Relapse in Schizophrenia: A Systematic Review of Criteria for Clinical Studies and International Consensus Guidelines to Improve Them

Oliver D Howes^{1

2}, Bernard R Bukala¹, Eric Y H Chen³, Christoph U Correll^{4

5}, Alkomiet Hasan^{6

7}, William G Honer^{8

9}, John M Kane^{10

11

12}, Stefan Leucht^{13

14}, Spyridon Siafis^{13

14}, Ofer Agid¹⁵, Dickens Akena¹⁶, Celso Arango¹⁷, Lukoye Atwoli¹⁸, Thomas R E Barnes¹⁹, Michael L Birnbaum²⁰, Istvan Bitter²¹, Alan Breier²², Robert W Buchanan²³, Leslie Citrome²⁴, David R Cotter²⁵, Nicolas Crossley²⁶, Michael Davidson^{27

28}, Andrea de Bartolomeis²⁹, Lynn E DeLisi³⁰, Sonia Dollfus³¹, Serdar M Dursun³², Bjørn H Ebdrup^{33

34}, Helio Elkis³⁵, Robin Emsley³⁶, Peter Falkai³⁷, Emilio Fernández-Egea³⁸, Wolfgang Fleischhacker^{39

40}, Oliver Freudenreich⁴¹, Ary Gadelha⁴², Wolfgang Gaebel⁴³, Ariel Graff-Guerrero⁴⁴, Ad Gridley¹, Jaime E C Hallak⁴⁵, Philipp Homan⁴⁶, René S Kahn⁴⁷, Stefan Kaiser⁴⁸, Maria Kapi¹, James L Kennedy^{49

50}, Euitae Kim⁵¹, Bruce J Kinon⁵², Jun Soo Kwon⁵¹, Stephen M Lawrie⁵³, Jimmy Lee⁵⁴, F Markus Leweke^{55

56}, Tao Li⁵⁷, Jan Libiger⁵⁸, Stephen R Marder⁵⁹, Ingrid Melle⁶⁰, Herbert Meltzer⁶¹, Armida Mucci⁶², Dieter Naber⁶³, Shinchiro Nakajima⁶⁴, Jimmi Nielsen^{65

66}, Oisín O'Brien¹, Akin Ojagbemi⁶⁷, Wolfgang Omlor⁴⁶, Christos Pantelis^{68

69

70}, Jozef Peuskens⁷¹, Thomas J Raedler⁷², Mao-Sheng Ran⁷³, Tiago Reis Marques^{1

2

74}, Gary Remington¹⁵, Susan Rossell⁷⁵, Jose M Rubio¹², Gabriele Sachs⁷⁶, James Scott¹, Tianmei Si⁷⁷, Dan Siskind⁷⁸, Cynthia O Siu⁷⁹, Iris E Sommer⁸⁰, Takefumi Suzuki⁸¹, Hiroyoshi Takeuchi⁶⁴, Rajiv Tandon⁸², David Taylor^{83

84}, Solomon Teferra⁸⁵, Neil Thomas⁷⁵, Jari Tiihonen^{86

87

88}, Hiroyoki Uchida⁶⁴, Alp Ucok⁸⁹, Daniel Umbricht⁹⁰, Ganesan Venkatasubramanian⁹¹, Elias Wagner^{6

