Diclorhidrato de zuclopentixol para la esquizofrenia
Información
- DOI:
- https://doi.org/10.1002/14651858.CD005474.pub2Copiar DOI
- Base de datos:
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- Cochrane Database of Systematic Reviews
- Versión publicada:
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- 16 noviembre 2017see what's new
- Tipo:
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- Intervention
- Etapa:
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- Review
- Grupo Editorial Cochrane:
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Grupo Cochrane de Esquizofrenia
- Copyright:
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- Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cifras del artículo
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Autores
Contributions of authors
Edward Bryan ‐ protocol revisions, review update and re‐write.
Marie Purcell ‐ Peer review and proof reading.
Ajit Kumar ‐ protocol, review development and writing.
Sources of support
Internal sources
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Sheffield Health and Social Care, Sheffield NHS Foundation Trust, UK.
Employs lead author Edward J Bryan.
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Market Surgery, Rotherham, UK.
Employs review author Marie Ann Purcell.
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Leeds Community Healthcare NHS Trust, Leeds, UK.
Employs review author Ajit Kumar.
External sources
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No sources of support supplied
Declarations of interest
Edward Bryan: none known.
Marie Purcell: none known.
Ajit Kumar: none known.
Acknowledgements
With thanks to Judy Wright, Gill Rizzello, Tessa Grant, John Rathbone and Clive Adams of the Cochrane Schizophrenia Group, University of Leeds, Leeds, UK. Thank you also to Mahesh Jayaram, Specialist Registrar, Leeds, UK. Additional thanks to Dr Marie Ann Purcell (Consultant General Practitioner, Market Surgery, Wath‐upon‐Dearne, Rotherham, UK). We would like to thank Daniel Strech for his contribution to the protocol and previous version of this review. We would also like to thank Amna Bibi, Michael Albert and Valerie Taylor for peer reviewing this version of the review.
Jun Xia helped us with data extraction for the update version by carrying out the reliability checks.
Parts of this review were generated using RevMan HAL v 4.2. You can find more information about RevMan here.
'Summary of findings' tables were generated by the online software GradPro. You can find more information about GradePro here.
Version history
| Published | Title | Stage | Authors | Version |
| 2017 Nov 16 | Zuclopenthixol dihydrochloride for schizophrenia | Review | Edward J Bryan, Marie Ann Purcell, Ajit Kumar | |
| 2005 Oct 19 | Zuclopenthixol dihydrochloride for schizophrenia | Review | Ajit Kumar, Daniel Strech | |
Differences between protocol and review
Differences have previously been clarified in the methods section. The main difference is in the comparisons (four in the original review and 12 in the update).
In the original publication the authors completed the following analyses (Appendix 3).
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Zuclopenthixol versus placebo (only short term)
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Zuclopenthixol versus other typical antipsychotics (only short term)
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Zuclopenthixol versus atypical antipsychotics (only short term)
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Cis (Z) zuclopenthixol versus cis (Z)/Trans (E) zuclopenthixol (only short term)
For this update the original four analyses were modified and adapted in an attempt to reflect the evidence base for realistic clinical questions e.g. Should I use zuclopenthixol instead of clozapine? It was felt that the original four comparisons were misleading to clinicians, patients and policy makers as they suggested that zuclopenthixol had been compared to all other possible antipsychotics. This was not the original authors intent.
This review update identified comparisons against nine alternative antipsychotics, only two of which were newer atypicals. Comparisons one and four remain and have been updated (see below).
Notes
No notes to be published.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
Medical Subject Headings Check Words
Humans;
PICO
Study flow diagram ‐ update 2016.
Comparison 1 ZUCLOPENTHIXOL versus PLACEBO ‐ all short term, Outcome 1 Leaving the study early (any reason).
Comparison 1 ZUCLOPENTHIXOL versus PLACEBO ‐ all short term, Outcome 2 Adverse effects: 1. Clinically important change in specific adverse effects ‐ cardiovascular ‐ orthostatic.
Comparison 1 ZUCLOPENTHIXOL versus PLACEBO ‐ all short term, Outcome 3 Adverse effects: 2. Clinically important change in specific adverse effects ‐ central nervous system ‐ arousal state.
Comparison 1 ZUCLOPENTHIXOL versus PLACEBO ‐ all short term, Outcome 4 Adverse effects: 3. Clinically important change in specific adverse effects ‐ endocrine ‐ menstruation started.
Comparison 1 ZUCLOPENTHIXOL versus PLACEBO ‐ all short term, Outcome 5 Adverse effects: 4a. Any general adverse effects ‐ movement disorders ‐ EPSEs (UKU side effect rating scale, no scores).
Comparison 1 ZUCLOPENTHIXOL versus PLACEBO ‐ all short term, Outcome 6 Adverse effects: 4b. Clinically important change in specific adverse effects ‐ movement disorders ‐ EPSEs.
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 1 Global state: 1. Average endpoint global state score ‐ Unchanged/worse (CGI, scores not reported).
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 2 Global state: 2. Average endpoint global state score ‐ No Recovery.
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 3 Global state: 3a. Average endpoint global state score (GAS, high score not reported, average score = 63.4).
