Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 6 weeks (preceded by a 7‐day single blind placebo washout).
Location: multicentre.
Design: parallel.
Setting: inpatients.
Country: USA and Canada.

Consent: written.

Participants

Diagnosis: (DSM‐III‐R) schizophrenia.
N = 361.
History: sub/chronic hospitalised, currently experiencing acute exacerbation of psychotic symptoms.
Sex: 76% M, 24% F.
Age: 18 ‐ 64 years (mean ˜ 37 years).
Exclusions: BPRS score < 27, CGI score < 4, history of seizures, other significant medical condition, participation in other drug trial within 30 days, use of depot antipsychotics within 1 dosing interval, pregnancy, placebo responders, non completion of dose escalation.

Interventions

1. Haloperidol: fixed dose (FD) 12 mg/day, increased day 1‐14. N = 52
2. Placebo. N = 51.
3. Quetiapine: (FD) 75 mg/day, increased day 1‐14. N = 53.
4. Quetiapine: (FD) 150 mg/day, increased day 1‐14. N = 48.
5. Quetiapine: (FD) 300 mg/day, increased day 1‐14. N = 52.
6. Quetiapine: (FD) 600 mg/day, increased day 1‐14. N = 51.
7. Quetiapine: (FD) 750 mg/day, increased day 1‐14. N = 54.
Chloral hydrate, lorazepam, benztropine mesylate as required.

Outcomes

Leaving the study early.

Unable to use ‐
Global effect: improved/not improved, CGI (> 50% loss).
Dose response (> 50% loss).
Time to response (> 50% loss).
Mental state: BPRS, SANS (> 50% loss).
Adverse events: AIMS, SAS, other various observed effects (> 50% loss).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomised" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind"; "[Blood] samples were shipped to the sponsor and analysed". No further details reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

"Of all patients evaluated, 149 (41%) completed 6 weeks of treatment. Lack of efficacy was the primary reason for withdrawal and was seen most often in the placebo group". No further details reported.

Selective reporting (reporting bias)

Low risk

All expected outcomes reported.

Other bias

High risk

Supported by a grant from Zeneca Pharmaceuticals.

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 6 weeks (preceded by a 4‐7 day single blind placebo washout).
Location: multicentre.
Design: parallel.
Setting: inpatients and outpatients.
Country: USA.

Consent: written.

Participants

Diagnosis: (DSM‐III‐R) schizophrenia.
N = 335.
History: currently suffering from acute exacerbation of symptoms.
Sex: 88% M, 12% F.
Age: 18 ‐ 65 years.
Exclusions: other serious physical or neurological disorder/condition, substance abuse within 3 months of study, abnormal lab results, placebo responders.

Interventions

1. Haloperidol: dose 10, 15 or 20 mg/day; initial dose 15 mg/day, adjusted accordingly thereafter. N = 69.
2. Placebo. N = 68.
3. Olanzapine: dose 2.5, 5 or 7.5 mg/day; initial dose 5 mg/day, adjusted accordingly thereafter. N = 65.
4. Olanzapine: dose 7.5, 10 or 12.5 mg/day; initial dose 10 mg/day, adjusted accordingly thereafter. N = 64.
5. Olanzapine: dose 12.5, 15 or 17.5 mg/day; initial dose 15 mg/day, adjusted accordingly thereafter. N = 69.
Lorazepam, benztropine mesylate as required.

Outcomes

Leaving the study early.

Unable to use ‐
Global effect: CGI, PGI (> 50% loss).
Hospitalisation: admission/discharge, days in hospital (> 50% loss).
Dose response (> 50% loss).
Mental state: BPRS, SANS (> 50% loss).
Adverse events: SAS, AIMS, BAS, other observed effects (> 50% loss).
Compliance (> 50% loss).

Notes

Data only taken from the initial 'acute phase' trial.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomised" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

 Losses to follow‐up ranged from 51% ‐ 68% in the five treatment arms.

Selective reporting (reporting bias)

High risk

Patient Global Impression (PGI) assessed but not reported.

Other bias

High risk

Source of funding from industry "From the Psychopharmacology Division, Lilly Research Laboratories, Eli Lilly and Company"

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 21 days (preceded by 3 days stabilisation with chlorpromazine and haloperidol followed by 2 day washout).
Location: hospital.
Design: parallel.
Setting: inpatients.
Country: Brazil.

Consent: not stated.

Participants

Diagnosis: (ICD‐9) schizophrenia.
N = 90.
History: recently admitted to hospital, currently acute.
Sex: male.
Age: mean ˜ 29 years.
Exclusions: substance abuse, other clinically significant medical or neurological pathologies.

Interventions

1. Haloperidol: dose 5 ‐ 20 mg/day. N = 30.
2. Placebo: N = 31.
3. Pipotiazine: dose 10 ‐ 40 mg/day. N = 29.
Biperiden and trihexyphenidyl as required on day 1 ‐ 3 only.

Outcomes

Adverse event: various observed effects.
Global effect: improved/not improved.
Leaving the study early.
Mental state: BPRS.

Notes

If, after entering the trial, participants showed improvement they could be discharged from hospital. If, however, they were readmitted due to relapse they could then re‐enter the study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"The patients were assigned to 3 groups of 30 each in a random and probabilistic manner, after stratification", no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"The assessments were always performed by the same investigator in a double‐blind trial. Only at the end of the study after the data were analysed were the patient group assignments identified".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"Five patients ran away between the 6th and 27th day of the study. Three belonged to the pipotiazine group, 1 belonged to the haloperidol group, and 1 to the placebo group". "These patients were excluded from the analysis".

Selective reporting (reporting bias)

High risk

Not all expected outcomes reported.

