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Cochrane Database of Systematic Reviews

Zuclopenthixol versus placebo for schizophrenia

Information

DOI:
https://doi.org/10.1002/14651858.CD010598.pub2Copy DOI
Database:
  1. Cochrane Database of Systematic Reviews
Version published:
  1. 01 December 2015see what's new
Type:
  1. Intervention
Stage:
  1. Review
Cochrane Editorial Group:
  1. Cochrane Schizophrenia Group

Copyright:
  1. Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

  • Michael Lacey

    Correspondence to: Department of Psychological Medicine, Humber NHS Foundation Trust, Hull, UK

    [email protected]

  • Mahesh B Jayaram

    Department of Psychiatry, Melbourne Neuropsychiatry Centre, Melbourne, Australia

Contributions of authors

ML ‐ Came up with the concept, devised and drafted the protocol.

MJ ‐ Helped with revising the protocol.

Sources of support

Internal sources

  • Leeds and York Partnerships NHS Foundation Trust, UK.

    Both authors were employed by this organisation at the time of writing this review

External sources

  • University of Leeds, UK.

    ML is undertaking a masters degree with this organisation and has access to their resources. An adapted version of this review will be submitted as ML's masters dissertation

  • Cochrane Collaboration Programme Grant 2011, Reference number: 10/4001/15, UK.

Declarations of interest

ML ‐ None known.

MJ ‐ None known.

Acknowledgements

The Cochrane Schizophrenia Group Editorial Base in Nottingham produces and maintains standard text for use in the Methods section of their reviews. We have used this text as the basis of what appears here and adapted it as required.

We would like to thank Christine Esbensen for help with the development of the protocol (also see Differences between protocol and review)

The search term was developed by the Trials Search Co‐ordinator of the Cochrane Schizophrenia Group, Samantha Roberts and the contact author of this protocol. We would also like to thank Shaimaa Abou Damaa for peer reviewing the protocol. Gabrielle Matta and Rahul Khanna provided peer review comments for the review version and Denise Mitchell copy edited.

Parts of this review were generated using RevMan HAL v 4.2. You can find more information about RevMan HAL here.

Version history

Published

Title

Stage

Authors

Version

2015 Dec 01

Zuclopenthixol versus placebo for schizophrenia

Review

Michael Lacey, Mahesh B Jayaram

https://doi.org/10.1002/14651858.CD010598.pub2

2013 Jun 18

Zuclopenthixol versus placebo for schizophrenia

Protocol

Michael Lacey, Mahesh B Jayaram, Christine Esbensen

https://doi.org/10.1002/14651858.CD010598

Differences between protocol and review

As only a small number of papers were identified the second author checked all data calculations as opposed to the originally planned 20%.

We added 'in schizophrenia' to objectives make the popluation clearer and match selection criteria.

Although CE was involved in the development of the protocol this author had to stop participation due to personal circumstances. Therefore MJ fulfilled this role. It was agreed that if there were conflicts between ML and MJ a third party would be involved to resolve these. However, there were no conflicts and this was unnecessary.

In the protocol the entries listed for inclusion in the summary of results table were, clinically significant response on global state ‐ as defined by each of the studies, clinically significant response on psychotic symptoms ‐ as defined by each of the studies, significant change in quality of life/satisfaction ‐ as defined by each of the studies and death. These outcomes were considered too narrow and limited so in the final version of the review a broader range of outcomes and ones with clinical usefulness were chosen

Keywords

MeSH

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Zuclopenthixol structure
Figures and Tables -
Figure 1

Zuclopenthixol structure

Processing search results
Figures and Tables -
Figure 2

Processing search results

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 3

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

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 4

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

Comparison 1 ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO, Outcome 1 Clinically significant response: Improvement (CGI) ‐ short term.
Figures and Tables -
Analysis 1.1

Comparison 1 ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO, Outcome 1 Clinically significant response: Improvement (CGI) ‐ short term.

Comparison 1 ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO, Outcome 2 Global state: Average score of severity of illness ‐ short term (CGI, high score=bad).
Figures and Tables -
Analysis 1.2

Comparison 1 ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO, Outcome 2 Global state: Average score of severity of illness ‐ short term (CGI, high score=bad).

Comparison 1 ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO, Outcome 3 Adverse effects: 1. Various ‐ short term.
Figures and Tables -
Analysis 1.3

Comparison 1 ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO, Outcome 3 Adverse effects: 1. Various ‐ short term.

Comparison 1 ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO, Outcome 4 Adverse effects: 2. Laboratory values ‐ abnormal ‐ short term.
Figures and Tables -
Analysis 1.4

Comparison 1 ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO, Outcome 4 Adverse effects: 2. Laboratory values ‐ abnormal ‐ short term.

Comparison 1 ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO, Outcome 5 Leaving the study early.
Figures and Tables -
Analysis 1.5

Comparison 1 ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO, Outcome 5 Leaving the study early.