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 4 Global state: 3b. Average endpoint global state score (CGI‐SI, high score not reported, average score = 2.2).
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 5 Mental state: 1. No clinically important change in general mental state ‐ Not improved (PANSS, scores not reported).
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 6 Mental state: 2. No clinically important change in general mental state ‐ No clinical response.
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 7 Mental state: 3. Average endpoint general mental state score (BPRS, high score = 34.2).
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 8 Leaving the study early (any reason).
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 9 Adverse effects: 1. Any general adverse effects ‐ side effects (CGI, high score not reported).
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 10 Adverse effects: 2. Average endpoint general adverse effect score ‐ average score (TESS, high score not reported, average score = 12.00).
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 11 Adverse effects: 3. Any change in specific adverse effects ‐ cardiovascular ‐ postural hypotension (dizziness/syncope).
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 12 Adverse effects: 4. Any change in specific adverse effects ‐ central nervous system ‐ arousal.
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 13 Adverse effects: 5. Any change in specific adverse effects ‐ metabolic ‐ weight change ‐ loss or gain of weight of 10 pounds.
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 14 Adverse effects: 6a. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs.
| Study | Zuclopenthixol | Chlorpromazine |
| Kingstone 1970 | n = 5, authors do not state which additional medication. | n = 2, authors do not state which additional medication. |
| Kordas 1968 | Benzhexol and diazepam if necessary. | Benzhexol and diazepam if necessary. |
| Wang 1995a | Trihexphenidyl or scopolamine used if necessary. Authors do not report frequency of use or which group used which. | Trihexphenidyl or scopolamine used if necessary. Authors do not report frequency of use or which group used which. |
Comparison 2 ZUCLOPENTHIXOL versus CHLORPROMAZINE ‐ all short term, Outcome 15 Adverse effects: 6b. Any change in specific adverse effects ‐ movement disorders ‐ additional medication use.
Comparison 3 ZUCLOPENTHIXOL versus CHLORPROTHIXENE ‐ all medium term, Outcome 1 Global state: Average endpoint global state score ‐ Unchanged/worse (CGI).
Comparison 3 ZUCLOPENTHIXOL versus CHLORPROTHIXENE ‐ all medium term, Outcome 2 Leaving the study early (any reason).
Comparison 4 ZUCLOPENTHIXOL versus CLOZAPINE ‐ all short term, Outcome 1 Leaving the study early (any reason).
| Study | Zuclopenthixol (n = 36) | Clozapine (n = 38) |
| Fischer‐Cornelssen 1976 | Drowsiness (12%); Stimulation (14%); Confusion (1%); GI (1%); anticholinergic (14%); dizziness (6%); Orthostatic reaction (1%); Headache (2%); Hypersalivation (2%); hypokinesia (4%); hyperkinesia (2%); dyskinesia (0.4%); rigor (5%); tremor (5%); akathisia (3%) | Drowsiness (12%); Stimulation (21%); Confusion (3%); GI (8%); anticholinergic (8%); dizziness (15%); Orthostatic reaction (6%); Headache (3%); Hypersalivation (4%); hypokinesia (2%); hyperkinesia (4%); dyskinesia (0%); rigor (1%); tremor (3%); akathisia (3%) |
Comparison 4 ZUCLOPENTHIXOL versus CLOZAPINE ‐ all short term, Outcome 2 Adverse effects: Any general adverse effects ‐ side effects ‐ frequency per day.
Comparison 5 ZUCLOPENTHIXOL versus HALOPERIDOL ‐ all short term, Outcome 1 Global state: 1. Average endpoint global state score ‐ Unchanged/worse (CGI).
Comparison 5 ZUCLOPENTHIXOL versus HALOPERIDOL ‐ all short term, Outcome 2 Global state: 2. Average endpoint global state score (CGI, mean score = 1.25).
Comparison 5 ZUCLOPENTHIXOL versus HALOPERIDOL ‐ all short term, Outcome 3 Leaving the study early (any reason).
Comparison 5 ZUCLOPENTHIXOL versus HALOPERIDOL ‐ all short term, Outcome 4 Adverse effects: 1. Any change in specific adverse effects ‐ interference with functioning.
Comparison 5 ZUCLOPENTHIXOL versus HALOPERIDOL ‐ all short term, Outcome 5 Adverse effects: 2. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs ‐ requiring medication.
Comparison 5 ZUCLOPENTHIXOL versus HALOPERIDOL ‐ all short term, Outcome 6 Adverse effects: 3. Any change in specific adverse effects ‐ requiring additional medication.
Comparison 5 ZUCLOPENTHIXOL versus HALOPERIDOL ‐ all short term, Outcome 7 Adverse effects: 4. Any change in specific adverse effects ‐ requiring hypnotics/sedatives.
Comparison 6 ZUCLOPENTHIXOL versus PERPHENAZINE, Outcome 1 Global state: Average endpoint global state score ‐ unchanged/worse (global rating ‐ investigator opinion) ‐ medium term.
Comparison 6 ZUCLOPENTHIXOL versus PERPHENAZINE, Outcome 2 Leaving the study early (any reason) ‐ short/medium term.
