind ("patients and authors were not aware of the allocated treatment”).

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

25% of the participants dropped out, all due to relapse. This may still be acceptable.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No clear other bias.

Methods

Randomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, placebo injections, no further details.
Duration: 48 weeks.
Design: parallel.
Location: single‐centre.
Setting: in‐ and outpatients.

Participants

Diagnosis: schizophrenia (Research Diagnostic Criteria), requiring neuroleptic maintenance treatment to prevent relapse.

N=43.
Gender: n.i..
Age: mean 51.7 (range 25‐65) years.
History: duration stable‐ remained in the study after 15 weeks of haloperidol decanoate, duration ill‐ n.i., number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ 60mg haloperidol decanoate per month (˜3.5mg/day haloperidol).

Interventions

1. Drug: haloperidol decanoate 60mg/4 weeks. Fixed dose. N=20.

2. Placebo: Duration of taper: 0 days, but all on depot medication before study. N=23.

Rescue medication: anticholinergics and sedation.

Outcomes

Examined:

Relapse: clinical judgement.

Leaving the study early.

Unable to use / Not included:

Mental state: Comprehensive Psychopathological Rating Scale (no mean, no SD / no prespecified outcome of interest).

Adverse effects: extrapyramidal side‐effects, tardive dyskinesia (no mean, no SD / continuous side‐effect results were not among the prespecified outcomes).

Physiological measures: laboratory (prolactin and haloperidol levels, no mean/SD / no prespecified outcomes of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, placebo injections, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, placebo injections, no further details.

Incomplete outcome data (attrition bias)
All outcomes

High risk

A considerable number of participants (42%) left the study early. The number was clearly higher in the placebo group and the reasons differed. Data were analysed on an intent‐to‐treat basis.

Selective reporting (reporting bias)

Low risk

No selective reporting.

Other bias

Low risk

No clear other bias.

Methods

Randomisation: random number table.
Allocation: all personnel except for the treating psychiatrist remained unaware of the code until the end of the study.
Blinding: double (patients, scientists, nurses, only the treating psychiatrist knew the treatment).
Duration: 12 days.
Design: parallel.
Location: single‐centre.
Setting: inpatient.

Participants

Diagnosis: chronic schizophrenia (clinical diagnosis).

N=14.
Gender: 14 women.
Age: n.i..
History: duration stable‐ n.i., duration ill‐ n.i., number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ n.i..

Interventions

1. Drug: chlorpromazine ‐ Fixed dose. Allowed dose range n.i.. Mean dose n.i.. N=7.

2. Placebo: Duration of taper: 0 days. N=7.

Rescue medication: benztropine.

Outcomes

Examined:

Relapse: worsening of psychotic symptoms.

Leaving the study early.

Unable to use / Not included:

Behaviour: NOSIE (no data / no prespecified outcome of interest).

Neurophysiological tests (no SDs / no prespecified outcome of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number table.

Allocation concealment (selection bias)

Low risk

All personnel except for the treating psychiatrist remained unaware of the code until the end of the study.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double (patients, scientists, nurses, only the treating psychiatrist knew the treatment).

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double (patients, scientists, nurses, only the treating psychiatrist knew the treatment).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

One participant in the placebo group left the study prematurely which is an acceptable rate.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No clear other bias.

Methods

Randomisation: participants were ranked for morbidity, then matched, then randomised.
Allocation: procedure not described.
Blinding: double, identical capsules, each participant was provided medication in individual container. Staff guessed on which medication the participants were but could not guess adequately.
Duration: 26 weeks.
Design: parallel.
Location: single‐centre.
Setting: in hospital.

Participants

Diagnosis: chronic, long term hospitalised male psychotics (clinical diagnosis), 86 schizophrenia, 6 chronic brain syndrome, 2 personality disorders, 2 n.i..

N=96.
Gender: 96 men.
Age: 43.6 years.
History: duration stable‐ treated with chlorpromazine for at least 2 months, not ready for discharge, not assaultive, duration ill‐ n.i. but duration of current hospitalisation 12.3 years, number of previous hospitalisations NI‐ , age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ 224 mg chlorpromazine per day.

Interventions

1. Drug: chlorpromazine ‐ Flexible dose. Allowed dose range: n.i.. Mean dose: n.i.. N=48.

2. Placebo: Duration of taper: 0 days. N=48.

Rescue medication: occasional use of sedatives, antipsychotics were not allowed.

Outcomes

Examined:

Relapse: condition worsened to such a point that ordinarily a complete change in treatment would be considered.

Leaving early due to inefficacy.

