Academic Journal
Effectiveness of Long-Acting Injectable Antipsychotics Versus Oral Antipsychotics in People With Bipolar Disorder: A Systematic Review and Meta-Analysis of Observational Studies: Efficacité des antipsychotiques injectables à action prolongée par rapport aux antipsychotiques oraux chez les personnes atteintes de troubles bipolaires : revue systématique et méta-analyse d'études observationnelles.
| Title: | Effectiveness of Long-Acting Injectable Antipsychotics Versus Oral Antipsychotics in People With Bipolar Disorder: A Systematic Review and Meta-Analysis of Observational Studies: Efficacité des antipsychotiques injectables à action prolongée par rapport aux antipsychotiques oraux chez les personnes atteintes de troubles bipolaires : revue systématique et méta-analyse d'études observationnelles. |
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| Authors: | Wagner E; Evidence-Based Psychiatry and Psychotherapy, Faculty of Medicine, University of Augsburg, Augsburg, Germany.; Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, University of Augsburg, Augsburg, Germany., Katyal S; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada., Lee IO; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada., Tasnim S; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada., El Wadia H; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada., Mortazavi M; Evidence-Based Psychiatry and Psychotherapy, Faculty of Medicine, University of Augsburg, Augsburg, Germany.; Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, University of Augsburg, Augsburg, Germany., García-Carmona JA; Department of Neurology, Santa Lucía University Hospital, Murcia, Spain.; Group of Clinical and Experimental Pharmacology, Institute for Biomedical Research of Murcia (IMIB), Murcia, Spain.; Faculty of Pharmacy and Nutrition, San Antonio Catholic University of Murcia (UCAM), Murcia, Spain., Hasan A; Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, University of Augsburg, Augsburg, Germany.; Department of Psychiatry, Psychotherapy and Psychosomatics Augsburg, DZPG (German Center for Mental Health), Augsburg, Germany., Colman I; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada., Taipale H; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.; Center for Psychiatry Research, Stockholm City Council, Stockholm, Sweden.; Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland.; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Tiihonen J; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.; Center for Psychiatry Research, Stockholm City Council, Stockholm, Sweden.; Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland., Correll CU; Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, USA.; Departments of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.; Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany.; German Center for Mental Health (DZPG), Partner Site Berlin, Berlin, Germany., Højlund M; Department of Psychiatry Aabenraa, Mental Health Services Region of Southern Denmark, Aabenraa, Denmark.; Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark., Solmi M; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada.; Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany.; SCIENCES Lab, Department of Psychiatry, University of Ottawa, Ontario, Canada.; Regional Centre for the Treatment of Eating Disorders and On Track: The Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa Hospital, Ontario, Canada.; Ottawa Hospital Research Institute (OHRI), Ottawa, Ontario, Canada. |
| Source: | Canadian journal of psychiatry. Revue canadienne de psychiatrie [Can J Psychiatry] 2026 Jun; Vol. 71 (6), pp. 420-435. Date of Electronic Publication: 2026 Jan 30. |
| Publication Type: | Journal Article; Systematic Review; Meta-Analysis; Comparative Study; Review |
| Language: | English |
| Journal Info: | Publisher: Sage Country of Publication: United States NLM ID: 7904187 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1497-0015 (Electronic) Linking ISSN: 07067437 NLM ISO Abbreviation: Can J Psychiatry Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2016- : Thousand Oaks, CA : Sage Original Publication: [Ottawa, Canadian Psychiatric Assn.] |
