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Haloperidol versus low-potency first-generation antipsychotic drugs for schizophrenia

  1. Magdolna Tardy1,*,
  2. Maximilian Huhn2,
  3. Werner Kissling1,
  4. Rolf R Engel3,
  5. Stefan Leucht4

Editorial Group: Cochrane Schizophrenia Group

Published Online: 9 JUL 2014

Assessed as up-to-date: 19 MAY 2012

DOI: 10.1002/14651858.CD009268.pub2


How to Cite

Tardy M, Huhn M, Kissling W, Engel RR, Leucht S. Haloperidol versus low-potency first-generation antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD009268. DOI: 10.1002/14651858.CD009268.pub2.

Author Information

  1. 1

    Technische Universität München Klinikum rechts der Isar, Klinik und Poliklinik für Psychiatrie und Psychotherapie, München, Germany

  2. 2

    Universitätsklinikum der Technischen Universität München, Klinik und Poliklinik für Psychiatrie und Psychotherapie, München, Bavaria, Germany

  3. 3

    Ludwig-Maximilians-University Munich, Psychiatric Hospital, Muenchen, Germany

  4. 4

    Technische Universität München, Department of Psychiatry and Psychotherapy, München, Germany

*Magdolna Tardy, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universität München Klinikum rechts der Isar, Möhlstr. 26, München, 81675, Germany. magdolnatardy@yahoo.de. tmaggie78@googlemail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 9 JUL 2014

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Characteristics of included studies [ordered by study ID]
Bi 1994

MethodsRandomisation: randomised, no further details.
Allocation: procedure not described.
Blinding: n.i., probably open.
Duration: 4 weeks.
Design: parallel.
Location: n.i..
Setting: n.i..


ParticipantsDiagnosis: schizophrenia (Research Diagnostic Criteria RDC) and (CCMD-2, Chinese classification of mental disorders).
N = 37.
Gender: 24 M, 26 F.
Age: 18-45 years.
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..


Interventions1. Haloperidol: fixed/flexible dose n.i., allowed dose range 5 to 100 mg/day, mean dose n.i.. N = 17.
2. Chlorpromazine: fixed/flexible dose n.i., allowed dose range 50 to 500 mg/day, mean dose n.i.. N = 20.
Other medication: n.i..


OutcomesResponse to treatment: BPRS (no clear definition).
Leaving the study early.
Mental state: BPRS.

Global state: CGI.

Adverse effects: at least one movement disorder, average score change in EPS.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised, no further details.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot indicated, probably open.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNot indicated, probably open.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information to permit judgement about incomplete outcome data.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgment about selective reporting.

Other biasLow riskNo clear other bias.

Blin 1996

MethodsRandomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, no further details.
Duration: 4 weeks.
Design: parallel.
Location: n.i..
Setting: inpatients.


ParticipantsDiagnosis: acute exacerbation of schizophrenia (DSM-III-R) and symptoms of anxiety (Psychotic Anxiety Scale > 34).
N = 41.
Gender: 24 M, 17 F.
Age: mean 34.05 years.
History: duration stable - n.i., duration ill - 3 participants < 1 year; 4 participants 1-3 years; 33 participants > 3 years, number of previous hospitalisations - n.i., age at onset - n.i., severity of illness - n.i., baseline antipsychotic dose n.i..


Interventions1. Haloperidol - flexible doses. Allowed dose range: 4 to 12 mg/day, mean dose 7.6 mg/day. N = 20.
2. Methotrimeprazine (levomepromazine) - flexible doses. Allowed dose range: 50 to 150 mg/day, mean dose 100 mg/day. N = 21.

Other medication: no other antipsychotics allowed except diazepam for extremely disturbed behavioUr; benzodiazepines, biperiden for EPS, heptaminol hydrochloride.


OutcomesResponse to treatment: at least 20% reduction in PANSS total score.

Mental state: PANSS, BPRS.

Global state: CGI.

Leaving the study early.

Adverse events: Extrapyramidal Symptom Rating Scale, movement disorders (tremor), adverse effects other (asthenia, constipation, dizziness, dry mouth, headache, hypotension, micturition disturbances, orthostatic symptoms, palpitations, repercussions on sexual life, somnolence, sleep disturbances, sweating).

Unable to use:

Mental state: PANSS anxiety reduction scores (incomplete data, no SD).

Mental state: Psychotic Anxienty Scale (incomplete data, no SD).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised, no further details.        

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble, no further details.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble, no further details.

Incomplete outcome data (attrition bias)
All outcomes
High risk25% of the participants in the haloperidol group left the study early, as compared to 38% in the levomepromazine group. The number was clearly higher in the low-potency group and the reasons differed. Data were analysed on a LOCF method, which is an imperfect method.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasLow riskNo clear other bias.

Borison 1989

MethodsRandomisation: randomised, no further details.
Allocation: procedure not described.
Blinding: double, no further details.
Duration: 6 weeks.
Design: parallel.
Location: n.i.,
Setting: n.i.,


ParticipantsDiagnosis: schizophrenia (DSM-III).

N = 10.
Gender: n.i.,
Age: range 18-60 years.
History: duration stable - n.i., duration ill - n.i., nr. of prev. hospitalisations - n.i., age at onset - n.i., severity of illness - min. 35 on BPRS, baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range 15 to 75 mg/t.i.d., mean dose n.i.. N = 8.
2. Thioridazine: flexible dose, allowed dose range 150 to 750 mg/t.i.d., mean dose n.i.. N = 8.

Other medication: chloral hydrate.


OutcomesResponse to treatment: BPRS (no definition).
Mental state: BPRS.

Relapse.

Leaving the study early.

Adverse events : movement disorders (akathisia, dystonia, rigor, use of antiparkinson medication), other adverse effects (hypotension, sedation).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised, no further details.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble, no further details.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble, no further details.

Incomplete outcome data (attrition bias)
All outcomes
High risk1 out of 8 participants from the thioridazine group (13%) left the study early due to inefficacy of treatment. 3 out of 8 participants from the haloperidol group (38%) left the study early to due improvement and administrative reasons. Drop-outs were not included in the final analysis.

