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Long-Acting Injectable Versus Oral Antipsychotics in Schizophrenia: A Systematic Review and Meta-Analysis of Mirror-Image Studies
Abstract
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.
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“In addition to the benefits of reduced treatment gaps with LAI versus oral antipsychotics, studies, particularly those in real-world samples, have demonstrated reduced psychopathology, relapses, hospitalizations, and mortality risk with LAI formulations [98–104].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [98]
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“On the other hand, it has been speculated that a mirror image study might be more appropriate for the evaluation of the effects of LAIAs in the psychiatric population, which is often difficult to enroll in RCTs and poorly adherent to pharmacological treatments [50].”
BackgroundChiang, C. N., Chinen, M., Daskiran, M., Wakamatsu, A., & Turkoz, I. (2024) · Neuropsychopharmacology Reports · doi:10.1002/npr2.12473 · Cited by 4
Yoshimura, B., Shinkawa, I., & Konishi, A. (2015) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2015.02.001 · Cited by 4
“The hospitalization risk in this study is in keeping with the previous meta-analysis that reported strong superiority of RLAI compared to oral antipsychotics in hospitalization (risk ratio = 0.46; 95% CI, 0.33, 0.64; P < 0.001) (Kishimoto et al., 2013).”
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“C urrently, long-acting injections (LAIs) hold an important position in maintenance therapy for schizophrenia because of their high adherence rate and their ability to prevent repeat hospitalizations.(1) However, there have been no naturalistic reports in Japan clarifying the difference in treatment continuation of se…”
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“They lower the possibility of a relapse [1], prevent from hospitalization [2], and lower the risk of death [3].”
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“An ample metaanalysis of 25 mirror-image studies on 5940 patients from 28 countries found that LAIs are superior to oral antipsychotics in terms of prevention of rehospitalizations of schizophrenic patients [9].”
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“These include fewer side effects [20], lower relapse rates [16, 21], preventing hospitalization, decreasing the number of hospitalizations in patients with SSD [17, 18, 22, 23], and an approximately 30% lower risk of death compared with oral agents [24].”
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“However, it is important to note that in both meta-analyses of mirror-image studies, heterogeneity was large; that is, effect sizes varied substantially across the meta-analysed studies (Kishimoto et al., 2013, 2021), which could also be an explanation for the differences in effect sizes.”
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“A meta-analysis of mirror-image studies also showed that compared with oral medication, long-acting injections result in better clinical outcomes.(14) In brief, medication adherence plays a crucial role in treatment outcomes of schizophrenia.”
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BackgroundInfluentialHospitalization Risk Before and After Discontinuation of Long-Acting Injectable Antipsychotics
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“A previous meta-analysis of mirror-image studies investigating hospitalization risk before and after initiation of long-acting injectable antipsychotics (LAI) showed that treatment with LAI avoids hospitalization in the treatment of schizophrenia.(1) To our knowledge, there is no evidence of hospitalization risk befor…”
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“I N A PREVIOUS meta-analysis of mirror-image studies, long-acting injection (LAI) significantly reduced the length of hospital stay compared to the reduction by an oral antipsychotic.(1) On the other hand, to our knowledge, reports that have evaluated the comparison between hospitalization risk before and after risper…”
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MethodResultInfluentialRetractedFactors Affecting Continuation of Aripiprazole Long-acting Injection in the Real World
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“B ecause of their effectiveness for relapse prevention, long-acting injectable antipsychotics (LAI-APs) are an important option in the maintenance treatment of schizophrenia.(1,2) However, they remain underutilized in most countries.”
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“This primarily relates to the demonstrated efficacy, safety and real-world effectiveness of LAIs when compared with oral antipsychotics, which was in turn attributed to, among others, better medication compliance 15 .”
BackgroundResultАндреевна, Б. Л., Golubev, S. A., Berezantsev, A. Y., & Shumakova, E. A. (2022) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro202212201213
Metadata
- Authors
- Kishimoto, T., Nitta, M., Borenstein, M., Kane, J. M., & Correll, C. U.
- Affiliations
- Keio University (JP)
- Sumitomo Dainippon Pharma (Japan) (JP)
- Biostat (United States) (US)
- Zucker Hillside Hospital (US)
- Corresponding author
- Correll, Christoph U.
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2013-10-15
- Volume
- 74
- Issue
- 10
- Pages
- 957-965
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W2088866491
- Cited by
- 427
- References
- 0
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 18 · 2023: 20 · 2022: 42 · 2021: 53 · 2020: 36 · 2019: 44 · 2018: 37 · 2017: 41 · 2016: 45 · 2015: 37 · 2014: 23 · 2013: 1
- FWCI
- 25.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (P30MH090590)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Social Sciences › Psychology › Clinical Psychology › Psychiatric care and mental health services
- Social Sciences › Psychology › Clinical Psychology › Historical Psychiatry and Medical Practices
- Keywords
- long-acting injectable antipsychotics, oral antipsychotics, schizophrenia, hospitalization, relapse prevention, mirror-image study, medication adherence, real-world effectiveness, length of hospital stay, antipsychotic adverse effects, antipsychotic switching, antipsychotic discontinuation
- MeSH terms
- Administration, Oral, Delayed-Action Preparations, Humans, Injections, Psychiatric Status Rating Scales, Schizophrenia, Antipsychotic Agents, Drug Monitoring, Patient Selection, Medication Adherence, Secondary Prevention, Comparative Effectiveness Research
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