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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\u2010making, 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\u2010resistant (e.g., due to inadequacy of treatment trials or non\u2010adherence 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\u2010response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co\u2010administered with an antidepressant) are established as efficacious in the management of TRD. Some second\u2010generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine\u2010fluoxetine combination has been studied in FDA\u2010defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA\u2010approved for individuals with TRD, with accelerated theta\u2010burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non\u2010inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual\u2010based 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.<\/jats:p>","DOI":"10.1002\/wps.21120","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T14:42:06Z","timestamp":1694788926000},"page":"394-412","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":860,"title":["Treatment\u2010resistant depression: definition, prevalence, detection, management, and investigational interventions"],"prefix":"10.1002","volume":"22","author":[{"given":"Roger S.","family":"McIntyre","sequence":"first","affiliation":[{"name":"Brain and Cognition Discovery Foundation  Toronto ON Canada"},{"name":"Department of Psychiatry University of Toronto  Toronto ON Canada"},{"name":"Department of Pharmacology and Toxicology University of Toronto  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Alsuwaidan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Toronto  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard T.","family":"Baune","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of M\u00fcnster  M\u00fcnster Germany"},{"name":"Department of Psychiatry University of Melbourne  Melbourne VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Berk","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Melbourne  Melbourne VIC Australia"},{"name":"Deakin University IMPACT Institute  Geelong VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Demyttenaere","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Faculty of Medicine KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph F.","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Gorwood","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Sainte\u2010Anne Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Psychological Medicine Yong Loo Lin School of Medicine, National University of Singapore  Singapore"},{"name":"Institute for Health Innovation and Technology National University of Singapore  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siegfried","family":"Kasper","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy and Center of Brain Research, Molecular Neuroscience Branch Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidney H.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Toronto  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefina","family":"Ly\u2010Uson","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Medicine University of The Philippines College of Medicine  Manila The Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo B.","family":"Mansur","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Toronto  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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