Zuclopenthixol dihydrochloride for schizophrenia

Edward J Bryan; Marie Ann Purcell; Ajit Kumar

doi:10.1002/14651858.CD005474.pub2

. 2017 Nov 16;2017(11):CD005474. doi: 10.1002/14651858.CD005474.pub2

Zuclopenthixol dihydrochloride for schizophrenia

Edward J Bryan ^1,^✉, Marie Ann Purcell ², Ajit Kumar ³

Editor: Cochrane Schizophrenia Group

PMCID: PMC6486001 PMID: 29144549

Abstract

Background

Oral zuclopenthixol dihydrochloride (Clopixol) is an anti‐psychotic treatment for people with psychotic symptoms, especially those with schizophrenia. It is associated with neuroleptic malignant syndrome, a prolongation of the QTc interval, extra‐pyramidal reactions, venous thromboembolism and may modify insulin and glucose responses.

Objectives

To determine the effects of zuclopenthixol dihydrochloride for treatment of schizophrenia.

Search methods

We searched the Cochrane Schizophrenia Group's Trials Register (latest search 09 June 2015). There were no language, date, document type, or publication status limitations for inclusion of records in the register.

Selection criteria

All randomised controlled trials (RCTs) focusing on zuclopenthixol dihydrochloride for schizophrenia. We included trials meeting our inclusion criteria and reporting useable data.

Data collection and analysis

We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention‐to‐treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random‐effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE.

Main results

We included 20 trials, randomising 1850 participants. Data were reported for 12 comparisons, predominantly for the short term (up to 12 weeks) and inpatient populations. Overall risk of bias for included studies was low to unclear.

Data were unavailable for many of our pre‐stated outcomes of interest. No data were available, across all comparisons, for death, duration of stay in hospital and general functioning.

Zuclopenthixol dihydrochloride versus:

1. placebo

Movement disorders (EPSEs) were similar between groups (1 RCT, n = 28, RR 6.07 95% CI 0.86 to 43.04 very low‐quality evidence). There was no clear difference in numbers leaving the study early (2 RCTs, n = 100, RR 0.29, 95% CI 0.01 to 6.60, very low‐quality evidence).

2. chlorpromazine

No clear differences were found for the outcomes of global state (average CGI‐SI endpoint score) (1 RCT, n = 60, MD 0.00, 95% CI ‐0.49 to 0.49) or movement disorders (EPSEs) (3 RCTs, n = 199, RR 0.94, 95% CI 0.61 to 1.45), both very low‐quality evidence. More people left the study early for any reason from the zuclopenthixol group (6 RCTs, n = 766, RR 0.54, 95% CI 0.36 to 0.81, low‐quality evidence).

3. chlorprothixene

There was no clear difference in numbers leaving the study early for any reason (1 RCT, n = 20, RR 1.00, 95% CI 0.34 to 2.93, very low‐quality evidence).

4. clozapine

No useable data were presented.

5. haloperidol

No clear differences between treatment groups were found for the outcomes global state score (average CGI endpoint score) (1 RCT, n = 49, MD 0.13, 95% CI ‐0.30 to 0.55) or leaving the study early (2 RCTs, n = 141, RR 0.99, 95% CI 0.72 to 1.35), both very low‐quality evidence.

6. perphenazine

Those receiving zuclopenthixol were more likely to require medication in the short term for EPSEs than perphenazine (1 RCT, n = 50, RR 1.90, 95% CI 1.12 to 3.22, very low‐quality evidence). Similar numbers left the study early (2 RCTs, n = 104, RR 0.63, 95% CI 0.27 to 1.47, very low‐quality evidence).

7. risperidone

Those receiving zuclopenthixol were more likely to require medications for EPSEs than risperidone (1 RCT, n = 98,RR 1.92, 95% CI 1.12 to 3.28, very low quality evidence). There was no clear difference in numbers leaving the study early ( 3 RCTs, n = 154, RR 1.30, 95% CI 0.84 to 2.02) or in mental state (average PANSS total endpoint score) (1 RCT, n = 25, MD ‐3.20, 95% CI ‐7.71 to 1.31), both very low‐quality evidence).

8. sulpiride

No clear differences were found for global state (average CGI endpoint score) ( 1 RCT, n = 61, RR 1.18, 95% CI 0.49 to 2.85, very low‐quality evidence), requiring hypnotics/sedatives (1 RCT, n = 61, RR 0.60, 95% CI 0.27 to 1.32, very low‐quality evidence) or leaving the study early (1 RCT, n = 61, RR 2.07 95% CI 0.97 to 4.40, very low‐quality evidence).

9. thiothixene

No clear differences were found for the outcomes of 'global state (average CGI endpoint score) (1 RCT, n = 20, RR 0.50, 95% CI 0.17 to 1.46) or leaving the study early (1 RCT, n = 20, RR 0.57, 95% CI 0.24 to 1.35), both very low‐quality evidence).

10. trifluoperazine

No useable data were presented.

11. zuclopenthixol depot

There was no clear difference in numbers leaving the study early (1 RCT, n = 46, RR 1.95, 95% CI 0.36 to 10.58, very low‐quality evidence).

12. Zuclopenthixol dihydrochloride (cis z isomer) versus zuclopenthixol (cis z/trans e isomer)

There were no clear differences in reported side‐effects ( 1 RCT, n = 57, RR 1.34, 95% CI 0.82 to 2.18, very low‐quality evidence) and in numbers leaving the study early (4 RCTs, n = 140, RR 2.15, 95% CI 0.49 to 9.41, very low‐quality evidence).

Authors' conclusions

Zuclopenthixol dihydrochloride appears to cause more EPSEs than clozapine, risperidone or perphenazine, but there was no difference in EPSEs when compared to placebo or chlorpromazine. Similar numbers required hypnotics/sedatives when zuclopenthixol dihydrochloride was compared to sulpiride, and similar numbers of reported side‐effects were found when its isomers were compared. The other comparisons did not report adverse‐effect data.

Reported data indicate zuclopenthixol dihydrochloride demonstrates no difference in mental or global states compared to placebo, chlorpromazine, chlorprothixene, clozapine, haloperidol, perphenazine, sulpiride, thiothixene, trifluoperazine, depot and isomers. Zuclopenthixol dihydrochloride, when compared with risperidone, is favoured when assessed using the PANSS in the short term, but not in the medium term.

The data extracted from the included studies are mostly equivocal, and very low to low quality, making it difficult to draw firm conclusions. Prescribing practice is unlikely to change based on this meta‐analysis. Recommending any particular course of action about side‐effect medication other than monitoring, using rating scales and clinical assessment, and prescriptions on a case‐by‐case basis, is also not possible.

There is a need for further studies covering this topic with more antipsychotic comparisons for currently relevant outcomes.

Plain language summary

Zuclopenthixol dihydrochloride for schizophrenia

Background

Schizophrenia is a serious mental illness where people experience delusions (strange thoughts/ideas) and/or hallucinations (hearing or seeing things that are not real). These are often known as positive or acute symptoms. People also experience negative or chronic symptoms which usually follow acute symptoms. These can include withdrawing from social contact, lack of interest in everyday activities, depression as well as problems with memory and thought processing.

Treatment usually involves a package of care involving medications known as antipsychotics, and if necessary, additional therapies such as Cognitive Behavioural Therapy, Psychoeducation or Occupational therapy.

There are many different antipsychotics available; knowing how effective each one is compared with no treatment or placebo (dummy treatment) and with other antipsychotics is important. This review compares the oral form of the antipsychotic zuclopenthixol dihydrochloride with other antipsychotics and placebo.

Searching for evidence

An electronic search was run on 9 June 2015, searching for trials that randomised people with schizophrenia into treatment groups that received either zuclopenthixol dihydrochloride or placebo or another antipsychotic.

Evidence found

The review authors found 20 trials with 1850 participants. Most of these participants were patients in psychiatric hospitals.

The trials compared oral zuclopenthixol dihydrochloride to placebo and nine other oral antipsychotics (chlorpromazine, chlorprothixene, clozapine, haloperidol, perphenazine, risperidone, sulpiride, thiothixene, and trifluoperazine). There were also trials that compared oral zuclopenthixol dihydrochloride with an injection of zuclopenthixol dihydrochloride and some that compared two different versions of zuclopenthixol dihydrochloride.

The review authors were interested in finding evidence for zuclopenthixol dihydrochloride's effect on seven main outcomes: global state, mental state, adverse effects, death, duration of stay in hospital, leaving the study early and general functioning. Unfortunately many data provided by the trials were unusable, data were available only for global state, mental state, leaving the study early and the adverse effect of movement disorders. The trials comparing zuclopenthixol dihydrochloride with sulpiride and trifluoperazine did not provide any useable data for any of these main outcomes.

Overall results suggest zuclopenthixol dihydrochloride's effect on global and mental state, and number of participants leaving the study early is similar to the other anti‐psychotics listed above.

Zuclopenthixol dihydrochloride may cause more movement disorders than clozapine, risperidone or perphenazine, but there was no difference for the other drug comparisons or placebo.

Conclusions

The evidence currently available is of very low to low quality and the meaning is therefore unclear. Data for many important outcomes are not available making conclusions about overall effectiveness of zuclopenthixol dihydrochloride difficult.

Evidence available suggest that zuclopenthixol dihydrochloride is not any worse than other antipsychotics in treating the symptoms of schizophrenia, however more trials providing good‐quality data are needed before firm conclusions can be made.

Summary of findings

Background

Description of the condition

Schizophrenia afflicts about 1% of the world's population across geographical, racial and gender barriers (Jablensky 1992).

It is characterised by distortions in thinking and perception in the context of inappropriate and/or blunted affects. It often includes the following psychopathological phenomena:

thought echo, thought insertion/withdrawal, thought broadcasting;
delusional perception and delusions of control, influence or passivity;
hallucinations (often auditory);
thought disorders;
negative symptoms.

The course of the illness can be continuous or episodic and outcomes are polymorphic (WHO 2010).

Description of the intervention

There is one oral preparation (marketed as Cisordinol, Clopixol) and two depot forms of zuclopenthixol dihydrochloride: zuclopenthixol acetate (Cisordinol‐Acutard, Clopixol‐Acuphase, Clopixol‐Acutard), and zuclopenthixol decanoate (Cisordinol depot, Clopixol depot, Clopixol Inj.). Zuclopenthixol dihydrochloride (Clopixol tablets) was manufactured by Lundbeck Pharmaceuticals, licensed in 1982 and is currently approved for use in 71 countries.

