Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium

Sophie E Smart¹, Deborah Agbedjro², Antonio F Pardiñas³, Olesya Ajnakina⁴, Luis Alameda⁵, Ole A Andreassen⁶, Thomas R E Barnes⁷, Domenico Berardi⁸, Sara Camporesi⁹, Martine Cleusix¹⁰, Philippe Conus¹¹, Benedicto Crespo-Facorro¹², Giuseppe D'Andrea⁸, Arsime Demjaha¹³, Marta Di Forti¹⁴, Kim Do¹⁰, Gillian Doody¹⁵, Chin B Eap¹⁶, Aziz Ferchiou¹⁷, Lorenzo Guidi¹⁸, Lina Homman¹⁹, Raoul Jenni¹⁰, Eileen Joyce²⁰, Laura Kassoumeri¹³, Ornella Lastrina¹⁸, Ingrid Melle⁶, Craig Morgan²¹, Francis A O'Neill²², Baptiste Pignon¹⁷, Romeo Restellini⁹, Jean-Romain Richard²³, Carmen Simonsen²⁴, Filip Španiel²⁵, Andrei Szöke¹⁷, Ilaria Tarricone¹⁸, Andrea Tortelli²⁶, Alp Üçok²⁷, Javier Vázquez-Bourgon²⁸, Robin M Murray¹³, James T R Walters³, Daniel Stahl², James H MacCabe²⁹

Affiliations

¹ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. Electronic address: SmartS1@cardiff.ac.uk.
² Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
³ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
⁴ Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Department of Behavioural Science and Health, Institute of Epidemiology and Health Care, University College London, London, UK.
⁵ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Centro de Investigacion en Red Salud Mental (CIBERSAM), Sevilla, Spain; Department of Psychiatry, Hospital Universitario Virgen del Rocio, IBiS, Universidad de Sevilla, Spain; TIPP (Treatment and Early Intervention in Psychosis Program), Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
⁶ Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁷ Division of Psychiatry, Imperial College London, UK.
⁸ Department of Biomedical and Neuro-motor Sciences, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Bologna, Italy.
⁹ TIPP (Treatment and Early Intervention in Psychosis Program), Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
¹⁰ Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
¹¹ TIPP (Treatment and Early Intervention in Psychosis Program), Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
¹² Centro de Investigacion en Red Salud Mental (CIBERSAM), Sevilla, Spain; Department of Psychiatry, Hospital Universitario Virgen del Rocio, IBiS, Universidad de Sevilla, Spain.
¹³ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹⁴ Social Genetics and Developmental Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.
¹⁵ Department of Medical Education, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, UK.
¹⁶ Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, Switzerland; School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland; Center for Research and Innovation in Clinical Pharmaceutical Sciences, University of Lausanne, Switzerland; Institute of Pharmaceutical Sciences of Western, Switzerland, University of Geneva, University of Lausanne.
¹⁷ Univ Paris Est Creteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Creteil, France; AP-HP, Hôpitaux Universitaires H. Mondor, DMU IMPACT, FHU ADAPT, Creteil, France.
¹⁸ Department of Medical and Surgical Sciences, Bologna Transcultural Psychosomatic Team (BoTPT), Alma Mater Studiorum - University of Bologna, Bologna, Italy.
¹⁹ Disability Research Division (FuSa), Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
²⁰ Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, UK.
²¹ Health Service and Population Research, King's College London, London, UK; Centre for Society and Mental Health, King's College London, London, UK.
²² Centre for Public Health, Institute of Clinical Sciences, Queens University Belfast, Belfast, UK.
²³ Univ Paris Est Creteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Creteil, France.
²⁴ Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Early Intervention in Psychosis Advisory Unit for South East Norway (TIPS Sør-Øst), Division of Mental Health and Addiction, Oslo University Hospital, Norway.
²⁵ Department of Applied Neuroscience and Neuroimaging, National Institute of Mental Health, Klecany, Czechia; Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague, Czechia.
²⁶ Univ Paris Est Creteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Creteil, France; Groupe Hospitalier Universitaire Psychiatrie Neurosciences Paris, Pôle Psychiatrie Précarité, Paris, France.
²⁷ Istanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey.
²⁸ Centro de Investigacion en Red Salud Mental (CIBERSAM), Sevilla, Spain; Department of Psychiatry, University Hospital Marques de Valdecilla - Instituto de Investigación Marques de Valdecilla (IDIVAL), Santander, Spain; Department of Medicine and Psychiatry, School of Medicine, University of Cantabria, Santander, Spain.
²⁹ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.

PMID: 36242784
PMCID: PMC9834064
DOI: 10.1016/j.schres.2022.09.009

Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium

Sophie E Smart et al. Schizophr Res. 2022 Dec.

. 2022 Dec:250:1-9.

doi: 10.1016/j.schres.2022.09.009. Epub 2022 Oct 12.

