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.

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.

Read the full 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 strategy: 

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).

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