Comparison 6 ZUCLOPENTHIXOL versus PERPHENAZINE, Outcome 3 Adverse effects: 1. Any change in specific adverse effects ‐ central nervous system ‐ arousal ‐ requiring medication ‐ medium term.
Comparison 6 ZUCLOPENTHIXOL versus PERPHENAZINE, Outcome 4 Adverse effects: 2. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs ‐ requiring medication ‐ medium term.
Comparison 7 ZUCLOPENTHIXOL versus RISPERIDONE, Outcome 1 Mental State: 1. Average endpoint general mental state score (PANSS, average score = 45.8) ‐ medium term.
Comparison 7 ZUCLOPENTHIXOL versus RISPERIDONE, Outcome 2 Mental State: 2. Average endpoint general mental state score (PANSS General, average score medium term = 20.5) ‐ short/medium term.
Comparison 7 ZUCLOPENTHIXOL versus RISPERIDONE, Outcome 3 Mental State: 3. Average endpoint general mental state score (PANSS Positive, average score = 9.8) ‐ medium term.
Comparison 7 ZUCLOPENTHIXOL versus RISPERIDONE, Outcome 4 Mental State: 4. Average endpoint general mental state score (PANSS Negative, average score 11.5) ‐ medium term.
Comparison 7 ZUCLOPENTHIXOL versus RISPERIDONE, Outcome 5 Leaving the study early (any reason) ‐ short/medium term.
| Study | Zuclopenthixol | Risperidone |
| Fagerlund 2004 | Benzodiazepines n = 7 Anticholinergics n = 11 | Benzodiazepines n = 8 Anticholinergics n = 7 |
| Glenthoj 2007 | Anticholinergic n = 10, Benzodiazepines n = 11, Antidepressant n = 1 | Authors do not differentiate the use of additional medication between the two groups, totals only given. |
Comparison 7 ZUCLOPENTHIXOL versus RISPERIDONE, Outcome 6 Adverse Effects: 1. Any change in general adverse effects ‐ additional medication use ‐ short/medium term.
Comparison 7 ZUCLOPENTHIXOL versus RISPERIDONE, Outcome 7 Adverse effects: 2a. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs ‐ requiring medication ‐ short term.
Comparison 7 ZUCLOPENTHIXOL versus RISPERIDONE, Outcome 8 Adverse Effects: 2b. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs (ESRS) ‐ short term.
Comparison 7 ZUCLOPENTHIXOL versus RISPERIDONE, Outcome 9 Adverse effects: 3. Any change in specific adverse effects ‐ negative and cognitive symptoms of schizophrenia ‐ short term.
Comparison 8 ZUCLOPENTHIXOL versus SULPIRIDE ‐ all short term, Outcome 1 Global state: 1. Average endpoint global state score ‐ Unchanged/worse (CGI).
Comparison 8 ZUCLOPENTHIXOL versus SULPIRIDE ‐ all short term, Outcome 2 Global State: 2. Average endpoint global state score ‐ Moderately or severely ill (CGI).
Comparison 8 ZUCLOPENTHIXOL versus SULPIRIDE ‐ all short term, Outcome 3 Mental State: Average endpoint general mental state score (BPRS, average = 5.7).
Comparison 8 ZUCLOPENTHIXOL versus SULPIRIDE ‐ all short term, Outcome 4 Leaving the study early (any reason).
| Study | Zuclopenthixol | Sulpiride |
| Mahadevan 1991 | n = 4 Amitriptyline | n = 4 Amitryptyline |
Comparison 8 ZUCLOPENTHIXOL versus SULPIRIDE ‐ all short term, Outcome 5 Adverse Effects: 1. Any change in general adverse effects ‐ additional medication use.
Comparison 8 ZUCLOPENTHIXOL versus SULPIRIDE ‐ all short term, Outcome 6 Adverse Effects: 2. Any change in specific adverse effects ‐ metabolic ‐ weight change.
Comparison 8 ZUCLOPENTHIXOL versus SULPIRIDE ‐ all short term, Outcome 7 Adverse effects: 3. Any change in specific adverse effects ‐ requiring additional medication ‐ hypnotics/sedatives.
Comparison 9 ZUCLOPENTHIXOL versus THIOTHIXENE ‐ all medium term, Outcome 1 Global state: Average endpoint global state score ‐ unchanged/worse (CGI).
Comparison 9 ZUCLOPENTHIXOL versus THIOTHIXENE ‐ all medium term, Outcome 2 Leaving the study early (any reason).
Comparison 10 ZUCLOPENTHIXOL versus TRIFLUOPERAZINE ‐ all short term, Outcome 1 Leaving the study early (any reason).
Comparison 11 ZUCLOPENTHIXOL versus ZUCLOPENTHIXOL DEPOT ‐ all long term, Outcome 1 Leaving the study early (any reason).
Comparison 11 ZUCLOPENTHIXOL versus ZUCLOPENTHIXOL DEPOT ‐ all long term, Outcome 2 Behaviour: Average change in specific aspects of behaviour ‐ Violence during follow‐up.
| Study | Zuclopenthixol | Depot |
| Arango 2006 | n = 1 Propanolol | n = 1 venlafaxine n = 1 Lithium |
Comparison 11 ZUCLOPENTHIXOL versus ZUCLOPENTHIXOL DEPOT ‐ all long term, Outcome 3 Adverse Effects: 1a. Any general adverse effects ‐ additional medication use.