How the intervention might work

Zuclopenthixol belongs to the class of thioxanthene derivatives. Zuclopenthixol is the cis (Z)‐isomer of clopenthixoland has a high affinity for both dopamine D1 and D2 receptors. It is rapidly absorbed from the gastrointestinal tract and maximum serum concentration occurs after about four hours following a single oral dose. The elimination half‐life is approximately 20 hours (range 12 to 28 hours). It has a moderately high pre‐systemic metabolism and about 40% of the drug is eliminated this way (Dollery 1999).

Why it is important to do this review

Antipsychotic medication remains a key means of treating people with schizophrenia (Awad 1997; Dally 1967). Since the introduction of chlorpromazine in the early 1950's numerous antipsychotic drugs have been developed. These include haloperidol, thioridazine, trifluoperazine and zuclopenthixol and they are now inexpensive and accessible to millions. Zuclopenthixol has been licensed since the early 1980's and is used in at least 71 countries including many European countries, Australia, New Zealand and Canada.

A newer generation of so called 'atypical' antipsychotics have been developed and are increasingly prevalent for treating schizophrenia, especially in high‐income countries (Taylor 2000). This increase in the use of newer drugs is mirrored by a decline in the use of the older generation antipsychotics such as zuclopenthixol dihydrochloride although they are still used for treating schizophrenia and related psychotic conditions (Kozyrev 2003; Mace 2005; Percudani 2005). However, we have found it difficult to identify reviews on the effects of the oral preparation and we found no relevant meta‐analyses. This Cochrane review is the third review relevant to this compound and concentrates on the oral form of zuclopenthixol dihydrochloride. The first review investigated the effects of zuclopenthixol acetate for rapid tranquillisation of disturbed people with serious mental illnesses (Jayakody 2012), and the second concentrates on the decanoate preparation of zuclopenthixol as this is used as a long‐acting depot preparation (da Silva Freire Coutinho 1999).

Objectives

To determine the effects of zuclopenthixol dihydrochloride for the treatment of schizophrenia.

Methods

Criteria for considering studies for this review

Types of studies

We included all relevant randomised controlled trials. Where a trial was described as 'double‐blind' but it was implied that the study was randomised, we included these trials in a sensitivity analysis. If there was no substantive difference within primary outcomes (see Types of outcome measures) when these 'implied randomisation' studies were added, then we included these in the final analysis. If there was a substantive difference, only clearly randomised trials were utilised and the results of the sensitivity analysis described in the text. We excluded quasi‐randomised studies such as those allocating by using alternate days of the week.

Types of participants

We included people with schizophrenia and schizophrenia‐like disorders such as schizophreniform disorder, delusional disorder or schizoaffective disorder, diagnosed by any criteria. We also included those with 'serious/chronic mental illness' or 'psychotic illness'. Where possible we excluded people with dementia, depression and problems primarily associated with substance misuse.

Types of interventions

1. Zuclopenthixol dihydrochloride administered in oral form, any dose.

2. Placebo or no treatment.

3. Other antipsychotic drugs: any dose, administered in depot form.

4. Other antipsychotic drugs: any dose, administered in oral form.

Types of outcome measures

All outcomes were reported for the short term (up to 12 weeks), medium term (13 to 26 weeks), and long term (more than 26 weeks). None of the included studies went beyond one year.

Primary outcomes

1. Global state: average endpoint global state score

2. Adverse effects: clinically important general adverse effect

Secondary outcomes

1. Death ‐ suicide and natural causes

2. Global state

2. 1 Relapse  2. 2 Time to relapse  2. 3 Clinically important change in global state  2. 4 Any change in global state  2. 5 Average change in global state scores

3. Service outcomes

3. 1 Hospitalisation  3. 2 Time to hospitalisation  3. 3 Duration of stay in hospital

4. Mental state

4. 1 Clinically important change in general mental state  4. 2 Any change in general mental state  4. 3 Average endpoint general mental state score  4. 4 Average change in general mental state scores  4. 5 Clinically important change in specific symptoms  4. 6 Any change in specific symptoms  4. 7 Average endpoint specific symptom score  4. 8 Average change in specific symptom scores

5. Leaving the study early

5. 1 For specific reasons  5. 2 For general reasons

6. General functioning

6. 1 Clinically important change in general functioning  6. 2 Any change in general functioning  6. 3 Average endpoint general functioning score  6. 4 Average change in general functioning scores  6. 5 Clinically important change in specific aspects of functioning, such as social or life skills  6. 6 Any change in specific aspects of functioning, such as social or life skills  6. 7 Average endpoint specific aspects of functioning, such as social or life skills  6. 8 Average change in specific aspects of functioning, such as social or life skills

7. Behaviour

7. 1 Clinically important change in general behaviour  7. 2 Any change in general behaviour  7. 3 Average endpoint general behaviour score  7. 4 Average change in general behaviour scores  7. 5 Clinically important change in specific aspects of behaviour  7. 6 Any change in specific aspects of behaviour  7. 7 Average endpoint specific aspects of behaviour  7. 8 Average change in specific aspects of behaviour

8. Adverse effects

8. 1 Any general adverse effects  8. 2 Average endpoint general adverse effect score  8. 3 Average change in general adverse effect scores  8. 4 Clinically important change in specific adverse effects  8. 5 Any change in specific adverse effects  8. 6 Average endpoint specific adverse effects  8. 7 Average change in specific adverse effects

9. Engagement with services

9. 1 Clinically important engagement  9. 2 Not any engagement  9. 3 Average endpoint engagement score  9. 4 Average change in engagement scores

10. Satisfaction with treatment

10. 1 Recipient of care satisfied with treatment  10. 2 Recipient of care average satisfaction score  10. 3 Recipient of care average change in satisfaction scores  10. 4 Carer satisfied with treatment  10. 5 Carer average satisfaction score  10. 6 Carer average change in satisfaction scores

11. Quality of life

11. 1 No clinically important change in quality of life  11. 2 Not any change in quality of life  11. 3 Average endpoint quality of life score  11. 4 Average change in quality of life scores  11. 5 No clinically important change in specific aspects of quality of life  11. 6 Not any change in specific aspects of quality of life  11. 7 Average endpoint specific aspects of quality of life  11. 8 Average change in specific aspects of quality of life

12. Economic outcomes

12. 1 Direct costs  12. 2 Indirect costs

Summary of findings

We used the GRADE approach to interpret findings (Schünemann 2011) and used the GRADE profiler to import data from Review Manager (RevMan) to create 'Summary of findings' tables. These tables provide outcome‐specific information concerning the overall quality of evidence from each included study in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on all outcomes we rated as important to patient‐care and decision making.

We selected the following main outcomes for inclusion in the 12 'Summary of findings' tables.

Global state: Average endpoint global state score (clinically improved) [primary outcome]
Adverse effects: Clinically important general adverse effect [primary outcome]
Death: Suicide and natural causes [secondary outcome]
Service outcome: Duration of stay in hospital [secondary outcome]
Mental state: Average endpoint general mental state score (clinically improved) [secondary outcome]
Leaving the study early: any reason [secondary outcome]
General functioning: Average endpoint general functioning score (clinically improved) [secondary outcome]

Search methods for identification of studies

Electronic searches

Cochrane Schizophrenia Group’s Trials Register

On June 09, 2015, the Trials Search Co‐ordinator (TSC) searched the Cochrane Schizophrenia Group’s Study‐Based Register of Trials using the following search strategy which has been developed based on literature review and consulting with the authors of the review:

*Zuclopenthixol* in Intervention of STUDY

In such a study‐based register, searching the major concept retrieves all the relevant keywords and studies because all the studies have already been organised based on their interventions and linked to the relevant topics.

The Cochrane Schizophrenia Group’s Register of Trials is compiled by systematic searches of major resources (including AMED, BIOSIS, CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings (see Group Module). There is no language, date, document type, or publication status limitations for inclusion of records into the register.

For previous searches, please see Appendix 1.

Searching other resources

1. Reference searching

We inspected references of all included studies for further relevant studies.

2. Personal contact

Where necessary, we contacted the first author of each included study for information regarding unpublished trials. We noted the outcome of this contact in the included or awaiting assessment studies tables.

Data collection and analysis

For previous data collection and analysis see Appendix 2.

Selection of studies

For this update, review author EJB independently inspected citations from the searches and identified relevant abstracts. A random 20% sample was independently re‐inspected by Dr Marie Ann Purcell (MAP) to ensure reliability. Where disputes arose, the full report was acquired for more detailed scrutiny. Full reports of the abstracts meeting the review criteria were obtained and inspected by EJB. Again, a random 20% of full reports were‐inspected by MAP in order to ensure reliable selection. Where it was not possible to resolve disagreement by discussion, we attempted to contact the authors of the study for clarification.

Data extraction and management

1. Extraction

For this update, review author EJB extracted data from all included studies. In addition, to ensure reliability, JX (see Acknowledgements) independently extracted data from a random sample of these studies, comprising 10% of the total. Again, any disagreements were discussed, decisions documented and, if necessary, authors of studies contacted for clarification. With remaining problems MAP helped clarify issues and these final decisions were documented. Data presented only in graphs and figures were to be extracted whenever possible, but included only if two review authors independently had the same result. We attempted to contact authors through an open‐ended request in order to obtain missing information or for clarification whenever necessary. If studies were multi‐centre, where possible, we extracted data relevant to each component centre separately.

2. Management

2.1 Forms

We extracted data onto simple standard forms.

2.2 Scale‐derived data

We included continuous data from rating scales only if:    a) the psychometric properties of the measuring instrument have been described in a peer‐reviewed journal (Marshall 2000); and  b) the measuring instrument has not been written or modified by one of the trialists for that particular trial.    Ideally, the measuring instrument should either be i. a self‐report or ii. completed by an independent rater or relative (not the therapist). We realise that this is not often reported clearly, in Description of studies we noted if this was the case or not.

2.3 Endpoint versus change data

There are advantages of both endpoint and change data. Change data can remove a component of between‐person variability from the analysis. On the other hand, calculation of change needs two assessments (baseline and endpoint) which can be difficult in unstable and difficult to measure conditions such as schizophrenia. We decided primarily to use endpoint data, and only use change data if the former were not available. Endpoint and change data were combined in the analysis as we used mean differences (MD) rather than standardised mean differences (SMD) throughout (Higgins 2011).

2.4 Skewed data

Continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non‐parametric data, we aimed to apply the following standards to all data before inclusion:

Please note, we entered data from studies of at least 200 participants, for example, in the analysis irrespective of the following rules, because skewed data pose less of a problem in large studies. We also entered change data as when continuous data are presented on a scale that includes a possibility of negative values (such as change data), it is difficult to tell whether data are skewed or not. We presented and entered change data into the statistical analyses.