Table 4. Excluded studies

Excluded Study

Comparison

Existing review

Clark 1970

Chlorpromazine versus molindone

Bagnall 2007

Clark 1970a

Chlorpromazine versus placebo

Adams 2014

Serafetinides 1971

Chlorpromazine versus placebo

Adams 2014

Lemmens 1994

Clopenthixol versus risperidone

Hunter 2003

Goodall 1988

D‐fenfluramine versus placebo

Faulkner 2007; Hahn 2014

Figures and Tables -
Table 4. Excluded studies
Table 5. Suggested format for zuclopenthixol dihydrochloride study

Methods

Allocation: randomised, full description of methods of randomisation and allocation concealment.
Blinding: blinded and independent raters.
Duration: at least 6 months.

Participants

Diagnosis: people with schizophrenia (according to a diagnostic criteria).
N: total randomised is 300.
Age: adults.
Sex: both male and female.

Interventions

1. Zuclopenthixol dihydrochloride. N = 150.

2. Placebo. N = 150.

Outcomes

Global state: clinically important response to treatment, average score/change of the global state.

Mental state: general measurement and specific domains (depressive symptoms, positive symptoms, negative symptoms).

Leaving the study early, due to any reason, due to inefficacy of treatment, and due to adverse events.

Adverse events: any serious adverse event recorded.

Service use: number of hospitalisations, days in hospital.
Quality of life outcomes.
Economic outcomes.

Figures and Tables -
Table 5. Suggested format for zuclopenthixol dihydrochloride study
Table 6. Zuclopenthixol acetate versus placebo in the management of acute disturbed behaviour in schizophrenia

Methods

Allocation: randomised, fully explicit description of methods of randomisation and allocation concealment.
Blinding: blinded and independent raters
Duration: 14 days

Participants

Diagnosis: people with schizophrenia (according to a diagnostic criteria). Acutely disturbed behaviour as described by the study
N: total randomised is 300.
Age: adults.
Sex: both male and female

Interventions

1. Zuclopenthixol acetate either alone or in combination with other medications. n = 150

2. Placebo. n = 150

Outcomes

Global state: clinically important response to treatment, average score/change of the global state.

Mental state: general measurement and specific domains (such as depressive symptoms, positive symptoms, negative symptoms)

Leaving the study early, due to any reason, due to inefficacy of treatment, and due to adverse events.

Adverse events: any serious adverse event recorded.

Pharmacological interactions.

Figures and Tables -
Table 6. Zuclopenthixol acetate versus placebo in the management of acute disturbed behaviour in schizophrenia
Summary of findings for the main comparison. ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO for schizophrenia

ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO for schizophrenia

Patient or population: people with with schizophrenia
Settings: inpatient
Intervention: ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO

Clinically significant response on global state ‐ as defined by each of the studies, Improvement (CGI) ‐ short term ‐ as rated by nurse
Improvement (CGI) ‐ short term ‐ as rated by psychiatrist
Follow‐up: mean 12 weeks

Study population

RR 2.57
(1.06 to 6.2)

29
(1 study)

⊕⊝⊝⊝
very low1,2

For this SOF table outcome CGI data as rated by a nurse and a psychiatrist were both available. The nurse data were chosen as it includes both control event and

286 per 1000

734 per 1000
(303 to 1000)

Relapse as defined by the studies

No studies reported these important outcomes

Clinically significant response on psychotic symptoms ‐ as defined by each of the studies.

Adverse effects: Sedation

Low

RR 4.67
(1.23 to 17.68)

29
(1 study)

⊕⊝⊝⊝
very low1,2

No use of formal rating scales.Several other adverse events were recorded but sedation considered important.

50 per 1000

234 per 1000
(62 to 884)

Moderate

150 per 1000

701 per 1000
(185 to 1000)

High

250 per 1000

1000 per 1000
(308 to 1000)

Leaving the study early

Study population

RR 0.93
(0.06 to 13.54)

29
(1 study)

⊕⊝⊝⊝
very low1,2

100 per 1000

93 per 1000
(6 to 1000)

Average change in quality of life/satisfaction

No studies reported these important outcomes

Significant change in quality of life/satisfaction ‐ as defined by each of the studies

*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 'very serious' ‐ randomisation method unclear as describes "randomly assigned". Incomplete outcome data and does not accurately describe losses. Patients blinded but unclear if raters and clinicians are blinded
2 Imprecision: rated 'very serious' ‐ very wide confidence intervals, small population studied

Figures and Tables -
Summary of findings for the main comparison. ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO for schizophrenia
Summary of findings 2. ZUCLOPENTHIXOL ACETATE versus PLACEBO for schizophrenia

ZUCLOPENTHIXOL ACETATE versus PLACEBO for schizophrenia

Patient or population: people with schizophrenia
Settings: inpatient
Intervention: ZUCLOPENTHIXOL ACETATE versus PLACEBO

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Control

ZUCLOPENTHIXOL ACETATE versus PLACEBO

Clinically significant response on global state

No studies reported any of these important outcomes

Relapse as defined by the studies

Clinically significant response on psychotic symptoms ‐ as defined by each of the studies.

