Chlorpromazine versus penfluridol for schizophrenia

Naemeh Nikvarz; Mostafa Vahedian; Navid Khalili

doi:10.1002/14651858.CD011831.pub2

Clorpromazina versus penfluridol para la esquizofrenia

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Referencias

References to studies included in this review

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estudios excluidos
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otras versiones publicadas

Chouinard G, Annable L. Penfluridol in the treatment of newly admitted schizophrenic patients in a brief therapy unit. American Journal of Psychiatry 1976;133(7):850‐3. [PUBMED: 937582]

Chouinard G, Annable L, Cooper S. Antiparkinsonian drug administration and plasma levels of penfluridol, a new long‐acting neuroleptic. Communications in Psychopharmacology 1977;1(4):325‐31. [PUBMED: 615695]

Chouinard G, Annable L, Kolivakis TN. Penfluridol in the maintenance treatment of schizophrenic patients newly discharged from a brief therapy unit. Journal of Clinical Pharmacology 1977;17(2‐3):162‐7. [PUBMED: 833344]

Claghorn JL, Mathew RJ, Mirabi M. Penfluridol: a long acting oral antipsychotic drug. Journal of Clinical Psychiatry 1979;40(2):107‐9. [PUBMED: 368045]

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References to studies excluded from this review

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otras referencias
otras versiones publicadas

Bao XQ. A double‐blind study on the effect of clozapine, penfluridol and chlorpromazine in the treatment of schizophrenia. Chinese Journal of Neurology and Psychiatry 1988;21(5):274‐6, 318. [PUBMED: 3069382]

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References to other published versions of this review

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estudios incluidos
estudios excluidos
otras referencias

Khalili N, Vahedian M, Nikvarz N, Piri M. Chlorpromazine versus penfluridol for schizophrenia. Cochrane Database of Systematic Reviews 2015, Issue 8. [DOI: 10.1002/14651858.CD011831]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Chouinard 1977

Methods	Allocation: randomised. Blindness: double‐blind. Location: inpatient and outpatient. Duration: 13 weeks (3 weeks inpatient, 10 weeks outpatient).
Participants	Diagnosis: schizophrenia (DSM‐II). N = 33. Age: 19‐60 years ( mean 35.7 ± 12.6). Sex: 15M and 14F* . History: 15 participants had been hospitalised for less than a year.
Interventions	1. Chlorpromazine: oral ‐ 300 mg/day the first week, 600 mg/day second week, and 900 mg/day third week. N = 19. 2. Penfluridol: oral ‐ 40 mg/day the first week, 80 mg/day second week, and 120 mg/day third week. N = 14.
Outcomes	Adverse events: general (needing antiparkinson medication, reduction in antipsychotic dose due to side effects, specific (extrapyramidal and various other effects). Leaving the study early. Unable to use ‐ Global state: average score/change CGI (no data). Need for additional medication: not outcome prespecified in protocol. Mental state: average score/change BPRS and IMPS (no SD).
Notes	* 4 participants left early during inpatient phase‐not included in follow‐up analyses at 13 weeks.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Subjects were assigned to one of two evaluating psychiatrists in such a way that each psychiatrist evaluated a group that included both male and female patients, permitting the examination of a possible sex effect. Individuals in each group were randomly assigned to one of the two drug treatments, penfluridol or chlorpromazine, which were administered under double‐blind conditions".
Allocation concealment (selection bias)	Unclear risk	No description regarding allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Described as double blind‐no further details reported.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details about blinding of outcome assessment given "Assessment of symptoms was based on clinical interviews conducted by one of the two psychiatrists, the same psychiatrist always evaluating the same group of patients".
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition low and clearly described.
Selective reporting (reporting bias)	Unclear risk	All outcomes reported, but poor reporting of scale data.
Other bias	Unclear risk	Source of funding not reported.