For endpoint data:

(a) when a scale starts from the ﬁnite number zero, we subtracted the lowest possible value from the mean, and divided this by the standard deviation (SD). If this value was lower than 1, it strongly suggests a skew and the study was excluded. If this ratio was higher than 1 but below 2, there is suggestion of skew. We entered the study and tested whether its inclusion or exclusion changed the results substantially. Finally, if the ratio was larger than 2, the study was included, because skew is less likely (Altman 1996; Higgins 2011).

b) if a scale starts from a positive value (such as the Positive and Negative Syndrome Scale (PANSS) (Kay 1987), which can have values from 30 to 210), the calculation described above was modified to take the scale starting point into account. In these cases skew is present if 2 SD > (S‐S min), where S is the mean score and 'S min' is the minimum score.

2.5 Common measure

To facilitate comparison between trials, we intended to convert variables that can be reported in different metrics, such as days in hospital (mean days per year, per week or per month) to a common metric (e.g. mean days per month).

2.6 Conversion of continuous to binary

Where possible, we made efforts to convert outcome measures to dichotomous data. This can be done by identifying cut‐off points on rating scales and dividing participants accordingly into 'clinically improved' or 'not clinically improved'. It is generally assumed that if there is a 50% reduction in a scale‐derived score such as the Brief Psychiatric Rating Scale (BPRS, Overall 1962) or the Positive and Negative Syndrome Scale (PANSS, Kay 1986), this could be considered as a clinically significant response (Leucht 2005; Leucht 2005a). If data based on these thresholds were not available, we used the primary cut‐off presented by the original authors.

2.7 Direction of graphs

Where possible, we entered data in such a way that the area to the left of the line of no effect indicates a favourable outcome for Zuclopenthixol dihydrochloride. Where keeping to this made it impossible to avoid outcome titles with clumsy double‐negatives, we reported data where the left of the line indicates an unfavourable outcome. This is noted in the relevant graphs.

Assessment of risk of bias in included studies

Again, review author EJB worked independently to assess risk of bias by using criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess trial quality. This set of criteria is based on evidence of associations between overestimate of effect and high risk of bias of the article such as sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting. A random 20% was screened for validity independently by MAP.

If the raters disagreed, the final rating was made by consensus, with the involvement of another member of the review group. Where inadequate details of randomisation and other characteristics of trials were provided, we contacted the authors of the studies in order to obtain further information. We reported non‐concurrence in quality assessment , but if disputes arose as to which category a trial was to be allocated, again, we resolved this by discussion.

We noted the level of risk of bias in both the text of the review and in the 'Summary of findings' tables.

Measures of treatment effect

1. Binary data

For binary outcomes we calculated a standard estimation of the risk ratio (RR) and its 95% confidence interval (CI). It has been shown that RR is more intuitive (Boissel 1999) than odds ratios and that odds ratios tend to be interpreted as RR by clinicians (Deeks 2000). The number needed to treat for an additional beneficial outcome/number needed to treat for an additional harmful outcome (NNTB/NNTH) statistic with its confidence intervals is intuitively attractive to clinicians but is problematic both in its accurate calculation in meta‐analyses and interpretation (Hutton 2009). For binary data presented in the 'Summary of findings' tableS, where possible, we calculated illustrative comparative risks.

2. Continuous data

For continuous outcomes we estimated mean difference (MD) between groups. We preferred not to calculate effect size measures (standardised mean difference (SMD)). However, if scales of very considerable similarity were used, we presumed there was a small difference in measurement, and we calculated effect size and transformed the effect back to the units of one or more of the specific instruments.

Unit of analysis issues

1. Cluster trials

Studies increasingly employ 'cluster randomisation' (such as randomisation by clinician or practice), but analysis and pooling of clustered data poses problems. Firstly, authors often fail to account for intra‐class correlation in clustered studies, leading to a 'unit of analysis' error (Divine 1992) whereby P values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated. This causes type I errors (Bland 1997; Gulliford 1999).

Where clustering was not accounted for in primary studies, we presented data in a table, with a (*) symbol to indicate the presence of a probable unit of analysis error. In subsequent versions of this review we will seek to contact first authors of studies to obtain intra‐class correlation coefficients (ICCs) for their clustered data and to adjust for this by using accepted methods (Gulliford 1999). Where clustering had been incorporated into the analysis of primary studies, we presented these data as if from a non‐cluster randomised study, but adjusted for the clustering effect.

We sought statistical advice and have been advised that the binary data as presented in a report should be divided by a 'design effect'. This is calculated using the mean number of participants per cluster (m) and the ICC [Design effect = 1+(m‐1)*ICC] (Donner 2002). If the ICC was not reported it was be assumed to be 0.1 (Ukoumunne 1999).

If cluster studies have been appropriately analysed taking into account ICCs and relevant data documented in the report, synthesis with other studies was possible using the generic inverse variance technique.

2. Cross‐over trials

A major concern of cross‐over trials is the carry‐over effect. It occurs if an effect (e.g. pharmacological, physiological or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase the participants can differ systematically from their initial state despite a wash‐out phase. For the same reason cross‐over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in severe mental illness, we only used data of the first phase of cross‐over studies.

3. Studies with multiple treatment groups

Where a study involved more than two treatment arms, if relevant, the additional treatment arms were presented in the comparisons. If data were binary, we simply added and combined them within the two‐by‐two table. If data were continuous, we combined data following the formula in section 7.7.3.8 (Combining groups) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Where the additional treatment arms were not relevant, we did not use these data.

Dealing with missing data

1. Overall loss of credibility

At some degree of loss of follow‐up, data must lose credibility (Xia 2009). We chose that, for any particular outcome, should more than 50% of data be unaccounted for, we would not reproduce these data or use them within the analyses. If, however, more than 50% of those in one arm of a study were lost, but the total loss was less than 50%, we addressed this within the 'Summary of findings' tables by down‐rating quality. Finally, we also downgraded quality within the 'Summary of findings' tables should loss be 25% to 50% in total.

2. Binary

In the case where attrition for a binary outcome was between 0% and 50% and where these data were not clearly described, we presented data on a 'once‐randomised‐always‐analyse' basis (an intention‐to‐treat (ITT) analysis). Those leaving the study early were all assumed to have the same rates of negative outcome as those who completed, with the exception of the outcome of death and adverse effects. For these outcomes, the rate of those who stayed in the study ‐ in that particular arm of the trial ‐ were used for those who did not. We undertook a sensitivity analysis to test how prone the primary outcomes were to change when data only from people who completed the study to that point were compared to the ITT analysis using the above assumptions.

3. Continuous

3.1 Attrition

In the case where attrition for a continuous outcome was between 0% and 50%, and data only from people who completed the study to that point were reported, we reproduced these.

3.2 Standard deviations

If standard deviations (SDs) were not reported, we first tried to obtain the missing values from the authors. If not available, where there were missing measures of variance for continuous data, but an exact standard error (SE) and confidence intervals available for group means, and either 'P' value or 't' value available for differences in mean, we could calculate them according to the rules described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011): When only the SE is reported, SDs are calculated by the formula SD = SE * square root (n). Chapters 7.7.3 and 16.1.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) present detailed formulae for estimating SDs from P values, t or F values, confidence intervals, ranges or other statistics. If these formulae did not apply, we calculated the SDs according to a validated imputation method which is based on the SDs of the other included studies (Furukawa 2006). Although some of these imputation strategies can introduce error, the alternative would be to exclude a given study’s outcome and thus to lose information. We nevertheless examined the validity of the imputations in a sensitivity analysis excluding imputed values.

3.3 Assumptions about participants who left the trials early or were lost to follow‐up

Various methods are available to account for participants who left the trials early or were lost to follow‐up. Some trials just present the results of study completers, others use the method of last observation carried forward (LOCF), while more recently methods such as multiple imputation or mixed‐effects models for repeated measurements (MMRM) have become more of a standard. While the latter methods seem to be somewhat better than LOCF (Leon 2006), we feel that the high percentage of participants leaving the studies early and differences in the reasons for leaving the studies early between groups is often the core problem in randomised schizophrenia trials. We therefore did not exclude studies based on the statistical approach used. However, preferably we used the more sophisticated approaches. For example, MMRM or multiple‐imputation were preferred to LOCF and completer analyses were only presented if some kind of ITT data were not available at all. Moreover, we addressed this issue in the item "incomplete outcome data" of the 'Risk of bias' tool.

Assessment of heterogeneity

1. Clinical heterogeneity

We considered all included studies initially, without seeing comparison data, to judge clinical heterogeneity. We simply inspected all studies for clearly outlying people or situations which we had not predicted would arise. When such situations or participant groups arose, we fully discussed these.

2. Methodological heterogeneity

We considered all included studies initially, without seeing comparison data, to judge methodological heterogeneity. We simply inspected all studies for clearly outlying methods which we had not predicted would arise. When such methodological outliers arose, we fully discussed these.

3. Statistical heterogeneity

3.1 Visual inspection

We visually inspected graphs to investigate the possibility of statistical heterogeneity.

3.2 Employing the I² statistic

We investigated heterogeneity between studies by considering the I² method alongside the Chi² 'P' value. The I² provides an estimate of the percentage of inconsistency thought to be due to chance (Higgins 2003). The importance of the observed value of I² depends on i. magnitude and direction of effects and ii. strength of evidence for heterogeneity (e.g. 'P' value from Chi² test, or a confidence interval for I²). An I² estimate greater than or equal to around 50% accompanied by a statistically significant Chi² statistic, was interpreted as evidence of substantial levels of heterogeneity (Section 9.5.2 ‐ Higgins 2011). When substantial levels of heterogeneity were found in the primary outcome, we explored reasons for heterogeneity (Subgroup analysis and investigation of heterogeneity).

Assessment of reporting biases

1. Protocol versus full study

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results. These are described in section 10.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We attempted to locate protocols of included randomised trials. If the protocol was available, we compared outcomes in the protocol and in the published report. If the protocol was not available, we compared outcomes listed in the methods section of the trial report with actually reported results.

2. Funnel plot

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Egger 1997). Again, these are described in Section 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We are aware that funnel plots may be useful in investigating reporting biases but are of limited power to detect small‐study effects. We did not use funnel plots for outcomes where there were 10 or fewer studies, or where all studies were of similar sizes. In other cases, where funnel plots were possible, we planned to seek statistical advice in their interpretation.

Data synthesis

We understand that there is no closed argument for preference for use of fixed‐effect or random‐effects models. The random‐effects method incorporates an assumption that the different studies are estimating different, yet related, intervention effects. This often seems to be true to us and the random‐effects model takes into account differences between studies, even if there is no statistically significant heterogeneity. There is, however, a disadvantage to the random‐effects model. It puts added weight onto small studies which often are the most biased ones. Depending on the direction of effect, these studies can either inflate or deflate the effect size. We chose a random‐effects model for all analyses. The reader is, however, able to choose to inspect the data using the fixed‐effect model.

