Management of Treatment-Resistant Depression: An Updated Narrative Review of Current and Emerging Treatments.

Treatment-resistant depression (TRD) is defined as failing to achieve remission after at least two adequate antidepressant trials. It causes persistent functional impairment, higher morbidity, and greater healthcare use. This narrative review covers conventional pharmacological strategies, augmentation approaches, ketamine and esketamine, and neuromodulatory interventions including electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), theta burst stimulation (TBS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). Emerging psychedelic-assisted treatments are also discussed. While new modalities expand options for severe cases, limitations remain in cost, accessibility, response durability, and long-term outcomes. Individualized treatment selection and sequencing based on patient history and illness severity are emphasized.

Study at a glance

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.