92}, James T R Walters⁹³, Chuanyue Wang⁹⁴, Mark Weiser^{95

96}, Charlie Wright¹, Xin Yu⁷⁷, Robert A McCutcheon^{1

97

98}

Affiliations

¹ King's College London, London.
² Imperial College London, Hammersmith Hospital, London.
³ Institute of Mental Health, LKC School of Medicine, Nanyang Technological University, Singapore.
⁴ Charité Universitätsmedizin, Berlin.
⁵ Zucker Hillside Hospital, New York.
⁶ Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Augsburg, Augsburg, Germany.
⁷ DZPG (German Center for Mental Health), partner site München/Augsburg, Augsburg, Germany.
⁸ Department of Psychiatry, University of British Columbia, Vancouver.
⁹ British Columbia Mental Health and Substance Use Services Research Institute, Vancouver.
¹⁰ Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY.
¹¹ Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY.
¹² Institute of Behavioral Sciences, Feinstein Institute for Medical Research, Northwell Health, New Hyde Park, NY.
¹³ Department of Psychiatry and Psychotherapy, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.
¹⁴ German Center for Mental Health, partner site München/Augsburg, Augsburg, Germany.
¹⁵ Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto.
¹⁶ Department of Psychiatry, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
¹⁷ Institute of Psychiatry and Mental Health, Department of Child and Adolescent Psychiatry, Hospital General Universitario G. Marañón, School of Medicine, Universidad Complutense, CIBERSAM, Madrid.
¹⁸ Medical College East Africa, Aga Khan University and Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
¹⁹ Division of Psychiatry, Imperial College London, London.
²⁰ Department of Behavioral Health Services and Policy Research, New York State Psychiatric Institute, New York.
²¹ Department of Psychiatry, Semmelweis University, Budapest.
²² Indiana University School of Medicine, Indianapolis.
²³ Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore.
²⁴ Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla.
²⁵ Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin.
²⁶ Department of Psychiatry, Pontificia Universidad Católica de Chile, Santiago.
²⁷ Department of Basic and Clinical Sciences, Psychiatry, University of Nicosia Medical School, Nicosia, Cyprus.
²⁸ Minerva Neurosciences, Burlington, MA.
²⁹ Clinical Section on Psychiatry and Psychology, Unit of Treatment Resistant Psychosis, Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University of Naples Federico II, Naples.
³⁰ Department of Psychiatry, Cambridge Health Alliance, Harvard Medical School, Boston.
³¹ Caen Normandie University, Caen, France.
³² Department of Psychiatry, University of Alberta, Edmonton, Canada.
³³ Center for Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, Copenhagen University Hospital-Mental Health Services, Copenhagen.
³⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen.
³⁵ Department and Institute of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil.
³⁶ Department of Psychiatry, Stellenbosch University, Cape Town, South Africa.
³⁷ Department of Psychiatry and Psychotherapy, Munich University Hospital, Munich.
³⁸ Cambridge Psychosis Centre, Cambridgeshire and Peterborough NHS Foundation Trust and Department of Psychiatry, University of Cambridge, Cambridge, UK.
³⁹ Medizinische Universität Innsbruck, Innsbruck, Austria.
⁴⁰ Department of Psychiatry, Weill Cornell Medicine, New York.
⁴¹ Department of Psychiatry, Massachusetts General Hospital, Boston.
⁴² Department of Psychiatry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
⁴³ WHO Collaborating Centre DEU-131, LVR-Klinikum Düsseldorf, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
⁴⁴ Department of Psychiatry, University of Toronto, Toronto.
⁴⁵ Neuroscience and Behavioral Sciences Department, Ribeirao Preto Medical School, University of São Paulo, Brazil.
⁴⁶ Department of Adult Psychiatry and Psychotherapy, University of Zurich, Zurich.
⁴⁷ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York.
⁴⁸ Department of Psychiatry, Geneva University Hospitals, Geneva.
⁴⁹ Molecular Brain Science Department, University of Toronto, Toronto.
⁵⁰ Tanenbaum Centre for Pharmacogenetics, Centre for Addiction and Mental Health, University of Toronto, Toronto.
⁵¹ Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea.
⁵² Biopharmaceutical consultant, Mineola, NY.
⁵³ Division of Psychiatry, University of Edinburgh, Edinburgh.
⁵⁴ North Region, Institute of Mental Health, Singapore and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁵⁵ Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
⁵⁶ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁵⁷ Affiliated Mental Health Center and Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁵⁸ Department of Psychiatry, Charles University Prague, Medical Faculty and Faculty Hospital in Hradec Králové, Czech Republic.
⁵⁹ Semel Institute for Neuroscience at UCLA and VA Desert Pacific Mental Illness Research, Education, and Clinical Center, Los Angeles.
⁶⁰ Department of Adult Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo.
⁶¹ Feinberg School of Medicine, Northwestern University, Chicago.
⁶² Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples.
⁶³ Department of Psychiatry and Psychotherapy, University of Hamburg, Hamburg, Germany.
⁶⁴ Department of Neuropsychiatry, Keio University School of Medicine, Tokyo.
⁶⁵ Unit for Complicated Schizophrenia, Mental Health Centre Glostrup, Copenhagen.
⁶⁶ Copenhagen University Hospital, Copenhagen University, Copenhagen.
⁶⁷ Department of Psychiatry, University of Ibadan College of Medicine, Ibadan, Nigeria.
⁶⁸ Department of Psychiatry, University of Melbourne and Melbourne Health, Parkville, Australia.
⁶⁹ Western Centre for Health Research and Education, University of Melbourne and Western Health, Sunshine Hospital, St Albans, Australia.
⁷⁰ Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
⁷¹ Division of Psychiatry at KU Leuven and University Psychiatric Hospital KU Leuven, Belgium.
⁷² Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Canada.
⁷³ Department of Social Psychiatry, Mental Health Center, West China Hospital, Sichuan University, Chengdu.
⁷⁴ Pasithea Therapeutics, Miami Beach, FL.
⁷⁵ Centre for Mental Health and Brain Sciences, Swinburne University of Technology, Melbourne.
⁷⁶ Medical University of Vienna, Vienna.
⁷⁷ Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders Peking University Sixth Hospital, Beijing.
⁷⁸ Faculty of Medicine, University of Queensland and Addiction and Mental Health Service, Metro South Health, Brisbane, Australia.
⁷⁹ Data Science Toronto, Toronto.
⁸⁰ Department of Biomedical Sciences, University Medical Center Groningen, Groningen, Netherlands.
⁸¹ Department of Neuropsychiatry, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
⁸² Department of Psychiatry, Homer Stryker Western Michigan University College of Medicine, Kalamazoo.
⁸³ Institute of Pharmaceutical Sciences, King's College London, London.
⁸⁴ Pharmacy Department, South London and Maudsley NHS Foundation Trust, Denmark Hill, London.
⁸⁵ Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Ethiopia.
⁸⁶ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm.
⁸⁷ Center for Psychiatry Research, Stockholm City Council, Stockholm.
⁸⁸ Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio.
⁸⁹ Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey.
⁹⁰ Xperimed LLC, Basel, Switzerland.
⁹¹ Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, India.
⁹² Evidence-Based Psychiatry and Psychotherapy, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
⁹³ Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales.
⁹⁴ Beijing Anding Hospital, Capital Medical University, Beijing.
⁹⁵ Zachai Division of Psychiatry, Sheba Medical Center, Ramat-Gan, Israel.
⁹⁶ Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel.
⁹⁷ Department of Psychiatry, University of Oxford, Oxford, UK.
⁹⁸ Oxford Health NHS Foundation Trust, Oxford, UK.