Unable to use / Not included:

Behaviour: Lyon’s Behaviour Scale (no SD / no prespecified outcome of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were ranked for morbidity, then matched, then randomised.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Low risk

Double, identical capsules, each participant was provided medication in individual container. Staff guessed on which medication the participants were but could not guess adequately.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, identical capsules, each participant was provided medication in individual container. Staff guessed on which medication the participants were but could not guess adequately.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

It can be that there were participants leaving the study early but this was not clearly reported.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

High risk

Blind was broken once a participant relapsed.

Methods

Randomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, no further details.
Duration: 12 weeks.
Design: parallel.
Location: single‐centre.
Setting: inpatient.

Participants

Diagnosis: severely ill, chronically hospitalized people with schizophrenia (clinical diagnosis).

N=50.
Gender: 25 men, 25 women.
Age: medium 41.5 years.
History: duration stable‐ 12 weeks stabilisation phase., but how long the participants were stable is unclear, duration ill‐ n.i., number of previous hospitalisations‐ n.i., but median duration of current hospitalisation 15.5 years, age at onset‐ n.i., severity of illness‐ all severely ill (Clinical Global Impression Score=6), baseline antipsychotic dose‐ 100‐160 mg/week penfluridol.

Interventions

1. Drug: penfluridol once weekly. Fixed dose. Allowed dose range: 40‐160 mg/week. Mean dose: n.i.. N=25.

2. Placebo: Duration of taper: 0 days. N=25.

Rescue medication:  antiparkinson medication.

Outcomes

Examined:

Relapse: worsening of global state.

Leaving the study early.

Global state: number of participants according to the Clinical Global Impression Scale.

Adverse effects: extrapyramidal side‐effects.

Unable to use / Not included:

Mental state: Brief Psychiatric Rating Scale (no mean, no SD / no prespecified outcome of interest).

Behaviour: Nurses´ Observation Scale for Inpatient Evaluation (no mean, no SD / no prespecified outcome of interest).

Physiological measures: laboratory, ECG, photosensitivity tests, ophthalmologic examinations, vital signs (no clear data / no prespecified outcomes of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, no further details.

Incomplete outcome data (attrition bias)
All outcomes

High risk

It is not entirely clear, whether there were dropouts in addition to 18 participants (7 drug, 11 placebo, 36%) who left the study early due to relapse. However, the 36% drop out rate can be a problem for other outcomes.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No evidence for other bias.

Methods

Randomisation: randomised, 3:1 ratio.
Allocation: procedure not described.
Blinding: double, ‘matching placebos’ and sesame oil for fluphenazine decanoate treated participants.
Duration: 10 weeks.
Design: parallel.
Location: two centres.
Setting: outpatient.

Participants

Diagnosis: chronic psychotic outpatients (DSM‐III), schizophrenia (n=26), mental retardation with psychosis (n=9), organic brain syndrome (n=1).

N=36.
Gender: 17 men, 19 women.
Age: mean 45.8 years.
History: duration stable‐ n.i., but all receiving maintenance neuroleptic therapy, all for at least 5 years, duration ill‐ n.i., but mean duration of neuroleptic treatment 13.4 years, number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ mean 365 mg/day chlorpromazine equivalents.

Interventions

1. Drug: various antipsychotic drugs. Fixed dose: keeping the dose of the antipsychotic the participant was on at the beginning of the study. Mean dose: 365mg/day chlorpromazine equivalents. N=9.

2. Placebo: Duration of taper: 28 days. N=27.

Rescue medication: n.i..

Outcomes

Examined:

Relapse: major clinical deterioration.

Leaving the study early.

Unable to use / Not included:

Global state: Clinical Global Impression (no data for each group separately/no prespecified outcome of interest).

Mental state: Brief Psychiatric Rating Scale, Profile of Mood Symptoms (no data for each group separately/no prespecified outcome of interest).

Adverse effects: extrapyramidal side‐effects (Abnormal Involuntary Movement Scale, Dyskinesia Rating Scale, no data for each group separately / continuous side‐effect results were not among the prespecified outcomes), other adverse effects (Treatment Emergent Symptoms Scale, no data for each group separately / continuous side‐effect results were not among the prespecified outcomes).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised, 3:1 ratio (information obtained from author).

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, ‘matching placebos’ and sesame oil for fluphenazine decanoate treated participants.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, ‘matching placebos’ and sesame oil for fluphenazine decanoate treated participants.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

The differential dropout rate (placebo group 8/27, 0/9 maintenance group, all due to relapse) can have biased other outcomes than relapse and leaving the study early. But data on such other outcomes were not available anyways.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No evidence for other bias.

Methods

Randomisation: matched in three groups according to age and hospitalisation, then randomised using a table of random numbers.
Allocation: procedure not described.
Blinding: double, no further details.
Duration: 22 weeks (experimental phase).
Design: parallel.
Location: single‐centre.
Setting: inpatient.