Comparison 11 ZUCLOPENTHIXOL versus ZUCLOPENTHIXOL DEPOT ‐ all long term, Outcome 4 Adverse Effects: 1b. Any change in specific adverse effects ‐ additional medication use ‐ benzodiazepine use at least once.
Comparison 12 CIS‐(Z) ZUCLOPENTHIXOL versus CIS(Z)/TRANS(E) ZUCLOPENTHIXOL ‐ all short term, Outcome 1 Global state: Average endpoint global state score ‐ Unwell.
Comparison 12 CIS‐(Z) ZUCLOPENTHIXOL versus CIS(Z)/TRANS(E) ZUCLOPENTHIXOL ‐ all short term, Outcome 2 Mental state: Average endpoint general mental state score ‐ Not improved.
Comparison 12 CIS‐(Z) ZUCLOPENTHIXOL versus CIS(Z)/TRANS(E) ZUCLOPENTHIXOL ‐ all short term, Outcome 3 Leaving the study early (any reason).
Comparison 12 CIS‐(Z) ZUCLOPENTHIXOL versus CIS(Z)/TRANS(E) ZUCLOPENTHIXOL ‐ all short term, Outcome 4 Adverse Effects: 1a. Any general adverse effects ‐ side effects reported.
| Study | Cis Z | Cis(Z)/Trans(E) |
| Gravem 1981 | EPSEs most frequent. Authors state no significant difference between two isomers. | EPSEs most frequent. |
| Heikkila 1981 | Dry mouth, Disturbance of accommodation, Disturbance of urination, Constipation, Dizziness, Headache, Increased sweating, Drowsiness, Anxiety, Parkinsonism, Akathisia, Tardive dyskinesia and others | Dry mouth, Disturbance of urination, Constipation, Dizziness, Drowsiness, Parkinsonism, Akathisia, Tardive dyskinesia, others |
Comparison 12 CIS‐(Z) ZUCLOPENTHIXOL versus CIS(Z)/TRANS(E) ZUCLOPENTHIXOL ‐ all short term, Outcome 5 Adverse Effects: 1b. Any change in specific adverse effects ‐ individual side effects.
| Patient or population: people with schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with PLACEBO (short term) | Risk with ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Adverse effects: Clinically important general adverse effect (extrapyramidal effects ‐ UKU side effect rating scale) | 80 per 1000 | 486 per 1000 | RR 6.07 | 28 | ⊕⊝⊝⊝ | Risk assumed to be moderate and rounded from 7.69% to 8%. |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Service outcomes: Duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Leaving the study early (any reason) | 40 per 1000 | 12 per 1000 | RR 0.29 | 100 | ⊕⊝⊝⊝ | Risk assumed to be moderate and rounded from 3.85% to 4%. Low number of events in both RCTs. |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated 'very serious' ‐ possible selection bias, blinding may have been single, attrition bias and reporting bias. 2 Risk of bias: rated 'very serious' ‐ selection, attrition and reporting bias 3 Risk of inconsistency: rated 'not serious' ‐ suspected but not found. 4 Risk of publication bias: rated 'strongly suspected' ‐ multiple papers published with the same patient cohort. 5 Risk of large effect: rated 'very large' ‐ RR 6.07, small n number but result likely when versus placebo. 6 Risk of imprecision: rated 'very serious' ‐ low n numbers | ||||||
| Patient or population: schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with CHLORPROMAZINE (short term) | Risk with ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (CGI‐SI, high score not reported, average score = 2.2) | The mean CGI‐SI endpoint score in the intervention group (MD) was 0 (‐0.49 lower to 0.49 higher) | ‐ | 64 | ⊕⊝⊝⊝ | Translated study. | |
| Adverse effects: Clinically important general adverse effect (EPSEs) | 300 per 1000 | 282 per 1000 | RR 0.94 | 199 | ⊕⊝⊝⊝ | Risk control rounded to 30% and set to moderate. Mixture of inpatient and outpatient, though predominantly hospitalised patients. |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (BPRS, high score = 34.2) | The mean mental state: average endpoint score (BPRS, high score = 34.2) in the intervention group was 0.4 more (2.43 fewer to 3.23 more) | ‐ | 221 | ⊕⊕⊝⊝ | Mixture of inpatient and outpatient, though predominantly hospitalised patients. | |
| Leaving the study early (any reason) | 70 per 1000 | 38 per 1000 | RR 0.54 | 766 | ⊕⊕⊝⊝ | Mixture of inpatient and outpatient, though predominantly hospitalised patients. Risk control set to moderate and rounded to 7%; extreme values not likely. |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated 'serious' ‐ Selection and attrition bias likely. 2 Risk of bias: rated 'serious' ‐ Selection attrition bias. 3 Risk of bias: rated 'serious' ‐ Selection, attrition and reporting bias. 4 Risk of bias: rated 'serious' ‐ Selection, attrition and reporting bias. Risk of inconsistency: rated as 'serious' ‐ All three papers reported on differing population sizes and obtained different levels of EPSEs in the experimental and control groups. 5 Risk of imprecision: rated 'very serious' ‐ low n numbers 6 Risk of indirectness: rated 'very serious' ‐ mixed samples For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | ||||||
| Patient or population: schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with CHLORPROTHIXENE (medium term) | Risk with ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Adverse effects: Clinically important general adverse effect (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Leaving the study early (any reason) | 400 per 1000 | 400 per 1000 | RR 1.00 | 20 | ⊕⊝⊝⊝ | |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated as 'serious' ‐ selection, reporting bias likely. 2 Risk of publication bias: rated as 'strongly suspected' ‐ several papers published using the same cohort of patients. 3 Risk of imprecision: rated 'very serious' ‐ low n numbers For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | ||||||
