Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies

J Clin Psychiatry. 2013 Oct;74(10):957-65. doi: 10.4088/JCP.13r08440.


Objective: Recent, large, randomized controlled trials (RCTs) showed no benefit of long-acting injectable (LAI) antipsychotics over oral antipsychotics in preventing relapse in schizophrenia, nor did a recent meta-analysis incorporating these studies. However, RCTs might enroll a disproportionate number of patients with better treatment adherence and lower illness severity. Mirror-image studies, which compare periods of oral antipsychotic versus LAI treatment in the same patients, might therefore better reflect the real-world impact of LAIs.

Data sources: A systematic literature search without language restriction was conducted using MEDLINE/PubMed, Cochrane Library, Web of Science, PsycINFO, and CINAHL until May 31, 2012. Search terms included synonyms of (1) antipsychotic(s) AND (2) schizophrenia and related disorders AND (3) depot, (long-acting) injection(s), microsphere, decanoate, palmitate, enanthate.

Study selection: Of 5,483 identified citations, 607 articles were fully inspected, and 582 were ineligible. Finally, 25 mirror-image studies from 28 countries that followed 5,940 patients with schizophrenia for ≥ 12 months (≥ 6 months each on oral antipsychotic and LAI treatment) met the inclusion criteria and were analyzed.

Data extraction: Coprimary outcomes were hospitalization risk and number of hospitalizations. Secondary outcomes included hospitalization days and length of stay.

Data synthesis: LAIs showed strong superiority over oral antipsychotics in preventing hospitalization (16 studies, N = 4,066; risk ratio = 0.43; 95% CI, 0.35-0.53; P < .001) and in decreasing the number of hospitalizations (15 studies, 6,342 person-years; rate ratio = 0.38; 95% CI, 0.28-0.51; P < .001). This strong advantage was also observed for secondary outcomes and in multiple clinically relevant subpopulations and treatment groups.

Conclusions: Results from mirror-image studies in patients eligible for clinical use of LAIs showed strong superiority of LAIs compared to oral antipsychotics in preventing hospitalization. The results were in contrast to the recent meta-analysis of RCTs, which showed no superiority of LAIs. Given the possible biases in mirror-image studies, such as expectation bias, natural illness course, and time effect, a cautious interpretation is required. Nevertheless, the population in mirror-image studies better reflects the population receiving LAIs in clinical practice.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Systematic Review

MeSH terms

  • Administration, Oral
  • Antipsychotic Agents* / administration & dosage
  • Antipsychotic Agents* / adverse effects
  • Antipsychotic Agents* / pharmacokinetics
  • Comparative Effectiveness Research / methods
  • Delayed-Action Preparations / administration & dosage
  • Drug Monitoring / methods
  • Humans
  • Injections
  • Medication Adherence
  • Patient Selection
  • Psychiatric Status Rating Scales
  • Schizophrenia* / diagnosis
  • Schizophrenia* / drug therapy
  • Secondary Prevention


  • Antipsychotic Agents
  • Delayed-Action Preparations