PMID: 41058236
DOI: 10.1176/appi.ajp.20241040

Relapse in Schizophrenia: A Systematic Review of Criteria for Clinical Studies and International Consensus Guidelines to Improve Them

Oliver D Howes et al. Am J Psychiatry. 2025.

. 2025 Oct 8:appiajp20241040.

doi: 10.1176/appi.ajp.20241040. Online ahead of print.

Authors

Affiliations

¹ King's College London, London.
² Imperial College London, Hammersmith Hospital, London.
³ Institute of Mental Health, LKC School of Medicine, Nanyang Technological University, Singapore.
⁴ Charité Universitätsmedizin, Berlin.
⁵ Zucker Hillside Hospital, New York.
⁶ Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Augsburg, Augsburg, Germany.
⁷ DZPG (German Center for Mental Health), partner site München/Augsburg, Augsburg, Germany.
⁸ Department of Psychiatry, University of British Columbia, Vancouver.
⁹ British Columbia Mental Health and Substance Use Services Research Institute, Vancouver.
¹⁰ Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY.
¹¹ Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY.
¹² Institute of Behavioral Sciences, Feinstein Institute for Medical Research, Northwell Health, New Hyde Park, NY.
¹³ Department of Psychiatry and Psychotherapy, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.
¹⁴ German Center for Mental Health, partner site München/Augsburg, Augsburg, Germany.
¹⁵ Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto.
¹⁶ Department of Psychiatry, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
¹⁷ Institute of Psychiatry and Mental Health, Department of Child and Adolescent Psychiatry, Hospital General Universitario G. Marañón, School of Medicine, Universidad Complutense, CIBERSAM, Madrid.
¹⁸ Medical College East Africa, Aga Khan University and Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
¹⁹ Division of Psychiatry, Imperial College London, London.
²⁰ Department of Behavioral Health Services and Policy Research, New York State Psychiatric Institute, New York.
²¹ Department of Psychiatry, Semmelweis University, Budapest.
²² Indiana University School of Medicine, Indianapolis.
²³ Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore.
²⁴ Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla.
²⁵ Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin.
²⁶ Department of Psychiatry, Pontificia Universidad Católica de Chile, Santiago.
²⁷ Department of Basic and Clinical Sciences, Psychiatry, University of Nicosia Medical School, Nicosia, Cyprus.
²⁸ Minerva Neurosciences, Burlington, MA.
²⁹ Clinical Section on Psychiatry and Psychology, Unit of Treatment Resistant Psychosis, Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University of Naples Federico II, Naples.
³⁰ Department of Psychiatry, Cambridge Health Alliance, Harvard Medical School, Boston.
³¹ Caen Normandie University, Caen, France.
³² Department of Psychiatry, University of Alberta, Edmonton, Canada.
³³ Center for Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, Copenhagen University Hospital-Mental Health Services, Copenhagen.
³⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen.
³⁵ Department and Institute of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil.
³⁶ Department of Psychiatry, Stellenbosch University, Cape Town, South Africa.
³⁷ Department of Psychiatry and Psychotherapy, Munich University Hospital, Munich.
³⁸ Cambridge Psychosis Centre, Cambridgeshire and Peterborough NHS Foundation Trust and Department of Psychiatry, University of Cambridge, Cambridge, UK.
³⁹ Medizinische Universität Innsbruck, Innsbruck, Austria.
⁴⁰ Department of Psychiatry, Weill Cornell Medicine, New York.
⁴¹ Department of Psychiatry, Massachusetts General Hospital, Boston.
⁴² Department of Psychiatry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
⁴³ WHO Collaborating Centre DEU-131, LVR-Klinikum Düsseldorf, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
⁴⁴ Department of Psychiatry, University of Toronto, Toronto.
⁴⁵ Neuroscience and Behavioral Sciences Department, Ribeirao Preto Medical School, University of São Paulo, Brazil.