Claghorn 1979

Methods	Allocation: randomised. Blindness: double‐blind. Location: inpatient. Duration: 52 weeks.
Participants	Diagnosis: schizophrenia. N = 56. Age: mean ˜37 years. Sex: 32M, 24F. History: duration ill ˜10 years, duration of present episode ˜8 years.
Interventions	1. Chlorpromazine: oral‐maximum 380 mg/day‐initially , maximum 760 mg/day thereafter; final mean 300mglday. N = 28. 2. Penfluridol: oral‐ maximum 80 mg/week‐initially, maximum 160 mg/week thereafter; final mean 74 mg/week. N = 28. Both groups received antiparkinsonian medication, chloral hydrate as required.
Outcomes	Adverse events: any, central nervous system, hepatic‐"increased alkaline phosphatase, bilirubin, SGOT". Leaving the study early. Unable to use ‐ Adverse events: "aberrations in physical or laboratory data" (no data reported), systems other than central nervous system (some listed but stated to be "infrequent"‐no numbers), physical examination, electrocardiograms, slit lamp tests, laboratory studies, vital signs (no data). Global state: CGI (> 50% loss to follow‐up). Social functioning: ESF (> 50% loss to follow‐up). Mental state: BPRS (> 50% loss to follow‐up).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	..."randomly assigned in blocks of 8 or 10".
Allocation concealment (selection bias)	Unclear risk	No description regarding allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Described as "double blind"‐placebo tablet given to penfluridol group to cover non‐drug days. No further details reported.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details about blinding of outcome assessment.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Attrition high but clearly described.
Selective reporting (reporting bias)	High risk	Adverse effects mostly reported if frequent (unclear how frequent), poor reporting of scale data.
Other bias	Unclear risk	Source of funding not reported.

Wang 1982

Methods	Allocation: randomised. Blindness: double blind. Location: inpatient. Duration: 20 weeks.
Participants	Diagnosis: schizophrenia. N = 41 (double‐blind phase).* Age: 20‐60 years. Sex: all male. History: chronic schizophrenia for at least 18 months prior to the start of the study. Excluded: all participants were stabilised on penfluridol before the trial, participants who did not complete dose titration were excluded before randomisation.
Interventions	1. Chlorpromazine: oral (150 mg/day to 1050 mg/day). N = 20. 1. Penfluridol: oral (20 mg to 140 mg once a week). N = 21.
Outcomes	Adverse events: use of antiparkinson medication, extrapyramidal. Leaving the study early. Unable to use ‐ Global state: average score/change CGI (no SD). Use of additional antipsychotic: not outcome prespecified in protocol. Mental state: average score/change BPRS (no SD). Behaviour: average score/change NOSIE (no SD). Social functioning: average score/change ESF (no SD).
Notes	Trial had a dose titration phase where all participants stabilised on penfluridol and a double‐blind phase where participants randomised to continue penfluridol or switch to chlorpromazine, we only used data from the double‐blind phase. It is indicated in the paper that there were no statistical differences in scale‐derived data, and that patients on penfluridol had more akathisia than patients on chlorpromazine, but no data presented.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"When the patients were stable, they were randomly assigned to a penfluridol or a chlorpromazine group".
Allocation concealment (selection bias)	Unclear risk	No details regarding allocation concealment given.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"All patients received identical appearing capsules on a special "blister pack" medication card allowing the patient to take the medication on a twice‐a‐day schedule".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not clear if outcome assessor was blind‐"The rating scales for evaluating efficacy ...... were completed by the psychiatrist investigator".
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition low and clearly described.
Selective reporting (reporting bias)	Unclear risk	All outcomes reported, but poor reporting of scale data.
Other bias	Unclear risk	No further details.

BPRS‐Brief Psychiatric Rating Scale
CGI‐Clinical Global Impression
ESF‐Evaluation of Social Functioning
IMPS: Inpatient Multidimensional Psychiatric Scale
NOSIE‐Nurse's Observation Scale for Inpatient Evaluation
SD: standard deviation
SGOT: serum glutamic oxaloacetic transaminase

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study

Reason for exclusion

Bao 1988

Allocation: quasi‐randomised.