Participants

Diagnosis: schizophrenia (clinical diagnosis), undifferentiated type (n=10), hebephrenic (n=6), catatonic (5), paranoid (5), acute undifferentiated (n=1).

N=27.
Gender: 27 women.
Age: mean 42.4 years.
History: duration stable‐ on continuous phenothiazine medication at sufficient dose for at least 6 months, then stabilised another 2 months on the ward, total 8 months, duration ill NI‐ duration of current hospitalisation mean 11.42 years, number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ chlorpromazine mean 610mg/day (n=17), thioridazine mean 480mg/day (n=5), trifluoperazine mean 25mg/day (n=3), perphenazine 24mg/day (n=1), prochlorperazine 60mg/day (n=1).

Interventions

1. Drug: remained on previous antipsychotic medication (chlorpromazine, thioridazine, trifluoperazine, perphenazine, prochlorperazine). Fixed/flexible dose: not clear, but probably fixed. Allowed dose range: n.i.. Mean dose: n.i., because it is unclear which patients were allocated to which group. N=9.

2. Placebo: Duration of taper: 7 days. N=9**.

Rescue medication: tranquilizer (=benzodiazepine).

Outcomes

Examined:

Relapse: worsening by three points on the factor scores of the IMPS or withdrawn due to being worse.

Leaving the study early.

Global state: improvement by three points on the factor scores of the IMPS or withdrawn due to being ready for discharge.

Unable to use / Not included:

Mental state: Inpatient Multidimensional Psychiatric Scale (no data / no prespecified outcome of interest).

Behaviour: Psychotic Reaction Profile (no data / no prespecified outcome of interest).

Notes

** a second placebo group that was referred to a specialised ward was not used in our calculations (n=9).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Matched in three groups according to age and hospitalisation, then randomised using a table of random numbers.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, no further details.

Incomplete outcome data (attrition bias)
All outcomes

High risk

There was a considerable number of participants leaving the study early (28%). The approach how missing data were handled is not specified.

Selective reporting (reporting bias)

Low risk

Only two factors of the IMPS were presented, but this was no outcome of interest.

Other bias

Low risk

No clear other bias.

Methods

Randomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, no further details.
Duration: 24 weeks (but we used only the first 12 weeks of this cross‐over study).
Design: cross‐over.
Location: single‐centre.
Setting: inpatient.

Participants

Diagnosis: schizophrenia (n=10), schizoaffective disorder (n=2) according to Research Diagnostic Criteria, first episode no more than 2 years ago.

N=12.
Gender: 8 men, 4 women.
Age: mean 25 years.
History: duration stable‐ all stabilised on 12.5mg/two weeks fluphenazine depot for one year, duration ill‐ < 3years, number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ n.i.,  baseline antipsychotic dose‐ 12.5 mg/two weeks fluphenazine i.m..

Interventions

1. Drug: fluphenazine i.m. Fixed dose 12.5mg/two weeks fluphenazine i.m.. Mean dose: 12.5mg/two weeks fluphenazine i.m.. N=n.i..

2. Placebo: Duration of taper 0 days, but depot study. N=n.i..

Rescue medication: n.i..

Outcomes

Unable to use / Not included:

Relapse: no data for first cross‐over phase.

Prolactin levels (no data for first cross‐over phase / no prespecified outcome of interest).

Notes

Depot study, at six weeks the full plasma level could still be measured, even at the end of 12 weeks 33% still had substantial fluphenazine plasma levels. 

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, no further details.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Unclear, because not indicated.

Selective reporting (reporting bias)

High risk

Data not presented for both groups separately.

Other bias

Unclear risk

Unclear ‐ baseline imbalance can not be addressed.

Methods

Randomisation: randomly assigned.
Allocation: procedure not described.
Blinding: double, placebo injection.
Duration: 6 weeks.
Design: parallel.
Location:  single‐center.
Setting: outpatient.

Participants

Diagnosis: chronic schizophrenic outpatients (DSM‐III).

N=31.
Gender: n.i..
Age: 37 years.
History: duration stable‐ 2 years on fluphenazine decanoate 3 weekly, duration ill‐ n.i., number of previous hospitalisations‐ n.i., age at onset‐ 24 years, severity of illness‐ mean GAS (Global Assessment Scale Endicott 1976by Spitzer & Endicott 1976), baseline antipsychotic dose‐ 39.3mg/ 3 weekly fluphenazine decanoate.

Interventions

1. Drug: fluphenazine decanoate‐ Fixed doses. Allowed dose range: n.i. ‐ same dose as before. Mean dose: n.i.. N=14.
2. Placebo: Duration of taper: 0 days, but all on depot. N=17.
Rescue medication: n.i..