Other bias

Unclear risk

Source of funding not reported.

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 6 weeks (preceded by a 7 day single blind placebo wash out).
Location: not stated.
Design: parallel.
Setting: not reported.
Country: not reported.

Consent: written.

Participants

Diagnosis: (DSM‐III) schizophrenia.
N = 32.
History: not stated.
Sex: not stated.
Age: 18 ‐ 60 years.
Exclusions: unstable physical health.

Interventions

1. Haloperidol: dose 15 ‐ 75 mg/day. N = 8.
2. Placebo. N = 8.
3. Tiospirone: dose 45 ‐ 225 mg/day. N = 8.
4. Thioridazine: dose 150 ‐ 750 mg/day. N = 8.
Chloral hydrate as required.

Outcomes

Adverse events: various observed effects, use of antiparkinson medication.
Leaving the study early.

Unable to use ‐
Mental state: BPRS (no SD).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"...subjects were assigned on a randomized blind schedule to treatment" no further details reported.

Allocation concealment (selection bias)

Unclear risk

"...subjects were assigned on a randomized blind schedule to treatment" no further details reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐ blind" no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Losses to follow‐up or missing data were balanced across intervention groups, with similar reasons for missing data. "...three placebo‐treated patients were terminated prior to study completion due to lack of efficacy. Two patients receiving haloperidol terminated early due to positive response and the desire to leave the hospital, and one patient in the haloperidol treatment group was terminated for administrative reasons. The only patient who left the study prematurely due to an apparent adverse reaction was one receiving placebo, who developed chest pain and electrocardiographic changes"

Selective reporting (reporting bias)

Unclear risk

Study does not state in methods which outcomes will be measured, and/or no protocol available.

Other bias

High risk

Researchers currently imprisoned for research fraud.

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 7 weeks (preceded by a 7‐day single blind placebo washout).
Location: multicentre, part of larger trial.
Design: parallel.
Setting: inpatients.
Country: not reported.

Consent: written.

Participants

Diagnosis: (DSM‐III‐R) schizophrenia.
N = 36.
History: chronic.
Sex: 97% M, 3% F.
Age: ˜ 31‐52 years.
Exclusions: substance abuse, other clinically significant medical or neurological pathologies, women of child bearing capacity.

Interventions

1. Haloperidol: dose 4‐20 mg/day, dose adjusted as required days 1‐18. N = 12.
2. Placebo. N = 12.
3. Risperidone: dose 2‐10 mg/day, dose adjusted as required days 1‐18. N = 12.
Lorazepam, sodium amytal, chloral hydrate, benztropine or trihexyphenidyl as required.

Outcomes

Adverse events: various observed effects.
Leaving study early.
Mental state: no clinical improvement (< 20% reduction in BPRS score).

Unable to use ‐
Adverse events: AIMS (no data), ESRS (no SD).
Global effect: CGI (no SD).
Mental state: BPRS, SANS (no SD).

Notes

Participants already part of larger multicentre trial.
May be part of North American Trial.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomised" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No details reported.

Selective reporting (reporting bias)

High risk

Several outcomes not fully reported (BPRS, CGI, SANS, or ESRS).

Other bias

High risk

Source of funding not reported.

Richard Borison, MD, former psychiatry chief at the Augusta Veterans Affairs medical center and Medical College of Georgia, was sentenced to 15 years in prison for a $10 million clinical trial fraud.

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 8 weeks (preceded by a 7‐day single blind placebo washout).
Location: multicentre.
Design: parallel.
Setting: inpatients.
Country: Canada.

Consent: written.

Participants

Diagnosis: (DSM‐III‐R) schizophrenia.
N = 135.
History: chronic, hospitalised.
Sex: 71% M, 29% F.
Age: mean ˜ 37 years.
Exclusions: other clinically significant neurological or psychical disorder, substance abuse, pregnancy, placebo responders.

Interventions

1. Haloperidol: dose 20 mg/day, initial dose 2 mg/day increased in fixed increments day 2‐7. N=21.
2. Placebo. N = 22.
3. Risperidone: dose 2 mg/day
4. Risperidone: dose 6 mg/day, initial dose 2 mg/day increased in fixed increments day 2‐4.
5. Risperidone: dose 10 mg/day, initial dose 2 mg/day, increased in fixed increments day 2‐5.
6. Risperidone: dose 16 mg/day, initial dose 2 mg/day, increased in fixed increments day 2‐7.
Chloral hydrate, benzodiazepine, biperiden or procyclidine as required.

Outcomes

Leaving the study early.

Unable to use ‐
Global effect: CGI (> 50% loss).
Level of medication required (> 50% loss).
Mental state: BPRS, GPS, PANSS (> 50% loss).
Adverse events: ESRS, various observed effects (UKU), use of antiparkinson medication (> 50% loss).
Cost of treatment (> 50% loss).

Notes

Part of North American Trial.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomly assigned" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Double‐blind", "Study medication was administered under double‐blind conditions as identical tablets of risperidone, haloperidol and placebo".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind", "Assessment of symptoms was based on clinical interviews conducted by a psychiatrist". No further details reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

A total of 65 participants (48.1%) left the study early: 16 (72.7%) from the placebo group and 13 (61.9%) from the haloperidol group.

"Statistical analyses of efficacy and safety parameters were conducted according to the intent‐to‐treat analysis principle".

Selective reporting (reporting bias)

Low risk

All expected outcomes reported.

Other bias

Unclear risk

Source of funding not reported.

Methods

Allocation: random assignment.
Duration: 10 days ‐ 3 months (mean 3 weeks).
Location: hospital.
Design: parallel.
Setting: inpatients.
Country: not reported.