Selective reporting (reporting bias)Low riskNo evidence for selective reporting.

Other biasLow riskNo clear other bias.

Clark 1969

MethodsRandomisation: n.i. but double-blind.
Allocation: procedure not described.
Blinding: double, no further details.
Duration: 12 weeks.
Design: parallel.
Location: n.i.,
Setting: inpatients.


ParticipantsDiagnosis: schizophrenia (clinical diagnosis).

N = 28.
Gender: 11 M, 17 F.
Age: range 22-61 years.
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.,


Interventions1. Haloperidol: flexible dose, allowed dose range 3 to 15 mg/day, mean dose n.i.. N = 14.
2. Chlorpromazine: flexible dose, allowed dose range 200 to 1600 mg/day, mean dose n.i.. N = 14.

Other medication: n.i..


OutcomesLeaving the study early.

Adverse effects: at least one adverse effect, movement disorders (use of antiparkinson medication).
Unable to use:

Mental state: BPRS (incomplete data, no mean, no SD).

Global state: CGI (incomplete data, no mean, no SD).

Behaviour: NOSIE (incomplete data, no mean, no SD).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported. but double-blind.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble, no further details.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble, no further details.

Incomplete outcome data (attrition bias)
All outcomes
High risk21% of participants from the chlorpromazine group left the study early. A completer analysis was applied.

Selective reporting (reporting bias)High riskCGI, BPRS, no mean and no SD.

Other biasUnclear riskThere is insufficient information to permit judgment about other bias.

Dufresne 1993

MethodsRandomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, identical capsules.
Duration: 6 weeks.
Design: parallel.
Location: n.i.,
Setting: n.i.,


ParticipantsDiagnosis: schizophrenia (DSM-III).

N = 30.
Gender: 20 F, 10 M.
Age: mean 34 years.
History: duration stable - n.i., duration ill - mean 13 years, nr. of prev. hospitalisations - 7, age at onset - mean 21 years, severity of illness - BPRS at baseline 59.9 (SD12.3), baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range 5 to 40 mg/day, mean dose n.i.. N = 16.
2. Thioridazine: flexible dose, allowed dose range 100 to 800 mg/day, mean dose N = 14.

Other medication: amantadine (antiparkinson medication), chloral hydrate.


OutcomesResponse to treatment: at least 20% reduction in BPRS total score.

Leaving the study early.

Adverse effects: at least one adverse effect, movement disorders (use of antiparkinson medication), other adverse effects (confusion, dry mouth, hypotension).
Unable to use:

Mental state: BPRS (incomplete data, no SD).
Depression: HAM-D (incomplete data, no SD).

Global state: CGI (incomplete data, no SD).

Adverse effects: weight (incomplete data).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised, no further details.       

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble, identical capsules.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble, identical capsules.

Incomplete outcome data (attrition bias)
All outcomes
High risk25% of haloperidol participants left the study early. A completers-only method was used in the study.

Selective reporting (reporting bias)High riskNo complete data for BPRS and HAM-D, SDs are missing.

Other biasLow riskNo clear other bias.

Fox 1964

MethodsRandomisation: randomly selected, no further details.
Allocation: procedure not described.
Blinding: double, no further details.
Duration: 1 month.
Design: parallel.
Location: single centre.
Setting: inpatient.


ParticipantsDiagnosis: chronic schizophrenic reaction (clinical diagnosis).

N = 30.
Gender: 45 F.
Age: mean 43.1 years.
History: duration stable - n.i., duration ill - n.i., number of previous hospitalisations - years mean 14.3, age at onset - n.i., severity of illness - n.i., baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range 2 to 16 mg/day, mean dose 13 mg/day. N = 15.
2. Chlorpromazine: flexible dose, allowed dose range 100 to 800 mg/day, mean dose 593 mg/day. N = 15.

Other medication: Cogentin.


OutcomesResponse to treatment: clinical judgement.

Unable to use:

Mental state: BPRS (incomplete data, no mean).

Global state: CGI (incomplete data, no mean).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomly selected, no further details.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble, no further details.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble, no further details.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence for incomplete outcome data.

Selective reporting (reporting bias)High riskIncomplete BPRS results (no SDs).

Other biasLow riskNo clear other bias.

Gallant 1967

MethodsRandomisation: randomly assigned, no further details.
Allocation: procedure not described.
Blinding: double, all drugs were supplied in identical capsules and dispensed from individual medication bottles, which were prepared and coded prior to the study.
Duration: 4 weeks.
Design: parallel.
Location: single centre.
Setting: inpatients.


ParticipantsDiagnosis: acute schizophrenia patients, clinical diagnosis.

N = 28.
Gender: 30 M, 28 F.
Age: mean 33.4 years.
History: duration stable - n.i., duration ill - n.i., nr. of prev. hospitalisations - n.i., age at onset - n.i., severity of illness - n.i., baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range max. 16 mg/day, mean dose n.i.. N = 19.
2. Chlorpromazine: flexible dose, allowed dose range max. 800 mg/day, mean dose n.i.. N = 19.

Other medication: antiparkinson medication.


OutcomesResponse to treatment: clinical judgement.

Adverse effects: movement disorders (at least one movement disorder, akathisia, dyskinesia), other adverse effects (blurring of vision, dry mouth, hypotension, rash, somnolence).

Unable to use:

Mental: Beckomberga Rating Scale (incomplete data, no SD).

Behaviour: MACC Behavioral Adjustment Scale (incomplete data, no SD).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomly assigned, no further details.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble, all drugs were supplied in identical capsules and dispensed from individual medication bottles, which were prepared and coded prior to the study.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble, all drugs were supplied in identical capsules and dispensed from individual medication bottles, which were prepared and coded prior to the study.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence for incomplete outcome data.

Selective reporting (reporting bias)High riskSDs were not reported for any of the outcome scales.

Other biasLow riskNo evidence for other bias.

Klimke 1993

MethodsRandomisation: randomised, no further details.
Allocation: procedure not described.
Blinding: double, patients and psychiatrists were blind to treatment conditions.
Duration: 24 days.
Design: parallel.
Location: single centre.
Setting: inpatients.