| Patient or population: schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with CLOZAPINE (short term) | Risk with ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Adverse effects: Clinically important general adverse effect (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Leaving the study early (any reason) | 0 per 1000 | 0 per 1000 | not estimable | 407 | ⊕⊕⊝⊝ | Multi‐centre, multi‐drug trial with disproportionate numbers of people in different arms of the study. The authors did not report that anybody left the study in the Zuclopenthixol and clozapine arms. |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated as 'serious' ‐ selection, attrition, reporting and performance bias likely. 2 Risk of indirectness: rated 'serious' ‐ Multiple study arms For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | ||||||
| Patient or population: schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with HALOPERIDOL (short term) | Risk with ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (CGI, mean score = 1.25) | The mean CGI endpoint score in the intervention group (MD) was 0.13 more (‐0.3 fewer to 0.55 more) | ‐ | 49 | ⊕⊝⊝⊝ | Small study, multiple scales used (NOSIE30, BPRS, CGI). Paper only reported outcomes of some of these scales. | |
| Adverse effects: Clinically important general adverse effect (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Leaving the study early (any reason) | 300 per 1000 | 297 per 1000 | RR 0.99 | 141 | ⊕⊝⊝⊝ | Risk control rounded to 30% from 29.25% and, as extreme values unlikely, it was set to moderate. |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated as 'very serious' ‐ likely selection, attrition, reporting and diagnostic purity bias. 2 Risk of bias: rated as 'serious' ‐ likely selection, attrition, reporting and diagnostic purity bias. Risk of inconsistency: rated as 'serious' ‐ both papers generated differing values for people leaving the study and do not appear consistent (face validity). 3 Risk of imprecision: rated 'serious' ‐ low n numbers 4 Risk of indirectness: rated 'serious' ‐ not all scales reported For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | ||||||
| Patient or population: schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with PERPHENAZINE (short and medium term) | Risk with ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Adverse effects: Clinically important general adverse effect (EPSEs requiring medication ‐ medium term) | 400 per 1000 | 760 per 1000 | RR 1.90 | 50 | ⊕⊝⊝⊝ | |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Leaving the study early (any reason, short and medium term) | 207 per 1000 | 130 per 1000 | RR 0.63 | 104 | ⊕⊝⊝⊝ | |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated as 'serious' ‐ likely selection and reporting bias. 2 Risk of imprecision: rated 'very serious' ‐ low n numbers For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | ||||||
| Patient or population: schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with RISPERIDONE (short and medium term) | Risk with ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Adverse effects: Clinically important general adverse effect ‐ short term (EPSEs requiring medication) | 271 per 1000 | 520 per 1000 | RR 1.92 | 98 | ⊕⊝⊝⊝ | |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (PANSS, average score = 20.5) ‐ medium term | The mean PANNS endpoint score in the intervention group (MD) was 3.2 fewer (‐7.71 fewer to 1.31 more) | ‐ | 25 | ⊕⊝⊝⊝ | Small study. Standard deviations may be standard errors. Open label trial. | |
| Leaving the study early (any reason, short and medium term) | 310 per 1000 | 403 per 1000 | RR 1.30 | 154 | ⊕⊝⊝⊝ | Risk control taken as mean of extremes: high + low / 2 (changed from 21.43% to 31%) |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated as 'very serious' ‐ open label trial, likely selection bias. 2 Risk of imprecision: rated as 'very serious' ‐ strongly suspect reported standard deviations are standard errors, low n numbers 3 Risk of publication bias: rated as 'strongly suspected' ‐ all studies published findings across several consecutive years in different journals and at conferences. 4 Risk of bias: rated as 'very serious' ‐ study 1 (selection, reporting, diagnostic purity and attrition bias likely ‐ author emailed); study 2 (open label); study 3 (reporting and attrition bias). 5 Risk of publication bias: rated as 'strongly suspected' ‐ multiple papers over consecutive years published with the same data. 6 Risk of bias: rated as 'serious' ‐ diagnostic purity and attrition bias; likely selection and reporting bias (authors contacted) For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | ||||||
| Patient or population: schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with SULPIRIDE (short term) | Risk with ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (CGI ‐ unchanged/worse) | 226 per 1000 | 266 per 1000 | RR 1.18 | 61 | ⊕⊝⊝⊝ | The study did not report clinical improvement so unchanged/worse is reported for this outcome. Usually we report clinical improvement. |
| Adverse effects: Clinically important general adverse effect ‐ requiring hypnotics/sedatives | 419 per 1000 | 252 per 1000 | RR 0.60 | 61 | ⊕⊝⊝⊝ | |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (BPRS) | The mean BPRS endpoint score in the intervention group (MD) was 1.3 fewer (‐5.08 fewer to 2.48 more) | ‐ | 61 | ⊕⊝⊝⊝ | ||
| Leaving the study early (any reason) | 230 per 1000 | 476 per 1000 | RR 2.07 | 61 | ⊕⊝⊝⊝ | Control of risk rounded up from 22.58% to 23%. |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated as 'serious' ‐ diagnostic purity, attrition bias. Per‐Protocol analysis suspected. 2 Risk of imprecision: rated as ' very serious' ‐ percentages used to describe data and comparisons are made against an assumption of baseline measurements. Low n numbers. For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | ||||||
