Difficult-to-treat depression: A clinical and research roadmap for when remission is elusive
Abstract
Objectives: The report considers the pros and cons of the most commonly used conceptual model that forms the basis for most clinical practice guidelines for depression. This model promotes the attainment of sustained symptom remission as the treatment goal based on its well-established prognostic and functional importance. Sustained remission is very unlikely, however, after multiple treatment attempts. Our current model propels many clinicians to continue to change or add treatments despite little chance for remission or full functional restoration and despite the increasing risk of more adverse events from polypharmacy. An alternative ‘difficult-to-treat depression’ model is presented and considered. It accepts that the treatment aims for some depressed patients may shift to optimal symptom control rather than remission. When difficult-to-treat depression is suspected, the many treatable causes of persistent depression must be assessed and addressed (given the importance of remission when attainable) before difficult-to-treat depression can be ascribed. The clinical and research implications of the difficult-to-treat depression model are discussed. Conclusion: Suspected difficult-to-treat depression provides a practical basis for considering when to conduct a comprehensive evaluation. Once difficult-to-treat depression is confirmed, treatment may better focus on optimal disease management (symptom control and functional improvement).
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The construct of difficult-to-treat depression (DTD) relies on a biopsychosocial approach when considering causal, perpetuating and treatment factors of poor outcomes in depression.
“This construct relies on a biopsychosocial approach when considering causal, perpetuating and treatment factors of poor outcomes in de pression 70 .”
From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [70]
An unintended consequence of a TRD framework that is hierarchical is encouraging multiple unproven treatment strategies, with polypharmacy and the possibility of associated safety and tolerability concerns.
“Furthermore, an unintended consequence of a TRD framework that is hierarchical is encouraging mul tiple unproven treatment strategies, with poly pharmacy and the possibility of associated safety and tolerability concerns 70,75 .”
From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [70]
Even amongst patients classified as 'responders', many continue to manifest debilitating residual symptoms.
“Indeed, even amongst patients classified as 'responders' , many con tinue to manifest debili tating residual sym ptoms 69,70 .”
From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [70]
The therapeutic emphasis in DTD pivots away from symptomatic remission towards symptomatic control, functional recovery and quality of life improvement as part of chronic disease management.
“The therapeutic emphasis in DTD pivots away from symptomatic remission to wards symptomatic control, functional recovery and quality of life improvement as part of chronic disease management 70 .”
From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [70]
There is a large variety of definitions about the number and type of unsuccessful treatment attempts required to meet the criteria for treatment-resistance, in particular for treatment of depression.
“However, there is a large variety of definitions about the number and type of unsuccessful treatment attempts required to meet the criteria for treatment-resistance, in particular for treatment of depression [16].”
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 [16]
It has been recently suggested to prefer the more comprehensive term 'difficult-to-treat' depression.
“To avoid the theoretical difficulties of categorially excluding any response to a treatment, it has been recently suggested to prefer the more comprehensive term ‘difficult-to-treat’ depression [16, 17].”
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 [16]
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- Authors
- Rush, A. J., Aaronson, S. T., & Demyttenaere, K.
- Affiliations
- National University of Singapore (SG)
- University of Maryland, Baltimore (US)
- KU Leuven (BE)
- Corresponding author
- Rush, Augustus John
- Venue
- Australian & New Zealand Journal of Psychiatry
- Publisher
- SAGE Publications
- Published
- 2018-10-31
- Volume
- 53
- Issue
- 2
- Pages
- 109-118
- ISSN
- 0004-8674 (ISSN-L)
- 1440-1614
- OpenAlex
- W2899390091
- Cited by
- 120
- References
- 66
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 23 · 2023: 19 · 2022: 18 · 2021: 10 · 2020: 12 · 2019: 4
- FWCI
- 0.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Australian & New Zealand Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Social Sciences › Psychology › Social Psychology › Mental Health Treatment and Access
- Keywords
- difficult-to-treat depression, dysthymia, treatment-resistant depression, symptom remission, symptom management, functional recovery, polypharmacy, adverse drug reactions, treatment goals, comprehensive evaluation
- MeSH terms
- Humans, Models, Psychological, Disease Management, Depressive Disorder, Treatment-Resistant
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