Authors

Affiliations

¹ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. Electronic address: SmartS1@cardiff.ac.uk.
² Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
³ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
⁴ Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Department of Behavioural Science and Health, Institute of Epidemiology and Health Care, University College London, London, UK.
⁵ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Centro de Investigacion en Red Salud Mental (CIBERSAM), Sevilla, Spain; Department of Psychiatry, Hospital Universitario Virgen del Rocio, IBiS, Universidad de Sevilla, Spain; TIPP (Treatment and Early Intervention in Psychosis Program), Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
⁶ Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁷ Division of Psychiatry, Imperial College London, UK.
⁸ Department of Biomedical and Neuro-motor Sciences, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Bologna, Italy.
⁹ TIPP (Treatment and Early Intervention in Psychosis Program), Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
¹⁰ Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
¹¹ TIPP (Treatment and Early Intervention in Psychosis Program), Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
¹² Centro de Investigacion en Red Salud Mental (CIBERSAM), Sevilla, Spain; Department of Psychiatry, Hospital Universitario Virgen del Rocio, IBiS, Universidad de Sevilla, Spain.
¹³ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹⁴ Social Genetics and Developmental Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.
¹⁵ Department of Medical Education, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, UK.
¹⁶ Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, Switzerland; School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland; Center for Research and Innovation in Clinical Pharmaceutical Sciences, University of Lausanne, Switzerland; Institute of Pharmaceutical Sciences of Western, Switzerland, University of Geneva, University of Lausanne.
¹⁷ Univ Paris Est Creteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Creteil, France; AP-HP, Hôpitaux Universitaires H. Mondor, DMU IMPACT, FHU ADAPT, Creteil, France.
¹⁸ Department of Medical and Surgical Sciences, Bologna Transcultural Psychosomatic Team (BoTPT), Alma Mater Studiorum - University of Bologna, Bologna, Italy.
¹⁹ Disability Research Division (FuSa), Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
²⁰ Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, UK.
²¹ Health Service and Population Research, King's College London, London, UK; Centre for Society and Mental Health, King's College London, London, UK.
²² Centre for Public Health, Institute of Clinical Sciences, Queens University Belfast, Belfast, UK.
²³ Univ Paris Est Creteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Creteil, France.
²⁴ Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Early Intervention in Psychosis Advisory Unit for South East Norway (TIPS Sør-Øst), Division of Mental Health and Addiction, Oslo University Hospital, Norway.
²⁵ Department of Applied Neuroscience and Neuroimaging, National Institute of Mental Health, Klecany, Czechia; Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague, Czechia.
²⁶ Univ Paris Est Creteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Creteil, France; Groupe Hospitalier Universitaire Psychiatrie Neurosciences Paris, Pôle Psychiatrie Précarité, Paris, France.
²⁷ Istanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey.
²⁸ Centro de Investigacion en Red Salud Mental (CIBERSAM), Sevilla, Spain; Department of Psychiatry, University Hospital Marques de Valdecilla - Instituto de Investigación Marques de Valdecilla (IDIVAL), Santander, Spain; Department of Medicine and Psychiatry, School of Medicine, University of Cantabria, Santander, Spain.
²⁹ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.

PMID: 36242784
PMCID: PMC9834064
DOI: 10.1016/j.schres.2022.09.009

Abstract

Introduction: Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR.

Methods: We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction.

Results: Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %).

Implications: Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR.

Keywords: First episode psychosis; Machine learning; Prediction modelling; Prospective longitudinal cohort; Stratification; Treatment resistant schizophrenia.

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Conflict of interest statement

Declaration of competing interest The Authors declare no Competing Non-Financial Interests but the following Competing Financial Interests: J.T.R.W. is an investigator on a grant from Takeda Pharmaceuticals Ltd. to Cardiff University, for a project unrelated to the work presented here. S.E.S. is employed on this grant. M.D.F. has received a fee for educational seminars from Lundbeck and Janssen. O.A.A. is a consultant to HealthLytix and has received speakers honorarium from Lundbeck and Sunovion. T.R.E.B. has been a member of an advisory board for Gedeon Richter. C.B.E. received honoraria for conferences from Forum pour la formation médicale, Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Sysmex Suisse AG, Takeda, Vifor-Pharma, and Zeller in the past 3 years. B.C.F. has received honoraria for participation as a consultant and/or as a speaker at educational events from ADAMED, Mylan, Angelini, Janssen Johnson & Johnson, Lundbeck, and Otsuka Pharmaceuticals. R.M.M. has received payments for non-promotional lectures from Janssen, Otsuka, Sunovian, and Lundbeck. J.H.M. has received research funding from H Lundbeck.

References

1. Ajnakina O., Agbedjro D., Lally J., Forti M.D., Trotta A., Mondelli V., Pariante C., Dazzan P., Gaughran F., Fisher H.L., David A., Murray R.M., Stahl D. Predicting onset of early- and late-treatment resistance in first-episode schizophrenia patients using advanced shrinkage statistical methods in a small sample. Psychiatry Res. 2020;294 - PubMed
1. Albert N., Bertelsen M., Thorup A., Petersen L., Jeppesen P., Le Quack P., Krarup G., Jorgensen P., Nordentoft M. Predictors of recovery from psychosis analyses of clinical and social factors associated with recovery among patients with first-episode psychosis after 5 years. Schizophr. Res. 2011;125(2–3):257–266. - PubMed
1. Andrews A., Knapp M., McCrone P., Parsonage M., Trachtenberg M. 2012. Effective Interventions in Schizophrenia: The Economic Case. A Report Prepared for the Schizophrenia Commission. Rethink Mental Illness, London.
1. Austin P.C., Steyerberg E.W. Events per variable (EPV) and the relative performance of different strategies for estimating the out-of-sample validity of logistic regression models. Stat. Methods Med. Res. 2017;26(2):796–808. - PMC - PubMed
1. Azur M.J., Stuart E.A., Frangakis C., Leaf P.J. Multiple imputation by chained equations: what is it and how does it work? Int. J. Methods Psychiatr. Res. 2011;20(1):40–49. - PMC - PubMed

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Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium

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Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium

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Abstract

Conflict of interest statement

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