COMPARATIVE EFFICACY AND ACCEPTABILITYOF PHARMACOLOGICAL TREATMENTSFOR ACUTE MANIA:A MULTIPLE TREATMENTS META-ANALYSIS

Background: Mania is the hallmark feature of bipolar disorder. Clinically, mania can quickly escalate out of control, and cause severe disruption to the lives of individuals with the disorder. This is particularly important as mania can result in disturbed behavior that, when extreme, can be a risk to the safety of the patient and others. Mood stabilizers and antipsychotic agents have long been the mainstay of treatment of acute mania. In recent years several atypical antipsychotics agents have been licensed to treat mania (aripiprazole, olanzapine, risperidone and quetiapine). However, conventional meta-analyses have shown inconsistent results for efficacy of pharmacological treatments for acute mania. The aim of this study was to compare the efficacy and acceptability of pharmacological treatments for acute mania, in order to inform clinical practice and mental health policies. We carried out a multiple-treatments meta-analysis (MTM), a statistical technique that allows both direct and indirect comparisons to be undertaken, even when two of the treatments have not been directly compared. Methods: Double-blind randomized controlled trials (RCTs) comparing one active drug (antipsychotic, mood stabiliser or benzodiazepine) with another active drug (antipsychotic, mood stabiliser or benzodiazepine) or placebo as oral therapy in the treatment of acute mania were included. All combination and augmentation studies were included as well. Participants were patients aged 18 or older of both sexes with a primary diagnosis of acute mania or bipolar disorder (manic or mixed episode) according to the standardised diagnostic criteria used by the study authors. Overall efficacy was primarily measured as the mean change of the total score of the Young Mania Rating Scale (YMRS) from baseline to endpoint. We also estimated efficacy as the proportion of patients who responded to treatment (reduction of at least 50% on the total score between baseline and endpoint on a standardized rating scale for mania possibly YMRS). Acceptability was defined as the proportion of patients who left the study early for any reason, out of the total number of randomized patients. Results: We systematically reviewed 68 RCTs (16 073 participants) from 1980 to 2010, which compared any of the following 14 drugs at therapeutic dose range: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. 15 673 patients contributed to the efficacy analysis as continuous outcome (63 studies), 15 626 to the acceptability analysis (65 studies); for secondary outcome 12 649 patients (47 studies) contributed to efficacy analysis as dichotomous data. All anti-manic drugs –with exception of topiramate and gabapentin- showed significant efficacy than placebo. Antipsychotic drugs were significantly more effective than mood stabilizers. In terms of efficacy, haloperidol, risperidone, and olanzapine outperformed other drugs. In terms of dropouts, olanzapine, risperidone, and quetiapine were better than haloperidol. Risperidone, olanzapine, and haloperidol seem to be the best of the available options for the treatment of manic episodes. Conclusions: This MTM is the first analysis that incorporates direct and indirect comparisons between pharmacological treatments for acute mania. These findings have potential clinical implications that should be considered in the development of clinical practice guidelines