Subgroup analysis and investigation of heterogeneity

1. Subgroup analyses

1.1 Primary outcomes

No subgroup analysis was expected.

1.2 Clinical state, stage or problem

We proposed to undertake this review and provide an overview of the effects of zuclopenthixol dihydrochloride for people with schizophrenia in general. In addition, however, we tried to report data on subgroups of people in the same clinical state, stage and with similar problems. This was not done in this update.

2. Investigation of heterogeneity

If inconsistency was high, this was reported. First, we investigated whether data had been entered correctly. Second, if data were correct, the graph was visually inspected and outlying studies were successively removed to see if homogeneity was restored. For this review we decided that should this occur with data contributing to the summary finding of no more than around 10% of the total weighting, data were presented. If not, data were not pooled and issues discussed. We know of no supporting research for this 10% cut‐off but are investigating the use of prediction intervals as an alternative to this unsatisfactory state.

When unanticipated clinical or methodological heterogeneity were obvious we simply stated hypotheses regarding these for future reviews or versions of this review. We do not anticipate undertaking analyses relating to these.

Sensitivity analysis

1. Implication of randomisation

We aimed to include trials in a sensitivity analysis if they were described in some way as to imply randomisation. For the primary outcomes, we included these studies and if there was no substantive difference when the implied randomised studies were added to those with better description of randomisation, then all data were employed from these studies.

2. Assumptions for lost binary data

Where assumptions had to be made regarding people lost to follow‐up (see Dealing with missing data), we compared the findings of the primary outcomes when we used our assumption/s and when we used data only from people who completed the study to that point. If there was a substantial difference, we reported results and discussed them but continued to employ our assumption.

Where assumptions had to be made regarding missing SDs data (see Dealing with missing data), we compared the findings of the primary outcomes when we used our assumption/s and when we used data only from people who completed the study to that point. A sensitivity analysis was undertaken to test how prone results were to change when completer‐only data only were compared to the imputed data using the above assumption. If there was a substantial difference, we reported results and discussed them but continued to employ our assumption.

3. Risk of bias

We analysed the effects of excluding trials that were judged to be at high risk of bias across one or more of the domains of randomisation (implied as randomised with no further details available) allocation concealment, blinding and outcome reporting for the meta‐analysis of the primary outcome. If the exclusion of trials at high risk of bias did not substantially alter the direction of effect or the precision of the effect estimates, then data from these trials were included in the analysis.

4. Imputed values

We also undertook a sensitivity analysis to assess the effects of including data from trials where we used imputed values for ICC in calculating the design effect in cluster‐randomised trials.

If substantial differences were noted in the direction or precision of effect estimates in any of the sensitivity analyses listed above, we did not pool data from the excluded trials with the other trials contributing to the outcome, but presented them separately.

5. Fixed and random effects

We synthesised all data using a random‐effects model, however, we also synthesised data for the primary outcome using a fixed‐effect model to evaluate whether this altered the significance of the results.

Results

Description of studies

Accross all comparisons there was a significant lack of data for the primary outcomes and the secondary outcomes. The majority of data were for the short term only, for inpatient populations and focused on adverse effects. Most studies were small with the exception of Fischer‐Cornelssen 1976.

Results of the search

Details of the search results are illustrated in the PRISMA tableFigure 1

After obtaining the initial results of the search, removing duplicates and clearly irrelevant material, the original review authors inspected 79 abstracts. Out of these 79 papers, they selected 71 full‐text papers to be assessed for eligibility. The original authors then grouped these into 'studies' where several of the reports referred to the same trial. Fifty‐three articles were excluded with reasons and 18 studies were included in the 2005 meta‐analysis.

During the update we identified 117 potential reports for the review. We had to exclude 73 (84 reports) of these studies. So, at the end of this review update we have identified 33 reports of 20 trials for inclusion in the 2016 meta‐analysis. At the time of writing zero studies are awaiting assessment and we know of no ongoing studies at the time of writing.

Included studies

We identified 20 studies (from 33 references) spanning the period 1968 to 2008 covering 12 comparisons for inclusion in this update. Fifteen were described as randomised and in the remaining five, randomisation was implied. One trial was a cross‐over trial and one was an open‐label trial. Two authors need to be contacted for additional information at the next update (Arango 2006 and Fagerlund 2004). Ban 1975 data has been updated to reflect the two‐week washout period not originally included in the initial publication.

The trial authors were not always explicit in their descriptions of randomisation or blinding and an assumption of either or both was made based on implication and context of the discussions and/or data. The majority of the data were short term and from inpatient samples. The studies used relatively small cohorts with the exception of Fischer‐Cornelssen 1976.

Where authors published research from the same cohort in several different reports the data were pooled and used only once in the meta‐analysis. Some degree of interpretation on our part was required during this process.

Further information on the included studies can be obtained in the Characteristics of included studies table.

Excluded studies

We excluded 73 studies: two had healthy volunteers, 42 used the wrong intervention (predominantly depot), four used the wrong type of participant, eight were not randomised, 16 did not have any useable data (either data that could be extracted for meta‐analysis or no data provided), and one duplicated data from elsewhere. Galdersi 1994 was originally included but excluded in this update because it was not a randomised trial.

Further information on the excluded studies can be obtained in theCharacteristics of excluded studies table.

Risk of bias in included studies

Most information is from studies at low or unclear risk of bias. It is difficult to provide a generalised assessment of the risk of bias given the low number of studies in this update. We would advise reviewing the 'Risk of bias' tables in the Characteristics of included studies table of the review.

Risk of bias overall: Unclear.

Allocation

Three studies were graded as low risk, 16 as unclear risk and one as high risk. All included studies were randomised or had implied randomisation. Most of the included studies did not explicitly describe the method by which randomisation was done.The majority of patients came from inpatient samples and there was a degree of diagnostic purity to the samples. Review of demographic tables (where published) indicated a roughly equal spread between different arms within the different studies.

Overall risk of selection bias: unclear.

Blinding

Thirteen studies were graded as low risk, four as unclear risk and three as high risk. Two of the studies were open‐label and all included studies used some form of established rating scale or modified rating scale to measure changes in global state, adverse effects and mental state. Several of the papers were vague on their methods for blinding, but it was generally implied in the majority. Only a few papers explicitly stated that blinding was conducted and this was usually mentioned in the title and/or abstract.

Overall risk of performance/detection bias: low risk.

Incomplete outcome data

Nine studies were graded as low risk, five as unclear risk and six as high risk. Reasons for loss to follow‐up are well‐reported and we have recorded these in the outcomes. Most studies, however, have not clearly described how they used data for people who were lost to follow‐up and we found no reporting of attempts to validate any assumptions by following up those who dropped out early. Per‐protocol analysis was used in eight studies.

Overall risk of attrition bias: low risk.

Selective reporting

Five studies were graded as low risk, five as unclear risk and 10 as high risk. Overall, due to poor reporting, we were unable to use a lot of the data (missing data were detected in nine of the studies). Findings presented as graphs, whether as percentiles or as inexact P values, are often of little use to a reviewer. Many studies failed to provide standard deviations when reporting mean changes. Three of the studies published the same data in multiple locations. One study presented its data inaccurately requiring EJB to make a professional judgement on what the authors intended.

Overall risk of reporting bias: high risk.

Other potential sources of bias

Two studies were graded as low risk, two as unclear risk and 16 as high risk. The predominant biases in this category are: response bias, instrument bias, interviewer bias and the Hawthorne effect. The authors of the included studies did not discuss these biases in any detail, if at all.

Overall risk of other bias: high risk.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9; Table 10; Table 11; Table 12

Summary of findings for the main comparison. Zuclopenthixol dihydrochloride versus placebo.

Patient or population: people with schizophrenia  Setting: Hospital  Intervention: ZUCLOPENTHIXOL  Comparison: PLACEBO (short term)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with PLACEBO (short term)	Risk with ZUCLOPENTHIXOL	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
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  (69 to 1000)	RR 6.07  (0.86 to 43.04)	28  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{2, 3,4, 5, 6}	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  (0 to 264)	RR 0.29  (0.01 to 6.60)	100  (2 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1, 6}	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).    CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Patient or population: schizophrenia  Setting: Outpatient and inpatient (predominantly hospitalised)  Intervention: ZUCLOPENTHIXOL  Comparison: CHLORPROMAZINE (short term)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with CHLORPROMAZINE (short term)	Risk with ZUCLOPENTHIXOL	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
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  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 5}	Translated study.
Adverse effects: Clinically important general adverse effect (EPSEs)	300 per 1000	282 per 1000  (183 to 435)	RR 0.94  (0.61 to 1.45)	199  (3 RCTs)	⊕⊝⊝⊝  VERY LOW ^{2 4 5 6}	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  (3 RCTs)	⊕⊕⊝⊝  LOW ^{2 6}	Mixture of inpatient and outpatient, though predominantly hospitalised patients.
Leaving the study early (any reason)	70 per 1000	38 per 1000  (25 to 57)	RR 0.54  (0.36 to 0.81)	766  (6 RCTs)	⊕⊕⊝⊝  LOW ^{3 6}	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).    CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Adverse effects: 6b. Any change in specific adverse effects ‐ movement disorders ‐ additional medication use
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.

Adverse effects: Any general adverse effects ‐ side effects ‐ frequency per day
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%)

Adverse Effects: 1. Any change in general adverse effects ‐ additional medication use ‐ 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.

Adverse Effects: 1. Any change in general adverse effects ‐ additional medication use
Study	Zuclopenthixol	Sulpiride
Mahadevan 1991	n = 4 Amitriptyline	n = 4 Amitryptyline

Adverse Effects: 1a. Any general adverse effects ‐ additional medication use
Study	Zuclopenthixol	Depot
Arango 2006	n = 1 Propanolol	n = 1 venlafaxine n = 1 Lithium

Adverse Effects: 1b. Any change in specific adverse effects ‐ individual side effects
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

Date	Event	Description
25 October 2017	New citation required but conclusions have not changed	New data do not substantively alter the overall conclusions of this review.
3 May 2017	New search has been performed	Results from 2012 and 2015 searches added to review. Two new studies included, 20 new studies excluded. Review now includes 20 trials, reporting data for 12 comparisons.

