Chlorpromazine versus penfluridol for schizophrenia

Naemeh Nikvarz; Mostafa Vahedian; Navid Khalili

doi:10.1002/14651858.CD011831.pub2

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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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