⁴⁶ Department of Adult Psychiatry and Psychotherapy, University of Zurich, Zurich.
⁴⁷ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York.
⁴⁸ Department of Psychiatry, Geneva University Hospitals, Geneva.
⁴⁹ Molecular Brain Science Department, University of Toronto, Toronto.
⁵⁰ Tanenbaum Centre for Pharmacogenetics, Centre for Addiction and Mental Health, University of Toronto, Toronto.
⁵¹ Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea.
⁵² Biopharmaceutical consultant, Mineola, NY.
⁵³ Division of Psychiatry, University of Edinburgh, Edinburgh.
⁵⁴ North Region, Institute of Mental Health, Singapore and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁵⁵ Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
⁵⁶ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁵⁷ Affiliated Mental Health Center and Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁵⁸ Department of Psychiatry, Charles University Prague, Medical Faculty and Faculty Hospital in Hradec Králové, Czech Republic.
⁵⁹ Semel Institute for Neuroscience at UCLA and VA Desert Pacific Mental Illness Research, Education, and Clinical Center, Los Angeles.
⁶⁰ Department of Adult Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo.
⁶¹ Feinberg School of Medicine, Northwestern University, Chicago.
⁶² Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples.
⁶³ Department of Psychiatry and Psychotherapy, University of Hamburg, Hamburg, Germany.
⁶⁴ Department of Neuropsychiatry, Keio University School of Medicine, Tokyo.
⁶⁵ Unit for Complicated Schizophrenia, Mental Health Centre Glostrup, Copenhagen.
⁶⁶ Copenhagen University Hospital, Copenhagen University, Copenhagen.
⁶⁷ Department of Psychiatry, University of Ibadan College of Medicine, Ibadan, Nigeria.
⁶⁸ Department of Psychiatry, University of Melbourne and Melbourne Health, Parkville, Australia.
⁶⁹ Western Centre for Health Research and Education, University of Melbourne and Western Health, Sunshine Hospital, St Albans, Australia.
⁷⁰ Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
⁷¹ Division of Psychiatry at KU Leuven and University Psychiatric Hospital KU Leuven, Belgium.
⁷² Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Canada.
⁷³ Department of Social Psychiatry, Mental Health Center, West China Hospital, Sichuan University, Chengdu.
⁷⁴ Pasithea Therapeutics, Miami Beach, FL.
⁷⁵ Centre for Mental Health and Brain Sciences, Swinburne University of Technology, Melbourne.
⁷⁶ Medical University of Vienna, Vienna.
⁷⁷ Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders Peking University Sixth Hospital, Beijing.
⁷⁸ Faculty of Medicine, University of Queensland and Addiction and Mental Health Service, Metro South Health, Brisbane, Australia.
⁷⁹ Data Science Toronto, Toronto.
⁸⁰ Department of Biomedical Sciences, University Medical Center Groningen, Groningen, Netherlands.
⁸¹ Department of Neuropsychiatry, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
⁸² Department of Psychiatry, Homer Stryker Western Michigan University College of Medicine, Kalamazoo.
⁸³ Institute of Pharmaceutical Sciences, King's College London, London.
⁸⁴ Pharmacy Department, South London and Maudsley NHS Foundation Trust, Denmark Hill, London.
⁸⁵ Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Ethiopia.
⁸⁶ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm.
⁸⁷ Center for Psychiatry Research, Stockholm City Council, Stockholm.
⁸⁸ Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio.
⁸⁹ Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey.
⁹⁰ Xperimed LLC, Basel, Switzerland.
⁹¹ Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, India.
⁹² Evidence-Based Psychiatry and Psychotherapy, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
⁹³ Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales.
⁹⁴ Beijing Anding Hospital, Capital Medical University, Beijing.
⁹⁵ Zachai Division of Psychiatry, Sheba Medical Center, Ramat-Gan, Israel.
⁹⁶ Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel.
⁹⁷ Department of Psychiatry, University of Oxford, Oxford, UK.
⁹⁸ Oxford Health NHS Foundation Trust, Oxford, UK.

