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Aust N Z J Psychiatry. 2019 Feb;53(2):109-118. doi: 10.1177/0004867418808585. Epub 2018 Oct 31.

Difficult-to-treat depression: A clinical and research roadmap for when remission is elusive.

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1 Duke-National University of Singapore Medical School, Singapore.
2 Department of Psychiatry & Behavioral Sciences, Duke University, School of Medicine, Durham, NC, USA.
3 Department of Psychiatry, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
4 Clinical Research Programs, Sheppard Pratt Health System, Baltimore, MD, USA.
5 Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
6 University Psychiatric Centre, University of Leuven, Leuven, Belgium.
7 Faculty of Medicine, Department of Neurosciences, Research Group Psychiatry, University of Leuven, Leuven, Belgium.



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.


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).


Treatment-resistant depression; depression; difficult-to-treat depression; managing depression; outcomes


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