The definition of treatment resistance in anxiety disorders: a Delphi method-based consensus guideline

Katharina Domschke; Patrik D Seuling; Miriam A Schiele; Borwin Bandelow; Neeltje M Batelaan; Wicher A Bokma; Igor Branchi; Karl Broich; Julius Burkauskas; Simon J C Davies; Bernardo Dell'Osso; Harry Fagan; Naomi A Fineberg; Toshi A Furukawa; Stefan G Hofmann; Sean Hood; Nathan T M Huneke; Milan Latas; Nicky Lidbetter; Vasilios Masdrakis; R Hamish McAllister-Williams; Antonio E Nardi; Stefano Pallanti; Brenda W J H Penninx; Giampaolo Perna; Steve Pilling; Stefano Pini; Andreas Reif; Soraya Seedat; Gemma Simons; Shrikant Srivastava; Vesta Steibliene; Dan J Stein; Murray B Stein; Michael van Ameringen; Anton J L M van Balkom; Nic van der Wee; Peter Zwanzger; David S Baldwin

doi:10.1002/wps.21177

The definition of treatment resistance in anxiety disorders: a Delphi method-based consensus guideline

World Psychiatry. 2024 Feb;23(1):113-123. doi: 10.1002/wps.21177.

Authors

Katharina Domschke¹, Patrik D Seuling¹, Miriam A Schiele¹, Borwin Bandelow², Neeltje M Batelaan³, Wicher A Bokma³, Igor Branchi⁴, Karl Broich⁵, Julius Burkauskas⁶, Simon J C Davies^{7

8}, Bernardo Dell'Osso^{9

10}, Harry Fagan^{11

12}, Naomi A Fineberg¹³, Toshi A Furukawa¹⁴, Stefan G Hofmann¹⁵, Sean Hood¹⁶, Nathan T M Huneke^{11

12}, Milan Latas^{17

18}, Nicky Lidbetter¹⁹, Vasilios Masdrakis²⁰, R Hamish McAllister-Williams^{21

22}, Antonio E Nardi²³, Stefano Pallanti^{24

25}, Brenda W J H Penninx³, Giampaolo Perna²⁶, Steve Pilling²⁷, Stefano Pini²⁸, Andreas Reif^{29

30}, Soraya Seedat³¹, Gemma Simons^{11

32}, Shrikant Srivastava³³, Vesta Steibliene³⁴, Dan J Stein³⁵, Murray B Stein³⁶, Michael van Ameringen³⁷, Anton J L M van Balkom³, Nic van der Wee^{38

39}, Peter Zwanzger^{40

41}, David S Baldwin^{11

12

35}

Affiliations

¹ Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
² Department of Psychiatry and Psychotherapy, University Medical Center, Göttingen, Germany.
³ Department of Psychiatry and Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands.
⁴ Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.
⁵ Federal Institute for Drugs and Medical Devices, Bonn, Germany.
⁶ Laboratory of Behavioral Medicine, Neuroscience Institute, Lithuanian University of Health Sciences, Palanga, Lithuania.
⁷ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁸ Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁹ Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
¹⁰ Department of Mental Health and Addictions, ASST Fatebenefratelli-Sacco, Milan, Italy.
¹¹ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
¹² Southern Health NHS Foundation Trust, Southampton, UK.
¹³ University of Hertfordshire & Hertfordshire Partnership, University NHS Foundation Trust, Hatfield, UK.
¹⁴ Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan.
¹⁵ Department of Clinical Psychology, Philipps University Marburg, Marburg, Germany.
¹⁶ Division of Psychiatry, Medical School, University of Western Australia, Perth, WA, Australia.
¹⁷ Clinic for Psychiatry, University Clinical Center of Serbia, Belgrade, Serbia.
¹⁸ Belgrade University School of Medicine, Belgrade, Serbia.
¹⁹ Anxiety UK, Manchester, UK.
²⁰ First Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
²¹ Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
²² Cumbria, Northumberland, Tyne & Wear NHS Foundation Trust, Newcastle, UK.
²³ Panic & Respiration Laboratory, Institute of Psychiatry, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
²⁴ Institute of Neuroscience, Florence, Italy.
²⁵ Albert Einstein College of Medicine, New York, NY, USA.
²⁶ Department of Biological Sciences, Humanitas University, Milan, Italy.
²⁷ Centre for Outcomes Research and Effectiveness, Research Department of Clinical, Educational & Health Psychology, University College London, London, UK.
²⁸ University of Pisa School of Medicine, Pisa, Italy.
²⁹ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University Frankfurt, Frankfurt am Main, Germany.
³⁰ Fraunhofer Institute for Translational Medicine and Pharmacology, Frankfurt am Main, Germany.
³¹ Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
³² Solent NHS Trust, Southampton, UK.
³³ Geriatric Mental Health, King George's Medical University, Lucknow, India.
³⁴ Neuroscience Institute and Clinic of Psychiatry, Faculty of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania.
³⁵ South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³⁶ Department of Psychiatry and School of Public Health, University of California San Diego, San Diego, CA, USA.
³⁷ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
³⁸ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
³⁹ Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
⁴⁰ Clinical Center for Psychiatry, Psychotherapy and Psychosomatic Medicine, Kbo-Inn-Salzach Hospital, Wasserburg am Inn, Germany.
⁴¹ Department of Psychiatry and Psychotherapy, Ludwigs-Maximilians-University Munich, Munich, Germany.

Abstract

Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment-resistant anxiety disorders (TR-AD) informing such trials is currently lacking. We used a Delphi method-based consensus approach to provide internationally agreed, consistent and clinically useful operational criteria for TR-AD in adults. Following a summary of the current state of knowledge based on international guidelines and an available systematic review, a survey of free-text responses to a 29-item questionnaire on relevant aspects of TR-AD, and an online consensus meeting, a panel of 36 multidisciplinary international experts and stakeholders voted anonymously on written statements in three survey rounds. Consensus was defined as ≥75% of the panel agreeing with a statement. The panel agreed on a set of 14 recommendations for the definition of TR-AD, providing detailed operational criteria for resistance to pharmacological and/or psychotherapeutic treatment, as well as a potential staging model. The panel also evaluated further aspects regarding epidemiological subgroups, comorbidities and biographical factors, the terminology of TR-AD vs. "difficult-to-treat" anxiety disorders, preferences and attitudes of persons with these disorders, and future research directions. This Delphi method-based consensus on operational criteria for TR-AD is expected to serve as a systematic, consistent and practical clinical guideline to aid in designing future mechanistic studies and facilitate clinical trials for regulatory purposes. This effort could ultimately lead to the development of more effective evidence-based stepped-care treatment algorithms for patients with anxiety disorders.

Keywords: Anxiety disorders; agoraphobia; consensus guideline; evidence-based care; generalized anxiety disorder; operational criteria; panic disorder; social anxiety disorder; treatment resistance.