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Representation and Outcomes of Individuals With Schizophrenia Seen in Everyday Practice Who Are Ineligible for Randomized Clinical Trials
Open accessAbstract
IMPORTANCE: Most evidence about efficacy and safety of antipsychotics in schizophrenia spectrum disorders relies on randomized clinical trials (RCTs). However, owing to their strict eligibility criteria, RCTs represent only a part of the real-world population (ie, unselected patients seen in everyday clinical practice), which may result in an efficacy-effectiveness gap. OBJECTIVE: To quantify the proportion of real-world individuals with schizophrenia spectrum disorders who would be ineligible for participation in RCTs, and to explore whether clinical outcomes differ between eligible and ineligible individuals. DESIGN, SETTING, AND PARTICIPANTS: This study applied eligibility criteria typically used in RCTs for relapse prevention in schizophrenia spectrum disorders to real-world populations. Individuals with diagnoses of schizophrenia spectrum disorders recorded in national patient registries in Finland and Sweden were identified. Individuals who had used antipsychotics continuously for 12 weeks in outpatient care were selected. Individuals were followed up for up to 1 year while they were receiving maintenance treatment with any second-generation antipsychotic (excluding clozapine). Follow-up was censored at treatment discontinuation, initiation of add-on antipsychotics, death, and end of database linkage. MAIN OUTCOMES AND MEASURES: Proportions of RCT-ineligible individuals with schizophrenia spectrum disorders owing to any and specific RCT exclusion criteria. The risk of hospitalization due to psychosis within 1-year follow-up in ineligible vs eligible persons were compared using hazard ratios (HR) and corresponding 95% CIs. RESULTS: The mean (SD) age in the Finnish cohort (n = 17 801) was 47.5 (13.8) years and 8972 (50.4%) were women; the mean (SD) age in the Swedish cohort (n = 7458) was 44.8 (12.5) years and 3344 (44.8%) were women. A total of 20 060 individuals (79%) with schizophrenia spectrum disorders would be ineligible for RCTs (Finnish cohort: 14 221 of 17 801 [79.9%]; Swedish cohort: 5839 of 7458 [78.3%]). Most frequent reasons for ineligibility were serious somatic comorbidities and concomitant antidepressant/mood stabilizer use. Risks of hospitalization due to psychosis was higher among ineligible than eligible individuals (Finnish cohort: 18.4% vs 17.2%; HR, 1.14 [95% CI, 1.04-1.24]; Swedish cohort: 20.1% vs 14.8%; HR, 1.47 [95% CI, 1.28-1.92]). The largest risks of hospitalization due to psychosis were observed in individuals ineligible owing to treatment resistance, tardive dyskinesia, and history of suicide attempts. Finally, with more ineligibility criteria met, larger risks of hospitalization due to psychosis were observed in both countries. CONCLUSIONS AND RELEVANCE: RCTs may represent only about a fifth of real-world individuals with schizophrenia spectrum disorders. Underrepresented (ineligible) patients with schizophrenia spectrum disorders have moderately higher risks of admission due to psychosis while receiving maintenance treatment than RCT-eligible patients. These findings set the stage for future studies targeting real-world populations currently not represented by RCTs.
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“Research of RCTs on medications for schizophrenia highlights the significant disparity between the broader patient population and those who qualify for trials, primarily due to exclusion criteria that eliminate many individuals with comorbid conditions and more severe manifestations of the disorder: 79% of individuals with schizophrenia spectrum disorders would be deemed ineligible for RCTs.15”
From Evaluating ADHD medication trial representativeness: a Swedish population-based study comparing hypothetically trial-eligible and trial-ineligible individuals (2025) · cites this paper as [15]
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“a study found only about 20% of people who have schizophrenia spectrum disorders would be eligible for inclusion in a typical randomised clinical trial.”
From Developing clinical prediction models: a step-by-step guide (2024) · cites this paper as [46]
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“Patients who are ineligible had a higher risk of hospital admission with psychosis than those who are eligible.46”
From Developing clinical prediction models: a step-by-step guide (2024) · cites this paper as [46]
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“(2) The selection criteria used for our analysis are typical for a specific, relatively common type of RCTs (ie, relapse prevention of schizophrenia with antipsychotics) and specific real-world samples (Finland and Sweden).”
BackgroundMethod
Research works printed but not linked: 1
- Luykx, 2020, What is the Impact of Randomized Controlled Trials Inclusion and Exclusion Criteria on Outcomes in People using Antipsychotics in the Real World? A Systematic Analysis in National Registries
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Metadata
- Authors
- Taipale, H., Schneider-Thoma, J., Pinzón-Espinosa, J., Radua, J., Efthimiou, O., Vinkers, C. H., Mittendorfer-Rutz, E., Cardoner, N., Pintor, L., Tanskanen, A., Tomlinson, A., Fusar-Poli, P., Cipriani, A., Vieta, E., Leucht, S., Tiihonen, J., & Luykx, J. J.
- Affiliations
- University of Eastern Finland (FI)
- Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Munich, Germany
- Universidad de Panamá (PA)
- Divisions of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- University of Bern (CH)
- Amsterdam Neuroscience (NL)
- Department of Mental Health, Parc Tauli University Hospital, Sabadell, Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERSAM, Barcelona, Spain
- Oxford Health NHS Foundation Trust (GB)
- Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
- Hospital Clínic de Barcelona (ES)
- Technical University of Munich (DE)
- Utrecht University (NL)
- Corresponding author
- Luykx, Jurjen J.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2022-03-01
- Volume
- 79
- Issue
- 3
- Pages
- 210
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC8792792
- OpenAlex
- W4210419267
- Cited by
- 129
- References
- 36
- Citations by year
- 2026: 30 · 2025: 28 · 2024: 33 · 2023: 26 · 2022: 12
- FWCI
- 16.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Greater South Information System
- Funders
- National Science Foundation
- Eli Lilly and Company
- Pfizer
- GlaxoSmithKline
- Sanofi
- Ministerio de Ciencia, Innovación y Universidades
- National Institute for Health and Care Research (AI_AWARD02183, RP-2017-08-ST2-006, BRC‐1215‐20005, NIHR Research Professorship (grant RP-2017-08-ST2-)
- European Commission (CPII19/00009)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (20005, 180083)
- Academy of Finland (320107, 315969)
- Fondazione Cariplo
- Sigrid Juséliuksen Säätiö
- Angelini Pharma
- Otsuka Pharmaceutical
- Casen Recordati
- H. Lundbeck A/S
- Neuraxpharm
- Instituto de Salud Carlos III ((CPII19/00009), PI19/00394)
- European Regional Development Fund (CPII19/00009)
- Janssen Pharmaceuticals
- Cilag
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Mental Health Treatment and Access
- Social Sciences › Psychology › Clinical Psychology › Psychiatric care and mental health services
- Keywords
- schizophrenia spectrum disorders, antipsychotic drugs, relapse prevention, long-term antipsychotic treatment, atypical antipsychotics, efficacy-effectiveness gap, somatic comorbidity, real-world outcomes, patient registry, Finland, Sweden
- MeSH terms
- Adult, Clozapine, Female, Humans, Male, Middle Aged, Psychotic Disorders, Schizophrenia, Antipsychotic Agents, Randomized Controlled Trials as Topic
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