Oliver D Howes1, Rob McCutcheon1, Ofer Agid1, Andrea de Bartolomeis1, Nico J M van Beveren1, Michael L Birnbaum1, Michael A P Bloomfield1, Rodrigo A Bressan1, Robert W Buchanan1, William T Carpenter1, David J Castle1, Leslie Citrome1, Zafiris J Daskalakis1, Michael Davidson1, Richard J Drake1, Serdar Dursun1, Bjørn H Ebdrup1, Helio Elkis1, Peter Falkai1, W Wolfgang Fleischacker1, Ary Gadelha1, Fiona Gaughran1, Birte Y Glenthøj1, Ariel Graff-Guerrero1, Jaime E C Hallak1, William G Honer1, James Kennedy1, Bruce J Kinon1, Stephen M Lawrie1, Jimmy Lee1, F Markus Leweke1, James H MacCabe1, Carolyn B McNabb1, Herbert Meltzer1, Hans-Jürgen Möller1, Shinchiro Nakajima1, Christos Pantelis1, Tiago Reis Marques1, Gary Remington1, Susan L Rossell1, Bruce R Russell1, Cynthia O Siu1, Takefumi Suzuki1, Iris E Sommer1, David Taylor1, Neil Thomas1, Alp Üçok1, Daniel Umbricht1, James T R Walters1, John Kane1, Christoph U Correll1. 1. From King's College London, Institute of Psychiatry, Psychology, and Neuroscience; MRC Clinical Sciences Centre; Institute of Clinical Sciences, Imperial College, and Hammersmith Hospital London; the Department of Psychiatry, University of Toronto, and the Centre for Addiction and Mental Health, Toronto; the Section of Psychiatry and Treatment Resistant Psychosis and the Laboratory of Translational Psychiatry, School of Medicine of Naples Federico II, Naples; the Departments of Psychiatry and Neuroscience, Erasmus Medical Center, and Antes Mental Health Care, Rotterdam, the Netherlands; the Feinstein Institute for Medical Research, Psychiatry Research, Zucker Hillside Hospital, Hofstra Northwell School of Medicine; the Division of Psychiatry, University College London; Laboratorio Interdisciplinar de Neurociencia Clinica, Universidade Federal de São Paulo, São Paulo; the Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore; the University of Melbourne and St. Vincent's Hospital, Sydney; the Department of Psychiatry and Behavioral Sciences, New York Medical College, New York; the Department of Psychiatry, Tel Aviv University, Tel Aviv; the Division of Health Sciences, School of Psychology and Mental Health, Faculty of Biology, Medicine, and Health, University of Manchester, and the Manchester Academic Health Science Centre, Manchester Mental Health and Social Care NHS Trust, Manchester; the Department of Psychiatry, University of Alberta, Edmonton; the Center for Neuropsychiatric Schizophrenia Research and the Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, University of Copenhagen, Copenhagen; the Department of Psychiatry, University of São Paulo Medical School, São Paulo; the Department of Psychiatry, University of Munich, Munich; the Department of Psychiatry, Psychotherapy, and Psychosomatics, Medical University Innsbruck, Innsbruck, Austria; Programa de Esquizofrenia and Laboratorio Interdisciplinar de Neurociencia Clinica, Universidade Federal de São Paulo, São Paulo; the National Psychosis Service, South London and Maudsley NHS Foundation Trust; the Neuroscience and Behavior Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo; the Department of Psychiatry, University of British Columbia; Lundbeck LLC, Deerfield, Ill.; University Department of Psychiatry, Royal Edinburgh Hospital, Edinburgh; the Department of General Psychiatry, Institute of Mental Health, Singapore; the Deparment of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg; the Brain and Mind Centre, University of Sydney, Sydney; the School of Pharmacy, University of Auckland, Auckland, New Zealand; the Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago; the Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich; the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo; the Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne, and Melbourne Health, Victoria; the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto; the Centre for Mental Health, Swinburne University, the Monash Alfred Psychiatry Research Centre, and the Department of Psychiatry, St. Vincent's Hospital Melbourne, Sydney; the School of Pharmacy, University of Otago, Otago, New Zealand; COS and Associates Ltd., Hong Kong; the Department of Neuropsychiatry, Keio University School of Medicine, Keio, Japan; the Department of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands; Swinburne University and Monash Alfred Psychiatry Research Centre, Brain and Psychological Sciences Research Centre, Melbourne; the Istanbul Faculty of Medicine, Istanbul University, Istanbul; Clinical Research and Early Development, F. Hoffmann -La Roche Ltd., Basel, Switzerland; the Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, and the MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff; Psychiatry Research, Zucker Hillside Hospital, Long Island Jewish Medical Center, Hofstra Northwell School of Medicine, and the Feinstein Institute for Medical Research, New York.
Abstract
OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHOD: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.
OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHOD: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.
Entities:
Keywords:
Clinical Drug Studies; Other Aspects Of Psychopharmacology; Psychosis; Schizophrenia; Treatment Resistance
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