Outcomes

Examined:

Relapse: clinical judgement.

Leaving the study early.

Adverse effects: tardive dyskinesia (AIMS).

Unable to use / Not included:

Social Adjustment Scale.

Depression: SADS (no mean, no SD / no prespecified outcome of interest).

Functioning: GAS (no mean, no SD / no prespecified outcome of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random, no further deatils.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, placebo injection.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, placebo injection.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3 out of 30 participants (10%) left the study early which is an acceptable rate, irrespective of the statistical analysis (completer analysis).

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No evidence for other bias.

Methods

Randomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, unidentifiable capsules.
Duration: 6 months.
Design: parallel.
Location: single‐centre.
Setting: outpatient.

Participants

Diagnosis: chronic psychotic patients (mainly schizophrenia, clinical diagnosis).

N=144.
Gender: n.i..
Age: n.i..
History: duration stable‐ "observed on the same drugs for 4.5 months”, duration ill‐ n.i., number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ n.i..

Interventions

1. Drug: continuation of antipsychotic taken before the study ‐ Fixed/flexible dose: unclear. Allowed dose range: unclear. Mean dose: n.i.. N=46.

2. Placebo: Duration of taper: "4 weeks to five months, usually 2 months”. N=98.

Rescue medication: n.i..

Outcomes

Examined:

Relapse: clinical diagnosis.

Unable to use / Not included:

Social adjustment: (not reported for the randomised participants / no predefined outcome of interest).

Rehospitalisation (unclear numbers).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, unidentifiable capsules.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, unidentifiable capsules.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Whether participants left the study early is unclear.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

High risk

In case of relapse the blind was broken.

Methods

Randomisation: randomised, no further details.
Allocation: procedure not described.
Blinding: double, identical capsules.
Duration: 16 weeks.
Design: parallel.
Location: single‐centre.
Setting: inpatient.

Participants

Diagnosis: chronic schizophrenia (clinical diagnosis) with positive or negative symptoms, responsive to treatment with antipsychotic drugs, all so ill that they required continuous treatment with antipsychotic medication for at least 3 months.

N=61.
Gender: 37 men, 24 women.
Age: mean 45.7 years.
History: duration stable‐ all participants had received a neuroleptic for at least 4 weeks, then stabilized on a fixed dose for 2 weeks, the last 2 weeks of which they were stabilized on a fixed dose, duration ill‐ at least 2 years, number of previous hospitalisations‐ n.i., age at onset‐ n.i. , severity of illness‐ n.i., baseline antipsychotic dose‐ chlorpromazine maximum dose 500mg/day, thioridazine 500mg/day, fluphenazine 30mg/day, trifluoperazine 30mg/day, other equipotent antipsychotics or combinations not exceeding the maximum doses.

Interventions

1. Drug: pimozide ‐ Flexible dose. Allowed dose range: 2‐12 mg/day. Mean dose: 6.3 mg/day. N=21.

2. Drug: trifluoperazine. Flexible dose. Allowed dose range: 5‐30 mg/day. Mean dose: 17.5 mg/day. N=20.

3. Placebo: Duration of taper: 21 days. N=20.

Rescue medication: chloralhydrate, antiparkinson medication.

Outcomes

Examined:

Relapse: at least minimally worse on CGI.

Leaving the study early.

Unable to use / Not included:

Mental state: BPRS (no predefined outcome of interest).

Global state: CGI (no predefined outcome of interest).

Social activity: Family Rating Form (no SD / no predefined outcome of interest).

Social adjustment: Harbor View House Residents Rating Report (no SD / no predefined outcome of interest).

Adverse effects: open interview (no data).

Physiological measures: vital signs, laboratory (both no data / no predefined outcome of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, identical capsules.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, identical capsules.

Incomplete outcome data (attrition bias)
All outcomes

High risk

The overall number of participants leaving the study early (41%) was considerable, with a higher drop‐out rate in the placebo group.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No clear evidence for other bias.

Methods

Randomisation: randomised, no further details.
Allocation: capsules dispensed by the hospital pharmacist who was the only person who knew what the capsules were and to whom they were given.
Blinding: double, placebo capsules, no further details.
Duration: range 13‐22 weeks, mean 16 weeks.
Design: parallel.
Location: 2 centres.
Setting: inpatient.

Participants

Diagnosis: chronic schizophrenia (clinical diagnosis), >70% of them with extrapyramidal side effects after long treatment with phenothiazines.