ParticipantsDiagnosis: acute schizophrenia (ICD-9).

N = 50.
Gender: 21 M, 29 F.
Age: mean 36.6 years.
History: duration stable - n.i., duration ill - mean 6.7 years, number of previous hospitalisations - mean 2.7, age at onset - mean 29.9 years, severity of illness - BPRS score mean 47.8 SD 14.1, baseline antipsychotic dose - 15 mg/day haloperidol i.v..


Interventions1. Haloperidol: fixed dose, mean dose 15 mg/day. N = 25.
2. Perazine: fixed dose, mean dose 300 mg/day. N = 25.
Other medication: 2 mg flunitrazepam (sleep disturbance), biperiden.


OutcomesRelapse.

Leaving the study early.

Unable to use:

Response to treatment: BPRS (no definition, results analysed by early responders and non-responders).

Mental state: BPRS (incomplete data, no SD).

Global state: global judgment of therapeutic efficacy (incomplete data, no SD).

Adverse effects (no usable data, results analysed by early responders and non-responders).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised, no further details.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble, patients and psychiatrists were blind to treatment conditions.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble, patients and psychiatrists were blind to treatment conditions.

Incomplete outcome data (attrition bias)
All outcomes
High risk13 out of 25 participants from the haloperidol group (52%) and 8 out of 25 participants from the perazine group (32%) left the study early. A LOCF methods was applied.

Selective reporting (reporting bias)High riskBPRS results only available for subgroups or independent of treatment condition.

Other biasLow riskNo evidence for other bias.

McCreadie 1977

MethodsRandomisation: randomly assigned, no further details.
Allocation: procedure not described.
Blinding: double, no further details, but tested at the end of the study before blind was broken. Psychiatrists guessed correctly in 8 participants, wrongly in 6.
Duration: 12 weeks.
Design: parallel.
Location: single centre.
Setting: inpatients.


ParticipantsDiagnosis: schizophrenia (Schneiderian first rank symptoms).

N = 20.
Gender: all male.
Age: mean 52 years.
History: duration stable - n.i., duration ill - n.i., number of previous hospitalisations - mean length 20 years, age at onset - n.i., severity of illness - n.i., baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range 15 to 100 mg/day, mean dose n.i.. N = 10.
2. Chlorpromazine: flexible dose, allowed dose range 100 to 600 mg/day, mean dose n.i.. N = 10.

Other medication: antiparkinson medication.


OutcomesResponse to treatment: clinical judgement.

Relapse.

Leaving the study early.

Adverse effects: movement disorders (akathisia, dystonia, use of antiparkinson medication), other adverse effects (photosensitivity, somnolence, weight gain).

Unable to use:

Mental state: Lorr Rating Scale modification - Hamilton scale (unpublished rating scale).

Behaviour: NOSIE (incomplete data).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomly assigned, no further details.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
High riskDouble, no further details, but tested at the end of the study before blind was broken. Psychiatrists guessed correctly in 8 participants, wrongly in 6.

Blinding of outcome assessment (detection bias)
All outcomes
High riskDouble, no further details, but tested at the end of the study before blind was broken. Psychiatrists guessed correctly in 8 participants, wrongly in 6.

Incomplete outcome data (attrition bias)
All outcomes
High risk2 out of 10 (20%) participants in the CPZ group left the study early due to adverse effects and inefficacy and were not included in the final analysis (completers only).

Selective reporting (reporting bias)Low riskNo evidence for selective reporting.

Other biasLow riskNo evidence for other bias.

Nishizono 1994

MethodsRandomisation: randomised, no further details.
Allocation: procedure not described.
Blinding: n.i., probably open.
Duration: 4 weeks.
Design: n.i.,
Location: multicentre.
Setting: n.i.,


ParticipantsDiagnosis: schizophrenia (ICD-10).

N = 109.
Gender: n.i.,
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.,


Interventions1. Haloperidol: flexible dose, allowed dose range n.i., dose max. 21 mg/day. N = 57.
2. Chlorpromazine: flexible dose, allowed dose range n.i., dose max. 450 mg/day. N = 52.

Other medication: n.i..


OutcomesResponse to treatment: at least 50% reduction in BPRS total score.

Unable to use:

Mental state: BPRS (incomplete data, no SD).

Global state: Global Assessment Scale (incomplete data, no SD).

Leaving the study early (no data available).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised, no further details.  

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
High riskn.i., probably open.

Blinding of outcome assessment (detection bias)
All outcomes
High riskn.i., probably open.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot enough information to permit judgement about incomplete outcome data.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement about selective reporting.

Other biasUnclear riskInsufficient information about other sources of bias.

Prasad 1966

MethodsRandomisation: not described, but double-blind.
Allocation: procedure not described.
Blinding: double, drugs were supplied in identical bottles marked by serial number without disclosing identity.
Duration: 12 weeks.
Design: parallel.
Location: single centre.
Setting: inpatients.


ParticipantsDiagnosis: schizophrenia symptoms (clinical diagnosis).

N = 40.
Gender: 3 males, 37 females.
Age: mean 51.8 years.
History:
duration stable - n.i., duration ill - mean 15.07 years, nr. of prev. hospitalisations - n.i., age at onset - mean 36.7 years, severity of illness - n.i., baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range 2 to 24 mg/day, mean dose 16.1 mg/day. N = 20.
2. Thioridazine: flexible dose, allowed dose range 60 to 720 mg/day, mean dose 518.6 mg/day. N = 20.

Other medication: trihexyphenicyl, benztropine.


OutcomesResponse to treatment: clinical judgement.

Leaving the study early.

Adverse effects: at least one adverse effect, other adverse effects (hypotension, weight gain, weight loss).

Unable to use:

Mental state: Lorr Rating Scale (incomplete data, no mean, no SD).

Adverse effects: diminished vision, corneal haziness, nasal congestion, agitation, akathisia, rigidity, drowsiness, drooling, flushed face, nictitation, tremor, nervous, dysphagia, sluggishness, confusion (all number of incidences, not number of participants).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation not described, but double-blind.      