Li 1987

Allocation: randomised.

Participants: people with schizophrenia.

Intervention: penfluridol versus chlorpromazine versus clozapine.

Outcome: all data unusable data as numbers allocated to each group not reported.

Data and analyses

Open in table viewer

Comparison 1. CHLORPROMAZINE versus PENFLURIDOL

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Service utilisation: 1. Hospital readmission Show forest plot	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 3.60]
Open in figure viewer Analysis 1.1 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 1 Service utilisation: 1. Hospital readmission.
1.1 short term	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 3.60]
2 Adverse effects: 1a. General ‐ needing antiparkinsonian medication Show forest plot	2	74	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.51, 0.95]
Open in figure viewer Analysis 1.2 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 2 Adverse effects: 1a. General ‐ needing antiparkinsonian medication.
2.1 short term	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.46, 1.46]
2.2 medium term	1	41	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.43, 0.91]
3 Adverse effects: 1b. General ‐ need to reduce antipsychotic dose due to side effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.3 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 3 Adverse effects: 1b. General ‐ need to reduce antipsychotic dose due to side effects.
3.1 medium term	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.26, 2.06]
4 Adverse effects: 2a. Specific ‐ extrapyramidal events (moderate or severe) ‐ short term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.4 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 4 Adverse effects: 2a. Specific ‐ extrapyramidal events (moderate or severe) ‐ short term.
4.1 akatisia	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 dyskinesia	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 dystonia	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 rigidity	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.90]
4.5 tremor	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Adverse effects: 2b. Specific ‐ extrapyramidal events (moderate or severe) ‐ medium term Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.5 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 5 Adverse effects: 2b. Specific ‐ extrapyramidal events (moderate or severe) ‐ medium term.
5.1 akathisia	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.04, 1.06]
5.2 dyskinesia	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.14, 6.52]
5.3 dystonia	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.06, 13.54]
5.4 muscle spasm	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 70.64]
5.5 rigidity	2	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.04, 1.20]
5.6 tremor	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.14, 3.43]
6 Adverse effects: 2c. Specific ‐ anticholinergic (moderate or severe) ‐ short term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.6 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 6 Adverse effects: 2c. Specific ‐ anticholinergic (moderate or severe) ‐ short term.
6.1 constipation	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	4.42 [0.60, 32.71]
6.2 dry mouth	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.10, 51.46]
6.3 increased salivation	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.01, 5.72]
7 Adverse effects: 2d. Specific ‐ anticholinergic (moderate or severe) ‐ medium term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.7 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 7 Adverse effects: 2d. Specific ‐ anticholinergic (moderate or severe) ‐ medium term.
7.1 blurred vision	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.01, 7.09]
7.2 constipation	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	3.73 [0.47, 29.49]
7.3 dry mouth	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	2.81 [0.12, 63.83]
8 Adverse effects: 2e. Specific ‐ central nervous system (moderate or severe) ‐ short term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.8 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 8 Adverse effects: 2e. Specific ‐ central nervous system (moderate or severe) ‐ short term.
8.1 agitation	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.10, 51.46]
8.2 drowsiness	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	8.25 [0.49, 137.94]
8.3 dizziness	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.12]
8.4 insomnia	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.10, 51.46]
9 Adverse effects: 2f. Specific ‐ central nervous system (moderate or severe) ‐ medium term Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.9 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 9 Adverse effects: 2f. Specific ‐ central nervous system (moderate or severe) ‐ medium term.
9.1 drowsiness	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.54, 2.05]
9.2 dizziness	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.05, 4.60]
9.3 excitement	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	2.81 [0.12, 63.83]
9.4 faintness	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.15, 5.76]
9.5 insomnia	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.17 [0.03, 0.93]
10 Adverse effects: 2g. Specific ‐ various other effects (moderate or severe) ‐ short term Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.10 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 10 Adverse effects: 2g. Specific ‐ various other effects (moderate or severe) ‐ short term.
10.1 heartburn	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 increased alkaline phosphatase, bilirubin, SGOT	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.85]
10.3 systemic allergic reaction	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	5.25 [0.29, 94.14]
11 Adverse effects: 2h. Specific ‐ various other effects (moderate or severe) ‐ medium term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.11 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 11 Adverse effects: 2h. Specific ‐ various other effects (moderate or severe) ‐ medium term.
11.1 depression	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 3.60]
11.2 decreased sexual drive	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.05, 4.60]
11.3 impotence	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	2.81 [0.12, 63.83]
11.4 photosensitivity	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	2.81 [0.12, 63.83]
11.5 poor appetite	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.06, 13.54]
12 Leaving the study early: 1a. Any reason Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.12 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 12 Leaving the study early: 1a. Any reason.
12.1 medium term	3	130	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.83, 1.77]
13 Leaving the study early: 1b. Due to adverse events Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.13 Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 13 Leaving the study early: 1b. Due to adverse events.
13.1 short term	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	6.75 [0.39, 116.00]
13.2 medium term	2	74	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.72, 3.28]