| Patient or population: schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with THIOTHIXENE (medium term) | Risk with ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (unchanged/worse ‐ CGI) | 600 per 1000 | 300 per 1000 | RR 0.50 | 20 | ⊕⊝⊝⊝ | The study did not report clinical improvement so unchanged/worse is reported for this outcome. Usually we report clinical improvement. |
| Adverse effects: Clinically important general adverse effect (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported on this outcome. | |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported on this outcome. | |
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported on this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported on this outcome. | |
| Leaving the study early (any reason) | 700 per 1000 | 399 per 1000 | RR 0.57 | 20 | ⊕⊝⊝⊝ | |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No studies reported on this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated as 'serious' ‐ likely selection and reporting bias. 2 Risk of publication bias: rated as 'strongly suspected' ‐ several papers published using the same cohort. 3 Risk of imprecision: rated as 'serious' ‐ low n numbers For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | ||||||
| Patient or population: schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with TRIFLUOPERAZINE (short term) | Risk with ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Adverse effects: Clinically important general adverse effect (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Leaving the study early (any reason) | 0 per 1000 | 0 per 1000 | not estimable | 72 | ⊕⊝⊝⊝ | Multi‐centre and multi‐drug trial with low numbers in each arm. |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated as 'serious' ‐ selection, attrition, reporting and performance bias likely. 2 Risk of imprecision: rated 'very serious' ‐ low n numbers 3 Risk of indirectness: rated 'very serious' ‐ multiple arms, some missing For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | ||||||
| Patient or population: schizophrenia | |||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | ||
| Risk with ZUCLOPENTHIXOL DEPOT (long term) | Risk with ZUCLOPENTHIXOL | ||||||
| Global state: Average endpoint global state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | ||
| Adverse effects: Clinically important general adverse effect (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | ||
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | ||
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | ||
| Mental state: Average endpoint general mental state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | ||
| Leaving the study early (any reason) | 80 per 1000 | 156 per 1000 | RR 1.95 | 46 | ⊕⊝⊝⊝ | Control of risk rounded from 7.69% to 8%. | |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | ||
| *The risk in the intervention group (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). | |||||||
| GRADE Working Group grades of evidence | |||||||
| 1 Risk of bias: rated as 'very serious' ‐ single researcher did randomisation, selection bias likely, open label trial and incomplete outcome data. 2 Risk of publication bias: rated as 'strongly suspected' ‐ several papers published using the same data and cohort. 3 Risk of imprecision: rated 'very serious' ‐ low n numbers For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | |||||||
| Patient or population: schizophrenia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with CIS(Z)/TRANS(E) ZUCLOPENTHIXOL (short term) | Risk with CIS‐(Z) ZUCLOPENTHIXOL | |||||
| Global state: Average endpoint global state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Adverse effects: Clinically important general adverse effect | 470 per 1000 | 630 per 1000 | RR 1.34 | 57 | ⊕⊝⊝⊝ | Control of risk set at moderate and rounded up from 46.4% to 47%. |
| Death: Suicide and natural causes (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Service outcomes: duration of stay in hospital (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Mental state: Average endpoint general mental state score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| Leaving the study early: Any reason | 28 per 1000 | 61 per 1000 | RR 2.15 | 140 | ⊕⊝⊝⊝ | |
| General functioning: Average endpoint general functioning score (clinically improved) (no data) | not pooled | not pooled | not estimable | (0 studies) | No study reported this outcome. | |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Risk of bias: rated as 'serious' ‐ selection bias throughout. Very difficult to ascertain from published materials if selection bias has been minimised. 2 Risk of imprecision: rated 'very serious' ‐ low n numbers For risks rated as serious, we downgraded by 1. For risks rated as very serious we downgraded by 2. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Leaving the study early (any reason) Show forest plot | 2 | 100 | Risk Ratio (M‐H, Random, 95% CI) | 0.29 [0.01, 6.60] |
| 2 Adverse effects: 1. Clinically important change in specific adverse effects ‐ cardiovascular ‐ orthostatic Show forest plot | 1 | 28 | Risk Ratio (M‐H, Random, 95% CI) | 0.29 [0.01, 6.60] |
| 3 Adverse effects: 2. Clinically important change in specific adverse effects ‐ central nervous system ‐ arousal state Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 excitation | 1 | 28 | Risk Ratio (M‐H, Random, 95% CI) | 2.62 [0.12, 59.40] |
