Efficacy of aripiprazole for the treatment of schizophrenia: What dose is required?

Objective. - Problem of the choice of antipsychotic dose is a key issue in clinical practice. It determines the efficacy and safety of treatment. Aripiprazole is recommended at a dose of between 10 and 15 mg/day in the treatment of schizophrenia, with a dose range considered to be effective, between 10 and 30 mg/day. This wide therapeutic range prompted us to investigate the existence of a possible dose-effect relationship for aripiprazole in the treatment of schizophrenia. Method. - We conducted a literature review from PubMed and EMBASE database, with the keywords: aripiprazole, schizophrenia. We limited it to studies published in English and French, with the main objective to assess the efficacy of aripiprazole in patients with schizophrenia. We selected only randomized clinical trials, double-blind, controlled against placebo or against an active comparator. Studies in which aripiprazole was studied added to another antipsychotic were not retained. Results. - Twenty-two randomized, double-blind, controlled studies were selected. Three studies assessed the efficacy of aripiprazole on agitation symptoms in patients with schizophrenia and for which a dose of aripiprazole between 1 and 15 mg showed significant efficacy compared to placebo. Seven clinical trials focused on the effect of aripiprazole short term (less than 12 weeks). For the primary endpoint (PANSS scores), aripiprazole was superior to placebo or equivalent to active comparators (risperidone, olanzapine or haloperidol). These short-term studies revealed a range of effective doses from 10 mg/day to 20 mg/day. Five studies, lasting between 16 and 52 weeks, with a primary endpoint being the time to discontinuation for any cause for two studies, the time before relapse in one study, and the improvement in PANSS scores for the two other studies. On these different endpoints, aripiprazole was effective at average doses between 15 and 28.1 mg/day. The safety of aripiprazole was particularly favourable in these trials. Finally, we listed seven post-hoc analyses. In support of these long-term analyses on different endpoints, aripiprazole showed significant efficacy at higher doses (20 and 30 mg/day) than those used in the agitation treatment. Conclusions. - No study was designed to compare aripiprazole doses in schizophrenia. Nevertheless, efficacy on agitation and hostility components had been observed for doses of 10 mg/day, or lower; whereas the antipsychotic effect in acute or maintenance phase appeared optimal for doses ranging from 10 to 25 mg/day. Only one study retained a minimum effective dose of 10 mg/day on the PANSS scores. This literature review reveals an effective dose range between 10 and 25 mg/day for aripiprazole in schizophrenia. Less than 10 mg/day did not show significant efficacy on symptoms of schizophrenia, apart from a specific short-term effect on agitation, at very low doses (starting at 1 mg). Optimization of treatment, at doses above 25 mg/day, cannot be the subject of evidence-based recommendations. (C) L'Encephale, Paris, 2014.