The definition of treatment resistance in anxiety disorders: a Delphi method‐based consensus guideline
Open accessAbstract
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.
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A Delphi method-based consensus proposed the term 'difficult-to-treat' anxiety disorder due to its usefulness in the clinical context.
“In line with this recommendation, a Delphi method-based consensus on the definition of treatment-resistant anxiety disorders [18] proposed the term “difficult-to-treat” anxiety disorder due to its usefulness in the clinical context.”
From Process-based therapy vs. routine-CBT for difficult-to-treat mood and anxiety disorders: study protocol for a randomized controlled trial (2024) · cites this paper as [18]
In “TR-AD vs. difficult-to-treat AD” (p. 7), the panel acknowledges that “difficult-to-treat” may be more useful in a clinical context. But it agreed to use “treatment-resistant” anxiety disorders; it did not propose adopting “difficult-to-treat” as its preferred term. (LLM, conf=0.88)
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Optimizing Treatment in Social Phobia: A Review of Treatment Resistance
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Management of Treatment-Resistant Panic Disorder
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“A prerequisite for conducting these clinical trials and mecha nistic studies is an international consensus on the definition of TR AD, which is currently lacking 17,26 .”
Self-citationPARADISE 24: A Measure to Assess the Impact of Brain Disorders on People’s Lives
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Self-citationPsychopharmacologic Treatment of Pediatric Anxiety Disorders
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What is treatment resistance in psychiatry? A “difficult to treat” concept
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Ministry of Health Clinical Practice Guidelines: Anxiety Disorders
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A clinical staging approach to improving diagnostics in anxiety disorders: Is it the way to go?
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Self-citationA neurobiological framework of separation anxiety and related phenotypes
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Diretrizes da Associação Médica Brasileira para o tratamento do transtorno de ansiedade social
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Self-citationUnderstanding depression beyond the “mind‐body” dichotomy
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Self-citationFrom treatment resistance to sequential treatments of depression
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Chapter 18. Social Anxiety Disorder (Social Phobia)
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Predicting the course of anxiety disorders: The role of biological parameters
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Self-citationDiscovering Digital Biomarkers of Panic Attack Risk in Consumer Wearables Data
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Social Anxiety Disorder (Social Phobia)
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Self-citationDoes treatment‐resistant depression need psychotherapy?
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Flagged first, then by citations
Research works printed but not linked: 2
- [36]36. Levitan MN, Chagas MH, Crippa JA et al. Guidelines of the Brazilian Medical Association for the treatment of social anxiety disorder. Rev Brasil Psiquiatr 2011;33:292-302.
- [4]4. ysis. J Affect Disord 2023;326:168-92.
Cited by
Sorted by citations
Obsessive-compulsive disorder – A state-of-the-art review
Endres, D., Schiele, M. A., von Zedtwitz, K., Dressle, R. J., Maier, A., Hohagen, F., Baldermann, J. C., Coenen, V. A., Jelinek, L., Domschke, K., et al. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106320 · Cited by 11 · see citing works
Self-citationStangier, U., Kohl, V., Görg, N., Sendig, L., Hufschmidt, B., Bonarius, D., Nemani, A., Ebert, M., & Hofmann, S. G. (2024) · Trials · doi:10.1186/s13063-024-08689-3 · Cited by 2 · see citing works
Self-citation
- Authors
- Domschke, K., Seuling, P. D., Schiele, M. A., Bandelow, B., Batelaan, N. M., Bokma, W. A., Branchi, I., Broich, K., Burkauskas, J., Davies, S. J. C., Dell'Osso, B., Fagan, H., Fineberg, N. A., Furukawa, T. A., Hofmann, S. G., Hood, S., Huneke, N. T. M., Latas, M., Lidbetter, N., Masdrakis, V., McAllister‐Williams, R. H., Nardi, A. E., Pallanti, S., Penninx, B. W. J. H., Perna, G., Pilling, S., Pini, S., Reif, A., Seedat, S., Simons, G., Srivastava, S., Steibliene˙, V., Stein, D. J., Stein, M. B., van Ameringen, M., van Balkom, A. J. L. M., van der Wee, N., Zwanzger, P., & Baldwin, D. S.