| 3.2 sleepiness / sedation | 1 | 28 | Risk Ratio (M‐H, Random, 95% CI) | 2.89 [1.01, 8.30] |
| 4 Adverse effects: 3. Clinically important change in specific adverse effects ‐ endocrine ‐ menstruation started Show forest plot | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 7.0 [0.39, 126.48] |
| 5 Adverse effects: 4a. Any general adverse effects ‐ movement disorders ‐ EPSEs (UKU side effect rating scale, no scores) Show forest plot | 1 | 28 | Risk Ratio (M‐H, Random, 95% CI) | 6.07 [0.86, 43.04] |
| 6 Adverse effects: 4b. Clinically important change in specific adverse effects ‐ movement disorders ‐ EPSEs Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 6.1 parkinsonism | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 5.00 [0.26, 97.37] |
| 6.2 oculogyric crisis | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.13, 69.09] |
| 6.3 tremor | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 5.00 [0.26, 97.37] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global state: 1. Average endpoint global state score ‐ Unchanged/worse (CGI, scores not reported) Show forest plot | 2 | 135 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.75, 1.13] |
| 2 Global state: 2. Average endpoint global state score ‐ No Recovery Show forest plot | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.89, 1.16] |
| 3 Global state: 3a. Average endpoint global state score (GAS, high score not reported, average score = 63.4) Show forest plot | 1 | 60 | Mean Difference (IV, Random, 95% CI) | ‐0.60 [‐8.12, 6.92] |
| 4 Global state: 3b. Average endpoint global state score (CGI‐SI, high score not reported, average score = 2.2) Show forest plot | 1 | 60 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐0.49, 0.49] |
| 5 Mental state: 1. No clinically important change in general mental state ‐ Not improved (PANSS, scores not reported) Show forest plot | 1 | 120 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.81, 1.18] |
| 6 Mental state: 2. No clinically important change in general mental state ‐ No clinical response Show forest plot | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.25, 2.42] |
| 7 Mental state: 3. Average endpoint general mental state score (BPRS, high score = 34.2) Show forest plot | 3 | 221 | Mean Difference (IV, Random, 95% CI) | 0.40 [‐2.43, 3.23] |
| 8 Leaving the study early (any reason) Show forest plot | 6 | 766 | Risk Ratio (M‐H, Random, 95% CI) | 0.54 [0.36, 0.81] |
| 9 Adverse effects: 1. Any general adverse effects ‐ side effects (CGI, high score not reported) Show forest plot | 1 | 94 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.77, 0.97] |
| 10 Adverse effects: 2. Average endpoint general adverse effect score ‐ average score (TESS, high score not reported, average score = 12.00) Show forest plot | 1 | 60 | Mean Difference (IV, Random, 95% CI) | 4.48 [‐2.38, 11.34] |
| 11 Adverse effects: 3. Any change in specific adverse effects ‐ cardiovascular ‐ postural hypotension (dizziness/syncope) Show forest plot | 1 | 43 | Risk Ratio (M‐H, Random, 95% CI) | 0.11 [0.01, 1.73] |
| 12 Adverse effects: 4. Any change in specific adverse effects ‐ central nervous system ‐ arousal Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 12.1 excitation | 1 | 43 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.07, 5.47] |
| 12.2 sedation | 2 | 163 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.73, 1.70] |
| 13 Adverse effects: 5. Any change in specific adverse effects ‐ metabolic ‐ weight change ‐ loss or gain of weight of 10 pounds Show forest plot | 1 | 29 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.22, 1.75] |
| 14 Adverse effects: 6a. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs Show forest plot | 3 | 199 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.61, 1.45] |
| 15 Adverse effects: 6b. Any change in specific adverse effects ‐ movement disorders ‐ additional medication use Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global state: Average endpoint global state score ‐ Unchanged/worse (CGI) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2 Leaving the study early (any reason) Show forest plot | 1 | 20 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.34, 2.93] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Leaving the study early (any reason) Show forest plot | 1 | 407 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2 Adverse effects: Any general adverse effects ‐ side effects ‐ frequency per day Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global state: 1. Average endpoint global state score ‐ Unchanged/worse (CGI) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2 Global state: 2. Average endpoint global state score (CGI, mean score = 1.25) Show forest plot | 1 | 49 | Mean Difference (IV, Random, 95% CI) | 0.13 [‐0.30, 0.55] |
| 3 Leaving the study early (any reason) Show forest plot | 2 | 141 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.72, 1.35] |
| 4 Adverse effects: 1. Any change in specific adverse effects ‐ interference with functioning Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 5 Adverse effects: 2. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs ‐ requiring medication Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 6 Adverse effects: 3. Any change in specific adverse effects ‐ requiring additional medication Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 7 Adverse effects: 4. Any change in specific adverse effects ‐ requiring hypnotics/sedatives Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global state: Average endpoint global state score ‐ unchanged/worse (global rating ‐ investigator opinion) ‐ medium term Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2 Leaving the study early (any reason) ‐ short/medium term Show forest plot | 2 | 104 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.27, 1.47] |
