Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

doi:10.1176/appi.ajp.2016.16050503

Review

. 2017 Mar 1;174(3):216-229.

doi: 10.1176/appi.ajp.2016.16050503. Epub 2016 Dec 6.

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

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

Affiliations

Affiliation

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.

PMID: 27919182
PMCID: PMC6231547
DOI: 10.1176/appi.ajp.2016.16050503

Free PMC article

Review

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

Oliver D Howes et al. Am J Psychiatry. 2017.

Free PMC article

. 2017 Mar 1;174(3):216-229.

doi: 10.1176/appi.ajp.2016.16050503. Epub 2016 Dec 6.

Authors

Affiliation

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.

PMID: 27919182
PMCID: PMC6231547
DOI: 10.1176/appi.ajp.2016.16050503

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.

Keywords: Clinical Drug Studies; Other Aspects Of Psychopharmacology; Psychosis; Schizophrenia; Treatment Resistance.

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Figures

**Figure 1. Summary of criteria used in clinical trials of treatment resistant schizophrenia**
NS – Not specified. CPZ – Chlorpromazine equivalents

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References

1. Howes O, Murray R. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet. 2014;6736:1–11. - PMC - PubMed
1. López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry. 2005;17:113–135. - PubMed
1. Claghorn J, Honigfeld G, Abuzzahab FS, Wang R, Steinbook R, Tuason V, Klerman G. The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol. 1987;7:377–384. - PubMed
1. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–796. - PubMed
1. National Institute For Clinical Excellence. Schizophrenia: The NICE guideline on core interventions in the treatment and management of schizophrenia in primary and secondary care; National Clinical Practice Guidelines Number CG82. 2014.

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[1] Howes O, Murray R. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet. 2014;6736:1–11. - PMC - PubMed

[2] Howes O, Murray R. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet. 2014;6736:1–11. - PMC - PubMed

[3] López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry. 2005;17:113–135. - PubMed

[4] López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry. 2005;17:113–135. - PubMed

[5] Claghorn J, Honigfeld G, Abuzzahab FS, Wang R, Steinbook R, Tuason V, Klerman G. The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol. 1987;7:377–384. - PubMed

[6] Claghorn J, Honigfeld G, Abuzzahab FS, Wang R, Steinbook R, Tuason V, Klerman G. The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol. 1987;7:377–384. - PubMed

[7] Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–796. - PubMed

[8] Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–796. - PubMed

[9] National Institute For Clinical Excellence. Schizophrenia: The NICE guideline on core interventions in the treatment and management of schizophrenia in primary and secondary care; National Clinical Practice Guidelines Number CG82. 2014.

[10] National Institute For Clinical Excellence. Schizophrenia: The NICE guideline on core interventions in the treatment and management of schizophrenia in primary and secondary care; National Clinical Practice Guidelines Number CG82. 2014.

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Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

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Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

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