N=63.
Gender: 32 men, 31 women.
Age: mean 57 years.
History: duration stable‐ n.i., duration ill‐ n.i., but currently hospitalised for at least 4 years and treated with phenothiazines for a mean duration of 9.4 years, number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ mean 17mg/day trifluoperazine (86% of the participants).

Interventions

1. Drug: trifluoperazine ‐ Fixed dose (maintaining the initial dose, necessity of dose increase was considered to be a relapse). Mean dose: 17 mg/day. N=31.

2. Placebo: Duration of taper: 0 days. N=32.

Rescue medication: n.i..

Outcomes

Examined:

Relapse: deterioriation of participant’s condition to such a degree that additional antipsychotic medication was necessary.

Unable to use / Not included:

Adverse effects: movement disorders (no randomised data).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised, no further details.

Allocation concealment (selection bias)

Low risk

Capsules dispensed by the hospital pharmacist who was the only person who knew what the capsules were and to whom they were given.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, placebo capsules, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, placebo capsules, no further details.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

16% left the study early, all but one due to relapse. This appears acceptable. relapse and death were the only outcomes.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

High risk

Participants with a relapse were probably removed from the study and the blind broken. Study was probably terminated early.

Methods

Randomisation: randomly allocated by research assistant.
Allocation: a part from the research assistant no one knew who was on drug or placebo until the data were analysed.
Blinding: double, sesame oil injections, unmarked ampoules. Blinding was tested at the end of the trial and it worked.
Duration: 9 months.
Design: parallel.
Location: two centres.
Setting: outpatient.

Participants

Diagnosis: chronic schizophrenia (Present State Examination), chronicity defined by at least 2 admissions or 1 admission lasting longer than 6 months, 71 schizophrenic psychosis with delusions or auditory hallucinations, six non affective delusional psychoses, three catatonic schizophrenia.

N=81.
Gender: 52 men, 29 women.
Age: mean 43.4 years.
History: duration stable‐ at least 8 weeks, duration ill‐ n.i., number of previous hospitalisations‐ 24 had ≤3 and 57 had ≥4), age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ 86% fluphenazine depot 25mg/month, no additional antipsychotic medication.

Interventions

1. Drug ‐ Fixed/flexible dose: Allowed dose range: 25mg/month ‐ no upper limit. Mean dose: 26.4mg/month. N=41.

2. Placebo: Duration of taper: n.i.. N=40.

Rescue medication: antidepressants, antiparkinson medication

Outcomes

Examined:

Relapse: deterioration of condition to a degree that participant had to be taken out of the trial to ensure that active medication was prescribed, prescription of oral phenothiazines.

Adverse effects: use of antiparkinson medication.

Unable to use / Not included:

Mental state: Present State Examination (no data / no predefined outcome of interest).

Social functioning: Social Performance Schedule, Events Schedule of Bron and Birley (both no predefined outcome of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomly allocated by research assistant.

Allocation concealment (selection bias)

Low risk

Apart from the research assistant no one knew who was on drug or placebo until the data were analysed.

Blinding (performance bias and detection bias)
Subjective outcomes

Low risk

Double, sesame oil injections, unmarked ampoules. Blinding was tested at the end of the trial and it worked.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, sesame oil injections, unmarked ampoules. Blinding was tested at the end of the trial and it worked.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Overall, 43% of the participants left the study early (no complete ITT for some outcomes).

Selective reporting (reporting bias)

Low risk

No evidence for selected reporting.

Other bias

Low risk

No evidence of other bias

Methods

Randomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, no further details.
Duration: one year.
Design: parallel.
Location: single‐centre.
Setting: outpatient.

Participants

Diagnosis: schizophrenia (DSM‐III‐R).

N=21.
Gender: data on randomised subsample are not available.
Age: data on randomised subsample are not available.
History: duration stable‐ for at least 6 months and all on maintenance treatment, duration ill‐ n.i., number of previous hospitalisations‐ n.i., age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ n.i..

Interventions

1. Drug: fluphenazine depot. Fixed dose of 25mg/2 weeks. N=11.

2. Placebo: Duration of taper: 0 days. N=10.

Rescue medication:
Haloperidol was given to participants who developed prodromal symptoms and was continued for 2 weeks unless relapse occurred.

Outcomes

Unable to use / Not included:

No data could be used because they have not been presented for the randomised subset.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, no further details.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Uncear, whether there were any drop‐outs.

Selective reporting (reporting bias)

High risk

No useable data because data of the randomised subsample have not been presented.

Other bias

Low risk

No clear evidence for other bias.

Methods

Randomisation: randomly assigned, no further details.
Allocation: procedure not described.
Blinding: double, identical capsules, no further details.
Duration: 2‐3 years (data available up to 2 years).
Design: parallel.
Location: three centres.
Setting: outpatient.

