Abstract: Ten studies (3340 participants) were included in the review. Seven studies compared aripiprazole monotherapy versus placebo (2239 participants); two of these included a third comparison arm—one study used lithium (485 participants) and the other used haloperidol (480 participants). Two studies compared aripiprazole as an adjunctive treatment to valproate or lithium versus placebo as an adjunctive treatment (754 participants), and one study compared aripiprazole versus haloperidol (347 participants). The overall risk of bias was unclear. A high dropout rate from most trials (> 20% for each intervention in eight of the trials) may have affected the estimates of relative efficacy. Evidence shows that aripiprazole was more effective than placebo in reducing manic symptoms in adults and children/adolescents at three and four weeks but not at six weeks (Young Mania Rating Scale (YMRS); mean difference (MD) at three weeks (random effects) -3.66, 95% confidence interval (CI) -5.82 to -2.05; six studies; N = 1819, moderate quality evidence) - a modest difference. Aripiprazole was compared with other drug treatments in three studies in adults—lithium was used in one study and haloperidol in two studies. No statistically significant differences between aripiprazole and other drug treatments in reducing manic symptoms were noted at three weeks (YMRS MD at three weeks (random effects) 0.07, 95% CI -1.24 to 1.37; three studies; N = 972, moderate quality evidence) or at any other time point up to and including 12 weeks. Compared with placebo, aripiprazole caused more movement disorders, as measured on the Simpson Angus Scale (SAS), on the Barnes Akathisia Scale (BAS) and by participant-reported akathisia (high quality evidence), with more people requiring treatment with anticholinergic medication (risk ratios (random effects) 3.28, 95% CI 1.82 to 5.91; two studies; N = 730, high quality evidence). Aripiprazole also led to more gastrointestinal disturbances (nausea (high quality evidence), and constipation) and caused more children/adolescents to have a prolactin level that fell below the lower limit of normal. Significant heterogeneity was present in the meta-analysis of movement disorders associated with aripiprazole and other treatments and was most likely due to the different side effect profiles of lithium and haloperidol. At the three-week time point, meta-analysis was not possible because of lack of data; however, at 12 weeks, haloperidol resulted in significantly more movement disorders than aripiprazole, as measured on the SAS, the BAS and the Abnormal Involuntary Movement Scale (AIMS) and by participant-reported akathisia. By 12 weeks, investigators reported no difference between aripiprazole and lithium (SAS, BAS, AIMS), except in terms of participant-reported akathisia (RR 2.97, 95% CI 1.37 to 6.43; one study; N = 313). Aripiprazole is an effective treatment for mania in a population that includes adults, children and adolescents, although its use leads to gastrointestinal disturbances and movement disorders. Comparative trials with medicines other than haloperidol and lithium are few, so the precise place of aripiprazole in therapy remains unclear.

Plain-language summary: Ten studies are included (3340 participants). Most studies compared aripiprazole versus placebo, but some researchers compared aripiprazole versus haloperidol (two studies) and versus lithium (one study). Two studies examined the effect of adding aripiprazole to another treatment (valproate or lithium) and compared this combination versus placebo combined with these other treatments. We assessed the overall risk of bias in the ten studies as unclear. The main measure of effect was the mean change on the Young Mania Rating Scale from the start to the end of the trial; this tool is used by clinicians to assess the severity of mania. After three weeks of treatment, aripiprazole was better than placebo at reducing the severity of mania when used on its own or when added to other mood stabilisers. The effect was modest. However, aripiprazole caused more inner restlessness (akathisia), nausea, and constipation than placebo. Aripiprazole was similarly effective in reducing the symptoms of mania when compared with other drug treatments (haloperidol and lithium). Aripiprazole caused fewer movement disorders and less raised prolactin (a hormone secreted by the pituitary gland) than haloperidol. People taking aripiprazole were more likely to remain on treatment than those taking haloperidol but were no more or less likely than those taking placebo or lithium. The main reason for the difference in dropouts between aripiprazole and haloperidol groups was the adverse effects associated with haloperidol. In summary, aripiprazole is an effective treatment for mania when compared with placebo. This finding is based on studies that included mixed populations (i.e. children, adolescents and adults). For the adult population, studies have directly compared aripiprazole versus haloperidol, lithium and placebo, but evidence obtained for treatment of the child and adolescent population is available only from placebo-controlled studies. Given the lack of evidence obtained by comparing aripiprazole versus other drugs, its exact place in therapy is unclear. Further studies focused on particular populations are needed to determine whether this treatment is equally effective in different age groups.