title: Long-Acting Injectable Antipsychotics for Prevention of Relapse in Bipolar Disorder: A Systematic Review and Meta-Analyses of Randomized Controlled Trials.
abstract: 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, long-acting 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.
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. tarok@fujita-hu.ac.jp.
authors.forename: Taro
authors.initials: T
authors.lastname: Kishi
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Oya
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
keywords: bipolar disorder; efficacy; long-acting injectable antipsychotics; meta-analysis; safety; systematic review