Participants

Diagnosis: schizophrenia (DSM‐II, undifferentiated type 46.3%, paranoid 39%, acute differentiated 8%, schizoid affective 2.7%, other 3.8%), currently hospitalised for less than 2 years.

N=374.
Gender: 159 men, 215 women.
Age: mean 34.4 years.
History: duration stable‐ 2 months transition phase, those who relapsed during this time were replaced, duration ill‐ n.i., number of previous hospitalisations‐ mean 2.6, age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ mean 265mg chlorpromazine per day.

Interventions

Previous medication was gradually shifted to chlorpromazine for two months.
1. Drug: chlorpromazine ‐ Flexible dose. Allowed dose range: 100mg/day. Mean dose: ˜ 260mg/day. N=192.

2. Placebo: Duration of taper: 0 days. N=182.

Rescue medication: not indicated, but probably not allowed.

Outcomes

Examined:

Relapse: clinical deterioration of such magnitude that hospitalisation appeared imminent.

Unable to use / Not included:

Leaving the study early (numbers not specified for each group separately).

Mental state: Brief Psychiatric Rating Scale, Inpatient Multidimensional Psychiatric Scale, Springfield Symptom Index, Hopkin’s Symptom Distress Check List (all no SDs and data only given for subgroups / no predefined outcome of interest).

Social behaviour and adjustment: Katz Adjustment Scale, Major Role Adjustment Inventory (both no SDs and data presented only for subgroups / no predefined outcome of interest).

Notes

Half of the participants randomly received major role therapy in addition to chlorpromazine or placebo. For the purpose of this review the four resulting groups were pooled as described above.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomly assigned, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, identical capsules, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, identical capsules, no further details.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Relatively few participants left the study early due to reasons other than relapse which was the only outcome (n=31). Although it is unclear in which group they occurred the small percentage does not represent an important risk of bias.

Selective reporting (reporting bias)

Low risk

No clear evidence for selective reporting.

Other bias

Low risk

No clear other bias.

Methods

Randomisation: patients were randomised in a 1 to 1 ratio (via a sponsor prepared, computer generated randomisation scheme, assigned by an interactive voice system).
Allocation: interactive voice system.
Blinding: double, no further details.
Duration: variable (the trial was terminated early after an interim analysis).
Design: parallel.
Location: multi‐centre.
Setting: n.i..

Participants

Diagnosis: schizophrenia (DSM‐IV‐TR).

N=410.
Gender: 220 men, 88 women.
Age: mean 39 years.
History: duration stable‐ 12 weeks prospectively stable on fixed dose paliperidone, duration ill‐ mean 12 years, number of previous hospitalisations‐ median 2.6, age at onset‐ mean 27.3 years, severity of illness‐ PANSS total mean 53 points, baseline antipsychotic dose‐ n.i..

Interventions

1. Drug: paliperidone palmitate depot ‐ Fixed dose: originally 25, 50 or 100mg/4 weeks; this dose was maintained. Mean dose: n.i.. N=206.

2. Placebo: Duration of taper: 0 days. N=204.

Rescue medication: n.i..

Outcomes

Examined:

Relapse: psychiatric rehospitalisation, deliberate self‐injury or violent behaviour, suicidal or homicidal ideation, certain predefined PANSS score.

Leaving the study early.

Rehospitalisation.

Death natural causes and suicide.

Unable to use / Not included:

Mental state: Positive and Negative Syndrome Scale (no predefined outcome of interest).

Adverse effects: open interviews (only a few adverse events were indicated and these were not of interest for the review).

Prolactin levels (no predefined outcome of interest).

Notes

The study was stopped early after a significant interim analysis.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Patients were randomised in a 1 to 1 ratio (via a sponsor prepared, computer generated randomisation scheme, assigned by an interactive voice system).

Allocation concealment (selection bias)

Low risk

Interactive voice system.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, no further details.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Overall high drop‐out rate (45%). Clearly more participants in the placebo group (95) than in the drug group (31) left the study early due to relapse. This imbalance may have biased the results of other outcomes such as adverse events. Kaplan‐Meier survival curve analysis was used for the primary outcome relapse.

Selective reporting (reporting bias)

Low risk

Those adverse events that occurred in at least 2% of the participants and severe adverse events were presented. We feel that's acceptable.

Other bias

High risk

Study was stopped early after an interim analysis.

Methods

Randomisation: matched then each pair randomised, no further details.
Allocation: procedure not described.
Blinding: double, no further details.
Duration: 6 months.
Design: parallel.
Location: single‐centre.
Setting: outpatient.

Participants

Diagnosis: probable or definite schizophrenia, any subtype (Research Diagnostic Criteria), in remission for at least 4 weeks or at stable clinical plateau despite vigorous chemotherapy.

