Representation and Outcomes of Individuals with Schizophrenia Seen in Everyday Practice Who Are Ineligible for Randomized Clinical Trials

Heidi Taipale; Johannes Schneider-Thoma; Justo Pinzón-Espinosa; Joaquim Radua; Orestis Efthimiou; Christiaan H. Vinkers; Ellenor Mittendorfer-Rutz; Narcís Cardoner; Luis Pintor; Antti Tanskanen; Anneka Tomlinson; Paolo Fusar-Poli; Andrea Cipriani; Eduard Vieta; Stefan Leucht; Jari Tiihonen; Jurjen J. Luykx

doi:10.1001/jamapsychiatry.2021.3990

Representation and Outcomes of Individuals with Schizophrenia Seen in Everyday Practice Who Are Ineligible for Randomized Clinical Trials

Heidi Taipale, Johannes Schneider-Thoma, Justo Pinzón-Espinosa, Joaquim Radua, Orestis Efthimiou, Christiaan H. Vinkers, Ellenor Mittendorfer-Rutz, Narcís Cardoner, Luis Pintor, Antti Tanskanen, Anneka Tomlinson, Paolo Fusar-Poli, Andrea Cipriani, Eduard Vieta, Stefan Leucht, Jari Tiihonen, Jurjen J. Luykx^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

56 Citations (Scopus)

Abstract

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 = 17801) 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 20060 individuals (79%) with schizophrenia spectrum disorders would be ineligible for RCTs (Finnish cohort: 14221 of 17801 [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.

Original language	English
Pages (from-to)	210-218
Number of pages	9
Journal	JAMA Psychiatry
Volume	79
Issue number	3
DOIs	https://doi.org/10.1001/jamapsychiatry.2021.3990
Publication status	Published - Mar 2022

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10.1001/jamapsychiatry.2021.3990

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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. (2022). Representation and Outcomes of Individuals with Schizophrenia Seen in Everyday Practice Who Are Ineligible for Randomized Clinical Trials. JAMA Psychiatry, 79(3), 210-218. https://doi.org/10.1001/jamapsychiatry.2021.3990

@article{da6822258c0c4e33880d5a4e60ef2882,

title = "Representation and Outcomes of Individuals with Schizophrenia Seen in Everyday Practice Who Are Ineligible for Randomized Clinical Trials",

abstract = "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 = 17801) 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 20060 individuals (79%) with schizophrenia spectrum disorders would be ineligible for RCTs (Finnish cohort: 14221 of 17801 [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.",

author = "Heidi Taipale and Johannes Schneider-Thoma and Justo Pinz{\'o}n-Espinosa and Joaquim Radua and Orestis Efthimiou and Vinkers, {Christiaan H.} and Ellenor Mittendorfer-Rutz and Narc{\'i}s Cardoner and Luis Pintor and Antti Tanskanen and Anneka Tomlinson and Paolo Fusar-Poli and Andrea Cipriani and Eduard Vieta and Stefan Leucht and Jari Tiihonen and Luykx, {Jurjen J.}",

note = "Funding Information: Funding/Support: Dr Efthimiou was supported by Funding Information: reported grants and personal fee from Janssen Pharmaceuticals, grants from Eli Lilly and Company, and personal fees from Otsuka Pharmaceutical outside the submitted work. Dr Pinz{\'o}n-Espinosa reported personal fees and nonfinancial support from Lundbeck, Angelini, Neuraxpharm, and Pfizer and nonfinancial support from Janssen Pharmaceuticals and Casen Recordati outside the submitted work. Dr Mittendorfer-Rutz reported grants from Janssen Pharmaceuticals outside the submitted work. Dr Cardoner has received grants and acted as a CME consultant, advisor, or speaker for the following entities in the last 5 years (all unrelated to the present work): Angelini, Esteve, Exeltis, Janssen Pharmaceuticals, Lundbeck, Novartis, Pfizer, and Servier. Dr Tanskanen reported other support from Janssen and Eli Lilly and Company outside the submitted work. Dr Tomlinson reported personal fees from INCiPiT (Italian Network for Paediatric Trials) and Angelini Pharma outside the submitted work. Dr Fusar-Poli reported personal fees from Lundbeck, Angelini Pharma, and Menarini outside the submitted work. Dr Cipriani reported personal fees from INCiPiT (Italian Network for Paediatric Trials) and CARIPLO Foundation and personal fees and grants from Angelini Pharma outside the submitted work. Dr Vieta reported grants from AB-Biotics, Ferrer, GlaxoSmithKline, Janssen Pharmaceuticals, and Sanofi-Aventis; personal fees from AbbVie, Aimentia, Angelini Pharma, Celon Pharma, Sumitomo Dainippon Pharma, Gedeon Richter, Janssen Pharmaceuticals, Organon, Otsuka Pharmaceutical, Sunovion, and Takeda; and received grants and served as consultant, advisor, or CME speaker from GH Research, Lundbeck, and Sage outside the submitted work. Dr Leucht reported personal fees from Alkermes, Angelini Pharma, Eisai, Gedeon Richter, Janssen Pharmaceuticals, Johnson & Johnson, Lundbeck, Medichem, Merck Sharp & Dohme, Otsuka Pharmaceutical, Casen Recordati, Rovi, Sandoz, Sanofi, Sunovion, Teva Pharmaceuticals, Boehringer Ingelheim, and LTS Lohmann outside the submitted work. Dr Tiihonen reported personal fees from Finnish Medicines Agency, European Medicines Agency, Eli Lilly and Company, Janssen-Cilag, Otsuka Pharmaceutical, and Lundbeck and grants from the Stanley Foundation and the Sigrid Jus{\'e}lius Foundation outside the submitted work. No other disclosures were reported. Publisher Copyright: {\textcopyright} 2022 Taipale H et al.",