Consent: unknown.

Participants

Diagnosis: schizophrenia (40%), neurosis (60%).*
N = 84 (schizophrenia 34, neurosis 50).
History: unknown.
Sex: 60% M, 40% F.
Age: mean ˜ 39 years.
Exclusions: unknown.

Interventions

1. Haloperidol: dose 2‐25 mg/day, mean 6 mg/day. N = 19.
2. Placebo. N = 15.

Outcomes

Global effect: improved/not improved.
Leaving the study early.

Unable to use ‐
Adverse events: various observed effects (no data).

Notes

* use only data for those suffering from schizophrenia

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"...all drugs were given at random" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No details reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"...'pharmacotherapeutically blind unit,' that is, in a hospital service where all drugs were given at random and used without the service team (made up of one intern, two assistant residents, one resident, one psychologist, two to four nurses, one social worker and one occupational therapist) knowing what drugs were being investigated."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"The assessment of the patients (and the drugs) was a result of the pooling of the opinions of the different members of the team."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

There were no drop‐outs from the study.

Selective reporting (reporting bias)

High risk

Details on side effects were not fully reported although "Side effects were relatively numerous and disturbing to the patients."

Other bias

Unclear risk

"Haloperidol was generously supplied by G. D. Searle & Co." 

Methods

Allocation: randomised.
Blinding: double‐blind.
Duration: 6 weeks.
Design: parallel.
Setting: inpatient.
Country: USA, Bulgaria, the Czech Republic and Russia.

Consent: written.

Participants

Diagnosis: schizophrenia DSM‐4.
N = 307.
Age: 18‐65 (Mean 38.1, SD 11.1).
Sex: M 183, F 124.
History: acute exacerbation of illness, hospitalised for < 2 weeks at screening due to the exacerbation. PANSS score of at least 70.
Exclusions: patients improving > 20% in the PANSS total score or 1 point in the CGI‐S scale at baseline compared with screening; resistant to antipsychotic treatment; DSM‐IV‐TR‐defined substance abuse/dependency within the preceding 3 months (or a positive urine drug test); treated with depot antipsychotics, unless the last injection was administered within greater than one treatment cycle before study entry;clinically significant or currently relevant illness or those judged by the investigator to be at serious suicidal risk.

Interventions

1. Blonanserin: dose 2.5 mg/day. N = 61.

2. Blonanserin: dose 5 mg/day. N = 58.

3. Blonanserin: dose 10 mg/day. N = 64.

4. Haloperidol: dose 10 mg/day. N = 60.

5. Placebo. N = 64.

Outcomes

Leaving the study early

Global state: No overall improvement (< 20% reduction in PANSS‐total score)

Mental state: PANSS‐total score, mean change from baseline at 6 weeks

Mental state: PANSS‐positive score, mean change from baseline at 6 weeks

Mental state: PANSS‐negative score, mean change from baseline at 6 weeks

Global state: CGI‐S, mean change from baseline at 6 weeks

Adverse effects: Extrapyramidal symptoms (akathisia, dyskinesia, dystonia, parkinsonism, rigidity, tremor)

Adverse effects: Cardiovascular (bradycardia)

Adverse effects: Other (insomnia, drooling, headache, weight loss, agitation, anxiety, sleepiness)

Unusable data (no measurement of variance reported) ‐

Adverse effects: Extrapyramidal symptoms: SAS, BAS and AIMS scales

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomization of medication was performed using a computer‐generated schedule".

Allocation concealment (selection bias)

Unclear risk

 No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

“Double‐blind”, "...blinding was ensured by over‐encapsulating all capsules to ensure the same appearance".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

“Double‐blind”, no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Losses to follow‐up or missing data were balanced across intervention groups, with similar reasons for missing data. Missing data have been imputed using appropriate methods (intention‐to‐treat analysis).

Selective reporting (reporting bias)

High risk

 Not all of the study's pre‐specified primary outcomes have been reported (BPRS, UKU assessments).

Other bias

High risk

"Laboratorios Almirall SA provided financial support for performing the study and Dainippon Sumitomo Pharma Co., Ltd funded the preparation of this manuscript. Drs Garcia, Robert and Peris are employees of Laboratorios Aimirall SA. H. Nakamura, Dr Sato and Y. Terazawa are employees of Dainippon Sumitomo Pharma Co., Ltd. Drs Garcia and Peris have received stock options from Laboratorios Almirall SA." 

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 12 weeks (preceded by a 2‐week medication free period).
Location: not stated.
Design: parallel.
Setting: inpatients.
Country: not stated.

Consent: not stated.

Participants

Diagnosis: schizophrenia.
N = 52.
History: chronic, hospitalised.
Sex: 62% M, 38% F.
Age: mean ˜ 46 years.
Exclusions: not stated.

Interventions

1. Haloperidol: dose 0.75 ‐ 4.5 mg/day, increased day 1 ‐ 42. N = 26.
2. Placebo. N=26.

Outcomes

Adverse events: various observed effects*
Global effect: improved/not improved.
Leaving the study early.

Notes

*Adverse effects reported for haloperidol group only, reviewers assumed that placebo group had no adverse effects.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants "were divided into two groups on the basis of a list of random numbers supplied by the drug company"

Allocation concealment (selection bias)

Low risk

Central allocation "Our pharmacist allotted the patients from an alphabetical list supplied  by us"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"Two patients were withdrawn from the trial, one had a recurrence of a skin rash (he was eventually found to be on the placebo) and the other was found to have early pulmonary tuberculosis on routine chest X‐ray. We were finally left with 50 patients (25 on drug and 25 on controls) who completed the trial".