N=16.
Gender: 14 men, 2 women.
Age: 26.7 years.
History: duration stable‐ mean 22.9 months in remission (minimum 6 months), duration ill‐ mean 6.1 years, number of previous hospitalisations‐ n.i., but a mean of 2.4 previous episodes, age at onset‐ mean 20.6 years, severity of illness‐ n.i., baseline antipsychotic dose‐ 3.8mg fluphenazine biweekly.

Interventions

1. Drug: fluphenazine decanoate ‐ Flexible dose. Allowed dose range: 1.25‐5.0mg biweekly. Mean dose: n.i.. N=8.

2. Placebo: Duration of taper: 0 days, but previously treated with depot medication. N=8.

Rescue medication: minor tranquilisers, additional antipsychotic drugs were not allowed.

Outcomes

Examined:

Relapse: increase in or re‐emergence of significant symptoms suggesting imminent psychotic relapse.

Unable to use / Not included:

Leaving study early (no data).

Adverse effects (no data).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Matched, then each pair randomised, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, no further details.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Two participant in the drug group (1 relapse, 1 unclear) left the study early, and 7/8 participants in the placebo group dropped out due to relapse. As relapse and dropout were the only outcomes, this did not lead to bias.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Low risk

No clear evidence for other bias.

Methods

Randomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, all participants received both pills and injections (active or placebo) to maintain double‐blind conditions.
Duration: 1 year.
Design: parallel.
Location: single‐centre.
Setting: outpatient.

Participants

Diagnosis: first episode schizophrenia (clinical diagnosis), no evidence of drug abuse or important medical illnesses. When diagnoses were reassessed by Research Diagnostic Criteria, 19 had schizophrenia, 3 had unspecific schizophrenic psychoses, 4 had other psychiatric disorders, one mania with schizotypal features and one depression with schizotypal features.

N=28.
Gender: 14 men, 14 women.
Age: mean 21.9 years.
History: duration stable‐ stable remission of at least 4 weeks, mean 16.9 weeks, duration ill‐ mean 17.6 weeks, number of previous hospitalisations‐ 0, age at onset‐ mean 21.5 years, severity of illness‐ n.i., baseline antipsychotic dose‐ n.i..

Interventions

1. Drug: oral fluphenazine ‐ Flexible dose. Allowed dose range: 5‐20mg/day. Mean dose: n.i.. N=n.i..

2. Drug: depot fluphenazine ‐ Flexible dose. Allowed dose range: 12.5‐50/mg biweekly. Mean dose: n.i.. N=n.i..

2. Placebo: Duration of taper: 0 days. N=17.

Rescue medication: not indicated.

Outcomes

Examined:

Relapse: a substantial clinical deterioration with a potential for marked social impairment. Patients were considered dropouts only if they showed no signs of clinical deterioration at the time they left the study.

Leaving the study early.

Unable to use / Not included:

Social aspects of premorbid personality: Premorbid Asocial Adjustment Scale (data on placebo group only / no predefined outcome of interest).

Notes

The design was changed during the study in that only non‐compliant patients were randomised to depot fluphenazine or depot placebo, and the randomisation was changed to 2‐1‐1 (placebo, oral fluphenazine, depot fluphenazine).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, all participants received both pills and injections (active or placebo) to maintain double‐blind conditions.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, all participants received both pills and injections (active or placebo) to maintain double‐blind conditions.

Incomplete outcome data (attrition bias)
All outcomes

High risk

20 out of 28 participants  left the study early, 10 for other reasons than relapse, which was the only outcome apart from leaving the study early. This may present a bias.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

Unclear risk

The design was changed during the study in that only non‐compliant patients were randomised to depot fluphenazine or depot placebo, and the randomisation was changed to 2‐1‐1 (placebo, oral fluphenazine, depot fluphenazine). It is unclear whether this biased the results.

Methods

Randomisation: randomly assigned, no further details.
Allocation: procedure not described.
Blinding: double, placebo treated participants received injections of sesame oil in a similar amount.
Duration: 12 weeks.
Design: parallel.
Location: single‐centre.
Setting: outpatient.

Participants

Diagnosis: chronic schizophrenia (clinical diagnosis), 12 paranoid, 3 hebephrenic, 2 catatonic, 1 simple, 6 chronic undifferentiated, on antipsychotic medication for a mean duration of 2 years.

N=24.
Gender: 4 men, 20 women.
Age: mean 36 years.
History: duration stable‐ minimum six weeks stable on oral fluphenazine, duration ill‐ mean 12.4 years, number of previous hospitalisations‐ n.i., age at onset‐ mean 23.6 years , severity of illness‐ n.i., baseline antipsychotic dose‐ mean 28.5 mg fluphenazine decanoate biweekly.