PMID: 41058236
DOI: 10.1176/appi.ajp.20241040

Abstract

Objective: Relapse prevention is a major goal of schizophrenia treatment. However, there is no standard definition of relapse. To address this, the authors reviewed recent approaches and developed consensus criteria to operationally define relapse.

Methods: To evaluate current criteria, a systematic review was performed of randomized controlled trials of relapse conducted from 2012 to 2024. To develop consensus criteria, the authors used a multiphase Delphi approach involving over 100 experts from 37 countries, including people with lived experience of relapse.

Results: The review showed only two pairs of studies that used the same criteria. Clinical judgment alone was sufficient to define relapse in 85% of studies, and 58% used relative symptom change. The recommended criteria cover the pre-baseline, baseline, and relapse components with optimum and minimum criteria and provide a reporting checklist. The recommendations include using standardized, validated measures that can be applied across settings, and using absolute symptom change. The authors also identify criteria that should not be used and make reporting recommendations, including for specific symptom domains (positive, negative, or cognitive) and across symptom domains, hospitalization, home treatment, and risky, violent, or suicidal behavior.

Conclusions: There are limitations and heterogeneity in current definitions of relapse, which limit study comparisons, potentially bias meta-analyses, and question the validity of some studies. Adopting the consensus recommendations for a standardized approach should improve the validity and reliability of study outcomes, facilitate cross-study comparisons, and also standardize research into risk factors for relapse.

Keywords: Academic Psychiatry; Clinical Drug Studies; Research Design and Methods; Schizophrenia Spectrum and Other Psychotic Disorders.

