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.
“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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“Results of meta-analyses comparing LAIs and OAPs in terms of hospitalization rates are also heterogenous, with several showing that LAIs are superior to OAPs in terms of hospitalization rates (Kishimoto et al., 2013; Kishimoto et al., 2018), and another finding no significant differences between the two formulations (…”
BackgroundResultClinical factors related to schizophrenia relapse
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“Second-generation LAI antipsychotics have been studied extensively in patients with schizophrenia, with several systematic reviews and metaanalyses pointing to their safety and efficacy [6, 7].”
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“Importantly, LAIs may reduce the risk of relapse and hospitalization, which can affect health outcomes, quality of life, and health care costs.(12) Although meta-analyses of early randomized controlled trial data failed to show consistent superiority of LAIs over oral antipsychotics with regard to relapse prevention,…”
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“The main strength of this study is its naturalistic design, which takes into account real-life treatment settings and focuses on a bad prognosis FEP population that randomized controlled trials (RCTs) and trials with other designs tend to exclude (Hofer et al., 2000; Kishimoto et al., 2013; Subotnik et al., 2015).”
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Self-citationCurrent and emerging long-acting antipsychotics for the treatment of schizophrenia
de Filippis, R., Fazio, P. D., Gaetano, R., Steardo, L., Cedro, C., Bruno, A., Zoccali, R., & Muscatello, M. (2021) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2021.1910674 · Cited by 43 · see citing works
Citrome, L. (2015) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2016.1121809 · Cited by 37 · see citing works
“tics.[39,46] Additional approved indications for long-acting injectable antipsychotics may also increase their overall”
BackgroundOkoli, C. T. C., Kappi, A. A., Wang, T., Makowski, A., & Cooley, A. T. (2021) · International Journal of Mental Health Nursing · doi:10.1111/inm.12964 · Cited by 36 · see citing works
Bioque, M., Parellada, E., García‐Rizo, C., Amoretti, S., Fortea, A., Oriolo, G., Palau, P., Boix-Quintana, E., Safont, G., & Bernardo, M. (2020) · European Psychiatry · doi:10.1192/j.eurpsy.2020.72 · Cited by 36 · see citing works
“The duration of 6months was prespecified, considering that paliperidone palmitate steady state may not be reached until 4–5 months after commencing treatment [35] and that other similar mirror-image studies involving LAI antipsychotics also covered 6 months before and after initiating the studied strategy [36].”
ResultThe treatment of schizophrenia: Can we raise the standard of care?
Catts, S. V., & O’Toole, B. I. (2016) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867416672725 · Cited by 35 · see citing works
“Are LAIAs more effective in reducing relapse rate compared to oral formulations?”
ResultInfluentialGlutamatergic agents for schizophrenia: current evidence and perspectives
Zink, M., & Correll, C. (2015) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2015.1040393 · Cited by 36 · see citing works
“In contrast to randomized controlled trials, more naturalistic approaches support the use of LAIs compared to oral treatment in schizophrenia.”
BackgroundInfluentialSelf-citationBaandrup, L., Rasmussen, J. Ø., Klokker, L., Austin, S. F., Bjørnshave, T., Bliksted, V., Fink‐Jensen, A., Fohlmann, A., Hansen, J. P., Nielsen, M. K., et al. (2015) · Nordic Journal of Psychiatry · doi:10.3109/08039488.2015.1074285 · Cited by 35 · see citing works
Bartoli, F., Cavaleri, D., Nasti, C., Palpella, D., Guzzi, P., Riboldi, I., Crocamo, C., Pappa, S., & Carrà, G. (2023) · Therapeutic Advances in Psychopharmacology · doi:10.1177/20451253231163682 · Cited by 34 · see citing works
Aymerich, C., de Pablo, G. S., Pacho, M., Pérez-Rodríguez, V., Bilbao, A., Andrés, L. G., Pedruzo, B., Castillo-Sintes, I., Aranguren, N., Fusar‐Poli, P., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02694-3 · Cited by 34 · see citing works
Bossie, C. A., Alphs, L. D., & Correll, C. U. (2015) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000082 · Cited by 33 · see citing works
“Although mirror-image studies, which arguably include more broadly representative patient populations, have reported advantages on the basis of this difference in modality (Kishimoto et al., 2013), randomized-controlled trials have frequently failed to show advantages (Fusar-Poli et al.”