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble, drugs were supplied in identical bottles marked by serial number without disclosing identity.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble, drugs were supplied in identical bottles marked by serial number without disclosing identity.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence for incomplete outcome data.

Selective reporting (reporting bias)High riskLorr Scale no means and SDs.

Other biasLow riskNo clear other bias.

Rompel 1978

MethodsRandomisation: random, no further details.
Allocation: procedure not described.
Blinding: double, tablets were in ordinary commercial form and in numbered bottles, issued by senior nursing staff, who were strictly forbidden to tell, in order to maintain investigator blind.
Duration: 8 weeks.
Design: parallel.
Location: single centre.
Setting: inpatients.


ParticipantsDiagnosis: firmly diagnosed as schizophrenics (clinical diagnosis).

N = 24.
Gender: 15 M, 10 F.
Age: mean 43.3 years.
History: duration stable - n.i., duration ill - n.i., number of previous hospitalisations - years mean 11.8, age at onset - n.i., severity of illness - n.i., baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range 5 to 30 mg/day, mean dose n.i.. N = 12.
2. Chlorpromazine: flexible dose, allowed dose range 50 to 600 mg/day, mean dose n.i.. N = 12.

Other medication: antiparkinson medication (Kemadrin).


OutcomesResponse to treatment: clinical judgement.

Adverse effects: at least one adverse effect, movement disorders (at least one MD).

Unable to use:

Leaving the study early (no data available).

Mental state: assessment on 18-symptom criteria by unpublished rating scale.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom, no further details.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
High riskDouble, tablets were in ordinary commercial form and in numbered bottles, issued by senior nursing staff, who were strictly forbidden to tell, in order to maintain investigator blind. This means that at least part of the personnel was not blind which can have led to performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble, tablets were in ordinary commercial form and in numbered bottles, issued by senior nursing staff, who were strictly forbidden to tell, in order to maintain investigator blind.

Incomplete outcome data (attrition bias)
All outcomes
High risk3 out of 13 participants from the chlorpromazine group left the study early but were replaced with others to keep the total up to 25 participants, thus having a total of 28 participants.

Selective reporting (reporting bias)Low riskNo evidence for selective reporting.

Other biasLow riskNo clear other bias.

Schmidt 1982

MethodsRandomisation: randomised, no further details.
Allocation: procedure not described.
Blinding: double, no further details.
Duration: 4 weeks.
Design: parallel.
Location: single centre.
Setting: inpatients.


ParticipantsDiagnosis: acute paranoid hallucinatory psychosis (ICD 9).

N = 32.
Gender: 32 M.
Age: mean 31.3 years.
History: duration stable - n.i., duration ill - mean 3.8 years, number of previous hospitalisations - mean 3, age at onset - mean 27.5, severity of illness - n.i., baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range 15 to 45 mg/day, mean dose 27.68 mg/day. N = 15.
2. Perazine: flexible dose, allowed dose range 300 to 900 mg/day, mean dose 612 mg/day. N = 17.

Other medication: biperiden.


OutcomesResponse to treatment: CGI Scale (no definition).

Relapse.

Leaving the study early.

Adverse effects: at least one adverse effect, movement disorders (dystonia, use of antiparkinson medication).

Unable to use:

Behaviour: weekly records of ward behaviour (incomplete data, no SD).

Mental state: subjective well-being EWL-K Jahnke & Debus 1977 (incomplete data, no Sd).

Global state: global clinical impression (incomplete data, no mean, no SD).

Adverse effects: gait, drooling (number of incidence, not number of participants).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised, no further details.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble, no further details.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble, no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk2 out of 17 participants from the perazine group (12%) left the study early due to inefficacy and had to be switched to haloperidol.

Selective reporting (reporting bias)High riskOutcomes of interest reported incompletely (Simpson Angus Scale - only sum scores, CGI - no data, EWL - no data, fine motor skills - no data).

Other biasLow riskNo clear other bias.

Serafetinides 1972

MethodsRandomisation: randomly assigned, no further details.
Allocation: procedure not described.
Blinding: double, all medications prepared in identically appearing capsules.
Duration: 12 weeks.
Design: parallel.
Location: single centre.
Setting: inpatients.


ParticipantsDiagnosis: chronic schizophrenia, clinical diagnosis.

N = 28.
Gender: 25 M, 32 F.
Age: mean 41.5 years.
History: duration stable - n.i., duration ill - mean 15 years, number of previous hospitalisations - 10.5, age at onset - mean 26.5 years, severity of illness - n.i., baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range n.i., mean dose 12.3 mg/day. N = 14.
2. Chlorpromazine: flexible dose, allowed dose range n.i., mean dose 830 mg/day. N = 14.

Other medication: concomitant medications for Parkinsonism, bedtime sedation.


OutcomesResponse to treatment: CGI Scale (no definition).

Relapse.

Leaving the study early.

Adverse effects: at least one movement disorder, adverse effects - other (ankle oedema, constipation, excitement, photosensitivity, sedation, weight gain, weight loss).

Unable to use:

Mental state: BPRS (incomplete data).

Global state: CGI scale for Severity of Illness and Severity of Improvement (incomplete data).

Behaviour: NOSIE, OBRS (all analysed by single items, no total score).

Cognitive: Purdue Pegboard Test, Digit Symbol test (incomplete data)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomly assigned, no further details.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble, all medications prepared in identically appearing capsules.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble, all medications prepared in identically appearing capsules.

Incomplete outcome data (attrition bias)
All outcomes
High risk3 out of 14 participants in the CPZ group (21%) left the study early due to worsening and were not included in the final analysis (completers only). No participant from the HAL group left the study early.

Selective reporting (reporting bias)High riskIncomplete data for BPRS, NOSIE and OBRS (no SD´s).

Other biasLow riskNo evidence for other bias.

Shalev 1993

MethodsRandomisation: randomly assigned, no further details.
Allocation: treating psychiatrists were blind to the sequence in which the drugs were to be given to the patient.
Blinding: not described, probably open.
Duration: 4 weeks.
Design: parallel (second part cross-over).
Location: single centre.
Setting: inpatients.


ParticipantsDiagnosis: chronic or subchronic schizophrenia (DSM-III).