Selective reporting (reporting bias)

Low risk

All expected outcomes reported.

Other bias

Unclear risk

Messrs. G. D. Searle and Co. Ltd. supplied the haloperidol and control tablets.

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: max 12 weeks (preceded by a 14 day placebo washout).
Location: hospital.
Design: parallel and cross‐over.
Setting: inpatients and outpatients.
Country: USA.

Consent: not stated.

Participants

Diagnosis: schizophrenia (80%).
N = 49.
History: treatment resistant, hospitalised.
Sex: female.
Age: 25 ‐ 65 years.
Exclusions: other serious physical or neurological disorder, pregnancy, severe hyposensitivity to haloperidol or thiothixene, placebo responders.

Interventions

1. Haloperidol: dose < 200 mg/day. N = 17.
2. Placebo. N = 16.
3. Thiothixene: dose < 200 mg/day. N = 16.

Outcomes

Global effect: improved/not improved.
Hospital discharge.
Leaving the study early.
Adverse events: various observed effects.

Unable to use ‐
Behaviour: NOSIE (no SD).
Mental state: BPRS (no mean, no SD), MSC (data given only for those remaining in hospital).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"the patients were randomly assigned" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No details reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"The study medications were prepared in identical appearing capsules".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

 No details reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

 Losses to follow‐up were balanced across intervention groups, with similar reasons for missing data.

Selective reporting (reporting bias)

High risk

All outcomes were not fully reported (no SD s were reported for BPRS and NOSIE).

Other bias

Unclear risk

Insufficient information to assess whether an important risk of bias exists (does not report source of funding).

Methods

Allocation: random assignment.
Blindness: unsure.
Duration: 6 weeks.
Location: not stated.
Design: parallel.
Setting: inpatients.
Country: not reported.

Consent: written.

Participants

Diagnosis: (DSM‐III‐R) schizophrenia.
N = 36.
History: not stated.
Sex: not stated.
Age: ˜ 25 ‐ 43 years.
Exclusions: not stated.

Interventions

1. Haloperidol: dose up to 75 mg/day, dose individually adjusted weekly. N = 18.
2. Placebo. N = 18.
Lorazepam or chloral hydrate as required.

Outcomes

Adverse events: various observed effects.
Leaving the study early.
Mental state: BPRS.

Unable to use ‐
Adverse events: AIMS (no data).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomly assigned" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Identical looking capsules" were used.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information provided.

Incomplete outcome data (attrition bias)
All outcomes

High risk

"Only 8 patients in the placebo group completed the 6‐week study". "For the haloperidol group, 12 patients completed the study".

Selective reporting (reporting bias)

High risk

All pre‐stated outcomes were not reported (no data reported for the AIMS scale).

Other bias

Unclear risk

Source of funding not reported.

Methods

Allocation: random.
Blindness: double‐blind.
Duration: 4 weeks.
Location: hospital, multicentre.
Design: parallel.
Setting: inpatients.
Country: USA.

Consent: given.

Participants

Diagnosis: (DSM‐IV) schizophrenia or schizoaffective disorder.
N = 414*.
History: acute relapse, hospitalised.
Age: 18 ‐ 65 years.
Sex: 70% M, 30% F.
Exclusions: other psychiatric disorder, history of violence or self‐harm.

Interventions

1. Aripiprazole: dose 15 mg/day. N = 102.
2. Aripiprazole: dose 30 mg/day. N = 102.
3. Haloperidol: dose 10 mg/day. N = 104.
4. Placebo. N = 106.
lozepam for anxiety or insomnia

Outcomes

Leaving the study early.
Adverse events: various observed effects.

Unable to use:
Global effect: CGI (no SD).
Mental state: BPRS, PANSS (no SD).

Notes

Data taken from haloperidol and placebo groups only.
Data provided for some outcomes have only 103 people in haloperidol group and 104 in placebo group.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomly assigned" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" no further information reported.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"The same rater conducted the assessment throughout the study and was blinded to the patient's treatment".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Number of losses and reasons for leaving the study similar across groups. "Analysis of efficacy parameters was performed on an intention‐to‐treat basis using data obtained from each patient's last visit (i.e. last observation carried forward analysis at week 4".

"Of the 414 randomised patients, 248 competed the 4‐week study period".

Selective reporting (reporting bias)

High risk

All pre‐stated outcomes were not fully reported (SDs were not reported for PANSS, BPRS, CGI, AIMS, SAS and BAS scales, weight and serum prolactin levels).

Other bias

High risk

Sponsored by Otsuka Pharmaceutical Co. Ltd (Tokyo, Japan) and Bristol‐Meyers Squibb Company (Princeton, NJ).

Methods

Allocation: randomised.
Blinding: double‐blind.
Duration: 6 weeks.
Design: parallel.
Setting: inpatients and outpatients*.
Country: 43 centres (United States, 17 sites; Russia, 11 sites; India, 7 sites; Romania, 7 sites; Canada, 1 site).

Consent: written.

Participants

Diagnosis: schizophrenia, DSM‐IV.
N = 458.
Age: 37 to 40 years.
Sex: M 270, F 188.
History: acute exacerbation of psychotic symptoms.
Exclusions: a clinically significant medical condition or abnormal laboratory or physical examination findings; diagnosis of residual‐type schizophrenia, schizoaffective disorder, or coexisting psychiatric disorder coded on Axis I; current or past substance abuse; 20% or higher decrease in PANSS total score from screening to baseline; known allergy or sensitivity to haloperidol; imminent risk of self‐harm or harm to others; previous participation in an asenapine trial.