| MeSH Terms: | Bipolar Disorder*/drug therapy , Antipsychotic Agents*/administration & dosage , Antipsychotic Agents*/pharmacology , Observational Studies as Topic*/statistics & numerical data , Outcome Assessment, Health Care*/statistics & numerical data, Humans ; Delayed-Action Preparations ; Administration, Oral ; Injections |
| Abstract: | Background: Randomised trials suggest long-acting injectable antipsychotics (LAIs) may outperform oral antipsychotics (OAPs) regarding adherence and relapse prevention in bipolar disorder (BD). We aimed to compare the effectiveness and tolerability of LAIs versus OAPs in observational studies. Methods: Searching MEDLINE/Embase/PsycINFO until March-25-2025, we conducted a systematic review and random-effects meta-analysis (pre-registered protocol: https://osf.io/gkwrp) of observational studies comparing LAIs versus OAPs in people with BD (primary outcome = study-defined relapse/psychiatric hospitalisation). Results: Seventeen studies (4 = cohort, 13 = mirror-image studies; 6186/3676 participants with BD, respectively, high-quality per Newcastle-Ottawa Scale Score ≥7 = 47.1%) were included. The relative risk (RR) for study-defined relapse/psychiatric hospitalisation was significantly lower with LAIs versus OAPs in cohort (k = 4, RR = 0.63, 95% confidence interval (CI) = 0.44;0.90, P = 0.026) and mirror-image studies (k = 5, RR = 0.46, 95% CI = 0.28;0.77, P = 0.013). LAIs were not significantly superior to OAPs in high-quality cohort studies (k = 3, P = 0.78) but in those adjusted for >5 factors (k = 2, RR = 0.56, 95% CI = 0.37;0.84, P = 0.006) nor in high-quality mirror-image studies (k = 2, P = 0.38), but in each second-generation antipsychotic-LAIs study (aripiprazole-LAI: k = 2, risperidone-LAI: k = 1) (k = 3, RR = 0.40, 95% CI = 0.20;0.80, P = 0.03). In cohort studies, LAIs and OAPs did not differ regarding psychiatric hospitalisations (k = 3, P = 0.078) but data on discontinuation and mortality risk were lacking/not meta-analysable. In mirror-image studies, LAIs were associated with significantly lower psychiatric (k = 4, RR = 0.50, 95% CI = 0.25;0.99, P = 0.048) and depression-related (k = 2, RR = 0.46, 95% CI = 0.24;0.86, P = 0.014), but not mania-related hospitalisation risk (k = 2, P = 0.075). LAIs were associated with fewer psychiatric hospitalisations (k = 7, SMD = -1.73, 95% CI = -2.88;-0.57, P = 0.011), hospitalisation days (k = 9, SMD = -1.35, 95% CI = -2.19;-0.52, P = 0.006), mania-related hospitalisations (k = 3, SMD = -0.87, 95% CI = -1.19;-0.56, P < 0.001) and manic episodes (k = 3, SMD = -1.13, 95% CI = -2.00;-0.26, P = 0.03), but not any mood (k = 4, P = 0.13) or depressive episodes (k = 3, P = 0.14). Tolerability outcomes were missing, and GRADE certainty-of-evidence was "low" to "very low". Discussion: LAIs were superior versus OAPs in preventing relapse/hospitalisation in cohort and mirror-image studies, in the latter particularly for mania-related outcomes. More robust mirror-image and controlled cohort studies are needed to better assess the effectiveness and tolerability of LAI antipsychotics in BD.Plain Language Summary TitleEffectiveness of Long-Acting Injectable Antipsychotics versus Oral Antipsychotics in People with Bipolar Disorder: A Systematic Review and Meta-Analysis of Observational Studies. |
| Competing Interests: | Declaration of Conflicting InterestsThe authors declare that there are no conflicts of interest in relation to the subject of this study. General declaration of potential conflict of interests: EW was invited to advisory boards from Recordati, Teva and Boehringer Ingelheim. AH reported receiving personal fees from AbbVie, Advanz Pharma, Boehringer-Ingelheim, Janssen-Cilag, Teva, Lundbeck, Recordati, Rovi and Otsuka outside the submitted work; serving as editor of the German schizophrenia treatment guidelines and as first author of the World Federation of Societies of Biological Psychiatry schizophrenia treatment guidelines; and serving on advisory boards