Date	Event	Description
9 June 2015	Amended	Search updated and 16 References (14 Studies) were added to 'Studies awaiting classification' section of the review.
5 June 2015	Amended	July 2012 update included in analyses. Risk of bias tables updated. Original included and excluded studies reviewed. Text revised. Structure revised.
23 July 2012	Amended	Update search of Cochrane Schizophrenia  Group's Trial Register (see Search methods for identification of studies), 8 studies added to Studies awaiting classification.
23 April 2008	Amended	Converted to new review format.
10 July 2005	New citation required and conclusions have changed	Substantive amendment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Leaving the study early (any reason)	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	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	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	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)	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	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]

Methods	Allocation: randomised.  Blindness: double.  Duration: 1 week before cross‐over.  Design: cross‐over.  Country: Denmark. Funding: Not mentioned.
Participants	Diagnosis: paranoid schizophrenia.  History: not clear in article but states duration of illness 2 months ‐ 2 years.  N = 9.  Age: mean 58 years, range 39‐81.  Sex: all male.  Inclusion criteria: all patients who had been previously treated with cis(Z)/trans(E)‐clopenthixol (from 2 months to several years). Exclusion: not mentioned.  Setting: not reported.
Interventions	1. Cis(Z)‐clopenthixol hydrochloride: dose range 5 mg to 50 mg/day. Taken twice daily. N = 4.  2. Clopenthixol hydrochloride (cis(Z) and trans(E) forms): dose 10 mg to 100 mg/day. Taken twice daily. N = 5.
Outcomes	5.2 Leaving the study early for General Reasons (zero people left the study early). Unable to use: Physiological ‐ serum concentrations of Cis(Z)‐clopenthixol and clopenthixol. Non‐clinical data all reported post‐cross‐over.
Notes	Cross‐over trial. Patient 4 excluded during statistical analysis (also received multiple drugs).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Done "in a randomised way". Authors do not state how. Attempted to contact authors but Dikemark Hospital no longer exists.
Allocation concealment (selection bias)	Unclear risk	Authors do not comment. Attempted to contact authors but Dikemark Hospital no longer exists.
Blinding	Low risk	Authors state "Double blindly".
Incomplete outcome data (attrition bias)   None	Low risk	None detected.
Selective reporting (reporting bias)	Low risk	All data appear to have been reported that was sought by the study's aims.
Other bias	High risk	Selection bias (n = 9) ‐ diagnostic purity bias.

Methods	Allocation: randomised.  Blindness: double.  Duration: 10 weeks.  Design: outpatient and Inpatient  Country: UK.
Participants	Diagnosis: acute functional psychosis (schizophrenia n = 68, schizoaffective n = 7, hypomania n = 4, unknown n = 4 and unreported n = 11.  History: acutely ill / exacerbation of chronic illness, 0‐20 episodes.  N = 94.  Age: mean ˜ 36.9 years, range 18‐65. Age of one patient not recorded.  Sex: 48 male, 34 female, 13 unspecified (12 patients not analysed by authors and sex not reported in 1 patient). Lundbeck UK contacted to request information.  Inclusion criteria: BPRS 15 or more.  Exclusion criteria: previous intolerance to neuroleptics, additional serious psychiatric or neurological disorder, serious physical illness, pregnant or lactating women and those of child‐bearing potential who intend to become pregnant, addiction to drugs or alcohol, depot neuroleptic at an unstable dose or dosing frequency.  Setting: hospital and community.
Interventions	1. Zuclopenthixol: dose range 25 mg to 150 mg/day. N = 50.  2. Chlorpromazine: dose range 100 mg to 600 mg/day. N = 44. Additional medication: amitriptyline, temazepam, procyclidine.
Outcomes	2. Global state: CGI. Table 1 5. Leaving the study early. Zuclo n = 32 completed study, Chlor n = 21 completed the study.  8. Adverse effects. Table 1 Unable to use:  Mental state: BPRS (> 50% loss to follow‐up in one group).  Adverse effects: UKU side effects rating scale (data not reported by group).
Notes	Zuclopenthixol group previous episodes 0‐17. Chlorpromazine group previous episodes 0‐20. Most common zuclopenthixol dose 75 mg/day. Most common chlorpromazine dose 600 mg/day
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors do not mention. Lundbeck UK contacted to request information regarding potential biases 5th January 2016.
Allocation concealment (selection bias)	Unclear risk	Authors do not mention.
Blinding	Low risk	Clearly stated in the paper as double‐blind design.
Incomplete outcome data (attrition bias)   None	High risk	11 patients were excluded and not analysed. Missing outcome data.
Selective reporting (reporting bias)	Low risk	All data appear to have been reported on.
Other bias	High risk	Attrition bias ‐ per protocol analysis.

Methods	Allocation: randomised.  Blindness: double.  Duration: 12 weeks.  Design: single‐centre.  Country: Canada. Funding: Public health service research grant ‐ Pfizer
Participants	Diagnosis: schizophrenia.  N = 30.  Age: mean 37 years, range 18‐58.  Sex: 13 male, 17 female.  Inclusion: diagnosis of schizophrenia Exclusion criteria: not reported.  Setting: hospital.
Interventions	1. Clopenthixol: dose range 50 mg to 200 mg/day. Average 150 mg/day. N = 10.  2. Thiothixene: dose range 10 mg to 40 mg/day. average 30 mg/day. N = 10.  3. Chlorprothixene: dose range 150 mg to 600 mg/day. Average 450 mg/day. N = 10.
Outcomes	Useable: 2. Global state: CGI. 5. Leaving the study early  8. Adverse effects: number of adverse effects in every group, partial TESS Unable to use:  4. Mental state: BPRS (data not reported by group).  7. Behaviour: NOSIE (no data available).  8. Adverse effects: TESS (no data available).
Notes	15 chronic and 15 new admissions. Original Cochrane authors did not include the two‐week washout period in the duration of the study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Suggested but not reported by authors. "10 week double blind."
Allocation concealment (selection bias)	Unclear risk	Not mentioned.
Blinding	Low risk	"10 week double blind."
Incomplete outcome data (attrition bias)   None	Low risk	None obvious and none mentioned by authors.
Selective reporting (reporting bias)	High risk	Multiple areas where data not reported. Several papers produced with same data.
Other bias	High risk	Selection bias ‐ sampling ‐ Berkson

Methods	Allocation: Random Blindness: open‐label Duration: 13 weeks Funding: Danish Medical Counscil, H:S Research council, University of Copenhagen Faculty of Humanities Location: Copenhagen
Participants	Diagnosis: ICD10 F20 Schizophrenia N = 31 Age: 27.3 years (+/‐5.9), range 19‐37 Sex: not discussed History: untreated psychosis 4‐78 months Inclusion: anti‐psychotic naive admitted for treatment and written informed consent Exclusion: known retardation, need acute medication, compulsorily hospitalised
Interventions	1. Zuclopenthixol 6 mg to 26 mg average 9.6 mg. N = 10 2. Risperidone 2 mg to 7 mg average 3.6 mg. N = 15 3: Healthy controls N = 25 Additional Medication: Benzodiazepiens and anticholinergics but not on the day of examination
Outcomes	Usable: 4. Mental State: PANSS ‐ table 2 5. Leaving the study Early Not Useable: 6. General Functioning: Cognitive Functions (CANTAB, WCST, verbal fluency, Figural fluency, trail making tests A & B, DART) ‐ no useable data 8. Adverse Effects: ESRS ‐ no data
Notes	Not all data published by authors. When review next updated the authors should be contacted to obtain this information.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated but not elaborated on.
Allocation concealment (selection bias)	High risk	Open‐label.
Blinding	High risk	Open‐label.
Incomplete outcome data (attrition bias)   None	Unclear risk	Authors state they will publish other data elsewhere though not found in searches to date.
Selective reporting (reporting bias)	Unclear risk	Authors state they will publish other data elsewhere though not found in searches to date.
Other bias	High risk	Selection bias, Berkson

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)	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	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)	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)	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)	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	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)	3	221	Mean Difference (IV, Random, 95% CI)	0.40 [‐2.43, 3.23]
8 Leaving the study early (any reason)	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)	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)	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)	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	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	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	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			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)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2 Leaving the study early (any reason)	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)	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			Other data	No numeric data

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	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	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	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	1	25	Mean Difference (IV, Random, 95% CI)	‐1.5 [‐4.05, 1.05]
5 Leaving the study early (any reason) ‐ short/medium term	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			Other data	No numeric data
7 Adverse effects: 2a. Any change in specific adverse effects ‐ movement disorders ‐ EPSEs ‐ requiring medication ‐ short term	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	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	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 Leaving the study early (any reason)	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	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			Other data	No numeric data
4 Adverse Effects: 1b. Any change in specific adverse effects ‐ additional medication use ‐ benzodiazepine use at least once	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	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	1	57	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.45, 2.07]
3 Leaving the study early (any reason)	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	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			Other data	No numeric data

Methods	Allocation: randomised Blindness: none ‐ open‐label Duration: 1 year Funding: Theodore and Vada Stanley Foundation Grant Setting: 3 inpatient units
Participants	Diagnosis: schizophrenia N = 46 Age: mean ˜34 years, range 24‐44 Sex: 38 male, 8 female Inclusion: DSM IV criteria for schizophrenia, a violent episode in the previous year with a score of greater than or equal to 3 on the physical aggression sub‐scale or the MOAS. A family member living with the patient and willing to collaborate with the researchers. Informed consent signed by the patient and the informant. Exclusion: Any other axis I disorders, including alcohol and/or drug abuse/dependence, mental retardation.
Interventions	1. Zuclopenthixol (oral) 35 mg/day n = 20 2. Zuclopenthixol (depot) 233 mg every 14 days (˜16.6 mg/day) n = 26 Additional medication: All received biperiden, other psychotropics were permitted.
Outcomes	Useable: 4. Mental State ‐ PANSS positive only 5. Leaving the study Early 7. Behaviour ‐ number of violent episodes 8. Adverse Effects ‐ additional medication Unable to use: 7. Behaviour ‐ MOAS, baseline data only 8. Adverse effects ‐ UKU ‐ no data provided by group
Notes	Madrid Inclusion criteria do not match included data and significant selective reporting. Authors will need to be contacted at next update to obtain clarification.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	A researcher at one centre did the randomisation.
Allocation concealment (selection bias)	Unclear risk	Not stated.
Blinding	High risk	Open‐label.
Incomplete outcome data (attrition bias)   None	High risk	Missing UKU, missing PANSS.
Selective reporting (reporting bias)	High risk	MOAS not reported other than at baseline.
Other bias	High risk	Selection bias ‐ Berkson

Methods	Allocation: inpatient Blindness: randomised by specially assigned person Duraton:: 6 weeks
Participants	Diagnosis: CCMD ‐ 3 N = 120 Age: mean ˜33 years, range 24‐42 Exclusion: severe physical diseases, alcohol and substance dependence
Interventions	1. Clopenthixol 40 mg to 70 mg/day. N = 60 2. Chlorpromazine 300 mg to 550 mg/day. N = 60 Other antipsychotics were not allowed during the treatment. Benzhexol and diazepam were used if necessary.
Outcomes	Able to use: 4. Mental state: BPRS, PANSS 8. Adverse Effects: EPSEs and excessive sedation Unable to use: 4. Mentals State: SANS ‐ no useable data
Notes	Paper kindly translated and data extracted by Jun Xia.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Not mentioned. No detailed information was described in the study. No Concerns raised by the data extractor.
Allocation concealment (selection bias)	Low risk	Not mentioned. No detailed information was described in the study. No Concerns raised by the data extractor.
Blinding	Low risk	Randomised. No detailed information was described in the study. No Concerns raised by the data extractor.
Incomplete outcome data (attrition bias)   None	Low risk	All outcomes reported.
Selective reporting (reporting bias)	Low risk	None found.
Other bias	Low risk	None obvious.