PubMed Disclaimer

Conflict of interest statement

Dr. Howes has received investigator-initiated research funding from and/or participated in advisory or speaker meetings organized by AbbVie, Alkermes, Angelini, Autifony, Biogen, Boehringer Ingelheim, Bristol Meyers Squibb (Karuna), Clinical Ink, Delix, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Janssen, Karuna, Lundbeck, Merck, Neumora, Neurocrine, Ono, Ontrack/Pangea, Otsuka, Sunovion, Teva, Recordati, Roche, Rovi, and Viatris/Mylan; he was previously a part-time employee of Lundbeck. Dr. Bukala has served as a consultant for Candesic and Relation Therapeutics. Dr. Chen has received honoraria and lecture fees from Johnson & Johnson, Osuka, and Sumitomo, and he has received investigator-initiated research support from Johnson & Johnson. Dr. Correll has served a consultant and/or adviser for or has received honoraria from AbbVie, Acadia, Adcock Ingram, Alkermes, Allergan, Angelini, Aristo, Autobahn, Biogen, 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, Intra-Cellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, Medincell, MedLink, Merck, Mindpax, Mitsubishi Tanabe Pharma, MapLight, Mylan, Neumora Therapeutics, Neuraxpharm, Neurelis, Neurocrine, NeuShen, Newron, Noven, Novo Nordisk, Orion Pharma, Otsuka, PPD Biotech, Recognify Life Science, Recordati, Relmada, Response Pharmaceutical, Reviva, Rovi, Sage, Saladax, Sanofi, Seqirus, Servier, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Terran, Teva, Tolmar, Vertex, Viatris, and Xenon Pharmaceuticals; he has provided expert testimony for Janssen, Lundbeck, Neurocrine, and Otsuka; he has served on data safety monitoring boards for Compass Pathways, Denovo, Intra-Cellular Therapies, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; he has received grant support from Boehringer Ingelheim, Janssen, and Takeda; he has received royalties from UpToDate; and he holds stock options in Cardio Diagnostics, Kuleon Biosciences, LB Pharma, MedLink Global, Mindpax, Quantic, and Terran. Dr. Hasan has served as a consultant for AbbVie, Angelini, Boehringer Ingelheim, Lundbeck, and Otsuka; he has served as an advisory board member for and/or received speakerships from AbbVie, Advanz, Boehringer Ingelheim, Janssen, Lundbeck, Otsuka, Recordati, and Rovi; and he is the editor of the German schizophrenia guideline. Dr. Honer has served as a consultant for AbbVie, Bausch Health, Boehringer Ingelheim, Newron, and Translational Life Sciences. Dr. Kane has served as a consultant or speaker for or received honoraria and/or travel support from AbbVie, Alkermes, Allergan, Boehringer Ingelheim, Bristol Meyers Squibb, Cerevel, Dainippon Sumitomo, Lundbeck, HealthRhythms, HLS Therapeutics, Indivior, Intra-Cellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, Karuna Therapeutics/Bristol Meyers Squibb, LB Pharmaceuticals, Mapi, MapLight, Merck, Minerva, Neurocrine, Newron, Novartis, NW PharmaTech, Otsuka, Roche, Saladax, Sunovion, and Teva; he has served on advisory boards for AbbVie, Alkermes, Boehringer Ingelheim, Cerevel, Click Therapeutics, Karuna/Bristol Meyers Squibb, Lundbeck, Merck, Newron, Novartis, Otsuka, Sumitomo, Teva, and Terran; he has received grant support from Janssen, Lundbeck, Otsuka, and Sunovion; he is a shareholder and/or holds stock options in Cerevel, HealthRhythms, Karuna/BMS, LB Pharmaceuticals, Medincell, North Shore Therapeutics, NW PharmaTech, Saladax, Reviva, Terran, and Vanguard Research Group; and he receives royalties from UpToDate. Dr. Leucht has served as an adviser, consultant, and/or provided lectures or educational material for Angelini, Apsen, Boehringer Ingelheim, Eisai, Ekademia, Gedeon Richter, Janssen, Karuna, Kynexis, Lundbeck, Medscape, Neurotorium, Novo Nordisk, Orion Pharma, Otsuka, Roche, Rovi, and TEVA. Dr. Agid has served as a consultant, adviser, advisory board member, and/or speaker for Allergan/AbbVie, HLS Therapeutics, Janssen-Ortho (Johnson & Johnson), Lundbeck, Mylan/Viatris, Newron, Otsuka, and Teva; and he has had research contracts with Boehringer Ingelheim, Janssen-Ortho (Johnson & Johnson), Lundbeck, and Otsuka. Dr. Arango has served as a consultant for or received honoraria or grants from Abbott, Acadia, Ambrosetti, Amgen, Angelini, AstraZeneca, Biogen, Boehringer, Bristol Myers Squibb, Caja Navarra, Carnot, CIBERSAM, Fundación Alicia Koplowitz, Forum, Instituto de Salud Carlos III, Gedeon Richter, Janssen-Cilag, Lundbeck, Medscape, Menarini, Merck, Minerva, Ministerio de Ciencia e Innovación, Ministerio de Sanidad, Ministerio de Economía y Competitividad, Mutua Madrileña, Otsuka, Pfizer, Roche, Rovi, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, Takeda, and Teva. Dr. Bitter has served as consultant for Gedeon Richter, Janssen/Johnson & Johnson, and Newron; he has served as a speaker for Gedeon Richter, Janssen/Janssen-Cilag/Johnson & Johnson, KRKA, Lundbeck, and Medichem Pharmaceuticals (Unilab); and he has received a research grant from Gedeon Richter and royalties from Oxford University Press. Dr. Breier has served as a consultant for Clexio, Bristol Meyers Squibb, Neumarker Bioscience, and Terran Therapeutics. Dr. Buchanan has served as a consultant for Boehringer-Ingelheim; he has served on data safety and monitoring boards for Merck, Newron, and Roche; and he has served on advisory boards for Acadia, Karuna, Merck, and Neurocrine. Dr. Citrome has served as a consultant for AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Autobahn, Avanir, Axsome, Biogen, BioXcel, Boehringer Ingelheim, Bristol Myers Squibb, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Delpor, Draig Therapeutics, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Luye, Lyndra, MapLight, Marvin, MedAvante-ProPhase, Merck, Mitsubishi-Tanabe Pharma, Neumora, Neurocrine, Neurelis, Noema, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sumitomo/Sunovion, Supernus, Teva, University of Arizona, Vanda, and Wells Fargo, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research; he has served as a speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Bristol Myers Squibb, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neopharm, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, Teva, and Vanda, and in CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and universities and professional organizations/societies; he is a stockholder in Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, and Pfizer and has stock options in Reviva; and he has earned royalties or publishing income from Taylor & Francis (Editor-in-Chief, Current Medical Research and Opinion), UpToDate (reviewer), Springer Healthcare (book), Elsevier (topic editor, Psychiatry, Clinical Therapeutics). Dr. Davidson is an employee of Minerva Neurosciences. Dr. de Bartolomeis has received grants/research support from Janssen, Eli Lilly, Lundbeck, Otsuka, and Pfizer; he has received honoraria or consultation fees from Gedeon Richter, Janssen, Lundbeck, Mylan, Newron, Otsuka, Recordati, Roche, Takeda, and Viatris; and he has participated in company-sponsored speakers bureau for Angelini, Chiesi, Gedeon Richter, Ikma, Janssen, Lundbeck, Otsuka, Roche, Rovi, Tabuk, Takeda-Sunovion, and Viatris. Dr. Dollfus has served as a consultant for Clarivate Analytics, and he has received honoraria for conferences from Janssen, Lundbeck, and Otsuka. Dr. Ebdrup has served on advisory boards for Boehringer Ingelheim, Lundbeck, and Orion, and he has received lecture fees from Boehringer Ingelheim, Lundbeck, and Otsuka Pharma Scandinavia AB. Dr. Elkis has served as an advisory board member or speaker for ADIUM, Boehringer Ingelheim, Cristália, Janssen, and Teva. Dr. Emsley has served as a speaker and/or on advisory boards and received honoraria from Janssen, Lundbeck, and Otsuka. Dr. Falkai has received research support or honoraria for lectures or advisory activities from Boehringer Ingelheim, Janssen, Lundbeck, Otsuka, Recordati, and Richter. Dr. Fernández-Egea has served as a consultant for Atheneum, Boehringer Ingelheim, and Rovi and as a speaker for Adamed, Otsuka, and Viatris, and he has received training and editorial honoraria from Spanish Society of Psychiatry and Mental Health. Dr. Fleischhacker has served as a speaker for Forum für medizinische Fortbildung and Sumitomo Pharma, and he has received grant support from Lundbeck and Otsuka. Dr. Freudenreich has received research funding from and served as an advisory board member for Karuna; he has served as a consultant for APA, Karuna, Medscape, the National Council for Mental Wellbeing, Neurocrine, and Vida; and has served as a speaker for Medscape and the Psychopharmacology Institute. Dr. Gadelha has received a research grant from FAPESP (São Paulo’s Research Support Foundation) and has served as a consultant or adviser or received honoraria from Aché, Adium, Boehringer Ingelheim, Cristália, Daiichi Sankyo, EMS, Janssen, Lundbeck, Mantecorp-Hypera, and Teva. Dr. Homan has received grants and honoraria from Boehringer Ingelheim, Janssen, Lundbeck, Mepha, Neurolite, Novartis, and OM Pharma. Dr. Kahn has served as a consultant for Alkermes, Boehringer, and Merck. Dr. Kaiser has served on advisory boards for Boehringer Ingelheim and Exeltis and has received royalties from Schuhfried for cognitive test and training software. Dr. Kapi is an employee of Otsuka Pharmaceutical Europe Ltd. Dr. Kennedy has served as a scientific advisory board member for Myriad Neuroscience, and he is an author on several patents related to pharmacogenetic testing in psychiatry. Dr. Kim has participated in advisory or speaker meetings organized by Boehringer Ingelheim, Bukwang Pharm Company, Janssen Korea, and Otsuka Korea and served as principal investigator of research projects from Otsuka. Dr. Kinon is an employee of MycoMedica Life Sciences and a former employee of Cyclerion Therapeutics, and Karuna Therapeutics, and he holds equity in AbbVie, Acadia, Bristol Myers Squibb, Corcept, and Eli Lilly. Dr. Lee has received honoraria from or served as a consultant or advisory board member for Boehringer Ingelheim, Janssen, Lundbeck, Otsuka, Singapore Deep-Tech Alliance, Sumitomo Pharmaceuticals, and ThoughtFull World. Dr. Leweke has received an investigator-initiated trial grant from Endosane Pharmaceuticals, and he is a shareholder in and part-time employee of Curantis UG and Endosane Pharmaceuticals. Dr. Marder has received research support from Boehringer Ingelheim, and he has served as a consultant for Boehringer Ingelheim, Karuna, Merck, Newron, Otsuka, Sunovion, and Syneos. Dr. Mucci has served as a consultant or advisory board member for Angelini, Boehringer Ingelheim, and Rovi Pharma. Dr. Nakajima has received grants from the Japan Society for the Promotion of Science (18H02755, 22H03002), the Japan Agency for Medical Research and Development, the Japan Research Foundation for Clinical