World Psychiatry, volume 22, issue 3, pages 394-412

Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions

Roger S. McIntyre 1, 2, 3
Mohammad Alsuwaidan 3
Bernhard T. Baune 4, 5
Michael Berk 5, 6
Demyttenaere Koen 7
JOSEPH F. GOLDBERG 8
Philip Gorwood 9
Roger Ho 10, 11
Siegfried Kasper 12
Sidney H. Kennedy 3
Josefina Ly Uson 13
Rodrigo B Mansur 3
R. Hamish McAllister-Williams 14
James W. Murrough 8
Charles B. Nemeroff 15
Andrew A. Nierenberg 16
Joshua D. Rosenblat 3
Gerard Sanacora 17
Alan F. Schatzberg 18
Richard Shelton 19
Stephen M. Stahl 20
Madhukar H. Trivedi 21
Eduard Vieta 22
Maj Vinberg 23
Nolan Williams 18
Allan H. Young 24
Mario Maj 25
Show full list: 27 authors
1
 
Brain and Cognition Discovery Foundation Toronto ON Canada
9
 
Department of Psychiatry Sainte‐Anne Hospital Paris France
13
 
Department of Psychiatry and Behavioral Medicine University of The Philippines College of Medicine Manila The Philippines
Publication typeJournal Article
Publication date2023-09-15
Journal: World Psychiatry
scimago Q1
SJR15.827
CiteScore64.1
Impact factor60.5
ISSN17238617, 20515545
Psychiatry and Mental health
Pshychiatric Mental Health
Abstract

Treatment‐resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision‐making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision‐making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo‐resistant (e.g., due to inadequacy of treatment trials or non‐adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non‐response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co‐administered with an antidepressant) are established as efficacious in the management of TRD. Some second‐generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine‐fluoxetine combination has been studied in FDA‐defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA‐approved for individuals with TRD, with accelerated theta‐burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non‐inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual‐based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

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