Figure 1

Chlorpromazine structure

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Figure 2

Penfluridol structure

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Figure 3

Study flow diagram.

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Figure 4

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 5

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 1 Service utilisation: 1. Hospital readmission.

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Analysis 1.2

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 2 Adverse effects: 1a. General ‐ needing antiparkinsonian medication.

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Analysis 1.3

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 3 Adverse effects: 1b. General ‐ need to reduce antipsychotic dose due to side effects.

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Analysis 1.4

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 4 Adverse effects: 2a. Specific ‐ extrapyramidal events (moderate or severe) ‐ short term.

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Analysis 1.5

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 5 Adverse effects: 2b. Specific ‐ extrapyramidal events (moderate or severe) ‐ medium term.

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Analysis 1.6

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 6 Adverse effects: 2c. Specific ‐ anticholinergic (moderate or severe) ‐ short term.

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Analysis 1.7

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 7 Adverse effects: 2d. Specific ‐ anticholinergic (moderate or severe) ‐ medium term.

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Analysis 1.8

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 8 Adverse effects: 2e. Specific ‐ central nervous system (moderate or severe) ‐ short term.

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Analysis 1.9

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 9 Adverse effects: 2f. Specific ‐ central nervous system (moderate or severe) ‐ medium term.

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Analysis 1.10

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 10 Adverse effects: 2g. Specific ‐ various other effects (moderate or severe) ‐ short term.

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Analysis 1.11

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 11 Adverse effects: 2h. Specific ‐ various other effects (moderate or severe) ‐ medium term.

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Analysis 1.12

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 12 Leaving the study early: 1a. Any reason.

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Analysis 1.13

Comparison 1 CHLORPROMAZINE versus PENFLURIDOL, Outcome 13 Leaving the study early: 1b. Due to adverse events.

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Table 2. Suggested design of study

Methods	Allocation: randomised, fully explicit description of methods of randomisation and allocation concealment. Blinding: single‐blind or double‐blind, but tested. Setting: anywhere. Duration: follow‐up to at least 52 weeks.
Participants	Diagnosis: schizophrenia. N = 300.* Age: adults. Sex: both.
Interventions	1. Chlorpromazine: oral‐maximum around 400 mg/day. N = 150. 2. Penfluridol: oral‐maximum around 80 mg/week. N = 150. Both groups could receive antiparkinsonian medication as required.
Outcomes	Service utilisation: Hospital admission, time to admission. Global state: Clinically significant response in global state, relapse. Mental state: Clinically significant response in mental state. Adverse effects: Clinically significant extrapyramidal side effects, death. Leaving the study early. Functioning: Employed, days working, in supportive relationship, healthy days. Economic outcomes.
Notes	* Powered to be able to identify a difference of ˜ 20% between groups for primary outcome with adequate degree of certainty.