Interventions

1. Asenapine: dose 5 mg/day. N = 114.

2. Asenapine: dose 10 mg/day. N = 106.

3. Placebo. N = 123.

4. Haloperidol: dose 4 mg/day. N = 115.

Outcomes

Leaving the study early

Global state: no overall improvement (no CGI‐I score of 1 [very much improved] or 2 [much improved]) (also measured as < 30% reduction in PANSS total score, not used)

Mental state: PANSS subscale scores (positive, negative), mean change from baseline at 6 weeks

Global state: CGI‐S and CGI‐I, mean change from baseline at 6 weeks

Mental state: Calgary Depression Scale for Schizophrenia (CDSS), mean change from baseline at 6 weeks

Adverse effects: Extrapyramidal symptoms (SAS, BAS and AIMS scales), mean change from baseline at 6 weeks

Adverse effects: Extrapyramidal symptoms (parkinsonism, akathisia, dystonia, rigidity)

Adverse effects: Other (insomnia, oral hypoaesthesia, sleepiness, agitation, headache, anxiety, weight loss, weight gain)

Adverse effects: Autonomic (sedation)

Use of anti‐Parkinson medication

Unable to use (measurements of variance not reported) ‐

PANSS total score mean change from baseline to day 42 (primary outcome)

Modified International Suicide Prevention Trial (InterSePT) Scale for Suicidal Thinking

Readiness to Discharge Questionnaire (RDQ)

Notes

*Patients were hospitalised for at least 2 weeks.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

“Randomized”, no further details provided.

Allocation concealment (selection bias)

Unclear risk

“Randomized”, no further details provided.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind", no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"Safety assessments were made using data from the treated population (all patients who received >1 dose of study medication); efficacy analyses were based on data from the intent‐to‐treat (ITT) population (treated patients who had >1 postbaseline PANSS assessment)"

Selective reporting (reporting bias)

High risk

Not all pre‐specified outcomes were reported fully.

Other bias

High risk

"funded by Schering‐Plough Corporation, now Merck & Co, Inc" 

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 3 weeks.
Location: hospital.
Design: parallel.
Setting: inpatients.
Country: not reported.

Consent: not stated.

Participants

Diagnosis: schizophrenia (63%), major depressive disorder (37%).
N = 120.
History: chronic, hospitalised.
Sex: 41% M, 59% F.
Age: mean ˜ 43 years.
Exclusions: not stated.

Interventions

1. Haloperidol: dose 20 mg/day. N = 20*.
2. Placebo. N = 16.
3. Trazodone: dose 400 mg/day. N = 17.
4. Amitriptyline: dose 150 mg/day. N = 22.
Biperiden as required.

Outcomes

Leaving the study early
Mental state: BPRS.

Notes

*number of people with schizophrenia.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomised" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Number of losses from each treatment group and reasons for loss to follow‐up not reported. "Fourteen patients left the study on day 3, 19 patients left on day 7, and 6 patients left on day 14".

Selective reporting (reporting bias)

High risk

Not all expected outcomes were reported.

Other bias

Unclear risk

Source of funding not reported.

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 8 weeks (preceded by 1 week placebo wash out).
Location: multicentre.
Design: parallel.
Setting: inpatients.
Country: USA.

Consent: given.

Participants

Diagnosis: (DSM‐III‐R) schizophrenia.
N = 388.
History: hospitalised, chronic.
Sex: 89% M, 11% F.
Age: mean ˜37 years.
Exclusions: physically unhealthy, schizoaffective disorder.

Interventions

1. Haloperidol: dose 20 mg/day. N = 66.
2. Placebo: N = 66.
3. Risperidone: dose 2 mg/day. N = 63.
4. Risperidone: dose 6 mg/day. N = 64.
5. Risperidone: dose 10 mg/day. N = 65.
6. Risperidone: dose 16 mg/day. N = 64.
Lorazepam or chloral hydrate as required.

Outcomes

Leaving the study early

Unable to use ‐
Global state: CGI (> 50% loss).
Mental state: PANSS (> 50% loss).
Adverse events: EPS, UKU scale (> 50% loss).

Notes

Part of 'North America 1997'.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"...randomization was in blocks of 12" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

"early termination in 53% of the patients...62 % of the placebo patients; and 38% of patients receiving haloperidol...Both observed case and last observation carried forward (or end point) analyses were performed".

Selective reporting (reporting bias)

Low risk

All expected outcomes are reported.

Other bias

Unclear risk

Source of funding from a pharmaceutical company "Supported by a grant from the Janssen Research Foundation".

Methods

Allocation: randomised.
Blinding: double‐blind.
Duration: 6 weeks.
Design: parallel.
Setting: inpatients up to day 15 after randomisation.
Country: USA.

Consent: written.

Participants

Diagnosis: schizophrenia and schizoaffective disorder DSM‐IV.
N = 481.
Age: 18‐64 ( range 35.4‐37.5).
Sex: M 355, F 126.
History: hospitalised at baseline; a total score on the PANSS greater than 65 at screening and baseline, a minimum severity of illness score of 4 (moderately ill) on the CGI at screening and baseline.
Exclusions: patients with other axis I DSM‐IV diagnoses; patients considered by the investigator to have been non‐responsive to treatment with at least two different classes of antipsychotic medications; patients with any clinically significant medical illnesses; patients with clinical laboratory or ECG abnormalities; patients with evidence of current substance abuse or dependence; patients who were a danger to themselves or others.

Interventions

1. Haloperidol: dose 10 mg/day. N = 98.

2. Placebo. N = 98.

3. 5‐HT2A/2C antagonist: dose 5 mg/day. N = 70.