| 3 Adverse effects: 1. Any change in specific adverse effects ‐ central nervous system ‐ arousal ‐ requiring medication ‐ medium term Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4 Adverse effects: 2. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs ‐ requiring medication ‐ medium term Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mental State: 1. Average endpoint general mental state score (PANSS, average score = 45.8) ‐ medium term Show forest plot | 1 | 25 | Mean Difference (IV, Random, 95% CI) | ‐3.20 [‐7.71, 1.31] |
| 2 Mental State: 2. Average endpoint general mental state score (PANSS General, average score medium term = 20.5) ‐ short/medium term Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 2.1 Short term | 1 | 19 | Mean Difference (IV, Random, 95% CI) | ‐2.40 [‐4.52, ‐0.28] |
| 2.2 Medium term | 1 | 25 | Mean Difference (IV, Random, 95% CI) | ‐0.30 [‐2.72, 2.12] |
| 3 Mental State: 3. Average endpoint general mental state score (PANSS Positive, average score = 9.8) ‐ medium term Show forest plot | 1 | 25 | Mean Difference (IV, Random, 95% CI) | ‐1.0 [‐2.69, 0.69] |
| 4 Mental State: 4. Average endpoint general mental state score (PANSS Negative, average score 11.5) ‐ medium term Show forest plot | 1 | 25 | Mean Difference (IV, Random, 95% CI) | ‐1.5 [‐4.05, 1.05] |
| 5 Leaving the study early (any reason) ‐ short/medium term Show forest plot | 3 | 154 | Risk Ratio (M‐H, Random, 95% CI) | 1.30 [0.84, 2.02] |
| 6 Adverse Effects: 1. Any change in general adverse effects ‐ additional medication use ‐ short/medium term Show forest plot | Other data | No numeric data | ||
| 7 Adverse effects: 2a. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs ‐ requiring medication ‐ short term Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 8 Adverse Effects: 2b. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs (ESRS) ‐ short term Show forest plot | 1 | 19 | Mean Difference (IV, Random, 95% CI) | 4.5 [0.67, 8.33] |
| 9 Adverse effects: 3. Any change in specific adverse effects ‐ negative and cognitive symptoms of schizophrenia ‐ short term Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 9.1 UKU ‐ asthenia/lassitude/increased fatiguability | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.67, 1.01] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global state: 1. Average endpoint global state score ‐ Unchanged/worse (CGI) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2 Global State: 2. Average endpoint global state score ‐ Moderately or severely ill (CGI) Show forest plot | 1 | 61 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.75, 1.30] |
| 3 Mental State: Average endpoint general mental state score (BPRS, average = 5.7) Show forest plot | 1 | 61 | Mean Difference (IV, Random, 95% CI) | ‐1.30 [‐5.08, 2.48] |
| 4 Leaving the study early (any reason) Show forest plot | 1 | 61 | Risk Ratio (M‐H, Random, 95% CI) | 2.07 [0.97, 4.40] |
| 5 Adverse Effects: 1. Any change in general adverse effects ‐ additional medication use Show forest plot | Other data | No numeric data | ||
| 6 Adverse Effects: 2. Any change in specific adverse effects ‐ metabolic ‐ weight change Show forest plot | 1 | 61 | Mean Difference (IV, Random, 95% CI) | ‐1.60 [‐8.35, 5.15] |
| 7 Adverse effects: 3. Any change in specific adverse effects ‐ requiring additional medication ‐ hypnotics/sedatives Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global state: Average endpoint global state score ‐ unchanged/worse (CGI) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2 Leaving the study early (any reason) Show forest plot | 1 | 20 | Risk Ratio (M‐H, Random, 95% CI) | 0.57 [0.24, 1.35] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Leaving the study early (any reason) Show forest plot | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Leaving the study early (any reason) Show forest plot | 1 | 46 | Risk Ratio (M‐H, Random, 95% CI) | 1.95 [0.36, 10.58] |
| 2 Behaviour: Average change in specific aspects of behaviour ‐ Violence during follow‐up Show forest plot | 1 | 46 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.44, 1.71] |
| 3 Adverse Effects: 1a. Any general adverse effects ‐ additional medication use Show forest plot | Other data | No numeric data | ||
| 4 Adverse Effects: 1b. Any change in specific adverse effects ‐ additional medication use ‐ benzodiazepine use at least once Show forest plot | 1 | 46 | Risk Ratio (M‐H, Random, 95% CI) | 1.3 [0.59, 2.86] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global state: Average endpoint global state score ‐ Unwell Show forest plot | 3 | 131 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.80, 1.17] |
| 2 Mental state: Average endpoint general mental state score ‐ Not improved Show forest plot | 1 | 57 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.45, 2.07] |
| 3 Leaving the study early (any reason) Show forest plot | 4 | 140 | Risk Ratio (M‐H, Random, 95% CI) | 2.15 [0.49, 9.41] |
| 4 Adverse Effects: 1a. Any general adverse effects ‐ side effects reported Show forest plot | 1 | 57 | Risk Ratio (M‐H, Random, 95% CI) | 1.34 [0.82, 2.18] |
| 5 Adverse Effects: 1b. Any change in specific adverse effects ‐ individual side effects Show forest plot | Other data | No numeric data | ||
