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Asenapine is a second-generation antipsychotic with a unique pharmacological profile that was recently approved for the treatment of moderate/severe manic episodes. Real-world data on rapidity of action in inpatient settings are lacking.The aims of the current real-world observational study were to evaluate: (i) short-term efficacy of asenapine after 7 days (T0-T1) in patients hospitalized for a manic episode in the course of bipolar I disorder or schizoaffective disorder (group A), (ii) differences in length of stay (LoS), and (iii) rehospitalization compared to a control population (group B) with a 6-month follow-up.Twenty patients were included in each group. The mean total Young Mania Rating Scale score decreased by 12.6 (SD ±10.3; t(17) = 5.2, P < 0.005), implying a mean 37.8% improvement. A statistically significant reduction was observed for all Young Mania Rating Scale items, except for “sexual interest.” The mean total BPRS score decreased by 17.2 (SD ±14.9; t(17) = 4.9, P < 0.005). A statistically significant reduction was observed for several items, including “conceptual disorganization,” “grandiosity,” “unusual thought content,” and “excitement”. Length of stay was 17.9 (SD ±9.0) days for group A and 14.7 (SD ±12.7) days for group B; the result of the Kruskal-Wallis test showed no significant differences (χ2 = 2.199, P = 0.138). Despite a high discontinuation rate, only 17.7% of patients in group A were rehospitalized in the following 6 months compared to 41.2% of those in group B (relative risk = 0.43, 95% confidence interval, 0.13–1.39).Findings from this small, preliminary study at least partially support the results of previous trials, confirming effectiveness and tolerability in the context of comorbidity and polypsychopharmacology.