of AbbVie, Boehringer-Ingelheim, Janssen-Cilag, Lundbeck, Recordati, Rovi and Otsuka. JAGC received speaking honoraria from Janssen-Cilag, Johnson & Johnson, Lundbeck and Organon, advisoring honoraria from Teva and Angelini Pharma and research honoraria from Neuraxpharm and Roche, all of them outside the submitted work. MH has received honoraria for consultancy/speaking from Lundbeck and Otsuka. CU Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Alkermes, Allergan, Angelini, Aristo, Autobahn, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Draig, Eli Lilly, Eumentis Therapeutics, Gedeon Richter, GH, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedInCell, MedLink, Merck, Mindpax, Mitsubishi Tanabe Pharma, Maplight, Mylan, Neumora Therapeutics, Neuraxpharm, Neurocrine, Neurelis, NeuShen, Newron, Noven, Novo Nordisk, Orion Pharma, Otsuka, PPD Biotech, Recognify Life Science, Recordati, Relmada, Response Pharmaeutical, Reviva, Rovi, Saladax, Sanofi, Seqirus, Servier, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Terran, Tolmar, Vertex, Viatris and Xenon Pharmaceuticals. He provided expert testimony for Janssen, Lundbeck, Neurocrine and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, IntraCellular Therapies, Relmada, Reviva, Rovi. He has received grant support from Boehringer-Ingelheim, Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, MedLink Global, Mindpax, Quantic, Terran. HT has participated in research projects funded by grants from Janssen to her employing institution and reports personal fees from Gedeon Richter, Janssen, Lundbeck and Otsuka. MS reported receiving honoraria from AbbVie, Angelini, Bausch Heallth, Lundbeck, Otsuka and Teva, outside the submitted work. Other authors report no conflict of interest. |
| Contributed Indexing: | Keywords: bipolar disorder; cohort study; hospitalisation; long-acting injectable; mirror-image study Local Abstract: [plain-language-summary] Clinical trials have suggested that long-acting injectable antipsychotics (LAIs) may help people with bipolar disorder stay on their medication and reduce relapse risk better than oral antipsychotics. This review looked at real-world studies to see how well LAIs work compared to oral antipsychotics in everyday clinical settings.We searched several medical databases up to March 2025 and included 17 studies that compared LAIs and OAPs in people with bipolar disorder. These studies followed people over time or compared outcomes before and after switching from oral to injectable medication. The main outcome was relapse or psychiatric hospitalization. Across studies, people using LAIs had a lower risk of relapse or psychiatric hospitalization compared to those taking oral antipsychotics. This benefit was seen in both types of studies (cohort and mirror-image).In studies that adjusted for more factors or focused on second-generation LAIs (like aripiprazole or risperidone), LAIs appeared particularly effective. LAIs were linked to fewer psychiatric hospitalizations overall, fewer days spent in hospital, and fewer manic episodes.There was no clear difference for depressive episodes. Information on side effects or tolerability was often missing. The overall certainty of the evidence was rated as low to very low, meaning more high-quality studies are needed. Long-acting injectable antipsychotics may help people with bipolar disorder stay well and avoid relapse or hospitalization better than oral medications, especially for mania. However, because most existing studies have limitations, more rigorous research is needed to confirm these findings and to understand the side effects of LAIs compared to oral antipsychotics. |
| Substance Nomenclature: | 0 (Antipsychotic Agents) 0 (Delayed-Action Preparations) |
| Entry Date(s): | Date Created: 20260130 Date Completed: 20260701 Latest Revision: 20260707 |
| Update Code: | 20260707 |
| PubMed Central ID: | PMC12858392 |
| DOI: | 10.1177/07067437251412576 |
| PMID: | 41615846 |
| Database: | MEDLINE |
| ISSN: | 1497-0015 |
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| DOI: | 10.1177/07067437251412576 |