4. NK3 antagonist: dose 200 mg/day. N = 67.

5. CB1 antagonist: dose 20 mg/day. N = 69.

6. NTS1 antagonist: dose 180 mg/day. N = 63.

Outcomes

Leaving the study early*

Unable to use (losses to follow‐up > 50%) ‐

Mental state: PANSS (total, positive, negative, general), mean change from baseline at 6 weeks

BPRS (total), mean change from baseline at 6 weeks

Global state: CGI‐I, mean endpoint score at 6 weeks

Global state: CGI‐S, mean change from baseline at 6 weeks

Mental state: Calgary Depression Scale (CDS), mean change from baseline at 6 weeks

Adverse effects: Extrapyramidal symptoms: various scales (SAS, BAS, AIMS), mean change from baseline at 6 weeks

Adverse effects: Other (headache, insomnia, psychosis, agitation, abdominal pain, dyspepsia, vomiting, extrapyramidal symptoms, hyperkinesia)

Notes

*This study had > 50% losses to follow‐up, only the outcome Leaving the study early could be used.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

“Randomized”, no further details reported.

Allocation concealment (selection bias)

Unclear risk

 No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

“Double‐blind”, no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

“Double‐blind”, no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Losses to follow‐up greater than 50%.

Selective reporting (reporting bias)

Low risk

 All expected outcomes are reported.

Other bias

High risk

Funding sources are pharmaceutical companies, "Dr. Meltzer has received grant support from and is a consultant to Acadia, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutica, Lundbeck, Novartis, Pfizer, Sanofi‐Synthelabo, and Solvay. He is a consultant to Psychiatric Genomics, Precision Med, Pharmacia, and Roche. Drs. Arvanitis and Rein and Ms. Bauer are employees of Sanofi‐Synthelabo."

Methods

Allocation: randomised.
Blinding: double‐blind.
Duration: 6 weeks.
Design: parallel.
Setting: inpatients.
Country: USA.

Consent: not stated.

Participants

Diagnosis: schizophrenia.
N = 330.
Age: mean (SD): 41.2 (10.0) years.
Sex: M 262, F 91.
History: hospitalised with acute or relapsing schizophrenia within 3 weeks of screening, a duration of illness of at least one year.
Exclusions: psychiatric hospitalisations other than current hospitalisations within 1 month prior to screening; treatment resistant; substance abuse; prolactin level of > 200 ng/mL at baseline; pregnancy.

Interventions

1. Lurasidone: dose 20mg/day. N = 71.

2. Lurasidone: dose 40mg/day. N = 69.

3. Lurasidone: dose 80mg/day. N = 71.

4. Haloperidol: dose 10mg/day. N = 73.

5. Placebo. N = 72.

Outcomes

Leaving the study early*

Unable to use (losses to follow‐up > 50%) ‐

Adverse effects: Extrapyramidal symptoms (akathisia, tremor, dystonia, EPS)

Adverse effects: Autonomic (sedation)

Adverse effects: Cardiovascular and gastric (dizziness, diarrhoea, constipation, abdominal discomfort)

Adverse effects: Other (nausea, vomiting, headache, sleepiness, agitation, anxiety, insomnia)

Mental state: BPRS total, mean change from baseline at 6 weeks

Mental state: PANSS, mean change from baseline at 6 weeks

Global state: CGI‐S, mean change from baseline at 6 weeks

Mental state: MADRS, mean change from baseline at 6 weeks

Notes

ClinicalTrials.gov Identifier: NCT00044044.

*This study had > 50% losses to follow‐up, only the outcome Leaving the study early could be used.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

“Randomized”, no further details reported.

Allocation concealment (selection bias)

Unclear risk

“Randomized”, no further details reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The placebo was an "Oral Capsule matching treatment" indicating blinding of participants. Further, the study was described as “Double blind”, but there were no further details on blinding of personnel.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

“Double blind”, no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

There was a high rate of drop‐outs (> 50%).

Selective reporting (reporting bias)

Low risk

All pre‐stated outcomes were reported.

Other bias

High risk

"Sponsored by: Sumitomo Pharmaceuticals America" 

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 3 years*.
Location: not stated.
Design: cross‐over.
Setting: outpatients.
Country: Japan.

Consent: not stated.

Participants

Diagnosis: schizophrenia
N = 55.
History: outpatients, currently in remission, but have a history of several relapse episodes.
Sex: 67% M, 33% F.
Age: ˜ 25 ‐ 41 years.
Exclusions: history of taking medication irregularly.

Interventions

1. Haloperidol: dose 3 mg/day. N = 10.
2. Placebo. N = 10.
3. Chlorpromazine: dose 75 mg/day. N = 10.
4. Diazepam: dose 15 mg/day. N = 13.
5. Imipramine: dose 50 mg/day. N = 12.
Nitrazepam or biperiden as required.

Outcomes

Relapse: number remaining in remission < 1 year.

Unable to use ‐
Leaving the study early (unclear when losses occurred, no individual group data given).

Notes

*Initial 'cross‐over' design of trial was disregarded after participant/clinician reluctance to switch neuroleptics. Data taken from first arm only.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomly assigned" no further information reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Double‐blind", "Drug appearance, with respect to powder colour, taste and volumes, was made identical by adding a kind of stomachics, SMP (Sankyo, Japan)."

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Study does not report which treatment groups the losses to follow‐up were from "Nine patients were dropped from the study for various reasons. The reasons included: failure to report to the hospital for scheduled appointment (N=3); admissions to other hospitals (N=2); strong requests from the patient not to change the previous drug (N=3); and a suicide after admission to the hospital (N=1)".

Selective reporting (reporting bias)

High risk

Not all expected outcomes were reported.

