title: Zuclopenthixol versus placebo for schizophrenia.
abstract: BACKGROUND
  Zuclopenthixol is an older antipsychotic that has three distinct formulations (zuclopenthixol dihydrochloride, zuclopenthixol acetate or Acuphase and zuclopenthixol decanoate). Although it has been in common use for many years no previous systematic review of its efficacy compared to placebo in schizophrenia has been undertaken.
  
  
  OBJECTIVE
  To evaluate the effectiveness of all formulations of zuclopenthixol when compared with a placebo in schizophrenia.
  
  
  METHODS
  On 6 November 2013 and 20 October 2015, we searched the Cochrane Schizophrenia Group Trials Register, which is based on regular searches of MEDLINE, EMBASE, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and registries of clinical trials. We also checked the references of all included studies and contacted authors of included studies for relevant studies and data.
  
  
  METHODS
  We included all randomised controlled trials comparing zuclopenthixol of any form with placebo for treatment of schizophrenia or schizophrenia-like psychoses.
  
  
  METHODS
  We extracted and cross-checked data independently. We identified only a small number of studies so we cross checked all studies. We calculated fixed-effect relative risks (RR) and 95% confidence intervals (CI) for dichotomous data. We analysed by intention-to-treat. Where possible we converted continuous outcomes into dichotomous outcomes. When this was not possible we used mean differences (MD) for continuous variables. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to create a 'Summary of findings' table.
  
  
  RESULTS
  Only two studies, with a total of 65 participants, were eligible for inclusion in the review. Overall the quality of the two studies was low, with small study populations and significant sources of bias, so we were not able to use all the data in our comparisons. . The studies were old from 1968 and 1972, and would be unlikely to pass modern peer review standard. We were only able to find short-term data and only trials randomising zuclopenthixol dihydrochloride. We also hoped to identify data for zuclopenthixol acetate versus placebo and zuclopenthixol decanoate versus placebo comparisons. We were unable to identify any studies that included data on these two fairly widely used drugs.For our primary outcome of interest, clinically significant improvement, we found one study that provided useable data. Global state measured by clinical global impression scale (CGI) improvement showed different ratings when assessed by a psychiatrist or a nurse.The psychiatrist scores failed to achieve statistical significance, however when assessed by nursing staff, the difference favouring zuclopenthixol did reach statistical significance (1 RCT n = 29, RR 2.57 95% CI 1.06 to 6.20, very low quality data). There was also evidence of increased sedation with those treated with zuclopenthixol when compared with placebo (1 RCT n = 29, RR 4.67 95% CI 1.23 to 17.68, very low quality data). 'Leaving the study early' data were equivocal. No useable data were available for outcomes such as relapse, mental state, death, quality of life, service use or economic costs.
  
  
  CONCLUSIONS
  For people with schizophrenia this review shows that zuclopenthixol dihydrochloride may help with the symptoms of schizophrenia. The review provides some trial evidence that, if taking zuclopenthixol dihydrochloride, people may experience some adverse effects and sedation compared with placebo. However this evidence is of very low quality and with some significant sources of bias. There are no data for zuclopenthixol decanoate or zuclopenthixol acetate.For clinicians, the available trial data on the absolute effectiveness of zuclopenthixol dihydrochloride do support its use but the limited nature of the data and significant sources of bias make conclusions hard to draw. Zuclopenthixol in all three forms is a commonly used antipsychotic and it is disappointing that there are so few data regarding its use.
authors.affiliation: Department of Psychological Medicine, Humber NHS Foundation Trust, 220-36 Anlaby Road, Hull, UK, HU3 2RW.
authors.forename: Michael
authors.initials: M
authors.lastname: Lacey
authors.forename: Mahesh B
authors.initials: MB
authors.lastname: Jayaram
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use; D003006:Clopenthixol / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D012559:Schizophrenia / Q000188:drug therapy*
chemical_list: D014150:Antipsychotic Agents; C060342:clopenthixol acetate ester; C029674:clopenthixol decanoate; D003006:Clopenthixol