year = "2022",

month = mar,

doi = "10.1001/jamapsychiatry.2021.3990",

language = "English",

volume = "79",

pages = "210--218",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "American Medical Association",

number = "3",

}

Taipale, H, Schneider-Thoma, J, Pinzón-Espinosa, J, Radua, J, Efthimiou, O, Vinkers, CH, Mittendorfer-Rutz, E, Cardoner, N, Pintor, L, Tanskanen, A, Tomlinson, A, Fusar-Poli, P, Cipriani, A, Vieta, E, Leucht, S, Tiihonen, J & Luykx, JJ 2022, 'Representation and Outcomes of Individuals with Schizophrenia Seen in Everyday Practice Who Are Ineligible for Randomized Clinical Trials', JAMA Psychiatry, vol. 79, no. 3, pp. 210-218. https://doi.org/10.1001/jamapsychiatry.2021.3990

TY - JOUR

T1 - Representation and Outcomes of Individuals with Schizophrenia Seen in Everyday Practice Who Are Ineligible for Randomized Clinical Trials

AU - Taipale, Heidi

AU - Schneider-Thoma, Johannes

AU - Pinzón-Espinosa, Justo

AU - Radua, Joaquim

AU - Efthimiou, Orestis

AU - Vinkers, Christiaan H.

AU - Mittendorfer-Rutz, Ellenor

AU - Cardoner, Narcís

AU - Pintor, Luis

AU - Tanskanen, Antti

AU - Tomlinson, Anneka

AU - Fusar-Poli, Paolo

AU - Cipriani, Andrea

AU - Vieta, Eduard

AU - Leucht, Stefan

AU - Tiihonen, Jari

AU - Luykx, Jurjen J.

N1 - Funding Information: Funding/Support: Dr Efthimiou was supported by Funding Information: reported grants and personal fee from Janssen Pharmaceuticals, grants from Eli Lilly and Company, and personal fees from Otsuka Pharmaceutical outside the submitted work. Dr Pinzón-Espinosa reported personal fees and nonfinancial support from Lundbeck, Angelini, Neuraxpharm, and Pfizer and nonfinancial support from Janssen Pharmaceuticals and Casen Recordati outside the submitted work. Dr Mittendorfer-Rutz reported grants from Janssen Pharmaceuticals outside the submitted work. Dr Cardoner has received grants and acted as a CME consultant, advisor, or speaker for the following entities in the last 5 years (all unrelated to the present work): Angelini, Esteve, Exeltis, Janssen Pharmaceuticals, Lundbeck, Novartis, Pfizer, and Servier. Dr Tanskanen reported other support from Janssen and Eli Lilly and Company outside the submitted work. Dr Tomlinson reported personal fees from INCiPiT (Italian Network for Paediatric Trials) and Angelini Pharma outside the submitted work. Dr Fusar-Poli reported personal fees from Lundbeck, Angelini Pharma, and Menarini outside the submitted work. Dr Cipriani reported personal fees from INCiPiT (Italian Network for Paediatric Trials) and CARIPLO Foundation and personal fees and grants from Angelini Pharma outside the submitted work. Dr Vieta reported grants from AB-Biotics, Ferrer, GlaxoSmithKline, Janssen Pharmaceuticals, and Sanofi-Aventis; personal fees from AbbVie, Aimentia, Angelini Pharma, Celon Pharma, Sumitomo Dainippon Pharma, Gedeon Richter, Janssen Pharmaceuticals, Organon, Otsuka Pharmaceutical, Sunovion, and Takeda; and received grants and served as consultant, advisor, or CME speaker from GH Research, Lundbeck, and Sage outside the submitted work. Dr Leucht reported personal fees from Alkermes, Angelini Pharma, Eisai, Gedeon Richter, Janssen Pharmaceuticals, Johnson & Johnson, Lundbeck, Medichem, Merck Sharp & Dohme, Otsuka Pharmaceutical, Casen Recordati, Rovi, Sandoz, Sanofi, Sunovion, Teva Pharmaceuticals, Boehringer Ingelheim, and LTS Lohmann outside the submitted work. Dr Tiihonen reported personal fees from Finnish Medicines Agency, European Medicines Agency, Eli Lilly and Company, Janssen-Cilag, Otsuka Pharmaceutical, and Lundbeck and grants from the Stanley Foundation and the Sigrid Jusélius Foundation outside the submitted work. No other disclosures were reported. Publisher Copyright: © 2022 Taipale H et al.

PY - 2022/3

Y1 - 2022/3

N2 - 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 = 17801) 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 20060 individuals (79%) with schizophrenia spectrum disorders would be ineligible for RCTs (Finnish cohort: 14221 of 17801 [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.

AB - 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 = 17801) 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 20060 individuals (79%) with schizophrenia spectrum disorders would be ineligible for RCTs (Finnish cohort: 14221 of 17801 [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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Representation and Outcomes of Individuals with Schizophrenia Seen in Everyday Practice Who Are Ineligible for Randomized Clinical Trials

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