Methods	Allocation: randomised not clear.  Blindness: double.  Duration: 7 weeks.  Design: multicentre.  Country: Switzerland. Funding: not stated
Participants	Diagnosis: acute paranoid schizophrenia.  History: moderate to severe hospitalised acute patients with schizophrenia.  N = 723.  Age: not reported.  Sex: not reported.  Inclusion criteria: moderate to severe acute patients with schizophrenia.  Setting: hospital.
Interventions	1. Clopenthixol: dose 100 mg/day. N = 36.  2. Clozapine: dose 200 mg to 300 mg/day. N = 371.  3. Chlorpromazine: dose 200 mg to 350 mg/day. N = 212.  4. Haloperidol: dose 4 mg to 8 mg/day. N = 78.  5. Trifluoperazine: dose 20 mg to 30 mg/day. N = 36.
Outcomes	Useable: 8. Adverse effects: drowsiness, stimulation, confusion, gastrointestinal side‐effects, anticholinergic side‐effects, dizziness, orthostatic reaction, headache, hypersalivation, hypokinesia, hyperkinesia, dyskinesia, rigor, tremor, akathisia. Unable to use:  2. Global state: number of patients completing the study not provided.  4. Mental state: BPRS (no clear data).
Notes	All of the higher dose ranges are medians.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported. Sandoz UK contacted by online form to clarify bases and seek additional data 5th January 2016.
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding	Unclear risk	Authors state double‐blind but do not say how.
Incomplete outcome data (attrition bias)   None	Unclear risk	Total figures are not provided.
Selective reporting (reporting bias)	High risk	Sandoz side‐effect check list not reported.
Other bias	High risk	Selection bias, performance bias, unclear if intention‐to‐treat analysis was used.

Methods	Allocation: random Blindness: not reported Duration: 12 weeks Funding: committee on medicine and science ‐ personal grant and an undisclosed non‐restricted grant
Participants	Diagnosis: F20 schizophrenia n = 45 Age: ˜21‐33 years Sex: 25 male, 13 female, 7 unknown Included: drug naive first episode patients with schizophrenia, F20 ICD10 criteria for schizophrenia Excluded: mental retardation, severe somatic diseases, severe head trauma, pregnancy, presence of MRI contraindications, acute need of medication, compulsory hospitalisation in patients, presence of psychotic illness in controls or their first‐degree relatives.
Interventions	1. Zuclopenthixol (n = 8) 10.3 mg/day average (3.8 mg to 16.8 mg) 2. Risperidone (n = 11) 3.4 mg/day average (1.9 mg to 4.9 mg) 3. Control (n = 20) Of the original n = 45 it is unclear as to which groups the remaining n = 6 were attributed. Other medication: Anticholinergic n = 1‐, antidepressant n = 1, benzodiazepines n = 11
Outcomes	Usable: 4. Mental State: PANSS ‐ table 2 (PANSS general, mean and SD baseline and follow‐up). 5. Leaving the study early 8: Adverse effects ‐ ESRS ‐ table 2
Notes	3 patients minimally medicated prior to the start of the study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Not reported. DRCMR research group contacted 5th January 2016 to clarify these biases and seek any missing information.
Allocation concealment (selection bias)	High risk	Not reported.
Blinding	High risk	Not reported.
Incomplete outcome data (attrition bias)   None	High risk	Conflicting reports from several papers using same population cohort.
Selective reporting (reporting bias)	High risk	Supplementary publications highlight dropout and inconsistencies in the randomisation.
Other bias	High risk	Berkson bias

PERMALINK

Zuclopenthixol dihydrochloride for schizophrenia

Edward J Bryan

Marie Ann Purcell

Ajit Kumar

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

1. Zuclopenthixol dihydrochloride administered in oral form, any dose.

2. Placebo or no treatment.

3. Other antipsychotic drugs: any dose, administered in depot form.

4. Other antipsychotic drugs: any dose, administered in oral form.

Types of outcome measures

Primary outcomes

1. Global state: average endpoint global state score

2. Adverse effects: clinically important general adverse effect

Secondary outcomes

1. Death ‐ suicide and natural causes

2. Global state

3. Service outcomes

4. Mental state

5. Leaving the study early

6. General functioning

7. Behaviour

8. Adverse effects

9. Engagement with services

10. Satisfaction with treatment

11. Quality of life

12. Economic outcomes

Summary of findings

Search methods for identification of studies

Electronic searches

Searching other resources

1. Reference searching

2. Personal contact

Data collection and analysis

Selection of studies

Data extraction and management

1. Extraction

2. Management

2.1 Forms

2.2 Scale‐derived data

2.3 Endpoint versus change data

2.4 Skewed data

2.5 Common measure

2.6 Conversion of continuous to binary

2.7 Direction of graphs

Assessment of risk of bias in included studies

Measures of treatment effect

1. Binary data

2. Continuous data

Unit of analysis issues

1. Cluster trials

2. Cross‐over trials

3. Studies with multiple treatment groups

Dealing with missing data

1. Overall loss of credibility

2. Binary

3. Continuous

3.1 Attrition

3.2 Standard deviations

3.3 Assumptions about participants who left the trials early or were lost to follow‐up

3.2 Employing the I² statistic

Methods	Allocation: unclear. "In the investigation patients ... were allocated." Implied when table 1 reviewed.  Blindness: double.  Duration: 4 weeks  Design: RCT  Country: Norway
Participants	Diagnosis: acute and chronic psychoses, mainly schizophrenia  N = 20  Age: 20‐66 years (mean 36)  Sex: 13 male, 7 female  Inclusion criteria: acute psychoses and chronic exacerbations. Exclusion: below 15 years age, serious somatic disease, pathological laboratory findings, pregnant patients.  Setting: Inpatient
Interventions	1. Cis(Z)‐clopenthixol 48mg/day range 10 mg to 150 mg/day. N = 10.  2. Cis(Z)/trans(E) ‐ clopenthixol 88 mg/day range 10 mg to 200 mg/day. N = 10.
Outcomes	2. 6 Average Endpoint in global state scores Table 7, CGI 5. Leaving the study early n = 2, (one for refusal due to side‐effects, oculogyric crisis and one for non‐compliance) Unable to use:  Physiological: serum concentrations of Cis(Z)‐clopenthixol and clopenthixol (non‐clinical data all reported post‐cross‐over). 4. 4 Average endpoint general mental state score Table 3 and 4 ‐ CGI time 0, 2 weeks and 4 weeks no SD 4. 4 Average change in general mental state scores Table 5 ‐ BPRS ‐ total score time 0, 2 weeks and 4 weeks. no SD 4. 8 Average change in specific symptom scores Thinking disturbance: Table 5 ‐ BPRS ‐ time 0, 2 weeks and 4 weeks. no SD 4. 8 Average change in specific symptom scores Withdrawal ‐ retardation: Table 5 ‐ BPRS ‐ time 0, 2 weeks and 4 weeks. noS.D 4. 8 Average change in specific symptom scores Hostile‐suspiciousness: Table 5 ‐ BPRS ‐ time 0, 2 weeks and 4 weeks. no SD 4. 8 Average change in specific symptom scores Anxious‐depression: Table 5 ‐ BPRS ‐ time 0, 2 weeks and 4 weeks. no SD 8. 1 Clinically important general adverse effects Table 8, individual side‐effects and totals. Frequencies not patient numbers.
Notes	none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported but implied; "A double blind clinical investigation".
Allocation concealment (selection bias)	Unclear risk	patients were "allocated" Attempted to contact authors but Dikemark Hospital no longer exists. Google search did not reveal any contact details of the authors.
Blinding	Low risk	Authors state double‐blinding but the details are not clear in the paper.
Incomplete outcome data (attrition bias)   None	Low risk	The two excluded patients had reasons given by the authors.
Selective reporting (reporting bias)	Low risk	Reported all outcomes stated in the study aims.
Other bias	Unclear risk	Berkson and diagnostic purity bias.

Methods	Allocation: patients are allocated to each group and it is unclear if a process of randomisation occurred. A review of table one suggests an element of randomisation ‐ implied randomisation.  Blindness: double.  Duration: 8 weeks.  Design: cross‐over.  Country: Denmark. Funding: not declared.
Participants	Diagnosis: chronic schizophrenia.  History: illness duration 5‐20 years  N = 57  Age: mean ˜50 years, range 24‐79  Sex: 53 male and 4 female  Inclusion criteria: chronic patients already in neuroleptic treatment, preferably clopenthixol Exclusion: not mentioned  Setting: inpatient
Interventions	1. Cis(Z)‐clopenthixol hydrochloride, n = 29 average dose 47.6 mg/day  2. Clopenthixol hydrochloride (cis(Z) and trans(E) forms), n = 28 average dose 150 mg/day Table 2 dosing reported by authors is unclear.
Outcomes	2.6 Global State ‐ Average change in global state scores (Table 1) 4.3 Average endpoint general mental state score 5.2 Leaving the study early (for general reasons) ‐ zero people left the study 6.3 General Functioning ‐ average endpoint general functioning scores (Table 4) Unable to use: Physiological ‐ serum concentrations of Cis(Z)‐clopenthixol and clopenthixol (non‐clinical data all reported post‐cross‐over).
Notes	none.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported but implied; "A double blind clinical investigation".
Allocation concealment (selection bias)	Unclear risk	Not reported.
Blinding	Low risk	Stated in paper. "The drugs were given double blindly in a randomised way."
Incomplete outcome data (attrition bias)   None	Low risk	No incomplete outcome data.
Selective reporting (reporting bias)	Low risk	None noted.
Other bias	Unclear risk	Berkson and diagnostic purity bias.