- Affiliations
- University of Freiburg (DE)
- Universitätsmedizin Göttingen (DE)
- Amsterdam Public Health (NL)
- Istituto Superiore di Sanità (IT)
- Federal Institute for Drugs and Medical Devices (DE)
- Lithuanian University of Health Sciences (LT)
- Centre for Addiction and Mental Health (CA)
- Department of Biomedical and Clinical Sciences University of Milan Milan Italy
- Southern Health NHS Foundation Trust (GB)
- University of Hertfordshire (GB)
- Kyoto University (JP)
- Philipps University of Marburg (DE)
- The University of Western Australia (AU)
- University of Belgrade (RS)
- Anxiety UK Manchester UK
- National and Kapodistrian University of Athens (GR)
- Translational and Clinical Research Institute Newcastle University Newcastle UK
- Panic & Respiration Laboratory, Institute of Psychiatry Medical School, Federal University of Rio de Janeiro Rio de Janeiro Brazil
- Albert Einstein College of Medicine (US)
- Humanitas University (IT)
- University College London (GB)
- University of Pisa (IT)
- Goethe University Frankfurt (DE)
- Stellenbosch University (ZA)
- Solent NHS Trust (GB)
- King George's Medical University (IN)
- Neuroscience Institute and Clinic of Psychiatry, Faculty of Medicine Lithuanian University of Health Sciences Kaunas Lithuania
- South African Medical Research Council (ZA)
- University of California San Diego (US)
- Department of Psychiatry and Behavioural Neurosciences McMaster University Hamilton ON Canada
- Department of Psychiatry and Amsterdam Public Health Research Institute Amsterdam University Medical Center, Vrije Universiteit Amsterdam The Netherlands
- Department of Psychiatry Leiden University Medical Center Leiden The Netherlands
- Inn-Salzach-Klinikum (DE)
- ORCID
- Domschke, Katharina
- Schiele, Miriam A.
- Bandelow, Borwin
- Batelaan, Neeltje M.
- Bokma, Wicher A.
- Branchi, Igor
- Broich, Karl
- Burkauskas, Julius
- Davies, Simon J.C.
- Fagan, Harry
- Fineberg, Naomi A.
- Furukawa, Toshi A.
- Hofmann, Stefan G.
- Hood, Sean
- Huneke, Nathan T.M.
- Latas, Milan
- Lidbetter, Nicky
- Masdrakis, Vasilios
- Pallanti, Stefano
- Penninx, Brenda W.J.H.
- Perna, Giampaolo
- Pini, Stefano
- Reif, Andreas
- Seedat, Soraya
- Simons, Gemma
- Srivastava, Shrikant
- Stein, Dan J.
- Stein, Murray B.
- Zwanzger, Peter
- Baldwin, David S.
- Venue
- World Psychiatry
- Publisher
- Wiley
- Published
- 2024-01-12
- Volume
- 23
- Issue
- 1
- Pages
- 113-123
- ISSN
- 1723-8617 (ISSN-L)
- 2051-5545
- PMC
- PMC10785995
- OpenAlex
- W4390795688
- Cited by
- 46
- References
- 121
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 11
- FWCI
- 18.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- World Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- UWA Profiles and Research Repository (UWA) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- ePrints Soton (University of Southampton) (acceptedVersion)
- University of Hertfordshire Research Archive (University of Hertfordshire) (acceptedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- University of Hertfordshire Research Archive (University of Hertfordshire) (submittedVersion)
- Lithuanian University of Health Sciences (submittedVersion)
- Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institute for Health and Care Research (ACF-2022-26-003)
- European College of Neuropsychopharmacology
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Social Sciences › Psychology › Social Psychology › Mental Health Treatment and Access
- Social Sciences › Sociology and Political Science › Delphi Technique in Research
- Keywords
- operational criteria, staging model, comorbidities, expert consensus
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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