Management of Treatment-Resistant Depression: An Updated Narrative Review of Current and Emerging Treatments.
Cureus April 1, 2026 Peer reviewed DOI: 10.7759/cureus.107343 via PubMed
Summary
Treatment-resistant depression (TRD) is a significant challenge in psychiatric care, affecting many patients with major depressive disorder. It is characterized by lack of remission after at least two antidepressant trials and is linked to ongoing functional impairment and reduced quality of life. This review discusses both traditional and emerging treatment strategies for TRD, including pharmacological options, ketamine, esketamine, and various neuromodulatory therapies such as ECT and rTMS. While newer treatments offer hope, challenges like cost and long-term efficacy remain.
Study at a glance
| Design | narrative review |
|---|---|
| Population | patients with treatment-resistant depression |
| Key finding | Conventional therapies are central to managing treatment-resistant depression, but newer modalities have broadened treatment options for patients with severe symptoms. |
Abstract
Treatment-resistant depression (TRD) remains a major clinical challenge in psychiatric practice and affects a substantial proportion of patients with major depressive disorder (MDD). It is commonly defined as failure to achieve remission after at least two adequately conducted antidepressant trials. TRD is associated with persistent functional impairment, increased morbidity, reduced quality of life, and greater healthcare utilization. This narrative review summarizes current and emerging evidence on the management of TRD, with emphasis on conventional pharmacological strategies, augmentation approaches, ketamine and esketamine, and neuromodulatory approaches. Neuromodulatory interventions discussed include electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and innovative modalities such as theta burst stimulation (TBS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). Emerging therapies, including psychedelic-assisted treatments, are also considered as potential future directions in the management of TRD. While conventional therapies remain central to management, newer treatment modalities have expanded available options, particularly for patients with severe or persistent symptoms. Nevertheless, significant limitations remain, including cost, accessibility, durability of response, and uncertainty regarding long-term outcomes and side effects. This review also highlights the importance of individualized selection and clinical sequencing based on patient characteristics, prior treatment response, and illness severity. Continued research is needed to better define treatment sequencing and improve management strategies for patients with TRD.