Zuclopenthixol versus placebo for schizophrenia

Michael Lacey; Mahesh B Jayaram

doi:10.1002/14651858.CD010598.pub2

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Figure 1

Zuclopenthixol structure

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Figure 2

Processing search results

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Figure 3

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 4

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

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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).

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

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

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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

Table 4. Excluded studies

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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.

Table 5. Suggested format for zuclopenthixol dihydrochloride study

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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.

Table 6. Zuclopenthixol acetate versus placebo in the management of acute disturbed behaviour in schizophrenia

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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 low^1,2	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 low^1,2	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 low^1,2
	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

Summary of findings for the main comparison. ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO for schizophrenia

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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

Summary of findings 2. ZUCLOPENTHIXOL ACETATE versus PLACEBO for schizophrenia

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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

Summary of findings 3. ZUCLOPENTHIXOL DECANOATE versus PLACEBO for schizophrenia

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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

Table 1. Related reviews

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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

Table 2. Table of CGI Severity score for zuclopenthixol dihydrochloride (Clopenthixol) from Serafetinides 1972

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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

Table 3. Table of CGI Severity score for placebo from Serafetinides 1972

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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]

Comparison 1. ZUCLOPENTHIXOL DIHYDROCHLORIDE versus PLACEBO

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