Table 2. Suggested design of study

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Chlorpromazine versus Penfluridol for schizophrenia
Patient or population: patients with schizophrenia Settings: hospital inpatients and outpatients Intervention: Chlorpromazine versus penfluridol
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk³	Corresponding risk
	Penfluridol	Chlorpromazine
Service utilisation: hospital admission (short term)	150 per 1000	28 per 1000 (1 to 540)	RR 0.19 (0.01 to 3.60)	29 (1 study)	⊕⊕⊝⊝ low ^1,2
Global state: clinically important change in global state	See comment		Not estimable	0 (0)	See comment	No studies reported 'clinically important change in global state'. Change in global state was measure using global state scales but all data were presented without SD.
Global state: relapse	See comment		Not estimable	0 (0)	See comment	No studies reported this outcome.
Mental state: clinically important change in mental state	See comment		Not estimable	0 (0)	See comment	No studies reported 'clinically important change in mental state'. Change in mental state was measure using mental state scales but all data were presented without SD.
Adverse effect/event: clinically important extrapyramidal adverse events ‐ akathisia (medium term)	200 per 1000	38 per 1000 (8 to 212)	RR 0.19 (0.04 to 1.06)	85 (2 studies)	⊕⊕⊝⊝ low ^1,2	The same studies reported data for other extrapyramidal adverse events such as rigidity, tremor, dystonia and dyskinesia. There was no observable difference between chlorpromazine and penfluridol regarding any of these adverse effects.
Adverse effect/event: death	See comment		Not estimated	2 RCTs (0)	See comment	No deaths reported.
Leaving the study early: any reason (medium term)	400 per 1000	484 per 1000 (332 to 708)	RR 1.21 (0.83 to 1.77)	130 (3 studies)	⊕⊕⊝⊝ low ^1,2
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; SD: standard deviation
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 Serious risk of bias: downgraded by one level ‐ study had an unclear risk of bias for random sequence generation and blinding of assessors. ² Serious risk of imprecision: downgraded by one level ‐ studies had small sample sizes and number of events. ³ We have used the risk of an event in the penfluridol group within the trial/s the benchmark, rounding to nearest five for clarity of presentation in the table.

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Table 1. Cochrane reviews on chlorpromazine for people with schizophrenia

Review title	Reference
Acetophenazine versus chlorpromazine	Bazrafshan 2015
Chlorpromazine dose for people with schizophrenia	Dudley 2009
Cessation of medication for people with schizophrenia already stable on chlorpromazine	Almerie 2007
Chlorpromazine versus atypical antipsychotic drugs for schizophrenia	Saha 2013
Chlorpromazine versus clotiapine for schizophrenia	Developing protocol
Chlorpromazine versus haloperidol for schizophrenia	Leucht 2008
Chlorpromazine versus metiapine	Zare 2015
Chlorpromazine versus penfluridol for schizophrenia	Current review
Chlorpromazine versus piperacetazine	Eslami 2015
Chlorpromazine versus placebo for schizophrenia	Adams 2014
Chlorpromazine for psychosis induced aggression or agitation	Ahmed 2010

Table 1. Cochrane reviews on chlorpromazine for people with schizophrenia

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Comparison 1. CHLORPROMAZINE versus PENFLURIDOL

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Service utilisation: 1. Hospital readmission Show forest plot	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 3.60]

1.1 short term	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 3.60]
2 Adverse effects: 1a. General ‐ needing antiparkinsonian medication Show forest plot	2	74	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.51, 0.95]

