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Background: Psychomotor agitation is a common condition in patients with psychotic disorders. One treatment possibility is intramuscular (IM) second-generation antipsychotics. Yet their efficacy in this formulation and for this aim is unclear. This network meta-analysis aims to evaluate the efficacy of short-acting IM second-generation antipsychotic drugs, haloperidol and placebo in patients with diagnosis of schizophrenia and schizophrenia-like disorders that present acute agitation., Methods: We searched the Cochrane Schizophrenia Group Controlled Trials Register, MEDLINE, EMBASE, PsycINFO, Cochrane Library, PubMed, BIOSIS, ClinicalTrials.gov and WHO ICTRP up to November 2018 and PubMed until March 2020. Study selection and outcome extraction were performed independently by two reviewers. Pairwise and network meta-analyses were conducted to compare the different IM second-generation antipsychotics among themselves and with IM haloperidol and placebo. The primary outcome was the number of responders at 2 h after the first injection. Responders at 24 h were also analysed., Results: 10 studies with 1964 patients were included in the meta-analysis. Ziprasidone, olanzapine, aripiprazole and haloperidol were more efficacious than placebo in calming patients at 2 h after administration. Furthermore, olanzapine was superior to aripiprazole. The results at 24 h confirmed the superiority of aripiprazole, olanzapine and haloperidol over placebo, while for ziprasidone no data were available., Conclusions: All second-generation antipsychotics available as intramuscular medications were effective in reducing agitation in people with schizophrenia. Olanzapine was somewhat more efficacious than aripiprazole., Competing Interests: Declaration of competing interest In the past 3 years, SL has received honoraria for service as a consultant or adviser and/or for lectures from Angelini, Boehringer Ingelheim, Gedeon Richter, Janssen, Johnson & Johnson, LB Pharma, LTS Lohmann, Lundbeck, MSD, Otsuka, Recordati, Sandoz, Sanofi-Aventis, Sunovion, and TEVA. In the last two years, AV received support directly or indirectly for clinical studies or trials, conferences, consultancies, Congress presentations, advisory boards from Angelini, Boheringer Ingelheim, Eli Lilly, Fidia, Innovapharma, Janssen- Cilag, Lundbeck, Otsuka, Recordati, Takeda. All other authors declare no competing interests., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Recently, many authors highlighted the potential advantages of a broader prescription of long-acting injectable antipsychotics (LAIs) based on various assumptions, including favorable pharmacokinetic features. In this systematic review, data from randomized controlled trials comparing LAIs versus the oral formulation of the same antipsychotic were meta-analyzed in order to ascertain whether the route of administration may be associated with a different efficacy and tolerability profile. Of 21 included studies, 18 contributed to the meta-analysis, providing data for risperidone, olanzapine, aripiprazole, zuclopenthixol, fluphenazine and haloperidol. For all drugs, the number of dropouts for any reason (primary outcome) did not differ between the two formulations, except for a small effect in favor of LAI aripiprazole (2 comparisons; 986 patients; relative risk (RR) 0.78; 95% confidence interval (CI) 0.64 to 0.95). Similarly, no differences emerged in terms of dropouts for adverse events, extrapyramidal symptoms, prolactin increase (except for a small advantage for LAI risperidone), weight gain, non-response rate, relapse rate, and dropouts for inefficacy (except for a small advantage for oral olanzapine). Data on aripiprazole proved to be of high quality according to the GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation), therefore we are confident that the effect estimate is close to the true effect. Data on risperidone were of moderate quality, while data on olanzapine, fluphenazine, zuclopenthixol and haloperidol were of low quality. In conclusion, there is no robust evidence to support doctors in choosing LAI instead of oral formulations in order to obtain better tolerability and efficacy., (Copyright © 2016 Elsevier B.V. All rights reserved.)