Key messages
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There are only small differences between zuclopenthixol acetate and standard treatments: probably more people are sedated (in a sleepy state) at 24 and 48 hours when given zuclopenthixol acetate, and they may need fewer additional doses of benzodiazepines (a type of sedative medicine). Doses of zuclopenthixol acetate of 25 mg to 50 mg per injection may be as effective as doses of 50 mg to 100 mg per injection.
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There may be no clear difference in side effects between zuclopenthixol acetate and standard medications.
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Further high-quality studies are needed to better understand the benefits and risks of zuclopenthixol acetate.
What is schizophrenia?
Schizophrenia is a serious mental health condition that can cause long-term disability and major disruption to daily life. People with schizophrenia may experience difficulty telling the difference between what is real and what is not (psychosis), including hearing voices (auditory hallucinations) or seeing things that are not there (visual hallucinations) and holding strong beliefs that are not true (delusions). These experiences can be frightening and distressing. At times, this distress may lead to aggressive or violent behaviour towards themselves or others. However, people with schizophrenia are also at increased risk of being victims of violence. Managing aggression and violence in people with schizophrenia is important and should aim to reduce negative attitudes from other people (stigma) and promote safe, respectful care.
What medications are used to treat schizophrenia?
Medications have a calming effect (tranquillising effect), reduce the feeling of being very worried or bothered (severe agitation) or aggression, and help induce sleep (sedative effect). Ideally, these medicines should treat psychotic symptoms (such as hallucinations and delusions), not be used too often and cause few side effects (for example, pain at the injection site or involuntary shaking).
Zuclopenthixol acetate is an injectable antipsychotic medication that can last for two to three days. This review examined whether zuclopenthixol acetate is effective for managing psychosis, aggression or violence, compared with other standard medications used in mental health settings.
What did we want to find out?
We wanted to find out if zuclopenthixol acetate was better than the usual medicines to help manage short-term (acute) behaviour changes that people with schizophrenia may have. We looked at how quickly the medicines helped people to feel calm and sleepy, what their overall effect was on the person and their behaviour, and whether there were any unwanted side effects.
What did we do?
We searched for studies that looked at the drug zuclopenthixol acetate given to people with schizophrenia and similar major mental illnesses who were experiencing short-term (acute) behavioural disturbance, compared to other standard treatments. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We included 11 studies with a total of 714 people. We found only small differences between zuclopenthixol acetate and standard treatments. Probably more people receiving zuclopenthixol acetate were sedated around 24 hours after treatment, but not in the first 15 minutes. People given zuclopenthixol acetate may need fewer doses of benzodiazepines. Doses of zuclopenthixol acetate of 25 mg to 50 mg per injection may be as effective as doses of 50 mg to 100 mg per injection. There may be no clear difference in side effects between zuclopenthixol acetate and standard medications.
What are the limitations of the evidence?
Many of the included studies were small and had weaknesses in their design and reporting, so our confidence in the evidence is limited. Further high-quality studies are needed to better understand the benefits and risks of zuclopenthixol acetate.
How up to date is this evidence?
The evidence in this review is current to September 2025.
Read the full abstract
Background
Medication used for acute aggression in psychiatry must have rapid onset of effect, low frequency of administration and low levels of adverse effects. Zuclopenthixol acetate is said to have these properties.
Objectives
To evaluate the clinical effectiveness of zuclopenthixol acetate in the management of acute behavioural disturbance in people with acute schizophrenia and similar major mental illnesses, compared with other pharmacological agents used for the treatment of similar clinical presentations.
Search strategy
We searched the Cochrane Schizophrenia Study-Based Register of Randomised Controlled Trials, CENTRAL and MEDLINE, supplemented by citation searching and contacting study authors. The date of the last search was 8 September 2025.
Selection criteria
All randomised clinical trials involving people thought to have serious mental illnesses comparing zuclopenthixol acetate with other drugs.
Data collection and analysis
Two review authors extracted and cross-checked data independently. We calculated fixed-effect relative risks (RR) and 95% confidence intervals (CI) for dichotomous data. We analysed by intention-to-treat. We used mean differences (MD) for continuous variables.
Main results
We found no data for the primary outcome, tranquillisation. Compared with haloperidol, zuclopenthixol acetate was no more sedating at two hours (n = 40, 1 RCT, RR 0.60, 95% CI 0.27 to 1.34). People given zuclopenthixol acetate were not at reduced risk of being given supplementary antipsychotics (n = 134, 3 RCTs, RR 1.49, 95% CI 0.97 to 2.30) although additional use of benzodiazepines was less (n = 50, 1 RCT, RR 0.03, 95% CI 0.00 to 0.47). People given zuclopenthixol acetate had fewer injections over seven days compared with those allocated to haloperidol IM (n = 70, 1 RCT, RR 0.39, 95% CI 0.18 to 0.84, NNT 4, CI 3 to 14). We found no data on more episodes of aggression or harm to self or others. One trial (n = 148) reported no significant difference in adverse effects for people receiving zuclopenthixol acetate compared with those allocated haloperidol at one, three and six days (RR 0.74, 95% CI 0.43 to 1.27). Compared with haloperidol or clotiapine, people allocated zuclopenthixol did not seem to be at more risk of a range of movement disorders (< 20%). Three studies found no difference in the proportion of people getting blurred vision/dry mouth (n = 192, 2 RCTs, RR at 24 hours 0.90, 95% CI 0.48 to 1.70). Similarly, dizziness was equally infrequent for those allocated zuclopenthixol acetate compared with haloperidol (n = 192, 2 RCTs, RR at 24 hours 1.15, 95% CI 0.46 to 2.88). There was no difference between treatments for leaving the study before completion (n = 522, RR 0.85, 95% CI 0.31 to 2.31). One study reported no difference in adverse effects and outcome scores, when high dose (50-100 mg/injection) zuclopenthixol acetate was compared with low dose (25-50 mg/injection) zuclopenthixol acetate.
Authors' conclusions
Based on the evidence in this review, there may be no difference between zuclopenthixol acetate and standard medications in the management of acute psychiatric symptoms, tranquillisation and adverse events. Zuclopenthixol acetate was probably associated with a greater degree of sedation at 24 and 48 hours of administration. The use of zuclopenthixol acetate may be associated with a lower requirement for adjunctive benzodiazepines, but this is uncertain.
Doses of zuclopenthixol acetate of 25 mg to 50 mg per injection may be as effective as doses of 50 mg to 100 mg per injection (very low-certainty evidence). Recommendations favouring zuclopenthixol acetate over standard medications for the management of acute behavioural disturbance should be interpreted with caution, given the methodological limitations of most included studies.
Funding
This study received no external funding.
Registration
Original review (2001) DOI: 10.1002/14651858.CD000525
Review update (2004) DOI: 10.1002/14651858.CD000525.pub2
Review update (2012) DOI: 10.1002/14651858.CD000525.pub3