Other bias

Unclear risk

Source of funding was not reported.

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 1 year.
Location: not stated.
Design: parallel.
Setting: outpatients.
Country: Japan.

Consent: not stated.

Participants

Diagnosis: (DSM III) schizophrenia.
N = 87.
History: in recovery stage of remission.
Sex: 61% M, 39% F.
Age: ˜ 28 ‐ 54 years.
Exclusions: not stated.

Interventions

1. Haloperidol: dose 1 mg/day. N = 13.
2. Haloperidol: dose 3 mg/day. N = 12.
3. Haloperidol: dose 6 mg/day. N = 12.
4. Placebo. N = 13.
5. Propericiazine: dose 10 mg/day. N = 13.
6. Propericiazine: dose 30 mg/day. N = 13.
6. Propericiazine: dose 60 mg/day. N = 13.
Each drug combined with nitrazepam and biperiden.

Outcomes

Relapse: number remaining in remission < 1 year.
Leaving the study early.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomly assigned" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Double‐blind", "Drug appearance, with respect to powder colour, taste and volume, was made identical by gastric aid, SMP (Sankyo, Japan)".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

"Among the entire group of 87 patients, 19 patients continued to receive the assigned drugs since they were in remission during the entire year of the trial, while other patients discontinued use of the assigned drugs due to overdose (N=16), relapse (N=48) and drop‐out (N=4)".

Selective reporting (reporting bias)

High risk

Results not reported for placebo group for number of symptom free days and serum prolactin.

Other bias

Unclear risk

Source of funding not reported.

Methods

Allocation: randomised.
Blinding: double‐blind.
Duration: 6 weeks.
Design: parallel.
Setting: not stated.
Country: not stated.

Consent: written.

Participants

Diagnosis: schizophrenia, DSM‐IV.
N = 621.
Age: 18‐65, (range 37‐40.1).
Sex: M 443, F 178.
History: acute or subacute exacerbation of schizophrenia and PANSS total score of at least 60 at screening and at baseline.
Exclusions: not stated.

Interventions

1. Iloperidone: dose 4 mg/day. N = 121.

2. Iloperidone: dose 8 mg/day. N = 125.

3. Iloperidone: dose 12 mg/day. N = 124.

4. Haloperidol: dose 15 mg/day. N = 124.

5. Placebo. N = 127.

Outcomes

Leaving the study early*

Unable to use (losses to follow‐up > 50%, variance not reported) ‐

Mental state: PANSS total, PANSS positive, PANSS negative, PANSS general psychopathology, BPRS, mean change from baseline at 6 weeks

Adverse effects

Notes

*This study had > 50% losses to follow‐up, only the outcome Leaving the study early could be used.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

“Randomized”, no further details reported.

Allocation concealment (selection bias)

Unclear risk

 No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

“Double‐blind”, no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

 “Double‐blind”, no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Losses to follow‐up greater than 50%.

Selective reporting (reporting bias)

High risk

SDs not reported for PANSS or BPRS.

Other bias

High risk

Source of funding from pharmaceutical companies. "Dr Potkin has received grant funding from Astra‐ Zeneca, Bioline, Bristol‐Myers Squibb, Dainippon‐Sumitomo, Elan, Forest Laboratories, Fujisawa Healthcare, Janssen Pharmaceutica, Merck, Novartis, Ono, Organon, Otsuka, Pfizer Inc, Solvay Pharmaceuticals, Roche"

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 12 weeks (preceded by a 2 week medication free period).
Location: not stated.
Design: parallel.
Setting: inpatients.
Country: USA.

Consent: not stated.

Participants

Diagnosis: schizophrenia.
N = 87.
History: acute, hospitalised.
Sex: 80% M, 20% F.
Age: mean ˜ 33 years.
Exclusions: other significant physical or neurological disorder, < 16 or > 60 years, females of child bearing age, epileptics, substance abuse.

Interventions

1. Haloperidol: dose 4‐12 mg/day. N = 29.
2. Loxapine: dose 50‐150 mg/day. N = 29.
3. Placebo. N = 29.
Chloral hydrate or paraldehyde as required.

Outcomes

Adverse effects: various observed effects.
Global effect: CGI improved/not improved.
Leaving the study early.

Unable to use ‐
Mental state: BPRS (no SD).
Behaviour: NOSIE (no SD).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomly assigned" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"A double‐blind process was used in which neither patient nor investigator knew what medication was received until after the study was completed", "All medication was administered in identically appearing capsules".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"A double‐blind process was used in which neither patient nor investigator knew what medication was received until after the study was completed".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

"Eight patients were excluded (1 loxapine, 3 haloperidol and 4 placebo", "All eight were dropped for administrative reasons such as unauthorised departure from the hospital or family objections to patients' participation in the study".

Last observation carried forward method used "Patients who continued beyond the fourth week but did not complete the full 12 weeks were included in the analysis through their final rating period, at either 4 or 8 weeks. These included 29 patients".

Selective reporting (reporting bias)

High risk

All pre‐stated outcomes were not fully reported (SDs were not reported for the BPRS and NOSIE scales).

Other bias

High risk

Loxitane (Loxapine succinate) supplied by Lederle Laboratories, Division of America Cyanamid Co, Pearle River, New York, who also supported the study.

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration 3 months.
Location: not stated.
Design: parallel.
Setting: inpatients.
Country: not stated.

Consent: not stated

Participants

Diagnosis: schizophrenia.
N = 57.
History: chronic.
Sex: 42% M, 48% F .
Age: mean ˜ 42 years.
Exclusions: other physical or neurological disorder.

