Sixty-eight studies (n=16,073 participants) were included in the review; 54 of these were two-armed and 14 were three-armed. The overall quality of studies was rated as good, although around three-quarters of the studies were rated as having unclear adequacy of allocation concealment.
All treatments except gabapentin, lamotrigine and topiramate were more effective than placebo. Haloperidol showed more significant differences from comparators than any other treatment and showed superior efficacy to all other active treatments except risperidone and olanzapine. Risperidone and olanzapine showed similar efficacy profiles and both had statistically superior efficacy compared to five other treatments (valproate, ziprasidone, lamotrigine, topiramate and gabapentin).
Efficacy results compared to placebo using the mean change in score on the Young Mania Rating Scale were: haloperidol (SMD -0.56, 95% CrI -0.68 to -0.43), risperidone (SMD -0.50, 95% CrI -0.63 to -0.38) and olanzapine (SMD -0.43, 95% CrI -0.54 to -0.32); these treatments had the highest probability of being the most effective treatment.
Olanzapine, risperidone and quetiapine led to significantly fewer discontinuations than lithium, lamotrigine, placebo, topiramate and gabapentin; haloperidol was also inferior to olanzapine. Results of pairwise meta-analyses were reported.
Statistical heterogeneity was generally moderate, although there were wide confidence intervals for most comparisons. Four of the pairwise analyses showed an I2 value above 75%, which indicated very high levels of heterogeneity. Inconsistency was low and found in only three of 33 loops for efficacy as a continuous outcome and in none of the 34 acceptability loops or the 18 binary efficacy loops. Sensitivity analyses did not significantly alter the results.