N = 39.
Gender: 35 F, 25 M.
Age: mean 33 years.
History: duration stable - n.i., duration ill - mean 4.8 years, number of previous hospitalisations - mean 4.2, age at onset - mean 28.2 years, severity of illness - n.i., baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range n.i., mean dose 29.3 mg/day (SD 19.9). N = 18.
2. Levomepromazine: flexible dose, allowed dose range n.i., mean dose 379 mg/day (SD 128). N = 21.

Other medication: antiparkinson medication.


OutcomesResponse to treatment: clinical judgement.

Unable to use:

Mental state: BPRS (analysed by responders and non-responders, not by medication).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomly assigned, no further details.        

Allocation concealment (selection bias)Unclear risk"Treating psychiatrists were blind to the sequence in which the drugs were to be given to the patient."

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot described, probably open

Blinding of outcome assessment (detection bias)
All outcomes
High riskNot described, probably open

Incomplete outcome data (attrition bias)
All outcomes
High risk15 participants left the study early but it is not mentioned how many from which drug group

Selective reporting (reporting bias)Low riskNo clear selective outcome reporting.

Other biasLow riskNo evidence for other bias.

Weston 1973

MethodsRandomisation: randomly assigned, no further details.
Allocation: procedure not described.
Blinding: double - drugs supplied as tablets of identical colour and form, each patient being provided with a coded drug container.
Duration: 12 weeks.
Design: parallel.
Location: single centre.
Setting: inpatients.


ParticipantsDiagnosis: chronic schizophrenic patients (clinical diagnosis).

N = 86.
Gender: 45 M, 41 F.
Age: mean 49.9 years.
History: duration stable - n.i., duration ill - mean 21 years, number of previous hospitalisations - 2.1, age at onset - mean 27.8 years, severity of illness - n.i., baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range 4.5 to 9 mg/day, mean dose 5.25 mg/day. N = 42. 
2. Thioridazine: flexible dose, allowed dose range 300 to 600 mg/day, mean dose 331.08 mg/day. N = 44.

Other medication: antiparkinson medication.


OutcomesResponse to treatment: clinical judgement.

Leaving the study early.

Adverse effects: movement disorders (akathisia, dystonia, tremor), adverse effects - other (allergic reactions, amenorrhoea, blurring of vision, constipation, dizziness, dry mouth, drooling, headache, hypotension, loss of associated movement, nausea, oculogyric symptoms, photosensitivity, somnolence, syncope, tongue changes, urinary retention).

Unable to use:

Mental state: Psychiatric Reaction Profile, IMPS (all analysed by sex and single items).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomly assigned, no further details.       

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble - drugs supplied as tablets of identical colour and form, each patient being provided with a coded drug container.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble - drugs supplied as tablets of identical colour and form, each patient being provided with a coded drug container.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskTwo participants in the haloperidol group are missing from global assessment, yet there were no drop-outs according to the authors. It is not clear what happened with these two participants.

Selective reporting (reporting bias)Unclear riskNo evidence for selective reporting.

Other biasLow riskNo clear other bias.

White 1981

MethodsRandomisation: not mentioned, but double-blinded.
Allocation: procedure not described.
Blinding: double, no further information.
Duration: 4 weeks.
Design: parallel.
Location: n.i.,
Setting: inpatients.


ParticipantsDiagnosis: schizophrenia (Feighner criteria).

N = 39.
Gender: 18 M, 21 F.
Age: mean 25.3 years.
History: duration stable - n.i., duration ill - n.i., number of previous hospitalisations - n.i., age at onset - n.i., severity of illness - mean BPRS 43.36 (SD 7.46), mean CGI 3.18 (SD 0.96), baseline antipsychotic dose - n.i.,


Interventions1. Haloperidol: flexible dose, allowed dose range 2 to 100 mg/day, mean dose 28 mg/day. N = 21.
2. Mesoridazine: flexible dose, allowed dose range 100 to 800 mg/day, mean dose 421 mg/day. N = 18.

Other medication: antiparkinson medication.


OutcomesMental state: BPRS (no definition).

Global state: CGI scale for Severity of Illness and Severity of Improvement.

Adverse effects: movement disorders (at least one movement disorder, dystonia, use of antiparkinson medication), other adverse effects (somnolence).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot mentioned, but double-blind.

Allocation concealment (selection bias)Unclear riskProcedure not described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble, no further information.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble, no further information.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo participant left the study early. No evidence for other incomplete outcome data.

Selective reporting (reporting bias)Low riskNo evidence for selective reporting.

Other biasUnclear riskNo clear evidence for other bias, the study had a short duration.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Azima 1960Allocation: not randomised.

Bagne 1992Allocation: randomised.

Participants: chronic schizophrenic patients.

Intervention: haloperidol, thioridazine.

Outcome: no relevant outcome, testing of benefit/harm scores.

Blum 1969Allocation: not randomised.

Cassano 1975Method: not randomised, but double-blind.

Participants: chronic schizophrenic patients.

Intervention: haloperidol versus sulpiride, which is not a low-potency antipsychotic because it has similar properties as amisulpride and is not within the scope of the review. Moreover, sulpiride does not cause a lot of sedation at all.

Cosar 1999Allocation:randomised.
Participants people with schizophrenia.
Intervention: haloperidol versus chlorpromazine.
Outcomes: no usable data.

Crow 1986Allocation: randomised.

Participants: first episode schizophrenia.

Intervention: haloperidol, flupenthixol, trifluoperazine, pimozide, chlorpromazine versus placebo.
Outcomes: no usable data, results of drugs pooled, no data for single drugs.

Davies 2007Allocation: randomised.

Participants: schizophrenia, schizoaffective disorder or delusional disorder.

Intervention: first- generation (e.g. chlorpromazine, loxapine, sulpiride, haloperidol) and second-generation antipsychotics (risperidone, olanzapine, amisulpride, quetiapine).

Outcome: no usable data, no efficacy of treatment.

de Lima 2005Allocation: randomised.

Participants: schizophrenia.

Intervention: first- generation (chlorpromazine, haloperidol, trifluoperazine) versus olazapine, data not available for single FGAs separately.