Interventions

1. Haloperidol: dose up to 15 mg/day. N = 14.
2. Placebo. N = 14.
3. Clopenthixol: dose up to 250 mg/day. N = 15.
4. Chlorpromazine: dose up to 1000 mg/day. N = 14.

Outcomes

Adverse events: various observed effects.
Global effect: CGI improved/not improved.
Leaving the study early.

Unable to use ‐
Mental state: BPRS (no SD).
Behaviour: NOSIE, OBRS (no SD).
Cognitive response (no data given).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomly assigned" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Double‐blind", "All medications were prepared in identically appearing capsules".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"Four of the 57 subjects, three on CPZ, and one on PL, failed to complete the 12 weeks of study. The PL subject and one CPZ subject were terminated because of behavioural deterioration after 4 and 8 weeks respectively. The other two CPZ subjects developed intestinal obstruction and were terminated in the 7th week of study".

Selective reporting (reporting bias)

High risk

All pre‐stated outcomes were not reported (no data reported for cognitive response, no SDs reported for the BPRS, NOSIE and OBRS scales).

Other bias

Low risk

Study supported in part by US Public Health Service Grant MH 11666 and by National Institute of Mental Health Research Scientist Development Award K135278.

Methods

Allocation: random assignment.
Blindness: double‐blind.
Duration: 14 weeks.
Location: not stated.
Design: parallel.
Setting: inpatients.
Country: not stated.

Consent: not stated.

Participants

Diagnosis: schizophrenia.
N = 24.
History: chronic, hospitalised.
Sex: male.
Age: ˜ 37 years.
Exclusions: other significant physical or neurological disorder.

Interventions

1. Haloperidol: dose 6 mg/day. N = 8.
2. Haloperidol: dose 30 mg/day. N = 8.
3. Placebo. N = 8.
Benztropine mesylate as required.

Outcomes

Adverse events: use of antiparkinson medication.
Global effect: improved/not improved.
Leaving the study early.

Unable to use ‐
Mental state: IMS, PRP (no SD).

Notes

Group numbers not stated in text, reviewers have assumed that they were divided into three sets of 8 (see table 1).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomly assigned" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind"; "the staff correctly guessed which patients were on active medication in a high percentage of cases".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The code was broken at the end of the study.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No details reported.

Selective reporting (reporting bias)

High risk

All pre‐stated outcomes were not fully reported (SDs were not reported for IMPS and PRP).

Other bias

Unclear risk

"The haloperidol (HALDOL®) used in this study was supplied by McNeil Laboratories. Inc.," 

Methods

Allocation: random assignment.
Blindness: double‐blind, cross‐over.
Duration: 10 weeks (preceded by a 2‐week single blind placebo washout).
Location: not stated.
Design: cross‐over.
Setting: inpatients.
Country: USA.

Consent: not stated.

Participants

Diagnosis: (DSM‐III‐R) schizophrenia.
N = 12.
History: hospitalised.
Sex: 75% M, 25% F.
Age: ˜ 6 ‐ 12 years.
Exclusions: other significant physical or neurological disorder, receipt of psychoactive medication within 4 weeks of study.

Interventions

1. Haloperidol: dose 4 weeks 0.5‐10 mg/day followed by 4 weeks placebo. N = 12.
2. Placebo: 4 weeks followed by 4 weeks 0.5‐10 mg/day haloperidol. N = 12.

Outcomes

Global effect: improved/not improved.
Leaving the study early.

Unable to use ‐
Global effect: CGI (no SD).
Mental state: CPRS, BPRS‐C (no SD).
Adverse events: various observed effects (no data for placebo group).
Cognitive response: WISC‐R, WPPSI, DICA‐R (no data).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Random assignment" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" no further details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind" For CPRS (one of the outcomes scales), the raters were "all blind to treatment status", no further details reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

There were no drop‐outs.

Selective reporting (reporting bias)

High risk

No SDs reported for CGI, CPRS, BPRS‐C. No data reported for adverse events for placebo group. No data reported for cognitive assessments (WISC‐R, WPPSI, DICA‐R).

Other bias

Unclear risk

Study supported by NIMH Child and Adolescent Mental Health Academic Award MH‐00763 and NIMH Institutional Training Grant MH‐18915.

Haloperidol and placebo tablets provided by McNeil Pharmaceutical.

Methods

Allocation: random assignment.
Blindness: double‐blind, cross‐over.
Duration: 12 weeks (preceded by 4 weeks drug free period).
Location: hospital.
Design: cross‐over.
Setting: inpatients.
Country: Thailand.

Consent: unknown.

Participants

Diagnosis: schizophrenia.
N = 30.
History: hospitalised, chronic.
Sex: female.
Age: mean ˜ 40 years.
Exclusions: unknown.

Interventions

1. Haloperidol: dose 6 weeks 4.5 mg/day followed by 6 weeks placebo. N = 30.
2. Placebo: 6 weeks placebo followed by 6 weeks 4.5 mg/day haloperidol. N = 30.

Outcomes

Global effect: FFS, improved/not improved.

Unable to use ‐
Adverse events: various observed effects (no group data).
Leaving the study early (no group data).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomized" no further details reported.

Allocation concealment (selection bias)

Unclear risk

No information reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind"; "The code was worked out by the head of Female In‐patient section, which kept it secret until the investigation had ended."; "...it soon became clear that the trial was not, in fact blind. The patients on haloperidol showed extrapyramidal symptoms".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind"; "The code was worked out by the head of Female In‐patient section, which kept it secret until the investigation had ended."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only one drop‐out reported.

Selective reporting (reporting bias)

Unclear risk

Side‐effects in placebo group not mentioned.

Other bias

Unclear risk

Does not report source of funding.