Neuromodulation Therapies for Depression: Current Status and Future Directions

Major depressive disorder is a leading cause of disability worldwide, and many patients fail to achieve sustained remission with first-line pharmacotherapy or psychotherapy. This unmet need has traditionally been framed as treatment-resistant depression (TRD), defined by an inadequate response to antidepressant treatment. Within this context, neuromodulation has assumed an increasingly important role by providing mechanistically distinct interventions when medication-based approaches are insufficient, poorly tolerated, or too slow. In this expert opinion article, we present a targeted, clinically oriented review of two established neuromodulation therapies for depression, electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS), encompassing conventional repetitive TMS (rTMS), deep TMS, and theta-burst stimulation (TBS), as well as magnetic seizure therapy (MST), the most clinically advanced investigational convulsive modality. ECT remains the benchmark treatment for severe, urgent, psychotic, or otherwise refractory depression due to its rapid and robust efficacy, although its use is limited by anesthesia requirements, cognitive adverse effects, and associated stigma. TMS has the strongest evidence base among nonconvulsive neuromodulation treatments, with pivotal sham-controlled multicenter trials supporting conventional rTMS and deep TMS, while TBS protocols are improving feasibility, access, and scalability. MST is conceptually appealing as a more focal convulsive treatment designed to preserve antidepressant efficacy while reducing cognitive burden; recent Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) data have strengthened its evidence base, but its routine clinical role remains to be defined through regulatory approval, durability data, and implementation evidence. We argue that future progress will depend not only on the development of new stimulation protocols but also on improved clinical sequencing, patient selection, and maintenance strategies that help sustain acute gains. The concept of difficult-to-treat depression (DTD) broadens the clinical framework beyond antidepressant nonresponse to include persistent burden, partial response, tolerability constraints, functional impairment, and patient-centered goals. This perspective may inform earlier and more strategic use of neuromodulation, although most randomized controlled trials remain focused on TRD. Further studies are needed to determine whether DTD-based approaches improve real-world outcomes. Advances are likely to arise from integrating protocol refinement, individualized targeting, scalable home-based approaches, depression-relevant extensions such as bipolar depression, and durable maintenance strategies rather than identifying a single universally superior modality.