Psychotherapy and the Operational Definition of Treatment-Resistant Depression

See reply by Marques et al and article by Marques et al

To the Editor: We read with interest the consensus-based recommendations by Marques and colleagues¹ regarding next-step treatment selection for treatment-resistant depression (TRD). Their effort to contextualize treatment decisions according to patient-specific clinical factors, such as metabolic health and age, offers a useful contribution to the practical management of TRD in real-world settings.¹

Operational definitions of TRD remain heterogeneous across the literature, particularly regarding what constitutes adequate prior treatment exposure.² Within this broader conceptual variability, an important issue is illustrated by one assumption underlying the clinical vignette. For the purposes of the consensus exercise, the authors specified that the patient had already completed an “adequate course of psychotherapy,” thereby excluding psychotherapy from consideration among next-step treatment options.¹ While methodologically reasonable within the study design, this assumption reflects a broader pattern in TRD research and practice, wherein psychotherapy is often treated as a background prerequisite rather than an explicit component of resistance staging. The authors further note that it is “uncommon to encounter patients” in routine practice who present with such structured psychotherapy exposure alongside full medication adherence.¹

As noted by Markowitz and colleagues,³ current operational definitions of TRD continue to rely predominantly on failed pharmacologic trials. This framework may contribute to overclassification of pharmacotherapy-resistant presentations as globally treatment resistant, particularly when prior psychotherapy is inconsistent or absent.³ The clinical relevance of this issue is underscored by contemporary research; in the recent pragmatic Lithium versus Quetiapine in treatment resistant Depression (LQD) trial, a substantial minority of participants meeting TRD criteria (32%) had not received psychological therapy during their current depressive episode.⁴

As efforts toward more individualized TRD care advance, future staging frameworks may benefit from more explicit incorporation of psychotherapy adequacy into the operational definition of treatment resistance.³ Aligning TRD classification more closely with the full range of evidence-based interventions may help ensure that patients are not advanced to resource-intensive augmentation strategies before evidence-based psychosocial interventions have been adequately incorporated into treatment planning.³ Otherwise, TRD may remain a construct defined more by pharmacologic sequencing than by comprehensive treatment exposure.

Article Information

Published Online: August 19, 2026. https://doi.org/10.4088/JCP.26lr16517
© 2026 Physicians Postgraduate Press, Inc.
J Clin Psychiatry 2026;87(3):26lr16517
To Cite: De Oliveira Reis V, Nardi AE, Zakhour S. Psychotherapy and the operational definition of treatment-resistant depression. J Clin Psychiatry. 2026; 87(3):26lr16517.
Author Affiliations: Treatment-Resistant Depression Outpatient Clinic (DeReTrat), Institute of Psychiatry, Federal University of Rio de Janeiro (IPUB-UFRJ), Rio de Janeiro (RJ), Brazil.
Corresponding Author: Verônica de Oliveira Reis, Treatment-Resistant Depression Outpatient Clinic, Institute of Psychiatry (IPUB) – Federal University of Rio de Janeiro (UFRJ), Av. Venceslau Brás, 71, Fundos, Botafogo, Rio de Janeiro, Brazil. CEP: 22290-140 ([email protected]).
Financial Disclosure: The authors report no financial or other relationship relevant to the subject of this letter.
Funding/Support: None.
Use of AI-Assisted Technologies in the Writing Process: In the writing of this manuscript, the authors used ChatGPT (OpenAI, GPT-5) for language refinement. The authors have reviewed the content and take full responsibility for the content of the publication.
ORCID: Verônica de Oliveira Reis: https://orcid.org/0009-0009-4598-5337; Antonio E. Nardi: https://orcid.org/0000-0002-2152-4669; Stephanie Zakhour: https://orcid.org/0000-0002-5936-2634