Methods	Allocation: "The patients were allocated..." Implied randomisation.  Blindness: double.  Duration: 8 weeks  Design: RCT  Country: Finland Funding: not stated
Participants	Diagnosis: 40 patients with schizophrenia and 14 patients with oligophrenia.  History: vast majority ill or hospitalised more than 5 years.  N = 54  Age: Mean ˜45 years  Sex: 28 male, 26 female  Inclusion/exclusion: not reported  Setting: not reported.
Interventions	1. Cis(Z)‐clopenthixol 73 mg/day (10 mg to 150 mg/day). N = 26  2. Cis(Z)/Trans(E)‐clopenthixol 114 mg/day (20 mg to 300 mg/day). N = 28
Outcomes	2. 5 Average endpoint global state score Table 3 and 5: Severity of illness, scale unclear 5. Leaving the study early Table 3 and 5: n = 5 left, reasons not stated in the article. 8. 3 Average endpoint general adverse effect score Table 7: Single side‐effects week 8 total Unable to use: 8. 4 Average change in general adverse effect scores Table 6: Side‐effects interfering with patient's functioning ‐ CGI. No SD. 8. 8 Average change in specific adverse effects Table 7: Single side‐effects. No SD.  Physiological: serum concentrations of Cis(Z)‐clopenthixol and clopenthixol (non‐clinical data all reported post‐cross‐over).
Notes	none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported ‐ Finland Central Hospital contacted by email 5th January 2016.
Allocation concealment (selection bias)	Unclear risk	Not reported ‐ Finland Central Hospital contacted by email 5th January 2016.
Blinding	Unclear risk	Reported but not detailed
Incomplete outcome data (attrition bias)   None	High risk	At week 8, five patients were not included in the outcome data and not accounted for by the authors.
Selective reporting (reporting bias)	Unclear risk	Not enough information to make a clear decision.
Other bias	Low risk	Per protocol analysis, attrition bias

Methods	Allocation: not stated  Blindness: double, implied randomisation  Duration: 12 weeks.  Design: multicentre.  Country: Finland. Funding: Not stated
Participants	Diagnosis: chronic schizophrenia (n = 58) or other psychotic (n = 5, paranoic state, depressive/PD)  History: n = 40 duration of illness > 10 years and n = 11 for > five years.  N = 63.  Age: mean ˜ 43 years.  Sex: 41 male, 22 female.  Inclusion criteria: chronic schizophrenic inpatients or other psychotic inpatients who might benefit from either of these drugs or already receiving such treatment.  Exclusion criteria: patients under 15 years of age, with serious concomitant somatic illness or pathological laboratory findings, and pregnant patients.  Setting: hospitalised.
Interventions	1. Cis(Z)‐zuclopenthixol: dose 40 mg/day. N = 30.  2. Haloperidol: dose 10 mg/day. N = 33.
Outcomes	Useable: 2. Global state: CGI. 5. Leaving the study early [n = 27 left (13 Zuclo and 14 Halo) ‐ only 13 accounted for: n = 1 discharge, n = 9 insufficient effect and side‐effects, n = 3 reasons unrelated to treatment]  8. Adverse effects: use of other therapeutic drugs. CGI, frequency only. Unable to use ‐  2. Global State: NOSIE 30 (unable to use data). CGI ‐ percentages only  4. Mental state: BPRS (no SD).
Notes	Previous neuroleptic medication: 14 different neuroleptics.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated. Hospital District of South West Finland contacted to seek further information on biases 5th January 2016.
Allocation concealment (selection bias)	Unclear risk	Not stated.
Blinding	Low risk	Double‐blind.
Incomplete outcome data (attrition bias)   None	High risk	27 patients dropped out and only 12 accounted for by the authors.
Selective reporting (reporting bias)	Unclear risk	Not able to ascertain from paper.
Other bias	High risk	Berkson bias, diagnostic purity bias

Methods	Allocation: "Patients were subsequently allocated" ‐ randomisation implied  Blindness: single (patient)  Duration: 6 weeks.  Design: single centre.  Country: Greece.
Participants	Diagnosis: chronic schizophrenia.  History: duration of illness 6 years and over.  N = 54.  Age: mean ˜43 years, range 26‐64.  Sex: 29 male, 25 female.  Inclusion: established diagnosis of schizophrenia in hospital records Exclusion criteria: not reported.  setting: hospital.
Interventions	1. Clopenthixol: dose 150 mg/day. N = 18.  2. Chlorpromazine: dose 300 mg/day. N = 18.  3. Placebo. N = 18. Additional Medication: Artane and Phenergan.
Outcomes	Used: 5. Leaving the study early n = 0 8. Adverse effects: number of patients experiencing side‐effects. (all on clopenthixol, n = 3 restarted menstruation, n = 2 parkinsonism, n = 1 oculogyric crisis Not used: 7. Behaviour: behavioural scale, Aof V (table III) ‐ no usable data
Notes	none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not mentioned. Contacted Dromokaītion Hospital Athens to obtain further information on bias 5th January 2016.
Allocation concealment (selection bias)	Unclear risk	"...patients were subsequently allocated into three groups..." Unclear how.
Blinding	Unclear risk	"He was the only person knowing the identity of the tablets and to which group the patients belonged." Unclear if single‐ or double‐blind.
Incomplete outcome data (attrition bias)   None	Unclear risk	First rating deleted from analysis as was considered to be training by the researchers.
Selective reporting (reporting bias)	High risk	See above
Other bias	High risk	Hospitalised patients used ‐ Berkson bias.

Methods	Allocation: randomised.  Blindness: single.  Duration: 10 weeks.  Design: multicentre.  Country: UK. Funding: not declared.
Participants	Diagnosis: acute schizophrenia (RDC).  N = 61.  Age: mean ˜ 39 years, range 18‐65.  Sex: 26 male, 35 female. Inclusion criteria: aged 18‐65 years inclusive, were experiencing an acute schizophrenic episode according to RDC and minimum BPRS score of 15. Exclusion criteria: concurrent serious physical illness, patients who had previously demonstrated intolerance to neuroleptics, received a depot neuroleptic in the previous 2 weeks, or were suffering from a serious additional psychiatric or neurological disorder, patients who were pregnant or lactating; dependence or addiction to drugs or alcohol. Setting: hospital.
Interventions	1. Zuclopenthixol dihydrochloride: dose range 25 mg to 150 mg/day. N = 30.  2. Sulpiride: dose 200 mg to 1200 mg/day. N = 31. Additional medication: temazepam (insomnia), procyclidine (EPSEs), amitriptyline (depression).
Outcomes	usable: 2. Global state: CGI.  4. Mental state: BPRS. 5. Leaving the study Early  8. Adverse effects: change in mean weight.
Notes	Multicentre
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised but not elaborated on by authors. Bolton General Hospital contacted 5th January 2016 to seek clarification from the first author regarding biases.
Allocation concealment (selection bias)	Low risk	Randomly allocated but not elaborated on.
Blinding	Low risk	Clearly stated.
Incomplete outcome data (attrition bias)   None	Low risk	Authors discuss
Selective reporting (reporting bias)	High risk	Not all data was reported in the paper.
Other bias	High risk	Diagnostic purity bias, attrition bias, per‐protocol analysis

Methods	Randomised, double‐blind, 12 weeks
Participants	Acute psychosis N = 54 Age: 20‐60 years (mean 38) Sex: 25 female, 15 male, 14 unspecified Inclusion: hospitalised in the preceding 7 days, acute psychosis, exacerbation of chronic psychosis, neuroleptic treatment was anticipated to be at least 3 weeks, informed consent. Excluded: mania/depression, serious somatic disease, organic brain damage, pregnant, history of abuse, previous good response to neuroleptic
Interventions	1. Zuclopenthixol 37 mg/day (10 mg to 20 mg) n = 27 2. Perphenazine 30 mg/day (8 mg to 72 mg) n = 27 Additional medication: benzodiazepines, methotrimeprazine, anti‐parkinsonism medication
Outcomes	5. Leaving the study early Unable to use: 2. Global state: CGI 4. Mental state: CPRS 8 Adverse effects
Notes	Multicentre
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated. Glostrup hospital contacted 5th January 2016 to obtain further information to clarify biases and seek additional outcome data if available.
Allocation concealment (selection bias)	Unclear risk	Not stated.
Blinding	Low risk	Double‐blind stated.
Incomplete outcome data (attrition bias)   None	Low risk	Not detected.
Selective reporting (reporting bias)	High risk	Multiple data not reported and often unclear.
Other bias	High risk	Berkson bias evident.

Methods	Allocation: Quote” Patients were randomly divided into two groups ”(p.4)  Blinding: Double‐blind  Duration: Quote”8 weeks”(p. 4)  Location: Quote ”Inpatients, WuHan, China” (p.4)
Participants	Schizophrenia, CCMD‐3;  Sex: male 31 female 29  Age：mean˜34.1 years, SD ˜12.5  Total N = 64  Inclusion and exclusion criteria:  Patients with schizophrenia fulfilled CCMD‐3 were included;  Patients with severe heart, liver, kidney diseases were excluded.
Interventions	1. Zuclopenthixol Group: (n = 33)  Management: newly hospitalised patients had to stop the previous drugs for three days and then were randomly divided into Zuclopenthixol Group or Chlorpromazine Group.  Chlorpromazine or Zuclopenthixol was enclosed in the same colour, style capsule by pharmacist.  In the first week of treatment, the dosage of Zuclopenthixol was 20 mg/day and from the second week, it was increased 10 mg/day every week.  No other antipsychotic drugs were allowed during the treatment.  Trihexyphenidyl or scopolamine was used when necessary.  MECT was used two times per week for 12 times. 2. Chlorpromazine Group: (n = 27)  management:  Newly hospitalised patients had to stop the previous drugs for three days and then were randomly divided into Zuclopenthixol Group or Chlorpromazine Group.  Chlorpromazine or Zuclopenthixol was enclosed in the same colour, style capsule by pharmacist.  In the first week of treatment, the dosage of Chlorpromazine was 200 mg/day and from the second week, it was increased 50 mg/day every week. No other antipsychotic drugs were allowed during the treatment; Trihexyphenidyl or scopolamine was used when necessary;
Outcomes	2. Global State ‐ Clinical response  4. Mental State ‐ BPRS score  8. Adverse effects ‐ Adverse events, TESS; Unable to use: electrocardiogram; electroencephalogram; liver function; blood routine examination.
Notes	We have noticed that the N number does not always add up in this study, for example, the total sample size randomised was claimed to be 64, and 61 completed, but the number randomised to each group was reported as 33 and 27. Author to be contacted at next update.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors state patients randomised, not how
Allocation concealment (selection bias)	Unclear risk	Not reported after translation and data extraction
Blinding	Low risk	Double‐blind
Incomplete outcome data (attrition bias)   None	Unclear risk	N number unclear
Selective reporting (reporting bias)	Unclear risk	Not reported after translation and data extraction
Other bias	High risk	Berkson bias