Interventions

1. Drug: fluphenazine decanoate ‐ Flexible doses. Allowed dose range: 12.5‐75/mg biweekly. Mean dose: n.i.. N=13

2. Placebo: sesame oil injections. Duration of taper: 0 days. N=11.

Rescue medication: antiparkinson medication, additional fluphenazine decanoate ‐ but this was considered to be a relapse.

Outcomes

Examined:

Relapse: clinical deterioration requiring additional antipsychotic drug treatment.

Leaving study early.

Unable to use / Not included:

Global state: 7 point scale of severity (no data / no predefined outcome of interest).

Mental state: scale published by the authors (no SD / no predefined outcome of interest).

Adverse effects: scale published by the authors (no numbers).

Physiological measures: ECG, EEG, laboratory (all no data / no predefined outcomes of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomly assigned, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, placebo treated participants received injections of sesame oil in a similar amount.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, placebo treated participants received injections of sesame oil in a similar amount.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No participant left the study early.

Selective reporting (reporting bias)

Low risk

No evidence for selective reporting.

Other bias

High risk

In case of deterioration the participants received additional antipsychotic drugs. This is a problem for the analysis of side‐effects.

Methods

Randomisation: randomised, computerized randomisation and stratification scheme.
Allocation: interactive voice‐response system.
Blinding: double, 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‐ 10.8mg/day paliperidone.

Interventions

1. Drug: paliperidone‐ Flexible doses. Allowed dose range: 3 ‐ 15mg/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 Positive and Negative Syndrome Scale (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).

Quality of life: Schizophrenia Quality‐of‐Life Scale.

Unable to use / Not included:

Mental state: PANSS (no predefined outcome of interest).

Behaviour: suicide, aggression (only mean scores which were no predefined outcomes of interest).

Functioning: Personal and Social Performance Scale (no predefined outcome of interest).

Global state: CGI‐severity (only mean score which was no predefined outcome of interest).

Adverse effects: World Health Organization Adverse Reaction Terminology dictionary (no data / no predefined outcome of interest), movement disorders (Simpson Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale (all no data / continuous side‐effect results were not among the predefined outcomes 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, computerized randomisation and stratification scheme.

Allocation concealment (selection bias)

Low risk

Interactive voice‐response system.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, no further details.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, 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.

Methods

Randomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, identical capsules.
Duration: 12 weeks.
Design: parallel.
Location: single‐centre.
Setting: inpatient.

Participants

Diagnosis: chronic schizophrenia (clinical diagnosis).

N=35.
Gender: 19 men, 16 women.
Age: mean 43.9 years.
History: duration stable‐ maintained on neuroleptic for at least 3 months, prospective 12 week stabilization phase during which participants were switched to penfluridol, duration ill‐ n.i., number of previous hospitalisations‐ mean 1.34, age at onset‐ n.i., severity of illness‐ n.i., baseline antipsychotic dose‐ mean 64.1mg/week penfluridol.

Interventions

1. Drug: penfluridol ‐ Flexible dose. Allowed dose range: 20‐120mg/week. Mean dose:n.i.. N=18.

2. Placebo: Duration of taper: 0 days. N=17.

Rescue medication: antiparkinson medication, it seems that haloperidol was not allowed in the double‐blind phase.

Outcomes

Examined:

Relapse: psychiatric decompensation that could not be controlled by dose increase.

Leaving the study early.

Unable to use / Not included:

Global state: Clinical Global Impression Scale (no numbers / no predefined outcomes of interest).

Mental state: Brief Psychiatric Rating Scale (no numbers / no predefined outcomes of interest).

Behaviour: Nurses Observation Scale for Inpatient Behaviour (no numbers / no predefined outcomes of interest).

Physiological measures: vital signs (weight, pulse, blood pressure, respiratory frequency, temperature ‐ no numbers / no predefined outcomes of interest).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised, no further details.

Allocation concealment (selection bias)

Unclear risk

Procedure not described.

Blinding (performance bias and detection bias)
Subjective outcomes

Unclear risk

Double, identical capsules.

Blinding (performance bias and detection bias)
Objective outcomes

Low risk

Double, identical capsules.

Incomplete outcome data (attrition bias)
All outcomes

High risk

12 of 35 participants left the study early (34%), 11 of them were in the placebo group. As all participants in the placebo group discontinued due to relapse, the primary outcome is not affected. But the results of all other outcomes are biased by this effect.

Selective reporting (reporting bias)

Low risk

Results on rating scales have not been reported, but these were not outcomes of interest in our review.

Other bias

Low risk