Long-acting injectable antipsychotics for prevention of relapse in bipolar disorder: A systematic review and meta-analyses of randomized controlled trials

Background: This meta-analysis of randomized controlled trials aimed to examine the advantages of long-acting injectable antipsychotics over placebo or oral medications regarding efficacy and safety for patients with bipolar disorder. Methods: Two categorical meta-analyses of randomized controlled trials were performed to compare study-defined relapse rate (primary), discontinuation rates, and individual adverse events: (1) risperidone-long-acting injectable vs placebo, and (2) long-acting injectable antipsychotics vs oral medications. Results: We identified 7 randomized controlled trials (n = 1016; long-acting injectable antipsychotics [flupenthixol (1 randomized controlled trial) and risperidone (6 randomized controlled trials) = 449]; oral medications [mood stabilizers, antidepressants, antipsychotic, or any combination of these agents = 283]; and placebo = 284). Risperidone-long-acting injectable antipsychotic was superior to placebo for study-defined relapse rate (risk ratio = 0.63, P < .0001), relapse of manic symptoms (risk ratio = 0.42, P < .00001), and all-cause discontinuation (risk ratio = 0.75, P = .007). Risperidone-long-acting injectable was associated with higher incidence of prolactin-related adverse events (risk ratio = 4.82, P = .001) and weight gain (risk ratio = 3.80, P<.0001) than placebo. The pooled long-acting injectable antipsychotics did not outperform oral medications regarding primary outcome but with significant heterogeneity (I2 = 74%). Sensitivity analysis, including only studies with rapid cycling or high frequency of relapse patients, revealed that long-acting injectable antipsychotics were superior compared to oral medications (I2 = 0%, RR = 0.58, P = .0004). However, the comparators in this sensitivity analysis did not include second-generation antipsychotic monotherapy. In sensitivity analysis, including only studies with second-generation antipsychotic monotherapy as the comparator, longacting injectable antipsychotics did not outperform second-generation antipsychotic monotherapy. Risperidone-long-acting injectable was also associated with higher incidence of prolactin-related adverse events than oral medications (RR = 2.66, P = .03). Conclusions: Long-acting injectable antipsychotics appear beneficial for relapse prevention in patients with rapid cycling. Furthermore, randomized controlled trials comparing long-acting injectable antipsychotics and oral second-generation antipsychotic using larger samples of rapid cycling patients are warranted.