Management of Treatment-Resistant Depression: An Updated Narrative Review of Current and Emerging Treatments.
Cureus April 1, 2026 Juan Pablo Berlin Viniegra
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.