Use of neurostimulation in patients with treatment-resistant depression: current options and future directions

Treatment‑resistant depression (TRD) reflects persistent dysfunction across large‑scale neural networks despite adequate pharmacotherapy. Neuromodulation offers mechanistically grounded interventions capable of directly modulating circuit‑level abnormalities implicated in TRD.

This expert review synthesizes established, emerging, convulsive, and invasive neuromodulation modalities, including repetitive transcranial magnetic stimulation (rTMS), theta burst stimulation, accelerated TMS, deep TMS, transcranial electrical stimulation, temporal interference stimulation, photobiomodulation, low-field magnetic stimulation, transcranial focused ultrasound, electroconvulsive therapy, magnetic seizure therapy, vagus nerve stimulation, and deep brain stimulation. For each modality, technological foundations, mechanisms, efficacy, safety, and implementation considerations are summarized. Recent regulatory approvals of at-home prescription devices highlight the growing role of accessible home-based neuromodulation. Comparative effectiveness across effect size, tolerability, cost, and patient selection is reviewed. Advances in connectivity-informed targeting, tractography-guided neuromodulation, dose optimization, and biomarker-driven stratification illustrate the transition toward precision platforms. Literature for this review was identified through a non-systematic PubMed search.

Neuromodulation is evolving from a last-line intervention to a precision tool for circuit recalibration. Future progress will be driven by individualized targeting, closed-loop and multimodal stimulation, mechanistic trials, and scalable home-based delivery models. International collaborative research will be essential for validating biomarkers and accelerating development of next-generation circuit-based therapeutics.