Abstract: The systematic review currently includes 63 randomised trials with 3675 participants. Bromperidol (n = 9), loxapine (n = 7), and trifluoperazine (n = 6) were the most frequently administered antipsychotics comparator to haloperidol. The included studies were published between 1962 and 1993, were characterised by small sample sizes (mean: 58 participants, range from 18 to 206) and the predefined outcomes were often incompletely reported. All results for the main outcomes were based on very low or low quality data. In many trials the mechanism of randomisation, allocation, and blinding was frequently not reported. In short-term studies (up to 12 weeks), there was no clear evidence of a difference between haloperidol and the pooled group of the other first-generation antipsychotic agents in terms of the primary outcome "clinically important response to treatment" (40 RCTs, n = 2132, RR 0.93 CI 0.87 to 1.00). In the medium-term trials, haloperidol may be less effective than the other first-generation antipsychotic group but this evidence is based on only one trial (1 RCT, n = 80, RR 0.51 CI 0.37 to 0.69). Based on limited evidence, haloperidol alleviated more positive symptoms of schizophrenia than the other antipsychotic drugs. There were no statistically significant between-group differences in global state, other mental state outcomes, behaviour, leaving the study early due to any reason, due to inefficacy, as well as due to adverse effects. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. The findings of the meta-analytic calculations support the statements of previous narrative, unsystematic reviews suggesting comparable efficacy of first-generation antipsychotics. In efficacy-related outcomes, there was no clear evidence of a difference between the prototypal drug haloperidol and other, mainly high-potency first-generation antipsychotics. Additionally, we demonstrated that haloperidol is characterised by a similar risk profile compared to the other first-generation antipsychotic compounds. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. The results were limited by the low methodological quality in many of the included original studies. Data for the main results were low or very low quality. Therefore, future clinical trials with high methodological quality are required.

Plain-language summary: Previous small studies and unsystematic reviews have found no difference between the various first- generation antipsychotic drugs. This has led to the assumption that these drugs are similar in effectiveness (despite observations by psychiatrists and health professionals that these drugs do sometimes differ in their effectiveness and side effects). Because of high prescription-rates, research on haloperidol is very important. A search for randomised trials was run in 2012. This review includes 63 trials with 3675 participants. Haloperidol was compared with a large number of other first-generation antipsychotic drugs (including bromperidol, loxapine and trifluoperazine) to assess its effectiveness, acceptability and tolerability. The findings of the review support the evidence of previous small, narrative studies and unsystematic reviews. There was no difference between haloperidol and other mainly high-potency first-generation antipsychotic drugs. In addition, haloperidol was characterised by a similar risk profile and side effects to other first-generation antipsychotic drugs. People receiving haloperidol were less likely to experience akathisia in the medium term. Occurrence of other specific side effect such as tremor, dystonia, dyskinesia and rigor were all similar between treatment groups. Psychiatrists and people with schizophrenia should know that haloperidol and other first-generation antipsychotic drugs are similar in their effectiveness and risk of side effects. These drugs should also be similar in their acceptability for people with schizophrenia. However, results were limited due to the low quality of many of the included studies and low quality of evidence provided. Future studies of higher quality are required. This plain language summary has been written by a consumer Ben Gray: Senior Peer Researcher www.mcpin.org.