2.1 short term	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.46, 1.46]
2.2 medium term	1	41	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.43, 0.91]
3 Adverse effects: 1b. General ‐ need to reduce antipsychotic dose due to side effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 medium term	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.26, 2.06]
4 Adverse effects: 2a. Specific ‐ extrapyramidal events (moderate or severe) ‐ short term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 akatisia	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 dyskinesia	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 dystonia	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 rigidity	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.90]
4.5 tremor	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Adverse effects: 2b. Specific ‐ extrapyramidal events (moderate or severe) ‐ medium term Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 akathisia	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.04, 1.06]
5.2 dyskinesia	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.14, 6.52]
5.3 dystonia	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.06, 13.54]
5.4 muscle spasm	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 70.64]
5.5 rigidity	2	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.04, 1.20]
5.6 tremor	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.14, 3.43]
6 Adverse effects: 2c. Specific ‐ anticholinergic (moderate or severe) ‐ short term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 constipation	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	4.42 [0.60, 32.71]
6.2 dry mouth	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.10, 51.46]
6.3 increased salivation	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.01, 5.72]
7 Adverse effects: 2d. Specific ‐ anticholinergic (moderate or severe) ‐ medium term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 blurred vision	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.01, 7.09]
7.2 constipation	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	3.73 [0.47, 29.49]
7.3 dry mouth	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	2.81 [0.12, 63.83]
8 Adverse effects: 2e. Specific ‐ central nervous system (moderate or severe) ‐ short term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.1 agitation	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.10, 51.46]
8.2 drowsiness	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	8.25 [0.49, 137.94]
8.3 dizziness	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.12]
8.4 insomnia	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.10, 51.46]
9 Adverse effects: 2f. Specific ‐ central nervous system (moderate or severe) ‐ medium term Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 drowsiness	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.54, 2.05]
9.2 dizziness	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.05, 4.60]
9.3 excitement	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	2.81 [0.12, 63.83]
9.4 faintness	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.15, 5.76]
9.5 insomnia	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.17 [0.03, 0.93]
10 Adverse effects: 2g. Specific ‐ various other effects (moderate or severe) ‐ short term Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 heartburn	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 increased alkaline phosphatase, bilirubin, SGOT	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.85]
10.3 systemic allergic reaction	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	5.25 [0.29, 94.14]
11 Adverse effects: 2h. Specific ‐ various other effects (moderate or severe) ‐ medium term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

11.1 depression	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 3.60]
11.2 decreased sexual drive	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.05, 4.60]
11.3 impotence	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	2.81 [0.12, 63.83]
11.4 photosensitivity	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	2.81 [0.12, 63.83]
11.5 poor appetite	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.06, 13.54]
12 Leaving the study early: 1a. Any reason Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

12.1 medium term	3	130	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.83, 1.77]
13 Leaving the study early: 1b. Due to adverse events Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

13.1 short term	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	6.75 [0.39, 116.00]
13.2 medium term	2	74	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.72, 3.28]

Comparison 1. CHLORPROMAZINE versus PENFLURIDOL

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Referencias

References to studies included in this review

Chouinard 1977 {published data only}

Claghorn 1979 {published data only}

Wang 1982 {published data only}

References to studies excluded from this review

Bao 1988 {published data only}

Li 1987 {published data only}

Additional references

Adams 2005

Adams 2014

Ahmed 2010

Almeida‐Filho 1997

Almerie 2007

Altman 1996

Bazrafshan 2015

Bland 1997

Boissel 1999

Caldwell 1992

Crow 1980

Deeks 2000

Deeks 2011

Divine 1992

Donner 2002

Dudley 2009

Egger 1997

Elbourne 2002

Eslami 2015

Fioravanti 2005

Furukawa 2006

Gerlach 1975

Gulliford 1999

Higgins 2003

Higgins 2011

Higgins 2011a

Hutton 2009

Ionescu 1983

Janssen 1970

Kay 1986

Leon 2006

Leucht 2005a

Leucht 2005b

Leucht 2008

Liddle 1987

Lindstrom 2000

Manu 2011

Marshall 2000

Moher 2001

Overall 1962

Perala 2007

Rees 1960

Reynolds 1982

Saha 2013

Schünemann 2011

Soares 2006

Sterne 2011

Ukoumunne 1999

van Praag 1971

WHO 2015

Xia 2009

Zare 2015

References to other published versions of this review

Khalili 2005

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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