Dubin 1985Allocation: randomised.

Participants: mostly bipolar disorder, manic, etiology unknown, not schizophrenia or schizophrenia-like illnesses.

Eitan 1992Allocation: not randomised.

Fux 1991Allocation:randomised.
Participants: people with chronic schizophrenia.
Intervention: haloperidol versus chlorprothixene (low-potency).
Outcomes: no usable data, results only available for combined cross-over phase, no results for first part separately.

Garry 1962Allocation: randomised.

Participants: schizophrenia.

Intervention: haloperidol versus placebo.

Gerlach 1978Allocation: not randomised.

Gillis 1977Allocation: not randomised.

Giordana 1984Allocation: randomised.

Participants: chronic delusional psychosis or schizophrenic psychosis.

Intervention: haloperidol versus pipotiazine, no low-potency antipsychotic.

Gonier 1970Method: randomised, but randomisation did not work.

Guazzelli 1995Allocation: randomised.

Participants: chronic schizophrenic patients.

Intervention: haloperidol versus sulpiride, which is not a low-potency antipsychotic because it has similar properties as amisulpride and is not within the scope of the review. Moreover, sulpiride does not cause a lot of sedation at all.

Harris 1992Allocation: randomised.

Participants: ambulatory psychiatric patients, not exclusively psychosis, also dementia.

Hayano 1989Allocation: not randomised.

Hogan 1992Allocation:randomised.
Participants people with schizophrenia.
Intervention: haloperidol versus chlorpromazine (low-potency).
Outcomes: no usable data, results analysed by dysphoric and non-dysphoric patients, not by drugs.

Horodnicki 1985Allocation: not randomised.

Lempérière 1962Allocation: randomised.
Participants people with paranoid schizophrenia.
Intervention: haloperidol versus chlorpromazine (low-potency).
Outcomes: no usable data, only abstract available without data.

Liu 1996Allocation: not randomised.

Marjerrison 1971Allocation: randomised.
Participants people with acute schizophrenia.
Intervention: haloperidol versus chlorprothixene (low-potency), placebo.
Outcomes: no usable data, no data for haloperidol versus chlorprothixene, just versus placebo.

Mechri 2006Allocation: not randomised.

Minami 1990Allocation: not randomised.

Mori 1989Method: probably randomised, double-blind.

Participants: schizophrenia.

Intervention: haloperidol versus sulpiride, which is not a low-potency antipsychotic because it has similar properties as amisulpride and is not within the scope of the review. Moreover, sulpiride does not cause a lot of sedation at all.

Mori 1990Allocation: not randomised.

Munk-Andersen 1984Method: randomised.

Participants: hebephrenic and paranoid schizophrenic participants.

Intervention: haloperidol versus sulpiride, which is not a low-potency antipsychotic because it has similar properties as amisulpride and is not within the scope of the review. Moreover, sulpiride does not cause a lot of sedation at all.

Nahunek 1982Method: controlled trial, but double-blind.

Participants: schizophrenia.

Intervention: haloperidol, oxyprothepine (not low-potency antipsychotic), placebo.

Okuda 1979Method: not randomised, but double-blind.

Participants: schizophrenia.

Intervention: haloperidol versus sulpiride, which is not a low-potency antipsychotic because it has similar properties as amisulpride and is not within the scope of the review. Moreover, sulpiride does not cause a lot of sedation at all.

Palma 1997Allocation: randomised.

Participants: schizophrenia.

Intervention: chlorpromazine, haloperidol, thioridazine, fluphenazine decanoate.

Outcomes: no usable data, data not available for drugs separately.

Rama 1981Allocation: randomised.

Participants: chronic schizophrenic patients.

Intervention: haloperidol versus sulpiride, which is not a low-potency antipsychotic because it has similar properties as amisulpride and is not within the scope of the review. Moreover, sulpiride does not cause a lot of sedation at all.

Ropert 1989Method: randomisation not mentioned, but double-blind.

Participants: acutely psychotic patients.

Intervention: haloperidol versus sulpiride, which is not a low-potency antipsychotic because it has similar properties as amisulpride and is not within the scope of the review. Moreover, sulpiride does not cause a lot of sedation at all.

Shvartsburd 1984Allocation: randomised.

Participants: schizophrenia, schizoaffective disorder or delusional disorder.

Intervention: haloperidol and thioridazine.

Outcome: no usable outcome, only data on plasma and levels of antipsychotics.

Singh 1975Allocation: randomised.

Participants: schizophrenia.

Intervention: haloperidol and chlorpromazine versus haloperidol and chlorpromazine in combination with benztropine.

Smith 1985Allocation: randomised.

Participants: chronic schizophrenic patients.

Intervention: only haloperidol, no comparator drug, comparison of haloperidol dosages (7.5 mg, 10, mg, 25 mg, 40mg).

Teja 1975Allocation: randomised.
Participants people with chronic schizophrenia.
Intervention: haloperidol versus chlorpromazine (low-potency), placebo, amitriptyline.
Outcomes: no usable data, no data available for haloperidol versus chlorpromazine.

Terminska 1989Allocation: not randomised.

Wang 2000Allocation: not randomised.

Zuoning 1999Allocation: not randomised.

 
Comparison 1. Comparison 1: HALOPERIDOL versus LOW-POTENCY ANTIPSYCHOTIC DRUGS

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Response to treatment14574Risk Ratio (M-H, Random, 95% CI)1.11 [0.86, 1.44]

 2 Mental state: 1a. General - overall symptoms - average endpoint score/change (BPRS, high = poor)4133Mean Difference (IV, Random, 95% CI)-0.09 [-2.15, 1.96]

 3 Mental state: 1b. General - overall symptoms - average endpoint score/change (PANSS, high = poor)1Mean Difference (IV, Random, 95% CI)Subtotals only

    3.1 total
141Mean Difference (IV, Random, 95% CI)-4.0 [-20.69, 12.69]

    3.2 positive
141Mean Difference (IV, Random, 95% CI)-1.0 [-6.77, 4.77]

    3.3 negative
141Mean Difference (IV, Random, 95% CI)-0.10 [-5.20, 5.00]