BackgroundResultInfluentialSelf-citationSchreiner, A., Bergmans, P., Chérubin, P., Keim, S., Llorca, P., Cosar, B., Petralia, A., Corrivetti, G., & Hargarter, L. (2015) · Journal of Psychopharmacology · doi:10.1177/0269881115586284 · Cited by 33 · see citing works
“…of relapse compared with oral AP formulations (Leucht et al., 2011), although data from some recent randomized controlled trials (RCTs) and meta-analyses are ambiguous (Kishimoto et al., 2013, 2014), with results depending on variables such as study design and methodology (Kirson et al., 2013).”
BackgroundLähteenvuo, M., Luykx, J. J., Taipale, H. T., Mittendorfer‐Rutz, E., Tanskanen, A. J., Batalla, A., & Tiihonen, J. (2022) · The British Journal of Psychiatry · doi:10.1192/bjp.2022.117 · Cited by 30 · see citing works
Cheung, S., Hamuro, Y., Mahlich, J., Nakahara, T., Sruamsiri, R., & Tsukazawa, S. (2017) · Clinical Drug Investigation · doi:10.1007/s40261-017-0517-0 · Cited by 33 · see citing works
Citrome, L. (2017) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2017.1371014 · Cited by 34 · see citing works
“A meta-analysis that examined mirror-image studies [48], and thus included studies that are more generalizable to routine clinical practice than randomized clinical trials [49], LAI antipsychotics demonstrated strong superiority over oral antipsychotics in preventing hospitalization (16 studies, N = 4,066; risk ratio…”
A review on schizophrenia and relapse—a quest for user‐friendly psychopharmacotherapy
Suzuki, T., Uchida, H., Takeuchi, H., Tsuboi, T., Hirano, J., & Mimura, M. (2014) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.2421 · Cited by 32 · see citing works
Alphs, L. D., Mao, L., Starr, H. L., & Benson, C. J. (2015) · Schizophrenia Research · doi:10.1016/j.schres.2015.12.012 · Cited by 32 · see citing works
“The literature regarding this question is conflicting (Fusar-Poli et al., 2013; Kirson et al., 2013; Kishimoto et al., 2013, 2014).”
MacEwan, J. P., Kamat, S., Duffy, R. A., Seabury, S. A., Chou, J. W., Legacy, S. N., Hartry, A., Eramo, A., & Karson, C. N. (2016) · Psychiatric Services · doi:10.1176/appi.ps.201500455 · Cited by 32 · see citing works
Vincent, P. D., Demers, M., Doyon-Kemp, V., Duchesneau, J., Halme, A. S., & Masson, V. (2017) · Schizophrenia Research · doi:10.1016/j.schres.2017.01.013 · Cited by 32 · see citing works
“Furthermore, ameta-analysis of 25mirror-image studies comparing oral antipsychotic treatment with a subsequent period of LAI treatment showed LAI superiority over oral antipsychotics in preventing hospitalizations with a risk ratio of 0.43 in 14 out of 16 studies (Kishimoto et al., 2013).”
InfluentialGoldstone, L. W., DiPaula, B. A., Werremeyer, A. B., Botts, S. R., Hepburn, B. M., Liu, H. Y., Duckworth, K., Young, A. S., & Kelly, D. L. (2021) · Psychiatric Services · doi:10.1176/appi.ps.202000066 · Cited by 32 · see citing works
Schöttle, D., Janetzky, W., Luedecke, D., Beck, E., Correll, C. U., & Wiedemann, K. (2018) · BMC Psychiatry · doi:10.1186/s12888-018-1946-x · Cited by 30 · see citing works
Self-citationGannon, J. M., Conlogue, J., Sherwood, R., et al. (2020) · Schizophrenia Research · doi:10.1016/j.schres.2020.05.001 · Cited by 31 · see citing works
“LAIs are considered a mainstay treatment in persons with schizophrenia and schizoaffective disorder (Kishimoto et al, 2013) .”
BackgroundUribe, E., Navarro, F. C., Medrano, A. F. G., Cervantes, K., Villalobos, N. A. Á., Rocha, V., Hernández, M., Alanís, J. M., Cavada, C., Hernández, J., et al. (2020) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2020.06.013 · Cited by 6 · see citing works
Wu, C., Hsieh, M. H., Tang, C., & Chang, C.-J. (2016) · Journal of Affective Disorders · doi:10.1016/j.jad.2016.03.043 · Cited by 31 · see citing works
“Long-acting injectable (LAI) antipsychotics could improve medication adherence (El-Mallakh, 2007; Vieta et al., 2008), with a growing body of evidence demonstrating their effectiveness in the treatment of schizophrenia (Kishimoto et al., 2013; Mauri et al., 2009).”
Background
- 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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