TY - JOUR

T1 - Treatment-resistant depression

T2 - definition, prevalence, detection, management, and investigational interventions

AU - McIntyre, Roger S.

AU - Alsuwaidan, Mohammad

AU - Baune, Bernhard T.

AU - Berk, Michael

AU - Demyttenaere, Koen

AU - Goldberg, Joseph F.

AU - Gorwood, Philip

AU - Ho, Roger

AU - Kasper, Siegfried

AU - Kennedy, Sidney H.

AU - Ly-Uson, Josefina

AU - Mansur, Rodrigo B.

AU - McAllister-Williams, R. Hamish

AU - Murrough, James W.

AU - Nemeroff, Charles B.

AU - Nierenberg, Andrew A.

AU - Rosenblat, Joshua D.

AU - Sanacora, Gerard

AU - Schatzberg, Alan F.

AU - Shelton, Richard

AU - Stahl, Stephen M.

AU - Trivedi, Madhukar H.

AU - Vieta, Eduard

AU - Vinberg, Maj

AU - Williams, Nolan

AU - Young, Allan H.

AU - Maj, Mario

N1 - Publisher Copyright: © 2023 World Psychiatric Association.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Depression

KW - difficult-to-treat depression

KW - electroconvulsive therapy

KW - esketamine

KW - ketamine

KW - neurostimulation

KW - patient-reported outcomes

KW - personalized medicine

KW - precision medicine

KW - second-generation antipsychotics

KW - treatment-resistant depression

U2 - 10.1002/wps.21120

DO - 10.1002/wps.21120

M3 - Journal article

C2 - 37713549

AN - SCOPUS:85171267670

VL - 22

SP - 394

EP - 412

JO - World Psychiatry

JF - World Psychiatry

SN - 1723-8617

IS - 3

ER -