 4 Global state: Average endpoint score/change (CGI, high = poor)3117Mean Difference (IV, Random, 95% CI)0.09 [-0.31, 0.50]

 5 Relapse5141Risk Ratio (M-H, Random, 95% CI)0.64 [0.26, 1.57]

 6 Leaving the study early11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 due to any reason
11408Risk Ratio (M-H, Random, 95% CI)0.82 [0.38, 1.77]

    6.2 due to adverse effects
11408Risk Ratio (M-H, Random, 95% CI)0.44 [0.16, 1.20]

    6.3 due to inefficacy
10378Risk Ratio (M-H, Random, 95% CI)0.63 [0.31, 1.29]

 7 Adverse effects: 1. General - at least one adverse effect5158Risk Ratio (M-H, Random, 95% CI)1.97 [0.69, 5.66]

 8 Adverse effects: 2a. Specific - movement disorders12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    8.1 at least one movement disorder
5170Risk Ratio (M-H, Random, 95% CI)1.64 [1.22, 2.21]

    8.2 akathisia
4160Risk Ratio (M-H, Random, 95% CI)1.27 [0.56, 2.90]

    8.3 dyskinesia
138Risk Ratio (M-H, Random, 95% CI)3.0 [0.34, 26.33]

    8.4 dystonia
5193Risk Ratio (M-H, Random, 95% CI)4.71 [1.95, 11.36]

    8.5 loss of associated movement
186Risk Ratio (M-H, Random, 95% CI)7.33 [0.39, 137.68]

    8.6 oculogyric crisis
186Risk Ratio (M-H, Random, 95% CI)3.14 [0.13, 74.98]

    8.7 rigor
116Risk Ratio (M-H, Random, 95% CI)5.0 [0.28, 90.18]

    8.8 tremor
2127Risk Ratio (M-H, Random, 95% CI)2.17 [0.16, 29.13]

    8.9 use of antiparkinson medication
6165Risk Ratio (M-H, Random, 95% CI)2.88 [1.19, 7.00]

 9 Adverse effects: 2b. Specific - movement disorders - average endpoint score/change (ESRS, high = poor)278Mean Difference (IV, Random, 95% CI)2.01 [1.35, 2.68]

 10 Adverse effects: 3. Others9Risk Ratio (M-H, Random, 95% CI)Subtotals only

    10.1 allergy - allergic reactions
186Risk Ratio (M-H, Random, 95% CI)3.14 [0.13, 74.98]

    10.2 allergy - rash
138Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 69.31]

    10.3 allergy - tongue alterations
186Risk Ratio (M-H, Random, 95% CI)0.50 [0.28, 0.90]

    10.4 anticholinergic - blurring of vision
2124Risk Ratio (M-H, Random, 95% CI)0.78 [0.35, 1.70]

    10.5 anticholinergic - constipation
3155Risk Ratio (M-H, Random, 95% CI)1.53 [0.21, 11.20]

    10.6 anticholinergic - drooling
186Risk Ratio (M-H, Random, 95% CI)2.10 [0.20, 22.26]

    10.7 anticholinergic - dry mouth
4195Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

    10.8 anticholinergic - micturition disturbances
141Risk Ratio (M-H, Random, 95% CI)0.21 [0.01, 4.11]

    10.9 anticholinergic - repercussions on sexual life
141Risk Ratio (M-H, Random, 95% CI)0.21 [0.01, 4.11]

    10.10 anticholinergic - sweating
141Risk Ratio (M-H, Random, 95% CI)3.15 [0.36, 27.83]

    10.11 anticholinergic - urinary retention
186Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.12 cardiovascular - ankle edema
128Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.13 cardiovascular - dizziness
2127Risk Ratio (M-H, Random, 95% CI)0.36 [0.21, 0.62]

    10.14 cardiovascular - hypotension
6251Risk Ratio (M-H, Random, 95% CI)0.32 [0.10, 1.07]

    10.15 cardiovascular - orthostatic symptoms
141Risk Ratio (M-H, Random, 95% CI)0.35 [0.16, 0.78]

    10.16 cardiovascular - palpitations
141Risk Ratio (M-H, Random, 95% CI)0.30 [0.07, 1.28]

    10.17 cardiovascular - syncope
186Risk Ratio (M-H, Random, 95% CI)0.15 [0.01, 2.81]

    10.18 central nervous system - asthenia
141Risk Ratio (M-H, Random, 95% CI)2.10 [0.98, 4.51]

    10.19 central nervous system - confusion
130Risk Ratio (M-H, Random, 95% CI)2.65 [0.12, 60.21]

    10.20 central nervous system - excitement
128Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.21 central nervous system - headache
2127Risk Ratio (M-H, Random, 95% CI)2.67 [0.50, 14.19]

    10.22 central nervous system - nausea
186Risk Ratio (M-H, Random, 95% CI)1.57 [0.28, 8.94]

    10.23 central nervous system - photosensitivity
3134Risk Ratio (M-H, Random, 95% CI)0.41 [0.05, 3.39]

    10.24 central nervous system - sedation
244Risk Ratio (M-H, Random, 95% CI)0.30 [0.11, 0.82]

    10.25 central nervous system - sleep disturbances
141Risk Ratio (M-H, Random, 95% CI)6.30 [0.83, 47.80]

    10.26 central nervous system - somnolence
5224Risk Ratio (M-H, Random, 95% CI)0.91 [0.49, 1.72]

    10.27 hormonal - amenorrhoea
186Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.28 metabolic - weight gain
388Risk Ratio (M-H, Random, 95% CI)0.22 [0.06, 0.81]

    10.29 metabolic - weight loss
268Risk Ratio (M-H, Random, 95% CI)0.60 [0.06, 6.06]

 
Comparison 2. Subgroup analysis

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Response to treatment - each low-potency antipsychotic separately13558Risk Ratio (M-H, Random, 95% CI)1.10 [0.85, 1.42]

    1.1 versus chlorpromazine
7290Risk Ratio (M-H, Random, 95% CI)1.31 [0.97, 1.77]

    1.2 versus levomepromazine
280Risk Ratio (M-H, Random, 95% CI)0.86 [0.50, 1.49]

