Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: A meta-analysis of randomized trials

Taishiro Kishimoto, Alfred Robenzadeh, Claudia Leucht, Stefan Leucht, Koichiro Watanabe, Masaru Mimura, Michael Borenstein, John M. Kane, Christoph U. Correll

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317 Scopus citations


Background: While long-acting injectable antipsychotics (LAIs) are hoped to reduce high relapse rates in schizophrenia, recent randomized controlled trials (RCTs) challenged the benefits of LAIs over oral antipsychotics (OAPs). Methods: Systematic review/meta-analysis of RCTs that lasted ≥6 months comparing LAIs and OAPs. Primary outcome was study-defined relapse at the longest time point; secondary outcomes included relapse at 3, 6, 12, 18, and 24 months, all-cause discontinuation, discontinuation due to adverse events, drug inefficacy (ie, relapse + discontinuation due to inefficacy), hospitalization, and nonadherence. Results: Across 21 RCTs (n = 5176), LAIs were similar to OAPs for relapse prevention at the longest time point (studies = 21, n = 4950, relative risk [RR] = 0.93, 95% confidence interval [CI]: 0.80-1.08, P =. 35). The finding was confirmed restricting the analysis to outpatient studies lasting ≥1 year (studies = 12, RR = 0.93, 95% CI:0.71-1.07, P =. 31). However, studies using first-generation antipsychotic (FGA)-LAIs (studies = 10, RR = 0.82, 95% CI:0.69-0.97, P =. 02) and those published ≤1991 (consisting exclusively of all 8 fluphenazine-LAI studies; RR = 0.79, 95% CI: 0.65-0.96, P = 0.02) were superior to OAPs regarding the primary outcome. Pooled LAIs also did not separate from OAPs regarding any secondary outcomes. Again, studies using FGA-LAIs and those published ≤1991 were associated with LAI superiority over OAPs, eg, hospitalization and drug inefficacy. Conclusions: In RCTs, which are less representative of real-world patients than naturalistic studies, pooled LAIs did not reduce relapse compared with OAPs in schizophrenia patients. The exceptions were FGA-LAIs, mostly consisting of fluphenazine-LAI studies, which were all conducted through 1991. Because this finding is vulnerable to a cohort bias, studies comparing FGA-LAI vs second-generation antipsychotics-LAI and LAI vs OAP RCTs in real-world patients are needed.

Original languageEnglish
Pages (from-to)192-213
Number of pages22
JournalSchizophrenia Bulletin
Issue number1
StatePublished - 1 Jan 2014
Externally publishedYes


  • adherence
  • antipsychotics
  • depot
  • long-acting injection
  • meta-analysis
  • relapse
  • schizophrenia
  • treatment discontinuation


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