Study	Reason for exclusion
Aaes‐Jorgensen 1981a	Allocation: randomised.  Participants: healthy volunteers.
Ahlfors 1980	Allocation: randomised.  Participants: people with chronic schizophrenia.  Interventions: clopenthixol decanoate versus perphenazine enanthate, not oral form of zuclopenthixol.
Al Haddad 1996	Allocation: randomised.  Participants: people with acute psychosis.  Interventions: zuclopenthixol acetate versus haloperidol, not oral form of zuclopenthixol.
Arango 2002	Allocation: randomised.  Participants: people with schizophrenia.  Interventions: oral ziclopenthixol versus depot zuclopenthixol.  outcomes: frequency of violent episodes (no data reported by group).
Baastrup 1993	Allocation: randomised.  Participants: people with acute psychosis, mania.
Bereen 1987	Allocation: not randomised, case‐series.
Bhattacharya 1987	Allocation: not randomised, case series.
Bobon 1989	Allocation: randomised.  Participants: people with acute psychosis.  Interventions: zuclopenthixol acetate versus haloperidol, not oral form of zuclopenthixol.
Bourdouxhe 1987	Allocation: randomised.  Participants: people with acute psychosis.  Interventions: zuclopenthixol acetate versus haloperidol, not oral form of zuclopenthixol.
Brook 1998	Allocation: randomised.  Participants: people with acute psychosis.  Interventions: zuclopenthixol acetate versus haloperidol, not oral form of zuclopenthixol.
Burke 2002	Allocation: randomised.  Participants: people with schizophrenia.  Interventions: risperidone versus sulpiride, chlorpromazine, trifluoperazine, haloperidol, flupenthixol, zuclopenthixol.  Outcomes: SAPS and SANS scale, unable to use data.
Chin 1998	Allocation: randomised.  Participants: people with acute schizophrenia.  Interventions: zuclopenthixol acetate versus haloperidol, not oral form of zuclopenthixol.
Chouinard 1991	Allocation: randomised.  Participants: people with acute schizophrenia.  Interventions: zuclopenthixol acetate versus liquid haloperidol, not oral form of zuclopenthixol.
Clark 1969	Allocation: not clear, double‐blind.  Participants: people with chronic schizophrenia.  Interventions: sordinol versus chlorpromazine versus placebo (unable to use data)
CTRI‐2014‐07‐004712	Wrong intervention.
Den 2000	Allocation: not clear, double‐blind.  Participants: people with schizophrenia.  Interventions: ritanserin versus placebo with other neuroleptics one of which was zuclopenthixol.  Outcomes: PANSS, CGI, ESRS, no usable date.
Dencker 1980	Allocation: randomised.  Participants: people with schizophrenia.  Interventions: clopenthixol decanoate vesus flupenthixol palmitate, not oral form of zuclopenthixol.
Dom 1978	Allocation: randomised.  Participants: people with chronic schizophrenia.  Interventions: variable doses versus constant dose of zuclopenthixol decanoate, not oral form of zuclopenthixol.
Fagerlund 2003	Allocation: randomised, blindness not clear.  Participants: people with first‐episode schizophrenia.  Interventions: zuclopenthixol versus risperidone.  Outcomes: PANSS, cognitive function, no usable data.
Fan 1999	Not clear if oral or depot. Authors need to be contacted at next update.
Fensbo 1990	Allocation: randomised, double‐blind.  Participants: people with acute psychosis, exacerbation of chronic psychosis and mania.  Interventions: zuclopenthixol versus haloperidol.  Outcomes: leaving the study early, CGI, BPRS, no usable data.
Fricchione 2010	Depot not oral intervention.
Galdersi 1994	Originally included but excluded at this update. It is not an RCT and blindness is not mentioned.
Glenthoj 2000	Allocation: randomised.  Participants: people with first‐episode schizophrenia.  Interventions: risperidone versus zuclopenthixol.  Outcomes: PANSS, PPI, cognitive functions, no data provided.
Gravem 1990	Allocation: randomised.  Participants: people with schizophrenia, manic‐depressive illness, psychosis.  Interventions: zuclopenthixol acetate and zuclopenthixol decanoate, not oral form of zuclopenthixol.
Hicklin 1967	Allocation: not randomised.
Hovens 2003	Allocation: randomised.  Participants: people with acute psychosis.  Interventions: risperidone + lorazepam versus zuclopenthixol + lorazepam; zuclopenthixol and lorazepam administered either in oral/injection form, not stated specifically for individual group.
Hovens 2005	Not randomised. Not blinded.
Huang 2001	Allocation: randomised.  Participants: people with schizophrenia.  Interventions: zuclopenthixol decanoate versus clorpromazine, not oral form of zuclopenthixol.
Karsten 1981	Allocation: randomised.  Participants: people with oligophrenia.
Knegtering 2002a	Allocation: randomised.  Participants: people with psychosis.  Interventions: risperidone versus quetiapine, not oral form of zuclopenthixol.
Koskinen 1991	Allocation: randomised.  Participants: people with chronic schizophrenia.  Interventions: zuclopenthixol decanoate versus haloperidol decanoate, not oral form of zuclopenthixol.
Kristiansen 2001	Allocation: randomised.  Participants: healthy individuals.
Kristiansen 2003	No data.
Lamure 2003	Not oral form.
Lemmens 1994	Study duplicates data presented by authors already included in review.
Liu 1997b	injection not oral.
Liu 1998a	Injection not oral.
Loza 2001	Allocation: randomised.  Participants: people with first‐episode paranoid schizophrenia.  Interventions: typical antipsychotics (zuclopenthixol, perphenazine, haloperidol, perazine) versus atypical antipsychotics (risperidone, olanzapine, quetiapine).  Outcomes: PANSS, DL, WCST, no usable data.
Lublin 1991	Allocation: randomised.  Participants: Psychotic psychiatric in‐patients with tardive dyskinesia.  Interventions: concomitant use of zuclopenthixol and haloperidol.  Outcomes: CGI, BPRS, UKU side effects rating scale, no usable data.
Mackeprang 2001	Allocation: randomised.  Participants: people with first‐episode schizophrenia.  Interventions: zuclopenthixol versus risperidone.  Outcomes: SPECT, MRI, cognitive functions test, rapid visual information processing test.  E‐mailed author for outcomes. Deceased. Colleague replied that the data had not yet been published.  Unable to use data.
Malt 1995	Allocation: randomised.  Participants: people with learning disability.
Mann 1985	Allocation: not randomised, case series.
Martyns 1993	Allocation: randomised.  Participants: people with chronic schizophrenia.  Interventions: clopenthixol decanoate versus flupenthixol decanoate, not oral form of zuclopenthixol.
Mazurek 2003	Allocation: randomised.  Participants: people with paranoid schizophrenia.  Interventions: typical antipsychotics (zuclopenthixol, perphenazine, haloperidol, perazine, levomepromazine) vs atypical antipsychotics (risperidone, olanzapine, clozapine). Information about number of patients using each drug is not provided.
Meyers 1972	Allocation: not randomised.
Mosolov 2000	Allocation: randomised.  Participants: people with acute schizophrenia.  Interventions: after 2 day wash‐out period for group 1. clopixol acuphase i.m. for 7 days and then oral clopixol for 14 days. Group 2. halopeidol i.m. for 7 days and then oral form for 14 days (no usable data).
NCT00206960	No data.
Pagsberg 2004	Wrong intervention, no data.
Ropert 1988	Allocation: randomised.  Participants: people with psychosis, mania, chronic schizophrenia.  Interventions: zuclopenthixol acetate versus chlorpromazine, not oral form of zuclopenthixol.
Rubio 2005	Not oral form.
Rubio 2006	Zuclopenthixol depot.
Rubio 2009	Not oral form.
Rubioz 2006	Not oral form.
Saxena 1990b	Depot zuclopenthixol.
Saxena 1996	Allocation: not clear, double ‐blind.  Participants: people with schizophrenia.  interventions: zuclopenthixol decanoate versus fluphenazine decanoate, not oral form of zuclopenthixol.
Schooler 1993	Allocation: randomised.  Participants: people with schizophrenia.  Interventions: antipsychotics (not mentioned) and family management.
Shelton 1969	Allocation: randomisation not clear.  Participants: people with schizophrenia.  Interventions: zuclopenthixol versus trifluoperazine.  Outcome: measurement of achilles reflex, no other data reported by group, unable to use data.
Singh 1992	Allocation: randomised.  Participants: mentally handicapped in‐patients with behavioural disorder with or without a psychiatric diagnosis.
Sofronov 2013	Depot zuclopenthixol.
Svestka 1986	Allocation: randomised.  Participants: people with schizophrenia.  Interventions: clopenthixol decanoate versus oxyprothepine decanoate, not oral form of zuclopenthixol.
Syvalahti 1997	Allocation: randomised.  Participants: people with schizophrenia.  Interventions: citalopram versus placebo with other neuroleptics i.e. haloperidol, chlorpromazine, levomepromazine, zuclopenthixol, thioridazine and perphenazine.  Outcomes: plasma concentrations of drugs, no usable data.
Taymeeyapradit 2002	Allocation: randomised.  Participants: people with acute psychosis.  Interventions: zuclopenthixol acetate versus haloperidol, not oral form of zuclopenthixol.
Tegeler 1985	Allocation: randomised.  Participants: people with schizophrenia.  Interventions: clopenthixol decanoate versus fluphenazine decanoate, not oral form of zuclopenthixol.
Uys 1996	Allocation: randomised.  Participants: people with acute psychosis.  Interventions: zuclopenthixol acetate versus clothiapine, not oral form of zuclopenthixol.
Venkateswarlu 1990	Allocation: not randomised, case series.
Viala 1988	Allocation: randomised.  Participants: people with chronic psychosis.  Interventions: zuclopenthixol decanoate versus fluphenazine decanoate, not oral form of zuclopenthixol.
Walker 1983	Allocation: randomised.  Participants: people with chronic schizophrenia.  Interventions: clopenthixol decanoate versus fluphenazine decanoate, not oral form of zuclopenthixol.
Weiser 1975	Allocation: randomised.  Participants: people with acute schizophrenia.  Interventions: droperidol versus clopenthixol i. m. versus clozapine i.m., not oral form of zuclopenthixol.
Wisted 1990	Depot zuclopenthixol.
Wistedt 1991	Allocation: randomised.  Participants: people with chronic schizophrenia.  Interventions: zuclopenthixol decanoate versus haloperidol decanoate, not oral form of zuclopenthixol.
Xiaanao 1999	Allocation: randomised.  Participants: people with schizophrenia.  Interventions: concomitant use of clopenthixol and other psychotropics.
Youssef 1991	Allocation: not clear.  Participants: people with psychosis.  Interventions: haloperidol decanoate versus other neuroleptics (fluphenazine decanoate, flupenthixol decanoate, clopenthixol decanoate, oral thioridazine, oral haloperidol, oral pimozide), not oral form of zuclopenthixol.