Other adverse effects, general and specific

Leaving the study early

Average change in quality of life/satisfaction

Significant change in quality of life/satisfaction ‐ as defined by each of the studies

Figures and Tables -
Summary of findings 2. ZUCLOPENTHIXOL ACETATE versus PLACEBO for schizophrenia
Summary of findings 3. ZUCLOPENTHIXOL DECANOATE versus PLACEBO for schizophrenia

ZUCLOPENTHIXOL DECANOATE versus PLACEBO for schizophrenia

Patient or population: people with schizophrenia
Settings: inpatient
Intervention: ZUCLOPENTHIXOL DECANOATE versus PLACEBO

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Control

ZUCLOPENTHIXOL DECANOATE versus PLACEBO

Clinically significant response on global state

No studies reported any of these important outcomes

Relapse as defined by the studies

Clinically significant response on psychotic symptoms ‐ as defined by each of the studies

Other adverse effects, general and specific

Leaving the study early

Average change in quality of life/satisfaction

Significant change in quality of life/satisfaction ‐ as defined by each of the studies

Figures and Tables -
Summary of findings 3. ZUCLOPENTHIXOL DECANOATE versus PLACEBO for schizophrenia
Table 1. Related reviews

Focus of the review

Participants

Reference

Zuclopenthixol acetate

acutely ill people with schizophrenia

Jayakody 2012

Zuclopenthixol decanoate

people with schizophrenia

da Silva 1999

Zuclopenthixol dihydrochloride

people with schizophrenia

Kumar 2005

Figures and Tables -
Table 1. Related reviews
Table 2. Table of CGI Severity score for zuclopenthixol dihydrochloride (Clopenthixol) from Serafetinides 1972

Individual data

Mean

Sum of mean squares

SD

CGI severity score clopenthixol

3

4

4

5

5

5

5

5

5

5

6

6

6

6

6

5.07

396

0.88

Figures and Tables -
Table 2. Table of CGI Severity score for zuclopenthixol dihydrochloride (Clopenthixol) from Serafetinides 1972
Table 3. Table of CGI Severity score for placebo from Serafetinides 1972

Individual data

Mean

Sum of mean squares

SD

CGI Scores Placebo

4

5

5

6

6

6

6

6

6

6

6

6

6

5.69

426

0.63

Figures and Tables -
Table 3. Table of CGI Severity score for placebo from Serafetinides 1972
Comparison 1. ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinically significant response: Improvement (CGI) ‐ short term Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 as rated by psychiatrist

1

29

Risk Ratio (M‐H, Random, 95% CI)

8.44 [0.50, 143.77]

1.2 as rated by nurse

1

29

Risk Ratio (M‐H, Random, 95% CI)

2.57 [1.06, 6.20]

2 Global state: Average score of severity of illness ‐ short term (CGI, high score=bad) Show forest plot

1

29

Mean Difference (IV, Random, 95% CI)

‐0.62 [‐1.17, ‐0.07]

3 Adverse effects: 1. Various ‐ short term Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 extrapyramidal effects

2

65

Risk Ratio (M‐H, Random, 95% CI)

10.07 [1.36, 74.61]

3.2 sedation

1

29

Risk Ratio (M‐H, Random, 95% CI)

4.67 [1.23, 17.68]

3.3 weight gain ‐ to an important extent

1

29

Risk Ratio (M‐H, Random, 95% CI)

4.69 [0.24, 89.88]

3.4 weight loss ‐ to an important extent

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.27 [0.07, 1.07]

4 Adverse effects: 2. Laboratory values ‐ abnormal ‐ short term Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 urine abnormalities

1

29

Risk Ratio (M‐H, Random, 95% CI)

1.87 [0.19, 18.38]

4.2 haematological abnormalities

1

29

Risk Ratio (M‐H, Random, 95% CI)

1.87 [0.40, 8.65]

4.3 liver abnormalities

1

29

Risk Ratio (M‐H, Random, 95% CI)

8.44 [0.50, 143.77]

4.4 cholesterol <170mg per cent

1

29

Risk Ratio (M‐H, Random, 95% CI)

2.81 [0.12, 63.83]

4.5 triglycerides

1

29

Risk Ratio (M‐H, Random, 95% CI)

2.8 [0.33, 23.86]

4.6 zinc < 70microgram

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.31 [0.01, 7.09]

4.7 zinc > 120microgram per cent

1

29

Risk Ratio (M‐H, Random, 95% CI)

2.81 [0.12, 63.83]

5 Leaving the study early Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.06, 13.54]

Figures and Tables -
Comparison 1. ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO