Neuromodulation for treatment-resistant depression: a narrative review and clinical translation framework
Year: 2026
Type: review
Abstract: Background Treatment-resistant depression (TRD) is a common and disabling clinical problem associated with persistent symptoms, functional impairment, relapse risk, suicidality, and high health-system burden. Neuromodulation has become an increasingly important treatment pathway because it directly modulates neural circuits implicated in mood regulation rather than relying exclusively on pharmacological mechanisms. Objective To review and critically synthesize current evidence on neuromodulation for TRD, with emphasis on electroconvulsive therapy, repetitive transcranial magnetic stimulation (rTMS), intermittent theta-burst stimulation (iTBS), transcranial direct current stimulation, vagus nerve stimulation, deep brain stimulation, safety, clinical translation, and implementation challenges. Methods We conducted a structured narrative review of clinically relevant literature identified through searches of PubMed/MEDLINE, Scopus, Web of Science, guideline repositories, and reference lists. The search was intended to improve the breadth and transparency of the narrative synthesis and was not conducted as a formal systematic review. No protocol was registered, and no duplicate screening, formal risk-of-bias assessment, certainty-of-evidence evaluation, or quantitative synthesis was performed. Results The literature supports a provisional multidimensional clinical-positioning framework rather than a head-to-head efficacy hierarchy. Electroconvulsive therapy remains the most established intervention for severe, psychotic, catatonic, suicidal, or life-threatening depression. Repetitive transcranial magnetic stimulation is a validated non-invasive outpatient treatment with favorable tolerability and expanding protocol options. Intermittent theta-burst stimulation provides similar clinical utility with shorter sessions, whereas accelerated and image-guided iTBS protocols are promising but require further replication, durability, and maintenance data. Transcranial direct current stimulation, including supervised home-based models, is being investigated as a potentially scalable approach, but its TRD-specific evidence and real-world implementation remain less established than those of rTMS. Vagus nerve stimulation and deep brain stimulation may benefit selected highly refractory patients, but delayed response, invasiveness, cost, evidentiary heterogeneity, and long-term device-management requirements limit routine use and largely restrict these modalities to specialized services. Conclusions Neuromodulation may be incorporated as a staged, protocol-based component of multidisciplinary TRD care where appropriate expertise, infrastructure, and follow-up are available, rather than being viewed as a single interchangeable device category. Broader adoption requires standardized definitions, individualized targeting, maintenance planning, adverse-event monitoring, equitable access, and pragmatic implementation research.
Author: Abdulrhman H.M. Muhaisen
Institution: Yarmouk University
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: diamond
Funder: Yarmouk University
OpenAlex ID: W7203767428