Pharmacology, the Naito Foundation, the Takeda Science Foundation, the Uehara Memorial Foundation, the Watanabe Foundation, the Osake-no-Kagaku Foundation, and the Astellas Foundation; and he has received research support, manuscript fees, or speaking honoraria from Meiji Seika Pharma, MSD, Otsuka, PDR Pharma, and Sumitomo Pharma. Dr. Ojagbemi has received funding from the Department of Health and Social Care, the National Institute for Health and Care Research, and Wellcome Trust Global Health Research Partnership International Intermediate Fellowship. Dr. Pantelis has received honoraria for talks at educational meetings and has served on advisory boards for Lundbeck, Australia Pty Ltd, and Servier Australia. Dr. Raedler has received honoraria and clinical trial support from AbbVie, Allergan, Bausch Health, Biohaven, Boehringer Ingelheim, HLS, Janssen, Lundbeck, Newron, Otsuka, Sunovion, SyneuRx International, and Teva. Dr. Marques is an employee and shareholder of Pasithea Therapeutics, and he has received employee stock options; he has served as consultant or advisory board member for Pfizer and Viatris. Dr. Remington has received research support from the Canadian Institutes of Health Research, HLS Therapeutics, and University of Toronto. Dr. Rossell has received an investigator-initiated clinical study grant from Woke Pharmaceuticals. Dr. Rubio has received honoraria from Karuna/Bristol Myers Squibb and has received grant funding from or performed contracted research for Alkermes, Bristol Myers Squibb, Neurocrine, and Saladax; and royalties from UpToDate. Dr. Sachs has served as a speaker and an advisory panel member for Boehringer Ingelheim. Dr. Si has received research support from Eli Lilly, Janssen, Lundbeck, Otsuka, Pfizer and lecture fees for unrestricted educational meetings from Janssen, Lundbeck, Otsuka, Sumitomo Pharma, and Sunovion, and has served on advisory boards for Jansen, Lundbeck, and Otsuka. Dr. Siskind has served on the Viatris Quality Assurance Committee and served as a speaker for Servier. Dr. Siu has served as a consultant for the Chinese University of Hong Kong, Seaport Therapeutics, and Sunovion. Dr. Sommer has served as a speaker for Lundbeck. Dr. Suzuki has received manuscript or speaking fees from Astellas, Eisai, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Nihon Medi-Physics, Novartis, Otsuka Pharmaceutical, Shionogi, Shire, Sumitomo Pharma, Takeda Pharmaceutical, Tsumura, Viatris, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Eisai, Meiji Seika Pharma, Mochida Pharmaceutical, Shionogi, and Sumitomo Pharma. Dr. Takeuchi has received grants from Daiichi Sankyo, Novartis Pharma, and Otsuka; he has served as a speaker for EA Pharma, Eisai, Janssen, Kracie, Kyowa, Lundbeck, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka, Sumitomo Pharma, Takeda, and Yoshitomiyakuhin; and he has served as a consultant for Boehringer Ingelheim, Bristol Myers Squibb, EA Pharma, Janssen, Mitsubishi Tanabe Pharma, Nippon Chemiphar, Ono, and Sumitomo Pharma. Dr. Taylor has received research funding from Janssen and Otsuka; he has served as a speaker for Janssen, Lundbeck, and Otsuka; and he is a shareholder in 428 Pharma, Myogenes, and Saladax. Dr. Tiihonen has participated in research projects funded by grants from Janssen to his employing institution; he has served as a consultant for, received honoraria from, given expert testimony for, and/or received support for attending meetings from Healthcare Global Village, HLS Therapeutics, Janssen, Lundbeck, Orion Pharma, Otsuka, Teva, WebMD Global. Dr. Uchida has received grants from Daiichi Sankyo, Eisai, Mochida, Otsuka, and Sumitomo Pharma; speaking fees from Boehringer Ingelheim Japan, Daiichi Sankyo, Eisai, Lundbeck, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka, Takeda, Sumitomo Pharma, and Viatris; and advisory board fees from Boehringer Ingelheim Japan, Lundbeck, Shionogi, Sumitomo Pharma, and Takeda Pharmaceutical. Dr. Ucok has served as a consultant and/or adviser for or received honoraria from Abdi Ibrahim Otzuka, Janssen, and Nobel. Dr. Umbricht is owner of Xperimed; he has worked on a contracting basis for Autifony Therapeutics and Gilgamesh pharmaceuticals; he has served as a consultant for AbbVie, Biogen, Draig, ERG, Forbion, HealthRhythms, Kynexis, Pontifax, Psychogenic, Roche, and Siesta; and he is a stockholder in Hoffman–La Roche and Novartis and has stock options in Gilgamesh Pharmaceuticals. Dr. Wagner has served as an advisory board member for Boehringer Ingelheim, Recordati, and Teva. Dr. Walters has received research grants from Akrivia Health and Takeda Pharmaceuticals and has served as a consultant for Akrivia Health and Teva. Dr. McCutcheon has served as a speaker or consultant for Boehringer Ingelheim, Janssen, Karuna, Newron, Otsuka, and Viatris, and he codirects a company that designs digital resources to support treatment of mental illness. The other authors report no financial relationships with commercial interests.

LinkOut - more resources

Full Text Sources
- Atypon

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Relapse in Schizophrenia: A Systematic Review of Criteria for Clinical Studies and International Consensus Guidelines to Improve Them

Affiliations

Relapse in Schizophrenia: A Systematic Review of Criteria for Clinical Studies and International Consensus Guidelines to Improve Them

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources