Psychotherapy, Pharmacotherapy, and Neuromodulatory Interventions in Operational Definitions of Treatment-Resistant Depression: Reply to De Oliveira Reis et al

See letter by De Oliveira Reis et al and article by Marques et al

To the Editor: We thank De Oliveira Reis and colleagues¹ for their interest in our study² and for their thoughtful commentary on the role of psychotherapy in treatment resistance staging and classification. We agree that treatment-resistant depression (TRD) and difficult-to-treat depression classifications should not be limited to failure of pharmacotherapy alone. Indeed, studies have consistently demonstrated that combined treatment is more effective than either psychotherapy or pharmacotherapy alone in achieving response.³ Contemporary frameworks, such as the Antidepressant Treatment History Form-Short Form-2 (ATHF-SF2), do include failure of an evidence-based psychotherapy (encompassing acceptance and commitment therapy, behavioral therapy, cognitive behavioral therapy, problem-solving therapy, interpersonal therapy, short-term psychodynamic psychotherapy, and others), defined as participation in a recognized therapy for ≥12 sessions over 15 weeks targeting depressive symptoms, without marked clinical improvement and with substantial adherence, as a component of treatment resistance.⁴ In real-world practice, most patients with TRD receive both pharmacotherapy and psychotherapeutic interventions concurrently, and our consensus group discussions presumed that the patient in the vignette would continue to engage in psychotherapy and exercise. In our study, the vignette assumed the patient had been consistently engaged in weekly psychotherapy for the last 6 months, without further details on psychotherapy treatment, to minimize heterogeneity of the baseline condition rather than a formal staging criterion, primarily for the sake of simplicity in the hypothetical scenario.

We therefore fully support the notion that evidence-based interventions, including psychotherapy, intensive psychotherapy programs such as intensive outpatient and residential treatment programs, and resource-intensive augmentation strategies, including but not limited to novel treatments such as ketamine/ esketamine, transcranial magnetic stimulation, electroconvulsive therapy, and vagus nerve stimulation, should be recognized within treatment resistance frameworks and considered as viable treatment options. We hope that future TRD clinical trials and consensus statements will more explicitly operationalize psychotherapy adequacy as a component of treatment resistance staging and that study designs will examine the differential contributions of specific evidence-based modalities to outcomes in this population. As we noted in our conclusion, “Treatment selection must account for each patient’s unique clinical profile, comorbidities, and preferences,” which inherently includes psychotherapy as a viable and individualized treatment option where appropriate.

Article Information

Published Online: August 19, 2026. https://doi.org/10.4088/JCP.26lr16517a
© 2026 Physicians Postgraduate Press, Inc.
J Clin Psychiatry 2026;87(3):26lr16517a
To Cite: Marques MG, Frye MA, Singh B. Psychotherapy, pharmacotherapy, and neuromodulatory interventions in operational definitions of treatment-resistant depression: reply to De Oliveira Reis et al. J Clin Psychiatry 2026;87(3):26lr16517a.
Author Affiliations: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota.
Corresponding Author: Balwinder Singh, MD, MS, Department of Psychiatry and Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 ([email protected]).
Author Contributions: Dr Singh drafted the letter. All authors reviewed the final manuscript and agreed to its publication.
Financial Disclosure: Dr Singh has received research grant support from Mayo Clinic, the National Network of Depression Centers, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and National Institutes of Health. He is a KL2 Mentored Career Development Program scholar, supported by CTSA Grant Number KL2TR002379 from the National Center for Advancing Translational Sciences. Dr Frye received grant support from Assurex Health, Mayo Foundation, and BD2; received CME travel and honoraria from Carnot Laboratories and American Physician Institute; and has financial interest/stock ownership/royalties from Chymia LLC. Dr Marques reports no potential conflicts of interest.
Funding/Support: None.
Use of AI-Assisted Technologies in the Writing Process: In the writing of this manuscript, the authors used Claude Sonnet 4.6 by Anthropic to improve the readability of the draft. The authors have reviewed the content and take full responsibility for the content of the publication.
ORCID: Balwinder Singh: https://doi.org/0000-0001-7062-8192