    1.3 versus perazine
132Risk Ratio (M-H, Random, 95% CI)1.13 [0.62, 2.08]

    1.4 versus thioridazine
3156Risk Ratio (M-H, Random, 95% CI)0.78 [0.31, 1.97]

 2 Response to treatment - treatment resistance13558Risk Ratio (IV, Random, 95% CI)1.10 [0.85, 1.42]

    2.1 not treatment resistant
11499Risk Ratio (IV, Random, 95% CI)1.16 [0.89, 1.51]

    2.2 treatment resistant
259Risk Ratio (IV, Random, 95% CI)0.91 [0.38, 2.17]

 
Comparison 3. Sensitivity analysis

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Response to treatment - fixed-effect model13558Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.91, 1.36]

 2 Response to treatment - exclusion of studies in which randomisation was assumed from blinding12518Risk Ratio (M-H, Random, 95% CI)1.09 [0.82, 1.44]

 3 Response to treatment - exclusion of non double-blind studies11412Risk Ratio (M-H, Random, 95% CI)1.11 [0.80, 1.54]

 4 Response to treatment - exclusion of outlier study leading to heterogeneity (Dufresne 1993)12528Risk Ratio (IV, Random, 95% CI)1.13 [0.93, 1.39]

 
Summary of findings for the main comparison. HALOPERIDOL versus LOW-POTENCY ANTIPSYCHOTIC DRUGS for schizophrenia

HALOPERIDOL versus LOW-POTENCY ANTIPSYCHOTIC DRUGS for schizophrenia

Patient or population: patients with schizophrenia
Settings:
Intervention: HALOPERIDOL versus LOW-POTENCY ANTIPSYCHOTIC DRUGS

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlHALOPERIDOL versus LOW-POTENCY ANTIPSYCHOTIC DRUGS

Clinical response to treatment
Follow-up: 2-12 weeks
Study populationRR 1.11
(0.86 to 1.44)
574
(14 studies)
⊕⊕⊝⊝
low1,2

361 per 1000401 per 1000
(310 to 520)

Moderate

334 per 1000371 per 1000
(287 to 481)

Leaving the study early - Due to any reason
Follow-up: 1-3 months
Study populationRR 0.82
(0.38 to 1.77)
408
(11 studies)
⊕⊕⊝⊝
low1,2

164 per 1000135 per 1000
(62 to 291)

Moderate

136 per 1000112 per 1000
(52 to 241)

Adverse effects - at least one adverse effectStudy populationRR 1.97
(0.69 to 5.66)
158
(5 studies)
⊕⊝⊝⊝
very low1,3,4

346 per 1000681 per 1000
(239 to 1000)

Moderate

235 per 1000463 per 1000
(162 to 1000)

Adverse effects - movement disorders - At least one movement disorder
Follow-up: 1-3 months
Study populationRR 1.64
(1.22 to 2.21)
170
(5 studies)
⊕⊕⊝⊝
low1,2

414 per 1000679 per 1000
(505 to 914)

Moderate

375 per 1000615 per 1000
(458 to 829)

Adverse effects - other - Sedation
Follow-up: 6-12 weeks
Study populationRR 0.3
(0.11 to 0.82)
44
(2 studies)
⊕⊕⊕⊝
moderate1

500 per 1000150 per 1000
(55 to 410)

Moderate

420 per 1000126 per 1000
(46 to 344)

DeathSee commentSee commentNot estimable0
(0)
See comment

Quality of lifeSee commentSee commentNot estimable0
(0)
See comment

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Risk of bias: rated 'serious' - many studies did not report the methods for sequence generation and/or allocation concealment, missing or unclear results for incomplete outcome data and selective reporting.
2 Imprecision: rated 'serious' - the total number of events is less than 300 and the estimate of effect includes appreciable benefit/harm.
3 Inconsistency: rated 'serious' - the P value for heterogeneity was statistically significant and the I-square higher than 80%, the direction of the effect was not the same for all the studies.
4 Imprecision: rated 'serious' - only a few studies contributed to this event and the confidence interval was large.
 
Table 1. Series of similar reviews

TitleReference

Haloperidol versus first-generation antipsychotics for schizophreniaDold 2012

Perphenazine versus low-potency antipsychotic drugsTardy 2011b

Fluphenazine versus low-potency antipsychotic drugsTardy 2011c

Trifluoperazine versus low-potency antipsychotic drugsTardy 2011d

Flupenthixol versus low-potency antipsychotic drugsTardy 2011e

 
Table 2. Comparisons suggested by excluded studies

ComparisonExcluded study tagCurrent relevant Cochrane review

Amitriptyline for schizophreniaTeja 1975Whitehead 2002

Antipsychotic (various) withdrawal versus continuation for schizophreniaCrow 1986-

Benztropine plus antipsychotic combinations for schizophreniaSingh 1975-

Haloperidol dose for schizophreniaSmith 1985Donnelly 2013

Haloperidol versus mid/high-potency antipsychotic drugs for schizophreniaGiordana 1984 (pipotiazine), Nahunek 1982 (oxyprothepine)-

Haloperidol versus placeboGarry 1962, Marjerrison 1971, Nahunek 1982, Teja 1975Adams 2013

Olanzapine versus first-generation antipsychotic drugs for schizophreniade Lima 2005Duggan 2005

Sulpiride for schizophreniaCassano 1975, Guazzelli 1995, Mori 1989, Munk-Andersen 1984, Okuda 1979, Rama 1981, Ropert 1989Omori 2009, Soares 1999

 
Table 3. Design of a future study

MethodsAllocation: randomised - clearly described generation of sequence and concealment of allocation.
Blinding: double - described and tested.
Duration: 6 months.

ParticipantsPeople with schizophrenia or schizophrenia-like disorder.
N = 500.
Age: any.
Sex: both.
History: any.

Interventions1. High-potency antipsychotic drug (haloperidol).

2. Low-potency antipsychotic drugs.

OutcomesResponse (primary outcome)

Global state (number of participants improved)

Leaving the study early (including specific causes)

Death (natural and unnatural causes)

Quality of life

Satisfaction with care

Days in hospital

Number of healthy days

Side-effects

Employment and other measures of functioning