OBJECTIVES: Asenapine is a novel antipsychotic indicated for the treatment of moderate to severe manic episodes associated with bipolar I disorder. The clinical programme included one 12-week trial versus olanzapine in monotherapy and one 12-week adjunct therapy trial versus placebo. While no head-to-head data were available to compare asenapine with all atypical antipsychotics, the objective of this project was to provide comparative efficacy data of asenapine versus olanzapine, quetiapine and aripiprazole in both monotherapy and adjunct therapy using indirect comparison techniques. METHODS: All twelve-week randomised controlled trials of olanzapine, quetiapine and aripiprazole conducted in monotherapy or in adjunct therapy were identified through a literature review. Five monotherapy studies were found, allowing the comparison of asenapine versus quetiapine and aripiprazole, with olanzapine and haloperidol as common references, using Bucher’s method (Bucher et al., J Clin Epidemiol 1997). One twelve-week and four six-week placebo-controlled adjunctive therapy trials were identified, enabling the comparison of asenapine to olanzapine, quetiapine and aripiprazole through pairwise comparisons using placebo as a common reference. The outcomes used for comparison were the Young Mania Rating Scale (YMRS) change from baseline, YMRS response and remission rates. RESULTS: In monotherapy, the differences of mean YMRS change from baseline to week 12 between asenapine versus quetiapine and aripiprazole were 0.10 (p=0.959) and 1.76 (p=0.342), respectively. Relative risks for response and remission were close to one. In adjunct therapy, the differences of mean YMRS change from baseline to week 6 between asenapine versus olanzapine, quetiapine and aripiprazole were 0.63 (p=0.656), 0.10 (p=0.967) and -0.10 (p=0.946), respectively. Relative risks for response and remission were numerically in favour of asenapine but not statistically significant. CONCLUSIONS: The results of these indirect comparisons consistently showed comparable efficacy of asenapine versus the investigated atypical antipsychotics.