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Psychomotor agitation can be associated with a wide range of medical conditions. Although clinical practice advocates the use of several drugs for the management of psychomotor agitation, there are still very few controlled studies comparing the profiles of action and the adverse effects of different drugs that induce tranquilization.The purpose of this study was to compare the efficacy and safety of 4 low-dose pharmacological interventions used to control psychomotor agitation guided by the clinical response.Using a randomized, rated-blind design, 100 agitated patients were assigned to receive 1 of 4 treatments: haloperidol (2.5 mg) + promethazine (25 mg) (HLP + PMZ), haloperidol (2.5 mg) + midazolam (7.5 mg) (HLP + MID), ziprasidone (10 mg) (ZIP), or olanzapine (10 mg) (OLP). Patients were evaluated just before the intervention and after 30, 60, and 90 minutes, using the Agitation-Calmness Evaluating Scale. Adverse effects were assessed within 24 hours after the intervention, using selected items from the UKU Scale (Ugvalg Klinisk Undersgelser Side Effect Scale). According to the clinical indication, medication could be repeated twice after the first injection. Data were analyzed using general linear model with repeated measures and logistic regression.All treatment options promoted a reduction in agitation, without causing excessive sedation, although a lower reduction in agitation was observed with HLP + PMZ and ZIP compared with HLP + MID and OLZ. The need for an additional dose of medication was observed in 22 patients, and only 8 remained agitated during the entire 90-minute period. A higher risk for the development of extrapyramidal symptoms within the following 24 hours was observed with HLP + PMZ.Low doses of haloperidol combined with midazolam can be as effective as olanzapine in reducing psychomotor agitation without increasing the risk of extrapyramidal effects. Because of the higher risk for the occurrence of extrapyramidal symptoms, the combination of haloperidol with promethazine should be considered a second-line treatment option.